DOSAGE FORM DESIGN CONSIDERATIONS

The drugs of biological origins have attracted the attention of many pharmaceutical companies where it is essential to protect the heterogeneous nature and the optimal three dimensional structures of the different macromolecules. These molecules are used in both the investigation and therapy purposes, so their maximum activities should be maintained. This requires the designing of certain delivery formulations that suits the macromolecule nature, its target organ, the required dose and delivery route, and that's why the biotech companies invest millions of dollars towards achieving that. The fi rst main focal point of this article includes the recent developments in the formulation technologies for several biomacromolecule classes. The second focal point concentrates on the current considerations for optimizing their delivery for a maximum performance in the body.

Preformulation is a group of studies that focus on the physicochemical properties of a new drug candidate that could affect the drug performance and the development of a dosage form. This could provide important information for formulation design or support the need for molecular modification. Every drug has intrinsic chemical and physical properties which has been consider before development of pharmaceutical formulation. This property provides the framework for drugs combination with pharmaceutical ingredients in the fabrication of dosage form. Objective of preformulation study is to develop the elegant, stable, effective and safe dosage form by establishing kinetic rate profile, compatibility with the other ingredients and establish Physico-chemical parameter of new drug substances. Among these properties, drug solubility, partition coefficient, dissolution rate, polymorphic forms and stability are plays important role in preformulation study. Polymorphism having crystal and amorphous forms shows different chemical physical and therapeutic description of the drug molecule. This article explains some properties and techniques for preformulation evaluation parameters of drug.

DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank ADVANCES IN PHARMACEUTICAL PRODUCT DEVELOPMENT AND RESEARCH SERIES DOSAGE FORM DESIGN CONSIDERATIONS VOLUME I Edited by RAKESH K. TEKADE National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India; Formerly with the Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright r 2018 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-814423-7 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Andre Wolff Acquisition Editor: Erin Hill-Parks Editorial Project Manager: Jennifer Horigan Production Project Manager: Debasish Ghosh Cover Designer: Mark Rogers Typeset by MPS Limited, Chennai, India Dedication This book is dedicated to all the gurus, saints, vaidyas, doctors, avatars, yogis, philosophers, professors, mentors, postdocs, doctoral-, master’s-, and graduate-students, scientists, medical and pharmacy workforces, volunteers, social workers, funding agencies, and societies of ancient civilizations who have kept the science of health flourishing for the past plentiful eras, and contributed universally to the evolution of medical and pharmaceutical science. Rakesh K. Tekade This page intentionally left blank Contents 2. Physicochemical Aspects to Be Considered in Pharmaceutical Product Development List of Contributors xiii About the Editor xvii 1. Preformulation in Drug Research and Pharmaceutical Product Development PRAN KISHORE DEB, OMAR AL-ATTRAQCHI, ABDULMUTTALEB YOUSEF JABER, BASANT AMARJI AND RAKESH K. TEKADE PRATAP CHANDRA ACHARYA, SARITHA SHETTY, CLARA FERNANDES, DIVYA SUARES, RAHUL MAHESHWARI AND RAKESH K. TEKADE 2.1 Introduction 58 2.2 Physical Characteristics of Solid Substances Used in Pharmaceutical Product Development 58 2.3 Chemical Characteristics to be Considered in Pharmaceutical Product Development 67 2.4 Solubility Aspects in Pharmaceutical Products Development 74 2.5 Conclusion 78 Acknowledgement 79 Abbreviations 79 References 79 Further Reading 83 1.1 1.2 1.3 1.4 Introduction 2 Parameters of Preformulation Studies 8 Role of Preformulation in Drug Discovery 31 Role of Preformulation in Drug Development 35 1.5 Preformulation Studies of Proteins and Peptides 37 1.6 Preformulation in Vaccine Development: Critical Views 40 1.7 Preformulation Studies of Packaging Components 41 1.8 Preformulation in 21st Century: Technological Advancements 42 1.9 Case Studies on Preformulation of Dosage Forms 45 1.10 Pharmacokinetics and Preformulation: Point to Note 46 1.11 Rules and Regulations in Preformulation Studies: Role of Regulatory Bodies 47 1.12 Future Remarks and Conclusion 48 Acknowledgment 48 Abbreviations 48 References 49 Further Reading 53 3. Role of Physicochemical Parameters on Drug Absorption and Their Implications in Pharmaceutical Product Development YOGENDRA PAL, PRAN KISHORE DEB, SHANTANU BANDOPADHYAY, NABAMITA BANDYOPADHYAY AND RAKESH K. TEKADE 3.1 Introduction 86 3.2 Drug Absorption Process: Basic Ideology and Illustrations 87 3.3 Barriers in Drug Absorption: Obstacle in Product Development 90 vii viii CONTENTS 3.4 Physicochemical Parameters and Their Effect on Drug Absorption 92 3.5 Drug Absorption Through GIT: Role of Saturation Solubility 107 3.6 Relationship Between Structure of Drug and Their Physicochemical Properties/Biological Properties 111 3.7 Conclusions 112 Abbreviations 112 References 112 Further Reading 115 4. Physiologic Factors Related to Drug Absorption PRATAP CHANDRA ACHARYA, CLARA FERNANDES, SANTANU MALLIK, BIJAYASHREE MISHRA AND RAKESH K. TEKADE 4.1 Introduction 118 4.2 Barriers to Drug Absorption 4.3 Conclusion 139 Acknowledgment 140 Abbreviations 141 References 141 Further Reading 147 125 5. Physicochemical, Pharmaceutical, and Biological Considerations in GIT Absorption of Drugs VENKAT RATNAM DEVADASU, PRAN KISHORE DEB, RAHUL MAHESHWARI, PIYOOSH SHARMA AND RAKESH K. TEKADE 5.1 Introduction 150 5.2 Mechanism of Gastrointestinal Absorption of Drugs 150 5.3 Barriers in GI Absorption of Drugs: An Overview 153 5.4 Various Physicochemical Factors Affecting Gastrointestinal Absorption of Drugs 155 5.5 Pharmaceutical Factors 163 5.6 Biological Factors 167 5.7 Conclusion 174 Acknowledgment 174 Abbreviations 175 References 175 6. Influence of Drug Properties and Routes of Drug Administration on the Design of Controlled Release System ARPNA INDURKHYA, MAHENDRA PATEL, PIYOOSH SHARMA, SARA NIDAL ABED, ABEER SHNOUDEH, RAHUL MAHESHWARI, PRAN KISHORE DEB AND RAKESH K. TEKADE 6.1 Introduction 180 6.2 Rationale for the Design of Controlled Release System 184 6.3 Factors Influencing the Design of Controlled Release System 186 6.4 Physiochemical Properties of a Drug Influencing Design of Controlled Release System 188 6.5 Pharmacokinetic Factors Influencing the Design of Controlled Release System 192 6.6 Pharmacodynamic Factors Influencing the Design of Controlled Release System 195 6.7 Patient Compliance 196 6.8 Controlled Release From Different Formulations: Importance of Route and Effect of Varying Properties 197 6.9 Drug Targeting Using Controlled Release System 208 6.10 Current Developments in Controlled Release Formulations 209 6.11 Patented Controlled Release Drug Delivery Systems 211 6.12 Conclusion 214 Acknowledgments 215 Abbreviations 215 References 216 7. Stability and Degradation Studies for Drug and Drug Product RAHUL MAHESHWARI, POOJA TODKE, NEETU SONI, NIDHI RAVAL, PRAN KISHORE DEB, BASANT AMARJI, N.V. ANIL KUMAR RAVIPATI AND RAKESH K. TEKADE 7.1 Introduction 226 7.2 Stability Studies of Drug and Drug Product 228 7.3 Degradation Studies of Drug and Drug Products 231 7.4 Evaluation of Stability Data to Determine Retest Period/Shelf-Life Determination 236 ix CONTENTS 7.5 Regulatory Aspects and Requirements for a Stability Testing Program 236 7.6 Stability Testing of Biotechnological Product 238 7.7 Stability Testing of Phytopharmaceuticals 239 7.8 Stability Indicating Assay Method (SIAMs): Current Update 243 7.9 Reduced Stability-Testing Plans 247 7.10 Conclusion 251 Acknowledgment 251 References 251 Further Reading 256 8. First-Pass Metabolism Considerations in Pharmaceutical Product Development ASHOK K. SHAKYA, BELAL O. AL-NAJJAR, PRAN KISHORE DEB, RAJASHRI R. NAIK AND RAKESH K. TEKADE 8.1 Introduction 260 8.2 Role of Liver and Small Intestine in First-Pass Metabolism 260 8.3 First-Pass Metabolism Considerations in Prodrug Development 278 8.4 Perspectives on First-Pass Metabolism Considerations in Pharmaceutical Product Development 280 8.5 Conclusion 281 Acknowledgment 282 Abbreviations 282 References 283 Further Reading 286 9. Dissolution Profile Consideration in Pharmaceutical Product Development DISHA MEHTANI, ANKIT SETH, PIYOOSH SHARMA, RAHUL MAHESHWARI, SARA NIDAL ABED, PRAN KISHORE DEB, MAHAVIR B. CHOUGULE AND RAKESH K. TEKADE 9.1 Introduction: Drug Dissolution Concept 289 9.2 Theories of Dissolution 290 9.3 Factors Affecting Dissolution Rate (In Vitro) 294 9.4 Physiological Factors Affecting In Vivo Drug Dissolution Rate 300 9.5 Dissolution Testing 303 9.6 Dissolution Profile: Analysis and Comparison 306 9.7 In Vitro-In Vivo Correlation (IVIVC) 306 9.8 Biopharmaceutical Classification System (BCS) and Biopharmaceutical Drug Disposition Classification System (BDDCS) 309 9.9 Role of Dissolution Testing in Pharmaceutical Product Development 311 9.10 Dissolution Mechanism: Role of Density Functional Theory (DFT) 325 9.11 Dissolution Controlled Drug Delivery Systems 326 9.12 Conclusion and Prospects 327 Acknowledgments 328 Abbreviations 328 References 329 10. Drug Disposition Considerations in Pharmaceutical Product RAHUL MAHESHWARI, PIYOOSH SHARMA, ANKIT SETH, NEHA TANEJA, MUKTIKA TEKADE AND RAKESH K. TEKADE 10.1 Introduction 338 10.2 Factors Affecting the Interplay of Drug Disposition 341 10.3 Role of ADME in Product Development 346 10.4 Biopharmaceutics Classification System 348 10.5 Various Factors Affecting Drug Disposition 349 10.6 Transporters in Drug Disposition 354 10.7 Experimental Models for Drug Disposition Investigations During Product Development 355 10.8 Effect of Disease State on Drug Disposition 359 10.9 Conclusion 362 Acknowledgment 363 References 363 11. Protein and Tissue Binding: Implication on Pharmacokinetic Parameters PRAN KISHORE DEB, OMAR AL-ATTRAQCHI, MAILAVARAM RAGHU PRASAD AND RAKESH K. TEKADE 11.1 Introduction 372 11.2 Binding Kinetics 372 11.3 Overview of Plasma Proteins 376 x CONTENTS 11.4 Tissue Binding 381 11.5 Plasma and Tissue Protein Binding Implications on Pharmacokinetics Parameters 382 11.6 Factors Influencing Protein Binding 387 11.7 Plasma Protein Binding Determination Methods 389 11.8 Conclusion 395 Acknowledgment 395 Abbreviations 396 References 396 Further Reading 399 12. Preformulation Studies of Drug Substances, Protein, and Peptides: Role in Drug Discovery and Pharmaceutical Product Development SHANTANU BANDOPADHYAY, NABAMITA BANDYOPADHYAY, PRAN KISHORE DEB, CHHATER SINGH AND RAKESH K. TEKADE 12.1 Introduction 402 12.2 Preformulation Studies: Vital Concepts 403 12.3 Preformulation: Drug Substances 404 12.4 Preformulation: Proteins and Peptides 415 12.5 Role of Preformulation Studies in Drug Discovery and Pharmaceutical Product Development: Drug Substances 418 12.6 Role of Preformulation Studies in Drug Discovery and Pharmaceutical Product Development: Proteins and Peptides 420 12.7 Conclusion 429 Abbreviations 429 References 430 13. Role of Salt Selection in Drug Discovery and Development PRATAP CHANDRA ACHARYA, SARAPYNBIANG MARWEIN, BIJAYASHREE MISHRA, RAJAT GHOSH, AMISHA VORA AND RAKESH K. TEKADE 13.1 Introduction 436 13.2 Selection of the API and Counterions for Pharmaceutical Salt Preparations 440 13.3 Characterization of the Pharmaceutical Salt 451 13.4 Regulatory Requirements 13.5 Conclusion 464 Acknowledgment 465 Abbreviations 465 References 466 Further Reading 471 459 14. Drug Complexation: Implications in Drug Solubilization and Oral Bioavailability Enhancement HIRA CHOUDHURY, BAPI GORAIN, THIAGARAJAN MADHESWARAN, MANISHA PANDEY, PRASHANT KESHARWANI AND RAKESH K. TEKADE 14.1 Introduction: Complexation in Pharmaceutical Products 474 14.2 Fundamental Methods of Formation of Drug Complexes 480 14.3 Characterization of Drug Complexation 485 14.4 Factors Influencing Complex Formation 489 14.5 Effect of Complexation on Drug Solubility and Bioavailability 492 14.6 Thermodynamics and Kinetics of Complex Formation 497 14.7 Protein Complex Formation: Role in Oncology 498 14.8 Application of Complexation in Drug Delivery 499 14.9 Conclusion 504 Acknowledgment 504 Abbreviations 504 References 505 15. Solubility and Solubilization Approaches in Pharmaceutical Product Development PRATAP CHANDRA ACHARYA, CLARA FERNANDES, DIVYA SUARES, SARITHA SHETTY AND RAKESH K. TEKADE 15.1 Understanding the Concept of Solubility 514 15.2 Relationship Between Solubility and Biopharmaceutical Classification Systems (BCS) 521 15.3 Approaches to Modulate Drug Solubility 522 xi CONTENTS 15.4 Excipient-Based Solubilization 530 15.5 Conclusion 538 Acknowledgments 538 Abbreviations 538 References 539 16. Rheology and Its Implications on Performance of Liquid Dosage Forms PRATAP CHANDRA ACHARYA, DIVYA SUARES, SARITHA SHETTY, CLARA FERNANDES AND RAKESH K. TEKADE 16.1 Understanding the Basic Concepts of Rheology 550 16.2 Rheology of Pharmaceutical Dosage Forms 558 16.3 Pharmaceutical Considerations 567 16.4 Rheological Instruments for Fluids and Their Limitations 578 16.5 Rotational-Type Rheometer 579 16.6 Broad-Gap Concentric Cylinder Viscometer 580 16.7 Cone and Plate Viscometer 581 16.8 Parallel-Plate Viscometer 581 16.9 Tube-Type Rheometers 582 16.10 Dilation Rheology 583 16.11 Applications of Rheology 583 16.12 Conclusion 588 Acknowledgment 588 Abbreviations 589 References 589 17.5 17.6 17.7 17.8 17.9 Powders 624 Suspensions 627 Emulsions 627 Novel Drug Delivery Systems 628 Relation Between Crystallization and Micromeritics of Drug Substances 630 17.10 Conclusion 631 Acknowledgment 632 Abbreviations 632 References 632 Further Reading 635 18. Four Stages of Pharmaceutical Product Development: Preformulation, Prototype Development and Scale-Up, Biological Aspects, and Commercialization BASANT AMARJI, SARA NIDAL ABED, UJJAWAL BAIRAGI, PRAN KISHORE DEB, OMAR AL-ATTRAQCHI, ANUP AVIJIT CHOUDHURY AND RAKESH K. TEKADE 18.1 Introduction 638 18.2 Preformulation Aspects in Pharmaceutical Product Development 640 18.3 Prototype Development 642 18.4 Biological Aspects in Pharmaceutical Product Development 650 18.5 Commercialization Aspects in Pharmaceutical Products Development 658 18.6 Conclusion 663 Abbreviations 663 References 664 Further Reading 667 17. Micromeritics in Pharmaceutical Product Development 19. Scale-Up Studies in Pharmaceutical Products Development RAHUL MAHESHWARI, POOJA TODKE, KAUSHIK KUCHE, NIDHI RAVAL AND RAKESH K. TEKADE NIDHI RAVAL, VISHAKHA TAMBE, RAHUL MAHESHWARI, PRAN KISHORE DEB AND RAKESH K. TEKADE 17.1 Introduction 600 17.2 Particle Size 600 17.3 Methods to Determine Particle Size Distribution 607 17.4 Significance of Micrometrics in Product Development: Tablet and Capsule 620 19.1 19.2 19.3 19.4 19.5 Introduction 670 Solid Dosage Forms 670 Parenteral Dosage Forms 685 Semisolid Dosage Forms 686 Scale-Up of Nanoformulations: Case Studies 691 19.6 Quality by Design (QbD) for Scale-Up 692 xii CONTENTS 19.7 Problems Encountered During Scale-Up 19.8 Conclusions 694 Acknowledgments 695 References 695 Further Reading 699 693 20. Manipulation of Physiological Processes for Pharmaceutical Product Development RAHUL MAHESHWARI, KAUSHIK KUCHE, ANKITA MANE, YASHU CHOURASIYA, MUKTIKA TEKADE AND RAKESH K. TEKADE 20.1 Introduction 702 20.2 Various Physiological Factors Affecting Product Development 703 20.3 Modeling Procedures for Transport, Metabolism, and Efflux of Drug 718 20.4 Bioavailability: The Ultimate Goal to Achieve 722 20.5 Role of Computer in Physiological Process Manipulations 723 20.6 Conclusion 723 Acknowledgments 724 References 724 21. Impact of Pharmaceutical Product Quality on Clinical Efficacy VANDANA SONI, VIKAS PANDEY, SAKET ASATI AND RAKESH K. TEKADE 21.1 Introduction 732 21.2 Risk Assessment and Management of Medicine 734 21.3 Elements of Pharmaceutical Development 743 21.4 Factors Affecting Drug Product Performance 748 21.5 Drug Product Quality and Drug Product Performance 759 21.6 Scale-Up and Postapproval Changes 760 21.7 Postmarketing Surveillance 763 21.8 Conclusion 764 Acknowledgment 764 Abbreviations 764 References 765 Further Reading 771 22. Formulation Additives Used in Pharmaceutical Products: Emphasis on Regulatory Perspectives and GRAS SATISH MANCHANDA, AKHILESH CHANDRA, SHANTANU BANDOPADHYAY, PRAN KISHORE DEB AND RAKESH K. TEKADE 22.1 Introduction: Background of Additives 775 22.2 Role of Additives in Pharmaceutical Formulation 776 22.3 Classification and Sources of Formulation Additives 777 22.4 Processing of Additives as per Good Manufacturing Practice 779 22.5 Additives Interaction in Pharmaceutical Products 785 22.6 Formulation Additives for Designing of Solid Dosage Forms 786 22.7 Formulation Additives for Designing of Semisolid Dosage Forms 789 22.8 Formulation Additives for Designing of Liquid Dosage Forms 791 22.9 Current Guidelines for Pharmaceutical Additives (FDA, EU, Japan) 792 22.10 Regulatory Aspects of Additives Approval 796 22.11 Regulatory Perspectives of Formulation Additives 798 22.12 WHO Perspectives 802 22.13 Study of Different Types of Additives 805 22.14 Functional and Coprocessed Additives 812 22.15 Classification of Pharmaceutical Diluents 815 22.16 Pharmaceutical Solvents 816 22.17 Evaluation and Quality Testing of Pharmaceutical Additives 820 22.18 Current Developments in Additive Science 823 22.19 International Patented Additives 824 22.20 FDA GRAS Additives 826 22.21 Conclusion 828 Abbreviations 828 References 829 Further Reading 831 Index 833 List of Contributors Pran Kishore Deb Faculty of Pharmacy, Philadelphia University, Amman, Jordan Abeer Shnoudeh Faculty of Pharmacy, Philadelphia University, Amman, Jordan Mahavir B. Chougule Translational Drug and Gene Delivery Research (TransDGDR) Laboratory, Department of Pharmaceutical Sciences, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS, United States; Pii Center for Pharmaceutical Technology, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, United States; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, United States Sara Nidal Abed Faculty of Pharmacy, Philadelphia University, Amman, Jordan Bapi Gorain Faculty of Pharmacy, Lincoln University College, Petaling Jaya, Selangor, Malaysia Hira Choudhury Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia Belal O. Al-Najjar Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy and Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan Vandana Soni Department of Pharmaceutical Sciences, Dr. H.S. Gour Central University, Sagar, Madhya Pradesh, India Thiagarajan Madheswaran Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia Pratap Chandra Acharya Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India Omar Al-Attraqchi Faculty of Pharmacy, Philadelphia University, Amman, Jordan Basant Amarji Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India N.V. Anil Kumar Ravipati Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India Arpna Indurkhya Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India Abdulmuttaleb Yousef Jaber Faculty of Pharmacy, Philadelphia University, Amman, Jordan Akhilesh Chandra Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research (DIPSAR), New Delhi, India Anup Avijit Choudhury Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India Ujjawal Bairagi Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India xiii xiv LIST OF CONTRIBUTORS Clara Fernandes Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Santanu Mallik Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India Satish Manchanda Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research (DIPSAR), New Delhi, India Prashant Kesharwani Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India Rajat Ghosh Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India Rahul Maheshwari National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India Saket Asati Department of Pharmaceutical Sciences, Dr. H.S. Gour Central University, Sagar, Madhya Pradesh, India Shantanu Bandopadhyay Department of Pharmacy, Saroj Institute of Technology & Management, Lucknow, Uttar Pradesh, India Nabamita Bandyopadhyay Molecular Biology Division, National Institute of Malarial Research (NIMR), Dwarka, Delhi, India Kaushik Kuche National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India Yashu Chourasiya Shri Bherulal Pharmacy Institute, Indore, Madhya Pradesh, India Ankita Mane Acropolis Institute of Pharmaceutical Education and Research, Indore, Madhya Pradesh, India Sarapynbiang Marwein Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India Disha Mehtani Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India Bijayashree Mishra Department of Chemistry, Tripura University (A Central University), Suryamaninagar, Tripura, India Vikas Pandey Department of Pharmaceutical Sciences, Dr. H.S. Gour Central University, Sagar, Madhya Pradesh, India Mahendra Patel Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India Mailavaram Raghu Prasad Pharmaceutical Chemistry Division, Sri Vishnu College of Pharmacy, Bhimavaram, Andhra Pradesh, India Nidhi Raval National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India Ankit Seth Department of Ayurvedic Pharmacy, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur, Uttar Pradesh, India Ashok K. Shakya Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy and Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan Piyoosh Sharma Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India Saritha Shetty Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Yogendra Pal Department of Pharmacy, Pranveer Singh Institute of Technology, Bhauti, Kanpur, Uttar Pradesh, India LIST OF CONTRIBUTORS xv Divya Suares Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Vishakha Tambe National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India Neha Taneja Pharmaceutical Analysis & Quality Assurance Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, Punjab, India Pooja Todke National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India Amisha Vora Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Chhater Singh Mahaveer College of Pharmacy, Meerut, Uttar Pradesh, India Neetu Soni Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom Institute of Agriculture, Technology and Sciences (Deemed University), Allahabad, Uttar Pradesh, India Rajashri R. Naik Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy and Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan Manisha Pandey Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia Venkat Ratnam Devadasu University of Hail, Hail, Saudi Arabia Muktika Tekade TIT College of Pharmacy, Technocrats Institute of Technology Campus, Bhopal, Madhya Pradesh, India Rakesh K. Tekade National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India; Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia This page intentionally left blank About the Editor Rakesh K. Tekade - Series Editor Dr. Rakesh K. Tekade was born in the central province of India (Sarni, M.P) in 1981. He received his Bachelor’s degree in Pharmacy from IPS Academy affiliated to R.G.P.V University, Bhopal. He received his master’s and doctoral degree in “Pharmaceutical Sciences” from the Dr. H.S. Gour University, Sagar (India) with Prof. Jain’s group. After his master’s, he served as Research and Development Scientist at Ranbaxy Research Laboratories, Dewas (India). He is a recipient of several nationally and internationally acclaimed fellowships and awards, viz. Irish Government Postdoctoral Fellowship 2012 (Ireland), Young Scientist Award 2012 (India), Commonwealth Fellowship 2009 (Preston, UK; Advisor: Prof. Antony D’Emanuele), National Doctoral Fellowship 2008 (AICTE, India), CSIR Senior Research Fellowship 2008 (CSIR, India), AICTE junior Research Fellowship-2004 (AICTE, India), and to his credit there are many meritorious awards. After his doctorate, he worked as a postdoctoral fellow in The University of Texas Southwestern Medical Center (Dallas, USA; Supervisor: Prof. Xiankai Sun) and The University of Hawaii (Hilo, USA; Supervisor: Prof. Mahavir Chougule). Dr. Rakesh K. Tekade, currently working as the Assistant Professor in the Department of Pharmaceutics, is an academician, formulation scientist, and industry expert with years of experience in drug design, delivery, and therapeutics development. Dr. Tekade has over 100 publications in peer-reviewed international journals, one patent, 40 reference book chapters, and five editorial articles. He has delivered several invited research talks and presented research findings in more than 40 scientific conferences. He has published two Authored Books and is a series editor for a widely recognized “Advances in Pharmaceutical Sciences and Research” Book Series. His research interests encompass design, development, and characterization of targeted nanotechnology-based formulations for the site-specific delivery of therapeutic drugs, siRNA, microRNA, plasmids, proteins, and peptide for the treatment of cancer, arthritis, diabetes, and neurodegenerative disorders. He also has extensive experience in polymer chemistry, nanotechnology, molecular biology, pharmacokinetics/pharmacodynamics, and imaging techniques. His research objectives focus on translational nanomedicine, biomaterials synthesis, nanoformulation design and development, and evaluation of different biocompatible nanoparticle-based platform technologies for targeted delivery and imaging applications. Affiliations National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India; Formerly with the Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia xvii This page intentionally left blank C H A P T E R 1 Preformulation in Drug Research and Pharmaceutical Product Development Pratap Chandra Acharya1,*, Saritha Shetty2,*, Clara Fernandes2,*, Divya Suares2, Rahul Maheshwari3 and Rakesh K. Tekade3,4 1 Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India 2Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 4Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 1.1 Introduction 1.1.1 An Overview of Formulation Life Cycle and Management 1.1.2 Need of Preformulation: First Stage of Formulation Development 1.1.3 Major Hurdles Impeding Successful Product Development 1.1.4 Role of Preformulation During Product Development 1.2 Parameters of Preformulation Studies 1.2.1 Solubility 1.2.2 The Permeability of the Drug 1.2.3 Bulk Characterization: Physical, Analytical, and Physicochemical 1.2.4 Inherent Properties: pH, pKa, Log P, Log D, and Intrinsic Dissolution 1.2.5 Stability: The Solution, Solid State, & ICH Photostability 2 3 4 5 7 8 8 12 14 15 19 * Authors having equal contribution in this book chapter. Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00001-0 1 © 2018 Elsevier Inc. All rights reserved. 2 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT 1.2.6 1.2.7 1.2.8 1.2.9 1.2.10 1.2.11 Drug-Excipient Compatibility Particle Size and Distribution Thermal Properties Hygroscopicity Bulk Properties Mechanical Properties and Compatibility 1.2.12 Crystallinity and Polymorphism 25 27 28 28 30 30 30 1.3 Role of Preformulation in Drug Discovery 31 1.3.1 Material Properties in Lead Selection, High Throughput Preformulation Studies 32 1.3.2 “Drugability” of New Chemical Entities 32 1.3.3 Tools to Assist in Lead Selection 34 1.4 Role of Preformulation in Drug Development 35 1.4.1 Identification of Challenges During Formulation Development: Pre-Assumptions 36 1.4.2 The Dosage Form Specific Studies 36 1.5 Preformulation Studies of Proteins and Peptides 37 1.6 Preformulation in Vaccine Development: Critical Views 1.7 Preformulation Studies of Packaging Components 1.8 Preformulation in 21st Century: Technological Advancements 1.8.1 Computerization and Aid of Software in the Preformulation Studies 1.8.2 Artificial Neural Network Tool Used in the Factorial Design: An Optimization Approach 1.9 Case Studies on Preformulation of Dosage Forms 41 42 42 43 45 1.10 Pharmacokinetics and Preformulation: Point to Note 46 1.11 Rules and Regulations in Preformulation Studies: Role of Regulatory Bodies 47 1.12 Future Remarks and Conclusion 48 Acknowledgment 48 Abbreviations 48 References 49 Further Reading 53 40 1.1 INTRODUCTION The pharmaceutical industry is playing a key role in contributing to global health science. The research and development team have unique responsibilities to develop new drugs, vaccines, medical devices, technologies, and so on, to improve patient compliance worldwide. This only becomes possible by adopting fundamental research into innovation. The success of any pharmaceutical company is based on its continuous innovation especially for preventing and treating the common, complex diseases, neglected diseases, and improving the existing treatments. From an industrial perspective, preformulation is often considered as a multidepartment activity which involves coordinated efforts between different skill domains such as analytical, formulation development, regulatory, and others throughout the development cycle. DOSAGE FORM DESIGN CONSIDERATIONS 1.1 INTRODUCTION 3 FIGURE 1.1 Drug product life cycle. 1.1.1 An Overview of Formulation Life Cycle and Management In any pharmaceutical company, the R&D team is at the forefront in generating newer concepts for furthering the brand development of the company. This department is responsible for identifying a new potential moiety amongst several screened compounds based on the physicochemical as well as biological activities for treatment of target maladies. This moiety is tested extensively for ensuring its safety and efficacy. This entire process is demanding, challenging and time-consuming, i.e., it can extend over a period of 10 15 years as shown in Fig. 1.1. For example, in 2015, 56 new medicaments were introduced, while currently, more than 7,000 composites are at various developmental phases globally. Understanding the enormity of the task to generate one Investigational new drug (IND) application for a company, it becomes imperative to minimize the propensity of failure by conducting suitable and well-defined studies to predict the success of new chemical entities (NCEs). In this perspective, preformulation becomes an effective tool assisting researchers in generation of physicochemical and biopharmaceutical data for screening of lead compounds. Hence, this necessitates a scientific collaboration between drug discovery and formulation scientists for avoiding the risk of failure in the later stage of product development. Various challenges that pharmaceutical companies encounter during the product development are: need for approvals and reimbursements of new molecule entity, target identification, lack of predictive animal models, clinical trial of management, low risk tolerance of regulatory body, type of ventures, i.e., codevelopment licensing or joint ventures, changing strategy dynamics, growing demands of commercial and decreasing number of research-driven pharmaceutical companies. These challenges often contribute to high capitalized costs for research and development resulting in low new molecule entity (NME) output thereby decreasing R&D efficiency of research-driven pharmaceutical ventures. Consequently, the need of innovation at reduced or competitive economic cost, companies adopt growth options such as mergers and acquisitions, cost-efficient outsourcing collaborating opportunities with universities-of-repute and/other DOSAGE FORM DESIGN CONSIDERATIONS 4 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT biotechnology/pharmaceutical research organizations, leverage their expertise by licensing the existing drug in all phases of R&D, by entering into strategic alliance with venture capitalists, and possibly by crowdfunding (Schuhmacher et al., 2016). The sales estimate for the global pharmaceutical industry was of B$967 billion ($446 billion, or 46%, in the United States alone). Alone in 2016, it was stated that 157 billion US dollars were spent on pharmaceutical research and development. It is estimated to increase to over 180 billion dollars in 2022 (Statista, 2017). Recognizing the need for inventiveness and understanding the exorbitant expenses incurred by the pharmaceutical industry, it becomes imperative to design tools to distinguish the active moiety among the numerous chemical structures for product development. The selection will be governed by bioavailability, since the physicochemical properties influence the manufacturing, processing, stability, and interactions with excipients to lead to therapeutically active safe and effective dosage form. Conceptually, preformulation provides comprehensive knowledge about the characteristics of new chemical entity that is crucial at the early development stage. This will also enhance the fundamental knowledge required for screening and the design of appropriate dosage form. Thus, reducing the overall drug development expenditure and facilitate the commercialization of the product (Gaisford and Saunders, 2012). The objective of preformulation studies is to select the right drug substance, excipients, and packaging material used in product development. This evaluates the physicochemical properties and generates meticulous data of the material stability under the varied conditions. Product lifecycle management creates a strategic scaffold for making well-versed decisions through the discovery, preclinical, clinical, regulatory approval, and full commercialization processes. These scaffolds enable companies to have a high rank of visibility and possibility in value-added collaborations and assessment points to manage a drug for its most favorable profitability throughout its product lifecycle. 1.1.2 Need of Preformulation: First Stage of Formulation Development Recently an FDA review on the approval stats, states that most products fail in clinical studies at phase-II stage as well as phase-III stage possibly due to inefficacy of drug (B55%), toxicity issues (30%), commercial reasons (5%), operational hurdles (5%), and unknown errors (5%) (Arrowsmith and Miller, 2013). Hence to minimize all these formulation and delivery issues during the later stages of product development and registration, there is always a need for preformulation studies before the development stage (Cook et al., 2014). Preformulation study is a critical component of product development wherein it supports formulation development for various stages of clinical trials. The word preformulation—pre- means prior, and formulation means the design of final dosage form. As iterated earlier, for development of drug formulation, preformulation studies are undertaken to ascertain fundamental physicochemical as well as other derived properties of the drug molecule which can influence the formulation development process (Arrowsmith and Miller, 2013). Fundamentally, preformulation science includes use of biopharmaceutical codes for the physicochemical characterization of NCE for the sole purpose of obtaining optimum dosage form. Apart from the above terms, designing and developing assay at early stages of preformulation determines its bioavailability, dose, and toxicity data. Fundamental concepts of DOSAGE FORM DESIGN CONSIDERATIONS 5 1.1 INTRODUCTION TABLE 1.1 List of Molecular Sample Properties and their Assay Techniques Property Assay Techniques Solubility: Aqueous and Nonaqueous UV pKa UV or potentiometric titration Po/w / logP UV/TLC/HPLC Hygroscopicity TGA Stability: Hydrolysis, Photolysis and Oxidation HPLC and storage conditions required for the studies. TABLE 1.2 Macroscopic Bulk Properties and their Techniques Derived Property Technique Melting point DSC or melting point apparatus Enthalpy of fusion or so ideal solubility DSC Physical forms (polymorphs, pseudopolymorphs or amorphous) DSC, XPRD, microscopy Particle shape, size distribution, morphology, rugosity and habit Microscopy, BET surface study Density: Bulk, tapped and true Tapped densitometer Flow property Angle of repose Compressibility Carr’s Index and Hausner’s ratio Excipient compatibility DSC, FTIR solubility and developing a suitable assay are initial steps to formulate a suitable effective dosage form. Lists of various molecular properties (derived from molecular structure) to be evaluated during preformulation studies are enlisted in Table 1.1 and lists of various macroscopic (or bulk) properties (result from intermolecular interactions) of the drug candidate that are measured are tabulated in Table 1.2 (Gaisford and Saunders, 2012). 1.1.3 Major Hurdles Impeding Successful Product Development In the successful development of pharmaceutical products several baseline difficulties such as regulatory dossier and site documentation needed to be solved first. Other problems incudes poorly defined project, pre-submission hurdles, nonquality consequential changes, and cost (Gibson, 2016). A complete summary of problems are also summarized in Table 1.3. Specifically, in the case of nanotechnology-based medicines, selecting the right effective candidate for targeting the intended disease is important as it has to enhance its efficacy DOSAGE FORM DESIGN CONSIDERATIONS 6 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 1.3 Major Obstacles Impeding Successful Product Development, its Registration and Sale Departments Obstacles Research Novel compound Is it patentable? Novel biological mechanism - Is it patentable? Unmet medical needs Potent and effective Safety High margin of safety Nontoxic (not mutagenic. Carcinogenic and teratogenic, etc.) Clinical Tolerable side effects profile Efficacious Acceptable duration of action Drug Process Bulk drug can be synthesized/scaled up Pharmaceutical Acceptable formulation/pack (meets customer needs) Drug delivery/product performance acceptable Stable /acceptable shelf life. Robust clinical trial process, which can be scaled up and transferred into operations. Regulatory Quality of data/documentation/data integrity. Manufacturing Manufacturable, acceptable cost of goods. Able to pass preapproval inspection. Marketing/ commercial Competitive meets customer needs. and minimize the side effects. However, it should be noted that nanomedicines can result in modulation of the biopharmaceutics and pharmacokinetics predisposition of the active moiety. For instance, there are incidences where it has been observed that change in the density of surface ligands may elicit undesired complement activation and other immune responses. This may limit the broad utilization of multifunctional and multicomponent nanoparticles and thus calls for judicious selection of nanoparticulate system as cargoes for drug (Havel et al., 2016). For any solid dosage forms, preformulation studies become essential to predict the possible process-induced transformations of drugs during a typical manufacturing process. For example, during tableting, the poor flow characteristics exhibited by the powder blend may be improved by adding suitable glidants. Similarly, in the case of poor compressible blend, capsule dosage form can be considered as a suitable alternative. Further through well designed preformulation studies, a thermolabile drug can be subjected to drying temperatures well below its glass transition temperature (Tg) to prevent polymorphic conversion. Another example which emphasizes preformulation is the coating process wherein for efficient film coating of moisture-sensitive tablet cores, a seal coat using low viscosity solution sprayed at low rate would be more appropriate. Thus, the aforementioned DOSAGE FORM DESIGN CONSIDERATIONS 1.1 INTRODUCTION 7 examples clearly outline the relevance of preformulation studies in rational selection of components, process variables and formulation, minimizing the risk of unanticipated failures in later stages of product development. 1.1.4 Role of Preformulation During Product Development The International Council for Harmonization (ICH) recommends criteria for stability and testing conditions and these guidelines may be implemented in designing a formulation with minimal stability risks (Lawrence et al., 2014). Due to the unique nature of each molecule, the development began as an empirical science. Intense knowledge about the resources, technologies, regulatory, product development is required to rationalize the design for any type of formulation development in a given product strategy. For preclinical studies, a prototype is needed that can be optimized and chosen for better formulation needed for clinical trials. It is essential to ensure the safety and efficacy of a therapeutic protein or any peptide moiety, and as the development progresses, it becomes hard to make any changes in the product. Important questions to be considered during product development are: • What kind of disease condition will the product treat? Is it chronic or acute? Target product profile is important to understand the selection of the route of administration. • What about the therapeutic window? Is it broad or narrow do we need to be specific when we target the product? • Administration or consumption is done personally at home or with an assistant at clinics or hospitals? • What is the market status? Is any other drug molecule indicated for the same treatment? • How is our developed product going to be advantageous over the existing treatments and those that may emerge? For a stable and robust product, it is required that the performance of the formulations does not compromise on stability and bioavailability of the active moiety. Special emphasis should be laid on regulatory compliance especially with production and commercialization. There are four stages observed for formulating a successful drug product: (i) preformulation; (ii) bulk substance stabilization; (ii) drug delivery formulation strategies; and then the final (iv) manufacturing activities (fill and finish process). Preformulation study is an essential tool for drug development that commences during the initial pharmaceutical development process. These studies are systematically designed to generate comprehensive information related to the physicochemical properties, drug-initial excipients compatibility, develop analytical investigations, and other information to directly or indirectly support formulation development. Results obtained from the preformulation investigations reflect useful groundwork information towards formulation attempts. Successful formulations are considered for the stability and data is documented for drug’s interactions with other excipients, food, etc. and the safety and stability of the final product are studied so that it is a beneficial DOSAGE FORM DESIGN CONSIDERATIONS 8 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.2 Various stages of product lifecycle and management. and marketable product. A systematic appraisal of various stages involved in drug product development along with a brief summary of is developmental life cycle, as well as its management, is presented in Fig. 1.2 and Fig. 1.3. 1.2 PARAMETERS OF PREFORMULATION STUDIES The parameters of preformulation investigation permit a formulator to select various additives and formulation conditions for the successful and effective drug delivery. The physicochemical parameters include solubility, stability, pH, pKa, log P, log D, etc. Some of the important and characteristic parameters of preformulation are summarized in Table 1.4. 1.2.1 Solubility Solubility can be a major impediment in product development. Commonly, failure in drug discovery and development is often ascribed to poor solubility of the drug. The developability of the compound can be hampered by inadequate solubility as it may pose a problem in assay development as well as unfavorably influence the in vivo disposition of the compound. Thus, lack of adequate solubility may prove to be an obstacle to drug DOSAGE FORM DESIGN CONSIDERATIONS 9 1.2 PARAMETERS OF PREFORMULATION STUDIES FIGURE 1.3 pH-solubility profiles of a new chemical entity E2050 constructed with different amounts of starting material as the Di-HCl salt. Adapted with permission from (Augustijns and Brewster, 2007). discovery and development. The complications that occur during product development because of poor aqueous solubility are: • Precipitation of compounds during dilution in the buffer, in assays like biochemical assays, functional assays, and cell-based assays. • Target specificity is reduced, and low bioavailability is observed. • Precise solubility data and solubility profile are imperative towards the development of a successful liquid dosage formulation. It also ensures that a specified quantity of API is in the finished product to affirm desired therapeutic effect following its administration. It may be noted that if a drug demonstrates poor aqueous solubility, it is assumed that it may exhibit poor dissolution characteristics and/solubility-limited absorption profile within the gastrointestinal (GI) tract. This fact underlines the constitution of biopharmaceutics classification system (BCS) which states that a drug has low soluble if its aqueous solubility in 250 mL aqueous solution (pH 1 7.5) is less than its total dose (Lobenberg et al., 2000; Amidon et al., 1995). Generally, Maximum absorbable dose (MAD), a conceptual tool (Equation 1.1) has been devised that correlates the solubility needed for defining the oral absorption of the dose considering its permeability, GI volume, and transit time (Johnson and Swindell, 1996). MAD½mg 5 S½mg=mL 3 Ka½1=min 3 SIWV½mL 3 SITT½min (1.1) wherein “S” is the aqueous solubility of drug at pH 6.5; “Ka” is the intrinsic absorption rate constant, “SIWV” is the water volume in small intestine (generally considered to be B 250 mL); and “SITT” is the transit time in small intestine (typically B 270 min) (Amidon et al., 1995). DOSAGE FORM DESIGN CONSIDERATIONS TABLE 1.4 Some Characteristic Parameters of Preformulation Investigation Parameter Formula/Method Unit Limit Bulk density (D) M/V g/ml 0 1 Tapped density (D) M/TV g/ml 0 1 - 0 50 21 h/r Angle of repose θ 5 tan Carr’s Index (CI) TD-D/TD % 5 40 Hausner ratio TD-D - 1 1.60 Loss on drying First of all, dry a weighing bottle for about 30 minutes under the prescribed conditions, allow to cool it in a desiccator if heated, and weigh it accurately. If the sample is large crystals or lumps, promptly crush it into particles not larger than about 2 mm in diameter and, unless otherwise specified, place 1 to 2 g into the weighing bottle, spread the sample so that the layer is not thicker than 5 mm, and weigh it accurately. Place the bottle in the drying oven, remove the stopper (placing it nearby), dry under the specified conditions, stopper again, take the bottle out of the oven, and weigh it again. If heated, unless otherwise specified, allow to cool it in a desiccator, and weigh it accurately. If the sample melts at a temperature lower than the specified drying temperature, dry it at a temperature 5 10 C lower than the melting temperature for 1 to 2 hr, and dry it under the specified conditions. % When “dry to constant weight” is specified in a monograph, drying shall be continued until two consecutive weighings do not differ by more than 0.50 mg/g of substance taken, the second weighing following an additional hr of drying Melting point (MP) Capillary method is one of the official methods in various pharmacopeia including USP. C As specified in monograph % As specified in monograph Capillaries specification as per USP: 10 cm length, 0.8 1.2 mm internal diameter and 0.2 0.3 mm wall thickness. Capillary tubes must be charged with sufficient amount of the dry powder to form a column in the bottom of the tube 2.5 3.5 mm high when packed down as tightly as possible by tapping on a solid surface. The most common MP procedure (Class Ia, Apparatus I) requires inserting the capillary with the sample into the heating block 5 C below its expected MP and ramping at 1 1 /- 0.5 C/ minute until the melt is complete. The MP range is recorded at the end of the melt Moisture content Using a dry device, inject or add directly an accurately measured amount of the sample or sample preparation estimated to contain between 0.5 and 5 mg of water, or an amount recommended by the instrument manufacturer into the anolyte, mix, and perform the coulometric titration to the electrometric endpoint. Read the water content of the liquid Test Preparation directly from the instrument’s display, and calculate the percentage that is present in the substance. Perform a blank determination, as needed, and make any necessary corrections. M 5 mass of substance, V 5 volume of substance, TV 5 tapped volume of material, h 5 height, r 5 radius. 1.2 PARAMETERS OF PREFORMULATION STUDIES 11 Generally, the solubility of a drug is influenced by parameters such as the lipophilicity, hydrogen bonding, molecular volume, crystal energy, and ionizability in the solubilizing solvent. Similarly, solution conditions are affected by pH, cosolvents, additives, ionic strength, time, and temperature. Thus, overall the factors that affects the solubility profile of drug may include type of solvent, solvent temperature, pH of media (in case of ionizable API compound), additives, physical state of the solid API compound (fine, course etc), crystalline nature of drug, existence of common ions in the release medium, solubilizing additives in the solvent, etc. Methods to determine solubility are classified into equilibrium and nonequilibrium methods. The prominent example of equilibrium method is the “saturation shake-flask method” wherein solubility is determined after the establishment of equilibrium. It prominently comprises of the following steps: sample preparation in various buffers, equilibration execution, separation of solid and solution phases, analysis of the saturated drug solution, followed by data analysis and interpretation (Yalkowsky and Banerjee, 1992). In nonequilibrium methods, as the term suggests, these methods do not involve the establishment of equilibrium. Prominent examples being turbidity and ultraviolet detection that are designed into high-throughput instrumentation. Besides this, a potentiometric method is also employed. In general, to assess the solubility, the drug is subjected to solubilization in pH range 1.2 to 8 using different buffer compositions (i.e., pH 1.2 hydrochloric acid buffer, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and pH 7.4 phosphate buffer). Besides this, to mimic biological milieu, the solubility of the NCE in bio-relevant media such as Fasted State Simulated Intestinal Fluid (FaSSIF) and Fed State Simulated Intestinal Fluid (FeSSIF) is determined (Shah et al., 2014). Additionally, kinetic solubility is ascertained to determine the solubility of the amorphous form of the drug. However, it is reported that such solubility is often an overestimation of the drug solubility in comparison to its thermodynamic solubility (Saal and Petereit, 2012). Apparent solubility can be improved by incorporating an ionic form of a drug candidate that is used as a starting material. These difference are observed when varying amounts of salt are added to the solution. For example, Brewster et al. studied their experimental compound E2050 for pH-solubility profile: they observed that when excess amount of the di-hydrochloride (2*HCl) salt of this compound is used in this study, the solubility in the pH region where the mono-hydrochloride salt controls the solubility is suppressed by the excess chloride ion resulting from the conversion of the di-HCl salt to the mono-HCl salt (Augustijns and Brewster, 2007). In the extreme case of kinetic regime, surface pH is equal to that in bulk solution, whereas the surface concentration is close to 0 (under sink conditions), and therefore, the intrinsic dissolution rate (IDR) is directly proportional to the equilibrium solubility at bulk solution pH. Shaw et al. designed a study to investigate the dissolution behavior of paracetamol and ibuprofen in the presence of a range of selected potential excipients (Shaw et al., 2005) as depicted in Fig. 1.4. First, for paracetamol, it was observed that dissolution rate was inhibited by all the excipients, especially lactose at higher concentrations which showed the largest effect. In the case of ibuprofen, it was witnessed that both lactose as well as sodium chloride at higher concentrations inhibit the IDR. Whereas sodium and potassium salts of bicarbonate were demonstrated to massively increase the dissolution rate. DOSAGE FORM DESIGN CONSIDERATIONS 12 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.4 IDR of Paracetamol in 0.05 M HCl Containing Dissolved Excipients. Results are the Mean of at least five replicates at 50 rpm (Shaw et al., 2005). 1.2.2 The Permeability of the Drug Apparent permeability coefficient is important to be determined for consideration of the right active molecule to proceed to preclinical animal testing. Caco-2 monolayer permeability technique (13) is heterogeneous human epithelial colorectal adenocarcinoma cells that possess P-glycoprotein efflux transporters, various enzymes (such as peptidases and esterases), microvilli, and tight cellular junctions mimicking the intestine. This assay assesses the permeability of the actives in the formulation and always used an in vitro diagnostic tool during product development. It has the property to screen large sizes of the sample data in a short time and gives accurate and precise results. After the successful screening using this Caco-2 permeability technique, this can be further taken for in vivo pharmacokinetic studies. Hence it is used for the drugs that undergo excessive Pglycoprotein efflux and/or for drugs that get metabolized extensively by enterocytic enzymes. It is a good tool for evaluating BCS Class II and IV drugs too. In recent times, permeability is also assayed using artificial membranes, such as parallel artificial membrane permeability assay (PAMPA) (Bennion et al., 2017; Mensch et al., 2010), especially drugs that are absorbed by passive diffusion (Liu et al., 2011; Leung et al., 2012). Fig. 1.5 gives the flow of for important considerations in selecting a final salt form (Huang and Tong, 2004) and Fig. 1.6 describes Preclinical formulation scenarios encountered for improving oral bioavailability (Shah et al., 2014) (Fig. 1.7). Pawar et al. studied the effect of formulation factors on in vitro permeation behavior of drug moxifloxacin and aqueous drop on freshly excised corneas of sheep, goat, and DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 13 FIGURE 1.5 Important considerations in selecting a final salt form. FIGURE 1.6 Preclinical formulation scenarios encountered for improving oral bioavailability. buffalo (Harapanhalli, 2017). Presence of excipients like EDTA (0.01% w/v) and benzalkonium chloride (BAK) (0.01% w/v) in the formulation showed enhanced permeation to the maximum in all the corneas. With respect to permeability and bioavailability studied performed on the formulated 0.5% ophthalmic solution (pH 7.2), it was recommended that DOSAGE FORM DESIGN CONSIDERATIONS 14 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.7 Flow of the bulk characteristics of a material. moxifloxacin solution with EDTA (0.01%w/v) and BAK (0.01%w/v) increased in vitro ocular availability through goat, sheep, and buffalo corneas. 1.2.3 Bulk Characterization: Physical, Analytical, and Physicochemical Surface science is used to evaluate the surface and physicochemical properties to design formulation strategies. During the preformulation stages, powder characterization is mandatorily performed on the certified and calibrated equipment that assists the formulator to characterize the material, be it active or any excipients. The formulations are developed with emphasis on their surface, physicochemical properties of whether their functionality can be used either for oral or inhaler dosage forms. Some of the bulk characterization parameters are highlighted/presented below: • Bulk characterization involves the investigation of interparticle interactions as well as the interaction of different particulate surfaces with water vapor. • Particle agglomeration and subsequently, flow property. • Surface adhesion of particles to different processing equipment and/substrates. • Quantification of the effects of the surface variability on the product’s performance to establish the acceptance criteria. • Initial stage to access the degradation pathways by stress testing or forced degradation studies. • Stability studies for processing and storage. • Study the process of milling, drying, hot melt extrusion, spray drying on particulate properties, i.e., segregation and agglomeration, stability and performance, solubilization and dispensability. For particle size analysis to flow characterization, a few techniques DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 15 are used like particle size analysis using laser diffraction analyzer (0.7 400 µm), light scattering analysis (0.04 200 µm) (Hao et al., 2015), sieve analysis, air jet sieve (Meier et al., 2015; Muller et al., 2015.), Rototap (Maginness et al., 2015), sedimentation analysis (0.01 µm- 50 µm), aerated and packed bulk density (Serrano et al., 2016), angle of repose (Sharma et al., 2016; Kaur et al., 2016), angle of spatula, cohesion, uniformity, contact angle measurement, water uptake (water isotherms) and moisture analysis, microscopy (optical, SEM) (Goldstein et al., 2017; Furukawa et al., 2017), and surface energy analysis (Skoog et al., 2017). 1.2.4 Inherent Properties: pH, pKa, Log P, Log D, and Intrinsic Dissolution It is well known that for drugs to exert their therapeutic effect, it is essential that they interact with specific receptors which further depends on the concentration of drug in the vicinity of the receptor. pH profile is generally done to assess the solubility of drugs with ionizable functional groups in different pH. In liquid formulation development, pHsolubility profile gives an insight into approaches to be adopted for solubilization of the poorly soluble compounds, i.e., buffer. Findings of Li et al. suggested that ionization of the drug affects drug solubilization, droplet size formation, drug-loading, and drug dispersion/precipitation profiles for the self-emulsifying formulations (Omar et al., 2018). However, multiple buffer systems may be required to control the entire pH range, resulting in salt formation with the buffer species (Tong and Whitesell, 1998). Dean (1979), proposed the “p” scale, where numbers such as KW would be expressed as the negative of their base10 logarithms. In an endothermic reaction, especially during the autoionization of water, an increase in temperature increases KW (Dean, 1979). This temperature dependence relation is plotted in Fig. 1.8. Pramar et al. during the preformulation studies of spironolactone studies the effect of ionic strength, temperature, pH, two buffer species on stability. As depicted in Fig. 1.9A and 1.9B, the optimum pH of stability appears to be approximately 4.5. When there was an increase in the concentration of buffer, both the species hastened the degradation of spironolactone but stability of the drug was not affected by ionic strength. At pH 4.3, the energy of activation (Ea) was estimated to be approximately 78.8 kJ/mol. The unionized spironolactone is subject to general acid base catalysis. The Kh and Koh values at 40 C have been estimated to be 1.63 and 2.8 3 105/day, respectively. The HPO4-2 ion had approximately 10 times more catalytic effect than the H2PO4 ion. Moreover, for all the higher temperatures (40 C, 50 C, and 60 C) decomposition followed first-order law (Fig. 1.9C). This is a platform wherein one can develop a stable oral liquid dosage form of spironolactone and other drugs (Osorio and Muzzio, 2016). For optimum drug receptor interaction, both lipophilicity and aqueous solubility are essential. If given orally, it is necessary that the drug be in a dissolved state to traverse the membrane barriers by passive diffusion to reach the site of action. Passive diffusion depends on lipophilicity of a molecule which in turn is governed by pKa of the drug. However, a compound with high lipophilicity suffers from the drawback of poor aqueous solubility (except N-methylated peptides). Hence, in drug discovery programs, it is desirable that at lead optimization stage, the optimized lead must have adequate solubility and DOSAGE FORM DESIGN CONSIDERATIONS 16 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.8 Temperature dependence of the autoionization constant of water. The figure was developed from data given in (Akers, 2002). lipophilicity to achieve a delicate balance of both pharmacological activity and desirable formulation favorable physicochemical attributes. Lipophilicity of a compound is represented by Log P, wherein Log P of 0 represents that the compound has equal solubility in water and n-octanol. While Log P of 5 and 2 reflects that it is lipophilic and hydrophilic, respectively. Ideally, Log P values between 1 and 3 exhibit good absorption profile, whereas Log P values of .6 or ,1 demonstrate poor permeability. Another important parameter includes distribution coefficient, Log D at pH 7.4 which gives an estimate of lipophilicity in pH of blood plasma. Unlike log P, wherein it is assumed that the drug molecules are in a neutral form, log D assumes that compound molecules may be partially in the ionic form. Besides this, ionization constant (pKa) is a parameter which takes into account the ionization state of a compound. For a prediction of the site of absorption of weakly acidic or basic drugs, knowledge of pKa is very important. Together these parameters, provide crucial information for predicting the drug absorption profile across the gastrointestinal tract, especially most importantly understanding of pH-solubility profiles. By definition, it is well known ionized drugs have good solubility (except for amino acids), however they have poor passive permeation. DOSAGE FORM DESIGN CONSIDERATIONS 17 1.2 PARAMETERS OF PREFORMULATION STUDIES 4.5 –1.0 Log K (B) 0.0 % Remaining (A) 5.0 4.0 –2.0 –3.0 3.5 –4.0 3.0 0 10 20 30 40 50 60 70 Time (Days) 80 90 100 1 2 3 4 5 6 pH 7 8 9 10 (C) 4.8 4.6 Keywords % Remaining 4.4 pH 2.3 pH 3.4 4.2 pH 4.5 pH 5.2 4.0 pH 6.2 pH 7.3 3.8 pH 8.3 3.6 0 20 40 60 80 100 120 140 160 Time (Days) FIGURE 1.9 (A) Effect of pH on the stability of spironolactone at 40 C. (B) pH-rate profile curve of spironolactone at 40 C. (C) First-order plots of spironolactone at higher temperatures. Adapted with permission from (Osorio and Muzzio, 2016). Lipophilicity of the drug and its ability to cross the cellular membrane can be indicated by measurement of partition coeffcient. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. The major contributing factor in any drug delivery system is the lipophilic/hydrophilic balance that affects the rate and extent of drug absorption. Rate of drug transfer for passively absorbed drugs is DOSAGE FORM DESIGN CONSIDERATIONS 18 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT directly related to the lipophilicity of the molecule since the biological membranes are lipoidal in nature. In general, during laboratory practice, the shake-flask method is used to determine the partition coefficient of the pharmaceutical substance. In this method, the drug dissolved in one solvent is shaken with the other partitioning solvent for 30 min. The mixture is allowed to stand for 5 min. The aqueous solution is centrifuged and then assayed for drug content. It has a number of applications, such as being used in solubility determination in both aqueous and mixed solvents. It is applied to a homologous drug series for structure activity relationships in drug absorption in vivo. Partition chromatography can be helpful for column and stationary phase selection (HPLC), choice of plates for TLC, and choice of mobile phases (eluents). This information can be effectively used in the crude drug extraction, recovery of antibiotics from fermentation broths, and recovery of biotechnology-derived drugs from bacterial cultures. It can also be applied for therapeutic drug monitoring in the process of extracting drugs from biologic fluids, in understanding the pharmacokinetic behavior of drug absorption from various dosage forms like ointments, creams, transdermal systems, suppositories, and study of the distribution of flavoring oil between oil and water phases of emulsions. A remarkable study by Pongcharoenkiat et al. demonstrated the effect of partition coeffcient and surface charge on the chemical stability of solutes in O/W emulsions. By substituting various parabens for methyl parabens (MP) like propylparaben (PP), ethylparaben (EP) and butylparaben (BP) in the emulsions the effect of surface charge was studied along with the rate of hydrolysis. Rate of hydrolysis was inversely related to the partition coefficient. An evident result on the effect of surface charge on rate of hydrolysis was observed in the emulsions containing MP and EP. The greatest effect on the partition coefficient was reported in the emulsion containing PP and BP. In general, the effect of surface charge predominated when the partition coefficient was small, whereas the partition coefficient had a greater effect than surface charge when the partition coefficient was large (Pongcharoenkiat et al., 2002). The literature states that partition coefficient can be determined using different procedures such as: a. b. c. d. e. f. g. h. Analysis using 96-well plate method along with RP-HPLC. Shake/stir flask method. Two-phase titrations. Generator column method. HPLC analysis based on retention time or capacity factor method. Countercurrent chromatography/centrifugal partition chromatography. Flow-injection extraction. Calculations method. However, due to the complexity associated with these methods they have inherent drawbacks, such as possibility of variation in results, they often require a large volume of media, sample requirement is also large (ranging from 1 mg to 3000 mg), and the need of specialized sophisticated instruments or reagents; all these limit their efficacy in drug discovery. Nevertheless, efforts have been undertaken to create concise protocols by indirect DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 19 methods which rely on empirical correlations. These are based on the molecular property of the compound, like determination of retention time and capacity factor (HPLC) and by direct method which involves partitioning of a compound between n-octanol and water (shake-flask method) Similarly, for estimation of pKa, potentiometric titration is used to estimated pKa from the titration curve, UV spectra, and HPLC chromatograms (recorded in different buffers) and capillary electrophoresis wherein relative mobility of ions is noted in different buffer solutions. 1.2.5 Stability: The Solution, Solid State, & ICH Photostability For a therapeutically active drug product, the formation of minor degradation products during storage and administration often derails the product (Singh et al., 2013). Since the drug substances have known to have light-induced side effects in vivo by interaction with endogenous substances. Hence, drug photostability is considered for both in vitro and in vivo stability (ICH, European Medicines Agency, August 2003). There are reports which demonstrate photostability of derivatives of the drug nifedipine of only a few minutes, while other drugs show lesser photo-instability after several weeks’ exposure (Tough and Mengesha, 2015). Hence, it is imperative to know the photostability of drug substances and drug products to define handling, packaging, and labeling conditions, to estimate possible adverse effects and the impact on therapeutic aspects and new drug delivery systems. Carney et al. studied the stability of N-cyclohexanecarbonyl-3-(4-morpholino)-sydnone imine hydrochloride (ciclosidomine) in solution as a function of pH, temperature, ionic strength, and buffer species (Liu et al., 2016). In absence of light, the rate of hydrolysis was found to be apparent first order in drug and general acid and base-catalyzed reactions. At an ionic strength of 0.1 M at 60 C, the pH-rate profile had a minimum value near pH 6.0. At 60 C, during the change in ionic strength in the range of 0.05 to 0.2 M, the rate of degradation at pH 7.0 (carbonate buffer) or pH 2.0 (phosphate buffer) was not affected. In absence of light, at pH 3.0, 5.0, and 6.0 and in presence of air or nitrogen, similar degradation rates were reported. However, in the presence of light the degradation rate was rapid in either case at pH 3.0, 5.0, and 6.0. Hence it was recommended to protect the solutions from light during all the studies. At pH 6.0 in dilute phosphate or citrate buffer with an ionic strength of 0.154 M, t90% or the time for 10% drug loss in solution was projected to be 9 M at 20 C and 2.6 M at 30 C. Stability can also be affected by the level of moisture. Carstensen (1988) investigated the problem that arises with limited amounts of moisture and the bulk moisture theory. Using different water concentration from 1% to 2%, they also explored the aspirin moisture system as presented in Fig. 1.10. Photostability of drugs and excipients is desired to be evaluated at the formulation development stage to assess the effects of formulation and packaging on the stability of the final product. Knowing the significance of the photostability studies, a photo essay should be designed such that it reveals the degradation pathways, the resultant degradation products, sensitizing potential of the parent compound, or in vivo metabolites. Fig. 1.11 shows an image of a photostability chamber. DOSAGE FORM DESIGN CONSIDERATIONS 20 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.10 Stability analysis of aspirin at different moisture content. Adapted with permission from (Carstensen, 1988). The ICH Photostability Guideline recommends that drug substance photostability testing be carried out under the same conditions as those used for product, in order for direct comparisons to be made. The recommended exposure is 1.2 million lux and 200 W/m2 UV. During purification and manufacture of the drug substance, total exposure of the substance is extremely unlikely to exceed 100 klux of visible light with no UV exposure. On this basis, the European Federation of Pharmaceutical Industries (EFPIA) Expert Working Group agreed informally that 100 klux h exposure was appropriate for the simulation of exposure during manufacture. Although such a test is not part of the ICH Guideline, it may be useful for internal control purposes. The guideline recommends that samples be exposed side by side with a validated chemical actinometric system (e.g., quinine for nearUV region) to ensure that the specified exposure is obtained. Alternatively, exposure for the appropriate duration of time may be employed when conditions are monitored using calibrated radiometers/lux meters. The procedure used should ensure that any unevenness in the irradiance of sample area is taken into account. Any protected samples (e.g., wrapped in aluminum foil) used as dark controls to compensate for temperature effects should be placed alongside the authentic samples. However, foil-wrapped samples may, in fact, be at a lower temperature than unwrapped samples due to the reflecting properties of the foil. To explore the oxidative stability, formulation variables and the effects of adjacent residues on tyrosine oxidation were examined in model dipeptides (glycyl tyrosine, N-acetyl tyrosine, glutamyl tyrosine, and tyrosyl arginine) and tripeptide (lysyl tyrosyl lysine). It was reported that zero-order reaction is observed in the tyrosyl peptides that were DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 21 FIGURE 1.11 Instruments used for the determination of Moisture content, Loss on drying and stability of the product. oxidized in presence of light under alkaline conditions. The rate of the photoreaction was dependent on tyrosyl pKa, which was perturbed by the presence of neighboring charged amino acid residues. The strength of light exposure, oxygen headspace, and the presence of cationic surfactant, cetyltrimethylammonium chloride, had a significant effect on the kinetics of tyrosyl photooxidation. Tyrosine and model tyrosyl peptides were also oxidized by hydrogen peroxide/metal ions at neutral pH. Metal-catalyzed oxidation followed first order kinetics. Adjacent negatively charged amino acids accelerated tyrosine oxidation owing to affinity of the negative charges to metal ions, whereas positively charged amino acid residues disfavored the reaction. The oxidation of tyrosine in peptides was greatly affected by the presence of adjacent charged residues, and the extent of the effect depended on the solution environment. DOSAGE FORM DESIGN CONSIDERATIONS 22 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT Effect of microencapsulation on photostability of nifedipine was studied by Dinarvand et al. wherein he showed the photodegradation of nifedipine in the form of powder, in buffer or acidic solution as well as microsphere formulation (Dinarvand et al., 2010). The Fig. 1.12A showed the highest photodegradation rate was observed in soluble form. There FIGURE 1.12 (A) Comparison of the photostability of nifedipine in the form of powder, acidic or buffer solution and microsphere. (B) Effect of different amounts of ethyl cellulose on nifedipine degradation. (C) Effect of titanium oxide on photostability of nifedipine in ethyl cellulose microspheres. (D) Effect of Titanium oxide percentage on photostability of nifedipine in ethyl cellulose microspheres. (E) Effect of different polymers used for microencapsulation on nifedipine photostability. Adapted with permission from (Dinarvand et al., 2010). DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 23 was no significant difference between buffer or acid solution. While both acidic and buffer solutions of nifedipine degraded within one day of light irradiation, 80% of nifedipine content of ethyl cellulose and titanium oxide microspheres remained intact. It was concluded that, in presence of light, the nifedipine soluble form degrade at higher rate. Different ratios of polymers such as ethyl cellulose was screened for preparation of nifedipine microspheres and were studied for photostability. Fig. 1.12B show that the ratio of ethyl cellulose in microspheres had no significant effect on photostability of drug. It was observed that there was a loss of drug content (NIF) after one daylight exposure amongst all the formulations prepared with EC: NIF ratios of 90:10, 70:30, and 50:50. Hence it is evident that no protection is rendered by ethyl cellulose for nifedipine against light degradation. But when opaque material such as titanium oxide is used in combination with EC there is an enhanced photostability of NIF and about 20% of NIF remained intact inside the microspheres after 6 days of light irradiation (Fig. 1.12C). Protective effect was observed to be similar for all different ratios of EC: titanium oxide (99:1,95:5 and 90:10) as it is shown in Fig. 1.12D. Fig. 1.12E shows the effect of different polymers used for microencapsulation on nifedipine photostability. Among four formulations, microspheres prepared with pectin provided the highest photoprotection for nifedipine. The photoprotection ability of polymers was in the following order: Pectin . ethyl cellulose 1 titanium oxide . gelatin . NIF powder . ethyl cellulose. The photostability of tablets are significantly influenced by formulation variables and the manufacturing process. Formulation variables and their effects were investigated by Aman et al. along with manufacturing parameters during formulation development of nifedipine and molsidomine tablets as highly light-sensitive drugs (Aman and Thoma, 2002). With respect to the variables in formulation, drug loss varied between 30% and 55% after 12 h of irradiation in a light testing cabinet (Suntests CPS 1 ) (Fig. 1.13). Moreover, irradiation of 100% drug powders of different particle sizes revealed marked differences of the photostability. After 2 h irradiation drug losses were about 5% 10% higher in the finer powders (Fig. 1.14A and B). However, after incorporating drug powders into tablets no influence of the particle size on the photostability could be deduced from the results. Nevertheless, the photodegradation of nifedipine and molsidomine tablets was extraordinarily high: more than 30% of the initial drug content were decomposed after 12 h light exposure (Fig. 1.14C and D). Furthermore, as can be seen from Fig. 1.15A the compression diluent had a significant effect on the photostability of molsidomine tablets. In tablets prepared with microcrystalline cellulose, the residual amount of molsidomine was 68% after 12 h irradiation, whereas in lactose tablets only 61% of the drug substance remained intact. The lowest photostability was observed with tablets made of modified starch. Only 50% of the initial molsidomine content was found after the same light exposure. In addition, the influence of the lubricant on the photostability of molsidomine tablets was not significant. Photodecomposition was similar with each formulation, resulting in a drug loss of 35% 40% after 12 hr light exposure (Fig. 1.15B). Apart from that, by increasing the diameter the photostability of molsidomine tablets was improved. The effect was a minor one, but nevertheless significant. After 12 h irradiation, 72% of the drug was undecomposed in 12 mm tablets, whereas the residual amount DOSAGE FORM DESIGN CONSIDERATIONS 24 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT 80 70 60 50 80 70 60 40 0 3 6 9 Irradiation time (hr) 12 0 3 6 9 Irradiation time (hr) 12 (D) Loss of drug substance (mg) 0 –1 –2 –3 –4 –5 –6 –7 0 3 6 9 Irradiation time (hr) 12 0 , 20 mg; , 20 mg; (C) Loss of drug substance (mg) 90 , 4 mg , 4 mg Loss of drug substance (mg) 90 100 , 10 mg; , 10 mg; (B) 100 Loss of drug substance (mg) (A) –1 –2 –3 –4 –5 0 3 6 9 Irradiation time (hr) 12 FIGURE 1.13 Influence of the drug content on the photodegradation of tablets. A, B, relative drug loss; C, D, drug amount decomposed; A, C, nifedipine tablets (biplanar, d 5 8 mm) (Suntest CPS 1 , 720 W/m2, UV special filter); 20 mg; 10 mg; 4 mg; B, D, molsidomine tablets (biplanar, d 5 8 mm) (Suntest CPS 1 , 415 W/m2, window glass filter). Adapted with permission from (Aman and Thoma, 2002). of 5 mm tablets was only 65% (Fig. 1.15C). Moreover, shape was also found to affect the stability as the irradiation of biconvex tablets gives higher photodegradation than of biplanar tablets (both 8 mm in diameter). However, the difference was only 3% (Fig. 1.15D). In addition, as the irradiation test revealed, the photostability of molsidomine tablets decreased with increasing compression force. After 3 h irradiation, only 12% of the drug was destroyed when tablets were prepared at 3.5 kN, whereas more than 20% was degraded when compression forces of 9.0 and 21.0 kN were chosen (22% and 24%, respectively) (Fig. 1.15E). At last, the influence of granulation on the photostability was investigated. Purified water or a solution of polyvinylpyrrolidone 5% in isopropyl alcohol, respectively, were used as granulation liquids. water content was found to be 4.9% for directly compressed molsidomine tablets, 5.7% after watery granulation, and 4.8% after alcoholic granulation reduced the photostability of molsidomine tablets. Whatever the granulation liquid was, the drug loss was about 4% higher than in directly compressed tablets (Fig. 1.15F). DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 25 FIGURE 1.14 Influence of particle size on the photostability of nifedipine preparations (Suntest CPS 1 , 720 W/m2, UV special filter). A, nifedipine powder; C, nifedipine tablets 20 mg (biplanar, d 5 8 mm); Influence of particle size on the photostability of molsidomine preparations (Suntest CPS 1 , 415 W/m2, window glass filter). B, molsidomine powder; D, molsidomine tablets 20 mg (biplanar, d 5 8 mm). Adapted with permission from (Aman and Thoma, 2002). 1.2.6 Drug-Excipient Compatibility This is an important aspect of preformulation studies to assess the impact of excipients on the physical and chemical stability of the drug and eventually the performance of the dosage form. Understanding the extensive nature of this study, the choice of excipients for this study is solely restricted to the type of dosage form that is intended to be developed. Hence, it can be stated that preformulation gives an overall insight for product development of a robust formulation that sustains the rigidities of manufacturing and storage DOSAGE FORM DESIGN CONSIDERATIONS 26 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.15 (A) Influence of the compression diluent on the photostability of molsidomine tablets 4 mg (biplanar, d 5 8 mm) (Suntest CPS 1 , 415 W/m2, window glass filter). (B) Influence of the lubricant on the photostability of molsidomine tablets 4 mg (biplanar, d 5 8 mm) (Suntest CPS 1 , 415 W/m2, window glass filter). (C) Influence of the diameter on the photostability of molsidomine tablets 4 mg (biplanar). (D) Influence of the shape on the photostability of molsidomine tablets 4 mg. (E) Influence of the compression force on the photostability of molsidomine tablets 4 mg. (F) Influence of the preparation method on the photostability of molsidomine tablets 4 mg. Adapted with permission from (Aman and Thoma, 2002). DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 27 conditions concerning stability. Thus, a well-defined preformulation can minimize the cost of the product and can overcome the challenges during product development. Initially, the preformulation studies are often initiated by conducting in-depth literature surveys/reviews pertaining the drug, therapeutic properties, projected dose, tentative cost, and amount of drug. The primary source of information is the manufacturer’s technical data package which provides a varied information ranging from manufacturing processes of raw materials, molecular formula, chemical structure, physical and chemical properties, i.e., degradation pathways, handling hazards, stability conditions along with the quality and safety (exposure limits) of the raw material, and in some cases, may also include, method of analysis. Depending on the dosage form to be developed, a parameter associated with physicochemical and physicomechanical characteristics of the dosage form along with in vitro release profile and stability as per Figure 1.16 must be studied. Figure 1.17 describes various parameters to be considered in the preformulation stages. 1.2.7 Particle Size and Distribution One of the important characters of a drug molecule that has an intense impact on its performance is particle size and its distribution. In order to achieve optimum production of efficacious medicines, the dimensions of particulate solids are essential. Particle size affects a wide range of critical parameters such as uniformity in drug FIGURE 1.16 Various properties in preformulation process. DOSAGE FORM DESIGN CONSIDERATIONS 28 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.17 Parameters to be considered for preformulation studies. content and its distribution, suspendibility, dissolution rate, penetrability, and lack of grittiness. Various methods to evaluate the particle size include microscopy, sieving, sedimentation rate method, light energy diffraction, laser holography, and cascade impaction. 1.2.8 Thermal Properties Melting point determination is the most accurate determination of thermal properties. It is needed in order to characterize the formulation during a robust product. A procedure for melting point determination using the capillary method is given in Table 1.1. A typical apparatus for the determination of the melting point is shown in Figure 1.11. There are a few sophisticated analytical instruments like differential scanning calorimetry (DSC) and differential thermal analysis (DTA) that enable the determination of such a thermal characteristic of pharmaceutical compounds. 1.2.9 Hygroscopicity Adsorption, absorption, deliquescence, and lattice incorporation are the different ways of moisture interactions in solids. Any substance which absorbs sufficient moisture from the atmosphere to dissolve itself is deliquescent, e.g., sodium hydroxide. Any substance that loses water to form a lower hydrate or becomes anhydrous is termed efflorescent. DOSAGE FORM DESIGN CONSIDERATIONS 1.2 PARAMETERS OF PREFORMULATION STUDIES 29 These are extreme cases, and most pharmaceutical compounds are usually either impassive to the water available in the surrounding atmosphere or lose or gain water from the atmosphere, depending on the relative humidity (RH). Materials unaffected by RH are termed nonhygroscopic, whereas those in dynamic equilibrium with water in the atmosphere are hygroscopic. A procedure for moisture content is depicted in Table 1.11. A typical apparatus for the determination of melting point is shown in Figure 1.11. It is a long-known fact that in the presence of moisture, the drug substances affect the physicochemical properties of the drug and its stability. Aspirin is a classic example and that’s why it is not granulated during product development. Even during storage, the moisture content needs to be evaluated and taken into consideration. Presence of moisture also impacts the effectiveness of super disintegrants in promoting in vitro dissolution (Tanner et al., 2017). In a study, Rohrs et al. investigated the cause for decrease in delavirdine mesylate 200 mg tablet dissolution upon exposure to high humidity. The study suggested that between 4.4 4.6 weight % water dissolution extent drops from above 80% to less than 70% and continues to reduce as the amount of water in the tablet increases (Figure 1.18). Water is thought to act as both a reaction medium and a plasticizer for disintegrants used in this study (croscarmellose sodium) which facilitate protonation of the carboxyl sites on disintegration (Rohrs et al., 1999). The presence of hydrogen bonds in water molecules and due to the polarity, these polar moieties bind/adsorb on the solid surface of the pharmaceutical solid, and these factors govern the affinity toward water adsorption. Particle size plays a key role as it is dependent on its size and surface area available for moisture uptake or hydrolysis reaction. Moisture content evaluation for the drug substance should be mandatorily performed to help in product development in order to select the excipients, drug excipient compatibility, stability, process design, flowability, compactibility, and packaging. FIGURE 1.18 Effect of weight% water in tablets on tablet dissolution. Adapted with permission from (Rohrs et al., 1999). DOSAGE FORM DESIGN CONSIDERATIONS 30 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT 1.2.10 Bulk Properties Most of the pharmaceutical materials are available in multiphasic form known as powders as they exhibit as solids and fluids. The uniqueness of powder is critical in the physical properties that they possess. For instance, a powder can be evaluated by its size, shape, density, porosity, compressibility. Bulk flow, formulation homogeneity, and surface areacontrolled processes such as dissolution and chemical reactivity are affected directly by size, shape, and surface morphology of the drug particles. 1.2.11 Mechanical Properties and Compatibility Various arrangements are observed in various pharmaceutical solids. The properties and level of interactions among the molecules differ in different solids. Naturally, under mechanical stress, one can expect that these materials may react contrarily. Likewise, the suitability of a drug substance is based on the particle size distribution, flowability, and morphology. Hence when roller compaction or any tableting processes are used during development, it is vital to assess the mechanical stuffs and suitability of the drug substance and excipients used in manufacturing the dosage form. 1.2.12 Crystallinity and Polymorphism The structure of a solid compound refers to crystallinity and these structures disappear in the liquid and vapor states. It can be classified by internal structures (cubic, tetragonal, hexagonal, rhombic, etc.) and solid habits (plate, needle, tabular, prismatic, bladed, etc.). Changing the internal structures alters the crystal habits. Changing the chemical form (e.g., salt formation) alters both the internal structure and crystal habit. Different polymorphs are obtained by crystallization from different solvents and by solidification after melting. When the incorporated solvent is water, it is called “hydrates.” The compound not containing any water within its crystal structure is called “anhydrous.” Atoms in crystalline matter are arranged in regular and repeating patterns in three dimensions, e.g., metal and mineral and atoms or molecules randomly placed without a regular atomic arrangement in amorphous solids. They have different physicochemical properties (melting point, density, vapor pressure, X-ray, color, crystal shape, hardness, solubility, dissolution rate, and bioavailability). A stable polymorph has low free energy, low solubility, and high melting point. A metastable polymorph is less stable with higher solubility and bioavailability and lower melting point. Crystals and polymorphs are characterized by microscopy, thermal analysis, and X-ray diffraction methods. Significances of identification of crystal shape and internal structure can influence solubility and stability, e.g., Chloramphenicol palmitate exists in three crystalline polymorphic forms (A, B, and C) and an amorphous form (D). Increasing the concentration of the form B led to an increase in the serum level due to its higher water solubility. Melting point can also have an influence. For example, Cacao butter as an oily base for suppositories exists in four polymorphic forms (α, β-prime, γ, and β-stable). Only the β-stable form can be used as a suppository base due to its higher DOSAGE FORM DESIGN CONSIDERATIONS 1.3 ROLE OF PREFORMULATION IN DRUG DISCOVERY 2.00 FIGURE 1.19 Solvent-mediated transformation of carbamazepine polymorphs in ethyl acetate at 25 C and initial c/s Form III 5 2.0. Adapted with permission from (Kelly, 2003). Metastable Form Dissolution Supersaturation 1.80 31 C/S form III Nucleation 1.60 Form II Growth Stable Form 1.40 1.20 Form III 1.00 0 1 2 3 4 5 Temperature (ºC) melting point. Density and crystal shape influences the flow properties of powders. Tablet hardness influences the compression properties and grinding processes. For example, Figure 1.19 shows the de-supersaturation profile for the solvent-mediated polymorphic transformation of carbamazepine in ethyl acetate at 25 C and initial c/sCBZ (III) 5 2.0 (Kelly, 2003). Initially, the form II nucleates as this polymorph is favored due to inhibition of form III nucleation as a result of specific solvent solute interactions, as discussed earlier. This is followed by dissolution/equilibration of form II to form a solution that is supersaturated with respect to form III. This leads to subsequent nucleation and growth of form III until the entire suspension consists of the thermodynamically most stable form, carbamazepine form III (Kelly, 2003). 1.3 ROLE OF PREFORMULATION IN DRUG DISCOVERY The new product development includes the following major processes starting from the drug discovery to early-stage clinical trials: 1. Discovery and early development of a New Chemical Entity (NCE). 2. Drug repurposing, i.e., discovery of innovative and favorable pharmacological activity of currently marketed drugs against newer drug targets, 3. Improvement of the delivery of currently marketed drug by applying novel technological platform. The product development team should develop various decision points to develop a New Chemical Entity (NCE), a description for the exploratory Investigational new drug (IND) repurposing as well as drug delivery technologies and then rationalize their importance for the new drug discovery and development programs. This will help to discover DOSAGE FORM DESIGN CONSIDERATIONS 32 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT the therapeutic hypotheses, validation of the target and its pathway, proof of concept, and cost analyses at various stages of early drug discovery (Strovel et al., 2016). 1.3.1 Material Properties in Lead Selection, High Throughput Preformulation Studies Selection of disease, target identification, target validation, lead generation, lead selection, lead optimization, and candidate selection are the major activities of drug discovery. These activities are preclinical in nature and use a host of tools that may be in vitro, in situ, ex situ, and in vivo animal models. Drug development involves clinical trials on “new chemical entities.” Figure 1.20 explains the flow of drug discovery process from the stages of identification to NCE discovery and Figure 1.21 explains the lead phases for identification from natural sources (Guido et al., 2011). The definition and evaluation of both chemical and biological space have strengthened the screening model and emphasized the significance of engaging the intrinsic complementary nature of classical as well as modern methods in drug research (Edwards, 2009). The extensive usage of combinatorial chemistry has produced many small organic molecules for a range of drug discovery projects On the other hand, the improvements in robotics and miniaturization has advanced the development of high throughput screening (HTS) (Figure 1.22) as a versatile method for the rapid and large-scale biological screening of chemical libraries (Macarron, 2006). 1.3.2 “Drugability” of New Chemical Entities During the drug discovery, a crucial step is selectivity and potency of the molecule for the target site. There has been a paradigm shift in past decades, ADME and material characterization with properties has played a major role in selecting the lead molecules. Many FIGURE 1.20 Drug discovery process from the stages of Hit identification to NCE discovery. DOSAGE FORM DESIGN CONSIDERATIONS 1.3 ROLE OF PREFORMULATION IN DRUG DISCOVERY 33 FIGURE 1.21 Schematic phases for lead identification from natural sources. FIGURE 1.22 HTS flow path. drug molecules fail because of low absorption or, because of nonoptimal biopharmaceutical properties, that include pharmacokinetics and drug delivery characteristics. Pharmacokinetics and material properties govern the delivery of the molecule to the site of action and thus contribute to its “drugability.” Modern drug discovery tools like combinatorial chemistry and high throughput screening have also contributed to the nonoptimal DOSAGE FORM DESIGN CONSIDERATIONS 34 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.23 Parameters in fragment based drug discovery. material properties. Combinatorial chemistry involves the reaction of a small number of chemical reagents to produce, simultaneously, a large number of compounds, which are known as libraries. Figure 1.23 explains the various parameters in fragment-based drug discovery. These compounds are then screened using high throughput screening to identify drug candidates. Before this, computational tools like target docking studies are performed to propose the lead molecules that are then synthesized using combinatorial chemistry platforms. Initial lead generation and selection are thus solely guided by molecule target interactions. This approach, over the years, has led to a gradual increase in molecular weight and lipophilicity of the lead molecules. 1.3.3 Tools to Assist in Lead Selection Material properties are a set of physicochemical properties that include solubility, dissolution rate, partition coefficient, solid-state properties, stability, and hygroscopicity. Various terms like “preliminary preformulation” and “discovery pharmaceutics” are used to describe this preformulation activity done during drug discovery. The main objective of this preformulation activity is candidate selection. In silico tools for preliminary preformulation: Preliminary preformulation can be carried out using in silico and experimental platforms to generate the preformulation profile of the lead molecule. Numerous computational software like PALLAS, gastro plus, ACD/ Phys Chem and ALOGPS are available and require structural formula as an input to calculate physicochemical parameters like ionization constant, the pH dependence of partition DOSAGE FORM DESIGN CONSIDERATIONS 1.4 ROLE OF PREFORMULATION IN DRUG DEVELOPMENT 35 coefficient, solubility, and permeability. Similarly, computation of ADME properties is also possible. Experimental tools for preliminary preformulation: Despite the enhanced accuracy of predictive tools, experimental measurements are essential as the level of complexity of prediction, renders calculations of little utility. High throughput miniaturized experimental tools are used during drug discovery stage to enable screening of large number of candidates, using small quantities of NCEs. The most important issue at this stage is the oral absorption of the molecule. High throughput solubility screening can be carried out using commercially available equipment like PION-pSOL and Sirius CheqSOL. However, these equipments require a solid sample for solubility analyses which may not be available in early stages. A popular means for early solubility experiments is the “precipitative solubility” using DMSO stock solutions. Automation using robotics allows faster screening of a large number of compounds. Similarly, high throughput permeability studies can be performed using “parallel artificial membrane permeability assay” (PAMPA) (Strovel et al., 2016). Fail early fail cheap: Every pharmaceutical company targets the goal of “fail early fail cheap,” during drug discovery, by shortlisting molecules that have all the criteria of drugability. It is disastrous to spend a lot of money on research of molecules that fail later in the drug development. We can thus conclude that preliminary preformulation helps in candidate selection during drug discovery and thus enhances of conversion of “a molecule” to “a drug.” Additionally, it lays out a framework for designing of preformulation protocol to support drug development activities later on. 1.4 ROLE OF PREFORMULATION IN DRUG DEVELOPMENT Preformulation helps the scientists to screen and select the new chemical entities for preclinical efficacy and toxicity studies which lead to investigational new drug application. The screening of the lead candidates is based on their physicochemical and biopharmaceutical properties. Extensive knowledge based on the drug discovery and formulation development helps the NCEs to reduce the failure rate in the later stage of product development. Based on the decisive parameters of characterization it helps in predicting and selecting the suitable physical form (salt, polymorph, etc.) of the candidate. Phase 1 clinical studies can be designed based on pharmacokinetic and efficacy/toxicity studies. This contributes to efficacy/toxicology evaluation, allowing pharmacologically effective. This helps in developing the molecules and opening new avenues for clinical and eventually to market. For lead optimization and chemogenomics, various computational approaches are often used for selective chemical structures having biological activity. There are also several other parameters, such as initial drug formulation whose process identification depends on the biopharmaceutical classification system (BCS); in vitro in vivo correlation (IVIVC). Drug candidates to be screened for lipophilicity and acidity. These two parameters can suitably be predictable by gradient reversed-phase HPLC (Leucuta, 2014). Bharate et al. have studied the importance of structural aspects, pKa and other physicochemical properties, absorption, distribution, metabolism, excretion, toxicity (ADMET), DOSAGE FORM DESIGN CONSIDERATIONS 36 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT and biological characteristics of substance including bioavailability as an essential parameter in drug discovery and drug dosage forms design. Preclinical investigations for ADMET method development of ligand characters are also studied in this process (Bharate and Vishwakarma, 2013). 1.4.1 Identification of Challenges During Formulation Development: Pre-Assumptions All formulation strategies are based on assumptions, so it is important to identify their presence and manage them. Approach implementation should be based on the capability to select specific actions, execute them, and ties act and outcomes to landmarks. Preassumptions are planning tools, and the basic definition of an assumption is “Parameters that are marked as true, real, or certain to create a common appreciative of the plan.” Molds are made to plan, employing the best judgment/data. Otherwise, the “the plan” is simply a document. Typical solubilization methods like physical alterations of drug crystals (e.g., surface modification of drug, micronization) result in increase in dissolution and solubility to limited extent. However, while developing a formulation with relatively higher doses, the novel formulation strategies are become more utilized, especially in the case of water-insoluble compounds which are characterized by high melting point and very high lipophilicity (Ali and Kolter, 2012). The factors considered are polymers, surfactants and solubilizers types, thermal stability, aqueous and organic solubility and compatibility, pH-dependent invariability, and solubilization capability among others. In all, these formulation approaches are excipients-driven. Hence, functional excipients are gaining lots of market attention for developing newer safe and efficacious dosage forms with latest technologies for better performance that require a complete evaluation of dosage stability, therapeutic efficacy, and mitigation of food effect among other factors. 1.4.2 The Dosage Form Specific Studies The greatest challenges in the dosage forms are in pediatric dosage forms. Pharmacists or caregivers often require manipulating adult therapeutics in a fashion which is not a product characteristic. Simple approaches like breaking tablets without a score line with a tablet splitter, or preparing a suspension employing tablets as a source of drugs are used for this purpose. Sometimes the pharmacists may need to compound medicine based on the API. However, this process itself can increase the errors in the dosage accuracy increases product variability. The WHO Model Formulary for Children, 2010, offers selfgoverning data on dose/dosage and therapy guidance for therapeutics depends on the WHO Model list of desired pediatric medicaments. This program was first developed in 2007 and is reviewed and updated every two years (WHO, 2011). An important feature in designing of the product and the formulation is the cost. Safe and effective pharmacotherapy requires the timely development of medicines as well as information on their proper use to suit the age, physiological condition, and body sizes. The assessment of risks related to specific products and starting materials as well as the DOSAGE FORM DESIGN CONSIDERATIONS 1.5 PREFORMULATION STUDIES OF PROTEINS AND PEPTIDES 37 identification of hazards at specific stages of production or distribution during the development of pharmaceutical products will enable to enhance the quality assurance mechanisms, such as the implementation of good manufacturing practices (GMP). In this way, manufacturers who have developed the product using a more systematic approach would follow the development within a broader context of quality assurance principles, including the use of quality risk management and pharmaceutical quality systems (McNeil et al., 2015; WHO, 2016). Currently, pediatric medicine use across a wide population displayed the variety of dosage forms and routes of administration utilized for adults. General routes of administration in pediatric patients are oral, intravenous, skin, pulmonary, rectal, nasal, and ocular. (Zisowsky et al., 2010; Lal et al., 2017). 1.5 PREFORMULATION STUDIES OF PROTEINS AND PEPTIDES Over the last few decades, there has been intense research focused on biotherapeutics. Biotherapeutics constitutes various biological products such as proteins (like antibodies), smaller peptides (e.g., hormones), DNA for gene-transfer therapies, vaccines and blood fractionation product, allergens, and RNA. They occupy a therapeutic niche between small molecules and large biologics as they exhibit improved selectivity, potentials for decreased off-target side effects, increased potency, and decreased systemic toxicity. The stability and structural integrity of the active molecule during transit and storage, target delivery, development cost, and the commercial value of the final product are some of the key concerns in the biotherapeutic formulation. Several factors such as packaging materials, delivery devices and dosage forms, excipients, stabilizers, and compatibility of ingredients play a crucial role in the stability of biotherapeutics along with physicochemical properties, analytical methods, and testing protocols. The decision tree demands the following types of choices during the formulation strategy planning: 1. 2. 3. 4. 5. 6. 7. 8. Route of drug delivery and its method of administration (Parenteral, pulmonary, etc.). Dosage form of the final product (Solution, lyophilized cake, etc.). Depending on multidose or single-dose its requirements for the use of preservatives. Types of ingredients in the formulation (Excipients, stabilizers, preservatives, etc.). Details of dosage its concentration, dose, frequency, etc. Storage conditions, logistics, shelf life, etc. Final packaging and labeling instructions, i.e., vials, ampules, etc., even labeling. Process of manufacture, i.e., scale-up tech-transfer, equipment, protocols, etc. For success of any drug product, experience in process and product development along with regulatory guidance is important. (Cheryl, 2006). Preformulation should be an iterative process. Unique attributes of purified peptides and proteins must be accounted during the stages of product development in preformulation studies, i.e.: DOSAGE FORM DESIGN CONSIDERATIONS 38 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT 1. The general structure and molecular weight of a molecule to be studied. E.g., The cyclic peptide cyclosporine A is 1.2 kDa but a typical monoclonal antibody (mAb) is 144 kDa; and maintenance of the 3D structure. 2. Solubility and conformation at various pH values, its pKa values leading to chemical and physical instability, its shelf life, and accordingly to decide to formulate liquid versus solid state (lyophilized) or the type of formulations. In the case of lyophilization techniques, the glass transition temperature of the frozen solution (Tg), as well as the collapse temperature of the lyophilized cake (Tc), are important parameters. (Henninot et al., 2017). 3. Behavior at air water interfaces and during freezing/thawing. 4. High water solubility increases the viscosity at concentrations above 50 mg/mL, especially for subcutaneous injections; interacts with packaging, such as silicone-coated glass syringes. 5. Surface adsorption. Product stabilization must be compatible with aseptic processing and manufacturing, which may use nonconventional technologies like freeze or spray drying (Chris, 2011). 6. Compatibility with organic solvents. 7. General aggregation tendencies. Stability studies to understand the degradation profile that may occur due to changes in buffer (pH and ionic strength), metal impurities, temperature, irradiation, gases (particularly oxygen and moisture), shear and surface adsorption. Various analytical techniques are central in preformulation studies and include methods such as: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Chromatography and light scattering, for the determination of purity and aggregation. Microscopy to observe the particulates of 2 to 10 microns size. Circular dichroism and infra-red spectroscopy, for conformational changes. Iso-electric focusing, for the determination of the isoelectric point (Pi) and changes in charge. Mass spectrometry for determination of chemical degradation. Calorimetry and fluorescence for determination of unfolding or stabilization. Rheometry. Electrophoresis. Biological assays for the determination of its functionality. Ultrafiltration (for solubility), and differential scanning calorimetry (for melting temperature). Forced or stress degradation studies are performed under extreme thermal, pH, and oxidative conditions where some changes will be obvious and degradation pathways can be profiled by chromatography techniques. Knowledge on the scientific literature helps put analyses into context (Cheryl, 2006). Table 1.5 gives the degradation pathways indicating the instability of proteins and peptides along with the barriers to protein delivery. Chemical and Physical Stability: Product liability should be kept in mind during the development of any drug product. Concerning clinical and commercial space, a satisfactory peptide drug should remain chemically and physically stable over a minimum of a DOSAGE FORM DESIGN CONSIDERATIONS 39 1.5 PREFORMULATION STUDIES OF PROTEINS AND PEPTIDES TABLE 1.5 Degradation Pathways Indicating Instability of Proteins and Peptides Along with the Barriers to Protein Delivery Degradation Pathways Mechanism Barriers Physical Instability: Denaturation Nonproteolytic modification of a unique structure of a native protein that affects definite change in physical, chemical and biological properties. Enzymatic barrier Intestinal epithelial barrier Capillary endothelial barrier E.g.: Urea, alcohol, acetic acid, sodium dodecyl sulfate, PEG Adsorption Amphiphilic natures of protein cause adsorption at various interfaces like air water and air solid. Aggregation and Precipitation The denatured unfolded protein may rearrange in such a manner that hydrophobic amino acid residue of various molecules associates together to form aggregates. If aggregation is on macroscopic scale, precipitation occurs. Chemical Stability: Deamidation The hydrolysis of the side chain amide linkage of an amino acid residue leading to the formation of free carboxylic acids Oxidation and reduction Oxidation occurs during isolation, synthesis, and storage of proteins. Temperature, pH, traces of metal ions, light and buffers influence the reactions. Proteolysis Exposing proteins to harsh conditions like prolonged exposure to extreme pH or high temperature or enzymes. Disulfide exchange A peptide chain with more than one disulfide can enter into this reaction and thereby change in conformation Racemization It is alteration of L-amino acids to D, L- mixtures. Racemization form peptide bonds that are sensitive to proteolytic enzymes. β- Elimination Proceeds to carbonation intermediate. Protein residues susceptible to it under alkaline conditions includes Cys., Lys., Phe., Sre., Thr., Blood brain barrier 2-year shelf life. In protein and peptide therapeutics, few physicochemical properties are routinely evaluated for their degradation liabilities as summarized in Table 1.6. In addition to chemical stability risks, the physical stability of peptides must be carefully monitored to ensure a consistent formulation, which can otherwise lead to differences in performance and to immunogenicity safety concerns. These risks include aggregation and selfassociation, changes in secondary and tertiary structure, and adsorption to surfaces (Menzen and Friess, 2013). Changes in conformation may increase solvent exposure of the hydrophobic regions of the peptide sequence, leading to self-association, particularly at higher concentrations. Cryoprotectants such as nonreducing sugars (e.g., sucrose and trehalose) and polyethylene glycol (PEG) are added to stabilize proteins at the time of formulation, processing, and DOSAGE FORM DESIGN CONSIDERATIONS 40 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 1.6 Stability Risks and Strategies for Mitigating These Risks Through Formulation Stability Risk Formulation Strategy Solubility pH modification and salt formation, Optimization of ionic strength and addition of solubilizing excipients, i.e., surfactants or co. solvents. Hydrolysis Evaluation of stability across pH 3 10. Addition of buffer excipients to control pH. Low-temperature storage. Oxidation Addition of anti-oxidants, chelating agents, maintenance of pH , 7, anaerobic processing, protecting from light. Low-temperature storage. Aggregation Lower peptide concentration, pH modification, and salt formation, Addition of buffer excipients, solubilizing excipients, optimization of ionic strength. Adsorption Addition of surfactant and polymers, albumin. Selection of right containers and surface modification. Denaturation Addition of metal ions and adjusting the pH, low-temperature storage Microbial contamination Addition of preservative and storage at low temperature. Adapted from (Bak et al., 2015). also to increase the shelf life. Stabilization mechanism also depends on the bulk sugar concentration by preferential exclusion from the protein/polypeptide surface leading to a thermodynamically stable folded state, or by forming hydrogen bonding with polar groups on the surface of the protein. PEG generally increases the solution viscosity and decreases the protein structural mobility by steric hindrance of protein interactions (Chris, 2011). Table 1.6 explains the stability risks and strategies (Bak et al., 2015). 1.6 PREFORMULATION IN VACCINE DEVELOPMENT: CRITICAL VIEWS Apart from the drug product development, preformulation is indeed an unavoidable parameter from vaccine development point of view. White et al. aimed an investigation to develop sensitive techniques to identify low concentrations of double mutant heat-labile toxin (DMH-LT) and to employ the tests in preformulation investigations to observe whether DMH-LT remains stable under conditions encountered by an oral vaccine (White et al., 2017). The authors demonstrated a sandwich ELISA specific for intact DMH-LT and a sensitive sodium dodecyl sulfate-polyacrylamide gel electrophoresis densitometry technique, and determined the stability of DMH-LT in glass and plastic containers, in saliva, at the pH of stomach fluid, and in high osmolarity buffers. The developed ELISA had a quantification range of 65.2 to 0.8 ng/mL and lower limit of detection of 0.4 g/mL; the limit of quantification of the sodium dodecyl sulfate-polyacrylamide gel electrophoresis is 10 µg/mL. Authors concluded that the application of DMH-LT assays in DOSAGE FORM DESIGN CONSIDERATIONS 1.7 PREFORMULATION STUDIES OF PACKAGING COMPONENTS 41 preformulation studies in developing an oral vaccine containing DMH-LT. Assays reported in that study facilitating the understanding and application of DMH-LT as an adjuvant. Another critical point from vaccine development is that aluminum-containing adjuvants which activate immune activity have been used since 1926, although their characteristics and interactions with antigens have been poorly known until recently. Recently, preformulation investigations became an important step in the production of biopharmaceuticals (e.g., monoclonal antibodies). It is supposed that it is time to finance/invest more in preformulation investigations to make them more explorative and include some important parameters like isoelectric point, surface OH/PO4 ratio, and microenvironment pH to design the most efficacious aluminum adjuvant containing vaccines (Russel, 2010). 1.7 PREFORMULATION STUDIES OF PACKAGING COMPONENTS Pharmaceutical packaging is always considered to be the last stage of product development; it is now a core expedient element of the development process. A pharmaceutical packaging system generally involves a combination of a suitable container along with a well-fitting closure enclosed in an outer cover, suitably complemented with an appropriate label. During the preformulation studies, the stability data of a developed product in final pack system over the projected shelf life gives the prerequisite of the product to obtain approval from regulatory agencies to market any drug product. The components or combination of components that are essential to protect, preserve, contain, and deliver a safe, efficacious drug product are called pharmaceutical packaging. There are two types of package system, viz., primary and secondary package system. In a primary package system, they are in direct contact with the product and may have a direct effect on the product shelf life. Secondary or tertiary package systems are cartons, corrugated shippers, and pallets. While preformulation screening the packaging, components must meet the following criteria: 1. Susceptibility of the drug product and its stability in environment condition: Its compatibility with the contents, moisture, oxygen, temperature, light, fire, etc., e.g., Requires a packing material with low MVTR and OTR values. 2. Type of dosage form; e.g., High-density polyethylene (HDPE) bottles are used in solid orals, Collapsible/noncollapsible tubes are used for semisolids, glass or low-density polyethylene bottles for liquid orals and ampoules, vials or prefilled injectors for sterile parenteral. 3. Nonreactive with the product: Strength of container and the degree of protection required and moisture proofness, protection against salt. 4. Should not impart any kind of tastes or odors to the product: Odor retention and transmission. 5. Inert and Nontoxic with FDA approval: Resistance to corrosion by Acids or Alkalis, grease. 6. Protection of the dosage form against damage or breakage. DOSAGE FORM DESIGN CONSIDERATIONS 42 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT 7. Meet tamper-resistance requirements, wherever applicable: Machine suitability of packaging and the filling method. 8. Compliant with high-speed newer technology equipment. 9. Resistance to microorganisms, insects, and rodents. 10. Material should have aesthetic effect and be economical. 11. Convenient to the pharmacist, physician, and to the patient (size, weight, method of opening/re-closing, legibility of printing). 12. Various regulatory requirements and approvals. For example, in the United States, solid dosage forms are essential to be delivered either in HDPE pack/blister pack with child-resistant features only. 13. Intellectual property aspect; while selecting the pack and its material this issue is of key concern while especially when the innovator has filed a patent or design for a certain type of packaging. 14. Permeability of packaging material especially to moisture and oxygen. The water vapor and oxygen transmission, i.e., moisture/water vapor transmission rate (MVTR/ WVTR) and oxygen transmission rate (OTR), respectively. For instance: Glass and aluminum are impermeable to moisture and oxygen. (Kamal et al., 1984; Weeren and Gibboni 2002). 1.8 PREFORMULATION IN 21ST CENTURY: TECHNOLOGICAL ADVANCEMENTS New technical breakthroughs are observed in pharmaceutical technology developments in the 21st century. Rapid progress is expected in avenues like information technology, genetics technology, new materials, environmental protection, and energy technologies. New possible combinations and interactions of the various technologies will also be of major importance. Examples of few newer technologies in formulation development are hot melt extrusion (Tiwari et al., 2016; Cossé et al., 2017; Zhang et al., 2017) and 3D printing (Goyanes et al., 2015; Choonara et al., 2016; Hsiao et al., 2017). The “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach” initiative by the US Food and Drug Administration (FDA) covers a range of topics, such as risk-based inspections, dispute resolution, process analytical technology (PAT), whereas the 21 CFR Part 11 focuses on principles of efficient risk management (Methfessel, 2004). A few approaches of drug design are shown in Table 1.7. 1.8.1 Computerization and Aid of Software in the Preformulation Studies Few physiologically relevant biomodeling are used during the development stages, and this predictive biomodeling offers a beneficial device in the finding and initial steps of product development. Compounds can be grouped into different classes with more precision in comparison to the basic guidelines of the BCS systems using these predictions. Predictive models also help to predict the ability of the solubilization technologies for oral delivery of a given molecule or set of compounds. While commercial software packages DOSAGE FORM DESIGN CONSIDERATIONS 1.8 PREFORMULATION IN 21ST CENTURY: TECHNOLOGICAL ADVANCEMENTS 43 TABLE 1.7 Drug Design Approaches for Biologically Active Molecules Approaches Chemical Technology Natural Products Compound isolation and structural characterization Analog design Molecular modification, SAR and QSAR investigations Combinatorial chemistry/High Throughput screening(HTS) Parallel synthesis /automated large-scale assays Virtual Screening Structure and ligand based drug design (SBDD/LBDD) Fragment based drug discovery Structure and ligand based drug design (SBDD/LBDD) have been developed for pK modeling, Bend Research has recently developed a physiologically relevant compartmental model to predict the oral absorption of drugs. Bloom et al. has used to predict the drug absorption using the Bend Research bio model. The absorption of hypothetical compounds has been predicted for bulk crystalline drug and SDD formulations. Several assumptions have been made for selected parameters, such as permeability (assumed to be a function of Log P), dose (assumed to be constant at 10 mg/kg for this comparison), feeding state (fasted for this comparison), and dissolution rate. If the cases arise when compounds and formulations have acceptable absorption the problems with metabolism/permeability should be judged and exploited before moving to the next formulation development step (Table 1.8). 1.8.2 Artificial Neural Network Tool Used in the Factorial Design: An Optimization Approach Application of Design of Experiments (DoE) as a statistical analysis tool is widely followed in the pharmaceutical field, especially in product development and analytical method development aspect as a Quality by Design (QbD) strategy. Response-surfacemethodology (RSM) is also another frequently employed tool in DoE. Alongside the application of a statistical approach, machine learning tools also has its vital place in product development. Novel technologies like Artificial Neural Networks (ANN) have been employed in investigating production process parameters, drug release profile, stability assessment, and other attributes related to the quality of pharmaceutical products. During the product development as well as process optimization stage, DoE is one of the most convenient approaches to relate the characteristics of drug/excipient and the process parameters to define the Critical Quality Attributes (CQAs). Design Space is the multidimensional interface of input variables (such as material properties) and the process parameters which have direct effects on the products quality (Ibrić et al., 2012). DOE practice is extremely helpful in establishing as well as regulating DOSAGE FORM DESIGN CONSIDERATIONS 44 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 1.8 Specification for Product Development Active Phase 1 Phase II Phase III Commercial Product Analysis of the batch, certificate of analysis and developing test methods Draft specification, Method development, and validation. Full specification, Method development, and validation. Full specification, Method development, and validation. Excipients Certificate of analysis. For functional properties, methods are developed Packaging Certificate of analysis and limited testing methods for functional properties to be developed. Finished Product Batch Analysis, draft specification, test method developed Refined draft specification, test methods developed and partially validated. Adapted from Chris (2011). the required design and the design space. It works on artificial neural networks (ANNs), which are computer programs to identify the trends in a given set of study data and produce a relevant model for those data (Agatonovic-Kustrin and Beresford, 2000; Sun et al., 2003). The factorial design methodology is utilized for rationally designing a scientific experiment and investigate the effect of assigned project related variables. During this exercise, every factor is regarded as an independent variable and thus investigated at an array of different levels. Fisher and his group were among the first to present this concept and the term “factorial” through his research work. Typically, the factorial designs are classified into full factorial designs and the fractional factorial designs. By utilizing a full factorial design, the study is performed by presuming the combinations of factor with all the other factors at all the possible levels. Consequently, in these experiments, all the probable experiment combinations are being conducted. Generally, two- or three- levels are considered for each experiment relevant factor; and the factorial design is then named after the number of factors as per the number of levels for each factor, for instance, a 2 3 2 or a 22-factorial design. A comparable representation is utilized in cases with factors with diverse number of levels, for instance, 35 3 2 signifies that there are five factors with three distinct levels each and one factor with two levels, i.e., a total 35 3 2 5 486 experiments has to be performed. However, it is apparent that such a design leads to an unachievable number of forced experiments to be conducted. This design ultimately results in a significantly high amount of workload or additional experimental cost. On the other hand, fractional factorial design requires a firm subset/fraction of the total number of representative experimental runs that occur as a result of a full factorial design. This subset experiments are judiciously selected employing a suitable statistical procedure to investigate the original problem which contains sufficient information about the experiment. When denoting DOSAGE FORM DESIGN CONSIDERATIONS 1.9 CASE STUDIES ON PREFORMULATION OF DOSAGE FORMS 45 to fractional factorial strategy, a representation relevant to the full factorial design is utilized, for instance, a 24 2 2 design implies that only 25% of the required experiments has to be conducted. Apart from the two major categories, other types of existing multifactor designs are randomized block designs (RBD), Plunkett Burman designs, Taguchi designs, and designs related to the response surface methodology (RSM). For the large family of DOE, there is a significant amount of theoretical efforts regarding the mathematical fundamentals of factorial design approach has to be carried out (Markopoulos et al., 2016). 1.9 CASE STUDIES ON PREFORMULATION OF DOSAGE FORMS In recent times novel formulations are coming into the market, such as hydrogels, liposomes, and therefore preformulation strategies are more important. The coming time will belong to the formulations developed using nanotechnology-based platforms (Tekade et al., 2017b). This may involve liposomes (Maheshwari et al., 2015b; Maheshwari et al., 2012), dendrimers (Soni et al., 2017; Kumar Tekade et al., 2015), solid lipid nanoparticles (Tekade et al., 2017c), carbon nanotubes (Tekade et al., 2017a), and polymeric nanoparticles (Sharma et al., 2015; Maheshwari et al., 2015a). In such an investigation McKenzie et al. developed cysteamine gels for treatment of the ophthalmic abnormalities in cystinosis (Cho et al., 2017). To undertake this investigation authors first performed preformulation studies as to reduce the frequency of developed dosage form and improve its efficacy. Authors tested eight different gel carriers before preparing the formulation and a preformulation study. They basically checked the appropriateness of these carriers as ophthalmic vehicles. After extensive literature search, authors choose eight different carriers based on their reported use as ophthalmic polymers. The parameters for preformulation check were nontoxicity in the eye, pseudoplastic rheology, bioadhesive nature, suitable optical clarity, stability, and compatibility with cysteamine. The eight gels formulations composed of eight different polymers were tested for unmediated preformulation evaluation of rheology and optical clarity. The polymers were dissolved in water for injection (WFI) and neutralized to pH 7.4 with sodium hydroxide if required and permitted to fully hydrate at 4 C for 24 hrs before testing. Outcomes revealed that sodium hyaluronate showed optimum performance in the preformulation tests, being pseudoplastic (decrease in apparent viscosity at increased shear rate), bioadhesive, release out cysteamine over 39 min, and displayed stability over time (Figure 1.24). The investigation concluded that sodium hyaluronate may be a safer substitute to the available aqueous-based eye drop formulation of cysteamine. Recently, Linares-Alba et al. demonstrated preformulation investigation of novel liposomal formulation loaded with sirolimus (macrocyclic lactone produced by Streptomyces hygroscopicus) indicated for dry eye disease (Russel, 2010). Liposomal evaluation parameters include size, zeta potential, polydispersity, differential scanning calorimetry, morphology, entrapment efficiency, phospholipid content, thermal stability, and sterility. The study concluded that the heating method permitted easy preparation of formulation with higher entrapment capability liposomes to potentially minimize preparation time and to DOSAGE FORM DESIGN CONSIDERATIONS 46 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 1.24 % Cysteamine HCL content over 3-month period. The sodium hyaluronate control was a beaker sealed with parafilm, maintained at 4 C. Adapted with permission from (Walther and Domanski, 2017). avoid the use of alcohol. The heating technique is a substitution for manufacturing process characterized by the absence of solvents like chloroform and methanol or tensio-actives for the solubilization of lipids, representing an advantage regarding toxicity and fabrication time (Russel, 2010). Kuehl et al. performed preformulation study of Imexon drug which is an aziridinecontaining iminopyrrolidone that is of significant interest due to its selective growth inhibitory effect against multiple myeloma. Regrettably, administration of Imexon has proven difficult largely due to its rapid degradation in aqueous medium. The collective aim of their research was to conduct preformulation studies to characterize and understand the stability and solubility of Imexon in both aqueous and nonaqueous systems (Medvedev et al., 2017). 1.10 PHARMACOKINETICS AND PREFORMULATION: POINT TO NOTE Systemic and optimized drug administration not only required the understanding and mechanisms of drug disposition that is ADME, but also the rate and degree at which they occur (pharmacokinetics) (Rajadhyaksha et al., 2016). As a fact, more than 75% of drug molecules even fail to enter into clinical investigations due to problems with pharmacokinetics of which the majority involves compromised bioavailability and small plasma halflives in animals. Preferably, to be capable of analyzing the pharmacokinetic nature of a DOSAGE FORM DESIGN CONSIDERATIONS 1.11 RULES AND REGULATIONS IN PREFORMULATION STUDIES: ROLE OF REGULATORY BODIES 47 molecule from its molecular characteristics, like solubility, lipophilicity, molecular size, crystallographic information, etc., alone would be advantageous, as then only the molecule with desirable properties may be produced and studied further. The logical and scientific determination of the drug’s activity in vivo is recognized via evaluating its physicochemical properties. Henceforth, preformulation is a major area, and the researchers working in this field (formulation) should develop the understanding about interpreting the preformulation data and, through it, the significant pharmacokinetics signals to address effective navigation via the drug development cycle. In one study, Sanghvi et al. performed preformulation, solubility, and ADME evaluation of antalarmin, a stress inhibitor (Sanghvi et al., 2009). It is established that antalarmin has low solubility in water (,1 µg/mL) and is weakly basic in nature (pK 5.0.) Three of these formulations are aqueous solutions (10% ethanol 1 40% propylene glycol; 20% cremophor EL; 20% sulfobutyl ether-beta-cyclo dextrin) each buffered at pH 1. Apart from these three formulations, the next one was a lipid-based formulation consist of 20% oleic acid, 40% cremophor EL, and 40% Labrasol. Outcomes suggest that it was only the fourth formulation that successfully resisted drug precipitation following dilution with enzyme-free simulated intestinal fluid. Apart from that this formulation also showed 15-times greater bioavailability in contrast to the other three formulations which were of suspension type. The lipid-based formulation resulted in over 13 times enhanced bioavailability in comparison to the suspension formulation, the greatest amongst the formulations investigated. 1.11 RULES AND REGULATIONS IN PREFORMULATION STUDIES: ROLE OF REGULATORY BODIES Pharmaceutical regulations are crucial in research for product approval and eventual marketing of the product. Hence it has a series of complex laws and guidance documents depending on the regulatory bodies. The product development should comply with most regulatory authorities, like FDA (US), EMA (Europe), PMDA (Japan), to provide global access to the beneficial therapeutic products, safe and maximum returns on the investments. International Conference on Harmonization (ICH) harmonizes the requirements for stability testing in the three areas of Europe, Japan, and the United States. ICH guidance documents are classified as safety, efficacy, and quality. This guidance helps in identifying the critical elements that are involved in product development and found the stipulations that turn into the basis for defining a product (Chris 2011). Table 1.7, gives an outline of the development of specifications. Regulatory authorities recognize that modifications are performed during early phases of product development. Regulations are emphasized to provide information for development of a stable formulation which can support a shelf life suitable for the complete duration of the initial clinical studies. During the Phase I and II clinical trials, stability data (1 2 years) is required for the developed product. Appropriate quality data is generated for quality submission to regulatory authorities that supports a Clinical Trials Application (CTA) or Investigational New Drug (IND) submission. It also provides supporting data for a Product Licence Application too. This information will examine the changes in product DOSAGE FORM DESIGN CONSIDERATIONS 48 1. PREFORMULATION IN DRUG RESEARCH AND PHARMACEUTICAL PRODUCT DEVELOPMENT performance behavior and identify formulation degradation that is observed in actual storage conditions. Adequate stability data will help to develop the final formulation, and also to select the most suitable primary container and closure packaging materials. Detailed regulatory guidelines are available to assist the pharmaceutical companies in making the regulatory submissions, including the recommendations to design, conduct, and use of stability studies. Examples of such guidelines are FDA guidance on “Stability Testing of Drug Substances and Drug Products” and the Committee for Proprietary Medicinal Products’ (CPMP) notes on “Stability Testing: Testing of New Drug Substances and Products” (CPMP/ICH/ 380/95). Information is readily available from the Web sites of various national and international regulatory authorities and manufacturers’ associations (Gibson, 2016), (FDA guidance), (CPMP guidance), (ICH guidance). 1.12 FUTURE REMARKS AND CONCLUSION In the pharmaceutical product development lifecycle, the preformulation stage plays an integral part. It supports the fabrication/designing of the dosage form for any new drug and its quality control process results in an effective pharmaceutical. Use of newer technologies and statistical software based on artificial neural networking are emerging to smoothen the process of preformulation stages. Optimization process has become easier and more convenient. Physicochemical properties along with the biopharmaceutical characterization of NCEs should be screened accurately and made as a decisive parameter during the product development. Based on these pharmacokinetic and toxicity data, clinical studies can be developed at earlier stages which overall helps in streamlining the pharmacological effects and developing molecules for clinical practice. Acknowledgment Authors express their heartfelt thanks to NMIMS University, Mumbai for providing support for the research activities. Dr. Acharya also wishes to acknowledge UGC, New Delhi for the research grant [(F.30 376/2017 (BSR))] and CSIR, New Delhi for the extramural research grant [02(0329)/17/EMR] to work to work on chemo preventive measures of colon cancer. Dr. Acharya also expresses his heartfelt thanks to Tripura University (A Central University), Suryamaninagar, for providing all necessary research facilities. The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant (Grant #ECR/2016/ 001964) allocated to Dr Tekade for research work on gene delivery and N-PDF funding to Dr. Maheshwari (PDF/ 2016/003329) for work on targeted cancer therapy in Dr. Tekade’s Laboaratory. The authors also acknowledge the support by Fundamental Research Grant (FRGS/1/2015/TK05/IMU/03/1) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. 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(Accessed on July 2017). ,http://pharmtech.com/quality-systems-21st-century-process-analytical-technology. (Accessed on August 2017). ,http://www.aaps.org/News/Press_Room/Press_Releases/ Understanding_the_Role_of_Preformulation_in_Drug_Development__New_AAPS_eCourse, _Preformulation_101,_Now_Available!/http://jbpr.in/index.php/jbpr/article/view/484. (Accessed on August 2017). ,http://www.biopharminternational.com/preformulation-means-characterization. (Accessed on July 2017). ,http://www.bioprocessintl.com/2017/august-2017/quality-design-transforming-21st-century-pharmaceutical-manufacturing/(Accessed on August 2017). ,http://www.bioprocessintl.com/upstream-processing/assays/enabling-technologies-349771/. (Accessed on August 2017). ,http://www.realregulatory.com/pharmaceuticals. (Accessed on July 2017). ,http://www.tandfonline.com/doi/abs/10.3109/03639045.2016.1160105. (Accessed on August 2017). ,http://www.who.int/childmedicines/partners/SabineKopp_Partners.pdf. (Accessed on August 2017). ,https://books.google.co.in/books? id 5 qwTLBQAAQBAJ&pg 5 PA321&lpg 5 PA321&dq 5 Preformulation 1 in 1 21st 1 century: 1 Technological 1 advancements&source 5 bl&ots 5 R0c4Yxo8bx&sig 5 u-kp4rk_-lZ3ogC2bXx1HaPWjE&hl 5 en&sa 5 X&ved 5 0ahUKEwiduazOiJ7XAhWIrY8KHaOKACQQ6AEILTAB#v 5 onepage&q 5 Preformulation%20in%2021st%20century%3A%20Technological%20advancements&f 5 false. (Acccessed August 2017). ,https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Published 10/06/2017., Accessed August 2017. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 2 Physicochemical Aspects to Be Considered in Pharmaceutical Product Development Pran Kishore Deb1, Omar Al-Attraqchi1, Abdulmuttaleb Yousef Jaber1, Basant Amarji2 and Rakesh K. Tekade3 1 Faculty of Pharmacy, Philadelphia University, Amman, Jordan 2Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 2.1 Introduction 2.2 Physical Characteristics of Solid Substances Used in Pharmaceutical Product Development 2.2.1 Crystalline Solid-State Substances 2.2.2 Amorphous Solids 2.2.3 Particle Size 2.2.4 Wettability 2.2.5 Hygroscopicity Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00002-2 58 58 60 63 64 65 66 57 2.3 Chemical Characteristics to be Considered in Pharmaceutical Product Development 2.3.1 Degradation Reactions of Drugs 67 67 2.4 Solubility Aspects in Pharmaceutical Products Development 2.4.1 Aqueous Solubility 74 75 2.5 Conclusion 78 © 2018 Elsevier Inc. All rights reserved. 58 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT Acknowledgement 79 References 79 Abbreviations 79 Further Reading 83 2.1 INTRODUCTION The physicochemical properties of the active pharmaceutical ingredient (API) and the excipients in the pharmaceutical product formulation require careful consideration, since they are responsible for determining the different aspects of the pharmaceutical product characteristics at various stages of the drug life, such as the physical and chemical stability of the drug throughout production, storage, as well as following the administration of the drug to the patient. The physical properties of solid substances that are present in a pharmaceutical product can influence the properties of the formulation (Aulton, 2007; Kesisoglou and Wu, 2008). For example, the particle size has significant effect on the flowability of the powders, a property that is important in the production process as different flow rates may lead to different rates of filling by the equipment used for tablet or capsule production. As a result of fluctuation of the flow rates, the uniformity of content of the produced tablets or capsules can vary significantly, thus the pharmaceutical product may fail the uniformity of content tests. Consequently, the proper adjustment of such properties is critical in the development of pharmaceutical products formulation (Fichtner et al., 2005). Other physical properties like hygroscopicity can also play a vital effect on the stability of the pharmaceutical products since highly hygroscopic substances can adsorb high amounts of the atmospheric moisture which can be detrimental to many API or excipients used in the pharmaceutical products. The chemical stability of drugs is also taken into utmost considerations because many of the substances used in pharmaceutical product formulations are prone to a variety of possible chemical reactions that are undesirable for the product (Newman et al., 2008). Such chemical reactions not only result in the loss of the API or excipients in pharmaceutical products but also lead to the formation of toxic substances that can show various harmful effects if administrated to the patient. Thus, prior understanding of any such probable chemical reactions that may take place even after the formulation of a pharmaceutical product is of paramount importance in order to prevent any undesirable effects on the product’s integrity as well as on patient’s safety (Waterman and Adami, 2005). 2.2 PHYSICAL CHARACTERISTICS OF SOLID SUBSTANCES USED IN PHARMACEUTICAL PRODUCT DEVELOPMENT The physical properties of solid substances (API and excipients) used in pharmaceutical formulations are of particular importance because these properties can have significant impact on the production process of the pharmaceutical products as well as on the biological performance of the drugs. In general, solid-state substances can be categorized according to the order of their molecular packing, either as crystalline or amorphous substances. DOSAGE FORM DESIGN CONSIDERATIONS 2.2 PHYSICAL CHARACTERISTICS OF SOLID SUBSTANCES USED IN PHARMACEUTICAL PRODUCT DEVELOPMENT 59 FIGURE 2.1 Classification of solid-state substances based on their molecular packing. FIGURE 2.2 Differences in the molecular packing in various forms of solid state. The crystalline substances can further be classified as polymorphs, solvates, hydrates, or cocrystals (Fig. 2.1). The differences in the arrangement and packing of molecules in these different crystalline forms are summarized in Fig. 2.2 (Alexander and Florence, 2013). The crystalline or amorphous form in which the drug may exist can have important effects on various aspects of the pharmaceutical product such as the stability of the drug in solid state and in solution as well as on some pharmacokinetics processes such as the absorption of the drug. Thus, it is important to characterize the state of solid substances used in pharmaceutical products and to understand the differences between these various states and the consequences associated with using each one of them in the development of different pharmaceutical dosage forms. Other physical properties like hygroscopicity can also influence the stability of pharmaceutical product formulations as mentioned above. The particle size of substances can affect the processes involved in the production of the DOSAGE FORM DESIGN CONSIDERATIONS 60 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT pharmaceutical products such as the flowability of powders, and can also affect properties related to the solubility of the substance. In the following sections, various physical properties and their effects on the production and performance of pharmaceutical products (Fu et al., 2012; Steed, 2013), shall be discussed. 2.2.1 Crystalline Solid-State Substances Crystalline solids are substances that have a highly defined and ordered internal structure of molecules and atoms that is constantly repeated. The molecules or atoms in the crystal structure are held together by weak intermolecular interactions such as hydrogen bonding, ionic, and van der Waal’s interactions. An example of crystal structure is the potassium chloride salt as depicted in Fig. 2.3, which shows a repeated ordered structure in which the potassium ions and the chloride ions are held together by intermolecular ionic bonding interaction. The three-dimensional arrangement of molecules or atoms in a crystal structure can be represented by using points to describe the molecules or atoms and the lines connecting these points are the bonds between the molecules or atoms, this three-dimensional array of the repeated structure is called the crystal lattice (Datta and Grant, 2004; Brent, 2015). Crystalline substances can exist in various crystal lattice forms, some of these forms are shown in Fig. 2.4. Since the crystals of the same substance can have different sizes, type of faces and external overall shape, they are said to have different crystal habits. The crystal FIGURE 2.3 Crystal structure of potassium chloride. FIGURE 2.4 DOSAGE FORM DESIGN CONSIDERATIONS Some forms of crystal lattices. 2.2 PHYSICAL CHARACTERISTICS OF SOLID SUBSTANCES USED IN PHARMACEUTICAL PRODUCT DEVELOPMENT 61 habits of a substance have important effects mainly in the production process, and in some cases, can affect the drug behavior such as the rate of bioavailability of the drug (Brent, 2015; Modi et al., 2013). Crystals of a specific substance are produced by the crystallization process, which involves the transformation of substances from liquid state into solid state. Generally, the substance to be crystallized is present as a solute in a solution, and crystals are formed as a result of changes induced to the system, for example, in a supersaturated solution, the amount of solute present exceeds the maximum possible amount of dissolved solute in the solvent as a result of which the solute undergoes precipitation from the solution in the form of crystals until equilibrium is reached between the precipitate and the solute in the saturated solution. In order to achieve supersaturation of a solution and cause the crystals to precipitate as solid substances from the solution, it is possible to reduce the amount of solvent in the solution by evaporation process which would increase the concentration of solute relative to the solvent present. Also, reducing the temperature of the solution can cause precipitation of crystals of the solute substance because most solutes have higher solubility in a particular solvent at higher temperature while exhibiting lower solubility in the same solvent under lower temperatures (Vippagunta et al., 2001). It is also possible to add a precipitant to the solution to facilitate the precipitation of crystal, or using an antisolvent, which is a liquid substance that can mix with solution but is unable to dissolve the solute substances to be crystallized from the solution. Following supersaturation of the solution, the crystal formation process starts with the formation of the crystal nuclei (a small amount of crystals that are formed initially) followed by the addition of more solute to the nuclei which is also known as the crystal growth stage (Vippagunta et al., 2001; Li et al., 2012). 2.2.1.1 Polymorphism The conditions in which the crystallization of a particular substance takes place can have different effects on the crystals that are being formed, resulting in different crystal habits. The change in conditions of the crystallization medium can cause the molecules and atoms to be arranged in different orientations, and examples of these conditions include the solvent used in the crystallization process, the stirring pattern and the type of impurities present in the crystallization medium. The different arrangement of molecules and atoms in the crystal also display repetition in the ordered structures. Substances exhibiting this possibility of having different crystals depending on the crystallization process’ conditions are said to have the ability to crystallize into different polymorphs (Purohit and Venugopalan, 2009; Pangarkar et al., 2013). Since many substances that are used in pharmaceutical formulations including the API and the excipients can exhibit polymorphism, it is important to characterize and control the different polymorphic forms for each substance, because polymorphisms can have significant consequences on the behavior of the drug, such as the bioavailability of the drugs. For example, chloramphenicol palmitate (an antibacterial prodrug) has two polymorphs, designated as polymorph A and polymorph B, respectively. It has been demonstrated that the rate of absorption of the chloramphenicol palmitate polymorph B is much higher than the rate of absorption of the chloramphenicol palmitate polymorph A, which leads to different rates of bioavailability and plasma levels (Singhal and Curatolo, 2004). DOSAGE FORM DESIGN CONSIDERATIONS 62 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT In general, substances exhibiting polymorphism can be classified as either substances exhibiting monotropic polymorphism or enantiotropic polymorphism. In the case of substances with monotropic polymorphism, there is only one stable polymorphic form and all other polymorphic forms are inherently unstable which spontaneously convert to a stable polymorphic form. On the other hand, in the case of substances exhibiting enantiotropic polymorphisms, there are more than one stable polymorphic form, and the substance can reversibly convert back and forth between these different stable polymorphic forms depending on the conditions in which the substance exists such as the pressure and heat. Generally, most substances used in pharmaceutical formulations belong to the substances exhibiting monotropic polymorphisms (Saifee et al., 2009). 2.2.1.2 Hydrates During the crystallization process of a substance, it is possible that some molecules of the solvent get trapped within the crystal structure of the substance. If water molecules are trapped then the resulting crystal structures are called hydrates, while if organic solvent molecules are trapped then the resulting crystal structures are called solvates (Lawrence et al., 2003). Substances that are crystallized as hydrates can be generally classified according to the ratio of the number of water molecules trapped in the crystal structure for each molecule of the crystallizing substance. If the number of water molecules trapped in the crystal structure of the substance is one for each molecule of the substance then the structure is called monohydrate, while if the number of water molecules trapped in the crystals is two for each molecule of the crystallizing substance then the structure is called dihydrate and so on (Khankari and Grant, 1995). The presence of water molecules in the crystal structure of the hydrates can have substantial effects on the properties of the substance as compared to the anhydrous form of the same substance which is a water molecule-free structure. For example, hydrates can have a different rate of dissolution (faster or slower) as compared to the anhydrous form. In general, the hydrates tend to have slower dissolution rate, since the water molecules trapped in the crystal lattice can form intermolecular hydrogen bonds with the substance’s molecules within the structure of the crystal, thus, highly strengthening of the structure of the lattice with a consequent decrease in the rate of dissolution of the substance (Aitipamula et al., 2010). Although the hydrates of a particular substance or drug are expected to have lower dissolution rate as compared to the anhydrous form of the same substance, there have been exceptions, where the hydrates show higher rate of dissolution as compared to the anhydrous form. In this case, the water molecules trapped in the crystal structure can disrupt or weaken the interactions of the molecules of a substance in the crystal lattice, thus weakening the crystal structure. This weakening would lead to a faster rate of dissolution of the substance, for example, caffeine monohydrate has much lower aqueous solubility as compared to its anhydrous form (Zaheer et al., 2011; Madusanka et al., 2014). 2.2.1.3 Solvates As discussed above, most of the drug molecules are crystalized from organic solvents as a result of which some of the solvent molecules may get trapped in the crystal lattice of the crystallizing substance leading to the formation of solvates. The ratio of solvent molecules trapped in the crystal lattice to the number of molecules of the crystallizing DOSAGE FORM DESIGN CONSIDERATIONS 2.2 PHYSICAL CHARACTERISTICS OF SOLID SUBSTANCES USED IN PHARMACEUTICAL PRODUCT DEVELOPMENT 63 substance can be unusual and rather difficult to predict. For instance, some solvates can show a ratio of 0.5 or 0.9 of solvent molecules for each molecule of the crystallizing substance. The solvent molecules present in a solvate structure need to be taken into consideration during the process of pharmaceutical products development since these solvent molecules can have undesirable side effects toxicity (Kelley et al., 2013). Like hydrates, solvates can also exhibit differences in the rate of solubility and dissolution which is rather unpredictable, since it depends on the type of the solvent molecules present in the crystal lattice as well as their effect on the crystal structure’s strength. These differences in solubility and dissolution rate can consequently cause substantial variations in the bioavailability of the drug, and to a lesser extent, the absorption process of the drug can also be affected by the use of different solvates. For example, the antidiabetic agent glibenclamide can exist as solvates of pentanol and toluene, both of these solvates display higher solubility and dissolution rate as compared to other nonsolvated forms (Suleiman and Najib,1989; Kelley et al., 2013; Stumpe et al., 2011). 2.2.1.4 Cocrystals Cocrystals are formed when molecules of another solid substance get trapped inside the crystal structure of the crystallizing substance, the difference between cocrystals as compared to solvates or hydrates lies in the fact that the molecules trapped in cocrystals are not from a liquid substance. The ratio of molecules between the crystallizing substance’s molecules and the trapped molecules in the cocrystal can vary, and they can have different effects on various properties of the resulting cocrystal structure. For example, alterations of solubility and hygroscopicity of a particular substance can be observed depending on the type of molecules trapped in the crystal lattice. The principle of cocrystals can be used as an advantageous approach in order to alter some physical characteristics of a particular substance. For example, to enhance the solubility of a drug substance, it is possible to use specific molecules to crystallize with the required drug substance in order to form cocrystals with improved solubility as compared to crystals that contain only the drug substance. It is also possible to crystallize the hygroscopic drug as cocrystal with other substances in order to reduce the hygroscopicity of the drug (Thakuria et al., 2013; Babu and Nangia, 2011; Qiao et al., 2011). 2.2.2 Amorphous Solids When the molecules of a solid-state substance are not arranged in repetitive ordered structure, the solid substance is considered to be amorphous. Generally, the amorphous state is formed instead of the crystalline state for a substance when the solidification process of the substance takes place rapidly because the molecules will not have time to arrange themselves in an ordered structure. Also, it is possible to convert the crystalline form of a substance to the amorphous form by means of a thermal energy or mechanical energy. Molecules of polymeric substances and high molecular weight substances in general, do not have the ability to arrange themselves in repetitive ordered crystal structure even in slow solidification rates because of their large size and high flexibility. However, it is possible for these molecules to have regions that display ordered structure with DOSAGE FORM DESIGN CONSIDERATIONS 64 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT alternating regions of randomness in structure, such an arrangement is said to be in a semicrystalline state (Babu and Nangia, 2011). The amorphous form of a particular substance can display different properties as compared to the crystalline form of the same substance, for example, the amorphous form can have different solubility, chemical stability, and dissolution rate. Additionally, amorphous state and semicrystalline state substances do not have a sharp melting point. An important property of the amorphous state substances is the glass transition temperature (designated as Tg). At temperatures below the Tg, the substance exhibits a state called the glassy state where it becomes brittle, while at temperatures exceeding the Tg, it will exhibit a rubbery state and have flexible properties. It is possible to lower the Tg of a substance by adding a class of molecules known as plasticizers which provide higher mobility to the molecules of the substance, water is an example of a plasticizer (Berthier and Biroli, 2011; Murdande et al., 2010). Because of the higher energy that the amorphous state of a substance exhibits in comparison with the crystalline state, it tends to be inherently more unstable, but with time it will spontaneously convert to the more stable crystalline form. Additionally, because of the higher degree of freedom of molecules of the amorphous state substances, they tend to be chemically more reactive as compared to the crystalline state of the same substance, thus it is chemically more unstable. On the other hand, amorphous state substances have higher solubility than the crystalline state, which in turn can be beneficial for substances with low water solubility, as formulating them in the amorphous state enhances their water solubility and consequently, their bioavailability (Ohtake and Shalaev, 2013; Mallamace et al., 2010; Koop et al., 2011). 2.2.3 Particle Size The particle size of solid substances has significant importance in various stages of drug development including formulation of the drug. The particle size also has great influences on the production process of drugs, as it affects many properties like the powder flow rate, bulk density, and others. The particle size of drugs also influences the dissolution process of the drug inside the body. The particle size greatly affects the specific surface area of solids, which in turn is considered as one of the factors that determines the rate of dissolution of solid substances. Generally, reduction in particle size causes an increase in the specific surface area of particles which in turn leads to a higher rate of dissolution of the solid substance. On the other hand, an increase in the particle size of a solid substance results in the decrease in the specific surface area leading to reduction in the dissolution rate of the solid substance. It should be noted that higher dissolution rate generally leads to a higher bioavailability of the drug, thus, size reduction can be a useful method to enhance the bioavailability of some drugs. For example, griseofulvin exhibits low oral bioavailability because of its low aqueous solubility, but the size reduction of the griseofulvin particles would increase the specific surface area, and consequently the rate of dissolution as well as its bioavailability. In some cases, however, it may be undesirable to have highly reduced sized particle of the drug, for example, a high size reduction in the particles of nitrofurantoin can lead to high DOSAGE FORM DESIGN CONSIDERATIONS 2.2 PHYSICAL CHARACTERISTICS OF SOLID SUBSTANCES USED IN PHARMACEUTICAL PRODUCT DEVELOPMENT 65 absorption rate, leading to rapid toxic levels of the drug. Thus, particle size can be used to adjust the rate of absorption and bioavailability of drugs (Aulton, 2007). Particle size also has significant influence on the production process of the drugs, mainly the filling process of tablets and capsules can be affected by the particle size of the powders. As the filling machines use volumetric filling to control the mass the of the powder, any alterations in the filling volume can lead to changes in the mass of the filled powders and thus cause variations in the content uniformity of the drug (Sandler and Wilson, 2010). Since the particle size carries a significant importance in both the production phase as well as the behavior of drug inside the body, a proper understanding, and knowledge regarding the size of the particles of the drug is necessary. There have been various methods developed for the particle size analysis, most of these methods are used to determine the equivalent diameter of the particles—the equivalent diameter is a hypothetical diameter that is used to approximate the true diameter of a particle—because particles with irregular shape are often considered to be approximate spheres, and the diameter of these hypothetical spheres is called the equivalent diameter. Thus, it is possible to have more than one equivalent diameter for a particle depending on the type of the method used to determine it. Each of the methods used in particle size analysis has its own advantages and drawbacks, also, each method has a range of particle diameters that can be measured (Shekunov et al., 2007; Khadka et al., 2014; Savjani et al., 2012). Apart from that, current medical science is moving towards the nanotechnology-based products in which particle size plays an essential role (Tekade et al., 2017a; Tekade et al., 2017b). It is a well-known fact that reducing the size of bulk material to nanoscale tremendously affects the physicochemical properties and therefore alters the biological action. Many nano-based drug delivery carrier systems are reported to have superior action in biological systems in comparison with conventional systems (Soni et al., 2016; Tekade et al., 2017a; Tekade et al., 2017d). 2.2.4 Wettability The process of liquid adsorption on the surface of a solid substance is called wettability. The wettability of a substance has considerable importance in pharmaceutical products development because it affects different biopharmaceutical processes like dissolution of the drug. The wettability of a substance is measured by using the contact angle (θ), which is defined as the angle that the surface of a solid makes with the liquid spreading on its surface. The value of θ can be used to know the extent of the substance’s wettability. As values of θ approach zero degrees, a high or complete wetting of the substance is expected, while values of θ approaching 180 degrees indicate low or no wetting of the substance. The wettability process of a solid substance by a liquid depends mainly on the intramolecular and intermolecular attraction forces. If the attractive intermolecular forces between the solid substance’s molecules and liquid’s molecules are equal or greater than the intramolecular forces between the liquid molecules, then a spreading of the liquid and complete wetting is favored and a contact angle of zero degrees is observed. On the other DOSAGE FORM DESIGN CONSIDERATIONS 66 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 2.5 The wetting process and contact angle: (A) a case of low and high contact angle; (B) a case of high wettability and low contact angle. FIGURE 2.6 The general structure of surfactants. hand, if the intramolecular forces between the liquid molecules is much greater than the intermolecular forces between the solid substance’s molecules and the liquid’s molecules, then the spreading of the liquid on the solid substance will be an unfavorable process and a high contact angle is observed. Fig. 2.5 shows the wetting process and contact angle (Yuan and Lee, 2013). It is possible to lower the contact angle between the liquid and the solid substance by using a wetting agent in order to enhance the wettability of the solid substance. There are various types of wetting agents that can be used in pharmaceutical products such as surfactants, hydrophilic colloids, a combination of different solvents, and others. The structure of surfactants consists of both a hydrophilic part (called the head) and a lipophilic part (called the tail), the general structure of surfactants is shown in Fig. 2.6. Surfactants can reduce the interfacial tension between the liquid and the solid causing the displacement of air between them and thus lowering the contact angle and enhancing the wettability. The HLB (Hydrophilic-Lipophilic balance) scale of the surfactants ranging from 7 to 9 are mainly used as wetting agent, for example, sodium lauryl sulfate (SLS), sorbitan esters and polysorbates are widely used as surfactants in pharmaceutical products formulation. Hydrophilic colloids are also used to lower the contact angle and enhance the wettability of a substance. They can act by coating the hydrophobic surface of the solid substance with multilayers and thus allowing the surface to be wetted by the liquid molecules. Examples of hydrophilic colloids used in pharmaceutical formulations include acacia, tragacanth, and cellulose derivatives. It is also possible to use miscible solvents with water to enhance the wettability of a substance. Examples of solvents are glycerin, glycols, and alcohols, respectively (Lu et al., 2014; Karde and Ghoroi, 2014). 2.2.5 Hygroscopicity Hygroscopicity can be defined as the ability of a substance to take up and retain moisture from the atmosphere. Solid substances have different hygroscopicity based on their affinity to adsorb water from the surrounding environment. Water molecules can be adsorbed on the surface of solid substance by various intermolecular interactions such as ion-dipole interactions and hydrogen bonding with specific functional groups present in DOSAGE FORM DESIGN CONSIDERATIONS 2.3 CHEMICAL CHARACTERISTICS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT 67 the solid substance. The presence of water molecules in pharmaceutical products due to the presence of a hygroscopic substance in the formulation can significantly affect the stability and performance of the drug, as water can hydrolyze various common functional groups that are found in many drug molecules. Thus, it is important to characterize the presence of a hygroscopic substance in a pharmaceutical formulation and to select proper excipients in order to demolish or minimize the effect the possible detrimental effects of the presence of water molecules on the drug (Allada et al., 2016; Tereshchenko, 2015). 2.3 CHEMICAL CHARACTERISTICS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT The chemical characteristics of any drug play an important role in the pharmaceutical products development since chemical reactivity of the drug determines its stability in a particular dosage form. Thus it is important to characterize the possibilities of undesirable reactions that a drug may undergo in the pharmaceutical product because the degradation of the drug in the pharmaceutical product can lead to a decrease in the potency as well as therapeutic effects of the drug. The decrease in potency is not the only concern regarding chemical degradation of the drug, the products formed as a result of drug degradation might be toxic in nature that can lead to a serious undesirable side effects if administrated to a patient. Drug degradation can also lead to esthetically unacceptable pharmaceutical products, because the chemical degradation that the drug undergoes may result in color or odor changes in the product. Thus, the chemical stability of the drug should be thoroughly evaluated and tested in order to avoid drug degradation or the formation of harmful substances resulting from chemical reactions in the pharmaceutical product formulations (Baertschi et al., 2016). 2.3.1 Degradation Reactions of Drugs The API in the pharmaceutical product encounters various sources that can cause chemical degradation of the drug at various stages, for example, the water present in the surrounding atmosphere can cause hydrolysis of many functional groups of drugs. Similarly, oxygen present in air has the ability to chemically react and oxidize the API or the excipients, which in turn can affect the product’s integrity. Light is also considered as a source that can cause degradation of various drugs and protective measures need to be taken into consideration while handling and storing such drugs. Changes in pH of the solution can also result in chemical degradation, as the changes in solution’s pH can trigger various reactions that normally do not take place otherwise. The reactions initiated by pH changes can be intramolecular reactions (i.e., a functional group reacts with another one in the same molecule) as is evident in the case of penicillin where the acidic pH can cause an internal reaction to take place and gives inactive products as shown in Fig. 2.7. The pH changes can also initiate a reaction between the API and an excipient or a reaction between two or more excipients that usually does not take place under the original pH of the formulation. It should be noted that a particular drug may undergo more than one reaction DOSAGE FORM DESIGN CONSIDERATIONS 68 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT HS O H N Ph S OH NH [H+] O N H2O O N O OH O Ph O Benzylpenicillin FIGURE 2.7 Degradation reaction of benzylpenicillin at acidic pH. that can cause the degradation of the API, which makes its analysis rather difficult. There are many different possible reactions that a drug may undergo, the following sections discuss the effects and mechanisms of these possible reactions. The knowledge of the pH influencing the drug chemical stability is also important to evaluate the drug stability inside the gastrointestinal tract, since the pH varies considerably between different parts of the gastrointestinal tract, for example, many drugs can be degraded in the extremely low pH in media of the stomach, or in the alkaline media of intestine. Thus, knowledge of the drug’s chemical stability at different pH values is important (Kawabata et al., 2011). 2.3.1.1 Hydrolysis Hydrolysis is a reaction between water and a substance that causes the breakage of a bond in the substance by using a molecule of water. There are various functional groups present in a drug that can undergo hydrolysis including esters, amides, imides, and lactones. The rate of hydrolysis varies between these functional groups, for example, the rate of hydrolysis of ester is generally higher as compared to the hydrolysis of amides of a similar structure due to electronic effects. The hydrolysis rate is also affected by steric effects, as bulky substituents surrounding the ester or amide, functional groups are shown to reduce the rate of hydrolysis significantly. The hydrolysis of esters gives the corresponding carboxylic acid and alcohol products, for example, procaine is an anesthetic agent that undergoes ester hydrolysis as shown in Fig. 2.8 (Alexander and Florence, 2013). The hydrolysis of amides gives the corresponding carboxylic acid and amine products, both acyclic amides and cyclic amides (lactams) are susceptible to hydrolysis reaction. Examples of drugs containing amide functional groups are procainamide, cinchocaine, and acetaminophen, all of which can undergo hydrolysis at their amide linkage to give the corresponding carboxylic acid and the amine. The amide hydrolysis of acetaminophen is shown in Fig. 2.9 (Koshy and Lach, 1961). The presence of electron withdrawing groups on the alpha carbon atom is considered as one of the important factors affecting the rate of amide hydrolysis, as increasing the DOSAGE FORM DESIGN CONSIDERATIONS 2.3 CHEMICAL CHARACTERISTICS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT 69 O O N H2O OH O H2N H2N + Procaine N HO FIGURE 2.8 Hydrolysis of the ester functional group present in procaine structure. O OH NH H2O HO O + [H+] H2N HO Acetaminophen FIGURE 2.9 Hydrolysis of the amide functional group present in acetaminophen structure. electrophilicity of the carbonyl carbon increases the rate of amide hydrolysis. Similarly, another important factor is the presence of steric hindrance surrounding the amide linkage, as more hindered amides are less susceptible to hydrolysis compared to less sterically hindered amides. Cyclic amides (lactams) can also undergo hydrolysis reaction, in fact, the beta-lactam class of antibiotics are highly susceptible to hydrolysis of the lactam ring present in their structure and show even higher hydrolysis rates as compared to the acyclic amides, this high rate of hydrolysis is believed to be due to the high ring strain present in these cyclic structure which gives them higher reactivity in general and hence higher hydrolysis rate as compared to the acyclic or less strained amides. The hydrolysis of the beta-lactam ring is shown in Fig. 2.10 (Mitchell et al., 2014). There are various other types of hydrolysis reactions that can occur with different drug substances, for example, the barbiturates class of drugs can undergo ring-opening as a result of the hydrolysis reaction (LePree and Connors, 2006). 2.3.1.2 Dehydration The dehydration reaction involves the loss of water molecules from a particular substance, which can be either acid or base catalyzed reaction. There are many drugs that are known to undergo dehydration reaction, for example, the antibiotic erythromycin is susceptible to dehydration at acidic pH in the stomach media, which would form an inactive DOSAGE FORM DESIGN CONSIDERATIONS 70 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT R R H N H N S S [H+] O O HN OH N H2O O O OH OH O O beta-lactam compound FIGURE 2.10 Hydrolysis of the beta-lactam ring. N N O HO HO OH O HO O HO O O O O O HO O O O O O OH FIGURE 2.11 OH O O O O Dehydration reaction of erythromycin. OH N N OH OH [H+ ] NH2 NH2 OH OH O OH OH O OH O FIGURE 2.12 OH OH O O Dehydration reaction of tetracycline. metabolite as shown in Fig. 2.11. Another example of a drug that is known to undergo a dehydration reaction is tetracycline as shown in Fig. 2.12, this reaction can be avoided by simply removing the hydroxyl group present at the site of reaction in the molecule (Schlecht and Frank, 1975; Fiese and Steffen, 1990). 2.3.1.3 Oxidation Oxidation is another very common degradation reaction of many drugs, it usually proceeds via the molecular oxygen which is abundantly available in air. The reaction can take DOSAGE FORM DESIGN CONSIDERATIONS 2.3 CHEMICAL CHARACTERISTICS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT HO O COOH 71 COOH Oxidation NH2 HO NH2 O FIGURE 2.13 Oxidation reaction of methyldopa. place during the production process or in the long-term storage of the drug. The oxidation of a drug substance depends mainly on the presence of susceptible functional groups in the molecular structure of the drug. For example, oxidation of the alpha-adrenergic receptor agonist methyldopa results in the formation of the corresponding quinine metabolite as shown in Fig. 2.13. Other drugs that are known to be susceptible to oxidation reactions include the steroids, catechols, and polyene antibiotics, respectively. A common method used to protect the formulation of drugs (API or excipients) that are susceptible to oxidation reactions is the use of an antioxidant agents like ascorbic acid (LoBuglio and Jandl, 1967; Kalász and Antal, 2006). 2.3.1.4 Photochemical Degradation The photochemical degradation represents another common degradation pathway for many drugs. The photochemical degradation of drugs is considered to be highly complex as compared to other degradation reactions such as hydrolysis or oxidation. In general, the photochemical degradation results in different degradation products from the same drug substance, also, the presence of oxygen can cause the reaction to proceed via different mechanisms and thus yield different products. The photochemical reactions are more difficult to predict than other degradation reactions such as hydrolysis, and the reactions can happen during production, storage, or the use of the drug. An example of a drug that undergoes photochemical degradation is the reaction of the calcium channel blocker nifedipine, which undergo a dehydrogenation reaction in the presence of light as shown in Fig. 2.14 (Yoshioka and Stella, 2000). Protection of pharmaceutical products against photochemical degradation can be made by using amber storage containers that prevent the light from reaching the susceptible substances in the pharmaceutical formulations (Pareek and khunteta, 2014). 2.3.1.5 Isomerization An isomerization reaction is a reaction where one isomer of a substance converts to another isomer, which can be a constitutional (geometrical) isomer or a stereoisomer. Since the isomers including stereoisomers can have considerably different biological activities and different toxicity profiles, the conversion of one isomer to another in a pharmaceutical product is not acceptable and can have serious consequences on various aspects of the drug biological performance, thus it is important to study and identify the drug substances that can undergo isomerization reactions at different conditions. An example of a drug that can undergo isomerization reaction is the epimerization of tetracycline under acidic conditions, which involves the interconversion of the stereogenic center at carbon 4 to give DOSAGE FORM DESIGN CONSIDERATIONS 72 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT NO 2 H3 COOC NO 2 COOCH 3 H3 COOC COOCH 3 N H FIGURE 2.14 HO N Photochemical degradation of nifedipine (calcium channel blocker). N H HO N H OH OH NH2 NH2 OH OH O OH OH O OH O FIGURE 2.15 O OH O O Racemization reaction of tetracycline under acidic conditions. OH OH HO H N HO H N [H+ ] HO HO FIGURE 2.16 Racemization reaction of epinephrine under acidic conditions. the 4-primer of tetracycline which is not only inactive but can also cause toxic effects. Fig. 2.15 shows the racemization reaction of tetracycline under acidic conditions (Yoshioka and Stella, 2000). Another example of a substance that can undergo racemization under acidic conditions is the adrenergic agonist epinephrine; the reaction is shown in Fig. 2.16 (Schroeterand Higuchi, 1958). 2.3.1.6 Polymerization Polymerization is a reaction in which two or more molecules (monomers) of one substance react to form a new molecule which is a polymer of the substance. Examples of DOSAGE FORM DESIGN CONSIDERATIONS 2.3 CHEMICAL CHARACTERISTICS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT NH 2 73 H H S O HN O COOH NH H H S O HN O COOH NH H H S O HN O COOH NH H H S O O HN OH COOH FIGURE 2.17 Polymerization reaction product of aminopenicillin. drugs that can undergo polymerization reaction include the antibiotics like aminopenicillins in which the amino group of one molecule of aminopenicillin can react with the carbonyl carbon of the highly reactive beta-lactam ring to form a new dimer molecule, then the amino group of the dimer formed can initiate a reaction with the beta-lactam ring of another aminopenicillin molecule, and this process is repeated to form larger polymer molecules (Fig. 2.17). The polymer molecules produced are not only inactive but also because of their high molecular weight and large size, can be antigenic in nature causing allergic reactions when administrated to a patient. Thus, avoidance of polymers formation is important and it needs to be taken into consideration during the development as well as the storage of pharmaceutical products (Robinson-Fuentes et al., 1997). 2.3.1.7 Other Reactions There are various other reactions that can cause chemical degradation of the drug, for example, decarboxylation reactions can occur with drugs containing a carboxyl group. Several drugs are known to undergo this reaction at highly acidic conditions to eliminate a carbon dioxide (CO2) molecule from the structure of the substance. In addition to DOSAGE FORM DESIGN CONSIDERATIONS 74 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT RN O RHN RHN HO HO O HO OH HO RNH 2 OH HO HO OH OH OH FIGURE 2.18 OH OH HO OH OH OH OH OH The Maillard reaction of chlorpromazine with dextrose. decarboxylation, other different elimination reactions are also known for various drugs (Zhou et al., 2012; Zhou et al., 2016). An important aspect to be taken into consideration is the possibility of reactions that can take place between the API and an excipient or between two excipients. An example of such a chemical incompatibility between an API and an excipient is the possibility of a Maillard reaction that occurs between the primary amino group that is present in the structure of chlorpromazine and the dextrose (a reducing sugar). The product of this reaction is the imine compound which further breaks down to other compounds. The Maillard reaction of chlorpromazine with dextrose is shown in Fig. 2.18 (Fathima et al., 2011; Bharate et al., 2010; Narang et al., 2015). 2.4 SOLUBILITY ASPECTS IN PHARMACEUTICAL PRODUCTS DEVELOPMENT The solubility of a drug substance has a significant importance in pharmaceutical products development, as it affects various aspects of the drug formulation and biological performance. Solubility can be defined as the process of dissolving a solute (solid, liquid, or gas) in a single solvent or a mixture of solvents in order to make a homogenous system or solution. In a solution, the solvent may be considered as the component that is present in higher amount than the solute, although there are exceptions to this. The solvent can also be a solid, liquid, or gas just as the solute, however, in most pharmaceutical products that contain solutions, the solvent is usually a liquid substance and the solute dissolved in the solvent is usually a liquid or a solid substance (Savjani et al., 2012). The oral route of drug administration represents a highly popular method of drug administration, because of the higher patient compliance. Also, the oral route of administration has less sterility issues as compared to parenteral routes, thus the production process can be less costly. However, the bioavailability of the drug is considered as one of the main challenges in the development of oral drugs, since the drugs administrated through the oral route need to be solubilized in the surrounding media prior to absorption across the membranes to the systemic circulation (Krishnaiah, 2010). Since the gastrointestinal media is an aqueous media, drugs with poor aqueous solubility tend to have low DOSAGE FORM DESIGN CONSIDERATIONS 2.4 SOLUBILITY ASPECTS IN PHARMACEUTICAL PRODUCTS DEVELOPMENT 75 dissolution rate and low bioavailability. However, it is possible to use various strategies to enhance the solubility of a particular drug substance in order to enhance the bioavailability, thus solubility represents an important property that affects the bioavailability of drugs (Chaudhary et al., 2012; Rahman et al., 2014). 2.4.1 Aqueous Solubility Water is considered to be a useful solvent in pharmaceutical product formulations because it has many attractive properties as a solvent such as biological compatibility, nontoxicity, and economic. The water can be used as a solvent for many hydrophilic drugs, as it possesses a high dielectric constant, it is capable of dissolving many ionizable substances, and however, this property can also have certain drawbacks and limitations, since it can also dissolve various impurities that are undesirable in the pharmaceutical products. A major concern of using water as a solvent in pharmaceutical products is the possibility of microbial growth, since water represents a suitable medium for many microorganisms which can be detrimental to the product’s components or can have toxic effects when administrated to a patient, however, this problem can be alleviated by various approaches like using a suitable preservative in the pharmaceutical formulation in order to prevent the growth of microorganisms in the media (Carr et al., 2011). In spite of the attractive properties of water as a solvent that can be used in pharmaceutical products, many substances or drugs can have low aqueous solubility, as a result of which it is difficult to formulate those substances in aqueous media, because those substances may undergo precipitation even with little evaporation of the solvent, pH changes, and other factors. There are many different strategies that can be used in order to enhance the solubility of drug substances with relatively poor aqueous solubility such as by controlling the pH, use of cosolvents, use of solubilizing agents, as well as by modification of the molecular structure (Sharma et al., 2009). 2.4.1.1 Effect of pH Many drug molecules are either weak acids or bases, a property that makes the pH of the solution a critical factor in the determination of their solubility in the solvent. If the pKa of the weak acid or base is known, it is possible to use the Henderson Hasselbalch equation (Eq. 2.1) to predict the solubility of the substance at a given pH. pH 5 pKa 2 log ½HA ½A2 (2.1) In Eq. (2.1), [HA] represents the protonated form of the substance at the given pH, and [A2] represents the concentration of the deprotonated form of the substance at the given pH. Thus in the case where the pH is equal to the pKa of the substance, half of the substance will exists in the protonated form and the other half in the deprotonated form. In general, in the case of weak bases, lowering the pH of the solution below the pKa of the weak base causes the weak base to be ionized and to have higher solubility in the solvent, on the other hand, in the case of a weak acid, increasing the pH above the pKa of the weak acid causes the weak acid to exist in an ionized state which has a higher solubility DOSAGE FORM DESIGN CONSIDERATIONS 76 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 2.19 The relationship between the pH and the ionization percentage of acid and base substances. as compared to the unionized state; the relationship between the pH and the ionization of a substance is shown in Fig. 2.19 (Sinko, 2011). However, there are various limitations in controlling the pH of the solution to enhance the solubility of a drug substance in a pharmaceutical formulation. For example, the pH usually has significant influence on the stability of both the drug or API and the excipients. It has been observed that decreasing or increasing the pH values can cause chemical modification on the molecular structure of many drugs by triggering their chemical reactions in the solution. Thus in many cases, the optimum pH required for the stability of the drug in the solution is not the same as the optimum pH required to have the best solubility of the drug substance in the solution (Vemula et al., 2010). Another limitation to pH control is that many drug formulations need to have their pH adjusted to be compatible with the pH of application site, for example, if there is a high difference between the pH of a pharmaceutical formulation that is intended to be applied on the ocular membrane and the pH of the ocular membrane, then there’s a possibility of damage occurrence or irritation in the ocular membrane. Pharmaceutical formulations intended for parenteral administration should also have their pH adjusted properly in order to avoid any irritation or damage due to extremity in pH difference with the application site. Also, the optimum pH for the formulation is usually not same as the optimum pH to achieve the best solubility of the drug substance in the formulation. The pH of a drug solution can also influence other important processes like absorption and bioavailability of the drug, thus the pH of the pharmaceutical formulations requires proper and careful adjustment in order to achieve the best solubility while avoiding the alteration in the stability of the formulation as well as the incompatibilities with the pH at the site of application of the drug (Parve et al., 2014; Völgyi et al., 2010). 2.4.1.2 Cosolvent Effect In the case of substances with low solubility in aqueous solution due to their hydrophobic nature, it is possible to add another solvent that is miscible with the aqueous solvent and has the ability to dissolve the substance that has low solubility in aqueous solvents, this effect is referred to as the cosolvent effect. The use of cosolvents can greatly enhance the solubility of a substance or drug in a particular solvent that originally has low solubility (Shinde et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 77 2.4 SOLUBILITY ASPECTS IN PHARMACEUTICAL PRODUCTS DEVELOPMENT The use of cosolvents in pharmaceutical formulations in order to enhance the solubility of a particular substance has certain limitations like toxicities. Generally, the most widely used solvents with water include ethanol, glycerol, and propylene glycol because these solvents tend to have good safety profile in addition to their ability to enhance the solubility of various drug substances that otherwise show poor solubility in water alone (Jouyban, 2008; Jouyban-Gharamaleki et al., 1999). 2.4.1.3 Solubilizing Agents Another strategy that can be used to enhance the solubility of substances with poor aqueous solubility is the use of a solubilizing agent (Prajapati et al., 2009). Solubilizing agent is an excipient that is added to the pharmaceutical formulation in order to enhance the solubility of the drug. The most widely used solubilizing agents are the surface-active agents (surfactants), the surfactant can cause various substances to dissolve in aqueous solutions through the formation of different forms of micelles which are structures consisting of both a hydrophobic portion and a hydrophilic portion. The hydrophobic substance to be solubilized is buried in the inner hydrophobic portion of the surfactant molecules, while the hydrophilic portion which points outward interacts with the surrounding aqueous media and thus helping the substance to dissolve in the solution through the micelles. There are different forms of micelles structures among which the most commonly formed ones are the spherical shaped micelles as shown in Fig. 2.20, although other more complex liposomes can also be formed. Liposomes and similar structures are also proven for their enhanced ability to address the issues related with poor water solubility of drug (Maheshwari et al., 2012; Maheshwari et al., 2015). Many other novel nanocarriers are developed for increasing the solubility of drug and their site specific placement into body for indicated disease (Lalu et al., 2017; Maheshwari et al., 2015a; Sharma et al., 2015). FIGURE 2.20 Spherically representation. DOSAGE FORM DESIGN CONSIDERATIONS shaped micelles 78 2. PHYSICOCHEMICAL ASPECTS TO BE CONSIDERED IN PHARMACEUTICAL PRODUCT DEVELOPMENT The selection process of proper surfactants to be used as solubilizing agents is important, because not every surfactant can be used for this purpose. Generally, surfactants with HLB value of 15 or higher can be used as a solubilizing agent to dissolve various substances in an aqueous medium. The toxicological aspects of the use of surfactants should also be carefully considered since many surfactants can have potential toxicity if they are used in excess or via inappropriate route of administration. The quantity of surfactants present in the pharmaceutical formulations also require proper adjustment (Borenfreund and Puerner, 1985), because high amounts of surfactants can not only have toxic effects but can also influence the absorption as well as the bioavailability of the drug. The high quantity of surfactants as a solubilizing agent in the formulation can cause strong adsorption of the drug into the micelles and prevent the drug from being in a free form that is required to cross biological membranes in order to reach the systemic circulation. Examples of surfactants that can be used as a solubilizing agents in pharmaceutical formulations are the polysorbates which can be used to enhance the aqueous solubility of different drug substances in aqueous solutions (Rosen and Kunjappu, 2012; Söderlind et al., 2003; Strickley, 2004). 2.4.1.4 Particle Size Reduction The particle size of a substance can have important effects on the solubility of the substance in the aqueous solutions, as previously mentioned. The particle size controls the specific surface area of the particles which has significant influence on the solubility process. In general, a reduction in particle size causes an increase in the specific surface area of the particles and increases the solubility in aqueous solutions, while on the contrary, an increase in the particle size can cause a decrease in the specific surface area of the particles and hence a lowered solubility in aqueous solutions. Thus, particle size reduction can be a useful strategy to enhance the solubility of a poorly water-soluble drug which can also increase the bioavailability of the drug (Khadka et al., 2014; Liversidge and Cundy, 1995). 2.4.1.5 Molecular Modifications The molecular modification of the chemical structure of the drug represents another approach to enhance the solubility of poorly water-soluble drug substances. However, this approach has many limitations and is difficult to apply, and usually, it is only used when other strategies do not give appropriate results in enhancing the solubility of the drug substance. The chemical modification is limited due to the presence of certain functional groups in the chemical structure of the drug substance in addition to the synthetic accessibility of these groups. Moreover, any chemical modification of the structure can result in significant differences in the drug’s activity, toxicity and pharmacokinetic profile, thus any chemical modification on the structure of the drug would require proper assessment of the new structure (Jorgensen and Duffy, 2002; Savla et al., 2015). 2.5 CONCLUSION The physicochemical properties of both the API and excipients used in a pharmaceutical formulation require precise consideration in order to ensure the stability and proper performance of the drug. Physical characteristics like the crystalline and amorphous states of a DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 79 solid substance significantly influence the various important properties like solubility, dissolution rate, and bioavailability of the drug. Thus, the physical state in which the substance exists should be characterized and controlled in order to avoid alterations in the drug performance. On the other hand, chemical characteristics also play a crucial role in determining the chemical stability of the pharmaceutical formulation. Different components (API or excipients) of a formulation may undergo degradation into inactive or toxic products due to uncontrolled reactions during the process of production or storage of a drug formulation. Therefore, a proper insight and critical analysis of the possibility of such chemical degradation reactions in a pharmaceutical formulation along with the characterization of various physical properties of API and excipients are of paramount importance in order to ensure the integrity as well as the performance of the pharmaceutical product. Acknowledgement The author Pran Kishore Deb acknowledge the internal Philadelphia University Research Grant, Jordan (Project ID: 46/34/100PU) as a start-up financial support to his research group. The author Basant Amarji would also like to acknowledge that the views, thoughts, and opinions expressed by him in the text belong solely to the author, and not necessarily to the author’s employer, organization, committee or other group or individual. ABBREVIATIONS API Tg θ HLB SLS CO2 [HA] [A2] pKa active pharmaceutical ingredient glass transition temperature contact angle hydrophilic-lipophilic balance sodium lauryl sulfate carbon dioxide molecule concentration of protonated form of the substance at the given pH, concentration of the deprotonated form of the substance at the given pH measure of acid strength References Aitipamula, S., Chow, P.S., Tan, R.B.H., 2010. Polymorphs and solvates of a cocrystal involving an analgesic drug, ethenzamide, and 3,5-dinitrobenzoic acid. Cryst. Growth Des. 10, 2229 2238. Alexander, T., Florence, D.A., 2013. Physicochemical principles of Pharmacy. J. Chem. Inf. Model. 53, 1689 1699. Allada, R., Maruthapillai, A., Palanisamy, K., Chappa, P., 2016. 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Scientific considerations of pharmaceutical solid polymorphism in abbreviated new drug applications. Pharm. Res. 20 (4), 531 536. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 3 Role of Physicochemical Parameters on Drug Absorption and Their Implications in Pharmaceutical Product Development Yogendra Pal1, Pran Kishore Deb2, Shantanu Bandopadhyay3, Nabamita Bandyopadhyay4 and Rakesh K. Tekade5 1 Department of Pharmacy, Pranveer Singh Institute of Technology, Bhauti, Kanpur, Uttar Pradesh, India 2Faculty of Pharmacy, Philadelphia University, Amman, Jordan 3 Department of Pharmacy, Saroj Institute of Technology & Management, Lucknow, Uttar Pradesh, India 4Molecular Biology Division, National Institute of Malarial Research (NIMR), Dwarka, Delhi, India 5National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 3.1 Introduction 3.2 Drug Absorption Process: Basic Ideology and Illustrations 3.2.1 Passive Diffusion 3.2.2 Facilitated Passive Diffusion 3.2.3 Active Transport 3.2.4 Endocytosis Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00003-4 3.3 Barriers in Drug Absorption: Obstacle in Product Development 3.3.1 Barriers of Gastro-Intestinal Tract 3.3.2 Bloodstream Barriers 3.3.3 Blood Tissue Barrier 3.3.4 Blood Brain Barrier (BBB) 86 87 87 88 89 89 85 90 90 91 91 91 © 2018 Elsevier Inc. All rights reserved. 86 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION 3.4 Physicochemical Parameters and Their Effect on Drug Absorption 3.4.1 Chemical Nature of Drug 3.4.2 Effect of Particles Size & Effective Surface Area 3.4.3 Effect of Dissolution Rate 3.4.4 Effect of Drug Form 3.4.5 Solvates & Hydrates 3.4.6 Ionization State 3.5 Drug Absorption Through GIT: Role of Saturation Solubility 3.5.1 Polymorphism 92 92 101 102 104 106 107 107 107 3.5.2 Surfactant Based Solubilization 3.5.3 Complexation 109 109 3.6 Relationship Between Structure of Drug and Their Physicochemical Properties/Biological Properties 111 3.7 Conclusions 112 Abbreviations 112 References 112 Further Reading 115 3.1 INTRODUCTION The physicochemical properties of a drug considerably influence its pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) (Benjamin et al., 2010). Besides, these properties also affect the pharmacodynamics properties by modulating the interaction of drug with it targets like enzyme, receptor, ion channels, and carriers molecules, etc. (Flynn et al., 1974). In particular, the movement of a drug across the cell or biological membranes is mainly determined by certain factors like molecular size, solubility, ionization state, concentration gradient as well as interactions with membrane transport proteins. Further, it is worth mentioning that the pharmacological effects of a drug demand its presence in adequate concentration at the site of action which in turn is greatly dependent on the relationship between the rate of absorption, distribution, and metabolism of drug (Varma et al., 2017). A biologically active molecule cannot be considered as a drug without having satisfactory physicochemical properties as well as ADME properties. It is important to note that apart from physicochemical properties, the bioavailability of a drug also depends on numerous biological and intrinsic factors like peristaltic movement of the gastrointestinal tract (GIT), site of drug absorption, membrane transporters, firstpass metabolism, and extrinsic factors such as food or drug-mediated interactions (Shekhawat and Pokharkar, 2017). This chapter discusses the role of physicochemical properties in drug absorption, with a special emphasis on approaches to minimize their effect on drug disposition. A dosage form or a drug delivery system greatly influences as well as decides the numbers and types of barriers for a drug. Therefore, modifications in the formulation are likely to alter the quantity and release rate of drug at the site of action. Hence, prior to discussing physicochemical properties and their role in absorption, an outlook on standard drug absorption process and a study about various types of barriers are also illustrated in this chapter. DOSAGE FORM DESIGN CONSIDERATIONS 3.2 DRUG ABSORPTION PROCESS: BASIC IDEOLOGY AND ILLUSTRATIONS 87 3.2 DRUG ABSORPTION PROCESS: BASIC IDEOLOGY AND ILLUSTRATIONS Basically, drug absorption is a mechanism of drug movement wherein its original form is maintained during the transition from the site of administration to systemic blood circulation. Amongst the various factors, several aspects of formulation and route of administration also play a vital role for determining the drug absorption process. Dosage forms containing active pharmaceutical ingredient (API) as well as other ingredients are administered to the human body by various routes of administration. The drug must be in solution form to undergo absorption, whereas, in the case of solid forms, it should be able to disintegrate and disaggregate. To reach up to the systemic blood circulation, drugs have to cross one or more semipermeable cell membranes which are made up of bipolar lipid matrix, the property of which also influences the membrane permeability of drugs (Abuhelwa et al., 2017). Drug absorption mechanism is basically explained in four ways, as summarized in Fig. 3.1. 3.2.1 Passive Diffusion In this mechanism, a drug diffuses through the cell membrane from the region of higher concentration to a region of lower concentration. The diffusion rate of a drug is directly proportional to the concentration gradient which in turn depends on its lipid solubility, particle size, the degree of ionization, and absorption surface area. The drugs containing small molecules penetrate the cell membrane rapidly as compared to a large molecule (Scott et al., 2017). Owing to the lipoidal nature of the cell membrane, a lipophilic drug diffuses more rapidly. As the drugs are either of a weak acid or weak base, in an aqueous environment it attains both unionized and ionized forms (Kramer et al., 2009). The unionized form is lipophilic, i.e., lipid soluble in nature which diffuses readily across the cell membrane, while the ionized form is hydrophilic in nature with high electrical resistance as a result of which it cannot undergo diffusion across the cell membrane easily. The weak acidic drugs like salicylates, barbiturates etc. remain unionized in acid gastric juice where it can easily undergo absorption inside the stomach having an acidic medium as compared to weak basic drugs like, morphine, quinine etc. which are highly ionized and prefer to undergo absorption at duodenum. Passive diffusion is expressed by Fick’s First Law of Diffusion (Equation 3.1). dq DAK 5 Cgi 2 Cp dt h (3.1) where dq/dt 5 rate of diffusion; D 5 diffusion coefficient; K 5 partition coefficient; A 5 surface area of the membrane; h 5 membrane thickness; and (CGI Cp) 5 difference between the concentrations of drug in the GI tract and in the plasma. DOSAGE FORM DESIGN CONSIDERATIONS 88 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION FIGURE 3.1 Schematic representation of mechanism of drug absorption process. 3.2.2 Facilitated Passive Diffusion In this mechanism, a carrier molecule combines with the drug molecule or substrate molecule at the surface of the cell membrane forming a carrier substrate complex (Friedman, 2008). Then this complex rapidly diffuses through the cell membrane and then releases the substrate at the interior surface and carrier become free to combine to another substrate molecule. The use of carriers is limited as the membrane allows only substrate to transport with a relatively specific molecular configuration. It is an energy-independent transport mechanism where transport against concentration gradient generally does not occur. A significant feature of this absorption is that it is saturable. In case a drug to be transported is available in an extremely high concentration outside the cell, the carrier will be utilized entirely and will become the rate-limiting step. Under this condition, there will DOSAGE FORM DESIGN CONSIDERATIONS 3.2 DRUG ABSORPTION PROCESS: BASIC IDEOLOGY AND ILLUSTRATIONS 89 be no effect on the transport rate, upon increasing the outside concentration of the drug. The highest rate of transportation is dependent on concentration of carrier molecules and the speed with which they can carry drug through the membrane. 3.2.3 Active Transport This type of transport requires the energy expenditure for diffusion. It is capable of moving drug against a concentration gradient, i.e., drug may move from lower concentration to higher concentration. It is driven by the hydrolysis of ATP. This mechanism is limited to the drug(s) which are similar in structure to the endogenous substances. In this mechanism, either solutions or drug molecules are engulfed by a cell (Bottse et al., 1976). Further on the basis of ATP utilization, it can be classified into two types, namely, primary active transport and secondary active transport. 3.2.3.1 Primary Active Transport In this process, ATP is directly required where only one ion or molecule can be transferred in one direction and hence it is also known as uniporter, for e.g., glucose absorption (Stillwell, 2016). There are various types of primary active transporters. • • • • P-type ATPase: sodium-potassium pump, calcium pump, proton pump F-ATPase: mitochondrial ATP synthase, chloroplast ATP synthase V-ATPase: vacuolar ATPase ABC (ATP binding cassette) transporter: MDR, CFTR, etc. 3.2.3.2 Secondary Active Transport In this process, there is a benefit of previously existing concentration gradient and hence, no direct ATP usage. The ATP energy is used for transporting ions or molecules either in the same direction by a process known as symport (cotransport) or in the opposite direction known antiport (counter-transport) (Stillwell, 2016). 3.2.4 Endocytosis It is also a type of active transport process where the transportation occurs within vesicles present inside the cell (Ghanghoria et al., 2016). This mechanism can also be classified as transcellular because the process involves the transportation of substance across the cell membrane (Ericson, 1981). Endocytosis of drugs can be classified into two categories. 3.2.4.1 Pinocytosis (Cell Drinking or Uptake of Fluid Solute) In this process, a small sac is formed on the surface of the cell membrane and gradually the sac is enclosed due to the movement of cell membrane and finally engulfed inside the cell. As the mechanism can be spontaneous in certain cells, it may cause a partial amount of extracellular fluid to enter inside the cell (Levin et al., 2015). DOSAGE FORM DESIGN CONSIDERATIONS 90 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION 3.2.4.2 Phagocytosis (Cell Eating or Uptake of Solid Stuff Through Adsorption) It is another well-known process wherein a particle or solid is eaten or taken up through adsorption inside a cell. This process is mainly used for engulfing or neutralizing foreign matter like bacterium and virus by macrophagic system (Levin et al., 2015). 3.3 BARRIERS IN DRUG ABSORPTION: OBSTACLE IN PRODUCT DEVELOPMENT Whenever a drug is administered in the human body, it has to overcome various barriers in the body depending on the routes of administration. Often the bioavailability is reduced form the specific site of action owing to the barriers leading to decrease in the potency of the drug (Kerns and Di, 2008a,b). The various routes of drug(s) administration are summarized in Table 3.1. 3.3.1 Barriers of Gastro-Intestinal Tract 3.3.1.1 Barriers of Mouth The membrane of the buccal cavity is the first barrier that any oral drug encounters. The absorption of any drug depends upon the extent of its permeability through this membrane into the bloodstream (Reddy et al., 2011). 3.3.1.2 Barriers of Stomach The barriers in the stomach for a drug are dissolution rate, solubility, permeability, pH of stomach, influence of hydrolytic enzymes as well as chemical instability. As the surface area of stomach is greater, it leads to an increase in solubility thereby augmenting the absorption of drug through the membrane (Lopes Carla et al., 2016). TABLE 3.1 Different Routes for the Administration of a Drug Name of Route Way of Administration Oral Drug is administered through mouth Intravenous (parental) Drug is given in the veins directly Subcutaneous Drug is given beneath the skin Transdermal patches Drug is administered in the dermal region Topical Drug is applied over the skin Intramuscular Drug is administered into the skeletal muscles Suppository Drug is given through the anal region Sublingual Drug is crushed under the tongue in the sublingual region Intraperitoneal Drug is administered in the abdomen DOSAGE FORM DESIGN CONSIDERATIONS 3.3 BARRIERS IN DRUG ABSORPTION: OBSTACLE IN PRODUCT DEVELOPMENT 91 3.3.1.3 Barriers of Intestine The pH of intestine, pka value, solubility, and hydrolytic enzymes present in the intestine may act as barriers for the absorption of drug. In intestine, the bile salts act as a surfactant and microvilli increase the surface area for the absorption. So, absorption rate is increased for the drugs which are compatible with bile (Stojančević et al., 2013). 3.3.1.4 Barriers of Liver Bile extraction and drug metabolism are the two main barriers in the liver. Metabolism of a drug results in generation of polar molecules which later on turn out to be an obstacle for drug absorption or exposure and cause low bioavailability. 3.3.1.5 Barriers of Kidneys When the drug is processed through the kidney, the properties of the drug (hydrophobicity and pka) and factors (surface area, pH etc.) affecting the functioning of the kidney act as barriers for the drug absorption. Hydrophilic moieties eliminate easily from renal tubules while lipophilic drugs are reabsorbed (Gleeson, 2008). 3.3.2 Bloodstream Barriers The bloodstream barriers can be presented at three levels, viz: (i) Hydrolytic action of enzymes: Here enzymes present in the blood plasma interact with the drug and breaks them; (ii) Plasma protein binding: It is quite known that only unbound drug shows the action in the body. If the drug is in unbound state then the concentration and subsequently the bioavailability of the drug decreases in the blood; and (iii) Binding with the RBC: Interaction occurring between the RBC and the drug is lipophilic in nature which decreases the effect of the drug (Kerns and Di, 2008a,b). 3.3.3 Blood Tissue Barrier There are some organs in the body which do not allow the drug to enter into them and so they act as a barrier between the drug and its target. The drug could not enter the organ because of the tight junctions and manner in which the cells are arranged thereby prohibiting the entry of drug. 3.3.4 Blood Brain Barrier (BBB) Cerebrospinal fluid encompasses the brain from all the sides where the lipophilic drug can enter through the BBB, whereas it is almost impossible for hydrophilic drugs to pass through this barrier to the cerebrospinal fluid. Furthermore, blood capillaries present in the brain are densely packed, forming a dense junction which in turn inhibits the entrance of the drug as a result of which only drugs with high hydrophobicity and low molecular weight can pass through this barrier (Pardridge, 2012). Various novel approaches also reported to circumvent the problem of BBB (Dwivedi et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 92 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION The term “physicochemical” indicate the combination of physical property (viz. particle size, surface area) and chemical properties (viz. solubility, pH value). Physicochemical properties play a vital role in determining the rate of absorption, distribution, onset of action, metabolism, and excretion of a drug. This section discusses the effect of various aspects of physicochemical parameters on pharmacokinetic properties, particularly the absorption of drugs. 3.4.1 Chemical Nature of Drug Chemical properties have a direct influence on drug absorption as well as on its solubility, acidic/basic property, and tendency to resist change or decomposition, i.e., chemical stability. Further, these properties are correlated with the drug’s pKa value, dissolution rate, and ability to permeate the membrane. 3.4.1.1 Effect of Solubility Solubility is a phenomenon whereby a solute (solid/liquid/gas) forms a homogeneous solution with the solvent (solid/liquid/gas). The solubility of a drug in a particular solvent system reaches to a state known as saturation concentration, wherein any further addition of drug does not raise the concentration of the solution (Lachman et al., 1986). Solubility or extent of solubility can be expressed in many as mentioned in Table 3.2 (Sokoloski, 1985). Biopharmaceutical classification system (BCS) is used to improve as well as enhance the rate of drug development process by following a simplified approach. The objective of the BCS is to predict the in vivo fate of drug products from in vitro quantification of permeability and solubility. As per BCS, drugs are classified into four types (I IV) as shown in Fig. 3.2 (Benet, 2013). TABLE 3.2 Different Types of Solubility Type Specifications Very soluble Less than 1-part solvent needed to dissolve 1-part solute Freely soluble From 1 to 10 parts solvents needed to dissolve 1-part solute Soluble From 10 to 30 parts solvents needed to dissolve 1-part solute Sparingly soluble From 30 to 100 parts solvents needed to dissolve 1-part solute Slightly soluble From 100 to 1000 parts solvent needed to dissolve 1-part solute Very slightly soluble From 1000 to 10,000 parts solvents needed to dissolve 1-part solute Practically insoluble More than 10,000 parts solvents needed to dissolve 1-part solute DOSAGE FORM DESIGN CONSIDERATIONS 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION 93 FIGURE 3.2 Biopharmaceutical classification system (BCS) of drugs. 3.4.1.1.1 ESTIMATION OF SOLUBILITY The solubility of a drug depends on its relative affinity towards solvent molecules and the strength of this affinity or molecular interactions depends on ionic character, Van Der Waals force, dispersion, and hydrogen bonding. The extent of hydrogen bonding of a drug with water molecules significantly influences its preferential distribution between noctanol and water which in turn determines the aqueous solubility of the drug. More hydrogen bonding of drug with water results in its better aqueous solubility (Stenberg et al., 1999). 3.4.1.1.2 INFLUENCE OF SOLUBILITY ON DRUG ABSORPTION Owing to solution form, the drug molecules become independent and attain molecular dimensions and thus facilitate the absorption of a drug. Due to a direct effect on dissolution and disintegration, solubility is considered as a most important physicochemical parameter for absorption of the drug (Savjani et al., 2012). For orally administered drug, better solubility in GIT leads to better bioavailability and vice versa. Poor aqueous solubility imposes the biggest challenge in the pharmaceutical development of a drug, limiting it’s biological application. Although, good aqueous solubility is the essence for the fast dissolution rate, on the other hand, good lipophilicity is also required for permeation across the cell membrane, hence a balance between hydrophilicity and lipophilicity of a drug is very essential to avail maximum bioavailability as depicted in Fig. 3.3 (Savjani et al., 2012). The dynamic energy property of a compound is evident to show better descriptions of solubility as compared to the lipid/water partitioning. The cohesive energy of a molecule that is required to fraction it into its constituent atoms, can also be utilized as a solubility parameter of the drug. Solubility parameters must be equivalent for two materials to be mixed. The scale of solubility parameter extends from 10 (nonpolar) to 48 (water). Drug molecules show high oral absorption (.80%) with a solubility parameter in the range of 20 6 25 MPa1/2 (Martini et al., 1999). DOSAGE FORM DESIGN CONSIDERATIONS 94 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION FIGURE 3.3 Role of solubility in the absorption of drugs. 3.4.1.1.3 MODIFICATION OF SOLUBILITY The solubility of a compound can be changed by modification in its solid state as well as solution state as the properties and nature of interaction depend on both the states of a compound (Mantri et al., 2017). Modifications in the solid state can be accomplished by the use of prodrugs, use of metastable crystal forms or amorphous state of the drug, salt formation, co-crystal formation, and modifications in the solution state can be accomplished by changing solution pH (for ionizable drugs), use of additives like complexing agents, surfactants, or co-solvents. Use of surfactants also reported to increase the solubility of drug in different delivery systems (Maheshwari et al., 2012). Various techniques to increase solubility are summarized in Fig. 3.4 (Sharma et al., 2009). 3.4.1.2 Effect of Permeability Permeability is considered as one of the vital factors of drug absorption. A proper understanding, consideration, and investigation of the effect of permeability indifferent organs are therefore very important for the prediction of interactions, ADME, elimination routes, solubility/dissolution limitations, and toxicity as well as for the selection of suitable candidate drugs, clinical doses, and formulations, and for lead optimization recommendations. Permeability may be defined as the ability of any drug molecule or any substance to permeate a cell membrane, endothelium, or epithelium. It can also be defined as the ability of the cell wall to allow the passage of drug molecules (Fagerholm, 2010). Permeability also plays an important role in achieving desirable oral bioavailability. Permeability can be classified into four categories as follows: Class I: These compounds are expected to be well absorbed, and eliminated from the blood circulation through metabolism. In this class, compounds are having very high permeability; higher than for amlodipine, haloperidol, and nifedipine. DOSAGE FORM DESIGN CONSIDERATIONS 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION 95 FIGURE 3.4 Techniques to increase the solubility of a compound. Class II: Compounds of this class are expected to be completely or almost completely absorbed or reabsorbed by the intestines, liver, and renal tubules without active secretion and metabolism. High Permeability: lower limit similar to the permeability of cimetidine, caffeine, probenecid, and warfarin. Class III: Compounds of this class have intermediate passive uptake in the intestines, liver, and renal tubuli and therefore, are potentially sensitive to the involvement of active efflux. Intermediate permeability and incomplete fraction absorbed: lower limit similar to the Permeability of nadolol and sulpiride. Class IV: Compounds of this class have highest excretion potential, and low/incomplete passive absorption in the intestines, liver, and renal tubule. DOSAGE FORM DESIGN CONSIDERATIONS 96 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION 3.4.1.2.1 PERMEABILITY VERSUS FRACTION ABSORBED The extent and fraction of absorption during each passage through organs are described by the interplay between membrane permeability, solubility, pH, transit time and dispersion, blood component, binding capacity, and the molecular characteristics. Different shapes and shifts of permeability and fraction absorbed relationship due to the differences between organs (Dahan and Miller, 2012). A relationship between permeability and fraction absorbed from the gastrointestinal tract has been established for compounds that undergoes passive transport. The uptake of substance with permeability versus fraction absorbed is potentially most sensitive to efflux as compared to the compounds with high passive permeability. When active efflux is involved such compounds often deviate significantly from the relationship between passive permeability and fraction absorbed (Fagerholm, 2010). For compounds with low passive permeability, it is important to undergo active organ uptake. Examples include Levodopa, ACE inhibitors, and many antibiotics, which are taken up by nutrient transporters. For many other important organs, such relationships (including shapes and shifts) have not been available until recently. BCS classification which was developed by Amidon et al. (1995) made known that the elementary key constraints for the oral drug absorption are permeability of the drug through GI membrane and the solubility/dissolution of the drug. To maximize the oral absorption, the solubility permeability relationship must be taken into consideration. This interplay or relationship may be system dependent. Dahan and Miller (2012) studied each of these two parameters separately and also revealed the significance of their interplay from the binding system as well as the nonbinding system as follows. 3.4.1.2.2 SOLUBILITY-PERMEABILITY INTERPLAY FROM THE BINDING SYSTEM The use of the binding system (e.g., cyclodextrin, surfactants) has long been a primary drug delivery strategy to increase the apparent aqueous solubility of lipophilic drugs. Indeed, surfactants often play a crucial role in providing the solubilization power to enable the oral absorption of poorly soluble drugs that otherwise could not be delivered. Along the GI tract, naturally occurring surfactants such as sodium taurocholate (STC) are present and play important roles in the solubilization of lipophilic drugs. Likewise, artificial surfactants such as sodium lauryl sulfate (SLS) are routinely added to the dosage form to increase the apparent aqueous solubility of poorly soluble drugs. 3.4.1.2.3 SOLUBILITY PERMEABILITY INTERPLAY FROM THE NONBINDING SYSTEM Use of surfactants as well as complex formation with cyclodextrin results in the reduction of the free fraction of the drug that leads to lower concentration gradient and consequently thermodynamic driving force for membrane permeation. Therefore, free fraction may possibly be endorsed to reduce permeability with increased solubility. An approach to investigating the direct solubility permeability interplay is the use of co-solvents. Riad and Sawchuk (1991) assessed the consequence of diverse altitudes of polyethylene glycol 400 on the intestinal permeability of carbamazepine and concluded that the intestinal permeability co-realted inversely with the percentage of PEG-400. DOSAGE FORM DESIGN CONSIDERATIONS 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION 97 3.4.1.3 Effect of pH The solubility of a drug depends on the partitioning behavior of a drug from lipid to aqueous environment. It should be noted that the pH of the solvent influences the extent of ionization as well as partitioning behavior of a drug. Therefore, the ionized drugs exhibit extreme superior aqueous solubility as compared to the unionized drugs (Seydel and Schaper, 1982). 3.4.1.3.1 pH-Partition Theory In 1957 Brodie et al. proposed a hypothesis known as “pH-Partition theory” to explain the effect of pH of GIT and pKa of drug moiety upon absorption of the drug. As per this theory, three factors responsible for transportation of a drug compound having molecular weight more than 100 across the membrane by passive diffusion method are pKa (Negative logarithm of acid dissociation constant) of the drug, the lipophilic property of the unionized drug (partition coefficient), and the pH at the absorption site, respectively (Brahmankar and Jaiswal, 2015a,b). A postulation that GIT is a lipoidal hurdle for the transportation of drug moieties became the foundation of the above proposition. A portion of the unionized drug with soaring lipophilicity should be high for faster absorption. 3.4.1.3.2 pH OF GASTROINTESTINAL TRACT (GIT) & PLASMA FLUID As most of the available drugs are weak electrolytes, hence it is the pH of GIT fluid which determines the solubility or dissolution rate of a drug. The pH of GI fluid may be varied due to many factors such as presence of localized disease condition, types and amount of food ingested, and drug therapy (e.g., anticholinergic drugs reduce gastric secretion) (Sinko, 2006). Considering the normal condition, the pH of various parts of GIT is illustrated in Fig. 3.5. 3.4.1.3.3 CALCULATION OF BUFFERING CAPACITY A buffer solution is a solution which resists the change in pH when a small amount of acid or base is added to it. Chemically we can define pH buffer or hydrogen ion buffer as an aqueous solution consisting of a mixture of a weak acid and its conjugate base, or mixture of weak base and conjugated acid. Due to of an equilibrium between the acid (HA) and its conjugate base (A2) buffer solutions achieve their resistance pH (Equation 3.2). HA " H1 1A2 (3.2) A quantitative measure of the resistance of a buffer solution to pH change upon addition of acid or base is known as Buffer capacity (β). In other words, buffer capacity is the maximum quantity of either strong acid or strong base that can be added prior to a noteworthy change in the pH arising. It can be defined by the Equation 3.3. β5 dn dpH (3.3) Where n is the number of equivalents of added strong base or acid (per 1 Liter of the solution). DOSAGE FORM DESIGN CONSIDERATIONS 98 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION FIGURE 3.5 pH of gastrointestinal tract (GIT). 3.4.1.4 Concept and Effect of pKa and Partition Coefficient As discussed earlier, it is essential to have high aqueous solubility in order to achieve fast dissolution, whereas high lipophilicity is also required to achieve permeability across the membrane. As a result, the partitioning behavior of a drug molecule between aqueous and nonaqueous solvents is considered as one of the most critical properties. Partition coefficient theory is not only applied to the absorption and distribution of drug but also considered in many other areas like protein binding and hemodialysis, drug metabolism, enzyme inhibition, drug receptor interactions etc. because it directly quantifies the hydrophobic-bonding tendency of drugs. It should be noted that all proteins (enzyme, membrane, plasma, and receptor proteins) contain almost 25% to 45% of amino acids with nonpolar groups. As a consequence, partition coefficients have been emerged as an important physicochemical parameter influencing the biological activity as well as structure activity relationship of drugs (Lien Eric and ShijunRen, 2007). 3.4.1.4.1 pH pKa RELATIONSHIP WITH PROPORTION UNIONIZED The pH of a solution characterizes the concentrations or extent of H1 ions which have significant influence on the solubility of the majority of the weakly acidic or weakly basic DOSAGE FORM DESIGN CONSIDERATIONS 99 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION FIGURE 3.6 Role of pH on weak acid and base. drugs. The more positive the value of pKa (i.e., negative logarithm value of acid dissociation constant), the lower the dissociation of the molecule at a given pH, which means the weaker the acid. Henderson-Hasselbalch equations (Equations 3.4 and 3.5) allow the difference in the proportion of the two forms with changeable pH which may be described as: ionized conc ðsaltÞ unionizedconc ðacidÞ (3.4) ionized conc: ðbaseÞ un 2ionized conc: ðsaltÞ (3.5) For an acid: pH 5 pKa 1 log For a base: pH 5 pKa 1 log From the above equations, a presumption can be made that pKa for a drug is equivalent to the pH at which half fraction or 50% of the drug molecules are ionized. Weak acids, at a pH below their pKa, will be more unionized, and at a pH above their pKa, they will be more ionized. The reverse is true for weak bases (Fig. 3.6). For example, aspirin is a weak acid (pKa 5 3.5) which mostly undergoes ionization in the duodenum (pH 6.5). From the above enlightenment, one can figure out that in the stomach and in the entrance of intestine weakly basic drugs are more soluble as compared to the weakly acidic drugs which are more soluble in the duodenum or after that (Muro, 2016). Due to the lipoidal nature of the biological membrane, only the unionized part of a drug is able to cross the cell membrane. Conclusively, it is the molecular structure of the drug and the pH of the solution which determines the degree of ionization. Steady-state distribution of drug molecules between compartments of different pH as well as the rate of crossing the biological membrane are affected by the degree of ionization. 3.4.1.4.2 EFFECT OF PKA ON DRUG DISTRIBUTION BETWEEN STOMACH AND BLOOD From Equation 3.4 we can derive and illustrate the two more equations (Equations 3.6 and 3.7). log½A2 =½HA 5 ðpH 2 pKaÞ (3.6) ½A2 =½HA 5 10ðpH-pKaÞ (3.7) or Just to understand the influence of pH and pKa, let us consider the absorption of a weak acid (pKa 5 3.4) between gastric juice (pH 5 1.4) and plasma (pH 5 7.4). On putting these values in Equation 3.7, we can derive and illustrate two more equations (Equations 3.8 and 3.9) DOSAGE FORM DESIGN CONSIDERATIONS 100 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION In plasma: ½A2 =½HA 5 10ð7:423:4Þ 5 104 5 10; 000 (3.8) In gastric juice: ½A =½HA 5 10ð1:423:4Þ 5 1022 5 0:01 (3.9) 2 From the above results, it is quite clear that weakly acidic drugs are very less ionized in the stomach and easily cross the lipophilic membrane to reach the blood plasma where they undergo ionization very well. The reverse will be applicable to the weakly basic drug that can undergo absorption in a less acidic or basic medium. It is worth mentioning that to skip ionization of such a weakly basic drug in the stomach, an enteric coating or other controlled drug delivery is applied (Aulton et al., 1995). In a formulation, frequently the solvent system is attuned to a definite pH to attain an assured level of ionization of the drug for solubility and stability (Mahto and Narang, 2012). Potentiometric titration is mostly applied to establish the dissociation constant or pKa. 3.4.1.4.3 MEASUREMENT OF PKA To calculate pKa values, the Henderson-Hasselbalch equations are still the most commonly used equations (Equations 3.4 and 3.5). They relate pH and pKa to the equilibrium concentrations of dissociated acid [A2] and nondissociated acid [HA] respectively (Equation 3.10). pKa 5 pH 2 logð½A2 =½HAÞ (3.10) Techniques for Determination of pKa Values (Reijenga et al., 2013) are: • • • • • • • • • • • Potentiometry Conductometry Voltammetry Calorimetry Nuclear magnetic resonance Electrophoresis High-performance liquid chromatography UV/Visible spectrometry Polarimetry Kinetic method Computational method 3.4.1.4.4 MEASUREMENT OF LOGP In 1872 Berthelot and Jungfleisch illustrated the partition coefficient P by (Equation 3.11) P5 Co 5 equilibrium constant K Caq (3.11) Where C0 5 concentration of solute in organic solvent and Caq 5 concentration of solute in the aqueous solvent. In the early 1950s, Collander presented the standard linear freeenergy relationship, using water and different alkanols (Equation 3.12). log P2 5 a log P1 1 b DOSAGE FORM DESIGN CONSIDERATIONS (3.12) 101 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION FIGURE 3.7 Dissociation of weak acid. Where “a” is a coefficient, and “b” is a constant. Additionally, Collander also demonstrated that the penetration rate of plant cell membranes by various organic compounds was related to their oil water partition coefficients. In the early 1960s, Salame and Pinsky derived the permachor method for calculation of the P factor for the prediction of chemicals permeation through a plastic membrane as shown in (Equation 3.13). logPf 5 16:55 2 3700=T 2 0:22π (3.13) Where, π is the permachor constant, and T is the absolute temperature. 3.4.1.4.5 APPARENT VERSUS TRUE PARTITION COEFFICIENT (LOG P0 VERSUS LOG P) If a solute is ionizable (either acidic or basic), two different species can exist in the aqueous phase, and therefore the apparent partition coefficient (P0) or the true partition coefficients (P) can be measured, as shown below (Fig. 3.7) P 5 ½HAo =½HAaq (3.14) P0 5 ½HAo =½HAaq 1 ½A2 (3.15) And P 5 Poð1 2 αÞ Where, α is the degree of ionization: for acids: α 5 1/ [1 1 antilog (pKa for bases: α 5 1/ [1 1 antilog (pH pH)] pKa)] Rises and falls of the apparent partition coefficient (P0) are directly related to the change in pH of the aqueous phase (usually a buffer solution), whereas the true (or corrected) partition coefficient (P) remains constant (Lien Eric and ShijunRen, 2007). 3.4.2 Effect of Particles Size & Effective Surface Area The solubility of a drug is fundamentally associated with its particle size. Reduction in particle size will lead to the amplified surface area available for solvation process (Khadka et al., 2014). Particle size reduction technologies are consequently and consistently used to enhance the bioavailability of badly soluble drugs (Williams et al., 2013). Better solubility results in better dissolution rate and ultimately into better absorption. For example, the DOSAGE FORM DESIGN CONSIDERATIONS 102 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION normal particle size of Griseofulvin shows poor solubility as well as poor absorption while upon milling or size reduction it shows improved condition in both phenomenon (Elamin et al., 1994). Formulation of ultramicro size particles shows better absorption than the micro size particles (Prokop and Davidson, 2008). Particle size and surface area share an inverse relationship. The greater the effective surface area, the better the dissolution and so the absorption. Surface area can be classified into the absolute surface area and effective surface area. The absolute surface area can be converted to the effective surface area by use of surfactants like polysorbate 80 and by adding hydrophilic diluents like PEG, PVP etc. (Brahmankar and Jaiswal, 2015a,b). Nowadays many nanoscale drug carriers are the hot topic in the drug delivery field due to their ability to transport the drug to desired sites in body (Tekade et al., 2017; Sharma et al., 2015; Maheshwari et al., 2015a). 3.4.3 Effect of Dissolution Rate Dissolution is the process by which a solid particle is surrounded with a liquid medium for which it has an affinity. It is a primary requirement for the drug absorption for the reason that merely dissolved drug molecules or ions or atoms are capable of diffusing all the way through living tissues (Siepmann and Siepmann, 2013). Drugs with very high hydrophobicity or lipophilicity are considered as the driving force for studying their rate of dissolution in a particular solvent medium. Schematic representation of dissolution of a drug particle in the gastrointestinal (GI) fluid is depicted in Fig. 3.8. 3.4.3.1 Diffusion Gradient or Concentration Gradient Film theory or the diffusion layer model is the most common hypothesis to characterize the drug dissolution process. It is based on the postulation that the dissolution takes place by the transport process. During the dissolution process, first, a saturated layer of drug solution known as diffusion layer or stagnant layer which encircles the surface of the solid drug particle is established by the drug molecules on its surface (outermost layer) by entering into solution. The drug molecules get ahead of the diffusion layer throughout the FIGURE 3.8 Schematic representation of dissolution of a drug particle in the gastrointestinal (GI) fluid. DOSAGE FORM DESIGN CONSIDERATIONS 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION 103 dissolving fluid and make contact with the biological membranes. As soon as the drug molecules leave the diffusion layer, immediately the layer is refilled with the dissolved drug which is available on the surface of the drug particle (Brahmankar and Jaiswal, 2015a,b). 3.4.3.2 Noyes Whitney Equation The Noyes Whitney equation is possibly the most regularly used equation to explain the drug dissolution method and the physicochemical properties that play a pivotal part in influencing drug dissolution (Noyes and Whitney, 1897) as shown in Equation 3.16. dc=dt 5 kSðCs 2 Ct Þ (3.16) Where dc/dt is the rate of dissolution, S is the surface area of the solid, Ct is the concentration of the solid in the bulk dissolution medium, and Cs is the concentration of the solid in the diffusion layer surrounding the solid. In 1904, Nernst and Brunner modified the Noyes Whitney equation and postulated the Equation 3.17 (Bruner and Nernst, 1904). dx=dt 5 Aðd=hÞðCs 2 Xd =VÞ (3.17) where dx/dt is the rate of dissolution, A is the available surface area, D is the diffusion coefficient or diffusivity, h is the thickness of the diffusion or boundary layer adjacent to the dissolving drug surface, Cs is the equilibrium or saturation solubility of the drug, Xd is the amount of the dissolving solid, and V is the volume of the dissolution fluid. The rate of dissolution of a solute depends on its rate of diffusion through the stagnant layer into the solution. This equation clearly reveals that higher value of A and Cs will increase the dissolution rate of a drug. The intensity of agitation of the vehicle, as well as the diffusion coefficient of the dissolving drug, are also considered as two important factors governing the rate of dissolution of a drug. The diffusion coefficient and concentration of the drug in the diffusion layer are directly proportional to temperature. Further, rate of dissolution of a drug can also be enhanced by decreasing the viscosity of solvent. 3.4.3.3 Effect of Salt Form on Dissolution Rate The dissolution rate of a salt form of a drug is generally quite different from that of the parent compound. Sodium and potassium salts of weak organic acids and hydrochloride salts of weak organic bases dissolve more readily as compared to their respective free acids or bases. This results in a more rapid saturation of the diffusion layer surrounding the dissolving particle and consequently more rapid diffusion of the drug takes place to the absorption sites. For example, the addition of the ethylenediamine moiety to theophylline increases the water solubility of theophylline by five-fold. The use of the ethylenediamine salt of theophylline has allowed the development of oral aqueous solutions of theophylline and diminished the need to use hydro-alcoholic mixtures such as elixirs. 3.4.3.4 Sink Condition In the pharmaceutical technology, sink condition is a term used in the methods related to dissolution testing. In this technology, a sheer volume of solvent is taken which is usually about five to ten times greater than the volume present in the saturated solution of the dosage form, having the chemical which is targeted and being tested (Kalepua and DOSAGE FORM DESIGN CONSIDERATIONS 104 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION Nekkanti, 2015). During this testing, “sink condition” is a must requirement, otherwise the test result will not be precise because the concentration begins to get closer to the saturation point (Liu, 2008). Although the total soluble amount still remains the same, the dissolution rate will gradually begin to decrease in significant amounts (Ghosh and Jasti, 2004). 3.4.3.5 Factors Affecting Drug Dissolution As discussed earlier, drug dissolution rate depends on the hydrodynamics of the GI fluid, surface area (A) of the drug, drug solubility (Cs) in the dissolution fluid, and drug diffusivity (D). There are various factors which either control a few or all abovementioned properties such as intestinal and gastric pH, particle size, polymorphism, complexation with GIT components, or the excipients of the dosage forms, surface active agent etc. as depicted in Fig. 3.9 (Jambhekar, Breen, 2013). Stability of drug is also an important parameter which affects dissolution. For instance, if a drug for oral use is destabilized either in the GIT or during its shelf life, it directly results in poor absorption. One of the prime stability troubles is the conversion of an active form of drug into an inactive form having poor absorption like in case of Penicillin G (enzymatic degradation). Another major problem is complexation of a drug molecule with other components of dosage form or with the compound available in the GIT which results in formation of poorly absorbable complex or moiety. These problems further lead to poor bioavailability. The stability profile of drugs in GI conditions must be studied before selecting a particular drug for improved dissolution (Mark Saltzman, 2001). 3.4.4 Effect of Drug Form Parental preparations are given directly to systematic circulation, so drugs in parental form face the least number of barriers to reach the target and show the fastest action with the highest bioavailability while oral dosage forms of the same drug show low bioavailability due to more barriers for the absorption. Even among different types of the oral dosage form, the solution form shows the highest bioavailability due to skipping of the dissolution problem, whereas sustained release products show the lowest bioavailability. The scope of designing a drug formulation is to make available a striking, constant, and convenient FIGURE 3.9 Factors affecting drug dissociation process. DOSAGE FORM DESIGN CONSIDERATIONS 3.4 PHYSICOCHEMICAL PARAMETERS AND THEIR EFFECT ON DRUG ABSORPTION 105 method to use products (Welling, 2007). To increase solubility and dissolution rate, some drugs like Griseofulvin are given in solid solution form in which the drug is trapped in a monomolecular dispersion in a water-soluble matrix (Goldberg et al., 1966). For increased bioavailability, another widely used oral dosage form is emulsion form which is used due to higher solubilization capacity and rapid onset of action, whereas in suspension form, solid particles are finely divided for rapid diffusion between the stomach and small intestine (Gupta et al., 2013). Tablets and capsules are the universally used oral dosage forms in which capsule shows better absorption due to the speedy dispersion of granules. Reports are available on the use of novel tablet formulations such as by using microsponge granules for enhancing the solubility of nifedipine (Maheshwari et al., 2017). The effect of various dosage forms on the absorption of drugs is summarized in Fig. 3.10. On the basis of decreasing bioavailability, oral dosage forms can be arranged in following order: Solutions . Emulsions . Suspensions . Capsules . Tablets . Coated Tablets . Enteric coated Tablets . Sustained Release Products FIGURE 3.10 Effect of dosage forms on the absorption of drugs. DOSAGE FORM DESIGN CONSIDERATIONS 106 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION 3.4.4.1 Prodrugs and Its Implications First pass metabolism in the liver may cause conversion of orally administered drug into another form or a degraded form which results in poor bioavailability. A potential approach to get better absorption, as well as bioavailability, is the conversion of active moiety to a prodrug form. The prodrug approach is used to improve the delivery of drugs to their site of action by modulation of physicochemical properties that affect the absorption or by targeting specific enzymes or membrane transporters (Barot et al., 2012). The concept of the prodrug was first introduced in medicinal chemistry by Albert in 1951: “A prodrug is a molecule which does not have any intrinsic biological activity but which is capable during the different phases of its metabolism to generate a biologically active drug” (Albert, 1958). IUPAC definition states that “a prodrug is a compound that undergoes biotransformation before exhibiting pharmacological effects” (Wermuth et al., 1998). Prodrugs can be categorized into two types, namely carrier-linked prodrugs and bioprecursor-prodrugs. In case of carrier-linked prodrugs, the drug is connected to a carrier moiety by a temporary covalent linkage which upon fission generates a molecular moiety of increased bioactivity (drug) and at least one side product, the carrier, which may be biologically inert (e.g., PEG) or may have targeting properties (e.g., antibodies) (Testa, 2009). In the case of bioprecursor-prodrugs, molecular modification of active moiety takes place which generates a new compound able to be a substrate for the metabolizing enzymes (Kokil and Rewatkar, 2010). The principal objectives of the prodrug approach are to improve drug water-solubility, absorption as well membrane permeability, targeted release, and to reduce metabolism and side effects (Abet et al., 2017). 3.4.4.2 Complex Form Properties of drug complexes such as solubility, molecular size, and lipid water partition coefficient differ significantly from those of the respective free drugs. The molecular complex consists of components held together by weak forces like hydrogen bonding. Bonding interaction between the two molecules is rapidly reversible, provided the complex is soluble in biological fluids (Kerns and Di, 2008a,b). 3.4.4.3 Clathrate Forms Clathrates are formed if a substance is capable of forming channels or cages which can take up another substance into the intraspace of the structure. Clathrate forming substances are gallic acid urea, thiourea, amino, and zeolites. Clathrates are formed by crystallization of an organic solution of clathrate-forming substance with the drug. The drug normally exists as a monomolecular dispersion in the clathrate complex. On exposure to water or dissolution medium, clathrate-forming vehicle dissolves rapidly and exposes the drug molecule to dissolution medium. Drugs that have been presented in clathrate forms include vitamin A, sulphathiazole, chloramphenicol, and reserpine (Threlfall, 2006). 3.4.5 Solvates & Hydrates The state of hydration of a drug molecule can affect its solubility and pattern of absorption. Usually, the anhydrous form of an organic molecule is more readily soluble than the DOSAGE FORM DESIGN CONSIDERATIONS 3.5 DRUG ABSORPTION THROUGH GIT: ROLE OF SATURATION SOLUBILITY 107 hydrated form. This characteristic was demonstrated with the drug ampicillin when the anhydrous form was found to have a greater rate of solubility than the trihydrate form (Poole, 1968). Moreover, the anhydrous form of ampicillin shows a greater extent of absorption from hard gelatin capsule or aqueous suspension dosage forms than the less soluble, slower dissolving crystalline form. 3.4.6 Ionization State As described earlier, unionized drug or part of drug is favorable to pass the cell membrane. If there is pH difference between two or more compartments of body like gastric cavity as well as parietal cells (pH 5 1 to 3), duodenum (pH 5 7.5) and blood circulation (pH 5 7.3), then the unionized form of the drug would prefer to cross easily from duodenum via blood circulation to the gastric parietal cells. Then inside the parietal cells under acidic medium, the same drug may undergo ionization and get trapped, as a result of which it becomes difficult for the drug to efflux back from inside the cell to the outer environment and such phenomenon is known as ion trapping. This is separated by the membrane of the gastric mucosa in the case of acidic drugs which are ionized less in an acidic medium; the unionized drug crosses the gastric mucosa and converts to ionized species and after that passes slowly through the cell membrane. For example, all the proton pump inhibitors like omeprazole enter the parietal cell and exert their function after getting ionized or by following ion trapping. 3.5 DRUG ABSORPTION THROUGH GIT: ROLE OF SATURATION SOLUBILITY Formulations that maintain drug insolubilized and supersaturated conditions for prolonged periods of time diligently support absorption under almost all conditions. Even a brief time period of supersaturation may be sufficient to drive absorptive drug flux for periods of up to an hour. 3.5.1 Polymorphism Polymorphism is a Greek word representing a combination of two different words, where “Poly” means many and “morphe” means form. Polymorphism is most absolutely defined by McCrone who states that “polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two crystalline arrangements of the molecules of that compound in the solid state.” When a solid material has the ability to exist in two or more crystalline forms with different arrangements or different conformations in the crystal lattice, then this phenomenon of solid material is known as polymorphism. Hence, it refers to different structural arrangements of any chemical substance. More than 50% of active pharmaceutical ingredients (APIs) have more than one polymorphic form. Polymorphism is generally categorized into two forms, namely, monotropic system and enantiotropic system (Bényei, 2014). Gibbs free energy (∆G) determines the DOSAGE FORM DESIGN CONSIDERATIONS 108 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION relative stability and driving force for the polymorphic transformations at constant temperature and pressure which states the internal energy available for chemical form, as portrayed by Equation 3.18. ∆G 5 ∆H 2 T∆S (3.18) Where ∆G 5 Gibbs free energy, ∆H 5 Signifies the enthalpy change, ∆S 5 Accounts for the entropy change. The negative value of ∆G assures the spontaneity of the polymorphic transitions, whereas the positive value renders the process nonspontaneous. 3.5.1.1 Methods of Polymorph Preparation In the Solvent Evaporation Method (Rota Evaporation), by using an appropriate solvent, the saturated solution of the drug is prepared and then the solvent is removed by rotatory evaporation. By employing air drying techniques at various temperature, potential polymorphs can also be obtained. In slow cooling approach, polymorphic forms of less soluble drugs in the solvent systems, which have boiling points in the range of 30 to 90 C, are frequently employed. When the amount of the drug available is less, and the drug is sensitive to the air or solvent, solvent diffusion technique is employed. Similarly, vapor diffusion method is analogous to the solvent diffusion technique and is applicable for the lower quantities of the sample (Raza et al., 2014). 3.5.1.2 Role of Polymorphism in Drug Absorption The equilibrium solubility is the most critical issue related to the drug substance polymorphism. Equilibrium solubility may be defined as the dissolved drug concentration when there is equilibrium established between solid drug substance and solution. The effect of crystal structure or polymorphism can be understood by the study of equilibrium solubility. By processing parameters, the particle size and wettability of a solid can be modified but equilibrium solubility is determined by polymorphic form. Polymorphs of a drug substance can have different apparent aqueous solubility and dissolution rate which leads to change in the bioavailability of the drug and by using different polymorphs; it is difficult to form a bioequivalent drug product. Any difference in the solubility of various polymorphs will affect the drug’s bioavailability, bioequivalence, gastrointestinal motility, and intestinal permeability. The polymorphic form affects the bioavailability by a drug with dissolution as the rate-limiting step. Polymorphs of a pharmaceutical substance may have different physical as well as chemical solid-state properties. As it has the lowest potential to convert from one polymorphic form to another, the most stable polymorphic form of a drug substance is often used while the metastable form may be used to increase the bioavailability of a drug substance. With the help of appropriate examination of the relative apparent solubility of a supersaturated solution of polymorphic pairs, the relative polymorphic stability may be determined. During manufacturing and storage, one polymorph may convert to another, particularly when a metastable form is used (Prasanthi et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 3.5 DRUG ABSORPTION THROUGH GIT: ROLE OF SATURATION SOLUBILITY 109 3.5.1.3 Amorphism The molecules which are present in amorphous materials are not organized in a definite lattice pattern as compared to solid forms. This means that the active sites, which would be interacting with each other to build the crystal, are now exposed directly to the environment. Product stability, storage, processing, compatibility, hygroscopic nature, and dissolution are some properties which can be affected by structure modification. An amorphous translucent solid is called glass. Amorphous solids are isotropic in nature as their physical properties will remain the same in all directions. It provides advantages in terms of dissolution rate and bioavailability (Einfalt et al., 2013). There is no need for energy to break up the crystal lattice, so amorphous forms generally dissolve faster than crystalline forms. For this reason, the amorphous form is often preferred in comparison to a crystalline form and several drugs including hydrocortisone and prednisolone are marketed in their amorphous forms (Shargel and Andrew, 1999). 3.5.2 Surfactant Based Solubilization Surface active agents or surfactants have wide applications like wetting of substances, reduction of surface tension of a liquid, micelle formation, solubilization of organic solutes in micelles, emulsification, dispersion formation etc. For hydrophobic drugs, micellarsolubilization has emerged as a commendable approach. It is found that the aqueous solubility of the drug (e.g., ibuprofen) increases linearly with increasing surfactant concentration (Stephenson et al., 2006). Recently, the use of nonionic surfactant based systems is reported to increase the solubility and efficacy of ofloxacin (Maheshwari et al., 2015a,b). 3.5.3 Complexation Intermolecular relation of substrate and ligand molecules or ions is known as a complex. This relation is kept by strong coordinate covalent bonds. Aqueous solubility of a lipophilic drug can be increased by using mainly three types of complexes, namely, coordination complexes, organic molecular complexes, and inclusion complexes, respectively (Loftsson, 2007). • Coordination complexes: It consists of a drug acting as a complexing agent (i.e., a ligand) and a metal ion (i.e., substrate), e.g., tetracycline-metal ion complexes. • Organic molecular complexes: It consists of a drug that is considered as a small substrate along with a small ligand (e.g., caffeine) or a large ligand (e.g., polyvinylpyrrolidone). • Inclusion complexes: Here the substrate (drug) is either partly or completely enclosed by a complexing agent like cyclodextrin. 3.5.3.1 Pi (π) Donor or Pi (π) Acceptor Complexes It is also known as organic molecular complexes in which instead of metal ions, small molecules like caffeine or nicotinamide are used which act as a ligand. For example, nicotinamide increases the solubility of progesterone by about 600 times to its aqueous solubility (Horter and Dressman, 2001). DOSAGE FORM DESIGN CONSIDERATIONS 110 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION 3.5.3.2 Cyclodextrin As discussed earlier, complexation with cyclodextrin moiety is considered as one of the most suitable processes to enhance the stability as well as the aqueous solubility of hydrophobic drugs. Cyclodextrins are cyclic oligosaccharides of (α-1,4)-linked α-D-glucopyranose units (Fig. 3.11), with lipophilic central cavity surrounded by hydrophilic outer FIGURE 3.11 Structure of a β-cyclodextrin. DOSAGE FORM DESIGN CONSIDERATIONS 3.6 RELATIONSHIP BETWEEN STRUCTURE OF DRUG AND THEIR PHYSICOCHEMICAL PROPERTIES 111 surface. The aqueous solubility of many poorly soluble lipophilic compounds can be increased by forming their aqueous-soluble inclusion complexes with cyclodextrins. For example, aqueous solubility of aspirin can be increased many fold by forming a complex with cyclodextrin (Semalty et al., 2010). 3.6 RELATIONSHIP BETWEEN STRUCTURE OF DRUG AND THEIR PHYSICOCHEMICAL PROPERTIES/BIOLOGICAL PROPERTIES Physicochemical properties like hydrophobicity of the molecule, electronic effect, and steric effect are directly related to the chemical structure of the compound and can be related quantitatively to the pharmacological activity. Fig. 3.12 shows the change in the value of logP due to change in substitution (Patrick, 2008). Hence, it is the structure of the drug which is responsible for the physicochemical property as well as biological properties. Change in structure of the drug molecule leads to change in its physicochemical properties as well as biological activity. Another suitable example is the solubility difference between 2-acetaminophen and 3-acetaminophen (Fig. 3.13) at a particular temperature (Perlovich et al., 2008). FIGURE 3.12 Effect of substitution on logP value of a molecule. FIGURE 3.13 Structure and solubility difference in 2-acetaminophen and 3-acetaminophen. Source: Adapted with permission from Perlovich, G.L., Volkova, T.V., Manin, A.N., Annette Bauer-Brand, 2008. AAPS Pharm. Sci. Tech. 9 (1). https://doi.org/10.1208/s12249-008-9033-0. Copyright Springerr. DOSAGE FORM DESIGN CONSIDERATIONS 112 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION 3.7 CONCLUSIONS The designing of a good dosage form formulation necessitates proper insight and consideration of different factors affecting the absorption as well as bioavailability of the drug. To reach the systemic circulation, the drug has to cross biological membranes/barriers either by the passive or active diffusion method/s. For this crossing, the role of physicochemical properties, which are quite related to molecular structures, should be considered with high preference because we cannot change the barriers but we can design such dosage forms in which the influence of physicochemical properties like solubility, pH, dissolution rate, etc. can be altered in a positive direction. A lot of improved technologies/methodologies have been scrutinized with varying accomplishments. A few such current technologies/methodologies like prodrug formation, clathrate formation, and complexation with cyclodextrin have proved to have significant potential to enhance the absorption of orally administered drugs. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. 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Williams, H.D., Trevaskis, N.L., Charman, S.A., 2013. Strategies to address low drug solubility in discovery and development. Pharmacol. Rev. 65, 315e499. Further Reading Allen, Loyd V., Popovich, Nicholas G., Ansel, Howard C., 2011a. 9th Edition Chapter 4, Pharmaceutical and Formulation Considerations, Ansel’s Pharmaceutical, 145. Dosage Forms and Drug Delivery Systems. Allen, Loyd V., Popovich, Nicholas G., Ansel, Howard C., 2011b. Chapter 4, Pharmaceutical and Formulation Considerations, Ansel’s Pharmaceutical, 9th Edition Dosage Forms and Drug Delivery Systems, pp. 152 153. Allen, Loyd V., Popovich, Nicholas G., Ansel, Howard C., 2011c. Chapter 4, Pharmaceutical and Formulation Considerations, Ansel’s Pharmaceutical, 9th Edition Dosage Forms and Drug Delivery Systems, pp. 116 117. Boron, Walter, Boulpaep, Emile, 2016. Medical Physiology, 3rd edition Elsevier Saunders, 9780323377966 pp. 56 71. DOSAGE FORM DESIGN CONSIDERATIONS 116 3. ROLE OF PHYSICOCHEMICAL PARAMETERS ON DRUG ABSORPTION Crum, Matthew F., Trevaskis, Natalie L., Pouton, Colin W., Porter, Christopher J.H., 2017. Transient Supersaturation Supports Drug Absorption from Lipid-Based Formulations for Short Periods of Time, but Ongoing Solubilization Is Required for Longer Absorption Periods. Mol. Pharmaceutics 14 (2), 394 405. Available from: https://doi.org/10.1021/acs.molpharmaceut.6b00792. Feher, Joseph, J, 2012, Quantitative Human Physiology: An Introduction. Lipinski, C.A., 2000. Drug-like properties and the causes of poor solubility and poor permeability. JPharmacolToxicol Methods 44, 235 249. Martinez, Marilyn N., Amidon, Gordon L., 2002. A Mechanistic Approach to Understanding the Factors Affecting Drug Absorption:A Review of Fundamentals. J ClinPharmacol. 42 (6), 620 643. Palatini, P., De Martin, S., 2016. Pharmacokinetic drug interactions in liver disease: An update. World J Gastroenterol. 22 (3), 1260 1278. Roche, Victoria F., 2007. Improving Pharmacy Students’ Understanding and Long-term Retention of Acid-Base Chemistry. American Journal of Pharmaceutical Education 71 (6), Article 122. Tripathi, K.,D., 2008. Essential of Medical Pharmacolgy, sixth edition Jaypee Brothers Medical Publishers(P) Ltd, p. 16. Washington, Neena, Clive Washington, Clive G. Wilson, 2000, Pharmaceutical Barriers to Drug Absorption, 2nd Edition, 12 17. DOSAGE FORM DESIGN CONSIDERATIONS C H A P T E R 4 Physiologic Factors Related to Drug Absorption Pratap Chandra Acharya1,*, Clara Fernandes2,*, Santanu Mallik1,*, Bijayashree Mishra3 and Rakesh K. Tekade4,5 1 Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India 2Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India 3Department of Chemistry, Tripura University (A Central University), Suryamaninagar, Tripura, India 4National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 5Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 4.1 Introduction 4.1.1 Events Involved in Drug Absorption 4.1.2 Pathways of Drug Absorption 118 4.2 Barriers to Drug Absorption 4.2.1 Mucus Thickness 4.2.2 Mucus Clearance 4.2.3 Unstirred Water Layer (The Steric Barrier) 125 126 126 119 120 126 4.2.4 Peristalsis (The Dynamic Barrier) 127 4.2.5 Nonmucosal Barrier to Drug Absorption 127 4.2.6 Drug Transporters as Determinants for Drug Absorption 128 4.2.7 Metabolism as Barrier to Drug Absorption 132 4.2.8 Lymphatic Absorption 134 * Authors having equal contribution in this book chapter. Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00004-6 117 © 2018 Elsevier Inc. All rights reserved. 118 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION 4.2.9 Indirect Factors Affecting Physiological Factors of Drug Absorption 135 4.3 Conclusion 139 Acknowledgment 140 Abbreviations 141 References 141 Further Reading 147 4.1 INTRODUCTION The drug absorption process can be defined as the movement of drugs from the application site into the bloodstream via the physiological membrane or barrier. The eventual goal of the absorption process is to make the drug available at the specific site of action in a fitting concentration to produce the desired pharmacological action. In the case of systemic applications, the drug is available completely and consistently at the site of action in the appropriate concentration and therefore does not have any physiological barrier towards the absorption (Brahmankar and Jaiswal, 2015). Whereas, in the case of extended release drug formulations, it is desirable that the drug has to be positioned near the site of application for slow release and thereby leads to slow absorption (Rahul et al., 2017). On the other hand, in case of topical or local applications, it is desirable to minimize the systemic absorption to avoid severe systemic side effects (Costa, 2001). However, the anatomy and physiology of the physiological barriers has a great impact on the successful absorption of the drug from its formulation. Therefore, it is very important for a formulation scientist to judiciously consider the physiological conditions as well as pathologic factors during the fabrication of drug products (Sugano, 2012). The dosage form design many times depends on the routes of applications, such as oral, parenteral, topical, intranasal, pulmonary, ocular, vaginal, and uterine routes. However, all the routes have their own physiologic conditions including nature of cell membrane, pH differences, differences in splanchnic blood flow, transport processes (Nunn et al., 2012). The oral route is one of the utmost sensitive and complex routes of drug application where gastric emptying time, gastrointestinal motility, pH, presence of food and nutrients are the foremost constraints for the efficacious drug absorption at the site of action (Table 4.1). The oral route is considered safe, convenient, and dosage forms like tablet, capsule, sirup, suspension, emulsion, etc. can be self-administered. However, the major disadvantage is the slow onset of action of drug due to diminished absorption process. On the other hand, unpalatable drugs like quinine, clarithromycin, flucloxacillin usually have lesser patient compliance and can cause nausea and vomiting to the patients (Benet, 2013). The first pass effect or first-pass metabolism or presystemic metabolism is another major drawback of oral administration that can lead to excessive biotransformation and thereby cause diminished biological activity. Buccal and sublingual routes have great absorption rate and permeability of drugs, but the physicians recommend only small doses because of the limited surface area of mucosa (Meng, 2010). For unconscious patients, the rectal route is usually a better choice for the administration of drugs but is marred with irregular or incomplete absorption and also causes irritation to the rectal mucosa. Drug administration through parenteral route shows rapid onset DOSAGE FORM DESIGN CONSIDERATIONS 119 4.1 INTRODUCTION TABLE 4.1 Physiological Conditions of Gastrointestinal Tract (Washington, 2001) Parts of Gastrointestinal Tract pH Supply Membrane of Blood Surface Area Transit Time Buccal 6 Thin Good, fast absorption with low dose Small Short unless controlled Esophagus 6 7 Very thick 2 Small Short, typically a few seconds, except for some coated tablets Stomach 1.7 4.5 Decomposition, weak acid unionized Normal Good Small 30 min (liquid) 120 min (solid food), delayed stomach emptying can reduce intestinal absorption Duodenum 5 7 bile duct, surfactant properties Normal Good Very large Very short (6 inches long), window effect Small Intestine 6 7 Normal Good Very large 10 14 feet, 80 cm2/cm About 3 h Large Intestine 6.8 7 Good Not very large 4 5 feet Long, up to 24 h of action of drug molecule as the drug is injected directly into the bloodstream and also makes the drug 100% bioavailable. However, the major demerit of the route is withdrawal of drug from the body of patient is not possible, and it may also induce hemolysis, thrombophlebitis of vein, and necrosis of adjoining tissues (Pantuck et al., 1984). Topical drug delivery provides a constant plasma drug profile of the administered drug with the easy option to withdraw drug therapy by removing the transdermal patches or other formulations. Albeit the complex relationships between skin physiology, vehicle, and drug sometimes jeopardize the pharmacological effect of the formulation and can lead to severe allergic skin reactions (Keni et al., 2012). A prerequisite condition during drug formulation design is the selection of appropriate administration route, which needs extensive knowledge of biopharmaceutical properties of drug molecules. It is therefore pertinent to consider the physiological barriers that can affect the drug absorption from the site of application and overall can alter the biopharmaceutical aspects of the drug candidate and these are discussed in the following sections. 4.1.1 Events Involved in Drug Absorption 4.1.1.1 Physiology of Membrane The fluid mosaic model (Fig. 4.1) has been widely accepted for the perspective of the biological membrane which describes the diffusion of the transcellular polar molecules and the globular proteins to be embedded in a lipid bilayer matrix, dynamic fluid. These proteins act DOSAGE FORM DESIGN CONSIDERATIONS 120 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION FIGURE 4.1 Cell membrane structure (fluid mosaic model). as a pathway only for selective transfer of several charged ions and polar molecules through the lipid barrier. The model depicts that the trans-membrane proteins are interdispersed throughout the membrane causing pores of about 50 2 70 nm (Abuhelwa et al., 2016). 4.1.2 Pathways of Drug Absorption Drug absorption process includes three major routes, viz, enteral, parenteral, and topical. The enteral route comprises gastrointestinal, rectal, and sublingual routes. The topical route includes eye and skin, where drugs need to be applied topically, whereas the parenteral routes indicate all routes of administration under or through the skin. 4.1.2.1 Passive Diffusion 4.1.2.1.1 PASSIVE TRANSPORT: SIMPLE DIFFUSION Diffusion or transport across a cell membrane which does not need energy is usually known as passive transport. Although the cell membrane comprises a phospholipid bilayer, the inner and outer parts of a cell are aqueous in nature. The middle part of the cell membrane is a hydrophobic region and is a strong barrier to anything that is charged, large, and hydrophilic. On the other hand, hydrophobic molecules can diffuse easily through the cell membrane via simple diffusion owing to the hydrophobic nature (Arcizet et al., 2008). Therefore, the simple diffusion is considered to be the flow of small, nonpolar or hydrophobic molecules to a lower concentration gradient from a higher concentration without any energy expenditure or any other assistance (Fig. 4.2). However, sometimes the unassisted passage of hydrophilic molecules is also possible if their size is very small as these molecules can traverse the cell membrane (Wayman and Mattey, 2000). 4.1.2.1.2 PASSIVE TRANSPORT: FACILITATED DIFFUSION Integral membrane proteins help to transport highly charged polar and hydrophilic molecules across a concentration gradient through the process of passive facilitated diffusion. The phospholipid bilayers are spanned along with integral membrane proteins which connect the inner and outer side of the cell (Borbas, 2016). Carrier proteins and channel proteins are the two integral membrane protein types which assist in transporting the polar molecules and ions which cannot diffuse through the hydrophobic layer. Carrier proteins are bound to a molecule which can facilitate the transportation through the cell membrane. But the channel proteins create a passageway for the transportation of ions and molecules through the cell membrane (Fig. 4.3). This makes the passage of polar molecules via the hydrophilic tunnel of channel proteins created along the hydrophobic cell membrane (David, 2009). DOSAGE FORM DESIGN CONSIDERATIONS 4.1 INTRODUCTION 121 FIGURE 4.2 Pathways of drug absorption. FIGURE 4.3 Occurrence of passive transport during the transport across a concentration gradient. A large number of drugs can cross the biological membranes through passive diffusion. Diffusion takes place when there is a difference in concentration, i.e., the concentration of a drug is higher on one side of the membrane than the other side. The process of passive diffusion is an effort to balance the concentrations of a drug on both sides of the membrane (Larhed et al., 1997). The absorption of several drugs from the gastrointestinal tract often follows first-order kinetics, and therefore a concentration gradient can be established during the partition of drug into the lipid membrane (Fig. 4.4). DOSAGE FORM DESIGN CONSIDERATIONS 122 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION FIGURE 4.4 Passive transport with a concentration gradient. Fick’s first law of diffusion can describe the transport rate of drug across the membrane (Manfred et al., 1998): Rate of diffusion 5 dM=dt 5 D A ðCh 2 ClÞ=X. . . where, D: diffusion coefficient. Diffusion coefficient is related to the lipid solubility and size of the drug and the viscosity of the membrane, and the diffusion medium. A: surface area. Rate of diffusion increases with the increase in surface area X: membrane thickness. The diffusion process accelerates in case of smaller membrane thickness. For example, fast inhalation absorption process is observed in the lung due to the thin membrane. (Ch-Cl): difference in concentration. The apparent volume of distribution (V) is much higher in comparison with the concentration of drug in plasma or blood and will be relatively low in comparison with the concentration in the GI tract. 4.1.2.2 Active Diffusion 4.1.2.2.1 TRANSPORT AGAINST A CONCENTRATION GRADIENT The gradual difference in the concentration of solute between two areas is known as concentration gradient (Rhie et al., 1998). Passive transport is required by the cell when it requires transporting something along a concentration gradient. However, chemical energy is required if the transportation is needed against the concentration gradient (Lee, 2000). (Fig. 4.5). Active transport is a process of equalizing the concentration gradient which is assisted by the consumption of chemical energy. Molecules or ions are moved in a specific direction through integral membrane protein in the active transport system. For this purpose, three types of protein membranes, i.e., uniport, antiport, and symport are required to transport substances against the concentration gradient (Andrianifahanana et al., 2016). Uniport is a transmembrane protein which passes a molecule or an ion in one direction, whereas antiport passes one molecule or ion in one direction and simultaneously moves another substance in the opposite direction. On the other hand, symport can move two molecules or ions in the same direction (Lodish et al., 2000). Both antiport and symport can pass two distinct substances through the single integral membrane protein and hence come under coupled transport system. Most significantly, all the three protein types utilize chemical energy to trigger the active transport process. Thus, the process permits a cell to sustain the substance concentrations different from its surroundings (Ayrton and Morgan, 2001). DOSAGE FORM DESIGN CONSIDERATIONS 123 4.1 INTRODUCTION FIGURE 4.5 Integral membrane protein actively transports molecules or ions. FIGURE 4.6 Drug absorption by facilitated diffusion. 4.1.2.3 Facilitated Drug Absorption Facilitated drug absorption is a carrier-mediated system where there is no need for energy involvement. It is a much faster process in comparison to the passive diffusion process. Molecules can transport at a lower concentration from higher concentration due to the difference in the concentration gradient. Such process is a spontaneous passive diffusion of molecules or ions across the biological membrane via specific trans-membrane integral proteins (Fig. 4.6). Facilitated diffusion plays an insignificant role in absorption. One such example is the entry of glucose into RBCs by the facilitated diffusion. Absorption of vitamins B1, B2, and B12 also take place by the facilitated diffusion process (Macheras and Iliadis, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 124 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION Examples of some facilitated diffusion transporters: Equilibrative nucleoside transporter (ENT): Uptake of: 1. Nucleosides: purine and pyrimidine nucleosides (e.g., Cytidine, Uridine) 2. Nucleoside analogs: a. Antiviral drugs: Zalcitabine, Zidovudine, Lamivudine, Stavudine, etc. b. Anticancer drugs: Cytarabine, Floxuridine, Gemcitabine, etc. Glucose transporters (GLUT1 GLUT5): Uptake of glucose from the blood into cells or export of glucose from cells into the blood. GLUT also takes up dehydroascorbate into cells, which is then reduced intracellularly to ascorbate (Pao et al., 1998). 1. GLUT1-Red Blood Cells (RBC) 2. GLUT2-Hepatocyte 3. GLUT4-Skeletal muscle 4.1.2.3.1 ENDOCYTOSIS Endocytosis is an energy driven process wherein the small intracellular membranebound vesicles enclose some volume of material. The vesicles are formed by the folding of the plasma membrane of the cell to engulf the substance into the cell. The molecules are often transferred to other vesicles or lysosomes and digested. Some material can escape the process of cellular digestion and migrate to the basolateral surface of the cell, where it is exocytosed. It is believed that endocytosis is the primary mechanism of transportation of the macromolecules (Bach, 2005). CLASSIFICATION OF ENDOCYTOSIS Pinocytosis (Cell Drinking) Pinocytosis (“pino” means “to drink”) is a process by which the cell takes in the fluids along with dissolved small molecules. In this process, the cell membrane folds and creates small pockets and captures the cellular fluid and dissolved substances. The cell membrane then closes around this little pocket forming vesicles to trap the liquid and small molecules to take inside the cell. Such a vesicle fuses with a lysosome and the digestive enzymes break down the molecules so that it can be recycled (Germain, 2004). Phagocytosis (Cell Eating) Élie Metchnikoff discovered the process of phagocytosis (“Phago” derived from the Greek word “phagein,” means “to eat”) where cells engulf and digest larger molecules. Several projections known as pseudopodia come out of the cytoplasm which engulfs the molecule by trapping it inside a cellular vesicle and finally the cell membrane fuses around. The vesicle again attaches with a lysosome to break down the engulfed molecule. However, all cells cannot follow this process. White blood cells, amoebae, and a few other cells which can change their shape can participate in phagocytosis process (Freeman and Grinstein, 2014). Receptor-Mediated Endocytosis or Clathrin-Mediated Endocytosis Pinocytosis is a conventional procedure in the eukaryotic cells. The receptor-mediated endocytosis is the best endocytosis form to selective uptake the specific macromolecules. At the initial phase, macromolecules bind to specific cell surface receptors such as clathrin-coated pits. Pits DOSAGE FORM DESIGN CONSIDERATIONS 125 4.2 BARRIERS TO DRUG ABSORPTION FIGURE 4.7 Process of endocytosis (Wu, 2014). bud through the membrane to develop tiny clathrin-coated vesicles which contain the receptors and their bound macromolecules. Finally, clathrin-coated vesicles fuse with early endosomes and are driven for transportation to the lysosomes or recycled to the plasma membrane (Nassberger and DePierre, 1994) (Fig. 4.7). 4.2 BARRIERS TO DRUG ABSORPTION Mucin, a large polysaccharide, is the primary component of mucus formed of 500,000 Daltons subunits and contains a protein backbone with approximately 800 hydroxylated amino acids like serine and threonine. Majority of the hydroxyl residues are associated with side chains of the oligosaccharide to strengthen the backbone. The oligosaccharide chains consist of galactose, N-acetylgalactosamine, N-acetylneuraminic acid, acetylglucosamine (Laine et al., 2008). Due to the presence of 95% water, mucus can make close association with the hydrophilic surfaces. Smaller particles with size less than B600 µm are buried under the surface and firmly held because of the mucus stickiness. However, the mucus is secreted continuously to move the particles away from the mucosa. Larger molecules diffuse at a very slow rate and stay for longer periods with the mucosa. However, small hydrated molecules can easily transport through the mucus (Mitra and Kesisoglou, 2013). The viscosity and hydrophilicity of mucus oppose the equal distribution of molecules to the mucus layer from the lumen. There is limited diffusion of hydrophobic drugs into the mucus. Mucus can form several low-affinity interactions with toxins, drugs, or other substances available at the mucosal surfaces. The lipids of mucus, protein core of mucin, and the diffusing compounds can participate in hydrophobic interactions. Furthermore, the mucin contains carbohydrates which may impart various hydrogen bond donors and acceptors along with the potential site for ionic interactions (Oshima and Miwa, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 126 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION 4.2.1 Mucus Thickness Scientific studies reveal that mucus has two layers. Firstly, a firmly bound mucus layer connected with the epithelial glycocalyx and secondly, an overlying loosely adherent mucosal layer. The mucosal turnover time changes with the physiological surface area and can last from minutes to a few hours. For example, the gastrointestinal mucosal turnover time is quite long and has been estimated to be four to six hours in comparison with other mucosal surfaces (Schreiber et al., 2013). It is also reported that the adherent human gastrointestinal mucus layer is thicker (about 200 mm) in comparison with other mucosal sites like the airways (7 30 mm) adherent mucus. The greater thickness has been found in the stomach followed by the gastrointestinal segment which contains the large intestine and small intestine and comes after the stomach in term of mucus thickness. The adherent mucus layer thickness is in disparity to the loosely adherent layer thickness and does not depend on the degree of hydration or luminal activity (Macierzanka et al., 2014). This dissimilarity can also be assigned to the employed methods for the measurement of mucus thickness as only limited studies have been done in this regard, and these studies do not elucidate the discrepancy between individuals, physiological site, and species. The difference of mucus features with health and nutritional state also requires further research (Gustafsson et al., 2012). 4.2.2 Mucus Clearance In mucosal epithelium, the mucous layer acts as a semipermeable barrier. It permits the exchange of gases, water, and small molecules. On the other side, it prevents the transport of pathogen, bacteria, and other particulates. The gene carriers and drugs can target the tissue epithelial cells and should penetrate the barrier before the mucosal clearance removes them. However, due to the high viscoelasticity and stickiness of mucus, the transportation of particles becomes limited (Button, 2013). The absorption of drugs is usually influenced by the residence time between the drug and the epithelial tissue. The mucociliary clearance is inversely proportional to the absorption of administered drugs and therefore inversely related to the residence time (Hansson, 2012). 4.2.3 Unstirred Water Layer (The Steric Barrier) The network of mucin can act as size exclusion filter in case of larger compounds. The unstirred water layer and viscosity of the mucus have been found to be additional contributors in the steric properties of the mucosal barrier (Marrannes, 2013). Porter et al. (2007) has reported that this unstirred layer, owing to its poor flow properties, has been shown to remain relatively unmixed with the bulk fluid phase of gastrointestinal content. This frequently results in the generation of an acidic microenvironment adjoining to the brush border membrane which is estimated at only 25 µm thick layer in humans (El-Kattan, and Varma, 2012). Hence, for lipophilic molecules present in the bulk phase of the gastrointestinal content, this layer can present itself as a major diffusional barrier to enter into the brush border membrane due to their extremely low solubility in aqueous media (Pang, 2003). DOSAGE FORM DESIGN CONSIDERATIONS 4.2 BARRIERS TO DRUG ABSORPTION 127 4.2.4 Peristalsis (The Dynamic Barrier) The secretion of mucus is a continuous process which also acts like a shed. Therefore, a drug should diffuse upstream to reach and cross the epithelium. Concurrently, a horizontal flow is contributed along the mucosal surfaces through the peristaltic movement. The local effects can be exerted at the mucosal surface due to the drugs which are adhered to the outermost mucus layer (Gupta et al., 2009). Therefore, the mucosal barrier signifies a hydrophilic barrier to many lipophilic drugs envisioned for oral formulations. The formulation scientist needs to consider the mucosal thickness as well as the location of the mucus for drug delivery for efficient absorption into systemic circulation. 4.2.5 Nonmucosal Barrier to Drug Absorption 4.2.5.1 Skin as Barrier The skin provides the largest port between the human body and the external environment. In general, the skin is designed to allow very little entry, since other tissues like permeable epithelia of the GI tract and lung, offer the prime means of regulated entry into the body (Hänel et al., 2013). However, skin prevents excessive loss of water and other bodily constituents. Stratum corneum, the thin outer epidermis layer, provides the skin’s remarkable barrier properties. In case of other tissues in the body, the stratum corneum consists of corneocytes which are surrounded by an extracellular milieu of lipids organized as multiple lamellar bilayers. These structured lipids only allow the entry of lipid-soluble and low molecular weight drug molecules, but prevent excessive loss of water from the body and likewise, block entry of most topically applied drugs. This is a substantial challenge to administering medications through the skin either for local effects or as systemic therapy (Rook et al., 2016). As a barrier, skin keeps microorganisms and noxious chemicals out and body water in. Topical drugs, the first line treatment in dermatology, are applied in the expectation that the percutaneous absorption will be minimal and that systemic side effects will be negligible. But the fact is that the skin is not as pretty impermeable as often believed. Undoubtedly, drugs can be absorbed through the skin and yield either unwanted or intended systemic effects (Goebel et al., 2012). In recent years, many nanotechnology-based delivery systems have been proposed to enhance the absorption through skin which includes liposomes (Maheshwari et al., 2012) and polymer-based biocomposites materials (Tekade et al., 2017). 4.2.5.2 Nail as Barrier For the treatment of nail diseases, orally administered drugs are extensively used, and they are systematically distributed and subsequently reach the infected site of the nail bed. But unluckily, drugs like antifungals through systemic administration have been obstructed due to the limited blood circulation in the affected nail bed which results in low transport of drug. Many patients are not able to respond followed by oral therapy, resulting in severe adverse effects; hence the success rate is inadequate in treatment of nail diseases (Baswan et al., 2016). The nail plate creates a much longer diffusional pathway due to its thickness to deliver a drug. The restriction of drug penetration in a nail is due to DOSAGE FORM DESIGN CONSIDERATIONS 128 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION the stable bonds of disulfide, which is also the reason behind the hardness of nail. As a barrier, nail acts as a hydrophilic gel rather than lipophilic making it convenient for drug delivery systems across other body tissues having a bi-lipid membrane (Brown et al., 2009). The long treatment time and lack of efficacy of topical formulations is due to the chemical and physical differences between the stratum corneum and the nail plate. Therefore, any formulation prepared for such drug delivery must be according to physicochemical properties of the drug molecule, viz, charge log P, shape, size, etc., the formulation characteristics, viz, vehicle, pH, drug concentration, possible interactions between penetration enhancers, drug, and keratin (Smith et al., 2011). The nonmucosal barrier such as skin and nail, unlike the mucosal barrier, are more penetrable by lipophilic drugs. Therefore, the topical formulations are more apt for nonmucosal barriers while designing a pharmaceutical formulation. 4.2.6 Drug Transporters as Determinants for Drug Absorption The interplay of drug transporters and drug metabolizing enzymes is crucial for the overall pharmacokinetic profile of drugs or xenobiotics. Generally, for eliciting the desired activity, it is imperative to achieve desired intracellular concentration. This, in turn, is an outcome of coordinated events of several efflux and uptake transporters which facilitate the movement of drugs across biological membranes. Having established the pivotal role of transporters in governing the drug pharmacokinetics, the understanding of the transporters and their impact on drug predisposition is essential. These carrier-mediated transporters are widely known to be large, membrane-bound proteins expressed in tissues such as epithelia of major organs of secretion and absorption like intestine, liver, and kidney as well as brain, testes, and placenta (DeGorter et al., 2012). Broadly, they are classified into: solute carrier (SLC) superfamily; uptake transporters and ATP-binding cassette (ABC) transporter superfamily; and efflux transporters. Both these transporters are found to be expressed in epithelial cells (on both, basolateral and apical surfaces) that occur on the partition of various body fluid compartments (such as cerebrospinal fluid, urine, or bile), and in brain endothelial and as circulating cells in the blood (Nigam, 2015; El-Kattan, 2017). The various efflux transporters and substrates have been reported in Table 4.2. 4.2.6.1 ATP-Binding Cassette (ABC) Transporters It is a prominent class of multidomain integral membrane proteins which relies on ATP hydrolysis to translocate solutes like amino acids, ions, proteins, peptides, sugars, cholesterol, toxins, and metabolites across cellular membranes and implicated in resistance to pathogenic microbes to drugs and cancers (Löscher and Potschka, 2005). They are also known as primary active transporters which restrict the intracellular drug content by inhibiting the influx and facilitate the efflux. Broadly, they comprise of a family of genes which encode for various proteins (i.e., both exporters and importers) for translocation of substrates (Benadiba and Maor, 2016; El-Awady et al., 2016). They are further classified into P-glycoprotein (ABCB1, MDR1, P-up), multidrug resistance-associated proteins (MRPs) including nine members (MRP1 (ABCC1), MRP2 (ABCC2), MRP3 (ABCC3), MRP4 (ABCC4), MRP5 (ABCC5), MRP6 (ABCC6), MRP7 (ABCC10), MRP8 (ABCC11), MRP9 DOSAGE FORM DESIGN CONSIDERATIONS 4.2 BARRIERS TO DRUG ABSORPTION 129 TABLE 4.2 Factors Affecting Gastric Emptying (GE) Food Type Remarks Carbohydrates Decreases Fatty substances Decreases Food temperature Emptying rate of foods increases with increases in temperature Body posture Left side lying decreases emptying rate of food DRUGS Analgesic (e.g., Aspirin) Decreases Narcotic (e.g., Morphine) Anticholinergics (e.g., Atropine) Domperidone Increases Erythromycin Number of ingested consumables (in volume) Initial increase and followed by decreases of GE. Liquid type materials get emptied very fast (ABCC12)), and breast cancer resistance protein (ABCG2, BCRP). Some MRPs play a significant role in the intestinal drug absorption, although several transporters are found to be expressed in the enterocytes. Drugs often encounter MRP2, BCRP, and P-gp on brush-border membrane of the intestinal epithelia and MRP3 is expressed on basolateral membrane (Murakami and Takano, 2008). 4.2.6.1.1 ATP-BINDING CASSETTE (ABC) TRANSPORTERS SUCH AS P-GLYCOPROTEIN (P-GP) P-gp (MDR1; ABCB1), is a 170 kDa polypeptide, that confers protection to tissues from endogenous metabolites and toxic xenobiotics. It is one of the most researched transporters influencing the uptake and distribution of drugs. This transporter is responsible for shuttling the structurally dissimilar hydrophobic amphipathic compounds as well as peptides, therapeutic drugs, and lipid-like compounds. It is widely distributed across the blood brain barrier, pancreatic ducts, intestine, proximal kidney tubules, bile ducts, adrenal gland and it is overexpressed in most of the human cancers, contributing to the cancer chemotherapy resistance (Sharom, 2011; Amin, 2013). Although it is tough to comprehend the accurate mechanism of drug P-gp binding, it is widely believed that binding is based on an alternating access model. The protein comprises of two domains: two transmembrane domains (TMD) and two cytosolic nucleotide-binding domains (NBD) (Sharom, 2006; Ter Beek et al., 2014). It is reported that two ATP molecules bind between the NBDs at the respective binding sites where hydrolysis of ATP takes place providing energy for efflux of substrate through binding to TMD (Subramanian et al., 2016). Initially, the drug present in the intracellular environment binds to the inner-faced conformation from the membrane cytosolic side (TMD). Following which, using the energy derived from ATP DOSAGE FORM DESIGN CONSIDERATIONS 130 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION hydrolysis (catalyzed by NBD), the membrane switches to the outer-faced conformation thereby reorienting the binding site to the extracellular side, which results in drug expulsion (Sharom, 2014; Silva et al., 2015). Prominently, there are two widely known models to describe drug P-gp interaction; outwardly directed drug/lipid flippase model and hydrophobic vacuum cleaner model. According to flippase model, the drug first partitions into the membrane, following which it spontaneously translocates to the inner leaflet and interacts with the P-gp substratebinding pocket. After that, the drugs are projected to the leaflet of outer membrane where it rapidly undergoes passive diffusion into the extracellular aqueous phase (Higgins and Gottesman,1992; Helvoort et al., 1996). As per the vacuum cleaner model, it is assumed that the drug partitions into the membrane, followed by spontaneous translocation to the cytoplasmic leaflet, and interaction with the P-gp substrate-binding pocket within the interior bilayer (Higgins and Gottesman, 1992). After that, the drug is effluxed into the extracellular aqueous phase, which leads to rapid partitioning into the outer leaflet. Thus, in both theories, it is believed that the concentration gradient is generated due to disproportionate concentration of drug in both the leaflets resulting in rapid partitioning of drug from the membrane into the extracellular aqueous phase on either side of the membrane (Sharom, 2014; George and Jones, 2012). Various studies have been undertaken to establish the relevant descriptors for P-gp substrate interactions. Recently, using molecular dynamics simulation studies, Jagodinsky and Akgun (2015) reported that hydrophobic packing, hydrogen bonding, and the formation of cage by the aromatic residues throughout the drug were prominent mechanisms of interaction of cardiovascular drugs such as Amiodarone, Diltiazem, Nicardipine, Dipyridamole, Bepridil, Nifedipine, Propranolol, and Quinidine with P-gp protein. (Jagodinsky and Akgun, 2015). The extensive research undertaken by Seelig and coworkers elucidates that the interaction of a substrate with P-gp is a two-step process; first, the rate-limiting step of lipid water partitioning involving hydrophobic interactions; and then a cavity binding step in the lipid membrane occurring only through interactions of weak electrostatic hydrogen-bond. Recently, the group carried out a study using polyoxyethylene alkyl ethers with different numbers of ethoxy and methylene residues as substrates for model P-gp. The study demonstrated that the partitioning step of lipid water was governed by hydrophobic interactions which increase linearly with the methylene residues and decrease with the ethoxy residues. The cavity binding step needed at least two ethoxy residues and increased linearly with the ethoxy residues. The study outlined the polar part of the substrate formed weak electrostatic interactions with the cavity, and the hydrophobic part was shown to be linked with the lipid membrane. The interaction between the two types and the strength and number of the hydrogen bonds formed between the transporter and the substrate most likely effect the substrate flipping (Desai et al., 2012; Li-Blatterand Seelig, 2010, Seelig and Gatlik-Landwojtowicz, 2005). It is reported that van der Waals interactions are less prominent within the lipid environment. Hence, electrostatic or dipolar interactions between substrate-P-gp are thought to be dependent upon the dielectric constant of the membrane lipid core region. Reports suggested that weak electrostatic interactions within the membrane environment may include dipole dipole interactions between a cation and π-electrons of aromatic rings or H-bond DOSAGE FORM DESIGN CONSIDERATIONS 4.2 BARRIERS TO DRUG ABSORPTION 131 interaction. (Seelig and Gatlik-Landwojtowicz, 2005; Raub, 2006). The P-gp are pharmacologically and structurally different positively or neutral charged hydrophobic compounds. 4.2.6.1.2 ATP-BINDING CASSETTE (ABC) TRANSPORTERS SUCH AS MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS (MRPS) MRP (ABCC), 190 kDa polypeptide, are the second most significant human ABC transporter group which are applicable for drug transport (Murakami and Takano, 2008; Sodani et al., 2012; Fricker and Miller, 2002). In general, this transporter is responsible for effluxing lipophilic anionic xenobiotics, hydrophilic conjugated molecules and naturally occurring metabolites of physiological organic anions like cysteinyl leukotriene C(4) LTC (4), the conjugated estrogen, E217βG, glucuronosyl-, or sulfatidyl steroids and reduced and oxidized glutathione (GSH and GSSG) (Cole, 2014a,b).Specifically, endogenous compounds, such as (LTC(4) are transported by bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), MRP1/ABCC1, cGMP (MRP5/ABCC5, MRP4/ABCC4, and MRP8/ ABCC11), prostaglandins E1 and E2 (MRP4/ABCC4), to name a few (Zhou et al., 2008). MRPs are widely distributed across the blood brain barrier, proximal kidney tubules, pancreatic ductules, bile ductules, intestine, testes, lung, skin, placenta, peripheral blood mononuclear cells, skeletal muscle. It is also overexpressed in most of the human cancers, contributing resistance to the chemotherapy treatment (Bodó et al., 2003). Similar to P-gp, the transporters which contains nucleotide binding domains (NBD1 and NBD2) present between two TMD. Based on the structure, the MPs are broadly classified as short MRPs (MRP4, MRP5, MRP8, and MRP9) which are characterized by four domains comprising two TMD 1 and TMD2. They are followed by NBD1 and NBD2 and long MRPs (MRP1, MRP2, MRP3, MRP6, and MRP7) which are characterized by five domains and an extra domain, TMD0, located at the N-terminus of these transporters (Deeley et al., 2006; Slot et al., 2011). Since this transporter also transports hydrophilic substrates, it is postulated that the amino acids present in the TMDs contribute to the hydrogen-bonding resulting in the formation of interhelical and intrahelical ion pairs and hydrogen bonds between the substrate and the transporter TMDs. Although unclear, it is believed that both mediate the transport of molecules by MRP through ATP and GSH (Cole, 2014a,b). Owing to their capability to transport glutathione and glucuronate conjugates, their role in phase II metabolism and cellular detoxification is studied (Ishikawa, 1992). 4.2.6.1.3 ATP-BINDING CASSETTE (ABC) TRANSPORTERS SUCH AS BREAST CANCER RESISTANCE PROTEIN (BCRP) BCRP (ABCG2), is a 72 kDa polytopic transmembrane (TM) protein with 655 amino acids which is also called as placenta-specific ABC protein (ABCP) or mitoxantroneresistance protein (MXR) (Allikmets et al., 1998; Miyake et al., 1999). Unlike the previous transporters, this transporter is characterized by two unique features. First, it is considered a half-transporter having one TMD and NBD and is believed to homodimerize bridged by disulfide bonds function (Staud and Pavek, 2005; Doyle and Ross, 2003). Secondly, in BCRP domain, the NBD precedes the TMD, a stark different domain organization as observed to that of P-gp and MRP1 (Natarajan et al., 2012; Ni et al., 2010; Mao and Unadkat, 2015). In general, this transporter is associated with transport of lipophilic xenobiotics, hydrophilic conjugated anions. It is widely distributed across the blood brain DOSAGE FORM DESIGN CONSIDERATIONS 132 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION barrier, intestine, placenta, testes, pancreas, ovary, heart, liver, kidney, the population of primitive stem cells, human bone marrow, mammary gland. It is also widely overexpressed in most of the human cancers and thus contributes towards the resistance to chemotherapy treatment (Maliepaard et al., 2001; Jonker et al., 2005). Like the P-gp, the drug transport using this transporter is found to be dependent on ATP (McDevitt et al., 2009). Quality structure activity relationship study indicates that for drug interactions with BCRP, it is essential to have either one amine attached to one carbon of a heterocyclic ring or fused heterocyclic ring(s) and two substituents on a carbocyclic ring of the fused heterocyclic ring(s) on the substrate (Nicolle et al., 2009; Giacomini et al., 2010). A study involving 14 camptothecin (CPT) analogs demonstrated that for interaction with BCRP, molecules showed the presence of one hydroxy or amino group. It was hypothesized that the presence of amino and hydroxyl functional groups facilitated hydrogen bonding with the residues of amino acid present at the BCRP binding site (Yoshikawa et al., 2004). Similarly, substrate specificity of BCRP increases with greater number of hydrogen bond acceptors and the aromaticity and electronegativity of the C2 substitution (Kaliszczak et al., 2010). In general, P-gp, BCRP, and other efflux pumps substrates have a similar set of molecular properties (Varma et al., 2010). The drug transporters therefore possess a great barrier to drug absorption and also a threat to chemotherapeutic intervention. The mutation in these transportation proteins can lead to excessive drug resistance cases in bacteria and cancer. 4.2.7 Metabolism as Barrier to Drug Absorption Metabolism is widely associated with liver; however, literature implicates the role of the gut microflora and gut metabolizing enzymes in drug metabolism, absorption, and overall efficiency. It is well documented that together the gut microflora, intestinal mucosa, and gut-luminal fluids, are responsible for various enzymes which contribute to the oxidation, hydrolysis, and conjugation of drugs impacting the drug efficacy and safety (Stojančević et al., 2013). 4.2.7.1 Gut Luminal Enzymes The gut lumen comprises of enzymes present in the gut fluids and those secreted from the pancreas and intestinal membrane, namely, peptidases which catalyze the breakdown of peptidyl drugs such as Insulin, calcitonin, tera gastrin, to name a few. Besides, it contains esterase that catalyze hydrolysis of ester bonds presents in prodrugs (Gavhane and Yadav, 2012). 4.2.7.2 Gut Wall Metabolism by Cytochrome P450 These enzymes constitute alcohol dehydrogenase, mainly present in the stomach, that inactivates ethanol and Phase I and Phase II enzymes present in the intestinal and colonic mucosa (Gavhane and Yadav, 2012). Most of the enzymes included in Phase I and Phase II involve uridine diphosphate glucuronosyltransferases, cytochromes P450 (CYPs), sulfotransferases, glutathione S-transferases, acetyltransferases, esterase, alcohol dehydrogenase, and epoxide hydrolase. Among these, CYPs have been implicated in phase-I-dependent DOSAGE FORM DESIGN CONSIDERATIONS 4.2 BARRIERS TO DRUG ABSORPTION 133 drug metabolism of a large number of dietary molecules, endogenous chemicals, and drugs like steroids and carcinogens (Thelen and Dressman, 2009). These enzymes have shown variability in their distribution across the gastrointestinal tract, they are found in large numbers in the duodenum jejunum and then to a smaller extent in the ileum. Besides this, they have found to locate majorly in mature enterocytes lining the small intestinal villus tip and to lesser extent in the epithelial cells and goblet cells of the crypts between the villi (Watkins, 1997). Characteristically, CYP isoenzymes are enzymes containing heme and rooted particularly in the lipid bilayer of the endoplasmic reticulum of hepatocytes (Guengerich, 1992). CYP mediate the oxidative biotransformation of lipophilic xenobiotics and drugs (Zanger and Schwab, 2013). Although more than 50 CYP450 enzymes have been identified, it has been reported that only six members; CYP2C9, CYP1A2, CYP2C19, CYP3A4, CYP2D6, and CYP3A5 enzymes metabolize 90% of drugs (Lynch and Price, 2007). Among this, CYP3A4 is known to be present in large numbers in intestinal enterocytes and found to be accountable for the metabolic elimination of several drugs (Thummel, 2007). 4.2.7.3 Metabolism in Skin Being a physical barrier, the skin plays a vital role in protecting the body from xenobiotics. It has been established that skin comprises the metabolizing enzymes, located mostly within the epidermal keratinocytes, at lower levels in comparison to liver (Oesch et al., 2007). The study carried out (Van Eijl et al., 2012), revealed that skin was capable of carrying out phase I metabolism through series of reactions such as dehydrogenation, oxidation, reduction, hydrolysis, as well as phase II metabolism, illustrated by various forms of glutathione S-transferase. Besides this, the skin shows the presence of metabolizing enzymes such as flavin monooxygenases, cytochromes P450, sulfotransferases, and N-acetyltransferases (Svensson, 2009). Studies reveal that polycyclic aromatic hydrocarbons and their dihydrodiols are widely metabolized by CYP1B1 in the skin (Sharma and Uetrecht, 2014). Whereas, endogenous compounds like all-trans-retinoic acid, testosterone, 17-estradiol, and estrone have shown to undergo CYP2A6-mediated metabolism (Oesch et al., 2007). The flavin monooxygenases have shown to metabolize sulfamethoxazole, arylamines, and dapsone to aryl hydroxylamines in human epidermal keratinocytes (Vyas et al., 2006). 4.2.7.4 Microbial Metabolism In humans, diverse microflora composed of 1013 to 1014 microorganisms has been found to colonize on the skin, genitourinary, gastrointestinal, and respiratory tracts. Among these locations, the gastrointestinal tract, especially the colon, comprises almost 70% of the complete microbes in the human body (Sekirov et al., 2010). Commonly, the intestinal bacterial population in human comprises of obligate anaerobes belonging to the Clostridium, Bacteroides, Lactobacillus, Escherichia, Bifidobacterium, yeasts and many other microorganisms that forms an intricate ecosystem containing more than 1000 species (Wilson and Nicholson, 2009). It has been well-known that the role of these bacteria existing in the large intestine is to primarily to assist in the fermentation of carbohydrate and protein into absorbable energy. Most of the reductive, hydrolytic, acetylation, dihydroxylation, proteolysis, deacetylation, deglycosylation, and deconjugation processes included in the xenobiotics metabolism in the DOSAGE FORM DESIGN CONSIDERATIONS 134 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION intestine are mediated by microflora (Sousa et al., 2008; El-Kattan and Varma, 2012). Through a host of enzymes such as lyases, hydrolases such as proteases, glycosidases, and sulfatases, gut microbiota is known to metabolize numerous pharmaceuticals into metabolites with altered pharmacological properties (Koppel et al., 2017; Spanogiannopoulos et al., 2016; Swanson, 2015). Recently, gut microbiota has been shown to play a important role in the metabolism of drugs like simvastatin (Aura et al., 2011), prednisolone (Yadav et al., 2013), fostamatinib (Sweeney et al. 2013), tacrolimus (Lee et al., 2015), to name a few. 4.2.8 Lymphatic Absorption The lymphatic system is a closed and one-way system of lymph channels, through which flow of the lymph occurs and permits the tissue spaces of lymph to the blood. The lymphatic system is of two categories, firstly, the conducting system and secondly, the lymphoid tissue (Wiig and Swartz, 2012). The conducting system contains the lymph and tubular vessels which involve the lymph vessels, the right and thoracic ducts and the lymph capillaries. The lymph is transported back to the blood and replaces the lost volume of blood at the time of the interstitial fluid formation. These channels are usually called lymphatics (Barrowman and Tso, 2010). The lymphatic system has a significant role in the nutrients absorption. The absorption of fat from the GI tract occurs via the lymphatic system and also imparts a route for protein, fluids, and electrolytes, to be returned to the blood from the interstitial spaces. It is also accountable to remove the lost red blood cells from tissues due to hemorrhage or bacterial infection (Tancharoenrat et al., 2014). Due to the unique anatomy and physiology of the lymphatic system, targeting of drugs into the lymph has lots of advantages which involve first pass metabolism bypass, direct delivery of drugs to particular regions of the lymphatic circulation and the possibility of regulating the rate of drug delivery into the systemic circulation (Iqbal and Hussain, 2009). The factors that can affect apparent lymphatic transport include the physicochemical and metabolic properties of the drug, administration route, the site, the drug delivery design system. Therefore, several strategies to the lymphatic transport of the particulates, lipid vehicles, prodrugs must be evaluated for successful optimization (Porter and Charman, 2000). There is enormous anatomical and physiological difference in between the lymphatic capillaries and blood. The intercellular junctions are held tightly at the cellular level of blood capillaries, whereas it is less organized at the basement membrane of lymphatic capillaries and the junctions between the endothelial cells are much leakier. Colloidal particles such as chylomicrons and macromolecules are therefore selectively taken up from the interstitial space through the lymphatics. This represents a molecular sieving mechanism which can be utilized for the drug delivery (Ohtani and Ohtani, 2014). The anatomy and physiology of the lymphatic system also change at the various body parts. The small intestine lymphatics are characterized by centrally located lacteal present in the villi which further join lymphatic capillaries plexus and drain into the cisterna chyli through the mesenteric lymph vessel. The thoracic duct further drains the lymph from the cisternchyli that clears directly at the left subclavian veins and left internal jugular junction into the general circulation. This distinctive physiology allows the orally administered drugs to bypass the liver and prevent the first pass metabolism (O’Driscol, 1992). DOSAGE FORM DESIGN CONSIDERATIONS 4.2 BARRIERS TO DRUG ABSORPTION 135 4.2.9 Indirect Factors Affecting Physiological Factors of Drug Absorption 4.2.9.1 Food Habit Presence of food in the stomach increases splanchnic blood flow of few drugs, viz., propranolol, chloramphenicol, lithium carbonate. As a result, higher plasma concentration has been observed after food intake. However, the absorption of drugs like ampicillin, aspirin, L-dopa is reduced due to the presence of food. The splanchnic blood flow is reduced in hypovolemic state. Hence, absorption of the drug is also decreased gradually (Applegate et al., 2013). The bioavailability of oral drugs is often impacted by the presence of food in GI tract. The impact of food on the oral drug’s bioavailability include (Toothaker and Welling, 1980): • Delaying the gastric emptying time (Table 4.2). • Bile flow stimulation. • Chemical or physical interaction of drug substances with metal. The nutrient and caloric contents of the food influence drug product luminal dissolution, drug permeability, systemic availability, and transit time and influence the absorption of drug. • Splanchnic blood flow increase. • Variation in the drug’s luminal metabolism. • Change in the pH of GI tract. • Absorption of antibiotics like penicillin, tetracycline decreases when administered with food. When lipid soluble drugs, for example, Metaxalone, are administered with food, it increases the absorption of drugs. The bile flow increases with the solubility of fat-soluble drugs through micelle formation which gets stimulated due to the presence of food in the GI lumen. Absorption of basic drugs like Cinnarizine may sometime participate in rapid dissolution due to the presence of food in the stomach which decreases the pH and limited aqueous solubility (Hunt et al., 2015). Drugs which are irritating to GI mucosa, viz, NSAIDs, Aspirin, Erythromycin, etc., if given without food can diminish the irritation by lowering the drug absorption rate. Nondisintegrating, and enteric coated drug products cannot rapidly reach the duodenum due to the presence of food, thereby delaying the drug release and systemic drug absorption (Lücker et al., 1987). Absorption of water-soluble vitamins like folic acid and B-12 in the stomach are facilitated by complex formation with intrinsic factors. Absorption of calcium is smoothed by vitamin D by increasing calcium binding protein in the duodenum which binds calcium in the intestinal cell and transfers it to the blood circulation (Wilson et al., 2012). 4.2.9.2 Age and Gender Under the age of five, the ability to metabolize drugs is lower as it also is in the elderly, aged over 60 years. However, the actual changes vary according to the individual and their lifestyle. In the case of the fetus and the neonates (very young), a lot of metabolic routes are not entirely developed because the enzymes required by metabolic processes are not produced in sufficient quantities after birth. The high mortality rate has been DOSAGE FORM DESIGN CONSIDERATIONS 136 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION observed when Chloramphenicol is used in premature babies to treat bacterial infections. This high mortality rate is attributed to the low concentration of glucuronate transferase which catalyzes the conversion of the drug to its water-soluble glucuronate conjugates leading to the fatal levels concentration. However, the smaller body volume also means that smaller doses can be fixed to achieve the desired therapeutic effect. The ability of a person to metabolize drugs decreases with age. This decline in ability of a person to metabolize drugs is due to the physiological changes followed by aging (Lazzer et al., 2010). In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is low resulting in altered absorption pattern in comparison to adults. In elderly persons, causes of impaired drug absorption include altered gastric emptying, decreased intestinal surface area and GI blood flow, higher incidents of achlorhydria and bacterial over growth in small intestine. Different species often respond differently to a drug. The main reason for the different responses to a drug is due to differences in metabolism by members of different species. Such metabolic differences may take either the form of different metabolic pathways for the same drug, or different rates of metabolism with the same pathway. The deviations are thought to be due to enzyme variations, deficiencies, and sufficiency (Ruhnke et al., 2012). The metabolic pathway for both males and females is normally the same for a specific drug. However, in the metabolism of anxiolytics, hypnotics, and some other drugs, some sex-related differences have been observed. The rate of metabolism of some drugs, in case of pregnant women, may also show a few changes. For example, the metabolism of both the antipsychotic chlorpromazine and analgesic pethidine are reduced during pregnancy (Merchant et al., 2016). 4.2.9.3 Diseased Conditions Disease conditions which causes changes drug absorption in (Titus et al., 2013): • • • • • • • • • Gastric pH. GI motility. Changes in stomach emptying time. Secretion of bile. pH of intestine. Gut wall permeability. Alteration of normal GI flora. Secretion of digestive enzyme. Intestinal blood flow. Difficulty to swallow and significantly diminished GI motility has been reported in a patient with Parkinson’s disease. Diminish GI motility which retards absorption of drug has been observed in a patient using tricyclic antidepressants and antipsychotic drugs. Weak-base drugs like Dapsone stay undissolved in the stomach of an achlorhydric patient due to inadequate acid. Patients with acid reflux disorder show fluctuating drug absorption in case of drugs like proton pump inhibitors like Omeprazole, contribute stomach achlorhydric (Wilson and Bromberg, 1981). Patients suffering from HIV-AIDS diseases show some GI disturbances like diarrhea, enhanced gastric transit time. Congestive Heart DOSAGE FORM DESIGN CONSIDERATIONS 4.2 BARRIERS TO DRUG ABSORPTION 137 Failure (CHF) patients having persistent edema diminishes the flow of blood to the intestine and intestinal motility leading to reduced drug absorption, such as Furosemide. Reduced surface area and thicker gut wall in patients with Crohn’s disease causes impaired absorption, e.g., higher Propranolol plasma concentration (Dressman and Reppas, 2016). Drug metabolism is also affected by disease condition. Diseases such as cirrhosis and hepatoma that affect the liver will seriously impair the metabolism of some drugs. The less important centers for metabolism, like kidneys and lungs, will also affect the excretion of the resulting metabolic products (Tchambaz, 2004). In gastrointestinal disorders, the reduced gastric acid discharge and the simultaneous rise in gastric pH (the condition known as “achlorhydria”) has a major effect on the gastrointestinal emptying rate and the drug absorption. This situation is of major concern especially in case of acidic drugs that lead to its reduced gastrointestinal absorption (for instance aspirin). Celiac disease and the Crohn’s disease represents gastrointestinal disorders that are associated with the malabsorption disorder that effects the drug bioavailability. In the case of cardiovascular ailments, numerous changes associated with congestive heart failure affect the availability of a drug in the body. These conditions include pathological conditions like intestinal angioedema, reduced GI blood flow, reduced gastric emptying time and transformed GI-pH, GI-secretions, or altered microbiological flora of GIT. In the case of liver diseases (example: hepatic cirrhosis) the bioavailability of drugs that predominantly undergo substantial first-pass metabolism (example: propranolol) are hampered. 4.2.9.4 Gastric Emptying and Motility Numerous approaches are utilized to determine gastric emptying parameters, such as gastric emptying rate, gastric emptying half-life, and gastric emptying time. All these parameters are drastically affected by several conditions, such as presence of food, type of food with drug administered, type and stage of diseases, presence of other drugs (drug drug interaction concept) etc. For the case in hand, metoclopramide encourages the gastrointestinal residence and the absorption of swiftly water-soluble drugs. On the other hand, the anticholinergic drugs inhibit the gastrointestinal dwelling of drugs and promote the absorption of poorly water-soluble bioactives. In the meantime, the gastrointestinal transit time is the major factor that influences the absorption of drugs, a longer gastrointestinal transit time is required for the complete absorption of drugs. The gastrointestinal transit time is different for regions of the intestine (Fig. 4.8; Table 4.2). 4.2.9.5 Gastrointestinal pH The proportion of a drug that exists in the unionized form at the site of absorption is contingent upon its pKa and nature of the drug (acidic or basic), which is covered in pH partition hypothesis. The pH of GI fluid affects the drug absorption in numerous ways. The degranulation and disintegration of some drugs given as enteric coating medication is pH sensitive wherein its outer coat dissolves only in the intestine at specific alkaline pH. A large number of drugs whose aqueous solubility is influenced by pH of surrounding media are either weak acids (like phenytoin, pentobarbital, phenylbutazone, warfarin, tolbutamide, phenobarbital, etc.) or weak bases (chlorpromazine, propranolol, pentazocin, antipyrine, etc.). The weakly acidic drugs dissolve fast in alkaline intestinal pH; on the other hand basic drugs dissolve rapidly in the acidic gastric pH. It must also be noted that DOSAGE FORM DESIGN CONSIDERATIONS 138 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION FIGURE 4.8 Influence of transit time and blood flow effect on various types of drugs. the gastric pH too significantly influences the chemical stability of drugs. For instance, the acidic gastric pH promotes the degradation of penicillin-G and erythromycin. Hence, care must be taken in cases of such drugs when formulated as prodrugs, viz., carindacillin and erythromycin estolate, respectively. 4.2.9.6 Blood Flow Through GIT The gastrointestinal tract is abundantly supplied by the networks of blood vessels and the blood flow rate to gastrointestinal tract (known as splanchnic circulation) is almost 30% of the total cardiac output. Consequently, it assists in preserving sink conditions and offers the required concentration gradient for the absorption of drug by swiftly eliminating drug from the site of absorption (Fig. 4.8). 4.2.9.7 Gastrointestinal Contents (Type and the Amount of Food Material) The type and the amount of food material with which the medicine has been administered also expressively influences the absorption of drug. The phrase food drug interaction denotes the effect imposed by the presence of food type and its amount on the absorption of a drug. Such food drug interactions can delay the absorption of drug in the case of drugs like digoxin, aspirin, diclofenac, paracetamol, nitrofurantoin, etc. On the other hand, the decreased absorption of drug is detected in case of drugs like levodopa, penicillin, tetracycline, erythromycin, etc. when they are administered after a meal. The presence of food sometimes increases the drug absorption, for instance in the case of grieseofulvin, diazepam, vitamins etc. Notably, it was also found in some cases that the presence of food does not alter the rate of drug absorption as observed in the case of drugs like propylthiouracil, methyldopa, etc. DOSAGE FORM DESIGN CONSIDERATIONS 4.3 CONCLUSION 139 FIGURE 4.9 Sites for presystemic metaboolism and absorption of drug. The administration of a drug with a large volume of fluid results in improved dissolution pattern, fast gastrointestinal emptying rat and boosted drug absorption. In the case of certain drugs like erythromycin, the drug absorption is better when administered with a glass of plain water under the fasting state than when taken after the meals. The normal gastrointestinal constituents such as mucin (a protective mucopolysaccharides was observed to be interacting with certain drugs like streptomycin. It was also described that the bile salts influence the absorption of lipid soluble drugs like grieseofulvin, vitamins etc. It must also be noted that the presystemic metabolism (that comprises gut wall enzymes, luminal enzymes, mucosal enzymes, hepatic enzymes, and bacterial enzymes) is also one of the chief reasons for the diminished bioavailability of orally administered drug (Fig. 4.9). Consequently, it can be stated that the above discussed indirect factors can also significantly alter the drug absorption and the overall bioavailability of a drug. Therefore, these factors must be considered before the dosage form is formulated as well as being considered while making the prescription. 4.3 CONCLUSION Absorption of a drug is a complicated process, that depends on both the physiological conditions of the body and drug’s physicochemical properties. Therefore, for years scientists have been striving to improve these aspects to enhance the absorption of drug, thus to sort out and optimize some various drug candidates and promote development of drug consequently. Especially, permeability and solubility are essential physicochemical DOSAGE FORM DESIGN CONSIDERATIONS 140 4. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION properties that affect the process of drug absorption. Moreover, most other physicochemical properties like pKa, lipophilicity, log P value, molecular size, hydrogen bonding dynamics, etc. are all interrelated with permeability and solubility and eventually with the bioavailability of drug. Thus, permeability and solubility can be considered as the most important parameters as the “final bridge” toward drug absorption. On the contrary, physiological variables can also significantly influence the absorption properties of a drug. Drugs are absorbed in the unionized state that depends on the pH of GI; also, the varying intestinal transit time and gastric emptying rate can influence drug absorption. The drug is metabolized by enzymes present in intestine and liver as well as due to the gut microflora activity. Thus, the performance of oral drug formulations depends on the physicochemical properties as well as the in vivo delivery process of the drug. Moreover, formulation scientists have been exploring to enhance the oral bioavailability by the invention and utilization of new dosage form formulations. Improvement in formulation also depends on the physiological and physicochemical factors for the absorption of drug. This can be achieved by increasing the surface area of the drug particle and thereby varying its physicochemical properties. With the recognition of the physiological processes affecting absorption of a drug as well as the BCS characteristics of a drug, pharmaceutical scientists can speculate the absorption of a drug so that they can develop new formulations with maximum bioavailability. Factors affecting drug absorption are mainly focused on food effects and physiological properties. Other factors, like age, condition of a patient, and metabolism enzymes, affect the physiology of drug absorption. These factors will have an impact on the relationship between clinical response and drug intake. The process of aging is profoundly characterized by functional and structural changes of complete organ systems and leads to the diminished homeostatic capacity. Though the particular system function may be sustained during resting conditions, the decrease of a functional reserve is accountable for increased stress vulnerability. These variations lead to increasing the plasma elimination half-life. The aging also tends to have significant pharmacodynamic changes thereby increasing the sensitivity to drugs. The diminished functional reserve itself also results in an increase in sensitivity through impairing homeostatic compensatory mechanisms. Therefore, the knowledge of the aging effects on the efficacy of the therapeutic agents can significantly increase the prescribing quality. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant allocated to Dr. Tekade (Grant #ECR/2016/001964) for research work on gene delivery and N-PDF funding (PDF/2016/003329) for work on targeted cancer therapy. RT would also like to thank NIPER- Ahmedabad for providing research support for research on cancer and diabetes. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Dr. Acharya and Dr. Fernandes express gratitude to SPPSPTM, SVKM’S NMIMS for the seed grant support towards their research work on glycolipid based drug delivery approaches. Dr. Acharya also wishes to acknowledge UGC, New Delhi for the research grant [(F.30-376/2017 (BSR))] to work on chemo preventive measures of colon cancer. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 141 ABBREVIATIONS ABC ATP ABCP ABCC ABCG BCRP CHF CPT ENT GLUT GI GSH GSSG LTC MXR MRPs NBD NSAIDs P-gp SLC TMD TM ATP-binding cassette adenosine triphosphate ATP-binding cassette protein C subfamily of ATP-binding cassette G subfamily of ATP-binding cassette breast cancer resistance protein congestive heart failure camptothecin equilibrative nucleoside transporter glucose transporters gastro intestinal glutathione oxidized glutathione leukotriene mitoxantrone-resistance multidrug resistance-associated proteins nucleotide-binding domain nonsteroidal anti-inflammatory drugs P-glycoprotein solute carrier two transmembrane domain polytopic transmembrane References Abuhelwa, A.Y., Foster, D.J., Upton, R.N., 2016. A quantitative review and meta-models of the variability and factors affecting oral drug absorption—part I: gastrointestinal pH. AAPS. 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DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 5 Physicochemical, Pharmaceutical, and Biological Considerations in GIT Absorption of Drugs Venkat Ratnam Devadasu1, Pran Kishore Deb2, Rahul Maheshwari3, Piyoosh Sharma4 and Rakesh K. Tekade3 1 University of Hail, Hail, Saudi Arabia 2Faculty of Pharmacy, Philadelphia University, Amman, Jordan 3National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India 4Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India O U T L I N E 5.1 Introduction 5.2 Mechanism of Gastrointestinal Absorption of Drugs 150 5.4.3 Particles Size and Effective Surface Area 5.4.4 Polymorphism and Amorphism 5.4.5 Solvates and Hydrates 5.4.6 Salt Form of Drug 5.4.7 Ionization State 5.4.8 Drug pKa, Lipophilicity, and GI pH 5.4.9 pH Partition Hypothesis 5.4.10 Drug Stability 150 5.3 Barriers in GI Absorption of Drugs: An Overview 153 5.4 Various Physicochemical Factors Affecting Gastrointestinal Absorption of Drugs 155 5.4.1 Chemical Nature 157 5.4.2 Drug Solubility and Dissolution Rate 158 Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00005-8 5.5 Pharmaceutical Factors 5.5.1 Disintegration Time 149 159 160 160 160 161 161 162 162 163 163 © 2018 Elsevier Inc. All rights reserved. 150 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS 5.5.2 Dissolution Rate 5.5.3 Manufacturing Variables 5.5.4 Nature and Type of Dosage Form 5.5.5 Pharmaceutical Ingredients 5.5.6 Product Age and Storage Conditions 5.6 Biological Factors 5.6.1 Membrane Physiology 5.6.2 Gastrointestinal Physiology 163 164 164 165 5.6.3 5.6.4 5.6.5 5.6.6 Age Gender Disease State Presence of Other Drugs 173 173 173 173 5.7 Conclusion 174 167 Acknowledgment 174 167 167 168 Abbreviations 175 References 175 5.1 INTRODUCTION Drugs are administered in the form of formulations or dosage forms. These formulations contain at least one other inactive ingredient termed as excipient, primarily to facilitate dispensing of proper dose of the drug to the patient (Dressman and Reppas, 2016). However, the excipients have evolved eventually to modify the drug release properties. The preferred route of administration for conscious adult is oral dosage form most of the times which is due to the ease of administration. While there are several advantages of administering drugs through this route there are certain limitations also. The main hurdle in drug delivery through oral route is poor absorption of some drugs and first-pass metabolism (Chillistone and Hardman, 2017). Drug absorption is the amount of drug that reaches the systemic circulation in the unchanged form through various routes of drug administration. For more understanding, drug absorption can be defined as the “process of movement of drug from the site of administration to systemic circulation.” Drugs are absorbed through the gastrointestinal tract when administered orally (Ashford, 2017) (Fig. 5.1). While considering the gastrointestinal absorption of drugs, it is also important to understand the complete pharmacokinetics and all other processes involved in eliciting the therapeutic effect. The acronym “LADMER” can be used to describe them. LADMER is liberation, absorption, distribution, metabolism, excretion, and response. Liberation of the drug from the formulation is a prerequisite for the absorption of drugs. This means absorption is dependent on the liberation which in turn is dependent on physicochemical properties, pharmaceutical and biological parameters of the drug, and the gastrointestinal tract (GIT) (Cunningham et al., 2014). These factors are described in the following sections. 5.2 MECHANISM OF GASTROINTESTINAL ABSORPTION OF DRUGS Drugs once liberated from the dosage forms in the GIT are supposed to be in molecular dispersion form or solution form and ready for absorption. There are reports nowadays suggesting that the drug is not required to be in solution form for absorption as this is the DOSAGE FORM DESIGN CONSIDERATIONS 5.2 MECHANISM OF GASTROINTESTINAL ABSORPTION OF DRUGS 151 FIGURE 5.1 Schematic depiction of oral absorption of drug. The process of drug absorption involves the breakdown of ingested dosage form as a first step followed by deaggregation. After that dissolution takes place in GIT, followed by the absorption of drug via absorption sites to reach systemic circulation and produce clinical effects. case with nanoparticles of drugs that are absorbed intact (Siepmann et al., 2016). However, it is understood that the nanoparticles will dissolve and release the drug product contents at the action site to elicit any therapeutic effect or response (Kumar Tekade et al., 2015; Lalu et al., 2017). Once the drug is in solution form, for most of the dosage forms, it can cross the GIT through passive transport, active transport, or cytosis. Drugs are absorbed in a similar way to the absorption of nutrients through GIT (Keogh et al., 2016). Passive transport is the movement of drugs across the cell membranes without the need for energy. Passive transport can be of two types, namely passive diffusion and facilitated or carrier-mediated diffusion. Passive diffusion is the major mechanism through which most of the drugs are absorbed (Smith et al., 2014). Diffusion is described by Fick’s law, which says that the rate of diffusion is proportional to the concentration gradient. R 5 DA ∆C ∆X (5.1) In equation (5.1), R is the rate of diffusion in moles/ s, A is membrane area through which drug is being transported, ∆C is the concentration gradient between the two sides of the membrane, ∆X is the membrane thickness, and D is a constant known as the diffusion coefficient. DOSAGE FORM DESIGN CONSIDERATIONS 152 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS The thickness of the membrane and area cannot be altered because they are subject to related parameters but we can choose the drugs to have high D and ∆C to increase the rate of diffusion. The diffusion coefficient of the drug is determined by many factors but solubility and molecular weight are important factors governing this parameter (Ashford, 2017). Solubility in water and lipid are equally important as both sides of the membrane are aqueous in nature and the membrane itself is lipidic in nature. The solubility in lipid is estimated by the partition coefficient and diffusion can be explained by the pH-partition hypothesis which is discussed later in this chapter. Another type of diffusion known as facilitated or carrier-mediated diffusion takes place with the help of membrane proteins. These membrane proteins are known as permeases. A typical example of a compound that is transported by this type of diffusion is glucose. Similar to the passive diffusion this type of transport doesn’t need any energy (Li et al., 2015). However, there is a difference when compared to passive diffusion that this process can be saturated as the permeases can be utilized fully at certain concentration, and after that increasing the concentration will not help in increase in the diffusion rate, which is the rate-limiting step in the process of absorption. Examples of drugs that utilize this mechanism include amoxicillin and cyclacillin which show saturable kinetics (Kell and Oliver, 2014). Active transport needs energy to make it happen. Active transport is possible from lower concentration to higher concentration, unlike diffusion mechanism. Adenosine triphosphate (ATP) hydrolysis provides the energy required for this process. Active transport is selective in a sense that drugs structural similarities with endogenous substances that are transported through this process are benefited. These drugs are usually absorbed from specific sites in the small intestine (Choonara et al., 2014). Active transport is of two types, namely primary and secondary. Primary or direct active transport uses metabolic energy directly, while secondary active transport, also known as coupled transport or cotransport uses electrothermal potential created by the ions across the membrane. This is again the two types known as antiport and symport (Rafiq et al., 2016). Movement of ions and molecules in one direction is termed symport and movement in the opposite direction is termed antiport. Examples of drugs that are absorbed through active transport are 5-fluorouracil, methyldopa, and levodopa. Larger molecules are sometimes not able to cross the membranes either by diffusion or active transport as the pores in the membrane are too small for them to cross. In these cases, the molecules are taken up by the process known as cytosis. In this process membrane forms envelop surrounding the larger molecule or particles. There are three main variants of this process that occur in the cells (Tari et al., 2017). They are phagocytosis, pinocytosis, and receptor-mediated endocytosis. Phagocytosis occurs when the cell engulfs and internalizes a solid particle or cell. Pinocytosis occurs when a large volume of extracellular fluid is taken as vesicles into the cells. Receptor-mediated endocytosis happens with the help of receptors on the cell surface to which the drug adheres and is then taken up into the cell. Oral poliovirus vaccine and high molecular weight peptides are absorbed through cytosis (Morishita et al., 2016). Drugs can enter the blood circulation from GIT either through the paracellular pathway or transcellular pathway. In the paracellular pathway, the drug will be passing over the tight junctions present in the cellular and transcellular pathway. The drug crosses the cell DOSAGE FORM DESIGN CONSIDERATIONS 5.3 BARRIERS IN GI ABSORPTION OF DRUGS: AN OVERVIEW 153 FIGURE 5.2 Mechanisms involved in absorption of drugs through GIT. Mostly, the drugs are absorbed in the blood through two pathways: paracellular and transcellular. In the paracellular pathway, the drug will be passing over the tight junctions of the cell membrane. In the transcellular pathway, the drug molecules are absorbed either through passive diffusion or carrier-mediated transport. Large molecules such as proteins and peptides are not able to cross the membranes either by diffusion or active transport as the pores in the membrane are too small for them to cross, such molecules are mostly absorbed by the process of endocytosis. membrane of the GIT epithelial cells and reaches the blood circulation (Kell, 2016). Fig. 5.2 illustrates various types of mechanisms involved in absorption of drugs through the gastrointestinal tract. 5.3 BARRIERS IN GI ABSORPTION OF DRUGS: AN OVERVIEW When a drug is being absorbed it crosses many layers of cells from the site of absorption to the blood. As we discussed in the previous section, drugs can be transported paracellularly or transcellularly. The barrier the drugs encounter is the cell membrane when it is being absorbed through the transcellular route. The junctions between the cells are the barriers in the paracellular pathway. As the cell membrane has distinct roles in protection of cell contents and in providing sufficient nutrition it will allow only certain molecules to cross the membrane (Maheshwari et al., 2012). Sometimes the drugs also need to cross the epithelia that are present in most of the organs or at least the blood vessels to enter the blood Fig. 5.3 illustrates the various intestinal barriers present in absorption of drug molecules. As the cell membrane retains the cell contents, it only permits specific molecules to pass through the cell contents in a controlled fashion. Electron micrographs of the cell membrane indicate that the cell membrane is a bilayer lipid membrane having 3 nm width and 8 12 nm thickness. The widely accepted model of the cell membrane is the fluid mosaic model (Labhasetwar, 2016). It suggests that proteins are interspersed within phospholipids. The lipid bilayer is a liquid crystalline in nature. In this, the tails are in the center and the heads are in the aqueous environment. By varying the contents of the fatty acids, membrane cells can modulate their fluidity. The sterols which are fatty in nature are present in cell membranes at varying concentrations. In animals cholesterol is the main sterol of the cell membranes (Maheshwari et al., 2015b). DOSAGE FORM DESIGN CONSIDERATIONS 154 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS FIGURE 5.3 Schematic illustration of various intestinal barriers present in absorption of drugs. Diagram represents various organs through which a solid dosage form gets passed. Most of the drugs are absorbed through the small intestine. There are several intestinal barriers present through which the drug molecules pass to reach the systemic circulation; various barriers include mucus layer, glycocalyx, microvilli, enterocytes, lamina propria, and cellular capillaries. Integral and peripheral are the two types of proteins existing in the cell membranes. Integral proteins consist of lipophilic groups, so are surrounded in the lipoid membrane. Conversely, peripheral type of proteins are absorbed over the membrane surface. Spectrin and ankyrin are the examples of peripheral type of proteins (Rebmann et al., 2016). Transport proteins are integral proteins and are responsible for the transport of substances in and out of the cell. Cell surface receptors are also part of the integral proteins. Glycoproteins (GPs) are also one of the important examples of integral type of proteins. GPs are mainly accountable for immunological actions of the cells. Epithelia consist of some layer structural proteins normally collagen that is called as the basal lamina on which epithelial cells sit. Epithelial cells are polarized owing to their unequal dissemination of transporter proteins. This leads to the differences in the transportation ability of the epithelial cells in the apical and basolateral membrane. Sometimes the nutrients are transported by the carrier-mediated mechanisms into the cell, but at the basal side, the contents are transported out of the cellular membrane and reach the systemic circulation through various transporter proteins (Sansom et al., 2016). Cells are interconnected with tight cellular junctions. These cellular membranes are mostly not interconnected very closely, but they are spaced irregularly with around 20 nm between them. This irregular space is filled with glycocalyx, GPs, and fibronectins. This space is also filled with the extracellular fluid and is comparatively more permeable so the smaller sized drug molecules can cross the cell layer easily (Bennett, 2016). A typical example is an intramuscular injection from which the drug rapidly diffuses into muscular cells and into the blood circulation. In epithelial cells, the junctions are more close and tight with the presence of tight junctions (zonulae occludens), gap junctions, and desmosomes (zonulae adherens) (Guo et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 5.4 VARIOUS PHYSICOCHEMICAL FACTORS AFFECTING GASTROINTESTINAL ABSORPTION OF DRUGS 155 Tight junctions are belt-like structures forming with the interaction of particular proteins intracellularly between two neighboring plasma membranes. The tight junctions will bring the cells as close as 2 Å. These junctions can be disrupted to increase the permeability by certain enzymes causes proteolysis with chelation of Ca21 and Mg21. Tight junctions are important to maintain the specific barrier functionality of the epithelial cells of the intestine. Gap junctions are present in most of the cells as these were present in most animal cells and act as a means of communication between cells and exchange cytoplasm. The cells are brought closer by 2 3 nm in these junctional gaps. These junctional gaps have connexins proteins that form pores through the cell membranes. Desmosomes are other important cell junctions that are highly rich in tissues exposed to mechanically stressed condition (Zihni et al., 2016). 5.4 VARIOUS PHYSICOCHEMICAL FACTORS AFFECTING GASTROINTESTINAL ABSORPTION OF DRUGS Physicochemical properties of the drug have tremendous effect on the absorption of drugs. These parameters are often taken into consideration while screening for a compound’s success as a drug in drug discovery. Many of the new drug candidates fail to possess optimum physicochemical properties and they fail as drugs. Chemical modification and drug delivery strategies sometimes help in developing a successful drug if the lead compound is found to have pharmacological activity (Chillistone and Hardman, 2017). Various physicochemical factors which affect the absorption of drugs are illustrated in Fig. 5.4. Chemical nature Drug solubility Drug stability Dissolution rate Physicochemical factors Pka and pH Ionization state Particle size and effective surface area Polymorphism and amorphism Salt form of drug Solvates and hydrates FIGURE 5.4 Illustrations of various physicochemical factors affecting drug absorption. DOSAGE FORM DESIGN CONSIDERATIONS 156 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS Solubility, permeability, and stability of the molecule can influence the absorption of the drug from GIT. These three parameters are affected by many factors that are related to physicochemical and pharmaceutical factors of the drug and biological properties of the GIT (Siepmann et al., 2016). Biopharmaceutical classification system of the drugs is classified on the basis of solubility and permeability characteristics. It has been proposed to get the bioequivalence waiver if the drugs meet certain criteria. This system can be utilized to understand the absorption of drugs based on solubility and permeability. According to this classification system drugs are classified into four categories, namely class I, II, III, and IV (Bou-Chacra et al., 2017). Class I are highly soluble and highly permeable, class II are poorly soluble and highly permeable, class III are highly soluble and poorly permeable, and class IV are poorly soluble and poorly permeable. This concept explores the dosing, dissolution profile, and absorption properties of the drug product given by the oral route. These three numbers are dependent on various physicochemical properties and stability (Vasconcelos et al., 2017). The US food and drugs administration (USFDA) and other regulatory agencies use this classification system to eliminate the requirement of performing costly bioequivalence studies of Class I drug product (Table 5.1; Fig. 5.5). Moreover, in case of in vitro dissolution, the main driving force is concentration gradient and the condition is called nonsink conditions. In contrast, in the in vivo conditions the dissolution is always more rapid than in vitro. This is because that in the body the drug dissolves rapidly and is quickly taken up into systemic circulation. Some concentration gradient is always maintained and Cs is .. Ct. Therefore, in the case of dissolution rate studies to achieve a good correlation between in vitro and in vivo, the in vitro studies should always be done under “sink conditions.” A diagrammatic representation of the effect of conditions on absorption is shown in Fig. 5.6. In general, in the in vitro studies sink conditions are always maintained that Ct is always less than 10% of Cs. TABLE 5.1 Different Classes of Biopharmaceutical Classification System With Their Characteristics Rate Limiting Solubility/ Class Permeability Absorption Step Techniques to Enhance Solubility I High/high Well absorbed Gastric emptying No treatment required Acetaminophen, Metoprolol, Diclofenac sodium, verapamil II Low/high Variable Dissolution Precipitation, Salt formation (Pramod et al., 2016) Carbamazepine, Digoxin, Griseofulvin, Spironolactone III High/low Variable Permeability Micronization, use of Surfactant (Rahul et al., 2017) IV Low/low Poorly absorbed Case by case Examples Bisphosphonates, Captopril, Insulin, Furosemide Neomycin, Taxol Nanotechnology-based approaches such as liposomes, solid lipid nanoparticles, carbon nanotubes, exosomes, dendrimers and nanoparticles (Maheshwari et al., 2017) DOSAGE FORM DESIGN CONSIDERATIONS 5.4 VARIOUS PHYSICOCHEMICAL FACTORS AFFECTING GASTROINTESTINAL ABSORPTION OF DRUGS 157 FIGURE 5.5 Illustration of Biopharmaceutical Classification System (BCS) with examples. Class I (green color), maximum solubility and maximum permeability class; Class II (red color), maximum permeability but minimum solubility; Class III (green and white), maximum solubility but minimum permeability and; Class IV (white), Minimum solubility and minimum permeability. FIGURE 5.6 Dissolution and sink conditions. (A) In vitro dissolution pattern; (B) Release pattern under nonsink condition; (C) In vivo dissolution pattern; (D) Release pattern under nonsink condition. Furthermore, another rule that is Lipinski’s rule of five says that the absorption of a drug product is poor in cases where the Log P . 5, molecular weight . 00 Daltons, hydrogen bond donors .5, and hydrogen bond acceptors .10 (Lipinski, 2016). These important physicochemical properties that affect the drug absorption are discussed in the following sections. 5.4.1 Chemical Nature Drug’s chemical nature can govern the solubility, permeability, and stability. Drugs fall into various types of chemical classes. Most important classes are acids and bases. Acids DOSAGE FORM DESIGN CONSIDERATIONS 158 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS and bases are best solubilized in their salt forms and can result in increased absorption of these types of drugs. The soluble salts forms of penicillin have increased absorption in comparison to freely acidic form (Sharma, 2016). However, this is not applicable to salts of the basic drugs as the pH of the stomach is very low. The low pH diffusion layer that is formed by the dissolution of the weakly basic drug might not drastically affect further dissolution as the pH of the stomach is very low. However, salts of weak bases are used for ease of handling and solubility but not for improved dissolution (Vioglio et al., 2017). Chemical nature can sometimes have an effect on the drug’s permeability. The lipophilicity of and partition coefficient of the drug, which are related to the chemical nature, are the most important factors that affect permeability. These are explained in Section 5.4.8. Chiral molecules will have the same physicochemical properties but their absorption can be stereospecific if there is a stereoselective carrier for the transport of the molecule (Wang et al., 2016). Drugs that are unstable in GIT undergo one of three processes, namely hydrolysis, oxidation, and reduction. These reactions are driven by pH, GI, and intestinal enzymes catalysis. The stability of the drugs can be increased by chemical modification. For example, acidic drug’s stability can be increased by the ester form that is hydrolyzable after absorption to release the drug. Or for drugs that are unstable in acidic pH like erythromycin, an enteric coated dosage form will be helpful in increasing the absorption (Ansari and Parveen, 2016). 5.4.2 Drug Solubility and Dissolution Rate Solubility is the major contributor to the absorption of drugs. Any drug molecule needs to be in the form of molecular dispersion before absorption with a few exceptions where the drugs are delivered as nanoparticles. For compounds with limited solubility, the supersaturation of the intestinal fluid plays a major part in their absorption (Grohganz et al., 2014). Values of desired solubility correlated with therapeutic dose are presented in Table 5.2. The maximum absorbable dose (MAD) theory has been developed to understand the role of solubility on drug absorption of many compounds. It is a useful tool to correlate the drug absorption by the concept of MAD. It is expressed as: TABLE 5.2 Summarizing Different Solubility Values and Impact on Permeability Desired Solubility Values for Drugs With Dose (mg/kg) High Permeability (mg/mL) Medium Permeability (mg/mL) Low Permeability (mg/mL) 0.1 1 5 21 1 10 52L 207 10 100 520 2100 DOSAGE FORM DESIGN CONSIDERATIONS 5.4 VARIOUS PHYSICOCHEMICAL FACTORS AFFECTING GASTROINTESTINAL ABSORPTION OF DRUGS mg 1 MAD mg 5 S 3 Ka 3 SIWVðmLÞ 3 SITTðminÞ mL min 159 (5.2) Where S is solubility (pH 6.5); Ka 5 intestinal absorption rate constant; SIWV 5 small intestinal water volume; SITT 5 small intestinal transit time. 5.4.3 Particles Size and Effective Surface Area Particle size plays a crucial part in determining the dissolution rate and thus the absorption of the drug. All the solid dosage forms that are administered orally contain particles of drugs. These particles need to be solubilized before the drug can get absorbed into the systemic circulation. Particles with large size will have a small surface area when compared to particles that have a small size (Maheshwari et al., 2015a; Sharma et al., 2015). The role of particle size in drug dissolution can be explained by the Noyes Whitey equation (proposed in 1987) (Eq. (5.3) which is as following: dm DS 5 ðCs 2 CtÞ dt Vh (5.3) Where, dm/dt 5 rate of dissolution; D 5 diffusion coefficient; S 5 surface area of drug; h 5 diffusional layer thickness; Cs 5 saturation solubility of drug; Ct 5 drug concentration in solution, and V 5 volume of dissolution medium. From this equation, it can be understood that the surface area has a direct relationship with the dissolution rate, meaning higher surface area increases the dissolution rate. Reducing the particle size is known as micronization (Tonnard and Verpaele, 2017). Particle size and surface area are inversely proportional to each other, that is, the smaller the particle the greater the surface area. A drug dissolves rapidly when it has larger surface area of particles. Two types of surface area are important (Absolute/effective) (Javadzadeh et al. 2015). Absolute surface area is the total surface area of any particle, whereas effective surface area is the surface area of any particle exposed to the dissolution medium. For use in absorption studies, the effective surface area is of much more importance than absolute as dissolution is thought to take place at the surface area of the solute. To increase the effective surface area up to a very acceptable extent we have to reduce the size of particles up to few microns. But the most important thing to be considered is the type of drug that is to be micronized (hydrophilic or hydrophobic). In case of hydrophilic drugs, small particles have higher energy than the bulk resulting in an increased interaction with the solvent. For example, Griseofulvin (dose can be reduced to half due to micronization), Spironolactone (dose can be decreased to 20 times), Digoxin (bioavailability is 100% in micronized form). In the case of hydrophobic drugs, micronization may result in decreased effective surface area and therefore reduction in dissolution rate. The hydrophobic surfaces of the drugs adsorbs air on to their surface which inhibits their wettability. The particles reaggregate to form large particles, which either float on the surface or settle on the bottom of the dissolution medium. This, in turn, develops charge followed by electrically associated agglomeration which prevents intimate contact of the drug with the dissolution medium. More recently, studies to develop nanoparticles of drugs that can dissolve very rapidly are DOSAGE FORM DESIGN CONSIDERATIONS 160 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS being undertaken. Increases in absorption for some drugs like sirolimus, megestrol acetate are observed when the particle size was reduced to nanosize (Lowell and Shields, 2013). 5.4.4 Polymorphism and Amorphism Polymorphism is the ability of a compound to exist in at least two different arrangements or crystal habits. Polymorphism is very common in drugs with at least one-third of them exhibiting it. Different polymorphs will have different dissolution rate and solubility and it is of utmost importance when the dissolution is the rate-determining step in the absorption process (Brittain, 2016). They exist in metastable and stable forms. Metastable forms generally have low melting temperature and have better dissolution rate. A new polymorphic form of metoprolol has been discovered recently and it is found to have better dissolution rate than form I. The classic example for differences in solubility and thus absorption is different polymorphs of chloramphenicol (Mellor et al., 2013). Amorphous forms of the drugs are the solid forms that have no long-range order or crystal lattice structure. These materials are thermodynamically unstable and tend to form crystals with time. It will have the highest free energy when compared to any available polymorphs. Unlike the improvement in solubility which is just two-fold in the case of different polymorphs, the solubility improvement of amorphous material ranges from less than 2- to 100-fold. The dissolution rate of amorphous materials is higher than that of crystalline forms because they don’t need any energy to break up the crystal lattice (Persson et al., 2010). Drugs like hydrocortisone and prednisolone are marketed in amorphous form for this reason. To keep the amorphous material stable they are generally made as coamorphous materials for enhanced absorption, especially for poorly soluble compounds. 5.4.5 Solvates and Hydrates Solvates are the crystal structures of molecules with solvent molecules. If water is the solvent molecule in the crystal then it is termed as a hydrate. These solvates are generally termed as pseudopolymorphs. As a general rule anhydrous forms are more soluble than hydrates. Carbamazepine and ampicillin are the best examples of higher solubility with anhydrous forms (Aitipamula et al., 2012). 5.4.6 Salt Form of Drug Mostly drugs are developed as salts of weak bases or weak acids to have good solubility and absorption. These salt forms are ionizable and therefore their solubility is pH dependent. The following equations can be derived to understand the pH-dependent solubility of the drugs from the dissociation of monoprotonated conjugate acid from a base. Its dissociation can be expressed as Eq. (5.4): 0 ka BH1 1 H2 O " B 1 H3 O1 DOSAGE FORM DESIGN CONSIDERATIONS (5.4) 5.4 VARIOUS PHYSICOCHEMICAL FACTORS AFFECTING GASTROINTESTINAL ABSORPTION OF DRUGS 161 0 where BH1 is the protonated species, B is the free base, and ka is the apparent dissociation constant of BH1, which can be written as Eq. (5.5). 0 ka 5 ½H3 O1 ½B ½BH1 (5.5) At any pH the total concentration of a compound ST, is the sum of the individual concentrations of its respective species (Eq. (5.6)): ST 5 BH1 1 ½B (5.6) At low pH where the solubility of BH1 is limiting, the following relationship holds Eq. (5.6): 0 1 1 ka ST ; pH , pHmax 5 BH s 1 ½B 5 BH s 1 1 (5.7) ½H3 O1 Where pHmax 5 pH at which solubility is maximum (valid only for equation where pH is lesser than pHmax). If the same does not hold valid then the equation can be written as Eq. (5.8): ½H3 O1 ST ; pH . pHmax 5 BH1 1 ½Bs 5 ½Bs 1 1 (5.8) k0a In the market also several drugs are formulated according to their dissolution rate profile, for example, barbiturates are often available in the form of sodium salt to achieve a rapid onset of sedation. In addition, nonsteroidal anti-inflammatory drugs are well marketed as the free acids for the treatment of rheumatoid and osteoarthritis. New indications are in treatment of mild to moderate pain including dysmenorrhea, prompting development of naproxen sodium (Shamshina et al., 2015). Moreover, in a recent finding, it was reaffirmed that for acidic drugs solubility was most influenced by the pH and for basic drugs, bile salts and fats influence the drug solubility in simulated fed state intestinal fluid (Williams et al., 2013). 5.4.7 Ionization State For drugs to cross the lipid membrane they need to have some solubility in the lipid membrane and to get dissolved in GIT they have to have aqueous solubility. Unionized forms can undergo passive diffusion to get transported as they has lipid solubility, but the ionized form is required for the solubility of the drug in the GIT. Drugs that are weakly acidic and weakly basic, generally undergo ionization (Yang et al., 2012). 5.4.8 Drug pKa, Lipophilicity, and GI pH Drugs that are weakly acidic or weakly basic generally undergo ionization and their absorption can be explained by the drug’s pKa, lipophilicity, and GI pH (Di and Kerns, 2015). DOSAGE FORM DESIGN CONSIDERATIONS 162 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS 5.4.9 pH Partition Hypothesis In contrast to the capillary walls, cell membranes were able to act as effective barriers during the absorption of drugs. MH Jacobs in 1940 reported the cellular permeation characteristics of weakly electrolytic solutions designated the permeability of nonionic species quantitatively. After his studies, many studies followed and led to the hypothesis of pHpartition theory (Mazák and Noszál, 2014). This theory compared the dissociation constant, lipophilicity, and pH with absorption. Knowledge of the exact ionization of the drug is important as the unionized form has greater lipophilicity than its ionized counterpart. pH partition hypothesis can be explained by the Henderson Hasselbach equations (5.9 and 5.10) as follows: For acids, pH 5 pKa 1 log ionized unionized (5.9) pH 5 pKa 1 log unionized ionized (5.10) And for bases, Most of the absorption studies confirmed the accuracy of this hypothesis. However, there are certain limitations to it. These are related to the unstirred water layer, the microclimate pH, and the mucous coat adjacent to the epithelial cells. 5.4.10 Drug Stability Stability of the drug is dependent on the chemical nature that can affect the solubility and in turn the absorption of the drug. Peptidic or peptidomimetic drugs have poor oral absorption because of instability in the GIT. Acid-labile compounds can undergo chemical hydrolysis in the stomach (Soni et al., 2016). Drugs can also undergo nonspecific or enzymatic hydrolysis in the intestine. The enzymes that are responsible for degradation of drugs include pepsin, pancreatic enzymes, and peptidases. If the drug has poor stability in the GIT a more stable form can be synthesized that can cleave into active form after reaching the blood circulation. If drug is acid labile then an enteric coating can be a beneficial approach to increase the drug absorption. Sometimes the amorphous form of the drug might not be stable and can result in variations in the absorption of the drugs. Other than these some drugs undergo presystemic metabolism and result in poor absorption. Stability of the drug product on storage is a major consideration that can affect absorption. There are five types of stability that are important, namely chemical, physical, microbiologic, therapeutic, and toxicologic stability. Unintentional alterations in either the rate or amount of drug absorption can lead to ineffective oral therapy on the one hand, or toxic reactions on the other (Tekade et al., 2018). DOSAGE FORM DESIGN CONSIDERATIONS 5.5 PHARMACEUTICAL FACTORS 163 5.5 PHARMACEUTICAL FACTORS A drug has to be liberated from the dosage form to get absorbed into the blood circulation. Various dosage forms will have various effects on the liberation of drug from them. Some advanced formulations like nanoparticles are claimed to be absorbed intact through the gut wall (Tekade et al., 2017c; Tekade et al., 2017d). However, the drug needs to be liberated later to elicit any drug response. The simplest dosage form is solution which has no further process required to get absorbed. Other dosage forms need to undergo processes like disintegration, dissolution, deaggregation to form a molecular dispersion that can be absorbed from the GIT (Fig. 5.1). Bioavailability is used as a measure of the drug’s absorption. Pharmaceutical equivalents are the drug products with similar drug content in same salt or ester form. These equivalents are used in similar dosage and strength with the same intended use but with other excipients. These drug products are generally called generic drugs. The absorption of a drug from the GIT has to face a wide range of pHs, enzymes to be able to get absorbed. The major problems in drug absorption can be related to poor solubility, permeability, and metabolic instability. Formulation strategies sometimes help in overcoming these factors (Tekade et al., 2017a). In the following text, we will study how the drug formulation affects the absorption of drugs. 5.5.1 Disintegration Time Disintegration of the dosage form is the first step in the liberation of the drug from it and is mostly applicable to tablets and to some extent capsules. Drugs form capsules to be absorbed have to have a disintegrated capsule shell. Tablets with faster disintegration result in rapid absorption and vice versa (Bandari et al., 2014). Tablets intended for sustained release and controlled release are not generally intended to disintegrate. Fast disintegrating tablets will have additional excipients to facilitate the rapid disintegration of the tablet. After disintegration, the tablets will be in the form of aggregates which will eventually dissolve and get absorbed. Disintegration time is affected by the amount of binder and compression force (Mohapatra et al., 2014). 5.5.2 Dissolution Rate The absorption rate often determines the biological activity of the drug products. When the tablets, capsules, or suspensions are under consideration, this is affected by the dissolution rate. Dissolution rate is the rate at which drug dissolves in the gastrointestinal (GI) fluids. It can be the rate-limiting step of the absorption (Chillistone and Hardman, 2017). Drug dissolution is thought to take place by forming a diffusion layer around the particle. The rate of drug dissolution with poor solubility can be given by the Noyes Whitney equation as follows: dc DA 5 ðCs 2 CÞ dt hν DOSAGE FORM DESIGN CONSIDERATIONS (5.11) 164 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS where D 5 diffusion coefficient; h 5 diffusional layer thickness at solid-liquid interface; A 5 drug’s surface area; ν 5 volume of the dissolution medium; Cs 5 concentration of a saturated solution of the solute in the dissolution medium, and C is the concentration of drug in solution at time t and dissolution rate is dc/dt. According to this model, dissolution rate is a function of drug solubility, diffusional transport through diffusion layer, and solid surface area (Choonara et al., 2014). 5.5.3 Manufacturing Variables Manufacturing variables of oral dosage units will have direct effects on the performance of dosage forms in releasing the drug and thus can affect absorption of the drug. Tablets are the most widely used dosage forms that have more process variables than other oral dosage forms. The following are the important manufacturing variables that affect the drug absorption from tablets (Nur et al., 2014). 5.5.3.1 Method of Granulation Tablets can be prepared using different types of granulation methods. Wet granulation method has many variables that can affect the tablet disintegration and dissolution. Direct compression method can yield tablets that dissolve at a faster rate. A new method of granulation is agglomerative phase of comminution. In this method, drugs are grinded using a ball mill for long enough that it results in spontaneous agglomeration. The tablets produced by this method are having higher strength and rapid dissolution rate as compared to other methods. The internal surface area of the granules prepared by this technique is higher than other techniques and thus can result in rapid dissolution. This rapid dissolution will help in rapid absorption. The tablets will disintegrate at different rates depending on the roller compaction and tableting pressure used during dry granulation method (Kulinowski et al., 2016). 5.5.3.2 Compression Force The compression force employed in tablet preparation has direct effect on tablet disintegration time and dissolution rate. It does so by affecting the density, porosity, and hardness of the tablets. The effect of compression force on dissolution rate is hard to predict and it has to be studied case by case. Any type of pattern in the following figure is possible with varying compression force during tablet manufacturing (Akseli et al., 2017). 5.5.4 Nature and Type of Dosage Form There are many types of dosage forms that are used through the oral route. Most important are solutions, suspensions, capsules, and tablets among others. They can be arranged in the increasing requirement for the dissolution in the same order (Jones, 2016). Aqueous solutions, sirups, elixirs, and emulsions do not pose any hindrances in dissolution as the active ingredient is already in the molecular dispersion form and just needs to be transported across the GIT. Solutions generally are used as positive controls or standards for bioavailability when comparisons need to be carried out with other dosage DOSAGE FORM DESIGN CONSIDERATIONS 165 5.5 PHARMACEUTICAL FACTORS forms. Solid solutions are another form of dosage forms that are closely related to liquid solutions. In solid solutions, the drug is molecularly distributed in another soluble matrix. Griseofulvin solid solution is an example of marketed formulation. Emulsions have been proven to be more effective than suspensions for poorly soluble lipophilic compounds in enhancing the absorption (Berner et al., 2017). Suspensions have particles suspended in a liquid. Due to the small particle sizes, suspensions can have rapid dissolution after solution resulting in rapid absorption. Factors that influence the absorption of drugs from suspensions are particle size, polymorphism, wetting agents, viscosity of the medium, suspending agents etc. (Choudhury et al., 2017). Powders and granules are administered generally in hard gelatin capsules and viscous fluids and oils in soft shells. Fine particles with large surface area are rapidly absorbed. Soft shells dissolve faster than hard gelatin capsules and tablets and show better drug absorption. From tablets, the drug has to be liberated in the form of granules and then these granules need to be dissolved in the GI fluids to be absorbed. Tablets have higher number of steps to be followed before the drug can be absorbed in comparison to any other conventional oral dosage form. Tablets also come in variety of variations like sustained release, modified release, coated and uncoated forms (Tekade et al., 2017b). Table 5.3 summarizes several routes of drug administration with their mechanism of absorption and specific examples. 5.5.5 Pharmaceutical Ingredients Dosage forms contain at least one inactive excipient with it to facilitate accurate dosing and to serve other purposes. Excipients are inactive but still, they can have effects on the drug absorption (Augsburger and Hoag, 2016). Diluents also known as fillers are generally added to produce necessary bulk if the drug is not manageable at the doses used. Hydrophilic diluents can help in dissolution of TABLE 5.3 The pH Range of Gastrointestinal Tract Main Organ Subpart pH Range Mouth Saliva 5.5 7.5 Stomach Upper stomach (Fundie) 4 6.5 Lower stomach 1.0 2.0 Proximal (Duodenum) 7 8.5 Distal 4 7 Ascending colon 5.7 Traverse 6.6 Descending 7.0 Feaces 6.5 Small intestine Large intestine DOSAGE FORM DESIGN CONSIDERATIONS 166 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS poorly soluble drugs by forming a coat around it. A classic example for drug diluent interaction resulting in poor absorption is tetracycline and dicalcium phosphate. Tetracycline forms a divalent calcium tetracycline complex which is poorly soluble and results in poor absorption (Aulton and Taylor, 2017). Binders and granulating agents are used to form granules that can be compressed to make tablets or filled into the capsules. Large amounts of binders can negatively affect the dissolution of drugs by increasing the hardness of the tablets. This, in turn, affects the absorption of drugs. Disintegrants are used to break the tablet into granules when in contact with water. A decrease in disintegrant generally reduces the absorption. However, at higher compression forces a good disintegrant like microcrystalline cellulose may retard the drug dissolution (Osamura et al., 2016). Lubricants are generally hydrophobic in nature and thus can inhibit wettability, aqueous penetrability, and thereby delay the disintegration and dissolution of the tablets. To have minimal effect the lubricant amount should be kept to a minimum or a soluble lubricant like sodium lauryl sulfate and carbowaxes can be used (Patadia et al., 2016). Tablet coatings can delay the disintegration time in the following order: nonenteric film enteric coat . sugar coat . coat. Dissolution profile of shellac-coated tablets is affected with age negatively (Boehling et al., 2016). Buffers can increase the absorption by changing the diffusion layer pH as in the case of aspirin tablets. Certain buffers containing potassium ions inhibit the absorption of vitamin B2 and sulfanilamide. It can be avoided if the buffer and drug have the same cation (Salis and Monduzzi, 2016). Complexing agents can increase or decrease the absorption. Ergotamine tartrate caffeine complex and hydroquinone digoxin complexes are soluble and enhance absorption. Similarly, lipophilicity can also be increased by complex formation in caffeine para aminobenzoic acid complex that enhances permeability and absorption. Complexing agents can also modify the membrane properties. Ethylenediamine tetraacetic acid (EDTA) chelates calcium and magnesium ions from the membrane and enhances permeation and thus absorption of drugs like heparin. Complexation of tetracycline with calcium ions forms an insoluble complex and limits absorption (Pohl et al., 2016). Colorants are deposited on to the crystal surface of drugs and can resist or delay dissolution of drugs. This can happen even at very low concentrations of dyes. Brilliant blue retards dissolution of sulfathiazole. Crystal growth inhibitors like polyvinyl pyrrolidone and polyethylene glycol can prevent conversion of high energy metastable polymorph into stable and less soluble polymorph. This can prevent the changes in the absorption by the polymorphic changes (Chung et al., 2016). Vehicles also known as solvents are the major component of liquid dosage forms. There may be aqueous, water miscible, and immiscible nonaqueous solvents that are used in oral liquid dosage forms. The miscibility of these solvents can affect the drug absorption through oral route. In case of water immiscible solvents, the drug partitioning into the aqueous system influences the drug absorption. Similarly, the diffusion of drug from viscous fluids into GI fluids might take a longer time than nonviscous vehicles and can influence the absorption negatively (Hallouard et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 5.6 BIOLOGICAL FACTORS 167 Suspending agents or viscosity modifiers in liquid or semisolid dosage forms are mostly gums, sugars or polymers. Macromolecular agents can sometimes form unabsorbable complexes with drugs, for example, sodium carboxymethylcellulose forms a poorly soluble complex with amphetamine (Basha et al., 2016). Surfactants have variety of roles in formulations as wetting agents, solubilizers, emulsifiers, etc. These may enhance or retard absorption and can interact with the drug as well as membrane or both. The absorption can be increased if the surfactant promotes wetting and dissolution of drugs, increases the contact of drug with the membrane, and enhances the membrane permeability of the drug. Decreased absorption is seen if the nonabsorbable drug micelle complex is formed or due to the laxative action induced by large surfactant concentration (Pinazo et al., 2016). 5.5.6 Product Age and Storage Conditions The drug product should have sufficient shelf life before its usage by the patient. The selected packaging must be appropriate to enhance stability and compliance. Many changes occur in the formulations with time, like changes in physicochemical properties and chemical stability. In solutions, the drug might precipitate due to changes in solubility over time (Desai and Rustomjee, 2016). In suspension dosage forms particle size distribution has been affected during the storage leading to alterations in absorption. In tablets and capsules, the metastable polymorph might convert to stable polymorph with time. Other than this, due to aging and storage conditions, the properties like disintegration and dissolution are affected. An increase in these is observed due to hardening of polyvinyl pyrrolidone or acacia and decrease due to softening of binder during storage like carboxy methyl cellulose. The changes that are brought up on storage are due to the variations in temperature and humidity. Prednisolone tablets containing lactose as filler when stored at high temperatures and high humidity resulted in tablets with high disintegration time and slow dissolution (Pramod et al., 2016). 5.6 BIOLOGICAL FACTORS Biological factors that are subject related factors which are beyond the control of the formulation scientist can also influence the absorption of drugs (Parikh, 2016). 5.6.1 Membrane Physiology The wall of GIT is almost similar throughout its length with four distinct histological layers. On the inner side, GIT is covered with varying thickness of mucus over the length. This viscoelastic gel acts as a protective layer and mechanical barrier to the GI mucosa. Major content of mucus is water and mucins. Mucins are glycoproteins that make up the structure of the mucus. Mucus is constantly removed and is supplemented for the loss continuously (Rebmann et al., 2016). This mucus and water content in it forms an unstirred water DOSAGE FORM DESIGN CONSIDERATIONS 168 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS layer on the inner side of the GIT lumen. There will be an unstirred water layer on the other side as well which makes the actual barrier as a triple barrier of unstirred water layer membrane unstirred water layer. Unstirred mucosal layer diffusion is the ratelimiting step for many neutral and ionic drugs in absorption through GIT (Pramod et al., 2016). 5.6.1.1 Nature of Cell Membrane Cell membranes are lipid bilayers. Thus any drug that needs to cross the cell membrane has to possess lipophilicity to be able to cross the membrane or it has to have a special mechanism like carrier-mediated diffusion, through which the drug can be absorbed (Labhasetwar, 2016). 5.6.1.2 Transport Processes Specific drugs are absorbed through specific transport processes depending upon their molecular structure and chemical nature. Basic transport mechanisms are passive diffusion, active transport, and endocytosis (Keogh et al., 2016). 5.6.2 Gastrointestinal Physiology Anatomical barrier, physiological functionalities, and gastric contents are major factors that directly affect the orally administered drugs. Processes like secretion, digestion, and absorption take place in the GIT. The GIT or alimentary canal starts from the oral cavity and ends at the anus. Oral cavity secrets saliva with a pH around 7. It contains amylase and mucin enzymes that help in digestion and lubrication, respectively. These enzymes can interact with drugs. After the oral cavity is the esophagus that joins the pharynx and the cardiac orifice. The pH here drops to 5 6. However, drug dissolution here is negligible. After the esophageal sphincter is the stomach, which secretes acid to digest food (Lipinski, 2016). This acidity is the cause of degradation in many compounds. The pH here is about 1.5 and an enzyme called pepsin is secreted here which digests proteins. This enzyme is responsible for the digestion and degradation of peptide drugs, due to this reason peptide drugs are not given orally. Weakly acidic drugs are generally absorbed through the stomach. After the stomach starts the small intestine which is divided into three main parts, namely duodenum, jejunum, and ileum. Small intestine is the major site of absorption for majority of the drugs due to the large available surface area. Next is the colon and it lacks the villi that increase the surface area of the small intestine, for this reason, it has limited help in absorption. Some drugs like theophylline and metoprolol are absorbed from the colon. The colon is also a place for aerobic and anaerobic bacteria. The enzymes from these bacteria sometimes metabolize some drugs like L-dopa and lactulose. The last part of the intestine is the rectum ending at the anus. Drugs can be absorbed well here as this site is perfused well with blood (Kulinowski et al., 2016). Some of the physiological processes of GIT that affect drug absorption are discussed in the following subsections. DOSAGE FORM DESIGN CONSIDERATIONS 5.6 BIOLOGICAL FACTORS 169 5.6.2.1 Gastric Emptying Time The medicine given by oral route can reach the stomach very quickly. However, it cannot stay for long in the stomach as the stomach contents are emptied into the small intestine. Mostly the drugs are absorbed through duodenum and delay in entry into duodenum will affect the onset time and possible extent of absorption. Various factors affect the gastric emptying time. Some important factors like fat content in meal, anticholinergic drugs delay stomach emptying. Particles with sizes lesser than 1 mm could not be effectively retained in the stomach due to the high basal pressure of the stomach when compared to duodenum (Li et al., 2015). Larger starting volume facilitates initial faster gastric emptying, later on it slows down. Reduction in emptying rate happens with food containing fatty acids, triglycerides, carbohydrates, and amino acids. At lower concentrations of salts and nonelectrolytes that affect the osmotic pressure, the rate of emptying will increase, and higher concentrations decrease the rate of emptying. Solutions and suspensions are emptied rapidly when compared to solid material that must be size reduced before emptying (Tari et al., 2017). Lower molecular weight acids reduce the rate of emptying more effectively than the higher molecular weight acids. Bases like sodium bicarbonate will increase the emptying rate at lower concentrations and decrease the rate at higher concentrations. Drugs like anticholinergics, narcotic analgesics, and ethanol reduce the rate of emptying and metoclopramide increases the rate of emptying. Emptying rate is minimal in the case of patient lying on the left side. Aggression increases and depression reduces the rate of emptying. Bile salts and exercise reduces the rate of emptying (Siepmann et al., 2016). 5.6.2.2 Gastrointestinal pH The pH of GIT differs throughout. The pH turns very acidic in the range of 1 to 3.5 in fasted state. With the assimilation of food, the gastric juice turns less acidic in the pH range of 3 to 7. Thus drugs administered with or just after meals will experience the higher pH of the stomach which can last up to 2 2 3 hours after food intake. This can affect the stability and dissolution of the drugs in the stomach. The intestinal pH is higher than stomach due to the bicarbonate ions released from pancreas into the small intestine. Distal duodenum will have a pH of around 5, jejunum around 6.5, and ileum around 7. In the colon, the pH drops due to the breakdown of undigested carbohydrates by the bacterial enzymes to short chain fatty acids to around 6.5. Examples of drugs that are affected by the GI pH are penicillin G, erythromycin, and omeprazole (Abuhelwa et al., 2017). Table 5.4 summarizes the pH ranges throughout gastrointestinal tract. 5.6.2.3 Surface Area of GIT Drugs can be absorbed from all parts of the GIT through passive diffusion. However, the major site of drug absorption is the duodenum due to enormous surface area for the absorption of drugs. Larger area of the duodenum is due to the presence of small projections known as villi. These villi contain even small projections known as microvilli. These microvilli appear as brush border on the luminal side of the intestine. Apart from this, the duodenum is supplied with a greater capillary network which can DOSAGE FORM DESIGN CONSIDERATIONS 170 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS TABLE 5.4 Mechanism of Drug Absorption Through Various Routes of Administration Route of Administration Onset of Absorption Mechanism of Absorption Examples Buccal/Sublingual 3 5 min Passive diffusion/carrier-mediated Nitrates, nifedipine, and morphine Rectal 5 30 min Passive diffusion Aspirin, acetaminophen, and theophylline Transdermal Minutes-hours Passive diffusion Nitroglycerine, lidocaine, and testosterone Subcutaneous 15 30 min Passive diffusion Insulin, heparin, and implants Inhalation 2 3 min Passive diffusion/pore transport Salbutamol, cromolyn, and beclomethasone Intramuscular 10 20 min Passive diffusion/pore transport/ endocytosis Phenytoin, digoxin, and antibiotics Intranasal 3 5 min Passive diffusion/pore transport Antihistaminics Intraocular 2 5 min Passive diffusion Atropine, pilocarpine, and adrenaline Vaginal 10 20 min Passive diffusion Steroids and contraceptives be beneficial in maintaining the concentration gradient for the diffusion of drugs into blood (Mondal et al., 2017). 5.6.2.4 Gastrointestinal Motility and Intestinal Transit Time GI motility helps in the movement of dosage form from the oral cavity to the lower parts of the intestine. There may be an anatomic absorption window for drugs that are given orally, through which the drug gets absorbed efficiently. It is highly important for drugs intended for sustained or controlled release. Drugs should have efficient transit time for good extent of absorption. Normal average small intestine transit time is about 3 4 hours in fasting state. In fed state, the transit time would be around 8 12 hours. It was found that there is no effect of high caloric food on the intestinal transit time. Colonic transit time is highly variable with a tendency for smaller particles to be transported at a slower rate than the larger particles (Kim and Pritts, 2017). A greater capillary networks and lymphatic vessels perfuse the duodenum and peritoneum. The splanchnic circulation which serves the GIT receives 28% of the cardiac output and it increases after ingestion of food. Drugs absorbed through the upper GIT enter the mesenteric vessels and the portal vein to reach the liver before entering the systemic circulation. Any decrease in mesenteric blood flow like in the case of heart failure will affect the drug absorption. Absorption of lipidic drugs bypasses this portal vein and avoids hepatic first-pass metabolism as these drugs enter the lymph through the lacteals present in the microvilli (Infante et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 5.6 BIOLOGICAL FACTORS 171 5.6.2.5 Gastrointestinal Contents GIT contains food, fluids, enzymes and sometimes other drugs along with the drugs of interest. These all can influence the absorption of the drug from GIT. These are discussed in the following text (Ashford, 2017). 5.6.2.6 Effect of Food Food can also affect the rate and extent of absorption of drugs from the GIT. Drugs can form complexes with the food components that are not absorbed well from the GIT. This is a real issue when an irreversible or insoluble complex is formed. Tetracycline for example forms nonabsorbable complexes with calcium and iron, thus concomitant intake of milk or iron preparation will prevent the drug’s absorption (Abuhelwa et al., 2017). Food can also alter the pH of the GIT. In general, food increases the stomach pH by acting as a buffer. This can increase the dissolution and absorption rate of a weakly acidic drug. Gastric emptying can be altered by the food particularly those containing high fat content. Food slows the rate of absorption due to delayed gastric emptying of some drugs like lamivudine and Zidovudine but it is not clinically significant. Food can stimulate the secretion of enzymes and if the drugs are prone to enzymatic degradation their absorption will be affected. Competition between food components and drugs for transporters might also affect the absorption (Infante et al., 2017). 5.6.2.7 Effect of Fluid Large amounts of fluids in the stomach favor rapid dissolution of the dosage form and rapid gastric emptying resulting in increased absorption. The absorption of erythromycin is better in an empty stomach and when taken using a glass of water compared to the absorption under fed state (Aulton and Taylor, 2017). 5.6.2.8 Effect of Other Normal GI Contents Regular GI contents like mucin, bile salts, and enzymes can affect the drug absorption. Mucin interacts with streptomycin to hinder its absorption. Mucin acts as a barrier in drug diffusion to other drugs as well. The bile salts help in solubilization and absorption of lipophilic drugs like griseofulvin and vitamins A, D, E, and K. Bile salts sometimes can also inhibit the absorption of certain drugs like neomycin and kanamycin by forming water-insoluble complexes. Enzymes can influence the absorption drastically of drugs that are susceptible. The metabolism by these enzymes is known as presystemic metabolism and is discussed in the Section 6.2.10 (Mamadou et al., 2017). 5.6.2.9 Drug Stability in GIT Drug stability in the GIT can be influenced by extreme acidic pH and enzymes. Drugs that are unstable in acidic environment are generally coated with protective materials that protect the drug from acidic environment. This is called an enteric coating. Drugs that undergo metabolism by the enzymes cannot be given orally and need to be administered via other routes of drug administration, generally. This is true in the case of proteinous and peptide drugs. These drugs are administered by other routes to avoid degradation by the proteolytic enzymes in the GIT (Chillistone and Hardman, 2017). DOSAGE FORM DESIGN CONSIDERATIONS 172 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS 5.6.2.10 Effect of Presystemic Metabolism Drugs absorbed from GIT will reach the liver initially through portal vein except for the drugs that are absorbed from colon. During the absorption process simultaneously metabolism starts. The metabolizing enzymes are present in the lumen, gut wall, and liver. In colon there are enzymes that are being produced by the bacteria that can also to some extent metabolize the drugs. The drugs absorbed from upper GIT will pass through the liver and if they are highly sensitive to metabolism in liver some amount of the unchanged form reaching the blood circulation is lost. This metabolism is termed as first-pass metabolism or effect and affects the absorption of many drugs given orally. Other than liver luminal enzymes, gut wall enzymes can also metabolize the drug to some extent. The metabolism that is taking place before the drug is termed as presystemic metabolism including first-pass metabolism (Mamadou et al., 2017). 5.6.2.10.1 LUMINAL ENZYMES Luminal enzymes are the enzymes secreted into the GIT lumen by various types of cells and organs of the body. Pancreas secretes various luminal enzymes such as lipases, amylases, and proteases. Apart from that gastric juice contains pepsin. Lipases, amylases, and proteases are secreted by the pancreas into the small intestine. Mostly, degradation of high molecular weight peptides and proteins occur through these luminal enzymes. Several nucleotides and fatty acids are also degraded by these enzymes (Moscovitz et al., 2016). 5.6.2.10.2 GUT WALL ENZYMES Gut wall enzymes contribute to the presystemic metabolism of the drugs. These enzymes can degrade the drugs before they can reach the blood circulation which is called as presystemic metabolism. The major enzyme CYP3A belonging to the cytochrome family is present in the intestinal mucosa, thus absorption of substrates to this enzyme is affected. CYP levels are higher in the intestine than in the colon (Hatley et al., 2017). 5.6.2.10.3 BACTERIAL ENZYMES Bacteria in the colonic region secrete certain enzymes and can also affect the drug absorption. Sometimes these enzymes are used in designing drugs that target the colon. Sulfasalazine is an example of a prodrug in which 5-ASA connected to sulfapyridine through azo linkage. This sulfapyridine moiety makes the drug too large for absorption in the upper GIT. In the colon bacterial enzymes reduce the azo bond and release the active drug, 5-aminosalicylic acid, for local action in colonic diseases such as inflammatory bowel disease (de Gonzalo et al., 2016). 5.6.2.10.4 HEPATIC ENZYMES Liver is the primary site of drug metabolism. It can also be a barrier to drug absorption as the drugs that are absorbed through the GIT go directly to the liver before going anywhere else. So if the drug is metabolized to a great extent in the liver then the amount of drug reaching the site of action is very limited. This metabolism is known as first-pass metabolism. Propranolol is absorbed well through the GIT but due to firstpass metabolism only 30% of the oral dose is available to the systemic circulation. Other DOSAGE FORM DESIGN CONSIDERATIONS 5.6 BIOLOGICAL FACTORS 173 examples include atorvastatin, lidocaine, imipramine, diazepam, pentazocine, and morphine (Dugan et al., 2016). 5.6.3 Age GI physiology is not the same in all ages. Owing to the different physiologies observed in different ages drug absorption is not similar in all cases. Infants have indifferent absorption as compared to adults due to higher gastric pH and lower intestinal surface and blood flow. In elderly people drug absorption is impaired because the gastric emptying is different (Villiger et al., 2016). 5.6.4 Gender Men, women, and pregnant women have different gastrointestinal physiologies. Gastric pH is lower in men than in women followed by pregnant women. This can affect the absorption of ionizable drugs. Males have higher gastric emptying rate and intestinal motility. Women have smaller body weight and volume of distribution, a pharmacokinetic parameter explaining the drug distribution. These factors can also give differences in drug absorption (Christiansen et al., 2016). 5.6.5 Disease state Disease states and physiological disorders associated with the gastrointestinal tract are likely to influence the absorption of orally administered drugs. The absorption mechanisms discussed at the start of this chapter are true for healthy subjects. In diseased conditions, the intestinal wall integrity can be varied. Gut wall integrity is breached in many inflammatory disorders leading to enhancement in drug absorption. Local diseases of GIT can cause alterations in GI pH that can affect the absorption of drugs. Acquired immunodeficiency syndrome (AIDS) patients often have oversecretion of gastrin which increases the acid secretion and thus a low pH is observed in stomach. This can affect the dissolution of weakly basic drugs such as antifungal ketoconazole. Diseases like Crohn’s disease and ulcerative colitis will also lower the pH of the GIT (Almukainzi et al., 2016). 5.6.6 Presence of other drugs Presence of other drugs in the GIT might affect the absorption of the drug of interest physiochemically or physiologically. Antidiarrheal preparations containing adsorbents like attapulgite or kaolin-pectin retard/prevent absorption of some drugs coadministered with them. Examples include promazine and lincomycin. Antacids, mineral substitutes containing heavy metals such as aluminum, calcium, iron, magnesium, or zinc retard the absorption of tetracyclines through formation of unabsorbable complexes. Anion exchange resins cholestyramine and colestipol bind to bile salts and drugs and prevent absorption of some drugs. Basic drugs dissolving in stomach increase the stomach pH and decrease the dissolution rate or cause precipitation of tetracyclines (Taylor and Zhang, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 174 5. PHYSICOCHEMICAL, PHARMACEUTICAL, AND BIOLOGICAL CONSIDERATIONS IN GIT ABSORPTION OF DRUGS Some drugs affect GI physiology and thus affect the absorption of other drugs. Drugs like anticholinergics retard the GI motility and promote absorption of drugs like ranitidine and digoxin while they delay absorption of paracetamol and sulfamethoxazole. Metoclopramide increases GI motility and enhances absorption of tetracycline, pivampicillin, and levodopa. Antibiotics inhibit the bacterial enzymes and can prevent the metabolism of drugs caused by these enzymes. Digoxin has increased efficacy due to the presence of erythromycin due to this reason (Sansom et al., 2016). 5.7 CONCLUSION Drug absorption from the GIT can be limited by various factors with the most common one being poor aqueous solubility and poor permeability of a drug molecule. When delivering an active ingredient orally, it must first dissolve in gastrointestinal fluids before it can then permeate the membranes of the gastrointestinal tract to reach systemic circulation. Therefore, a drug with poor aqueous solubility will exhibit dissolution rate-limited absorption. Chemical nature and physicochemical behavior of a drug play key roles for its oral bioavailability. For example, for some drugs solubility presents a challenge to the development of a suitable formulation for oral administration. Screening methods for identifying potential drug candidates identified a number of poorly soluble drugs as potential therapeutic agents. It has been estimated that 40% of new chemical entities currently being discovered are poorly water soluble. Many of the potential drugs are abandoned in the early stages of development due to solubility problems. Therefore it is more important that methods for overcoming solubility limitations should be identified and applied commercially, so that potential therapeutic benefits of these agents can be realized. Dissolution of drug is the rate determining step for oral absorption of the orally administered drug and for that drug properties like chemical nature, pH, PKa, salt form, solubility, dissolution, and tableting properties should be such that they must not act as a barrier for the absorption of the drug from GIT. The various factors described in the chapter alone or in combination can be used to predict the absorption characteristics of the drugs in vitro and in vivo. Proper selection of the solubility enhancement method is the key to ensure the goals of a good formulation like good absorption from the site of application, oral bioavailability, reduce frequency of dosing, and better patient compliance combined with a low cost of production. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology (DST), Government of India for grant (#ECR/2016/001964) allocated to Dr. Tekade for research work on drug and gene delivery. The author also acknowledges DST-SERB for N-PDF funding (PDF/2016/003329) to Dr. Rahul Maheshwari in Dr. Tekade’s lab for work on targeted cancer therapy. Authors would also like to acknowledge Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India, for supporting research on cancer and diabetes at NIPER, Ahmedabad. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 175 ABBREVIATIONS AIDS ATP EDTA GPs CYP GI GIT MAD USFDA acquired immunodeficiency syndrome adenosine triphosphate ethylene diamine tetraacetic acid glycoproteins cytochrome P gastrointestinal gastrointestinal tract maximum absorbable dose United States Food and Drugs Administration References Abuhelwa, A.Y., Williams, D.B., Upton, R.N., Foster, D.J., 2017. Food, gastrointestinal pH, and models of oral drug absorption. Eur. J. Pharm. Biopharm. 112, 234 248. Aitipamula, S., Banerjee, R., Bansal, A.K., Biradha, K., Cheney, M.L., Choudhury, A.R., et al., 2012. Polymorphs, salts, and cocrystals: what’s in a name? Cryst. Growth Des. 12 (5), 2147 2152. 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Tekade3,4 1 Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India 2Faculty of Pharmacy, Philadelphia University, Amman, Jordan 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 4Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 6.1 Introduction 6.1.1 Objective of Sustained and Controlled Release Formulations 6.1.2 Advantages of Sustained and Controlled Release Dosage Forms 6.1.3 Limitations of Sustained and Controlled Release Dosage Form 6.1.4 Current Market Share of Controlled Release Pharmaceutical Formulations Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00006-X 180 182 182 182 183 179 6.2 Rationale for the Design of Controlled Release System 184 6.3 Factors Influencing the Design of Controlled Release System 186 6.4 Physiochemical Properties of a Drug Influencing Design of Controlled Release System 6.4.1 Molecular Weight and Diffusivity 6.4.2 Aqueous Solubility 6.4.3 pH and pKa 6.4.4 Partition Coefficient 6.4.5 Permeability 188 188 189 190 190 190 © 2018 Elsevier Inc. All rights reserved. 180 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION 6.4.6 Mechanism and Site of Absorption 6.4.7 Drug Stability 6.4.8 Ionization 190 191 191 6.5 Pharmacokinetic Factors Influencing the Design of Controlled Release System 6.5.1 Absorption 6.5.2 Distribution 6.5.3 Metabolism 6.5.4 Elimination Half-Life 6.5.5 Duration of Action 6.5.6 Drug Protein Binding 6.5.7 First-Pass Metabolism 192 192 193 193 193 193 194 194 6.6 Pharmacodynamic Factors Influencing the Design of Controlled Release System 6.6.1 Drug Dose 6.6.2 Frequency of Dosing 6.6.3 Margin of Safety 6.6.4 Role of Disease State 6.6.5 Side Effects 6.6.6 Disease Condition and the Patient Condition 195 195 195 195 195 196 6.7 Patient Compliance 196 196 6.8 Controlled Release From Different Formulations: Importance of Route and Effect of Varying Properties 197 6.8.1 Oral Controlled Release Drug Delivery Systems 197 6.8.2 Buccal/Sublingual Controlled Release Drug Delivery Systems 197 6.8.3 Parenteral Controlled Release Drug Delivery Systems 198 6.8.4 Transdermal Controlled Release Drug Delivery Systems 201 6.8.5 Ocular Controlled Release Drug Delivery Systems 202 6.8.6 Nasal Controlled Release Drug Delivery Systems 203 6.8.7 Pulmonary Controlled Release Drug Delivery Systems 205 6.8.8 Rectal Controlled Release Drug Delivery Systems 206 6.8.9 Vaginal Controlled Release Drug Delivery Systems 207 6.8.10 Intrauterine Controlled Release Drug Delivery Systems 207 6.9 Drug Targeting Using Controlled Release System 208 6.10 Current Developments in Controlled Release Formulations 209 6.11 Patented Controlled Release Drug Delivery Systems 211 6.12 Conclusion 214 Acknowledgments 215 Abbreviations 215 References 216 6.1 INTRODUCTION Traditionally, dosage forms such as tablets, injections, creams, capsules, ointments, and suppositories have been used to treat different diseases. Controlled release system (CRS) have been developed for many purposes that include the enhancement of patients’ compliance (Rahul et al., 2017; Anselmo and Mitragotri, 2014), the avoidance of drugs degradation (Weiser and Saltzman, 2014), and the improvement of the quality control during the manufacturing of pharmaceutical dosage forms as well (Parikh, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 6.1 INTRODUCTION 181 Physicochemical properties that influence the performance of drug are solubility, stability, lipophilicity, and molecular interactions. Solubility is a measure of the amount of solute that can be dissolved in the solvent. It is required for a drug to be dissolved first in the physiological medium of the body at a considerably fast rate of dissolution to be absorbed by the intestinal lumen. Drug molecules with very low aqueous solubility often have lower bioavailability because of the limited amount of dissolved drug at the site of absorption (Di and Kerns, 2015). Drugs with water solubility ,10 mg/mL are expected to undergo compromised bioavailability. Once the drug is taken by the oral route, biological fluids that are in direct contact with a drug molecule may influence the stability of the drug. Drugs may be susceptible to both chemical and enzymatic degradation, which results in a loss of activity of the drug. Drugs with poor acidic stability, when coated with enteric coating materials, will bypass the acidic stomach and release the drug at a lower portion of the gastrointestinal tract (GIT). Drugs can also be protected from enzymatic cleavage by modifying the chemical structure to form prodrugs (Li and Chen, 2016). It is not always the deciding factor that only physical and chemical properties of drugs govern the safe and efficacious treatment, but also a function of how the human body responds to the administration of medication. The study of the bodily processes that affect the movement of a drug in the body is referred to as pharmacokinetics. To understand the pharmacology of drugs, the pharmacy technician must also understand the four fundamental pathways of drug movement and modification in the body. First, drug absorption from the site of administration permits entry of the compound into the blood stream. Once absorbed, the drug may then leave the bloodstream and disperse into the tissues and intracellular fluids where it can reversibly bind to receptors. This dispersal is called distribution. While some drug molecules are binding to receptors, others may be released from the receptors and be picked up again by the bloodstream. Drug particles in the blood stream are available to undergo biochemical changes, referred to as metabolism, in the liver or other tissues. Finally, the drug and its metabolites are excreted from the body in urine or feces. Metabolism and excretion are both pathways of drug elimination from the body. Conventional dosage forms are still used nowadays in both types of prescription drugs as well as over the counter (OTC) drugs. A significant increase has been observed regarding the use of CRS since they have been shown to widely improve the efficiency and safety of these formulations or systems (Pundir et al., 2017). In conclusion, it can be stated that an ideal drug delivery system should deliver precise amounts of a drug at a predetermined rate to achieve a drug level necessary for treatment of the disease. For most drugs that show a clear relationship between concentration and response, the drug concentration will be maintained within the therapeutic range, when the drug is released by zero-order rate. To design a controlled release (CR) delivery system, many factors such as physicochemical properties of the drug, route of drug administration, and pharmacological and biological effects must be considered. Considering the increasing demand and their therapeutic effectiveness, CRS based products are in demand nowadays. However, to develop a suitable CRS, the formulation scientist has to justify the proper rational and objective of the medication system. Considering this, the next section is designed to provide the reader an understanding of the designing of CRS. DOSAGE FORM DESIGN CONSIDERATIONS 182 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION 6.1.1 Objective of Sustained and Controlled Release Formulations CRS is considered as delivery system that aims to deliver the drug to the site of action at a precontrolled rate for a certain period. The development of CRS is known to be essential to achieve the required therapeutic effect while maintaining the suitable therapeutic plasma-drug concentration. Studies have shown that several advantages that can be obtained by the use of CRS, such as the achievement of better drug exposure control, the assessment of the best drug permeability across the biological barriers, the insurance of delivering the drug to the desired site of action, in addition to the prevention of the premature elimination of drug substances (Siepmann et al., 2011). Another objective of this chapter to provide readers, a complete understanding about the biological factors, such as age, weight, gender, ethnicity, physiological processes, and disease state, that can alter the way that the drug will be absorbed and eliminated from the body. For example, newborn infants require precaution while dosing due to their immature hepatic function and higher water content in the body (Lau, 2014). Geriatric patients may suffer from the reduced sensitivity of certain receptors that may lead to insensitivity to certain drugs. It has been found that different ethnic groups respond to drugs differently. Diuretics and calcium channel blockers are recommended as first-line therapy in hypertensive Black patients, while beta blockers work better for Caucasian patients. Pathological changes may influence the distribution and bioavailability of the drug by altering the physiological process. Decreased kidney and liver functions will affect the clearance of many drugs. 6.1.2 Advantages of Sustained and Controlled Release Dosage Forms The development of CRS is considered as an interesting issue for several reasons. Firstly, new systems are now able to deliver products that are genetically engineered, i.e., engineered proteins and peptides, to specific sites of action while avoiding the body immune system reactions or the biological inactivation (Banga, 2015). Secondly, reducing the dosing in the case of cancer therapies and enzyme deficient disease, by better targeting of drug molecule (Park, 2014; Liao et al., 2014). Nowadays, various nanotechnology-based formulations are developed, with many of them coming with a CR profile (Sharma et al., 2015a) These include liposomes (Maheshwari et al., 2015a), dendrimers (Tekade et al., 2015; Soni et al., 2017), solid lipid nanoparticles (Tekade et al., 2017d), polymeric nanoparticle (Tekade et al., 2017b), carbon nanotubes (Tekade et al., 2017a), and genetic material based formulations (Tekade et al., 2015; Maheshwari et al., 2017). These formulations showed promising results for the delivery of therapeutic molecules for a variety of diseases. 6.1.3 Limitations of Sustained and Controlled Release Dosage Form There are also various limitations of the CRS that include dose dumping (Jedinger et al., 2014), toxicity, and higher manufacturing costs. These delivery systems have some significant disadvantages that cannot be overlooked. One of them is the toxicity that must be considered while developing CRS (Tekade et al., 2018). Recently, many formulations DOSAGE FORM DESIGN CONSIDERATIONS 6.1 INTRODUCTION 183 meant for the sustained or CR show potential toxicity. Another major problem is the dose dumping (Jesus et al., 2015). For example, if the patient is suffering from cancer and missed a single dose of CRS formulation, it may create severe problems. In line, many CR based devices demand surgical procedures to insert/implant/remove them. The surgical procedures are not patient friendly and sometimes pose an extra economic burden on the patient too (Weiser and Saltzman, 2014). In the pharmaceutical industry, design and development of CRS-based systems are employed as a strategic means to prolong the proprietary status of drug products that are reaching the end of their patent life. A typical example is altering an available drug formulation that needs numerous doses per day to a single daily dosing to sustain the control over the generic competition. For some drugs, controlled delivery is required, since fast release dosage forms cannot provide the intended pharmacological response. These involve hydrophilic drugs that need gentler release and extended duration of action whereas lipophilic bioactives demand increments in solubility to attain satisfying clinical outcomes. Moreover, short half-life drugs that necessitate frequent administration, and drugs with nonspecific action that require the delivery to target sites are the other examples. 6.1.4 Current Market Share of Controlled Release Pharmaceutical Formulations The global market for CRS is expected to gain attraction during the forecast period due to increasing commercialization of new technologies by some modified product launches. Recent advancements in the development of CRS including the gastroretentive drug delivery, the buoyant systems, in addition to the regulated-releases mucoadhesive systems, were shown to cause a global increase in the CRS mechanism of infiltration in the pharmaceutical market. The worldwide market for CRS is determined by increasing the need for CRS because of high acceptance of CRS due to once-a-day dosing nature (Lembhe and Dev, 2016). On the other hand, some of the major factors limiting the global market for CRS are the requirements of a high dose of active pharmaceutical ingredient (API), fewer excipients are satisfactory, and a high price of CRS compared with conventional pharmaceutical formulations. Some of the biopharmaceutical challenges for the development of CRS are risk management of dose dumping, set up of desired release profiles for new chemical entities, and selection of biodegradable and biocompatible materials with the required CR properties (Tice, 2017). Completion of some of the CRSs would give an opportunity for generic players to penetrate the market, e.g., epic osmotic delivery system Osmotically-controlled Release Oral Delivery System (OROS) is off patent July 2017 (Zhou, 2015). It can be concluded that most of the existing CRS in the market for the systemic delivery of drugs utilize oral, parenteral, and transdermal route for their administration. Advances in biotechnology produced many genes, peptide, and protein drugs with specific demands on route of delivery. Thus, other routes such as buccal, nasal, ocular, pulmonary, rectal, and vaginal are gaining more attention. DOSAGE FORM DESIGN CONSIDERATIONS 184 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION 6.2 RATIONALE FOR THE DESIGN OF CONTROLLED RELEASE SYSTEM The alteration of both the pharmacokinetic as well as the pharmacodynamic properties are considered to be the fundamental rationales of the controlled-release drug delivery systems (CRDDS), which can be achieved by either utilizing innovative drug delivery systems or by the modification of the drug’s molecular structures and/or the physiological properties in such a manner that its effectiveness is maximized by minimizing the adverse-effects and treating the disease with the proper least quantity of the active drug by the most suitable route of administration in the shortest period (Brahankar and Jaiswal, 2009; Prabu et al., 2015). Typically, researches and experiments have shown that the pharmacokinetic properties of drugs are dependent on the characteristics of the delivery system used rather than the characteristics of the drug itself. Drugs pharmacokinetic, as well as pharmacodynamics profiles, were shown to provide the time-course dynamic effects that are related to the drug concentration and its target, which are considered to be essential in the development process of new strategies of drug delivery (Rafiei and Haddadi, 2017). Generally, CRS are basically aiming to ensure drugs safety and improved efficacy, in addition to fulfilling patients’ compliance. Therefore, in order to achieve those aims, plasma drug levels have to be superiorly controlled over time with the minimal dosing frequencies, so that drugs will be able to simply cross physiological barriers, to avoid the premature elimination, and to be delivered drug to the proper site target (Yang et al., 2014; Wiedersberg and Guy, 2014; Weiser and Saltzman, 2014). Each drug has its own dose (D) and dosing interval (τ) which vary from other drugs, each drug has a specific therapeutic plasma concentration, where fewer concentrations lead to insufficient activity, and higher concentrations can cause serious toxic effects (Siepmann et al., 2011). CRS provide an improvement of drug release kinetics and therapeutic effectiveness as well; an increase in the level of drug in the bloodstream occurs and is then followed by a constant range that is referred to as the effective range between the least effective and most effective levels (Park, 2014), as illustrated in Fig. 6.1. Drug release is considered as the process that involves the release of the active substance from the product. As CRS differ, the profile of the drug release will differ as well, i.e., burst release, lag followed by sudden burst, zero order, pulsatile, and diffusion CR (Fig. 6.2). Ideal CR delivery systems of drugs offered the zero order type of release. Most formulations were shown to release a large initial quantity of the drug substance immediately when placed in the releasing medium, even before reaching the steady state level of the rate of drug release. This phenomenon is basically called the “burst release.” Burst release phenomenon usually leads to delivering a higher initial amount of the drug while reducing the life time of the delivery device. Pulsatile drug release system represents a drug release with a lag time that is well-defined. These systems were shown to be advantageous over other types of systems (Thampi et al., 2016). A circadian rhythm was shown to be followed by the symptoms of various diseases including myocardial infarction, bronchial asthma, hypertension, angina pectoris, and rheumatic diseases (Surana and Kotecha, 2010). DOSAGE FORM DESIGN CONSIDERATIONS 6.2 RATIONALE FOR THE DESIGN OF CONTROLLED RELEASE SYSTEM 185 FIGURE 6.1 Plasma drug concentration release profile of different delivery systems. FIGURE 6.2 Plasma profile from different delivery systems. DOSAGE FORM DESIGN CONSIDERATIONS 186 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION In a diffusion-controlled drug delivery system the dissolved drug molecule diffuses through the rate-controlling element (Kamaly et al., 2016). The rate-controlling element in such a system is thus insoluble, nonerodible and nondegradable. Diffusion plays a significant role in a large number of controlled drug delivery systems. Diffusion as a mechanism can be referred to as the movement of a substance from a highly concentrated region to a low concentrated one and is also considered as the driving factor in CRS (Kalinin et al., 2015). In CRS acting by the mechanism of diffusion, drugs are being entrapped and then released by the diffusion mechanism into an insoluble polymeric membrane of inert water, which is typically referred to as the reservoir system or in other terms is called the polymeric matrices (monolithic systems). Diffusion CRS are basically classified into four main types depending on factors such as the systems’ structures, as well as the method used for drug loading. Diffusion systems types include the constant drug source reservoir, the nonconstant drug source reservoir, in addition to the monolithic dispersion and monolithic solution (Macheras and Iliadis, 2016). Administering an i.v. drug ensures that the entire dose enters the general circulation. An i.v. dose of injection makes sure of the rapid achievement of very high peak concentration, as may be required for some drugs, but contraindicated for others and may give side effects and toxicity. A single dose of drug maintains the concentration above the minimum therapeutic concentration for some time, which results in a limited duration of action, after its decline and no more therapeutic response (Elzoghby et al., 2012). If we administer the double dose of the drug, it will result in toxicity and adverse effects because the concentration of drug crosses the maximum therapeutic concentration. The CRS occurs in a way that maintains the therapeutic concentration within the predefined range for a long period as illustrated in Fig. 6.3. 6.3 FACTORS INFLUENCING THE DESIGN OF CONTROLLED RELEASE SYSTEM CRS depend on their designing process on several factors that both researchers and formulators have to take into account before proceeding for drug development of CRS. One of the most important factors includes a drug’s physicochemical properties such as the solubility, charge, partition coefficient, as well as the tendency for protein binding, which all play a major role in the determination of systems design as well as their final performance (Peppas and Narasimhan, 2014). Another factor of importance is the route of drug delivery. Technological methods are now used in the optimization of the site of release and action, which facilitate the application of the properly CR mechanism or the device as well. There are some limitations that were reported to have an influence on the performance of the CRS, these limitations were related to some physiological factors that include the first-pass metabolism, blood supply, the motility of the GIT, and the sequestration mechanism of the small foreign particles that occurs mainly in the liver and spleen (Safari and Zarnegar, 2014). To avoid the possible adverse effects, it is essential to increase the fraction of the dose to the maximum at the specific target site of action. This can be possibly achieved in the case of locally administered drugs, or in other cases, the use of carriers may be beneficial DOSAGE FORM DESIGN CONSIDERATIONS 6.3 FACTORS INFLUENCING THE DESIGN OF CONTROLLED RELEASE SYSTEM 187 FIGURE 6.3 Plasma profile of different doses. also. However, the majority of drugs having large molecules are facing the limitation of impermeability across most surfaces, which necessitates the use of intravascular or intraarterial routes of administration (Gibson and Tipton, 2014; Kamaly et al., 2016). Formulators of CRS have to take into consideration the expected cure, the degree of disease control, along with the required period of drug therapy, since these factors are crucial when designing the CRS (Chou et al., 2015). Also, the pathological changes were also shown to have a role in the determination of the proper design of the drug delivery system. Correlation between clinical signs and biochemical markers of diseases may be advantageous during the design process of the CRS, such as in the case of unique tumor biomarkers that include selective enzyme expression, low extracellular pH, and hypoxia. Various agents were shown to exhibit preferential cytotoxicity by reductive activation of hypoxic cells. These agents include nitro compounds, quinones, and aromatic N-oxides, i.e., Mitomycin C (Aulton and Taylor, 2017; Donin et al., 2017). The design process of CRS has been shown to be influenced by the patient-related factors also, regardless of the age of the patient, obese or not, ambulatory or bedridden along with other related factors. For example, if a drug is to be injected intramuscularly to an ambulatory patient, there is a possibility it will perform differently to that in the case of a bedridden patient. On the other hand, some other factors can be exclusively associated with an individual patient in which variations cannot be well-controlled during research stages, while other factors are necessarily needed to be considered during the formulation DOSAGE FORM DESIGN CONSIDERATIONS 188 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION of CRS. Although many factors contribute to the CR of drug delivery, our discussion in this chapter is mainly focusing on the properties and routes of administration of drugs (Kamaly et al., 2016). Discussing the influence of both the drug properties and its route of administration on the design of CRS focuses on: the drug’s behavior in the delivery system, i.e., drug release from the delivery system, and the behavior of both the drug and the delivery system inside the body, i.e., the movement of the drug and the delivery system to the site of action. The first fundamental describes the influence of the drug’s physicochemical properties on the characteristics of drug’s release from the delivery system, whereas the other one is considered as a complex fundamental which mainly depends on the pharmacokinetic profile of the drug (Pundir et al., 2017). A drug’s absorption across body’s biological membranes, for instance, the gastrointestinal (GI) wall, is considered as the rate-limiting step in drugs delivery. While in a CRS, a drug’s release from the dosage form is considered as the rate determining step rather than the absorption of the drug. Thus, the drug release kinetics are what determines the bioavailability rather than absorption which is much smaller than the intrinsic absorption rate for the drug (Lu and Ten Hagen, 2017). There are several techniques that are followed when developing CRS including dissolution, swelling, diffusion, osmotic pressure, ion-exchange, complexation, and magnetic field application. The releasing temporal pattern is determined by the relationship between the drug’s physiochemical properties and the delivery system characteristics. 6.4 PHYSIOCHEMICAL PROPERTIES OF A DRUG INFLUENCING DESIGN OF CONTROLLED RELEASE SYSTEM There are various physicochemical properties (Fig. 6.4) that influence the CRS design. 6.4.1 Molecular Weight and Diffusivity It is reported that drugs having low molecular weights are absorbed faster and completely. Around 95% of the pharmaceutical drugs were shown to be absorbed by the mechanism of passive diffusion. Diffusivity can be referred to as the ability of the drug to diffuse within the biological membrane, which has been reported to be disproportional to the molecular size (Weaver et al., 2014). Drugs of sustained release (SR) systems have to diffuse through a matrix or a rate-controlling membrane in addition to their diffusion through the biological membranes. The molecular size of the diffusing materials is considered as an important factor that affects the value of diffusivity (D). The value of D has been reported to be related to properties including the size and shape of the cavities and the drugs as well. Typically, diffusion coefficient values of drugs having molecular weights between 150 and 400 Da were reported to range from 1026 to 1029 cm2/s. Whereas for large drugs with molecular weight more than 500, the values were shown to be very small and difficult to be quantified, i.e., less than 10212 cm2/s. Therefore, drugs DOSAGE FORM DESIGN CONSIDERATIONS 6.4 PHYSIOCHEMICAL PROPERTIES OF A DRUG INFLUENCING DESIGN OF CONTROLLED RELEASE SYSTEM Permeability Physicochemical properties of drug influencing design Partition coefficient FIGURE 6.4 Schematic representation of various physicochemical parameters influencing the designing of CRS. Drug stability Mechanism & absorption site 189 Mol. weight & diffusivity Aqueous solubility Ionization & unionization pH & pKa with high molecular weights are expected to represent very slow release from SR devices, in which the release of these drugs through the matrix is achieved by the releasing mechanism (Peppas and Narasimhan, 2014; Loira-Pastoriza et al., 2014). Studies have shown that drugs having large molecular weights are poorly-favorable candidates for oral CRS, e.g., proteins and peptides. Experiments have also reported that the upper limit of molecular weights for drugs intended for oral administration by the mechanism of passive diffusion is 600 Da. For drugs with a molecular weight greater than 500 Da, their diffusion coefficient in many polymers are frequently so small that they are difficult to quantify. Thus high molecular weight drugs should be expected to display very slow release kinetics in extended release devices using diffusion through polymeric membrane or matrices as releasing mechanism (Kim et al., 2016). 6.4.2 Aqueous Solubility The good aqueous solubility of pH-independent drugs provides good candidates for the formulation of oral CRS. Researchers have determined the lowest solubility limit of drugs intended to be manufactured as CRS which relatively equals 0.1 mg/mL. A drug’s solubility determines the choice of the proper mechanism to be employed for CRS, e.g., some diffusional systems are unsuitable for drugs having poor water solubility. Absorption of drugs with poor solubility profile is limited by the dissolution rate. Hence, the controlling release device will not be able to control the absorption process, so these drugs are therefore considered as poor candidates for such CRS (Balogh et al., 2017). The biopharmaceutical classification system (BCS) is a tool that facilitates the estimation of the contribution of three factors affecting the oral absorption: the solubility, the dissolution, and the intestinal permeability. As presented by the BCS, drugs that are put in class III (High solubility-Low permeability) and class i.v. (Low solubility-Low permeability) are considered as poor candidates to be formulated as a CR dosage form (Sharma, 2016; Jiang et al., 2014; Wu et al., 2015b). DOSAGE FORM DESIGN CONSIDERATIONS 190 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION 6.4.3 pH and pKa An acidic drug whose ionization is sensitive to pH has pKa values within the range of 3.0 7.0 whereas basic drugs pKa values range from 7.0 to 11.0. To obtain an optimum absorption, drugs have to be in the unionized form at the required site of absorption at least to the extent that ranges from 0.1% to 5%. Drugs that largely exist in the ionized form are considered as poor candidates for the formulation of CRS (Liu et al., 2014; Porchetta et al., 2015; Kaur et al., 2016). 6.4.4 Partition Coefficient The drug which is administered through the oral route has to cross different biological membranes in order to exert the desired therapeutic effect when reaching another area in the body. It is proven that these membranes are naturally composed of lipids; hence, it has become essential to characterize the partition coefficient of oil-soluble drugs due to their importance in the determination of the effectiveness of penetration through the membrane barriers (Kamaly et al., 2016; Natarajan et al., 2014). The partition coefficient P is commonly used to describe equilibrium of drug concentration in two phases. P5 Concentration of drug in oil phase Concentration of drug in aqueous phase (6.1) As given by (Eq. 6.1) Partition coefficient (P) is calculated in the terms where Coil 5 drug’s concentration in the oil phase and Cwater 5 drug’s concentration in the water phase. For certain drugs: If log P 5 0, equal distribution is there for the drug in the liquid and the oil phase; if log P . 0, the drug is considered to be lipid soluble. For example, Oxcarbazepine (log P 5 1.76) and p-dichlorobenzene (log P 5 3.37); and if log P , 0, the drug is considered to be water soluble. For example, acetylcholine (log P 5 22.9) and acetamide (log P 5 21.16). 6.4.5 Permeability The three major drug properties that determine the permeability of drugs for passive transport across intestinal epithelium (Kobayashi et al., 2014; Mekaru et al., 2015) are log P, expressed lipophilicity, and molecular size. Other than this, the polarity of the drug which is measured by the number of H-bond acceptors and number of H-bond donors on the drug molecule is also an important factor. 6.4.6 Mechanism and Site of Absorption Drugs to be absorbed by the mechanism of carrier-mediated transport are considered as poor candidates for the formulation of CRS, e.g., several Vitamins B (Wong and Choi, 2015). Vitamin B12 is a well known water-soluble vitamin necessary for a number of metabolic reactions and prevention of medical complications, most commonly hematopoietic DOSAGE FORM DESIGN CONSIDERATIONS 6.4 PHYSIOCHEMICAL PROPERTIES OF A DRUG INFLUENCING DESIGN OF CONTROLLED RELEASE SYSTEM 191 disorders and spinal cord related neuropathies. If vitamin B12 is ingested in its free (or nonprotein bound form), it will bind to a carrier protein known as R-binders or transcobalamin I that is secreted by both the salivary glands in the oropharynx and the gastric mucosal cells within the stomach. 6.4.7 Drug Stability Once the drug is administered, biological fluid that is in direct contact with a drug molecule may influence the drug’s stability. Drugs may be susceptible to chemical as well as enzymatic degradation, which results in a loss of activity of the drug molecule. GI-unstable drugs cannot be formulated for orally-administered CRS, due to the associated bioavailability problems. Therefore, other routes of administration have to be chosen, i.e., the transdermal route. Drugs unstable in gastric pH coated with the enteric coated material will bypass the stomach acidic environment and release the drug at intestine (El-Zahaby et al., 2014). On the other hand, a drug unstable in the intestine can be formulated as a gastroretentive dosage form (Vo et al., 2016; Tadros and Fahmy, 2014; Nafei, 2014). Another method to protect drugs from being enzymatically degraded is achieved by modifying the chemical structure and the formation of prodrugs (Vemula et al., 2013; Wang et al., 2014a). 6.4.8 Ionization Many drugs are formulated in the form of weak electrolytes, in which the degree of ionization is dependent mainly on the values of pKa and pH of the solution. In the case of transcellular passive diffusion, the GIT acts as a simple barrier of lipophilic properties where ionized molecules are considered to be more water-soluble with a relatively small lipid solubility as compared to unionized, lipid-soluble molecules, i.e.: Unionized drug 5 Lipophilic . Membrane transport; Ionized drug 5 Hydrophilic . Minimum membrane transport Solutions pH values have been reported to influence the overall partition coefficient of ionized molecules. In the case of ionized drugs, the value of log P is dependent on the solution’s pH. Therefore, the log distribution coefficient log D is usually employed rather than log P at different pH values, as a way to estimate or predict the absorptive potential of the drug. pH values should be reported when the log D is measured. Nevertheless, values were observed to correspond in a normal manner to the determinations that are achieved at a physiological pH of 7.4 (Alvarez-Lorenzo and Concheiro, 2014; Pundir et al., 2017). Log D is referred to as the log partition coefficient of the drug in the unionized form and at a given pH. The following Eq. (6.2) describes the relationship of the overall partition coefficient with the distribution coefficient. D 5 P ð1 2 αÞ where α represents the degree of drug’s ionization. DOSAGE FORM DESIGN CONSIDERATIONS (6.2) 192 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION pH-partition theory of drug absorption is represented by the terms of the interrelationship between a drug’s lipid solubility and its dissociation constant, in addition to the pH value at the site of absorption, which in other terms is referred to as the rapid transcellular passive diffusion. In transcellular diffusion, movement of solute takes place through the cells, i.e., movement of glucose from GIT through the epithelial cell. Rapid transcellular passive diffusion of the drug results from either a high amount of unionized molecules, high log P (high lipophilicity), or a combination of both. Different physiochemical properties of the drug influence the selection of drugs for CRS. Diffusion of drugs from the biological membrane depends on the molecular weight as well as the lipophilic nature of the drugs. Solubility and ionization also important parameters for the selection of the drug, as drugs having low solubility are a poor candidates for CRS. The permeability of an ionized drug is low compare to an unionized drug so an ionized drug faces problem in the absorption of the drug. Drugs should have better stability in the environment of the GIT. 6.5 PHARMACOKINETIC FACTORS INFLUENCING THE DESIGN OF CONTROLLED RELEASE SYSTEM Pharmacokinetics provides the time course between the concentration of drug and target when developing optimal drug delivery system. The target in pharmacokinetics of a drug is the plasma concentration that is usually between the minimum effective concentration (MEC) and minimum toxic concentration (MTC), fluctuation from these results in unwanted side effects or lack of intended therapeutic benefits to the patient (Vazzana et al., 2015; Onoue et al., 2014). The major rate-limiting step is absorption for the drug to be bioavailable, but in the case of CRS, the rate-limiting step is the release of a drug from its dosage form. CRS is known for its ability to prolong and maintain the drug’s concentration within its therapeutic range for a longer period of time in order to increase the exposure of the drug to the maximum. Systems that are well-designed have been shown to display a narrow, expected residence time and drug release by a controlled mechanism. A detailed knowledge of the absorption, distribution, metabolism, and elimination of a drug is important in the design of a CRS. CRS is necessary because immediate release dosage forms cannot achieve the desired pharmacological action. Every pharmacokinetic parameter has a useful range for the design of CRS outside of which CRS design becomes difficult or impossible. In the following discussion, it is assumed that the level of drug in blood or body tissue parallels biological activity of the drugs. 6.5.1 Absorption In a CRS, an efficient absorption is required, because the rate-limiting step is the drug releasing rate. If a drug is absorbed through active transport, absorbed from a specific region of GIT, or absorbed slowly, it is not a good candidate for CRS since continuous drug release usually results in unabsorbed as well as accumulated drug substances. DOSAGE FORM DESIGN CONSIDERATIONS 6.5 PHARMACOKINETIC FACTORS INFLUENCING THE DESIGN OF CONTROLLED RELEASE SYSTEM 193 To obtain a constant blood concentration, the drug has to be released and then absorbed from the CRS in a uniform manner. The amount of drug absorbed from a conventional drug delivery system is sometimes quite low for various reasons, like degradation of the drug by solvolysis or metabolism, physical loss, protein bindings, and dose-dependent absorption (Dressman and Reppas, 2016; Carvalho et al., 2015). 6.5.2 Distribution Distribution of drug is an important parameter for the elimination kinetics of drug, because it lowers the drug’s concentration in the blood. The rate-limiting factor in the distribution of the drug is protein binding, which lowers the free amount of the drug in blood and makes it inactive for distribution as well as pharmacological action. Distribution of the drug is illustrated by the apparent volume of distribution, which is a hypothetical volume of body in which the drug is distributed. Apparent volume of distribution affects the amount of the drug in blood or the target sites and elimination rate kinetics of the drug (Kobayashi et al., 2014; Lee et al., 2013). 6.5.3 Metabolism The liver is known as the main organ in which the drugs’ metabolism process takes place; the metabolism process can either inactivate the drug or in other cases may convert the inactive drugs into active metabolites. This type of alteration also occurs in another organ of tissues having a rich amount of metabolic enzymes. A drug is a suitable candidate for CRS, if metabolized completely, but not in a rapid manner. The drugs metabolism extent has to be uniform and able to be predicted with various routes of drug administration. Certain drugs that either increase or decrease the metabolism are poor candidates for the CRS (Kamaly et al., 2016). 6.5.4 Elimination Half-Life The goal of CRS is to maintain the therapeutic blood concentration for an extended time within a range of the therapeutic window. Elimination is the main process for the drug removal, and t1/2 is the time to removal of 50% of drug from the body. A drug is a good candidate for CRS if the rate of absorption and rate of elimination are equal. Drugs having higher t1/2 are themselves extended systems and do not need to form a CRS. Drugs with smaller t1/2 within the range of 2 4 hours are good candidates for the CRS. If elimination t1/2 of the drug is less than 2 hours, it will then need to incorporate a higher amount of the drug in the dosage form (Lin et al., 2014; Ratnaparkhi and Gupta Jyoti, 2013). 6.5.5 Duration of Action The duration of action of pharmaceutical products has an important impact in the formulation of CRS; there are several factors affecting the drugs’ duration of action, which DOSAGE FORM DESIGN CONSIDERATIONS 194 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION are the distribution, metabolism, and the elimination of the drug. The t1/2 reflects the residence time of the drug inside the body. For drugs having higher elimination half-lives (more than 8 hours) are sufficiently sustained in the body, CRS is not necessary for that. Whereas drugs with short half-lives (less than 2 hours) undesirable dosage forms of large amounts of drug may result (Mitragotri et al., 2014). 6.5.6 Drug Protein Binding Drugs after administration usually bind to body components such as blood cells, tissue proteins, macromolecules, and plasma proteins. Drug protein binding is considered as a reversible process in most cases; where the bound drug is unavailable for liver binding, which results in a reduced rate of metabolism because drug protein complexes are not allowed to pass through the glomerular capillaries. Hence, only unbound drugs can be eliminated, and an increase in the elimination half-life of drugs is observed as a response to an increase in the drug protein binding. Drugs with high protein binding characteristics are not good candidates for the CRS (Nguyen and Alsberg, 2014; Elzoghby et al., 2011). 6.5.7 First-Pass Metabolism Defined as intestinal and hepatic degradation or alteration of a drug or substance taken by mouth, after absorption, removing some of the active substance from the blood before it enters the general circulation. The liver is usually assumed to be the major site of the first-pass metabolism of a drug administered orally, but other potential sites are the GIT, blood, vascular endothelium, lungs, and the arm from which venous samples are taken. Drugs in this category include amitriptyline, 5-fluorouracil, hydralazine, isoprenaline lignocaine, lorcainide, pethidine, metoprolol, morphine, neostigmine, nifedipine, pentazocine, and propranolol. Delivery of the drug to the body in desired concentrations is seriously troubled in the case of drugs undergoing extensive hepatic first-pass metabolism when administered in CR forms (Yanamandra et al., 2014). Drugs having variation in bioavailability because of the first-pass metabolism will make the formulation of CRS difficult, the problem of the drug loss would be dosedependent, and that would result in significant reduction in bioavailability if the drug is slowly released over an extended period. If a drug has an extensive first-pass metabolism, it affects the desired concentration for the therapeutic effect adversely (Ashford, 2017). Pharmacokinetic parameters like absorption, distribution, metabolism, elimination t1/2, duration of action, drug protein binding, and first-pass metabolism are some limiting factors in the development of CRS. All the limitations can be overcome and successfully controlled by using different approaches to CRS alone or in combination. However, the understanding of pharmacodynamic factors is also important as they affect the development of the product. DOSAGE FORM DESIGN CONSIDERATIONS 6.6 PHARMACODYNAMIC FACTORS INFLUENCING THE DESIGN OF CONTROLLED RELEASE SYSTEM 195 6.6 PHARMACODYNAMIC FACTORS INFLUENCING THE DESIGN OF CONTROLLED RELEASE SYSTEM 6.6.1 Drug Dose The dose of the conventional dosage form affects the selection of the drug as CRS. If the dose of the drug is high, it is not suitable for the CRS. Generally, 1.0 g dose of the drug is considered the maximum for the CRS. CRS is helpful in the reduction of the total dose of a drug required to treat a disease, resulting in a decrease in local or systemic side effects (Makadia and Siegel, 2011; Mansour et al., 2010). 6.6.2 Frequency of Dosing The number of times a dose of the drug is administered within a specific period is defined as the frequency of dosing. A reduced dose frequency has been observed in welldesigned CRS in addition to a maintenance of the steady drug concentration in the blood as well as in the target tissue cells (Mansour et al., 2010). Chandasana and coworkers have designed nanoformulation to reduce the dosing frequency of natamycin suspension (5%); initial frequency of dose include one drop hourly or two hourly reduced to one drop in every 5 hours, results showed an increase in patient compliance, prolonged release of natamycin, and studies showed reduction of dose to one-fifth of the initial one (Chandasana et al., 2014). 6.6.3 Margin of Safety The difference between the usual effective dose and the dose that causes severe or lifethreatening side effects is called the margin of safety. CRS candidate drugs must provide a wide therapeutic range so that the difference between the MEC and MTC should be high. The variations in the release rate should not be beyond this level. In developing the CRS for narrow therapeutic index drugs, it is very essential for the pattern of drug release to be accurate so that the concentration of the drug in the plasma is maintained within the effective and safe range (Chauhan and Patel, 2012; Gupta and Brijesh, 2012). Flecainide is an antiarrhythmic agent that has the potential to be considered a narrow therapeutic index, resulting in potential of proarrhythmic effects or lack of efficacy (Tamargo et al., 2015). 6.6.4 Role of Disease State Diseased states of the patient also affect the development of the CRS; on a few occasions, they are very important as drug properties. Pathological changes may affect the distribution and bioavailability of the drug by changing the physiological process. Altering the function of liver and kidney may affect the clearance of the drugs. For example, in designing an ocular CR formulation for an external inflammation, the time course of changes in protein content in an ocular fluid and the integrity of ocular barrier would have to be taken into consideration (Sharma et al., 2015b). DOSAGE FORM DESIGN CONSIDERATIONS 196 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION 6.6.5 Side Effects Conventional dosage forms have various side effects because the drug circulates in the blood. Drug targeting reduces the side effects caused by the drugs, as it reduces the circulation of drug to the nontargeted site. CRS is also helpful in reducing the gastric irritation caused by some drugs, by controlling the drug release rate which reduces the exposure of drug to GI mucosa. Injecting CTLA-4 blocking antibody in a slow-release formulation close to the tumor is an effective way of activating the antitumor T-cell response. This administration method is associated with very low serum levels of antibody, which decreases the risk of treatment-induced side effects (Fransen et al., 2013). 6.6.6 Disease Condition and the Patient Condition The CODAS (Chronotherapeutic Oral Drug Absorption System) drug delivery system is tailored to allow the release of the drug by circadian patterns of the disease in which in vivo drug availability is timed to match circadian rhythms of disease to optimize therapeutic outcomes and minimize side effects. Research has shown that certain diseases are affected by the rhythmic changes of the human body (e.g., heart attacks appear to be more likely to occur during the early morning hours than in the evening). For a formulation intended to treat Parkinson’s progression, in order to achieve the therapeutic activity at different levels of the disease, various formulation approaches have been conducted as drug delivery enhancers of anti-Parkinson’s disease drugs. Wen (2012) have summarized the anti-Parkinson’s disease drugs in addition to the underinvestigated prototypes intended for oral, transdermal, transmucosal, pulmonary, intranasal, rectal, and parenteral routes. These delivery systems are expected to be extremely important since they can increase the therapeutic efficacy while reducing the undesirable complications during treatment of Parkinson’s disease (PD) (Wen, 2012). Apart from therapeutic efficacy, the final goal of any formulation is to provide patient compliance and therefore we added a special mention for the patient compliance. 6.7 PATIENT COMPLIANCE It is a very important factor which is affected by a combination of several factors like a patient’s faith in therapy, awareness of disease process, regimens complexity, and degree of both the local and the systemic side effects of the formulations as well. Lack of compliance is generally observed with long-term therapy of the chronic disease conditions. The problem can be overcome to some extent by administering CRS. High pill burden is an important factor for patient compliance, which has been overcome through CRS by using less frequent dosing. By targeting the drug to specific parts of the body also reduces the side effects and increases the safety potential (Choi et al., 2010; Taghdisi et al., 2011). CRS maintains the steady state concentration for the longer duration of action and also reduces the side effects of the drug by delivering the maximum fraction of the dose at the specific target site of the action. The next section deals with the CR pattern from different formulations. DOSAGE FORM DESIGN CONSIDERATIONS 6.8 CONTROLLED RELEASE FROM DIFFERENT FORMULATIONS 197 6.8 CONTROLLED RELEASE FROM DIFFERENT FORMULATIONS: IMPORTANCE OF ROUTE AND EFFECT OF VARYING PROPERTIES 6.8.1 Oral Controlled Release Drug Delivery Systems Oral drug delivery is considered as one of the most desired routes of administration as compared to other routes, since it has been shown to be convenient, less costly, and highly complied by patients. About 90% of active pharmaceutical products are being used orally. The oral route has been the most popular and successful route for controlled delivery of drugs because of flexibility in dosage forms than other routes. The duration of action of many drug products after being orally-administered is shown to be dependent on the drug’s related properties which include the absorption rate, clearance, and residence time at the absorption site of the delivery system. Mostly, CRS’ residence time is basically determined by the process of gastric emptying along with the intestinal motility. The gastric emptying process has been reported to be influenced by various factors including hormonal and autonomic activity, volume, viscosity, composition, pH, osmolarity, temperature, caloric value, stomach contents, in addition to the presence of many other drugs (Sato et al., 2014). It is known that the proper site of absorption is typically the proximal and midintestine. Most delivery systems have a transit time of only 2 3 hours long. As a result, a SR formulation having a duration of about 12 hours or even longer can be only achieved by slowing the process of gastric emptying. Various approaches have been conducted to prolong the transit time of the GIT, i.e., tablet and capsule flotation, bioadhesive polymers, etc. For designing oral controlled drug delivery system, various new polymers have been developed and investigated to be administered orally with a CR profile. Zhang and coworkers have developed covalently cross-linked chitosan-poly (ethylene glycol) (PEG) 1540 derivatives designed for CRS with a delivery potential of protein drug (Jing et al., 2017). Hydrogels swelling characteristics are based on the developed derivatives as the function of different PEG contents along with the releasing pattern of the model protein (bovine serum albumin, BSA), where their evaluation has taken place in simulated gastric fluid in the presence and absence of enzyme, to evaluate the conditions of the GIT. Difunctional PEG1540-dialdehyde hydrogel and its cross-linked derivatives can swell in a medium of alkaline pH via reductive amination reaction and hence are shown to be insoluble in the acidic pH medium. A relatively low amount of BSA cumulative release amount has been reported in the first 2 hours and then increased at a pH value of 7.4, also affecting intestinal lysozyme for about 12 hours. Results have proven that the behavior of release-and-hold of the cross-linked CS PEG1540H-CS hydrogel has given a swell effect along with an intestinal enzyme CR carrier system, which has been shown to suit the formulation objectives of oral protein drug delivery systems (Jing et al., 2017). 6.8.2 Buccal/Sublingual Controlled Release Drug Delivery Systems There are two basic routes of absorption for orally-delivered drugs through the oral mucosa. Sublingually (under the tongue), and buccally (between the cheek and gingiva). The delivery of drugs via the two routes is considered a promising process since they DOSAGE FORM DESIGN CONSIDERATIONS 198 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION provide an easy way of administration and because of the considerably rich supply of blood and lymphatic vessels. Also, delivering drugs by the buccal/sublingual route provides drugs with a high permeability characteristics and good reproducibility as well. Drugs that are intended to be absorbed via the buccal mucosa were observed to directly enter the systemic circulation by jugular vein. This route of delivery has been reported to provide a considerably rapid onset of action as well as a protection toward the effect of hepatic first-pass metabolism, the hydrolysis effect of gastric acid, as well as the intestinal enzymatic degradation (Dam et al., 2013). Conventional dosage forms that follow the buccal and sublingual routes of drug delivery were observed to be typically short-acting, due to the limited observable contact time between the drug and the oral mucosa. Due to the interference of some factors with sublingually administered drugs, such as eating, drinking, and talking, the sublingual route is considered an unsuitable route of delivery when requiring a prolonged administration. On the other hand, saliva-activated adhesive troches were not associated with such problems as compared to sublingual administration. Unfortunately, the commercial success of buccal nitroglycerin adhesive troches has not been achieved yet (Kumar et al., 2016). 6.8.3 Parenteral Controlled Release Drug Delivery Systems The parenteral administration route is the most common and efficient for delivery of active drug substances with poor bioavailability and the drugs with a narrow therapeutic index. Practically, the parenteral administration is defined as injecting substances subcutaneously, intramuscularly, intravenously, or by intraarterial routes. However, the parenteral route offers rapid onset of action with rapid declines of systemic drug level. For the sake of effective treatment it is often desirable to maintain systemic drug levels within the therapeutically effective concentration range for as long as treatment calls for. It requires frequent injection, which ultimately leads to patient discomfort. For this reason, a drug delivery system which can reduce a total number of injections throughout the effective treatment, improves patient compliance as well as pharmacoeconomics (Lee et al., 2017). Administration of drug via this route is basically referred to as the process of introducing the drug substances directly delivered to the site of action without the need to pass through the GIT. Injections intended to be applied to certain body organs to achieve targeted delivery of drugs will be mentioned in many therapeutic areas. Drugs parenteral administration is now considered as a determined part of medical practice as it also reflects the most widely used method in drug delivery. For this reason, whatever drug delivery technology that can reduce the total number of injection throughout the drug therapy period will be truly advantageous not only regarding compliance but also for the potential to improve the quality of the therapy. Such reduction in the frequency of drug dosing is achieved, in practice, by the use of specific formulation technologies that guarantee that the release of the active drug substance happens in a slow and predictable manner. It may be possible to reduce the injection frequency from daily to once or twice monthly or even less frequently depending on the dose of several drugs. In addition to improving patient compliance, less frequent injection of drugs in the form of depot formulation smoothes out the plasma concentration-time DOSAGE FORM DESIGN CONSIDERATIONS 6.8 CONTROLLED RELEASE FROM DIFFERENT FORMULATIONS 199 profiles by eliminating the peaks and valleys. Such smoothing out of the plasma profiles has the potential to not only boost the therapeutic benefit but also to reduce unwanted events and side effects (Gilroy et al., 2016). The release can either be continuous or pulsatile depending on the structure of the device and the polymer characteristics, continuous release profiles are suitable to generate an “infusion like” plasma level time profile in the systemic circulation without the necessity of hospitalization. 6.8.3.1 Intravenous Controlled Release Drug Delivery Systems The intravenous route of administration is attractive since drugs are directly introduced into the systemic circulation, which in turn gives an immediate response. However, intravenous injection of SR drugs is considered as a challenge for drug developers. Continuous infusion of intravenously injected drugs can be tailored to assess a constant as well as a sustained drug concentration within a proper therapeutic range during the whole treatment period. Nevertheless, numerous factors stand behind the lack of commercially intravenous products with SR characteristics (Naahidi et al., 2013). Thus, to avoid the blockage result of the body’s small capillaries, it is essential that only extremely small particles should be used for physical systems during the formulation of intravenous injections. However, the reticuloendothelial system (RES), which basically consists of the spleen, lung, liver, and bone marrow, is responsible for the rapid removal of the foreign substances out of the blood, which in turn makes it difficult to obtain a sustained drugs release via this route (Mitragotri et al., 2014). However, due to the abovementioned reasons and due to the introduction of various drug delivery technologies, it is possible to reduce the total number of the given injections throughout the period of the treatment therapy, which is obviously advantageous not only for the sake of compliance but, also for quality improvement of the therapy itself. Depottype of parenteral CR formulations has been reported to increase the benefits of continuous intravenous infusion route with the avoidance of its potential distress. Many approaches have been used, such as viscous vehicles, suspension formulations, and sparingly soluble derivatives as well (Householder et al., 2015; Lam et al., 2015). Another investigation suggested the factors influencing the biodistribution of Poly(lactic acid)-poly(ethylene)glycol (PLA)-PEG nanoparticles and payload in rats and mice to characterize PLA-PEG nanoparticles as a platform for drug delivery. The dose-linearity and the absence of saturation effects in nanoparticle biodistribution at injected doses of up to 140 mg/kg demonstrate the predictability of this platform. In accordance with the expectations, the degree of PEGylation is considered as a significant factor in the determination of the “stealthiness” of PLA-PEG nanoparticles: nanoparticles containing less PEG are more prone to elimination from the bloodstream by the organs of the RES, which results in a lower amount of drug delivery to the proper site of action (Meunier et al., 2017). The ongoing clinical protocol for therapy using CR-nanocarriers is intravenous injection followed by local targeting to the cancer site. 6.8.3.2 Intraarterial Controlled Release Drug Delivery Systems Injecting the drug substance directly into the arteries is considerably an uncommonly used route for therapeutic drug administration. Intraarterial drug administration has been DOSAGE FORM DESIGN CONSIDERATIONS 200 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION reported to be associated with several safety implications, i.e., arterial occlusion, embolization, and localized drug toxicity as well (Luigi and Kennedy, 2016). The majority of intraarterial injections or even the arterial perfusions via catheters that are placed in the arteries are intended for regional chemotherapy treatments of some body organs and limbs (Kitano et al., 2014; Paul and Sharma, 2014). Intraarterial chemotherapy is a treatment that is basically used for malignant brain tumors. This treatment has been proposed to target diclofenac sodium to the proper site of action via magnetic gelatin microspheres. The gelatin magnetic microspheres that are loaded with 8.9% w/w of diclofenac sodium and 28.7% w/w of magnetite were produced by the process of emulsification/cross-linking with glutaraldehyde. The formulated microspheres were then given as an intravenous injection after achieving a suitable magnet right near the target area. An encapsulated form of diclofenac sodium was released slowly for longer than 18 days (Qi et al., 2016). 6.8.3.3 Intramuscular Controlled Release Drug Delivery Systems Intramuscular (IM) route of administration, involves the crossing of drugs through one biological membrane or more to be able to enter the systemic circulation at the end. Intramuscular injection is considerably applied in the case of drugs and vaccines that are unable to be absorbed orally. Examples of such drugs include insulin, aminoglycosides, and hepatitis vaccine. The IM route of administration is often applied for sustained medication and specialized vehicles, i.e., (aqueous suspensions, complexes, oily vehicles and microencapsulation), to provide slow drug delivery (Hamidi et al., 2013; Guo et al., 2017). 6.8.3.4 Subcutaneous Controlled Release Drug Delivery Systems Drug delivery by this route involves introducing the drug through a layer of subcutaneous fatty tissue by using a hypodermic needle. Factors including the size of the molecules, the anatomical characteristics of the injection site, and the viscosity, in addition to the vascularity and fatty tissue amount, were shown to influence the drug’s rate of absorption delivered by the subcutaneous route. Subcutaneous injections show a considerably lower absorption rate and a slower onset of action as compared to intramuscular or even intravenous routes of administration. A way to enhance the absorption rate of drugs is achieved by the process of infiltration with the enzyme hyaluronidase (Bhusal et al., 2016). Several self-administered subcutaneous injection systems have been developed and shown to include conventional syringes, pen pumps, prefilled glass syringes, needleless injectors, and the autoinjectors as well. Subcutaneous route is still considered as a predictable route of delivery for peptides and macromolecules (Mulyasasmita et al., 2014; Choonara et al., 2014). MEDIPAD (Elan Pharmaceutical Technologies), which is referred to as a combination of “patch” concept and a complex miniaturized pump operated by the generation of gas, is considered as an example of refinement of subcutaneous delivery that is observed to be highly convenient and less costly for prolonged and repeated delivery (Gong et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 201 6.8 CONTROLLED RELEASE FROM DIFFERENT FORMULATIONS 6.8.4 Transdermal Controlled Release Drug Delivery Systems Skin basically comprises two layers, one is the epidermis, and the other is the dermis, and the two layers are separated by a basement membrane zone. Delivering the drug through the skin has benefits of easier accessibility, more convenience, prolonged therapy as applied to the larger surface area, and also avoidance of first-pass metabolism (Gupta, 2014; Maity, 2016). A drug’s passage through the stratum corneum layer is known as the rate-limiting step during the percutaneous absorption (Tekade et al., 2017c). Drug movement pathway through the stratum corneum is believed to mainly be a transcellular movement, although drugs of small molecular weights move through the paracellular pathway (Marwah et al., 2016; El Maghraby, 2017). In addition to serving as a barrier to drug diffusion, the stratum corneum layer also functions as a reservoir for certain drugs including corticosteroids, Griseofulvin, and many others. In most cases, drugs are carried away when reaching the subcutaneous tissue by a capillary network, whereas in other cases, some drugs, i.e., thyroxin, estradiol, β-methoxypsoralen, and corticosteroids, were shown to stay in in the subcutaneous layer for an extended period (Wang et al., 2016; Kassem et al., 2017; Yang et al., 2015). Traditionally, topical dermatological formulations were intended to be used for local diseases of the skin. Nowadays, after the considerable understanding of the skin anatomy and physiology, in addition to the better understanding of the percutaneous absorption and the skin’s limited permeability, they have also been used for systemic treatments (Wiedersberg and Guy, 2014). The drugs’ transdermal route of application has been reported to combine the benefits of the oral route of administration, and the intravenous infusion route as well (Table 6.1). Transdermal drugs application has been reported to be even more advantageous as compared to other controlled-release formulations. On the other hand, some limitations are associated with this route, including the variation in the efficiency of absorption at different sites of the body skin, the adhesion difficulty related to certain skin types, along with the required time period for which the intended patch is to be left in any affected area due to the permeability changes associated (usually not more than 7 10 days) (Azagury et al., 2014). TABLE 6.1 Advantages of Transdermal Drug Delivery System Over Other Devices Advantages Oral i.v. Transdermal Reduced first-pass effects No Yes Yes Constant drug level Noa Yes Yes Self-administration Yes No Yes Unrestricted patient activity Yes No Yes Noninvasive Yes No Yes a Sometimes can be achieved with controlled release. Transdermal delivery of therapeutic agents offers some potential benefits such as, issues like significant presystemic metabolism are circumvented, i.e., direct prevention of degradation of drug in gastrointestinal tract or in liver. DOSAGE FORM DESIGN CONSIDERATIONS 202 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION Ethylene vinyl acetate (EVA) is a commercial excipient that is considered to be wellinvestigated for dosage forms of SR characteristics. EVA has been shown to be featured by good properties and a respectable compatibility to various manufacturing processes of pharmaceutical formulations, which have enabled it to be used in dosage forms of complex characteristics to deliver active pharmaceutical ingredients of a wide variety. APIs were shown to be delivered in vivo from implants of EVA-base such as the soluble and insoluble small molecules, nucleic acids, peptides, and proteins in addition to growth factors and monoclonal antibodies. Several studies have shown that EVA is an inert excipient when added to drug molecules, stable under human body conditions and hence, ideal for the long-term use as an implantable drug (Schneider et al., 2017; Cilurzo et al., 2014). Castleberry et al. have presented a new topical delivery concept for retinoids by bonding the drug through a covalent ester linkage that is considerably hydrolytically degradable to a polymer of respectable hydrophilicity, polyvinyl alcohol (PVA), which then tends to create nanomaterial of amphiphilic characteristics that is at the same time water soluble. This PVA bound all-trans retinoic acid (ATRA) can function as a prodrug that accumulates after the topical application within the skin, and allows for ATRA sustained controlled delivery. This concept was established to in vitro release the active ATRA for 10 days while observably enhancing the accumulation of the active material within the pig skin. In vivo applications have demonstrated that the prodrug has reduced the application on the site of inflammation as compared to the free form of ATRA and has retained the drug on the application site for up to 6 days (Fig. 6.5) (Castleberry et al., 2017). 6.8.5 Ocular Controlled Release Drug Delivery Systems The eye is the specialized photoreception sensory organ, which is featured by its considerable ease of accessibility for local or even systemic drug delivery formulations (Lalu et al., 2017). The drug is eliminated from the precorneal region within 1 2 min after application when instilled as an aqueous solution. About less than 3% of the dose applied can penetrate the aqueous humor. Therefore, a brief and frequent dosing is needed (Patel et al., 2013; Kang-Mieler et al., 2014). There are two common approaches that are used to extend the duration of drug action in the eye, these are: (1) the slowdown drainage that is achieved by using viscosityenhancing agent, suspension, emulsion, ointments, as well as the erodible and the nonerodible matrices; and (2) the improvement of the corneal penetration of drug by using ionophores, ion-pairs, liposomes, in addition to nanoparticles or nanocapsules and prodrugs as well (Morrison et al., 2017; Chen et al., 2016; Sharma et al., 2015b; Cholkar et al., 2013). Viscous solution and hydrogels are based on the addition of hydrocolloids to aqueous drug solution. The most common polymers used in such formulations are cellulose derivatives, carbomers, PVA, polyvinyl pyrrolidone (PVP), and hyaluronic acid. Gel formulations provide a longer residence time of the active drug in the precorneal region as compared to viscous solutions. Hence, gel drug formulations have appeared to be more acceptable in the conjunctival cul-de-sac. Such formulations are typically described as in situ gel forming systems (Achouri et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS 6.8 CONTROLLED RELEASE FROM DIFFERENT FORMULATIONS 203 FIGURE 6.5 Retention of PATRA in the skin of mice.(A) IVIS imaging of fluorescently labeled PATRA over 7 days. Unconjugated dye is seen to disappear after only 2 days while PATRA conjugated dye stays for up to 5 days. Material was added at two locations on the midline of the backs of mice. (B) Quantification of total radiant efficiency for each application site for PATRA and dye treated mice. (C) Half-life and t95 measured from first-order exponential fits of fluorescent data. Source: Adapted with permission from Castleberry, S.A., Quadir, M.A., Sharkh, M.A., Shopsowitz, K.E., Hammond, P.T., 2017. Polymer conjugated retinoids for controlled transdermal delivery. J. Controlled Release, 262, 1 9. Polymers’ bioadhesion was shown to reduce the drainage loss of drug after instilling ophthalmic formulations, in addition to the improvement of drug absorption as well as the prolonged action of local treatments. Many polymers of high molecular weights and various functional groups (such as carboxyl, hydroxyl, amino, and sulfate) are shown to be capable of forming hydrogen bonds along with their ability to cross various biological membranes, and such polymers have been established as possible mucoadhesive excipients in the formulation of ocular delivery systems (Maheshwari et al., 2012, 2015b). Ophthalmic inserts (films, erodible, and nonerodible inserts, rods, and shields) are aimed to remain in front of the eye for a long period. Such solid devices are placed in the conjunctival sac and are typically used for drug delivery at a considerably slow rate (Sharma et al., 2015b). 6.8.6 Nasal Controlled Release Drug Delivery Systems A few years ago, the nasal cavity was considered as an alternative route to deliver drugs, which attracted the researchers and formulators in the pharmaceutical industry. Nasal formulations were more specifically intended for the systemic drug delivery that DOSAGE FORM DESIGN CONSIDERATIONS 204 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION can be delivered only by drug injection formulation. Nasal drug delivery route has been reported to be an advantageous route due to its rich blood supply, high accessibility, noninvasiveness, low overdose risks, in addition to the possibility to be self-medicated (Touitou and Illum, 2013). Nasal drug delivery route is considerably more favorable for drugs that are intended to be given in small doses and usually require rapid onset of action, in addition to their extensive GI and hepatic degradation, and is mainly used for chronic diseases (Alagusundaram, 2016). As compared to other biological membranes, the nasal cavity was reported to differ in its physicochemical properties including the charge and lipophilicity which in turn may not be of an observable importance for transnasal delivery of drugs having molecular weights of less than 300 Da. It was also reported that small molecules are absorbed via the membrane’s aqueous channels (Deutel et al., 2016). Factors associated to the anatomy and physiology of the nasal cavity were shown to be responsible for affecting nasal absorption; these factors include the transportation through the membrane, drug deposition, enzymatic degradation, as well as the mucociliary clearance. The relative bioavailability of small nasal formulations having lipophilic properties has been reported to be approximately 100% with a good absorption profile. On the other hand, the relative bioavailability of macromolecules such as proteins and polar drugs of molecular weights greater than 1000 Da are considerably low and range from 0.5% to 5% owing to a considerable low permeability characteristics through the membrane (Djupesland et al., 2014; Sánchez-López et al., 2017). Delivering drugs by the nasal route protects the formulation of the hepatic first-pass metabolism. Nevertheless, the pseudo-first-pass effect is still a concern in the nasal drug delivery. Enzymes such as carboxylesterase, glutathione transferases, aldehyde dehydrogenase, epoxide hydrolases, uridine diphosphate (UDP)-glucoronyl transferase, cytochrome P (CYP)-dependent monooxygenases, exo- and endopeptidases, as well as proteases, were shown to take place in the nasal mucosa. CYP enzymes have been reported to abundantly present in the olfactory epithelium (Alagusundaram, 2016). Substances intended to deposit within the nasal cavity were shown to possess a slow absorption and clearance in about 15 20 minutes by mucociliary clearance. Nasal formulations have to deposit and remain within the nasal cavity for a sufficiently long period to achieve effective drug absorption. Aerosols, as well as particulate dosage forms, have to comprise particles with sizes greater than 4 µm to minimize the possible passage into the lung, in which mucociliary mechanism of clearance will act by removing most of the particulate materials. However, before developing nasal delivery drugs as an alternative systemic absorption route, it is essential to sufficiently understand the control of reproducible particle deposition in the nasal cavity, the interaction of drug particles with the mucus, in addition to the understanding of the disease states of nasal mucosa that may influence the rate and the extent of drug absorption (Fortuna et al., 2014; Djupesland, 2013). CR intranasal formulations are aimed to use a bioadhesive delivery system to prolong the contact time of the drug to achieve both an increase in drug release along with a sustained characteristics. Several systems are intended for delivering CR intranasal formulations, including liquid solution, emulsion, gel, powder, microspheres, liposomes, and nanoparticles. One of the most commonly used bioadhesive polymers is chitosan. DOSAGE FORM DESIGN CONSIDERATIONS 6.8 CONTROLLED RELEASE FROM DIFFERENT FORMULATIONS 205 Pectin-based nasal liquid preparations have also been tried since pectin gels on contact with nasal mucosa (Sherje and Londhe, 2017; Jafarieh et al., 2015; Casettari and Illum, 2014). In situ nasal gelling systems with smart polymers (stimuli-responsive polymers) came into the picture. These polymers are liquid at room temperature, and can be instilled easily or sprayed in the nasal cavity and where they attain semisolid or gel form to get retained in the nasal cavity. Nasal cavity has the temperature of about 32 6 2 C and pH 5.5 6.5 and also mucous secreted by nasal submucosal glands comprises of sodium, calcium, and potassium ions. In response to these conditions certain temperature, pH, and ion responsive polymers can undergo reversible gelation upon exposure to the nasal cavity and can be used in delivering the drug in a controlled manner (Karavasili and Fatouros, 2016; Chonkar et al., 2015). Glucocorticoids and sympathomimetic amines were used in intranasal formulations to exert their local effects on the nasal mucus membrane (Laccourreye et al., 2015). Absorption of these drugs systematically may cause undesirable effects, i.e., hypertension. Nasal mucosal epithelium has a noteworthy absorptive profile, in addition to its capability to absorb intact complex peptides that are unable to be administered orally because they might be exposed to digestion. This has provided an area of therapeutics that was prelimited by the undesirable repeated injections. Nasally administered drugs include (DDAVP, an analog of antidiuretic hormone) for the treatment of diabetes insipidus (Murakami et al., 2014; Kataoka et al., 2015) and buserelin (gonadotrophin-releasing hormone analog) for prostate cancer (Fortuna et al., 2014; Labrie, 2014). Gulati et al. have successfully formulated sumatriptan succinate-loaded chitosan nanoparticles by using the ionotropic gelation technique based on the Taguchi design for optimization purposes. The resultant nanoparticles were shown to penetrate the nasal mucosa easily due to the desired particle size that was achieved. The formulation has provided a sustained drug release up to 24 hours, which in turn can help to reduce the multiple daily doses required to only once per day (Gulati et al., 2013). 6.8.7 Pulmonary Controlled Release Drug Delivery Systems Pulmonary route is referred to as a noninvasive administration of therapeutic agents intended for systemic delivery (often peptides and proteins), because lungs were observed to provide a large surface area for drug absorption (up to 100 m2) but extremely thin mucosal absorptive membrane (0.1 0.2 µm) in addition to a good blood supply. However, recently, several promising advances have been established. However, the delivery of peptides- or protein-based drugs as pulmonary formulations is considered as a very complicated route due to the anatomic complex structure of the respiratory system as well as the deposition effect associated with the respiration process (Martin and Finlay, 2015). Pulmonary drug delivery has become an interesting target that is of significant scientific and biomedical benefits in the area of health care research because the lung has reflected an ability to absorb pharmaceutical substances efficiently for both local deposition and the systemic delivery. Respiratory epithelial cells play a significant role in the airway tone regulation and the airway lining fluid production. Therefore, an increased attention has been DOSAGE FORM DESIGN CONSIDERATIONS 206 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION provided to the pulmonary route potential as a noninvasive route of administration intended for both systemic and local delivery of drug substances, due to the considerably high permeability characteristics, the large area of absorption of lungs (about 70 140 m2 in adult humans with extremely thin (0.1 0.2 µm) absorptive mucosal membrane) and the good blood supply (Paranjpe and Müller-Goymann, 2014; Pham et al., 2015). The alveolar epithelium in the distal lung is considered as the absorption site for the majority of drugs and macromolecules. Furthermore, pulmonary drug delivery has been shown to be more advantageous as compared to the oral route since pulmonary formulations are less susceptible to enzymatic degradation, have rapid absorption, in addition to the higher capacity to overcome the hepatic first-pass metabolism. It was reported that local respiratory diseases, as well as some systemic diseases, are capable of being wellcontrolled by the use of pulmonary formulations. Presently, formulations including intravenous biotherapeutics such as growth hormones, glucagons, or insulin, are capable of being given by inhalation, and experiments have also shown that drug delivery by inhalation is more efficient. It is essential to understand the mechanisms of transport and deposition of aerosols to obtain an efficient inhalation therapy (Beck-Broichsitter et al., 2016; Hittinger et al., 2015). Pulmonary formulations are administered by two techniques: the first is the aerosol inhalation (that is also used for intranasal applications) and the second is the intratracheal instillation. The aerosol technique has been shown to provide a uniform distribution with a relatively great extent of penetration through the alveolar or the peripheral regions of the lung. However, this technique is considerably costlier and exhibit some difficulties regarding dose measurements inside the lungs. Whereas the instillation technique is simpler, less expensive, and does not provide a uniform distribution of drugs (Sellers et al., 2015). Bailey et al. have produced formulations of nanosized particles to be delivered by the pulmonary route. Pulmonary nanoparticles have provided new options for dosage forms of dispersed liquid droplets including metered dose inhalers and nebulizers, and dosage forms of dry powder as well. Pulmonary nanoparticle formulations have been shown to be more advantageous over the traditional formulations, and advantages include the enhanced dissolution profile and the higher potential to deliver drugs intracellularly. Specifically, polymeric nanoparticles, pure drug nanoparticles, drug-loaded liposomes, and polyelectrolyte complexes were shown to offer interesting results for drug delivery to and through the lungs (Soni et al., 2016). Other techniques are also being investigated to formulate nanoparticles with the desirable properties that aim to improve the access of drugs to the peripheral lung (Ruiz et al., 2016; Bailey and Berkland, 2016). 6.8.8 Rectal Controlled Release Drug Delivery Systems To avoid the limitations associated with the oral route of drug delivery. Much attention has been concerned with the rectal route of drug delivery. Rectal drug delivery has counted for various advantages that most importantly include the protection of drugs from the hepatic first-pass metabolism. The human rectum is about 15 20 cm long. Rectum does not show active motility during the resting state, and in the normal condition, rectum is empty except for about 2 3 mL of inert mucous fluid (pH 7 8) having no DOSAGE FORM DESIGN CONSIDERATIONS 6.8 CONTROLLED RELEASE FROM DIFFERENT FORMULATIONS 207 enzymatic activity or even buffering capacity. Due to the absence of villi or microvilli in the rectal mucosa, a very limited surface area of about 200 400 cm2 has been reported to be available for drug absorption. Rectum internal volume is mainly dependent on the exerted pressure resulting from the surrounding organs and affecting the rectum area. This pressure in addition to the active motility can influence the spreading efficiency of the dosage form (Seo et al., 2013). Blood and lymphatic vessels have accounted for a considerable abundancy in the rectal submucosal region. Nevertheless, the bioavailability of the systemic formulations have been shown to be dependent on the absorption site of the rectum, the rectal motility, and the animal species (Allen and Ansel, 2013). Rectal formulations were shown to have a slow rate of absorption to a lesser extent if compared to oral administration of a certain dose of drug. Rectal route was used for a long time only for specific therapeutics that include local anesthetics, vermifugal, antihemorrhoidal, and laxative agents (Candy et al., 2015; Muir and Hubbell, 2014). 6.8.9 Vaginal Controlled Release Drug Delivery Systems The vaginal region is described as a fibromuscular tube of about 10 15 cm long that extends in an upward and a backward direction that arises from the vulva until reaching the lower uterine cervix. The vagina is supplied by blood through the uterine and pudendal arteries. Blood is being drained from the vaginal region by a rich plexus that flows directly into the internal iliac veins. Vaginal epithelium surface is typically moist with cervical secretions (Vanić et al., 2014). Vaginal fluid features a pH ranging from 4 to 5. Drugs intended to be delivered by the vaginal route are mostly used for local effects. Nevertheless, vaginal absorption is also capable of providing rapid as well as efficient systemic delivery. Due to the efficient systemic absorption along with the ability to retain delivery devices, many vaginal therapeutics have been formulated, particularly, for steroid contraceptives. There are numerous numbers of vaginal CR formulations recently available, such as biodegradable microspheres and vaginal rings (das Neves et al., 2015; Wu et al., 2015a; Notario-Pérez et al., 2017). Zhang and coworkers have developed an intravaginal ring (IVR) that contains drospirenone. In IVR, a hot vulcanization technique with silicone elastomer acting as a matrix polymer is used to provide the core intended for drug loading. The drug-loaded core has been encapsulated by the same silicone elastomer polymer membrane. Daily drug release from the reservoir system was approximately 0.5 mg, which sustained this releasing rate for about 21 days, in addition to a significantly decreased burst effect as compared to the matrix system. When the drug is modified by PVPk30, the daily release quantity has been shown to increase and sustain for about 21-days at a release rate of 1.0 mg/day (Zhang et al., 2013). 6.8.10 Intrauterine Controlled Release Drug Delivery Systems Human uterus appears as a pear-shaped muscular structure, of a length that accounts for about 3 in. by 2 in. in width, consisting of fundus, thymus, and cervix. Uterus wall has basically three layers that are the perimetrium, myometrium, and endometrium. Uterus DOSAGE FORM DESIGN CONSIDERATIONS 208 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION typically faces dynamic changes regarding its size and shape during the menstrual cycle different phases. Drugs of high molecular weights and peptides, particularly hormones, are typically given parenterally due to the poor absorption properties and the susceptibility to be degraded in the GIT. For a suitable therapy optimization, it is more recommended to avoid the parenteral route of drug delivery as much as possible. New improvements include the long-acting contraceptives formulations: Hormonal intrauterine device (Mirena—also known as intrauterine contraception (IUC) or intrauterine system (IUS)), nonhormonal intrauterine device with copper (US—Paragard) (Kleiner et al., 2014). An application of IUS based on EVA is Progestasert. Progestasert releases progesterone from a T-shaped intrauterine platform for one year. The platform is an EVA membrane that is known to control the rate of progesterone release from a silicone oil reservoir. The benefits of an EVA IUS over the incumbent oral dosage forms are the minimization of the serum levels of the drugs, annual replacement of the drug, and the hormonal side effects (Schneider et al., 2017). 6.9 DRUG TARGETING USING CONTROLLED RELEASE SYSTEM Treatment of disease via conventional therapy requires an excess amount of drug dose to provide an efficient drug delivery to the cells, tissues, or organs to achieve the required effective concentration at the receptor site, which may result in unwanted adverse effects related to other body sites rather than the target site. The main aim of drug targeting is to provide the desired pharmacological effect at a particular site without any side effects (Mitragotri et al., 2014). There are many diseases having a challenge in their treatment, i.e., treating cancer, in general, requires technology for a controlled targeted drug delivery and release to eradicate tumor cells while sparing normal cells. Nanoparticles display promise for overcoming the fundamental problem of multidrug resistance in targeted cancer therapies. Rodzinski et al. used magnetoelectric nanoparticles (MENs) to control drug delivery and release. The physics is due to electric-field interactions (1) between MENs and a drug and (2) between drug-loaded MENs and cells. MENs distinguish cancer cells from normal cells through the membrane’s electric properties; cancer cells have a significantly smaller threshold field to induce electroporation. MENs and control ferromagnetic and polymer nanoparticles conjugated with HER2-neu antibodies, all loaded with paclitaxel were administrated intravenously weekly. According to the results, only the mice which were subjected to the magnetic field treatment following each weekly injection of PTX-loaded MENs were completely cured of the tumor after approximately 3 months of weekly i.v. injections as confirmed through infrared imaging and posteuthanasia histology studies via energy-dispersive spectroscopy and immunohistochemistry (Fig. 6.6) (Rodzinski et al., 2016). By the development of CRSs using different types of polymers, it is possible to achieve temporal (time CR) and/or spatial (site specific) control over the release of drugs which may reduce the unwanted side effects. DOSAGE FORM DESIGN CONSIDERATIONS 6.10 CURRENT DEVELOPMENTS IN CONTROLLED RELEASE FORMULATIONS 209 FIGURE 6.6 A mouse cured throughout the treatment. (A) Tumor photographs at its peak on July 11 (268 mm3) and on October 13 (no visible tumor). (B) IR images (with fluorescent agent Her2Sense 645 taken before (top) and after the completion of the MEN treatment. The agent had excitation and emission maxima at 643 and 661 nm, respectively. Source: Adapted from Rodzinski, A., Guduru, R., Stimphil, E., Stewart, T., Liang, P., Runowicz, C., et al., 2016. Targeted, controlled anticancer drug delivery and release with magnetoelectric nanoparticles. AACR 6 20867 (Open access). 6.10 CURRENT DEVELOPMENTS IN CONTROLLED RELEASE FORMULATIONS The field of CRSs is well recognized and continually presents many promising technologies for future drug delivery. CRSs improve the performance of a drug by controlling its releasing rate and extent. Currently, various technologies of CRS are basically based on polymers of various properties, many of these polymers were reported to be safe for the use of drug delivery. Technologies of controlled drug delivery have been established over the last six decades. This establishment began in the year of 1952 when the first SR formulation was introduced. Between 1950 and 1980 first generation drug delivery basically focused on the development of SR systems for both oral and transdermal use and the establishment of controlled drug release mechanisms as well. Moreover, between 1980 and 2010, the second generation of drug delivery was concerned with the developing zero-order release systems, long-term depot formulations, self-regulated drug delivery systems, and nanotechnology-based delivery systems (Park, 2014). Jing et al. (2017) have successfully used a new simple method to formulate a crosslinked chitosan with PEG. Pegylation method of chitosan has resulted in a hydrogel that improved the protein release with less toxicity. The study revealed that the release-andhold behavior of the cross-linked CS PEG1540H-CS hydrogel delivered a swell and DOSAGE FORM DESIGN CONSIDERATIONS 210 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION FIGURE 6.7 Release-andhold behavior of BSA from CS PEG1540H-CS hydrogels in pH-gradient. Source: Adapted with permission from Jing, Z.-W., Ma, Z.-W., Li, C., Jia, Y.-Y., Luo, M., Ma, X.-X., et al., 2017. Chitosan cross-linked with poly (ethylene glycol) dialdehyde via reductive amination as effective controlled release carriers for oral protein drug delivery. Bioorg. Med. Chem. Lett., 27 (4), 1003 1006. intestinal enzyme CR carrier system, which is suitable for oral protein drug delivery (Fig. 6.7). The derivatives of synthesized PEG-chitosan are considered as good carriers for the oral CR delivery of biomolecules including proteins, peptides, and nucleotides. Bajpai et al. (2017) successfully employed Gum acacia/poly(sodium acrylate)-based hydrogels to deliver the antibiotic drug doxycycline through oral route. The most widely commercialized CR technology is the OROS, which was developed by Alza (Johnson & Johnson). These systems are composed of a tablet core that contains a drug of respectable water solubility in addition to osmotic agents including sugars, sodium chloride, and hydrophilic polymers. The tablet core involves an external coating of a semipermeable polymer, i.e., cellulose acetate, which provides permeability for water while preventing the permeation of the drug. Within the GIT, aqueous materials enter the OROS tablet through the membrane and tend to push the drug outside the delivery orifice in a release rate that was reported to be controlled and constant (Conley et al., 2006; Wang et al., 2014b). Drugs of poor water solubility were shown to be incompletely released. Alza Corporation has made improvements on the OROS push-pull technology, in which tablets were composed of several drug layers in addition to a push layer—a water-swellable polymer—located at the bottom. The swollen layer tends to push a solution from the upper layers outside through the delivery orifice. L-OROS has been developed mainly for drugs with high water solubility (i.e., hormones and steroids) and liquid drugs, consisting of a soft-gel that is filled-up with a liquid and coated with multiple layers. An example of such systems includes the osmotic push layer and the semipermeable layer. The internal osmotic layer forces the liquid drug to move out from the delivery orifice that is typically present in the outer layers of the coated capsule. Glucotrol XL (glipizide extended release, Pfizer) and Procardia XL (nifedipine extended release, Pfizer) are classic examples of OROS tablets (Ghosh and Ghosh, 2011). Astellas Pharma (Tokyo) has developed a dosage form that provides the incorporation of a polymer having the highly water-retaining capacity that tends to drag and retain water during GIT transit, which then uses colon’s drug releasing medium—where only a DOSAGE FORM DESIGN CONSIDERATIONS 6.11 PATENTED CONTROLLED RELEASE DRUG DELIVERY SYSTEMS 211 little surrounding fluid is there—to facilitate both the drug’s release and absorption. This Oral Controlled Absorption System (OCAS) technology has been applied to tamsulosin and with the brand of Alna OCAS, Omnic OCAS, Flomaxtra XL, Urolosin OCAS, and Prof T. These reformulated products not only show higher night-time maintenance of plasma concentrations but also no change to their pharmacokinetic profiles by food (Wang et al., 2014a; Park, 2014). TIMERx CR tablet formulation tend to form a hydrophilic matrix within the aqueous media that controls the release of the drug for 24 hours. Its advantages include costeffectiveness, ease of manufacture, good patient compliance, and suitability to a wide variety of actives with different drug loading and solubility. Different release profiles are assessed by adjusting two constituent polysaccharides (xanthan gum and locust bean gum) that slow the penetration of water into the formula and thereby control drugs release (Martin et al., 2016). In the design of CRS polymers have played an integral role in the advancement of drug delivery technology by providing CR of therapeutic agents in constant doses over long periods, cyclic dosage, and tunable release of both hydrophilic and hydrophobic drugs. In the next section, we discuss some of the patented technologies which used different types of polymers for the designing of innovative CRS. 6.11 PATENTED CONTROLLED RELEASE DRUG DELIVERY SYSTEMS Lv and coworkers have developed Ranitidine bismuth citrate intragastric floating SR tablet which is composed of a tablet core containing ranitidine bismuth citrate and a coating film wrapped around the tablet core. The tablet core is prepared from raw materials at least containing, by weight, 110 120 parts of ranitidine bismuth citrate, 30 60 parts of skeletal material, 5 20 parts of a foaming agent, and 45 130 parts of a bleaching assistant. The coating film accounts for 1% 5% of the weight of the tablet. The tablet provided by the invention can effectively adjust the rate of constant speed release of the drug ranitidine bismuth citrate and enables a steady and lasting effective plasma concentration to be obtained, so side effects of the drug, frequency of administration, and influence of the drug on an in vivo environment are reduced, and compliance of a patient is improved (Lv et al., 2013). Zhao et al. have prepared xanthan gum vildagliptin intragastric retentive floating SR tablet. Substrates degraded by dipeptidyl peptidase (DPP-IV) are extensive, so the DPP-IV inhibitor has a potential effect on blood pressure, immune system, and the like; and the drug has a short half-life, so new technology is necessary to the increase the period with an effective drug concentration, the increase of bioavailability, and the reduction of side effect. The invention adopts xanthan gum as a skeleton, and some additives are added to facilitate the decrease of the preparation density, and the prevention of skeleton hydration. The invention mainly solves the problems of release speed control, drug release from the skeleton by a corrosion mechanism, and optimization of prescription drug release characteristics to meet a Higuichi equation, and thus increases the bioavailability and prolongs the action time (Zhao et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS 212 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION Zhang et al. have prepared an intragastric floating type cuttlebone SR tablet for treating gastric ulcer is prepared from the following raw materials: cuttlebone, nanomontmorillonite, hydroxy propyl methyl cellulose (HPMC), octadecanol, microcrystalline cellulose (MCC), and magnesium stearate. Compared with the prior art, the SR tablet overcomes the defect that the residence time of a typical oral preparation drug at the nidus part is short. The intragastric floating type SR preparation is prepared so that the reaction rate of calcium carbonate in the cuttlebone and gastric acid can slow down as far as possible, and the hyperacidity relief and pain relief time is prolonged. The prepared intragastric floating tablet can stay in the stomach for 6 8 hours so that the release of the tablet is delayed and the absorption is increased. The medicine taking frequency is reduced, and the bioavailability is improved. Also, the cuttlebone is selected from edible marine animals, so that the advantages are that it is not toxic and no side effects are caused, thus the safety is high (Zhang et al., 2014). Zerbe et al. have prepared a multilayer oral dosage form that provides controlled release of an active compound that includes a nonerodible core that contains either or both of pharmaceutically and nutritionally active compounds, in addition to at least one layer for release-modulating that is laminated to each side of the core. The dosage form is prepared by the use of simple as well as inexpensive tablet compression techniques (Zerbe et al., 2014). Konatham et al. have designed Imatinib formulations. In this study, they prepared the pharmaceutical formulations involving Imatinib or its salts, isomers, metabolites, enantiomers, racemates, hydrates, polymorphs, solvates, and their mixtures. Further aspects regarding the preparation processes of pharmaceutical formulations comprise imatinib or its salts, with at least one excipient that is proven to be pharmaceutically acceptable (Konatham et al., 2013). Loeches et al. have provided a tablet for CR of mesalazine in addition to a pharmaceutically acceptable salt as an active ingredient with a gastroresistant outer coating and a core, that comprises mesalazine and a hydrophilic matrix. The matrix basically consists of a mixture of HPMC with a different viscosity while the gastroresistant outer coating represents a polymer that is pH dependent, and then the pharmaceutical excipients. The invention also represents the process by which both oral pharmaceutical tablet and oral CR pharmaceutical tablet of mesalazine are obtained for the treatment of ulcerative colitis (Blas et al., 2013). Pilgaonkar et al. have related drug delivery systems that are osmotically controlled and comprise fenugreek osmopolymer. They also provided processes for the preparation of these compositions along with the methods used for such compositions. Fenugreek osmopolymer employed in the present osmotically controlled drug delivery system hydrates and swells and exerts force or push required to deliver the active agent present in the adjacent drug layer component of the delivery system through the selectively permeable membrane, thereby resulting in CR delivery of the active ingredient of the drug (Pilgaonkar et al., 2013). Saltel et al. have developed CR formulations of lorazepam. CR of lorazepam has been shown to be able to provide enhanced options regarding the drug’s dosing that include once daily dosing which maintains the therapeutic effect for 24 hours under steady-state conditions. The pharmaceutical composition can provide substantially zero order release DOSAGE FORM DESIGN CONSIDERATIONS 6.11 PATENTED CONTROLLED RELEASE DRUG DELIVERY SYSTEMS 213 and 90% release within 7 12 hours in a pharmaceutical dissolution test. The release can be achieved using polyethylene oxide as a matrix polymer (Saltel and Vachon, 2014). Hsu et al. have developed CR formulations of levodopa and used thereof. They have provided an oral CR formulation of levodopa at the solid state, and comprised levodopa, decarboxylase inhibitor, in addition to a carboxylic acid. Other formulations that are provided by this invention comprise: (1) a CR component with a levodopa mixture, a rate controlling excipient and a decarboxylase inhibitor; (2) a carboxylic acid component; and (3) an immediate release component having a levodopa mixture in addition to a decarboxylase inhibitor (Hsu et al., 2012). More details about patents on CR formulations are provided in Table 6.2. TABLE 6.2 List of Patented Formulations as Controlled Release System Patent No. Innovation Reported Final Remark/Outcome Reference EP1147767A1 Development of controlled release formulation of nimesulide Nimesulide in combination with hydrophilic matrix forming polymer provides release up to 24 h Doshi et al. (2001) WO2014110248 A1 Development of controlled release formulation of lorazepam Lorazepam controlled release formulation with polyethylene oxide as a matrix polymer was able to provide substantially zero order release and 90% release within 7 12 h in a pharmaceutical dissolution test Saltel and Vachon (2014) US6068859 A Reduced side effects with enhanced release profile Curatolo et al. (2000) WO2011036677 A2 Development of controlled release formulation of ranolazine Carbopol and alginic acid used as pH-dependent polymers provides extended release of ranolazine Bhasale et al. (2011) EP1216704 A1 The formulation reduces the variation between peak and trough plasma levels of valproate over a 24 h dosing period following zero order Bollinger et al. (2002) WO2012146592 A1 Development of controlled release formulation of Ginkgo biloba Novel tablet of Ginkgo biloba composed of ethyl-cellulose, silicon dioxide, and magnesium stearate or stearic acid. The release profile can be optimized and controlled through the variation of the proportions of the different ingredients Herrmann et al. (2012) US7402156 Development of counter pressure device for controlled ophthalmic drug delivery A counterpressure device was designed to prevent reflux and facilitate placement of drug to the site of administration Kiehlbauch et al. (2008) US7141048 Development of vitreoretinal instrument for controlled ocular delivery A device was developed to facilitate removal of subretinal fluid and to perform fluid exchange in vitreoretinal surgery Charles (2006) Development of controlledrelease dosage form of azithromycin Development of controlled release formulation of valproate DOSAGE FORM DESIGN CONSIDERATIONS 214 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION Nowadays the focus on the development of CRS has increased, as very few drugs are coming out of research and development. Pharmaceutical scientists have renewed their interest in improving existing dosage by developing their CRSs. 6.12 CONCLUSION During the last two decades, there has been a remarkable increase in interest in the CRDDS. This has been due to various factors, viz., the prohibitive cost of developing new drug entities, expiration of existing international patents, the discovery of new polymeric materials suitable for prolonging the drug release, and the improvement in therapeutic efficiency and safety achieved by these delivery systems. In the past two decades, an observable great deal of research has been associated with the preparation of CRSs of various drugs via different routes to achieve a constant and predetermined drug release. The need for CRS often arises due to: (1) undesirable drug properties, i.e., short biological half-life, local irritation, extensive metabolism, degradation during transit and narrow therapeutic window; (2) nature of diseases state; or (3) patient incompliance of conventional dosage form due to unwanted side effects of the drug. Most important is the need to develop improved efficacy and safety of the drug through proper temporal and spatial control of drug release. For the drug consideration via this mode of delivery, certain criteria have to be examined and evaluated. These are the physicochemical, pharmacokinetic, and pharmacodynamic properties of the drug. Each drug parameter has ranges of values that lend itself to the design of CRS and outside of that create design difficulties. Higher aqueous solubility, partition coefficient, tissue binding, extensive metabolism, less stability during transit, narrow therapeutic index are some of the limiting factors in designing an effective CR product. Theoretically, each of these limitations can be overcome, and successful CRS can be developed by using physical, chemical, biological, and biomedical engineering approaches, either alone or in combination. In this chapter, we have also elaborated the importance and limitations of routes for the delivery of CRS with the examples of CR formulation administered via these routes. Although the oral route is mostly preferred for the majority of drugs, it is still beset with numerous problems such as possible degradation, first-pass metabolism, and variable and limited residence time. The transdermal has proved to be effective for CRS of many drugs. The rectal route offers a longer residence time than nasal and buccal route and may allow controlled the release of drugs. The nasal and intrauterine route is potentially used for delivering of drugs undergoes extensive first-pass metabolism, i.e., protein and peptides. The parenteral route is currently the preferred route to achieve drug targeting since other routes are commonly impermeable to drug carrier’s complexes. Pulmonary route significantly delivers specifically, polymeric nanoparticles, pure drug nanoparticles, drug-loaded liposomes, and polyelectrolyte complexes and offers interesting results for drug delivery to and through the lungs. In the final analysis, a complete knowledge and understanding of the behavior of a drug and the limitation of a particular route of administration, as well as the judicious selection of the approach, is indispensable to the process of designing a useful CRS. DOSAGE FORM DESIGN CONSIDERATIONS ABBREVIATIONS 215 The constant and CR of the drug has provided the opportunities for drug delivery systems development that is capable of meeting various clinical cases and can achieve the proper patients’ compliance, cost-effective formulations, and drugs with considerably safe profiles. With CRS development, there is an increase in the protein and macromolecular drugs and the start of new challenges and opportunities for the design of CRS. This chapter also described the current progress and latest patents of CR formulations. Acknowledgments The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology (DST), Government of India for grant (#ECR/2016/001964) allocated to Dr Tekade for research work on drug and gene delivery. The author also acknowledges DST-SERB for N-PDF funding (PDF/2016/003329) to Dr. Rahul Maheshwari in Dr Tekade’s lab for work on targeted cancer therapy. Authors would also like to acknowledge Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India, for supporting research on cancer and diabetes at NIPER- Ahmedabad. RT would also like to thank NIPER-Ahmedabad for providing research support for research on cancer and diabetes. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. ABBREVIATIONS API ATRA BSA CODAS CRDDS CRS CYP DDAVP DPP-IV EVA HPMC i.v. IM IUC IUS IVR MCC MEC MTC OCAS OROS OTC OVA PD PEG PLA PVA Active pharmaceutical ingredient All-trans retinoic acid Bovine serum albumin Chronotherapeutic Oral Drug Absorption System Controlled release drug delivery system Controlled release system Cytochrome P Desmopressin Dipeptidyl peptidase-IV Ethylene vinyl acetate Hydroxy propyl methyl cellulose Intravenous Intramuscular Intrauterine contraception Intrauterine system Intravaginal ring Microcrystalline cellulose Minimum effective concentration Minimum toxic concentration Oral Controlled Absorption System Osmotic-Controlled Release Oral Delivery System Over the counter Ovalbumin Parkinsonism disease Polyethylene glycol Polylactic acid Polyvinyl alcohol DOSAGE FORM DESIGN CONSIDERATIONS 216 PVP RES SR UDP 6. INFLUENCE OF DRUG PROPERTIES AND ROUTES OF DRUG ADMINISTRATION Polyvinyl pyrrolidone Reticuloendothelial system Sustained release Uridine diphosphate References Achouri, D., Alhanout, K., Piccerelle, P., Andrieu, V., 2013. 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Zhao, R.-y., Guo, X.-m., Wang, J.-f., Zhang, Y., Li. W.-H., Xing-bo, W., January 2, 2013. Preparation of Xanthan Gum Vildagliptin Intragastric Retentive Floating Sustained-Release Tablet. China patent application CN201210072510. Zhou, M., September 16, 2015. Extended Release of Neuregulin for Improved Cardiac Function. Europe patent application EP20150151306. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 7 Stability and Degradation Studies for Drug and Drug Product Rahul Maheshwari1, Pooja Todke1, Neetu Soni2, Nidhi Raval1, Pran Kishore Deb3, Basant Amarji4, N.V. Anil Kumar Ravipati4 and Rakesh K. Tekade1,5 1 National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 2Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom Institute of Agriculture, Technology and Sciences (Deemed University), Allahabad, Uttar Pradesh, India 3Faculty of Pharmacy, Philadelphia University, Amman, Jordan 4Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India 5 Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 7.1 Introduction 7.1.1 Significance of Stability Studies 7.1.2 Methods for Stability Study 226 226 227 7.2 Stability Studies of Drug and Drug Product 228 7.2.1 Steps Involved and Practical Considerations During Development of Stability-Testing Protocol 229 7.2.2 Stability Testing Equipment 230 7.3 Degradation Studies of Drug and Drug Products 7.3.1 Chemical Degradation Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00007-1 231 231 225 7.3.2 Physical Stability of Drug Substances 7.3.3 Photodegradation 233 234 7.4 Evaluation of Stability Data to Determine Retest Period/Shelf-Life Determination 236 7.5 Regulatory Aspects and Requirements for a Stability Testing Program 7.5.1 Regulatory Status of Stability Testing Program 7.5.2 Requirements for a Stability Testing Program 236 237 238 © 2018 Elsevier Inc. All rights reserved. 226 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT 7.6 Stability Testing of Biotechnological Product 7.6.1 Stability Tests for Biologic or Biological Products 7.7 Stability Testing of Phytopharmaceuticals 7.7.1 Requirements of Stability Testing of Herbal Products 7.7.2 Protocol: Stability Testing of Phytopharmaceuticals/Herbal Products 238 239 239 241 241 7.8 Stability Indicating Assay Method (SIAMs): Current Update 243 7.8.1 Regulatory Status of StabilityIndicating Assays 244 7.8.2 Current Updates in Regulation of Stability Indicating Assay 244 7.8.3 Development of Stability Indicating Assay Method (SIAM) 245 7.9 Reduced Stability-Testing Plans 7.9.1 Bracketing and Matrixing Design 7.9.2 Bracketing 7.9.3 Matrixing 247 247 248 249 7.10 Conclusion 251 Acknowledgment 251 References 251 Further Reading 256 7.1 INTRODUCTION Stability testing is a comprehensive practice coupled with numerous aspects to determine the stability of different pharmaceutical drug products. Such aspects comprise of the active ingredients stability, interaction of active ingredients with excipients, manufacturing process followed, dosage form type, packaging products, i.e., container or closure system, in addition to light, heat, moisture conditions encountered during shipment, storage, and also handling (Hotel, 2016). Further chemical degradation reactions, such as oxidation, reduction, hydrolysis, and racemization, impart a crucial role in a pharmaceutical product’s stability. The conditions such as reactant concentration, pH, radiation, catalysts, raw materials, and the duration between manufacture and usage of the product also affect the stability of the drug product. The physical changes, such as vibration, and temperature variations, like freezing, shearing, and thawing, may impact, on the product stability, which may result in loss of potency of the active pharmaceutical ingredient (Blessy et al., 2014). The information about the stability of a drug molecule assists in selecting the proper formulation in addition to packaging, as well as providing the proper storage conditions and shelf life, which are essential for regulatory documentation (Bharate et al., 2016). Various objectives are demonstrated in Fig. 7.1. Stability studies are measured as requirements for the final recognition along with approval of any medical device/product. It validates the product quality maintenance and safety, in addition to efficacy throughout the shelf life. Stability studies are mandatory to be carried out in a deliberate way as per the laws governed by ICH, WHO, and similar bodies (Blessy et al., 2014). 7.1.1 Significance of Stability Studies Stability testing of pharmaceutical products imparts a considerable role, including significant economic burden, time period, and technical skill, in developing the product from a DOSAGE FORM DESIGN CONSIDERATIONS 227 7.1 INTRODUCTION FIGURE 7.1 Various objectives study. of stability quality perspective. In addition to commercial accomplishment of a pharmaceutical drug product might merely confirm with the perceptive of the drug development process with the several targets and milestones that are important to the suitable development plan. Stability study is just not the part of physiochemical aspects of the drug but also give details about the safety and efficacy of the product during its entire shelf life (Karn et al., 2013). 7.1.2 Methods for Stability Study Stability testing is carried out on pharmaceutical drug products at different developmental stages of the product as part of the routine procedures. At earlier stages, accelerated stability testing is employed for the determination of the degradation product types that may be observed during extended period of storage (Erhayem and Sohn, 2014). The shelf life and expiration of product dates are determines at somewhat elevated temperatures. Depending upon the objectives in addition to the criteria followed, stability investigation methods have been categorized into the four classes (McClements and McClements, 2016). Fig. 7.2 demonstrates the different methods of stability testing. 7.1.2.1 Real-Time Stability Testing Usually, stability studies are carried out for a longer period of time to permit degradation of product under suggested storage conditions so that each degradant product can be accessed and analysed further from safety point of view. One of the important purpose of DOSAGE FORM DESIGN CONSIDERATIONS 228 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT FIGURE 7.2 Different methods of stability testing. stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a retest period for the drug substance (Augsburger and Hoag, 2016). 7.1.2.2 Accelerated Stability Testing In such stability investigations, the formulation is subjected to higher temperatures and the breakdown of the product is determined. Such data are then used to calculate shelf life or employed to evaluate the relative stability of other products. This typically offers an early indication of the shelf life of the product (Duggirala et al., 2016). 7.1.2.3 Retained Sample Stability Testing Such testing is employed for each marketed product for which stability information is essential. At least one batch every year of stability samples are reserved for storage. If the batch numbers of the marketed product exceeds 50, two batches are suggested to be taken in the form of stability samples (Booth et al., 2015). 7.1.2.4 Cyclic Temperature Stress Testing This technique is not frequently used for the products in the market. The duration of cycle is mainly recommended at 24 h because of the diurnal rhythm of 24 h, which is common for marketed pharmaceuticals under storage conditions (Lim et al., 2014). 7.2 STABILITY STUDIES OF DRUG AND DRUG PRODUCT The stability protocols for conventional dosage forms such as tablets, capsules, ointments are well-established, however, the protocols for newer drug delivery systems need to be established. The emerging delivery systems include liposomes (Maheshwari et al., 2012; Maheshwari et al., 2015b), dendrimers (Tekade et al., 2015; Soni et al., 2016; Soni et al., 2017), polymeric nanoparticles (Maheshwari et al., 2015a; Tekade et al., 2017b), ophthalmic nanocarriers (Lalu et al., 2017), and carbon nanotubes (Tekade et al., 2017a). DOSAGE FORM DESIGN CONSIDERATIONS 229 7.2 STABILITY STUDIES OF DRUG AND DRUG PRODUCT 7.2.1 Steps Involved and Practical Considerations During Development of Stability-Testing Protocol 7.2.1.1 Steps of Stability Studies The pharmaceutical product’s stability throughout its complete shelf life in its finishing packaging is a significant aspect. Such study does not only cover the drug product’s physiochemical characteristic but also elucidates the product’s safety in addition to efficacy throughout its whole shelf life (Blessy et al., 2014). Forced degradation investigations assist to ease formulation, production, production, and packaging of pharmaceutical drug products, moreover data related to chemical performance are able to be employed to improve drug products. Stability studies are carried out at each stage of the life cycle of the drug from the first stages of product improvement to the later stages of follow-up investigations (Baertschi et al., 2016). Different steps involved in the stability study are demonstrated in Fig. 7.3. 7.2.1.2 Practical Considerations During Development of Stability-Testing Protocol The well-defined and explicit stability testing protocol is a prime requirement for initiating stability testing. The stability testing conditions depend primarily on the intrinsic stability profile of a compound, the type of dosage form, and the given container-closure system (Hassan, 2016). The design of a stability protocol is also based on the nature of whether it is FIGURE 7.3 Various steps involve in the stability study. DOSAGE FORM DESIGN CONSIDERATIONS 230 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT a new drug, new drug product, or already marketed formulation. The stability regulations must also project the region where the product is planned to be marketed, such as climatic zones I III, IVa, and IVb; the stability protocol has to comprise such zones. A well-planned protocol of stability testing must hold the subsequent information (Spies et al., 2017). 7.2.1.2.1 BATCHES At developmental phases, the stability testing is usually performed on a single-batch, moreover such investigations are planned for documentation of novel formulations or unstable established formulation. Such studies are performed on production batches of the first three batches, whereas for batches of formulations which are stable and well established, two batches are permitted (Schymanski et al., 2015). On long-term studies of batches of drug product, the first three manufactured postapproval must be monitored if the primary observations are not on a broad-scale manufacturing batch. The data acquired from the pharmaceuticals development on laboratory scale batches are not accepted as initial observation data although they do represent helpful information. Typically, from the population of pilot or production batches, the selection of batches has to comprise a random sample (Allison et al., 2015). 7.2.1.2.2 CONTAINERS AND CLOSURES Stability testing is performed on the containers/closures anticipated for marketing. The packaginf materials comprise aluminum strip packs, blister packs, Alu-Alu packs, HDPE bottles etc. Such material may also contain secondary packagaing. The products, whether intended for distribution for physician or as promotional samples, are to be tested separately for each of the various packaging materials (Chang et al., 2016). 7.2.1.2.3 ORIENTATION OF STORAGE OF CONTAINERS For stability studies, samples such as solutions, dispersed systems, as well as semisolid drug formulations have to be placed upright and inverted to permit complete contact between the product with the container closure system. Such direction facilitates the determination of the extraction of chemical components from the closure system or adsorption of product components into the container-closure during the interaction among the drug substance or solvent (Génio et al., 2015). 7.2.2 Stability Testing Equipment The stability of the pharmaceuticals drug and the drug products is tested by equipment known as a stability chamber. Stability chambers are specific climatic chambers which are used to analyze the effects of particular environmental conditions on biological items, industrial products, materials, and electronic devices and components (Jamakandi et al., 2014). Stability chambers can design for stability test requirements such as accelerated testing at more stressed conditions then ICH guideline, 40 C 6 1 C/75%RH 6 1%RH in addition to frost-free refrigeration for continuous operation. Such chambers can reproduce the storage conditions in addition to facilitating assessment of the stability of pharmaceutical DOSAGE FORM DESIGN CONSIDERATIONS 7.3 DEGRADATION STUDIES OF DRUG AND DRUG PRODUCTS 231 drug products and depend on real-time, accelerated, and long-term studies. These chambers are available in both walk-in and reach-in styles (Omkar, 2014). Generally, for stress condition testing, smaller chambers are ideal, due to the retention time of pharmaceutical drug products being very small in these cabinets, whereas for long-term study testing the walk-in chambers are favored. The stability testing chamber is a critical equipment and it has an effect on the quality of the product directly (Mohammed and Rudwan, 2016). Qualification of stability testing chambers ensure that accurate data will develop from samples kept under testing. A stability chamber should be properly designed, located, installed, operated, and maintained; they are constructed with proper recording, safety, and alarm devices. Additionally, photostability chambers are also utilized with the control of both humidity and temperature as well as without control of humidity and temperature. In photostability chambers, two types of light sources are frequently utilized, i.e., the first is cool white light and nearUV fluorescent tubes, whereas the second is the daylight lamps, such as xenon or metal halide (Siddiqui et al., 2014). 7.3 DEGRADATION STUDIES OF DRUG AND DRUG PRODUCTS Forced degradation involves degradation of drug and drug product in circumstances that are more rigorous in comparison to accelerated conditions. It offers an insight into the degradation pathways and the degradation products of the drug, as well as assisting in the elucidation of the degradation products structure. In the regulatory compliant stability program design of drug and drug products forced degradation study is an essential step. In 1993 such studies were formalized as a regulatory requirement in ICH Guideline Q1A (Singh et al., 2013). The principal cause of impurities in drug and drug product is degradation. The chemical, as well as physical degradation of the drug and drug product in conditions such as heat, humidity, solvent, pH, and light, occur at the time of manufacturing, isolation, purification, drying, storage, transportation, and formulation are the main reasons for its instability (Alsante et al., 2014). Table 7.1 demonstrates various stress conditions for the degradation of drug and drug product. Forced degradation studies are performed to develop the stability-indicating assays for drugs and drug products. For forced degradation studies the stress factors include acid and base hydrolysis, thermal degradation, and photolysis. Between 5% 20% degradation of drug substances through oxidation has been accepted as rationale for validation of chromatographic assays (Blessy et al., 2014). Degradation studies are undertaken in all stages of pharmaceutical development, manufacturing, production, and packaging. 7.3.1 Chemical Degradation Any change in any component of the drug whether it is an active or excipient either physically, chemically, microbiologically or a change in therapeutic properties could lead to the instability of the drug (Alsante et al., 2014). Most drug instability occurs through DOSAGE FORM DESIGN CONSIDERATIONS 232 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT TABLE 7.1 Types of Stability Testing Type of Stability Testing Purpose Use Accelerated (by introducing exaggerated storage conditions to elevate the chemical degradation and physical change of drug/ drug product) This study is useful for the selection of suitable dosage form and container closure systems For the development of the drug/drug product Accelerated and real-time (accelerated studies with long-term storage under nonaccelerated conditions) This study is useful in the determination of shelf life and storage condition of drug/drug product This information is important in registration dossier and in development of the drug/drug product Real-time (long-term) (drug/drug product store in conditions which are proposed for market to evaluate the real shelf life and confirm the projected shelf life and recommend storage conditions) To provide the evidence for the claimed shelf life This information is important in registration dossier Accelerated and real-time (accelerated studies with long-term storage under nonaccelerated conditions) For the verification of no changes occurred in the formulation or during manufacturing process, no adversely affect the stability of the drug/ drug product This information is important in quality assurance and quality control of drug product Stability testing ensures the quality of the product, there are four types of stability testing protocols which include accelerated, accelerated and real-time, real-time (long-term), accelerated and real time which provide information that is important in development of the product. chemical reactions resulting in a reduced potency, which is a well-recognized sign of poor quality of drug product. A drug may degrade to a toxic material, for example, pralidoxime degrades by pHsensitive pathways which are parallel to each other. At basic pH, cyanide is formed which is a toxic product. For instance, one tetracycline degradant is epianhydrotetracycline, which leads to Fanconi syndrome. Major changes in color or odor may take placed over time if products are degraded (Kleinman et al., 2014). For instance, adrenochrome, a extremely red colored material is an oxidized product of epinephrine. Drug substances used as pharmaceuticals have diverse molecular structures and are, therefore, susceptible to many and variable degradation pathways. Possible degradation pathways include hydrolysis, dehydration, isomerization and racemization, elimination, oxidation, photodegradation, and complex interactions with excipients and other drugs. It would be very useful if we could predict the chemical instability of a drug based on its molecular structure (Matzek and Carter, 2016). Different factors affecting chemical stability and physical stability are shown Fig. 7.4. 7.3.1.1 Hydrolysis For most parenteral products, the drug comes into contact with water and, even in solid dosage forms, moisture is often present, albeit in low amounts. Accordingly, hydrolysis is DOSAGE FORM DESIGN CONSIDERATIONS 7.3 DEGRADATION STUDIES OF DRUG AND DRUG PRODUCTS 233 FIGURE 7.4 Factors affecting stability of drug product. one of the most common reactions seen with pharmaceuticals. Hydrolysis is often the main degradation pathway for drug substances having ester and amide functional groups within their structure. Examples included procaine, aspirin, chloramphenicol, atropine, and methylphenidate (Bhairamadgi et al., 2014). 7.3.1.2 Oxidation Oxidation is a well-known chemical degradation pathway for pharmaceuticals. Oxygen, which participates in most oxidation reactions, is abundant in the environment to which pharmaceuticals are exposed, during either processing or long-term storage (Tran et al., 2016). Catechols such as methyldopa and epinephrine are readily oxidized to quinones. 5Aminosalicylic acid undergoes oxidation and forms quinoneimine, which is further degraded to polymeric compounds (Yin et al., 2013). 7.3.1.3 Drug Excipient and Drug Drug Interactions Drugs cannot be administered in the body alone. Additives or excipients are required in the formulation to solve many purposes such as increasing bulk, solubility, stability, plasticizer, and controlled release of medicament. Therefore, reactions between drugs and excipients may occur (Song et al., 2015). To avoid these type of interaction complete drug interaction studies are required (Panakanti and Narang, 2015). 7.3.2 Physical Stability of Drug Substances The physical state of a drug determines its physical properties such as its solubility. Because these properties, in turn, affect the efficacy and, potentially, the safety of a drug DOSAGE FORM DESIGN CONSIDERATIONS 234 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT substance, changes in the physical state of a drug substance need to be determined. Traditionally, changes in the physical state are assessed by differential scanning calorimetry and X-ray diffraction analysis (Guo et al., 2013). In addition, changes in the physical states of excipients or enabling agents in a dosage form may affect the stability of pharmaceuticals. This section will briefly describe the physical stability of drug substances and excipients (Narang et al., 2015). The components of pharmaceuticals (drug substances and excipients) exist in various microscopic physical states with differing degrees of order. Examples are amorphous and various crystalline, hydrated, and solvated states. Over time, the drug or the excipient may change from one state, usually unstable or metastable, to a more thermodynamically stable state. The rate of conversion will depend on the chemical potential corresponding to the free-energy difference between the states and the energy barrier (like that for chemical reactions) that must be overcome for the conversion to take place. The following sections address the physical changes that can occur in drug substances and excipients and describe factors affecting these physical changes as well as methods for stabilizing drugs in a fixed defined state (Bhardwaj et al., 2013). 7.3.2.1 Crystallization of Amorphous Drugs Crystallization may occur during long-term storage and may lead to drastic changes in the release characteristics of the drug and, hence, changes in its clinical and toxicological behavior. Changes in crystal habit during storage have been reported for many drug substances (Sibik et al., 2015). For example, the amorphous form of nifedipine (a calcium channel blocker) coprecipitated with PVP and underwent slight crystallization when subjected to storage at humid atmosphere. This change from a largely amorphous state to a partially crystalline state resulted in altered dissolution and solubility behavior (Laitinen et al., 2013). 7.3.3 Photodegradation In the pharmaceutical industry, photostability studies of drugs and drug products are an integral part in the growth phase of the dosage form containing the bioactive. Photostability studies are performed to assure quality, efficacy, as well as safety of the formulated drug products throughout manufacture, storage, in addition to use. The functional groups of the drug molecule are vital for the photoreactivity of drugs. One such study describes the photophysical process, in addition to the links with the photochemical kinetics reactions (Klementova et al., 2017). The various photodegradation approaches of drugs as well as the biological consequences of the effect of light on the drug degradation are described by these studies. There are ICH guidelines for the photostability testing of drugs and drug products. Any response of the drug or drug product to the exposure to solar, UV, or visible light in the solid, semisolid, or liquid state that leads to a physical or chemical change may be defined as the photostability of a drug (Ebeid et al., 2014). The drug response through the formation of free radicals or photosensitization reactions by intermolecular energy transfer in the presence of light through absorption and/or excitation can be considered photodegradation reactions. Photodegradation reactions include primary photochemical reactions in addition to secondary chemical reactions that present DOSAGE FORM DESIGN CONSIDERATIONS 235 7.3 DEGRADATION STUDIES OF DRUG AND DRUG PRODUCTS the ultimate products. The effect on stability and efficacy of the drug as a result of photochemical reactions can be understood by photochemistry. The degradation of the drug substances as a result of photochemical reactions can occur by different routes to form different products. The elucidation of these mechanism pathways needs systematic understanding of the nature of the drug as well as the type of the photochemical reactions concerned. Such reactions depend on the presence of specific functional groups, and physical characteristics such as light absorption, pKas, solubility, etc. (Ye et al., 2017). The estimation of a drug’s photostability is dependent on the factors that establish the rates as well as the mechanisms of the underlying photochemical reactions. The photodegradation rate of a drug is influenced by the number as well as the wavelength of incident photons. For example, the amount of photodegradation of nifedipine was proportional to the incident photons number. Tablets of nifedipine showed maximum photodegradation at 420 nm. Another example is that there is a difference in the discoloration rate of sulfisomidine in tablets irradiated by a mercury lamp versus ultraviolet light. Drug photodegradation strongly depends on the drug spectral properties as well as the spectral distribution of the light source. Sulpyrine discoloration is a major process under a mercury lamp, which is a good UV energy source, but only slight discoloration happens under a fluorescent lamp, which mainly radiates visible light (Anandam and Selvamuthukumar, 2014). The photostability evaluation of the drug depends on the various factors demonstrated Fig. 7.5. FIGURE 7.5 Factors for photostability evaluation. DOSAGE FORM DESIGN CONSIDERATIONS 236 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT 7.4 EVALUATION OF STABILITY DATA TO DETERMINE RETEST PERIOD/SHELF-LIFE DETERMINATION A suitable statistical method must be utilized to analyze the primary stability data in a long-term study. The principle of such analysis is to create, with a high degree of confidence, a retest period or shelf life within acceptance criterion for each batch manufactured, packaged, and stored under similar conditions. To evaluate data variability in long-term study, the identical statistical method should be employed (Peleg and Normand, 2015). A suitable approach to assessing the stability data is regression analysis for a quantitative characteristic as well as for establishing a retest period or shelf life. The character of the relationship between an attribute and time will determine whether data should be transformed for linear regression analysis. On an arithmetic/logarithmic scale, the relationship can be characterized by a linear/nonlinear function. Sometimes, a nonlinear regression can better reproduce the accurate relationship. For a retest period/shelf life assessment, a suitable approach is to analyze a quantitative attribute (e.g., assay, degradation products) via determining the first time at which the 95% confidence limit for the mean intersects the proposed acceptance criterion. For an attribute known to decrease with time, the lower one-sided 95% confidence limit should be compared to the acceptance criterion (Dasgupta et al., 2016). The statistical method offers suitable statistical inference for the approximate retest period or shelf life. Such a method employed for data analysis should take into description the stability study design. The approach described above can be used to estimate the retest period or shelf life for a single batch or for multiple batches when the data are combined after an appropriate statistical test (Andrews et al., 2017). 7.5 REGULATORY ASPECTS AND REQUIREMENTS FOR A STABILITY TESTING PROGRAM Stability testing programs ensuring the maintenance of the identity, strength, quality, purity, and efficacy of a drug substance/drug product within specifications are established by regulatory agencies (ICH, WHO, and or other agencies) (Niazi, 2014). The stability of active pharmaceutical ingredients (API) or API-containing products depends on the chemical and physical properties of excipients, the material of the container, and environmental factors such as temperature, humidity, and light, etc. The purpose of a stability testing program is to provide evidence by evaluating the drug product in four conditions like extreme, normal, intermediate, and particular conditions for a definite period of time such as accelerated or real time (Grimm, 1998). The main objectives of stability testing are listed in Table 7.1. Stability testing is important because unstable drug products may be converted into toxic products, or lose their activity, which could lead to the failure of the therapy. Also at the developmental stage, stability studies provide the data which are required for the proper selection of formulation excipients and packaging for the development of new product. Stability testing also helps to determine the shelf life and storage conditions of a new product and is required for the preparation of a registration dossier (Bajaj et al., 2012). DOSAGE FORM DESIGN CONSIDERATIONS 7.5 REGULATORY ASPECTS AND REQUIREMENTS FOR A STABILITY TESTING PROGRAM 237 The stability studies discover whether the drug has the required minimum stability and this will affect the manufacturing parameters and packaging development and labeling for the long-term shelf life. It also provides additional guidance for appropriate stabilizers in the formulation and for selection of packaging and dosage form. The solid state of API, i.e., the crystallinity of the drug (amorphous, crystalline, hydrate, solvate) has a huge impact on the solubility, efficacy, and safety of products. The different polymorphic forms have different properties and different sensitivity to environmental conditions. These data are also used to decide the adequate storage conditions and shelf life of the drug/drug product (Blessy et al., 2014). 7.5.1 Regulatory Status of Stability Testing Program The ICH is the International Conference on Harmonization for the registration of APIs and dosage forms for human use and is a joint group involving three regulatory bodies in the United States, EU, and Japan. ICH actively regulates scientific and technical requirements to ensure and assess the safety, quality, and efficacy of the API and API-containing dosage forms (Bakshi and Singh, 2002). The ICH guidelines of stability testing for new chemical entities and their products ensures consistent standards in the United States, EU, and Japan. The various ICH guidelines for stability testing are listed in Table 7.2. TABLE 7.2 List of ICH Guidelines for Stability Testing ICH Guideline Stability Testing Objective Q1A (R2) New drugs and products It outlines the stability of new drugs and products for registration of application within three regions of ICH, i.e., USA, EU, Japan Q1B Photostability testing It addresses the generation of photostability information (light exposure result in any unacceptable result) for submission in application of new drugs and products Q1C New dosage forms It addresses stability studies for products having different route of administration, new specific delivery for immediate or modified release tablet for submission in application of new drugs and products Q1D Bracketing and Matrixing designs The basic objective of application of bracketing and matrixing is without regulatory consideration and it also encourages the use of this design to reduce the cost and testing Q1E Evaluation of stability data It defines the retest period and shelf life of for submission in application of new drugs and products Q1F (withdraw in 2017) Stability Data Package for Registration in Climatic Zones III and IV Stability studies of drug package for application in climatic zones III and IV ICH guidelines actively regulate scientific and technical requirements for the new drugs or products, the above guideline are addressing the issues of stability testing. DOSAGE FORM DESIGN CONSIDERATIONS 238 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT 7.5.2 Requirements for a Stability Testing Program The development of drug or drug products should be in compliance with 21 CFR part 211 for acceptance and approval for market. The main objective of this guideline is the minimum current good manufacturing practice (cGMP) for preparation of drug products for administration to humans or animals. The cGMP resides in 21 CFR part 211.166 and provides the requirements of a stability testing program for developing new drug and drug products. According to 21 CFR part 211.166, the requirements of a stability testing program include: sample size and test intervals; storage conditions for samples; reliable, meaningful, and specific test methods; testing of drug product in marketed container; and testing of drug product for reconstitution at dispensing time and reconstituted time for the biologics/biotechnological products (Gold and Phelps, 2017). For the stability testing studies, companies must have a standard operating procedure which includes documentation on the stability program including stability profile and the expiry of the drug product, e.g., accelerated and real-time stability testing with testing interval time (0, 1, 2, 3, 6, or 12 months) and sampling sizes (Roberts et al., 2016). Analytical methods like stability indication assays are required for the determination of active pharmaceutical ingredients and degradation products in order to establish the storage condition and expiry of the drug or drug product. The cGMP also requires that the dosage form must be stored in same closed container system that is reported in the registration dossier. Additional requirements are elaborated in the section below (Lim, 2014). 7.6 STABILITY TESTING OF BIOTECHNOLOGICAL PRODUCT The European Union defined the term “biological substance which is a substance produced or extracted from a biological source and that needs for its characterization and the determination of its quality a combination of physicochemical-biological testing, together with production, process and its control.” The simple way to define biologics is as a substance which is produced or originates from a biological process, either by fermentation or by a specific cell-culture expression system, by a biotechnological process such as recombinant DNA (rDNA) technology, or by harvesting from a living organism. These biological substances are used to prepare pharmaceutical products, including blood plasma products, vaccines, antivenoms, immunoglobulins, and allergenic extracts (Bucar et al., 2013). To decide the specifications for stability testing of biologics (proteins, monoclonal antibodies, conjugated protein systems, and some polypeptides) is difficult because there is less knowledge on biologics than for drugs (Sangshetti et al., 2014). As earlier discussed, careful consideration needs to be taken when it comes to the approval and acceptance of biologicals products. The protein attains its biological activity not only from its primary conformation but also from its folded secondary and tertiary structure and the biological activity can be changed by altering the conformation of covalent bond but it can also be denatured which would result in a loss of therapeutic activity. A list of ICH guidelines for biotechnological products/biologics is shown in Table 7.3. DOSAGE FORM DESIGN CONSIDERATIONS 7.7 STABILITY TESTING OF PHYTOPHARMACEUTICALS 239 TABLE 7.3 List of ICH Guidelines for Biologics/Biotechnological Products ICH Guideline Stability Testing Objective Q5A Viral safety evaluation Viral safety evaluation of biotechnological products obtained from cell lines of human or animal origin Q5B Genetic stability Analysis of the expression construct in cells used for production of r-DNA derived protein Q5C Biotechnology products Stability testing of biotechnological products Q5D Cell substrates Derivation and characterization of cell substrates used for production of biotechnological products Q5E Manufacturing process Comparability of biotechnological products subject to changes in their manufacturing process Above ICH guidelines for biologics/biotechnological products provide specifications from their safety evaluation to manufacturing process for acceptance and approval of marketing. 7.6.1 Stability Tests for Biologic or Biological Products The basic objective of ICH guideline Q6B is to set out the principle and justification to set international specifications for biotechnological or biological products to support new marketing applications. The Q6B guideline details the specifications and tests, including appearance and description, impurities, potency, quantity, and determination of subvisible particles for immunological concern. In addition, other common tests for drug substances are to be applied, such as sterility, microbial limits, bacterial endotoxin, and pH. The potency of biologics/biotechnological product is determined by using bioassays and binding methods. In spite of the advantages of bioassays method, there are also problems in specificity and accuracy of potency (Raghavan and McCombie, 2018). Biotechnological products are derived from human or animal substances, and thus it is necessary to perform impurity profiling. Impurity evaluation is difficult because there are multiple decomposition routes which are not detected by a single chromatographic method. Size exclusion chromatography and SDS-PAGE are mostly used in impurity assessment and they have the ability to provide information on aggregation. For the determination of side-chain oxidation and deamidation, peptide mapping and isoelectric point is important (Garcı́a-Delgado et al., 2016). 7.7 STABILITY TESTING OF PHYTOPHARMACEUTICALS Over the last decades, there has been a significant and growing interest by people in using herbal products/phytopharmaceutical preparations and these can be defined as processed or unprocessed standardized substances obtained from an extract or fraction of a plant or parts of plant or combinations of them. The stability testing of phytopharmaceutical substance or products is a challenging task because the plant extract or fraction contains complex active constituent (Qureshi et al., 2014). Despite the complex nature of constituents, there is also the increasing requirement for analytical methods, such as DOSAGE FORM DESIGN CONSIDERATIONS 240 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT TABLE 7.4 Steps Involved in Development of Herbal Products Steps Details/Remark Step-1: Botanical characteristics of plant • Botanical source: genus, species, variety, chemotype • Usage of genetically modified organism • Parts of the plant used Contamination of other plant species Should be compliance with good agricultural practices (GAP) Cultivation parameters Site of collection plant or part of plants Time of harvesting the plant or part of plants Selection stage of growth Storage conditions post-harvest Pre and postharvest treatments (pesticide, fumigants) Step-2: Growth conditions • • • • • • • Step-3: Raw materials • Specifications according to standard method, i.e., pharmacopeia • Constituents determined by quantitative method • Stability database Step-4: Chemical or foreign matter • Identify • Assay • Limit tests Step-5: Raw material processing • Extraction procedure • Solvents • Methods applied Step-6: Final product • • • • • • Step-7: Characterization Macroscopic and microscopic characterization, phytochemical characteristics of the plant part constituents with known therapeutic activity or marker Step-8: Product profiling Profile of stability testing of the active constituents and formulation in packaging Step-9: Preclinical/clinical testing Formulation batches used in preclinical/clinical testing for determination safety, efficacy and quality of the product Standardization criteria (by using marker, plant/extract ratio) Specifications (level/range of marker) Purity criteria Limits for active constituents Formulation methodology Storage conditions HPTLC/HPLC fingerprinting, for accurate measurement of active constituents or toxic constituents or impurities, and regulatory rules for the realization of the herbal products (Souza et al., 2013). Stability testing of phytopharmaceutical products is concerned with how the purity and therapeutic activity alter with respect to time due to various environmental factors (temperature, oxygen, light, moisture), excipients in the dosage form, particle size of drug, microbial contamination, trace metal contamination, leaching from the container, etc. The stability testing allows the determining of storage conditions, retest period and shelf life (Bauer, 1998). The steps followed for the development of a herbal product are listed in Table 7.4. DOSAGE FORM DESIGN CONSIDERATIONS 7.7 STABILITY TESTING OF PHYTOPHARMACEUTICALS 241 7.7.1 Requirements of Stability Testing of Herbal Products The stability testing is required to ensure the product is good and a consistent quality is obtained. GMP provide documentation of each manufacturing step with process control data. All medicinal products require GMP to ensure that the manufacturing and composition of the finished product conforms to the declared composition. IPC testing is important in each and every stage during the preparation or addition of herbal substances and identification testing of the herbal material or herbal formulation before the manufacturing process of the final product assures the consistent quality and that the product conforms to declared composition (Matthews, 1999). In the herbal materials with composition of known biological activity, assay of their content is required with their test procedures and the content must be included as a range, there is less of a reproducibility issue in herbal medicinal product. In some cases where herbal materials withaveh compositions of unknown therapeutic activity, assay of marker substances are required with the test procedures. Stability studies must be done for herbal materials unless justification can otherwise be provided concerning the microbiological data and analysis of residues of pesticide and fumigation agents, toxic metals such as contaminants and adulterants etc. (Gafner and Bergeron, 2005). In the case of herbal medicinal products, control tests must be done on the finished product which allow to give qualitative and quantitative determination of the active constituents. When the quantitative determination of each active constituent is not possible, that determination can be carried out jointly for several active constituents with justification. 7.7.2 Protocol: Stability Testing of Phytopharmaceuticals/Herbal Products 7.7.2.1 Selection of Batches Stability study data of herbal products should be provided in at least three primary batches, where the primary batches should be of the same prepared formulation and packaging and in the same container closure system which is intended for registration dossier or marketing (Ascaso et al., 2015). The manufacturing process applied for the primary batches should be the same as that to be used for production batches and two out of three batches should be at least pilot scale batches while the third batch can be smaller with specified justification. Where possible, batches of drug products should be manufactured by using various batches of herbal substances. It should provide product of the same quality as the same specifications which are proposed for marketing. Stability studies of herbal products should be carried out on each individual strength and container size of the product, otherwise bracketing or matrixing is used (Phadtare et al., 2017). 7.7.2.2 Container Closure System Stability studies should be performed on the herbal product packaged in the container closure system which is intended for use along with secondary packaging and container label (Chang et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 242 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT TABLE 7.5 Application of Stability Testing Type of Data Stress Testing When Active substance and decomposed product are described in official monograph Stress testing is not required When Active substance and decomposed product are not described in official monograph Stress testing needs to be performed When Active substance and decomposed product are described in published literature Stress testing is not required Stability testing is an essential phase in the formulation development. Stability testing assesses how the quality of a drug substance or drug product (including its packaging) varies with time under the influence of environmental factors, including temperature, humidity, and light. When to apply stability testing is described in the above Table systematically. 7.7.2.3 Stress Testing Stress testing of the active composition can help to identify degradation products which will help to discover the degradation route and also help to establish intrinsic stability and validate the analytical procedure used for stability testing. The application of type of stability testing is dependent on the active molecule and dosage form involved (Borio et al., 2014). When to apply stress testing is listed in Table 7.5. 7.7.2.4 Specification The stability testing program should include the testing of those factors of dosage form which are susceptible to change during storage and which directly affect the safety, efficacy, and quality of the products. The studies should include experiments on physical, chemical, biological, and microbiological characteristics of the plant or herbal product and other added excipients as well as antioxidant and antimicrobial preservative testing (Jorgensen and Turnidge, 2015). The stability studies must be done by suitable analytical methods and validated using the stability indicating method assay. Types of stability studies are described in Table 7.6. 7.7.2.5 Frequency of Stability Testing In long-term studies, the frequency of testing should be such to establish the stability of the profile of a drug product. For drug products with intended shelf life of at least 12 months then the frequency of testing in long-term storage conditions must be every three months over the first year and every 6 months over the second year and annually after throughout the intended shelf life (Guo et al., 2013). In the accelerated stability studies, a 6-month study is recommended with a minimum of three time points for testing, i.e., 0, 3, 6 months. When a significant change occurs during accelerated storage conditions, there is need to perform an extra 6 months of studies with a fourth time point at the intermediate conditions (Kaur et al., 2016). The significant change specification is listed in Table 7.7. DOSAGE FORM DESIGN CONSIDERATIONS 7.8 STABILITY INDICATING ASSAY METHOD (SIAMS): CURRENT UPDATE 243 TABLE 7.6 Stability Studies Specification Type of Study Long-term Description Storage Condition Stability studies performed according to their climatic zone of product which are proposed for registration dossier or marketing. 25 C 6 2 C/60% RH 6 5% RH Minimum Time Period Covered by Data at Submission 12 months or 30 C 6 2 C/65% RH 6 5% RH 30 C 6 2 C/65% RH 6 5% RH 6 months 40 C 6 2 C/75% If significant change occurred between the 6 months studies at accelerated condition, there is RH 6 5% RH need to perform additional intermediate studies. 6 months Intermediate If long-term studies are performed at 30 C 6 2 C/65% RH 6 5% RH, then there is no need to perform intermediate studies But, when the long-term done at 25 C 6 2 C/60% RH 6 5% RH, there is a need to perform additional intermediate studies In the initial application, from 12 months studies of 6 months studies should be included Accelerated Generally, there are three types of stability studies are applied, i.e., long-term, intermediate, accelerated for the submission of registration dossier. TABLE 7.7 Significant Change Specification Herbal preparation constituents with known therapeutic activity Intended shelf-life should not exceed 6 5% of the declared assay value can be accepted, otherwise justified Herbal preparation constituents with unknown therapeutic activity Intended shelf-life variation 6 10% of the declared assay value, otherwise justified Herbal preparation containing vitamins or minerals Stability of vitamins/minerals should be demonstrated Herbal preparation physical changes like color, phase separation, etc during accelerated studies Failure to meet acceptance criteria During stability studies, intended shelf life variation is demonstrated for known therapeutic activity, unknown therapeutic activity, or physical change occurred in herbal formulation. 7.8 STABILITY INDICATING ASSAY METHOD (SIAMS): CURRENT UPDATE Stability indicating assay is a quantitative or analytical method that is defined as a validated analytical procedure that accurately and precisely discriminates each active ingredient content from its degradation products formed under defined storage conditions during the evaluation of stability of product. There are two types of SIAMs: specific stability DOSAGE FORM DESIGN CONSIDERATIONS 244 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT indicating assay method, which is a method with the ability to measure unequivocally the drug in the presence of decomposed products, excipients, and other additives in formulation; and selective stability indicating assay method, which is a method with the ability to measure unequivocally the drug in the presence of decomposed products, excipients, and other additives expected to be in the formulation. This method is capable for determination and quantification of one or more degradation products (Thummar et al., 2017). In the past, the pharmaceutical industries used stability studies such as long-term testing or temperature control but these studies did not always provide the specificity for measuring the quantity of active product compared to degradation products. In addition, FDA also recommends all the assay procedures should followed the stability method. The primary objective of SIAMs is to monitor the results of stability studies in order to assure the safety, quality, and efficacy of the product. SIAMs also act as powerful tools for investigation of out-of-trend or out-of-specification results in quality control processes. ICH guideline such as Q1A (R2), Q3B (R2), Q6A, and FDA 21 CFR Section 211 require stability indicating methods (Jain et al., 2015). 7.8.1 Regulatory Status of Stability-Indicating Assays The ICH guideline Q1A for stability testing of new active pharmaceutical ingredients and finished products mostly focuses on testing of those feature which are prone to change during storage and which ultimately affect the safety and efficacy. These stability studies must be undertaken by validated analytical stability-indicating assay methods (Baertschi et al., 2016). In stability-indicating methods, the forced degradation studies are done at a temperature increased 10 C above the specified temperature and at extreme pH. The studies should also be carried out in oxidative and photolytic conditions which give the information related the inherent stability characteristics and decomposition pathways to support the appropriate intended analytical procedures (Jain et al., 2015). Concerning impurities, the ICH guideline Q3B on impurities in new drug products states that documented evidence should be provided and analytical methods should be validated and appropriate for the detection and discrimination/quantification of decomposition products. The ICH guideline Q6A provides guidance on specification and also states the requirements of stability indicating assays under Universal Tests/Criteria for drug substances and drug products (Kale et al., 2014). The same requirement for guideline Q6A is mentioned in ICH guideline Q5C for stability testing biologics/biotechnological products as already described in Section 7.6. 7.8.2 Current Updates in Regulation of Stability Indicating Assay The current changes are listed in the new regulatory guidelines, i.e., the requirement of the introduction of validation and the analysis of decomposition products and other ingredients (excipients) apart from API. In addition, United States pharmacopoeia (USP) outlines the requirements of “stability studies in manufacturing,” in that it is mentioned that drug or drug products should be assayed for potency by using stability indicating DOSAGE FORM DESIGN CONSIDERATIONS 7.8 STABILITY INDICATING ASSAY METHOD (SIAMS): CURRENT UPDATE 245 assay (Maggio et al., 2013). Likewise, ICH guideline Q7A on GMP for API says that all stability studies of API should be done or validated by a stability-indicating method (Jadhav et al., 2015). 7.8.3 Development of Stability Indicating Assay Method (SIAM) 7.8.3.1 Step 1: Critical Study of the API Structure to Assess the Particular Degradation Pathway It is necessary to elucidate the functional group such as amides, esters, lactams, lactones which have tendency to undergo hydrolysis, and thiols, thioethers etc. that undergo oxidation. Drugs containing olefins, aryl halo derivatives, aryl acetic acid, and N-oxides are prone to undergoing photodecomposition (Di and Kerns, 2015). 7.8.3.2 Step 2: Collection of Information on Physicochemical Properties of API Physiochemical parameters include log P, pKa, solubility, absorptivity, and wavelength maxima of the API. The pKa is used predict the pH related shifting in retention time occurring at pH within 1.5 units of the pKa value. During HPLC, the ionization value of the drug is also used for choosing the pH of the buffer which is used in the mobile phase. Likewise, the information related to log p of drug and identified decomposition product is important to know the separation pattern to be obtained on a stationary phase (Rub et al., 2016). The solubility of the compound will help in the selection of appropriate aqueous, organic, HPLC grade solvent for the mobile phase. The reported wavelength of the existing drug and degradation products are important during HPLC analysis with UV detector. But in case of a new drug, when decomposed products have not yet been discovered, then the new drug needs to be subjected to stress studies to observe the shifting in the spectrum, firstly individually in all reaction solution and then in mixture of solution. These provide ideas on the changes in the spectrum during the reactionand if it is necessary to take more than one wavelength by using a multiwavelength detector like PDA photodiode array detector (Lin et al., 2014). 7.8.3.3 Step 3: Forced Degradation Studies The third step for the development of the stability indicating assay method is the forced degradation studies to generate the decomposition products of the drug. The Q1A (ICH guideline) provides stress testing parameters which are listed in Table 7.8. 7.8.3.4 Step 4: Preliminary Separation Studies on Stressed Sample To determine the number and type of degradation product formed during stress testing, at initial level start with a reversed-phase octadecyl column to give well separated and good quality peaks which help to discriminate the degradation products during stress conditions. At early stages the use of water methanol or water acetonitrile should be preferred and the use of phosphate buffer is not preferred at this stage (Mohanty et al., 2016). For the detection of the degradation products, the setting of wavelength is based on the spectral pattern, and the injection volume and flow rate are adjusted as per the length of column. DOSAGE FORM DESIGN CONSIDERATIONS 246 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT TABLE 7.8 Forced Degradation Parameters Degradation Factor Conditions Methodology References Thermal $ 60 TG-FTIR Niu et al. (2017) Humidity $ 75% RH Ion-pair in-tube solid phase microextraction Fernández-Amado et al. (2017) Acid 0.1 N HCL HPLC, HPTLC, UV Fiese and Steffen (1990) Basic 0.1 N NaOH HPLC, HPTLC, UV Singh and Bakshi (2000) Oxidative Oxygen gas or 3% H2O2 HPLC, HPTLC, UV, MS/TOF Akabari et al. (2017) Photolytic Metal halide, He, Xe lamp or UV-B UV, HPLC Cordenonsi et al. (2016) The main objective of this study to reveal the decomposition route, the degradation products are formed by introducing degradation factors such as heat, humidity, acid, base, oxidative, photolytic at extreme level. 7.8.3.5 Step 5: Method Development and Optimization The next stage is method development and optimization. At each reaction condition, the retention time and relative retention time of all products should be tabulated and special attention is required for close retention and relative retention of products (Zhang et al., 2014b). For the study of resolution of a sample, a mixture of samples is prepared and those reaction solutions are mixed so that different products are formed and the chromatographic pattern can be compard with the individual sample. A situation like close or coeluting chromatographic peaks can be separated by optimizing the method, changing the mobile ratio, pH, gradient, flow rate, solvent type, and changing the type of column (Bae et al., 2015). 7.8.3.6 Step 6: Identification and Characterization of Decomposition Products, and Preparation of Standards Prior to the validation of a stability indicating assay method, it is important to identify the drug decomposition products. These can be arranged for their standards, which are useful in specificity and selectivity stability indication methods (Stark et al., 2017). 7.8.3.7 Step 7: Validation of Stability Indicating Assay Method Two steps are carried out for the validation of the stability indicating assay method. The first step includes the early development of the drug where it is subjected to stress degradation studies and the stability indicating method is established according to the drug decomposition pattern. In the second step of validation, when the stability indicating method has been developed for any formulation, then it is important to provide some limited validation parameters of formulation, such as excipients and other ingredients (Schmidt and Molnár, 2013). The overall steps involved in the stability indicating assay method are shown in Fig. 7.6. DOSAGE FORM DESIGN CONSIDERATIONS 7.9 REDUCED STABILITY-TESTING PLANS 247 FIGURE 7.6 Steps involved in the development and validation of stability indicating assay method. Stability indicating assay method involves seven steps to monitor the obtained results of stability studies for ensuring the quality of the product. 7.9 REDUCED STABILITY-TESTING PLANS The reduced stability studies differ from a full study design. Samples of each parameter and their amalgamation are not measured at every time point. The decrement in testing is most suitable when stability studies involve multiple design factors and have the capability to accurately assume the shelf life of sample (Prasad, 2016). Prior to designing the reduced stability testing plan, particular predictions should be considered and explained. In terms of application, the reduced stability testing plans can be applied for most drug products and complex drug delivery systems if proper justification is provided, such as a large number of drug and device interaction. For the purpose of stability testing of any drug constituents, matrixing has a restricted usefulness and bracketing may usually not be used. Matrixing and bracketing are both reduced stability testing designs working on different principle. Therefore, proper justification and scientific consideration will decide the selection of the design (Bozkir et al., 2013). 7.9.1 Bracketing and Matrixing Design Performing and designing the full stability testing studies is very expensive. To reduce the cost of stability studies, many pharmaceutical companies used matrixing and DOSAGE FORM DESIGN CONSIDERATIONS 248 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT bracketing. The matrixing and bracketing are described in the glossary of ICH guideline (1993) (Bozkir et al., 2013). ICH guideline Q1D was approved on November 2000 and it was published on February 2002 with the basic objective of the application of bracketing and matrixing without regulatory consideration and it also inspired the utilization of this design to decrease the expense of testing (Teasdale et al., 2017). 7.9.2 Bracketing The definition of bracketing according to ICH guideline Q1D is “bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested.” (Munden, 2017). For example, if the range of tablets is 2, 4, 6 mg, in this design, we can omit the 4 mg tablet for testing. This method predicts that the stability of a particularly tested substance is representative of whole batch or intermediate level. This method is not considered as appropriate when the design fails to demonstrate that the strength of substance, size of container and/or container fill selected for testing are the extremes. Bracketing design also faces some problems. If not all batches have been put up for stability testing, it is difficult to return to full testing, and in some cases some batches could not achieve anticipated approval standards (Rao and Goyal, 2016). 7.9.2.1 Factors Related to Design In bracketing, design aspects are variable, for example, strength, size of container and/ or fill, and these are all assessed in this method and for product stability effect (Bozkir et al., 2013). 7.9.2.2 Strength The strength refere to the quality or state of the sample and when the range of sample strengths are identical or very similar in composition, bracketing is applicable. For example, if a range of tablets are prepared by varied weights of compression for granules, or an oral solution with different strength in composition. If they only differ in minor ingredients like colorants or flavoring agent or a different size of capsules are prepared with various plug fill weights of the similar simple ingredients then bracketing would be applicable (Cartwright, 2016). The bracketing is applicable to multiple strengths where only the related amount of API and excipients are modified in the dosage form. However, if numerous excipients are utilized for different strengths in formulation, bracketing cannot be applied. 7.9.2.3 Sizes of Container Closure and Fills When conducting the bracketing design, the stability study of parallel container closure systems varies the size of container or the filling of container but other parameters would remain constant. Due to the easy interpretation of the extremes, this bracketing design is mostly preferred. For application of this design, there is a need to take care of the selection of appropriate extremes, that is one needs to consider all the container closure attributes such as closure geometry, wall thickness of container, ration of surface area to volume, DOSAGE FORM DESIGN CONSIDERATIONS 249 7.9 REDUCED STABILITY-TESTING PLANS headspace to volume, water vapor permeation rate, or oxygen permeation rate per fill volume or per dosage component (Khan and Akhtar, 2015). 7.9.2.4 Design Instance The example of bracketing is directly taken from ICH guideline Q1D. Table 7.9 provides an example of bracketing. It represents 12 stability tests which are needed to show the strength extremes as well as the container closure systems, rather than 36 studies. The stability profiles of intermediate configuration can be anticipated to act in relation to the extreme, consequently, in bracketing the intermediary configuration is not essential (Munden, 2017). The following example shows three batches with strength 50 500 mg and container size from 50 250 mL. While designing the bracketing, it is a critical scenario if the expected trend is not followed in the case of one extreme stability profile. In this circumstance it has to be considered that the intermediate configurations do not match with data (Burdick et al., 2017). 7.9.3 Matrixing According to the definition given in ICH guideline Q1D, “matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested.” The design assumes that the samples tested represent the stability of all samples at that specific time point (Teasdale et al., 2017). Matrixing is a more conventional design than bracketing, therefore, it is recommended by regulatory agencies, although there are limitations. A stability statistician should be required because the interpretation of data is more complicated than bracketing. Matrixing is applied when differences are identified such as including diverse batches, different strengths, dissimilar sizes of container and closure, and in several instances numerous closure systems. Unlike bracketingwhere only extremes are evaluated (Freed et al., 2017), matrixing is applied all over the packaging system, where a secondary packaging is used for drug product stability. The main advantage of matrixing is the flexibility it offers to stability protocol design, i.e., storage situations for samples would be different and they can be tested distinctly via their particular matrixing. Thus realistic long period storing conditions should be matrixes. Matrixing is used where product stability support is available or data shows small variability. In thecase of moderate variability, statistical justification is needed to use a matrixing design. Statistical justification is required for the evaluation of an incorporated matrixing TABLE 7.9 Example of Simple Bracketing Design Strength 50 mg 100 mg Batch A B C Container size T T T T A 250 mg B C A 500 mg B A B C T T T T T T T T Above their three batches: A, B, C and three container sizes: 50, 100, and 250 mL; T, sample tested. DOSAGE FORM DESIGN CONSIDERATIONS C 250 7. STABILITY AND DEGRADATION STUDIES FOR DRUG AND DRUG PRODUCT TABLE 7.10 Example of Matrixing Design for One-Half Reduction Time Point (Months) Strength S1 S2 0 3 Batch 1 T Batch 2 T Batch 3 T Batch 1 T Batch 2 T Batch 3 T 6 9 12 T T T T T T T T T T T T T T T T T T 18 24 36 T T T T T T T T T 24 36 T T There are two strengths, S1 and S2, with three batches in each strength studied up to 36 months; T, sample tested. TABLE 7.11 Example of Matrixing Design for One-Third Reduction Time Point (Months) Strength S1 S2 0 3 6 Batch 1 T T Batch 2 T T Batch 3 T T Batch 1 T T Batch 2 T T Batch 3 T T 9 12 T T T 18 T T T T T T T T T T T T T T T T T T T T T There are two strengths, S1 and S2, with three batches in each strength studied up to 36 months; T, sample tested. systemic regarding its power to identify variability amongst the parameters in the degradation rates or its accuracy in the estimation of product shelf life (Rao and Goyal, 2016). 7.9.3.1 Design Influences The design parameters are variable, for example, strength, size of container and/or fill, and are assessed systematically along with their consequences on substance stability (Bhattacharyya, 2013). It is concluded that bracketing is applicable to multiple strengths where only the related amount of API and excipients are altered in the formulation. However, if different inactive ingredients are utilized in different strength formulations, then bracketing cannot be applied. 7.9.3.2 Design Examples In matrixing design, one-half reduction refers to a reduction strategy involving the removal of one in every two time points and a one-third reduction is the removal of one in every three time points (Prasad, 2016). Tables 7.10 and 7.11 show a matrixed design for one-half and one-third decrement representing a reduction of one-half and one-third, respectively. However, the half part of 24/48 and one-third part of 16/48 actually shows 15/48 and 10/48, respectively, because of added full testing of all factor combinations at some time points to balance the matrix design. DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 251 7.10 CONCLUSION The generation of stability data employing numerous stability tests is a comprehensive practice to determine the stability of different pharmaceutical drug products. Factors affecting stability comprise the active ingredients stability; interaction of active ingredients with excipients; manufacturing process followed; dosage form type; packaging products, i.e., container or closure system; light; heat; moisture; conditions encountered during shipment, storage, and handling etc. Stability testing is carried out on pharmaceutical drug products at different developmental stages of the product as part of the routine procedure. As discussed in this chapter, many testing procedures such as real-time stability testing, accelerated stability testing, retained sample stability testing, cyclic temperature stress testing ensure the high quality of the pharmaceutical end product with a well-defined stability period. Forced degradation studies assist in the development, manufacturing, production, and packaging of pharmaceutical drug products, and also data related to chemical performance can be employed to obtain better drug products. Stability studies are carried out at each stage of the life cycle of a drug from the very first stages of product development to late-stage follow-up studies. The stability testing program ensures the maintenance of the identity, strength, quality, purity, and efficacy of a drug substance/drug product within specifications which are established by regulatory agencies (ICH, WHO, and or other agencies). The stability protocols for conventional dosage forms such as tablets, capsules, and ointments are well-established, however, the protocols for newer drug delivery systems need to be established. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology (DST), Government of India for grant (#ECR/2016/001964) allocated to Dr Tekade for research work on drug and gene delivery. The author also acknowledges DST-SERB for N-PDF funding (PDF/2016/003329) to Dr. Rahul Maheshwari in Dr. Tekade’s lab for work on targeted cancer therapy. Authors would also like to acknowledge Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India, for supporting research on cancer and diabetes at NIPER- Ahmedabad. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. References Akabari, A.H., Suhagia, B.N., Saralai, M.G., Sutariya, V.A., 2017. Development and validation of stability indicating RP-HPLC method for estimation of fluvastatin sodium in bulk and capsule dosage form. Eurasian J. Anal. Chem. 12 (2), pp. Allison, G., Cain, Y.T., Cooney, C., Garcia, T., Bizjak, T.G., Holte, O., et al., 2015. 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Wang, J., Trinkle, D., Derbin, G., Martin, K., Sharif, S., Timmins, P., et al., 2016. Moisture adsorption and desorption properties of colloidal silicon dioxide and its impact on layer adhesion of a bilayer tablet formulation. J. Excipients Food Chem. 5 (1), pp. Yurov, V., Guchenko, S., Gyngazova, M.S., 2016. Effect of an electric field on nucleation and growth of crystals. IOP Conference Series: Materials Science and Engineering, . IOP Publishing, 012019. Zhang, S.-W., Yu, L., Huang, J., Hussain, M.A., Derdour, L., Qian, F., et al., 2014a. A method to evaluate the effect of contact with excipients on the surface crystallization of amorphous drugs. AAPS PharmSciTech. 15 (6), 1516 1526. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 8 First-Pass Metabolism Considerations in Pharmaceutical Product Development Ashok K. Shakya1, Belal O. Al-Najjar1, Pran Kishore Deb2, Rajashri R. Naik1 and Rakesh K. Tekade3 1 Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy and Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan 2Faculty of Pharmacy, Philadelphia University, Amman, Jordan 3National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 8.1 Introduction 8.2 Role of Liver and Small Intestine in First-Pass Metabolism 8.2.1 Physiological and Biochemical Factors Affecting Intestinal Metabolism 8.2.2 Hepatic and Intestinal Enzyme Induction 8.2.3 Effect of Hepatic Blood Supply on First-Pass Metabolism 8.2.4 Effect of Plasma Protein Binding on First-Pass Metabolism 8.2.5 Effect of Gastrointestinal Motility on First-Pass Metabolism Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00008-3 260 8.2.6 Effect of Dose-Dependent First-Pass Metabolism 8.2.7 Effect of Genetic Polymorphism on First-Pass Metabolism 8.2.8 Route of Administration and First-Pass Metabolism 260 261 263 268 268 269 8.3 First-Pass Metabolism Considerations in Prodrug Development 269 270 270 278 8.4 Perspectives on First-Pass Metabolism Considerations in Pharmaceutical Product Development 280 8.5 Conclusion 259 281 © 2018 Elsevier Inc. All rights reserved. 260 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT Acknowledgment 282 References 283 Abbreviations 282 Further Reading 286 8.1 INTRODUCTION The action of pharmaceutical oral dosage forms generally takes place in three phases. The first phase is the pharmaceutical phase which includes the disintegration of tablets or capsules in gastrointestinal intestinal tract (GIT) for orally administered drugs followed by the second pharmacokinetic phase that consists of the absorption of the drug from GIT into the blood. Finally, the drug interacts with the target to exert its pharmacological response; this third phase is known as the pharmacodynamics phase (Turner, 2010). Once the drug enters the body, it is subjected to a variety of enzymatic attacks that cause either degradation or modification of the parent molecule that facilitate its easier excretion from the body. Most of these drugs undergo metabolic reactions forming structures called metabolites. These metabolites of drugs might have either higher or lower activity or no activity at all, as compared to the parent drug. In exceptional cases, some of the metabolites may produce different pharmacological activity than the parent drug and might also exhibit toxicity. Thus, a proper understanding of drug metabolism and its potential metabolites can help in designing new drugs with less probability of unacceptable or toxic metabolites. Moreover, such metabolism study is also beneficial for medicinal chemists for the design and development of drugs that can be activated by enzymatic metabolism, known as prodrugs (Testa and Krämer, 2008). The term prodrug was initially used by Albert (Albert, 1973). It is a pharmacologically inactive, or has very low activity, compound that is converted into an active drug by a metabolic biotransformation. In a few cases, the prodrug can also be activated by nonenzymatic processes such as by hydrolysis. From the pharmaceutical point of view, prodrugs are generally designed and used to modify the pharmacokinetic properties to improve the absorption, distribution, metabolism, and elimination (ADME), as well as to reduce the toxicity of a drug. This chapter will discuss the main considerations of first-pass metabolism that are necessary for pharmaceutical product development. 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM The liver has a vital role in drug and xenobiotic metabolism, because of both its anatomic location and many biochemical functions. The liver receives blood from the veins of intestine as a result of which all the orally taken drugs and other xenobiotics reach the liver where they may undergo further metabolism before entering the systemic circulation (Pelkonen, 2015). While a majority of these processes result in largely nontoxic quantities of metabolites with favorable excretion profiles, a subportion of these reactions result in toxic compounds that can directly elicit liver damage. Other compounds generated from DOSAGE FORM DESIGN CONSIDERATIONS 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM 261 CYPs can result in activation of the inflammatory response that can either exacerbate or help to rectify ongoing liver damage. Moreover, inflammation during liver injury can affect expression and activity of CYPs, potentially altering ongoing drug metabolism and affecting toxicity by reducing or enhancing metabolism (Woolbright and Jaeschke, 2015). Cirrhosis of liver and metabolic diseases reduces the metabolism of drugs in liver. Adiponectin and proinsulin are commonly used as biomarkers in patients with metabolic syndrome to evaluate the efficiency (Malinowski et al., 2014). Metabolism of drugs by this enzyme system leads sometimes to more active and toxic compounds which produce liver injury, e.g., in the case of carbon tetrachloride (Tekade et al., 2018). Halothane is a volatile anesthetic currently used predominantly in developing countries, due to its low cost (Habibollahi et al., 2011). Unlike a number of the other volatile anesthetics, halothane induces drug-induced liver injury only in a subpopulation of patients (Uetrecht, 2009). Halothane-induced hepatitis is thought to be mediated by the conversion of halothane to trifluoroacetyl chloride (TFA) by CYPs, predominantly CYP2E1 (Bourdi et al., 2001). The role of small intestine is well-known as an absorptive organ in the uptake of drugs administered orally. Additionally, it is has the ability to metabolize drugs by phase I and phase II reactions. The term “first-pass” metabolism is referred to any metabolism of drugs before entering the systemic circulation. Although, the liver is considered as the major site of metabolism because of the presence of high amount of metabolizing enzymes, however, recent studies also indicate the significant contribution of the small intestine in metabolism (Joshita et al., 1936; Billat et al., 2017; Jones et al., 2016; Lin et al., 1999). 8.2.1 Physiological and Biochemical Factors Affecting Intestinal Metabolism 8.2.1.1 Mucosal Blood Flow The blood flow of the small intestine is related directly with the metabolic process as well as the functional activity. Blood flow in the villi and submucosal region is increased during the absorption phase. Following a meal, the blood flow increased 130%(range 31245%) of basal flow. In contrast, sympathetic stimulation decreases the intestinal blood flow due to the vasoconstriction effect of blood vessels. During heavy exercise, the blood flow can be shut for a short period of time by sympathetic vasoconstriction. It has been shown that the rate of midazolam metabolism was affected by exercise (Jacobs et al., 2015), in which it is attributed to a transitory decrease of mucosal blood flow. Thus, the bioavailability of any drug may be affected by intestinal blood flow, in which the higher the blood flow, the lower will be the intestinal metabolism (Sim, 2015). 8.2.1.2 Drug-Metabolizing Enzymes in the Small Intestine Several types of phase I and phase II metabolic reactions may occur in the liver and intestine. Nearly all of the metabolizing enzymes that are present in liver are also found in the small intestine but in low levels. A listing of classic enzymes responsible for phase I and phase II are represented in Table 8.1. CYP3A4 act as barrier against xenobiotics in the small intestine where it is present. The bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy human DOSAGE FORM DESIGN CONSIDERATIONS 262 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 8.1 Phase I and Phase II Enzymes Name of Enzymes Phase of Drug Metabolism Cytochrome P450 monooxygenase Phase I Azo and nitro group reductase Aldehyde dehydrogenase Alcohol dehydrogenase Epoxide hydrolase Monoamine oxidase Flavin monoamine oxidase Glucuronic acid transferase Phase II Catechol-O-methyltransferase (COMT) Phenylethanolamine N-methyltransferase (PNMT) Sulfokinase Glutathione transferase N-acyltransferase subjects after the intake of grapefruit juice, whereas the bioavailability of its metabolite is reduced to 25% which is due to the inhibition of metabolism. Some of the substrates of CYP3A4 show low bioavailability due to its first-pass metabolism. The ratio of the AUCs of the metabolite α-hydroxymidazolam to midazolam decreased from 0.77 to 0.11 (Andersen et al., 2002). After the ingestion of grapefruit juice in the patients with liver cirrhosis, the bioavailability of the midazolam is doubled due to the inhibition of the enzymes in liver. 8.2.1.3 Cytochromes P-450 The Fig. 8.1 shows the percentage participation of cytochrome P450 isoforms in drug and xenobiotics metabolism. These enzymes are considered as the most important enzymes that are responsible for Phase I reactions. Recently, eight mammalian CYP450 crystal structures have been uploaded into the Protein Data Bank (www.rcsb.org). Among them, CYP3A4 has the ability to metabolize approximately two-thirds of xenobiotics (Zanger and Schwab, 2013; Tracy et al., 2016). In the small intestine, the function of CYP3A4 is as a barrier against drugs and chemical compounds. Some of the substrates of CYP3A4 show low bioavailability due to its first-pass metabolism. There is significant change in such AUCs of CYP3A4 which is due to inhibition, induction, and saturation of CYP3A4 (Kato, 2008). Studies suggest that CYP3A and CYP2C9 represent the majority of the intestinal P450 pie, accounting for 80% and 15% of the total immunoquantified P450s, respectively. Median concentrations of microsomal protein CYP3A4 in human duodenum, distal jejunum, and distal ileum were 32, 23, and 17 pmol/mg, respectively (Paine et al., 1997). DOSAGE FORM DESIGN CONSIDERATIONS 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM 263 FIGURE 8.1 Percentage of drugs metabolized by different human CYP450 isoforms. Many interactions mediated by the inhibition of CYP3A4 have been reported. It is not so obvious which inhibitions, hepatic and/or intestinal CYP3A4, contribute to the drug drug interaction. Metabolism of Simvastatin and Lovastatin is greatly reduced by grapefruit juice. Coadministration of grapefruit juice with quinidine exhibits high bioavailability and low intestinal metabolism (Min et al., 1996). Therefore, the increase in the AUC of CYP3A4 substrates by the coadministration of grapefruit juice might be an index for intestinal first-pass metabolism, although it cannot be denied that the increase may be due to the inhibition of an efflux transporter such as P-glycoprotein. The distribution of these isoenzymes is not identical along the intestine, unlike the liver (Debri et al., 1995; Almazroo et al., 2017). The average content of CYP450 in intestine is about 20 pmol/mg microsomal proteins, which is much lower than that in the liver (Debri et al., 1995). CYP450 amount also varies along the villus in rats, where the CYP450 amount at the villus tip is observed to be around 10-fold higher than that at the crypts (Lin et al., 1999). 8.2.2 Hepatic and Intestinal Enzyme Induction 8.2.2.1 Cytochromes P-450 The CYP-450 enzymes comprise a superfamily of heme proteins, members of which are present in all branches of the phylogenetic tree from archaebacteria to higher mammals. In human liver, the abundance of major CYP enzymes has been reported. As the liver contains the greatest abundance of drug metabolizing CYPs (CYP2C9, 2C19,2D6, and 3A5), CYP substrates are susceptible to efficient hepatic first-pass metabolism, which leads to low bioavailability. For example, buspirone, cyclosporine, lovastatin, saquinavir, and DOSAGE FORM DESIGN CONSIDERATIONS 264 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT verapamil exhibit poor oral bioavailability (,30%), mainly due to the extensive CYP3Amediated first-pass metabolism (Shen et al., 1997). Several metabolizing enzymes activity can be increased by exposure to drugs and environmental chemicals, leading to enhanced rates of metabolism, thus altering drugs pharmacological activity and toxicity. Prolonged exposure of a drug or xenobiotic may increase the metabolism of itself and a several other compounds (Nelson, 2005). This phenomenon is called enzyme induction. Induction is the process whereby the rate of enzyme synthesis is increased relative to the rate of enzyme synthesis in the un-induced organism. Many drugs and xenobiotics may induce the expression of CYP450, as shown in Table 8.2. Stereoselective differences in pharmacokinetics between clausenamide (CLA) enantiomers have been found after intravenous and oral administration of each enantiomer to rats. In a pharmacological study, numerous models and indicators showed that ( )CLA is the active enantiomer, while (1)CLA is inactive and elicits greater toxicity than ( )CLA (Chu and Zhang, 2014). Stereoselective pharmacokinetics of CLA enantiomers could be resulted from their stereoselective excretion, first-pass metabolism, and induction to metabolizing enzymes(Zhu et al. 2013). Multiple oral administrations of rifampicin caused induction of CYP3A4 in the liver and intestine. Although rifampicin induces CYP3A4, it also induces P-gp. P-gp and CYP3A4 content in biopsy samples after treatment with rifampicin (600 mg/day) measured by Western blotting showed increases of 3.5- and 4.4-fold, respectively, as compared TABLE 8.2 Drugs That Induce the Expression of CYP450 Isoforms (Williams, 2012) Drug Isoform Amprenavir 3A4 Aprepitant 2C9 Barbiturates 3A4, 2C9, 2C19, 2B6 Carbamazepine 1A2, 3A4, 2C8, 2C9, 2D6, 2B6 Charbroiled meats 1A1/2, Cigarette smoke 1A1/2 Clotrimazole 1A1/2, 3A4 Ethanol 2D6, 2E1 Efavirenz 3A4 Erythromycin 3A4 Glucocorticoids 3A4, 2A6 Dexamethasone, prednisone 2C19 Griseofulvin 3A4 Lansoprazole 1A1/2, 3A4 DOSAGE FORM DESIGN CONSIDERATIONS 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM 265 with the values before treatment. Treatment with rifampicin caused 27% and 17% reduction in the AUCs of zolpidem and quinidine, respectively, both of which exhibited high bioavailability (Kato, 2008). The concentration in the intestine might be higher than unbound concentration in circulation, which would cause the saturation to be greater for intestinal metabolism than for hepatic metabolism. Midazolam and sildenafil shows nonlinear kinetics which might be due to the saturation of intestinal metabolism. 8.2.2.2 UDP Glucosyltransferases and Sulfotransferases Glucuronide conjugate process is perhaps the major and most common route for Phase II metabolism to form water-soluble metabolites. The importance of glucuronidation lies in the plentiful supply of glucuronic acid in the liver and in the numerous functional groups forming glucuronide conjugates (e.g., phenols, alcohols, carboxylic acids, and amines) (Zhu et al., 2016). Glucuronide conjugation involves the direct interaction of the drugs and xenobiotics (or its Phase I metabolite) with the cofactor UDP glucuronic acid (UDPGA) as shown in Fig. 8.2. Sulfate conjugation happens less frequently than does glucuronidation probably because of the limited availability of inorganic sulfate in mammals and furthermore a fewer number of functional groups (phenols, alcohols, arylamines, and N-hydroxy compounds) undergo sulfate conjugation (Rowland et al., 2013). FIGURE 8.2 Glucuronic acid conjugation reaction for drug metabolism. DOSAGE FORM DESIGN CONSIDERATIONS 266 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 8.3 Sulfate conjugation reaction for drug metabolism. A similar process applies to sulfate transferases in which the donor is 3’-phosphoadenosine-5-phosphosulphate (PAPS). The accepting groups in the molecule are phenols, alcohols, and hydroxylamines, as shown in Fig. 8.3 (Almazroo et al., 2017). The intestinal mucosa contains mainly of CYP3A4 isoform, glucuronosyl transferases, sulfotransferases, and GSTs, which make it significant for orally administered drugs liable to oxidation (Thelen and Dressman, 2009), glucuronidation, or sulfonation conjugation pathways (Oda et al., 2015). Intestinal UDPGT isoforms can glucuronidated orally administered drugs, such as morphine, acetaminophen, α- and β-adrenergic agonists, which lead to decrease their oral bioavailability (increasing first-pass metabolism), hence altering their pharmacokinetics and pharmacodynamics (Williams, 2012). The sulfotransferases in the small intestine can sulfonate orally administered drugs and xenobiotics, such as isoproterenol, albuterol, acetaminophen, and fenoldopam, hence decreasing their oral bioavailability and thus, affecting their pharmacokinetics and pharmacodynamics (Chen et al., 2015). 8.2.2.3 p-Glycoprotein Intestinal P-gp is considered another factor that must be studied in the oral bioavailability of many CYP3A4 substrates (Hennessy and Spiers, 2007). It can play an important role in compound absorption, distribution, metabolism, and elimination from the body (Hennessy and Spiers, 2007). Overexpression of P-gp was linked to multidrug resistance (MDR) in mammalian cell lines and human cancers, evoking intense interest first from molecular and cell biologists, and later, when purified P-gp became available, from biochemists and biophysicists. Moreover, it displays a broad specificity for a large number of substrates, inhibitors, and inducers as shown inTable 8.3 (Williams, 2012). Low oral bioavailability or high firstpass metabolism drugs can be mainly liable to alterations in the transport kinetics of P-gp. DOSAGE FORM DESIGN CONSIDERATIONS 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM 267 TABLE 8.3 Example of P-gp Substrates, Inhibitors, and Inducers (Williams, 2012; Robert and Jarry, 2003) Substrate Inhibitors Inducers Acetolol Carvedilol Dexamethasone Celiprolol Desipramine Prazosin Ciprofloxacin Dipyridamole Progesterone Colchicine Disulfiram Quercetin Enoxacin Doxepin Rifampin Quinolones Fluphenazine Ranitidine Glibenclamide Vincristine Quinidine Vinblastine Chloroquine Paclitaxel Reserpine Saquinavir Amiodarone Nelfinavir Terfenadine Indinavir Progesterone Triton X-100 Tamoxifen Rhodamine 123 Cortisol Tetramethylrosamine Verapamil Hoechst 33342 Nifedipine Actinomycin D Azidopine Ivermectin Dexniguldipine Since P-gp displays saturation kinetics, drugs with low dosages can increase their oral bioavailability by increasing its oral dosage, thus saturating the P-gp pump. The compounds 6,7-dihydroxybergamottin and other furano-coumarins that are present in grapefruit juice have the ability to inhibit P-gp. Their presence have been proven to be the main reason behind the inhibition of efflux transport of drugs and drug metabolism by CYP3A4 in case of drug grapefruit juice interaction (Shirasaka et al., 2011). A second class of compounds exists which interact with P-gp, the modulators (also known as MDR chemosensitizers, reversers, or inhibitors). Modulators are able to reverse MDR in intact cells in vitro, by interfering with the ability of P-gp to efflux drug and thus generate a drug concentration gradient. The ability to block the action of P-gp selectively is of importance clinically, whether the goal is to achieve more efficacious cancer chemotherapy, improve drug bioavailability and uptake in the intestine, or deliver drugs to the brain. Numerous pharmacologic agents have been identified as P-gp modulators, many by serendipity or trial and error. DOSAGE FORM DESIGN CONSIDERATIONS 268 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT Modulators are as diverse structurally as substrates (Robert and Jarry, 2003).They appear to interact with the same binding site(s) as drugs and compete with them for transport. Many modulators (e.g., verapamil, cyclosporin A, trans-flupenthixol) are themselves transported by the protein. 8.2.3 Effect of Hepatic Blood Supply on First-Pass Metabolism In general, blood flow through the liver affects drug delivery to the organ. Diseases involving other organ systems may affect drug bioavailability and first-pass metabolism. For instance, the hemodynamic and metabolic variations associated with congestive heart failure modify the absorption of numerous cardiovascular drugs. Any physiological processes or diseases, such as fever or food intake, that affect the blood flow in the liver may modify the systemic clearance of the compound with flow-dependent liver clearance, while this may not affect drug bioavailability. Studies showed that phenobarbitone may increase liver blood flow and intrinsic activity of microsomal enzymes (Branch et al., 1974). Whereas, other studies showed that the microsomal activity did not change in dogs (Esquivel et al., 1978). Hepatic metabolism may also be affected by pulmonary disease (Du Souich et al., 1978). It has been suggested that acute hypoxemia may lead to decrease intrinsic hepatic clearance, whereas chronic hypoxemia can increase intrinsic clearance leading to a change in drug binding to plasma proteins. Moreover, decreased hepatic blood flow in patients under mechanical ventilation may lead to an increase in the plasma concentration of drugs such as lidocaine (Taburet et al., 1990). 8.2.4 Effect of Plasma Protein Binding on First-Pass Metabolism Plasma protein binding plays a key role in drug therapy that affects pharmacokinetics and pharmacodynamics of drugs and may affect the metabolism of drugs (Fasano et al., 2005). Human serum albumin (HSA) is one of the most widely examined proteins in plasma. HSA is well known for its huge ligand binding capacity, providing a depot for a wide range of ligands that may exist in quantities beyond their plasma solubility. Optimization of drug-plasma protein binding showed to be very beneficial in the development of dipeptidyl peptidase IV(DPP-IV) inhibitors as well as for the treatment of type 2 diabetes mellitus. For example, studies showed that compound A (Fig. 8.4) exhibited a 32fold activity shift demonstrating very high plasma protein binding. Meanwhile, introduction of fused heterocycles as in compound B enhanced the plasma protein binding, as observed via the 11-fold in vitro activity shift in presence of serum. Moreover, introduction of extra fluorine, as in compound C, produced potent orally active DPP-IV inhibitor with low plasma protein binding (Edmondson et al., 2006). One more therapy, directed towards the treatment of type 2 diabetes mellitus is through the activation of the hepatic and pancreatic enzyme glucokinase. Increasing activity of the lead compound GKA22 (Fig. 8.4), through lowering plasma protein binding and enhancing its in vivo potency by decreasing clearance of unbound drug to produce higher exposure, was the lead optimization method implemented by the research group. The most active glucokinase activator, GKA50,13 with an approximately twofold reduction in plasma protein binding was selected for future development (Mckerrecher et al., 2006). DOSAGE FORM DESIGN CONSIDERATIONS 269 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM O N N O O N O N F N N NH2 F F (B) (C) COOH O N F N (A) N H NH2 N N N O O N N NH2 O O COOH O O O N H N O S GKA22 GKA50 FIGURE 8.4 Structures of (DPP-IV) inhibitors and glucokinase activators. Different isomers of the verapamil (R/S) are having different pharmacokinetic profile due to the stereoselective plasma proteins binding and first-pass effect (Thörnet et al., 2012). Absence of stereoselective PK was observed after intravenous administration indicating that the first-pass effect is an important factor in determining the difference in isomer plasma concentration after oral administration. 8.2.5 Effect of Gastrointestinal Motility on First-Pass Metabolism Intestinal motility as well as gastric emptying may affect the degree of drug absorption and may also affect the amount of hepatic first-pass metabolism. Increasing the motility of gastrointestinal tract may increase the transportation rate of drug to the liver (Pond and Tozer, 1984). As the small intestine is the optimal absorption site for most drugs, a decrease in gastric emptying rate (e.g., migraine attack, fatty meals, antimuscarinic medication) generally delays their oral absorption although it may not significantly affect the extent of absorption unless the drug is not stable in the stomach. On the other hand, increased intestinal motility with prokinetic drugs such as metoclopramide would enhance the intestinal absorption of most drugs. Excessively enhanced gut motility (e.g., during diarrhea) however may reduce oral absorption of drugs with poor lipid solubility due to insufficient time for drugs to cross the intestinal mucosa (Sim, 2015). 8.2.6 Effect of Dose-Dependent First-Pass Metabolism The activity of a drug is generally believed to be correlated directly to its concentration at the site of action, thus it will be affected by several processes including absorption, DOSAGE FORM DESIGN CONSIDERATIONS 270 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT distribution, biotransformation, and excretion. Absorption and elimination of most drugs follow linear kinetics. Nevertheless, dose-dependent pharmacokinetics has been described more frequently in preclinical studies, mostly in toxicity studies in which high doses are often employed (Lin, 1994). Choi et al. (2009) evaluated the pharmacokinetics of mirodenafil and its metabolites after intravenous (5, 10, 20, and 50 mg/kg) and oral administration (10, 20, and 50 mg/kg) of mirodenafil. The pharmacokinetics of mirodenafil was dose-dependent after both administrations. After oral administration, about 2.6% of drug was not absorbed. It was found that the pharmacokinetics of the drug and its main metabolite was dose-dependent after both administrations of mirodenafil due to the saturable hepatic metabolism of mirodenafil. The low F value of mirodenafil in rats was mainly due to considerable hepatic and gastrointestinal first-pass effects in rats. The plasma binding values of mirodenafil to rat plasma was 87.8%. Lee and Lee (2007) also observed the similar effect with telithromycin. Telithromycin exhibits a dose-dependent (increased with increasing doses) response after both intravenous and oral administration, which is possibly due to saturable metabolism of telithromycin. The first-pass effects of telithromycin in the lung, heart, stomach, and liver were almost negligible, in rats. 8.2.7 Effect of Genetic Polymorphism on First-Pass Metabolism It is well-known in drug therapy that several drugs do not work in all patients. Studies shows that the percentage of patients who will react preferably to a certain drug ranges from 20% to 80% (Williams, 2012). It is commonly recognized that genetic factors have a significant impact on the oxidative metabolism and pharmacokinetics of drugs (Božina et al., 2009). Genotype phenotype association studies (pharmacogenetics) have revealed that genetic mutations in P450 genes (alleles) result in diverse phenotypic subgroups. For example, mutations in the CYP2D6 gene result in poor (PM), intermediate (or extensive (EM)), and ultra-rapid (UM) metabolizers of CYP2D6 substrates (Ingelman-Sundberg et al., 1999). Each of these phenotypic subgroups involves different reactions to drugs extensively metabolized by the CYP2D6 pathway, ranging from severe toxicity to complete lack of efficacy. 8.2.8 Route of Administration and First-Pass Metabolism Normally, drugs are provided at sites away from the site of action. The major drug delivery routes are demonstrated in Table 8.4. The kinetics of a drug away from the site of administration is called the “absorption” of that drug and the amount to which a drug passes the barriers on its way to its site of action is called the “bioavailability.” The differentiation between the two terms is essential as a drug can be completely absorbed but has no oral bioavailability due to post-absorption metabolism (Beaumont, 2010). DOSAGE FORM DESIGN CONSIDERATIONS 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM 271 TABLE 8.4 Summary of the Various Routes of Administration of Drugs Route Comment Intranasal Limited to low doses (solubility) Buccal Limited to low doses (solubility) Inhalation Limited to low doses, patient needs device training Dermal Limited to low doses, accidental removal of dose by washing etc. Intravenous Limited to in-clinic delivery Oral Can deliver range of doses conveniently Subcutaneous and intramuscular Low Doses FIGURE 8.5 Summary of the barriers upon oral administration. 8.2.8.1 Oral Administration The oral route is the most preferable route of drug administration, as this route is the most convenient method of drug delivery for the patients. Nevertheless, from a pharmacokinetic perspective, drug developers will face significant challenges. There are many barriers via the oral route that can limit drugs oral bioavailability as shown in Fig. 8.5. The main reason for designing prodrugs is to increase oral bioavailability, and the intestinal absorption, which are enhanced by masking the polar moiety of the drug (Rooseboom et al., 2004). For example, dabigatran, a potent inhibitor of the active site of thrombin is very polar molecule with a logP of 22.4 (n-octanol/buffer pH 7.4), therefore its oral bioavailability is negligible (Capucha et al., 2012). Dabigatran etexilate, the first oral alternative to warfarin, was developed as a prodrug of dabigatran (Fig. 8.13). After oral DOSAGE FORM DESIGN CONSIDERATIONS 272 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 8.6 Structure of resveratrol and its acetal prodrug. H3C CH 3 O CH3 O HO OH HO H3C H3C Resveratrol CH3 O O O H3C O CH3 CH3 Resveratrol acetal drivative OH S H3C N O OH NH O S H3C H O Cefadroxil N HO NH2 O O H NH O O N NH2 O N N O O NH2 NH H2N Cephalexin Valacyclovir FIGURE 8.7 Structure of cefadroxil, cephalexin, and valacyclovir. administration, dabigatran etexilate is converted to the active drug dabigatran by esterases. The oral bioavailability of dabigatran etexilate is 6.5% (Knox et al., 1992). In particular, the use of ester-containing prodrugs in vivo can bring about improved bioavailability; the removal of ester functionalities is accomplished through enzyme catalysis or spontaneous hydrolysis. An example of a successful pharmaceutical masked with an ester group is enalapril (Patchett, 1984). The pharmacological exploitation of resveratrol is hindered by rapid metabolism. The pharmacological action can be increased by using the acetal prodrugs of resveratrol (Fig. 8.6). The journey of a drug from its site of administration upon the oral route may face a number of steps such as dissolution, permeation, active transport, active efflux, and firstpass metabolism. For any drug to be absorbed, it must be in solubilized form in the lumen of the gastrointestinal tract. The fluids in the lumen are mainly aqueous in nature with a pH ranging from acidic to 7.4. Therefore, drug solubility is considered as an important parameter for the medicinal chemist (Singh, 1999). Once in aqueous solution, a drug must cross the gastrointestinal tract epithelium to be absorbed. The drug can cross the enterocyte layer, gut wall epithelial cell by passive diffusion which depends upon the physicochemistry of the drug (He et al., 1998). Nevertheless, the idea of the enterocyte membrane as a simple lipid bilayer is too simplistic. Several proteins are found within the membrane that have the ability to either facilitate (active absorption) or hinder (active efflux) passing of drug molecules across the membrane. For instance, the human peptide transporter 1 (hPEPT1) has low affinity, and found on the apical brush border membrane of enterocytes. This influx transporter has been involved in the absorption of a various series of drugs like valacyclovir and β-lactam antibiotics such as cefadroxil and cephalexin (Guo et al., 1999; Dahan et al., 2012; Fig. 8.7). DOSAGE FORM DESIGN CONSIDERATIONS 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM O O N FIGURE 8.8 273 Structure of UK-224 671. N HN N N O S O N N Valacyclovir is the 5’-valyl ester prodrug of the antiviral drug acyclovir, which is a successful example of a modern transporter-targeted prodrug approach. The oral bioavailability of acyclovir is increased by three- to fivefold using this prodrug. This improved absorption provided by the prodrug has been shown to be attributable to carrier-mediated intestinal transport of the prodrug via hPEPT1 (Dahan et al., 2012). The efficiency and activity of valacyclovir, as an antiviral drug depends on the in vivo conversion of valacyclovir to acyclovir. Moreover, a number of efflux transporters are found at the gut lumen facing (apical) membrane of the enterocyte to prohibit the passage of drug molecules that might be potentially harmful to the body. The most well-studied drug efflux transporter is P-glycoprotein (P-gp). UK-224,671 is a potent selective NK2 receptor antagonist (Fig. 8.8) that has been shown to be a substrate for P-gp (Beaumont et al., 2000). 8.2.8.2 Transdermal Delivery Transdermal absorption of a drug through the skin to the systemic circulation can occur via a transfollicular or transepidermal pathway (Tekade et al., 2017). The degree of absorption is influenced by molecular weight and the lipophilicity of the drug. This route can be used to deliver small potent and lipophilic molecules that require minimum input rates to achieve effective therapy such as fentanyl as shown in Fig. 8.9 (Power, 2007). Permeability of the drug can be manipulated with the help of designing an appropriate prodrug; this strategy is commonly used. Using the prodrug approach it is easy to modify the physicochemical and pharmacokinetic properties of the drug molecule. The approach is useful in transdermal drug delivery research where it is used to facilitate transcutaneous flux (Clas et al., 2014). The aqueous solubility of the parent drug can be improved by using amino acid esters or amide prodrug. These moieties can be introduced to drugs having amino-, hydroxyl-, mercapto-, or carboxylic acid functional groups. The water solubility of drugs can also be increased by introducing the ionizable polar or neutral functional groups like phosphates, sugar, or amino acid residues (Huttunen et al., 2011). Cyclizine alkyl analogs were synthesized and their physicochemical properties and in vitro skin permeation was evaluated (Monene et al., 2005). The compound 1-(diphenylmethyl)-4-ethylpiperazine (Fig. 8.10) has good penetration. The results of this study suggest that alkylation is a potentially useful approach to enhance percutaneous penetration DOSAGE FORM DESIGN CONSIDERATIONS 274 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT O FIGURE 8.9 Structure of Fentanyl. N H3C N FIGURE 8.10 Structure of 1-(diphenylmethyl)-4-ethylpiperazine, a derivative of cyclizine. N N FIGURE 8.11 Aminoacyl prodrug of 6-β-naltrexol. N OH HO NH2 O n O O FIGURE 8.12 5-Hydroxy-N,N-dipropyl-2-amino-tetralin (5-OH-DPAT) and its glycine prodrug. N OH N O NH2 O of drug and controlling emesis. Many other approaches have also been devised to address the problem (Maheshwari et al., 2012). Eldridge et al. (2014) successfully designed amino acid ester prodrugs of 6-β-naltrexol and investigated their microneedle-assisted percutaneous penetration. Fig. 8.11 depicts the general structure of an amino acyl prodrug that releases naltrexol, an opioid neutral antagonist, in vivo after hydrolysis. Ackaert et al. (2011) synthesized and evaluated the efficacy of glycine-, proline-, valine-, and β-alanine prodrugs of 5-hydroxy-2-(di-n-propylamino) tetralin (5-OH-DPAT) which is a selective D2 and D3 dopamine receptor agonist, useful in the management of Parkinson’s disease (Fig. 8.12). DOSAGE FORM DESIGN CONSIDERATIONS 275 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM Morphine is the most widely used opioid analgesic for acute and chronic pain and is the standard against which new analgesics are measured. Morphine is inefficiently absorbed orally due to first-pass metabolism. Transdermal drug delivery offers a further improvement in its administration and enables the continuous systemic application of morphine through intact skin, producing constant plasma concentrations. Ester prodrugs of morphine-like morphine enanthate and morphine propionate are able to deliver morphine through a transdermal delivery system. These esters have enhanced delivery of morphine through ethanol-, a-terpineol-, and oleic acid-pretreated skin (Wang et al., 2007). Similarly, Wang et al. (2009) deliver buprenorphine (a partial agonist of µ-opioid receptors) through a transdermal delivery system utilizing C3, C5, and C7-ester prodrugs of buprenorphine. 8.2.8.3 Ocular Drug Delivery Prodrugs are used to increase lipophilicity so that the drugs are available for oral administration, ocular, or topical drug delivery. Ophthalmic administration of topically administered drugs is controlled by corneal barrier. A small percentage of applied drug is absorbed from the ophthalmic preparations. Various factors affecting the bioavailability of drug by ocular delivery are (A) tears, (B) conjunctiva, (C) cornea, (D) sclera, and (E) blood ocular barriers (Achouri et al., 2013). Dipivefrin, a pivalic acid diester of adrenaline (prodrug of adrenaline, Fig. 8.13) penetrates the cornea 17-fold more rapidly than adrenaline. This compound is 600 times more lipophilic than adrenaline, which is responsible for the absorption of the compounds from corneal mucosa and penetration into the anterior chamber. The prodrug releases adrenaline after hydrolysis inside the eye. Adrenaline, which is adrenergic agonist, stimulates α-adrenergic and/or β-adrenergic receptors, increasing humor outflow with fewer side effects than adrenaline (Kompella et al., 2010). The acyl ester of ganciclovir (Fig. 8.14) is effectively delivered to the cornea using hydroxypropyl beta-cyclodextrin (HPβCD). The HPβCD successfully stabilizes the prodrug of ganciclovir. These drugs are prone to enzymatic degradation by membrane-bound enzymes of the cornea such as acetyl and butyrylcholinesterases (Tirucherai et al., 2002). Similarly, the stability of Cloricromene can be improved by stabilizing its ester form with Eudragit. It is rapidly metabolized to cloricromene acid after ester hydrolysis. H3C CH3 H3C O H N O O CH3 NH HO Esterase / hydrolysis O H3C CH3 OH HO CH3 + (CH3)3-C-COOH (Pivalic Acid) CH3 Dipivefrin (An adrenaline prodrug) FIGURE 8.13 Dipivefrin, a pivalic acid diester of adrenaline. DOSAGE FORM DESIGN CONSIDERATIONS Adrenaline 276 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 8.14 Structure of ganciclovir and R = H, R' = H, ganciclovir its acyl prodrugs. R = H, R' = COCH3, mono acetate R = H, R' = COC2H5, monopropionate R = R' = COC2H5, Dipropionate R = R' = COC3H7, Dibutyrate O N HN H2N N N O OR OR OH HO HO HO OH HO O O F3C O Travoprost FIGURE 8.15 O O Latanoprost Structure of travoprost and latanoprost. Lipophilic prodrugs are also used to enhance ocular absorption. Isopropyl esters offer the best pharmacokinetic characteristics for a number of prostaglandins that are intended for the use in ocular application, especially in animal models. Latanoprost and travoprost (Fig. 8.15) are representatives of isopropyl ester prodrugs. These ester prodrugs have an increased lipophilicity, which enables them to penetrate the corneal epithelium. Recently Adelli et al. (2017) reported the delivery of ∆9-Tetrahydrocannabinol (THC) to the anterior segment of corneal tissue using various formulations of THC prodrug (Fig. 8.16). Theamino acid (valine)-dicarboxylic acid (hemisuccinate) ester of ∆9Tetrahydrocannabinol (THC-Val-HS) demonstrated markedly improved solubility (96-fold) and in vitro permeability compared to THC. In THC-Val-HS the OH group is masked with hydrolyzable ester functional group using valine and succinic acid. Other synthesized compounds were mono-valine and di-valine ester of THC. In an earlier report, ocular disposition of the hemiglutarate ester prodrug of ∆9-Tetrahydrocannabinol from various ophthalmic formulations has been reported by Hingorani et al. (2013). Synthesis of dimethylamino-propyl-gatifloxacin (DMAP-GFX) and carboxy-propylgatifloxacin (CP-GFX) prodrugs were designed to target OCT and MCT transporters. These prodrugs, in which the carboxylic group is masked, produce significant results. The synthesis of aminopropyl-(2-methyl)-gatifloxacin (APM-GFX) prodrug was designed to target the ATB (0, 1 ) transporter but was not able to target the transporter (Vooturi et al., 2012). 8.2.8.4 Subcutaneous and Intramuscular Administration Drugs in this route are either injected or delivered via a device located in the interstitial tissue underneath the dermis—most commonly in the upper arm, the upper thigh, the DOSAGE FORM DESIGN CONSIDERATIONS 8.2 ROLE OF LIVER AND SMALL INTESTINE IN FIRST-PASS METABOLISM CH3 CH3 O FIGURE 8.16 Structure of THC (∆9-Tetrahydrocannabinol) and its prodrugs THC-Val, THC-VALVAL, and THC-VAL-HS. CH3 O OH CH3 NH2 H3C O H3C H3C O H3C CH3 CH3 THC H3C THC-VAL HOOC CH3 O H2N O O CH3 HN H3C CH3 CH3 CH3 O H3C O H3C CH3 THC-VAL-VAL OH CH3 HN O O H3C O H3C HO 277 CH3 THC-VAL-HS FIGURE 8.17 H N Structure of Salmeterol. O HO Salmeterol lower part of the abdomen, and the upper part of the back. Intramuscular administration involves the injection of the drug into the muscular layer beneath the subcutaneous tissue. Absorption of most drugs administered via these routes is dependent on blood flow, dissolution rate, and lipophilicity. Interferon α2a used for the treatment of hepatitis C or certain cancers can be administered either subcutaneously or intramuscularly (Beaumont, 2010). 8.2.8.5 Inhalation and Buccal Administration The inhalation route has been used for the delivery of small molecules to the lung (e.g., in the treatment of asthma) such as β2 agonist, salmeterol (Fig. 8.17). These asthma drugs are administered by an inhalation device at doses as low as 50 µg for the management of the bronchoconstriction associated with an asthma attack(Cazzola et al., 2002). In addition, the lung has been considered as a delivery route for large macromolecules (Patton and Byron, 2007). The oral cavity is a useful route of drug administration. In the oral cavity, the primary absorptive areas are the buccal and sublingual mucosa. Drugs absorbed from the mouth pass directly into the systemic circulation without encountering the hepatic portal system, thus escaping first-pass metabolism as well as degradation by gastric acids. Drugs that are used to treat acute angina such as glyceryl trinitrate (Fig. 8.10) are given sublingually to bypass extensive first-pass metabolism following oral DOSAGE FORM DESIGN CONSIDERATIONS 278 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT ONO2 FIGURE 8.18 O2NO Structure of glyceryl trinitrate. ONO2 Glyceryl trinitrate FIGURE 8.19 Prodrug profile (ADME). administration. Its lipophilicity enhances the absorption via the sublingual route (Armstrong et al., 1979). (Fig. 8.18). 8.2.8.6 Rectal Administration The rectal mucosa is extremely vascularized with a high blood and lymph supply. However, absorption via the rectal mucosa is often unpredictable and incomplete. If a drug is absorbed from the lower rectum via the inferior or middle hemorrhoidal veins, it can avoid first-pass metabolism since these veins empty into the vena cava and bypass the liver portal system. Whereas compounds that cross the upper rectal mucosa will enter through the superior hemorrhoidal vein to the hepatic portal circulation (Beaumont, 2010). 8.3 FIRST-PASS METABOLISM CONSIDERATIONS IN PRODRUG DEVELOPMENT The term “prodrug” was first presented by Albert (Albert, 1973) about 66 years ago when he used this terminology to define compounds that need to be metabolised in order to produce their pharmacological response. Such biotransformation is either an inherent property of the parent compound (“accidental” prodrug) or a property purposely integrated into an active drug. Highlighting the latter, the term “drug latentiation” was also presented at almost the same time by Harper (Harper, 1959), and this was defined as “chemical modification of a biologically active compound to form a new compound which upon in vivo enzymatic attack will liberate the parent compound” as shown in Fig. 8.19 (Erhardt et al., 2003). Kupchan et al. (1965) later included nonenzymatic processes to produce the active compound within an in vivo setting, such as spontaneous hydrolysis as a function of pH. An essential set of metabolism-related principles that must be obeyed throughout prodrug design is illustrated in Fig. 8.20. DOSAGE FORM DESIGN CONSIDERATIONS 8.3 FIRST-PASS METABOLISM CONSIDERATIONS IN PRODRUG DEVELOPMENT 279 FIGURE 8.20 Prodrug metabolism relationship. Conversion (1) denotes a metabolic pathway or chemical transformation that achieves the desired activation whereas (2) and (3) represent another metabolic transformation and/or excretion processes. The aim in any prodrug design approach is to have the rate of (1) . (2) 1 (3) (Remmel, 2000). FIGURE 8.21 Prodrug technique to deliver dopamine into the CNS. Firstly, if the conversion rate of the prodrug to the active agent (arrow 1) is slower than the rate of the latter processes of degradation and excretion (arrow 2), then the parent drug and its desired pharmacological response will never be observed. Moreover, the programmed bioactivation process for a prodrug technique should not be the rate-limiting step in any stage of metabolic processes by which the active drug may undergo degradation. At the same time, transformation of prodrug to a metabolite other than the active compound, or alteration by some other process of xenobiotic excretion (arrow 3) should not be faster than the conversion of the prodrug to the desired active compound. In summary, prodrug usage preparation devise an overall system wherein threat for step (1) is at all times greater than that for step (2) and, preferably, also is larger than the sum of all of the competing pathways via (2) and (3). A typical example is the preparation of levodopa (L-DOPA) as a prodrug to deliver the dopamine in CNS as a treatment for Parkinsonism as shown in Fig. 8.21 (Stella, 1975). In this example, peripheral dopa decarboxylase has the ability to compete with central dopa decarboxylase resulting in early metabolism of L-DOPA, thus, preventing the crossing of DOSAGE FORM DESIGN CONSIDERATIONS 280 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT O N CH3 N H CNS/oxidation N H O C CH3 O Prodrug of dopamine OH O O O C CH3 OH N+ CH3 Hydrolysis A O OH 1-methyl-3-[N-(β-(3,4dihydroxyphenyl)-ethyl)carbamoyl]pyridinium salt B OH + H2N OH Dopamine FIGURE 8.22 N+ CH3 Delivery of dopamine from pyridinium/dihydropyridine redox carrier system (Bodor et al., 1981, 1983). L-dopa through the blood brain barrier (BBB). In this case, (1) is represented within the CNS site where the desired biotransformation takes place. Also from this example, it can be seen that subsequent degradation by central MAO-B can potentially diminish from the valuable effects of produced dopamine, reflecting a negative impact of arrow (2) on such strategies even when it is slower than (1). In this case, simultaneous administration of co- and adjuvantagents that inhibit the peripheral enzyme may aid a beneficial effect for the strategy. Bodor and coworkers proposed the brain-specific delivery of dopamine utilizing application of a chemical delivery system based on a pyridinium/dihydropyridine redox carrier (Bodor et al., 1981, 1983). This redox delivery system was successfully applied for brainspecific delivery of DA by using the dihydro derivative A to deliver the quaternary precursor B, which while “locked in” the brain provided a sustained release form of DA (Fig. 8.22). In vivo administration of the catechol protected DA resulted in brain-specific, high, and sustained concentration of the 1-methyl-3-[N-(β-(3,4-dihydroxyphenyl)-ethyl)-carbamoyl] pyridinium salt (B), the direct DA precursor, locked in the brain for many hours, while the systemic concentration decreased fast, with a t / of less than 30 min. Significant dopaminergic activity was observed in the brain, and this was sustained for hours. Fernández et al. (2000, 2003) reported the successful delivery of dopamine to CNS utilizing D glucose as a transportable agent. Glycosyl-DA derivatives (Fig. 8.23), bearing the sugar moiety linked to either the amino group or the catechol ring of DA through amide, ester, or glycosidic bonds, were evaluated as potential antiparkinsonian agents (Fernández et al., 2000, 2003). 1 2 8.4 PERSPECTIVES ON FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT In drug discovery, studies on metabolism and biotransformation of drugs are performed in order to choose molecules with superior ADME properties. In drug DOSAGE FORM DESIGN CONSIDERATIONS 281 8.5 CONCLUSION O NH HO HO O 6 O O H N HO HO 3 HO O OH 1 OH HO O O OH 6 O OH HO 3 OH 1 Glycosyl-dopamine derivatives as prodrugs FIGURE 8.23 Glycosyl-dopamine derivatives as prodrug. FIGURE 8.24 Metabolism study stages in drug discovery and development process. development, studies on the metabolism and biotransformation of drugs are performed in order to prepare detailed data about the disposition of these molecules in animals and humans. Metabolism studies in the initial stages of drug discovery often include assessing multiple molecules with the main purpose of choosing a molecule with high metabolic stability, various elimination pathways, low affinity for enzyme inhibition or induction, and lastly, low affinity for producing reactive intermediates. The nature of metabolism studies conducted depends on the phase of the drug development process (Fig. 8.24). One key goal for performing metabolism studies in both nonclinical and human subjects is to validate that the metabolites discovered in human circulation show exposure in the toxicology species. So, metabolism studies are performed both in humans and in the toxicology species used in the long-term safety studies (Iyer and Zhang, 2007). 8.5 CONCLUSION The first-pass metabolism of a drug that mainly takes place in the gastrointestinal tract (GIT) and liver greatly reduces the systemic bioavailability as well as the efficacy of an DOSAGE FORM DESIGN CONSIDERATIONS 282 8. FIRST-PASS METABOLISM CONSIDERATIONS IN PHARMACEUTICAL PRODUCT DEVELOPMENT orally administered drug as compared to the parenteral drugs. Thus it is very essential to understand and consider the various physicochemical and physiological factors like molecular properties of drug, enzyme induction and inhibition, disease state, age, gender, genetic polymorphism etc. affecting the first-pass metabolism of a drug. Such considerations during the process of drug development are of prime importance to design an appropriate formulation with proper excipients in order to enhance the bioavailability while maintaining the efficacy of drugs. The role of various physiological and biochemical factors affecting the first-pass metabolism of a drug in GIT and liver such as of gastrointestinal motility, hepatic blood supply, plasma protein binding, genetic polymorphism, dose, and route of administration of drugs that are discussed in this chapter would provide an impetus to the researchers to design and develop better formulation of drugs or prodrugs. Acknowledgment Prof. A.K. Shakya, Dr. B.O. Al-Najjar and Dr. Rajashri R. Naik, acknowledge the support from Dean, Faculty of Pharmacy and Medical Sciences; Dean, Higher Education and Research, Al-Ahliyya Amman University, Amman to conduct research on Medicinal Chemistry, Biological and Toxicological studies. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. ABBREVIATIONS ADME BBB CNS CYP2D6 CYP3A4 CYP450 DPP-IV EM GIT GSTs hPEPT1 HSA L-DOPA MAO-B NK2 PAPS P-gp PM UDPGA UDPGT UM absorption, distribution, metabolism, and elimination blood brain barrier central nervous system cytochrome P450 family 2 subfamily D member 6 [Homo sapiens (human)] cytochrome P450 family 3 subfamily A member 4 [Homo sapiens (human)] cytochrome P450 dipeptidyl Peptidase-IV extensive metabolizer gastrointestinal tract glutathione S-transferase human peptide transporter 1 human serum albumin levodopa monoamine oxidase type B neurokinin-2 3’-phosphoadenosine-5-phosphosulfate p-glycoprotein poor metabolizer uridine diphosphoglucuronic acid glutathione S-transferase ultra-rapid metabolizer DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 283 References Achouri, D., Alhanout, K., Piccerelle, P., Andrieu, V., 2013. Recent advances in ocular drug delivery. Drug Dev. Ind. 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(Eds.), Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice, second ed. Available from: https://doi.org/10.1016/B978-0-12-802447-8.00011-X. Further Reading Lallemand, F., Perottet, P., Felt-Baeyens, O., Kloeti, W., Philippoz, F., Marfurt, J., et al., 2005. A water-soluble prodrug of cyclosporine A for ocular application: a stability study. Eur. J. Pharm. Sci. 26, 124 129. DOSAGE FORM DESIGN CONSIDERATIONS C H A P T E R 9 Dissolution Profile Consideration in Pharmaceutical Product Development Disha Mehtani1, Ankit Seth2, Piyoosh Sharma1, Rahul Maheshwari3, Sara Nidal Abed4, Pran Kishore Deb4, Mahavir B. Chougule5,6,7 and Rakesh K. Tekade3,8 1 Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India 2Department of Ayurvedic Pharmacy, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur, Uttar Pradesh, India 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 4Faculty of Pharmacy, Philadelphia University, Amman, Jordan 5Translational Drug and Gene Delivery Research (TransDGDR) Laboratory, Department of Pharmaceutical Sciences, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS, United States 6Pii Center for Pharmaceutical Technology, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, United States 7National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, United States 8Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 9.1 Introduction: Drug Dissolution Concept 289 9.2 Theories of Dissolution 9.2.1 Diffusion Layer Model 9.2.2 Interfacial Barrier Model 9.2.3 The Danckwerts Model 290 291 291 291 Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00009-5 287 9.3 Factors Affecting Dissolution Rate (In Vitro) 294 9.3.1 Drug-Related Factors 294 9.3.2 Drug Product Formulation Related Factors 295 9.3.3 Manufacturing/Processing Related Factors 296 © 2018 Elsevier Inc. All rights reserved. 288 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT 9.3.4 Dissolution Testing Conditions Related Factors 9.4 Physiological Factors Affecting In Vivo Drug Dissolution Rate 9.4.1 Composition of GI Fluid 9.4.2 pH 9.4.3 Buffer Capacity 9.4.4 Osmolality 9.4.5 Surface Tension 9.4.6 Viscosity 9.4.7 Temperature 9.4.8 Volume 9.4.9 Hydrodynamics 9.4.10 Gastric-Emptying Rate and Forces 9.4.11 Concomitant Use of Antisecretory Therapy 9.5 Dissolution Testing 9.5.1 Approaches for Dissolution Test Method Design 9.5.2 Design of Dissolution Method 298 300 300 300 301 302 302 302 302 302 302 303 303 303 303 303 9.6 Dissolution Profile: Analysis and Comparison 306 9.6.1 Dissolution Profile 306 9.6.2 Analysis of Cumulative Dissolution Profiles 306 9.7 In Vitro-In Vivo Correlation (IVIVC) 9.7.1 Definition 9.7.2 Significance and Purpose of IVIVC 9.7.3 Levels of IVIVC Correlation 9.7.4 Applications of IVIVC 306 306 306 307 308 9.8 Biopharmaceutical Classification System (BCS) and Biopharmaceutical Drug Disposition Classification System (BDDCS) 309 9.8.1 BCS Classes and Parameters 309 9.8.2 Biopharmaceutical Drug Disposition Classification System (BDDCS) 311 9.9 Role of Dissolution Testing in Pharmaceutical Product Development 311 9.9.1 Pharmaceutical Product Development Phases 312 9.9.2 Determining Drug Developability at Preformulation Stage 314 9.9.3 Simulation of Food Effects 314 9.9.4 Determination of the Impact of Concomitant Use of Other Substances With Drug Product 315 9.9.5 Dissolution as a Key Feature for Biopharmaceutical Approach in QbD 316 9.9.6 Prediction of In Vivo Dissolution: Biorelevant Dissolution Testing 317 9.9.7 Biowaiver Application: Role of BCS, IVIVC, and Similarity Dissimilarity Factor 320 9.9.8 Prognosis of Drug Disposition 322 9.9.9 Identification of Critical Manufacturing Variables (CMVs) 323 9.9.10 Surrogate of Bioequivalence Study at Postapproval Changes of Drug Product (SUPAC) 323 9.9.11 Quality Control Tool 324 9.9.12 Determination of Product Storage Stability 324 9.9.13 Investigation of Drug Release Mechanisms 325 9.10 Dissolution Mechanism: Role of Density Functional Theory (DFT) 9.10.1 Basics of Density Functional Theory 9.10.2 DFT Application to Predict Dissolution Mechanisms DOSAGE FORM DESIGN CONSIDERATIONS 325 325 325 9.1 INTRODUCTION: DRUG DISSOLUTION CONCEPT 9.11 Dissolution Controlled Drug Delivery Systems 9.11.1 Dissolution of Solid Particles 9.11.2 Dissolution of Coated Systems 9.11.3 Dissolution of Matrix Systems 9.11.4 Examples of Dissolution Controlled Drug Delivery Systems 326 326 326 289 9.12 Conclusion and Prospects 327 Acknowledgments 328 Abbreviations 328 References 329 327 327 9.1 INTRODUCTION: DRUG DISSOLUTION CONCEPT Dissolution involves the interaction of solid drug with the dissolution medium resulting in the movement of drug molecules into the bulk solution (Qiu et al., 2016). It is fundamentally dependent on relative molecular affinities between the drug and dissolution media. Under specific experimental conditions, dissolution is also known as solubility. The maximum quantity of the solute dissolved in a pure solvent under fixed environmental conditions (temperature, pressure, and pH) is called absolute solubility (Khadka et al., 2014). The process of dissolution may thus be understood as the relocation of solute and solvent molecules involving intermolecular attraction forces as shown in Fig. 9.1. FIGURE 9.1 Diagrammatic representations of the processes involved in dissolution of a crystalline solute. Firstly, solute molecules are disintegrated; solvent molecules dispersed to form cavity; the cavity is filled with disintegrated solute molecules one by one to complete the process of dissolution. DOSAGE FORM DESIGN CONSIDERATIONS 290 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 9.2 Schematic representation of dissolution of a solid dosage form. There are two pathways for solid dosage forms to get absorbed into the blood. (1) It can be disintegrated into granules or aggregates and further deaggregates to form fine particles, which further go into solution and subsequently gets absorbed. (2) Solid dosage form can be directly gets dissolved into the solution and gets absorbed. The dissolution process gets initiated by the general movement of solid solute from the largest form to fine particles before becoming molecularly dispersed (dissolved). It is a multistep process involving wetting of the solid phase, followed by sequential penetration of solvent into the solid formulation. The dissolution of the solid formulations like tablet initially involves its breakdown into granular or fine particulate form followed by de-aggregation, leading to a considerable increase in the total solute surface area (Rahul et al., 2017). The last step involves the dissolution of the drug to be available for systemic circulation. However, dissolution can take place anytime during these steps as illustrated in Fig. 9.2. In the case of liquid formulations like suspension, dissolution can occur directly or involves a lesser number of steps as the solid present in the formulation is already in a fine particulate form. The site of these events can be stomach or intestine or both. The slowest step in the overall dissolution process is considered to be the rate determining step. For the drugs with poor solubility, solubilization is found to be slower in comparison to the disintegration or de-aggregation of the formulation, thus making it dissolution controlled. Conversely, if the disintegration is slower than solubilization, then the ratelimiting step is considered to be disintegration (Bourlieu et al., 2015). 9.2 THEORIES OF DISSOLUTION Each of the events of the drug dissolution process has its own rate. Various physical models have been drafted to explore the theoretical concepts, study these rates, and to get the deeper insight of dissolution mechanism (Babu et al., 2015). These models can precisely explain the parameters of the dissolution and highlight the corresponding factors that affect these parameters. This could act as a foundation of a dissolution method development. Dissolution mechanism can be explained by utilizing any of these models. DOSAGE FORM DESIGN CONSIDERATIONS 9.2 THEORIES OF DISSOLUTION 291 9.2.1 Diffusion Layer Model Nernst and Brunner initially proposed this model which is also called film theory. This model explains the dissolution of a single particle (sphere). It is the simplest and most useful theory in the estimation of the dissolution rate of pharmaceutical particles. According to this theory, the process comprises of two steps: first, the formation of the diffusion layer (stagnant liquid layer) around the solid particle by dissolution of the solid particle (drug) at the solid/liquid interface. Later this layer gets saturated by the drug (Wurster and Taylor, 1965). This is an instantaneous step, and the equilibrium is attained at the solid/liquid interface. The concentration of the drug in this stagnant layer is denoted as Cs. In the second step, the drug molecule diffuses through the stagnant layer to the interface and ultimately moves towards the bulk solvent. In this model, diffusion of the drug via a film layer is considered as the rate determining step (Siepmann and Siepmann, 2013). Noyes and Whitney coined the equation for dissolution rate concerning the difference in concentrations of the drug at stagnant layer Cs and in bulk at time Ct. The Noyes-Whitney equation assumes that during the dissolution process, the surface area of the solute remains constant, which is practically not possible for dissolving particles. In accounting for the change in the surface area concerning the decreasing particle size during dissolution, Hixon and Crowell’s cube root law of dissolution is used (Berthelsen et al., 2016). 9.2.2 Interfacial Barrier Model In contrast to the diffusion layer model, the interfacial barrier model suggests that the activity at the solute surface along with its subsequent diffusion across the interface is comparatively slower than the diffusion across the stagnant layer. Surface activity in this model is not considered to be instantaneous as in the case of the previous model. This is because of the presence of an obstruction of high activation energy that has to be overcome before the dissolution of the solid. Thus the rate of solubilization of the solute (drug) in the static layer is the rate determining step, instead of the diffusion of the solubilized drug towards the bulk solvent (Higuchi, 1967). This model also suggests that due to the solvation, an intermediate concentration is present at the interface as a function of solubility instead of diffusion. 9.2.3 The Danckwerts Model Similar to the diffusion layer model, Danckwerts model also postulates that the activity on the solute surface is instantaneous (Danckwerts, 1951). However, the mechanism of mass transfer of a solute from solid surface to bulk liquid varies. This model suggests that the macroscopic solvent packets or eddies in the fluid randomly approach to the characteristic solid liquid interface owing to agitation. Diffusion of the solute particles takes place into these solvent packets that deliver them to the bulk solvent. Due to penetration of these solvent packets into the solid liquid interface, this is called the Penetration theory. This is also known as the Surface Renewal theory because of the continuous replacement of solvent packets with fresh supplies of solvent which then interact with the new solid surface at each instance (Zhang and Chatterjee, 2015). DOSAGE FORM DESIGN CONSIDERATIONS 292 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 9.3 Schematic illustrations of (A) the Diffusion Layer Model, (B) the Interfacial Barrier Model, and (C) the Danckwerts Model. Cs 5 concentration of the drug in this stagnant layers; C 5 Concentration of the drug in the bulk at time t; h 5 Thickness of the stagnant layer. The transport phenomenon as per the three models is illustrated in Fig. 9.3 and the dissolution rate equations for the three theories are mentioned in Table 9.1. This section shed light on several theories of dissolution. However, there are many factors which may affect the rate of dissolution from the dosage form. The next section deals with the various factors affecting the rate of dissolution. DOSAGE FORM DESIGN CONSIDERATIONS 9.2 THEORIES OF DISSOLUTION 293 TABLE 9.1 Representing Fundamental Dissolution Theories Fundamental Dissolution Theories Equations Equation Characteristics Diffusion Layer Theory Fick’s First Law Jix 5 Di (λCi/λx) Diffusion depends on steady state conditions 2 2 Fick’s Second Law λC/λt 5 D (λ c/λx ) Governs by nonsteady state conditions Noyes and Whitney dc/dt 5 K (Js Constant surface area based description of dissolution of drug molecules Brunner and Tolloczko dc/dt 5 kdS (Js Nernst Brunner dc/dt 5 kdDS/vh (Js Jt) Jt) Manipulation of Noyes Whitney’s equation by incorporation of surface area term S. Proposed the formation of a stagnant layer around the dissolving particle, a layer through which solute diffuses through the bulk Jt) if Jt{Js (i.e. , 10% dc/dt 5 kDS/vhcs Manipulation of Fick’s first law and expansion of equation by incorporation of a diffusion coefficient D, stagnant layer thickness h, and volume of dissolution medium v if v and S are constant dc/dt 5 K Hixson and Crowell Cube Root wo1/3 w1/3 5 (4πρη/3)1/3 (DJs/hρ)t Originally developed for single particles but has been extended to use in multiparticulate systems Or wo1/3 w1/3 5 Kt Higuchi equation ft 5 Q 5 AO Description of drug dissolution 1/2 Surface Renewal Theory Vdc/dt 5 dW/dt 5 S(ϒ D) (Js Jt) Assumes solid-solution equilibrium is achieved at the interface and that mass transport is the rate-limiting step in the dissolution process Theory Limited Solvation G 5 kdi(Js An intermediate drug concentration less than saturation may exist at the interfacial barrier between the solid surface and solvent. Different faces of a crystal may have different interfacial barriers and therefore make different contributions to the dissolution process Surface energy Theory γ 5 dG/dA Jt) Increasing the surface by a length 2 21 Key to symbols and abbreviations: Jix: flux (mg/cm s ); Di: diffusion coefficient; λCi/λx: concentration gradient; λC/λt or dc/dt: drug dissolution rate; K: first-order dissolution constant; Js: equilibrium drug concentration; Jt: drug concentration at time t; kd: dissolution constant; S: surface area; v: volume of dissolution medium; h: thickness of stagnant layer; wo: initial powder weight; w: powder weight at time t; ρ: particle density; η: viscosity; h: thickness of diffusion layer; ϒ : interfacial tension; G: dissolution rate per unit area; ki: effective interfacial transport constant; Q is the amount of drug release per unit time area A. DOSAGE FORM DESIGN CONSIDERATIONS 294 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT 9.3 FACTORS AFFECTING DISSOLUTION RATE (IN VITRO) 9.3.1 Drug-Related Factors 9.3.1.1 Solubility The solubility of a drug substance is known to affect its intrinsic dissolution rate. Highly soluble drugs usually show faster dissolution rates. Thus, to predict the influence of solubility on drug dissolution, the solubility of the drug must be measured at different physiological pH (Hall, 2015). There are numerous techniques described for complex formation to increase the solubility, dissolution rate, and absorption of the drugs with low water solubility, e.g., conjugates of cyclodextrin with poorly soluble drugs (Gidwani and Vyas, 2014). 9.3.1.2 Drug Ionization: pH Effects, Salt Form of Drug A drug that exists in the ionized form in the gastrointestinal (GI) fluids tend to be more soluble as compare to its nonionized form. In general, the acidic drug ionizes at basic pH, and the basic drug ionizes at acidic pH. The drug in salt form also exhibits higher rates of dissolution as compared to a nonionized form of the drug (Qiu et al., 2016). 9.3.1.3 Particle Size Particle size reduction of a drug (micronization) increases its surface area and enhances its dissolution which ultimately increases the absorption of drug (Sharma et al., 2015; Maheshwari et al., 2012). An increase in effective surface area by particle size reduction also improves the wetting properties of the drug. However, this correlation is not applicable in the case of hydrophobic drugs where the augmentation in surface area decreases the rate of dissolution (Javadzadeh et al., 2015). 9.3.1.4 Solid State Characteristics 9.3.1.4.1 POLYMORPHISM A drug might exist in more than one crystalline form (polymorphs), which differ in their lattice energies, leading to the different solubility profiles. Metastable (high activation energy) polymorphs exhibit better dissolution profiles as compared to the other stable polymorphic forms (Brittain, 2016). A significant variation between dissolution rates of different polymorphic forms of carbamazepine was reported. The tablets of α-form exhibit higher dissolution rates as compared to β-form. In another experiment, it was demonstrated that two different polymorphic forms of oxytetracycline hydrochloride exhibit dissimilar dissolution rates from the conventional tablets (Reischl et al., 2015). 9.3.1.4.2 CRYSTALLINE/AMORPHOUS FORM The crystal lattice in the drug molecule may either be of particular conformations (crystalline phases) or be indistinguishable (amorphous phases). In general, amorphous drugs show better solubility and dissolution than that of a crystalline form. However, exceptions are also observed as in the case of erythromycin estolate whose crystalline form is more soluble than the amorphous form (Grohganz et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 9.3 FACTORS AFFECTING DISSOLUTION RATE (IN VITRO) 295 9.3.1.4.3 SOLVATE FORMATION A drug may exist in various forms as hydrates and solvates containing a stoichiometric or nonstoichiometric amount of solvent. The anhydrous forms of the drug may dissolve faster than the hydrated form, being thermodynamically more active (Reutzel-Edens and Stephenson, 2016). Toluene and pentanol solvates of glibenclamide have been reported to exhibit high dissolution rates when compared to its nonsolvated polymorphic forms (Censi and Di Martino, 2015). 9.3.1.4.4 COMPLEXATION Drugs may complex with the excipients that can affect the dissolution rate and thereby the therapeutic efficacy. Complex formation may result in alteration of biopharmaceutical or physicochemical properties of the drug (Panakanti and Narang, 2015). The solubility and diffusion coefficient of the complex thus formed may be more or less as compared to the parent drug (Dizaj et al., 2015). The precise use and understanding of complex formation techniques have been explored to increase the solubility, dissolution rate, and absorption of the drugs with poor aqueous solubility, for instance, the conjugates of cyclodextrin with poorly soluble drugs (Gidwani and Vyas, 2014). 9.3.2 Drug Product Formulation Related Factors Excipients have been reported to significantly affect the rate of drug dissolution. Both the nature as well as the proportion of excipients influences the rate of dissolution. Several excipients have been reported to increase the dissolution characteristics of the drug. This holds true for those excipients that tend to enhance the hydrophilic nature of the drug substance. However, the excipients which are hydrophobic in nature may adversely affect (decrease) the dissolution rate (Parr et al., 2016). The diluent like starch imparts hydrophilic properties to the exterior surface of the hydrophobic drug by forming a layer around it; thereby increasing the effective surface area and the drug dissolution rate. The disintegrants are generally observed to improve the dissolution process by various mechanisms. Starch, also being a disintegrant, swells with wetting, facilitates breaking up of tablet and deaggregation into a granule. Sodium starch glycolate also has the strong swelling capacity (Van Nguyen et al., 2016). The influence of binders on the dissolution rate is varied. The hydrophilic binders like gelatin impart hydrophilicity to the hydrophobic poorly wettable drug substance and improve their dissolution rate as in the case of phenobarbital tablet granulated with gelatin. On the other side, some factors may lead to slowing down of the dissolution process like a large amount of binders increases the hardness of tablets (Bandari et al., 2014). Lubricants that are mostly hydrophobic in nature (e.g., metallic stearates like magnesium stearate, stearic acid, and talc)form water repellant coats around the granules resulting in the reduced effective surface area, reduced wettability, and thereby decreased dissolution rate, e.g., as observed in the case of magnesium stearate used in salicylic acid tablets. When sodium lauryl sulfateis used in the salicylic acid tablet as lubricant, the surface activity of sodium lauryl sulfate increases wetting, promotes solvent penetration into the tablet, and thus enhances the dissolution rate (Li and Wu, 2014). DOSAGE FORM DESIGN CONSIDERATIONS 296 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT The surfactants incorporated in various dosage forms (especially poorly soluble drugs) by virtue of micelle formation, improve the wetting of the particles resulting in increased dissolution rates (Sharma, 2016). Some dyes are also observed to affect the dissolution, e.g., FD & C Blue No. 1 decreased the dissolution rate of sulphathiazole by inhibiting the surfactant-like properties of bile salts on the drug (Zishan et al., 2017). The decrease in dissolution rate of capsules prepared by using Polysorbate 80 as an excipient was observed (Dannenfelser et al., 2004). This is because of formation of an additional film due to the denaturation of the capsule’s inner surface. This denaturation occurs due to the formation of formaldehyde by autooxidation of Polysorbate 80. This results in reduced dissolution (Khadka et al., 2014). The polymers used in several formulations considerably impact the drug dissolution rate (Maheshwari et al., 2015; Tekade et al., 2017). They are generally incorporated to control the release of the drug from the dosage form. The nature and amount of these substances play a major role. The majority either form a coat over the drug particles or the formulation, delaying or slowing down the dissolution process. Also, they can form a matrix in which the drug is embedded and gets dissolved and released at a particular desired rate (Ma et al., 2014). In an investigation, it was found that the dissolution of indomethacin from cocrystals of indomethacin 2 saccharin increases in the presence of polyvinylpyrrolidone (Alhalaweh et al., 2013). In another experiment, it was revealed that the increase in the concentration of a polymer (Methocel K4M) decreases the release of carbamazepine from matrix tablet containing cocrystals of carbamazepine-succinic acid. However, it was also reported that the increase in concentrations of Soluplus and Kollidon VA/64 increases the release of carbamazepine from the same formulation (Ullah et al., 2015). 9.3.3 Manufacturing/Processing Related Factors 9.3.3.1 Methods Involve in Manufacturing Wet granulation, in general, is observed to enhance the rate of dissolution of poorly soluble drugs by imparting hydrophilic characteristics and improving the wetting properties of the drug (Wren et al., 2017). On the other hand, a sodium salicylate tablet prepared by direct compression method using spray-dried lactose revealed comparatively higher dissolution rate than those formulated by the wet granulation method (Singh and Van den Mooter, 2016). 9.3.3.2 Compression Force The force applied by the tablet compression machines affects the hardness of the tablet. There exists a linear relationship between the hardness of the tablet and the compression force as suggested by Higuchi et al. (Higuchi et al., 1953; Higuchi et al., 1954). The higher tablet compression may enhance the particle bonding, increase the hardness and density, alter its porosity, and thus inhibits solvent penetration inside the tablet. This ultimately results in lowering the dissolution rate (Ferrero and Jiménez-Castellanos, 2014). DOSAGE FORM DESIGN CONSIDERATIONS 9.3 FACTORS AFFECTING DISSOLUTION RATE (IN VITRO) 297 FIGURE 9.4 Water sorption uptake of selected acetaminophen tablets. When exposed to 25 C/30% RH then 40 C/75% RH then 25 C/30% RH, and photo of the DCPD/PVP/CrosPVP precompression blend after completion of the water sorption experiment. Adapted with permission from Sacchetti, M., Teerakapibal, R., Kim, K., Elder, E., 2017. Role of water sorption in tablet crushing strength, disintegration, and dissolution. AAPS PharmSciTech 1 13. 9.3.3.3 Moisture Content Chowhan et al. established the relationship between drug dissolution and crushing strength (Chowhan and Chow, 1981) and found different varying levels of moisture content present in the granules during compression. In another study, it was found that the rate of dissolution of benazepril hydrochloride tablets decreases with an increase in moisture content. This study was performed by storing the tablets under varying conditions of temperature and humidity. Fig. 9.4 shows a photomicrograph of the acetaminophen/ polyvinyl pyrrolidone (PVP)/dibasic calcium phosphate dihydrate/Cross PVP formulation after exposing it to 40 C/75% RH in the water sorption experiment. The outcomes displayed a great enhancement in tablet crushing strength, where it was found that a solid mass was made after exposure to 40 C/75% RH. This mass was readily collapsed to a powder with slight pressure from a spatula. Formulations that did not strengthen remained a powder postexposure to 40 C/75% RH. It was also found that the increased moisture induces structural changes in benazepril hydrochloride tablet due to DOSAGE FORM DESIGN CONSIDERATIONS 298 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT preactivation of disintegrating agent that causes reduction in dissolution rate (Sacchetti et al., 2017). The same type of results were obtained in another experiment in which the exposure of delavirdine mesylate tablets to increased humidity conditions resulted in significant reduction in the extent of dissolution (Nie et al., 2017). These studies suggest the control of processing conditions during the manufacturing process and the use of advanced packaging technology should be used to avoid the exposure of moisture in the formulations. 9.3.3.4 Machine The equipment used in various unit operations of drug product manufacturing sometimes markedly influence formulation properties. It was evident by the study which compared the preparation of granules with low porosity by high speed shear mixer to those made by planetary mixer with high porosity. More porous granules may show improved dissolution by facilitating solvent penetration (Reddy et al., 2017). 9.3.4 Dissolution Testing Conditions Related Factors 9.3.4.1 Dissolution Apparatus 9.3.4.1.1 AGITATION Agitation forces prevailing in the dissolution apparatus affects the stationary diffusion layer and can markedly affect diffusion-controlled dissolution. The shear forces applied by the dissolution medium affect the thickness of the stagnant layer, thereby influencing the dissolution. High agitation rates can possibly increase the drug dissolution (Jug et al., 2017). In a study, the effect of agitation has been investigated on FDA approved drugs (USP specifies 100 rpm paddle speed). The results of the dissolution test conducted at variable paddle speeds of 50, 75, and 100 rpm indicate that, an increase in the rate of agitation from 50 to 75 rpm enhances the rate of dissolution. However, with the augmentation of agitation rate from 75 to 100 rpm no considerable changes in dissolution rate has been observed (Seeger et al., 2015). In another research, it was demonstrated that the effect of agitation also depends upon the position of the tablet in the dissolution vessel, owing to variation in the agitation force intensity at distinct locations inside the dissolution vessel (Todaro et al., 2017). 9.3.4.1.2 VIBRATION Vibration may influence the dissolution process by altering the hydrodynamics of the dissolution media around the solute. Vibrational forces may be produced and transferred by several sources like walls, partitions, motors, other laboratory machines, operators, etc. High intensity vibrations may alter the diffusion layer and considerably influence the dissolution outcomes. Effects of vibration on the dissolution rate of Prednisone tablets have been reported in an investigation. It was also observed that the influence of vibration on drug dissolution depends upon multiple factors like properties of the drug, formulation factors, and type of dissolution method selected (Seeger et al., 2015). Marked influence of vibration induced by the laboratory scale mixer on the dissolution of disintegrating prednisone tablets was observed on USP basket as well as paddle-type apparatus. DOSAGE FORM DESIGN CONSIDERATIONS 9.3 FACTORS AFFECTING DISSOLUTION RATE (IN VITRO) 299 9.3.4.1.3 FLOW PATTERN NONUNIFORMITIES Variable flow rates of the dissolution medium have been observed at different sites inside the dissolution vessel. The difference in flow rates in the center of the vessel and near the wall and bottom of the vessel can possibly modify the dissolution profile of the formulation. Experimental findings have revealed variable flow patterns in the USP dissolution apparatus II, particularly at the bottom of the dissolution vessel where the tablet is mostly positioned during dissolution test (Wlodarski et al., 2015). 9.3.4.1.4 ECCENTRICITY OF AGITATING (STIRRING) ELEMENT Any minute deviation in the circularity of rotation of the central shaft in the dissolution vessel may affect the dissolution rates. As per the standard and officially documented procedures the rotation of the shaft in the dissolution apparatus must be smooth and devoid of any considerable wobble. As per USP XX/NF XV the permissible limit of eccentricity is not more than 6 2 mm from the axis of dissolution vessel, with a condition that it does not considerably influence the dissolution rate (Ameur, 2016). 9.3.4.1.5 SAMPLING PROBE POSITION AND FILTER Probes used for sampling in the dissolution process may alter the flow system of the dissolution medium and possibly cause considerable changes in dissolution rate. Experimental findings also revealed the differences in results obtained using automatic probe samplers and those acquired from manual sampling. USP/NF specifies that the sampling from the vessel must be done from the region halfway between the dissolution medium surface and the top of the rotating basket or paddle and minimum 1 cm from the vessel wall. Results of an investigation reveal the impact of size of the sample probe as well as location on the rate of dissolution of prednisone tablets. It was found that the large probe induces hydrodynamic variation which results in considerable changes in locationspecific dissolution rates as compared to manual sampling (Bredael et al., 2015). 9.3.4.2 Dissolution Test Parameters Parameters like pH, viscosity, temperature, components, volume, and nature of the dissolution medium may have considerable effects on the dissolution profile of a drug. These parameters might influence the diffusion coefficient of the solute (Miller, 1924). Stokes describes the effect of temperature and viscosity on the diffusion coefficient by the following equation (9.1): D 5 kT=6πηr (9.1) where k is the Boltzmann constant, T is the temperature, η is the viscosity of the solution, and r is the radius of a molecule in solution. It is clearly indicated from the equation that the diffusion is directly proportional to the temperature and inversely proportional to the viscosity. The specification for the temperature of dissolution medium as per USP/NF is 37 6 0.5 C which must be maintained in dissolution testing of oral dosage forms and suppositories. An important parameter, i.e., pH, of the medium also significantly influences the dissolution kinetics of the drug. For weak acids, the rate of dissolution enhances with a rise in pH. However, in the case of weak bases, the rate of dissolution increases with a drop in DOSAGE FORM DESIGN CONSIDERATIONS 300 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT pH. For the maintenance of sink conditions, around 1 L of dissolution medium is generally taken in a single vessel. Some additional factors that possibly influence the results of the dissolution include adsorption, water sorption (of drug or excipients), humidity, and detection errors in the analytical method (Dressman and Reppas, 2016). 9.4 PHYSIOLOGICAL FACTORS AFFECTING IN VIVO DRUG DISSOLUTION RATE Dissolution of pharmaceutical formulations is of paramount importance, as it is a prerequisite for a dosage form to get dissolved in the GI fluids before being absorbed. Several physiological factors are known to affect dissolution as well as absorption of the drugs. The most common physiological factor includes the composition, pH, temperature buffer capacity, viscosity, osmolality, and hydrodynamics of GI fluid. Apart from the nature of GI fluid, some other factors that may affect the drug dissolution include mean residence time, gastric emptying, the presence of luminal enzymes, intestinal motility, hydrodynamics, and shear rates, etc. 9.4.1 Composition of GI Fluid GI fluid is composed of liquid as well as solid materials. The liquids like water, gastric acid, electrolytes, and ingested fluids are commonly present along with viscous materials like mucus and swallowed saliva. Ingested solid food materials are also present in the GI fluid (Fuchs and Dressman, 2014). Hydrogen ion concentration of the gastric fluid influences the pH and ultimately affects the dissolution of ionizable drugs. Pepsin present in the gastric fluid can affect the stability of peptide and protein. Presence of lipase may interfere with the release of drug from lipid-based formulations. Bile salts are another important component of gastric fluid that can act as a surfactant. Bile salts along with lipids tend to form micelles that may increase the wetting and solubility of drugs. Fluids present in the small intestine contain pancreatic secretions like bicarbonate, amylases, proteases,and lipases (Ashford, 2017). Food is a variable component of the composition of GI fluid which results in varied values of the other physiological factors in the fed and the fasted condition. Variation in bioavailability of some drugs in the fed and fasted condition reveals the importance of food as an important component of GI fluids. 9.4.2 pH Variable pH values were reported throughout the entire length of the GI tract. Degradation of drugs owing to the pH-dependent hydrolysis may be possible in the GI tract. In the lumen also, the pH may affect the dissolution and absorption of some drugs if they are weak electrolytes. The marked effect of the pH on the solubility of weak electrolytes was also reported (Qiu et al., 2016). Influence of pH in dissolution profile of ketoconazole tablets was studied. It was found that the increase in pH decreases the dissolution rate as well as the extent. DOSAGE FORM DESIGN CONSIDERATIONS 9.4 PHYSIOLOGICAL FACTORS AFFECTING IN VIVO DRUG DISSOLUTION RATE 301 TABLE 9.2 Compositions of Various Types of Gastric and Intestinal Fluids S. No. Type of Fluid Compositions 1. FaSSGF Sodium taurocholate. . .80 µM Lecithin. . .. . .. . .. . .. . .. . .20 µM Pepsin. . .. . .. . .. . .. . .. . .. . .0.1 mg/mL Sodium chloride. . .. . .. . .34.2 mM Hydrochloric acid. . .. . .q.s. ad pH 1.6 2. FeSSGF Sodium chloride. . .. . .. . .237.06 mM Acetic acid. . .. . .. . .. . .. . .17.12 mM Sodium acetate. . .. . .. . .29.75 mM Milk/buffer. . .. . .. . .. . .. . .1:1 Hydrochloric acid. . .. . .q.s. ad pH 5 3. FaSSIF Sodium taurocholate. . .. . .3 mM Lecithin. . .. . .. . .. . .. . .. . . 0.75 mM NaH2PO4. . .. . .. . .. . .. . .. . .3.9 g KCl. . .. . .. . .. . .. . .. . .. . .. . .7.7 g NaOH. . .. . .. . .. . .. . .. . .. . .q.s. ad pH 6.5 Deionized water. . .. . .. . .q.s. ad 1 L 4. FeSSIF Sodium taurocholate. . .15 mM Lecithin. . .. . .. . .. . .. . .. . .3.75 mM Acetic acid. . .. . .. . .. . .. . .8.65 g KCl. . .. . .. . .. . .. . .. . .. . .. . .15.2 g NaOH. . .. . .. . .. . .. . .. . .. . .q.s. ad pH 5.0 Deionized water. . .. . .. . .q.s. ad 1 L FaSSGF, fasted-state simulated gastric fluid; FeSSGF, 1 fed-state simulated gastric fluid; FaSSIF, fasted state simulated intestinal fluid; FeSSIF, fed state simulated intestinal fluid. 9.4.3 Buffer Capacity The rate of dissolution of the ionizable drugs can be affected considerably owing to the buffer capacity of the fluids present in the GI tract. High buffer capacity may account for the resistance in pH change at the interface between drug and fluid. This may ultimately influence the rate of dissolution of the ionizable drugs (Augustijns et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 302 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT 9.4.4 Osmolality A number of electrolytes present in the lumen explains the osmolality of gastric fluids (Cl2, Na1, K1, Ca21; Table 9.2). Osmolality may influence the release profile as well as the dissolution of the drug. Various studies on osmolality were reported to have a significant influence on the dissolution profile (Walsh et al., 2016; Ali et al., 2017). 9.4.5 Surface Tension Surface tension can affect dissolution by influencing wetting of the dosage form, with a higher surface tension leading to decreased wetting (Yuan and Lee, 2013). Gastric surface tension values in the fasted and fed states range from about 41 46 and 30 31 mN/m, respectively (Xie et al., 2014). In the upper small intestine, surface tension values range from 28 46 mN/m in the fasted state, and 27 37 mN/m in the fed state (Verwei et al., 2016). 9.4.6 Viscosity The viscosity of the GI fluids depends upon the type and amount of food ingested. Generally the viscosity of the fluids in the GI tract increases in the fed state. Prolonged gastric emptying and GI transit time has been reported with the enhanced viscosity of GI fluids (Van Den Abeele et al., 2017). 9.4.7 Temperature The temperature of the GI fluids may influence the rate of dissolution. The solubility and diffusion coefficient of the drug may be affected by the variation in the temperature. The GI tract temperature at resting state was reported to be 37 C. This temperature may increase after a physical workout or in the disease condition (Savjani et al., 2012). 9.4.8 Volume The rate and extent of dissolution of the drug as well as absorption depends on the volume of water in the GI fluids especially in the stomach and small intestine (Mudie et al., 2014). The dissolved drug concentration mainly depends upon the volume of the GI fluids. 9.4.9 Hydrodynamics Marked effects of GI motility on the hydrodynamics of GI contents, intestinal transit, and gastric emptying time have been reported (Guerra et al., 2012). These contractile motions exert forces on the GI content in which the drug is present and thereby may affect its dissolution rate in multiple ways. These forces may break the drug aggregates and lead to an increase in the effective surface area, an increase in the agitation forces so as to enhance the solubility of the drug in the GI contents, resulting in increased drug dissolution rates. These motility forces may also reduce the thickness of the static diffusion layer. In an investigation, hydrodynamics of the dissolution medium was reported to affect the mass transfer and DOSAGE FORM DESIGN CONSIDERATIONS 9.5 DISSOLUTION TESTING 303 dissolution rate of theophylline and naproxen conventional release tablets. Also, variations in hydrodynamics of the dissolution medium have been observed in an experiment which is affected by the surface and location of the cylindrical tablet. The change in fluid velocity at specific regions thus influences the dissolution rate (Shekunov and Montgomery, 2016). 9.4.10 Gastric-Emptying Rate and Forces Gastric emptying generally refers to the rate at which the contents of the stomach exits into the small intestine. The rate-determining step in the absorption of fast dissolving drugs from immediate release dosage forms can possibly be gastric emptying. Several factors influencing the gastric emptying rate include the quantity of ingested food, the nature of ingested food, and the contraction phase at which the food was taken. The gastric emptying time also influences the contact time of the drug with GI fluids at specific pH, and thus may affect the dissolution of drugs which get preferentially dissolved in the stomach (Koziolek et al., 2015). 9.4.11 Concomitant Use of Antisecretory Therapy Dissolution and absorption profile of the different formulations of levothyroxine have been investigated on the patients taking proton pump inhibitors. The experimental results suggest that the dissolution rate of the tablet formulation was reduced and the intestinal absorption of levothyroxine was altered owing to the increase in pH by PPI as compared to control. However, the effect of increased pH on drug dissolution and absorption has not been observed in the case of the oral solution of levothyroxine (Vita et al., 2014; Brancato et al., 2014). 9.5 DISSOLUTION TESTING Dissolution testing is a tool used to measure the release of drug from the dosage form. It is the most important method used in all phases of drug development. 9.5.1 Approaches for Dissolution Test Method Design Dissolution test method is either discriminatory for QC purposes or biorelevant for IVIVC purpose. A balance is needed to be maintained between the two approaches. If the method is over discriminatory, the result is wasted and delays in development of new products to meet unmet needs, and if it is under discriminatory, it results in a lack of meaningful product quality control (Lawrence et al., 2014). 9.5.2 Design of Dissolution Method When developing a dissolution method, it is important to take a logical, systematic approach to the process, and ensure that all the scientifically and regulatory guidelines DOSAGE FORM DESIGN CONSIDERATIONS 304 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT given are borne in mind. A robust methodology should be free of significant interferences (e.g., matrix effects due to excipients), give low variability (precision), and produce a good profile shape. The methodology must also be challenged to distinguish amongst batches of material with varied quality attributes. Once the process of identifying suitable medium and apparatus are complete, further optimization of the method would be required to evaluate ionic strength of the medium, agitation rate, and, if required, surfactant concentration. The final developed method should have the ability to discriminate between different formulations/batches, but still maintain acceptable precision and robustness. With regards to precision, typical limits for early and later time-points would be ,20% and ,10% RSD, respectively. In special cases, like modified release or fixed-dose combination products, the relevant variations are done to the basic design of the method (Ashokraj et al., 2016). 9.5.2.1 Choice of Dissolution Equipment Different designs of dissolution apparatus are important requirements due to variable physicochemical properties of different drug products (Mann et al., 2017). Various types of USP apparatus are available in pharmacopoeias, the most common amongst them are Basket type (USP apparatus I), paddle type (USP apparatus II), reciprocating cylinder type (USP apparatus III), and flow through cell type (USP apparatus IV). If we need to use different types of dissolution medium simultaneously then a reciprocating cylinder type apparatus should be used. Flow through cell type (USP IV) is beneficial in overcoming the nonsink conditions. This apparatus IV is also advantageous in providing better IVIVC due to comparable hydrodynamic flow patterns of dissolution medium (Forrest et al., 2017). USP Dissolution Apparatus USP 1: This is a small basket attached to the shaft that contains the sample. The shaft and basket spin inside the test media. USP 2: This is the most common form of dissolution testing, where a flat paddle is attached to the shaft and spins in the test media. USP 3: This where the use of a reciprocating cylinder is employed. A sample is placed inside a glass tube with a mesh base and moved up and down in the media vessel. USP 4: This is where the sample is placed inside a static cell, called a flow-cell, and the test media is pumped through the cell in a continuous flowing motion, often referred to as flow-through. You can have different cells for different sample types. USP 5: This is the paddle-over-disk method. A USP 2 paddle is attached to the shaft, and a mesh disk is fixed beneath the media vessel. The sample is placed beneath the disk, holding it in place. USP 6: This is the use of a rotating cylinder. Often a patch is stuck to the outside of the cylinder, which is attached to the shaft and spins. USP 7: This is the reciprocating disk method. A disk is attached to the shaft which is raised and lowered in the test media. The sample placed above the disk (Vaghela et al., 2011). DOSAGE FORM DESIGN CONSIDERATIONS 9.5 DISSOLUTION TESTING 305 9.5.2.2 Selection of Agitation Rate The rotational speed is also an important parameter that needs to be appropriately controlled. Very low agitation speed may cause coning and lead to very slow dissolution (Higuchi et al., 2015). To avoid this issue, a faster rotation speed can be used. The high rate of agitation speed may also be problematic due to inability to distinguish amongst acceptable and nonacceptable batches. Rotational speeds in the range 50 100 rpm are validated to be appropriate for the paddle method. If the basket method is to be used, a rotational speed of up to 150 rpm may be appropriate, as the linear velocity generated in the vessel is considerably lower for a given rotational speed for the basket than for the paddle. Rotational speeds in these ranges should also be appropriate for quality control tests (Shohin et al., 2016). 9.5.2.3 Dissolution Medium For selecting the dissolution medium, the most important factor to be considered is the solubility data of the product and dosage regimen to maintain the sink conditions. Oral formulations should be analyzed firstly at the physiological pH range. The selection of medium also depends upon the stability of drug product in the medium and relevance of in vivo performance. For poorly aqueous soluble compounds, surfactants can be used to maintain the sink condition and improve the aqueous solubility of those drug products (Shohin et al., 2016; Lawrence, 2012). 9.5.2.4 Analytical Methods Associated With the Dissolutions UV and HPLC are the most commonly employed methods used to analyze the results of dissolution. With the advancement of analytical equipment, those techniques nowadays are replaced with UPLC or RR LC methods. HPLC is the method of choice in most cases as it is also beneficial in separating and detecting the degradation products. The equipment and methods employed for analyzing the results should be qualified and validated by following the standard guidelines. 9.5.2.5 Automation Automation of the dissolution methods not only helps in increasing the efficiency of methods but is also beneficial in reducing the manual errors. The fully automated system can free the dissolution scientist from 90% of the protocol steps in the laboratory as it is equipped with functional and mechanical automation (Al-Gousous and Langguth, 2015). 9.5.2.6 Data Simulation Various simulation tools like DDD plus are used as surrogates for dissolution testing. It enhances product understanding to help with risk assessment process and offer some mitigation options to increase speed in product development to allow for developing a clinically relevant dissolution specification strategy. This technique can be used in dissolution modeling and surrogate testing to achieve real-time release testing for dissolution. GastroPlus is also one of the most commonly used software for analyzing the dissolution data (Khurana et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 306 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT 9.6 DISSOLUTION PROFILE: ANALYSIS AND COMPARISON Dissolution testing for immediate release drug products could be a single point or two point/multipoint analysis. The quality of drug product is ensured by performing the multipoint dissolution analysis, especially for poorly water-soluble products (Wang et al., 2016). 9.6.1 Dissolution Profile The percentage of drug dissolved against various sampling time points are plotted. This plot can be termed as dissolution profile and gives a complete understanding of in vivo release characteristics. 9.6.2 Analysis of Cumulative Dissolution Profiles Various theories are proposed for dissolution profile analysis. Wagner’s theory interprets the results of plots because drug products follow first-order kinetics under sink conditions (Wagner, 1969). Kitazawa’s theory interpreted the results in the form of a straight line with two phases. The first phase suggests the disintegration or disruption of the drug product, while the second phase suggests the initiation of dissolution process (Kitazawa et al., 1977). Another approach is of Carstensen, which generated the skewed S-shaped curves followed by log-normal distributions. This curve gives the idea about the initial lag phase of the dissolution process (Carstensen et al., 1978). 9.7 IN VITRO-IN VIVO CORRELATION (IVIVC) 9.7.1 Definition The Food and Drug Administration (FDA) defines IVIVC as “a predictive mathematical model describing the relationship between an in vitro property of a dosage form and an in vivo response.” Various models have been proposed to predict the data observed by in vitro investigation to in vivo performance (Rohn, 2014). The IVIVC studies aimed to employ drug release kinetics from two or more formulations to correlate anticipated drug-plasma profile (Somnath, 2016). More exhaustive details have provided in the following subsections dealing with the significance and purpose of IVIVC. 9.7.2 Significance and Purpose of IVIVC Pharmaceutical product development required IVIVC to establish the release characteristics. IVIVC is also employed as an alternative for in vivo experiments in similar conditions (Kesisoglou et al., 2015b). However, even minor changes done in any process variable, demands the establishment of IVIVC making the process highly time consuming as well as expensive (Masaad et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 9.7 IN VITRO-IN VIVO CORRELATION (IVIVC) 307 FIGURE 9.5 Schematic representation of various aspects of IVIVC. IVIVC works in various levels of correlation from Level A to Level D. Level A correlation represents maximum degree of correlation and most preferred type of correlation; Level B correlation compares in vitro dissolution rates within vivo residence period and does not gives information about in vivo plasma profile; Level C correlation is the weakest level of correlation as it involves only a partial relationship between absorption and dissolution and does not represent the complete plasma drug profile; Level D correlation is a qualitative type of correlation and not beneficial for regulatory purposes. The formulation optimization may need to alter the percentage of compositional materials, formulation processing strategy, machines used to manufacture, and batch sizes. This leads to putting extra efforts for bioequivalence testing with an optimized formulation. IVIVC serves as an index to justify the therapeutic effectiveness of the formulation (Somayaji et al., 2016). A schematic presentation of IVIVC including classification, levels, software used, and applications is depicted in Fig. 9.5. 9.7.3 Levels of IVIVC Correlation With IVIVC of global dissolution time characteristics we are faced with a situation in which each of several different formulations must be tested, not only in an in vitro dissolution system but also, and even more importantly regarding effort and expense, in humans (Margolskee et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 308 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT 9.7.3.1 Level A Correlation It involves correlation amongst complete in vitro and in vivo profiles. Level A correlation is most preferred in pharmaceutical industries due to its regulatory relevance. Due to its industrial applicability and regulatory significance, this type of correlation represents a maximum degree of correlation. It involves point-to-point relation amongst in vitro in vivo dissolution data and drug release kinetic data from the pharmaceutical product. Another aspect of Level A correlation is that it permits a biowaiver to alter a manufacturing site, raw product vendors, and minute modifications in the formulation (Mittapalli et al., 2017). 9.7.3.2 Level B Correlation: The Statistical Moment Theory This correlation follows the principles of statistical moment analysis. It involves the comparison between in vitro dissolution rates of the formulation with an in vivo residence period. In contrast to Level A IVIVC, it does not give information about the in vivo plasma profile. Moreover, this type of correlation does not attribute to the quality standards as per the regulatory guidelines (Gelman et al., 2014). 9.7.3.3 Level C Correlation This is the weakest level of correlation as it involves the only partial relationship between absorption and dissolution and does not represent the complete plasma drug profile, which is very important to define the behavior of a drug product. This type of correlation shows the relation between dissolution and pharmacokinetics, but it is limited to one pharmacokinetic parameter only. 9.7.3.4 Multiple Level C Correlations This multiple correlation is important in justifying the biowaiver. This correlation establishes the relationship between one or more parameters related to pharmacokinetics with the dissolution. This correlation shows the relationship by multiple dissolution time points (more than three) such as in early, mid, and late stages of the product development (Kesisoglou et al., 2015a; Shen and Burgess, 2015). 9.7.3.5 Level D Correlation It is a qualitative type of correlation and not beneficial for regulatory purposes. This type of correlation is helpful only in assisting the product development of a formulation. 9.7.4 Applications of IVIVC 9.7.4.1 Application in Drug Delivery System Most of the literature available suggest that IVIVC is extensively used for the product development of oral dosage forms. IVIVC is an excellent tool for the prediction of the drug release rate from numerous systems such as modified release system, controlled, sustained, extended, and delayed release systems (Dressman and Reppas, 2016; Andhariya and Burgess, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 9.8 BIOPHARMACEUTICAL DRUG DISPOSITION CLASSIFICATION SYSTEM (BDDCS) 309 FIGURE 9.6 Illustration of various classes of biopharmaceutical classification system. Class I represents the maximum solubility and maximum permeability class; Class II—maximum permeability but minimum solubility; Class III— maximum solubility but minimum permeability and; Class IV—minimum solubility and minimum permeability. 9.7.4.2 Pharmaceutical Product Development One of the important requirement for product development is the selection of an appropriate drug molecule, and this selection depends on the drug “developability,” involving understanding its physicochemical characteristics. 9.8 BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS) AND BIOPHARMACEUTICAL DRUG DISPOSITION CLASSIFICATION SYSTEM (BDDCS) The biopharmaceutical classification system (BCS) is a scientific tool to classify drugs and depends on the solubility and intestinal permeability of drug molecules. The principle of the BCS says that if two products produce the similar concentration data along the GIT, they will exhibit the same plasma profile after oral administration. In context to bioequivalence, it assumed that drugs with high permeability, high solubility prepared as fast dissolving products will be bioequivalent. Unless significant alterations are made to the formulation, dissolution data can be employed as a surrogate for pharmacokinetic data to show the bioequivalence of two drug products (Mitra et al., 2015). 9.8.1 BCS Classes and Parameters According to the BCS, drug candidates are classified as follows (Fig. 9.6). Class Class Class Class 1: 2: 3: 4: High Solubility—High Permeability Low Solubility—High Permeability High Solubility—Low Permeability Low Solubility—Low Permeability The reason behind the difference in in vivo profiles of two dissimilar products resides in the differences in drug dissolution in vivo. However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid in relation to gastric emptying and the drug has high solubility, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or GI transit time (Khan et al., 2016). In these DOSAGE FORM DESIGN CONSIDERATIONS 310 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT conditions, the performance of in vivo bioavailability or bioequivalence may not be necessary for drug products containing class 1 and class 3 drugs, as long as the inactive ingredients employed in the dosage form do not significantly affect absorption of the active ingredients (Kubbinga et al., 2014). Dose number (Do) may be defined as the mass divided by the product of uptake volume and solubility of the drug or it may be regarded as the volume required for solubility of the maximum dose strength of a drug (Eq. 9.2). DO 5 M V Cs (9.2) where, M 5 highest dose strength (milligrams), Cs 5 Solubility (milligrams/milliliter), V 5 250 mL (Qiu et al., 2016). Dissolution number (Dn) can be defined as the ratio of the mean residence time to mean absorption time and can be evaluated concerning the time required for drug dissolution, which is the ratio of the intestinal residence time and dissolution time (Eqs. 9.3 and 9.4). Dn 5 Tsit =Tdiss (9.3) Dn 5 3DCs ðTsit Þ=r2 d (9.4) where D 5 diffusivity, d 5 density, r 5 initial particle radius, Tsit 5 intestinal residence time, Tdiss 5 dissolution time (Klutz et al., 2015). Absorption number (An) may be defined as the time required for absorption of the dose administered which is a ratio of mean residence time to mean absorption time of drug (Eq. 9.5). An 5 Tsit =Tdiss 5 Peff ðTsit Þ=r (9.5) where, Peff 5 permeability, r 5 gut radius. BCS Class I compounds (e.g., metoprolol) shows high absorption number (An) and a high dissolution number (Dn), signifying that the rate-determining step for drug absorption is possibly dissolution. Class I compounds are generally well absorbed if they are stable or are not affected by the first-pass effect. For immediate-release products of Class I compounds, the absorption rate is likely to be dominated by the gastric emptying time, and no direct correlation between in vivo data and in vitro dissolution data is expected. Therefore, dissolution analysis for such drug products should be designed chiefly to predict that the drug is released quickly from the dosage form under the particular test conditions. A dissolution specification for which 85% of drug contained in the IR dosage form is dissolved in less than 15 min may be sufficient to ensure bioavailability since the mean gastric half-emptying time is 15 20 min (Papich and Martinez, 2015). A Class II drug, for example, phenytoin, possesses a high absorption number (An) and a low dissolution number (Dn). Dissolution is the rate-limiting step for drug absorption. The influence of dissolution on the absorption of BCS Class II drugs can be classified into two scenarios: solubility-limited absorption or dissolution-limited absorption. These two scenarios are best illustrated by griseofulvin and digoxin. In the case of solubility-limited absorption, griseofulvin exhibits a high dose number (Do) and a low dissolution number (Dn). Although in theory, absorption of griseofulvin can be DOSAGE FORM DESIGN CONSIDERATIONS 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT 311 improved by taking more water with the administered dose (decreasing Do), this approach is impractical due to the limitation in the physiological and anatomical capacity of the stomach for water. Therefore, the only practical way to improve the absorption of griseofulvin is to decrease Do and increase Dn by enhancing its solubility through appropriate formulation approaches such as solid dispersion (Stiehler et al., 2015). On the other hand, in the case of dissolution-limited absorption, digoxin has a low dose number (Do) and a low dissolution number (Dn). Despite the small volume (21 mL) of fluids required to dissolve a typical dose of digoxin (0.5 mg), this drug dissolves too slowly for the absorption to take place at the site(s) of uptake. However, its dissolution rate can be improved simply by increasing Dn through the reduction in particle size. Thus, for BCS Class II drugs, a strong correlation between in vitro dissolution data and in vivo performance (e.g., Level A) is likely to be established. When a BCS Class II drug is formulated as an extended-release product, an IVIVC may also be expected. For BCS Class III drugs (e.g., cimetidine), permeability is likely to be a dominant factor in determining the rate and extent of drug absorption. Hence, developing a dissolution test that can predict the in vivo performance of products containing these compounds is generally not possible. Since BCS Class IV drugs, which are low in both solubility and permeability, present significant problems for effective oral delivery, this class of drugs is generally more difficult to develop in comparison to BCS Class I, II, and III drugs (Sandri et al., 2014). 9.8.2 Biopharmaceutical Drug Disposition Classification System (BDDCS) It divides compounds into four classes based on their permeability and solubility. This classification system is useful in predicting effects of efflux and uptake transporters on oral absorption as well as on post absorption systemic levels following oral and intravenous dosing. Wu and Benet recognized that for drugs exhibiting high intestinal permeability rates, the major route of elimination in humans was via metabolism, (e.g. the BCS/ BDDCS Class 1 drug letrozole) whereas drugs exhibiting a poor intestinal permeability rate were primarily eliminated in humans as unchanged drug in urine and bile, and they termed this as Biopharmaceutics Drug Disposition Classification System (BDDCS) (Camenisch, 2016). 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT Product development is a prolonged, arduous, and expensive task with high risk of failure. The pharmaceutical companies spend hundreds of millions of US dollars on research and development, and it takes around 12 to 14 years for the processes of “discovery” and clinical trials from the laboratory to end consumers (patients). Only one-tenth of the drugs entering the preclinical phase could actually reach the clinical phase. Further, regulatory approval is the utmost requirement to bring a drug to market. Regulatory requirements DOSAGE FORM DESIGN CONSIDERATIONS 312 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT have definitely up scaled the cost of pharmaceutical research and development. So, there is always a need to reduce the regulatory burden and minimize the time and cost involved in drug development (Pocock, 2013). Dissolution testing vexes the scientific, technical, and regulatory challenges related to drug development complexities. The major contribution of dissolution testing in Pharmaceutical Product Development includes making the product development process cost-effective and less time-consuming in two ways: reducing the regulatory burden at drug approval and postapproval stages and minimizing the probability of end product failure. Dissolution testing helps to reduce the regulatory burden by acting as a surrogate for in vivo product performance, by developing in vivo predictive in vitro dissolution methods, developing IVIVC, by using BCS, IVIVC as a criterion to waive the bioequivalence studies, predicting drug bioavailability and drug metabolism. The latter is achieved by routine use in QC to ensure batch to batch uniformity and product quality, in research and development, to develop, optimize, and assess the new drug product by QbD, monitoring critical manufacturing variables, and examining the stability of the formulation (Allen and Ansel, 2013). 9.9.1 Pharmaceutical Product Development Phases As depicted in Fig. 9.7 (Scheubel, 2010), dissolution testing is a necessary part at each stage of the drug development process from nonclinical to postmarketing, performing essential functions like drug selection, formulation selection, method optimization, IVIVC prediction, biowaiver assessment, quality, and stability checks. 9.9.1.1 Drug Product Approval Pharmaceutical product development cycle includes various stages, and at each stage, dissolution testing performs significant functions. Investigational New Drug Application (IND)—The application requires data of experiments done on laboratory animals and how clinical trials are planned. Dissolution testing enhances lead formulation quality by salt selection as per BCS and screens out poorperforming prototypes and saves animal resources (Guarino and Guarino, 2016). Institutional Review Board (IRB) drafts the clinical trial protocols comprising of four phases. Phase I trials test for safety. Dissolution testing performs various functions at phase 1 level, like designing phase I formulation, salt selection of drug substance, examining excipient compatibility, choosing toxicology formulations, and maintaining quality standards for the first clinical drug administration. This helps to identify formulations with improved dissolution characteristics (He et al., 2017). Phase II trials test for effectiveness in addition to further safety monitoring. The final dosage form to be tested in phase III studies is ascertained at this level. Dissolution testing can be carried out to serve many important roles at this stage, which include process and product development, a link establishment between design space and the target product profile, elucidation of the drug-release mechanism, regulation of the DOSAGE FORM DESIGN CONSIDERATIONS 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT 313 FIGURE 9.7 Various applications of dissolution testing in various phases of product development. Blue color showing initial phase and orange color showing late phase development; black color is for market; red arrows show interplay of dissolution and black arrows show the interaction between the different development phases. variations in drug product stability testing, and maintenance of batch release quality, as well as batch-to-batch uniformity (Blessy et al., 2014). Phase III includes joint working of the FDA and the drug’s sponsor to set the phase III study protocol and determine risk benefit data. The phase III drug development stage has the main purpose to develop in-depth expertise and robust data regarding the drug product and the manufacturing process for filing drug approval dossiers, to commence the stability studies, and to prepare for effective and profitable product launch. Dissolution testing at this stage serves as a surrogate for in vivo bioavailability or bioequivalence, as a tool to project the drug product’s clinical DOSAGE FORM DESIGN CONSIDERATIONS 314 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT performance, and is used for process development and optimization, as well as quality control testing. Further, the application review is at the discretion of the FDA under New Drug Application. Phase IV trials are conducted to analyze the outcomes evolving after the drug approval and its large-scale use. Dissolution testing at this stage contributes to SUPAC or biowaiver dossier filling. Dissolution testing also plays an important role in FDA’s attempts to decrease the regulatory load and unneeded clinical studies in developing consistently high-quality, safe, and effective generic drugs without compromising the drug product quality. Similarity factor data for test drug and reference listed drug can be employed for this purpose. 9.9.2 Determining Drug Developability at Preformulation Stage Besides being a quality control tool at the formulation stage, dissolution testing also performs some crucial roles at the preformulation level. Drug candidate selection: drug developability The complete journey of a drug molecule from thought to the market involves various steps. These are recognizing the target, selecting hit, optimizing hit, choosing lead and further optimizing it, recognizing candidate, and performing clinical trials. In this process, the number of compounds entering the clinical phase are very much fewer than the number of targets identified, almost one-tenth as mentioned earlier in the text. Further, the new screening technologies and automation quicken the process of lead identification and drug discovery. So, the concept of ensuring developability is used for drug candidate selection which focuses on all functional aspects (commercial, marketing, and medical) influencing the efficiency, success rate, and itinerary of a drug product development. This concept helps to set a target product profile with an aim to decrease the cost and time involved in the process (Aungst, 2017). The examination of the physicochemical properties of a new chemical entity (NCE) is also important along with pharmacokinetic properties such as the half-life and oral bioavailability. This must begin early in the research and development phase. One of the most significant physicochemical properties is the aqueous solubility of a drug substance that governs dissolution rate and ultimately developability. The dissolution characteristics of the candidates are determined so as to ensure their intended performance and bioavailability potential. For this criterion, the solid-state form or the salt with the best solubility, dissolution rate, and stability characteristics should be preferred to enter the full development cycle (Han and Wang, 2016). 9.9.3 Simulation of Food Effects The gastrointestinal tract exhibits changes in the environmental conditions with and without meals. Food intake is observed to have considerable impact on in vivo drug release DOSAGE FORM DESIGN CONSIDERATIONS 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT 315 FIGURE 9.8 In vitro release profiles of optimized ASDs (top) and prototype ASDs (bottom) stored at 40 C and 75% RH on fresh extrudates and 3, 6 months stability. Adapted with permission from Pawar, J., Tayade, A., Gangurde, A., Moravkar, K., Amin, P., 2016. Solubility and dissolution enhancement of efavirenz hot melt extruded amorphous solid dispersions using combination of polymeric blends: a QbD approach. Eur. J. Pharm. Sci. 88 (Supplement C), 37 49. and absorption and thus affecting drug performance in vivo. This necessitates the measurement of food-induced effects on the in vitro drug dissolution with an aim to minimize the potential risks during therapy. The physiological differences between fasted and fed state are particularly kept under consideration. Several attempts have been made to model the food-induced effects on drug dissolution by making use of bile salt and lecithin, pH changes, fat emulsions, such as intralipid or milk, well-defined nutritional drinks, enzymes, dynamic lipolytic models, presoaking in oil, viscosity enhancement. For example, an assessment could be performed in connection with an in vivo food interaction study to improve the interpretation of the bioavailability data obtained or be used more proactively to select the least-affected candidate formulation for further development. Thus, in vitro dissolution tests could clearly play an important role in predicting the influence of food on drug dissolution in vivo (Sjögren et al., 2014). 9.9.4 Determination of the Impact of Concomitant Use of Other Substances With Drug Product The dissolution tests can be modified to determine the impact of other substances administered with a drug product. One of such tests is in vitro dose dumping in alcohol test as requested by NDA and for generic MR drug products with respect to RLD using differing amounts of ethanol (0%, 5%, 20%, and 40%) representative of liquor consumption DOSAGE FORM DESIGN CONSIDERATIONS 316 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT in 0.1 N HCl media. The purpose of this test is to monitor the potential of dose dumping of modified release drug products occurring due to being coadministered with alcohol. The polymers used for coating or matrix modified release drug products may solubilize in alcohol to varying extents undesirably which may raise serious safety concerns. Since the major portion of ethanol is absorbed through the gastric mucosa, 0.1 N HCl is selected as a baseline medium to proximate the gastric environment conditions. Dissolution data expressed as percentage dissolved is calculated for all strengths of the test product and the reference product using 12 units each (Paixão et al., 2017). 9.9.5 Dissolution as a Key Feature for Biopharmaceutical Approach in QbD The goal of QbD is to use the recent pharmaceutical knowledge more efficiently throughout the lifecycle of a product to develop meaningful specifications. QbD contributes in establishing the relationships among raw material properties, formulation variables, and process parameters. The concept of integrating such criteria in the drug approval process is quite recent. QbD provides in-depth knowledge of the product properties. This aids in selecting a more justified dissolution method that may achieve the required IVIVR for drug release. In QbD, in vitro dissolution testing helps to associate the manufacturing/product design variables with clinical safety/efficacy (Sangshetti et al., 2017). QbD provides a high level of understanding of dissolution mechanisms and influence of pharmaceutical factors. It is a sequential process in which: quality target product profile (QTPP) (Design space) is described; accordingly, the product and method are designed with respect to all aspects affecting drug dissolution results; the appropriate risks to clinical quality are determined by performing Quality Risk Assessment (QRA); dissolution methods with relevance are developed; the correlation between alterations in manufacturing variables and the clinical quality is studied depending on dissolution data (inclusive of bioavailability/IVIVC, BCS data); and the dissolution characteristics ensuring clinical quality (as per design space) are established (Singh and Sharma, 2015; Bhoop, 2014). Pawar et al. developed a Qbd-based approach to increase the dissolution profile of efavirenz, a BCS class II drug (Pawar et al., 2016). They utilized Soluplus and (Hydroxypropyl methylcellulose acetate succinate (HPMCAS-HF)) polymers to form anamorphous solid dispersion of efavirenz. The investigation revealed that the maximum dissolution rate when Soluplus and HPMCAS-HF were used was in a ratio of 60:20 as optimized by QbD. Also, the authors found that the optimized amorphous solid dispersion was stable at 40 C, 75% RH over a period of 6 months without any dissolution rate alteration, and remained in anamorphous state (Fig. 9.8). QbD is an evolving process. The integration of QbD to the drug development process has been a little slow as it needs a good amount of time and work to collect enough data, especially in early development stages (Soans et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT 317 9.9.6 Prediction of In Vivo Dissolution: Biorelevant Dissolution Testing 9.9.6.1 Need of Bio-Relevant Dissolution Testing Human gastrointestinal physiology is complex and dynamic, inclusive of various physiological factors that impact in vivo drug dissolution to a great extent. Conventional pharmacopoeial dissolution tests are mainly used for QC purpose, and their design primarily depends on drug substance’s physicochemical properties and drug product characteristics. These methods utilize simple, nonphysiologic buffers and unrealistic hydrodynamic conditions (at times variable with extremely high fluid velocities). These shortcomings of the conventional methods need to be resolved if the results of these methods are to be used for the prediction of in vivo drug dissolution and absorption. The new innovative biorelevant dissolution methodologies shall thus be employed to bring close resemblance to the physiological environment in the gastrointestinal tract including major parameters like in vivo hydrodynamics, fluid content, etc. The main purpose of employing biorelevant dissolution techniques is to develop more appropriate in vivo in vitro correlation (IVIVC). This helps to improve the prediction accuracy of bioavailability from in vitro dissolution data. This provides more realistic assessment of licensed-in compounds, prevents potential development compounds from being falsely discarded, determines the potential for dosage forms with the modified release, renders QC tests more clinically relevant, and reduces the risk of failure in late-stage pivotal BE studies (Mann et al., 2017). 9.9.6.2 Development of Relevant Dissolution Test The BCS class of the drug, depending on its solubility and permeability, indicates the site of residence and absorption of the drug in GIT (Beig et al., 2016). This further can help to interpret the time for which drug resides in a specific part of GIT, i.e., how the drug movement is across the stomach, intestine, and colon and what are the major and minor sites of drug dissolution in vivo. This can subsequently help to decide the composition and volume of the biorelevant media as well as agitation conditions of the biorelevant dissolution apparatus needed for the intended purpose. For example, the gastrointestinal environment pH and pH-dependent solubility of ibuprofen and ketoprofen (BCS Class II drugs; pKa # 5 weak acid) lead to their absorption in higher amounts in the distal small intestine than in the proximal small intestine (Tsume et al., 2014). Biorelevant dissolution test design is a systematic method to select dissolution conditions taking into consideration all the important physiological parameters like the composition of the gastrointestinal fluid, buffer capacity, pH, surface tension, osmolality, temperature, viscosity, hydrodynamics, gastrointestinal residence time, and gastric emptying rates and forces. It can be utilized to simulate gastric conditions, intestinal conditions, or colonic conditions (Koziolek et al., 2014). Biorelevant dissolution test design (especially for immediate release drug products) can thus be understoodas 1. Classify the compound according to BCS. 2. Choose an appropriate medium. DOSAGE FORM DESIGN CONSIDERATIONS 318 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT Various dissolution media employed for QC and biorelevance purpose include simulated Gastric Fluid (SGF) (with and without pepsin), simulated intestinal fluid (SIF) (with and without pancreatin), fasted-state simulated gastric fluid (FaSSGF), fed-state simulated gastric fluid (FeSSGF), fasted state simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF), blank fasted and fed (GF) and (IF), and others (such as Ensure Plus for forecasting food-effect). Compositions of various fluids are given in Table 9.2 (Riethorst et al., 2016). Many drugs are observed to have varied solubilities in all these media, e.g., ketoconazole, danazol, etc. Class 1 drugs: The suitable media for class 1 drugs could be simulated gastric fluid without enzymes because of their good aqueous solubility and permeability through the gut membranes. More complex, biorelevant media (e.g., FaSSIF and FeSSIF) are unnecessary for dissolution of class 1 drugs. Class 2 drugs: Class 2 drugs have poor aqueous solubility but are readily permeable through the gut membranes. The appropriate biorelevant media for class 2 drugs could be SGF plus surfactant, to mimic the gastric fasted state, Ensure or milk (3.5% fat) to mimic the gastric fed state, and the two newly developed media, FaSSIF and FeSSIF, to mimic fasted and fed state in the small intestine, respectively. Sometimes use of synthetic surfactants (tweens etc.) in dissolution media is observed in research as using the bile components (lecithin and bile salts) is practically inconvenient on a routine basis. Use of hydroalcoholic mixtures as dissolution media is also reported but less preferred due to physiological insignificance. Class 3 drugs: A satisfactory IVIVC (level A, B, or C) is unlikely to be obtainable, and the membrane permeability is also a limiting factor to the absorption. So a simple aqueous medium can be used for quality assurance dissolution testing similar to class 1 drugs. Class 4 drugs: Class 4 drugs have both poor solubility as well as poor permeability. Hence unlike class 3 drugs, they may not achieve complete bioavailability in most cases. Further, IVIVC is unlikely for class 4 drugs, so recommendations can be limited to quality assurance media. Those are the two-basic media SGF and SIF with the use of a surfactant to ensure total drug release in the stipulated media volumes. Thus, for Class 1, 3 drugs use the most simple yet reliable media possible and addition of surfactants is unnecessary and for Class 2, 4 drugs biorelevant media are warranted for IVIVC SGFsp plus surfactant, FaSSIF (fasted state), Ensure, milk, FeSSIF (fed state), and for QC SGFsp/SIFsp plus suitable surfactant. 3. Choose an appropriate medium volume. In general, volumes for the fasted state will be lower than volumes for the fed state. 4. Choose an appropriate test duration and sampling times. Duration of the dissolution test should also be physiologically relevant based on BCS class of drug, transit times, prandial status and absorption site. Class 1, 3: short test (up to 30 min) with one-point sampling to verify that an appropriate amount (e.g., 90%) has dissolved. Class 2, 4: test duration depends on the region of gut permeable to the drug and whether the drug is to be administered in a fasted or fed state. Multiple sampling required to define the dissolution profile. DOSAGE FORM DESIGN CONSIDERATIONS 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT 319 FIGURE 9.9 Fed stomach model: (A) FSM gastric vessel, and (B) closed loop test configuration. Adapted with permission from Koziolek, M., Görke, K., Neumann, M., Garbacz, G., Weitschies, W., 2014. Development of a bio-relevant dissolution test device simulating mechanical aspects present in the fed stomach. Eur. J. Pharm. Sci. 57, 250 256. 5. Apparatus: USP II for IR products unless there is a strong reason for another tester type. 6. RPM: 50 or 75 rpm is usually suitable. 9.9.6.3 Biorelevant Dissolution Apparatus This section presents some examples to suggest how conventional apparatus is modified to develop biorelevant dissolution apparatus. 9.9.6.3.1 FED STOMACH MODEL The Fed Stomach Model is a modified paddle apparatus, simulating different mechanical aspects present during intragastrical transit. The pendular movement of the two blades placed at 90 degrees at certain driving velocities induces movement in small glass beads at the base of the apparatus. In this way, the dosage form movement is primarily caused by the motion of the glass beads. Pressures of biorelevant dimensions (100 500 mbar) can be exerted by inflation and deflation of a balloon attached to the apparatus (Fig. 9.9) (Koziolek et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 320 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT 9.9.6.3.2 ARTIFICIAL STOMACH DUODENAL MODEL This two-compartment model comprises a gastric compartment linked to a second intestinal compartment intended to simulate the duodenal area. After dispersion of the drug or formulation in the gastric compartment, contents (liquids) are pumped at a controlled rate to the duodenal compartment with simulated intestinal fluid (SIF). 9.9.6.3.3 DYNAMIC GASTRIC MODEL (DGM) DGM is claimed to exhibit a precise in vitro imitation of gastric mixing (including digestive addition around the gastric bolus), shear rates and forces, peristalsis, and gastric emptying. 9.9.6.3.4 TNO GASTRO-INTESTINAL MODEL (TIM) The TIM-1 system is a computer governed model of the human upper gastrointestinal tract with numerous dynamic compartments. The water forces exerted on the flexible membranes (that contain luminal contents) are monitored to govern the hydrodynamics related aspects. In vivo, muscular peristaltic contractions are simulated by the movements induced by the alternating rhythms of compression and relaxation of the flexible membranes. The passage of liquid and food/drug particles is controlled by regulating the closure (or opening) operation of the peristaltic valves connecting all the compartments. Whereas the TIM-1 system provides information on the bioaccessibility of a compound during passage through the upper GI tract, a combination with TNO’s TIM-2 system (that simulates the physiological conditions in the large intestine) enables an investigation of the release of a compound through the entire GI tract. 9.9.6.3.5 GASTRIC DIGESTION MODEL (GDM) Fernandez et al. developed a gastric digestion model for measuring gastric lipolysis using gastric lipase from dogs (Fernández-Garcı́a et al., 2009). 9.9.6.4 Limitations of Biorelevant Dissolution Testing Despite several advantages, biorelevant dissolution testing has some challenges in its practical applications. The major one includes absence of historical database especially when new method is to be established, developing a per run quality check, unestablished standards, handling regulatory aspects and most important unavailability of universal biorelevant methods. As a result, obtaining an IVIVC may involve the development of a different in vitro dissolution method each time, for even a small variation in the formulation of the same drug (Mann et al., 2017). 9.9.7 Biowaiver Application: Role of BCS, IVIVC, and Similarity Dissimilarity Factor 9.9.7.1 Definition and Purpose of Biowaiver Large numbers of bioequivalence studies are carried out by various industries for abbreviated new drug application (ANDA) for generic drugs or in the supplemental NDA for new indication. Biowaiver refers to a regulatory procedure where the application is DOSAGE FORM DESIGN CONSIDERATIONS 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT 321 approved for drug approval, by proof of equivalence apart from the actual in vivo equivalence testing. It aims at getting the in vivo bioavailability, and bioequivalence testing waived as these are both costly as well as time-consuming. So, biowaiver helps to lower the cost involved in drug approval and postapproval changes. Biowaivers find their applications in filling ANDA for generics, NDA supplements, and dossiers for various levels of SUPAC (Licht et al., 2016; Duggal et al., 2014). 9.9.7.2 Criteria for Biowaiver Recommended by USFDA BCS Guidance on Biowaivers The biowaiver criteria for class I drug products include high solubility, high permeability, rapid dissolution of the drug product (both test and reference), and absence of excipients affecting drug bioavailability. Those for class III drug products include high solubility, very rapid dissolution of the drug product (both test and reference), and qualitative sameness as well as the quantitative similarity between the test product and the reference product (Benet, 2013). As per the guidance specifications, a drug product is said to have (1) high solubility, when the maximum dose strength gets solubilized in #250 mL of the aqueous medium in pH 1 to 6.8; (2) high pemeability, when the absorption extent is $85% (applicable for class Idrugs but not for low permeability class III drugs); (3) rapid dissolution (for class Idrugs), when 85% or more drug dissolution is measured within 30 min in 500 mL or less of the dissolution medium of pH 1.2, 4.5, and 6.8 using basket apparatus (100 rpm) or paddle apparatus (50 rpm or 75 rpm); (4) Very rapid dissolution (for class III drugs), when 85% or more drug dissolution is measured within 15 min using the described dissolution conditions (Shah and Amidon, 2014). The BCS-Biowaiver guidance for immediate release drug products by USFDA requires few more criteria to be taken into consideration. Some of them are drug substance stability in gastrointestinal tract and the products, excipients should be previously approved by FDA (Burdick et al., 2017), and the similarity factor (f2:50 100) should be employed to analyze the similarity between the two dissolution profiles (Stevens et al., 2015). 9.9.7.2.1 ADDITIONAL CRITERIA FOR BIOWAIVER APPLICATION Excipients: (1) For BCS class I drug products, the biowaiver application must contain the data supporting no effect of the new excipients or the higher amounts of known/approved excipients on the bioavailability of the drug. Moreover, the excipient amount should be for the intended purpose (Garcı́a-Arieta, 2014). (2) The absorption of low permeability drugs can be affected to a greater extent by the use of excipients. So, for BCS class III drug products, the excipients employed in the test drug product should be the same as those in the reference product (unlike class I drug product) (Niazi, 2014). Prodrugs: The biowaiver application for IR products containing prodrugs requires the dissolution and pH-solubility data to be documented for both prodrug and drug. However, the decision of whether permeability measurement is to be done on prodrug or drug depends on the mode and site of prodrug conversion to drug substance. Fixed Dose Combinations: These can be divided into two categories concerning BCS (1) all active ingredients in the combination are class I drugs, (2) all active ingredients in the combination are class III drugs or a combination of class I and class III drugs. The DOSAGE FORM DESIGN CONSIDERATIONS 322 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT excipients considerations outlined previously, and the study of pK interactions between the components decides the need for in vivo bioequivalence testing. Dissolution data play a very important role in the approval of new generic drug products as well. BCS-based biowaiver for IR generic products with high solubility, high permeability, and rapid dissolution can be requested if similarity can be proved between the test drug product and the rapidly dissolving reference listed drug (RLD) product (Tampal et al., 2015; Verbeeck et al., 2017). 9.9.7.2.2 EXCEPTIONS BCS-based biowaivers are not applicable for the drug substance of a narrow therapeutic index and drug products intended to be absorbed in the oral cavity (Saluja et al., 2016). 9.9.7.3 Biowaiver Extension Potential 1. Biowaivers for class II drug products could be considered if permeability criterion is met and rapid dissolution is exhibited at pH of the small intestine. 2. However, biowaivers for class III drug products could be considered if rapid dissolution is observed under all physiological pH conditions. 3. The extension of BCS-based biowaiver concept to oral modified release drug products requires the role of intestinal metabolism to be identified (Parr et al., 2016; Bergström et al., 2014). 9.9.7.4 Data Required for Requesting Biowaiver 1. Data supporting Rapid and Similar Dissolution: drug products dissolution testing, a graph representing the mean dissolution profiles for 12 individual units (the test and the reference products) in the three-stipulated media, data at specified testing interval, and similarity data. 2. Data supporting High Permeability: pharmacokinetic data, permeability study method selection data, permeability data of drug substance, and absorption data for model drugs. 3. Data supporting High Solubility: description of test methods, drug physiochemical information data, detailed solubility data, and pH solubility profile (Davit et al., 2016). 9.9.8 Prognosis of Drug Disposition Drug bioavailability has two crucial components: dissolution and permeability. Dissolution testing has always been a predictor of drug bioavailability. IVIVC is a major tool to measure the degree of the flaws in anticipating the in vivo bioavailability outcomes from in vitro dissolution study compilations. This can be done by using the convolution method that refers to transforming in vitro dissolution data into plasma concentration data (input to output) (Poongothai et al., 2014). BCS and the advanced Biopharmaceutical Drug Disposition Classification System (BDDCS) and the Extended Clearance Classification System (ECCS) collectively connect the in vitro dissolution data to the pharmacokinetic parameters and could serve as the basis of predicting drug disposition. BDDCS divides the drugs into four categories by their permeability and solubility. DOSAGE FORM DESIGN CONSIDERATIONS 9.9 ROLE OF DISSOLUTION TESTING IN PHARMACEUTICAL PRODUCT DEVELOPMENT 323 As per BDDCS, the main path of elimination for drugs having high intestinal permeability is via metabolism, whereas those with poor intestinal permeability chiefly eliminate as unchanged drug in the urine and bile. The knowledge of the BDDCS class can help in predicting the main route of elimination. It also helps to measure drug drug interactions by assessing the effect of transporters and anticipating the development of drug-associated adverse drug reactions (ADRs) (e.g., idiosyncratic cutaneous ADRs with antiepileptic drugs) (Tekade et al., 2018; Camenisch, 2016). 9.9.9 Identification of Critical Manufacturing Variables (CMVs) Mapping is a tool to determine the correlation between critical manufacturing variables, in vitro dissolution data and in vivo bioavailability data. It describes the limits for in vitro dissolution profiles based on the acceptable bioequivalency standard. This correlation helps in recognizing critical manufacturing variables that majorly impact drug release from the product including method, machine, material, and formulation variables (Patil and Burgess, 2016). The aim is to set the product standards that will assure bioequivalence of forthcoming batches, manufactured within the boundary of acceptable dissolution criteria. The monitoring of the identified CMVs will constantly help in achieving conviction and prognosis of the drug product performance. Mapping-based dissolution criteria will enhance the reliability of an in vitro dissolution test as a surrogate for in vivo bioequivalence testing. 9.9.10 Surrogate of Bioequivalence Study at Postapproval Changes of Drug Product (SUPAC) The SUPAC-IR guidance explains the postapproval change levels (1, 2, and 3), stipulated tests involved, and supported data required to assure drug product quality, safety, and efficacy. The comparison of dissolution testing profiles of change batch (reference) to postchange batch (test) performs a crucial role in getting the scale-up and postapproval changes (SUPAC) approved (Van Buskirk et al., 2014). The USFDA guidelines for an immediate release oral drug product suggest that to get the SUPAC approved for any level 1 or level 2 change, a bioequivalence study is not required and dissolution testing may be sufficient. The difference being that for most level 2 changes, comparative dissolution testing of prechange and postchange products is required along with developing multipoint dissolution profiles in the different stipulated dissolution media (water, 0.1 N HCl, 4.5 pH and 6.8 pH USP buffer). No in vivo bioequivalence study is required, if the prechange and the postchange product dissolution profiles are found similar by employing the similarity factor (f2) (Stevens et al., 2015). For most level 3 changes, both in vivo bioequivalence study and dissolution testing are needed to support SUPAC approval except for “site change” level 3 changes (where dissolution testing may be sufficient, and no bioequivalence study is required). Further, developing a validated and relevant IVIVC may help getting in vivo bioequivalence study waived in most level 3 changes and the comparative dissolution testing between prechange and postchange product may be sufficient. As a result, the decreased number of in vivo bioequivalence studies required and reduced regulatory load renders the SUPAC DOSAGE FORM DESIGN CONSIDERATIONS 324 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT approval process more cost-effective and less time-consuming, especially when IVIVC is established at early stages of drug development. For example, a level “A” IVIVC was obtained for metoprolol succinate in the membrane-coated multiple-unit formulation. After regulatory approval of the original product, the formulation was altered to avoid organic solvents in the manufacturing process and to make the process more efficient. The application of an in vitro dissolution test as a surrogate for human bioequivalence studies was confirmed when a strong in vitro in vivo correlation was demonstrated (Mitra et al., 2015). 9.9.11 Quality Control Tool The dissolution testing is a valuable quality control tool for maintaining batch-to-batch uniformity and for discerning the influence of formulation or manufacturing process changes on drug product outcomes. It is used for batch quality study as well as batch quality control. The dissolution test for quality control purpose for a productis developed with respect to its dosage form. Dissolution testing measures the drug product quality aspects that are susceptible to formulation as well as process changes (Lawrence et al., 2016). For QC purposes, dissolution tests aim at the rate and extent to which the drug release occurs from the formulation. This depends on the physicochemical properties (solubility, particle size, polymorphic form) of a drug substance and its formulation (excipients) (Qiu et al., 2016). Dissolution acts as a quality control tool for the end product as well as in the process quality control. It brings many advantages to the drug development process, along with improved end product quality, which include savings as it reduces drug rejection rates, promotes faster troubleshooting, at line application as it cuts lead time in any trouble concerning a batch, and investigates the performance of new formulations by studying drug release. The dissolution test as a QC tool tends to maintain both manufacturing as well as product consistency (McCormick and McVay, 2016). For QC, dissolution must involve selection of media of proper discriminatory power; or else it will lead to variations in the dissolution test results, e.g., mebendazole showed nondiscriminating test results in 0.1 N HCl with 1% SLS and metoprolol showed overly discriminating test results (Prasanthi et al., 2014). The QC dissolution tests should provide the environmental settings under which more than 90% drug release can occur, and routine use can be conveniently possible. So, dissolution media (pH and volume), duration, time points, apparatus, and the other parameters should be selected likewise for both immediate release and modified release dosage forms. 9.9.12 Determination of Product Storage Stability Throughout the development lifecycle for product release, dissolution tests for all solid oral dosage forms are not only used for release testing but also can be used as an indicator of drug stability on aging, termed as storage stability studies. It can also be extrapolated to product degradation studies. It is a pivotal analytical test and can detect physical and chemical changes in a drug substance as well as a drug product (Aulton and Taylor, 2017). DOSAGE FORM DESIGN CONSIDERATIONS 9.10 DISSOLUTION MECHANISM: ROLE OF DENSITY FUNCTIONAL THEORY (DFT) 325 9.9.13 Investigation of Drug Release Mechanisms There are some dissolution kinetic models (zero order, Linear, Quadratic, Logistic, Probit & Weibull) that describe the overall drug release from the dosage form. Model fitting is done, and the regression coefficient values determine the best suitable model for that system, indicating the mechanism of drug release based on different mathematical functions (Ahmad et al., 2015; LeBlond, 2016). 9.10 DISSOLUTION MECHANISM: ROLE OF DENSITY FUNCTIONAL THEORY (DFT) 9.10.1 Basics of Density Functional Theory Density functional theory is based on computational quantum mechanics and makes use of the spatially dependent electron density as functional (that is functions of other functions) which in this case is for determining the properties of many-electron systems (Liu et al., 2016). The Hohenberg and Kohn theorem for DFT asserts that this electron density functional is a simple function of three coordinates (unlike the Schrödinger equation whose function has 126 coordinates and 42 electronic spin components), and can help to understand the total energetics of multibody system in a relatively simple manner (Medvedev et al., 2017). These energies include various potential energies like ion electron potential energy, ion ion potential energy, along with kinetic energy, exchange-correlation energy, and electron electron energy. It is used to examine the structure based, magnetic, and electronic properties of molecules. Although this theory produces accurate results, it faces difficulty in properly describing strongly correlated systems (Koch and Holthausen, 2015; Lejaeghere et al., 2016). 9.10.2 DFT Application to Predict Dissolution Mechanisms This concept has been exhaustively used in physics, chemistry, and material science but its application to pharmaceutical mass transfer process (like dissolution) is quite recent. Dissolution is a thermodynamic process involving a solute solvent interaction process at the molecular level. Moreover, the net Gibbs free energy should be negative for dissolution to take place. So, during the dissolution process, this theory helps to determine the nature of molecular interactions (bond formations and bond breakages) occurring by virtue of measuring changes in system energetics. This, in turn, helps to predict the mechanism of dissolution process (Jiang et al., 2015). This was first studied for dissolution of acetaminophen crystal into the aqueous solution. Some research findings on dissolution mechanisms studies undertaken by density functional theory are mentioned below. NaCl dissolution involves multiple steps, initiating with the initial discharge of Cl ions from the lattice and later followed by the subsequent release of Na ions calculated by free energy barriers. Cellulose triacetate (CTA) II crystal dissolution in dimethyl sulfoxide (DMSO) revealed that the major resistance to solvation was offered by the two stronger H-bonds. The three types of H-bonds with different bond strengths that were the basis of crystal formation vanished during the course of dissolution process (Hayakawa et al., 2011). DOSAGE FORM DESIGN CONSIDERATIONS 326 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT The dissolution of silicate as proposed by Kubicki et al. takes place by protonation and hydrolysis of bridging oxygen atoms interceded by intrasurface H-bonding (Kubicki et al., 2012). The dissolution mechanism of SiO2 in ionic solutions as investigated by Stritto et al. majorly involved proton transfer occurring due to ion-induced stronger H-bonding between terminal hydroxyl groups and bridging oxygen atoms (DelloStritto et al., 2016). The dissolution mechanism of α-cyclodextrin and chitobiose in 1-ethyl-3-methyl-imidazolium acetate was examined using DFT (Cao et al., 2017). Major interactions involved were noncovalent interactions in which hydrogen bonding interactions were predominant. Payal et al. carried out the dissolution of cellobiose and xylan representing cellulose and hemicellulose, correspondingly, in the gas phase, implicit and explicit solvent. The major contribution in the dissolution process was observed to be inter- and intramolecular hydrogen bonding (Payal et al., 2012). DFT can also be used to investigate the pattern of drug release or the order in which drug molecules release from the crystal surface and the site involved upon the crystal surface and if molecules were observed to leave the crystal surface in an organized fashion. The effect of NaCl on drug dissolution was also analyzed by DFT. DFT was employed successfully for structural elucidation of phosphatidylcholine based on the energetics of the dissolution system. Dissolution mechanism studies using DFT can also help to select the most stable drug form amongst all polymorphs, such as in the case of platinum nanoparticles where a truncated octahedral polymorph was found to be most stable to dissolution (Sanz-Navarro et al., 2008). 9.11 DISSOLUTION CONTROLLED DRUG DELIVERY SYSTEMS The need for a drug product is not only restricted to faster/improved drug dissolution (mainly for poorly soluble drugs) but the slowing down/delaying of drug dissolution may also be equally important in many cases to get the drug released at the desired rate and site to provide a long-term therapeutic effect. This becomes the basis for dissolution controlled drug delivery systems. Dissolution has emerged as an important tool in controlling the drug release and designing the drug delivery systems on three principles (Khadka et al., 2014; Pundir et al., 2017). 9.11.1 Dissolution of Solid Particles It follows the basic mechanism of Noyes Whitney principle (two key steps of solvation followed by diffusion). 9.11.2 Dissolution of Coated Systems It involves applying the coat of retardant (slowly dissolving) polymer material at drugdissolution medium interface and is majorly governed by the dissolution of the coat in the targeted release medium, such as in the case of enteric coated systems. DOSAGE FORM DESIGN CONSIDERATIONS 9.12 CONCLUSION AND PROSPECTS 327 9.11.3 Dissolution of Matrix Systems It involves the homogenous distribution of the drug in the polymer matrix. It is governed by the selection of the polymer as well as the design and geometry of the matrix. The matrix systems can be surface erodible matrix systems (dissolving type), nonerodible systems (diffusion type), or soluble matrix systems (swelling type). 9.11.4 Examples of Dissolution Controlled Drug Delivery Systems The low-aqueous-solubility penicillin G salts like penicillin G benzathine suspension can maintain the therapeutic plasma levels for almost a day or more (Rajadhyaksha et al., 2016). Zydis and DuraSolv are quick-dissolve formulations which show spontaneous dissolution in the oral cavity due to the higher values of surface area and solubility of excipients (AdchitreVaishali et al., 2016). NanoCrystals and DissoCubes utilize micronization or nanosizing concepts to improve dissolution for an immediate release dosage form (Lu et al., 2016). Enteric coating polymers like cellulose acetate phthalate exhibit delayed drug release by virtue of its dissolution at higher intestinal pH values and showing no solubility at low gastric pH values (Caillard et al., 2016). Precise demonstrates a zero-order drug release by keeping the dissolving surface area constant. The drug-containing tablet core experiences a decrease in its diameter while there is an increase in its thickness during the drug dissolution process. COSRx (a guar-gum-based tablet) shows improved controlled release rates making use of both aqueous soluble and aqueous insoluble polymers (Pundir et al., 2017). Smartrix tablet exhibits drug release by erosion of the outer layers leading to the increased drug release surface area (Pundir et al., 2017). TIMERx is based on slowly eroding matrix platform technology and consists of two polysaccharides, xanthan gum and locust bean gum (Silas et al., 2017). RingCap is a patented capsular matrix tablet whose rim is provided with the rings of insoluble material which control the surface area and thus the drug release (Tiwari and Batra, 2014). OROS tablets cause the drug release to occur through an orifice, initiated by the water inflow through a semipermeable membrane enforced by osmosis (Mendez et al., 2014). Other such technologies include Spheroidal oral drug absorption system (SODAS), Intestinal protective drug absorption system (IPDAS), Chronotherapeuticoral drug absorption system (CODAS), and Programmable oral drug absorption system (PRODAS) (Allen and Ansel, 2013; Park, 2014). 9.12 CONCLUSION AND PROSPECTS Dissolution testing has widened its contributions since its outset in early 1960s. Dissolution testing adds value to the overall drug development sequence right from the selection of phase 1 drug products to the criteria for being surrogate for bioequivalence studies in later stages of drug development and postapproval changes by using BCS and IVIVC attempts. It enable the process to be less time-consuming and more cost-effective due to reduced regulatory burden and increased potential of in vivo predictions. DOSAGE FORM DESIGN CONSIDERATIONS 328 9. DISSOLUTION PROFILE CONSIDERATION IN PHARMACEUTICAL PRODUCT DEVELOPMENT Dissolution testing has several significant applications as a quality control tool for ensuring batch to batch uniformity and in research and development to examine the performance and stability of new formulations. However, a major limitation is the need to develop a single dissolution test that is efficient to serve both the purpose of QC and biorelevance as both are governed by separate factors. Although success has been achieved in designing biorelevant dissolution media, the in vivo prediction results are still not found to be sufficiently precise. This may be due to inability to control the many variables affecting the dissolution in vivo. Further, these media are very complex and costly to be used on a regular basis. The dissolution data parameters vary at each phase of drug development based on the intended purpose. Secondly there are insufficient efforts being made in dissolution method development due to time pressure, leading to the lack of profound knowledge of the dissolution testing potential. The new techniques of QbD can thus help in generating detailed expertise of “causes and consequences” and lead to a science-based approach to improving the dissolution method. However, attaining this goal has always been a major challenge for pharmaceutical formulation development. Acknowledgments The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology (DST), Government of India for grant (#ECR/2016/001964) allocated to Dr Tekade for research work on drug and gene delivery. The author also acknowledges DST-SERB for N-PDF funding (PDF/2016/003329) to Dr. Rahul Maheshwari in Dr Tekade’s lab for work on targeted cancer therapy. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Dr. Chougule acknowledges the support of the National Institute of General Medical Science of the National Institutes of Health under award number SC3GM109873. The authors acknowledge the Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS, USA for providing start-up financial support to Dr. Chougule’s lab. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. ABBREVIATIONS ANDA API AUC BCS BDDCS CMV CODAS CTA DDD Plus DFT DMSO DoE ECCS EP abbreviated new drug application active pharmaceutical ingredient area under the curve biopharmaceutical classification system biopharmaceutical drug disposition classification system critical manufacturing variables chronotherapeutic oral drug absorption system cellulose triacetate dose disintegration and dissolution plus density functional theory dimethyl sulfoxide design of experiment extended clearance classification system European pharmacopoeia DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES FaSSGF FaSSIF FDA FeSSGF FeSSIF GDM GI GIT GMPs HPLC ICH IND IPDAS IQ IRB IVIVC IVIVE JP mOsm kg21 MR NCE NDA NF OQ PPI PQ PRODAS PVT QbD QC QRA QTPP R&D RLD RSD SGF SIF SODAS SUPAC TIM UPLC USP 329 fasted state simulated gastric fluid fasted state simulated intestinal fluid Food & Drug Administration fed state simulated gastric fluid fed state simulated intestinal fluid gastric digestion model gastrointestinal gastrointestinal tract good manufacturing practices high performance liquid chromatography International Council for Harmonization investigational new drug application intestinal protective drug absorption system installation qualification Institutional Review Board in vitro in vivo correlation In vitro in vivo extrapolation Japanese Pharmacopoeia milliosmole per kilogram modified release new chemical entity new drug application national formulary operational qualification proton pump inhibitors performance qualification programmable oral drug absorption system performance verification test quality by design quality control quality risk assessment quality target product profile research & development reference listed drug relative standard deviation simulated gastric fluid simulated intestinal fluid spheroidal oral drug absorption system scale-up and postapproval changes TNO gastro-intestinal model ultra performance liquid chromatography United States Pharmacopoeia References Adchitre Vaishali, B., Khadbadi, S., Patil, P.R., Shaikh, M., 2016. 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Ther. 7 (3), 19 27. DOSAGE FORM DESIGN CONSIDERATIONS C H A P T E R 10 Drug Disposition Considerations in Pharmaceutical Product Rahul Maheshwari1, Piyoosh Sharma2, Ankit Seth3, Neha Taneja4, Muktika Tekade5 and Rakesh K. Tekade1,6 1 National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 2Sri Aurobindo Institute of Pharmacy, Indore, Madhya Pradesh, India 3Department of Ayurvedic Pharmacy, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur, Uttar Pradesh, India 4Pharmaceutical Analysis & Quality Assurance Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, Punjab, India 5TIT College of Pharmacy, Technocrats Institute of Technology Campus, Bhopal, Madhya Pradesh, India 6Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 10.1 Introduction 10.1.1 General Principles of Drug Disposition 10.1.2 Routes of Administration 10.2 Factors Affecting the Interplay of Drug Disposition 10.2.1 Factors Affecting the Absorption 10.2.2 Factors Affecting the Metabolism 10.2.3 Factors Affecting Distribution 10.2.4 Factors Affecting Excretion Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00010-1 338 338 338 341 341 342 345 346 10.3 Role of ADME in Product Development 10.3.1 Role of Absorption in Product Development 10.3.2 Role of Distribution in Product Development 10.3.3 Role of Metabolism in Product Development 10.3.4 Role of Excretion in Product Development 10.4 Biopharmaceutics Classification System 10.4.1 Different Classes of BCS 337 346 346 347 347 348 348 349 © 2018 Elsevier Inc. All rights reserved. 338 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT 10.4.2 Applications of BCS in Biowaiver of Drugs 10.5 Various Factors Affecting Drug Disposition 10.5.1 Effects of Enzymes 10.5.2 Drug Drug Interaction 10.5.3 Herb Drug Interactions 10.5.4 Food Drug Interactions 10.5.5 Polypharmacy 10.5.6 Genetic and Environmental Factors 10.5.7 Drug Dose Frequency 10.6 Transporters in Drug Disposition 349 349 349 350 351 352 353 354 354 354 10.7 Experimental Models for Drug Disposition Investigations During Product Development 355 10.7.1 In Vitro Metabolic Models 10.7.2 In Vitro Transporter Models 10.7.3 In Situ Ex Vivo Models 10.8 Effect of Disease State on Drug Disposition 10.8.1 Effect of Cardiovascular Diseases 10.8.2 Effect of Gastrointestinal Diseases 10.8.3 Effect of Liver Diseases 10.8.4 Effect of Kidney Diseases 355 356 358 359 360 360 361 361 10.9 Conclusion 362 Acknowledgment 363 References 363 10.1 INTRODUCTION 10.1.1 General Principles of Drug Disposition The rate and extent of drug disposition are important for understanding, predicting the extent or duration of a drug’s effect, or interactions with internal targets. To achieve its therapeutic/toxic effect, a drug and or its active metabolite must be present in the suitable concentration (Tekade et al., 2018). The concentration of drug attained in the body will depend on many factors such as the type of formulation, dose, and route of administration, the rate of absorption, tissue bindings, distribution throughout body, and rate of metabolism and excretion, etc. (Siepmann et al., 2016). Pharmacodynamics is the term used to describe the mechanism of action of the administered drug (Soni et al., 2016). The prediction of drug disposition characteristics of a drug mainly depends upon its chemical and physiological factors. The one such important factor is the gastric changes caused by foodstuff that affects the degree and rate of drug absorption and further complexes the mechanism of drug disposition (König et al., 2013). The exposure of chemicals, such as xenobiotics, in a biological system, may be deliberate and accidental (Xia and Miwa, 2016). A general scheme of drug disposition is presented in Fig. 10.1. 10.1.2 Routes of Administration 10.1.2.1 Oral Route The oral route is in general the simplest, safest, and most economical way of drug administration, also known as per oral route. Being the widely explored route, most of the DOSAGE FORM DESIGN CONSIDERATIONS 10.1 INTRODUCTION 339 FIGURE 10.1 General events associated with drug disposition. currently available drugs are administered by this route (Green et al., 2017). Many reports suggest that absorption of drugs is influenced by food and physiology of gut. There is a need to assess the effect of food with the drug for successful early stage development of the drug. The rate and extent of availability of drug administered through this route is a function of drug’s physicochemical properties (water/lipid solubility), type of dosage form (tablet, capsule, liquid, semisolid), type of excipients used for formulation, physiological environment, and metabolism in the intestine environment. Changes in any of the factors will alter the absorption pattern of the administered drug. 10.1.2.2 Intravenous Route This route of administration delivers the drug directly into the bloodstream. This route bypasses the problems associated with GI tract absorption. This route is preferred for the rapid dose to effect adjustment. This route is employed for the prompt relief and rapid action of the drug (da Costa Gonçalves et al., 2014). Apart from the delivery of conventional injections, IV route is also the most preferred route for the delivery of nanotechnology-based products (Tekade et al., 2017b). These includes liposomes (Maheshwari et al., 2015b; Maheshwari et al., 2012), polymeric nanoparticles (Maheshwari et al., 2015a; Sharma et al., 2015), biopolymer-based composites (Tekade et al., 2017c), solid lipid nanoparticles, dendrimers (Soni et al., 2017; Tekade et al., 2015), carbon nanotubes (Tekade et al., 2017a), and gene delivery therapeutics (Maheshwari et al., 2017). 10.1.2.3 Subcutaneous Route This route involves the delivery of the drug into blood-perfusing tissue after loading the drug in the subcutaneous region beneath the skin (Jin et al., 2015). The subcutaneous route is more convenient as it allows flexible dosing to reduce the overall cost of therapy. This route was reported to be the most promising route for injecting a number of DOSAGE FORM DESIGN CONSIDERATIONS 340 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT FIGURE 10.2 Representative c-scintigraphy images after the subcutaneous injection of c-PGA-Phe-Tyr(125I) NPs (A and B) and Na125I (B) into mice (A) and rats (B). All images were computationally merged with magnetic resonance images that were obtained separately from the c-scintigraphic images. The yellow arrows (white arrows in print version) denote the injection sites. Adapted with permission from Toita, R., Kanai, Y., Watabe, H., Nakao, K., Yamamoto, S., Hatazawa, J., et al. 2013. Biodistribution of 125 I-labeled polymeric vaccine carriers after subcutaneous injection. Bioorg. Med. Chem. 21 (17), 5310 5315. medications like methotrexate, hepatitis B immunoglobulin, rituximab, hydrocortisone, bortezomib, recombinant interleukin-2, and several other injectables when compared to intravenous and intramuscular routes (Jin et al., 2015). This route has been explored for targetting nanoparticles to the lymphatic system for treating some lymphomas. Subcutaneously administered nanoparticles were also investigated for their potential to develop DNA vaccines (Cheng et al., 2015). In a study, the subcutaneously injected polymeric nanoparticles-based carriers for vaccine labeled with 125I were investigated. It was found that the carriers exhibit acceptable biodistribution profile and were proved to be safe and effective (Fig. 10.2; Toita et al., 2013). The findings of another experiment revealed that subcutaneously administered polymeric nanoparticles were found to effective in delivering and sustaining the release of low-molecular-weight heparin (Jogala et al., 2015). 10.1.2.4 Topical/Local Route of Administration This route is used for the local action of drugs and also avoids first-the pass effect. This route is suitable for sustained release dosage forms such as adhesive patches of various shapes and sizes. The topical route provides delivery of the drug into the blood at a constant rate by passing through the layer of stratum corneum (Akalkotkar et al., 2015). The topical device is made up of various layers, viz., occlusive backing film, rate controlling micropore membrane, and followed by an adhesive layer. The drug is sandwiched between an occlusive backing film and a micropore membrane in a reservoir. Transdermal drug absorption can considerably change drug kinetics. It depends on a variety of factors including the site of application, thickness, and integrity of the stratum corneum of the DOSAGE FORM DESIGN CONSIDERATIONS 10.2 FACTORS AFFECTING THE INTERPLAY OF DRUG DISPOSITION 341 epidermis, the permeability of the membrane, pH of the drug, and lipid solubility (Ahad et al., 2015). Drug disposition can help in predicting what the drug does to the body/organs (type of effects, interaction, accumulation, etc.). Drug disposition basically depends upon the physicochemical properties of a drug and also affects the absorption rate. Different routes of administration of a drug results in different absorption patterns and bioavailability, and ultimately the disposition. In addition to this, various factors affecting the absorption, distribution, metabolism, and excretion of drug are discussed in the next section. 10.2 FACTORS AFFECTING THE INTERPLAY OF DRUG DISPOSITION 10.2.1 Factors Affecting the Absorption Drug absorption involves the movement of the drug from its injection/administration site into the systemic circulation. The GI tract is the most favored site of absorption because of many reasons like high surface area available for absorption, availability of various transport mechanisms, high permissibility due to comparative larger intracellular spaces, etc. Therefore the oral route and GI tract is a primary focus in drug development and medicinal chemistry. The drug must reach systemic circulation to exhibit any biological effect which depends on factors like Log-P and abeyance of Lipinski rule that affect absorption (Di and Kerns, 2015). There are mainly three broad categories of factors that may affect absorption by the oral route. The first one is physicochemical characteristics which include solubility, pKa, lipid aqueous partitioning, and stability in the acidic and basic environment, particle size, and much more (Siepmann et al., 2016). Secondly there are physiological factors, such as GI pH and emptying rate, transition time to pass through the intestine, level of bile formation, absorption type, levels of cofactors, and others. The third category includes the effect of type of dosage form employed on absorption (Siepmann et al., 2016). 10.2.1.1 Physicochemical Properties of a Drug This is very broad topic to understand how physicochemical properties govern the absorption of a drug (Bergström et al., 2014). The absorption of the drug from its dosage form is dependent on hydrophilic as well as lipophilic characteristics of the drug. It has to be balanced, so that a drug first gets dissolved in polar medium and later passes through the lipidic cell membrane. Another critical factor is the acidic or fundamental nature of the drug. Many drugs are a weak acid or weak bases (Koyama et al., 2016). The pH of the stomach is acidic and basic drugs get ionized and cannot cross the lipidic biomembrane. Vice versa mechanism can be seen in the basic environment in the small intestine (Kataoka et al., 2016). Another important factor is permeability which needs to be considered during the drug discovery step to achieve a desirable oral bioavailability. Permeability gets affected by various factors, such as nature of drug molecule, the dynamic surface area of the molecule, the increasing molecular weight of the drug molecule. Needless to say, the stability of DOSAGE FORM DESIGN CONSIDERATIONS 342 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT such molecules in the GI tract is another concern. Therefore, we consider these factors as the “final bridge” toward drug absorption (Dressman and Reppas, 2016). Optimization of physicochemical properties is one of the important considerations in rational drug design and pharmaceutical product development. Some of the natural peptides were reported to have poor solubility in water and tended to form aggregates. These challenges can possibly be overcome by modifying their physicochemical properties by utilizing designing strategies and chemical modification (Fosgerau and Hoffmann, 2015). Remarkable development has been done in the past few decades in correlating various attributes of physicochemical properties of the drugs with its pharmacokinetics, especially for CNS drugs. With the accessibility of enormous in vitro data, in silico approaches have also been developed to predict the physicochemical parameters which corresponds to drug disposition (Rankovic, 2015). For example, p-glycoprotein (pgp) substrate assay of more than 2000 compounds have been exploited to develop robust in silico parameters based on physicochemical properties to predict drug-likeness to be a Pgp substrate (Desai et al., 2013). 10.2.1.2 Physiological Properties Affecting Drug Absorption An important factor in drug absorption is membrane physiology, such as inflammation which affects the intracellular spaces and consequently the bioavailability of a drug molecule (Chillistone and Hardman, 2014). Some other factors which significantly affect the drug absorption are the type of mechanism involved in absorption and gastrointestinal physiology such as GI movement, emptying rate, postcrandial changes, concurrent administration of two or more drugs, disease conditions (like dyspepsia), which affect normal secretions in GI tract, etc. (Ashford, 2017a). Considerable inconsistency in the pH of the entire length of GI tract has been reported amongst individuals, that mainly depends on disease conditions, fed/fasted conditions, genders, and age factor in human beings. Bioavailability of colon targeted drug delivery systems was found to be significantly influenced by the alteration in physiological pH (Amidon et al., 2015). It was also investigated that the enhanced permeability and retention effect of nanomedicines on solid tumors has been markedly affected by variation in a patient’s physiology and pathological condition (Maeda, 2015). 10.2.1.3 Pharmaceutical/Dosage Form Related Factors Affecting Absorption These factors vary concerning the dosage form and route through which it has been administered. The major factors in this category are dissolution rate, polymorphism, amorphism, drug pKa, lipophilicity, ionization state, solvates, hydrates, particle size and available surface area, and formulation factors, including method of manufacturing, pharmaceutical ingredients, product age, and storage conditions (Alomar, 2014). 10.2.2 Factors Affecting the Metabolism The main aim of drug metabolism is to change chemical compounds into more polar, water-soluble products so that they can be eliminated from the body. As soon as a drug enters the body, it begins to break down into metabolites, reducing the effect of the drug DOSAGE FORM DESIGN CONSIDERATIONS 10.2 FACTORS AFFECTING THE INTERPLAY OF DRUG DISPOSITION 343 on the body. Today, most xenobiotics which enter the human body through many sources tend to accumulate in the body due to lack of metabolic mechanisms, thus produce toxicity (Jones et al., 2015). Their elimination from the body becomes more complex due to their lipophilic nature. The majority of xenobiotics are eliminated from the body with the help of one or multiple pathways, which include phase 1 and phase 2 enzymatic systems. This process of biotransformation of xenobiotics increases their water solubility so that they can be eliminated from the body through urine or the bile (Varum et al., 2013). Phase I reactions often occur in the liver by oxidation, reduction, hydrolysis, cyclization, and decyclization, carried out by different enzymes including important class oxidases (Ruokolainen et al., 2014). The example of one such Phase I oxidation reaction is the conversion of C H bond to a C OH. This leads to conversion of an inactive compound to an active one, which exhibits pharmacological effects. Sometimes, it can also convert a nontoxic molecule into a poisonous molecule. Cytochrome P450 enzymes present in the liver carry out phase I oxidation reactions. The presence of several other enzymes also affects the rate of metabolism (Lindemalm and van den Anker, 2015). The activity of these enzymes can be affected by food, chemicals, and other drugs, which can potentially slow the rate of reaction. Phase II reactions are the next step in the metabolism which involve interactions with the end product of the first phase reaction. The second phase involves the addition of highly polar molecules to a functional group (Backman et al., 2016). Phase II reactions produce a metabolite with increased hydrophilicity which helps to facilitate the elimination of the drug from the tissue through urine and bile. Drugs get metabolized through various pathways including phase I and phase II reaction pathways, which include numerous enzyme system (Ruokolainen et al., 2016). It is therefore assumed that many internal and external factors will be responsible for alteration in metabolism of the drug. Some of the factors have been discussed below. 10.2.2.1 Species Different species may have the same route for metabolizing the same drug but it might be with a different rate along a particular pathway, considered as a quantitative difference, whereas some species may adopt different pathways for the metabolism of the same drug, i.e., the qualitative difference. For example, caffeine showed the quantitative species difference whenthe highest total metabolism was seen in human and decreasing in order in monkey, rat, and rabbit, respectively (Lin et al., 2016). 10.2.2.2 Age Newborn, young, and adults show a remarkable difference in the biotransformation and susceptible to drug action. The differences are due to the enzyme systems involved in biotransformation and the development of their metabolizing capacity (Nicolas et al., 2017). Due to age-dependent transformations, the metabolic activity of the liver may change, resulting in decreased metabolism of some drugs in elderly persons. Many drugs were reported to stay in the body for longer periods as compared to young individuals (Alomar, 2014). Opioids were investigated to be metabolized mainly by liver. The decrease in activity of cytochrome P450 3A4 (CYP3A4) with increasing age was reported which may subsequently cause a decrease in clearance of opioids like oxycodone and buprenorphine from systemic circulation as well as enhanced elimination half-life (Reid, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 344 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT 10.2.2.3 Sex Sex differences are important to study to correlate sex-dependent pharmacokinetic, pharmacodynamic, efficacy, and adverse reaction studies. This is more important in the case of pregnant women where the drug disposition changes significantly and has an impact on final drug effects (Laslo et al., 2017). Physiological and anatomical dissimilarities like renal and hepatic clearance, gastric motility, etc between females and males may considerably influence drug disposition. Comparatively high activity of CYP3A4 was reported in women as compared to men (Alomar, 2014). In an investigation, it was revealed that females (54%) are more prone to adverse effects of cardiovascular drugs like cardiac glycosides, vasodilators, and diuretics as compared to males (46%) (Rodenburg et al., 2012). 10.2.2.4 Pathological Status/Diseased State The way in which the body clears the drug is mainly affected by disease state and type, such as liver disorders, endocrine disease, diabetes mellitus, pituitary disorders, and many infections. Disease or disease conditions may sometime alter many physiological functions in the body which leads to unpredicted drug disposition (Dressman and Reppas, 2016). Rheumatoid arthritis-induced metabolic alterations have been reported by Chimenti and coworkers (Chimenti et al., 2015). The existence of some cytochrome P450s in the tumor cells was also reported. It was revealed that these enzymes are responsible for inactivation of anticancer drugs like 2-methoxyestradiol. It clearly indicates the alteration of the metabolic pathway of anticancer drug in the cancer patients, which may cause drug resistance (Ghosh et al., 2016). Furthermore, the probable effect of diabetes mellitus (DM) on the levels of CYP450 amongst patients as well as its subsequent effect on metabolism of drugs like antipyrine has been reported. Animal studies have also demonstrated the significant influence of DM on the levels of hepatic enzymes as well as on the metabolism of drugs like hexobarbital, aminopyrine, codeine, and chlorpromazine (Vahabzadeh and Mohammadpour, 2015). 10.2.2.5 Hormonal Control of Drug Metabolism Hormones play a major role in metabolism and control the biotransformation of drugs, in connection with factors like sex, age, physiological conditions, such as pregnancy; for example, thyroid hormones play a major role in metabolizing several drugs administered with equal doses (Wong et al., 2016). In an investigation, it was demonstrated that testosterone (sex hormone) causes downregulation of cerebral cytochrome P450 2D (CYP2D) via miRNAs, which resulted in decreased metabolism of tramadol (Li et al., 2015). 10.2.2.6 Environmental Factors Envionmental factors include all type of pollutants, chemical waste, industrial waste, pesticides, etc. Atmospheric pollutants like heavy metals can greatly influence biotransformation. Environmental factors are particularly important for the employees working in the industries where a variety of pollutants are released into an environment which may lead to adverse reactions (Kanehisa et al., 2017). For example, cigarette smoke was reported to inhibit cotinine metabolism and induce chlorzoxazone metabolism (Petros et al., 2012). DOSAGE FORM DESIGN CONSIDERATIONS 10.2 FACTORS AFFECTING THE INTERPLAY OF DRUG DISPOSITION 345 Exposure to pesticides like thiocarbamates was reported to modify the activity of metabolic enzymes by several mechanisms that can possibly affect the metabolism of xenobiotics (Mathieu et al., 2015). 10.2.3 Factors Affecting Distribution As the drug reaches the bloodstream by any of the routes of administration, the drug is subjected to some processes called disposition processes. Disposition is carried out in two different steps: distribution and elimination (Xia et al., 2016). Distribution is the process that involves the reversible transfer of a drug between compartments (or) from one location to another with the body. The distribution process is carried out by the circulation of blood; one of the compartments is always the blood (or) the plasma, and the other represents extravascular fluids and other body tissues (Abuhelwa et al., 2016). 10.2.3.1 Cell Membrane Composition Drug distribution is a very complex process, and therefore many factors can influence the movement of the drug in the body. These are predominantly physiological factors and govern rate and extent of distribution (Siepmann et al., 2016). The rate can be influenced by absorption and blood perfusion of the drug. The extent can be affected by lipid solubility, plasma protein binding, tissue protein binding, pH pKa of the drug (Lin et al., 2017). Cell membranes, which are made up of phospholipids, form the main barriers between the compartments in the body. Lipid soluble drugs pass through lipidic cell walls very easily. The movement of water-soluble drugs depends on the passive transport which happens slowly, and the rate is dependent on drug molecule size (Sánchez-López et al., 2017). The highly profuse organs tend to receive the major part of total drug molecules present in the systemic circulation. In addition to this, the nonionic form of the drug has higher lipid solubility and, in turn, better permeability in a different compartment of the body. An ionic or nonionic form of the drug depends on pKa. Variation in the pH in different body compartments plays an important role in drug disposition and accumulation of drugs in specific compartments. This aspect is well explored for target delivery of many anticancer drugs to tumor sites (Mitragotri et al., 2014). 10.2.3.2 Molecular Weight of Drug The molecular size of the administered drug also affects the rate of distribution; larger molecules find it difficult to cross biological membranes, while smaller ones pass through more easily, and therefore have an increased rate of distribution. Plasma comprises of a variety of proteins out of which albumin is major and constitutes 60% of total plasma protein (Veber et al., 2002). Albumin is basic in nature and easily binds with basic and neutral drug molecules. For example, Buddha et al. showed that albumin-bound drug is not available for diffusion to body tissues and hence acts as a reservoir for the drugs in the systemic circulations. Only an unbound drug can pass through the tissues and exhibit the biological effect. Distribution into the interstitial fluid surrounding tissues and organs occurs quickly if the drug is not bound to any plasma proteins (Budha et al., 2012). DOSAGE FORM DESIGN CONSIDERATIONS 346 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT 10.2.4 Factors Affecting Excretion The process of elimination of unchanged drug or its metabolites from the body is termed as excretion. Elimination is simply the removal of the drug from the body completely. Elimination comprises two steps: firstly the metabolism to convert the drug into polar metabolites and then excretion to remove the metabolites through the kidneys or bile (Chen et al., 2015). Chillistone and Hardman demonstrated that there are two main routes of excretion of xenobiotics and their metabolites from the body. Polar compounds get excreted by both the routes, i.e., liver and kidney more efficiently than lipophilic compounds. There are several routes of excretion depending upon the nature of drug molecule (Chillistone and Hardman, 2014). The major organs responsible for excretion are the liver and kidneys. Patients with impaired kidney function may lead to an alteration in the half-life of the drug and may lead to accumulation of drugs (Levey et al., 2015). Age is another important parameter which affects the rate of excretion; extremely young and very old patients have been found with a slow rate of excretion since either organs are not developed entirely or due to organ deterioration, respectively. Patients with liver damage can tolerate the drugs only if gets excreted via kidney (Krentel et al., 2013). Renal excretion takes place through filtration, secretion, and reabsorption, where the substances which are polar get excreted through filtration, whereas the secretion takes place via active transport mechanism for charged compounds. Reabsorption takes place for lipid soluble compounds which are poorly eliminated by kidneys (Levey et al., 2015). Bile excretion is mainly dependent upon lipophilic characteristics of that compound. The more lipophilic the compound is, the more it will be excreted in the form of bile. The chemical structure of xenobiotics, hydrophilic moieties, and the molecular weight of compounds are the most important factors that affect excretion through bile formation (Schaap et al., 2014). 10.2.4.1 Enterohepatic Circulation Many drugs get excreted into bile and back into the blood through intestinal reabsorption, which leads to bile secretion. It involves drug conjugate formation, hydrolysis, and reabsorption (Gao et al., 2017). Factors affecting ADME are discussed above and conclude that ADME of a drug depends upon different characteristics of the drug, that is, factors, which need to be balanced in order to get an ideal product development. Optimization of those factors can lead to the rational drug design. In a product development, it is also necessary to decide the suitable dosage form, route of administration, and dosing frequency, which can be decided by studying the ADME pattern of the particular drug. Therefore the next section is dealing with the role of ADME in product development. 10.3 ROLE OF ADME IN PRODUCT DEVELOPMENT 10.3.1 Role of Absorption in Product Development The designing of the drug is based on its delivery for local or systemic effects. The product development science is mainly dependent on lipophilicity and ability of drug DOSAGE FORM DESIGN CONSIDERATIONS 10.3 ROLE OF ADME IN PRODUCT DEVELOPMENT 347 product to permeate through the biological membrane, and hence these parameters are of special interest (Sjögren et al., 2013). The solubility profile of drug will suggest the class in which the particular drug falls as it is an important factor influencing the product development. However, the relationship between compound or formulation properties and oral absorption in vivo is complex and cannot always be captured solely by dissolution testing. More mechanistic approaches are required to understand the absorption in vivo which further can guide the steps required for product development. A drug as a pure chemical substance cannot be prescribed; it has to be formulated into palatable, dispensable, stable drug products. The design and manufacturing of the formulation development require a thorough knowledge of the biopharmaceutical system for the desired bioavailability of the drug. Therefore the factors mentioned above need to be studied thoroughly (Benet, 2013). From the last few decades, designing strategies involving in silico predictions have gained considerable attention in pharmaceutical product development. Pharmacokinetic (PBPK) modeling based on oral absorption by simulating physiological conditions has been developed as an additional approach to traditional dissolution methods and preclinical studies for guiding pharmaceutical product development (Kesisoglou, 2017). In silico models like GastroPlus 8.0, Simcyp 13.1, and GI-Sim 4.1 have emerged as a widely accepted tool for predicting gastrointestinal absorption of a drug candidate (Sjögren et al. 2013, 2016). 10.3.2 Role of Distribution in Product Development The drug distribution characteristics are of prime importance in determining the efficacy and toxicity of the drug. The drug product needs to penetrate and cross the blood brain barrier (BBB) to be efficacious in vivo for CNS activity (Rowland et al., 2013). The BBB limited the permeability of most of the drugs responsible for a high failure rate of product development for CNS drugs (Bozsak et al., 2014). Benserazide is an example of a peripherally acting drug for Parkinson’s disease, which is unable to cross the BBB (Saraiva et al., 2016). Volume of distribution (Vd) is also one of the key parameters in dose optimization, half-life determination, and dosage form design. By introducing basic and lipophilic functional groups the Vd can be enhanced. Fluoxetine and chlorpheniramine are the examples of basic drugs with high values of log P, low polar surface area, and high volume of distribution (Smith et al., 2015). 10.3.3 Role of Metabolism in Product Development Drug metabolism is one of the most important events a drug faces after administration (Casey Laizure et al., 2013). The wrong route of administration may lead to the metabolism of the drug before reaching the active site. Hence, metabolism plays a vital role to decide the dosage form chosen for the drug molecule. In addition to dosage form, the types and interaction pattern of metabolites formed in the body from the drug must be thoroughly studied. It may be possible that a metabolite is found to be toxic or accumulating in the body. If this occurred, the drug DOSAGE FORM DESIGN CONSIDERATIONS 348 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT would be rejected during the screening process (Kirchmair et al., 2015). Hence, it is a major criterion in the high-throughput screening of prospective drugs. In vitro and in vivo determination of metabolism is one of the integral parts of drug development. Drugs are subjected to in vitro and in vivo profiling of metabolites prior to their application in clinical settings. In an investigation, 4-hydroxyospemifene and 4’-hydroxyospemifene were identified as the two metabolites of the drug ospemifene (Tolonen et al., 2013). Moreover, it was also found that 4-hydroxy ospemifene significantly inhibits the activity of cytochrome P450 2C9 (CYP2C9) and some other cytochromes. The finding reveals the activity of the metabolite on the cytochromes responsible for metabolism of drugs, which clearly indicates the importance of the study in drug development (Turpeinen et al., 2013). 10.3.4 Role of Excretion in Product Development Most of the drugs are mainly excreted through the kidney; if the patient has a condition of renal dysfunction, then the dosage of the drug product needs to be reduced. So during the early stage of drug development, the renal excretion needs to be quantified and thoroughly studied. In an investigation, significant dosing errors have been reported in the patients with renal impairment. Doses of the drugs like cimetidine, vancomycin, digoxin, etc. have been adjusted as per the clearance of creatinine or glomerular filtration rate to improve the final outcome of the treatment (Getachew et al., 2015). Apart from the kidneys, the liver is also an important organ with a large number of metabolizing enzymes. Therefore, dose adjustment is also needed in patients with the condition of liver dysfunction to elude excessive accumulation of the drug (Di, 2014) and unwanted side reactions (Nigam et al., 2015). In an investigation, a safe and effective method was developed to adjust the dose of several drugs like antibiotics, analgesics, cardiovascular drugs, gastrointestinal drugs, diuretics, etc. in patients with liver cirrhosis (Weersink et al., 2016). ADME plays an important role in product development. An absorption study helps to know the solubility and bioavailability of drug that can help the focus on deciding the route of administration; distribution characteristics determine the efficacy and adverse effects; metabolism helps decide dosage form; and excretion pattern may help minimize the dosing errors. Based on solubility and permeability the drugs are classified by the biopharmaceutics classification system (BCS) and the different classes of BCS are described in further section. 10.4 BIOPHARMACEUTICS CLASSIFICATION SYSTEM Biopharmaceutics classification system of drugs is based upon their solubility profile and permeability characteristics. This classification system helps to understand in vivo pharmacokinetic behavior of drug substances (Chan et al., 2016). This classification system guideline has been provided by various regulatory agencies such as USFDA, WHO, and EMEA. The biopharmaceutical classification characterizes drugs into four classes according to their USFDA solubility and permeability (Ji et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 10.5 VARIOUS FACTORS AFFECTING DRUG DISPOSITION 349 10.4.1 Different Classes of BCS 10.4.1.1 Class I (High Solubility, High Permeability) Class I (high solubility, high permeability) has drugs with higher solubility which will ensure solubility will not limit dissolution and high permeability assures the drug will be completely absorbed in defined transit time. For example, Metaprolol, Verapamil (Somani et al., 2016). 10.4.1.2 Class II (High Permeability, Low Solubility) Class II (high permeability, low solubility) drugs from this class have higher absorption but lower solubility that limits its dissolution. This class of drugs has a lower absorption than class I products. For example, Ketoconazole, Glibenclamide (Somani et al., 2016). 10.4.1.3 Class III Drugs (Low Permeability, High Solubility) Class III drugs (low permeability, high solubility) have absorption limited by the permeation rate. This class of drugs displays variable absorption phenomenon. For example, Acyclovir, Neomycin B, Captopril (Sun et al., 2017). 10.4.1.4 Class IV (Low Solubility, Low Permeability) Class IV drugs (low solubility, low permeability) have poor bioavailability and are associated with many issues of absorption, which ultimately affect efficacy. For example, Taxol (Ghadi and Dand, 2017). 10.4.2 Applications of BCS in Biowaiver of Drugs Biowaiver of drugs means to waive off the expensive protocols of bioavailability (BA) and bioequivalence (BE) studies. This biowaiver is for class I, II, and III drugs with some conditions. If a drug product has 85% dissolution in 30 minutes in 3 recommended dissolution media, then that drug product can be considered for biowaiver (Davit et al., 2016). BCS provides information of absorption patterns of drugs and plays an important role to identify the drugs of different characters as classified in the four classes. Biowaiver uses the in vivo study and provides BA, BE data. Drug disposition may also depend upon the bioavailability of drug. Enzymes, various interactions, and multiple treatment may greatly affect the drug disposition and are discussed in detail in the next section. 10.5 VARIOUS FACTORS AFFECTING DRUG DISPOSITION 10.5.1 Effects of Enzymes Learning the dynamics of various enzymes and transporters responsible for drug metabolism is one of the crucial steps involved in drug development. Various factors regulate these enzymes and transporters which in turn are responsible for affecting drug disposition behavior. Drugs do or do not get excreted from the body in an unchanged form because they undergo multiple biochemical modifications in the presence of various DOSAGE FORM DESIGN CONSIDERATIONS 350 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT FIGURE 10.3 Some important metabolizing enzymes found in humans. NTCP, Na1 Taurocholate Ca transporting Polypeptide; OAT, Ornithine aminotransferase; MRP, mitochondrial RNA processing. enzymatic systems (Bright et al., 2016). Most of these enzymes are found in largest concentration in liver, followed by kidney and intestine, respectively. The superfamily of enzymes called cytochrome (CYP450) is involved in phase I metabolism. Enzymes of this family are involved in the transformation of more than 75% of exogenously administered substances. Among all CYPs, the most prominent metabolizing enzyme is CYP3A4, whereas 2D6, 2C19, 2C9, 2E1 are responsible for the metabolism of around 90% of drugs. Selectivity of these CYPs for drugs depends on inherent characteristics of drugs such as lipophilicity/hydrophilicity but not by the class of drugs (Varma and El-Kattan, 2016). Phase II metabolism is affected by many physiological enzymes such as UDP-glucuronosyltransferases (UGTs), similar to CYPs. These UGT enzymes have broad substrate specificity. Fig. 10.3 represents various human drug metabolizing enzymes. 10.5.2 Drug Drug Interaction Current therapies include the use of multidrug/combination of many drugs which may result in drug drug interactions. This type of interaction occurs when the effect of one product has been diminished or improved by another one when taken simultaneously (Hasnain et al., 2017). In the case of an alteration in pharmacokinetic or pharmacodynamic parameters of either or both, a drug drug interaction is taking place. A general structure of drug drug interaction and possible effects is shown in Fig. 10.4. Pharmacodynamic interactions are easy to anticipate in comparison with those of pharmacokinetic interactions. At the same time, these drug drug interactions may produce catastrophic and dangerous threat among the public. Pharmacokinetic interactions are majorly unwanted interactions, and clinicians look to avoid them (Hochheiser et al., 2016). Use of combination therapies is deliberately and strategically required to achieve therapeutic advantages to treat chronic disorders like cancer, diabetes, etc. It is crucial to understand such types of interaction during the drug development process itself, which in turn will assure the safety of combinations. For example, Ritonavir-boosted protease inhibitors have become standard treatment for patients with HIV disease; it can be given with Lopinavir, Saquinavir, and new protease inhibitors as well (Doogue et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 10.5 VARIOUS FACTORS AFFECTING DRUG DISPOSITION 351 FIGURE 10.4 Showing various types of drug interactions with other drugs, herbs, and food materials and the possible effects. 10.5.3 Herb Drug Interactions The unwanted interactions between herb and drug are a most common phenomenon when traditional herbal drugs are coadministered with other drug product. The herbal product can be any dietary nutritional supplement or herbs with some medicinal value. Many surveys and studies showed that a higher percentage of patients on prescription regimen combine their therapy with herbal products that may lead to unwanted toxic herb drug interactions or fatal clinical outcome (Deb et al., 2017). For example, herbal formulations having Hypericum perforatum have been reported for drug interactions with drugs like indinavir, simvastatin, cyclosporin, digoxin, and fexofenadine by inducing cytochrome P450 3A4 (CYP3A4). The resulting cytochrome activity causes an increase in metabolism and subsequent decrease in concentration of these drugs and affects the clinical outcome (David et al., 2015). A general structure of herb drug interactions and possible effects is shown in Fig. 10.3. 10.5.3.1 Pharmacokinetic Interactions Concomitant administration of herbs with conventional drugs affects absorption, distribution, metabolism, and excretion (ADME) leading to the toxic or subtherapeutic effect of the drug. Herbs affect the ADME of conventional drugs upon coadministration (Li et al., 2016). Herbs also modulate various efflux P-glycoprotein (P-gp) transporters and organic anionic and cationic transporter proteins required for transport of conventional drug present in gut, liver, kidney, brain, thus affecting the pharmacokinetics of coadministered drugs. Herbal drugs also have modulatory effect on several metabolizing enzymes including CYP P450 (e.g., CYP 3A4, 2C9, 2C19; 2D6, and 2B6 etc.) which act as receptors and are required for metabolism of conventional drugs, leading to pharmacokinetic interaction when coadministered with conventional drugs (Wu et al., 2016). There are various pharmacokinetic interaction studies documented based on animal models, clinical trials, and case reports for conventional drugs used in various chronic diseases. A few examples have been listed in Table 10.1. DOSAGE FORM DESIGN CONSIDERATIONS 352 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT TABLE 10.1 Examples of Pharmacokinetic Interaction Herb Drug Effect on Pharmacokinetics of Drug Garlic Alprazolam No effect Ginkgo biloba Alprazolam AUC of alprazolam decreased Kava Digoxin No effect Panaxquinquefolius Zidovudine Milk thistle No effect Metronidazole Increased clearance of metronidazole & decreased t1/2, Cmax and AUC TABLE 10.2 Examples of Pharmacodynamic Interactions Herb Drug Effect Mechanism Risk/Benefit Study Model Allium sativum Chloropropamide m Antidiabetic effect Additive Beneficial Case report Ginkgo biloba Haloperidol m Efficiency Synergistic Beneficial Clinical trial Hypericum-perforatum Warfarin k INR values Antagonistic Risk Case report Piper methysticm Levodopa Dopamine antagonistic Antagonistic Risk Case report m indicate an increase in activity and k indicate a decrease in activity. 10.5.3.2 Pharmacodynamic Interactions It involves the interaction of conventional drugs with herbs for the same targets such as enzymes or receptors leading to additive, synergistic, antagonistic effect. It has been considered that herbs contain thousands of compounds with diverse chemical nature and thereof, they have different affinities towards these primary or secondary therapeutic targets. The probability of possible interaction would be beneficial or unwanted. Several pharmacodynamic interaction studies have been reported in animal studies, clinical trials and many case reports have been published (Choi et al., 2016). We have listed a few in Table 10.2. 10.5.4 Food Drug Interactions An interaction between foods, nutritional substances, with the drug is mostly the consequence of the physical, chemical, or physiologic relationship between drug and the consumed substance as food. It is important to understand whether these food drug interactions produce desired effects or lead to detrimental effects on the body (Kane et al., 2017). For example, grapefruit juice was reported to interact with a number of drugs including amlodipine nifedipine, carbamazepine propafenone, atorvastatin etc. It was found that grapefruit inhibits the enzyme cytochrome P450 3A4 (CYP3A4) resulting in enhanced concentration of the nonmetabolized drugs in plasma (de Boer et al., 2015). Such DOSAGE FORM DESIGN CONSIDERATIONS 10.5 VARIOUS FACTORS AFFECTING DRUG DISPOSITION TABLE 10.3 353 Examples of Food Drug Interaction Which Improves the Absorption of Drugs Drug Mechanism Griseofulvin Lipid soluble drug when administered with high-fat diet leads to improved absorption Carbamazepine Increased bile production, enhanced dissolution, and further absorption Propranolol Food may reduce first-pass effect and supports absorption Spironolactone Food delays gastric emptying and further permits dissolution and absorption interactions produce one of two types of effects clinically; it either decreases the bioavailability of given drug which may lead to failure of treatment, or increases the bioavailability of drug which may lead to precipitate toxicities and increases the probability of adverse events (Kelley et al., 2017). A general structure of food drug interaction and possible effects is shown in Fig. 10.3. Examples of a few drug food interactions, where absorption of the drug will be increased when taken along with food/in the presence of food, are given in Table 10.3. Depending upon the mechanism through which interaction takes place they are classified as absorption interactions where food may alter the absorption of the drug in GI tract by altering gastric motility, by changing pH, this ultimately changes the rate and extent of absorption of both. For example, the absorption of azithromycin gets decreased in the presence of food; a 43% decrease in bioavailability was observed (Chavda et al., 2016). The presence of food may alter the hepatic metabolism of some drugs. For example, felodipine, when taken in the presence of grapefruit juice, has been found to have greater bioavailability. This may lead to unwanted effects like increased heart rate. Food may be responsible for alterations in urinary pH which further affects the half-life of drugs. Fish, meat, and cheese acidify the urine. Food may be also responsible for altering the pharmacological response of drugs and produce pharmacodynamic interactions. For example, food with high vitamin K content may produce antagonistic effects on warfarin, an anticoagulant drug (Food and Administration, 2016). 10.5.5 Polypharmacy According to World Health Organization (WHO), polypharmacy is the process of administration of many drugs at the same time or the administration of excessive drugs, which is mainly observed in elderly patients who suffer from chronic diseases with concomitant pathologies. Patients who get treated with polypharmacy regimen are more prone to adverse drug reactions or drug drug interactions (Naples and Hajjar, 2016). In the case of elderly patients, changes in the body composition take place, such as reduction in liver mass, reduced renal excretion, and many more, which might be responsible for alterations in pharmacokinetic or pharmacodynamics of administered drugs; aging decreases blood flow to gastrointestinal tract and reduces gastric motility, which will reduce the absorption and metabolism of many drugs (Hersh et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 354 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT 10.5.6 Genetic and Environmental Factors The study of specific genetic and environmental factors which produce interindividual variation affecting drug disposition has been coined as pharmacogenetics. The examples of various genetic and environmental factors include induction of metabolizing enzymes by phenobarbital administration (Nelson et al., 2016). Various chemicals such as DDT, polychlorinated hydrocarbons also induce the hepatic enzymatic activity. Another issue is that the diverse nature of a population shows heterogeneous influence on drug disposition concerning both these factors (Zgheib and Branch, 2017). 10.5.7 Drug Dose Frequency Drug dose frequency is called dosage regimen. Designing the correct dosage regimen is important for achieving the desired therapeutic efficacy and avoiding undesired effects. Because of significant homogeneity among humans, the dosage regimen is calculated on a population basis. Despite the same dose of drug, it produces variations in pharmacological response, which is generally attributed to intersubject variability (Ashford, 2017b). This intersubject variability leads to pharmacokinetic or pharmacodynamic variations for the same drug administered in the same frequency in different individuals (Ashford, 2017a). Various factors like metabolizing enzymes, interactions (drug drug, herb drug, food drug), multiple treatments, and dosage regimen affect the drug disposition. Enzymes regulate metabolism, interactions alter pharmacokinetic or pharmacodynamic parameters, genetic factors may produce individual variation, etc., hence resulting in drug disposition, and also transporters are involved in the disposition process. Proteins are the transporters in drug disposition. 10.6 TRANSPORTERS IN DRUG DISPOSITION The transport of drug molecules or endogenous molecules across the cell membrane is directed by a variety of protein molecules called drug transporters. These transporter protein molecules could be classified into two different categories: solute carrier (SLC) family members and ATP-binding cassette (ABC) family (Xia and Miwa, 2016). The basic function of these transporters is the mediation of the influx/bidirectional drive of drug molecules across the cell membrane. Many studies are available indicating the primary role of the drug transporter in the drug drug interactions, variable drug response, and drug toxicity (Xia et al., 2016). Drug molecules are transported by means of proteins known as transporters that play an important role in drug drug interaction, variations in dosing, and toxicity. Drug disposition studies can be performed on different experimental models. Some of them are further discussed in the next section. DOSAGE FORM DESIGN CONSIDERATIONS 10.7 EXPERIMENTAL MODELS FOR DRUG DISPOSITION INVESTIGATIONS DURING PRODUCT DEVELOPMENT 355 10.7 EXPERIMENTAL MODELS FOR DRUG DISPOSITION INVESTIGATIONS DURING PRODUCT DEVELOPMENT 10.7.1 In Vitro Metabolic Models 10.7.1.1 Expressed Enzymes The FDA drug disposition guidelines suggested that there is a need to conduct clinical studies for drug disposition if a drug product showed higher than 25% excretion from a particular pathway. The expressed enzyme system is specifically used for conducting reaction phenotyping in search of the potential drug candidate. The most common enzymatic system responsible for drug disposition belongs to the cytochrome family. There is a need to identify a particular isoform that leads to metabolic reaction (Wang et al., 2016). The expressed enzyme system is a very beneficial technique for quantitatively determining the specific type of CYP isoform-based metabolic reaction that is also known as CYP mapping (Ferl et al., 2016). Peters et al. noted that, while in most cases hepatic metabolism is performed by the primary drug-metabolizing CYPs, some other metabolizing enzymes also have considerable contribution in total metabolisms such as flavin-containing monooxygenases (FMO), UDP-glucuronosyltransferases (UGT), sulfotransferases (SULT), and aldehyde oxidases (AO) (Peters et al., 2016). This technology of enzymatic expression is also advantageous in evaluating mechanistic studies of a metabolic reaction. Li and coworkers have elucidated the time-dependent inhibition of the CYP2D6 enzyme by the metabolite generated by CYP3A4 (Vanhove et al., 2016). CYP families of enzymes are substrate specific that generate substrate specific metabolites. Therefore these expressed enzymes can be utilized further as bioreactors to generate that particular metabolite. A generated metabolite can be further utilized to test the pharmacological testing. This technology of expressed enzyme provides a superior platform and a better alternative than to use the hepatic microsomal system. The potential presence of additional metabolites adds difficulty to liquid chromatographic separation; however, the added expense of using expressed CYPs provides its own challenges (Wei et al., 2016). 10.7.1.2 Subcellular Fraction The subcellular fractions such as cytosol, S9, and microsomal fractions can also be utilized in the drug metabolism studies to address various questions. The cytosol, which is isolated as a supernatant from the S9 fraction, contains a group of soluble drug-metabolizing enzymes responsible for specific routes of drug metabolism. It is the simplest system of the three. The S9 fraction contains both cytosol and microsomes and represents a nearly complete collection of all drug metabolizing enzymes. However, the presence of so many enzymes can sometimes dilute the activities of the enzyme of interest. The microsomal fraction contains membrane-bound CYPs and primary conjugation (Mateus et al., 2017). The cytosol is often used to conduct mechanistic studies for identifying the soluble enzymes involved in particular metabolic pathways (Vrana et al., 2017). Additionally, cytosol assays are also used to assess metabolic studies. The S9, which contains both cytosol and microsomal enzymes, is the subcellular fraction prepared by collecting the supernatant after DOSAGE FORM DESIGN CONSIDERATIONS 356 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT centrifugation of tissue homogenate at 9000 g. The S9 fractions capture additional metabolisms mediated by nonCYP enzymes, such as sulfation and acetylation. Furthermore, S9 allows cost savings and is easier to handle when compared to primary hepatocyte incubations, which also provides a complete collection of enzymes. To predict in vivo clearance, the scale-up factor from S9 incubations is scarcely available in the literature (Argikar et al., 2016). 10.7.2 In Vitro Transporter Models 10.7.2.1 Immortalized Cell Lines Human colon cancer-derived Caco-2 cell lines are extensively used to study the permeability and efflux transport (via P-gp and BCRP). This is because these cell lines can go through enterocytic differentiation and form a polarized culture that resembles the human intestinal epithelium in transporter expression and tight junction formation. This assay procedure using Caco-2 cell lines is the most frequently employed method for identification of glycoprotein transport substrates and inhibitors in drug discovery among the various in vitro models (Larson et al., 2017). For pulmonary drug delivery, the mechanism of transportation of drug to the human lung is of vital importance. To understand the mechanism, Sakamoto et al. demonstrated drug transporter protein expression of five marketed immortalized lung cell lines isolated from tracheobronchial cells (Calu-3 and BEAS2-B), bronchiolar alveolar cells (NCI-H292 and NCI-H441), and alveolar type II cells (A549), employing liquid-chromatography tandem mass spectrometry-based techniques (Sakamoto et al., 2015). Authors revealed that among all the transporters tested, breast cancer-resistance protein in Calu-3, NCI-H292, NCI-H441, and A549 and OCTN2 in BEAS2-B displayed the maximum protein expression. In comparison with the earlier data published by the same group with data from our previous study (Sakamoto et al., 2013), NCI-H441 found similarity with primary lung cells from all regions in terms of protein expression of organic cation/carnitine transporter 1 (OCTN1). Finally, the protein expression data of transporters in five immortalized lung cell lines were determined, and these findings may contribute to a better understanding of drug transport in immortalized lung cell lines. In another study, Lee et al. tried to understand the transportation of 6-Mercaptopurine (6-MP) via blood placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs) (Lee et al., 2011). Nearly 51% of 6-MP was excreted from the cells within 32 minutes. The uptake of 6-MP was saturable with Michaelis Menten constant values of 197 µM and 251 µM in TR-TBT 18d-1 and TR-TBT 18d-2 cells, respectively (Fig. 10.5). These findings revealed that sodium-independent transporters, equilibration nucleoside transporter, may be involved in 6-MP uptake at the placenta. 10.7.2.2 Transfected Cell Lines CHO, MDCK, HEK293, and LLC-PK1 are commonly transfected to over-express a single transporter. For certain efflux transporters transfected in MDCK cells, coexpression of a corresponding uptake transporter is necessary. The transfection can be transient or permanent (Melikian et al., 2016). A stable transfection cell line is usually favored over transient transfection because the former produces more reproducible data. DOSAGE FORM DESIGN CONSIDERATIONS Saturable uptake clearance (V, pMoL/mg protein 5 min) 10.7 EXPERIMENTAL MODELS FOR DRUG DISPOSITION INVESTIGATIONS DURING PRODUCT DEVELOPMENT Uptake rate (V.pmoL/(mg protein 5 min) 900 FIGURE 10.5 Saturation kinetics of 6-MP uptake by TR-TBT 18d-1 cells (open, upper) and TRTBT 18d-2 cells (closed, lower). Uptake of [14 C]6-MP was measured in TRTBT cells with 5 minutes incubation in the presence of 0 500 : M unlabeled 6-MP at pH 7.4 and 37 C (bold line). The saturable component of 6-MP uptake (thin line) was corrected for nonsaturable uptake (dotted line) performed by the Michaelis Menten equation. The data (insert) are shown as an Eadie Hofstee plot of the saturable component. Adapted with permission from Lee, N.Y., Sai, Y., Nakashima, E., Ohtsuki, S., Kang, Y.S., 2011. 6-Mercaptopurine transport by equilibrative nucleoside transporters in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBTs. J. Pharm. Sci. 100 (9), 3773 3782. 5 4 3 2 1 100 200 300 400 500 600 0 Saturable uptake rate (V, pMoL/mg protein 5 min) 600 300 0 100 0 200 300 357 400 500 Saturable uptake clearance (V, pMoL/mg protein 5 min) 6 MP concentration (S, μm) Uptake rate (V.pmoL/(mg protein 5 min) 1200 900 4 3 2 1 0 100 200 300 400 Saturable uptake rate (V, pMoL/mg protein 5 min) 600 300 0 0 100 200 300 400 500 6 MP concentration (S, μm) 10.7.2.3 Hepatocytes The hepatic enzymes have a crucial role in drug disposition. Therefore, freshly isolated hepatocytes are regularly used to determine hepatic metabolism and clearance mediated by liver enzymes, as well as to assess hepatic uptake mediated by uptake transporters. In the laboratory, hepatocytic uptake can be quantitatively measured by the centrifugation method (Moreau et al., 2017). There have also been reports that cryopreserved hepatocytes can be used for studying hepatic uptake. Isolated hepatocytes cannot be directly used for efflux assay because the efflux transporters lose their function during the isolation process; however, primary cultures of hepatocytes can restore the function of efflux transporters even though the uptake transporters demonstrate decreased functionality in primary cultures (Stieger and Hagenbuch, 2016). 10.7.2.4 Membrane Vesicles Various organs such as liver, kidney, and intestine can be utilized to prepare the membrane vesicles. These membrane vesicles naturally express a high concentration of transporters. Various transfected cell lines that overexpress a single transporter have been used DOSAGE FORM DESIGN CONSIDERATIONS 358 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT to assess the transporter mechanisms in liver, kidney, and intestine. A technical benefit of using membrane vesicles is that it allows separate preparations of the blood and luminal side of cell membranes to fit the research needs (Pedersen et al., 2017). 10.7.3 In Situ Ex Vivo Models 10.7.3.1 In Situ Models (Perfusion) The organ perfusion model most closely mimics in vivo drug absorption, transport, metabolism, and excretion. Liver perfusion model is among the widely employed model for perfusion investigation. This is because of its ability to maintain the liver anatomy and architecture. It is also able to preserve all the mediators and cell-populations, as well as hepatocytes (the Kupffer cells are an important cellular structure for maintaining proinflammatory cytokines), and retains hepatocyte cellular interaction and zonal differentiation (Peters et al., 2016). As the final checkpoint, the perfusate, bile, and liver tissue itself can all be characterized for the parent composite and its metabolic products. This, in turn, gives riseto information on the degree of the liver first-pass effect, the effect of protein binding, parent uptake from the perfusate, metabolism, parent and metabolites elimination via canalicular transporters. Also, it determines the ability to produce toxic effects from reactive metabolites and eventually also plays a role in determining toxicological/pharmacological investigations. The liver perfusion technique has been validated for the investigational set-up, and the composites of the perfusates normally depend on the objective of the experiment. Liver perfusion can be conducted in situ or in an investigation where the liver is isolated (Lozoya-Agullo et al., 2016). This type of model usually demands minimum organ preparation, and thus, the reduced risk of damage to the organ. Although, isolated liver preparation solves the liver-specific mechanistic problems with no interference from other organs, this makes the model a more significant model. Harvard Apparatus is an example of an isolated liver perfusate system available in the market for ready use. While employing the liver perfusion method, the kind of perfusion system used serious consideration. The employed perfusion system consists of different amounts of the matrix (including albumin and red blood cell (RBC)), which can influence the extent of protein binding of the investigational substance and their fat (Bosquillon et al., 2017). It is always beneficial to collect whole heparinized blood from the same species employed in the test. Although, it is difficult every time to collect whole heparinized blood from the same species due to availability constraints. Also, the clotting problem makes the issue even more difficult. Many times, bovine blood, bovine serum albumin, and bovine or human erythrocytes are employed as substitutes to mimic in vivo conditions, as they deliver hemoglobin as the oxygen carrier and idyllic protein binding conditions (Lozoya-Agullo et al., 2017). 10.7.3.2 Ex Vivo Models for Induction and Toxicity Studies Ex vivo investigations denote studies where a drug is administered to an animal model followed by organ tissues removal, for example, making liver into microsomes, and employed for studying modifications in the expression level of enzymes or transporters (or any biomarkers) upon drug dosing (Gintant and Braam, 2017). Generally, mRNA levels are determined DOSAGE FORM DESIGN CONSIDERATIONS 10.8 EFFECT OF DISEASE STATE ON DRUG DISPOSITION 359 to designate the alterations in expression levels. This info can then be connected back to the toxicology or pathophysiology outcomes in the animal in-life investigations. Conduction of ex vivo experiments simultaneously with toxicokinetics investigations where drugs are administered at higher doses (near about maximal tolerable dose) (Maidana et al., 2016). This is followed by the collection of pharmacokinetic data and then linking them with the toxicokinetics, pharmacodynamics, or toxicity findings. Commonly, at the endpoint of the subchronic or chronic administration, organs are collected. The organ that is exposed to high drug concentrations is the liver, as suggested by many investigations. The enzyme expression alters may, in turn, elucidate alterations in pharmacokinetics or may be attached to toxicity outcomes. Among several observations, including modification of enzyme expression, pharmacokinetic, and toxicology, a few are well connected to each other, whereas others may display extended responses. PK/PD modeling permits further assessment via dissection of the response relationships (Maidana et al., 2016). Different experimental models have significance in being used for the drug disposition investigations as metabolic models consist of enzymes and subcellular fractions responsible for drug disposition and metabolism, respectively. The transporter model is the most commonly used method and produces reproducible data. The organ perfusion model maintains liver anatomy, etc. as various enzymes, interactions, and other factors play a vital role in drug disposition. Disease state also has an effect on drug disposition. The effect of cardiovascular, gastrointestinal, liver, and kidney diseases are therefore discussed below. 10.8 EFFECT OF DISEASE STATE ON DRUG DISPOSITION Drug responses are affected by disease states because of changes in both pharmacokinetics and pharmacodynamics. This is especially apparent with diseases that affect the processes of drug disposition and pharmacokinetics—absorption, protein binding, metabolism, and excretion (Yeung et al., 2014). Diseases rarely occur in isolation, and categorization of patients as being in one particular disease group is simplistic in approach. For example, liver disease can lead to compensation by renal activity, and vice versa or both can be impaired in parallel. Experimental difficulties arise with studies of one excretory organ when another one is involved as a complicating factor but not studied. It may be difficult to analyze for single factors (Sahajwalla, 2016). Subdivision of liver disease is a case in point. In many of the early studies it was rare to find a study restricted to one of (1) acute viral hepatitis; (2) cirrhosis; (3) drug-induced hepatic disease; or (4) other problems. Diseases commonly occur at particular stages in life, and therefore it can be difficult to separate the effects of disease on pharmacokinetic properties of drugs from such factors as age (Nigam, 2015). Patients in disease groups are commonly treated with drugs that affect each other, such as enzyme-inducing agents, as well as several drugs at any one time. For example, patients with liver disease are likely to have been treated with a large number of drugs including sedative drugs that complicate the objective assessment of any central nervous system (CNS) impairment caused by the disease. Measurements can be more difficult to make in patients compared with healthy controls because of the complexity of the scientific DOSAGE FORM DESIGN CONSIDERATIONS 360 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT problem involved and the extent to which intervention in the life of a patient is possible (Alomar, 2014). Longitudinal studies are needed, using the predisease subject as his or her control. Also, studies are often at different stages of what is sometimes referred to as “decompensation,” and this has not, in the past, been adequately recorded in the literature. Studies with diseased patients can raise ethical questions that do not apply to control subjects. Some drugs are designed to utilize healthy organs to relieve influences on diseased organs, for example, the use of diuretics to reduce the fluid load on the heart, while others are designed to reverse pathology at its site, for example, the use of oral hypoglycemic drugs to modify insulin utilization (Budha et al., 2012). 10.8.1 Effect of Cardiovascular Diseases In congestive heart failure (CHF) the cardiac output (the volume of blood pumped per minute) is reduced so that insufficient quantities of oxygen and nutrients are delivered to the tissues for their normal functioning. Associated with CHF are atrial fibrillation and flutter, which are disorders of the electrical discharge patterns of the heart, causing relatively fast atrial contraction, and also causing the ventricles to contract more rapidly and less efficiently than normal. There are obviously many other disorders of the heart that affect patient health—for pharmacokinetic purposes the primary need is to focus on reduced perfusion of the organs that are involved in the pharmacokinetic processes of absorption, tissue distribution, metabolism, and excretion, caused by the reduced cardiac output (Jochmann et al., 2005). 10.8.2 Effect of Gastrointestinal Diseases It is to be expected that gastrointestinal pathology will affect drug response by changing drug absorption. However, the pattern for any condition is complex. For example, changes in pH do not necessarily affect absorption because of the relation between pH, site of absorption, gastric emptying (Stieger et al., 2017). The conditions of inflammatory bowel are known as Crohn’s disease and ulcerative colitis. Their causes are basically unknown. They are characterized by abdominal cramps and diarrhea. Crohn’s disease affects the full thickness of the intestinal wall, most commonly occurring in the lower part of the small intestine, and in the large intestine (Keil et al., 2016). In contrast, ulcerative colitis affects only the large intestine and does not affect the full thickness of the bowel wall. Crohn’s disease is especially common in young people and is associated with inflammatory conditions of organs other than the gastrointestinal tract, such as the eyes and joints. Inflammatory diseases have the potential to change the surface area available for absorption, the thickness of the intestinal wall, and therefore the distance over which diffusion takes place, intestinal pH, mucosal enzymes that metabolize drugs, intestinal microflora, gastric emptying and peristalsis, and transporters that control inward and outward movement of nutrients and drugs. It is not surprising therefore that a variety of different observations has been made with various drugs in these conditions (Paintaud et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 10.8 EFFECT OF DISEASE STATE ON DRUG DISPOSITION 361 For example, in Crohn’s disease, the absorption of clindamycin and propranolol has been shown to be increased in extent, while that of many other drugs is decreased. The production of a1-acid glycoprotein (AAG) is increased. The expression of CYP3A4 and P-gp levels were significantly higher in biopsy samples from a group of children with Crohn’s disease compared with controls. These differences could account for decreased bioavailabilities. An in vivo study with radiolabeled prednisolone in adults showed reduced bioavailability in Crohn’s patients (by urinary excretion and AUC measurements). Fecal excretion was greater in Crohn’s patients (Wilson et al., 2017). In the case of paracetamol (acetaminophen), the mean rate constant of absorption was not reduced in Crohn’s disease, the conclusion being that any pharmacokinetic differences that occurred were related to slower gastric emptying. Similarly, absorption of trimethoprim, methyldopa, and lincomycin has been shown to be reduced while that of sulfamethoxazole was increased (Fung et al., 2016). Enhanced absorption of macromolecules has been observed in Crohn’s disease (e.g., horseradish peroxidase) using biopsy samples and in vitro methods of study. Thus it can be anticipated that a drug dependent on passive diffusion is likely to be relatively slowly absorbed in these patients, while a drug heavily affected by mucosal CYP3A4 or P-gp might show highly variable absorption. 10.8.3 Effect of Liver Diseases Liver disease can affect liver blood flow, creating the potential for effects on drugs with high extraction ratios such as propranolol and lidocaine, or hepatic intrinsic clearance, creating the potential for effects on drugs such as metoprolol, and (as the binding proteins are synthesized in the liver) on plasma protein binding, creating the potential for effects on warfarin and naproxen. Cirrhosis is a condition in which the normal liver tissue gets destructed and replaced by nonfunctioning wounded tissues. Many conditions can lead to cirrhosis, including alcoholic liver damage and chronic hepatitis (Daly, 2017). Interestingly, in cirrhosis, phenytoin and warfarin (which has its action in the liver) show inconsistent changes. Regarding drug-induced hepatic disease, there is a significant reduction in the rate of metabolism of paracetamol, phenytoin, and phenobarbital following paracetamol damage. In regard to other problems, azotemia has been shown to be associated with reduced thiopental binding. Thiopental anesthesia is prolonged in patients with hypoalbuminemia caused by the chronic liver disease. It is of special interest that bioavailability of many drug products increased in the condition of liver cirrhosis. Examples range from verapamil, with a 1.6-fold increase, to chlormethiazole, with an 11.6-fold increase, and include pethidine, morphine, nifedipine, midazolam, and most of the bblocking drugs. It seems likely that this results from portocaval shunting and reduced exposure to CYP3A4 (Clarke et al., 2017). 10.8.4 Effect of Kidney Diseases Kidney failure can be acute, with a rapid decline in function but equally rapid recovery if the pathology is reversed, or chronic with slow progression and little chance of recovery. In either case, there is an accumulation of metabolic waste products in the blood (azotemia DOSAGE FORM DESIGN CONSIDERATIONS 362 10. DRUG DISPOSITION CONSIDERATIONS IN PHARMACEUTICAL PRODUCT or uremia) especially urea and creatinine, plus the potential for anemia, acidosis, decreases in blood calcium and vitamin D, and increases in blood phosphate, parathyroid hormone, and potassium. The claim that kidney disease reduces the rate of elimination of drugs cannot be challenged (Tieu et al., 2016). However, it should be realized that drugs may be excreted unchanged to any extent, varying from 0% to 100%. Clearly, a drug that is 100% dependent on the kidney for its removal from the body might be greatly affected by kidney disease. In contrast, a drug that is not excreted unmetabolized is less likely to be affected. However, the excretion of the metabolites of this type of drug, as opposed to the excretion of the unchanged drug, will almost certainly be affected. The metabolites will accumulate in plasma, leading to an exaggerated response if the metabolites contribute to the pharmacological effect or, possible toxicity, that is not seen when the metabolites are normally excreted (Wu et al., 2017). If the presence of large quantities of metabolites reduces the rate of metabolism of the unchanged drug, by metabolite inhibition, then there is the theoretical possibility of accumulation of unmetabolized drug. Additionally, renal impairment is likely to lead to varying degrees of water loading, and this may lead to modification of the concentrations of the drug in the fluid compartments of the body, including plasma (Scotcher et al., 2017). Disease state may greatly affect the drug disposition by changing the pharmacokinetics and pharmacodynamics. Disease state occurring at a particular age make it hard to separate the effect of disease on PK and PD. 10.9 CONCLUSION Drug disposition represents a complex interplay between processes involved in pharmacokinetics. There is now an increasing appreciation of drug transporters expressed in organs such as the liver, kidney, intestine, and brain. These drug transporters are significant factors responsible for drug drug interactions, drug-induced organ toxicities, and diseases. This chapter has described some of the more prevalent experimental models used in drug metabolism and disposition. Most modern drugs are discovered and developed with the timely applications of the appropriate experimental models. Certainly, there will be additional, newer, and bettermodified models developed in the future to support an efficient drug discovery and development process. Drug discovery and development remain as complicated models-based experimental scientific exploration. Gastrointestinal disorders can modify both the rate and extent of absorption, with increases or decreases dependent on the interplay of pH, gastric motility, surface area available for absorption, and other pathological changes, and on the chemical and biochemical properties of the particular drug, permitting a logical prediction of the effect on the basis of general principles. CHF leads to changes in drug absorption, hepatic and renal blood flow, intrinsic hepatic clearance, and systemic elimination, mostly reductions in rate, and the effect on any particular drug will depend on which processes are predominant. It is not easy to separate the effects of edema from those of the disease. Hepatic disorders DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 363 reduce blood flow, intrinsic hepatic clearance, and plasma protein binding, but the consequences of these effects are modified in many cases by late onset, for multiple reasons including compensatory enzyme induction. Clearance calculations provide useful approaches to quantifying these effects. The significance for any particular drug will depend on the interplay and predominance of the various factors in its disposition. Centrally acting drugs show enhanced pharmacodynamic effects. Renal disease can cause reduced glomerular filtration and modified renal tubular transport. These changes mainly affect drugs dependent on urinary excretion of the unmetabolized drug, and this can be especially important in the dosing of digoxin, with its narrow margin of safety, and a whole range of antibiotics. Clearance calculations facilitate safe dosing of these drugs. There is a considerable incidence of concomitant occurrence of hepatic disease in renal disease patients. With exceptions, hyperthyroidism leads to enhanced rates of the drug disposition processes and hypothyroidism to the opposite. It has now become increasingly apparent that carriermediated processes, or transporters, also play critical roles in the overall disposition of numerous drugs in clinical use. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology (DST), Government of India for grant (#ECR/2016/001964) allocated to Dr. Tekade for research work on drug and gene delivery. The author also acknowledges DST-SERB for N-PDF funding (PDF/2016/003329) to Dr. Rahul Maheshwari in Dr. Tekade’s laboratory for work on targeted cancer therapy. 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Kidney Int. 85 (3), 522. Zgheib, N.K., Branch, R.A., 2017. Drug metabolism and liver disease: a drug gene environment interaction. Drug Metab. Rev. 49 (1), 35 55. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 11 Protein and Tissue Binding: Implication on Pharmacokinetic Parameters Pran Kishore Deb1, Omar Al-Attraqchi1, Mailavaram Raghu Prasad2 and Rakesh K. Tekade3 1 Faculty of Pharmacy, Philadelphia University, Amman, Jordan 2Pharmaceutical Chemistry Division, Sri Vishnu College of Pharmacy, Bhimavaram, Andhra Pradesh, India 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 11.1 Introduction 372 11.2 Binding Kinetics 11.2.1 Graphical Plots Used to Determine Binding Constants 372 11.3 Overview of Plasma Proteins 11.3.1 Albumin 11.3.2 Alpha-1-Acid Glycoprotein 11.3.3 Lipoproteins 376 377 379 380 11.4 Tissue Binding 381 375 11.5 Plasma and Tissue Protein Binding Implications on Pharmacokinetics Parameters 382 Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00011-3 11.5.1 11.5.2 11.5.3 11.5.4 11.5.5 11.5.6 Bioavailability Volume of Distribution Hepatic Clearance Renal Clearance Half-Life Drug Plasma Concentration-Time Profile 382 383 384 385 386 386 11.6 Factors Influencing Protein Binding 387 11.6.1 Physiologic Factors Influencing Protein Binding 387 11.6.2 Pathologic Factors Influencing Protein Binding 388 371 © 2018 Elsevier Inc. All rights reserved. 372 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS 11.6.3 Drug-Induced Changes in Protein Binding 11.7.6 In Silico Methods 388 11.7 Plasma Protein Binding Determination Methods 389 11.7.1 Equilibrium Dialysis Method 390 11.7.2 Ultrafiltration Method 391 11.7.3 Ultracentrifugation Method 392 11.7.4 Important Considerations When Using In Vitro Methods 393 11.7.5 In Vivo Methods 394 394 11.8 Conclusion 395 Acknowledgment 395 Abbreviations 396 References 396 Further Reading 399 11.1 INTRODUCTION Plasma and tissue protein binding of drugs is a major factor that affects both pharmacokinetics and pharmacodynamics of the drug. It is usually the free (unbound) form of the drug that can exert pharmacological activity, while the bound form of the drug is usually pharmacologically inactive (Ascenzi et al., 2014). Many drugs can bind to plasma proteins to form a drug protein complex, the binding is usually reversible, and the unbound (free) form of the drug exists in equilibrium with the bound form (Li et al., 2015). Drugs bind mainly with plasma proteins such as albumin, alpha-1-acid glycoprotein, lipoproteins, and other biological moieties, e.g., red blood cells (RBCs) (Pellegatti et al., 2011). The reversible binding of drugs to proteins has a significant impact on many pharmacokinetic parameters such as volume of distribution and clearance of the drug (Berezhkovskiy, 2010). Since the drug protein complex has a large size, this will limit its ability to leave the vascular space and enter into cells thus restricting its distribution, while the unbound (free) drug can readily diffuse into cells. Also, the drug protein complex is usually too large to be filtered by the glomeruli, and only the unbound drug can be filtered and excreted by the kidney. Thus, plasma protein binding also affects clearance of the drug by the kidney, and sometimes if the drug has a higher affinity for the plasma proteins than the liver enzymes, the drug will not be available for metabolism and clearance by the liver. Hence, only the unbound drug will be metabolized (Han et al., 2010). 11.2 BINDING KINETICS The reversible binding of drugs to proteins is governed by the law of mass-action according to Eq. (11.1): k1 ½D 1 ½P " ½DP k2 (11.1) where [D] is the unbound (free) drug concentration, [P] is the unoccupied protein binding concentration and [DP] is the drug protein complex concentration, and k1 and k2 are the association and dissociation constants of the drug protein complex, respectively. The DOSAGE FORM DESIGN CONSIDERATIONS 11.2 BINDING KINETICS 373 equilibrium between the unbound [D] and bound [DP] drug forms is established rapidly (usually in milliseconds), and at equilibrium, the association constant Ka is used to describe the affinity of the drug for the protein to which it binds according to Eq. (11.2). Ka 5 k1 ½DP 5 ½D 3 ½P k2 (11.2) The association constant Ka describes the affinity by which a drug binds to a protein to form a drug protein complex, the higher the association constant Ka value, the stronger the binding of a drug to the protein and more the drug protein complex forms and vice versa. However, in practice, it is usually the dissociation constant Kd that is more commonly used, as shown in Eq. (11.3) (Musteata, 2012). Kd 5 1 Ka (11.3) It is important to remember that the dissociation constant Kd is the inverse of the association constant Ka. The lower the dissociation constant Kd value, the stronger the binding of a drug to the protein and the more the drug protein complex forms and vice versa (note that in this aspect Kd is similar to the Michaelis Menten constant km, which describes the affinity of binding of a ligand to an enzyme). Two common ways are used to express the plasma protein binding of drugs. The first is to describe it as the unbound fraction in plasma (fup), which is the ratio of the unbound drug concentration [D] and the total drug concentration in the system [D] 1 [DP], as shown in Eq. (11.4). The second way is to express it as a percentage of the bound drug concentration [DP] to the total drug concentration [D] 1 [DP] in the system, as shown in Eq. (11.5). fup 5 ½D Cfree 5 ½D 1 ½DP Ctotal %PPB 5 Cbound 3 100 Ctotal (11.4) (11.5) The total protein concentration [Pt] is the sum of the unbound protein concentration [P] and the bound protein concentration [PD], as shown in Eq. (11.6). ½Pt 5 ½P 1 ½PD (11.6) By rearranging Eq. (11.6) and substituting into Eq. (11.2) we get Eq. (11.7): ½PD Ka ½D 5 ½Pt 1 1 Ka ½D (11.7) The ratio [PD]/[Pt] which is the moles of drug bound per moles of total protein is designated as r, and Eq. (11.7) can be written in the form of Eq. (11.8). r5 Ka ½D 1 1 Ka ½D DOSAGE FORM DESIGN CONSIDERATIONS (11.8) 374 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS Since the dissociation constant (Kd) is used more often than the association constant (Ka), and Kd is 1/Ka, then Eq. (11.8) can be written as Eq. (11.9): r5 ½D Kd 1 ½D (11.9) Eq. (11.9) assumes that the drug binds only to one independent binding site in the binding protein (i.e., one mole of the drug binds to one mole of the binding protein). In cases when there are more than one independent binding site for the drug in the binding protein, then Eq. (11.10) can be used. r5 n½D Kd 1 ½D (11.10) In Eq. (11.10), n represents the number of identical binding sites available for the drug in the binding protein. If the protein contains more than one type of binding sites (i.e., not identical binding sites) or if the drug binds to more than one protein in a given system, then Eq. (11.11) is used. r5 n1 K1 ½D n2 K2 ½D 1 1 1 K1 ½D 1 1 K2 ½D (11.11) In Eq. (11.11), the numbers associated with n and K represents the different types of binding sites which the drug binds to where n represents the number of binding sites per mole of protein and the K accounts for the binding constant associated with each type of different binding site. It should be noted that these equations assume that the drug binds independently to the different binding sites and the binding of drug molecules to a binding site does not alter the affinity of other binding sites to the drug molecules. However, some drugs may show cooperativity phenomena while binding to proteins. When binding of a drug molecule to one binding site on a binding protein affects the subsequent binding affinities of drug molecules to other binding sites, this is known as the cooperativity phenomena. An example of the cooperativity is the binding of oxygen molecules (O2) to hemoglobin, in which the binding of the first O2 molecule to the first binding site in hemoglobin increases the affinity of binding for the second O2 molecule to the second binding site in hemoglobin, and in turn, the binding of the second O2 molecule enhances the affinity of binding of the third O2 molecule to hemoglobin (Sinko, 2011; Shargel and Andrew, 2015). Binding of drugs to plasma proteins is usually linear (concentration-independent) when the molar concentration of the unbound drug is lower than the dissociation constant (Kd), which means that [D] and PPB% will be constant and independent of changes in drug concentration. At higher concentration of the drug or when the binding affinity for the protein is high (low Kd), the drug will display nonlinear (concentration-dependent) protein. As the drug reaches its site of action, it will interact with its target (which could be a receptor, enzyme, etc.) which would result in a pharmacological effect. Binding is usually reversible and can be written as shown in Eq. 11.12: k3 ½D 1 ½T " ½DT k4 DOSAGE FORM DESIGN CONSIDERATIONS (11.12) 375 11.2 BINDING KINETICS where [D] is the unbound (free) drug concentration, [T] is the target protein for the drug and [DT] is the drug target protein complex concentration. k3 and k4 are the association and dissociation constants of the drug target protein complex, respectively. Since the drug at the site of action may show a binding affinity for other proteins, which would result in a decrease in the pharmacological effect of the drug since these other proteins compete with the target protein for the free drug concentration. But in cases where the drug has a much higher binding affinity for its target than the other proteins (i.e., K3 * [T] is much larger than K4 * [P]), then the drug will bind preferentially to its target than to the other proteins (Schmidt et al., 2010). 11.2.1 Graphical Plots Used to Determine Binding Constants Several graphical methods can be used to determine binding constants between the drug and protein. A direct plot can be constructed if the receptor concentration is known, by plotting r which is the moles of drug bound to the total protein concentration against the free drug concentration [D], which gives a hyperbolic curve as shown in Fig. 11.1 which is a graphical representation of Eq. 11.10. By taking the reciprocal of Eq. 11.8, it is possible to obtain the number of binding sites and the dissociation constant with good precision. Eq. 11.13 is the reciprocal of Eq. 11.8, and by plotting a graph of 1/r versus 1/[D], a straight line is obtained as shown in Fig. 11.2, this graph is called a double reciprocal plot. The number of binding sites can be obtained from the y-intercept which is 1/n, and nKa value can be obtained from the slope of the curve which is 1/nKa. In cases where the graph obtained by plotting 1/r versus 1/[D] does not give a straight line, then this can be a result of the presence of more than one independent binding site (each with its own association constant Ka) (Shargel and Andrew, 2015). 1 1 1 5 1 r nKa ½D n (11.13) Another commonly used graphical method is the Scatchard plot. By rearranging Eq. (11.8), Eq. (11.14) is obtained, and by plotting, r/[D] (or [DP]/[D]) versus r gives a straight line as shown in Fig. 11.3. The association constant Ka can be obtained from the slope which is 2Ka and number of binding sites n is obtained from the y-intercept. FIGURE 11.1 General graphical representation of direct plot. DOSAGE FORM DESIGN CONSIDERATIONS a 376 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS FIGURE 11.2 General graphical representation of a double reciprocal plot. FIGURE 11.3 General graphical representation of a Scatchard plot. The Scatchard plot gives a straight line if there is one type of binding site and no cooperativity, while a curvature in the curve is observed if there is more than one type of binding site (Zhivkova, 2015). r 5 nKa 2 rKa ½D (11.14) 11.3 OVERVIEW OF PLASMA PROTEINS The human plasma contains many different proteins that are responsible for various functions such as transport of endogenous biomolecules, immunity, blood coagulation, etc. However, some of these plasma proteins are capable of binding to drug molecules, and the binding is usually reversible by noncovalent interactions such as electrostatic interactions and hydrophobic interactions. Although the plasma is known to have more than 60 different proteins, only a few of them are considered important in the drug binding phenomena (Putnam, 2012). The human serum albumin which constitutes about half of the total plasma proteins is of particular importance in drug binding; in addition to albumin, alpha-1-acid glycoprotein and lipoproteins also have a specific significance in drug binding in plasma. Acidic drugs bind to albumin while basic and neutral drugs bind to alpha-1-acid glycoprotein (although there are exceptions). The characteristics of these three-major drug-binding DOSAGE FORM DESIGN CONSIDERATIONS 377 11.3 OVERVIEW OF PLASMA PROTEINS TABLE 11.1 The Characteristics of Three Major Drug-Binding Proteins Protein Molecular Weight (g/mol) Plasma Concentration (g/dL) Half-life (t1/2, days) Albumin 66,700 3.5 5 19 Alpha-1-acid glycoprotein 42,000 0.04 0.1 5 Lipoproteins 200,000 240,000 5 Up to 6 FIGURE 11.4 3D structure of albumin with the major drugs binding sites I and II. proteins are summarized in Table 11.1. It should be noted that other plasma proteins such as transthyretin and antibodies can also participate in drug binding, but usually, they have affinities for specific drugs only (Howard et al., 2010; Han et al., 2010). 11.3.1 Albumin Human serum albumin is the major component of plasma proteins that is synthesized by the liver and has many essential functions, for instance, it acts as a transporter protein for various endogenous molecules and metals such as fatty acids, bilirubin, and calcium ions. Also, it plays a significant role in the maintenance and regulation of plasma colloidal pressure (Fanali et al., 2012). Human serum albumin can also be used as a biomarker for the diagnosis of various diseases. Structurally, albumin is a single polypeptide chain composed of 585 amino acids with a molecular weight of 66.7 kDa, usually nonglycosylated. The 3D structure of albumin has been determined using X-ray crystallography which can be seen as a globular heart-shape and the structure consists of three homologous domains (designated as domain I, II, and III); each of these three domains contains two subdomains (designated as A and B) as shown in Fig. 11.4. The structural organization of albumin is responsible for its high ability to bind a wide range of molecules, and it can bind nine equivalents of fatty acids. There are mainly two major binding sites in albumin that bind to drugs with high affinity (in addition to the presence of other binding sites that bind drugs with low affinity), these sites are named DOSAGE FORM DESIGN CONSIDERATIONS 378 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS site I (also called warfarin binding site) and site II (also known as benzodiazepam binding site). Another binding site that is not entirely elucidated is site III, which can specifically bind to digoxin. Human serum albumin has been shown to bind mainly acidic and neutral drugs, but it may also bind basic drugs such as diazepam. Table 11.2 shows some TABLE 11.2 Important Drugs that Bind Albumin with Their, Binding Site, Binding Constant, and Chemical Structure Respectively Drug Binding Site Association Constant (M21) Warfarin Site I 3.4 3 105 Structure O CH3 OH O Indomethacin Site I O 1.4 3 106 Cl O N H3C CH3 O O OH Phenylbutazone Site I 1.5 3 106 O N N O Tolbutamide Site I 4.0 3 104 O CH3 O O S N N H H CH3 H3C Diazepam Site II 1.3 3 106 H3 C N N Cl Ibuprofen Site II O 3.5 3 106 CH3 OH CH3 H3C DOSAGE FORM DESIGN CONSIDERATIONS O 11.3 OVERVIEW OF PLASMA PROTEINS 379 important drugs that bind albumin binding sites along with their respective binding constants (Yamasaki et al., 2013; Anguizola et al., 2013). Nowadays albumin is also utilized as a polymer to formulate nanobased drug delivery system (Tekade et al., 2015). An important factor to consider regarding the binding process of drug molecules to albumin and other plasma protein, in general, is the stereoselective binding of chiral drugs (Shen et al., 2013). Since albumin and other plasma protein are the chiral molecules, they can have different binding affinities to chiral drug molecules (Li and Hage, 2017). For example, during the study of albumin binding to the (S)- and (R)-enantiomers of the drug amlodipine, it was found that albumin binds the (S)-enantiomer of amlodipine with higher extent than binding with the (R)-enantiomer of amlodipine (Maddi et al., 2010). Finally, the ability of albumin to bind different drugs can be utilized to extend the drug’s half-life by adjusting its binding to albumin. Extension of a drug’s half-life can be beneficial for various purposes such as enhancing the patient compliance (Sleep et al., 2013). 11.3.2 Alpha-1-Acid Glycoprotein The alpha-1-acid glycoprotein is considered to be another major plasma protein that can bind many drugs, in spite of the fact that it has the lower concentration than albumin. An alpha-1-acid glycoprotein is a glycoprotein that is composed of a single polypeptide chain that is 183 amino acids length, with a molecular weight of about 41 kDa; the alpha-1-acid glycoprotein is extensively glycosylated with B45% of its components being carbohydrates. This high degree of glycosylation gives the alpha-1-glycoprotein a net negative charge at pH B7 and a high degree of water solubility. The 3D structure of alpha-1-acid glycoprotein is shown in Fig. 11.5. An alpha-1-acid glycoprotein is an acute phase protein, which means its concentration increases in response to conditions such as inflammation, infection, and injuries (Tesseromatis et al., 2011; Huang and Ung, 2013). The functions of alpha-1-acid glycoprotein are not completely well-understood. Although it has been shown that it acts as immunomodulation agent, it also acts as platelets aggregation inhibitor. Clinically, it can be used as a biomarker for some diseases (Bachtiar et al., 2010; Ren et al., 2010). Alpha-1-acid glycoprotein polymorphism can play a significant role in drug binding to alpha-1-acid glycoprotein which accounts for individual variations in drug binding level. Alpha-1-acid glycoprotein binds neutral and basic drugs, FIGURE 11.5 The 3D structure of alpha-1-acid glycoprotein. DOSAGE FORM DESIGN CONSIDERATIONS 380 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS examples of such drugs include diazepam, disopyramide, and chlorpromazine. Although alpha-1-acid glycoprotein binds mainly to basic and neutral drugs, studies have shown that it is capable of binding acidic drugs as well in some cases (Ascenzi et al., 2014). 11.3.3 Lipoproteins Since lipids are relatively insoluble in the aqueous media of plasma, they are usually transported in association with proteins in complexes called lipoproteins. Lipoproteins consist of both hydrophilic and hydrophobic portions. The hydrophilic portion typically consists of apoproteins and the hydrophilic part of phospholipids and cholesterol points outwards, interacting with the surrounding aqueous media. The hydrophobic portion consists of triglycerides and cholesteryl esters and is buried away from the aqueous media. Thus, lipoproteins act as soluble transporters of lipids in the circulation, and they also play an important role in lipid metabolism (Bishop et al., 2010, Voet and Voet, 2011). The general structure of lipoproteins is shown in Fig. 11.6. Based on their density, lipoproteins can be classified into four groups, namely chylomicrons, very low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Table 11.3 shows the general characteristics of lipoprotein classes (Voet, and Voet, 2011). As expected, lipoproteins bind mainly lipophilic substances. Drugs that bind to lipoproteins can sometimes show selective binding only to specific classes of lipoproteins, such as amphotericin B which binds only to LDL and eritoran which binds to HDL. Other drugs such as halofantrine can bind both HDL and LDL, while some drugs such as amiodarone can bind to all classes of lipoproteins (Ascenzi et al., 2014). Because of the characteristics of lipoproteins such as their biocompatibility, circulation half-life, particle size, and the ability to incorporate hydrophobic substances into them, they can be utilized as drug FIGURE 11.6 The general structure of lipoproteins. DOSAGE FORM DESIGN CONSIDERATIONS 381 11.4 TISSUE BINDING TABLE 11.3 General Characteristics of the Lipoprotein Classes Characteristics Features High-Density Lipoproteins Low-Density Lipoproteins Very Low-Density Lipoproteins Chylomicrons Density (g/cm) 1.063 1.210 1.019 1.063 ,1.006 ,0.95 Molecular weight (kDa) 175 360 2300 10,000 80,000 400,000 Diameter (A) 50 120 180 250 300 800 750 12,000 delivery systems. It is also possible to attach a tethering molecule to the protein portion of the lipoprotein which can lead the molecule to specific cells (e.g., cancer cells) to selectively target such type of cells (Huang et al., 2015; Thaxton et al., 2016; Jia et al., 2012). 11.4 TISSUE BINDING The tissue binding of drugs is as important as the plasma proteins binding and has a significant impact on the pharmacokinetics and pharmacodynamics of the drug as it affects both the distribution and elimination processes of the drug in addition to affecting the pharmacological effect of the drug. Generally, the greater the free fraction of the drug, the higher the rate of elimination, while extensive tissue binding will result in a lower elimination rate and a high volume of distribution. The pharmacodynamics of the drug is affected because only the unbound fraction of the drug can distribute to its target site and interact with its target to give a pharmacological effect. Following drug distribution phase, equilibrium will be established between the drug concentration in the plasma and the concentration in tissues. The ratio of tissues concentration to plasma concentration will be equivalent to the unbound (free) fraction of the drug in plasma (fup) to the unbound (free) fraction of the drug in tissue (fut) ratio (Shargel and Andrew, 2015). Tissue binding of drugs is different according to the type of tissue because drugs usually have different affinities for different kinds of tissues. And sometimes, binding of a drug in a particular organ is not homogenous, i.e., the drug concentration in a specific site in an organ is greater than the concentration in another site in the same organ. The liver is the organ with which most of the drugs show highest binding affinities regarding tissues binding, other organs with which drugs are found to bind to a lesser extent are the kidney and the lungs. There are many different components of tissues with which a drug may interact including macromolecules of the cell such as proteins, e.g., tubulin, actin, and myosin. Measurement of tissue binding of drugs is more difficult than the measurement of plasma protein binding, because of the difficulty of measuring drug unbound and bound concentrations inside the tissues, as this usually requires invasive techniques. However, various new methods have been developed to estimate drugs tissue binding such as in vivo microdialysis which as a semi-invasive method used to determine drug tissue binding (Kotsiou and Tesseromatis, 2011). DOSAGE FORM DESIGN CONSIDERATIONS 382 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS 11.5 PLASMA AND TISSUE PROTEIN BINDING IMPLICATIONS ON PHARMACOKINETICS PARAMETERS The extent to which a drug binds to plasma protein will have major consequences on its pharmacokinetic profile. As only the unbound (free) drug is able to diffuse across cell membranes to enter inside the tissues, the drug bound to plasma proteins will not be able to diffuse into tissues, which means that the distribution process will be affected by protein binding of the drug, and the volume of distribution depends on both the plasma proteins and tissue binding of the drug. Since the elimination process of the drug happens inside tissues such as the liver and kidney, the clearance and the half-life of the drug will be affected by the binding of drugs to plasma protein. Other pharmacokinetic parameters such as bioavailability can also be affected by protein binding, although in some cases, protein binding does not seem to affect it. The Fig. 11.7 provides a schematic representation of the effects of plasma protein binding on the pharmacokinetics of the drug (Lambrinidis et al., 2015; Bohnert and Gan, 2013). 11.5.1 Bioavailability Bioavailability (F) is the extent of active drug that reaches the systemic circulation after administration of the drug into the body. Thus, the bioavailability of a drug is affected by several factors such as the route of administration. For example, drugs administrated intravenously will have 100% bioavailability because the active drug is introduced into the systemic circulation. While drugs administrated orally usually have lower bioavailability because an absorption process must take place prior to reaching the systemic circulation. Also, drugs administrated orally are prone to presystemic clearance. For example, they can be metabolized to inactive metabolites in the first-pass metabolism process in the liver or intestinal (gut) wall and consequently will have lower bioavailability. In cases where FIGURE 11.7 Schematic representation of the effects of plasma protein binding on the pharmacokinetics of the drug. DOSAGE FORM DESIGN CONSIDERATIONS 11.5 PLASMA AND TISSUE PROTEIN BINDING IMPLICATIONS ON PHARMACOKINETICS PARAMETERS 383 the first-pass metabolism in the liver is the predominant presystemic clearance mechanism (high extraction ratio drugs), the bioavailability (F) is determined by Eq. (11.15): F512E512 QH fup 3 CLint: (11.15) In Eq. (11.15), E is the hepatic extraction ratio for the drug, CLint. is the intrinsic clearance of the liver, fup is the unbound (free) fraction of the drug. Thus, the bioavailability is inversely proportional to the unbound (free) fraction of the drug, and in such cases, drugs having higher protein binding are expected to have higher bioavailability (assuming no differences in other factors affecting bioavailability). In cases where the drug has negligible first-pass metabolism by the liver (low extraction ratio drugs), the bioavailability is considered as independent from protein binding (Han et al., 2010). Recently many novel pharmaceutical formulations have been tried to increase the bioavailability problems associated with drug molecules (Rahul et al., 2017; Maheshwari et al., 2012). 11.5.2 Volume of Distribution The volume of distribution (Vd) can be defined as a theoretical volume that is used to relate the total amount of drug in the body and the plasma concentration of the drug. Since the volume of distribution is a theoretical volume, it does not have a real physiological volume, and it is used to estimate the drug distribution in the body. For drugs that diffuse readily across capillaries to extravascular space, their volume of distribution will be high, while for drugs that do not diffuse readily across capillaries and remain confined to intravascular space, their volume of distribution will be low. The factors that affect the volume of distribution include the ability of the drug molecules to diffuse to the extravascular space and entering the tissue cells which is mainly determined by the physicochemical properties of the drug such as lipophilicity, size, and charge. Lipophilic molecules can diffuse readily across cell membranes and consequently will have larger volumes of distribution while hydrophilic molecules usually do not diffuse easily across the cell membranes and will have lower volumes of distribution, although the availability of transporter proteins for some molecules is an exception to this process. Binding to plasma proteins is also an important factor that influences the volume of distribution. Since the drug protein complex formed is significantly large to cross the cell membranes, binding to plasma proteins will restrict the bound molecule to the intravascular space and prevent their diffusion. Similarly binding to tissues will restrict the drug molecules from distributing back to plasma and confine them to the tissue space (Liu et al., 2011; Kotsiou, and Tesseromatis, 2011). The volume of distribution is affected by both the binding to plasma proteins as well as to tissues according to the Eq. (11.16): Vd 5 Vp 1 fup 3 Vt fut (11.16) where fup is the unbound (free) fraction of the drug in the plasma, fut is the unbound fraction of the drug in the tissues, Vp and Vt are the plasma volume (B0.07 L/kg) and tissue DOSAGE FORM DESIGN CONSIDERATIONS 384 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS volume, respectively. In cases where the drug can diffuse across the cell membranes, then as Eq. (11.16) describes, if fup is high, then the drug will distribute to tissue, and the volume of distribution will be large. And if the if fut is high, then the drug will distribute from the tissue back to the plasma and will have low volume of distribution. Assuming similar physical properties for a series of drugs (e.g., drugs from the same family having the same scaffold), the plasma protein binding can explain the differences in the volume of distribution for these drugs. Drugs that are highly bound to plasma protein will not diffuse across cell membranes and thus will have a lower volume of distribution, while drugs that are not bound to plasma proteins will diffuse to the tissues and will have a higher volume of distribution. For example, the difference in the volumes of distribution for a series of four cephalosporin drugs is explained by the difference in their plasma protein binding. The highest protein bound (lowest fup) drug is cefazolin, which has the lowest volume of distribution; on the other hand, the lowest protein bound (highest fup) drug is cefoperazone which corresponds to the highest volume of distribution among the four compared drugs (Shargel and Andrew, 2015). 11.5.3 Hepatic Clearance The liver is the major organ for the metabolism of drugs, and it contains enzymes that are responsible for the biotransformation of drugs, which results in inactive metabolites that are subsequently excreted (although in cases, some metabolites can be active or toxic). The hepatic clearance can be defined as the volume of blood (or plasma) that passes through the liver that is cleared from a substance per unit of time. The following Eq. (11.17) can be used to determine the hepatic clearance: CLhepatic 5 QH 3 fub 3 CLint: QH 1 fub 3 CLint: (11.17) In Eq. (11.17), QH is the hepatic blood flow, E is the extraction ratio, fub is the unbound (free) fraction of the drug in blood, and CLint. is the intrinsic clearance of the liver. The extraction ratio E is the fraction of drug that is cleared by the liver relative to hepatic blood flow. Generally, the extraction ratio for drugs can be divided into three classes, high extraction ratio (E . 0.7), moderate extraction ratio (E 5 0.3 0.7), and low extraction ratio (E , 0.3). The other factor that is important in hepatic clearance is the hepatic blood flow QH, which is about 90 L/h for healthy individuals, but the hepatic blood flow is subjected to a decrease in some conditions such as liver diseases (e.g., cirrhosis) or diseases affecting blood circulation (e.g., heart failure). The intrinsic clearance represents the metabolic capacity of the liver enzymes which is a crucial factor in the hepatic clearance, but in some conditions, these enzymes can be inhibited by some drugs or other substances which would affect the hepatic clearance of drugs metabolized by these enzymes. Since the drug protein complex formed in the plasma protein binding process is considered as large to diffuse across membranes and is unavailable for metabolism by other enzymes, it is assumed that only the unbound (free) fraction of the drug is metabolized by the liver. Thus, the protein binding is a factor that should be taken into consideration when determining the hepatic clearance (Schmidt et al., 2010; Liu et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 11.5 PLASMA AND TISSUE PROTEIN BINDING IMPLICATIONS ON PHARMACOKINETICS PARAMETERS 385 11.5.3.1 Restrictive and Nonrestrictive Clearance Drugs that undergo hepatic clearance are classified as being either restrictively cleared drugs or nonrestrictively cleared drugs. For drugs that bind strongly to a protein, then only the unbound (free) fraction of the drug will be available for metabolism. Such drugs are classified as restrictively cleared drugs, these drugs usually have extraction ratio E that is smaller than their unbound (free) fraction, and the product of the unbound (free) fraction as well as the intrinsic clearance Clint. are significantly lower than the hepatic blood flow QH, which allows for the simplification of Eq. (11.17) to Eq. (11.18): CLhepatic 5 fup 3 CLint: (11.18) Examples of restrictively cleared drugs include the oxicams such as isoxicam, tenoxicam, and piroxicam; these drugs have extraction ratio E lower than their unbound (free) fraction fup, and therefore they undergo restrictive hepatic clearance. On the other hand, for drugs which undergo hepatic clearance even though they are highly bound to proteins, they are classified as nonrestrictively cleared drugs. Drugs in this class have extraction ratio E higher than their unbound (free) fraction and the product of the unbound (free) fraction and the intrinsic clearance CLint. are significantly higher than the hepatic blood flow QH, which allows for the simplification of Eq. (11.17) to Eq. (11.19): CLhepatic 5 QH (11.19) The Eq. (11.19) shows that clearance of nonrestrictively cleared drugs is independent of protein binding and depends on the hepatic blood flow. An example of a nonrestrictively cleared drug is the beta blocker propranolol, which is highly protein bound but its extraction ratio E is higher than the unbound (free) fraction, which makes it a nonrestrictively cleared drug, it undergoes extensive hepatic metabolism (Schmidt et al., 2010). 11.5.4 Renal Clearance Renal clearance is the volume that is cleared from a substance by the kidney per unit of time. Renal clearance of drugs that are eliminated by the kidney can be calculated by Eq. (11.20): CLrenal 5 ð1 2 Fr Þ 3 ðFiltration rate 1 Secretion rateÞ Concentration in plasma (11.20) In Eq. (11.20), Fr is the reabsorbed fraction of the drug. In the case where no active secretion or tubular reabsorption takes place, and glomerular filtration is the only mechanism for clearance by the kidney, then Eq. (11.20) can be simplified to Eq. (11.21): CLrenal 5 fup 3 GFR (11.21) In Eq. (11.21), GFR is the glomerular filtration rate (generally B120 mL/min). Renal clearance decreases as protein binding increases because the drug protein complex is too large to diffuse across the glomeruli capillary membranes. However, for drugs that are actively secreted, then the protein binding may be insignificant if the transporter has a higher affinity for the drug than the binding protein (Han et al., 2010). DOSAGE FORM DESIGN CONSIDERATIONS 386 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS 11.5.5 Half-Life The half-life (t1/2) of a drug is the time required for the drug concentration to drop by one-half (50%). Two primary processes are important in determining the half-life of a drug which are the mechanism of elimination (metabolism and/or excretion) and the rate of drug movement from plasma into the tissue, and the t1/2 can be calculated by Eq. (11.22). t1=2 5 0:693 3 Vd CL (11.22) As Eq. (11.22) shows, the half-life of a drug is dependent on both the volume of distribution and clearance, and since both these parameters are affected by protein binding, the half-life will be affected by protein binding as well. Thus, because of that, it is difficult to predict the effect of altered protein binding on half-life directly. In general, drugs with higher tissue binding will have higher half-lives (Kotsiou, and Tesseromatis, 2011). 11.5.6 Drug Plasma Concentration-Time Profile When the rate of drug input is equal to the rate of drug elimination, the drug has reached the steady state. The total average steady-state concentration (Css(total)) is determined by the bioavailability of the drug, the dosing interval, and the clearance. Eq. (11.23) can be used to calculate the total average steady-state concentration (Css(total)): CssðtotalÞ 5 F3D CL 3 τ (11.23) In Eq. (11.23), F is the bioavailability, τ is the dosing interval, D is the dose administered, and CL is the clearance. The unbound free average steady-state concentration (C ss(free)) which is considered more important, can be calculated by using Eq. (11.24). CssðfreeÞ 5 fup 3 F 3 D CL 3 τ (11.24) where fup is the unbound (free) fraction of the drug in plasma. It is apparent from Eq. (11.23) and Eq. (11.24) that the total and unbound (free) average steady-state concentrations depend on the route of administration (which affect bioavailability) and clearance. If the hepatic clearance is the primary elimination method for the drug, then the effect of protein binding on the total and free (unbound) average steady-state concentrations depends on whether the drug has high or low extraction ratio E. If the drug has a high extraction ratio and the drug is administrated parenterally, then protein binding will affect the unbound (free) average steady-state concentration as described by Eq. (11.25). While protein binding will be insignificant for high extraction drugs that are administrated orally as shown in Eq. (11.26). CssðfreeÞ 5 fup 3 D D 5 QH 3 τ CL 3 τ DOSAGE FORM DESIGN CONSIDERATIONS (11.25) 11.6 FACTORS INFLUENCING PROTEIN BINDING 387 fup 3 Foral 3 D D 5 CLint: 3 τ CL 3 τ (11.26) CssðfreeÞ 5 If the renal clearance is the primary clearance method for the drug (assuming only glomerular filtration) then a decrease in protein binding (an increase in the unbound (free) fraction (fup) of the drug in plasma) will enhance the clearance of the drug which will result in a decrease in the total average steady-state concentration (Css(total)) as shown in Eq. (11.27). On the other hand, changing protein binding will not affect the free average steady-state concentration (Css(free)), because changing protein binding will not influence the clearance of free drug as depicted in Eq. (11.28) (Schmidt et al., 2010). F3D F3D 5 CL 3 τ fup 3 GFR 3 τ (11.27) fup 3 Foral 3 D F3D 5 GFR 3 τ CL 3 τ (11.28) CssðtotalÞ 5 CssðfreeÞ 5 11.6 FACTORS INFLUENCING PROTEIN BINDING Factors that can cause alterations in protein binding of drugs can be divided into three classes: physiologic conditions; pathologic conditions; and drug-induced changes. The alteration in protein binding can be caused by these physiologic and pathologic conditions that can occur by various mechanisms. The most common ones are changes in the binding protein concentration, changes in an endogenous substance concentration that binds the binding protein, or a change in the structure of the binding protein (e.g., glycosylation of albumin in diabetic patients) that would affect the binding affinity of the protein (Kotsiou and Tesseromatis, 2011; Joseph and Hage, 2010; Rondeau and Bourdon, 2011). Drug-induced change in binding can also occur by one of these mechanisms, but the most common one is by direct displacement of the drug form the binding protein by competing with it for the binding site of the binding protein (Heuberger et al., 2013). 11.6.1 Physiologic Factors Influencing Protein Binding Physiologic factors that can influence drug protein binding include age, gender, pregnancy, and others. Since concentrations of both albumin and alpha-1-acid glycoprotein in neonates are lower than adults and the higher concentrations of fatty acids and bilirubin which are both normal substances that bind albumin, drug-binding to albumin and alpha1-acid glycoprotein is lower in neonates. Albumin concentration in the elderly is also lower compared to normal adults. Also, a higher percentage of glycosylated albumin is found in the elderly which accounts for the observed decreased binding of albuminbinding drugs. Another physiologic factor is gender, the concentration of both albumin and alpha-1-acid glycoprotein are found to be lower in adult females (nonpregnant) as compared to adult males which explains the slight decrease in the bound fraction of some DOSAGE FORM DESIGN CONSIDERATIONS 388 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS drugs. During pregnancy (mainly in the third trimester), alterations in the binding of albumin-binding drugs can occur. Since albumin concentration is lower and there is an increase in the concentration of free fatty acids, the binding of albumin-binding drugs is reduced, and higher unbound fractions are observed (Fanali et al., 2012; Hanley et al., 2010; Tesseromatis et al., 2011). 11.6.2 Pathologic Factors Influencing Protein Binding Many pathologic conditions can influence drug protein binding. Several of these cause a change in the concentration of a binding protein(s), e.g., conditions characterized by a lowered plasma albumin concentration, such as hypoalbuminemia or analbuminemia, cause an increase in the unbound fraction of albumin-binding drugs, while hyperalbuminemia (which is relatively rare) is associated with increased plasma albumin concentration and thus an increase in the bound fraction of albumin-binding drugs. On the other hand, pathologic conditions can also cause an increase in an endogenous substance concentration that binds the binding-protein, such as the increased bilirubin concentration in hyperbilirubinemia, where bilirubin binds to albumin and causes an increase in the unbound fraction of albumin-bound drugs (Gatta et al., 2012; Dagnino et al., 2011). In a similar fashion, unbound fractions of alpha-1-acid glycoprotein-binding drugs will be affected by pathologic conditions that alter the concentration of alpha-1-acid glycoproteins, e.g., hepatitis, hepatic cirrhosis, pancreatic cancer, and nephrotic syndrome are diseases associated with a decrease in alpha-1-acid glycoprotein concentration and thus, an increase in the unbound fraction of alpha-1-acid glycoprotein-binding drugs. On the other hand, since alpha-1-acid glycoprotein is an acute phase protein, conditions that can result in an acute phase response will cause an increase in alpha-1-acid glycoprotein, which may result in reduced unbound fraction of alpha-1-acid glycoprotein-binding drugs that may require a dose adjustment, such pathological conditions include cancer and myocardial infarction (Stangier et al., 2010; Vivekanandan-Giri et al., 2011). Drugs binding to lipoproteins can also be affected by pathologic conditions, as changes in free fractions of lipoproteins-binding drugs have been observed in dyslipidemia (Anger and PiquetteMiller, 2010; Franssen et al., 2011). 11.6.3 Drug-Induced Changes in Protein Binding The coadministration of one drug can affect the protein binding of another administrated drug and thus change its unbound fraction. The mechanism by which one drug can alter the binding of another drug to a plasma protein is through direct displacement of the drug from the binding site. If the competing drug has a higher affinity for the protein, then it will displace the other one from the binding site and thus increase its unbound fraction which may lead to toxicity. For example, in patients taking the anticoagulant drug warfarin, the coadministration of phenylbutazone that binds to the same binding site of warfarin in albumin will cause displacement of warfarin from the binding site, which in turn may result in an increased free fraction of warfarin and an increase in prothrombin DOSAGE FORM DESIGN CONSIDERATIONS 11.7 PLASMA PROTEIN BINDING DETERMINATION METHODS 389 time with increased risk of bleeding. Another example is the coadministration of sulfonamides with tolbutamide which is a hypoglycemic agent, because the sulfonamides displace the hypoglycemic agent tolbutamide, increasing the free fraction. An increased hypoglycemic effect was observed in patients taking tolbutamide in addition to sulfonamides. However, mechanisms other than protein binding alterations have been observed in explaining the drug drug interactions between these drugs, such as alterations of the metabolism and excretion. The displacement of a drug can occur by the coadministrated drug or by one of its metabolites. Other mechanisms by which one drug can affect the protein binding of another drug is by causing a conformational change in the binding protein. In this case, the drug binds to an allosteric site in the binding protein and causes a conformational change in the protein which will modify the active site shape, thus reducing the affinity of binding to another drug (Fanali et al., 2012; Ansari, 2010; Hines and Murphy, 2011). 11.7 PLASMA PROTEIN BINDING DETERMINATION METHODS Various analytical methods and techniques are used to determine plasma protein binding, each of these methods have its own advantages and disadvantages, and they also vary in their cost, ease of use, and the ability to measure a little fraction of the unbound (free) fraction of the drug. The most common methods used in determining plasma protein binding are equilibrium dialysis, ultrafiltration, and ultracentrifugation, all of these of methods are conducted in vitro. Equilibrium dialysis is the most commonly used method and is regarded as the gold standard method for determining the plasma protein binding of drugs. The choice of method to use depends on various factors such as the discovery stage of the drug, as drugs in advanced development stages require more accurate details regarding their plasma protein binding. For example, determining the initial dose in clinical trials in phase I requires taking the plasma protein binding of the drug candidate into consideration and thus, sufficient data regarding plasma protein binding is required before clinical studies. Other factors affecting the choice of method to imply when studying the binding of a drug to plasma protein include the physicochemical properties of the drug because some properties can pose problems in measuring leading to inaccurate results. For example, compounds with high absorptivity can adsorb to various parts of the device being used which would give false results regarding their unbound (free) fraction. Another important property is the solubility of the compounds to be analyzed, as compounds with low solubility in the medium being used can pose a problem in the measurement process. Some of these problems can be alleviated by the proper choice of the method. There are also various software products commercially available that can predict the plasma protein binding of drugs. Usually these software predict the ADMET properties of the compounds which include the plasma protein binding, although there are software that are designed specifically to predict plasma protein binding only, and some are designed to predict the binding to a specific protein only, such as binding to albumin (Zhang et al., 2012; Howard et al., 2010). DOSAGE FORM DESIGN CONSIDERATIONS 390 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS 11.7.1 Equilibrium Dialysis Method The equilibrium dialysis method is the most frequently used method for determining the plasma protein binding of drugs. This method depends on the physical separation of the bound and unbound (free) fractions of the drug using a semipermeable membrane and then measuring the unbound (free) fraction of the drug by using a proper analytical method. The device used in equilibrium dialysis consists of two chambers separated by a semipermeable membrane as shown in Fig. 11.8. The solution containing the protein (usually serum) and the drug to be analyzed is added to one chamber, while a buffer solution is added to the other chamber. The semipermeable membrane allows the passage of the free drug molecules, while it is impermeable to the protein or the drug molecules bound to the protein. Thus, only the free drug molecules can freely diffuse across the membrane separating the two chambers. After equilibrium is established, the unbound (free) drug molecules concentration will be equal in both chambers, while the bound drug molecules are restricted to the chamber containing the protein solution. After measuring the total drug concentration in the chamber containing the protein solution and measuring the free drug concentration in the chamber containing the buffer solution, it is possible to calculate the bound drug concentration. The time required to reach equilibrium is different for each compound, generally higher molecular weight compounds require a longer time to reach equilibrium, compounds that are highly bound to proteins also tends to require a longer time to reach equilibrium. Long times required to reach equilibrium can pose problems which can lead to errors in the results, e.g., long times can lead to bacterial growth in the medium which can interfere with the binding or change the pH of the medium. One way to reach equilibrium faster can be done by adding the compound to the solution containing the protein and agitating it. Other disadvantages of the equilibrium dialysis method include nonspecific binding of drug molecules, leakage of the protein molecules through the semipermeable membrane, and volume shifts. The nonspecific binding of drug molecules occurs when the drug molecules bind to some parts of the device being used or bind the semipermeable membrane which would result in a lower value for the unbound (free) fraction of the drug. FIGURE 11.8 Equilibrium dialysis method device used in determining the protein binding of drugs. DOSAGE FORM DESIGN CONSIDERATIONS 11.7 PLASMA PROTEIN BINDING DETERMINATION METHODS 391 The nonspecific binding can be alleviated by the proper choice of the material of the device being used, as some materials can reduce nonspecific binding of drug molecules, however, in cases where nonspecific binding is too high, a different method should be considered which uses a different technique for separation, such as ultracentrifugation. The leakage of protein molecules occurs when the some of the protein molecules diffuse across the semipermeable membrane, this will happen if the membrane integrity is damaged. This would lead to a higher value of the unbound (free) fraction of the drug. Another potential problem is the volume shifts, which occurs when part of the buffer solution is transferred to the protein solution chamber because of the colloidal osmotic pressure, resulting in a diluted protein solution and causing an alteration in the equilibrium. A long time is required to reach an equilibrium which can potentiate volume shift. This problem can be alleviated by considering it during the calculation of the unbound (free) fraction of the drug. An alternative way is to add dextran to the solution of a buffer, which would counteract the effect of colloidal osmotic pressure. However, binding of a drug to dextran can give false results, thus it should be confirmed that dextran does not interfere with the binding of the drug. In cases where the volume shifts are of low values, they can be considered negligible (Howard et al., 2010; Ye et al., 2017; Vuignier et al., 2010; Van Liempd et al., 2011). 11.7.2 Ultrafiltration Method The ultrafiltration method is another method that is frequently used in measuring protein binding of drugs, it shares several characteristics of the equilibrium dialysis method but offers numerous advantages over the equilibrium dialysis method. The ultrafiltration method uses a device composed of two chambers, the upper and the lower chamber, with a semipermeable membrane in-between them, as shown in Fig. 11.9. The solution FIGURE 11.9 Ultrafiltration method’s device used in determining the protein binding of drugs. DOSAGE FORM DESIGN CONSIDERATIONS 392 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS containing the drug and the protein is added to the upper chamber of the device (the total concentration of the drug in the solution is determined prior to addition to the upper chamber) and then the solution is allowed to be filtered through the membrane to the lower chamber of the device. The driving force for filtration of the solution is usually positive pressure or centrifugation. The unbound (free) drug passes through the membrane to the lower chamber and is then measured, then the bound fraction of the drug can be calculated from the total drug concentration and the unbound (free) drug concentration in the lower chamber. The advantages that the ultrafiltration method has in comparison to the equilibrium dialysis method include the ease of use, as this technique is more simple and rapid than equilibrium dialysis method. Also, several problems encountered in equilibrium dialysis such as the passage of proteins across the semipermeable membranes and volume shifts are reduced using the ultrafiltration method. The disadvantages of the ultrafiltration methods include the difficulty to control the temperature and pH during the experiment, possible protein leakage across the semipermeable membrane and the permeability of the membrane to the drug and the plasma water. As in some cases, the permeability of the membrane for the water is different than the permeability for the drug molecules. For example, highmolecular-weight drugs may pass across the membrane at a lower rate than the water molecules which can result in a lower value of the unbound (free) fraction of the drug. The most significant disadvantage associated with the ultrafiltration method is the nonspecific binding of the drug molecules, as drug molecules can bind to the semipermeable membrane or the lower chamber which would result in a lower value of the unbound (free) fraction of the drug during measurement. Also, this issue is found to be more significant with the more lipophilic drugs. Various solutions to reduce nonspecific binding of drugs have been proposed, e.g., the pretreatment of the semipermeable membrane with Tween 80 (when the drug being tested is acidic or neutral) or with benzalkonium chloride (when the drug being tested is basic), this can substantially reduce nonspecific binding. Another way is the proper choice of the semipermeable membrane material, as some materials show reduced nonspecific binding in comparison with others (Wang and Williams, 2013; Howard et al., 2010). 11.7.3 Ultracentrifugation Method The ultracentrifugation method does not depend on the separation of the unbound and bound drug fractions by a semipermeable membrane as seen with the equilibrium dialysis and the ultrafiltration methods. Instead, the ultracentrifugation method uses centrifugation force to separate the unbound and the bound drug fractions. The plasma sample containing the drug is allowed to be centrifuged, which would divide the plasma sample into three layers. The upper layer contains VLDLs and chylomicrons, the middle layer is the aqueous layer, and the lower layer contains the plasma proteins such as albumin and alpha-1 acid glycoprotein, in addition to the lipoproteins (HDL and LDL). The drug is measured in each of these layers which were extracted prior to analysis if necessary by methods such as liquid liquid extraction. The drug in the lipoproteins and plasma protein layers represents the bound fraction of the drug, while the drug in the aqueous (middle) DOSAGE FORM DESIGN CONSIDERATIONS 393 11.7 PLASMA PROTEIN BINDING DETERMINATION METHODS layer represents the unbound (free) fraction of the drug. The total drug concentration in the plasma is determined before centrifugation. From these measurements, it is possible to calculate the plasma protein bound drug percentage. The main advantage of the ultracentrifugation method is the avoidance of nonspecific binding of drug molecules that is seen with methods using a semipermeable membrane for separation such as equilibrium dialysis and ultrafiltration which makes the ultracentrifugation method as the method of choice for compounds with high absorptivity. A disadvantage of the ultracentrifugation method is the high cost of the device, and also the device is considered more complex than the devices used for the equilibrium dialysis and the ultrafiltration method. Another disadvantage is the limited number of samples that can be tested at the same time. Also, it is hard to maintain physiological conditions during centrifugation, e.g., even if the pH at the beginning of centrifugation is 7.4, an increase in this value is observed during centrifugation (Zhang et al., 2012). 11.7.4 Important Considerations When Using In Vitro Methods Different parameters should be controlled during the measurement of plasma protein binding of drugs. These include the concentration of the drug and proteins, temperature, and pH, respectively. Also, the stability of the drug should be evaluated. Also, the drug displacement should be considered during measurement. In some cases, a slight change in one of these parameters can give different results, e.g., a slight shift in the value of the pH or the temperature of the experimental conditions can give substantial differences in the results of the bound drug concentration. Another factor that should be considered is the possibility of the presence of an active metabolite of the drug that has a high plasma protein bound fraction, in such a case the drug will have a high half-life value because of this metabolite, which means it is necessary to measure the plasma protein binding for the active metabolites of the drug as well. An example of such drugs is tasosartan which is an angiotensin receptor II antagonist. One of the active metabolites of tasosartan is enoltasosartan which was found to be highly bound to plasma protein, explaining a prolonged effect of tasosartan because enoltasosartan is much more tightly bound to the plasma proteins, the structures of tasosartan and its metabolite enoltasosartan are shown in Fig. 11.10 (Howard et al., 2010; Li et al., 2010). CH3 CH3 N N HN N N N N CH3 Metabolism N N HN N Tasosartan N N O O FIGURE 11.10 N CH3 OH Enoltasosartan Structure of tasosartan and its metabolite enoltasosartan. DOSAGE FORM DESIGN CONSIDERATIONS 394 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS 11.7.5 In Vivo Methods The in vivo methods involve the sampling of the unbound (free) drug directly from a biological fluid through a blood vessel or tissues. The in vivo microdialysis is a commonly used in vivo method to measure the unbound (free) drug from the extracellular fluid of various tissues. The method uses a microdialysis fiber semipermeable membrane and depends on the passive diffusion of the unbound (free) drug molecules across the membrane down their concentration gradient. The microdialysis is performed by inserting the microdialysis probe that is composed of a hollow fiber semipermeable membrane into the extracellular fluid of the tissue of which the unbound (free) drug is to be measured. The microdialysis probe is attached to an inlet and outlet tubing through which a physiologic buffer perfuses at a slow rate, and as the fluid perfuses, the unbound (free) drug molecules diffuse across the semipermeable membrane down their concentration gradient and flow in the outlet tube, then the drug can be measured. The microdialysis method is an important procedure in drug research and development. However, it is not very practical to be used routinely for the measurement of unbound (free) drug concentration (Zhang et al., 2012; Bulik et al., 2010). 11.7.6 In Silico Methods Because of the effects of the plasma protein binding on the pharmacokinetic profile of drugs, it is important to estimate it when selecting lead compounds during the drug discovery process, as many developed drugs with good pharmacodynamics fail to make it to the market because of poor pharmacokinetic profiles. There are variously developed in in silico approaches which can be a beneficial tool to estimate the plasma protein binding of lead compounds during drug discovery. These can be helpful in deciding the compounds to be developed or help in the design of drugs with the appropriate plasma protein binding property. There are two in silico models for the prediction of the binding of drugs to a plasma protein, the structure-based model, and the ligand-based model, although the usage of a model of a combination of both is possible. In the structure-based model, the crystal structure of the protein is required to study the binding of the drug to it. The 3D crystal structure is obtained using X-ray crystallography or other methods. The major plasma protein, albumin, and alpha-1-acid glycoprotein have been crystallized, and their 3D structures have been solved and are available at the protein data bank. The two common methods used in the structure-based model are molecular docking, and molecular dynamics, both of them aim to predict the binding of the drug to the protein by using the 3D structure of the protein. Both methods tried to find the best pose of the drug molecule inside the active site of the protein, and can even give an estimation of the binding affinity and free energy. Additionally, it also provides information about the intermolecular interactions involved between the protein and the ligand which can be useful in modifying the structure of the ligand to adjust the binding to a protein. However, since plasma proteins such as albumin are not the target protein for the drug, it is necessary to make sure that modifying the structure of the drug to adjust its binding to albumin does not significantly affect the binding to its actual target protein. DOSAGE FORM DESIGN CONSIDERATIONS 11.8 CONCLUSION 395 The ligand-based model depends on the development of quantitative structure property relationship models (QSPRs) (Moroy et al., 2012; Vallianatou et al., 2013). The models require a dataset of compounds with known binding to the plasma proteins, then using molecular descriptors (e.g., lipophilicity, topographical features, etc.) a model can be constructed to predict the binding of various compounds. Many QSPR models have been developed to predict the binding of drugs to albumin, some of them have good predictive power (Ghafourian, and Amin, 2013; Zhivkova and Doytchinova, 2012; Li et al., 2011). It is possible to use two more methods in studying the binding of a drug to plasma protein. Each in silico method has its own advantages and disadvantages, and the use of two more methods together can provide a better understanding of the binding process (Zhivkova and Doytchinova, 2012). 11.8 CONCLUSION The binding of drugs to plasma and tissue proteins has significant consequences on the pharmacokinetic parameters of the drug and subsequently will affect the pharmacodynamics of the drug. The major plasma proteins which drugs mostly bind are albumin, alpha-1-acid glycoprotein, and lipoproteins, respectively. The drug protein complex formed is unable to diffuse across the cell membranes which limits its ability to distribute into tissues, and as a result, highly protein bound drugs will have a low volume of distribution. The elimination process is also affected since the protein bound drug will not be available for metabolism in the case of restrictively cleared drugs, while protein binding is insignificant in the case of nonrestrictively cleared drugs. The half-life of a drug is also affected by protein binding because it depends on the volume of distribution and the clearance both of which are affected by protein binding of the drug. Different factors influence the protein binding of drugs which can be divided into three categories such as physiological factors, pathological factors, and drug-induced changes in protein binding respectively. Various methods have been used for the determination of protein binding of the drug, each has its strengths and weaknesses, and sometimes using more than one method is required. In summary, the binding of a drug to plasma and tissue proteins has major consequences on the pharmacokinetics and pharmacodynamics of the drug and should be taken into consideration in the drug discovery and development process. Acknowledgment The author Pran Kishore Deb acknowledge the internal Philadelphia University Research Grant, Jordan (Project ID: 46/34/100PU) as a start-up financial support to his research group for the development of selective inhibitors of cyclooxygenase-2 (COX-2) enzyme. The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for the grant allocated to Dr. Rakesh Tekade for research work on gene delivery and N-PDF funding (PDF/2016/003329) for work on targeted cancer therapy. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. DOSAGE FORM DESIGN CONSIDERATIONS 396 11. PROTEIN AND TISSUE BINDING: IMPLICATION ON PHARMACOKINETIC PARAMETERS ABBREVIATIONS [D] [DP] [DT] [P] [Pt] [T] CL CLhepatic Clint. CLrenal Css(free) Css(total) D E F Fr fub fup fut GFR HDLs Ka Kd LDLs n O2 QH QSPRs r RBCs t1/2 Vd VLDLs Vp Vt τ Free drug concentration Drug protein complex Drug target complex Unoccupied protein concentration Total protein concentration Unoccupied drug-target concentration Clearance Hepatic clearance Intrinsic clearance Renal clearance Free average steady state concentration Total average steady state concentration Drug dose Extraction ratio Bioavailability Fraction reabsorbed Fraction unbound in blood Fraction unbound in plasma Fraction unbound in tissue Glomerular filtration rate High-density lipoproteins Association constant Dissociation constant Low-density lipoproteins Number of binding sites Oxygen molecule Hepatic blood flow Quantitative structure property relationships Ratio of unbound drug to total protein concentration Red blood cells Half-life Volume of distribution Very low-density lipoproteins Plasma volume Tissue volume Dose interval References Anger, G.J., Piquette-Miller, M., 2010. 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Expert Opin. Drug Discov. 8 (5), 583 595. Van Liempd, S., Morrison, D., Sysmans, L., Nelis, P., Mortishire-Smith, R., 2011. Development and validation of a higher-throughput equilibrium dialysis assay for plasma protein binding. JALA: J. Assoc. Lab. Autom. 16 (1), 56 67. Vivekanandan-Giri, A., et al., 2011. Urine glycoprotein profile reveals novel markers for chronic kidney disease. Int. J. Proteom. 2011, 214715. Voet, D., Voet, J.G., 2011. Biochemistry, fourth ed. Wiley, USA. Vuignier, K., Schappler, J., Veuthey, J.L., Carrupt, P.A., Martel, S., 2010. Drug protein binding: a critical review of analytical tools. Anal. Bioanal. Chem. 398 (1), 53 66. Wang, C., Williams, N.S., 2013. A mass balance approach for calculation of recovery and binding enables the use of ultrafiltration as a rapid method for measurement of plasma protein binding for even highly lipophilic compounds. J. Pharm. Biomed. Anal. 75, 112 117. Yamasaki, K., Chuang, V.T.G., Maruyama, T., Otagiri, M., 2013. Albumin drug interaction and its clinical implication. Biochim. Biophys. Acta 1830 (12), 5435 5443. Ye, Z., Zetterberg, C., Gao, H., 2017. Automation of plasma protein binding assay using rapid equilibrium dialysis device and Tecan workstation. J. Pharm. Biomed. Anal. 140, 210 214. DOSAGE FORM DESIGN CONSIDERATIONS FURTHER READING 399 Zhang, F., Xue, J., Shao, J., Jia, L., 2012. Compilation of 222 drugs’ plasma protein binding data and guidance for study designs. Drug Discov. Today 17 (9), 475 485. Zhivkova, Z., Doytchinova, I., 2012. Quantitative structure—plasma protein binding relationships of acidic drugs. J. Pharm. Sci. 101 (12), 4627 4641. Zhivkova, Z.D., 2015. Studies on drug human serum albumin binding: The current state of the matter. Curr. Pharm. Des. 21 (14), 1817 1830. Further Reading Brown, J.R., 1977. Albumin: Structure, Function and Uses. Pergamon Press, Oxford, pp. 27 52b. Oyaert, M., Spriet, I., Allegaert, K., Smits, A., Vanstraelen, K., Peersman, N., et al., 2015. Factors impacting unbound vancomycin concentrations in different patient populations. Antimicrob. Agents Chemother. 59 (11), 7073 7079. Sinko, J.P., 2011. Martin’s Physical Pharmacy and Pharmaceutical Sciences, sixth ed. Lippincott Williams & Wilkins, Philadelphia, PA. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 12 Preformulation Studies of Drug Substances, Protein, and Peptides: Role in Drug Discovery and Pharmaceutical Product Development Shantanu Bandopadhyay1, Nabamita Bandyopadhyay2, Pran Kishore Deb 3 , Chhater Singh 4 and Rakesh K. Tekade 5 1 Department of Pharmacy, Saroj Institute of Technology & Management, Lucknow, Uttar Pradesh, India 2Molecular Biology Division, National Institute of Malarial Research (NIMR), Dwarka, Delhi, India 3Faculty of Pharmacy, Philadelphia University, Amman, Jordan 4Mahaveer College of Pharmacy, Meerut, Uttar Pradesh, India 5 National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 12.1 Introduction 402 12.2 Preformulation Studies: Vital Concepts 403 12.3 Preformulation: Drug Substances Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00012-5 404 12.3.1 Physical Factors 12.3.2 Biopharmaceutical Factors 12.4 Preformulation: Proteins and Peptides 12.4.1 Types and Structural Considerations 401 404 415 415 415 © 2018 Elsevier Inc. All rights reserved. 402 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT 12.4.2 Factors Influencing Preformulation Studies 416 12.5 Role of Preformulation Studies in Drug Discovery and Pharmaceutical Product Development: Drug Substances 418 12.5.1 Need for Drug Discovery 418 12.5.2 Stages in Drug Discovery Process 418 12.5.3 Preformulation as an Aid in Early Product Development 420 12.6 Role of Preformulation Studies in Drug Discovery and Pharmaceutical Product Development: Proteins and Peptides 420 12.6.1 Prodrug Approach 12.6.2 Degradation Pathways Indicating Instability of Proteins and Peptides 12.6.3 Influence of Preformulation on the Delivery of Protein and Peptides 12.6.4 Factors Causing Problems in Protein Delivery 420 421 425 428 12.7 Conclusion 429 Abbreviations 429 References 430 12.1 INTRODUCTION In order to design an optimum dosage form, it is imperative to have a technical know-how of various properties of a drug molecule. This information forms the basis of preformulation studies which provide the basic scientific knowledge for formulation development. As the name suggests, preformulation parameters are studied prior to the actual formulation of the drug into a suitable dosage form. Preformulation encompasses different sets of studies based on the physical and chemical properties of a new molecule. Holistically, these physical and chemical properties significantly influence the drug’s biofate as well as the formulation of a suitable drug delivery system (DDS) (Bharate and Vishwakarma, 2013). The notion of preformulation studies can be applied to both new drug moieties as well as to formulating the generic products which are already available as marketed drug. In the latter case, most of the vital information pertaining to drug as well as its excipients is already available. Whereas, in case of new drug moieties, the preformulation studies are initiated once the synthesized drug has shown adequate pharmacological action in animal subjects (preclinical study). The study is then extended to human beings, known as clinical trials (Pifferi et al., 1999). Proteins and peptides are fundamental components of cells that carry out important biological functions. Proteins are important for signal transmission from outside of the cell to its intracellular environment. However, peptides are vital in the regulation of different molecules present within the cell. Although, proteins and peptides are constituted of various amino acids, there are distinct dissimilarities both in their structure as well as their properties. Peptides are relatively smaller and simpler structures as compared to the large and complex architecture of proteins. Peptides are constituted of molecules varying between 2 and 50 amino acids, whereas proteins are comprised of 50 or more amino acids (Keil, 1965). Functionally, peptides are subdivided into oligopeptides having 2 20 amino acids and polypeptides having more than 20 amino acids. It is these polypeptides which form the DOSAGE FORM DESIGN CONSIDERATIONS 12.2 PREFORMULATION STUDIES: VITAL CONCEPTS 403 FIGURE 12.1 Basic conformation of peptides and proteins. basis of protein’s structure. Hence, proteins can also be viewed as very large groups of peptides. Fig. 12.1 demonstrates the basic platform for the formation of proteins and peptides. The objective of preformulation study is to promote a stable, safe, and affordable DDS by establishing physicochemical properties of new active pharmaceutical ingredients (APIs). 12.2 PREFORMULATION STUDIES: VITAL CONCEPTS The overall concept of preformulation is to create useful information which can be used by the innovator and/or industry to develop a stable formulation and marketable DDS. It is the primary process toward the final stage of formulation development, i.e., design of a DDS. Overall, it includes thorough understanding of the various physical and chemical properties of the drug right from development of an API, mixing with suitable excipients until the end design of a stable, safe, effective, and affordable DDS (Darji et al., 2018). Prior to preformulation studies, it is very crucial to have knowledge of the properties of the drug (Hageman, 2010). This information includes a molecule’s stability, viable route of drug administration, different pharmacokinetic data, and bioavailability of the available DDS in the market. It also encompasses molecular optimization of the API in terms of modification of its solubility and dissolution rates for, e.g., salt formation of a drug (Ephedrine HCl) and prodrug approach (Erythromycin Estolate). Besides, it establishes the relationship between physicochemical parameters and kinetic rate profiles (solubility analysis) of a new drug moiety and checks the compatibility of a new drug moiety with the common excipients. Holistically, it is the study of different properties focused on bulk, solubility analysis, and stability factors of an API. In brief, the aim is to surmount all the significant barriers for the proper development of a DDS which can be promoted in the market for patient’s consumption (Darji et al., 2018). As an alternative to synthetic molecules, research in the peptides and proteins has taken great strides, projecting them as potential drugs of future. This has been possible owing to the highly developed methods of fermentation and purification at the industrial scale as well as advanced analytical techniques. The therapeutic areas which have been targeted include autoimmune diseases, cancer, mental disorder, hypertension, cardiovascular, and metabolic diseases. This has been successful particularly due to the recombinant technology (Azhar et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 404 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT The traditional approach of DDS is vastly different when it comes to the formulation of drugs based on peptide and protein. This is particularly important owing to the complex architecture of the proteins as they are differentiated into primary, secondary, tertiary, and quaternary structures, which in turn are highly dependent on protein degradation (Rossmann and Argos, 1981). Hence, it is important to have an in-depth understanding of the physical and chemical description of a molecule before dosage form development. Thus, it will ultimately pave the way for the development of patient compliant and acceptable dosage forms having high stability, safety, effectiveness, and economy. 12.3 PREFORMULATION: DRUG SUBSTANCES Preformulation is that phase of R&D in which a preformulation scientist observes and distinguishes the different physical and chemicals factors of a new molecule so as to develop a safe and stable DDS. The different factors are discussed herewith. 12.3.1 Physical Factors In general, physical and chemical factors are studied in order to assess the influence of these factors on the drug performance (both in vitro and in vivo) as well as development of an efficient DDS. 12.3.1.1 Organoleptic Properties Organoleptic test provides information on appearance, color, odor, and taste of the drug (Garg et al., 2003). Color of a drug is an intrinsic property of its chemical structure which is related to the extent of conjugated unsaturation and chromophores. In some instances, the color may be due to structural saturation within its crystal lattice. Odor is a typical characteristic of the functional groups present and/or attached to the basic structure of the molecule. Taste is purely differentiated based on its palatability wherein due attention is given to its less soluble chemical form. Both the taste and odor can be masked using appropriate flavors and/or coatings with suitable excipients. Table 12.1 illustrates the various types of color, odor, and taste as is observed for a molecule. TABLE 12.1 Description of Various Organoleptic Properties Property Descriptive Terms Color Off-white, cream yellow, tan, shiny Odor Pungent, sulfurous, fruity, aromatic, odorless Taste Acidic, bitter, bland, intense, sweet, tasteless DOSAGE FORM DESIGN CONSIDERATIONS 12.3 PREFORMULATION: DRUG SUBSTANCES 405 12.3.1.2 Bulk Characteristics During formulation development, various solid-state properties are described for an API which is termed as bulk characterization. These solid-state properties are crystallinity, particle size, powder flow properties, compressibility, etc. Dissimilarities in any of these properties lead to significant problems at the formulation and process development levels (Pifferi et al., 1999). Hence, bulk property characterization includes: 12.3.1.2.1 CRYSTALLINE AND POLYMORPHISM Most of the drugs which are formulated are available as solids. Solid drug molecules exist in two forms, namely amorphous and crystalline. The presence of either amorphous or crystalline form of the drug molecule in a formulation can influence the stability and bioavailability of the formulation. Generally, the amorphous forms are more soluble and less stable than the crystalline forms (Vippagunta et al., 2001). Comparisons of physicochemical properties of amorphous or crystalline form are shown in Table 12.2. Basically, a crystal is a three-dimensional structure which comprise of atoms or molecules arranged in an orderly and repetitive manner. Powder flow and chemical stability is dependent on two properties, i.e., crystal habit and internal structure of molecule (Watanabe, 1997). Crystal Habit: It depicts the external appearance of a crystal and is of several different types, depending on the environment provided for the crystal growth. There are basically seven types which include cubic, monoclinic, orthorhombic, tetragonal, triclinic, trigonal, and hexagonal (Ferro and Saccone, 2008). The crystal habit of a new drug moiety may be subjected to changes during the course of preformulation studies. The drugs are available in different shapes known as crystal habits as are illustrated in Fig. 12.2. Internal Structure: The molecular arrangement of crystals within the crystal lattice is known as internal structure. In crystalline forms, atoms or molecules are closely packed and regularly arranged, whereas in amorphous forms, the atoms or molecules are placed randomly. Generally, an amorphous structure shows higher solubility and dissolution rate as compared to crystalline types. This is because the amorphous forms possess higher TABLE 12.2 Comparison of Physicochemical Properties of Different Crystalline Forms Properties Crystalline Amorphous Arrangements of atoms Regular arrangements of atoms or groupings of atoms in a lattice Arrangement of atoms are irregular Thermodynamic energy Low thermodynamic energy Thermodynamic energy is high compare to crystalline form Solubility Lesser solubility Increased solubility as compared to crystalline forms Melting point Sharp melting point Do not have sharp melting point Cleavage pattern Cleaved along definite planes Undergo irregular and conchoidal cleavage Nature Anisotrophic in nature Isotrophic in nature DOSAGE FORM DESIGN CONSIDERATIONS 406 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 12.2 Different crystal habit. thermodynamic energy. However, these amorphous forms are relatively unstable and have the tendency to convert to more stable forms (Hilden and Morris, 2004). Polymorphs: The phenomenon of the existence of more than one crystalline form of a drug is termed as polymorphism and the forms are known as polymorphs (Vippagunta et al., 2001). This atomic rearrangement causes the formation of different polymorphs with varying internal lattice and crystal forms. Owing to this rearrangement, the polymorphs differ in their physicochemical properties. For example, riboflavin has three different forms, i.e., I, II, and III forms of which form III has 20 times more aqueous solubility than form I. Polymorphism can be differentiated into two types, i.e., monotropes and enantiotropes. This differentiation is based their stability on varying the temperature and pressure. In the case of monotropes, occasionally only one polymorph is stable among the various available polymorphs and is soluble at all temperatures and pressures below its melting point. Whereas for enantiotropes, one of the polymorphs will be stable at a particular temperature and pressure and the other polymorph will be stable at different temperatures and pressures (Lee, 2014). DOSAGE FORM DESIGN CONSIDERATIONS 12.3 PREFORMULATION: DRUG SUBSTANCES 407 FIGURE 12.3 Thermal analysis. There are numerous approaches available for characterizing polymorphs and solvates. These methods include microscopy, fusion methods, differential scanning calorimetry (DSC), differential thermal analysis (DTA), X-ray powder diffraction, scanning electron microscopy, thermogravimetric analysis (TGA), etc. (Otsuka et al., 1999). Both DSC and DTA are associated with measuring the heat evolved or gained by the substance when exposed to a heat source. The endothermic processes (heat absorption) are melting, boiling, vaporization, desolvation, etc. Examples of exothermic processes (heat evolving) are crystallization and degradation. The crystalline form of the drug gives a deeper endotherm when compared to its corresponding amorphous form because the former requires greater energy to undergo melting (Zhang and Chen, 2017). Thermal analysis was illustrated in Fig. 12.3. Applications of DTA/DSC: • • • • • Sample purity. Types of polymorphs and proportion of each polymorph. Heat of solvation. Thermal degradation of a drug or excipients. Glass-transition temperature of a polymer. TGA methods provide the information wherein the alteration in the weight of the drug is measured as a function of time or temperature (isothermal changes). One of the most important applications of TGA is monitoring of desolvation and decomposition processes. X-ray powder diffraction technique is based on the concept that when a powder is subjected to X-rays, a diffraction pattern is obtained (Bettinetti, 1989). Each diffraction pattern is characteristic to a particular crystal lattice and in a mixture, these crystal lattice give rise to their individual pattern, independent of one another. Therefore, when the crystal lattice in a powder is randomly arranged the X-rays get scattered giving rise to peak intensities at distinct angles (θ) made with respect to the incident beam. The magnitude of peak intensities is a direct indicator of the crystalline nature of the substance. A reduction in the crystalline property of the substance can be ascertained if there occurs a reduction in peak intensities. However, the amorphous compound shows either few or no diffraction pattern. This technique has varied uses, like determination of drug crystallinity or amorphous nature and ascertaining the variation in crystalline properties between the batches. DOSAGE FORM DESIGN CONSIDERATIONS 408 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT 12.3.1.2.2 HYGROSCOPICITY Moisture is considered to be the vital factor that drastically affects the stability of a drug and its DDS (Garg et al., 2003). Depending on the effect of moisture, the pharmaceutical materials are classified as: • Deliquescent—when dissolved in the water these substances absorb moisture from the atmosphere to form a solution; • Efflorescent—observed in case of hydrated salts wherein there is a spontaneous loss of water as soon as its aqueous vapor pressure becomes higher than partial pressure of the water vapor in the air; and • Hygroscopic—substance that exists in a dynamic equilibrium with water (Mauer and Taylor, 2010). This process depends on the relative humidity of the surroundings. The properties such as crystal structure, powder flow, compaction, lubrication, dissolution rate, and polymer film permeability are some of the instances which are affected by moisture adsorption. Hygroscopicity is characterized by Karl Fischer, gravimetric, TGA, or gas chromatography methods (Reutzel-Edens and Newman, 2006). 12.3.1.2.3 PARTICLE SIZE AND SHAPE The particle size of drug molecule influences the dissolution rate of its dosages form. The dissolution rate, in turn, influences the absorption and bioavailability of drug (Chaumeil, 1998). As the particle size decreases (by micronization), the effective surface area increases. Consequently, the higher the effective surface area, the greater will be the contact between the drug particle’s surface and the aqueous solvent and hence, the quicker the dissolution. In the case of lipophilic drugs like aspirin, phenacetin, and phenobarbital, micronization actually results in decreases in effective surface area and dissolution rate. When a hydrophobic drug is micronized, particles may aggregate leading to poor wetting, hence poor dissolution. The particle size also has an influence on the sedimentation rate in suspension and emulsion. The sedimentation rate is directly proportional to the particle size of the dispersed phase. Thus particle size also influences the stability of formulations (Duban, 1963). Particle shape can influence both the flow properties and packing properties of powder due to differences in interparticle contact area. Spherical particles have minimum interparticle contact and thus offer good flow property. Methods of evaluation of particle size and distribution includes light microscope with a calibrated grid, sedimentation techniques, stream scanning, coulter counter, and surface area determination by BET nitrogen adsorption method (Avdeef et al., 2009). 12.3.1.2.4 DENSITIES Density is defined as weight per unit volume. Density is dived into three types, namely: 1. Bulk density. 2. Granular density. 3. True density. DOSAGE FORM DESIGN CONSIDERATIONS 12.3 PREFORMULATION: DRUG SUBSTANCES 409 Bulk Density (g/cm3): It is termed as the weight of the dry powder to the bulk volume of the powder when measured in a graduated cylinder. Bulk volume is the volume of the powder including interparticle spaces and intraparticle pore. Apparent bulk density 5 Weight of the powder Bulk volume (12.1) Bulk density is used to check the uniformity of bulk chemicals, selection of appropriate capsule size and gives an idea about tablet porosity and its relationship with disintegration time and hardness of a tablet. Granule Density: It is the weight of the powder to the granule volume. Granule volume is the volume of a powder which includes the intraparticle pores but does not include interparticle spaces. Granule density 5 Weight of the powder Granule volume (12.2) True density (g/cm3): It is defined as the weight of the powder to the true volume. True volume is the volume of the particles excluding the interparticle spaces and intraparticle spaces. Therefore, true density is the density of powder itself. True density 5 Weight of the powder True volume (12.3) 12.3.1.2.5 FLOW PROPERTIES In order to manufacture a suitable tablet, the flow property of the API is crucial during a tableting process (Rahul et al., 2017). A good flow property is required for proper mixing during granulation and acceptable weight uniformity after tablet compression. In case a drug is reported to be “poorly flowable” then its flow can be modified using apt excipients. However, there are certain cases where the API is also being precompressed to improve its flow properties. A few of the methods used to check the flow properties are angle of repose, flow through an orifice, compressibility index, etc. (Tan et al., 2015). Overall, powder flow properties are particularly dependent on angle of repose, density, particle size and shape, and electrostatic charge and adsorbed moisture (either during processing or formulation of DDS). Angle of Repose: This is the maximum angle possible between the surface of a heap of powder and the horizontal plane. It is an indicator of the frictional and cohesive forces in a loose powder. For most pharmaceutical powders, the angle-of repose values range from 25 to 45 degrees, with lower values indicating better flow characteristics. During the formulation development, a free-flowing API may form a lump owing to cohesive nature of the ingredients added (Tan et al., 2015). Hence, this problem may be solved by any of the following ways: • • • • Granulation. Densification via slugging. Filling special auger feed equipment (in case of powder). Changing the formulation. DOSAGE FORM DESIGN CONSIDERATIONS 410 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT 12.3.1.2.6 COMPRESSIBILITY It is the ability of a powder to decrease in volume when pressure is applied (Leuenberger, 1982). During tablet manufacturing, compression of powdered or granular drug into a cohesive mass is significantly influenced by compressibility. It is given by the following equation. ρ 2 ρ0 % Compressibility 5 t 3 100 (12.4) ρt ρt 5 Tapped bulk density. ρ0 5 Initial bulk density. 12.3.1.3 Solubility Analysis One of the principal objectives of preformulation is to keep the drug in solution form as this eventually leads to enhanced therapeutic efficacy. Besides, the solution form facilitates maximum amount of drug in the systemic circulation. Various solvents have been explored for analyzing the solubility of drug at room temperature, like distilled water, 0.9% sodium chloride, hydrochloride acid (0.01 and 0.1 M), 0.1 M sodium hydroxide, and buffers (pH 7.4) (Chrzanowski, 2008). Furthermore, for determining the drug concentration different analytical methods have been utilized, e.g., HPLC, UV-VIS spectroscopy, fluorescence spectroscopy, gas chromatography (Kerns et al., 2008). In brief, the solubility of a drug in a solvent depends on pH of the solvent, temperature of the solution in which drug is dissolved, ionic strength of the drug in a particular solvent, and effect of buffer concentration. Various significances of drug solubility are; • In order to stimulate the data of dissolution rate with that of in vivo conditions, it is important that the solubility of a drug must be determined in an isotonic saline solution and acidic pH. This analysis is of significance when the drug is administered orally. • Analysis of solubility of API in various solvents is highly useful while formulating suspension or solution dosage forms which ultimately have an impact on the toxicological and pharmacologic studies. • It aids in revealing the drug(s) having poor and/or reduced bioavailability, e.g., Biopharmaceutics classification system (BCS) Class II and IV drugs. This uniqueness helps in the development of a suitable DDS of a drug. Thus, solubility analysis is vital for understanding the various properties during the preformulation studies (Kerns et al., 2008). The properties are discussed under the next few sections. 12.3.1.3.1 IONIZATION CONSTANT (PKA) Although, a drug either weakly acidic or basic ionizes in the gastrointestinal tract (GIT) environment, it is only the unionized form that is rapidly absorbed. This correlation is given by the Handerson Hasselbach equation which provides an estimation of the ionized and unionized drug concentration at a particular pH. The pKa of a drug can be DOSAGE FORM DESIGN CONSIDERATIONS 12.3 PREFORMULATION: DRUG SUBSTANCES 411 estimated by either detecting the spectral shifts by UV or visible spectroscopy at varying pH or by potentiometric titration (Avdeef, 2001). For acidic drugs, e.g., HA 1 H2 O"H3 O1 1 Weak acid pH 5 pKa 1 log A2 Strong base ½ionized ½A2 ½base 5 pKa 1 log 5 pKa 1 log ½unionized ½HA ½acid (12.5) For basic drugs, e.g., B 1 H3 O1 " BH1 1 H2 O Weak base pH 5 pKb 1 log Strong acid ½unionized ½B ½base 5 pKa 1 log 1 5 pKa 1 log ½ionized ½acid ½BH (12.6) 12.3.1.3.2 PARTITION COEFFICIENT It is defined as the ratio of concentration(s) of unionized drug distributed between the organic and aqueous phases, at equilibrium. KO=W 5 Coil Cwater at equilibrium (12.7) The drug concentration in the organic phase is generally determined by employing n-octanol and chloroform. Further, this parameter has a significant influence on drug properties as the drug molecules having higher KO/W are said to be highly lipophilic. It is a direct indicator of a drug’s ability to traverse through the lipophilic cell membrane (Mayer and Reichenberg, 2006). Various methods of finding the partition coefficient include chromatographic method, shake-flask method, probe methods (countercurrent and Tomlinson’s filter) and micro-electrometric titration method. The concept of partition coefficient is applied for the following: 1. 2. 3. 4. 5. Measurement of Lipophilicity. Recovery of antibiotics following fermentation. Drug sampling from biological fluid for therapeutic monitoring. Drug absorption from different DDS, e.g., tablets, creams, suppositories, etc. Distribution of essential and volatile oils while preparing emulsions. 12.3.1.3.3 SOLUBILIZATION Preformulation studies for the drugs which are poorly soluble in aqueous or hydrophilic solvents must be subjected to minimal experimentation in order to understand the mechanisms for solubilization. Poor aqueous solubility of a drug is one of the key barriers for improved bioavailability. Majorly, two physicochemical properties are responsible for DOSAGE FORM DESIGN CONSIDERATIONS 412 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT controlling the solubility pattern of a drug namely, crystallinity and polarity (Ran et al., 2005). Accordingly, the modifications in the drug solubility can be of two types, i.e., • Transformation of the crystal structure of a solute (i.e., reduced particle size or change the crystal form). • Changes in the solvent by adding solubilization agents. The various approaches for solvent modification are pH control, cosolvency, micellization, and complexation. 12.3.1.3.4 DISSOLUTION Dissolution is an important step during preformulation studies because the rate of drug dissolution of a drug will exert a direct impact on bioavailability and drug delivery aspects (Bergstrom et al., 2014). Dissolution can be defined as the process through which drug particles tend to dissolve in the body fluids. Any change in drug dissolution will significantly affect the bioavailability. The modified Noyes Whitney equation describes the drug dissolution in which surface area is constant during disintegration. dc DA 5 ðCS 2 CÞ dt hV (12.8) where, D 5 diffusion coefficient of the drug in the dissolution medium. h 5 thickness of the diffusion layer at the solid/liquid interface. A 5 surface area of drug exposed to dissolution medium. V 5 volume of the medium. CS 5 Concentration of saturated solution of the solute in the dissolution medium at the experimental temperature. C 5 Concentration of drug in solution at time t. When A 5 constant and CScC the equation can be rearranged to dC DA 5 CS dt hV or; V dC DA 5 CS dt h or; W 5 kAt (12.9) where, k5 D h where, W 5 weight (mg) of drug dissolved at time t. k 5 intrinsic dissolution rate constant (mg/min cm2). 12.3.1.4 Stability Analysis Stability studies during preformulation are prerequisite for the quantitative determination of chemical stability of a new drug. This study is carried out during toxicological studies, formulation as solution state, DDS in solid state (Henry et al., 2016). As per the DOSAGE FORM DESIGN CONSIDERATIONS 12.3 PREFORMULATION: DRUG SUBSTANCES 413 ICH guidelines Q1A(R2), the stability studies are conducted as either accelerated or longterm stability studies depending upon the climatic zones. These studies are considerably useful for calculating the dose and establishing the safety ranges during human studies. Besides, PK-PD studies also indicate the possible process impurities and degradation products of API which are of immense help to prepare the safety profiles. This information is particularly useful during the product development lifecycle at the industrial level. 12.3.1.4.1 STABILITY STUDY IN TOXICOLOGICAL FORMULATION A new molecule when administered to the animals via oral route can fed through various ways, such as drug mixing with feed, solution, and suspension form. The constituents of the feed may vary for vitamins, minerals, and enzymes. These constituents may contain many active chemical groups that may decrease the functional effectiveness of the feed and thus affect the stability of the new molecule. Hence, the studies must be conducted for the feed at laboratory temperature. 12.3.1.4.2 SOLUTION-STATE STABILITY The basic objective of this study is to identify the conditions required to form a stable solution. Meanwhile, the stability of a molecule is largely affected by the factors, pH, ionic strength, cosolvents, light, temperature, and oxidation. pH stability study is carried out to corroborate the decay process at the highest possible conditions of pH and temperature. Therefore, three types of conditions are used for observing the stability, i.e., 0.1 N HCl at 90 C, water at 90 C, and 0.1 N NaOH at 90 C. These conditions are applied to testify the assay specifications and degradation rates. Presently, aqueous buffers having wide range of pH values are employed as these solutions maintain the levels of drug concentration, cosolvent, and ionic strength. Ionic strength is an important criterion for the DDS meant for parenteral route. Hence, it is imperative to assess the pH-stability which is observed at a constant ionic strength compatible with body fluids. Ionic strength for any buffer solution can be calculated as; 1X µ5 mi Zi 2 (12.10) 2 where, mi 5 molar concentration of the ion. Zi 5 valency of that ion. For computing, µ all the ionic species of the buffer solution and drugs are also taken into calculation. Cosolvents are added when some drugs are slightly soluble in a given solvent leading to variations in the sensitivity of analytical procedures. However, cosolvents considerably influence the rate constant of a process. The influence of “light,” also termed as photostability, is assessed after stocked the containers inside the cardboard package or wrapped in aluminum foil. The drug solutions are kept in various containers like clear glass ampoules, amber-colored glass, yellow-green colored glass. DOSAGE FORM DESIGN CONSIDERATIONS 414 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT Temperature accelerates the rate of reaction which in turn causes the rate constant (k) of degradation process of a drug to vary with the temperature. This process is best understood using the Arrhenius equation. This equation is employed to determine the shelf life of the drug. Ea Ea 1 k 5 Ae2RT or ln 5 ln A 2 (12.11) R T where k 5 rate constant. A 5 frequency factor. Ea 5 energy of activation. R 5 gas constant. T 5 absolute temperature. 12.3.1.4.3 SOLID-STATE STABILITY The basic aim is to identify the stability of solid drug under the prescribed storage conditions and exploring the compatible excipients for a DDS. The solid-state reactions are not so fast and that is why it is difficult to calculate the rate of appearance of decay product (Ahlneck and Lundgren, 1985). It can be calculated by various methods, i.e., • Thin layer chromatography, fluorescence, or UV/Visible spectroscopy: mechanism of degradation. • DSC or IR-spectroscopy: polymorphic changes. • Surface reflectance instrument: surface discoloration owing to oxidation or interactions with the excipients used. 12.3.1.4.4 DRUG-EXCIPIENTS COMPATIBILITY While developing a DDS, the basic information on drug-excipient interactions is highly critical for the selection of apt excipients. Although this information is available for the already existing marketed drugs, for the new molecules this is vital and it is usually generated during the preformulation. For example, formulation of tablet for a new molecule may consists of binders, disintegrants, lubricants, etc. Thus, compatibility screening of two or more variants in the different excipients is important (Ahlneck and Lundgren, 1985). The compatibility studies for the drug excipient are important in view of the following; • Increasing the stability of a DDS as any physical or chemical interaction between drug and excipient can substantially modify the bioavailability of a drug. • It facilitates in understanding the last-minute problems just before the final DDS. • It correlates drug discovery (i.e., designing a new molecule) with the drug development. • It helps in the selection of the suitable type of the excipients for a new molecule developed during drug discovery programs. It is also vital for investigational new drug (IND) submission which has been made mandatory by USFDA before its approval (Bharate and Vishwakarma, 2013). DOSAGE FORM DESIGN CONSIDERATIONS 12.4 PREFORMULATION: PROTEINS AND PEPTIDES 415 FIGURE 12.4 Biopharmaceutics classification systems for drugs. 12.3.2 Biopharmaceutical Factors While developing a DDS for a drug, it is very important to have knowledge of its various physicochemical and biopharmaceutical properties. In this regard, BCS provides a better idea for the formulation of a DDS. BCS is based on two major parameters, i.e., solubility and permeability. In the case of a highly soluble drug, it is meant as the highest dose strength of the drug which is soluble in 250 mL or less of aqueous media over the pH range of 1 7.5 at 37oC. Whereas, “highly permeable” indicates that the rate and extent of in vivo absorption is % or more of an administered dose (van de Waterbeemd, 1998; Amidon et al., 1995). 90% Fig. 12.4 depicts the various classes of BCS based on these two parameters. 12.4 PREFORMULATION: PROTEINS AND PEPTIDES One of the foremost challenges for the formulation development of peptides and proteins is to maintain the stability of these products over the storage period or shelf life. Thus, it is crucial to understand and initiate their preformulation studies encompassing solubility, stability, isoelectric point determination, pH, and characterization of impurities. Besides, choice of buffer system, pH of the solvent, selection of an apt solvent, selection of suitable excipients, and preservation of the formulation must be considered to develop a DDS of peptides and proteins while overcoming the stability issues in terms of various physical and chemical degradation pathways (Volkin et al., 2002). 12.4.1 Types and Structural Considerations Although proteins and peptides are known for their various therapeutic capabilities, they differ in many properties. Peptides are constituted of amino acid monomers wherein these short chains of amino acids are linked by peptide bonds. They are either produced naturally within the biological systems or synthesized artificially (Ahmed, 2017). On the basis of size, they can be differentiated as the peptides containing maximum 50 amino acids. The fundamental structure of proteins is based on arrangement of the DOSAGE FORM DESIGN CONSIDERATIONS 416 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT polypeptides with an additional attachment of ligands like coenzymes and cofactors, or any other protein or other macromolecule (e.g., DNA, RNA, etc.) (Eom et al., 2016). In comparison, proteins are long-chain peptides consisting of more than 100 amino acids. The proteins play major roles in the human body starting from cell signaling to the cellular locomotion. Depending on the various activities, proteins are of seven types, i.e., antibodies (immunoglobulin, IgG), enzymes (kinases), muscle contraction and movement (actin and myosin), hormones (insulin), structural proteins (keratin), storage proteins (ferritin), and transport proteins (Hemoglobin). In the recent years, the paradigm of research has shifted to proteins and peptides. The therapeutic areas where these molecules are actively worked on includes Alzheimer’s (Amyloid beta), Huntington’s (huntingtin), Parkinson’s diseases (alpha-synuclein), and Type 2 diabetes (amylin) (van der Wel, 2017). Hence, discussion of the various challenges in their preformulation studies is very crucial which will ultimately lead to the development of proteins and peptides with pronounced therapeutic activity. 12.4.1.1 Classification of Therapeutic Proteins Therapeutic proteins are the proteins which are designed for the individuals in whom proteins are absent or low as in the case of cancer, hemophilia, anemia, multiple sclerosis, hepatitis B/C, etc. The idea of therapeutic proteins was first conceptualized in the 1920s by engineering insulin for the treatment of diabetes. These types of proteins are artificially synthesized on a large scale in the labs wherein the targeted host cells are genetically modified and delivered for pharmaceutical use (Azhar et al., 2017). Accordingly, as per USFDA, they are broadly classified into four classes. • • • • Type Type Type Type I: Therapeutic proteins with enzymatic or regulatory activity. II: Therapeutic proteins with special targeting activity. III: Therapeutic proteins as vaccines. IV: Therapeutic proteins as diagnostics. 12.4.2 Factors Influencing Preformulation Studies The protein is the most abundant biological and organic molecule, it is soluble in water, and it can formed a colloidal solution with water. Protein and peptides are a physiochemically and metabolically stable system. In the case of absorption properties, the molecular weight and size of the particle, conformational studies, stereo specification of threedimensional arrangements in space, and immunogenicity of drug molecules, are affected by the rate of absorption of protein and peptide in oral DDS. 12.4.2.1 Effect of Molecular Size Diffusion of a drug across the epithelial layer of GIT is considerably influenced by its molecular weight and size. Drugs with the size range of ,75 100 Da, being small in size, are able to diffuse. However, as the proteins and peptides are constituted of large molecules and consequently of heavier molecular weight, they are able to diffuse through GIT with difficulty. In order to understand the structural constraints of a protein at the atomic level, X-ray crystallography or nuclear magnetic resonance are carried out. Although, the DOSAGE FORM DESIGN CONSIDERATIONS 12.4 PREFORMULATION: PROTEINS AND PEPTIDES 417 TABLE 12.3 Lipophilicity of Selected Peptides Selected Peptides Value of Partition Coefficient Insulin 0.0215 Thyrotropin-releasing hormone 0.0376 Luteinizing hormone-releasing hormone 0.0451 Glucagons 0.0633 Substance P 0.2750 Met-enkephalin 0.0305 Leu-enkephalin 1.1200 structural information (in nanometers) at the atomic level is invaluable, there are other methods which provide more profound information. Hydrodynamics-based methods like sedimentation and gel filtration provide such useful structural information and with additional electron microscopy studies can yield even more powerful information on structures (Nehete et al., 2013). 12.4.2.2 Factors Influencing Solubility Profile and Partition Coefficient Proteins and peptides are amphoteric in nature and usually have complex solubility profiles. Near to isoelectric point, the aqueous solubility is minimal. Peptides are highly hydrophilic in nature with critically lower partition coefficient. Hence, inhibiting at the N- and C-terminals of their structure increases their lipophilicity and consequently enhances absorption (Swami and Shahiwala, 2013). Lipophilicity of some of the selected peptides is shown in Table 12.3. 12.4.2.3 Complexity in Structural Conformation Unlike the marketed synthetic API, Proteins and peptides-based drugs are characterized by complex structures, i.e., primary, secondary, tertiary, and quaternary structures (Rossmann and Argos, 1981). Based on their size, they undergo conformational changes if presented as solutions. As such, it is highly desirable to maintain the pharmacologically active conformation during the formulation of a DDS and its sterilization. In case the active confirmation undergoes transitions then it highly hinders the GIT permeability. Owing to their immunogenicity, these molecules are formulated with the inert polymers like PEG, PVP, and albumin have the ability to reduce the proteolysis and ultimately surmount their immunogenicity. 12.4.2.4 Effect of Electrostatic Charges in Membrane Permeability Most of the proteins and peptides carry positive charge on their surface which when it interacts with the negatively charged GIT membrane facilitates their permeability. In fact, distribution of charge is more significant as compared to partition coefficient while assessing the permeability of these large molecules across GIT mucosa. Further, even if the DOSAGE FORM DESIGN CONSIDERATIONS 418 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT partition coefficient is considerably high, the terminal charges or zwitterionic peptides always create a negative outcome on membrane permeability (Swami and Shahiwala, 2013). 12.4.2.5 Biopharmaceutical Aspects Most pharmaceutical proteins and peptides are considered to be BCS Class III drugs, thus having a good solubility but poor permeability, which leads to an overall poor bioavailability. Furthermore, poor stability and short plasma half-life are major drawbacks. Therefore, most of the protein and peptide drugs in the market today are administered parenterally as injections. Patients receiving protein and peptide injections often experience discomfort and pain, which has resulted in peptide delivery not being considered in the last decades to have constituted the desired breakthrough. Physiochemical properties of therapeutic proteins like protein folding and/or instability is vital for calculating their pharmacokinetic parameters. These properties are crucial for the designing an apt DDS for their delivery as per the therapeutic requirements. Delivery of exogenous proteins may cause obstruction while interacting with the endogenous proteins and affect the normal physiology and functioning of endogenous protein. Besides, absorption enhancers can be employed to enhance the permeability of these molecules. Currently, DDS are developed using the modern techniques for augmenting their absorption into the systemic circulation using the transdermal route (Kintzing and Cochran, 2016). 12.5 ROLE OF PREFORMULATION STUDIES IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT: DRUG SUBSTANCES Preformulation studies of the drug substances or the API provide the essential knowledge of their physicochemical properties. This procedure is the prerequisite for development of a successful DDS (Dean, 1994; Peng et al., 2017). 12.5.1 Need for Drug Discovery Drug discovery is a continuous process due to the prevalence of many diseases. Research and development plays a vital role in drug discovery as well as the drug development process. Once scientists confirm interaction with the drug target, they typically validate that target by checking for activity versus the disease condition for which the drug is being developed. After careful review, one or more lead compounds are chosen. 12.5.2 Stages in Drug Discovery Process Typically, discovery of a new API and its further development by any pharmaceutical company can be processed into five steps. Holistically, the aim is to develop a therapeutically potential molecule which can be marketed properly. DOSAGE FORM DESIGN CONSIDERATIONS 12.5 ROLE OF PREFORMULATION STUDIES IN DRUG DISCOVERY 419 12.5.2.1 Strategic Research Initially, feasibility studies are carried out to observe interactions with an existing biological mechanism and collect the information for any kind of therapeutic effect, if any. Generally, the strategic research carried out by a pharmaceutical company is put forth by factors, viz., in-house research proficiency and know-how, medical requirements and records in a specific therapeutic segment, and market perspective or business feasibility. 12.5.2.2 Exploratory Research In the last decade, development of newer technologies has taken great strides for the synthesis of synthetic and biosynthetic molecules. This has paved the way to synthesize large and varied quantities of these molecules and also for their activity testing over a relatively shorter duration. These technologies are better known as “combinatorial chemistry” and automated “high-throughput screening” (HTS). The vital influence is to considerably increase the synthesis of these molecules, e.g., from a mere 50 molecules per year to over tens of thousands of molecules. Additionally, these technologies facilitate rapid analysis of these newer molecules against multiple biological targets like biological receptors or biochemical pathways. 12.5.2.3 Candidate Drug Selection The main purpose is to design a new molecule with a special focus on the optimal desired characteristics like potency, specificity, duration, safety, and pharmaceutical aspects. In order to develop a new molecule, various candidate drugs are selected by optimizing the data obtained from in vitro and in vivo studies. Of the desired characteristics, pharmacological properties like, suitable absorption, potency, duration of action, and selectivity for the receptor or enzyme is also taken into consideration. Safety characteristics normally include the detailed study of its carcinogenicity, teratogenicity, mutagenicity, and general toxicity. In order to affirm effectiveness of these characteristics short-term preclinical toxic pharmacological studies and in vitro tests are conducted. 12.5.2.4 Exploratory Development The objective of this step is to observe the absorption and metabolism pattern of the candidate drug in healthy human volunteers and subsequently the same studies in the patients. This step is termed as Phase I clinical studies or concept testing (proof of concept). During the Phase I studies, the drug candidate is formulated as a simple conventional DDS and administered to a small number of healthy volunteers. In the case where the candidate drug is unable show the expected therapeutic effects in humans or produces any adverse and serious side effects, the development of the candidate drug is most probably terminated at this stage. 12.5.2.5 Full Development It basically comprises of clinical Phase II and Phase III studies wherein long-term safety studies are completed in patients suffering from a particular disease. During the Phase II studies, dose and dosage regimen are evaluated to assess the therapeutic efficacy of the drug and its associated side and/or adverse effects. Following this, in Phase III, the drug DOSAGE FORM DESIGN CONSIDERATIONS 420 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT in the commercial marketable DDS is developed and the product/process is optimized, and ultimately scaled up to commercial production scale. 12.5.3 Preformulation as an Aid in Early Product Development Preformulation is increasingly progressing toward front-loading as several varieties and kinds of studies are measured so as to cut back the risks of last stage attrition and to attenuate expensive issues. This involves in-depth description of huge numbers of new molecules and analysis supported by varied criteria. It facilitates the issues in organizing, sharing, transferring, and evaluating knowledge in a much-synchronized mode. Initial preformulation study explains the molecular, physicochemical, and crystallographic characteristics of molecules. Besides, it presents complete development services to characterize API and interactions with other excipients, and to know the influence of process variables on properties of DDS. The characterization of API encompasses solubility studies, study of polymorphic forms, forced degradation studies, and scrutiny of the degraded product, authentication of chemical structure, analysis of impurities and photostability studies (Bharate and Vishwakarma, 2013). 12.6 ROLE OF PREFORMULATION STUDIES IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT: PROTEINS AND PEPTIDES Peptides and proteins became the alternative molecules for the management of various diseases owing to their enormous beneficial properties and their capability to produce therapeutically effective and strong activity. Holistically, they have huge prospects to mitigate various ailments and not just the symptoms while causing minimal side effects (Fosgerau and Hoffmann, 2015). At present, owing to newer technologies in biotechnology, extensive varieties of peptide and protein molecules are manufactured on a large scale in industry. These techniques have enabled the concept of recombinant technology to facilitate the engineering of modified genes from animal or human tissue (Fosgerau and Hoffmann, 2015). Protein- and peptide-based molecules are quickly turning into a significant category of therapeutics which are expected to substitute for the existing synthetic API very soon. Delivery of protein and peptides to the systemic circulation is very difficult and hence, varied DDS need to be developed to increase their systemic exposure. Newer and pertinent technologies are also being explored to make the proteins and peptides commercially feasible and therapeutically functional (Kaspar and Reichert, 2013). 12.6.1 Prodrug Approach Proteins are differentiated into various structures based on their types, i.e., secondary, tertiary, and quaternary which in turn influences their respective molecular size. Consequently, they are susceptible to proteolytic cleavage of their peptide backbones. DOSAGE FORM DESIGN CONSIDERATIONS 12.6 ROLE OF PREFORMULATION STUDIES IN DRUG DISCOVERY 421 TABLE 12.4 List of Prodrugs of Proteins and Peptides Parent Protein/Peptide Prodrug S-Gonadotropin releasing hormone S-Gn-RH-A Growth hormone GHRP-6 Luteinizing hormone-releasing hormone Buserelin, leuprorelin, goserelin Vasopressin Desmopressin Somatostatin Sandostatin Accordingly, they can be chemically modified into prodrugs with higher stability and improved plasma half-lives. A few of the approaches for prodrug development are olefinic substitution, D-amino acid substitution, dehydroamino acid substitution, carboxyl reduction, PEG attachment to amino group, and thio-methylene modification (Bruno et al., 2013). Nobex Technology, one of the latest technologies wherein an amphiphilic protein is conjugate developed. This technology hugely decreases the self-association, augments penetration, and enhances the compatibility of the formulation ingredients. An example of this technology is the designing of insulin conjugate in which a short-chain PEG and alkyl group are linked to Lys-29 of beta chain of insulin. The newly developed conjugated insulin was established as highly absorptive and therapeutically effective (Yang et al., 2011). A comprehensive list of proteins and peptides using the prodrugs concept are shown in Table 12.4. 12.6.2 Degradation Pathways Indicating Instability of Proteins and Peptides The aqueous solubility of proteins increases depending on the interaction of surfaceexposed residues of their native structure. Owing to their conformational changes as aggregation and/or precipitation in the aqueous environment, the solubility may get modified. Consequently, their physical stability can be expressed as their resistance to these unfolding forces which can change them into a less soluble conformational state (London et al., 2010). During the conformational changes, the proteins undergo transitions from their native and biologically active forms to nonnative and/or inactive conformations. Different proteins show varied levels of resistance to unfolding which is also termed as thermodynamic stability. The various forces which contribute to this thermodynamic stability originate from covalent bonds like disulfide bonds, electrostatic interactions, hydrophobic interactions, hydrogen bonds, and van der Waals interactions (Shakhnovich, 2006). Although, much research has been made in the domain of molecular biology, the area of peptide and protein DDS still remains to be explored properly. This problem is largely due to the restrictions imposed by the physicochemical and biological properties of these molecules as well as the routes of administration. The properties causing problems include molecule size, shorter plasma half-life, specialized transport mechanism, degradation DOSAGE FORM DESIGN CONSIDERATIONS 422 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT under varying physical and biological environments, tendency to undergo self-association, and complex feedback control mechanisms. 12.6.2.1 Physical Stability of Proteins and Peptides Owing to their complex architecture they are folded into either globular or fibrous forms which are vital for their biological action. Although, the peptide chains present in them are linear, they are transitioned into various patterns and conformations. The conformations are dependent on amino acids sequence, the covalent bonds between them, the disulfide bridges between cysteine residues, and the total conformational energy. All these factors contribute to their physical stability in terms of denaturation, adsorption, aggregation, and precipitation. 12.6.2.1.1 PHYSICAL DEGRADATION PATHWAYS Theoretically, proteins should be able to resist the conformational changes following the removal of stresses. The degradation pathways can be classified into following aspects: 12.6.2.1.1.1 FORMATION OF STABLE MISFOLDED SPECIES The basic structure of a protein is thermodynamically stable having the lowest free energy which is conceptualized that proteins may attain any conformation other than the native structure during the refolding process. However, diverse conformations have been observed during process development of refolding proteins from inclusion bodies leading to the formation of a metastable conformation. This metastable conformation can remain stable until additional energy is initiated to surmount its activation energy before refolding to the native conformation (Reid, 1999). 12.6.2.1.1.2 AGGREGATION OR PRECIPITATION OF MISFOLDED SPECIES Upon denaturation, the protein may unfold itself into a rearrangement in which the hydrophobic amino acid residues associate together to form aggregates. If this aggregation occurs on a large scale then precipitation occurs. The extent of both these processes depend on interfacial adsorption, i.e., relative hydrophilicity of the surfaces in contact with their solution. There are various factors causing these processes like huge air water interface, increased thermal motion of molecules, composition of solvents, dielectric constant, ionic strength, and pH (Reid, 1999). 12.6.2.1.1.3 SURFACE-INDUCED STRUCTURAL CHANGES/AGGREGATION Protein aggregation can also be caused during transportation wherein the formulations undergo the physical stresses of agitation or shaking. This occurs as a result of protein interactions with surfaces, e.g., the air water and air solid interfaces. In the case where protein unfolding occurs at air liquid interfaces, it may cause irreversible exposure of the interior hydrophobic core leading to intermolecular associations of nonpolar residues. In case where the protein concentration is increased, it may reduce the agitationinduced protein aggregation. Addition of small amounts of surfactants usually stabilizes the proteins against this type of stress. Previous literature indicates that with more denaturation at the interface, the adsorption process is irreversible. This fact is further DOSAGE FORM DESIGN CONSIDERATIONS 12.6 ROLE OF PREFORMULATION STUDIES IN DRUG DISCOVERY 423 supported by the formation of insoluble proteins at the interface due to the conformational changes (Reid, 1999). 12.6.2.2 Chemical Stability of Proteins and Peptides Any conformational change in these large molecules is due to the chemical reactions in the amino acid chain and/or peptide bonds. The chemical alternations and/or instability in the structure is described by varied reactions, i.e., deamidation, oxidation, reduction, hydrolysis, racemization, and beta-elimination (Reubsaet et al., 1998). 12.6.2.2.1 DEAMIDATION This reaction occurs due to the hydrolysis of the amide ( NH2) side chain within an amino acid sequence leading to the formation of a free carboxylic acid ( COOH) residue. It is best exemplified with the deamidation of asparagine and glutamine residues to aspartate and glutamate. Besides, it is transformation of a neutral residue to a negative charge residue and isomerization of the primary amino acid sequence. Deamidation process is often observed for enzyme and hormones like human growth hormone, insulin, etc. (Wright, 1991). The rate of deamidation is accelerated by the factors of pH, ionization constant, temperature, and tertiary structure. Utilization of genetic engineering and recombinant DNS technology can effectively surmount these problems. Deamidation has significant influence in treatment of diseases/disorders in humans. For instance, in the case of the cardiovascular problem i.e., atherosclerosis, there is a thickening of the cardiac arteries caused due to penetration and deposition of leukocytes in the arterial walls. In this clinical condition, there is a deamidation of Asn-Gly-Arg (NGR) residue of asparagine to isoDGR structures which bind to integrin αvβ3 on circulating leukocytes (Dutta et al., 2017). 12.6.2.2.2 OXIDATION Oxidation is a major concern and cause of degradation of proteins and peptides. The oxidation process occurs during isolation, synthesis, and storage of these molecules. Although atmospheric oxygen drastically influences the oxidative degradation, it is also facilitated in the presence of pH, temperature, and metal ions. Oxidation primarily occurs at the side chains of the proteins like histidine, lysine, tryptophan, and thyronine residues. In the case of methionine, the thioether group is highly prone to oxidation process. This oxidation process is observed under acidic conditions wherein thioether group is oxidized by the atmospheric oxygen (Deming, 2017). There are different methods/ways to control the oxidation process including: • • • • • • Oxidation scavengers, e.g., propyl gallate which block the catalysis process. Reducing agents, e.g., ascorbic acid. Chelating agents, e.g., EDTA. Storage at cold temperature. Protection from photo-lability. Addition of buffers to control the pH. DOSAGE FORM DESIGN CONSIDERATIONS 424 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT There are a number of diseases and/or disorders which occur due to oxidation of proteins leading to the formation of protein carbonyls, e.g., Alzheimer’s disease, muscular dystrophy, rheumatoid arthritis, and Werner’s syndrome (Berlett and Stadtman, 1997). 12.6.2.2.3 REDUCTION The reactions involving reduction, for instance, cause the cleavage of the intra- or intermolecular disulfide bonds of Cys Cys. The disulfide bonds are key for the stability of 3Dconformation of protein or peptide. Intramolecular bonds of Cys Cys are absolutely necessary for folding of the protein or peptide structure, leading to their biological activity. In order to stabilize the quaternary structure of the proteins, Intermolecular bonds of Cys Cys play a vital role (Bechtel and Weerapana, 2017). Folding enzymes like chaperones and oxidases belong to the family of protein disulfide isomerase. Both of these enzymes are responsible for the proper folding of proteins. In fact, various other enzymes of this family catalyze reduction and isomerization, which is useful information for the treatment of cancer and neurodegenerative diseases. 12.6.2.2.4 HYDROLYSIS The proteins are based on polypeptide chains which are linked together by peptide bonds containing various amino acids combinations. Under the influence of hydrolysis, also known as proteolysis, the peptide bonds are converted to unstable residues with significantly reduced biological activity. This occurs when these large molecules are subjected to the extreme conditions of pH, temperature, and enzymatic activity (i.e., bacterial actions) (Bull, 1950). The mechanism of proteolysis has manifold applications (Combaret et al., 2016): • It increases the immunity against the invasive pathogens. • It removes the abnormal or defective proteins and thus preventing any further aberrations at the gene level. • It provides the body with free amino acids which act as nutritious supplements in the event of lack of proper diet. • It modulates the cell metabolism by altering the functional protein levels. 12.6.2.2.5 RACEMIZATION Recemization is the process of conversion of L-amino acids into a mixture of D,L-amino acids. Apart from the amino acid, glycine, all the naturally occurring amino acids have two chiral centers in the carbon-containing chain. This chiral center is vulnerable to degradation by base-catalyzed reactions and proteolytic enzymes (Ollivaux et al., 2014). Racemization in peptides and proteins leads to the formation of diastereomers which are differentiated on the basis of their physicochemical properties like, hydrophobicity and polarity. Clinically, racemization has immense potential for the treatment of musculoskeletal disease/disorders. Under pathological conditions, the musculoskeletal tissues tend to have altered turnover rates. Owing to these turnover rates, racemized residues of the musculoskeletal protein act as valuable biomarkers (McCudden and Kraus, 2006). DOSAGE FORM DESIGN CONSIDERATIONS 12.6 ROLE OF PREFORMULATION STUDIES IN DRUG DISCOVERY 425 12.6.2.2.6 β-ELIMINATION The mechanism of β-elimination reaction is analogous to racemization process. For example, if both the temperature and pH are increased it will lead to protein inactivation. As a result, the disulfide bond will be broken, i.e., removal of SH group from the Cys residue. The degradation products from this reaction initiate various types of physical instability, viz., aggregation, adsorption, and precipitation. The β-elimination reaction can also be observed in the case of other amino acid residues, e.g., serine, threonine, phenylalanine, and lysine (Whitaker and Feeney, 1983). 12.6.3 Influence of Preformulation on the Delivery of Protein and Peptides The delivery of protein and peptides has always been challenging for the scientists both at the industrial and academic levels. The delivery of these molecules largely depends on the constraints based on the physicochemical properties like size, proteolysis, plasma halflife, permeability, immunogenicity, as well as various instabilities. Together these factors are responsible for their drastically low bioavailability. Hence, to deliver these molecules, different types of systems need to be developed and these too depend on the route of administration (Sanders, 1990). 12.6.3.1 Formulation Design Considerations Unique properties of the peptides and proteins combined with an additional drive into the latest technology have created a sense of urgency for their effective and novel DDS. However, these DDS need to be stable, bioavailable, easily manufacturable, and acceptable at the patient’s level. Though oral delivery has always been a conventional route, huge progressive research has been achieved through other routes too, e.g., nasal, parenteral, transdermal, etc. 12.6.3.2 Delivery Routes for Proteins and Peptides 12.6.3.2.1 ORAL ROUTE Delivery of these therapeutics via oral route has been a major objective for the formulation scientists but it has always been a challenge to develop a proper DDS. When administered orally, these molecules have to surmount the problems of the acidic environment of stomach, the proteolytic enzymes in GIT, and first-pass hepatic metabolism. At present, only two such drugs, i.e., Interferon alpha and human growth hormone are clinically approved to be given by oral route (Hamman et al., 2005). The other strategies include: • Permeability enhancers for paracellular transport via reversible opening of tight junctions in GIT. • Mucoadhesive delivery systems for prolonging the residence time at site of absorption thereby increasing the concentration gradient across the GIT. • Specialized DDS, e.g., macroemulsions, self-emulsifying DDS, micelles, etc. may also improve the absorption by reducing the surface resistance of the apical membrane. • Enzyme inhibitors. DOSAGE FORM DESIGN CONSIDERATIONS 426 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT 12.6.3.2.2 NASAL ROUTE Technologically, delivery through nasal cavity is far less problematic owing to fast drug absorption, adjustable particle size, bypassing of presystemic clearance, and ease of administration. This route also offers innovative pathway for the administration of systemically active drugs. The various DDS that can be developed for delivery via this route are nasal drops, nasal spray, and nasal gel. The striking characteristic of delivery through this route is the possibility of targeting brain trans-synaptically employing nanoparticles. Nanoparticles are nanosize particles having different properties to that of the material in the bulk and the current topic of research (Sharma et al., 2015; Maheshwari et al., 2015a; Lalu et al., 2017). Anatomically, the nasal epithelium has an area of approximately 150 cm2 which facilitates better permeation. However, this surface area poses limitations to the dose range to be administered. If enhancers are used then the permeability of the epithelium can be altered to achieve significantly improved bioavailabilities. Molecules whose delivery has been achieved by this route are luteinizing-hormone-releasing hormone (LHRH), thyrotropin-releasing hormone vasopressin, calcitonin, oxytocin, glucagon, insulin, etc. both in animal and human models (Thwala et al., 2017). 12.6.3.2.3 PULMONARY ROUTE The pulmonary route offers an attractive mode of transportation of proteins and peptides by virtue of large surface area (i.e., approximately 80 140 m2) of the lungs which supports in drug absorption. Anatomically, the thickness of alveolar epithelium is between approximately 0.1 and 0.5 mm which allows fast drug absorption. Therefore, delivery of drug through the alveoli can be effectively achieved by developing an aerosol formulation. Furthermore, the alveoli have a mass median aerodynamic diameter of less than 5 µm and bypass the systemic first-pass metabolism in GIT. Together all this presents the pulmonary administration as a promising route for delivery of proteins and peptides (Thwala et al., 2017). 12.6.3.2.4 BUCCAL ROUTE The buccal mucoadhesive formulations or, in short, mucoadhesive DDS provides an alternative route as compared to the conventional oral route. Owing to its mucous layer, the DDS containing a small quantity of API can easily adhere to the buccal mucosa wherein it remains adhered for a prolonged time and can be also be detached easily. The surface area of the buccal epithelium is very small, i.e., approximately 100 cm2. Various DDS that can be developed for delivery include matrix tablets, films, discs, microspheres, hydrogels, etc. However, limitation still persists for the innovative devices which can prove to be better than the conventional buccal systems. Possibly, the buccal mucosa can be a prospective route for controlled delivery of peptides and protein drugs (Sudhakar et al., 2006). 12.6.3.2.5 TRANSDERMAL ROUTE Besides the oral route, transdermal is second most desired route of drug administration (Tekade et al., 2017). Transdermal route has various therapeutic advantages like sustained drug delivery, steady plasma profile, beneficial for the API with shorter half-lives, reduced DOSAGE FORM DESIGN CONSIDERATIONS 12.6 ROLE OF PREFORMULATION STUDIES IN DRUG DISCOVERY 427 systemic side effects, easy dosing, avoidance of first-pass metabolism, and better patient compliance. All these benefits make it an attractive route. Transdermal delivery is basically through the skin which presents a large surface area. Delivery of therapeutic peptides is bit difficult as the molecules have to cross the stratum corneum, the uppermost skin barrier. Structurally, the stratum corneum is so developed that it obstructs the movement of the foreign molecules into the body and minimizes water loss. Thus, it acts as a strong barrier and strictly monitors the permeability of any molecule. In the case of peptides, delivery across skin is extremely difficult due to two physicochemical properties, i.e., polarity and size of these molecules (Naik et al., 2000). Various peptide molecules which have been formulated as transdermal DDS are insulin, calcitonin, and vasopressin, which are mostly based on the Iontophoresis technique (Banga and Chien, 1993). Apart from that, when we talk about novel delivery vehicles used for skin delivery, liposomes is the one which is exploited widely (Maheshwari et al., 2012). 12.6.3.2.6 OCULAR ROUTE Primarily, the ocular route is employed for localized delivery of peptide and protein. These molecules can be delivered by developing the formulations like solutions, suspensions, and ointment. Not only is ocular DDS exciting but it is also challenging, and it is being critically acclaimed by the pharmaceutical researchers (Behar-Cohen, 2004). In a few animal studies, various peptide drugs have been reported to be absorbed into the systemic circulation, e.g., enkephalins, thyrotropin-releasing hormone, LHRH, glucagon, and insulin (Chiou and Chuang, 1988). There are some common delivery systems which can also be employed for improving the ocular delivery of peptide-based drugs, e.g., nanoparticles, niosomes, gels, ocular inserts, and bioadhesive (Maheshwari et al., 2015b; Lalu et al., 2017) 12.6.3.2.7 RECTAL ROUTE Rectal route is one of the routes of drug administration which is trending in pharmaceutical research. The prime reasons for this include drastically reduced hepatic first-pass metabolism and decreased proteolytic degradation which eventually augments the systemic bioavailability (Ibraheem et al., 2014). As per reports, absorption of insulin can be increased utilizing the absorption enhancers like sodium glycocholate. Also, bile salts have been reported to improve the absorption of vasopressin, gastrin, calcitonin analogs, and human albumin. 12.6.3.2.8 VAGINAL ROUTE Since ancient time, the vaginal route has been acknowledged for delivery of substances. Due to its anatomical position, high blood perfusion, and larger surface area, it is now being extensively explored for systemic drug delivery. Of late, several studies have indicated its potential as a good site for permeability of macromolecules which can be applied for systemic delivery of peptides and proteins (Benziger and Edelson, 1983). Various drugs which have been formulated as vaginal DDS are bromocriptine, oxytocin, misoprostol, calcitonin, LHRH agonists, human growth hormone, and insulin. Currently, more focus has been given for vaccine delivery by the vaginal route which includes the cholera vaccine. DOSAGE FORM DESIGN CONSIDERATIONS 428 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT 12.6.4 Factors Causing Problems in Protein Delivery With the commercial launch of insulin, thyroid hormones, and coagulation Factor VIII in the early and mid-1900s much progress has been made in the field of proteins and peptides therapeutics. Earlier the production of these therapeutics was hampered by complex and expensive manufacturing processes. However, the recombinant technology and solidphase synthesis paved the way for considerable investment in the domain of proteins and peptides. To date, over 200 proteins and peptides have been approved by USFDA for the treatment of different human diseases/disorders. However, under in vivo conditions, these molecules have failed to deliver their therapeutic promise owing to their substantially compromised pharmacokinetics. The various reasons for the uncharacteristic pharmacokinetic profiles include low oral bioavailability, reduced stability and shelf life, immunogenicity, small plasma half-life, and poor permeability (Lu et al., 2006). There are various factors which restrict the therapeutic efficacy of these molecules and are discussed hereunder; 12.6.4.1 Biochemical and Biological Factors Selection of a protein drug for targeted delivery immensely depends on two important properties, viz., its biochemical and biological properties. As the conformations in the proteins can be of any type, i.e., secondary, tertiary, or quaternary, often a state of higher order is required for biological functions. Further, as already understood from the previous sections, physical and chemical instability also has a huge impact on their biological functions. The protein drugs are subjected to extreme conditions of proteolysis, pH variations, and effect of lysosomes during their delivery to a particular site which can cause unwanted changes in their confirmation. The immunogenicity is another serious issue during formulation development as it can initiate various adverse immune responses within the humans. For example, humanization of murine monoclonal antibodies is required to circumvent human antimouse antibody formation (Jiskoot et al., 2012). 12.6.4.2 Selection of Targeting Ligands Choice of a particular ligand for targeting a cell is particularly important in the case of cancer treatment (Srinivasarao and Low, 2017). This selection is dependent on some basic concepts; • Ideally, the ligand must be able to bind to the specific tumor cells. • The tumor-associated antigens are found in both normal as well as cancerous tissues. Hence, the ligand must be able to differentiate between them and selectively deliver the drug. The ligands employed for targeting of tumor cells can be of three types viz. • Small molecular ligands, e.g., vitamins. • Peptides based ligands, e.g., somatostatin. • Protein based (macromolecular) ligands, e.g., transferrin. DOSAGE FORM DESIGN CONSIDERATIONS ABBREVIATIONS 429 Holistically, the selection of a particular ligand must be based on its ability to achieve maximum specificity toward a cancerous cell. 12.6.4.3 Uptake of Protein Drugs In order to show their cytotoxic effects, the protein drugs have to overcome several barriers. The plasma membrane of the tumor cell presents the first barrier to the ligand conjugated protein. Apart from this, within the cell, various biochemical processes occur in a regulated manner and that too due to the coordination of the different compartments like cytosol and nucleus. These compartments present additional barriers to the extensive ligand-based targeting. The uptake mechanism is based on the endocytosis process wherein the ligand conjugated protein binds to a specific receptor on the cell surface. The conjugated material is folded inwards along with the plasma membrane. The so formed endocytic vesicles pinch off from the plasma membrane. After entry inside the cytosol, the vesicles are acidified to pH 4.5 5.0 and develop into endosomes. A further decrease in the pH causes the dissociation of conjugates from their receptors. Following this, the ligand protein complex is facilitated to enter into the endosomal compartments. Subsequently, the free receptors travel back to the surface of the cell for further transportation process (de Franciscis, 2018). 12.7 CONCLUSION The science of understanding the preformulation studies is of paramount importance for the design and development of a suitable DDS eventually leading to the effective treatment of a disease/disorder. The study of various parameters of preformulation is equally important both for the new molecules as well as for already existing marketed drug, or peptides and proteins. Although various synthetic drug molecules are already available in the market, their long-term success is hampered owing to their physical and chemical instability leading to poor bioavailability as well as various adverse effects. Recent advancements in the understanding of the structure and biochemistry of peptides and proteins has intensified the research in the field of recombinant technology in the pharmaceutical industry. It is interesting to note that in spite of having physicochemical constraints and complex structural conformations, peptide drugs have proved their therapeutic potential against several diseases. Further advancements in the science and understanding of physicochemical properties of drugs and proteins as well as the biological system of the human body would facilitate the design and development of novel DDS or formulations circumventing the various limitations associated with the current drug or peptide therapies. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. ABBREVIATIONS APIs BCS DDS Active pharmaceutical ingredients Biopharmaceutics classification system Drug delivery system DOSAGE FORM DESIGN CONSIDERATIONS 430 DSC DTA GIT HTS IND LHRH 12. ROLE IN DRUG DISCOVERY AND PHARMACEUTICAL PRODUCT DEVELOPMENT Differential scanning calorimetry Differential thermal analysis Gastrointestinal tract High-throughput screening Investigational new drug Luteinizing-hormone-releasing hormone References Ahlneck, C., Lundgren, P., 1985. Methods for the evaluation of solid state stability and compatibility between drug and excipient. Acta Pharm. 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Tekade4,5 1 Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India 2Department of Chemistry, Tripura University (A Central University), Suryamaninagar, Tripura, India 3Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India 4National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 5 Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 13.1 Introduction 13.1.1 Fundamentals of Salt Preparation 13.1.2 Merits and Demerits of Pharmaceutical Salts 13.1.3 Rationale of the Pharmaceutical Salt Preparation 13.2 Selection of the API and Counterions for Pharmaceutical Salt Preparations 13.2.1 Salt Selection Strategy Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00013-7 436 13.2.2 13.2.3 13.2.4 13.2.5 13.2.6 pKa Rule for Salt Formation Ionic Factors Biopharmaceutical Factors Biological Factors Dosage Form and Routes of Administration 13.2.7 Choice of Organic Solvent 13.2.8 Decision Tree for Salt Selection 437 438 439 440 440 13.3 Characterization of the Pharmaceutical Salt 13.3.1 Structure Confirmation 435 441 443 446 446 448 449 449 451 451 © 2018 Elsevier Inc. All rights reserved. 436 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT 13.3.2 Assessment of the Physicochemical Properties 13.3.3 Physical Properties 13.3.4 Assessment of the Process Impurities 13.3.5 Stability and Preformulation Assessments 13.3.6 Large-Scale Methods 13.3.7 Method Optimization and Large-Scale Production 452 453 453 454 455 457 13.4 Regulatory Requirements 13.4.1 Patenting Prospective 13.4.2 Safety and Efficacy 459 460 461 13.5 Conclusion 464 Acknowledgment 465 Abbreviations 465 References 466 Further Reading 471 13.1 INTRODUCTION Salt is defined as “A chemical compound consisting of an assembly of cations and anions” in the “Compendium of Chemical Terminology” published by the “International Union of Pure and Applied Chemistry,” which is also referred as the IUPAC Gold Book. Therefore, a pharmaceutical salt can be defined as the stoichiometrically charge balanced product of the chemical reaction between an active pharmaceutical ingredient (API) with one or more cationic or anionic atom, and a counterion (Jenkins, 2014). In the past decade, the pharmaceutical industry has been undergoing a lot of turmoil regarding new drug discovery and development. The increased economic constraints, regulatory burdens, and patent expiry of the blockbuster drugs are the prime causes for the increased requirement for new drug discovery and development. The advent of newer drug discovery tools, such as molecular modeling, combinatorial chemistry, and design software, and methodologies for high-throughput screening have resulted in large numbers of hits. However, the development of the new drug is restricted by the substantial problems in solubility, stability, toxicity, as well as pharmacokinetics properties (Davidov-Pardo and McClements, 2014; Khadka et al., 2014; Bhattachar et al., 2015). The physical form of drug substances is a prime matter of concern in the new drug development process and has given nightmares to the industrial pharmaceutical chemists and formulation scientists to develop an acceptable dossier properly regarding the analytical chemistry, pharmacokinetics, toxicology, clinical studies, quality assurance, regulatory and project management (Aitipamula et al., 2014; Sanphui et al., 2015; Duggirala et al., 2016). On the other hand, preparing the salt form of API has given a new sanguinity to solve many of these problems. If we look back, the first “vegetable alkalis” later known as alkaloids, were extracted, isolated, and purified as crystals of their acidic salt from the plant materials, e.g., morphine hydrochloride, quinine sulfate, codeine phosphate, atropine sulfate, or pilocarpine nitrate, etc. They were found to be highly water soluble and more stable than their free bases. Enhancement of these physical properties also enabled the pharmaceutical industry to formulate them as the preferred forms for therapeutic use. Similarly, the basic salt form of the acidic drugs, like aspirin, diclofenac, barbiturates, DOSAGE FORM DESIGN CONSIDERATIONS 13.1 INTRODUCTION 437 HMG CoA reductase inhibitors, or antibiotics like penicillin, have been used clinically for many years (Wermuth and Stahl, 2002; Kumar et al., 2007). The fact that half of the entire clinically used molecules of drugs are administered in salt form has paved the way for new drug development by preparing a proper salt form of the drug. The suboptimal physicochemical or biopharmaceutical properties of a new drug substance can often be overcome by formation of salt using a counterion. Thus, the investigation of the appropriate form of salt and strategies for salt selection can unlock new opportunities and fulfill a variety of objectives in the new drug development process (Wermuth and Stahl, 2002; Makary, 2014). 13.1.1 Fundamentals of Salt Preparation Chemically, salt is the product of a neutralization reaction between an acid and a base. Most of the drug substances are either a weak base or a weak acid in nature, and hence their salt formation is possible by using a counterion. The acidic nature of drug substances are attributed to the carboxylic COOH or phenolic OH functions, while the alkalinity is primarily because of the amino function of the presence of nitrogen atoms in the drug molecules. The ionic interaction between ionized drug molecules and an oppositely charged counterion, in a solution phase, leads to the neutralization reaction and forms crystals of the salt form (Bhattachar et al., 2015). The drug and the counterion remain ionized in the solvent or the liquid medium depending on the dielectric constant. However, under favorable conditions, the neutral salt form crystallizes out of the liquid medium due to the intermolecular columbic force of attraction between two charges species. The accomplishment and stability of formation of salt depend on the relative strength of the acidity or basicity of the two species involved (Bighley et al., 1996). The salt crystallizes out when the crystal lattice energy of the solid salt is higher than the solvation energy of the solvent. In other words, the salt solubility depends on the lipophilicity, polarity, molecular size crystal packing, ionization potential, and presence of solvates in the salt as well as the nature of the solvent (Florence and Attwood, 1998). Salts are prepared from the free base or acid of the drug substance by reacting with the counterion acid or base in stoichiometric molar ratios in an appropriate solvent system. Sometimes, the salt can also be prepared by salt exchange, where another salt with a counterion is treated with a free base or acid in a particular molar ratio in an appropriate solvent. The salt is finally recrystallized and isolated. In the initial phase, an assortment of salts are developed for every new drug substance, and their properties are evaluated during the preformulation study (Bastin et al., 2000). However, due to the limited availability of resources at the early stage of development of a drug, a balanced approach must be adopted. Commonly used salts like sodium or hydrochloride are beneficial because of their low toxicity and low molecular weight. However, if higher solubility and bioavailability is desired, then the salts like mesylate may offer the advantages (Engel et al., 2000). The salt formation process is summarized in Fig. 13.1. DOSAGE FORM DESIGN CONSIDERATIONS 438 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT Counter ion Drug Solvent Ionic interaction Ionized drug Ionized counter ion Crystallization FIGURE 13.1 The process of drug salt formation. 13.1.2 Merits and Demerits of Pharmaceutical Salts The salt form of the API has more applications in the pharmaceutical research and product development. Several objectives, such as quality, safety, and performance of drugs, can be fulfilled by the salt formation approach. The pharmaceutical properties of the drug can be considerably altered by choosing proper counterions which can have the edge over the API alone. Several advantages of the pharmaceutical salt are enumerated below. 1. The salt form can drastically enhance the dissolution and solubility profile of the API due to rapid ionization in physiological condition (Serajuddin, 2007; Stahl and Nakano, 2002; Elder et al., 2013). 2. The salt formation can impart enhanced chemical stability to the API by inducing crystallinity. It has also been observed that the salt formation can lead to improved thermal stability as well as photostability along with resistance to hydrolysis and DOSAGE FORM DESIGN CONSIDERATIONS 13.1 INTRODUCTION 3. 4. 5. 6. 7. 8. 439 hygroscopicity. The crystal form is practically easy to purify, more resistant to oxidation thereby giving longer shelf life to the drug (Di and Kerns, 2015; Bighley et al., 1996; Badawy, 2001; Huang and Tong, 2004; Walking et al., 1983). The crystalline nature of the salt forms has significantly affected the formulation design of the drug substances. The improved compressibility of the salt is helpful in the tablet formulation. Sometimes, it has also been extended to the controlled release dosage form and targeted drug delivery approaches (Šupuk et al., 2013; Kaur et al., 2016; Tacar et al., 2013). The industrial processing of isolation and purification of drugs including the final step of their synthesis can be achieved using salt formation and can prove to be an economical alternative to chromatographic techniques (Di and Kerns, 2015; Snead and Jamison, 2013; Baxendale et al., 2015). Salt formation approach has been utilized for improving the organoleptic properties of the drugs with bitter taste such as antibiotics. This property of the salt has given the opportunity to the formulation scientist to develop palatable pediatric dosage forms (Sohi et al., 2004; Pein et al., 2014). Due to better solubility, salt formation also diminishes the pain at the site of injection. This was a matter of concern for penicillin when given by intramuscular route (Berge et al., 1977). The salt form drastically improves the permeability across the membranes leading to enhanced efficiency and efficacy of the drug. At the same time, several other advantages such as dose reduction decreased toxicity, and improved bioavailability can also be accomplished due to greater permeability of the salt form of the drug (Dalpiaz et al., 2017; Brayden and Walsh, 2014). The salt formation approach has also been a concern of extending the patent protection of several blockbuster drugs (Abdel-Magid and Caron, 2006; Kapczynski et al., 2012a; Verbeeck et al., 2006). On the contrary, preparation of pharmaceutical salts is an additional step in the synthetic process. Therefore, it requires an additional process of purification and impurity profiling of the pharmaceutical salt and thereby increases the cost of the product. However, improper salt selection strategies may impart several drawbacks in the formulation design. The acids released from the salt can erode the punch tooling leading to a problem in the tableting. Also, the reduced percentage of API increases the powder volume of tablet and capsule filling. This is a highly occurring phenomenon in the case of hydrochloride salts which tend to release hydrochloride gas when mixed with incompatible excipients or process related chemicals. Frequently, the hydrochloride salts display reduced dissolution in gastric fluid causing precipitation of the free drug. As a result, the pH of the microenvironment is also altered (Stahl and Nakano, 2002; Tong, 2009). 13.1.3 Rationale of the Pharmaceutical Salt Preparation The pharmaceutical chemist, while designing the proper salt selection strategy, considers the issues like chemical process, rate, yield, cost, and quality of the crystallization, and the availability of counterions. On the other hand, the pharmaceutical formulator is more DOSAGE FORM DESIGN CONSIDERATIONS 440 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT concerned with the stability, hygroscopicity, processability, and solubility of the salt form. Similarly, the priority of the metabolism group is on the pharmacokinetic profile, whereas the pharmacologist targets the toxicological effects of the drug and its counterion. Therefore, choosing the proper salt form requires assessing the best salt form to screen for a particular drug candidate (Gould, 1986). Many pharmaceutical formulations are required to be dispensed in their salt form as the salt form provides a higher drug concentration in solution than the free acid or base (nonionized forms). Salts can undergo crystallization facilitating easy isolation, purification, and processing during dosage form preparation. In earlier days the number of available salts forms were limited, however, due to the advancement of knowledge these days, numerous counterions have been identified which are used as safer alternatives to one another. The stability of salt forms has also been particularly beneficial for developing pharmaceutical products with longer shelf life (Wiedmann and Naqwi, 2016). Therefore, the salt formation strategy can prove to be highly valuable in the preparation of pharmaceutical dosage form. However, to attain the suitable salt form of the API, it requires the combined efforts of several groups of pharmaceutical scientists with a rational and acceptable salt selection strategy. 13.2 SELECTION OF THE API AND COUNTERIONS FOR PHARMACEUTICAL SALT PREPARATIONS 13.2.1 Salt Selection Strategy The salt selection process has been well established and has not changed over the past decades. However, the ever-changing pharmaceutical industry has been compelled to rethink about newer considerations to improve the overall salt selection process, mainly because the salt can alter most of the physicochemical API properties. Therefore, it is imperative to access the impact of salt formation on the overall formulation and biological properties (Tong, 2009). Similarly, demand for novel drug delivery systems, improvement of the biopharmaceutical properties of new drug candidates, and moreover shorter timeframes for the development of the desired formulation are some of the compelling factors to select the precise salt form in the very first attempt. In the current era, novel drug delivery systems such as liposomes (Maheshwari et al., 2015b; Maheshwari et al., 2012), solid lipid nanoparticles (Tekade et al., 2017b; Soni et al., 2016), polymeric nanoparticles (Sharma et al., 2015; Maheshwari et al., 2015a), and carbon-based systems (Tekade et al., 2017a) are gaining vital popularity. Thus, the effect of the salt form selection on the drug performance in these systems must be assessed as part of the salt selection process. Ideally, the salt selection process starts before the clinical trials so that the drug development process becomes more reliable because altering the salt form at a later stage will lead to a recurrence of formulation, stability, and toxicological studies which in turn will increase the development time and cost. The change in the salt form will also force additional evaluations like impurity profiling, pharmacokinetic equivalence (PK-bridge), bioequivalence (bio-bridge), as well as toxicity equivalence (tox-bridge) studies to the previous salt form (Kumar et al., 2008). DOSAGE FORM DESIGN CONSIDERATIONS 13.2 SELECTION OF THE API AND COUNTERIONS FOR PHARMACEUTICAL SALT PREPARATIONS 441 Therefore, the selection of a proper salt form of the API should be rational and efficient as the deficiency of a suitable strategy will result in the preparation of various candidates for preformulation evaluation as well as the loss of drug products, time, and money. The selection process must consider all kinds of aspects to arrive at a suitable decision tree. 13.2.2 pKa Rule for Salt Formation Organic acid and base are commonly defined using the theory formulated by Johannes Nicolaus Brønsted (1923, Denmark) and Martin Lowry (1923; England) also known as the Brønsted Lowry theory. According to this theory, a substance that gives up or donates a proton (hydrogen ion, H1) is called as Brønsted Lowry acid (Designated as HA), and a substance that can accept a proton is called Brønsted Lowry base (Designated as B) (Wiedmann and Naqwi, 2016; Brittain, 2009). Therefore, acid and base can be expressed as: Ka Acid 5 HA " H1 1 A2 ðConjugate baseÞ Kb Base 5 B 1 H1 " BH1 ðConjugate acidÞ (13.1) (13.2) 2 The anion A acts as a base in the reverse direction and hence is called a conjugate base, whereas the cation BH 1 serves as an acid in the reverse direction and is known as a conjugate acid. The Ka and Kb are referred to as the dissociation constants/equilibrium constants/ionization constants of the acid and base, respectively. In the pharmaceutical and biological systems, water serves as an amphoteric solvent, acting as both an acid and a base, and therefore it is the basis of the hydrogen ions as well as hydroxide ions. As per the Brønsted Lowry theory, the dissociation of water into hydronium and hydroxide ions can be explained as: Kw H2 O 1 H2 O " H3 O1 1 OH2 (13.3) In this case, Kw is known as the dissociation constant of water. The value of log Kw (pKw) at 25 C is 14. In an aqueous system, the acid can contribute a proton to water or a base can accept a proton from water. In this case, the Brønsted Lowry equation will be Ka HA 1 H2 O " H3 O1 1 A2 Kb B 1 H2 O " BH1 1 OH1 (13.4) (13.5) Therefore, in a forward reaction where the acid is dissociating in aqueous medium the dissociation constant, Ka 5 ½H3 O 1 ½A2 ½HA whereas the dissociation constant, DOSAGE FORM DESIGN CONSIDERATIONS (13.6) 442 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT Kb 5 ½BH 1 ½OH2 ½B (13.7) Salt is the neutralization reaction product of a proton from an acid (HA) to a base (B). Ks HA 1 B " HB1 1 A2 H2 O Ks 5 (13.8) ½HB1 ½A2 ½H2 O ½HA½B (13.9) Now if we multiply eq. (13.6) with (13.7): Ka Kb 5 ½H3 O1 ½A2 ½HB1 ½OH2 ½HA½B (13.10) Since the product [H3O1] [OH2] is the ionization product of water, the Eq. (13.9) can be rearranged as: Ka Kb ½A2 ½HB1 ½H2 O 5 Kw ½HA½B (13.11) Now the Eq. (13.11) may be rewritten as Ka Kb 5 Ks Kw (13.12) If converted to the Sørensen scale the Eq. (13.12) becomes: pKS 5 pKa 1 pKb 2 pKw (13.13) Determination of pKa value of an API is the critical parameter for all ionizable functional groups to determine the strength of acids and bases (Table 13.1). Most of the drug substances and pharmaceutical products fall in the pKa range of 4.5 to 9.5 which means that the pharmaceutical products are fundamentally weak acids or weak base (Table 13.2). Similarly, the calculation of the pKa or pKb values of the API and counterions enables to estimate the pKs value as described in Eq. (13.13). The pKs value, in turn, can be used to determine the efficiency of salt formation by calculating the relative position of the TABLE 13.1 Relationship Between pKa and Strength of Acids and Bases Strength pKa Acid Base ,0 Very strong Extremely weak 0 4.5 Strong Very weak 4.5 9.5 Weak Weak 9.5 14 Very weak Strong .14 Extremely weak Very strong DOSAGE FORM DESIGN CONSIDERATIONS 13.2 SELECTION OF THE API AND COUNTERIONS FOR PHARMACEUTICAL SALT PREPARATIONS 443 TABLE 13.2 The pKa of Some Common Organic Functional Group Common Organic Functional Group pKa Acid ,1 Sulfonic acid 2 Phosphonates 2.5 5 Carboxylic acids Aromatic amines 7 10 Thiols, phenols, imides, sulfonamides Aliphatic amines Base NH2 S H2N O N S N N S NH2 NH2 FIGURE 13.2 Famotidine: sulfamoylpropanimidamide. O 3-[({2-[(diaminomethylidene)amino]-1,3-thiazol-4-yl}methyl)sulfanyl]-N- equilibrium. For example, if pKa 5 2 salt formation efficiency would be 90.91% and for pKa 5 3, the neutralization efficiency would be 96.93%. Let us consider the API case, famotidine, a proton pump inhibitor (shown in Fig. 13.2) which has an average pKa value of 6.7 considering there is multiple salt formation site due to the presence of more than one nitrogen atoms. It indicates that the API would be a weak base and the pKb for famotidine (Fig. 13.2) would be equal to 7.3 (Brittain, 2009). Now if we have a series of acids with variable pKa values, it is possible to calculate the corresponding pKs values and salt formation efficiencies. Table 13.3 summarizes the possibility of salt formation efficiency with acidic counterions of variable pKa. Because salt formation of around 98% yield will be most suitable, the selection of a salt former having pKa value less than 3.0 would be identified and prepared in the laboratory. A list of pharmaceutically acidic counterions which can be used for the salt formation of famotidine along with the percentage efficiency was compiled in Table 13.4. 13.2.3 Ionic Factors The degree of ionization or the pKa value of the drug and counterion is essential for the successful formation of salt as well as for the pharmacodynamics, solubility of the drug, and its formulation that depends on the pKa value of API as well as pH of the solution. The solubility of API increases significantly by the ionization process at pH values higher DOSAGE FORM DESIGN CONSIDERATIONS 444 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT TABLE 13.3 Salt Formation Efficiency of Various Counterions With Famotidine pKa of Acidic Counterion for Famotidine pKs 5 (pka of Counterion 1 pKb of Famotidine) 14 Calculated Percentage of Salt Formation 6.0 0.7 69.1 5.0 1.7 87.6 4.0 2.7 95.7 3.0 3.7 98.6 2.0 4.7 99.6 1.0 5.7 99.9 TABLE 13.4 Salt Formation Efficiencies of Several Pharmaceutically Acceptable Inorganic and Organic Counterions for the API Famotidine Name of the Counterion pKa of the Counterion Salt Formation Efficiency INORGANIC HCl 6.1 to 3 100 H2SO4 3 HNO3 1.32 99.99 H3PO4 1.96 99.58 CH3SO3 1.2 99.99 C6H5SO3 0.7 99.9 Oxalic acid 0.27 99.81 Maleic acid 1.92 99.59 Malonic acid 2.83 98.85 Salicylic acid 2.97 98.65 100 ORGANIC Tartaric acid 3.02 98.58 Fumaric acid 3.03 98.56 than the pKa of a weak acid and lower than the pKa of a weak base. This principle of pH-dependent solubility may be manipulated to obtain appropriate salt form of the drugs (Williams et al., 2013). The limiting pH below which in case of a weak base or above which in case of a weak acid the solid phase is the salt in spite of the free base, or free acid of the API is known to be the pH max. Therefore, the counterion must be adequately strong to shift the solution pH to pH max (Figs. 13.3 and 13.4). DOSAGE FORM DESIGN CONSIDERATIONS 13.2 SELECTION OF THE API AND COUNTERIONS FOR PHARMACEUTICAL SALT PREPARATIONS 445 FIGURE 13.3 The relationship between pH and solubility of a weak base of pKa 5 9. FIGURE 13.4 The relationship between pH and solubility of a weak acid of pKa 5 4. For example, the salts of a weak base will more readily form with strongly acidic counterions like hydrochloride than that of weakly acidic counterions like citrate (Williams et al., 2013). It has been observed that the salt forms of basic drugs require a counterion with minimum two pH less than the drug’s pKa. Whereas, in case of acidic drugs the pKa of the counterion is two pH higher than the drug’s pKa (Brittain, 2009; Williams et al., 2013). Where the pKa of the API and counterion are not different significantly, it leads to formation of a solid complex which is rapidly broken down into the individual ions in aqueous condition (Brittain, 2009; Williams et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS 446 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT The commonly used counterions for the pharmaceutically acceptable salt formation are published in the Orange Book database of the US Drug and Food Administration (FDA) (http://www.fda.gov/cder/ob/). These counterions have been evaluated for the frequency of use and occurrence in different dosage forms (Pudipeddi et al., 2002). Indicative examples of the used counterions along with their pKa value have been given in Table 13.5 (Wiedmann and Naqwi, 2016; Brittain, 2009; Williams et al., 2013; FDA; Pudipeddi et al., 2002). 13.2.4 Biopharmaceutical Factors The administration route of the salt form of the API can alter the pharmacodynamic properties of the drug at the site of action. Therefore, selection of a suitable salt form depends on the factors related to the technological aspect, manufacturing processes, and the biopharmaceutical issues related to the routes of the administration. Drug substances with pKa above 11 or acidic with pKa below 1 are hardly absorbed into the blood circulation as they remain ionized throughout the physiological pH range. These drugs are better substances for dissolution but poorest regarding membrane permeation due to lack of lipophilicity. The salt formation of such drug candidates can neutralize the charge by combining such ionic drugs with suitable counterions resulting in a liposoluble ion-pair. The lipid soluble ion-pair can diffuse via the intestinal membranes and reach the systemic circulation where it may again regenerate the individual ions (Stahl and Nakano, 2002). Many times, the essential metal ions salt complexes of Fe12, Mg12, Cu12, and Zn12 are given for better absorption of the drugs. However, these inorganic metal ions can alter the biopharmaceutical properties by the formation of chelate with the drug leading to adverse effects. This has been observed in the case of increased bioavailability of dicumarol when administered with antacids containing Al and Mg or negative interaction of Ca12 with tetracyclines. Therefore, the salt formation may lead to both harmful as well as beneficial effects, and hence it is obligatory to evaluate the biopharmaceutical properties of drug salt forms during the drug development process. 13.2.5 Biological Factors Currently, it is a regulatory requirement to adjust the doses of the salts to that of active drug substances regarding both pharmacokinetic, pharmacodynamics, and safety profile. Two different salts of the same API can have different ADME profile, especially during absorption. A systematic review can be found in the literature (Pfannkuch et al., 2002). The relative difference in the drug absorption affects the first pass metabolism, distribution, metabolism, and elimination. The altered pharmacokinetic profile leads to differences in the pharmacodynamic profile as well as the toxicity of the drug candidate. The degree of ionization can also alter the pharmacodynamic effects of drugs as seen in the case of barbiturates. More than 50% of the nonionized protein-bound drug reaches the brain while the other 50% remains ionized in the blood. Therefore, the salt formation can be used to prolong the duration of action or to reduce the adverse effects. For example, DOSAGE FORM DESIGN CONSIDERATIONS 447 13.2 SELECTION OF THE API AND COUNTERIONS FOR PHARMACEUTICAL SALT PREPARATIONS TABLE 13.5 List of Commonly Used Pharmaceutically Acceptable Acidic and Basic Counterions Percentage of Frequency Used in Counterions pKa Oral Formulations Injectable Acetate 4.756 0.9 5.8 Benzoate 4.19 0.3 Besylate 0.7 0.6 1.4 Bromide ,6 4.1 4.3 Camphorsulfate 2.14 0.5 Chloride 26 56.6 53.4 Chlortheophyllinate 5.28 0.3 0.5 Citrate 3.128 3.4 2.4 Ethandisulfonate 22.1 0.3 0.5 Fumarate 3.03 1.6 0.5 Gluceptate 0.5 Gluconate 3.76 0.3 0.5 Glucuronate 3.18 0.5 Hippurate 3.55 0.3 0.5 Iodide (most acidic) , 26 0.3 1 Isethionate 1.66 Lactate 4.9 0.3 2.9 Lactobionate 3.2 0.5 Laurylsulfate 1.3 0.3 Malate 3.459 0.3 0.5 Maleate 1.92 6.9 0.5 Mesylate 21.2 4.4 3.9 Napsylate 0.17 0.6 Nitrate 21.32 0.6 Octadecanoate 4.9 0.3 Oleate 0.4 0.5 Oxalate 1.271 0.3 Pamoate 4.9 0.9 Phosphate 1.96 2.5 ANIONS (ACIDIC) 0.5 0.5 3.4 (Continued) DOSAGE FORM DESIGN CONSIDERATIONS 448 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT TABLE 13.5 (Continued) Percentage of Frequency Used in Counterions pKa Oral Formulations Polygalacturonate 3.6 0.3 Succinate 4.207 1.9 0.5 Sulfate 23 7.5 8.2 Tartrate 3.02 2.8 3.9 Tosylate 21.34 0.3 0.5 Trifluoroacetate 0.52 Injectable CATIONS (BASIC) Benzathine 4.46 1.3 1 Calcium 12.6 12 2.9 Cholinate . 11 1.3 Diethanolium 9.28 1 Diethylamine 10.93 1 Lysine 10.93 1 Magnesium 11.4 2.7 Meglumine 9.5 4.9 Piperazine 5.68 1.3 Potassium (most basic) 14 13.3 Procaine 9 1 Sodium 14 65.3 85.4 Tromethamine 8.02 2.7 1 1 the tertiary chlorpromazine chloride is more potent and less toxic than the quaternary chlorpromazine chloride salt. In the case of salts of cyclohexylsulfamic acid (cyclamates), the bitter-tasting drugs can be made palatable owing to the sweet taste of cyclamate. However, it is noteworthy that the chosen counterions must not alter the therapeutic effects of the parent drug. Therefore, it is prerogative to study the complete biological profile of a new salt, considering it as a new chemical entity (Pfannkuch et al., 2002). 13.2.6 Dosage Form and Routes of Administration Because the salt form of a drug substance is considered as a new chemical entity, the salt is assessed for changes in its physical state during the product’s shelf life as well as the chemical stability. Solid dosage forms like capsules and tablets are the most commonly DOSAGE FORM DESIGN CONSIDERATIONS 13.2 SELECTION OF THE API AND COUNTERIONS FOR PHARMACEUTICAL SALT PREPARATIONS 449 utilized dosage form due to their economic and stability aspects. Therefore, the salt form of drug substances which are used as solid dosage forms via the oral route is evaluated for its solubility and dissolution in the gastrointestinal environment (Stahl and Nakano, 2002). Due to the rapidly changing pH of the gastrointestinal tract, the orally administered drug salt form encounters various changing environments. It may undergo precipitation and redissolution after the dissolution. Therefore, different approaches should be taken into consideration for the salt formation of acidic and basic API. For liquid oral dosage forms like suspension or solutions, the salt formation is typically used to either enhance the palatability and solubility of the drug or to increase the chemical stability of the drug in aqueous media. However, in the case of parenteral administration, the drug salt forms are used to increase the solubility as well as the chemical stability. However, the topical applications have different requirements altogether. The salt forms in topical formulations are used to nullify local irritation by neutralizing the pH. At the same time, the salt forms are considered to enhance the drug penetrability through the mucosal barrier and patient compliance (Serajuddin, 2007). 13.2.7 Choice of Organic Solvent Choice of the organic solvents in the salt formation leads to the formation of anhydrous salt which yields better solubility and dissolution profile than that of the hydrated form. The crystallization of the salt is achieved only when the drug concentration is adequate with a favorable pH of the solution. During the screening of salt formation in aqueous media, if the API does not form the salt, it is often advisable to recheck with organic solvents or water/organic cosolvent systems. Organic solvents may alter the solubility of API by increasing the unionized species or reducing the ionization of the API and thus decrease the solubility of the final salt form (Serajuddin and Pudipeddi, 2002). Due to this altered solubility of salts in organic solvents, they are used to enhance the rate of crystallization and isolation of salt forms especially by using solvents with relatively low dielectric constants. 13.2.8 Decision Tree for Salt Selection The steps involved in the salt screening process are summarized here, depicted in Fig 13.5, and described below (Kumar et al., 2007). 1. Salt selection starts with the structural characterization of the API for free acidic or basic functional groups, identification of ionizable groups, determination of pKa value and identification of possible counterions. A high-throughput screening using a 96-well plate is used to identify potential counterions at the micro level for the desired salts formation. 2. After determining the suitable counterions, the salts are subjected to chemical characterization and structural confirmation. 3. The salts are then screened for suitable biopharmaceutical properties, and the salt with optimum properties is selected for the assessment of its crystallinity to impart stability to the salt. DOSAGE FORM DESIGN CONSIDERATIONS 450 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT Physicochemical characterization, identification of ionizable functional group and pKa detemination Selection of ideal counterions Salt formation and structural characterization Crystallization No Crystalline salt? Reject the salt No Any favorable properties? No Yes Crystalline salt? Yes Reject the salt Hygroscopic? No Favorable solubility? No Reject the salt Yes Physicochemically stable No Reject the salt Yes Economically feasible? No Yes Accept the optimized salt FIGURE 13.5 The decision tree for optimized salt selection. DOSAGE FORM DESIGN CONSIDERATIONS Optimize the process 13.3 CHARACTERIZATION OF THE PHARMACEUTICAL SALT 451 4. Sometimes, the amorphous form may impart advantages for the formulation development. However, if the stability becomes an issue, it may be converted to crystalline form as seen in the case of atorvastatin calcium which was originally developed in an amorphous form and changed to crystalline form during phase III clinical trials. 5. The crystalline form of the salt is then subjected to assessment of its hygroscopicity profile under varying humidity conditions. The salts with acceptable hygroscopicity are subjected to further evaluation of their solubility profile. The salts forms with sufficient solubility are then evaluated for their polymorphic stability, physicochemical stability, and drug-excipient compatibility. 6. Salts with satisfactory stability, lower polymorphism, and better excipient compatibility are finally subjected to assessing the suitability for the pharmaceutical process parameters and economic feasibility, which are evaluated on a small scale by the medicinal chemist. The optimized salt is then subjected to pharmacological testing and toxicological profiling or long-term toxicology studies. 13.3 CHARACTERIZATION OF THE PHARMACEUTICAL SALT Salts have attracted much interest in the pharmaceutical industry for their potential in tailoring the physical and chemical properties of an active pharmaceutical ingredient (API) to fulfill the criteria needed for the drug product development and ultimately for the patient benefits (Lee 2014; Brittain, 1999). Discovery and characterization of the diverse salt forms of a drug substance provide options regarding the form selection which exhibits the appropriate critical properties balance to develop the drug product (Balk et al., 2015). Conventionally, the study of solid form assortment of active compounds depends on using some commonly accessible methods combined with the latest characterization methods for analysis (ReutzelEdens, 2012). Crystal engineering, which entails designing crystalline molecular solids with the aim of altering particular chemical or physical properties of salt and polymorph screening program, has become popular in the pharmaceutical industry for years. Crystallography, spectroscopy, microscopy, thermal analysis, and other physical techniques are widely used, alone or in combination with one another, to examine the form and function of salts in the solid state (Stevens et al., 2014; Hildebrand et al., 2014). The full characterization process of salt forms of different active pharmaceutical ingredients can be in the form of structure confirmation, physicochemical properties assessments, physical properties assessments, processrelated impurities evaluations, and stability and preformulation assessments. 13.3.1 Structure Confirmation The conversion of any active pharmaceutical ingredients into their salt forms involves the addition of salt formers (acetate, fumarate, carbonate, hydrochloride, hydrobromide, etc.) which are themselves chemical entities. Thus, the salt product of any pharmaceutical ingredient needs to undergo structure analysis. The structure and composition of the pharmaceutical salt can be investigated by techniques such as mass spectroscopy, UV spectrophotometry, NMR spectroscopy, IR/Raman spectroscopy, and elemental analysis (Baghel et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 452 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT The process of structure confirmation of pharmaceutical salts requires the detailed characterization of a pharmaceutical material to be performed at the level of the individual chemical environment of each atom in the solid compound, and the required information can be obtained by utilizing NMR spectroscopy. One of the most important techniques for the characterization of materials is the solid-state NMR spectroscopy. With the latest development in computer pulse sequences and instrumentation, these studies can now be regularly conducted in the solid state (Monti et al., 2014; Chattah et al., 2015). The analysis in 1H NMR requires the prior knowledge of a proper solvent to solubilize the target material. Otherwise, no quantitative analysis will be accurate and reproducible if the sample is partially soluble in the solvent. Moreover, it is also desirable to choose a solvent that has no overlapping residual signals with that of the sample. 13.3.2 Assessment of the Physicochemical Properties It is highly advantageous to predict the physicochemical properties at an early stage to discover a feasible salt candidate. These properties have a major impact on the various characteristics of the salt candidate which include the properties affecting the formulation process into its final product (flowability, particle size distribution, stability towards compression, compaction, and in aqueous condition, etc.). This also influence the storage stability as well as the prospective pharmacokinetic effects on the patient (Makary 2014; Yu et al., 2014). The physiochemical properties of pharmaceutical salts that are mostly taken into consideration can be evaluated by tests such as melting range, pKa, log P, polymorphism, X-ray diffraction, aqueous solubility, pH-solubility profile, cosolvent, and propellant solubility taken in propellants and propellant/cosolvent systems for inhalation dosage forms (Chaurasia, 2016). The assessment techniques for the physicochemical properties of salt are presented in Table 13.6. TABLE 13.6 The Physicochemical Properties Assessment Techniques Used for Pharmaceutical Salts Properties Techniques/Methods Employed Melting point Capillary melting point, hot-stage microscopy, DSC, VT-XRPD pKa Solubility method, potentiometry, calorimetry (ITC, ITM), UV spectrophotometric method, HPLC, capillary electrophoresis Log P Shake flask method, HPLC Polymorphism DSC, Raman microscopy, XRPD Solubility Phase solubility analysis along with HPLC, UV-Vis spectrophotometric method pH-solubility profile Potentiometric method Cosolvent solubility Solubility test in various cosolvents with the assistance of UV-Visible spectrophotometer and HPLC Propellant solubility Solubility test in HFAs propellant with the assistance of UV-Visible spectrophotometer and HPLC Dissolution Powder dissolution and intrinsic dissolution study followed by analysis with XRPD DOSAGE FORM DESIGN CONSIDERATIONS 13.3 CHARACTERIZATION OF THE PHARMACEUTICAL SALT 453 The melting point of a new organic substance is one of the first measured properties. Knowing the substance melting range can help the scientists in decision-making for storage condition and formulation conditions for a particular salt candidate (Tetko et al., 2014). Some techniques are available for the determination of the melting point, from immediate melting point to the capillary method as described in the various pharmacopeias, in which the substance is heated, and the transition to the liquid phase is observed visually or by hot-stage microscopy. A sample is filled into a one-end sealed capillary in the capillary melting point. The melting range is established visually through digital melting point apparatus. The other method, which is more popular, is the differential scanning calorimetry (DSC), in which heat capacity/heat flow, the energy of transitions, is measured as a function of temperature (Bag et al., 2014; Stewart et al., 2017). The acid base dissociation constant of substances (pKa value) is another significant parameter in the salt formation process and optimization. This parameter indicates a degree of ionization which can strongly affect solubility, permeability, and drug pharmacokinetic properties—absorption, distribution, metabolism, and excretion (ADME)(Paluch et al., 2013). 13.3.3 Physical Properties The assessment of the physical properties of the candidate salt is a task that requires comprehensive characterization of selected salts and their polymorphs or hydrates. It is extremely demanding regarding experimental effort. In reality, it is impractical to attempt the characterization of all aspects of every potential salt form, though it is desirable. The physical properties, which usually caught the attention of many formulation scientists for assessments, include the crystal form using powder X-ray diffractometer, crystallinity by optical microscopy; thermal properties and thermal behavior by DSC and TGA, crystal shape, size, and appearance by scanning electron microscopy (SEM) (Nobrega et al., 2014; Turner et al., 2017). Hygroscopicity indicates the extent and rate of moisture sorption under various conditions of humidity of drug substance, and is an important parameter in the product development process. The moisture uptake rate is dependent on environmental conditions and often affects the stability of the drug substance in the dosage form (ICH, 2002). Hygroscopicity can be determined utilizing dynamic vapor sorption (DVS) that needs a minimal quantity of compound (about 3 mg) (Kong et al., 2016; Simón et al., 2017). 13.3.4 Assessment of the Process Impurities To commercialize a pharmaceutical product, the identification and characterization of all unknown impurities present in the compound at a level of more than 0.1% has been made a mandatory requirement by regulatory authorities (Dobo et al., 2006; Reddy et al., 2016). These impurities are needed to be identified in pure form to evaluate the performance of HPLC method in areas like range, system suitability testing, linearity, limit of quantification (LOQ), accuracy, specificity, limit of detection (LOD), precision, robustness, and relative response factor (RRF). These related substances can also be utilized to ensure the accuracy of the analytical method of the active pharmaceutical ingredients DOSAGE FORM DESIGN CONSIDERATIONS 454 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT (Chen et al., 2017). The source of impurities varies widely, which could include intermediates, starting materials, degradation products of the active pharmaceutical salt, byproducts of the synthesis of an active pharmaceutical salt, or its impurities arising during manufacture or storage (Wollein et al., 2015; Szekely et al., 2015). Impurities that are not related to the active pharmaceutical salt may also be present which can arise from the synthetic or extractive process contamination from unrelated chemicals. Also during drug or product development, new impurities can suddenly appear due to changes in the synthetic protocol, starting materials, the source of starting materials, or even variability during scale-up processes (ICH, 2006; Bharate and Vishwakarma, 2013). Because of the reactive nature, few intermediates and starting materials may be suspected or known as carcinogens and/or mutagens. Regulatory agencies around the world are demanding the characterization of unknown impurities to ensure their nongenotoxicity, identification, and control to ascertain the efficacy, safety, and quality of drug substance. Moreover, International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) guidelines indicate that unknown impurities at or above 0.05% in the drug substance need identification, which depends on the maximum daily dosage (Lee and Hoff, 2002a). Therefore, it was felt necessary to characterize the unknown impurity observed in the drug substance. The assessment of the process-related impurities usually involves detection of the impurities with the help of conventional analytical liquid chromatography, isolation of the impurities by preparative HPLC (reverse phase-HPLC), followed by structure characterization and elucidation of impurities by mass spectrometry and NMR (Maggio et al., 2014; Azzam and Aboul-Enein 2015; Chen et al., 2017). 13.3.5 Stability and Preformulation Assessments Converting the API to a salt form enables the formulation scientists to alter the chemical, physical, pharmacological, and economic properties of the drug candidates to develop dosage forms with better bioavailability, manufacturability, stability, and compliance of patient (Korn and Balbach, 2013). Therefore, the preformulation assessment of the salt form is an essential step before formulation studies. For example, the hydrate form of salts can create difficulties during wet granulation which leads to the rejection of the salt form in further development (Nie et al., 2017; Bhattachar et al., 2017). The manufacturing routes for the salt can be the same or entirely different from the preliminary crystallization studies. Therefore, the medicinal chemist and preformulation scientist work together to ensure that the salt form is stable enough for further development. The preformulation approaches used for a new salt candidate is summarized in Fig. 13.6 (Lee and Hoff, 2002b). There are several instances which can justify the need for selecting the salt form with proper stability before the preformulation studies as lack of stability can influence the final formulation of the drug. For example, for the preparation of chlortetracycline suspension, the calcium salt is most appropriate owing to its superior stability over the highly unstable hydrochloride salt (Kasture and Wadodkar, 2007). However, in the case of penicillin G, although the potassium salt is less hygroscopic than sodium salt, it produces an DOSAGE FORM DESIGN CONSIDERATIONS 13.3 CHARACTERIZATION OF THE PHARMACEUTICAL SALT 455 Physical analysis Chemical analysis A. Structure detemination 1. UV; 2. FTIR; 3. NMR; 4. Mass; 5. Elemental analysis 1. Melting point 2. Hygroscopicity 3. DSC 4. TGA 5. X-ray crystallography 6. Microscopy 7. Particle size analysis 8. Powder compaction and flow B. Quantification using TLC and HPLC C. Impurity profiling 1. Synthetic impurities 2. Residual solvent and water 3. Heavy metals 4. Degradants 5. Microbial contaminant Salt form Pharmaceutical properties A. Biopharmaceutical properties 1. Monolayer adsorption 2. ADME B. Chemical compatibility 3. Process parameter 4. Excipient C. Regulatory Requiremets Physicochemical analysis A. Physicochemical properties 1. Log P 2. pKa 3. Solubility: a) Solvent b) pH c) Dissolution B. Chemical stability 1. Oxidation 2. Photostability 3. pH 4. Temperature 5. Solvent FIGURE 13.6 The process of stability and preformulation assessment of a new drug. unpleasant metallic aftertaste. Therefore, assessment of both the stability and the preformulation aspects are crucial before selection of final salt form (Stahly, 2007). The new salt form developed in milligram scale on the desk of the chemist needs to be transformed to the industrial production in the kilogram scale to enable the formulation scientist to make the suitable dosage form. The process of industrial production requires many skillful and automated processes. The scale-up steps may vary from that of the labscale preparation and sometimes require additional steps to complete the process (Chanda et al., 2015; Buskirk et al., 2014). It requires the optimization of the whole process development, synthetic route, and pilot plant scaling for the production of kilograms or even tons of the salt form. The salt being the solid form offers several advantages, such as ease of handling, ease of purification, stability towards oxidation and hydrolysis, longer shelf life, ease of converting to solid oral dosage forms, ease of manufacturing the dosage forms, and low contamination (Brittain, 1999). 13.3.6 Large-Scale Methods The large-scale salt production involves the following techniques. However, these are not exclusive and can be altered depending on the nature of the salt. DOSAGE FORM DESIGN CONSIDERATIONS 456 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT Method 1: Crystallization The salt formed in the large scale is subjected to crystallization and is a suitable solvent to form larger crystals which can be readily purified by filtration. Crystallization is a procedure that is considered during large-scale production of pharmaceutical salt due to its reproducibility and is especially suited to be utilized on a manufacturing-plant scale since the results obtained in laboratory experiments often translate smoothly and efficiently into large-scale processes (Myerson, 2002; Lee and Hoff, 2002a). Processes of crystallization can run in continuous or batch mode. Though batch crystallization is considered as the most utilized approach in the pharmaceutical industry, continuous processing affords the benefit of improved result reproducibility. This is because in the case of a continuous crystallization process all the materials get crystallized under uniform crystallization conditions. On the other hand, in the case of batch operations, there is a change in conditions over a time period, hence, results in crystal characteristics that are complex to control and not consistent from batch to batch (Pohar and Likozar, 2014). Pharmaceutical crystallization is carried out using the glasslined semibatch crystallizers on the production scale with the working capability of about 1 m3. Crystal properties like crystal size distribution (CSD), product morphology, polymorphic outcome, and crystal purity can be controlled either by optimal control or careful selection of the process variables or with the addition of external control in the feedback form (Rohani, 2010). For example, during antisolvent crystallization, factors controlling the parameters involve addition, residence time, supersaturation, and antisolvent mixing (Rohani et al., 2005). Method 2: Chromatographic isolation Chromatographic isolation is a low-yielding procedure of isolation and purification and requires a large amount of solvent and stationary phase. However, nowadays the scale-up chromatographic columns with a diameter of more than 300 mm are available and can yield the pure form of salt to a few kilograms. For instance, preparative HPLC and, at a large scale, process HPLC has become a primary tool to produce specialty chemicals. Many labs in the pharmaceutical industries, where rapid development and fast turnaround correspond to profits employ the HPLC process for their production. During the pilot and full production scales, process LC systems isolate compounds at rates of thousands or even millions of kilograms per year, in columns as large as 2 m in diameter (Bylda et al., 2014). The usefulness of preparative HPLC was also described by Welch et al. (2009), where they report the development of a pulse injection HPLC method with productivity in excess of 5.5 kkd (kilograms of desired product per kilogram of stationary phase per day), and use this method in the production of 7.5 kg of a stereo-isomerically pure intermediate for a pharmaceutical compound development (Leonard et al., 2016). Researchers have also described the use of high-performance thin-layer chromatography (HPTLC) to identify and control the consistency of batch-tobatch in the stability testing of drugs/salt form as well as control during the complete manufacturing process as well as quality control of the finished product (Raut et al., 2014). Additionally, the availability of chiral chromatography has been used to separate the optical isomers. The utilization of chromatographic resolution using chiral stationary phases (CSPs) and the availability of required CSPs have made this process be the most DOSAGE FORM DESIGN CONSIDERATIONS 13.3 CHARACTERIZATION OF THE PHARMACEUTICAL SALT 457 cost- and time-effective approach for resolution of enantiomer during the discovery stage in the pharmaceutical industry. The availability of larger amounts of the required CSP permits a beneficial separation of isomers identified at an analytical scale on a particular CSP to be scaled up. Thus, it enables the preparative-scale separation of isomers in a small timeframe (Shen et al., 2014; Sierra et al., 2014; Regalado and Welch, 2015). Method 3: Distillation Distillation is effective for separation of volatile substances, particularly solvents from the salt. Distillation columns up to 10 m in diameter and 100 m in height can be safely designed, constructed, and operated for the large-scale processes (Stichlmair and Fair, 1998). Batch extractive distillation (BED) is one of the distillation methods that impart the advantages of extractive distillation and batch distillation simultaneously. Therefore, the method is suitable for the separation and purification of close-boiling as well as azeotropic mixtures in solvent recoveries of fine chemicals and pharmaceutical industries (Yuan et al., 2015; An et al., 2015). 13.3.7 Method Optimization and Large-Scale Production The process of crystallization is the first step after the synthesis to yield large-scale salt forms and is an extensively used method. Therefore, the large-scale production requires the optimization of the crystallization process. The industrial crystallization depends on the following parameters. 13.3.7.1 Solvent Selection An appropriate solvent should have (Du et al., 2014; Martı́nez-Gallegos et al., 2015) • • • • Low toxicity as well as low trace in the dry product. Form stable solvates. High yield of crystallization. Lesser polymorphism. 13.3.7.2 Control of the Crystallization The process of crystallization involves following steps(Hou et al., 2014; Pohar and Likozar, 2014) 1. Dissolution of the salt in a suitable solvent by heating, followed by filtration to eliminate insoluble particles, and decolorization on activated charcoal if required. 2. Nucleation after seeding. 3. Crystal growth by slow cooling. The crystallization process depends on the following parameters (Hou et al., 2014; Choi and Jung, 2017): 1. Supersaturation state. 2. Seeding. 3. Rate of cooling. DOSAGE FORM DESIGN CONSIDERATIONS 458 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT 13.3.7.3 Filtration and Drying The desired crystals are obtained after the completion of crystal growth process which is then required to be separated from the mother liquor before drying. The drug salt crystal form is filtered by avoiding the contamination as well as cross-contamination from the surroundings. The most common methods that are employed for filtration and drying include the following: 1. The conventional method of Buchner filter and tray drying. 2. The double-cone spin dryer or conical dryer. 3. The use of sealed filter dryers with stirrers. Scaling-up of salt formation in the pharmaceutical industry employs data obtained in the laboratory for the development of procedures that will manufacture consistent quality products (size distribution, purity, crystal form, and shape) as the material demand increases during clinical trials and finally at full-scale commercial production. Scaling-up has become a challenging process in the pharmaceutical industry because specialized equipments are seldom employed, but processes are run on existing equipment (Chen et al., 2011). The scale-up of a salt form of an API is one of the vital concerns, and the following factors need to be considered. a. Time: Scale-up operations need more time in comparison to laboratory scale operations due to the involvement of a larger amount of materials. This often means that the crystallized material spends more time in the slurry before solid liquid separation, which results in enhancing the probability of transforming metastable forms to more stable forms by solution-mediated transformation determined by differences in the solubility (Lee et al., 2015). b. Addition of reactant: The amount of heat absorbed or released during the addition of reactants should be monitored and determined at the laboratory scale so that it can be controlled in the large-scale process. The thermal stability of intermediates and raw materials must be established using DSC and TGA to detect exothermic or endothermic behavior (Shen et al., 2014; Sun et al., 2015). c. Mixing: The mixing of slurries and solutions are a critical step of scale-up operations. Mixing issues related with cooling crystallizers include issues related to keeping the solids suspended and reducing secondary nucleation, growth on surfaces, and crystal breakage. Mixing issues in reactive crystallization or antisolvent are much more difficult and can lead to considerable problems in the scale-up process (Lepeltier et al., 2014). d. Stability: Chemical stability of pharmaceutical molecules is a factor of great concern as it has long-term effects on the efficacy and safety of the drug intermediate and drug product. The importance of stability testing is mentioned in the FDA and ICH guidance. This guidance states the condition of stability testing data to determine how the storage condition and various environmental factors can cause the changes and degradation of the pharmaceutical product with time. Thus, complete stability data profiles of the DOSAGE FORM DESIGN CONSIDERATIONS 13.4 REGULATORY REQUIREMENTS 459 metastable forms of the critical raw materials, intermediates, and the final products must be generated in the laboratory under similar conditions that will be in the large-scale plant process. By this data, storage and packaging conditions for critical intermediates and raw materials can be established (Blessy et al., 2014). e. Filtration: Separation processes are one of the crucial processes in chemical and pharmaceutical preparation since most organic syntheses are often carried out in organic solvents in which the resulting economically valuable product needs to be separated from the organic solvents. Filtration is the commonly used process for such kinds of separation. During filtration, the filter material compatibility with the process fluid is dependent on parameters like time flow, temperature, weight, pore size, shape, and pressure (Touffet et al., 2015; Saengchan et al., 2015; Hou et al., 2017). Depending upon the nature of the compounds to be separated, the solvent used for the reaction, etc., researchers opt for suitable filter material and filtration techniques. For example, organic solvent nanofiltration is used in the pharmaceutical industry as it permits separations of organic mixtures down to the molecular level with the application of a pressure gradient and retains or permits the target molecule for permeation while retaining the impurity and vice versa (Buonomenna and Bae, 2015). f. Other parameters Centrifugation, water content, drying, pH, and maintenance of temperature are other parameters. The product economics that depend on allowable cost and projected market size for manufacturing must be defined apart from the vital factors (Chen et al., 2011). 13.4 REGULATORY REQUIREMENTS The health regulatory bodies of the European Union and that of the United States consider alternative salts of approved drug substances as New Chemical Entities (NCE). The new salts of an active pharmaceutical ingredient are not entitled for ANDA submission as more extensive studies, and testing data are required for regulatory approval (CFR-Code of Federal Regulations Title 21). As mentioned in the FDA draft guidance (FDA Draft Guidance, 1999), a different API salt form constitutes a variation in active ingredient; thus, additional clinical trial data submission becomes necessary, although in some cases, a reference to previously published clinical data can be adequate. The constraint of supplementary clinical studies brings in other risks and cost for a generic company intending to market a substitute salt form of an approved product (Dawidczyk et al., 2014; Newton et al., 2015). However, one must also note that the application submission to register therapeutic products having another salt of an approved active substance as a generic product can be facilitated, under various conditions, with the utilization of previous knowledge of clinical reports obtained through the active moiety approved as a different salt form. Thus, in various cases of salt development for generic drug product based on an alternative salt form of the existed marketed active moiety, an abbreviated application may be submitted until the evidence can be given that the alternative salt form or newly developed does not DOSAGE FORM DESIGN CONSIDERATIONS 460 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT New salt (of an already approved product) Significant differences in physicochemical properties? No Yes Can the new salt be considered a new active substance? (see GL-7) Yes No Full application (Article 8(3), Dir. 2001/83/EC) Hybrid application (Article 10(3), Dir. 2001/83/EC) Differences in properties with respect to safety and/or efficacy and/or differences in pharmaceutical form? Yes No Additional clinical studies (e.g., impact of modified drug on safety/efficacy) Bioequivalence (BE) study (biowaiver if applicable) BE demonstrated? No Yes Generic application Article 10(1), Dir. 2001/83/EC FIGURE 13.7 Regulatory pathways in the EU for a new salt. interfere with the pharmacokinetics of the active moiety, neither toxicity nor pharmacodynamic characteristics, which could change the safety and efficacy profile (Gadade and Pekamwar, 2016; Makary, 2014). In the EU, Directive 2001/83/EC outlines three different approval pathways for a pharmaceutical alternative: a generic application, a hybrid application, or a full application. The regulatory pathway in the EU for a new salt form of pharmaceutical compounds is shown in Fig. 13.7. 13.4.1 Patenting Prospective Studies on salt selection give a possible extension of a patent for the drug because salts with higher quality and properties can be securely patented. It has been observed that new salt forms often possess novel physical properties associated with formulation and processability. They may also lead to the identification of new polymorphs. A new salt form may have a figure which makes it satisfactory for a new administration route. Approximately 51% of the new molecular entities approved through the FDA between 1985 2005 with at least one patent were claimed to be polymorphs, isomers, prodrugs, esters, or salts (or 24% where there is no NCE patent) (Kapczynski et al., 2012b). DOSAGE FORM DESIGN CONSIDERATIONS 13.4 REGULATORY REQUIREMENTS 461 Solid form patents are powerful tools to safeguard the Intellectual Property (IP) of pharmaceutical products since the solid form patents provide a composition of matter protection as the crystal structure is directly related to the chemical structure of the active pharmaceutical ingredient (API). Such patents are considered among the strongest line of defense (Van Triest and Vis, 2007). A well-drafted patent on crystalline form should not only specify the physical properties of the crystalline form (such as hygroscopicity, color, melting point, aqueous solubility, shape, density, and dissolution rate; Indian Patent IN 237261, 2009), but also the analytical characteristics, such as the crystal structure as determined by powder XRD, single-crystal X-ray diffraction (XRD), thermal data by DSC, TGA, spectral data obtained by Raman, infrared spectroscopy, and solid state NMR. Also, the patent should discuss the utility of the form regarding therapeutic activity and process utility, the making of the form regarding reproducibility, and the formulation containing the form (US Patent US8367693B1, 2013). Patentability of an initial solid form of a new chemical entity (NCE) is typically not an issue if the above points are taken into consideration. Problems may arise when new solid forms such as different suitable salt forms are discovered during the development phases of the API. In such cases, it is important to demonstrate anticipation (novelty), obviousness, and enablement. For instance, the case of Glivec (imatinib mesylate) produced by the company Norvatis whereby the Supreme Court stated that the new salt form of imatinib (imatinib mesylate) was not patentable even though it shows improved bioavailability (Gabble and Kohler, 2014). On the other hand, successful patenting of a new salt form of a drug includes that of diclofenac which is available in the market as the sodium salt (Voltaren). Other diclofenac salts such as diclofenac diethylamine having significant skin penetration properties were unveiled and patented before the expiry of the patent. These salts were appropriate particularly for topical applications. An exclusive market position can be secured by patenting new salts. Selection of a suitable salt form of a drug may also play a role in obstructing the generic drug product development (Kalepua and Nekkantib, 2015; Mathur, 2012). If a secondary patent of any new salt form is filed, the patent can create an additional 4 6 years of patent life beyond the original chemical compound patent. While secondary patents with independent secondary patents but without chemical compound patents can create an additional 7 10 years of patent life (Kapczynski et al., 2012a). 13.4.2 Safety and Efficacy The formulation of salts is crucial for the preparation of safe and effective dosage forms of many approved, marketed, or newly developed drugs. Whether the drug products are solutions or solids, the use of salt provides a higher concentration in solution than the nonionized forms, free acid, or free base. Typically, salts readily undergo crystallization, and the resulting material facilitates subsequent processing. Thus, the salt is often considered as the preferred form for isolating and purifying the drug. Historically, the number of available salts was rather limited; however, there is an extensive assortment of chemical entities available today that are recognized as being safe and can be used in the preparation of drug products (Wiedmann and Naqwi, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 462 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT In addition to solubility and manufacturing, the salt is typically a more stable form of the drug. The clear-cut knowledge of appropriate salt form is of vital importance towards the development of a product with a long shelf life. Although nonionized drugs often exist in multiple polymorphic forms, a limited number of salts can appear. The salt formation may be an inherent property of the ionic bond, but it should also be recognized that relatively little effort has been spent in the search for different polymorphic forms of salts. As such, there may be an untapped potential, because as it has been noted that the number of polymorphic forms appears to be a function of the time spent in their search (Basavaraj and Guru, 2014; Altman et al., 2015). The theoretical foundation for salts is given with an emphasis on the observed increased amount of drug in solution; consideration is given for the solubility of the nonionized form, acid solubility product, and dissociation constant, which are the limiting constraints. Some general guidelines must be reviewed and referred before screening and characterizing drugs as salts for the development of products (Blagden et al., 2007; Rodriguez-Aller et al., 2015). 13.4.2.1 ADME and Bioavailability The scientific literature is revealing that the water solubility of alternative salt forms having similar active pharmaceutical ingredient can be entirely dissimilar. Currently, the antidepressant drug trazodone is present in the market as the hydrochloride salt. Scientists prepared several alternative salts to discover a trazodone salt form with less aqueous solubility in comparison to trazodone hydrochloride. After final evaluation, it was observed that the pamoate and tosylate salts of trazodone were less water-soluble in comparison to the hydrochloride and sulfate salts. The tosylate salt showed the most interesting solubility profile with values ranging from 3 mg/mL at pH 1.0 to 0.2 mg/mL at pH 12.0. This property makes this salt as the unsurpassed candidate among the other salts, to develop an extended-release oral trazodone product which can enhance patient compliance in elderly patients. Due to the considerably less (8 10-times in the pH range of 1 5) soluble property of the tosylate salt in comparison to the marketed hydrochloride salt, the in vivo absorption rate of trazodone after the oral administration of the tosylate salt may be considerably less. As a result, two salts will probably be neither bioequivalent nor therapeutically equivalent (have the same extent of absorption and rate) (Rao, 2012). The dissolution rate of the active pharmaceutical ingredients in the gastrointestinal fluid is influenced by its aqueous solubility. Consequently, solid dosage forms having alternative salts of the same active pharmaceutical ingredient may exhibit variable in vivo dissolution characteristics. Bioequivalence studies to compare salt forms of basic drugs in humans have been studied, and it was found that there were no major variations in bioavailability between different salt forms even though they have differences in their aqueous solubilities (Censi and Di Martino, 2015). 13.4.2.2 Some Specific Examples and Case in Hands Paulekuhn et al. (2013) described the preparation of the hydrochloride, sulfate, mesylate, and tosylate salt form of albendazole. They performed the synthesis of salts of albendazole which exhibit poor aqueous solubility in organic solvents, tetrahydrofuran (THF). In their studies, they mainly used liquid acids, e.g., methanesulfonic acid, sulfuric acid, DOSAGE FORM DESIGN CONSIDERATIONS 13.4 REGULATORY REQUIREMENTS 463 and hydrochloric acid, as salt formers because these acids do not precipitate. Although para-toluenesulfonic acid is solid, it exhibits good solubility in many organic solvents and is therefore well suited for salt formation with poorly soluble compounds. They prepared the salts forms of the drug by dissolving albendazole in tetrahydrofuran (THF) followed by addition of the counterion, which included methanesulfonic acid, sulfuric acid solution, and para-toluenesulfonic acid monohydrate solution. They kept the solvents containing drug and salt formers under ambient conditions, after the solvent evaporated off, they deagglomerated the obtained solid. But for the hydrochloride salt, firstly, they dissolved the albendazole in THF and evaporated the solvent completely under ambient conditions, and the resulting partly amorphic, slightly brown material was dissolved in ethanol. Then they evaporated the ethanol under ambient conditions, and the material was deagglomerated. They carried out the characterization and confirmed the identity of the synthesized salts by vibrational spectroscopy, ion chromatography, and 1H NMR spectroscopy. For instance, they examined the solid state forms of the albendazole salts by SEM, XRPD, laser diffraction measurement of particle size distribution (PSD), 13C solid-state NMR spectroscopy, and B.E.T. measurement of the specific surface area; and the hygroscopicity and thermal behavior by DSC, thermogravimetric analysis (TGA), Karl Fischer titration (KFT), DVS, and through variable temperature XRPD. They also conducted the dissolution and solubility experiments for the synthesized salts. From their study, they noticed that the various salt forms demonstrate distinct variations in their physicochemical behavior, and were particularly better than the free base in their dissolution and hygroscopicity characteristics. They identified the mesylate salt to possess the highly improved physicochemical properties from amongst the prepared salts. They also suggest that widespread physicochemical characterization is required to choose the most appropriate form of salt for further pharmaceutical development (Paulekuhn et al., 2013). Han et al. (2016) described and notified the merits of salt formation of febuxostat, a medication used to treat hyperuricemia and chronic gout. They described the enhanced water-solubility and in vivo oral absorption of the choline salt form of febuxostat. The choline salt form of febuxostat was prepared from ethyl 2-(3-cyano-4-iso butoxy phenyl)-4methyl thiazole-5-carboxylate and choline chloride in organic solvents as described by Dwivedi et al. (2013). Han and his group carried out the characterization of febuxostat (FXT), choline febuxostat (CXT), choline chloride, and the physical mixture of FXT and choline chloride by differential scanning calorimetry, FT-IR spectroscopy, and X-ray powder diffraction, They carried out the pharmacokinetic studies of CXT in rats using UPLCMS/MS to compare with that of FXT regarding area under curve (AUC), P value, and relative bioavailability. According to their study, they concluded that the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization proved to be an effective way to increase the in vivo absorption of FXT (Han et al., 2016). Another example of pharmaceutical salt formation of drugs is the preparation of salt forms of carvedilol ( 6 )-1-(carbazol-4-yloxy)-3-[[2-(omethoxyphenoxy) ethyl]amino]-2-propanolas described by Hiendrawan and his group (Hiendrawan et al., 2017). Carvedilol is a nonselective β-blocker drug used for hypertension, mild to severe heart failure, myocardial infarction, and angina pectoris treatment (Planinsek et al., 2011). Practically, carvedilol DOSAGE FORM DESIGN CONSIDERATIONS 464 13. ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT represents pH-dependent solubility and is water-insoluble (Hamed et al., 2016). Its solubility is ,1 µg/mL at pH more than 9.0, 23 µg/mL at pH 7, and about 100 µg/mL at pH 5 at room temperature. Due to its poor aqueous solubility, carvedilol exhibits a maximum bioavailability only up to 30% or less (Kukec et al., 2012). Hiendrawan and his group (Hiendrawan et al., 2017) employed this characteristic of carvedilol and prepared the novel pharmaceutical salts of an antihypertensive drug carvedilol (CVD) with pharmaceutically acceptable salt formers like oxalic acid (OXA), fumaric acid (FUMA), benzoic acid (BZA), and mandelic acid (MDA) via conventional solvent evaporation technique. The pKa difference between CVD and selected acids was greater than 3, thus suggesting salt formation. Planinsek and his group also reported the preparation of two polymorphic forms of CVD/MDA salts and one p-Dioxane solvate of CVD/ FUMA salt in their study. They performed the analysis of solubility measurement in phosphate buffer pH 6.8 with the aid of HPLC. According to their study, the carvedilol salts exhibited higher solubility (1.78 times) in phosphate buffer solution pH 6.8 in comparison to the parent drug, carvedilol. From the study, they suggested that salt formation could be an alternative method to improve CVD solubility (Hiendrawan et al., 2017). 13.5 CONCLUSION Selection of a best possible salt form is a significant step in the drug development process and requires efforts from all divisions. Selection of a salt needs a well-designed screening strategy which must be based on the factors including pKa, ionic factors, biopharmaceutical factors, biological factors, routes of administration, and choice of solvents to produce an affordable salt. As the salt is considered as a new chemical entity, the new salt form has to undergo several studies which are usually required for the new chemical entity. They include structure confirmation by UV, mass, IR, NMR spectroscopy; assessment of physicochemical properties by techniques such as DSC, hot-stage microscopy, and X-ray diffraction; assessment of process impurities with the help of HPLC, NMR, HPTLC; assessment of stability, preformulation, biopharmaceutical, and toxicological requirements. Additionally, the regulatory, intellectual, and marketing requirements have to be looked upon for the final approval of the salt form. The bioavailability and bioequivalence comparisons are also essential to establish the final salt form of the API. Once the desired salt form for a chemical entity is obtained, the new salt form developed in milligram scale needs to be transformed to the industrial production in the kilogram scale to enable the formulation scientist to make the suitable dosage form. Scale-up steps require the optimization of the whole process development, synthetic route, and pilot plant scaling. Some of the techniques involved in the large-scale production include the crystallization process, chromatographic process, and distillation process. The factors, such as selection of solvent, filtration, and drying, time, addition of reactants, mixing, stability, pH, and temperature, need to be investigated at the lab scale and reconsidered before implementing those factors in a large-scale production. However, although the salt selection process required meticulous experiments and some drug development steps, the salt forms have numerous advantages over their parent APIs. Therefore, DOSAGE FORM DESIGN CONSIDERATIONS ABBREVIATIONS 465 the salt selection process will remain as one of the most reasonable approaches to obtain new drug candidates from the existing API. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant (Grant #ECR/2016/001964) allocated to Dr. Tekade for research work on gene delivery and N-PDF funding to Dr. Maheshwari (PDF/2016/003329) for work on targeted cancer therapy in Dr. Tekade’s Laboratory. The authors also acknowledge the support by Fundamental Research Grant (FRGS/1/2015/TK05/IMU/03/1) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. ABBREVIATIONS 1 H NMR ADME ANDA API AUC BED CSD CSPs CXT DSC DVS EU FDA FTIR FXT HFAs HMG CoA HPLC HPTLC ICH IP IR ITC ITM LOD LOQ NCE NMR PVPP RRF SEM TGA UPLC-MS/MS USFDA UV VT-XRPD XRPD proton nuclear magnetic resonance absorption, distribution, metabolism, excretion abbreviated new drug application active pharmaceutical ingredient area under curve batch extractive distillation crystal size distribution chiral stationary phases choline febuxostat differential scanning calorimetry dynamic vapor sorption European Union Food and drug administration Fourier transform infrared febuxostat hydrfluoroalkanes 3-hydroxy-3-methylglutaryl-coenzyme A high-performance liquid chromatography high-performance thin layer chromatography international conference on harmonization intellectual property infrared isothermal titration calorimetry isothermal titration microcalorimetry limit of detection limit of quantification new chemical entity nuclear magnetic resonance polyvinylpyrrolidone relative response factor scanning electron microscopy thermogravimetric analysis ultra performance mass spectrometry/mass spectrometry U. 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ROLE OF SALT SELECTION IN DRUG DISCOVERY AND DEVELOPMENT King, C.R., D’Ambrosio, S.G., Bristol, D.W., English, M.L., 2013. Opioid salts and formulations exhibiting antiabuse anti-dose dumping properties. US Patent US8367693B1. Mathew, J., Sivakumar, M.R., Acharya, P., 2009. A crystalline form B4 of atorvastatin magnesium and a process thereof. Indian Patent IN 237261. Schultheiss, N., Newman, A., 2009. Pharmaceutical cocrystals and their physicochemical properties. Cryst. Growth Des. 9, 2950 2967. DOSAGE FORM DESIGN CONSIDERATIONS C H A P T E R 14 Drug Complexation: Implications in Drug Solubilization and Oral Bioavailability Enhancement Hira Choudhury1, Bapi Gorain2, Thiagarajan Madheswaran1, Manisha Pandey1, Prashant Kesharwani3 and Rakesh K. Tekade1,4 1 Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia 2Faculty of Pharmacy, Lincoln University College, Petaling Jaya, Selangor, Malaysia 3Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India 4National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 14.1 Introduction: Complexation in Pharmaceutical Products 14.1.1 Types of Complexation 14.1.2 Application of Complexation 14.2 Fundamental Methods of Formation of Drug Complexes 480 14.2.1 Physical Blending Method 480 14.2.2 Kneading Method 481 14.2.3 Coprecipitation Technique 481 14.2.4 Solution/Solvent Evaporation Method 481 14.2.5 Neutralization Precipitation Method 483 Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00014-9 14.2.6 Milling/Cogrinding Technique 14.2.7 Atomization/Spray Drying Technique 14.2.8 Lyophilization/Freeze Drying Technique 14.2.9 Microwave Irradiation Method 14.2.10 Supercritical Antisolvent Technique 14.2.11 Extrusion 474 475 479 14.3 Characterization of Drug Complexation 473 483 483 483 484 484 485 485 © 2018 Elsevier Inc. All rights reserved. 474 14. DRUG COMPLEXATION 14.3.1 Determination of Guest Content 14.3.2 Thermo-Analytical Methods 14.3.3 Infrared Spectroscopy 14.3.4 X-ray Powder Diffraction 14.3.5 Scanning Electron Microscopy 14.3.6 Diffusion NMR Studies 14.4 Factors Influencing Complex Formation 14.4.1 Influence of Temperature on Complex Formation 14.4.2 Influence of Chemical Modification on Complex Formation 14.4.3 Influence of Enzymatic Modification on Complex Formation 14.4.4 Effect of Coacervate on Complex Formation 485 487 487 488 488 489 489 489 490 491 491 14.5 Effect of Complexation on Drug Solubility and Bioavailability 492 14.6 Thermodynamics and Kinetics of Complex Formation 497 14.7 Protein Complex Formation: Role in Oncology 498 14.8 Application of Complexation in Drug Delivery 14.8.1 Metal Ion Complex in Cancer 14.8.2 Cyclodextrin in Drug Delivery System 14.8.3 Polyelectrolyte Complexation in Drug Delivery 499 499 501 503 14.9 Conclusion 504 Acknowledgment 504 Abbreviations 504 References 505 14.1 INTRODUCTION: COMPLEXATION IN PHARMACEUTICAL PRODUCTS According to the basic definition, complexes result from a donor acceptor method or Lewis acid base reaction between two chemical components, where any nonmetallic ion or atom can act as a Lewis base (donate an electron pair) and any neutral atom or metallic ion can behave as a Lewis acid (acceptor of electron pair) (Amiji, n.d.). Lewis bases or ligands have lone pairs of electrons in the outer energy level that is used to make a coordinate bond with metal ions. In the ligand, the atom donates the lone pair of electrons and is known as the donor atom, for instance in hexamine cobalt(III) chloride cobalt complexes with six ammonia molecules in which cobalt act as the Lewis acid, ammonia acts as the Lewis base and nitrogen acts as the donor atom. It means binding of a metal ion or drug molecule or any organic molecule with ligands. Metal ions act as Lewis acids and accept the lone pair of the ion to form complexes with ligands. In chemistry, complex refers to molecules or molecular associations formed by the combination of substrates and ligands. Complexation may occur between the drug molecule and other small or large molecules. Covalent or different noncovalent interactions, such as van der Waals forces, hydrogen bonding, dipole forces, charge transfer, electrostatic forces, and hydrophobic interactions, are involved in complexation (Patil et al., n.d.). Complexation may result in a beneficial effect due to the altered physicochemical properties of its constituents, the substrate and the ligand, such as improved aqueous solubility DOSAGE FORM DESIGN CONSIDERATIONS 14.1 INTRODUCTION: COMPLEXATION IN PHARMACEUTICAL PRODUCTS 475 and dissolution rate. For example, the improvement of theophylline solubility by complexation with ethylenediamine to form aminophylline (Takenaka et al., 1982). During the recent research theophylline complex with β-cyclodextrin (β-CD) improved the solubility as well as bioavailability (Subuddhi, 2015), conductivity, partitioning behavior, chemical reactivity, stability, and other pharmacokinetic parameters (Tóth et al., 2017). Complexation can also affect the distribution in the body by alternating the protein binding of the drug. On the other hand, complexation can also result in poor solubility and absorption, for example, tetracycline solubility and absorption gets reduced by complexation with calcium ion (Aulton and Taylor, n.d.). Similarly, coadministration of antacid with therapeutic agents may lead to altering of the solubility and bioavailability, and complexation of the drug with a hydrophilic atom may enhance the excretion rate. Generally, complex formation is reversible, however some metal complexes are practically irreversible due to strong bonding. Complexes are generally classified as coordination complexes and molecular complexes based on the type of interaction involved between ligand substrate(Martin, 2006). 14.1.1 Types of Complexation 14.1.1.1 Coordination Complexes A coordination complex consists of an ionic substrate, usually a transition metal ion, and one or more attached ligands which may be either cations or anions. It is a product of Lewis acid base reactions; Lewis acids can accept a pair of a nonbonding valence electrons, thus forming a Lewis acid base complex. The metal ions in chemical reactions act as an acid (i.e., accept an electron pair) and the ligand acts as a base (i.e., donate an electron pair) and thereby a coordinate covalent bond forms between a metal ion and attached ligands (Fig. 14.1). Examples of such complexes are [Ag(NH3)2]1 and [Fe(CN)6]4 . 1 Ag1 1 2ð:NH3 Þ- AgðNH3 Þ2 (14.1) Silver ions (Ag1) interact with ammonia (NH3) to form [Ag(NH3)2]1 coordinate complex where both the ammonia molecules act as electron pair donors and form a covalent bond between ammonia and silver ion which is known as a coordinate covalent bond as both the FIGURE 14.1 Electron donation by Lewis base to Lewis acid to form a coordination complex. DOSAGE FORM DESIGN CONSIDERATIONS 476 14. DRUG COMPLEXATION electrons come from the same atom. There are other ligands which donate a pair of the electrons to form a complex, which include NC2, :H2O, :Cl2. Thus, [Ag(NH3)2]1complex ion can be neutralized with Cl2 to form [Ag(NH3)2]1Cl (Mahato and Narang, 2012). Metal coordination complexes can also be formed between amino acids and heavy metals. Therefore, coordination metal complexes play an eminent role in the biological system while maintaining the structure of the enzymes and controlling the biological functions. For example, copper maintains stability and conformation of several biological enzymes, including superoxide dismutase, hemocyanin, and cytochrome oxidase (Mahato and Narang, 2012). Organometallic complexes are also examples of coordination complexes, e.g., vitamin B12 (cyanocobalamin) is cobalt-containing, whereas heme is an iron-containing organometallic complex of the circulatory system that carries oxygen. When a metal ion binds with more than one site of a ligand, it is known as chelating (Mahato and Narang, 2012). 14.1.1.2 Molecular Complexes Molecular complexes form between ligand and substrate using noncovalent bonds such as van der Waals forces, electrostatic forces, hydrogen bonding, or hydrophobic effects, charge transfer, etc. Different forces between the ligand and substrates have been represented in Fig. 14.2. Based on the involved substrate and ligand, molecular complexes can be further subdivided into small molecule small molecule complex and small molecule large molecule complex (Mahato and Narang, 2012). Therefore, an interaction between small ligand and a small substrate can be borne because of opposite polarity. For example, interaction between benzocaine and caffeine takes place due to the dipole dipole interaction between the electrophilic nitrogen atom of caffeine and nucleophilic oxygen of benzocaine. It also includes molecular dimers, trimers, etc., pharmaceutical cocrystal, including other self-association to form aggregates (e.g., surfactant micelles) (Mahato and Narang, 2012). On the other hand, interactions between small substrates and large ligand also form molecular complexes via drug protein binding, enzyme substrate interaction, and FIGURE 14.2 Representation of different covalent and noncovalent interactions involved in complexation. DOSAGE FORM DESIGN CONSIDERATIONS 14.1 INTRODUCTION: COMPLEXATION IN PHARMACEUTICAL PRODUCTS 477 inclusion complexes. Therefore, a reversible molecular interaction exists between drug protein (albumin), intramolecular interactions (e.g., base base interactions in the DNA helix), attachment of small molecules into the small pockets of large molecules (Ras gene), and inclusion complexes (e.g., CD complexes), etc. Drug CD complexes are one of the examples of molecular complexes of relatively small substrates and large ligands (Mahato and Narang, 2012; Maurer et al., 2012). 14.1.1.3 Metal Ion Coordinate Complexes Metal ion coordinate complexes, also known as metal complexes, are where the ligands or counter ions (a base), such as nitrogenous base (e.g., ammonia), an aromatic compound (e.g., ferrocene), or anion (e.g., chloride ion), donate a pair of electrons to the central metal ion (an acid) to form the coordinate covalent bond. The number of bonds between the ligand or ligands and central metal ion is represented as coordination number of the complex (Morimoto et al., 2011). For example, in Eq. 14.1, the silver ammonia coordinate complex has two as the coordination number as two ammonia molecules (ligand) bind to the central metal ion Ag1. Similarly, the coordination number of [Co(NH3)6]31 complex is six. Most metal complexes having FIGURE 14.3 Chemical structure of (A) cisplatin, (B) carboplatin, (C) hemoglobin, (D) cyanocobalamin, and (E) ethylene diaaminetetraaceticacid. DOSAGE FORM DESIGN CONSIDERATIONS 478 14. DRUG COMPLEXATION coordination number of four have a square planar structure (e.g., cisplatin) (Fig. 14.3A) and most complexes with coordination number six are octahedral (Cook et al., 2013). Various metal complexes are essential components of our body. Iron complexes play a vital role in almost all living cells. Hemoglobin and heme proteins of myoglobin are the examples of iron complexes which are necessary for transporting oxygen in different parts of the body (Fig. 14.3C; Mansor, 2003). Cytochrome c is another example of an iron complex which is essential in both respiratory systems and photosynthetic process. Copper ion complexes such as hemocyanina and cytochrome oxidase are present in various proteins and enzymes. Cyanocobalamin is an example of a cobalt ion complex (Fig. 14.3D). Furthermore, zinc is present in many proteins and enzymes, including carboxypeptidase and carbonic anhydrase. It is the only metal ion found in crystalline insulin, where the insulin hexamer can bind up to nine atoms of zinc (University of the Sciences in Philadelphia, 2015). Various metal-containing complexes are widely used to treat a range of diseases. Metal complexes have also expanded their applications as diagnostic agents as well as anticancer agents. Platinum complexes such as cisplatin and carboplatin are widely used as anticancer drugs. Although cisplatin and carboplatin have shown similar activities against lung and ovarian cancers, carboplatin is less toxic to the peripheral nervous system and the kidneys due to the presence of bidentate dicarboxylate ligand in carboplatin structure (Fig. 14.3B) which slows down the degradation of carboplatin to a potentially toxic derivative (Mansor, 2003). When a single metal atom binds with more than one site of multidentate ligand, a chelate is formed and at the same time the ligand is called the chelating agent. Examples of such chelating agents are ethylenediaminetetraacetic acid (total six points (4: O and 2: N)) (Fig. 14.3E), tartaric acid, citric acid, etc. Some drugs can also act as chelating agents and bind with metal ions, for example, tetracycline can bind with different metal ions such as calcium (Ca21), iron (Fe31, Fe21), magnesium (Mg21), and form hydrophilic chelates which are less bioavailable (Palm et al., 2008). Ciprofloxacin and nalidixic acid also bind with polyvalent ions and may result in low oral bioavailability. In such cases, coadministration of drugs, such as minocycline and tetracycline that bind with metal ions and products such as milk products, and mineral supplements containing cations should be avoided (Leyden, 1985). 14.1.1.4 Inclusion Complexes Inclusion complex is one of the molecular complexes where interaction occurs between a substrate (guest) and a cage (host) containing one or more ligand molecules. The binding ability of hosts and guests is mainly attributed to hydrophobic interactions and the corresponding character of size and shape between their structures (Chen and Jiang, 2011). CD is one of the most important molecular complexes where a single ligand molecule interacts with one or more substrate molecules (Fig. 14.4). Other large molecules such as hydrophilic dextrins, calixarenes, etc. interact to form a monomolecular inclusion complex, whereas hydroquinone, urea, thiourea, bile acids form cages (e.g., hydroquinone over methanol), channels (e.g., urea around 13-cis-retinoic acid and straight chain hydrocarbon), molecular sandwiches, or polar nanostructures surrounding the lipophilic molecules (Brown and Hollingsworth, 1995; Kralj et al., 2008; Thakral and Madan, 2008). DOSAGE FORM DESIGN CONSIDERATIONS 14.1 INTRODUCTION: COMPLEXATION IN PHARMACEUTICAL PRODUCTS 479 FIGURE 14.4 Inclusion of drug molecules within the three-dimensional structure of cyclodextrin: formation of inclusion complex. Inclusion complex of drugs has shown several advantages in the pharmaceutical applications, including enhancement of stability, aqueous solubility, systemic availability, and safety of drugs. Stability of prostaglandin E2 and prostaglandin A2 has been evaluated with different inclusion complexes formed with different derivatives of β-CDs (methylated-, heptakis (2, 6-di-O-methyl)-, heptakis (2, 3, 6-tri-O-methyl)-) (Hirayama et al., 1984). All of the methylated CDs showed improved stability, although heptakis (2, 6-di-Omethyl)-β-CD at a ratio of 1:1 formed a comparatively kinetically stable complex over the others. This can be implemented to manufacture aqueous formulation of prostaglandins (Hirayama et al., 1984). The submaximal concentration of curcumin bioavailability has been shown to be improved via adopting this encapsulation technique. β-CD-curcumin self-assembly has shown to improve its antitumor efficacy against prostate cancer as compared to free curcumin (Yallapu et al., 2010). Finally, drug-induced toxicity has been shown to be reduced through such entrapment. The ulcerative potential of NSAIDs is well known. Such gastric ulceration potential of indomethacin or piroxicam (NSAID) has shown to be reduced via inclusion in β-CD or hydroxypropyl β-CD (HP-β-CD). Further, this inclusion complexation helped to protect the experimental animals from restraint and cold stress ulcer formation (Alsarra et al., 2010). 14.1.2 Application of Complexation Complexation is nothing but binding between a ligand and another molecule. This binding may affect the physicochemical properties of the molecule, or biological properties may also get affected. Therefore, complexation can be applied in various fields. Applications of complexation include (Tiwari et al., 2010; Jain et al., 2012): 1. Qualitative and quantitative analysis of metals, like silver, mercury, aluminum, etc.; 2. Colorimetric analysis of drug molecule using the color of the complex of transition metals; 3. Evaluation of water hardness; 4. Indication of oxidation reduction reaction; 5. Extraction of metal ion, such as silver, gold, nickel, etc.; DOSAGE FORM DESIGN CONSIDERATIONS 480 14. DRUG COMPLEXATION 6. Electroplating of metal, e.g., cyano complex of silver, copper used for electrodeposition of metals; 7. Coordination complexes including chlorophyll, hemoglobin, cytochrome, vitamin B12, etc. play a major role in animal and plant life; 8. Antibacterial and antifungal agent, e.g., ferric complex of oxine, silver sulfadiazine, etc.; 9. Treatment of metal poisoning, e.g., calcium EDTA is used to treat lead poisoning; 10. Promising anticancer activities, e.g., platinum complexes and ruthenium complexes; 11. Masking of unpleasant taste and odor of the drug molecule. CD complex can encapsulate and hide the molecules or functional groups that contribute to unpleasant tastes or odors from the sensory organ and produce complexes with little or no taste or odor; 12. Protection of labile drug molecules against various decomposition processes. CD complexes improve the stability of the several labile drug molecules and reduce the volatility of many volatile compounds, e.g., β-cyclodextrin improve the shelf life of glibenclamide for 4 years; 13. Enhancement of physical, chemical, and thermal stability of drugs. E.g., CD complexes protect the compound from oxygen, water, radiation, heat, or chemical exposure; 14. Improvement of aqueous solubility of poorly soluble drugs. E.g., CDs form inclusion complexes and hide most of the hydrophobic region of the drug into its core and only the hydrophilic portion is exposed to the external surface; 15. Improvement of bioavailability of drug molecules, e.g., CD enhances the solubility of poorly soluble compounds and consequently oral bioavailability. Percutaneous or rectal absorption can also be increased by reducing the hydrophobicity of drugs; 16. Drug safety by protecting the biological membranes from the direct contact of the drug molecule, therefore, CD complexes reduce local irritation without altering the efficacy of the drug. The toxicities associated with crystallization of poorly watersoluble drugs in parenteral formulations can often be reduced by formation of soluble CD complexes; 17. Reduction of drug drug or drug additive interactions by formation of CD complexes, as it physically separates the incompatible compounds; 18. Conversion of oil/liquid to microcrystalline forms via CD complexation, making it easy to handle. 14.2 FUNDAMENTAL METHODS OF FORMATION OF DRUG COMPLEXES 14.2.1 Physical Blending Method A physical blending method involves mechanical mixing of drug and complexing agents. For small-scale preparation, the drug complexing mixtures are triturated in a mortar, followed by passing through a suitable sieve to get the desired particle size. For industrial manufacturing, granulators like rapid mixer granulator are employed for blending drug and complexing agents. Then, the mixture is passed through a standard sieve DOSAGE FORM DESIGN CONSIDERATIONS 14.2 FUNDAMENTAL METHODS OF FORMATION OF DRUG COMPLEXES 481 assembly, if necessary. The above mixtures are stored in a controlled environment at a specified temperature and humidity conditions. 14.2.2 Kneading Method This method involves the addition of aqueous or hydro alcoholic solvents to the complexing agent to form a paste. Then, the drug is added to the paste and kneaded for a specific time. The kneaded mixture is dried using an appropriate drying technique and passed through a sieve to obtain a predetermined particle size. This is one of the simplest and most cost-effective methods for preparing drug complexes. Kane et al. prepared using the kneading method a CD inclusion complex containing telmisartan, a practically water-insoluble drug. The drug and CD were taken in the molar ratio of 1:2 and the solubility of the drug with complex prepared by physical mixing and coevaporation method were compared. The study showed that the highest improvement in solubility and in vitro drug release was observed in the inclusion complex prepared by the kneading method (Kane and Kuchekar, 2010). Patel et al. prepared etoricoxib-β-CD complex using the kneading method and compared it with the physical mixture. The results showed that the dissolution of etoricoxib was significantly higher when compared with the pure drug and physical mixture (Patel et al., 2007). 14.2.3 Coprecipitation Technique In this method of preparation, a drug is added to the solution of a complexing agent and allowed to mix under magnetic agitation with protection from light. The drug reacts with complexing agents and precipitates out as an insoluble complex. The precipitate is then vacuum filtered and dried at room temperature to prevent the loss of water in the inclusion complex. Mangolim et al. compared the different methods of preparation for a curcumin complex formation with β-CD. It was reported that inclusion compounds prepared by coprecipitation technique showed better complexation efficiency and improved drug solubility (Mangolim et al., 2014). Ghosh et al. studied the dissolution profile of silymarin-β-CD using four different methods, namely, physical mixing, kneading, coprecipitation, and solvent evaporation. Among the various methods studied, coprecipitation method showed better dissolution for poorly aqueous soluble silymarin with a sustained release property (Ghosh et al., 2011). 14.2.4 Solution/Solvent Evaporation Method In this method, a required amount of drug and a complex-forming agent are dissolved separately in two miscible solvents. Upon mixing the solution, a fine dispersion of drug complex is formed. Then, the solvent is evaporated under vacuum at a specified temperature to obtain a solid mass of drug complex (Fig. 14.5). For example, the alcoholic drug solution is generally added to aqueous solution of complexing agents. Finally, the dried mass size is reduced to obtain a uniform particle size distribution. Zu et al. has synthesized inclusion compound of γ-CD containing taxifolin using emulsion solvent evaporation and freeze drying method. The study showed that the solubility, dissolution rate, and DOSAGE FORM DESIGN CONSIDERATIONS 482 14. DRUG COMPLEXATION High speed agitation Ethyl acetate solution of taxifolin Deionized water Taxifolin emulsion Rotary evaporation The concentration of taxifolin solution is more than 3 The concentration of taxifolin solution isn’t more than 3 γ-CD High-concentration taxifolin solution Taxifolin nanosuspension Vacuum freeze-dry Inclusion complex of toxifolin-γ-CD FIGURE 14.5 Diagram of the solvent evaporation method of preparing the inclusion complex of taxifolinγ-cyclodextrin. Adapted with permission from (Zu et al., 2014). Copyright Elsevierr. bioavailability of taxifolin complexes were significantly enhanced as compared to the free taxifolin (Zu et al., 2014). Similarly, Loh et al., prepared norfloxacin-β-CD using the physical trituration method, kneading, and solvent-evaporation method. The authors have concluded that solvent evaporation method was the most efficient method to improve the solubility and dissolution rate of norfloxacin (Loh et al., 2016a). DOSAGE FORM DESIGN CONSIDERATIONS 14.2 FUNDAMENTAL METHODS OF FORMATION OF DRUG COMPLEXES 483 14.2.5 Neutralization Precipitation Method This method is based on the precipitation of drug complexes by neutralization technique. Drugs which are ionizable and solubilized in high-pH alkaline solvents, such as sodium or ammonium hydroxide solution, are added to aqueous solution of complexing agent. The above solution is neutralized with a suitable acidic solution until it reaches the equivalence point. Because of the neutralization, the drug complexes precipitate out due to the change in the pH. Then, the precipitate is filtered and air-dried. Precautionary arrangements to avoid solubilization of drug molecules outside the complex need to be done to have a proper control on pH adjustment technique. 14.2.6 Milling/Cogrinding Technique This method differs from physical blending in which extensive attrition and impact made to the drug complex powder blend using mechanical devices like a ball mill. Due to this milling/cogrinding technique, molecules are well mixed resulting in the formation of solid binary drug complexes. Bandarkar et al. utilized the ball mill technique to overcome the scale-up issues during the manufacturing process of meloxicam-β-CD complex. The results obtained from this study revealed that drug complex prepared by milling technique showed enhanced solubility and better dissolution rate compared with the marketed product (Bandarkar and Vavia, 2011). 14.2.7 Atomization/Spray Drying Technique Spray drying is the process in which drug complex solution is transformed into a dry powder form by spraying the feed (drug complex solution) into a hot drying medium. It is one of the most widely used industrial manufacturing processes because of its advantage in producing a powder with less water content, thereby increasing the product stability. Balakrishnan et al. formulated a complex containing clotrimazole and β-CD using the spray drying technique. The authors concluded that the inclusion compound prepared by the spray drying method significantly improved the bioavailability (Prabagar et al., 2007). 14.2.8 Lyophilization/Freeze Drying Technique Freeze drying or lyophilization technique is a widely accepted method to remove water content of all heat-sensitive materials and aromas. It is a multistep drying process that involves four main stages: freezing, sublimation (primary drying), desorption stage (secondary drying), and, finally, storage. The product obtained from lyophilization techniques is proven to possess superior quality and have a longer shelf life. The important advantage with this technique is getting a more porous and amorphous complex structure with a high degree of interaction between drug and a complexing agent. However, this technique suffers from several limitations such as long processing time and higher energy consumption. DOSAGE FORM DESIGN CONSIDERATIONS 484 14. DRUG COMPLEXATION Raza et al. prepared a drug containing HP-β-CD inclusion complex by freeze drying technique to enhance the aqueous solubility of kamebakaurin, a plant diterpenoid used as an anti-inflammatory agent. The results obtained from this study exhibited better stability of complex with higher solubilization effect (Raza et al., 2017). Similarly, Michalska et al. showed enhanced solubility and stability of ITH12674, a multitarget drug used in the treatment of brain ischemia using 2-HP-β-CD, where the authors prepared the complex by the freeze drying method (Michalska et al., 2017). Bhargava et al. compared the inclusion complex of cefpodoxime proxetil-β-CD prepared using various methods. The authors concluded that the complex prepared using the freeze-dried method enhanced aqueous solubility and dissolution rate (Bhargava and Agrawal, 2008). 14.2.9 Microwave Irradiation Method In this method, microwave irradiation from a microwave oven is applied to reactant molecules to produce drug complexes. Initially, the drug and complexing agents in a suitable molar ratio are dissolved in a blend with a definite amount of aqueous and organic solvent. The above mixture is subjected to microwave heating at 60 C for 60 120 seconds for complex formation. Following the complexation, the free drug and uncomplexed agents are removed by adding an appropriate amount of solvent mixture and filtered to separate the drug complex. Then, the precipitate, i.e., the drug polymer complex is vacuum-dried at 40 C for 2 days. Yatsu et al. prepared inclusion complex of an isoflavone enriched fraction with β-CD and HP-β-CD using various methods such as freeze drying, kneading, spray drying, coevaporation, and microwave method. This study compared the influence of different methods of the inclusion compound formation. The results showed that microwave method equally enhanced the complex formation compared with other methods except for freeze drying method (Yatsu et al., 2013). 14.2.10 Supercritical Antisolvent Technique This method uses carbon dioxide (CO2) as supercritical antisolvent because of its favorable lower critical temperature (31 C) and pressure (73.8 bar). This method offers an attractive advantage in processing thermolabile substance and is proven to enhance bioavailability of active compounds. Supercritical CO2 provides better conditions for complexation by enhancing mass transfer and improved solvating power. Further, the efficiency of CO2 can be enhanced by employing low amount cosolvent such as ethanol in a stainless-steel cylinder. This technique involves the spraying of the mixture of drug and complexing agent solution through a nozzle into a container maintained under supercritical pressure conditions. During this step, CO2 rapidly diffuses into the carrier liquid and counter diffuses into the antisolvent. Due to the larger expandability of CO2, the mixture becomes supersaturated resulting in the precipitation of the solute, and the solvent is carried away with the supercritical fluid flow. Rudrangi et al. prepared olanzapine-methyl-β-CD complexes by an organic solvent-free supercritical fluid process to enhance the dissolution of drug and compared with other DOSAGE FORM DESIGN CONSIDERATIONS 14.3 CHARACTERIZATION OF DRUG COMPLEXATION 485 FIGURE 14.6 Schematic representation of supercritical carbon dioxide processing using the extraction apparatus supplied by Thar Process Inc., USA (Rudrangi et al., 2015). methods such as coevaporation and freeze drying (Fig. 14.6). The olanzapine complex prepared by supercritical antisolvent technique exhibited the highest drug dissolution compared to the complexes prepared using other methods (Rudrangi et al., 2015). The above results were further supported by flurbiprofen-methyl-β-CD complexes prepared using the same method (Rudrangi et al., 2016). 14.2.11 Extrusion This method involves the combined process of thermal and blending. The technique involved a premixing drug, a complexing agent with very little water and allowed to pass through the nozzle of an extruder. It is essential to maintain necessary heating conditions and monitoring of the extruder container to avoid a significant loss of the drug complex which is thermosensitive. Several advantages and disadvantages of the above employed complex manufacturing methods have been represented in Table 14.1. 14.3 CHARACTERIZATION OF DRUG COMPLEXATION 14.3.1 Determination of Guest Content The amount of guest compound in a drug complex can be quantified using suitable analytical methods, such as ultraviolet spectroscopy, gas liquid chromatography, high-performance liquid chromatography, or any other advanced analytical tools. While to measure the content of volatile oils, measurement in the distillate for the oil is done. It is DOSAGE FORM DESIGN CONSIDERATIONS 486 14. DRUG COMPLEXATION TABLE 14.1 Advantages and Disadvantages of Different Methods Employed in Complex Preparation Preparation Method Advantages Disadvantages Drug Sources Kneading Very simple method Time-consuming process Telmisartan Kane and Kuchekar (2010) Faster Inexpensive Coprecipitation Commonly used method in laboratory Usage of organic Silymarin solvents Ghosh et al. (2011) Removal residual solvent is tedious Not suitable for large productions Solution/ solvent evaporation method Improves solubility Neutralization precipitation method Suitable for industrial preparation Milling/ Cogrinding Enhanced dissolution by transforming crystalline to amorphous by combining blending and attrition Better amorphization of drug Too many processing steps Taxifolin Zu et al. (2014) pH adjustment is Glibenclamide Prasad et al. needed (2015) Drug degradation by acids and alkali Friedrich et al. (2005) Time-consuming process Nifedipine More expensive Fernandes Nicardipine hydrochloride and Veiga (2002) Extended timeconsuming process ITH12674 Michalska et al. (2017) No toxic solvents are used Atomization/ Spray drying One-step process and save time Lyophilization/ Improved solubilization Freeze drying Faster dissolution of drug Expensive Microwave irradiation Highly suitable for industrial preparation, high yield Improper complexation Carvedilol Wen et al. (2004) Supercritical antisolvent Increased dissolution rate of drug, higher complexation efficiency, reduced process time, usage of CO2 is better than organics solvents Initial establish cost is high Flurbiprofen Rudrangi et al. (2016) Extrusion Suitable for industrial process and less consumption of water Not applicable for thermolabile substance Indomethacin Yano and Kleinebudde (2010) DOSAGE FORM DESIGN CONSIDERATIONS 14.3 CHARACTERIZATION OF DRUG COMPLEXATION 487 essential to dissociate the complex and solubilize the guest compound in a suitable solvent before analysis. For example, for determination of a guest in a cyclodextrin complex, it should be dissolved in a solution of 50% ethanol. And further dilution is required with pure ethanol before measurement using ultraviolet spectroscopy. Further, the moisture content in a cyclodextrin drug inclusion complex is determined by simply measuring the loss on drying at 60 C kept for several hours in vacuum (Saha et al., 2016). 14.3.2 Thermo-Analytical Methods Thermal methods are extensively used to characterize drug complexes and help in the identification of true complex formation. In general, the thermal methods examine the thermal behavior of drug, a complexing agent, and their drug complex. The most commonly used thermo-analytical methods are thermogravimetry analysis (TGA), differential thermogravimetry (DTG), and differential scanning calorimetry (DSC) (Rudrangi et al., 2015). TGA and DTG estimate the loss of mass of drug complex with the increase in temperature. The amount of heat absorbed or evolved in a drug complex will be measured in DSC with the temperature controlled program. The absence of drug melting point peak (197 C) in the DSC curve of drug complex indicates the formation of drug inclusion complex. For example, olanzapine-methylβ-CD complexes showed absence of drug endotherm which is ascribed to the transformation of drug from crystalline to amorphous form or complex formation (Fig. 14.7; Rudrangi et al., 2015). 14.3.3 Infrared Spectroscopy Infrared spectroscopy is a technique that can tell us about the molecule of analysis. Among the most widely used techniques in infrared spectroscopy, Fourier-transform FIGURE 14.7 DSC thermograms of olanzapine, complexing agent and inclusion compound prepared by various methods (Rudrangi et al., 2015). DOSAGE FORM DESIGN CONSIDERATIONS 488 14. DRUG COMPLEXATION infrared spectroscopy (FT-IR) has gained its importance in different fields, including medicine, biology, and biochemistry. Here, infrared light intensity versus property of light is plotted to represent the infrared spectrum (Smith, 2011). This characterization involves the comparison of spectral bands of drug and inclusion complex. The absence of the characteristic band of a drug in the complex indicates the encapsulation of drug molecules inside the cavity of an inclusion complex. Variation in shape, shift, and intensity of the FT-IR absorption peaks of “guest” and host can provide a lot of information to confirm the formation of inclusion complexes (Ol’khovich et al., 2016). 14.3.4 X-ray Powder Diffraction Diffraction is the method that allows the determination of structural evaluation of partially disordered complexes by the generations of simulated diffractograms of the particular structural model (Drits and Tchoubar, 2012). This characterization technique is beneficial for analysis of solid drug in the inclusion complex. The drug molecule entrapped inside the complex does not show any diffraction pattern. For example, Wei et al. prepared an inclusion complex composed of phloretin/HP-β-CD (HP-β-CD) and analyzed by powder X-ray diffraction (PXRD) technique. The PXRD patterns for HP-β-CD/phloretin, the physical mixture, and the phloretin/HP-β-CD inclusion complex was shown in Fig. 14.8. The absence of crystalline peak in HP-β-CD shows transformation of crystalline to amorphous form of the drug and complex formation (Wei et al., 2017). 14.3.5 Scanning Electron Microscopy The scanning electron microscope is one of the most versatile techniques used in the analysis and examination of microstructural characteristics including the morphological behavior of complex formation of solid components. In most of the cases, the complex appears as regular spherical particles of uniform particle size distribution. For example, Wei et al. has studied the morphological formulation of Glabridin/HP-β-CD inclusion complexes. The identification reveals that the morphology of inclusion complex will be FIGURE 14.8 Powder X-ray diffraction diagram of HP-β-CD (A), phloretin (B), the physical mixture (C), and the phloretin/HP-β-CD inclusion complex (D) (Wei et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 14.4 FACTORS INFLUENCING COMPLEX FORMATION 489 FIGURE 14.9 Scanning electron microscopy of HP-β-CD (A), glabridin (B), the physical mixture (C), and the glabridin/HP-β-CD inclusion complex (D) (Wei et al., 2017). different from the physical mixture, usually appearing as an organized bulky particle similar to the morphology of drug (Fig. 14.9; Wei et al., 2017). 14.3.6 Diffusion NMR Studies Diffusion NMR is a potential technique which aids in the simultaneous determination of diffusion coefficient of all the components in a solution, as long as they show distinct and non-superimposed peaks. Diffusion depends on the shape and size of the analyzing molecule, and thus analysis of host guest complexes can be analyzed by adopting this technique (Gómez et al., 2014). NMR analysis is used to explore the possible inclusion of drug inside the complex. The chemical shift obtained from NMR spectra of drug and inclusion complex is compared for the possible interaction of host and a complexing agent (Gómez et al., 2014). 14.4 FACTORS INFLUENCING COMPLEX FORMATION 14.4.1 Influence of Temperature on Complex Formation The hollow space of a complexing agent should hold the drug molecules, and the process of complex formation is affected by many factors for any inclusion compounds. In the majority of the inclusion compounds, the type of complexing agent and its physicochemical properties significantly influence the complex formation and its performance. It has been observed that changes in temperature during the process of complex formation significantly affect the inclusion complex. Increase in the temperature enhanced the DOSAGE FORM DESIGN CONSIDERATIONS 490 14. DRUG COMPLEXATION magnitude of molecular momentum and favored the complex formation. However, it also decreases the stability of the complex by increasing the molecular vibration of inclusion compounds and supports a faster release of the drug. Zarzycki et al. studied the temperature influence of an inclusion compound formed between β-CD and phenolphthalein (Zarzycki and Lamparczyk, 1998). The authors have concluded that lowering the temperature results in a decrease in the complex formation. This can be interpreted in another way that an increase in temperature has a relationship with the solubility of drug components, mostly it contributes towards an increase in solubility (Lutka, 2001). Further, prolonged complexation time also been reported with a decrease in the temperature (Ahmadi-Abhari et al., 2014). Alternatively, a derivative of HP-β-CD is widely used as a complexing agent to solubilize or stabilize drug components through the formation of a 1:1 complex. Solubilization of poorly soluble drugs can further be improved by forming a 1:2 polymer drug complex, which could be more useful in the pharmaceutical formulation. But the mechanism of 1:2 complex formation is ambiguous, preventing utilization of such systems (Loftsson et al., 2002). Complexation of celecoxib to achieve an improved solubilization at a 1:2 complex system was proposed to be achieved at a higher temperature with the same concentration of CD. This finding is a pioneer in the field of inclusion complexation process (Chiang et al., 2014). 14.4.2 Influence of Chemical Modification on Complex Formation Lipophilic compounds are employed in complex formation to improve solubility and stabilize the compound from oxidation, high temperature, and light. However, crystal formation and subsequent precipitation are the limitations towards the formation of the inclusion complexes, which further reduces solubility as well as the bioavailability of the incorporated component (Arijaje and Wang, 2015). To avoid such limitation for starch inclusion complexes, chemically modified starch is used. For example, hydroxy propylation of amylose with a 0.075 degree of substitution has been shown to form soluble complexes with sodium dodecyl sulfate (Wulff and Kubik, 1992). On the other hand, chemical modification can also lead to decreased complexing properties of ligands, e.g., acetylation of pea starch (Liu et al., 1997) or amylose maize starch (Eliasson et al., 1988). Alternatively, enhancement of metal complexation can be attempted via chemical modification. Polymerassisted ultrafiltration to remove heavy metals from the aqueous environment has been shown to be improved greatly by sulfonation of poly(vinyl alcohol) (Dambies et al., 2008). Derivatives of CDs at their outer hydroxyl groups have pointed towards solubility enhancement, which may be due to decreased crystallinity. Such an improvement in solubility and decreased crystallinity can subside the limitations by preventing kidney damage (Sobrinho et al., 2011). Furthermore, a citrate derivative of CD and albendazole inclusion complex prepared by the spray drying technique showed exceptional findings on physicochemical properties. The dissolution rate of the drug was surprisingly found to be 100% within 20 minutes, indicating a suitable excipient for oral delivery of albendazole (Garcı́a et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 14.4 FACTORS INFLUENCING COMPLEX FORMATION 491 14.4.3 Influence of Enzymatic Modification on Complex Formation Gelatinization and crystallization characteristics of starch are the significant challenges in the food industry. Such properties can be improved by chemical modifications and also by enzymatic modification of the basic structure. Modified starches depict superior physicochemical properties, like stability, resistance to retrogradation, etc. (Wurzburg, 2006). The average molecular weight of native starch can be decreased by this enzymatic hydrolysis, thus leading to decreased viscosity and modifying its dispersion characteristic. The most often employed enzymes for enzymatic medication of starch are α-amylase and β-amylase (Gallant et al., 1992). 14.4.4 Effect of Coacervate on Complex Formation Two oppositely charged polyelectrolytes form polyelectrolyte complexes in aqueous solutions. Such electrostatic interactions between the macromolecules (e.g., nucleic acids, peptides or proteins, branched dendrimers or linear polymers) result in complex coacervation, where the coacervated compound will remain in the soluble phase. In most of the cases, the functionality of the coacervates will remain unaltered, thus gaining interest in pharmaceutical protein preparations (Kayitmazer et al., 2013; Water et al., 2014). Such coacervation complexation could be formed between protein and polymer protein, nucleic acid and dendrimer, nucleic acid and polymer, etc. (Turgeon et al., 2007; Kayitmazer et al., 2013). Improvement of physicochemical properties without altering the biofunctionality of macromolecules provokes the utility of coacervation in the pharmaceutical field, where enhancement of stability, prevention of enzymatic degradation, controlled release characteristic, and inhibition on denaturation or aggregation of the macromolecule are the most attractive explorative areas. In this context, the authors in a recent study have suggested that hyaluronic acid is able to form coacervation complexes with proteins thereby stabilizing the developed protein formulation (Water et al., 2014). Hyaluronic acid has also been conferred as an enhancer for delivery of genetic materials with the formation of biocompatible carriers. From the biological point of view, use of hyaluronic acid in the delivery of nucleic acids through chitosan nanoparticle showed improvement in silencing activity and simultaneously improved cell viability when compared with chitosan nanoparticle of the same nucleic acid. Such reversible binding suggests improved biocompatibility and release of genetic material from the coacervate (Al-Qadi et al., 2013). Many other applications of chitosan have been explored for drug delivery (Tekade et al., 2017; Maheshwari et al., 2015). The hyaluronic acid could also serve as a controlled release platform for the macromolecules from the hydrogel network, where the release of the therapeutic protein can be controlled through the cross-linking density and degradability of hyaluronic acid hydrogel. Such controlled release delivery also serves with simple drug loading capacity without any degradation or denaturation of the incorporated proteins (Hirakura et al., 2010). Another group has also suggested that physical stability of the incorporated protein molecules could be improved through this coacervation complexation using hyaluronic acid (Water et al., 2014). A chitosan alginate capsule for entrapment of macromolecules has DOSAGE FORM DESIGN CONSIDERATIONS 492 14. DRUG COMPLEXATION been suggested by Dally and Knorr, where they coated the liquid chitosan core by a hard coating of alginate (Daly and Knorr, 1988). 14.5 EFFECT OF COMPLEXATION ON DRUG SOLUBILITY AND BIOAVAILABILITY The solubility of a solute in any stage is the property considered for the formation of a homogeneous solution within the solid, liquid, or gaseous solvent. Fundamentally, the solubility of a solute solely depends on the solvent characteristics and also on pressure and temperature, where the solubility of a solute can vary from poorly soluble (e.g., silver chloride in the aqueous phase) to infinitely soluble (ethanol in an aqueous phase). Thus, it reaches an equilibrium where solute will reach to a saturation concentration in a particular solvent. Supplementary addition of the solute cannot improve further the concentration of the solute in that solution (Savjani et al., 2012). Pharmaceutically useful complexes are mostly formed through complexation with ligands including caffeine, CDs, polyethylene glycol, urea, N-methylglucamine, etc. Several approaches to the improvement of therapeutic applicability in the pharmaceutical field have been summarized in Table 14.2. Complexation is the process that can improve the solubility of the solute in a solvent. Such improvement of solubility could proportionately affect bioavailability. Therefore, the improvement of bioavailability of lipophilic drugs could be effectively targeted through solubility enhancement of the poorly soluble drugs (Gorain et al., 2013). Thus, lipophilic moieties of insoluble drug molecules will be entrapped in such a way that the solubility of the drug will increase, thus forming a hydrophobic internal cavity and hydrophilic external cavity. Such entrapment of drug molecule does not allow formation or breaking down of the covalent bond between the ligand and drug molecule; however, the complex and free drug will rapidly reach an equilibrium state in the solution. Norfloxacin is an antibacterial drug with poor solubility, thus having low bioavailability. Using the concept of complexation with CD, the solubility of norfloxacin was improved. This enhancement in solubility was attributed to conversion of a crystalline form of the drug to an amorphous form (Loh et al., 2016b). Higuchi and Connors (1965) specified the two types of phase solubility profiles (A and B-type) of complexes (Fig. 14.10). To construct the phase solubility curve, an excess quantity of poorly aqueous soluble drug was incorporated into several vials with a constant quantity of water and varied concentrations of complexing ligand. In the type “A solubility profile,” the solubility of the poorly soluble drug increased with increasing concentration of complexing ligand, which further subdivided into three different subtypes, as follows. AL: where increase in solubility is linear with the increase in ligand concentration to obtain a first- or higher-order relationship with respect to substrate (i.e., poorly watersoluble solute) and first-order relationship with respect to ligand; AP: where the increase in solubility was found to be initially linear, however, at higher concentration of the ligand, solubility increment was not linear but higher, thus deviates DOSAGE FORM DESIGN CONSIDERATIONS TABLE 14.2 Drug Used for Complexation Complexation Approaches Applied to Improve the Characteristics of the Final Pharmaceutical Formulations Complexing Agent Objective Outcome References Phenolphthalein β-CD Temperature influence of inclusion compound formed between β-CD and phenolphthalein Lowering the temperature results in decreasing the complex formation Zarzycki and Lamparczyk (1998) Celecoxib β-CD Complexation of celecoxib to achieve improved solubilization 1:2 complex system was proposed to achieve at higher temperature with same concentration of CD Chiang et al. (2014) Albendazole Citrate derivative of Investigation of physicochemical properties of inclusion complex CD Dissolution rate of the drug was surprisingly found to be 100% within 20 minutes Garcı́a et al. (2014) siRNA-loaded chitosan nanoparticles Hyaluronic acid To investigate the role of hyaluronic acid on the nanoparticles’ formation and activity Improvement in silencing activity and improved cell viability of siRNA chitosan nanoparticle complexed with hyaluronic acid Al-Qadi et al. (2013) Taxifolin γ-CD To evaluate the water solubility enhancement of inclusion complex of taxifolin-γ-CD. Solubility, dissolution rate, and bioavailability of taxifolin complexes were significantly enhanced compared to the free taxifolin Zu et al. (2014) ITH12674, a multitarget drug 2-Hydroxypropylβ-CD To investigate the solubility and pharmacological effect of inclusion complex ITH12674 showed enhanced solubility and stability of used in the treatment of brain ischemia using 2-HP-β-CD Michalska et al. (2017) Norfloxacin CD To evaluate the effect of complexation on solubility of Norfloxacin Enhancement in solubility was observed which Loh et al. was attributed to conversion of crystalline form of (2016a) drug to amorphous form Curcumin Polyvinyl alcohol To examine aqueous solubility, stability, and bioavailability of curcumin in molecular complex of curcumin with pH-sensitive cationic copolymer Polyvinyl alcohol with curcumin formed amorphous complexes that showed the improved solubility 20 times and bioavailability 6 times Kumar et al. (2016) Curcumin Phospholipid To explore the effect of Curcumin-phospholipid complex on oral absorption and bioavailability Curcumin-phospholipid complex has depicted improved oral absorption and bioavailability of the drug due to enhancement of solubility of complex Shukla et al. (2017) Enalapril maleate Polymethacrylate Eudragit E100 To investigate intestinal permeability and oral bioavailability of enalapril maleate upon complexation Complex formation of the drug showed increase in intestinal permeation and oral bioavailability Ramı́rezRigo et al. (2014) (Continued) TABLE 14.2 (Continued) Drug Used for Complexation Complexing Agent Objective Outcome References Carvedilol CD To prepared and characterize buccal tablets of carvedilol and CD inclusion complex Dissolution and bioavailability of carvedilol was improved by making inclusion complex Hirlekar and Kadam (2010) Norfloxacin CD and crospovidone To evaluate the effect of water-soluble polymer on solubility of inclusion complex of poorly watersoluble drug Compressed tablets of inclusion complex having higher concentration of crospovidone showed faster release compared to inclusion complex of norfloxacin only Sharma and Bathe (2014) Ibuprofen CD To examine the effect of particle size on physiochemical property and dissolution of inclusion complexes Inclusion complex prepared with smaller particle size of the drug leads to higher solubility and dissolution compared with inclusion complex with bigger particle size of drug Ai et al. (2017) Unfolded α-lactalbumin Oleic acid Targeting the dynamic HSP90 complex in cancer Complex was able to destroy cancer cells, where the individual component does not possess tumoricidal properties Mossberg et al. (2007) [PtIICl2(AcGlcpyta)] Sugar To characterize and investigate the antitumor activities of platinum(II) and palladium(II) complexes with sugar-conjugated triazole ligands Conjugation showed less cytotoxic profile against human cervical tumor (HeLa cells) Yano and Kleinebudde (2010) Itraconazole 2-HP-β-CD, To investigate the influence of preparation method sulfobutylether-7of complex on the solubility of itraconazole β-CD, and maltosylβ-CD Dissolving method has great influence in the solubilization of the drug over the classical method Holvoet et al. (2007) Telmisartan β-CD To characterize, and study dissolution properties of inclusion complexes of telmisartan (TLM), with β-CD Improvement in solubility and in-vitro drug release of telmisartan was more with HP-β-CD as compared to β-CD Kane and Kuchekar (2010) Platinum (II) 2-Deoxyglucose To synthesize and evaluate antitumor activity of complex Complex exhibit improved cytotoxicity in cancer cell lines Mi et al. (2016) Glibenclamide CD To determine improvement in the aqueous solubility The solubility and dissolution rate of drug was of the oral hypoglycemic agent in inclusion complex enhanced when complex prepared by neutralization method Prasad et al. (2015) 14.5 EFFECT OF COMPLEXATION ON DRUG SOLUBILITY AND BIOAVAILABILITY FIGURE 14.10 495 Schematic presentation of A- and B-type phase solubility diagrams with applicable subtypes. the linear curve towards positive direction after the isotherm, representing higher order relationships at high concentration of the ligand (Higuchi and Connors, 1965); and AN: where the scenario is opposite to AP, deviating the linear curve towards negative direction as a function of the increased concentration of ligand, representing the formation of kosmotrope or chaotrope or alteration of physicochemical properties with the increase of ligand concentration (Higuchi and Connors, 1965). In contrast, B-type solubility profile showed limited aqueous solubility, and it is subdivided into two subtypes. According to the first subtype, BS, the solubility of the substrate is increasing with respect to increasing ligand concentration. However, at a particular point of the curve, this initial linear increase is stopped and follows zero-order rate. This attributed to the decrease in the solubilization of the drug owing to the precipitation of the solubilized complexes at higher concentration of the ligand. Finally, there was a BI subtype, without the initial solubilization phase (Higuchi and Connors, 1965). Improvement of oral bioavailability of the drug depends on various parameters, viz., aqueous solubility, rate of dissolution, permeability from the site of ingestion, hepatic degradation, and susceptibility towards efflux mechanism (Gupta et al., 2013). An increased number of lipophilic compounds in the modern drug discovery process is leading scientists to improve their solubility to facilitate the most convenient oral dosing. Therefore, solubilization of drug molecules is considered to be an important factor to facilitate absorption through the cellular membrane, leading towards the site of action to produce its desired effect. Thus, solubility proportionately is related with the bioavailability of the pharmaceutical products. The improved aqueous solubility of drugs through the process of complexation using inclusion complexing ligand, e.g., CD, have been shown to increase mucosal permeability and absorption, and also facilitate parenteral formulation development (Higuchi and Connors, 1965; Matsuda and Arima, 1999). DOSAGE FORM DESIGN CONSIDERATIONS 496 14. DRUG COMPLEXATION CD has also proved to improve the membrane fluidity through solubilization of the membrane lipid bilayer, thus facilitating passage of complexed drugs to the site of action. Literature is evident to support CD mediated improvement in bioavailability through complexation of drugs delivering via oral, nasal, rectal, etc. route (Gidwani and Vyas, 2015). Polyvinyl alcohol with curcumin formed amorphous complexes that showed improved solubility (.2 mg/mL), where hydrophobic interaction and the hydrogen bond between the polymer and drug participated in the complex. Kumar and team have recently optimized a complex to enhance curcumin loading in a pH-sensitive cationic polymer. The formed complexes were amorphous in nature with the solubility at pH 5. The stable complex was found to improve the oral bioavailability of curcumin by 20-fold with a peak concentration improvement by six times in experimental mice (Kumar et al., 2016). A similar approach to improvement of curcumin availability in the treatment of cancer has been made by Shukla and group. The authors developed phospholipid complexes of curcumin and thereby facilitated its incorporation in SNEDDS. A curcumin-phospholipid complex in Sprague-Dawley rats has shown improved oral absorption and bioavailability of the drug due to the enhancement of solubility of the complex. Increased bioavailability was further confirmed via 38.7% increase in in vitro cytotoxic action in breast cancer cell line and in vivo tumor reduction (58.9%) in 4T1 tumor-bearing BALB/c mice (Shukla et al., 2017). Oral bioavailability and stability of poorly water-soluble drug can be improved via development of a polyelectrolyte drug complex. A similar approach has been used to improve oral bioavailability of enalapril maleate via complexation with cationic polymethacrylate Eudragit E100. Complex formation of the drug showed 1.7 times increase in intestinal permeation due to the presence of cationic polymer, and subsequently, the oral bioavailability was enhanced significantly (1.39-fold) (Ramı́rez-Rigo et al., 2014). Similarly, dissolution and bioavailability of carvedilol was improved by making inclusion complex with CD and subsequently incorporating it inside a buccal tablet (Hirlekar and Kadam, 2010). On the other hand, the solubility of inclusion complexes and the drug itself can further be improved by the addition of water-soluble polymer. A similar approach has been used to increase the solubility of norfloxacin with CD via the addition of crospovidone. The results revealed that precompressed tablets of inclusion complex having higher concentration of crospovidone showed faster release compared to the inclusion complex of norfloxacin only (Sharma and Bathe, 2014). In another study, it was investigated that drug particle size plays a significant role in physiochemical property and dissolution of inclusion complexes. In this context, ibuprofen with a particle size of 3 and 45 µm was used as a model drug to prepare an inclusion complex with CD. Results of phase solubility diagram and dissolution study showed that the inclusion complex prepared with the smaller particle size of the drug led to higher solubility and dissolution compared with the inclusion complex with the bigger particle size of the drug. This could be due to rapid solubility of smaller drug particles from the complex and rapid formation of the inclusion complex with smaller drug particles (Ai et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 14.6 THERMODYNAMICS AND KINETICS OF COMPLEX FORMATION 497 14.6 THERMODYNAMICS AND KINETICS OF COMPLEX FORMATION The practical use of pharmaceutically developed formulation is restricted to its stability properties, especially for aqueous-based drug formulations which are prone to oxidation and hydrolysis. Complexation is the accepted technique to improve aqueous solubility, where inclusion of drug molecules within the void space of CD could affect the reaction potential of the drug in the aqueous environment (Shah et al., 2015). Thus, following solubility enhancement, which has been discussed in the earlier section, the second most common application of complexation in pharmaceutical development is to increase drug stability, thereby improving the drug kinetics. It can be assumed that the drug inclusion within the CD chemical structure can be associated with weak conjugation between the two or inclusion of the drug within the ring structure of the ligand (Shah et al., 2015). This was evident by the study to enhance stability and bioavailability of enalapril drug via complexation with cationic polymethacrylate Eudragit E100. Results showed no sign of degradation after a 14-month period which indicates that a complex can successfully improve the properties of the drug (Ramı́rez-Rigo et al., 2014). Thermodynamic and kinetic measurements of chemically unstable compounds with CD at a 1:1 ratio forms an equilibrium which supports the second hypothesis of inclusion theory. Further, inclusion of CD stabilizes thermodynamic stability against prone reactions in an aqueous environment which depends on concentration of complexing ligand, stability constant of the complex, and finally the rate constant for degradation of drug within the drug ligand complex (Mieda et al., 2014). As evident from the statement, the literature supports the improvement of stability of chemically unstable drugs, including prostaglandins, alkylating antitumor agents, steroidal moieties, prodrugs, etc. (Eliasof, 2015). Apart from chemical stability, physical stability of volatile components is also reduced through complex formation with CD. A peptide or protein-based chemicals could also be included within the structural environment of CD to promote its delivery via preventing its denaturation. Contrarily, the destabilizing effect of CD is also prominent in an alkali environment, where deprotonation of the external hydroxyl functional group of CD catalyzes degradation of the drug (Zhang et al., 2009). It is clear that there will always be an equilibrium between the dissociation and association molecules and complex in an aqueous environment, where dissociation or formation of a complex is diffusion controlled, and the stability constant can be determined through ligand stabilizing or destabilizing effect for a particular substrate (Morin-Crini et al., 2017). Cross-linking between CD and ligand does not affect this equilibrium property of the complexes. Scientists have reported similar consequences five decades ago (Hoffman, 1970; Hoffman, 1973). Thus, an increase of ligand concentration in an aqueous mixture of the poorly soluble substrate will cause the disappearance of the substrate from the solution and thus stabilize the substrate from degradation (Morin-Crini et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 498 14. DRUG COMPLEXATION 14.7 PROTEIN COMPLEX FORMATION: ROLE IN ONCOLOGY Once the drug molecules reach the systemic circulation following administration of drug formulation by any route, blood circulates the drug and distributes it to every part of the body. Following metabolism, the metabolites are again transferred to the elimination organs. During the process of circulation, various proteins are available to bind with the drug molecules. Mostly, the available proteins for plasma protein binding include serum albumin, glycoprotein, lipoprotein, and globulins, where albumin and globulin are the proteins binding to various drugs at high quantities with sufficient affinities (Trainor, 2007). Instead of complexation, such attachments are known as drug protein binding which differs from complexation in its reversibility (Vuignier et al., 2010). If a formulator does not judiciously consider the irreversible drug protein binding that is formed as a result of covalent bonding between drug and protein complex then this type of complexation may also account for adverse events. Usefulness of drug protein binding in a biological system refers to the availability of free drugs in the circulation, thus affecting the pharmacological action of the drug. There will always be an equilibrium existing between the free and bound drug components within the system. Only unbound/free drug can permeate the slit junctions of blood capillaries, reach the receptor site, or permeate the cell membrane to produce activity (Otagiri, 2009; Vuignier et al., 2010). Pharmaceutically, the protein complex is referred to as a complex of two or more proteins forming a special quaternary structure that serves to inhibit or to activate one or more associated proteins (Mossberg et al., 2007). A number of protein complexes have been identified to enrich its beneficial role in different diseased conditions. Therefore, protein protein interaction has become an important tool in proteomics research to recognize the dynamics and organizations of cell functions for the treatment and prevention of various pathological conditions, including cancer. A complex of partially unfolded α-lactalbumin and oleic acid (HAMLET) has been shown to destroy cancer cells, where the individual component does not possess tumoricidal properties (Mossberg et al., 2007). Selective destruction of cancer cells by HAMLET in an in vitro model is a potentially important property to explore its activity in in vivo application (Puthia et al., 2014). Topical application of HAMLET through in vivo intravesical instillations showed rapid shedding of dead cancer cells. Reduction of tumor size with numerous apoptotic changes in particularly malignant tumor cells without showing any adverse event through the application of HAMLET is evident in the literature (Mossberg et al., 2007). Alternatively, heat shock protein 90 (HSP90) is known to activate and stabilize more than 200 proteins. Those clients of HSP90 are playing an important role in stress-induced adaptive responses and in cell signaling. In the present cancer research, this HSP90 is accepted as a facilitator for various oncoproteins (Hamamoto et al., 2014). Trepel and group have mentioned that this is an essential component for cancer cells which facilitate functions of various oncoproteins. Although selective control or inhibition of this HSP90 should be understood before targeting to this protein complex to control tumor growth, it is essential because this HSP90 control various activities in healthy cells as well (Trepel et al., 2010). Studies on TWIST protein complex of Mi2/nucleosome remodeling and DOSAGE FORM DESIGN CONSIDERATIONS 14.8 APPLICATION OF COMPLEXATION IN DRUG DELIVERY 499 deacetylase (Mi2/NuRD), including Mi2β, MTA2, RbAp46, and HDAC2, in cancer cells also revealed similar findings. TWIST is also responsible for gene transcription leading to metastasis. A recent study suggested that depletion of the TWIST complex within the tumor cell effectively suppresses cell migration and invasion in culture as well as in lung metastasis in mice (Fu et al., 2011). Therefore, protein complexes have an important role in cancer chemistry, where regulation of such system could control the devastating role in human health and can modify the quality of life. In addition, complexation can also alter the protein conformation and protein secondary structure. In this context, Ouameur et al. revealed that human serum albumin conformation was altered due the change in α-helix from 60% 55% (free protein) to 49% 40% as well as β-structure was increased from 22% 15% (free protein) to 33% 23% in inclusion complexes. This change in conformation of protein attributed to partial unfolding of human serum albumin in inclusion complex (Ahmed-Ouameur et al., 2006). 14.8 APPLICATION OF COMPLEXATION IN DRUG DELIVERY 14.8.1 Metal Ion Complex in Cancer Metal ions have an important role in biological systems chosen by nature, and thus different metal ions including zinc, manganese, iron, and copper are directly involved in different biological reactions and also associated with active sites of enzymes and proteins. The discrepancy of such metal ions during biological processes may lead to serious physiological complications, including cancer (Yaman et al., 2007). However, therapeutic use of the metal compounds is not new; it is a rollover from the ancient use. However, the ancient use of metal compounds in the treatment of various complications was boosted up by Greek philosophers and supported by various physicians (Ndagi et al., 2017). Diseases like cancer are also stimulated following the use of arsenic trioxide as antiseptic, as used in the treatment of diseases like syphilis, rheumatoid arthritis, and psoriasis etc. (Ndagi et al., 2017). It was the first compound used in the treatment and control of leukemia until it was replaced with chemotherapy and radiation (Waxman and Anderson, 2001). Later serendipitous discovery of cisplatin (platinum-containing compound) by Barnett Rosenberg became the milestone for metal-based complexes in the treatment of cancer. Recent researches are in search of potential metal complexes that avoid the serious toxicities associated with conventional chemotherapy (Fricker, 2007). 14.8.1.1 Platinum-Based Analogs Introduction of cisplatin in chemotherapy opens up avenues for the treatment of several cancers, including head and neck, lung, breast, stomach, cervical, ovarian, prostate cancers, as well as Hodgkin’s and non-Hodgkin’s lymphoma, sarcoma, myeloma, and neuroblastoma. Resistance towards this cisplatin instigated further research with this metal compound, which resulted in the research outputs with carboplatin, carboplatin, sebriplatin, enloplatin, satraplatin, oxaliplatin, zeniplatin, ormaplatin, picoplatin, miboplatin, and DOSAGE FORM DESIGN CONSIDERATIONS 500 14. DRUG COMPLEXATION iproplatin (Ndagi et al., 2017). Out of most of the drugs approved by the regulatory agencies, most of them are made available in the form of a complex for the treatment of cancer (Monneret, 2011; Ndagi et al., 2017). Due to no superior role against cisplatin treatment associated systemic toxicities, and the development of resistance by the cancer cells, it led to research with platinum complexes. To achieve the desired outcome of platinum, different ligands are attached to the parent compound. Conjugation of sugar to platinum showed the improvement in the solubility and improvement of cellular uptake with decreased adverse effect. Research outcome of [PtIICl2(AcGlc-pyta)] with sugar conjugation showed less cytotoxic profile against human cervical tumor (HeLa cells) (Yano et al., 2012). Direct targeting of the platinum complex was attempted through conjugating with 2-deoxyglucose to target glucose transporter-1 because overexpression of such a receptor is common in cancer cells to metabolize more glucose in order to maintain growth, cellular homeostasis, and proliferation of cancer cells (Mi et al., 2016). 14.8.1.2 Platinum(IV) Complexes and Anticancer Activity The initial and most of the research on platinum was based on the diamine pharmacophore (platinum (II)), while in the last decade platinum(IV) complexes were synthesized with increased stability and other advantages over platinum(II) compounds. Six expanded saturated coordination spheres of platinum(IV) complexes resulted in kinetic stability of the product with comparable cytotoxicity with cisplatin against different cancer cell lines (Johnstone et al., 2013). 14.8.1.3 Ruthenium and Copper Complexes in Cancer Therapy Due to unavoidable limitations of platinum-based compounds, other metal-based complexes were targeted with ruthenium, iron, and gold to avoid drug resistance, to obtain a wide spectrum of activity with limited side effects. Octahedral structure of ruthenium complexes provides several modification opportunities to develop ruthenium complexes against cancer. Such an opportunity allows forming supramolecular or multimolecular architecture with different ligands or organic molecules to target specific sites of the cancer cell. Therefore, research with ruthenium has come up with several compounds (Ndagi et al., 2017). In vivo experimentation with Ru(II) arene complexes incorporated into amphiphilic 1,3,5-triaza-7-phosphaadamantane (PTA) ligand, i.e., Ru(η6-toluene)-(PTA)Cl2, RAPTA-T, Ru(η6-p-cymene)(PTA)Cl2, and RAPTA-C, depicted significant antitumor activity with less cytotoxicity. It has been demonstrated that the ligand in RAPTA-C specifically binds to the histone protein core in chromatin, leading to growth inhibition of experimental tumor models (Ndagi et al., 2017). Furthermore, copper complexes have not been elaborately investigated because the ingested copper cannot differentiate the normal and cancer cells, thereby it undergoes redox activities and can catalyze many biological reactions (Santini et al., 2014). However, it has been demonstrated that copper complexes can mimic superoxide dismutase enzyme and thus help in the protection of cells from harmful superoxide radicals. Owing to its potential antioxidant activity, low molecular weight copper complexes are used during imbalance between generated free radical and endogenous superoxide dismutase enzyme (Khalid et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS 14.8 APPLICATION OF COMPLEXATION IN DRUG DELIVERY 501 14.8.1.4 Gold and Silver Complexes in Cancer Therapy Gold (III) metal complexes are considered to be an alternate class to cisplatin in cancer treatment (Huang et al., 2015; Tekade et al., 2014). Apart from less toxicity, and tumor selectivity, these gold complexes gained versatile importance in the field of cancer imaging and treatment where flexible localized surface plasmon resonance and their optical property make them suitable for imaging, and for the localized and effective photothermal effect to kill the cancerous cells. Generation of thermal effect is due to electronic influence for oscillation of surface plasmon which converts light energy into heat (Suvarna et al., 2017). Based on these advantages of gold, several complexes have been formed in the treatment of cancer. Thus Br, Cl, P, or S ligands to the gold(III) complexes showed effective results, whereas other ligands are found to be more cytotoxic in nature (Ndagi et al., 2017). Similarly, antimicrobial potential of silver complexes is well accepted and used widely in burns and wounds. Anticancer activity of silver complexes is also evident from recent research. Silver(I) complexes are found to exhibit superior antitumor activity compared to conventional cisplatin, with greater selectivity, thus resulting in relatively low toxicity. Experimental results in B16 cancer cell line (murine melanoma) and noncancerous 10T1/2 are evident for the above statement (Kalinowska-Lis et al., 2016). Further heterocyclic carbine complexes of gold(I) and silver(I) revealed similar anticancer potential to cisplatin against H460 lung cancer cell line (Ndagi et al., 2017). 14.8.2 Cyclodextrin in Drug Delivery System CDs are macrocyclic oligosaccharides consisting of (1,4)-linked D-glucopyranose subunits, with a cage-like supramolecular structure, hydrophilic outer surface, and lipophilic central cavity. Naturally occurring CDs, α, β, and γ consist of six, seven, and eight glucopyranose units with 5, 6, and 7 Å diameters, respectively (Fig. 14.11; (Challa et al., 2005). Although CDs containing 9, 10, 11, 12, and 13 glucopyranose units have also been identified, pharmaceutical uses of those are limited (Tiwari et al., 2010). FIGURE 14.11 Structure of α, β, and γ cyclodextrins. DOSAGE FORM DESIGN CONSIDERATIONS 502 14. DRUG COMPLEXATION CDs in aqueous solution can include many lipophilic molecules by replacing centrally entrapped water molecules, to form inclusion complexes. During such replacement, the whole lipophilic molecule or the lipophilic part will be included. The inclusion of drugs changes the physicochemical and biopharmaceutical properties of the entrapped component including physical state, chemical stability, aqueous solubility, volatility, partition coefficient, dissolution rate, permeability, absorption, bioavailability, and finally its systemic activity (Loftsson et al., n.d.). Apart from these advantages CDs can also help in the reduction of drug irritancy, prevent incompatibility, and even mask the taste and odor (Tiwari et al., 2010). Recently, it has also been reported that apart from its inclusion complex forming ability, there is a self-association of the CDs molecule or the complex of drug and CDs occurs to form nanoparticles or nano-sized aggregates, thus enhancing the property of the complexes (Messner et al., 2010). Pharmaceutical applications of CD-based complexes are generally prepared with α, β, and γ CD or their derivatives and have been explored for oral, buccal, sublingual, ophthalmic, nasal, and parenteral use. A recent report on the improvement of oridonin oral bioavailability approaches on CD inclusion complexes has been made. Oridonin is a moderately permeable anticancer agent that undergoes marginal intestinal metabolism, therefore, the inclusion complex of the drug is attributed to improved dissolution followed enhanced permeability (Zhang et al., 2016). In a similar approach for clonazepam, an inclusion complex in randomly methylated β-CD has shown five-fold increase in drug flux and permeability and 100% unidirectional drug release made the developed formulation suitable for local as well as systemic action (Mura et al., 2016). HP-β-CD inclusion complex of promethazine HCl in a sublingual fast dissolving film showed 70% absorption in 10 minutes. Proper storage of the fast dissolving films can provide stability of the formulation, and during delivery it can mask the taste and promote faster pharmacological response (Shah et al., 2015). Enhancement of corneal permeability of timolol maleate allowed this permeability enhancer a good platform to formulate and deliver formulations via the ophthalmic route (Rodrı́guez et al., 2017). The solubility of a second-generation antihistaminic agent, loratadine, has been improved by the formation of β-CD inclusion complexes. Such improvement of solubility and in situ thermal gel formation of the nasal delivery system overcome the hepatic bypass problem of oral delivery, and thus aid in enhancement in systemic bioavailability (Singh et al., 2013). Parenteral α-CDs and prostaglandin E1 complexes are intended to be used in complications associated with Buerger’s disease, where intravenous injection of the complex is extended in oral sildenafil failure erectile dysfunction conditions (Shabsigh et al., 2000). However, uses of α and β CDs in parenteral formulations are limited due to associated toxic properties, and these are highly recommended for oral preparations. Although only a few products with α-CDs have been marketed for the parenteral application (Loftsson and Duchene, 2007). Moreover, extensive researches are ongoing with hydroxypropyl, maltosyl, and sulfobutyl ether derivatives of CDs and various formulations are commercially available in different countries nowadays for their associated advantages and safety profile (Tiwari et al., 2010). Another pharmaceutical product was developed with 2-HP-β-CD for itraconazole, where the solubility of the drug was possibly improved by 100,000-fold. However, this improvement has brought the product to the market, but the solubility of the product is DOSAGE FORM DESIGN CONSIDERATIONS 14.8 APPLICATION OF COMPLEXATION IN DRUG DELIVERY 503 not yet sufficient because of the high dose. Researchers are still working to improve the solubility of the drug. A group of researchers investigated 2-HP-β-CD, sulfobutylether-7-β-CD and maltosylβ-CD following different formulation processes: the classical and the dissolving method at pH 2 to investigate the influence of preparation method on the solubility of itraconazole. Interestingly the researchers observed that the dissolving method has great influence in the solubilization of the drug over the classical method. Inclusion capacity of the drug in the complexes formed were 1 g/100 mL of 25% 2-HP-β-CD or of 30% sulfobutylether-7β-CD, and 500 mg/100 mL of 40% maltosyl-β-CD. They attempted this approach of development for oral as well as parenteral administration because the derivatives of CD used in this current research were all reported to be safe (Holvoet et al., 2007). Thus, it can be inferred here that complexation is a process that can improve the solubility of drugs, but in certain instances, it can result in some incompatibilities between drug drug or drug excipient or food drug. 14.8.3 Polyelectrolyte Complexation in Drug Delivery Oppositely charged particles may be between the polymer and polymer, drug and polymer, polymer and surfactants, or polymer, drug, and polymer, and may lead to the formation polyelectrolyte complexes in aqueous solutions between oppositely charged polyions. This interesting approach in colloidal science is attempting to avoid the undesirable and associated toxicities with chemical cross-linking agents (Lankalapalli and Kolapalli, 2009). The interactions between the charged polyions are associated with the electrostatic and hydrophobic interactions between them. Several factors have direct influence on such interactions between the charged polyions, such as charge density or polar head, degree of branching or chain length, concentration of the incorporated polyions, its molecular weight, backbone rigidity, and concentration and nature of added salt (Langevin, 2009). Emerging applications of these polymeric complexes have been seen in different industries, including food, detergent, cosmetic, paint, etc. (Langevin, 2009). The concept of polyelectrolyte complexation between DNA and chitosan is well accepted and vastly used in the development of oral vaccination and gene therapy (Lankalapalli and Kolapalli, 2009). Polyelectrolyte complexation technique can also be used in the improvement of hydrogel beads, where the mechanical strength and permeability barrier of the hydrogel can be enhanced through the incorporation of electrolytes with opposite charge. For example, incorporation of polycations allows forming a membrane of polyelectrolyte complex over the alginate beads. Several natural and chemically modified polyelectrolytes have been introduced in the development of pharmaceutical polyelectrolyte complexes, viz., alginate, gellan gum, chitosan, and carboxymethyl cellulose (Patil et al., 2010). DOSAGE FORM DESIGN CONSIDERATIONS 504 14. DRUG COMPLEXATION 14.9 CONCLUSION Complexation is an extensively used technique in the pharmaceutical field to improve solubility of several pharmaceutical ingredients, and subsequently the bioavailability of poorly water-soluble drugs. All the three classes of complexation have been discussed including their applications in different sectors of the pharmaceutical field. The fundamental methods of drug complex formation and the characterization processes have also been described in this chapter. Thermodynamic and kinetic properties of different complexes were discussed in this chapter with the relevant examples in pharmaceutical science. All the complexing processes have their importance and help in the delivery of pharmaceutical drugs with improved bioavailability. Finally, based on the widespread use of complexation in cancer and other therapeutic fields it can be concluded that complexation can be included in drug delivery applications for the improvement of bioavailability with reduced toxicity. Acknowledgment The authors, Dr. Hira Choudhury, Dr. Manisha Pandey and Dr. Thiagarajan Madheswaran would like to acknowledge School of Pharmacy, International Medical University and Dr. Bapi Gorain would like to acknowledge Faculty of Pharmacy, Lincoln University College for providing resources and support in completing this work. The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for the grant allocated to Dr. Tekade for research work on gene delivery and N-PDF funding (PDF/2016/ 003329) for work on targeted cancer therapy. RT would also like to thank NIPER-Ahmedabad for providing research support for research on cancer and diabetes. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. ABBREVIATIONS CD HP HP-β-CD NSAID DNA EDTA C CO2 DTG TG TGA DSC FT-IR PXRD NMR Mg SNEDDS HSP90 NuRD cyclodextrin hydroxypropyl hydroxypropyl-β-cyclodextrin nonsteroidal antiinflammatory drug deoxy ribonucleic acid ethylene diamine tertracetic acid degree centigrade carbon dioxide differential thermogravimetry thermogravimetry thermogravimetry analysis differential scanning calorimetry Fourier-transform infrared spectroscopy powder X-ray diffraction nuclear magnetic resonance magnesium self-nanoemulsifying drug delivery system heat shock protein 90 nucleosome remodeling and deacetylase DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 505 References Ahmadi-Abhari, S., Woortman, A.J.J., Lizette Oudhuis, A.A.C.M., Hamer, R.J., Loos, K., 2014. The effect of temperature and time on the formation of amylose-lysophosphatidylcholine inclusion complexes. Starch - Stärke 66 (3 4), 251 259. 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DOSAGE FORM DESIGN CONSIDERATIONS 512 14. DRUG COMPLEXATION Zarzycki, P.K., Lamparczyk, H., 1998. The equilibrium constant of beta-cyclodextrin-phenolphtalein complex; influence of temperature and tetrahydrofuran addition. J. Pharm. Biomed. Anal. 18 (1 2), 165 170. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9863954 (Accessed: 1 September 2017). Zhang, L., Zhu, W., Song, L., Wang, Y., Jiang, H., Xian, S., et al., 2009. Effects of hydroxylpropyl-β-cyclodextrin on in vitro insulin stability. Int. J. Mol. Sci. 10 (5), 2031 2040. Available from: https://doi.org/10.3390/ ijms10052031. Multidisciplinary Digital Publishing Institute (MDPI). Zhang, X., Zhang, T., Lan, Y., Wu, B., Shi, Z., 2016. Nanosuspensions containing oridonin/HP-β-cyclodextrin inclusion complexes for oral bioavailability enhancement via improved dissolution and permeability. AAPS PharmSciTech 17 (2), 400 408. Available from: https://doi.org/10.1208/s12249-015-0363-4. Springer US. Zu, Y., Wu, W., Zhao, X., Li, Y., Zhong, C., Zhang, Y., 2014. The high water solubility of inclusion complex of taxifolin-γ-CD prepared and characterized by the emulsion solvent evaporation and the freeze drying combination method. Int. J. Pharm. 477 (1 2), 148 158. Available from: https://doi.org/10.1016/j.ijpharm.2014.10.027. DOSAGE FORM DESIGN CONSIDERATIONS C H A P T E R 15 Solubility and Solubilization Approaches in Pharmaceutical Product Development Pratap Chandra Acharya1,*, Clara Fernandes2,*, Divya Suares2, Saritha Shetty2 and Rakesh K. Tekade3,4 1 Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India 2Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 4 Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 15.1 Understanding the Concept of Solubility 514 15.1.1 Phenomenon of Solubilization 514 15.1.2 Solubility of Electrolytes, Weak Electrolytes, and Nonelectrolytes 516 15.1.3 Types of Solubility 517 15.1.4 Factors Influencing Drug Solubility 518 15.1.5 Solute Solvent Interaction 521 15.2 Relationship Between Solubility and Biopharmaceutical Classification Systems (BCS) 521 15.3 Approaches to Modulate Drug Solubility 15.3.1 pH Modification 15.3.2 Crystal Structure Manipulation 15.3.3 Prodrug Strategies 522 522 522 526 * Authors having equal contribution in this book chapter. Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00015-0 513 © 2018 Elsevier Inc. All rights reserved. 514 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT 15.3.4 Crystal Structure Disruption (Amorphization) 15.3.5 Size Reduction 15.4 Excipient-Based Solubilization 15.4.1 Cosolvency 15.4.2 Cyclodextrin 15.4.3 Ionic Liquids 527 528 530 530 531 534 15.5 Conclusion 538 Acknowledgments 538 Abbreviations 538 References 539 15.1 UNDERSTANDING THE CONCEPT OF SOLUBILITY The therapeutic effectiveness of any drug is principally relying on two central attributes, namely, its solubility in the biological milieus and its permeability across various biological barriers that persist in the biological domain (Dahan et al., 2016). The medicinal chemists intend to develop a drug molecule with optimal receptor drug binding via a specially designed and dedicated drug discovery program. However, the drug discovery programs are primarily yielding potent new chemical entities (NCEs); but, with high molecular weights as well as poor aqueous solubility. Altogether, these parameters are resulting in hampered drug dissolution profile in the aqueous gastrointestinal (GI) media and poor membrane permeability of the drug. Besides this, due to lipophilicity, these drugs become substrate for P-glycoprotein efflux pump transporters, and for metabolism via cytochrome P450 enzymes, resulting in noteworthy drug loss. Therefore, the failure of drug delivery is the manifestation of its poor and variable oral bioavailability (O’driscoll and Griffin, 2008). Hence, it is imperative to modulate the drug solubility characteristics of poorly water-soluble drugs to facilitate the dissolution rate and hence the bioavailability (Khadka et al., 2014). This chapter focuses on the solubility and solubilization approaches explored in pharmaceutical product development to enhance aqueous solubility. 15.1.1 Phenomenon of Solubilization Broadly, solubility can be stated as a process to generate a homogenous system maintained by achieving dynamic equilibrium between the simultaneous and opposite methods of dissolution and phase joining (e.g., precipitation of solids) (Myrdal and Yalkowsky, 2002; Savjani et al., 2012). Solubility is often predicted by the Hansen solubility parameters as well as the Hildebrand solubility parameters, along with other physical constants like enthalpy of fusion (Savjani et al., 2012). In quantitative aspect, solubility may be defined as the concentration of the solute in concentrated solution at a certain temperature. When it comes to qualitative measurement, solubility is assumed to be a spontaneous interaction of two or more components to produce a homogenous molecular dispersion in a given solvent. DOSAGE FORM DESIGN CONSIDERATIONS 15.1 UNDERSTANDING THE CONCEPT OF SOLUBILITY 515 15.1.1.1 Importance of Solubility and Solubilization in Product Development The efficient delivery of drugs is the issue of prime importance to the makers of pharmaceuticals. Approximately 40% of marketed drugs have low solubility and almost 80% 90% drug candidates in the R&D product development pipeline fail due to the solubility concerns. As discussed above, the therapeutic efficacy of a drug depends on the bioavailability, and ultimately upon the solubility of drug molecules. The solubility is one of the imperative parameters to accomplish the desired drug concentration in systemic circulation for achieve the required pharmacological. For the effective absorption of a drug, it must be present in the form of an aqueous solution at the site of absorption. Therefore, water is the solvent of choice for liquid pharmaceutical formulations. Most drugs are weakly acidic or weakly basic with poor aqueous solubility. For this reason, several techniques are used to improve the solubility of poorly water-soluble drugs. 15.1.1.2 Process of Solubilization The method of dissolving solute involves the breakage of intermolecular or interionic bonds in the solute molecule, the split-up of the solvent component to provide space in the solvent for the solute, and interaction between the solvent and the solute molecule or ion. The change in enthalpy of the solution denotes the total quantity of heat released/ absorbed during solubilization. 15.1.1.3 Solvent Solute Interactions During the product development, choice of the appropriate solvent depends on the principle of “like dissolves like,” which means solute preferentially dissolves in the solvent with alike physicochemical characteristics. In other words, two substances with similar intermolecular forces are soluble in each other. For example, polar solutes like common salt and sugar dissolve in polar solvents like water. Similarly, the nonpolar solutes dissolve in nonpolar solvents, for example, naphthalene solubilized in benzene. Fundamentally, the solubilization of a drug (solute) in an aqueous domain (solvent) is a consequence of three independent events and an energy driven process, as shown in Fig. 15.1. Generally, the first step involves the breaking of the solute solute bonds to permit removal of solute molecules from the solid-state. Herein, the energy is essential to diminish the strength of the bond arising out of the attractive intermolecular forces between solute solute molecules within solid. Due to presence of ionic attractive forces, it is pragmatic that the bond strength is higher for electrolytes than for nonelectrolytes which have nonionic forces. Likewise, due to condensed packing, solute solute bond is stronger in crystalline materials in contrast to amorphous solids, and planar nonelectrolytes compared with nonplanar molecules. Following the breaking of the bond, the second step involves the formation of a void in the solvent to accommodate the separated solute. Owing to weaker intermolecular forces between the solvent molecules, moderately low energy is consumed to create a void within the solvent domain. Finally, the third step includes insertion of the displaced solute in the solvent void, resulting in solvation of the solute. If the solute has attraction for the solvent, this process is dynamically favorable and actively drives the solubilization of a solute. Nevertheless, in this progression of energy is generated because of the reaction among solute and solvent (Williams et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS 516 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 15.1 Process of solubilization. However, there are some instances where molecules lacking high crystal bond energy, i.e., low melting solids and oils, demonstrate poor aqueous solubility, possibly due to poor solute solvent interactions. Hence, the aqueous solubility of a solute can be well interrelated with the characteristics of crystal lattice and its molecular geometry (e.g., activity coefficient) (Swarbrick and Boylan, 2000). The activity coefficient is often defined as the extent of the intermolecular forces of attraction that must be for eliminating a solute molecule from the solid (Step I in Fig. 15.1) (Martin et al., 1993). This is best explained by the general solubility equation (GSE) proposed by Yalkowsky and Valvani, which is as follows; logX a 5 logX i i logƔ (15.1) where Xa is the aqueous solubility of compound, Xi is the ideal solubility and Ɣ is the activity coefficient of the solute in water. 15.1.2 Solubility of Electrolytes, Weak Electrolytes, and Nonelectrolytes As established, besides the solute solute bonds, it is imperative to have favorable solute solvent affinity. This solute solvent affinity or solvation of solute molecules is greatly governed by the ionization potential of the solute molecules. It is known that the presence of a charged functional group governs the ion-dipole interactions with polar solvents like water, resulting in hydration of solute and enhancement in aqueous solubility. Although this holds true for strong electrolytes (such as NaCl), for an inorganic salt like DOSAGE FORM DESIGN CONSIDERATIONS 15.1 UNDERSTANDING THE CONCEPT OF SOLUBILITY 517 AgCl, though the dissociation is complete, due to the high bond energy between the solute molecules, it becomes a deterrent in the aqueous solubilization of AgCl. Though electrolytes are favorable molecules, unfortunately, most drugs are organic and can be broadly classified as nonelectrolytes (nondissociable) or weak electrolytes (partially dissociable) resulting in generation of both unionized solute and the dissociated ions exist in aqueous solution (He and Yalkowsky, 2006). For drugs which belong to the class of nonelectrolytes, pH has but little effect and herein, solubilization is solely governed by step I, i.e., strength of the of solute solute bond energy (Williams et al., 2013). 15.1.3 Types of Solubility 15.1.3.1 Based on pH 15.1.3.1.1 UNBUFFERED SOLUBILITY It is the solubility of a saturated solution of the analyte at ultimate pH of the solution. Such solubility is ascertained primarily in water (Alsenz and Kansy, 2007). 15.1.3.1.2 BUFFERED SOLUBILITY It is also known as apparent solubility. This solubility gives indication of solubility of analyte at a given pH, e.g., 3 or 7.6. It is ascertained by determining the solubility in a defined pH-buffered system and overlooks the effect of salt production with the counterions that exist in the buffering phase on the estimated solubility value. 15.1.3.1.3 INTRINSIC SOLUBILITY This reflects equilibrium solubility of the neutral form of an ionizable analyte, i.e., free acid or base form of an ionizable substance at a pH where it is completely unionized. 15.1.3.2 Based on Experimental Setup 15.1.3.2.1 KINETIC (OR NONTHERMODYNAMIC) SOLUBILITY It is defined as the concentration of the analyte in solution observed when an induced precipitate first appears in the solution. For this solubility, measurements are initiated from solubilized substance and the rate at which maximum (kinetic) solubility of the rapidly precipitating element of a compound is noted. Such kind of solubility measurement is solely governed by degree of supersaturation and is known to be nonreproducible and is shown to be strongly time-dependent. The data generated in the kinetic solubility assays does not focus on the type of precipitating material, i.e., whether the analyte is amorphous or crystalline, neutral or a salt, cocrystal or a combination of these possibilities. Owing to its dependence on the degree of supersaturation, the solubility in a few cases is shown to overpredict the thermodynamic solubility (Apley et al., 2015; Stuart and Box, 2005). 15.1.3.2.2 EQUILIBRIUM (OR THERMODYNAMIC) SOLUBILITY It can be defined as the concentration of a substance in a saturated solution which is in equilibrium with the excess of undissolved solid obtained at a given temperature and pressure. It is often considered as the “true” solubility of an analyte and as the “gold DOSAGE FORM DESIGN CONSIDERATIONS 518 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT standard” for development needs. For ascertaining the thermodynamic solubility, the dissolution rate of compounds in solvent at a given time is a crucial step. 15.1.3.3 Based on Solid Structure 15.1.3.3.1 CRYSTALLINE SOLUBILITY The solubility of the crystalline solid may be defined as the solute concentration obtained in solution achieved after establishing equilibrium among the crystal phase and the solution phase whereby the solvent is excluded from the crystalline phase and is given by (Sandler, 2017; Yalkowsky, 1999): (15.2) ln xD :γ D 5 µDc 2 µDo =RT where xD is mole fraction solubility of the crystalline drug (D) in water. γ D is the liquid phase activity coefficient of the drug at saturation. R is gas constant. T is experimental temperature. (µDc µDo) is chemical potential difference between the crystal (µDc) and the pure supercooled liquid (µDo). 15.1.3.3.2 AMORPHOUS SOLUBILITY It can be stated that the maximum enhancement in solution concentration may be gained with respect to the crystalline counterpart. Ideally, the amorphous “solubility” cannot be termed as a true thermodynamic solubility, since unlike crystalline solid, the amorphous solute is in apparent/metastable equilibrium with the solution. Nevertheless, it is postulated that if the metastable phase is kept for a reasonable period to establish its equilibrium with the bulk solution, the apparent “solubility” may be ascertained (Taylor and Zhang, 2016; Almeida e Sousa et al., 2014). 15.1.4 Factors Influencing Drug Solubility 15.1.4.1 Crystal Habit Crystal habit has shown to govern physicochemical properties such as solubility and eventually dissolution rate (Chadha et al., 2011). It has known to impact the most crucial attribute for drug solubility, i.e., intrinsic dissolution rate (Bukovec et al., 2016). Broadly, the crystal habit involves the external structure of the crystal, whereas polymorphism is concerned with the internal structure of crystal. Different crystal habits have been identified: tabular crystals, platy crystals, prismatic crystals, acicular crystals, or bladed crystals (Tiwary, 2001). Various parameters influencing crystallization, viz., type and volume of solvent, speed of agitation, temperature of crystallization, and degree of supersaturation, impact the crystal habit (Kumar et al., 2015). Sun et al. (2017) demonstrated enhancement of dissolution efficiency of tubular crystal habit of Vinpocetine, BCS Class II drug as compared to bulk drug thereby increasing the bioavailability by 1.3-fold of the new crystal habit. Another study revealed the influence of crystal habit on intrinsic dissolution rate (IDR). It was reported that the IDR of plate-shaped crystals of celecoxib was 46.3% higher than that DOSAGE FORM DESIGN CONSIDERATIONS 15.1 UNDERSTANDING THE CONCEPT OF SOLUBILITY 519 of acicular crystals in pH 12 phosphate buffer. The enhancement of IDR was ascribed to the presence and exposure of hydrophilic crystal facets (Modi et al., 2014). Similarly, a study comparing crystal habits, i.e., hexagonal and rod cilostazol showed improved dissolution rate, i.e., 72.63% and 68.63%, respectively in comparison to bulk drug but it was comparable to micronized cilostazol, i.e., 75.58%. Nonetheless, the different crystal habit showed improved flow properties as compared to bulk drug (Gouthami et al., 2015). 15.1.4.2 pH It is well understood that the pH greatly influences the aqueous solubility of a drug by altering its degree of ionization as a function of its pKa. For higher aqueous solubility of drug, it is highly desirable that the drug exists in its ionized form (Rodriguez-Aller et al., 2015; Stephenson et al., 2011). For unionizable drugs, the relationship between solubility of “unionized” drug (So intrinsic solubility) at a given pH (S) and pKa is often described using the Henderson Hasselbalch equations; for monobasic compounds; S 5 So 1 1 10ðpka2pHÞ (15.3) for monoacidic compounds; S 5 So 1 1 10ðpH2pkaÞ (15.4) For weakly basic drug, the pH-solubility profile can be classified into different regions as follows (Bhattachar et al., 2006) (Fig. 15.2). 1. The intrinsic solubility region (B pH .7). In this region, due to high pH, drug is completely unionized with lowest aqueous solubility. 2. Ionizing region (B pH 4 5.5). This region extends from around the pKa of the drug. Hence, it is anticipated that at the pKa the drug exists in both its ionized and unionized forms in the aqueous solution. 3. pH max region. Herein the drug attains maximum solubility due to increased ionization. On further decrease of pH, the drug remains in an incomplete ionization state and may be associated with an oppositely charged counterion. FIGURE 15.2 pH solubility profile for a compound with basic pKa. Adapted from Bassi, P., Kaur, G., 2010. pH modulation: a mechanism to obtain pH-independent drug release. Expert. Opin. Drug. Deliv. 7(7), 845 857. DOSAGE FORM DESIGN CONSIDERATIONS 520 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT 4. The salt plateaus. As the term suggest, in this pH range, the solubility of drug is maintained constant by the concept of salt solubility. In agreement with the Henderson Hasselbalch equations, it is stated that a slight shift in pH will modulate the aqueous solubility of drugs. Based on this, it can be assumed that within the gastric milieu, weak basic drugs would show a decrease in solubility in the lower part of GI tract. However, for weak acid drugs, the solubility would be greatly enhanced in the lower part of the GI tract. 15.1.4.3 Particle Size This is one of the most critical parameters governing the drug solubilization. The relationship between the particle size and drug solubilization can be well understood using the classical Noyes Whitney/Nernst Brunner equation. The basic assumption of this equation is that for a planar surface, the concentration gradient across the diffusion layer is linear at steady state (Jamei et al., 2009). The equation correlates the dissolution rate with particle surface area: dX=dt 5 A:D=h Cs Xd =v (15.5) where dX/dt is the dissolution rate, Xd is the amount dissolved drug, A is the particle surface area, D is the diffusion coefficient, V is the volume of dissolution medium, Cs is the saturation solubility, and h is the hydrodynamic boundary layer thickness. It has been observed that the saturation solubility increases with decreasing particle size below 1000 nm (Junyaprasert and Morakul, 2015). The Ostwald Freundlich equation demonstrates that the enhancement saturation solubility effect is relatively more pronounced for drugs that have particle size in the range of 1 2 µm or less especially well under 200 nm (Eq. 15.6). (15.6) log Cs =CN 5 2 γV=2:303 RT ρr where Cs is the saturation solubility, CN is the saturation solubility of an infinitely large drug crystal, γ is the interfacial tension between crystal and dissolution medium, V is the molar volume of the particle, r is particle radius, ρ is density, R is a gas constant, and T is the temperature. Using Eq. 15.6, Cs can be deduced as the function of γ and by virtue of this, it is indirectly influenced by interfacial energy G (G 5 γ A). From Eq. 15.5, another important parameter influencing the solubilization of the drug in an aqueous medium is the diffusional distance for the movement of solvating molecule from the surface into the bulk medium. As depicted by the Prandtl equation (Eq. 15.7), the increase in curvature of the particle surface achieved by reducing particle size will reduce the hydrodynamic boundary layer. hH 5 k L1=2 =V1=3 (15.7) where L represents the length of the solubilizing particle surface in the direction of flow, k represents a constant, V is the relative velocity of the flowing liquid surrounding the particle surface, and hH is the thickness of the hydrodynamic boundary layer. Consequently, it leads to a decrease in diffusional distance and an increase in dissolution velocity of the drug (Junyaprasert and Morakul, 2015). DOSAGE FORM DESIGN CONSIDERATIONS 15.2 RELATIONSHIP BETWEEN SOLUBILITY AND BIOPHARMACEUTICAL CLASSIFICATION SYSTEMS (BCS) 521 15.1.5 Solute Solvent Interaction Solubility of drug in an aqueous environment is governed by dipolarity/polarizability, hydrogen bond donating, as well as hydrogen bond accepting ability between solute and solvent. In addition to this, the chemical structure of solute, i.e., the ratio of polar to nonpolar groups. It is reported that due to inability of higher number of substitution such as 4/5-carbons containing straight chain monohydroxy alcohols and ketones to interact favorably through hydrogen-bonded structure of water results in their inadequate aqueous solubility. Whereas, branched carbon chain has been shown to reduce the nonpolar effect thereby leading to increased aqueous solubility. It has been reported that polar solvents solvate molecules through dipole interaction forces, hydrogen bonding with the solute molecules. Further, owing to their high dielectric constant for water, polar solvents also have been shown to minimize the force of attraction between ionic components and break covalent bonds of strong electrolytes by acid base reactions (Singh, 2006). 15.2 RELATIONSHIP BETWEEN SOLUBILITY AND BIOPHARMACEUTICAL CLASSIFICATION SYSTEMS (BCS) The parameters which are the underlying foundation for classification of drugs as per biopharmaceutical classification system (BCS) include permeation and solubility. It can be well illustrated by Fick’s first law. According to Fick’s First law, the flux (J) of a drug across the gastrointestinal membrane is primarily governed by its permeability coefficient (P) through the gastrointestinal barrier and the drug concentration (C) present in the gastrointestinal lumen (assuming sink conditions) (Amidon et al., 1995): J 5 PC (15.8) Considering the Eq. 15.8, for BCS class II and IV class drugs which are characterized as poor water-soluble molecules, it is challenging to achieve adequate intraluminal drug concentration making it the rate-limiting step for absorption (Brouwers et al., 2009). According to FDA, drug substance is termed as “highly soluble” when the highest dose strength is soluble either in 250 mL or less of aqueous media over the pH range of 1 7.5 at 37 C (FDA, 2000). Based on this understanding and based on their solubility and intestinal permeability, according to BCS, drug substances are categorized into one of four categories: BCS class I: high solubility/high permeability; BCS class II: low solubility/high permeability; BCS class III: high solubility/low permeability; and BCS class IV: low solubility/low permeability (Kawabata et al., 2011). Recently, a more refined classification system known as the Developability Classification System (DCS) has been introduced to predict critical factors related to in vivo performance as compared to BCS. DCS provides the formulator with a valuable insight about the type of formulation approaches to be adopted for delivery of poorly soluble drugs, i.e., by controlling size or more sophisticated solubilization techniques to ensure oral bioavailability by avoiding solubility related food effects. According to this classification, BCS class II drugs are further classified according to primary reasons attributed to poor bioavailability, i.e., dissolution rate-limited, solubility-limited, or permeability-limited bioavailability. The DOSAGE FORM DESIGN CONSIDERATIONS 522 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT dissolution rate-limited drugs are categorized under DCS class IIa and solubility-limited drugs are classified under DCS class IIb (Möschwitzer, 2013; Butler and Dressman, 2010). 15.3 APPROACHES TO MODULATE DRUG SOLUBILITY 15.3.1 pH Modification This technique is often the first-line strategy for altering the solubility of weak base drugs which demonstrate changes in solubility with respect to pH, for example, verapamil hydrochloride, papaverine hydrochloride, dipyridamole, to name a few (Gutsche et al., 2008). Lahner et al. (2009) have documented the clinical studies which clearly depict the impaired absorption of bioactives, for example, ketoconazole, itraconazole, enoxacin, cefpodoxime, atazanavir, and dipyridamole on suppression of gastric acid secretion. The plausible reason for impaired absorption is ascribed to the slow and incomplete dissolution of these drugs under high stomach pH conditions. Knowing this, for pH-dependent drug, the drug aqueous solubility is often modulated by creation of microenvironmental pH in the immediate vicinity surrounding drug particles. For doing so, acidic or basic pH-modifier excipients are used which generate the diffusion area having pH desirable for solubility of drug thereby resulting in an immediate layer of saturated solution and a higher driving force for diffusion (Streubel et al., 2000; Taniguchi et al., 2014; David et al., 2012). Agents which modify the microenvironment pH may include organic acids for weak bases, i.e., fumaric acid, tartaric acid, etc., and organic bases for weak acids, i.e., magnesium oxide, magnesium hydroxide, etc. Yang et al. (2014) demonstrated pH-independent solubility poorly antiprostate cancer, water-soluble weakly basic GT0918 drug by incorporation of organic acid citric acid as pH modifier in solid dispersion of the drug. Similarly, another study showed that in comparison to plain drug, citric acid, and tartaric acid contributed to many times higher dissolution at pH 6.0 (Adachi et al., 2015). Park et al. (2015) revealed the dual role of organic bases such as MgO, Na2CO3, Na2HPO4, and NaHCO3 in modulating the solubility as well as stability of Clarithromycin. According to the study, NaHCO3 greatly enhanced the drug release, however, MgO was found to retard drug dissolution (owing to its poor water solubility). Besides this, organic bases were found to maintain the microenvironment pH of the tablet above pH 5 under acidic conditions to ensure stability of drug. Despite the usefulness and simplistic nature of this technique, it has a major drawback of the possibility of drug precipitation after administration arising due to supersaturation (Rodriguez-Aller et al., 2015). 15.3.2 Crystal Structure Manipulation Crystal structure manipulation approach revolves around manipulation of noncovalent interactions between molecular or ionic components within the crystal lattice. By manipulating the crystal structure, these approaches provide a useful tool to improve the aqueous solubility and consequently the dissolution rate of drugs (Blagden et al., 2007). DOSAGE FORM DESIGN CONSIDERATIONS 15.3 APPROACHES TO MODULATE DRUG SOLUBILITY 523 15.3.2.1 Polymorphs Most of the crystalline solids exhibit polymorphism, wherein materials with the same chemical composition exhibit diverse lattice structures with or without different molecular conformations (Rodrı́guez-Spong et al., 2004; Lawrence et al., 2003; Lee, 2014). Broadly, polymorphs can be categorized as conformational polymorphism and packing or orientational polymorphism (Datta and Grant, 2004; Prasanthi et al., 2016; Higashi et al., 2016). In conformational polymorphs, flexible moieties in their molecular structures exist in different conformations in the crystalline state (Lee, 2014). Classical example of conformational polymorphism includes the anti-HIV drug, Ritonavir, which is found to exhibit two distinctive crystal structures with significantly altered solubility characteristics (Bauer et al., 2001). It was reported that the polymorphic form had lower bioavailability resulting in the market withdrawal in 1998 for a year for reformulation to the new and more stable form (Cruz-Cabeza and Bernstein, 2014). Recently, a nonsteroidal antiinflammatory drug (NSAID) and a COX-2 inhibitor, Nimesulide, exhibits the presence of two conformational polymorphs (Form I and Form II). The study revealed that the metastable Form II demonstrated faster dissolution as compared to stable Form I (Sanphui et al., 2011a). While in packing polymorphism, even though the molecular conformations remain unchanged, the packing arrangement differs in three-dimensional space (Lee, 2014; Lu et al., 2010). A classical example of packing polymorphs includes Form I and II of acetaminophen (Heng and Williams, 2006). Widely known, polymorphs differ in their crystal energy which influences their physicochemical properties, such as melting point, density, solubility, and stability (Blagden et al., 2007). This may impact the solubility of different crystalline polymorphic forms or hydrates, it is stated that it can differ by 2- to 10-fold between polymorphs (Hageman, 2010; Pudipeddi and Serajuddin, 2005; Di et al., 2012; Kumar and Nangia, 2014). Polymorphism can be introduced during process, viz., crystallization, milling, heating, solution cooling, solvent evaporation, antisolvent addition, and spray-drying, to name a few (Higashi et al., 2016). During these processes, metastable polymorphs which have higher kinetic solubility than stable polymorphs are generated (Censi and Di Martino, 2015). 15.3.2.1.1 PSEUDOPOLYMORPHS Hydrates and solvates are pseudopolymorphic multicomponent crystalline solid molecular adducts, wherein water and other solvent molecules form H bonds and coordinate covalent bonds in a crystal lattice with drugs or excipients. This phenomenon is more common with small molecular weight compounds. Since water molecules possess both hydrogen bond donor (the two hydrogens) and acceptor atoms (the two lone pairs of an oxygen atom), they have been shown to readily form intermolecular hydrogen bonding with host molecules. As a consequence, it is estimated one-third of active pharmaceutical substances exist as hydrates making it common type of solvated pseudopolymorph (Healy et al., 2017; Qu et al., 2011; Jeffrey and Maluszynska, 1990). From a pharmaceutical perspective, hydrates are more preferred, since solvates due to the presence of solvent may be associated with potential toxicity. Hydrates can be broadly classified based on the stoichiometry of water molecule relative to the host molecule. In stoichiometric hydrates, there is a particular but not necessarily numeral ratio of water to molecule present (Brittain, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 524 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT In stoichiometric hydrates, the water molecules are found to be important for the regulation of the molecular geometry. Hence, on desolvation, they generally form disordered or amorphous structure. Whereas in nonstoichiometric hydrates, water molecule is shown to localize in structural voids of the crystal lattice, as a result, on desolvation, the parent hydrate structure remains unchanged (Griesser, 2006; Tieger et al., 2016). Finally, in metal ion-associated hydrates, as the term advocates, the water molecules are bound to a metal ion (Tieger et al., 2016). Borgmann et al. (2013) studied pseudopolymorphs of Fluvastatin sodium molecule wherein Form I, monohydrate with 4% of water content, demonstrated a higher dissolution rate. A study was carried out with different pseudopolymorphs of rifampicin; rifampicin monohydrate, a rifampicin dihydrate, two amorphous forms, a 1:1 rifampicin: acetone solvate, and a 1:2 rifampicin:2-pyrrolidone. With an exception of 2-pyrrolidone solvate, all other pseudopolymorphs were transformed into amorphous forms after desolvation. With respect to solubility, 2-pyrrolidone solvate had the highest solubility in phosphate buffer at pH 7 and water. While in 0.1 M HCl, the dihydrate was found to have fastest dissolution rate. However, the amorphous form had poor solubility and dissolution rate which was attributed to the poor wettability and electrostatic forces in amorphous powder (Henwood et al., 2001). Similarly, a study was carried out using the antiretroviral drug, nevirapine, which showed that the least crystalline solvate had 1.7 times more aqueous solubility than a commercial sample (Chadha et al., 2010). The major limitation of hydrates is the occurrence of variable stoichiometry, low thermal or humidity stability making it difficult to incorporate them in drug products (Tong et al., 2010). 15.3.2.2 Salt Formation Another, most common approach explored for enhancing the drug aqueous solubility is salification (salt formation). IUPAC defines a salt as a “chemical compound consisting of an assembly of cations and anions.” Mostly, for charge balance, pharmaceutical salts frequently have definite stoichiometry of ionizable drugs (anionic, cationic, and zwitterionic) which via stable ionic bonds with protons transfer from an acid to a base to form salts (Serajuddin, 2007; Bond, 2011; Vioglio et al., 2017). For a stable ionic bond, it is hypothesized that the difference .3 between pKa of an acid and a base is desirable (Childs et al., 2007). This is best explained by the molar free energy of solution, ∆Gsoln (Eq. 15.9), encountered in dissolving salt in water; ∆Gsoln 5 ∆Ganions 1 ∆Gcations 2 ∆Gcrystal lattice (15.9) where ∆Gsoln, ∆Ganions, and ∆Gcations are molar free energies of hydration of the salt, its positively charged, and negatively charged parts, respectively, and ∆Gcrystal lattice is the crystal lattice energy. In theory, because of the intramolecular ionic interactions, salt formation is associated with higher lattice energy which may typically hinder the overall solubilization process (David et al., 2012; Jain et al., 2015). Besides this, the solubility is affected by the counterions in salt, which are present either molecularly (e.g., mesylate, acetate, etc) or atomically (e.g., bromide, sodium, etc) (Vioglio et al., 2017). The presence of counterions has been shown to change the microenvironment pH thereby driving a higher dissolution rate of the salts as compared to corresponding free DOSAGE FORM DESIGN CONSIDERATIONS 15.3 APPROACHES TO MODULATE DRUG SOLUBILITY 525 forms (Kawabata et al., 2011). Guerrieri et al. (2010) have stated that depending on the counterion, molar aqueous solubilities of the various salts may differ by more than two orders of magnitude. Banerjee et al. (2005) demonstrated enhancement of aqueous solubility saccharinates of different drugs, viz, quinine, mirtazapine, haloperidol, pseudoephedrine, risperidone, lamivudine, venlafaxine, sertraline, zolpidem, and amlodipine, when compared to free base. Similarly, ciprofloxacin hippurate demonstrated 22-fold times enhancement in aqueous solubility improvement and a faster dissolution rate as compared to the parent form of the drug (Chadha et al., 2016). Although counterions are useful in enhancement of solubility, they suffer a drawback, the common-ion effect. In most cases, the common-ion effect is responsible for reducing drug solubility (Eq. 15.10) (Elder et al., 2013): 1 2 BH X s2 BH1 D aq 1 ½X2 (15.10) where (BH1X2)s denotes the undissolved salt that is in equilibrium with dissolved salt, [BH1]D (aq) is the solubility of the salt, and [X2] is the counterion concentration These effects are more pronounced for salts which have less aqueous solubility. 15.3.2.3 Cocrystal In accordance to guidelines on pharmaceutical cocrystals drafted by Food and Drug Administration (FDA), cocrystals can be defined as “Solid materials which are crystalline materials made of 2 or more than 2 molecules in the same crystal lattice” (FDA, 2000). The guideline provides the distinction between polymorph, salt, and cocrystal. Basically, cocrystals can be described as multicomponent crystals with well-defined stoichiometry achieved by hydrogen bonding interactions without the transfer of hydrogen ions to form salts; i.e., unlike salt, Bronsted acid base chemistry does not become the underlying basis for formation of a cocrystal (Yadav et al., 2009; Kuminek et al., 2016). Cocrystals are of particular interest to modify the solubility of nonionizable drugs, as they involve noncovalent types of interaction, such as hydrogen bonding, π-π stacking, and van der Waals forces (Jain et al., 2015; Good and Rodrı́guez-Hornedo, 2009). Childs et al. (2007) made an observation that unlike salt, mostly when ∆ pKa is less than 0, the resultant molecular complexes can be termed as cocrystals. Few of the general techniques for generation of cocrystals include solution crystallization, mechanical grinding, and melt crystallization (Thakuria et al., 2013). Generally, cocrystals are the outcome of supramolecular chemistry involving API and a second component or “cocrystal former” (“conformer” or cocrystallizing agent) (Almarsson et al., 2012). Based on the conformers, Duggirala et al. (2016) have classified cocrystals into two types: “molecular” or “ionic.” By definition, molecular cocrystals (MCCs) comprise a stoichiometric ratio of two or more different neutral conformers, typically, but not always exclusively, held together by hydrogen bonds or halogen bonds. On the other hand, ionic cocrystals (ICCs) are comprised of ionic conformers typically held together by charge-assisted hydrogen bonds and/or coordination bonds (if metal cations are present) (Braga et al., 2010). Solubilization of cocrystals usually follows a trend, i.e., spring and parachute effect wherein they show initial fast dissolution rate resulting in saturation followed by the transformation to the less soluble crystal, i.e., precipitation (Stanton et al., 2011). During solubilization, it is assumed that the ionizable components (i.e., conformer) may undergo DOSAGE FORM DESIGN CONSIDERATIONS 526 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT simultaneous chemical reactions at the dissolving surface with the chemical species coming from the bulk solution during dissolution, thereby affecting the surface pH and solubility. In conjunction with surface saturation model, it can be hypothesized that in the case of a slower diffusing component (i.e., the drug), the surface concentration is maintained at the stoichiometric cocrystal solubility and influences the dissolution of the cocrystal whereas the faster-diffusing component has a lower surface concentration. To overcome this drawback, surfactants are explored to thermodynamically stabilize cocrystals by micellar solubilization (Huang and Rodrı́guez-Hornedo, 2010). Recently, it has been demonstrated that cocrystals in the presence of a solubilizing agent, exhibit a transition point in their solubility over the parent drug (Lipert and Rodrı́guez-Hornedo, 2015). This is illustrated by a study wherein indomethacin-saccharin cocrystal had solubility 26 times higher than indomethacin in pH 2 buffer (Alhalaweh et al., 2012; Lipert and Rodrı́guez-Hornedo, 2015). Moreover, Sanphui et al. (2013) demonstrated that Sildenafil pimelic forms cocrystals that dissolve faster than the citrate salt in 0.1 N HCl aqueous medium. Similarly, the study involving curcumin resorcinol and curcumin pyrogallol showed the dissolution rates of both cocrystals in 40% EtOH water were 6- and 13-fold more rapid in contrast to that for curcumin, respectively (Sanphui et al., 2011b). 15.3.3 Prodrug Strategies Classically, the prodrug approach involves chemical modification of the pharmacologically active agent which on in vivo enzymatic or chemical action gets transformed into the active drug. They have also other nomenclatures such as reversible or bioreversible derivatives, latentiated drugs, or biolabile drug carrier conjugates (Rautio et al., 2008; Huttunen et al., 2011). Broadly, prodrugs can be classified as the carrier-linked prodrugs and the bioprecursors (Testa, 2009). Characteristically, carrier-linked prodrugs comprise of drug and carrier (also known as a promoiety) joined by an ester linkage which are generally activated by enzymatic hydrolysis. In contrast, bioprecursors lack promoiety and are activated by mechanisms involving hydration or oxidation or reduction. Recently, based on the groups involved in the linkage, carrier-linked prodrugs are further classified as (1) bipartite prodrugs wherein carrier is directly bound to drug; (2) tripartite prodrugs, which comprises of spacer between the carrier and the parent drug; and (3) mutual /multiple prodrugs comprises of two active compounds acting as the carrier to each other (Jornada et al., 2015; Ala’Abu-Jaish and Karaman, 2014). Using this approach, the ionic or ionizable group is often introduced in the parent drug structure to increase aqueous solubility (Neau, 2008). Promoiety may include ester, amide, carbamate, carbonate, ether, imine, phosphate, and N-Mannich bases (Huttunen et al., 2011; Zawilska et al., 2013). These moieties which are covalently attached to the hydroxyl groups undergo enzymatic transformation by enzymes such as alkaline phosphatase, sugardigesting enzymes, peptidase, and esterase, respectively (Hamada, 2017). Besides this, macromolecules-based prodrugs have been explored to enhance drug aqueous solubility. Commonly used polymers include hyaluronic acid, polyethylene glycol, hydroxypropyl metacrylamide, and poly-amidoamines or nitrodiol dendrimers. DOSAGE FORM DESIGN CONSIDERATIONS 15.3 APPROACHES TO MODULATE DRUG SOLUBILITY 527 Skoda et al. (2014) have reported the prodrug of naproxen covalently linked neutral molecule, oxetanyl sulfoxide demonstrated a .10-fold increase in aqueous solubility compared to parent drug. A study demonstrated superior anticancer activity of water-soluble glycine-based prodrug conjugates of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs by vascular disruption (Devkota et al., 2016). Similarly, Dai et al. (2014) revealed the enhanced 290 750-fold aqueous solubility of betulinic acid prodrugs which comprised of multiarm-polyethylene glycol linkers as compared to parent drug and superior in vitro anticancer activity. Gund et al. (2015) investigated the anticancer activity of disulfide-containing prodrugs of paclitaxel. Another study reports a 50,000 fold increase in aqueous solubility of phosphono oxymethyl prodrug of “compound alpha” [5-chloro-2-(methylthio)-6-(1-naphthyloxy)-1H-benzimidazole] compared to plain compound alpha (Flores-Ramos et al., 2014). O’Dowd et al. (2015) has reported one of the most commonly used phosphate ester prodrug approaches to enhance water solubility of Benzimidazole 1, a dual inhibitor of bacterial DNA gyrase and topoisomerase IV. 15.3.4 Crystal Structure Disruption (Amorphization) Crystal structure or amorphization is a widely used approach to introduce disordered structure thereby resulting in increased free energy or a thermodynamic driving force which contributes to enhancement of kinetic solubility and, subsequently, dissolution rate (Baghel et al., 2016). The relevance of amorphization in the enhancement of an increase in solubility is illustrated in Eq. 15.11; ∆GT Amorphous;Crystalline 5 2RT ln σT Amorphous =σT Crystalline (15.11) where ∆GT Amorphous,Crystalline is the energy difference between the crystalline and the amorphous state, R is the gas constant, T is the absolute testing temperature, and σTAmorphous/ σTCrystalline is the ratio of the solubility of two forms. From Eq. 15.8, it can be deduced that unlike the crystalline form, the lack of crystal lattice makes it easy for the solute molecules in the amorphous state to interact with solvent molecules through intermolecular interactions and facilitate their solubilization (Singh and Van den Mooter, 2016). Due to higher free energy, it is reported that the amorphous form and crystalline form may differ in the aqueous solubility which can range between 1.1- and 1000-fold (Hancock and Parks, 2000; Kawabata et al., 2011). As shown in Fig. 15.3, the generation of an amorphous system is characterized by the presence of the glass state. Typically, on slow cooling of the solid-melt, drug crystallizes out at melting temperature (Tm) owing to the sudden decrease in thermodynamic parameters. (Laitinen et al., 2013). However, upon rapid cooling, a nonequilibrium state relative to crystalline state is achieved and instead of formation of a crystalline state, the melt enters into a supercooled liquid region. The supercooled liquid state is characterized by decreased temperature and increased viscosity in this region. As a consequence, molecular motions within the melt are markedly reduced resulting in impaired rearrangement of the molecule before the temperature is lowered further. This is clearly defined by the change of the slope (Fig. 15.3), and hence the material is termed to be a glassy state, a nonequilibrium state, and DOSAGE FORM DESIGN CONSIDERATIONS 528 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 15.3 Thermodynamic of amorphous system where Tg is glass transition temperature and Tm is melting temperature. the corresponding temperature depicting change in molecular motion is called the glass transition temperature (Tg) (Craig et al., 1999; Hancock and Zografi, 1994). Generally, an amorphous state is characterized by the presence of short-range order over a few molecular dimensions (e.g., via hydrogen bonding) in their molecular structure, which governs their aqueous solubility and physical stability (Karmwar et al., 2011). Most commonly used techniques to fabricate amorphous systems are broadly classified as solvent-based, temperature-based (fusion), and mechanical-based (activation). Widely known solvent-based techniques comprise of spray-drying, freeze-drying, precipitation, solvent evaporation, confined impinging jet reactor based technique, supercritical fluid-based techniques, and different types of electro-spraying. While temperature-based techniques include the classical melt-quenching/quench-cooling techniques and hot-melt extrusions. Mechanical-based techniques include milling based techniques (Edueng et al., 2017). Typically, amorphous systems are characterized by generation of transient high energy supersaturation solutions in the GI tract (Fig. 15.4). Owing to the free energy in the amorphous form, in biologic milieu, the amorphous system like a spring is able to attain higher drug concentration than that of its crystalline form (Guzmán et al., 2004). Although free energy is the driving force for solubilization, it is also responsible for the inherent drawbacks often encountered with amorphous material, i.e., crystallization during storage as well as precipitation during dissolution in the biological milieu arising due to thermodynamic instability (Grohganz et al., 2014). Rojas-Oviedo et al. (2012) have reported 2.76-fold increase in aqueous solubility of indomethacin when formulated as an amorphous solid dispersion in comparison to the pure drug. 15.3.5 Size Reduction Generally, size reduction technologies employed in pharmaceuticals are broadly characterized as “top-down” or as “bottom-up” processes. Top-down process includes fragmentation of larger particles into smaller particles. In bottom-up process, usually, it is DOSAGE FORM DESIGN CONSIDERATIONS 529 15.3 APPROACHES TO MODULATE DRUG SOLUBILITY FIGURE 15.4 Spring and parachute effect of amorphous system. observed that smaller particles are generated during recrystallization of a drug from a supersaturated solution (Williams et al., 2013). 15.3.5.1 Micronization This approach includes techniques which reduce the drug particle size less than 10 µm, generally between 2 and 5 µm (Vandana et al., 2014). Micronization is a classic method explored widely for the enhancement of dissolution rate of poorly soluble drugs such as griseofulvin, digoxin, and felodipine (Kawabata et al., 2011). Commonly, top-down approaches are used to generate microparticles resulting in an increase in the surface-tovolume ratio, thereby contributing to enhancing dissolution characteristics. However, if the drug has very limited solubility (,1 mg/mL), this approach does not contribute significantly to solubility enhancement (Gao et al., 2008). Widely known methods include milling techniques, such as jet milling, ball milling, pin milling, are based on shear forces. Owing to high shear forces, newer surfaces are created which are associated with high surface tension leading to increased agglomeration of the drug particles resulting in reduction of the overall surface area for dissolution. da Costa et al. (2012) demonstrated improved the dissolution profile of efavirenz, a nonnucleoside reverse transcriptase inhibitor (NNRTI) of the human immunodeficiency virus type 1 (HIV-1) achieved by micronization method. 15.3.5.2 Nanonization Nanonization is also referred to as “nonspecific” size reduction techniques. This approach yields particles with large specific surface area and high energy, resulting in higher dissolution rate. Widely known top-down techniques include distortion of bulk characteristics of drug using mechanical, chemical, or other form of energy; this introduces crystal defects in the structure rendering it aqueous soluble. Besides this, another popular approach is the bottom-up approach wherein material is built up from atomic or DOSAGE FORM DESIGN CONSIDERATIONS 530 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT molecular species through chemical reactions, forming precursor embryos and finally resulting in desired nanosize particles (Dizaj et al., 2015). In recent times, both the approaches have been combined, i.e., precipitation techniques and high energy top-down processes to reduce the processing times without comprising size reduction efficiency as compared to conventional techniques. Nanoedge technology by Baxter is a technique which combines drug precipitation technique followed by an annealing step using high energy high-pressure homogenization. The process of annealing is essentially done to stabilize a thermodynamically unstable sized particle by applying stress followed by thermal relaxation (Al-Kassas et al., 2017). Gora et al. (2016) has demonstrated the impact of nanosizing of Valsartan in enhancement of in vitro dissolution profile and pharmacokinetic profile as compared to plain drug. Reduction of particle size to nanoscale is a current hot topic in drug delivery applications (Sharma et al., 2015; Tekade et al., 2017a). Many investigators have explored nanosized delivery systems such as liposomes, polymeric nanoparticles, and ocular nanosystems (Lalu et al., 2017; Maheshwari et al., 2015; Maheshwari et al., 2012; Tekade et al., 2017b). 15.4 EXCIPIENT-BASED SOLUBILIZATION 15.4.1 Cosolvency Cosolvency is by far the most widespread approach utilized to enhance aqueous solubility. The widely known mechanism of cosolvent in drug solubilization involves reduction of the dielectric constant of water (Kalepu and Nekkanti, 2015). It is assumed that the incorporation of a cosolvent distorts the intermolecular hydrogen-bonding network in the water thereby reducing the polarity of water. Hence, understanding the solubilization ability of a cosolvent is generally governed by the extent to which the cosolvent distorts the structure of water. Sometimes cosolvents can act as a complexing agent too. As reported in the case of N-methyl pyrrolidone, owing to a polar disubstituted cyclic amide group it has been shown to interact easily with water molecules, while the nonpolar carbons of this cosolvent has been shown to reduce the intermolecular hydrogen-bonding structure of water. The most commonly used cosolvents include amphiprotic cosolvents, such as ethanol, polyethylene glycol (PEG), propylene glycol (PG), glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), aprotic solvents such as dimethylsulfoxide (DMSO) etc (Sanghvi et al., 2008). Generally, the solubilization of a drug in the presence of a cosolvent is expressed by the log-linear model (Rubino and Yalkowsky, 1987): log Smix 5 log Sw 1 f:σ (15.12) where Smix and Sw is the solubility of the nonpolar solute in the cosolvent water mixture and water, respectively, f is the volume fraction of cosolvent and σ is the solubilization capability of the cosolvent. The solubilization capacity is further explained using the octanol water partition coefficient, log P, of the nonpolar solute (Eq. 15.13); σ 5 S log P 1 t (15.13) where S and t are constants governed by the nature of the cosolvent. However, this model is found to be unsuitable if the nonpolar solute interacts with the cosolvent to form DOSAGE FORM DESIGN CONSIDERATIONS 15.4 EXCIPIENT-BASED SOLUBILIZATION 531 solvates or modification of crystal structure (Mallick et al., 2007). Prominent drawbacks of cosolvency are associated with its unpalatability, adverse physiological effects, alteration of the pharmacokinetic profile of the drug, and possibility of drug precipitation in vitro as well as in vivo (Williams et al., 2013). Seedher and Kanojia (2009) demonstrated the enhancement of antidiabetic drugs gliclazide, glyburide, glimepiride, repaglinide, glipizide, pioglitazone, and rosiglitazone by use of cosolvents. The study was also carried out to investigate the effect of cosolvents on the aqueous solubility of etoricoxib. It was demonstrated that there was significant improvement by incorporation of PEG 400, PG, and glycerin. Further, it was reported that among these cosolvents, the less-polar solvents by virtue of enhanced hydrophobic interaction were found to greatly increase the aqueous solubility (Nayak and Panigrahi, 2012). 15.4.1.1 Hydrotopes Hydrotropy is an organic solvent-free solubilizing approach. It is basically a molecular phenomenon occurring by blending poorly soluble solutes with the large amount of hydrotrope resulting in an enhancement of the aqueous solubility of poorly soluble solute (Kim et al., 2010). It is stated that the solubilization occurs due to weak interaction between the poorly soluble solutes and hydrotropic agents, such as sodium benzoate, sodium acetate, sodium alginate, urea, etc. (Kumar et al., 2014). Besides this, another hypothesis for the mechanism includes distortion of the tetrahedral water structure by the hydrotropic agents and the most popular hypothesis is the formation of micelles of hydrotropic agents at a concentration above the minimum hydrotrope concentration (MHC) (Ferreira et al., 1996). A study was undertaken to investigate the mechanism of solubilization of sparingly soluble riboflavin (solute) using hydrotrope nicotinamide. The study revealed that hydrotropic molecules self-associated by stacking of the pyridine rings, and formed sandwich complexes with riboflavin molecules. The self-aggregation of hydrotrope and the complexation between riboflavin and hydrotrope exerted influence on the hydrogen bonds between solute 2 water, hydrotrope 2 water, solute-solute, solute 2 hydrotrope, and hydrotrope 2 hydrotrope. Besides this, the electrostatic energy between solute and hydrotrope interaction also influenced the solubilization process (Das and Paul, 2017). Madan et al. (2017) demonstrated using a mixture of hydrotropic agents, i.e., sodium salicylate and sodium benzoate (25:15), that the dissolution rate of gliclazide was greatly enhanced. 15.4.2 Cyclodextrin Cyclodextrins have been utilized for solubility enhancement of poorly soluble drugs by forming inclusion complexes with the latter. Their safety profile is better than the other agents which are employed for the purpose of solubility enhancement such as surfaceactive agents, polymers, organic cosolvents, etc. (Loftsson and Brewster, 2012). They are cyclic oligosaccharides containing D-glucopyranoside units connected via glycosidic linkages. They are produced from the enzyme-mediated hydrolysis of cornstarch. Cyclodextrins having less than six glucose units are not formed owing to stoichiometric reasons, whereas cyclodextrins having more than eight units of glucose show weak DOSAGE FORM DESIGN CONSIDERATIONS 532 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT complexing ability with drugs. There are three cyclodextrins namely α, β, and γ cyclodextrin which have six, seven, and eight glucose units respectively (Miranda et al., 2011). γ-cyclodextrin is costly, whereas α-cyclodextrin has a small size cavity, which is unable to accommodate few large drugs. β-cyclodextrin is the one which is extensively used owing to its plentiful availability and its size which renders itself amenable to complexation with many drugs. However, it is not suitable for parenteral delivery due to its nephrotoxic effect (Challa et al., 2005). These cyclodextrins suffer from limited aqueous solubility. Hence, cyclodextrin derivatives such as hydroxyl propyl β-cyclodextrin and sulfobutyl ether β-cyclodextrin have been developed with superior solubility characteristics (Williams et al., 2013). Commonly employed pharmaceutical cyclodextrins include β-cyclodextrin, hydroxyl propyl β-cyclodextrin, sulfobutyl ether β-cyclodextrin sodium salt, randomly methylated β-cyclodextrin, and branched β-cyclodextrin (Rasheed and Vvns, 2008). The cyclodextrin molecules contain a hydrophilic external surface and a lipophilic internal cavity. Cyclodextrins are endowed with high solubility in water because of the plethora of hydroxyl groups and the glucopyranose units which are present in chain conformation provide the cavity or conical shape (Suvarna et al., 2017). Host guest interactions between the drug and the cyclodextrin enable the formation of inclusion complexes which show enhanced dissolution rate and increased oral bioavailability. During the formation of an inclusion complex between a drug and the cyclodextrin, removal of water from the cavity takes place followed by its substitution using a hydrophobic drug. All poorly soluble drugs cannot form inclusion complexes with cyclodextrins. Drugs which have a size, shape, and polarity complementing that of the cyclodextrin cavity are able to form complexes. Ideal characteristics of a drug candidate for forming drug cyclodextrin inclusion complexes: • Drugs have to be low dose potent drugs (Miranda et al., 2011). • Charge of the drug may also play an important role in complexation. For example, sulfobutyl ether β-cyclodextrin which is negatively charged has been shown to complex more efficiently with positively charged drugs than neutral hydroxyl propyl β-cyclodextrin (Okimoto et al., 1996). • Polarity of drug: The hydrophobic nature of the interior cavity of cyclodextrin results in increased binding affinity for hydrophobic drugs. • State of ionization of the drug: Unionized form of the drug shows better binding with cyclodextrin as compared to the ionized form. For cyclodextrin complexation, drug cyclodextrin complexation can be enhanced by the use of water-soluble polymers (Jambhekar and Breen, 2016). The complexation may be facilitated via electrostatic interactions when drug and cyclodextrin bear opposite charges. It can also be enhanced by the use of acids such as citric acid, tartaric acid, etc. The size of the cavity indicates the accommodation of the drug molecule which ultimately determines the degree of interaction between the drug and the cyclodextrin. It is not essential that the entire drug molecule be housed inside the cyclodextrin cavity, even a part of the molecule can bind with the cyclodextrin cavity and provide complexation. This phenomenon results in the formation of higher-order complexes between drugs and cyclodextrin in the case of drugs having numerous phenyl rings in their structure. Itraconazole and tacrolimus are DOSAGE FORM DESIGN CONSIDERATIONS 15.4 EXCIPIENT-BASED SOLUBILIZATION 533 examples of such drugs wherein a part of the drug fits into the cyclodextrin cavity. Literature states that the structure of β-cyclodextrin has been found to be appropriate for the binding of compounds containing phenyl rings in their structure. The overall drug solubility (ST) for a 1:1 drug-cyclodextrin inclusion complex (CDT) is given by the following equation (Rao et al., 2006); ST 5 S0 1 KD S0 =1 1 KD S0 3 CDT (15.14) where KD is the binding constant and S0 is the intrinsic solubility. Inclusion complexation between drug and cyclodextrin takes place in solid, liquid, and semisolid phases. Drug cyclodextrin inclusion complex formation takes place rapidly and also exhibits rapid dissociation kinetics in solution state. Binding constant or dissociation constant (Kc) is an index of the dissociation of the inclusion complex and is given by Kc 5 Drug 2 CD = Drug ½CD (15.15) Where [drug-CD], [drug], and [CD] are the concentrations of the complexed drug, free drug, and free cyclodextrin, respectively (Miranda et al., 2011). Majority of the drugs demonstrate a binding constant between 1 3 102 to 1 3 104 M (Williams et al., 2013). Guest molecules having Kc below 500 M are considered to be showing weak complexation with cyclodextrin and those having more than 20,000 M are considered to be showing very strong bonding with cyclodextrin. Complexation efficiency (CE) is the product of intrinsic drug solubility and stability constant of drug-cyclodextrin complex (Jambhekar and Breen, 2016). (15.16) CE 5 Drug 2 CD = Drug ½CD 3 S0 CE value of 1 is indicative of complete complexation of the drug with cyclodextrin. CE of 0.1 indicates that only 1 out of 11 cyclodextrin molecules complexed with drug (Takahashi et al., 2012). Complexation efficiency helps to select the particular cyclodextrin for solubility enhancement (Jambhekar and Breen, 2016). Drug cyclodextrin complexes are characterized by phase solubility diagrams and dissolution profiles. A phase solubility diagram is a plot of dissolved drug concentration versus cyclodextrin concentration and is obtained from the solubility data of the guest molecule at increasing cyclodextrin concentrations. There are two types of profiles, namely A type and B type. Solubility of the guest increases with an increase in the cyclodextrin concentration reflecting the formation of soluble complexes in the A type. In the B type, the complex formed is insoluble with a decrease in the concentration of the dissolved guest molecule at an increased concentration of cyclodextrin. A type profiles are of three kinds: AL (linear), AN (negative), and AP (positive). The AL profile shows a linear rise in solubility depending on the concentration of cyclodextrin. Slope of ,1 is reflective of 1:1 stoichiometry. Slope of .1 reflects the formation of a higher order complex between the drug and cyclodextrin. The AP profile reflects the formation of higher order complexes between drug and cyclodextrin after a particular concentration of cyclodextrin has been exceeded (Rao et al., 2006). B type profile reflects formation of drug cyclodextrin complexes having low aqueous solubility (Williams et al., 2013). Generally, β-cyclodextrin yields B type phase solubility profile whereas hydroxyl propyl β-cyclodextrin and sulfobutyl ether β-cyclodextrin yields A type solubility profile (Challa et al., 2005). DOSAGE FORM DESIGN CONSIDERATIONS 534 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT The solubility enhancement obtained through cyclodextrin inclusion complexes can further be enhanced by the incorporation of water-soluble polymers which act in combination with cyclodextrin to augment drug solubility and thereby decrease the amount of cyclodextrin needed. Such complexes are referred to as ternary complexes wherein a drug, cyclodextrin, and a water-soluble polymer undergo complexation. Generally, polymers which are inexpensive and biologically inert are employed. It is postulated that watersoluble polymers might reduce mobility of cyclodextrins and enhance the solubility of the drug-cyclodextrin inclusion complex (Miranda et al., 2011). Also, they increase the stability of the drug-cyclodextrin complex which increases the complexation efficiency (Jambhekar and Breen, 2016). Polymer concentrations need to be optimized so that increased viscosity of highly concentrated polymer solutions does not hinder complexation. Examples of some commonly used water-soluble polymers include pectin, agar, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), gelatin, carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, etc. Research papers have reported 80% decrease in the amount of cyclodextrin required for drug solubilization due to inclusion of water-soluble polymers. Heating of the ternary complexes using ultrasound energy, autoclaving, or microwave radiation has shown to stimulate the formation of bonds between the polymer, cyclodextrin, and drug (Miranda et al., 2011). Using β-cyclodextrin and hydroxyl propyl β-cyclodextrin, Norfloxacin was converted to amorphous form via inclusion complexation, as a result, there was enhancement in the rate of dissolution as compared to pure drug (Loh et al., 2016). Mono-6-deoxy-6-aminoethyl amino-β-cyclodextrin was shown to provide seven-fold solubility enhancement of ciprofloxacin than pure drug with improved antibacterial activity against methicillin-resistant Staphylococcus aureus. Similarly, sulfobutyl ether β-cyclodextrin was found to increase erlotinib dissolution as compared to pure drug (Devasari et al., 2015). The combination of hydroxypropyl β-cyclodextrin and hydroxypropyl methylcellulose demonstrated enhancement of solubility of carbamazepine by 95-fold and 1.5-fold increase in bioavailability than commercial tablets (Kou et al., 2011). Cyclodextrin nanosponges represent a recent development in the field of cyclodextrinbased drug solubilization. Nanosponges are cross-linked cyclodextrins having size less than 1 µm and yield opalescent dispersions in water. Nanosponges employed by the parenteral route may be in the range of 200 300 nm (Trotta et al., 2012). The porous structure yields a greater number of sites for better interaction with the drugs. Agents used for cross-linking include dimethyl carbonate, diphenyl carbonate, and carbonyl diimidazole (Torne et al., 2013). 15.4.3 Ionic Liquids In recent times, ionic liquids are emerging as a new class of powerful catanionic hydrotropes, possessing both the cation and the anion groups which synergistically contribute to enhancement of the aqueous solubility of drug candidates (Cláudio et al., 2015). It is interesting to note that the ionic liquids could be either the active pharmaceutical ingredient or the excipient facilitating the enhancement of aqueous solubility. By nature, ionic liquids are ionic salts which occur as liquid melt at temperature below 100 C (Shamshina et al., 2013; Dobler et al., 2013). This is ascribed to destabilization of the crystal lattice by the DOSAGE FORM DESIGN CONSIDERATIONS 15.4 EXCIPIENT-BASED SOLUBILIZATION 535 existence of weakly coordinating anions and bulky, asymmetric cations having a shielded or delocalized charge, thereby making it difficult for coordination and anion cation interaction. Consequently, it results in lower lattice energy, essential for crystallization (Dean et al., 2010; Hayes et al., 2015; Egorova et al., 2017). To achieve this, the selection of anion and cation is critical. It is assumed that for the Coulombic forces to disrupt lattice packing, cation alkyl chain must be adequately long (Bn , 12) to ensure that overall melting point is low. However, there are exceptions, by introducing a cis double bond “kink” on the alkyl group, researchers have successfully reduced the melting point of long-chain ( . C16) cations-based ionic liquids (Murray et al., 2010). Common techniques employed to prepare ionic liquids rely on one of the following approaches, i.e., simple acid base neutralization; solvent-based solution metathesis, or solvent-free metathesis using grinding or melting (Rogers and Seddon, 2002; Marrucho et al., 2014). Classically, the ionic liquids comprising of imidazolium cation combined with [BF4], [PF6], and [NTf2] anions, were explored for their drug solubilization ability. However, their usefulness was limited with their toxicity issues. To circumvent this issue, in recent times, low toxic, ionic liquids based on natural compounds, such as organic acids, amino acids, have been explored for their ability to develop drug delivery system. The tunability of properties makes it an attractive alternative for solvents used in enhancing the drug solubility. It has been reported that by modifying the anion/cation combination or by selecting biocompatible organic cations and inorganic anions within the structure, ionic liquids can be rendered nontoxic and/or biocompatible (Petkovic et al., 2010). In general, ionic liquids are classified as protic ionic liquids, i.e., proton donating, aprotic ionic liquids, i.e., nonproton-donating (Parker, 1962; Mirjafari et al., 2013). Besides these, there are other classifications based on structural and functional features. Protic ionic liquids are cheaper ionic liquids prepared easily by stoichiometric neutralization of Bronsted acids and Bronsted bases, characterized by the presence of proton on the cation (Greaves and Drummond, 2015). Aprotic ionic liquids are expensive ionic liquids formed by the covalent bond formation between two functional groups (Estager et al., 2014). Other types of ionic liquid, based upon distinct structural features, are chiral ionic liquids (Ding and Armstrong, 2005), a paramagnetic atom/group (magnetic ionic liquids) (Santos et al., 2014), a divalent ion (divalent ionic liquids), a polymeric or polymerizable ion (polymeric ionic liquids) (Mecerreyes, 2011), a fluorocarbon moiety (fluorous ionic liquids) (Shen et al., 2012), a coordinated ion (solvate ionic liquids) (Zech et al., 2009), or a specific functional group introduced on the ions (amino acid ionic liquids (Ohno and Fukumoto, 2007) and aryl alkyl ionic liquids (Ahrens et al., 2009)), or drug ingredient ionic liquids (API ILs) (Sahbaz et al., 2015). Physicochemically, ionic liquids’ structural features are being studied extensively to understand the factors contributing to their solvent behavior, such as negligible vapor pressure, high thermal stability, high ionic conductivity, and multiple salvation interactions with organic and inorganic compounds. Although, still unclear, it is assumed that ionic liquids may have similarity to concentrated salt solution or supramolecular structures such as ion pairs, ion clusters, or to mesoscopic structures, such as H-bond networks, micelle-like components, or bicontinuous structures (Izgorodina and MacFarlane, 2011; Evans et al., 1981; Ludwig, 2009; Canongia Lopes and Padua, 2006). Generally, to achieve low lattice energy, it is preferred that an ionic liquid comprises of counterions which are DOSAGE FORM DESIGN CONSIDERATIONS 536 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT asymmetric, bulky, monovalent, having minimal possibility of H-bonding between molecules, possessing flexible alkyl chains capable of steric inhibition among the salt components (Stoimenovski et al., 2010; Prakash, 2011). The bulkiness of the ions is responsible for the nonspherical shape and the delocalization of charge over a large volume. Owing to this large distribution, the overall charge density of the ionic liquid becomes much less than for smaller ions of inorganic salts resulting in the reduction of the strength of electrostatic repulsion between similarly charged organic ions. Due to attraction of the ions, it leads to noncovalent interactions between the ions and restructuring of the shape (Del Pópolo and Voth, 2004; Hayes et al., 2014). Together, these attributes provide an increase in the degree of rotational freedom, thereby reducing free enthalpy and the corresponding increase in an entropy gain of the salt formation process and lower melting point of the ionic liquid (Stoimenovski et al., 2012). With regards to drug solubilization in the ionic fluid, drug candidates can be solubilized into ionic liquids via ionic binding (e.g., API-ionic liquid), via covalent linkage; and by using both interactions (Egorova et al., 2015). Irrespective of the techniques, the first important consideration for solubilization is the type of counterions, i.e., anion or cation of the ionic liquid. It is reported that the cations exert negligible effect on the solvation capability, whereas the coordinating anion, owing to strong hydrogen bond acceptors, have superior solubilizing capacity. Similarly, in comparison to hydrophobic ionic liquids having noncoordinating anions, hydrophilic ionic liquids (possessing coordinating anions) have superior ability to dissolve drug molecules (Moniruzzaman et al., 2010; Kumar et al., 2007; Adawiyah et al., 2016). The study carried out to investigate the solubility of poorly water-soluble model drugs, albendazole and danazol in alkyl imidazolium salts (PF6 2 Br 2 Cl 2 ) revealed that the solubility of albendazole, 1-butyl-3- methylimidazolium hexafluorophosphate ([bmim]PF6 2 ) was increased by more than 10,000 times. The probable reasoning was due to the presence of solute solvent interactions such as hydrogen bonds, van der Waal’s forces, as well as interactions between aromatic rings. Further, the authors stated that the greater number of carbons in the alkyl chain in the imidazolium cation, enabled an increase in the solvency of the hydrophobic drugs (Mizuuchi et al., 2008). Another study provided an interesting insight into the influence of alkyl chain on the solubilization capacity of vanillin. For the compounds with lower number of carbons ([CnC1mim] Cl, n 5 2 6), ionic liquids exhibited hydrotropic behavior, i.e., the formation of coaggregates between the solute and the ionic liquids, which increased with the cation alkyl chain length. Whereas, for ionic liquids with self-aggregation ability in aqueous solution (above [C8C1mim] Cl), the micellar solubilization mechanism was more pronounced, i.e., the solubility increased up to the critical micellar concentration and later on plateau. However, in comparison to longer length of carbon chain, the solubility of vanillin was higher by the hydrotropic effect of [C6C1mim] Cl (Cláudio et al., 2015). The study comparing the micellar behavior of tetradecyltrimethylammonium bromide (TTAB) and C14mimBr, an imidazolium-based surface active ionic liquid demonstrated that the drugs dopamine and acetylcholine were located on the periphery of micelle. Further, in comparison to acetylcholine, dopamine was found to bind more strongly with the surfactants due to cation 2 π interactions between the positive charge of the surfactant molecules and the aromatic region of dopamine. While, in comparison to TTAB, DOSAGE FORM DESIGN CONSIDERATIONS 15.4 EXCIPIENT-BASED SOLUBILIZATION 537 dopamine showed greater binding constant value (K) with C14mimBr possibly due to π 2 π interactions of the π system of dopamine and imidazolium ring of C14mimBr (Mahajan et al., 2012). Similarly, another study demonstrates 1:1 stoichiometry stabilized highly surface active catanionic complexes (C12mim 1 Ibu-) by a combination of electrostatic, hydrophobic, cation-π, and π π interactions, which on dilution resulted in generation of larger aggregates from smaller micelles due to change in the solubility (Sanan et al., 2014). Ionicity is another important aspect of ionic liquid, it reflects the ionic nature of the ionic liquid and is a measure of the degree of presence by ions present in the liquid or presence of neutral ion-pairs (large aggregates) (Harris, 2010). It has been reported that this parameter is controlled by the magnitudes and balance of the intermolecular (interionic) forces, Coulombic interactions, and van der Waals attractions in the nonpolar domain, arising from the variations in the cationic and anionic structures. Researchers state that at the higher effective molar concentration of charged species in ionic liquid, the Columbic forces dominate the physicochemical properties such as surface tension, polarity, etc., while at low concentration of charged species, van der Waals forces exert influence on the properties (Ueno et al., 2010). Although there is dearth of literature about the mechanism of drug solubility using ionic liquids, it can be assumed that the mechanism of enhancement in drug aqueous solubility may include the achievement of degree of supersaturation in gastrointestinal lumen (Balk et al., 2015a). Supersaturation is a thermodynamically unstable high-energy state which demonstrates the strong tendency of drug precipitation to achieve the thermodynamically stable state (Brouwers et al., 2009). In the case of ionic liquid, it is observed that due to ionic interaction between the drug and the ions, the prolonged supersaturation can be achieved. The researchers compared the dissolution kinetics of acidic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA) antagonist (pKa of B6.7)-based ionic liquid, with its acid form, its potassium salt, and an acetylated prodrug. The researchers reported that in comparison to the potassium ion, the ionic counterion tetrabutyl phosphonium (TBP) stabilized the ionized state, resulting in supersaturation. At these supersaturated states, the drug was found to be maintained as amorphous precipitates of salt of anionic TBP and cationic counterion resulting in higher dissolution rate with minimal precipitation rate as compared to the potassium salt. Besides this, due to the presence of a charged apolar side chain of counterions, the ionic liquid was assumed to be in micellar state, further increasing the solubility and transport (Balk et al., 2015b). The study revealed that amino acid choline-based ionic liquids enhanced the solubility of both caffeine and salicylic acid as compared to imidazole ionic liquids. Further, in comparison to imidazole-based ionic liquids, amino choline-based ionic liquids were less toxic but relatively poor permeation enhancers (Santos de Almeida et al., 2017). Ion pairs have higher drug loading self-emulsifying drug delivery systems and significantly higher bioavailability (20-fold for itraconazole and 2-fold for cinnarizine) compared to the suspension formulations (or the physical mixture in the case of itraconazole) at the same dose (Sahbaz et al., 2015). Another study revealed that acyclovir ionic liquids exhibited two times the enhancement of aqueous solubility of acyclovir when compared to that of neutral acyclovir (Shamshina et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 538 15. SOLUBILITY AND SOLUBILIZATION APPROACHES IN PHARMACEUTICAL PRODUCT DEVELOPMENT 15.5 CONCLUSION Numerous methodologies have been given in the literature to enhance the water solubility of poorly water-soluble drugs, especially BSC class II drugs. Widespread techniques involve salt formation, pH modification, cocrystal formation, and use of metastable crystalline forms. In the pharmaceutical scenario, the choice of appropriate metastable form is an important issue for drug product development owing to its thermodynamic instability. Hence, from an industrial perspective, the thermodynamically stable crystalline forms achieved through salt formation and cocrystals have an advantage. From the formulation aspect, the usual approaches include micronization, canonization, amorphization, cosolvency, cyclodextrin complexation, ionic liquid, and pH modification. However, there is a dearth in number of pharmaceutical products reaching the market, primarily because these technologies necessitate the need of exhaustive and laborious manufacturing processes and most of the time difficult to scale-up techniques. Although there are numerous approaches available to enhance the drug solubilization to improve the physicochemical and pharmacokinetic properties of the poorly water-soluble drugs, the commercialization aspect is still a cumbersome task. Acknowledgments Dr. Acharya and Dr. Fernandes express gratitude to SPPSPTM, SVKM’S NMIMS for the seed grant support towards their research work on glycolipid-based drug delivery approaches. Dr. Fernandes wishes to acknowledge the technical assistance of Dr. Priyanka Prabhu in drafting the manuscript. Dr. Acharya also wishes to acknowledge UGC, New Delhi for the research grant [(F.30-376/2017 (BSR))] and CSIR, New Delhi for the extramural research grant [02(0329)/17/EMR] to work to work on chemopreventive measures of colon cancer. Dr. Acharya also expresses his heartfelt thanks to Tripura University (A Central University), Suryamaninagar, for providing all necessary research facilities. The authors RKT would also like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant allocated to Dr. Tekade for research work on gene delivery and N-PDF funding (PDF/2016/003329) for work on targeted cancer therapy. RT would also like to thank NIPER-Ahmedabad for providing research support for research on cancer and diabetes. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. ABBREVIATIONS GI pKa So HIV FDA MCCs ICCs G TBP AMPA gastrointestinal dissociation constant intrinsic solubility human immunodeficiency virus Food and Drug Administration molecular cocrystals ionic cocrystals Gibbs free energy tetrabutylphosphonium acidic α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES NNRTI HIV-1 PEG PG DMA NMP DMSO MHC 539 a nonnucleoside reverse transcriptase inhibitor human immunodeficiency virus type 1 polyethylene glycol propylene glycol dimethylacetamide N-methyl-2-pyrrolidone dimethylsulfoxide minimum hydrotrope concentration References Adachi, M., Hinatsu, Y., Kusamori, K., Katsumi, H., Sakane, T., Nakatani, M., et al., 2015. 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DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 16 Rheology and Its Implications on Performance of Liquid Dosage Forms Pratap Chandra Acharya1,*, Divya Suares2,*, Saritha Shetty2, Clara Fernandes2 and Rakesh K. Tekade3,4 1 Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India 2Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 4Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 16.1 Understanding the Basic Concepts of Rheology 550 16.1.1 Shear Viscosity, Its Dimensions, and Units 551 16.1.2 Pharmaceutical Systems Based on Rheological Behavior 552 16.1.3 Deformation of Liquids and Deformation Forces 555 16.1.4 Viscoelasticity 556 16.1.5 Determination of Molar Weight by Viscosity 556 16.2 Rheology of Pharmaceutical Dosage Forms 16.2.1 Rheology of Suspensions 558 558 16.2.2 Rheology of Emulsions 16.2.3 Rheology of Nano-Based Systems 563 563 16.3 Pharmaceutical Considerations 567 16.3.1 Influence of Physical Variables 567 16.3.2 Influence of Chemical Variables 574 16.3.3 Rheology Modifiers, Thickeners, and Gels 578 16.4 Rheological Instruments for Fluids and Their Limitations 578 16.4.1 Measurement of Rheological Parameters 579 * Authors having equal contribution in this book chapter. Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00016-2 549 © 2018 Elsevier Inc. All rights reserved. 550 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS 16.5 Rotational-Type Rheometer 579 16.11.2 16.11.3 16.11.4 16.11.5 16.11.6 16.11.7 16.6 Broad-Gap Concentric Cylinder Viscometer 580 16.7 Cone and Plate Viscometer 581 16.8 Parallel-Plate Viscometer 581 16.9 Tube-Type Rheometers 582 16.10 Dilation Rheology 583 16.11 Applications of Rheology 16.11.1 Materials Science 583 583 In Geophysics Physiology Food Rheology Concrete Rheology Filled Polymer Rheology Pharmaceuticals 584 584 585 585 586 586 16.12 Conclusion 588 Acknowledgment 588 Abbreviations 589 References 589 16.1 UNDERSTANDING THE BASIC CONCEPTS OF RHEOLOGY Rheology helps in understanding the flow characteristics of materials such as gases, liquids, semisolids, solids, and/or their combinations. Rheology plays a vital role during the physicochemical characterization of dosage forms at the formulation development stage. Rheological nature of the dosage form directly affects the quality of the input (raw) material and the output (final) product, dose uniformity, filling efficiency, product stability, and overall healthcare cost. Numerous factors hugely influence the flow property of dosage form, which are considered related to the properties of the materials included in the formulation (Mastropietro et al., 2013; Tatar et al., 2017). The term “Rheology” was initially conceived by Professor Bingham of Lafayette College, Easton, Pennsylvania, United States, which referred to the study of deformation and flow of matter and was accepted in 1929 by the American Society of Rheology. Theories on rheology date back to 1678, when Sir Robert Hooke developed his “True Theory of Elasticity” proposing that “the power of any spring is in the same proportion with the tension thereof,” and when doubled, it doubled the extension. His theory was later translated to the Hooke’s Law for solids (Eq. (16.1)) σ5G3γ (16.1) where, σ 5 Stress, γ 5 strain, G 5 rigidity modulus. On similar lines, in 1687 Sir Isaac Newton addressed the liquids and steady simple shearing flow in his “Principia” wherein he stated that “the resistance which arises from the lack of slipperiness of the parts of the liquid, other things being equal, is proportional to the velocity with which the parts of the liquid are separated from one another.” His theory was translated to Newton’s Law for liquids (Eq. 16.2). σ5η3γ (16.2) where, σ 5 stress, γ 5 strain, η 5 coefficient of viscosity. Thus, rheology can be described as the study of properties of a material determining its behavior, i.e., deformation and flow, under controlled conditions, characteristically DOSAGE FORM DESIGN CONSIDERATIONS 16.1 UNDERSTANDING THE BASIC CONCEPTS OF RHEOLOGY 551 measured using a rheometer. The term rheology originates from Greek words “rheo” meaning “material that flows” and “logia” meaning “the study of.” Rheology studies the structural changes in the materials under externally applied force. Thus, rheological measurements include the assessment of changes in dilute viscous and nonviscous solutions, suspensions, emulsions, concentrated protein formulations, semisolids such as ointments, pastes, gels, creams, and molten or solid polymers on application of stress (Malvern Instruments Ltd., 2016, 2017). Prior to discussing the various aspects of rheological characteristics of the abovementioned systems, it is important to understand various terminologies and their units facilitating rheological measurements which are mentioned in the following section. 16.1.1 Shear Viscosity, Its Dimensions, and Units According to Newton’s theory, the lack of slipperiness is known as viscosity or internal friction and termed as a measure of resistance of liquid to flow. The greater the viscosity of the systems, the higher is the resistance. Thus, the coefficient of viscosity may be defined as the force per unit area required to maintain unit difference in velocity between two parallel layers in a liquid block, 1 cm apart. As per Fig. 16.1, shear stress (F) is the force acting per unit area of the plane parallel to its surface, resulting in shear deformation of the “layers” of fluid as they flow past each other and produce a flow at a velocity U. This shear stress is denoted by F’/A and is directly proportional to the velocity gradient or shear rate denoted by U/d, with coefficient of viscosity (η) being the proportionality constant. The rheological behavior of fluids can be characterized by plotting shear stress versus shear rate (Barnes et al., 1989). SI unit of viscosity is Pascal-second (Pa.s) while earlier cgs system unit, i.e., Poise was widely used. Poise is defined as the shearing force required to produce a velocity of 1 cm per second between two parallel planes of liquid each 1 cm2 in area and separated by a distance of 1 cm. However, Poise is smaller than Pa.s by a factor of 10. This is exemplified in viscosity of water at 20.2 C is 1 mPa.s (milli-Pascal-second), which is 1 cP (centipoise). Dynamic viscosity and coefficient of viscosity are used to refer to Newtonian fluids, while the reciprocal of viscosity is termed as Fluidity bearing the units Poise21. Kinematic viscosity is another term used to describe Newtonian systems which designates dynamic viscosity divided by density (Steffe, 1996). The basic information on shear viscosity aids the formulation scientist in correlating the relationship between shear stress and shear FIGURE 16.1 Diagram depicting the phenomena of velocity on application of force. DOSAGE FORM DESIGN CONSIDERATIONS 552 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS strain which will help in defining various pharmaceutical systems, based on Newton’s law of flow, which is discussed in the following section of the chapter. 16.1.2 Pharmaceutical Systems Based on Rheological Behavior The concepts of elastic behavior and viscous behavior with respect to laws of Hooke and Newton are linear laws posing direct proportionality between shear stress and shear strain. “Theorem XXXIX” of the classical monograph of Newton discoursed a quantitative approach towards the flow of fluids wherein terminologies like “defects lubricitatus” and “attritus” were given which are relative to the current terms “internal friction’ and ‘”viscosity.” Newton proposed that resistance due to internal friction is directly proportional to relative velocity of fluid particles. Later, an analogous assumption was formulated by Navier and Stokes, who then reintroduced the Newton hypothesis (Malkin and Isayev, 2017). 16.1.2.1 Newtonian Systems The systems that obey Newton’s law of linearity are termed as Newton Stokes liquid or Newtonian systems, signifying that shear stress versus shear rate yield a straight line and the slope is defined as the viscosity of the fluid. As viscosity is the resistance of fluid to flow, the higher the viscosity of the fluid, the more effort is required to set the system in motion. Eq. (16.3) proposes that shear stress is proportional to deformation rate (Malkin and Isayev, 2017). (16.3) σ5η3γ where σ 5 shear stress, γ 5 shear rate, η 5 shear viscosity. Few examples of Newtonian systems include homogenous liquids like water, glycerin, honey, ethyl alcohol, chloroform, linseed oil, castor oil, etc. The rheogram of Newtonian systems are shown in Fig. 16.2. 16.1.2.2 Non-Newtonian Systems 16.1.2.2.1 TIME-INDEPENDENT NON-NEWTONIAN FLOW Systems that fail to obey the linear relationship of Newton’s law are known as nonNewtonian systems. Contrary to the Eq. (16.3), non-Newtonian systems do not exhibit FIGURE 16.2 Newtonian systems. DOSAGE FORM DESIGN CONSIDERATIONS Rheogram of 16.1 UNDERSTANDING THE BASIC CONCEPTS OF RHEOLOGY 553 linear relation between shear stress and shear rate and their proportionality constant is termed as apparent viscosity, which is not necessarily constant (Malkin and Isayev, 2017). Non-Newtonian systems may be further classified as plastic, pseudoplastic, and dilatant systems. Herschel Bulkley model (Eq. (16.4)) clearly describes the behavior of nonNewtonian systems. σ 5 K ðγ Þn 1 σ 0 (16.4) where K 5 consistency coefficient; n 5 index of nature of flow; σ0 5 yield stress. As per Herschel Bulkley model, the Newtonian power law is 0 , n , 1 for pseudoplastic systems and 1 , n , N for dilatant systems; while plastic systems are considered as special case and K value corresponds to plastic viscosity (Steffe, 1996). Plastic systems are considered as Bingham bodies which seem similar to Newtonian systems, wherein the viscosity does not change with added shear rate. However, minimum shear stress, also termed as yield stress, is desired to make the system flow (Fig. 16.3). Few examples of plastic systems include toothpaste, tomato paste, etc. Pseudoplastic systems are termed as shear thinning systems because their viscosity reduces with an increase in shear rate (Fig. 16.4). As shown in Fig. 16.5, the lower region of the rheogram represents Newtonian flow and the dominance of apparent viscosity (ηo) which is limiting at zero rate of shear; while the middle region represents change in apparent viscosity (η) with change in rate of shear. Finally, the upper region represents constant limiting viscosity (ηN) at infinite rate of shear. Few examples of pseudoplastic systems include 1% aqueous solution of carrageenan gum, liquid dispersions of tragacanth, sodium FIGURE 16.3 Rheogram of plas- tic system. FIGURE 16.4 Rheogram of pseudoplastic system. DOSAGE FORM DESIGN CONSIDERATIONS 554 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS FIGURE 16.5 Rheogram of dilat- ant system. alginate, methylcellulose, sodium carboxymethylcellulose, apple sauce, banana puree, orange juice concentrate, etc. Dilatant systems are known as shear thickening systems, as their viscosity increases with increased shear rate (Fig. 16.5). Few examples of dilatant systems include corn starch suspensions containing .50% dispersed solids, wet sand. 16.1.2.2.2 TIME-DEPENDENT NON-NEWTONIAN FLOW Professor Marcus Reiner introduced the “Deborah number (De)” stating that a material flows when waiting for a longer period of time and this is depicted in Eq. (16.5). De 5 τ=T (16.5) where τ 5 characteristic time of material, T 5 characteristic time of deformation process being observed. It was observed that high and low De number relate to Hookean elastic solids and Newtonian viscous liquids, respectively. This may be illustrated with infinite τ values for solid-like material and zero for liquid-like material. For example, τ for water in liquid state was 102l2 s, for lubricating oils at high pressure it was 1026 s, and for polymer melts, at processing temperature, it was few seconds. Thus, De number shows that liquids also show elastic properties either because it has a very long characteristic time or because the deformation process period is very fast. For example, lubricating oils while passing through gears behave like elastic solids in a very fast deformation process. Similarly, a solid-like material may not continuously change its shape when subjected to a given stress (Carraher, 2013). Ideally, time-dependent materials are inelastic with respect to viscosity wherein the shear stress may either increase or decrease with time of shearing. These variations may be reversible or irreversible. Thixotropy is defined as an isothermal process wherein gradual reduction of viscosity is observed when stress is applied followed by gradual regaining of structure on removal of stress. In contrast to this behavior is the negative thixotropy or antithixotropy wherein the process gains viscosity slowly under stress which is followed by recovery (Mahato and Narang, 2011). The above section focused on various types of systems based on their ability to follow Newton’s law of flow, i.e., Newtonian and non-Newtonian systems, and provided a brief overview of time-dependent materials with respect to viscosity. This time-dependent concept of thixotropy is crucial during the designing of pharmaceutical dispersions. In addition DOSAGE FORM DESIGN CONSIDERATIONS 16.1 UNDERSTANDING THE BASIC CONCEPTS OF RHEOLOGY 555 to this, the principle of deformation of liquids and solids on application of stress and its tendency to reform is an important aspect which is discussed in the following section. 16.1.3 Deformation of Liquids and Deformation Forces According to Newton’s law of liquids, the systems flow until the stress is applied, while Hookean law of solids states that the shear stress applied to surface of solid results in quick deformation, with no further movement and this deformation lasts until stress is applied (Murata, 2012). It is well-known that solids and liquids at rest maintain their physical shape and form, but when external forces are applied, these systems undergo deformation if the force exerted is greater than the internal forces of the system. The deformation of liquid linearly increases with time, whereas deformation of solid increases instantly up to a particular level and remains constant. When the force is withdrawn, the deformation of liquid remains at the level attained earlier depending on the viscosity of the system, but the deformation of solid immediately disappears. The phenomenon of slow progress of deformation is termed as creep, while the opposite of deformation is called retardation known as elastic recoil (Malkin and Isayev, 2017). Deformation conditions may be categorized into the following types: tension, compression, bending, shear, and torsion (Fig. 16.6). The term irreversible deformation may be applied when a perpetual change in shape is observed, while reversible deformation or elasticity may be applied when the system returns to its former state when the deformation energy is recovered. Deformation forces can be classified as static deformation forces (constant loading), wherein the forces act constantly and their direction and magnitude are constant. While dynamic deformation forces (variable loading) are forces whose magnitude and/or direction is variable as a function of time. In liquid systems, a constant shear causes the liquid to flow resulting in viscous deformation. In case of laminar flow, the liquid flows along the wall of the vessel as parallel layers. The flow rate of the liquid layers decreases from a maximal level to zero in the direction perpendicular to the wall (i.e., the layer nearest to the wall does not move). This gradient of shear in perpendicular direction is known as shear strain. Thus, γ 5 dx/dy. FIGURE 16.6 Different types of compression forces. DOSAGE FORM DESIGN CONSIDERATIONS 556 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS But as the layers of liquid are constantly moving (dx is not constant), the velocity gradient from the bulk to the wall can be termed as shear rate. Thus, D 5 (dx/dt)/dy 5 dvx/dy (unit: s21). 16.1.4 Viscoelasticity Viscoelastic systems exhibit both Newtonian viscous (i.e., liquid-like) and Hookean elastic (i.e., solid-like) behavior. These have a tendency to cause Weissenberg effect on stirring (Steffe, 1996). In comparison to viscous fluids, the viscoelastic material has the tendency to recoil when the applied force is discontinued. 16.1.5 Determination of Molar Weight by Viscosity Solution viscosity of synthetic polymer or biopolymer can be used as a quantitative tool to determine the molecular weight of the polymer, which was first identified by Hermann Staudinger in 1930. He recognized that a relative magnitude of increase in viscosity and molecular weight of the polymer are interrelated (Oberlerchner et al., 2015). Viscosity of pure solvent and polymer solution can be determined by using capillary Ubbelohde Utube viscometer and the following viscosities, i.e., relative viscosity (ηrel) (Eq. (16.6)), specific viscosity (ηsp) (Eq. (16.7)), reduced viscosity (ηred) (Eq. (16.8)), inherent viscosity (ηinh) (Eq. (16.9)), and intrinsic viscosity ([η]int) (Eq. (16.10)), can be deduced. Relative Viscosity: ηrel 5 ηsolution =ηsolvent Specific Viscosity: ηsp 5 ηrel 1 (16.6) (16.7) Reduced Viscosity: ηred 5 ηsp =C (16.8) Inherent Viscosity: ηinh 5 ln ηrel =C h i Intrinsic Viscosity: ½ηint 5 ηsp =C (16.9) c-0 (16.10) where, ηsolution 5 viscosity of solution; ηsolvent 5 viscosity of solvent; C 5 mass concentration of solution in g/100 mL. Polymer solvent systems have unique intrinsic viscosity, which is a function of its molecular mass. In dilute systems, the interactions between polymer and solvent give information on the hydrodynamic volume of the polymeric chain and its dimensions. Capillary viscometers provide such information, but this experimental method is time-consuming and laborious. Hence, quick methods which provide required information with minimal error, followed by application of mathematical equations such as Huggins (H) (Eq. (16.11)), Kraemer (K) (Eq. (16.12)), and Schulz Blaschke (SB) (Eq. (16.13)) using graphical extrapolation can be useful in calculating the intrinsic viscosities [η]int (Huggins, 1942; Kraemer, 1938; Schulz and Blaschke, 1941). ηsp = C 5 ½ηH 1 kH ½η2 H C (16.11) kK ½η2 K C (16.12) ln ηrel =C 5 ½ηK ηsp =C 5 ½ηSB 1 kSB ½ηSB ηsp DOSAGE FORM DESIGN CONSIDERATIONS (16.13) 16.1 UNDERSTANDING THE BASIC CONCEPTS OF RHEOLOGY 557 where [η]H 5 limC-0 ηsp/C 5 limiting (intrinsic) viscosity number of Huggins; [η]K 5 limc-0 lnrel/C 5 limiting (intrinsic) viscosity number of Kraemer; [η]SB 5 limsp-0 ηsp/s 5 limiting (intrinsic) viscosity number of Schulz Blaschke; and kH, kK, and kSB are coefficients of Huggins, Kraemer, and Schulz Blaschke, respectively. Other terminologies are discussed in Eqs. (16.6 16.10). Studies have shown that the values of kH , 0.50 and kK , 0 indicate good solvents, in contrast to kH . 0.50 and kK . 0, which indicate poor solvents (Silva et al., 2013). Combining Eqs (16.11 and 16.12) and considering kH 1 kK 5 0.5, Solomon and Ciuta in 1962 obtained Eq. (16.14) to determine the intrinsic viscosity by a single point, using a single concentration value (Costa et al., 2015). h i1=2 ½ηSC 5 2 ηsp 2lnηr Þ =C (16.14) where [η]SC 5 intrinsic viscosity number of Solomon-Ciuta. Further, Deb and Chatterjee in 1968, proposed an expression of intrinsic viscosity, which was also determined from a single point. h i1=3 ½ηDC 5 3 lnηrel 13 =2η2sp 23ηsp Þ =C (16.15) where [η]DC 5 intrinsic viscosity number of Deb-Chatterjee. The value for kSB as per Schulz Blaschke equation (i.e., Eq. (16.13)) was fixed at 0.28, which is widely used for singlepoint determination and found suitable for several polymer solvent temperature systems (Silva et al., 2013). Certainly, the experimentation time drastically reduced while using single concentration values during experimentation, making the application of the above equations very simple for quality control. However, determination of intrinsic viscosity with a single point should be validated, by initially studying the polymer solvent temperature system by graphical extrapolation. Later, single-point equations are employed by choosing the lowest concentration value (nearest to zero concentration). There is a relationship between intrinsic viscosity of a polymer in a given solvent with the molecular mass of the polymer. The Mark Houwink (also known as Kuhn Mark Houwink Sakurada) equation relates molecular weight of the polymer and solvent at a specified temperature to the intrinsic viscosity (Flory, 1953) and depicted by the Eq. (16.16) ½ηint 5 Kv Mv (16.16) where Kv and v can be established by calibrating with polymers of known molecular weights. This is followed by plotting log [η]int against log M, wherein [η] will provide the molecular weight for an unknown molecule. Scientists have explored the calculation of Mark Houwink parameters in determining the molecular weight of aqueous solutions of polysaccharides and proteins, for example, locust bean gum, guar gum, xanthan gum, polyvinyl alcohol-covinyl acetate, gelatin B, pectin etc. (Su, 2013; Masuelli, 2014; Harding et al., 2017). Oberlerchner et al. (2015) have discussed direct methods to determine the molecular weight of cellulose polymers, while Chen et al. (2008) have determined the intrinsic viscosity of chitosan using Huggins equation and average viscometric molar mass using Mark Houwink Sakurada equation. DOSAGE FORM DESIGN CONSIDERATIONS 558 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS Costa et al. (2015) carried out a viscometric study to measure the average viscometric molar mass of chitosan solutions (with dissimilar deacetylation degrees) in two aqueous solvent systems. This section showed the relationship between viscosity and molecular weight, which is an important aspect during rheological consideration of long-chain polymers or proteins. The following section helps the reader to understand the prominence of rheology in various pharmaceutical formulations including the advanced drug delivery systems such as nanoformulations. 16.2 RHEOLOGY OF PHARMACEUTICAL DOSAGE FORMS Liquid dosage forms are developed for oral administration, as syrups, elixirs, linctus, etc.; for external application as lotions, liniments, solutions; for parenteral purpose as injectables; and for instilling into body cavities as drops, sprays, enemas, douche, etc. Rheology of the pharmaceutical dosage form (necessary during processing and dosing) governs the pourability, flowability, draining property, spray behavior, and syringability and acts as a quality control tool. It also plays an important role in determining the stability of the formulation. Liquid dosage forms may be broadly classified as monophasic and biphasic dosage forms. The next section of the chapter deals with the rheology of suspensions and emulsions, which is discoursed using various case studies. Further, the advancement in technology has helped in developing nano-based liquid dosage forms whose rheological aspects are also discussed further in the chapter. 16.2.1 Rheology of Suspensions Suspensions are heterogeneous systems used to define fluids made up of solute particles distributed in the dispersion medium, which may be Newtonian or non-Newtonian. Ideally, a suspension exhibits three types of forces, Firstly, (1) forces of colloidal origin which ascend from particle interactions, which can cause an overall repulsion or attraction between dispersed particles. Repulsions predominate due to the presence of electrostatic charges or entropic repulsions on particle surface owing to the polymer or surfactant added, leading to deflocculated suspension. Attractions predominate due to van der Waals forces of attraction between dispersed particles, or due to electrostatic attraction between unlike charges on different parts of the dispersed particle, leading to flocculated suspension. Secondly, (2) Brownian randomizing force, which influences the distribution of dispersed particles and ensures that the particles are in constant movement in the system. Brownian motion is size-dependent and has highest influence on particles of smaller size (i.e., highest for particle of 1 pm). Finally, (3) viscous force acting on the particles which is proportional to the velocity difference between the dispersed particle and the dispersion medium and is given by “relative viscosity” (ηrel) (i.e., viscosity of suspension divided by viscosity of dispersion medium) (Chinesta and Ausias, 2015). Based on the nature of particles and type of excipients incorporated in the suspension, they can be broadly classified as deflocculated and flocculated suspensions. Depending on DOSAGE FORM DESIGN CONSIDERATIONS 16.2 RHEOLOGY OF PHARMACEUTICAL DOSAGE FORMS 559 the nature and concentration of dispersed particles, the suspensions may exhibit Newtonian flow or non-Newtonian flow, such as plastic, pseudoplastic, or dilatant flow. Following systems are usually present as suspensions i.e., pharmaceutical heterogeneous systems, cement, suspension-type paint, printing inks, coal slurries, drilling muds, certain food materials, etc. (Willenbacher and Georgieva, 2013). Suspensions containing less than 10% of solid particles and having less phase volume are usually termed as dilute dispersed suspensions and these systems usually behave as Newtonian liquids. Studies carried out by Einstein in 1911 suggested that the dispersed particles, as single entity, increased the viscosity of the suspension as a function of their phase volume, according to Eq. (16.17). η 5 ηs ð1 1 2:5 ϕÞ (16.17) where η and ηs are the viscosities of the suspension and dispersion medium, respectively; ϕ is phase volume. The Eq. (16.17) shows that the particle size and particle position have no influence on the viscosity of the suspension. In case of concentrated Newtonian suspensions, the effect of all dispersed particles is regarded as the sum of the effect of each particle added successively. Thus, according to Ball and Richmond in 1980, the Einstein equation could be modified to Eq. (16.18) dη 5 5η=2 dϕ (16.18) where dη is the increment of viscosity on the addition of a small increment of phase volume dϕ to a suspension of viscosity η. On integrating the phase volume between 0 and ϕ, for which the viscosity is ηs and η, respectively, then we obtain Eq. (16.19) as follows. (16.19) η 5 ηs exp 5ϕ=2 However, Eq. (16.19) doesn’t take into account the finite size of spherical particles. This relates to a condition where addition of a particle to a concentrated suspension requires more space than its volume dϕ due to packing difficulties and a factor for “crowding” effect can be incorporated. A theory by Krieger and Dougherty also states that the intrinsic viscosity representing dilute suspension of spherical particles must be replaced to permit evaluation of particles of any shape. Thus, the Krieger and Dougherty’s equation is given in Eq. (16.20). 2½ηϕm (16.20) η 5 ηs 1 ϕ=ϕm Here, ϕm is strongly dependent on distribution of particle-size, which increases with polydispersity. Interestingly, particle asymmetry strongly influences the intrinsic viscosity and maximum packing fraction of the systems. Studies have demonstrated that nonspherical particles have increased the viscosity of the system having same phase volume as spherical particles. Suspensions with rod-like particles have shown greater effect in increasing the viscosity than disc-like particles. Certain concentrated suspensions show shear-thinning behavior because when shear is applied to the system, it brings about a favorable two-dimensional arrangement of particles. Here, it is important to relate viscosity measurement at the same shear stress and not DOSAGE FORM DESIGN CONSIDERATIONS 560 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS shear rate. Krieger in 1972, recognized that although ϕm and [η] are stress-dependent, they are not dependent on the particle size of the dispersed particles. However, concentrated suspensions with nonaggregating particles usually exhibit shear-thickening behavior which is dependent on phase volume, particle-size distribution, and viscosity of dispersion medium. Application of stress to these systems leads to a random arrangement of particles and increases the viscosity. The level and slope of the viscosity shear rate rheogram above transition increases as particle concentration increases. Viscosity increases at very high shear rates in systems with high phase volume leading to difficulty in operation, due to flow instability. Similarly, increase in viscosity of dispersion medium increases the system viscosity and decreases the critical shear rate. In case of concentrated suspensions, the packing fraction of dispersed particles is an important aspect. At very high concentrations, the particles “jam up,” producing 3D networking throughout the suspension, leading to very high viscosity. The phase volume at this point is termed as maximum packing fraction. This phenomenon can be controlled by the type of packing, which is dependent on the particle-size distribution and particle shape. Particles with broader size distribution show higher value of ϕm because the smaller particles slide and fit into the gaps between the larger particles. Conversely, nonspherical particles show lower ϕm value due to lower capacity to fill the void spaces. Flocculated suspensions show low maximum packing fraction because flocs are loosely arranged. The influence of polymer (type and concentration), surfactants, electrolytes etc. on the rheological behavior of suspensions has been investigated by several formulation scientists. Nag (2005) had studied the physical stability and rheological behavior of concentrated barium sulfate in sodium carboxymethyl cellulose-, bentonite-, and polyvinyl pyrrolidone-based concentrated suspensions. The study showed that bentonite and polyvinylpyrrolidone had no influence on the sedimentation volume of the suspension, but increased the viscosity of the dispersion, whereas sodium carboxymethyl cellulose at concentration of 0.2% w/v, significantly increased the sedimentation volume, successfully adsorbed the suspended particles and provided maximum viscosity to the suspension, thus improving the physical stability of the dispersion. Similarly, Moghimipour et al. (2013a) has studied the effect of polymers, such as carboxymethyl cellulose, polyvinylpyrrolidone, tragacanth, and magnesium aluminum silicate, individually and in combination, on the rheological property of acetaminophen suspension. The systems developed exhibited good pseudoplastic behavior with thixotropic breakdown. Sodium chloride was also added for the purpose of controlled flocculation and it was observed that addition of polyvinyl pyrrolidone in suspensions containing sodium chloride was necessary to improve the viscosity of suspension, owing to cross-linking between the carbonyl group of polymer and sodium ions. Mohammad et al. (2012) developed dry suspension of artemether for pediatric use, where xanthan gum was used as a suspending agent to provide desired viscosity and physical stability to the suspension after reconstitution. Divya et al. (2010) evaluated the viscosity modifying behavior and the suspending nature of Leucaena latisiliqua seed gum in comparison to compound tragacanth and acacia on zinc oxide particles. The seed gum demonstrated a superior suspending ability as compared to the traditional natural gums, i.e., compound tragacanth and acacia and concluded that it could be successfully used as a stabilizer and thickener when high viscosity is desired. DOSAGE FORM DESIGN CONSIDERATIONS 16.2 RHEOLOGY OF PHARMACEUTICAL DOSAGE FORMS 561 The relationship between rate of settling of particles with viscosity in dilute suspensions was discussed using Stokes equation (Eq. (16.21)). V 5 r2 ∆ρg=18η (16.21) where V 5 rate of settling; r 5 radius of particles; η 5 viscosity of dispersion medium; g 5 acceleration due to gravity; and ∆ρ 5 difference in density between dispersed particles and dispersion medium. Eq. (16.21) shows that the physical stability of suspensions may be improved by increasing the low shear viscosity. However, the above relation in concentrated suspensions was slightly modified by introducing a crowding factor in the Stokes equation, as shown in Eq. (16.22) (Barnes, 1992). V 5 r2 ∆ρg=18η ð1 ϕÞ560:25 (16.22) where ϕ 5 phase volume. Researchers have reported that an increase in the phase volume decreased the rate of particle settling, due to an increase in system viscosity resulting from crowding. At low shear viscosity, the zeta potential increased due to large effective phase volume and reduced the sedimentation rate (Hill, 2015). Daneshfar et al. (2017) investigated the linear viscoelastic properties, yielding, and shear-thickening behaviors of concentrated bimodal suspensions of nanosilica in poly (ethylene glycol) 400 at varying volume fractions and particle size ratio. They observed a high reduction in the normalized elastic modulus and sol-like behavior with volume fraction ratio 0.6. When the relative volume fraction of small spheres exceeded that of large spheres, the following parameters, i.e., elastic modulus, yield stress, and viscosity of the system, increased. Various factors affecting the rheological behavior of suspensions include particle size, polydispersity index, volume fraction, particle charge (zeta potential), particle loading, and particle shape. For dispersed particles with size less than 1 µm, the colloidal effects (i.e., Brownian motion and attractive/repulsive forces) play a significant role; whereas particles more than 1 µm do not have a direct influence on rheology of suspension. However, the change in volume fraction of particles of same size has a positive impact on rheological property of the system. Similarly, for constant volume fraction, reduction in particle size increases viscosity. Concentrated colloidal suspensions also increase viscosity at low shear rate due to colloidal repulsion, nonetheless, at higher shear rates the weak forces are destroyed. The effect of particle loading on viscosity of suspension is described using the Krieger Dougherty equation (Eq. (16.23)). η=ηmedium 5 ½1 ðφ=φm Þ2½hφm (16.23) where η 5 viscosity of suspension; ηmedium 5 viscosity of dispersion medium; φ 5 volume fraction of solids in suspension; φm 5 maximum volume fraction of solids that can be incorporated in a suspension; and [η] 5 intrinsic viscosity (i.e., 2.5 for spherical particles). Eq. (16.23) shows the influence of volume fraction on increasing the viscosity of suspension, owing to the increased packing of dispersed particles. However, as the volume fraction reaches to maximum (φm in Krieger Dougherty equation), the viscosity decreases (Hill, 2015). Systems presenting φ/φm , 0.1 display Newtonian behavior; 0.1 , φ/φm , 0.5 display pseudoplastic behavior; and φ/φm . 0.5 display dilatant behavior (Mewis and Wagner, 2012). DOSAGE FORM DESIGN CONSIDERATIONS 562 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS Particle shape also influences the flow behavior of suspensions. Earlier researchers assumed that the dispersed particles in suspensions were smooth, nondeformable spheres. However, they noticed that these particles are present in various shapes possessing surface irregularities. Dispersed particles in a suspension experience shear and Brownian forces leading to particle rotation or tumbling causing changes in the viscosity of the suspension. When the longer axis of particle is aligned parallel to flow direction, the viscosity of the system is minimum; whereas, the orientation perpendicular to flow possesses maximum viscosity. Elongated particles confine larger circular paths than spheres of equivalent volume, occupying larger volumes at low rate of shear and are more efficient in increasing viscosity (Hill, 2015). Cwalina et al. (2016) studied the rheological behavior of nonspherical particles, i.e., cubic-shaped colloidal particles suspended in Newtonian fluid. The systems were investigated under steady and dynamic shear flow, wherein the suspensions exhibited a non-Newtonian rheology, i.e., shear thickening behavior and normal stress differences at high shear stress. Viscosity of the systems with surface roughness may vary from those containing smooth particles. Usually, surface roughness increases the viscosity of the system by increasing surface area and deviation in flow lines. In the case of suspensions with small particles and increased roughness, the mechanical friction between particles can be high and possess increased viscosity; however, the divergence in flow lines around the particle can obstruct close contact, thus lowering the viscosity (Hill, 2015). Nechyporchuk et al. (2016) reviewed the rheology of cellulose nanofibril suspensions and its influence on various aspects of production process, i.e., for efficient pumping, mixing, or coating. It was noted that the aqueous suspensions of cellulose nanofibril produced interconnected networks, exhibited gel-like, pseudoplastic property and thixotropic behavior. Study from various researchers revealed that the strength of the networks improved with higher cellulose concentration and ionic strength. While there was no influence of temperature on the strength of suspension in the linear viscoelastic region. On similar lines, Moberg et al. (2017) investigated the impact of three different nanocelluloses, fibril/ particle dimension, and surface features on the rheological behavior of aqueous-based cellulose nanofibril and nanocrystal suspensions. Likewise, Matsumiya et al. (2016) also studied the rheology of aqueous suspension of nanocellulose fibers and carboxymethylcellulose fibers. Ness et al. (2017) studied the effect of small-, medium-, and large-amplitude strains on the oscillatory rheology of hard sphere suspensions; while Marenne and Morris (2017) investigated the influence of oscillatory shear on the nonlinear rheology of colloidal hard-sphere suspensions. Effect of change of dispersion medium on the rheological property of suspension was investigated by Gálvez et al. (2017), wherein the dispersion medium of aqueous suspension of cornstarch was partly replaced with ethyl alcohol. Interestingly, the dilatant (i.e., shear thickening) nature of the aqueous-based suspension completely disappeared and showed a yield stress fluid state followed by a low viscosity shear thinning behavior. Atomic force microscopy revealed the presence of free dangling polymers (behaving as polymer brushes) on the surface of cornstarch. The addition of ethanol triggered the cosolvency phenomena which induced high microscopic adhesion causing macroscopic yield stress and shear thinning behavior. DOSAGE FORM DESIGN CONSIDERATIONS 16.2 RHEOLOGY OF PHARMACEUTICAL DOSAGE FORMS 563 16.2.2 Rheology of Emulsions Emulsions are thermodynamically unstable biphasic systems of immiscible liquids, stabilized using emulsifying agents. Rheology of emulsions is a very important physical attribute as it provides information with respect to measuring, mixing efficiency, pumping rate, volume adjustment, pouring capability, filling etc. during the manufacturing process. In addition to the above requirements, for better patient compliance, the visual and sensory properties, i.e., creaminess, consistency, texture, are also of utmost significance, which are related to the rheological properties of emulsions. Qualitatively emulsions range from Newtonian to non-Newtonian liquids and cream-like systems (Barnes, 1994). It can be stated that the evaluation of rheological properties of emulsions is more or less similar to that of suspensions (Derkach, 2009). In emulsions, the Brownian motion and dynamic forces are responsible for the movement of globules. The relationship between these dynamic forces (i.e., η γ )̇ and diffusional pathway (i.e., kBT/R3) can be expressed using Peclet number (Pe), which is described in Eq. (16.24). Pe 5 ðη γ : Þ= ðkB T=R3 Þ (16.24) where η 5 viscosity, γ ̇ 5 rate of shear, kB 5 Boltzmann constant, T 5 absolute temperature, and R 5 radius of globule/ solid particle. If Pec1, the diffusion (or Brownian) movement can be neglected and the fluid dynamic process can be analyzed. 16.2.3 Rheology of Nano-Based Systems The conventional formulations such as solutions, suspensions, emulsions, etc. are well accepted in the healthcare sector, however, researchers are continuously looking forward and exploring more effective methods to carry and target the actives directly to the diseased site, thus trying to minimize undesired adverse effects. During the development of the novel drug delivery systems, the study of rheology is very important as the flow property can influence the therapeutic efficacy of the delivery system. For convenience of the chapter, nano-based systems can be broadly categorized based on the type of excipients used in developing the formulation as follows: Lipid-based, Surfactant-based, Polymerbased, and Lipid polymer-based systems. 16.2.3.1 Lipid-Based Nanoformulations As per literature (Fernandes et al., 2011), lipid-based nanosystems can be further classified as Class I (microemulsions, nanoemulsions, self-micro-/nanoemulsifying systems, solid lipid nanoparticles, nanostructured lipid carriers, lipid drug nanoconjugates, lipid nanocapsules); Class II (liposomes, bolaamphiphiles); and Class III (lipid core micelles, lipid cubic phases, lipoplexes, targeted lipid nanocarriers, stimuli-responsive nanocarriers). These are categorized based on the structural alignment of lipid constituents in bulk phase of the formulation (Fernandes et al., 2018; Sharma et al., 2015; Maheshwari et al., 2015a). Microemulsions, thermodynamically stable systems of immiscible phases stabilized using surfactants/surfactant cosurfactant mixture or an additional cosolvent. Paul and Moulik (2000), have extensively reviewed the viscometric investigations of microemulsions DOSAGE FORM DESIGN CONSIDERATIONS 564 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS containing different oils and surfactants on the rheological behavior, structure, and dynamics of the systems. Few instances where researchers have studied the effect of viscosity on diverse parameters/delivery of the microemulsions include the investigations of Moghimipour et al. (2013b), Singh et al. (2015), Ranade et al. (2014), and Tagavifar et al. (2016) to mention a few. Nanoemulsions are thermodynamically unstable, kinetically stable colloidal dispersions comprising of water, oil, and surfactant prepared by high-energy emulsification or by lowenergy method (Pidaparthi and Suares, 2017). Gupta et al. (2016) and Singh et al. (2017) have broadly reviewed the formation, properties, and applications of nanoemulsions wherein they have emphasized the rheological considerations of nanoemulsions. Researchers have studied the effect of viscosity on successful delivery of nanoemulsions at the site of action (Ali et al., 2014; Arora et al., 2014; Parikh and Patel, 2016). Pal (2016) have thoroughly explored the influence of viscosity, solvation, and aggregation of nanodroplets and nanoparticles of concentrated nanoemulsions and nanosuspensions, respectively, using modeling studies. Self-emulsifying/self-microemulsifying/self-nanoemulsifying drug delivery systems are isotropic, clear mixtures of oils, surfactants, and cosurfactants/cosolvents designed to create oil-in-water microemulsion on mild agitation, followed by dissolution and absorption of actives (Meghani and Suares, 2013). Various scientists such as Madan et al. (2014), Weng et al. (2014), Jaiswal et al. (2014), Wu et al. (2015), and Hong et al. (2016) have demonstrated the influence of viscosity during the formulation development and delivery of actives by self-emulsifying systems. Solid lipid nanoparticles are submicron rigid colloidal carriers composed of physiological lipid, in aqueous surfactant solution (Tekade et al., 2017c; Soni et al., 2016; Suares and Prabhakar, 2016; Fernandes et al., 2013). The rheological properties of solid lipid nanoparticles in liquid- or gel-based formulations have been an important aspect during formulation development and this has been revealed by the studies carried out by Gaur et al. (2013), Omray (2014), Emami et al. (2015), and Ghorab and Ahmad Gardouh (2015), to mention a few. Nanostructured lipid carriers comprise of a solid lipid core consisting of a mixture of solid and liquid lipids. Souto et al. (2004) studied the rheological and viscoelastic properties of aqueous NLC dispersions of substances like sunflower oil and α-tocopherol. They found that the rheological behavior of both systems was different and dependent on the composition of oil phase and storage temperature. The sunflower oil-loaded NLC showed higher storage modulus, loss modulus, and complex viscosity. Souto et al. (2005) further converted aqueous dispersions of lipid nanoparticles into hydrogels using xanthan gum, hydroxyethylcellulose 4000, Carbopol 943, and chitosan, as gelling agents. Performing rheological investigations, they demonstrated that the physical properties of dispersed lipid particles greatly influence the rheological properties of gel formulations. They performed oscillation frequency sweep test to determine the difference in elastic response of SLN and NLC aqueous dispersions. Teeranachaideekul et al. (2008) developed ascorbyl palmitateloaded nanostructured lipid carrier gel wherein the viscoelastic measurements revealed that the system showed more elastic nature than the viscous behavior indicative of gel-like structure. On similar lines, Rajinikanth and Chellian (2016) developed nanostructured lipid carrier-based hydrogel for topical delivery of 5-fluorouracil using carbopol. Other investigators who have studied the influence of viscosity on the nanostructured lipid carrier DOSAGE FORM DESIGN CONSIDERATIONS 16.2 RHEOLOGY OF PHARMACEUTICAL DOSAGE FORMS 565 based formulations include Uprit et al. (2013), Choi et al. (2016), Liu et al. (2016), Yang et al. (2016), and Putranti et al. (2017), to mention a few. Lipid nanocapsules comprise of an oil-filled core surrounded by a polymer shell employed for encapsulating and delivering lipophilic drugs. Gonnet et al. (2012), Dimer et al. (2013), Moysan et al. (2014), and Xiao et al. (2017) are a few scientists who have developed drug-loaded lipid nanocapsules and have determined the rheological properties of the systems as such and on application of stimuli. Liposomes comprise of phospholipid vesicles consisting of one or more concentric lipid bilayers enclosing discrete aqueous spaces (Maheshwari et al., 2015b; Maheshwari et al., 2012). Chen et al. (2001) explored the influence of different concentration of water-soluble chitosan (with varying molecular weights) coating on the apparent viscosity of liposomes. They observed that the apparent viscosity of liposomes, when subjected to different passes of microfluidization treatment, was higher with higher concentration/higher molecular weight chitosan. Doisy et al. (1996) utilized the rheological approach to study the phospholipid drug interactions in liposomes. From the isotherms obtained and rheological behavior of mixed monolayers at low surface pressures, they interpreted that the drug would be localized between the phospholipids polar heads, while high surface pressure was indicative of drug being trapped in hydrophobic tail of phospholipidic layer. Several researchers studied the effect of liposomes on the rheological behavior of hydrogels (El Kechai et al. 2015). Bolaamphiphiles are two-headed/bipolar amphiphiles with the presence of two hydrophilic head groups, separated by either one, two, or three long hydrophobic spacers (Fariya et al., 2014). Graf et al. (2011) studied the influence of pH and salinity on the aggregation and rheological behavior of aqueous suspensions of bolaamphiphile dotriacontane1,32-diyl-bis[2-(dimethylamino)ethylphosphate]. They observed that the bolaamphiphiles self-assembled as crystalline nanofibers and wormlike micelles resulting in formation of switchable viscoelastic hydrogels at a desired pH and salinity. Lee et al. (2013) studied the rheological and electrochemical behavior of a sugar-based bolaamphiphile/functionalized graphene oxide composite gel exhibiting fibrillar structure. 16.2.3.2 Surfactant-Based Nanoformulations Surfactants are widely used excipients to facilitate the delivery of drug molecules. They form self-assembled structures, also termed as micelles. Berjano et al. (1993) studied the viscous behavior of sucrose laurate aqueous systems at varying temperature. Systems containing ,45%w/w concentration of surfactant exhibited Newtonian behavior, while concentrated systems showed complex viscous behavior. At increasing temperature, the systems rearranged as rod-like micellar aggregates of sucrose laurate. Fakoya and Shah (2013) have explored the impact of nanotechnology on the rheological properties of surfactant-based blends in oilfield applications. As nanotechnology is impacting the medical field very significantly (Tekade et al., 2017b), Liang and Binner (2008) investigated the effect of triblock copolymer nonionic surfactants, i.e., poly(ethylene oxide) and poly(propylene oxide), on the rheological properties of zirconia nanosuspension, wherein they found that the viscosity of system was directly proportional to the concentration of surfactant, due to the presence of polymer, which was also dependent on the molecular weight of the surfactant. DOSAGE FORM DESIGN CONSIDERATIONS 566 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS In addition to this, they observed that the viscosity of the suspension reduced on removal of free electrolytes which also reduced the ionic strength of the nanosuspension. Nevertheless, on addition of ammonium chloride as electrolyte, the phenomena reversed. Pidaparthi and Suares (2017) developed aqueous micelles system of paliperidone for intranasal delivery, wherein they observed that the viscosity had an important role to play on the spray pattern from the delivery device. Zhao et al. (2017) studied the influence of silica nanoparticles on the rheological properties of wormlike micelles prepared from cetyltrimethylammonium bromide and sodium salicylate. Viscoelasticity of the system increased with increase in addition of nanoparticles up to a certain point, however, further increase of nanoparticles, reduced the zero-shear viscosity and relaxation time. 16.2.3.3 Polymer-Based Nanoformulations Polymers are macromolecules used in various nanoformulations as polymeric nanoparticles, as viscosity modifiers and in the preparation of hydrogels/stimuli-responsive hydrogels. The effect of surface tension, density, and viscosity on the associative behavior of oxyethylene oxybutylene diblock copolymers has been investigated in aqueous systems at varying temperatures. From the study, the viscosity and density measurements projected the nonspherical shape of aggregates. Kola-Mustapha and Abioye (2016) developed ibuprofen diethylaminoethanol-dextran nanoconjugates using surfactant solubilization technique and evaluated the effect of various components on the viscosity of the system. They observed that the viscosity of ibuprofen aqueous solution reduced with increasing concentration of drug, whereas the viscosity of diethylaminoethanol-dextran in water increased with increasing concentration of pluronic solution. Finally, the viscosity of diethylaminoethanol-dextran nanoconjugate increased with increasing concentration of diethylaminoethanol-dextran. 16.2.3.4 Lipid Polymer-Based Nanoformulations Lipid polymer systems are emerging nanoformulations that deliver drugs effectively for better therapeutic action (Suares and Prabhakar, 2017). Coexistence of lipid and polymer, with varying physicochemical properties, in a single system provides the capability of loading lipophilic and hydrophilic drugs (Dave et al., 2017). Viscosity plays an important role during formulation development, as shown by Krishnamurthy et al. (2015) wherein they have discussed the importance of viscosity of polymer as one of the vital factors responsible for the particle diameter of lipid-coated polymeric nanoparticles. On the other hand, Hasan et al. (2016) studied the lipid polysaccharide interactions of chitosancoated curcumin-loaded liposomes. The viscosity measurements revealed that the liposomal systems transformed from Newtonian to non-Newtonian (pseudoplastic) on coating with chitosan. This was also seen by a reduction in the area of hysteresis loop (thixotropy). Nevertheless, this behavior was beneficial for improving the stability of the liposomal dispersion. The above section has cited a few researches which have been influenced by rheology or viscosity for their stability, efficacy, or delivery. The next section of the chapter will discuss the various pharmaceutical factors influencing the rheological measurements of formulations during their development. DOSAGE FORM DESIGN CONSIDERATIONS 16.3 PHARMACEUTICAL CONSIDERATIONS 567 16.3 PHARMACEUTICAL CONSIDERATIONS It is established that the rheology of liquid-based systems is greatly governed by the physicochemical attributes, such as shear rate, temperature, formulation components, aeration, light, sterilization, pH, polymer-related factors, presence of impurities, ions, electrolytes, and addition of additives such as sequestering agents, buffers, surfactants, etc. Hence, in this section, the influence of physical and chemical variables on the viscosity of various systems is discussed. 16.3.1 Influence of Physical Variables Various physical variables that have an impact on the rheological behavior of liquidbased systems include shear rate, temperature, formulation components, aeration, light, and sterilization. These variables are discussed using a few illustrations as given below. 16.3.1.1 Shear Rate Shear rate is defined as the rate of change of velocity when one layer of fluid passes over its adjacent layer (Pavlenko et al., 2015). Magnitude of shear rate plays a vital role in the number of industrial applications, stability of the product, customer satisfaction, etc. Shear rate in any process can be determined by dividing the velocity of material flowing by the dimension of geometry in which it is flowing. Shear rate majorly impacts sedimentation of particles in a suspension which further governs physical stability of the product, homogeneity, uniformity of dosing during administration and final bottle filling. Ovarlez et al. (2012) observed that sedimentation rate of particles increased with increase in shear rate and particle diameter, while it decreased with increasing yield stress of fluid. At low shear rate, the systems behaved like viscous fluid. Authors also established that an increase of particle volume fraction played contradictory roles, i.e., it hindered settling of particles and decreased the viscid resistance of interstitial fluid due to the shear concentration between the particles. Aliseda et al. (2017) investigated the influence of atomizer rate on the performance in tablet coating solution. The study demonstrated that highly viscous non-Newtonian liquids strongly affected the Rayleigh Taylor wavelength. According to the rheological model of fluids, non-Newtonian systems were subjected to low, moderate, and high shear rates. From the results, it was evident that high shear rates were desired for better atomization of the non-Newtonian viscous liquids. Similarly, high shear rates are desired to prevent drainage of the fluid under force of gravity during coating. Various scientists have reported that higher shear rates are desired for injection molding or extrusion of shear thinning non-Newtonian fluids (Aho, 2011). In the process of single-screw extrusion of polymer melt, shear rates may range from 200 s21 to 1000 s21 at various regions. Some die designers prefer shear rates less than 10 s21, to avoid hang-up of polymer melt. Sometimes, at very high shear rates, flow instability, i.e., melt fracture occurs (Vlachopoulos and Strutt, 2003). Effect of shear rate on the viscosity of the material during dip coating has been extended for preparation of capsule shells or tablet coating. Estellé and Lanos (2008) studied the rheological behavior of Newtonian and DOSAGE FORM DESIGN CONSIDERATIONS 568 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS non-Newtonian fluids for reconnoitering the geometry of mixing elements in an industrial setup. The mixing elements include impellers of varying geometries, i.e., anchors, helical ribbons, paddles, scraper blades, etc. The relationship between shear stress and shear rate from torque and speed of mixing probe is very important. Shear rate influences the blending of the formulation components during manufacture of monophasic or biphasic liquid dosage forms or semisolids. Viscosity of fluids and shear rate jointly decide the selection of pump for transport of fluids. Centrifugal pumps are preferred for less viscid fluids as pumping produces high shear. For high viscid systems, positive displacement pumps are most suitable as they operate at low speeds and impart low shear (Torabi and Nourbakhsh, 2016). Concept of shear rate is also relevant to application of semisolid formulations such as creams, gels, etc. on skin surface. These formulations are desired to be thixotropic and shear-thinning, in order to cover a greater surface area and retain on the skin surface after the stress is withdrawn (Nagelreiter et al., 2015; Patel et al., 2014). Similarly, viscosity of formulation and injection force decides the administration of parenteral preparations. The friction from the syringe plunger and resistance for tissue resistance will sum up to plunger force (Birk, 2015). Shear rate also influences the milling dyes or pigments in fluid bases (Xu et al., 2013). 16.3.1.2 Temperature It is well-known that the temperature dependent change of viscosity in aqueous-based biphasic systems may mainly dependent on the nature of the dispersion medium. However, if the dispersed phase undergoes melting in the system, it will result in a quick reduction in viscosity. While the dispersions possessing temperature-sensitive colloidal interactions between the particles will enhance the viscosity, which will be different from that of the dispersion medium. Surfactant- and polymer-based systems show phase changes with temperature which may either increase or decrease the viscosity depending on the system. Effect of temperature on viscosity of the systems was demonstrated on methyl derivatives of cellulose, which hold varying levels of methyl substitution, making them sensitive to temperature. These systems convert from sol-like nature to gel-like state at definite temperature (Nimroozi and Omidian, 2010). For example, methylcellulose converts to gel-like at about 50 C while hydroxypropyl methylcellulose forms gel at 55 C (Silva et al., 2008). Similarly, certain polymers like chitin have shown thermoresponsive nature. Chitin (1.5% by weight) in NaOH/urea aqueous solution was clear and nonviscous at 20 C, while it turned to a white weak gel at 30 C and an opaque strong gel at 40 C. It was also noted that higher concentration of chitin showed lower gelation temperature. Interestingly, chitin also showed thermoreversible property (when kept at 20 C for 24 h) with little effects on solution properties (Hu et al., 2011). Thermoresponsive polymers have shown their application in various areas such as biomedicine, controlled drug delivery, tissue engineering, theranostics, tumor therapy, cell therapy etc. (Nielsen et al., 2017). Stimuli-sensitive hydrogels (smart hydrogels), which are responsive to physical stimuli (i.e., light and temperature) and chemical stimuli (i.e., pH, ionic strength, and redox) are beneficial to a formulation scientist in various aspects. A few amphiphilic or hydrophilic polymers that display sol gel phase transformation DOSAGE FORM DESIGN CONSIDERATIONS 16.3 PHARMACEUTICAL CONSIDERATIONS 569 between room and body temperature include poly(N-isopropyl acrylamide), pluronic, poly(phosphazene), poly(ester)-based copolymers, poly(carbonate)-based copolymers, etc. (Chan et al., 2013; Nguyen and Alsberg, 2014). Various researchers have worked on delivering growth hormones by developing microspheres, adopting PEGylation, or in situ crystallization of actives for sustained delivery. These systems lead to concerns, viz, initial burst release, inefficient loading, use of organic solvents, etc. However, stimuli-responsive conversion of aqueous solutions to hydrogels in situ have provided several advantages such as structural similarity with extracellular matrix, ease of incorporation of hormone in the system, moldability, ease of administration, reduction in inflammation at the site due to the nature of hydrogel. Phan et al. (2016) investigated the influence of pH and temperature on the rheological properties of poly (ethylene glycol)-poly(amino carbonate urethane) for delivery of growth hormones. They found that in aqueous solutions, the copolymer presented as sol-like at pH 6.0 and temperature 23 C, whereas converted to gel-like at pH 7.4 and 37 C. On administration, the system formed a hydrogel depot at subcutaneous site and the sustained degradation of copolymers resulted in disruption of ionic and hydrophobic interactions, allowing sustained delivery of growth hormones. Xyloglucan, a polysaccharide, when partially degraded by β-galactosidase, causes lateral stacking of rod-like chains and results in formation of thermoreversible gel (Devasani et al., 2016). The temperature for sol gel transition depends on the degree of galactose elimination. This behavior is exploited, by orally administering chilled xyloglucan solution producing in situ gel in the GIT and causing sustained release of the drug. Pluronic F127, also shows similar behavior wherein the system converts from sol-to-gel when exposed from refrigeration temperature to heating. Cunha-Filho et al. (2012) evaluated the perspective of two Pluronic (poloxamer or Lutrol) varieties, F127 and P123 as carrier system for β-lapachone, an anticancer drug. Pluronic, an amphiphilic triblock copolymers of ethylene oxide and propylene oxide blocks, self-assemble as micelles which convert from sol-to-gel on heating, due to progressive dehydration of polymer blocks. At optimum concentration, these micelles entangle as 3D viscoelastic depot at 37 C. Another important aspect which governs the sol-to-gel transformation is the concentration of Pluronic (i.e., Pluronic F127— 18 28% and Pluronic P123—28%) which is critical for ease of syringeability and formation of depot in vivo. Wu et al. (2007) developed a temperature sensitive hydrogel for nasal delivery of insulin. The mixture of N-[(2-hydroxy-3-methyltrimethyl ammonium)propyl]chitosan chloride and poly (ethylene glycol) with traces of α-β-glycerophosphate was found to be sol-like at room temperature, while it formed into gel-like at body temperature, thus controlling the release of actives from the delivery system. A few scientists have demonstrated that the storage temperature of parenteral products have highly impacted the viscosity of the products. Palm et al. (2015) have shown that the viscosity of monoclonal antibodies as injectable preparation, when present at higher protein concentrations, showed exponential increase in viscosity; whereas at low concentrations, the viscosity of antibody solution increased moderately as a function of protein concentration. In addition to this, the viscosity of the system also led to an exponential increase with decrease in storage temperature (i.e., the system showed high viscosity at 2 8 C and 25 C). Therefore, the material’s viscosity can directly or indirectly influence drug product manufacturing and DOSAGE FORM DESIGN CONSIDERATIONS 570 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS the manufacturers need to map the concentration temperature viscosity profile with an intended unit operation and during administration. Bousmina et al. (2002) assessed the effect of low consulate temperature on phase segregation of poly(styrene-co-acrylonitrile)/poly (methyl methacrylate) blend. At low temperature, the blend was a uniform polymer melt, whereas, with increase in temperature, the change in morphology of the polymer blend led to increase in the width of long-time plateau and terminal relaxation time. 16.3.1.3 Formulation Components After understanding the effect of temperature on various systems, it is important to understand the influence of formulation component-based factors on the viscosity of the final formulation. Mastropietro et al., 2013 have discussed the various particle-based responses, such as shape (spherical, cylindrical, plate-like, asymmetric), high aspect ratio, size, surface area, nature of the particles (porous, nonporous, aggregated, nonaggregated), solid content in suspension, polymer system (single or multipolymer), etc., causing change from Newtonian to non-Newtonian systems. As discussed by Cunha-Filho et al. (2012), the presence of actives, cosolvents, etc. can majorly modify the gelling temperature of Pluronic-based systems. Fortunately, β-lapachone did not cause any significant changes in gel temperature, while ethanol (up to 20%) as cosolvent drastically decreased the gel temperature providing softer gels. Remarkably, ethanol caused 18% Pluronic F127 to be a low viscous solution at temperatures beyond 37 C, while 28% Pluronic F127 gel did not liquefy below 4 C. This distinct behavior of ethanol could be related to inhibition of micelle formation by ethanol, but once incorporated into the micellar core, it may lead to elongated/wormlike micelles. Similarly, incorporation of small amount of ethanol in suspensions may arrest various properties, i.e., solubility, swelling potential, and viscosity, enhancing the ability of polymers like polyacrylic acid, methylcellulose etc. It was also noted that the polymers with higher HLB value were more vulnerable to alcohol in the suspension (Mastropietro et al., 2013). Jung et al. (2017) demonstrated the influence of various solvents on the rheological properties of poly(ethylene glycol) hydrogels during UV photopolymerization. Solventbased prepolymerized cross-linked networks were less dense in comparison with nonsolvent systems. Among the two solvents used, water disturbed the cross-linking networks and reduced the activation energy during polymerization process due to hydrogen bonding nature of water, while ethanol affected the movement of radicals in the system. As reiterated earlier, the viscosity of injectable preparations of monoclonal antibodies (MAbs) reasonably increases at lower concentration of proteins, while the viscosity increases exponentially at higher proportions of protein ( . 100 mg/mL). Furthermore, addition of 90% 110% of protein concentration in low dose drug product has less effect on viscosity while it can lead to substantial variability in high dose drug products (Palm et al., 2015). 16.3.1.4 Aeration Aeration is a process of circulation of air through a liquid system or the substance. Arboleya et al. (2009) studied the effect of aeration on rheology of an emulsion. The study involved the preparation of emulsion using solid fat and liquid oil, wherein the interaction DOSAGE FORM DESIGN CONSIDERATIONS 16.3 PHARMACEUTICAL CONSIDERATIONS 571 between the emulsion globules was dependent on the concentration of the components which in turn influenced the rheology of the system. Addition of air to the emulsion forced the system to adopt a stronger organization by boosting partial coalescence. Viscosity of aerated and nonaerated emulsions was found to differ with change in temperature. Aerated systems were considerably more thermosensitive, depicting an increase of viscosity as the temperature was increased above a critical value. Tiwari and Bhattacharya (2011) prepared various sol-systems with gellan and agar at different solid concentrations. These systems were aerated and the rheological properties were determined. Various compression characteristics (i.e., fracture strain/stress/energy, firmness, and the total energy for compression) and stress relaxation characteristics (i.e., extent of relaxation and relaxation time) were investigated. It was observed that the fracture strain and extent of relaxation of aerated gels was higher and the relaxation time was reduced when compared to nonaerated gels. The delayed fracture and relaxation was due to the presence of incorporated air. It was also noted that the effect of aeration on low concentration of hydrocolloid was insignificant, while vice versa at high concentration. Tan et al. (2015) investigated the effect of protein concentration and ultrasound on aeration and rheological properties of protein foams. Foaming capacity, foam stability, and rheological properties increased with increased concentration of protein (10% 20%). The ultrasound treatment provided to suspension with optimal concentration of protein concentrations reduced the foam drainage and enhanced the foaming capacity, storage modulus, loss modulus, consistency index, and viscosity. 16.3.1.5 Light Light may be used as a trigger for changing the rheological properties of polymer-based systems due to the following reasons: (1) light is temperate and noninvasive; (2) light signal is easily available; and (3) light can target specific functional groups for benefit of medical application. Tronci et al. (2016) studied the covalent functionalization of collagen in presence of light. They interacted type I collagen with 4-vinyl benzyl chloride and methacrylic anhydride and the systems were subjected to photoinduced activation. The swelling and rheological properties of hydrogel systems were investigated, wherein, 4-vinylbenzene chloride based hydrogel showed significant increase in swelling ratio due to interactions with collagen; but the rheological storage module was found to be comparable with methacrylate collage network. The smart photorheological fluid has been developed, which changes its rheological property on light irradiation at specific wavelengths. They investigated various photoresponsive systems obtained by mixing traditional cationic surfactants, cetyltrimethylammonium salicylate/cetyl trimethylammonium bromide with a photosensitive compound, azobenzene. The rheological properties of the given system followed the Maxwell model. In the cetyltrimethylammonium salicylate solution, carboxyl groups of salicylate anions were linked to water molecules by hydrogen bonding, thus, the salicylate ions were found to be adsorbed at the interface of formed rod-like micelles due to the bridges between carboxyl groups of salicylate anions and water molecules by hydrogen bonding. These hydrogen bonds caused a pseudo-like network around the micelles. Addition of azobenzene to the above solution caused partial degradation of the network causing reduction in the viscosity of the surfactant solution. On exposure to UV radiation, the azobenzene molecules DOSAGE FORM DESIGN CONSIDERATIONS 572 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS resulted in photoisomerization (conversion from trans- to cis-form) which helped in strengthening the steric hindrance, altering the network at the interface and producing zero-shear viscosity. Whereas, on exposure to visible light, the cis-form of azobenzene converted to trans-form regaining the network between micelles and increasing the viscosity of the solution. Similar results were observed for cetyltrimethylammonium bromide/ sodium salicylate/azobenzene system when subjected to UV radiation; however, under visible light, there was no reversible change observed on viscosity, which may be related to the presence of sodium bromide in the system. Investigators have explored the rheological property of ionic- and photocross-linked methacrylated gellan gum hydrogels. They performed the steady shear analysis wherein they found that both the systems were non-Newtonian and showed shear thinning capability. Injectability of the systems was evaluated and they posed as promising biomaterials permitting easy gelation before or after injection. In addition to this, these systems also assisted in cell encapsulation and are remarkable systems for cellular-based tissue engineering. Zhou et al. (2017) investigated the 3D bioprinting capability of a biomaterial, i.e., gelatin methacryloyl, for fabricating into 3D cellular constructs. However, the biomaterial possesses low viscosity at body temperature and hinders 3D bioprinting. Thus, the researchers used an enzyme-based cross-linking triggered by Ca21-independent microbial transglutaminase, which caused the isopeptide bond formation between chains of the biomaterial. This had to be subsequently exposed to photo-based cross-linking, to stabilize the gelatin macromolecules. Hence enzymatic cross-linking enhanced the solution viscosity of biomaterial and photocross-linking helped in stabilization of the construct. 16.3.1.6 Sterilization Sterilization is a process that eliminates, removes, kills, or deactivates all types of microorganisms from the dosage form. Sterilization may be achieved through dry heat, moist heat, chemicals, gases, irradiation, and membrane filtration (Rutala and Weber, 2013). The pharmaceutical products intended for parenteral, ophthalmic, nasal administration, or into other body cavities, are desired to be sterile. Accordingly, they are subjected to in-process or terminal sterilization process to ensure the safety of the product. It is very important to understand the influence of sterilization on rheological properties of such preparations. Bindal et al. (2003) studied the influence of steam sterilization on the apparent viscosity of carbomer 940 P, guar gum, hydroxyethyl cellulose, and xanthan gum dispersions. Poststerilization, the guar gum and carbomer 940 P dispersions did not change their apparent viscosity, while hydroxyethylcelluloseose and xanthan gum dispersions showed reduction in their apparent viscosity. They also studied the effect of addition of sodium chloride, as tonicity adjusting agent, prior to and after sterilization, on the viscosity of xanthan dispersions. It was interesting to note that, there was no change in the behavioral pattern of apparent viscosity of xanthan dispersions that were made isotonic prior to sterilization, whereas, addition of sodium chloride to xanthan gum dispersion after steam sterilization resulted in full recovery of initial rheological properties. On similar grounds, Nanjundaswamy and Dasankoppa (2014) developed in situ guar gum derivative-based ophthalmic formulation by varying the composition of hydroxyl propyl guar, sodium alginate, and carbopol 940 P. The preparations were subjected to moist heat sterilization in an autoclave for 20 min at 121 C and 15 psig. The viscosity of DOSAGE FORM DESIGN CONSIDERATIONS 16.3 PHARMACEUTICAL CONSIDERATIONS 573 the systems at 25 C (before gelation) and 37 6 0.5 C (after gelation) were recorded. The percent viscosity variation (i.e., before and after sterilization; before and after addition of simulated tear fluid (in the ratio of 1:4)), consistency index, and flow behavior index were determined using power law model. It was observed that the formulations exhibited good gelling capability in simulated tear fluid after sterilization, which is an important prerequisite for in situ gels. As per the study, on sterilization the formulations containing guar gum-derivative only; guar gum-derivative:sodium alginate: carbopol 940 P (in the ratio 2:1:1) and guar gum-derivative:carbopol 940 P (in the ratio 2:1) exhibited reduction in viscosity, whereas guar gum-derivative:sodium alginate (in the ratio 2:1) and guar gumderivative:sodium alginate:carbopol 940 P (in the ratio 4:1:1) exhibited enhanced viscosity. This may be attributed to the presence of sodium alginate and the ratio of polymers used in the formulation. Likewise, Cunha-Filho et al. (2012) determined the gel strength of Pluronic dispersions before and after autoclaving. The dispersions maintained their physical integrity and did not show presence of crystal growth during and after moist heat sterilization. Thus, the authors suggested autoclaving as a suitable sterilization method for Pluronic-based preparations as demonstrated during preparation of β-lapachone system for intratumoral delivery. Fatimi et al. (2010) formulated an injectable calcium phosphate suspension with hydroxypropyl methylcellulose as biopolymer, for applications in dentistry and orthopedics. The study involved the assessment of effect of formulation on physical stability of calcium phosphate suspension pre- and post-steam sterilization. In the past, such polymeric preparations were sterilized by gamma irradiation, but it was found that it led to the formation of free radicals, reactive intermediates, etc. Thus, cellulose polymers were suggested unsuitable for sterilization by gamma radiation (Pekel et al., 2004). By steam sterilization, the polymer did not degrade and the product did not undergo chemical changes. Immediately after sterilization, the system converted to a heterogeneous solution with white precipitate, which converted to clear solution on standing at room temperature. This behavior of turbidity can be attributed to physical gelation of polymer due to strong hydrophobic interactions between the polymer chains, leading to a new spatial configuration. However, reduction in viscosity may be due to the formation of irreversible aggregates. Finally, the effect of steam sterilization on rate and compactness of sediment was differing slightly between unsterilized and sterilized suspensions (Fatimi et al., 2010). Budai et al. (2015) used chitosan, a polysaccharide, which possesses excellent rheological properties for ocular delivery. All the formulations, i.e., chitosan 2%w/v (F1), chitosan with glycerin (1 5 w/v %) (F2), chitosan with propylene glycol (1 20 w/v %) (F3), and chitosan with castor oil (1 5 w/v %) (F4), were subjected to steam sterilization. Poststerilization the formulation F1 lost its viscosity while the excipients in other formulations (i.e., F2, F3, and F4) helped to avoid loss of viscosity of chitosan gels. The protective effect of polyols (i.e., glycerin and propylene glycol) was more than that of castor oil. It was also noted that increase in the concentration of propylene glycol concentration had a positive protective influence on the rheology of chitosan systems. Likewise, Lapasin et al. (2016) assessed the rheological properties of the amidated carboxymethylcellulose-based fluids when subjected to various processing phases including sterilization. Steam sterilization caused loss of elastic and viscous moduli with polymer degradation being one of the DOSAGE FORM DESIGN CONSIDERATIONS 574 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS causes. Accordingly, in order to compensate the negative effects, researchers readjusted the polymer concentration and gel fraction in the formulations, with no compromise on viscoelasticity, stability, and ease of injectability. 16.3.2 Influence of Chemical Variables Various chemical variables that have an impact on the rheological behavior of liquidbased systems include pH, polymer related factors, presence of impurities/ions/electrolytes, and addition of additives such as sequestering agents, buffers, surfactants, etc. These variables are discussed using a few illustrations as given below. 16.3.2.1 pH pH is a numeric scale that specifies the acidity or alkalinity of an aqueous solution. It is the negative of base 10 logarithm of molar concentration, depicted using moles per liter, of hydrogen ions. Various researchers have studied the influence of pH on the interactions between particles in aqueous suspensions of clay and have reported the possibility of the following arrangements, i.e., face-to-face, edge-to-edge, and edge-to-face, wherein face-toface arrangement has provided suspensions with thicker and larger particles (Zbik and Williams, 2017). Benna et al. (1999) investigated the rheological and electrokinetic properties of purified sodium bentonite suspensions as a function pH, i.e., from acidic (2 or 3) to basic (about 12). The scientists noticed that in the range of pH around the isoelectric point, the yield stress of the suspension decreased when pH of the system was more than the pH of isoelectric point (pHip), whereas the yield stress increased sharply when pH of the system was less than pHip. This behavior may be attributed to the following reasons: (1) when pH , pHip, all the edges are positively charged, leading to gel-like structure due to edge-to-face interaction and Van der Waals attractions; (2) when pH . pHip all the edges are negatively charged, leading to breakdown of structure. In addition to this, there is low ionic strength and electric double layers that are not compressed. Subsequently, at strong acidic pH, the ionic strength of the system was very high, the double layers were compressed, there was reduction in edge-to-face conformation and breakdown of structure. Moreover, the system was probably attacked by the protons and thus reduction in yield stress was observed. There was a presence of a thin film of water at the surface of the sample, indicating sedimentation of aggregates. Similarly, at strong basic pH, the edges were negatively charged, diffuse double layer was very compressed, Van der Waals attraction was not dominant, and the yield stress increased sharply. Finally, it was concluded that the gels obtained at strong acid pH were opaque due to aggregated suspension; while at strong basic pH were translucent owing to creation of few compact structures due to long-range repulsion between particles. Mastropietro et al. (2013) discussed about the pH-dependent nature of polyacrylic acid, an anionic synthetic polymer having a pKa 4. The polymer is nonionized at lower pH and ionized at higher pH. In the nonionized form, the polymer has poor solubility and does not significantly increase the solution viscosity. This principle may be applicable to anionic polymers such as alginic acid, carbomers, etc. A reverse behavior is observed with polymers possessing cationic groups. DOSAGE FORM DESIGN CONSIDERATIONS 16.3 PHARMACEUTICAL CONSIDERATIONS 575 Polyacrylic acid (an anionic polymer) or its derivatives convert from liquid state (pH 5) to gel state (pH 7) and have been widely selected as ideal candidates for ocular delivery of actives through the epithelia of cornea and also for other applications (Sindhu et al., 2015; Rizwan et al., 2017). Another pH sensitive reaction is observed during addition of a cationic drug to an anionic polymer. This can cause strong intermolecular interactions and polymer drug binding, thus leading to an instability in drug suspension. Chen et al. (2007) studied the influence of ionic strength and pH on the zeta potential of suspended aerosil particles and rheological properties of the suspension. It was witnessed that strong attractions between particles occurred at the isoelectric point (i.e., pH 4) causing large agglomerates (i.e., 3D structures), leading to an increase in viscosity (Chen et al., 2005) and minimal energy barrier with net charge density zero. Krieger and Dougherty model was used to determine the relative viscosity of the suspensions which was related to the volume fraction. Interestingly, the suspension displayed elastic behavior at acidic pH and viscous behavior at alkaline pH. At a given pH, incorporation of salt enhanced the agglomerate size affecting the electrical double layer repulsions. Rheograms of aerosil suspensions at 0.01 M sodium chloride demonstrated Newtonian behavior at pH . 11; pseudoplastic behavior at pH 9 10 when sheared at low-to-intermediate range, and Newtonian plateau at higher shear rate; pseudoplastic behavior at pH 4 8 over whole shear rate range; and highest apparent viscosity with shear thinning effect at pH 4. Several researchers have correlated the effect of pH on the rheological property of guar gum and its hydroxyl propyl derivative (Li et al., 2012; Wang et al., 2016). Wang et al. (2015) demonstrated that the hydroxypropyl group in guar gum decreases intramolecular H-bonding interactions, exhibits higher steric hindrance, causes improved hydration, and enhances the viscosity properties. As per the pH-dependent study, the system exhibited higher zero shear viscosity, due to electrostatic repulsion at pH 8.5 12, causing high entanglement density. At pH 7 8, it caused weak electrostatic repulsion and reduced entanglement density. At pH 12.5 and 13, the system exhibited coiled conformation and reduced the entanglement density. The system showed decreased zero shear viscosity at pH 13.5 14, which was attributed to weakened electrostatic repulsion and coiled polymer conformation. As per the viscoelasticity and thixotropy study, at pH 7 12.5, gel rigidity and elasticity were found to be satisfactory, while at pH 13 14, it was found to gradually decrease. At pH 14, the gel mainly displayed viscous features and absence of hysteresis loop. 16.3.2.2 Polymer-Related Factors Various properties of polymers can produce advanced high-performance systems with better activities, which in turn may offer flexibility to the developed systems (SadikuAgboola et al., 2011). Locust bean gum and xanthan gum are good viscosity building components when dispersed in water, however, in combination, they gel due to intermolecular chain aggregation and may be used in controlled drug delivery (Renou et al., 2013). Similarly, alginic acid (anionic polymer) and chitosan (cationic polymer) are individually effective viscosity enhancers in aqueous media but when combined, tend to lose their property due to interpolymer interactions. Alternatively, alginate and chitosan interact to form gels and have been used to coat poly(lactic-co-glycolic acid) nanoparticles for controlled delivery of peptides (Büyüktimkin et al., 2012). DOSAGE FORM DESIGN CONSIDERATIONS 576 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS Copolymers possessing amphiphilic nature have an ability to self-assemble as micelles, leading to formation of hydrogel. Nielsen et al. (2017) assessed the influence of PEGspacer length (molecular weight “m” 5 1000 and 1500), temperature, and concentration of polymer on the self-assembling process in PCLA-PEGm-PCLA copolymer solution to create supramolecular structures. In this case, the copolymer possessed a low consulate temperature and length of PEG decided the cloud point. In dilute solutions, the copolymer with long PEG-spacer (i.e., PCLA-PEG(1500)-PCLA) displayed a spherical core-shell model at temperatures up to 35 C with modification in structure to cylinder-like at 40 C, however, on cooling, these entities were found to be stable. This may be due to high sticking nature leading to self-assembling of species in the form of strings. Nevertheless, copolymer with short PEG-spacer (PCLA-PEG(1000)-PCLA) displayed an ellipsoidal model at 10 35 C, and on cooling, these entities were found to be unstable. This may be indicative of the presence of a short hydrophilic block which is incapable of joining the same micelle core; instead it will protrude out and at increased temperature will cause stickiness, facilitating the PCLA moiety to accommodate in the neighboring micelle core, forming a string of micelles with extended structures. In semidilute solutions, copolymer with long PEG-spacer displayed a spherical core-shell model at temperatures up to 35 C, while the correlation peak vanished at 40 C and transformed to rod-like structures at 49 C. The copolymer with short PEG-spacer existed as cylinder-like structures at 10 25 C posing its potential as a good carrier for drug delivery applications. Finally, viscoelastic property of copolymer with short PEG-spacer was more intricate than the copolymer with long PEG-spacer and the latter showed higher storage modulus owing to bridging of micelles and exhibiting higher mechanical stability (Nielsen et al., 2017). 16.3.2.3 Presence of Impurities, Ions, and Electrolytes Presence of impurities, ions, and electrolytes in the formulations can have a positive or negative impact on the rheological properties of the systems. Polymers have a tendency to interact with water, which is triggered by osmotic pressure. Sodium carboxymethylcellulose attracts water until it remains stable, but in sodium containing aqueous suspensions, the system would reduce its viscosity due to suppression of osmotic forces (Mastropietro et al., 2013). Furthermore, the osmotic pressure will be suppressed in the presence of higher valence ions such as calcium or iron. For instance, carboxyl group of carboxymethylcellulose has the tendency to interact with cations (i.e., traces of calcium, aluminum or iron) which may be present in the excipients/drug/other polymers, causing a decrease in the viscosity of the suspension. This behavior may be attributed to the reduction in hydration of carboxylate groups and electrostatic interaction, viz., ion-binding and hydrogen bond (Yang et al., 2015). Presence of ions (or ionic salts) in polymer system (especially oppositely charged polymer) can lead to instability, reduced polymer solubility, and polymer precipitation resulting in reduced viscosity. Conversely, Ji et al. (2017) developed alkali lignin-based hydrogels from ionic liquids such as 1-ethyl-3-methylimidazolium acetate. Natural polymers like pectin, xyloglucan, gellan gum have shown great potential by transforming from sol-to-gel on oral delivery. Low methoxyl pectins (degree of esterification ,50%) have a tendency to gel in the presence of H1 ions, however, they also form a gel in the presence of divalent calcium ions (Ca21), due to the cross-linking with galacturonic acid chains in the pectin (Sundar Raj et al. 2012). This behavior was utilized by Saroj et al. (2012) DOSAGE FORM DESIGN CONSIDERATIONS 16.3 PHARMACEUTICAL CONSIDERATIONS 577 wherein they developed an oral in situ gelling pectin formulation for sustained delivery of hydrochlorothiazide. In addition to this, calcium ions could be used as cross-linkers to formulations containing sodium alginate as a polymer, wherein the formulation maintains sol-state, El Maghraby et al. (2014) has also developed a modified in situ gelling alginate formulation capable of sustaining dextromethorphan release throughout the GIT. Gellan gum, an anionic deacetylated exocellular polysaccharide, causes temperatureand cation-induced gelation due to the formation of double helical junction zones followed by aggregation of these segments to form a 3D network by complexation with cations and hydrogen bonding with water (Tako, 2015). Mishra (2015) studied the influence of mixed surfactant systems of Cetrimonium bromide (cationic) and Tergitol (R) NP-10 (non-ionic) and various electrolytes, i.e., sodium chloride, sodium sulfate, and sodium dihydrogen phosphate on the rheological properties of carboxymethyl cellulose. In the presence of surfactant and electrolytes, the viscosity of the polymer system was higher at low shear rate which decreased as the shear rate increased. It was also witnessed that with the rise in surfactant concentration and valency of electrolytes the shear stress decreased due to adsorption of surfactant molecules between the polymer molecules resulting in disruption of structured molecules. 16.3.2.4 Addition of Additives such as Sequestering Agents, Buffers, Surfactants, etc Presence of additives in the formulations such as chelating agents, buffers, surfaceactive agents, etc. have caused modifications in the rheological behavior of the dispersions and this can be exemplified by the interaction between polymer and surfactant which influence various physicochemical properties of solutions. For example, combinations of polymer surfactant are used for emulsification, colloidal stability, viscosity enhancement, gelation, solubilization, phase separation, etc. (Antunes et al., 2009; Kogej, 2010). Katona et al. (2014) used hydroxypropylmethylcellulose along with sodium dodecyl sulfate and found that the concentration of sodium dodecyl sulfate at critical micelle concentration is desired for the association of polymer and surfactant (Silva et al., 2011). Their interaction supports physical cross-links between the polymer chains, resulting in an increase in the viscosity of the solution. Formation of negatively charged micelles of surfactant with the polymer can convert the nonionic polymer into a polyanion. As the concentration of surfactant increases, the repulsive forces between the polymer chains increase, causing reduction in viscosity (Katona et al., 2014). Keowmaneechai and McClements (2002) demonstrated the effect of chelating agents (disodium ethylene diamine tetra-acetate and sodium citrate) on the physicochemical characteristics of whey protein isolate-stabilized oil-in-water emulsions containing calcium chloride. The oil-in-water emulsions (pH 7.0) were composed of soybean oil, whey protein isolate, sodium azide, tris buffer, calcium chloride, and chelating agent. Chelating agents reduced the droplet agglomeration in the emulsions indicative of pseudoplasticity, reduction in globule size, apparent viscosity, and creaming. Thus, chelating agents bind to calcium ions, enhancing the emulsion stability. Cross-linked hydrophilic polymers have the ability to swell in presence of water resulting in improved viscosity. Nonionic polymers usually swell independent of pH, while ionic polymers either shrink or swell in the influence of pH of the solution. For instance, the anionic structure of cross-linked acrylic acid polymers in aqueous solution expands and DOSAGE FORM DESIGN CONSIDERATIONS 578 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS gels at alkaline pH, while the viscosity reduces at acidic pH (Islam et al., 2004). Sen and Noronha (2009) developed a topical gel containing azelaic acid using cross-linked polyacrylic acid, which was neutralized using sodium hydroxide to produce a clear, stable gel. On a similar note, a loss of buffer capacity of the buffers incorporated in the formulation can also trigger changes in the polymer networks and lead to loss of desired viscosity. The physical and chemical attributes contributing to the rheology of various pharmaceutical systems has been described in the above section. Nevertheless, the following section discusses the types of rheology modifiers, thickeners, and gelling agents that could be incorporated in the dispersions to improve the stability of the product. 16.3.3 Rheology Modifiers, Thickeners, and Gels Rheological modifiers are components that increase the stability of a product by increasing the viscosity of the medium. They can be broadly classified into the following categories: 1a) repulsive interaction of materials causing gel-like nature; (2) self-structured systems produced due to weak flocculation of particles or droplets; (3) thickening agents such as high-molecular-weight polymers or finely divided particles that form threedimensional structure; (4) cross-linked polymers; (5) self-assembled surfactants; and (6) liquid-crystalline structures (Tadros, 2011). Generally, high-molecular-weight polymers with hydrophilic nature are preferred. However, the interaction of these polymers with an aqueous medium will crucially depend on the nature of the medium. Factors such as pH, ionic strength, temperature, and addition of other organic solvents in the medium can alter the polymer water interactions. Few high-molecular-weight polymers include polyacrylic acid, cellulose derivatives, such as methyl cellulose, carboxymethyl cellulose, hydroxyl propyl methyl cellulose, hydroxyethyl cellulose, carbomers, etc. (Nasatto et al., 2015). Other viscosity modifiers, thickening agents, or stiffening agents, include alginates, acacia gum, gellan gum, bentonite clay, laponite clay, tragacanth, xanthan gum (Lippert, 2013), tamarind seed polysaccharide (Joseph et al., 2012), associative polymers, and surfactant lamellar, to mention a few (Mastropietro et al., 2013). The effects of various rheological modifiers in various formulations is discussed under sections 16.3.1 and 16.3.2 of this chapter. Viscosity of pharmaceuticals should be sufficiently controlled in order to ensure proper mixing, accurate measurement, and ease of delivery. Increase in viscosity should be within the desired range to facilitate all operations during product handling and product consumption for better patient compliance. Whenever desired, the viscosity modifiers should be smartly selected to provide the desired viscosity and texture to the product. 16.4 RHEOLOGICAL INSTRUMENTS FOR FLUIDS AND THEIR LIMITATIONS Measurement of rheological properties of various pharmaceutical products is an important quality control parameter. An instrument designed to measure viscosity is termed as a viscometer, while an instrument used for measuring rheological properties is termed as DOSAGE FORM DESIGN CONSIDERATIONS 16.5 ROTATIONAL-TYPE RHEOMETER 579 a rheometer. Rheometers are found to be beneficial in determining the (1) viscosity of the product, (2) relationship between shear stress and shear strain rate, (3) pressure gradient of the system, (4) velocity profile of the system, (5) physical quantity such as torque, (6) rotational velocity (if any), (7) desired storage conditions, and (8) loss modulus. 16.4.1 Measurement of Rheological Parameters Viscometers/rheometers are instruments used to measure the flow or rheological properties of dispersed systems. The resistance of the system to flow usually arises from the internal friction of fluid. These viscometers have shown wide and varied applications in various industries and areas. Measurement of rheological properties is of prime importance for industries dealing with material science, pharmaceutical, chemical, food, textile, petroleum, paints/coatings, and personal-care products. Viscosity majorly affects the performance of various process conditions like mixing, filling, pumping, dipping, coating, etc. In addition to this, viscosity helps to indirectly measure the physical properties of materials, such as molecular weight and density, which affect the flow character of the material. Thus, viscometers are important quality control tools beneficial in determining the intrabatch and interbatch consistency of dispersions (Scoffin, 2013). The rheometers widely used in industry can be classified as follows. 1. Rotational type Rheometers a. Concentric cylinder rheometer: (i) narrow-gap and (ii) broad-gap types b. Cone and plate rheometer c. Parallel-plate rheometer d. Inclined-plane rheometer 2. Tube type Rheometers a. Glass capillary tube rheometer b. High-pressure capillary rheometer c. Pipe-type rheometers 16.5 ROTATIONAL-TYPE RHEOMETER In these viscometers, a simple shearing flow is measured based on either of the measurements, i.e., (1) driving one member of the unit and measuring the corresponding couple, or (2) by applying couple and measuring the subsequent rate of rotation. The former technique was introduced by Couette in 1888 and the latter by Searle in 1912. Here the rotation can be applied and the couple measured by two ways. The first one is to drive one member and measure the couple on the same member, whilst the second method is to drive one member and measure the couple on another member. Modern viscometers of Haake, Contraves, Ferranti-Shirley, and Brookfield instruments employed the former technique while Weissenberg and Rheometrics rheogoniometers followed the latter. DOSAGE FORM DESIGN CONSIDERATIONS 580 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS 1. The Concentric Cylinder Rheometer can be further classified into narrow-gap and broad-gap type concentric viscometers. a. Narrow-gap concentric cylinder viscometer: In this case, the gap between the concentric cylinders is less and both the cylinders are in relative rotation. Thus, the sample in the gap experiences constant shear rate. If the radii of outer and inner cylinder are given by ro and ri, respectively, and the angular velocity of the inner cylinder is Ωi, the shear rate γ is given by Eq. 16.25. γ 5 r o Ω i =ð r o ri Þ (16.25) If the couple on the cylinders is C, the shear stress σ in the liquid is given by Eq. (16.26), σ 5 C= 2πr20 L (16.26) From Eqs. (16.17) and (16.18), viscosity can be determined as depicted in Eq. (16.27) η 5 Cðro ri Þ=2πΩi r30 L (16.27) where L is the effective immersed length of the liquid being sheared; which would be the real immersed length, l, if there were no end effects. In practice, manufacturers of viscometers design the dimensions of the cylinders such that the ratio of depth of the liquid to the gap between the cylinders is .100, thus, end correction will be negligible. The bottom part of the inner cylinder provides undesired viscous drag during measurements. Thus, the gap between the cylinders, at the bottom, should be minimized by recessing the bottom of the inner cylinder to the maximum possible level, such that air is entrapped during filling, prior to taking measurements. Otherwise, a cone-shaped cylinder can be chosen such that the tip of the cone just touches the bottom of the outer cylinder. Care must be taken during the design of the cone so that the shear rate at the liquid between cylinders should be equal to the shear rate between the cone and the bottom. This arrangement is known after its inventor, the Mooney system (Barnes et al., 1989). 16.6 BROAD-GAP CONCENTRIC CYLINDER VISCOMETER In this case, the gap between the concentric cylinders is broader and thus, the limitations faced with narrow-gap concentric cylinder type viscometer has led to the development of broad/wide-gap concentric viscometers. Narrow-gap viscometers achieve parallel alignment and are not suitable for suspensions with larger solutes. The shear rate γ in the liquid at the inner cylinder is given by Eq. (16.28). γ 5 2Ω1 =n 1 b2=n (16.28) where b is the ratio of the inner to outer radius (i.e., b 5 ri/ro). The shear stress σ in the liquid at the inner cylinder is given by Eq. 16.29. σ 5 C= 2πr21 L (16.29) The value of n can be determined by plotting C versus Ω1, on a double-logarithmic scale and taking the slope at the value of Ω1 under consideration. DOSAGE FORM DESIGN CONSIDERATIONS 16.8 PARALLEL-PLATE VISCOMETER 581 From Eqs. (16.28) and (16.29), viscosity can be determined as depicted in Eq. (16.30). η 5 Cn 1 b2=n =4πΩ1 r21 L (16.30) In rotational viscometers, the lower limit of shear rate achievable is governed by the drive system, while the upper limit is controlled by the dispersion under examination. One of the major limitations is the incidence of viscous heating for which reliable correction is not possible. Other limitations include appearance of a steady (Taylor cone) vortex or turbulence when the cylinder is rotating at a critical speed causing breakdown of streamline flow. In both the cases, the energy required is higher than the streamline flow and the viscosity of the liquid outwardly increases. Such disturbances usually occur when the viscosity to be measured is ,10 mPa.s (Barnes et al., 1989). 16.7 CONE AND PLATE VISCOMETER In this type of viscometer, the shear rate is uniform throughout the sample due to the small gap θ0 provided. The shear rate γ is given by Eq. 16.31 γ 5 Ω1 =θ0 (16.31) where Ω1 represents angular velocity of the rotating plate. Unlike concentric cylinder type, the shear rate is not dependent on the properties of the liquid. The shear stress σ (measured via the couple C on the cone) is given by Eq. (16.32) σ 5 3C= 2πa23 (16.32) where a is the radius of the cone. From Eqs. (16.31) and (16.32), viscosity can be determined as depicted in Eq. (16.33) (16.33) η 5 3Cθ0 = 2π Ω1 a3 If the liquid to be examined has low viscosity then the viscometer has to be operated at high rotational speeds to produce torques large enough to be measured. However, these may cause “secondary flows” to arise, wherein the secondary flow will absorb extra energy, thus increasing the couple, and falsely representing shear-thickening property. For a 1 degree gap angle and a cone radius of 50 mm, every 10 µm of error in the axial separation produces an additional 1% error in the shear rate. To avoid error in contacting the cone tip (which may wear out) and the plate (which might become indented), the cone is often truncated by a small amount. In this case, it is necessary to set the virtual tip in the surface of the plate (Barnes et al., 1989). 16.8 PARALLEL-PLATE VISCOMETER For torsional flow between parallel plates, the shear rate at the rim (r 5 a) is given in Eq. (16.34) γ 5 aΩ1 =h DOSAGE FORM DESIGN CONSIDERATIONS (16.34) 582 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS The shear rate finds its way into the interpretation of experimental data for torsional flow. The viscosity can be determined as depicted in Eq. (16.35) η 5 3Ch=2πΩ1 a4 1 1 1d ln C=3d ln Ω1 (16.35) where C is the couple on one of the plates. For power-law models, Eq. (16.35) becomes η 5 3Ch=2πΩ1 a4 1 1 n=3n (16.36) Eq. (16.34) shows that the rim shear rate can be changed by adjusting either the speed Ω1, or the gap h (Barnes et al., 1989). 16.9 TUBE-TYPE RHEOMETERS 1. Capillary viscometer: If a Newtonian liquid flows down a straight circular tube of radius ‘a’ at a volume flow rate ‘Q’, the pressure gradient generated along it (dP/dL) is given by the Poiseuille equation (Eq. (16.37)). dP=dl 5 8Q η=πa4 (16.37) In this situation, the shear stress in the liquid varies linearly from (a/2)(dP/dl) zero, which is corresponding to the shear stress at the capillary wall to the center line, in the tube. For Newtonian liquids, the shear rate varies similarly from 4Q/(7ra3) in the immediate vicinity of the wall to zero at the centerline. However, in case the viscosity varies with shear rate, the situation becomes more complex. Thus, progress can be made by concentrating on the flow only near the wall. For a non-Newtonian liquid, the shear rate at the wall is modified to Eq. (16.38). (16.38) γ w 5 4Q=πa3 3=4 1 1/4 d ln Q=d ln σw when the shear stress at the wall σw, is unchanged at (a/2) (dP/dl). The terms in bracket in Eq. (16.38) is called the Rabinowitsch correction. Finally, we obtain Eq. (16.39). (16.39) η γ w 5 σw =γ w 5 πa4 ðdP:dlÞ=8Q 3=4 1 1/4 d ln Q=d ln σw When shear-thinning liquids are being tested, d(ln Q)/d(ln σw) is more than 1 and for power-law liquids, it is equal to l/n. Since n value can be as low as 0.2, the contribution of the d(ln Q)/d(ln σw) factor to the bracketed term can be highly significant in determining the true wall shear rate. Care has to be taken in defining and measuring the pressure gradient dP/dl. If the pressure in the external reservoir supplying the capillary and the receiving vessel are measured, then, unless the ratio of tube length to radius is very large ( . 100), allowance must be made for entrance and exit effects (Barnes et al., 1989). DOSAGE FORM DESIGN CONSIDERATIONS 16.11 APPLICATIONS OF RHEOLOGY 583 16.10 DILATION RHEOLOGY Dilational rheology is a tool used to investigate equilibrium and dynamic properties of interfacial layers containing surfactants, proteins, polymers, or micro/nano-sized particles (Ravera et al., 2010). As per experimental discussion, dilational and shear properties are relevant, however different techniques are required to measure each property. Shear properties can be determined by ring (Vandebril et al., 2010) and needle (Brooks et al., 1999; Dhar et al., 2010) geometry technique, while dilational behavior can be measured using pendant droplet, capillary wave, and Wilhelmy technique (Miller et al., 1996; Petkov et al., 2000). Erk et al. (2012) studied the shear and dilational rheological characteristics of surfactant-stabilized emulsion droplets. On the other hand, Noskov et al. (2014) reviewed the dilational rheology of silica nanoparticles at liquid gas interface. Li et al. (2016) investigated the effect of glyphosate isopropylamine on the dilational rheology property of polyoxyethylene tallow amine surfactant interface. Kazakov et al. (2011) studied dilational rheology as medical diagnostics of human biological liquids, i.e., cerebrospinal fluid, expired air condensate, and umbilical blood of newborns, since the dilational rheology of liquid air interface is very sensitive to the contents and composition of surface active molecules in the fluid. Dilation rheology studies of cerebrospinal fluid were used to diagnose neurosyphilis, wherein they suggested that high values of viscoelastic modulus unambiguously indicated the absence of pathology of the central nervous system, while reduction in viscoelasticity pointed towards presence of neurologic diseases. Similarly, changes in the values of phase angle between surface tension and drop area oscillations of expired air condensate/umbilical blood indicate congenital pneumonia or respiratory distress syndrome. Thus, the knowledge of rheological behavior of biological fluid can be used as diagnostics of diseases. 16.11 APPLICATIONS OF RHEOLOGY The applications of rheology are widespread in significant areas such as materials science, polymer engineering, geophysics, physiology, cosmeceuticals, concrete material, dentistry, pharmaceutics, etc. In addition, plasticity theory has been similarly important for the design of metal forming processes. 16.11.1 Materials Science Rheology in materials science consists of many aspects such as study of deformation of nanomaterials, biomaterials, polymers, composite materials, ceramics, glass, metal alloys, etc., which possess a number of industrial applications. These substances are involved in various cement, paint, food, pharmaceutical industry, showing complex flow characteristics. 16.11.1.1 Polymer Engineering Polymers are composed of basic components such as rubber, plastic, fibers, which have their vital importance in textile, petroleum, automobile, paper, food, and pharmaceutical DOSAGE FORM DESIGN CONSIDERATIONS 584 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS industries. The viscoelastic nature of the polymers/plastics governs the mechanical property of the final product and controls the processing stages during production. For instance, a silicone toy called as “Silly Putty” changes its viscoelastic nature based on the force applied. When pulled gently, it exhibits continuous liquid-like behavior, while when hit hard, it shatters like glass. 16.11.1.2 Biopolymers Biopolymer may be broadly classified as proteins, nucleic acids, and polysaccharides. Study of rheology of biopolymers in solution is important because it depends upon the “swept out” molecular volume. These systems help in developing cold- and heat-set protein gels. In addition to this, polysaccharides have been widely studied in various areas for their thickening property, gel-forming ability, in tissue scaffolds etc. This is because the polysaccharides have high molecular weight and are semiflexible, thus capable of occupying large volume in solution. This, in turn, contributes very significantly to solution viscosity, and some of these are gel formers. The other widely used biopolymers include cellulose, starch, and chitin (Picout and Ross-Murphy, 2003). 16.11.2 In Geophysics Geophysics mainly deals with the study of rheology of molten lava and flow of debris (i.e., fluid mudslides). This area also includes the study of solid earth materials that exhibit time-dependent changes in flow characteristics. Geological systems that display viscous behavior are termed as rheids. For instance, at room temperature, granite has the tendency to flow like a plastic material at negligible yield stress (i.e., it exhibits viscous flow), while long-term experiments have shown that the viscosity of granite and glass under ambient conditions is around 1020 Poise (Vannoni et al., 2011). 16.11.3 Physiology Physiology includes the study of bodily fluids exhibiting viscoelastic flow characteristics and the study of blood flow is termed as hemorheology (Baskurt and Meiselman, 2003). Understanding the rheology of blood has been well discussed in the following case study. Rheology of blood reflects the dynamics of circulatory system. Sickle cell anemia, an inherited RBC disorder in pediatrics, alters the microrheology of RBC causing a significant change in the flow property of blood. Blood plasma comprises of dissolved proteins, such as fibrinogen, salts, carbohydrates, etc. and exhibits Newtonian behavior. While whole blood is a biphasic system, consisting of plasma and hematocrit, it exhibits Bingham plastic and shear thinning behavior due to the presence of RBC. At low shear rates, the viscosity of blood is higher due to the formation of rouleaux of RBCs, but as shear rate increases the aggregates are dispersed and viscosity decreases. Furthermore, these RBCs deform under shear stress as bullet-shaped components allowing easy passage through fine capillaries. Whereas sickle cell RBC become inflexible due to dehydration and resist deformation at high shear rates, they also exhibit higher viscosity leading to clinical complications such as increased stress on heart to pump blood, tissue infarction, DOSAGE FORM DESIGN CONSIDERATIONS 16.11 APPLICATIONS OF RHEOLOGY 585 and organ failure. Vernengo et al. (2014) developed an experimental model to compare the flow property of healthy blood and blood in diseased condition like sickle cell anemia. Aqueous glycerol solution was considered as plasma, chitosan as RBC and chitosan crosslinked with glutaraldehyde as sickle cell RBC. The rheological behaviors were determined using a rotational viscometer and the data was characterized by Casson model. 16.11.4 Food Rheology Food rheology plays an important role in the manufacture, processing, sensory properties, shelf life and consumer compliance of food products (Ahmed et al., 2016). Various researchers have assessed the rheological properties or the influence of additives on the rheological properties of food products such as bread (Upadhyay et al., 2012), butter (Rønholt et al., 2012), cheese (Berta et al., 2016; Fox et al., 2017), mayonnaise (Maruyama et al., 2007), jam (Dı́az-Ocampo et al., 2014; Guo et al., 2017), chocolate (Gao et al., 2015), and tomato ketchup (Barbana and El-Omri, 2012; Juszczak et al., 2013), to mention a few. Usually, viscosity enhancers such as polysaccharides (e.g., starches, vegetable gums, and pectin), or proteins, are incorporated in the product as they undoubtedly increase the viscosity of aqueous systems, but it is important to note their influence on other properties, especially the organoleptic property like taste. Thickening agents are materials used to thicken and stabilize liquid solutions, emulsions, and suspensions while providing body to the product. They act by dissolving in the aqueous medium as a colloid system forming weak cohesive internal structure. In the food segment, Hosseini et al. (2017) focused on determining the effect of varying shear rate, concentration, temperature, pH, and salt on the rheological behavior of bitter almond gum exudate. According to Power law model, the exudate displayed nonNewtonian, shear-thinning behavior without the thixotropic effect at tested concentrations and temperatures. Apparent viscosity was directly proportional to the concentration of gum concentrations and inversely proportional to increased shear rate, at a specified temperature. The viscosity showed a maximum at pH 7 which reduced at lower and higher pH values. Addition of salts (such as calcium chloride and sodium chloride) reduced the viscosity of the exudate. 16.11.5 Concrete Rheology Concrete rheology mainly includes the rheological properties of fresh cement paste. The study of mechanical properties of cement paste has revealed that the hardness of concrete increases when less amount of water is incorporated in the concrete mix, however reduction in water-to-cement ratio can hinder the ease of mixing and application. Thus, addition of superplasticizers in the concrete mix has the tendency to reduce the apparent yield stress and the viscosity of the fresh cement paste, thereby improving the concrete and mortar properties (Ferrari et al., 2011). Researchers have assessed various drilling mud systems such as potassium chloride (basic mud), potassium chloride/partial hydrolytic polyacrylamide, potassium chloride/ graphene nanoplatelet, potassium chloride/nanosilica, and potassium chloride/ DOSAGE FORM DESIGN CONSIDERATIONS 586 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS multiwalled carbon nanotubes, for their ability to enhance rheological properties and cause shale inhibition. Rheological properties of drilling muds, i.e., density of mud, apparent viscosity, plastic viscosity, yield point, gel strength, etc. are essential for the drilling operations. Shale is a material that has high affinity to moisture and swells due to the presence of clay minerals like kaolinite, smectite, and montrolite in shale. Thus, researchers focused on modifying the rheological properties of shale by incorporating graphene nanoplatelet, nanoparticles, polymers etc. to overcome the instabilities of shale. Assaad and Issa (2017) also studied the influence of styrene butadiene rubber latex on the rheological property of lightweight polymer-modified self-consolidating concrete. A brief overview of carbon nanotubes was presented by Tekade et al. (Tekade et al., 2017a). 16.11.6 Filled Polymer Rheology This area mainly involves the study of the effect of various types of fillers into polymers and their influence on mechanical, thermal, electrical, and magnetic properties of the final material. These filled polymer systems increase the complexity in the rheological characteristics of material (Shenoy, 2013). Addition of spherical or near-spherical filler particles increase the level of both linear and the nonlinear viscometric properties, and decrease the level of the elasticity. However, the addition of high-aspect-ratio, fiber-like fillers can enhance both elasticity and viscosity. Different types of organic and inorganic fillers used in polymers include alumina, asbestos, barium sulfate, calcium carbonate, calcium fluoride, carbon black, clays, diatomaceous earth, ferromagnetics, fly ash, glass fibers, gypsum, jute fiber, kaolin, lignocellulosic, magnesium hydroxide, nylon fibers, mica flakes, microcrystalline cellulose, powdered metals, quartz, silica, starch, talc, titanium dioxide, wood, etc. (Barnes, 2003). Bhagawan et al. (1988) studied the influence of fillers like clay, silica, and carbon black on the rheological properties of 1,2 polybutadiene using a capillary rheometer. Among the fillers used, silica-filled compound exhibited the highest viscosity and clay-filled compound the lowest viscosity at all shear rates. 16.11.7 Pharmaceuticals Study of flow properties of liquids is important for pharmacists working in the manufacture of several dosage forms, such as simple liquids, suspensions, emulsion, lotions, ointments, creams, pastes, etc. Flow properties are used as important quality control tools to maintain the superiority of the product and reduce batch-to-batch variations. Viscosity of parenteral preparations helps to determine the inner diameter and length of the needle. The force required to administer appropriate dose volume is proportional to the viscosity of the preparation. In case of auto-injectors, as the actuation force is determined, the time taken to inject the preparation will be dependent on the viscosity of the product (Palm et al., 2015). Rheology can be used as a powerful tool for predicting process parameters during formulation development. Determination of rheological properties of dispersion of drug moiety in polymer system helps to select the best-suited method of preparation and the DOSAGE FORM DESIGN CONSIDERATIONS 16.11 APPLICATIONS OF RHEOLOGY 587 processing parameters during formulation development. Yang et al. (2016) revealed that the rheological studies act as a powerful tool developing formulations using hot melt extrusion technique. The study revealed that the crystalline nature of drug showed more elastic nature than its amorphous form. This was beneficial in selecting the processing temperature for hot melt extrusion wherein the melting point of drug was critical for complete dissolution of drug in polymer system. Rheological investigation was further interrelated with melting depression of drug in polymer system determined by DSC studies. The optimized formulation was identified by carrying out heating-cooling thermal rheological cycle of extrudates with various drug loadings. These studies also provided a correlation between microstructure and bulk physical stability of the systems. Thus, it was clear that the rheological studies act as a powerful tool in deciding the method and process parameters during formulation development. Kattige and Rowley (2006) studied the effect of rheological behavior of lactose-poloxamer molten dispersions during capsule filling. The amount of disperse phase, particle size distribution, and viscosity of dispersion medium were the principal factors governing the capsule filling process. The developed dispersions exhibited shear-thinning nature with thixotropy and showed a sudden increase in apparent viscosity above a limiting concentration of disperse phase, which was the critical for the capsule filling. Rheology in biofabrication and bioprinting is another area gaining a lot of interest. Advancement in research has led to development of bio-ink which can be printed as 3D constructs and implanted into damaged tissue for tissue bioengineering. The rheological property of bio-ink impacts the delivery and integrity of 3D constructs, its biocompatibility and biofunctionality (Rios, 2017). Chung et al. (2013) selected alginate as a major component of bio-ink and employed extrusion technique for printing of cells. They investigated the rheological properties of alginate gelatin blends and pre-cross-linked alginate and alginate solution for their ability to print and support cell growth. They observed that the 4% alginate solution showed fluidity with dominance of loss modulus and insufficient storage modulus to hold the shape of printed ink. While pre-cross-linked 4% alginate with calcium was also shown to lack required storage modulus to hold the structure together. Nevertheless, 2% alginate gelatin blend, at desired (i.e., low) temperature showed high viscosity, dominance in storage modulus indicating viscoelastic behavior suitable for extrusion printing. Similarly, Brindha and coworkers (2016) also studied the rheological property of Bovine Serum Albumin and Horse Radish Peroxidase bio-inks using 1% carboxymethylcellulose (CMC) and 0.1% Triton-X-100 as modifiers, on inkjet printing where inverse Ohnesorge number (Jang et al., 2009) was used to evaluate the interrelation between rheological properties like density, surface tension, and viscosity. These parameters were effective in deciding the actuating velocity, jetting capability of the bio-inks, and the drop shape. Addition of CMC, viscosity modifiers, and Triton X-100, nonionic surfactant produced stable and repeatable drops during printing and maintained the activity of biomolecules. He et al. (2016) have also discussed the importance of viscosity during printing wherein the authors have deliberated that deformation is seen while printing materials of low viscosity and nozzles jam with high viscosity materials. They have suggested that the DOSAGE FORM DESIGN CONSIDERATIONS 588 16. RHEOLOGY AND ITS IMPLICATIONS ON PERFORMANCE OF LIQUID DOSAGE FORMS viscosity of extruding material should be in the range of 300 30,000 cps. Materials with viscosity ,300 cps cause smearing, while materials with viscosity .30,000 cps, require large pressure to extrude the material. On similar lines, Diamantides et al. (2017) investigated the influence of riboflavin photocross-linking and pH on the rheological behavior and printability of collagen bio-inks. It was observed that the riboflavin cross-linking enhanced the storage moduli of bio-inks at lower concentration of collagen, which reduced at higher collagen concentrations. The cross-linked bio-inks provided smaller dot footprint areas as compared to uncross-linked bio-inks. The rate of gelation and gel moduli was pH-dependent and showed a maximum effect at pH 8. 16.12 CONCLUSION Rheology is a branch of science that is valuable in determining the mechanical properties of fluids (liquids, emulsions, suspensions, stimuli-responsive hydrogels, etc.) by describing the flow behavior on application of stress. Rheology interlinks the properties, nature, structure, and processing of various materials, viz, viscosity modifiers, polymers, thickeners, gels. Rheology is a suitable quality control tool and is widely used across all industries concerning food products, pharmaceutical products, polymer science, bioprinting, paints, textiles, plastics, metals, geology, concrete material, etc. Mathematical explanations are important in describing the relationship between viscosity of systems with components and/or other parameters. The effect of physical and chemical variables on rheological properties of formulations provides an idea about the behavior of the system and can predict the possible outcomes during formulation development. To understand the rheological characteristics of the systems, the selection of an appropriate rheometer is of great importance. Rheometers are essential tools for accurate simulation of real processes and complete material characterization. Rheology plays a pivotal role in areas such as material science, geophysics, physiology, food rheology, concrete rheology, pharmaceuticals, and diagnostics. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant (Grant #ECR/2016/001964) allocated to Dr. Tekade for research work on gene delivery and N-PDF funding to Dr. Maheshwari (PDF/2016/003329) for work on targeted cancer therapy in Dr. Tekade’s Laboaratory. The authors also acknowledge the support by Fundamental Research Grant (FRGS/1/2015/TK05/IMU/03/1) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. 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Biotechnol. 109. Zhao, M., Zhang, Y., Zou, C., Dai, C., Gao, M., Li, Y., et al., 2017. Can more nanoparticles induce larger viscosities of nanoparticle-enhanced wormlike micellar system (NEWMS)? Materials 10 (9), 1096. Zhou, M., Lee, B.H., Tan, L.P., 2017. A dual crosslinking strategy to tailor rheological properties of gelatin methacryloyl. Int. J. Bioprint. 3 (2), 130 137. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 17 Micromeritics in Pharmaceutical Product Development Rahul Maheshwari1, Pooja Todke1, Kaushik Kuche1, Nidhi Raval1 and Rakesh K. Tekade1,2 1 National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 2Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 17.1 Introduction 600 17.2 Particle Size 17.2.1 Effects Particle Size 17.2.2 Particle Size Distribution 600 602 604 17.3 Methods to Determine Particle Size Distribution 17.3.1 Microscopy 17.3.2 Sieving Method 17.3.3 Dynamic Light Scattering 17.3.4 Electronic Scanning Zone (Coulter Counter) 17.3.5 Cascade Impactor 17.3.6 Laser Diffraction 17.3.7 Elutriation 17.3.8 Acoustic Spectroscopy Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00017-4 607 607 611 615 615 617 617 618 619 599 17.4 Significance of Micrometrics in Product Development: Tablet and Capsule 17.4.1 Content Uniformity 17.4.2 Flow Properties 17.4.3 Particle Arrangement and Compaction 17.4.4 Weight Variation 17.4.5 Segregation 17.4.6 Hardness 17.4.7 Compressibility and Compatibility or Tablet Strength 620 622 622 622 622 623 623 623 17.5 Powders 17.5.1 Flow Properties 624 624 17.6 Suspensions 627 © 2018 Elsevier Inc. All rights reserved. 600 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 17.7 Emulsions 627 Acknowledgment 632 17.8 Novel Drug Delivery Systems 628 Abbreviations 632 References 632 Further Reading 635 17.9 Relation Between Crystallization and Micromeritics of Drug Substances 630 17.10 Conclusion 631 17.1 INTRODUCTION Accurate determination of particle size has become essential in many industries, as it is a fundamental physical characteristic that must be selected, monitored, and controlled from the raw material source to the finished product (Mastalerz et al., 2017). There is an optimum particle size, or at least a smallest and largest acceptable size, for most formulations involving particles. The key to accurate particle size determination is selecting the most appropriate sizing instrument for a particular application (Sun, 2017). If all particles were spheres, their size would be defined explicitly by their diameter or radius; if cubical, the length along one edge would be characteristic; and, if of another regular shape, another equally appropriate dimension could be chosen. Unfortunately, the great majority of particles are quite irregular and an arbitrary definition of size is the only simple solution. Moreover, typical collections of particles include many different sizes and shapes (Mörsdorf et al., 2015). Therefore, a definition is required that accommodates this diversity, and the “equivalent spherical diameter (or radius)” satisfies this requirement. Equivalence of size means that a specific, experimentally measured attribute of the particle is the same as that of a sphere of a certain size (Allen, 2013). In other words, when the particle under test and a sphere of a specific size are exposed to the same conditions, the identical reaction occurs. Examples of reactions that may occur are the light scattering characteristics (scattering equivalency), the attainment of a certain terminal settling velocity (settling equivalency), or the displacement of fluid (volume equivalency) (Xu, 2015). Therefore, obtaining particle size information about a material may be accomplished by a number of techniques, each of which test for a specific equivalency. Micromeritics offers instruments that use three different techniques. This allows one to select the best technique for a material and application rather than trying to adopt one method to all situations. The sizing techniques used by micromeritics are light scattering, sedimentation, and electric sensing zone. As is always the design objective with micromeritics instruments, each instrument provides the user with high data quality (resolution and accuracy) and with a dependable measuring tool (reliability, repeatability, reproducibility) (Richard et al., 2016). 17.2 PARTICLE SIZE Particles can be defined by size, shape (length, breadth, and height), volume (liter), and surface area (cm2) properties and can be either made of solid substance or liquid. All these DOSAGE FORM DESIGN CONSIDERATIONS 17.2 PARTICLE SIZE 601 parameters are important in bulk properties, product performance, processability, stability, and appearance of the end product when it comes to pharmaceutical formulation and manufacturing (Allen, 2013). In context, particle size is the term which is mostly used for denoting the dimensions of solid powders, liquid particles, and gases bubbles. In the pharmaceutical world, particle size is linked to development of new chemical entities (NCEs) which improve dissolution rate, i.e., the absorption rate of poorly soluble drug can be improvide by reducing the particle size which ultimately improves the bioavailability of drugs. Physical properties of active pharmaceutical ingredients and excipients largely depends on their particle size which are used to formulate pharmaceutical dosage form (Sun, 2017). That is because particle size and shape have profound impacts on each and every manufacturing step, including mixing, granulation, drying, milling, blending, coating, encapsulation, and compression. As per ICH Guidelines, particle size is critical to solid dosage form and liquids containing undissolved particles (for example Suspension and emulsion), influencing the safety, efficacy, and stability of the formulation. From the tablet and capsule manufacturing perspective, controlling the particle size is foremost to reach the product with acceptable standards for the FDA, because particle size influences a large number of parameters in processing, including capsule filling, porosity, and flowability. Likewise, in suspension, the physical properties of the fluid and the size of particles both have an effect on precipitation and aggregation which affect the stability of formulation. Fig. 17.1 representing the US standards for particle size and Fig. 17.2 illustrates the scale of particle size in drug delivery. The particle shape is playing a major role in particle size distribution. The shape of a particle is not always regular (symmetrical) and can be in asymmetrical or uneven. FIGURE 17.1 US standards for particle size. Standard is listed for very coarse particles which are .1000 µm, coarse particles (355 1000 µm), moderately coarse particles (180 355 µm), fine particles (125 180 µm) to very fine particle size, i.e., 90 125 µm. The finer is the particle, the more it will be soluble and bioavailable. DOSAGE FORM DESIGN CONSIDERATIONS 602 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 17.2 The scale of particle size in drug delivery. Importance of particle size in lymphatic drug delivery, oral, intranasal, ocular, transdermal, brain/tumor, aerosol, intraperitoneal delivery. Different delivery routes may require different particle size. Therefore, it is difficult to measure through a meaningful diameter. Complex statistical analysis of irregular shaped particles has been derived from different geometries. However, particle size is expressed as equivalent spherical diameter to correlate with the size of particles to that of a sphere with the same diameter, surface area, and volume. The measurement of size of irregular particles depends upon which type of method is applied (Lowell and Shields, 2013). The particle sizes expressed by diameter are shown in Table 17.1. Particle size is a simple concept but it is a most critical process parameter in preformulation and manufacturing. It is also true that the reduction of particle size impacts directly on the bioavailability of drug. Thus regulatory agencies are now more concerned about particle size specifications of active pharmaceutical ingredients and excipients. The major critical parameters, such as dissolution and manufacturing process issues, are largely influenced by particle size. 17.2.1 Effects Particle Size 17.2.1.1 Effect of Particle Size on Dissolution According to Noyes Whitney equation, dissolution depends on the solubility, concentration in solution, diffusion of drug particle to bulk solution, and most commonly surface area. The smaller particles have a larger surface area than larger ones, hence, they show DOSAGE FORM DESIGN CONSIDERATIONS 603 17.2 PARTICLE SIZE TABLE 17.1 List of all Equivalent Spherical Diameters With Their Respective Definition and Formulas Name of Diameter Symbol Definition Method Surface diameter Ds Diameter of a sphere having the same surface area as that of particle Adsorption Volume diameter dv Diameter of a sphere having the same volume as that of particle Laser diffraction Projected area diameter dp Diameter of a sphere having the same area as that of particle Microscopy Stokes’ diameter dst Sieve diameter Formula Dsurface 5 DVolume 5 6 sparticle π 6 vparticle π DA 5 1=2 Diameter of an equivalent sphere Sedimentation sediments at the same rate as Elutriation that of particle DS 5 sﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ 18ηV ðPS 2 PL Þg dsieve Diameter of a sphere that passes from same sieve aperture as that of particle Sieving DSIEVE Volume-surface diameter dvs Diameter of a sphere having same volume to surface ration as that of particle Adsorption Maximum length dmax Sphere of same maximum length Microscopy as that of particle being measured Hydrodynamic diameter DH Sphere of same translational diffusion coefficient as that of particle being measured Dynamic light scattering Diameter of a sphere with similar density as that settles with the same speed Cascade impactor Aerodynamic diameter 1=2 1=3 4A L DSV 5 DV 3 DS 2 Dmax DH 5 kT 3πηDtranslation Here, Ds, surface diameter: sphere diameter which have equal surface area as that of particle; dv, volume diameter: which defined as diameter of a sphere consuming similar volume of particle; dp, projected area diameter: diameter of a sphere having the same area as that of particle; dst, Stokes’ diameter: that is diameter of an equal circular sediments at the same rate as that of particle; dsieve, sieve diameter: sphere diameter that passes from same sieve; dvs, volume-surface diameter: sphere diameter having same volume to surface ration as that of particle; dmax, maximum length: maximum length of Sphere as that of particle being measured; DH, hydrodynamic diameter: spherical particle translational diffusion coefficient; Aerodynamic diameter: sphere diameter with parallel density of particle with same speed when particle settles. higher dissolution than larger particles. As an example, Sun et al. prepared two batches of nanocrystals, i.e., 80 and 120 nm of poorly soluble coenzyme Q10, and it was observed that the 80 nm nanocrystals had more kinetic solubility than the 120 nm nanocrystals. It was concluded that the reduction in particle size results in an increased surface area and differential concentration than larger particles of poorly soluble coenzyme Q10 by producing a thinner diffusion layer which ultimately increases the dissolution (B85%) (Sun et al., 2012). In this context, the disjoining pressure of smaller particles is greater than that of larger particles, so small particles are have a higher interfacial solubility than larger particles. The results concluded that the batch containing smaller particles gives a significantly higher bioavailability. DOSAGE FORM DESIGN CONSIDERATIONS 604 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT Conversely, reduction of particle size can lead to a decrease in rate of dissolution. As an example, theophylline tablet containing 30 50 µm particle size showed faster dissolution than that of 10 µm. The expected reason for the above statement is agglomeration of smaller particles which will lead to a decrease in the rate of dissolution and decrease the bioavailability. 17.2.1.2 Effect of Particle Size on Manufacturing Processing Parameters Particle size is often an important process parameter during granulation, spray drying compression, and capsule filling. In some cases, particle size of drug itself can be a factor in mixing uniformity. When a sample containing particles of different sizes are mixed, the smaller particles tend to travel between the bigger particles, i.e., they “percolate” downward. This behavior causes nonuniform mixing and undesirable weight variation. Particle size segregation can be controlled by various strategies. One technique uses ordered mixtures, where lactose as a carrier excipient is covered with a monolayer of fine particles of drug. To increase the amount of drug absorbed on the carrier by micronization, the carrier particle size should be as large as possible and the particle size should have a narrow distribution to improve homogeneity. Drug particle size acts as an important factor in content uniformity of low dose drugs to pass the USP content uniformity test. It is generally accepted that a reduction in particle size eliminates the issue of content uniformity but further reduction of size of particles increases the chances of failure in content uniformity. For example, Egermann suggested a reduction in the particle size of medazepam from 156 to 82 µm which improved the content uniformity but a further reduction from 82 to 32 µm drastically decreased the tablet uniformity. The reason behind the decrement of tablet uniformity is that smaller sized particles tend to impart cohesiveness and cause agglomeration (Egermann, 1985). In addition, one study involved granulation of lactose and chlorpheniramine maleate solutions and it was observed that fines of lactose adhered to the filter bag which resulted in an undesirable impact on tablet properties (Wan et al., 1992). All recent articles have proposed that there is a relationship between particle size and tablet properties and this becomes critical in tablet hardness, drug content, flow rate, and disintegration. The distribution of particles or the range of particle size can influence quality parameters such as safety, efficacy, and stability of product. As of now most pharmaceutical substances have a range of sizes or distribution of particle size which need to be determined. To determine the simple average of diameter of sample, the mean, median, and mode are largely used. 17.2.2 Particle Size Distribution Particle size distribution (PSD) is a primary factor referring to the list of values which defines the range of particle sizes on the basis of their mass or volume of particles. We cannot use the term average size because different sizes of particles cannot describe the distribution pattern of the whole sample (Allen, 2013). The same sample can be measured through different techniques. It is important to see that the particle size distribution (PSD) has numerous industrial applications such as it can be used to determine the setting time DOSAGE FORM DESIGN CONSIDERATIONS 17.2 PARTICLE SIZE 605 of cement, activity of catalyst, and in food and metallurgical materials. From a pharmaceutical point of view, it is vital to define the stability, esthetic appearance, rate of absorption, and bioavailability of drugs (Pol et al., 2014). In addition, regulatory agencies of different countries give special emphasis to clearly establishing the PSD of excipients as well as pharmaceutical formulations (Tinkle et al., 2014). 17.2.2.1 Types of Particle Size Distribution 17.2.2.1.1 NUMBER WEIGHTED DISTRIBUTIONS Product quality research institute (PQRI) suggested that the use of image analysis for particle size distribution will give a number-weighted distribution (number average diameter). Number weighted size is actually what one could see under a transmission electron microscope (TEM). This represents what a “normal brain” can understand. Volume weighted size means volume. It represents the population of particles, seen by their volume. It also means that particles having a diameter twice the diameter of another population of particles will be eight times more important than the smaller ones (due to the equation of a sphere volume (r3)) if the population number is the same in each case. As an example, consider the fine particles. Three particles are 1 µm, three are 2 µm, and three are 3 µm in size (diameter). Building a number distribution for these particles will generate a homogeneous distribution over the size, where each particle size accounts for one-third of the total. If this same result were converted to a volume distribution, the result would appear differently where 75% of the total volume comes from the 3 µm particles, and less than 3% comes from the 1 µm particles. When presented as a volume distribution it becomes more obvious that the majority of the total particle mass or volume comes from the 3 µm particles (Pol et al., 2014). For more understanding, the number average is obtained if we sum up the sizes of each particle and then divide by the number of particles. The result may or may not be also the most frequent particle size present in your sample, depending on whether the distribution is Gaussian or not. It will not tell you in which size of particles most of your material in terms of mass or volume is present. For example, if a sample contains one million of 1 nm particles and 10,000 of 10 nm particles, then, 99% of all particles are 1 nm, while 90% of the material in terms of its mass or volume is present in the form of 10 nm particles. So, a number average will be close to 1 nm, while a volume average will be close to 10 nm. This is why TEM gives often completely different results than dynamic light scattering (DLS) (Allen, 2013). 17.2.2.1.2 VOLUME WEIGHTED DISTRIBUTIONS Particle size distribution data are represented via the volume of the particle (volume average diameter) equivalent to mass, if density is the same in each particle, i.e., the relative contribution will be proportional to (size). Laser diffraction is the most popular technique used for volume weighted distribution. From a commercial perspective, this technique is extremely useful; it provides data for a sample in terms of its volume/mass (Krause et al., 2010). DOSAGE FORM DESIGN CONSIDERATIONS 606 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT By analogy with the number-average and weight-average molecular masses of a polymer sample, the number-average particle size will tend to be more influenced by the population of smaller particles, and vice versa, the volume-average size will be more sensitive to the presence of larger particles. In polymer science, both parameters (and even several additional ones) are used to characterize the sample weight distribution, a single parameter is not enough for a complete description, but can be used depending on the certain task. It is recommended that if one is interested in a fraction of “extra-super-nano” particles, the number-average size should be used, and if the agglomerated or microparticles admixture is to be followed, the volume-average size is better option. Also, the ratio of the volume-average and number-average sizes will characterize the width of the size distribution (i.e., size dispersity), again, by analogy with the polymer sample. 17.2.2.1.3 INTENSITY WEIGHTED DISTRIBUTIONS The intensity distribution is naturally weighted according to the scattering intensity of each particle fraction or family. For biomaterials, the particle scattering intensity is proportional to the square of the molecular mass. In itself, the intensity distribution could be slightly misleading, in that a small amount of aggregation agglomeration or the presence of a larger particle species can govern the distribution. However, this distribution can be employed as a sensitive detector for the presence of large material in the sample. For example, using Rayleigh approximation, the relative contribution for very small particles will be proportional to (size) 6 (Baalousha and Lead, 2012). 17.2.2.2 Particle Size Distribution Analysis of Data by Statistics The conventional way to represent the data of distribution of particles is in the form of frequency distribution curve or a cumulative distribution curve. The simplest way to determine the particle size distribution is by calculating the mean, median, and mode. Mean denotes the “average size” of a sample, but it is sensitive to higher values and therefore is not used. Types of mean are described in Table 17.2. TABLE 17.2 Types of Means Types of Means Description Uses Number length mean (arithmetic mean) It will give result of total number of particles in sample In particle counting applications Surface area moment mean (Sauter Mean Diameter) It most resembles where specific surface area is important In bioavailability, reactivity, dissolution Volume moment mean (De Brouckere Mean Diameter) It is most relevant where samples will represent It is mostly useful monitoring the size the data of size of those which having higher coarse particle which make the bulk of frequency in bulk of sample this sample. Note: average size of particles which assumed as spherical particles; type of diverse mean of spherical particle whch are categorized as arithmetic mean: number length mean; Sauter mean diameter: surface area moment mean; De Brouckere mean diameter: volume moment mean. DOSAGE FORM DESIGN CONSIDERATIONS 17.3 METHODS TO DETERMINE PARTICLE SIZE DISTRIBUTION 607 In addition, one-way ANOVA is used to compare one variable (say size) between three or more groups to provide information to see if they are different or the same—for instance if the size distribution is significantly different between the four groups. Apart from that, a two-way ANOVA also allows to determine the effect of two factors—for instance, what is the effect of milling on the four drugs. In this case, milling would be one factor, and the drug will be another factor. ANOVA would answer the questions such as “Is the response affected by milling by drug type?” and “Do the two factors interact?” However, software such as Prism would be additionally required to calculate the mathematical calculations. 17.3 METHODS TO DETERMINE PARTICLE SIZE DISTRIBUTION 17.3.1 Microscopy Generally, the most popular and accurate method for determination of smaller particle size is microscopy. Using microscopy, one can look directly at the shape of particle as well as check the dispersion and agglomeration in the sample. This method is reasonably cheap and can provide image analysis that can be used for examination of discrete particles. This is the reason microscopy is often referred to as an absolute measurement technique (Allen, 2013). A limitation of this method is that the diameter of the particle is obtained from only length and breadth of particle, i.e., it is two-dimensional and does not allow for estimation of thickness of particle (depth). PQRI (The Product Quality Research Institute) collaborated with FDA to provide the information regarding the selection of suitable particle-size analysis techniques, development and validation of particle-size methods, and the establishment of acceptance criteria for the particle size of drug substances used in oral solid-dosage forms. Some PQRI recommended techniques for particle size distribution are shown in Table 17.3. 17.3.1.1 Optical Microscopy Optical microscopy is usually used for the characterization of particles whose size is ranging between 0.25 µm and 100 µm. As compared to an ultramicroscope and electron microscope, the resolving power is lower in an optical microscope This technique serves as a most suitable and favored method for the routine optimization of some formulation variables. Optical microscopy technique is applied for determination of particle size in suspension, aerosol, and globule size of emulsions. In this method, the required sample size is less than 1 g. The particle size in optical microscopy is expressed by projected diameter (Dp), i.e., the diameter of a sphere having the same area as that of irregular particles when observed under a microscope (Pol et al., 2014). A sample, such as emulsion or suspension (diluted or undiluted), is mounted on a glass slide and placed on the mechanical stage of microscope. The eyepiece of the optical microscope is fitted with a micrometer which is used for particle size determination. The radial field can be projected on a screen for measurement and photographs of the projected site can be taken from the slide. The measurements are made horizontally across the center of DOSAGE FORM DESIGN CONSIDERATIONS TABLE 17.3 PQRI Recommended Techniques for Particle Size Distribution Size (µM) Methods Acoustic spectroscopy Shape of Particle Min 0.01 Max 10 Distribution Width Sample Modality Dispersion Wet Concentration Application High Measurement of macromolecules Measurement thermal and optical properties Chord length measurement 1 10000 Wet Low high Application in aerospace flow Disc centrifuge 0.005 100 Wet Low Analysis of agglomeration, analysis of liposome and microencapsulated drugs Dynamic image analysis 0.05 3500 Wet and dry Low Visualization actual particle Elipitically polarized light scattering 0.005 10 Wet Low Depth resolved particle image analysis Electrical sensing zone 0.4 1600 Wet Low Trace particle contamination, shape of particle Hydrodynamic chromatography 0.01 50 Wet Low Enantiomer separation, geology Laser diffraction 0.01 .5000 Wet and dry Low Determination stability of dispersion system, measurement of moisture level Light obscuration 0.5 5000 Wet Low Injectable preparation, process water supply Photon correlation spectroscopy 0.0003 3 Wet Low Bacteriology, Chemotaxis study, Conformation changes and protein denaturation study Polarization intensity diffraction scattering 0.004 0.4 Wet Low Sieve analysis 5 10000 Wet and dry High For sizing of nonspherical submicron particles Fertilizer industry, Cement industry Scanning electron microscopy 0.001 5 Wet and dry Low In micromeritics-particle size Static image analysis 1 10000 Wet and dry Low Histopathological studies Here, PQRI, product quality research institute; explain about acoustic spectroscopy; chord length measurement; disc centrifuge; dynamic image analysis; elipitically polarized light scattering; electrical sensing zone; hydrodynamic chromatography; laser diffraction; light obscuration; photon correlation spectroscopy; polarization intensity diffraction scattering; sieve analysis; scanning electron microscopy; static image analysis. 610 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 17.4 Types of Diameter. These Diameters Employed for the Measurements of Particle Size With Special Focus on Certain Parameters Diameter Definition Feret The distance between tangents on opposite sides of the particle parallel to some fixed direction that is Y direction Martin The length of a line that bisects the particle image Projected area The diameter of a circle with the same area as that of particle observed perpendicular to the surface on which the particle rests Note: The size of spherical particle definitely and quantitatively explained through diameter of particle. Particle of any material mostly to be asymmetrical in form and nonspherical. But when particle is hypothetically considered as spherical particle and diameter of spherical particle categorized as ferret diameter; martin diameter; projected area diameter. FIGURE 17.3 Diameter for measurements. Three main diameters of particle depicted here as projected area diameter, Martin diameter, and Feret diameter. Martin’s diameter is the averaged cord length of a particle which equally divides the projected area. Feret’s diameter is the averaged distance between pairs of parallel tangents to the projected outline of the particle. The projected area diameter is the diameter of a sphere having the same projected area as the particle. the particle (chosen fixed line). The mostly used diameters for measurements done by microscopy are shown in Table 17.4 and Fig. 17.3. 17.3.1.2 Electron Microscopy An electron microscope is a dynamic instruments that uses highly energetic electrons of beam for the determination of very fine scales of particles (up to 0.2 µm). It has a higher resolving power (0.3 nm) than an optical microscope that allows the examination of very small objects. The clear surface features of biological or any other materials can be observed under electron microscopy, e.g., histopathological studies, the shape and size of an organelles, and it is useful in the investigation of clinical specimens like renal diseases, tumor processes, storage disorders, and infectious agents. This method provides numerous advantages such as high magnification ( 3 10,000 and high resolution of 0.3 nm), individual particle examination, and particle shape measurement. However, this method is expensive and a trained operator is required. 17.3.1.2.1 SCANNING ELECTRON MICROSCOPY (SEM) AND TRANSMISSION ELECTRON MICROSCOPY (TEM) In SEM and TEM, the microscopical technique provides direct measurement of particle size as well as surface area by using electron beams (Maheshwari et al., 2012). The range DOSAGE FORM DESIGN CONSIDERATIONS 17.3 METHODS TO DETERMINE PARTICLE SIZE DISTRIBUTION 611 of particle size determination is about 0.001 5 µm. The principle of detection is the use of a fine beam of electrons of medium energy, i.e., 5 50 Kev, to scan the sample simultaneously, then these electrons produce secondary electron emissions such as scattered light, electrons, X-rays which get detected and produce image of particles. In the case of TEM, this is the more advanced technology which uses electron beams to transmit across the sample producing image on a photographic plate. SEM provides information related to the topography of particles but this equipment is expensive (cost is around US$100,000) and sample preparation for SEM is more complex and time-consuming than optical microscopy. SEM is faster than TEM in producing three-dimensional images of particles (Maheshwari et al., 2015b). 17.3.2 Sieving Method A most commonly used method is sieving and sorting a large quantity of particles into various size ranges. The characterization particles size ranges from 5 12,000 µm. Generally, it is a simpler and more cost-effective method for the particle size analysis than microscopy, but still, there is the requirement for a trained operator. Sieving method is not accurate for nonspherical particles but this limitation can be overcome by applying vibration to move particles from the aperture (Bernhardt, 2012). Vibratory sieving machines consist of vibratory screens which are rectangle-type sieving machines and they work on the principle of gyratory motion. In this method, series of sieves are used and are calibrated by National Bureau of Standards. The I.P Standard of sieve series are shown in Table 17.5. In this context, a series of sieves consists of apertures ranging from large (99 µm) to small (5 µm) which are produced by photo-etching and electroforming techniques. According to the US procedure for sieving analysis, a mass of sample is placed on the stack of sieve in mechanical shaker. The mass of the sample is shaken for definite period of time and the portion of sample that passes from one sieve to be retained on the next finer sieve is collected and weighed. Obtained data are analyzed for normal, log-normal cumulative percentage frequency distribution, and probability curve. It is a simple, rapid, inexpensive method, but still, it has issues since precision is tough to achieve using this technique and this method is also not applicable for all dispersed systems, also cohesive or nonspherical particle can clog the aperture. (Blott and Pye, 2012). 17.3.2.1 Air-Jet Sieving Air-jet sieving overcomes the problem of the formation of clumps on the sieve, which is a common problem associated with the simple sieving method. In this method, a series of plates are fitted with a reduced pressure stream of air which blows the particles that creates the blockage during sieving process. This method is suitable for particles having size below 40 µm. The sample is introduced into the sieve and covered with a lid. Sieves fitted with a powerful vacuum cleaner create a strong jet of air, which helps to disperse the clogged particles present on the sieve through the slotted nozzle rotating below the sieve mesh (Kaialy et al., 2012). The air-jet sieving is depicted in Fig. 17.4. DOSAGE FORM DESIGN CONSIDERATIONS 612 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 17.5 Mesh Size With Its Pore Size in µm as per IP U.S. Tyler Nominal Sieve Opening Mesh Number (#) Mesh Number (#) (µm) Inches 4 4 4760 0.0185 6 6 3360 0.131 8 8 2380 0.093 12 12 1680 0.065 16 14 1190 0.047 18 16 1000 0.039 20 20 840 0.033 30 28 590 0.0328 40 35 420 0.0232 50 48 297 0.0164 60 60 250 0.0116 70 65 210 0.0097 80 80 177 0.0082 100 100 149 0.0069 140 150 105 0.0058 200 200 74 0.0041 230 250 62 0.0029 270 270 53 0.0023 325 325 44 0.0017 400 400 37 0.0015 625 20 0.0008 1250 10 0.0004 2500 5 0.0002 Note: Through piling screen of sieves different size of particles separated which aid in particle size distribution. Here, two scales are mentioned for the classification of particle sizes; US sieve series and Tyler mesh size. 17.3.2.2 Sedimentation Method The sedimentation method is based on the principle of gravity that deals with the measurement of the rate of settling of the particles of powders which are uniformly dispersed in a fluid. This method is used for the measurement of particle size in the range of 1 200 µm. In this method, the particle size is expressed via Stokes diameter (dst) which is referred to as the diameter of an equivalent sphere having the same rate of sedimentation of the irregular particles. Sedimentation of particles can be studied by using Andreasen pipette, balance method, and hydrometer method (Bernhardt, 2012). DOSAGE FORM DESIGN CONSIDERATIONS 17.3 METHODS TO DETERMINE PARTICLE SIZE DISTRIBUTION 613 FIGURE 17.4 Schematic diagram of air-jet sieving. The material on the sieve is moved by a rotating jet of air: a vacuum cleaner which is connected to the sieving machine generates a vacuum inside the sieving chamber and sucks in fresh air through a rotating slit nozzle. The principle of sedimentation can be described by simple laboratory methods like “beaker decantation.” For this, the sample of mass under test is dispersed uniformly in water. A wetting agent may be added to ensure a complete and uniform dispersion of particles. A siphon tube is dipped into the water to a depth of “h” below the water level, about 90% of the water depth “L.” The particle size is measured by calculating the terminal velocity “V.” The law of gravity is applicable to asymmetrical particles of various sizes as long as one assumes that the diameter obtained is a relative particle size equivalent to that of a sphere-shaped particle falling at the same velocity as that of the particles considered. In this method agglomerated particles or clumped particles fall more rapidly than individual particles (Aulton, 2013). The formula of Stokes law is given in Eq. (17.1). v5 d2 gðDs Df Þ 18η (17.1) where, d is the Stokes diameter, g is the gravitational acceleration (m/s2), Ds is the mass density of the particles (kg/m3), Df is the mass density of the fluid, η the dynamic viscosity (kg /m*s). 17.3.2.2.1 ANDREASEN PIPETTE To analyze the particle size distribution of a powder in a wet sample, one of the most widely known and used techniques was developed by Andreasen and Lundberg and employs the sedimentation principle for the particle size analysis. It is commonly known as the Andreasen pipette method. This sedimentation method is based on the Stokes law and is expressed using Eq. (17.1). In this technique, the particle size analysis can be done via two methods, one is by measuring the particle retention in one particular zone and the other type which includes a nonretention measurement zone like in pipette method, wherein the known volumes of suspension are drawn off and the concentrations are measured with respect to time (Ryżak and Bieganowski, 2011). The Andreasen fixed pipette comprises of a 200 mm well-calibrated cylinder of volume capacity of 500 mL suspension as shown in Fig. 17.5, at the center of the cylinder is a pipette held in a position by glass stopper so that its tip overlaps with the zero level, and a three-way tap allows easy withdrawal of samples which can be centrifuged and weighed (Bergum et al., 2014). Thus, the weight of each residue taken out is termed as the weight of undersize and the sum of all weight is called the cumulative weight of undersize, thus, DOSAGE FORM DESIGN CONSIDERATIONS 614 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 17.5 Schematic representation of Andreasen pipette and hydrometer. (A) Representation of essential parts of a Andreasen pipette employed for vertical sampling used for particle size distribution, and (B) hydrometer. This method is rapid and is well within the usual accuracy of sampling and dispersion. The pipette samples are taken from a known depth, and the hydrometer is immersed in a suspension which is uniform throughout. this data of cumulative weight of undersize is used for estimating particle weight distribution and number distribution (Eqs. (17.2) and (17.3)). d2 ðρs 2 ρo Þg 18η᾿ 0 (17.2) sﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ 18η᾿ 0 h d 5 ðρs 2 ρo Þg (17.3) V5 Or 2 where, V 5 rate of particle settling h 5 is the distance of falling/settling d 5 mean diameter of the particles ρs 5 density of the particles ρo 5 density of the dispersion medium g 5 acceleration due to gravity η᾿ o 5 viscosity of the medium DOSAGE FORM DESIGN CONSIDERATIONS 17.3 METHODS TO DETERMINE PARTICLE SIZE DISTRIBUTION 615 This method has numerous advantages such as simplicity for measurement of particle size and it is cheaper than other methods. This method also helps in the identification of true fractional size analysis than other sieve analyses. It provides result of the analysis of particle size with accuracy and reproducibility (Mörsdorf et al., 2015). 17.3.3 Dynamic Light Scattering Dynamic light scattering, also called Photon correlation spectroscopy or quasi-elastic light scattering, is a popular, noninvasive method used for measuring submicron particles to 1 nm. This method is used for evaluation of samples such as proteins, polymers, micelles, carbohydrates, nanoparticles, colloidal dispersions, and emulsion. This technique typically provides information such as intensity-weighted average (i.e., z average) and polydispersity index, which is a useful quantification of distribution width. When compared with laser diffraction or microscopy, the results of mean values are transformed into volume-based or number-based distributions (Soni et al., 2016). When light from a laser light source enters into the sample to be measured, the particle suspended in the sample undergoes Brownian motion caused by thermally induced collisions between the suspended particles and solvent molecules. The fluctuation of scattering light is directly proportional to the particle size using the Stokes Einstein relationship (Sengupta et al., 2013). This method measures the hydrodynamic diameter and is defined by a sphere that has the same translational diffusion coefficient as the particle being measured. The laser source produces light which enters into the sample cell and a scattered light signal is produced. This signal is collected from a right angle detector (90 degree) and a back angle detector (120 degree). The obtained signal from the detectors shows some random changes because of the changing of the positions of particles due to Brownian motion (Power et al., 2013). The schematic representation of dynamic light scattering is shown in Fig. 17.6. This method has several advantages, such as less quantity of sample is required, fast analysis, noninvasive technique, and entire sample recovery is possible. It is used for nanosize particles measurement such as for biomaterials, drug delivery vehicles, etc. 17.3.4 Electronic Scanning Zone (Coulter Counter) This method is also commonly known as the Coulter counter method and is also considered to be the most accurate method for analyzing the particle size of a sample. This method is capable of counting the particles within the range of 0.1 1000 µm. However, for this method the sample is to be suspended in appropriate dilution in a electrolyte solution followed by ultrasonication so as to break the agglomerates, if formed (Aulton, 2013). It is based on the principle that as the voltage is applied across one side of the electrode, the other side which is outside the aperture is formed through a sapphire crystal (which is a blue colored gemstone formed from aluminum oxide) which lies in the wall of the hollow glass tube. Thus, a specific volume of suspension is taken through the orifice. As the volume of electrolyte fluid enters, it displaces some volume which causes a change in electrical resistance which is proportional to the volume of the particle. This change in the DOSAGE FORM DESIGN CONSIDERATIONS 616 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 17.6 Schematic representation of working principle of dynamic light scattering. Effect of particle size on final peak pattern. For example, the intensity of photon arriving at the detector depends on the particle size of a particular sample. The peak pattern varies with change in particle dimension. resistance is then converted to voltage pulse and then amplified and processed electronically and the pulses which have values within the precalibrated limits are used to split the particle size distribution (Bernhardt, 2012). The only care that must be taken is that while estimating particle size distribution in powder with coarser size, an orifice of wider diameter must be taken so as to prevent any coarser particle blocking it. Also, the orifice should not be so wide that when a relatively small particle passes through the orifice it creates a minor volume change that cannot be detected by accurately. Particle size distribution results can be achieved in a very short period of time using this method. This method provides the fastest counting and is reliable for counting 4000 particles in one second. Even though this method is considered to be the finest technique to analyze powder, it is still a sophisticated and expensive method for analysis (Fu et al., 2012). The principle of the Coulter counter is shown in Fig. 17.7. DOSAGE FORM DESIGN CONSIDERATIONS 17.3 METHODS TO DETERMINE PARTICLE SIZE DISTRIBUTION 617 FIGURE 17.7 Principle of Coulter counter. This technique is based on calculable alterations in electrical impedance generated by nonconductive particles suspended in an electrolyte. A small opening (aperture) between electrodes is the sensing zone via which suspended particles pass. 17.3.5 Cascade Impactor This method works on the principle of the law of inertia and, when sedimentation technique is inadequate for measurement of small particles, a cascade impactor is used. Cascade impactor is mostly used for particles in the range of about 0.1 100 µm. In principle, during the operation of the cascade impactor, the particles in the sample move and classify themselves according to the size of particles. Then, particles are collected in series on collecting plates. The deposition of the particles on each plate depends on the impact velocity of the gas stream. A schematic diagram of the cascade impactor is shown in Fig. 17.8. Sorting out different sizes of particles is possible with this method (Hinds, 2012). 17.3.6 Laser Diffraction Laser diffraction is most popular in particle size measurement of samples that ranges from 0.0001 1000 µm in size. Laser diffraction is widely used for of the determination of particle size distribution by measuring the angular variation in intensity of light scattered when a laser beam enters across a dispersed sample. Larger particles scatter light at a smaller angle than smaller particles (Polakowski et al., 2014). Laser diffraction works on the Mie theory of light scattering to measure the particle size distribution by determining particle size as a volume equivalent sphere diameter The Mie theory requires knowledge of optical properties of the sample, i.e., refractive index and imaginary component, but the most commercial light scattering instrument uses Fraunhofer diffraction which does not require knowledge of optical properties of sample and dispersant. The principle of Fraunhofer diffraction is also known as static light scattering and it is mostly applied to large particles. The principle of operation of laser diffraction is shown in Fig. 17.9. Analysis of particle size distribution using this technique is relatively rapid for submicron DOSAGE FORM DESIGN CONSIDERATIONS 618 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 17.8 Schematic representation of cascade impactor. Material arrives at a sequence of discs intended to accumulate particulate matter and it is collected as it passes through the disc series. The size of the discs is graduated, to properly determine the size of the particulate matter at each stage of the impactor. FIGURE 17.9 Principal of dynamic light scattering. The measurement is based on the intensity of light that is detected by the detector after the interaction with particle in suitable medium. This technique in physics that can be used to determine the size, polydispersity index, and zeta potential. to micrometers. It is one of the methods favored for routine analysis of samples and it is highly possible to analyze more than 100 sample in one day. Notably, this technique requires little or no calibration (Wang et al., 2012). (DOI: 10.1007/978-1-4020-9016-5_10) 17.3.7 Elutriation Elutriation is a method used for the separation of particles depending on their particle size, shape, density. This method follows the process of reverse gravity sedimentation. This is a physical process to separate fine and coarse particles from overflow liquid or fluid and suspended liquid or fluid. The particle size less than 1 µm can be determined DOSAGE FORM DESIGN CONSIDERATIONS 17.3 METHODS TO DETERMINE PARTICLE SIZE DISTRIBUTION 619 successfully using the elutriation method. In this methodology, the particle size is determined principally by using a stream of gas or liquid flowing in an opposite direction to the direction of sedimentation (Bernhardt, 2012). Elutriators usually comprise of one or more sorting columns in which fluid is rising in constant velocity, as shown in Fig. 17.10A. The sample is introduced into the sorting column and the particles are allowed to separate on the basis of their density, size, and shape. Finally, the particle size calculated using Stokes’ law is shown in Eq. (17.6) (Lowell et al., 2012). During elutriation, the smaller particles (lighter particles) rise to the top because their terminal velocity is less than that of the rising fluid. The mechanism of elutriation is shown in Fig. 17.10B. Advantages of this method include simplicity of measurement and and it is faster than decantation. 17.3.8 Acoustic Spectroscopy Acoustic spectroscopy is one of the emerging techniques for the measurement of particle size with a maximization of the quality and ensuring the safety of pharmaceutical formulation. Acoustic spectroscopy, sometimes referred as “electroacoustics,” can analyze particles in the range of about 0.01 10 µm. The main principle of operation of acoustic spectroscopy is based on the measurement of ultrasound pulse and phase after its propagation into the sample. When a pulsed electrical field is applied to the sample, particles start vibrating and thus creates ultrasonic sound waves of a range of frequencies, and the attenuation at each frequency is accurately measured. This attenuation spectrum can be FIGURE 17.10 Showing elutriator and elutriator process. (A) Schematic diagram of elutriator and (B) elutriation process for separating particle based on their size, shape, density, using gas or liquid flow which usually opposite to sedimentation direction (particle smaller than 1 µm). DOSAGE FORM DESIGN CONSIDERATIONS 620 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 17.11 Acoustic resonance spectroscopy work based on principles of sonication. Where electric field applied to sample and sound interacts with samples. The resultant attenuation is converted to size. converted to a particle size distribution and a measure of the concentration of the dispersed phase (Mascaro et al., 2013). In a dispersed system, such as suspension and emulsion, the particle size and surface charge are important and this method has no requirement of complex optical properties for measurement. This technique is most suitable for a concentrated sample (volume fractions above 40% 0.1%) which are unstable on dilution. The principle of operation of acoustic spectroscopy is shown in Fig. 17.11. All the above methods described have application in pharmaceutical analysis and formulation. The selection of the best method depends upon their time of analysis, range of particle size, cost of equipment, etc. Other factors of importance include the physicochemical properties of the sample, such as refractive index for microscopy and light scattering, solubility to prepare suspension for electron zone sensing, and light scattering and stability of samples during sieving. 17.4 SIGNIFICANCE OF MICROMETRICS IN PRODUCT DEVELOPMENT: TABLET AND CAPSULE Micromeritics is an important consideration in the development of solid dosage formulation, which is mostly used for physical, mechanical, and chemical process (Rahul et al., 2017). It has become an important area of study in the pharmaceutical field because it influences a large number of process parameters in research and manufacturing pharmaceutical formulation. For directly compressible tablets, particle size ranges from 100 200 mm are required for their compaction behavior and blend flow properties. Likewise, smaller particles of size ranging 20 50 mm are optimum for fast disintegrating tablets and chewable tablets, where grinding attrition and controlled release become more important, respectively. Besides the manufacturing aspects of tablets, the dissolution of drug, which is directly proportional to the surface area of drugs/drug particles, is highly dependent on the particle size distribution of drugs. This aspect is specifically important for coming under BCS DOSAGE FORM DESIGN CONSIDERATIONS 17.4 SIGNIFICANCE OF MICROMETRICS IN PRODUCT DEVELOPMENT: TABLET AND CAPSULE 621 (biopharmaceutics classification system) class 2, i.e., low solubility; high permeability. The extended, controlled, and burst release tablets largely depend on particle size of API and excipients (Leane et al., 2013). The knowledge and effect of particle size and particle size distribution of API, as well as excipients, will be useful to solve the difficulties in critical process parameters. In particular regards to tablet and capsule, controlling the particle size and particle size distribution is mainly important because they have direct impact on the flowability, tableting, content uniformity, weight variation, and dissolution rate which ultimately affect the bioavailability of drug. Various significances of micromeritics in pharmaceutical manufacturing of tablet and capsule are listed in Table 17.6. TABLE 17.6 Significance of Micromeritics in Tableting and Capsule Manufacturing Significance of Micromeritics Problems Solution Content uniformity Larger particles create content uniformity issue of low dose drug Proper particle size selection. Flow properties Particles having needle or lath shape Spherical particles increase the flowability Particle arrangement Closer packing arrangement Narrowing particle size distribution (PSD) Compaction Stronger tablet Increase particle size Weight variation Smaller particles-improper filling of die cavity Increase particle size Tablet hardness Harder tablet Increases particle size Feeder clearance Leakage Particle size should be larger than the feeder clearance Compressibility Failure to compress due to enlargement of particles Decreases the particle size Die fill Inconsistent die filling due large PSD Narrowing PSD Dust control Fine particles cause a dusty operation Proper size selection Electro static effects Electro static charge is increased with more percent of small particles. Reduces percent of smaller particles Friability Smaller particles cause chances of high friability Increases the particle size Cost Small dusty particles increase operating cost Proper particle size selection Lubrication levels Smaller particles are required higher level of lubrication than larger particles Increase the particle size Disintegration and dissolution rate Smaller particles reduce the disintegration rate because of harder tablet and increase the dissolution rate Proper size selection Weight control Final volume in die is final weight. Larger particles pulled out of the die cavity may reduce the final weight Reduce particle size Note: Utilization of micromeritics in tablet and capsule evaluation through depicted parameters: content uniformity; flow properties; particle arrangement; compaction; weight variation; tablet hardness; feeder clearance; compressibility; Die fill; dust control; electro static effects; friability; Cost; lubrication levels; disintegration and dissolution rate; weight control. DOSAGE FORM DESIGN CONSIDERATIONS 622 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 17.4.1 Content Uniformity Particle size has a critical role in the early stages of product development; it can have a direct impact on critical product characteristics, such as content uniformity of solid dosage formulation. In particular, content uniformity can create problems in low dose drugs (Dose ,100 µg) and proper particle size selection is essential. Larger particles have much greater impact on content uniformity than smaller particles. This is because small size particles may obstruct the processibility and due to their segregation and poor blend content uniformity. Rohrs et al. (2006) reported that larger particles have more impact than smaller particles. 17.4.2 Flow Properties Literature showed that the powder flow property is largely dependent on particle size and particle shape of a material. To improve the flowability of powder, researchers are now working on altering the crystal habit. Kaerger et al. explained that particle shape has an impact on flowability of powder; a decrease in the angle of repose improves flowability with spherical paracetamol particle compared with lath-shaped micronized particles (Andrews, 2007). Garekani et al. demonstrated that ibuprofen crystallized from different solvents developed various particle shapes and implied that the plate-shaped particles showed better flow properties than needle-shaped particles. It was demonstrated experimentally, that the finest size fraction of ibuprofen and narrow particle size distributions showed significantly better flowability than bulk powder. In some other cases, smaller particles improved the flowability, the reason behind this is some interparticulate attraction like mechanical interlocking, hydrogen bonding, electrostatic interaction, and van der Waals forces can predominate over gravity (Garekani et al., 2001). 17.4.3 Particle Arrangement and Compaction While tableting, the particle size, and particle size distribution both profoundly affects the particle arrangement and compaction. In this context, smaller particles enter into the voids between the larger particles and form a close packing arrangement. In the case of most powders, smaller particles form stronger tablets than larger particles, because the smaller particles have larger available surface area than the larger particles for bond formation. During compaction, particle size plays an important role in tensile strength (interparticulate bonding structure) in some compressing materials, such as sodium chloride which forms solid bridges (Malliaris and Turner, 1971). 17.4.4 Weight Variation The weight variation of tablet and capsule can be varied by many factors, including broad particle size distribution, poor flowability, and compressibility of powders or granules, improper mixing of a glidant into the granulation, nonuniform and noncleaned lower punches of the tablet press. A good flowability of powders confers less variation in tablet weight and yields good content uniformity. The research findings suggest that the weight variation of tablets increases tremendously by increasing the granule size. DOSAGE FORM DESIGN CONSIDERATIONS 17.4 SIGNIFICANCE OF MICROMETRICS IN PRODUCT DEVELOPMENT: TABLET AND CAPSULE 623 The smaller sized granules produce more weight variation than larger particles, because larger particles fill the die cavity consistently and better than smaller particles. For example, Kumar et al. (2013) reported that smaller size of granules has shown greater loss of weight due to friability of the granules. Sometimes bulk density can also be an issue for tablet weight because the weight of tablets is dependent on the packing conditions in the die. 17.4.5 Segregation Segregation of powder samples mostly occurs due to differences in physical and mechanical properties of the particles. Segregation is more profoundly observed in the case of a wide PSD range than a narrow PSD. Due to segregation phenomenon, the final PSD of the final mass can be changed during the manufacturing of a tablet and capsule which eventually causes final weight variation. During sifting of powder, smaller particles enter into larger particles matrix and separation may take place. In the case of uniformly distributed particle samples, segregation does not occur. The segregation occurs mainly by large particle size portion of the bulk. A method was reported to determine the segregation by colorimetry in which the segregation was determined by adding a dye (eosin) in the powder mass and the uniformity of dye distribution is then assayed in the tablet (Khinast et al., 2017). In addition, tablets were also collected and weighed and it was concluded that the variation in tablet weight decreases with decrease in the particle size. The particle size distribution of granules that corresponded to one tablet was measured individually to obtain the granule size distribution of the tablet. This measurement is a novel method and it enables segregation studies during the tableting process. 17.4.6 Hardness The hardness of tablet signifies mechanical strength of tablet to indicate its durability during handling. The hardness of a tablet directly affects its dissolution rate and is drastically affected by particle size. Tablet hardness decreases by increasing the particle size due to weak intermolecular interaction between particles. It is generally accepted that the hardness of the tablet increases with a decrease in particle size. For example, Femi et al. studied the effect of paracetamol granule size on tablet hardness and it was concluded that a 250 µm granule size gave a harder tablet than 500, 700, and 1000 µm granule size. 17.4.7 Compressibility and Compatibility or Tablet Strength Compressibility is the ability of a powder to reduce the bulk volume of powder under pressure and the compatibility is the ability of powder to form a strong intact tablet. During compressibility and compatibility, it was demonstrated that there are critical effects of crushing and bonding in particles, i.e., smaller particles agglomerate, larger particles are crushed, and medium-sized particles are not affected significantly (Nayak et al., 2017). From all reported studies it is suggested that there is no simple rule to predict the impact of granule size on compressibility and compaction but some research has been DOSAGE FORM DESIGN CONSIDERATIONS 624 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT reported that the smaller size of particles results in an increase in tablet strength because smaller particles have lower ability to lock together during compaction than larger particles. On the other hand, some research finding has confirmed that increases in the size of granule correspond to an increase in tablet strength. The summary of significance is represented in Table 17.6. 17.5 POWDERS Powder can be simply called the collection of dry particles which could be fine or produced by crushing, grinding, or disintegrating the coarse solid particles. When therapeutic powders are considered, part icle size distribution is a critical factor that governs the packing, flow, and drug uniformity in the powder blend. Thus, micrometrics plays a vital role in clarifying the particle size distribution, which affects several process parameters as well as the final formulation attributes, including drug distribution (Parikh, 2016). However, the powders could be classified depending upon their use. Powders for vegetable and animal drugs are officially defined with certain parameters, such as powders with particles which can entirely pass through sieve #8 and not more than 20% can pass through sieve #60 are termed as “very coarse powder.” Whereas, the powders that can entirely pass through sieve #20 but not more than 40% can pass through sieve #60 are termed as “coarse powder” (Monteyne et al., 2016). Powders whose particles can entirely pass through sieve #40 but not more than 40% can pass through sieve #80 are considered as “moderately coarse powder.” Powders with particles which can entirely pass through sieve #60 but not more than 40% can pass through sieve #100 are considered as “fine powders.” Lastly, the powders with particles which can entirely pass through sieve #80 are considered to be a “very fine powder” (Osorio-Fierros et al., 2017). Similarly, “powders for powdered chemical drugs” are officially defined as powders with particles which can entirely pass through sieve #20 and not more than 40% can pass through sieve #60. Such powders are termed as coarse powder whereas, powders with particles which can entirely pass through sieve #40 but not more than 60% can pass through sieve #60 are considered to be moderately coarse powder. Finally, powder with particles which can entirely pass through sieve #80 are considered to be fine powders. However, the flow properties of the powder are very essential to be determined as it depends on the particle size and shape and governs flow rate, thereby being a decisive factor in dosage and content uniformity (Moravkar et al., 2017). As size distribution is a major factor for powders, equally important are the flow properties, which could be determined by several methods as discussed below. 17.5.1 Flow Properties 17.5.1.1 Angle of Repose It is considered to be the most classical technique used for characterizing the flow properties of powder, wherein powder is allowed to flow through under the gravitational force DOSAGE FORM DESIGN CONSIDERATIONS 17.5 POWDERS 625 FIGURE 17.12 Diagrammatic representation of angle of repose of conical formed powder. AB and AC are the arms of triangle that formed during the measurement of angle of repose and are responsible for the final value. TABLE 17.7 Angle of Repose Corresponding to the Estimate Quality of Flow of Powder Angle of Repose Flow Property 25 30 Excellent flow 31 35 Good flow 36 40 Fair aid not needed 41 45 Passable but probability of hanging up 46 55 Poor flow, requires agitation and vibration to flow 56 66 Very poor flow Above 66 Very very poor flow Note: The dynamic angle of repose i.e. angles of slope among the flat plane and slope of cone of non-cohesive i.e., free-flowing granular substance and its flow property and corresponding angles is given in table. without external work and allowed to form a conical heap on a planar surface. Once the conical heap is formed, the circumference of the heap is drawn and also the height of heap is determined. Thus, it is considered that the greater the flow of powder, the lower would be the height and the longer would be the diameter of the circumference of the formed heap (Sun, 2016). Thus, consider a triangle “ABC” of the formed conical heap (Fig. 17.12), and if we want to determine the length “BC” (hypotenuse) of the triangle, then, according to the ratio of side in right angle we can determine the angle ϴ by Eqs. (17.4) and (17.5). We know that, tanϴ 5 Opposite AB i:e:; tanϴ 5 Adjacent AC 21 AB ϴ 5 tan AC (17.4) (17.5) Thus, the greater the hypotenuse, the smaller the ϴ and the higher the flow. The higher the angle, the more poor is the flow of powder. Thus, a characteristic feature about the powder can be determined by understanding the angle ϴ of the formed heap. Depending upon the angle ϴ, the flow property of a powder sample can be assigned straightforwardly as shown in the Table 17.7. DOSAGE FORM DESIGN CONSIDERATIONS 626 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 17.5.1.2 Bulk and Tapped Density Bulk and tapped density can be easily calculated by pouring a weighed quantity of powder into a calibrated cylinder and measuring its volume (bulk volume), then tapped for recommended number of times and then again the volume remeasured (tapped volume) (Huang et al., 2015). According to USP, the procedure followed consists of the use of a 250 mL measuring cylinder in which powder mass around 220 6 44 g is filled, the taps produced by the apparatus in 1 min should be around 250 6 15 taps from a height of 3 6 0.2 mm or 300 6 15 taps from a height of 14 6 2 mm. The density for bulk and tapped can be calculated by Eqs. (17.6) and (17.7), respectively. Following this, the obtained values can be used to calculate several other useful properties of a powder like compressibility index and Hausner’s ratio. In a free-flowing powder, difference between bulk and tapped density would be less, and the opposite is true for poorly flowing powders which could be interpreted by values from compressibility index and Hausner ratio, which can be calculated from Eqs. (17.8) and (17.9). Further, the values for compressibility index are given below in Table 17.8. Bluk density ðBDÞ 5 mass taken bulk volume ðVb Þ (17.6) mass taken tapped volume ðVt Þ (17.7) Vb 2 Vt 100 Vb (17.8) Tapped density ðTDÞ 5 Compressibility index ðCI Þ% 5 Hausners ratio 5 Vb Vt (17.9) TABLE 17.8 Flow Properties Estimate Depending on the CI and Hausners Ratio %CI Index Flow Property Hausner Ratio 1 10 Excellent flow 1.00 1.11 11 15 Good flow 1.12 1.18 16 20 Fair flow 1.19 1.25 21 25 Passable flow 1.26 1.34 26 31 Poor 1.35 1.45 32 37 Very poor flow 1.46 1.59 Above 38 Very-very poor flow Above 1.6 Note: The flowability of powder or granular material demonstrated through scale of flowability based on Carr’s index and Husners ratio. DOSAGE FORM DESIGN CONSIDERATIONS 17.7 EMULSIONS 627 17.6 SUSPENSIONS In general, suspensions have a suspending phase and a continuous phase wherein the suspending phase, also called the dispersant, is uniformly distributed within the continuous phase thereby forming a thermodynamically stable heterogeneous system. The size of the suspended particles and the viscosity of the continuous phase plays a vital role in deciding the time frame for which the system would remain stable (Lalu et al., 2017). The relationship between stability of suspension, the viscosity of continuous phase and the dispersant phase along with particle size can be well understood using Einstein’s equation as mentioned in Eq. (17.10). The density of the medium can be determined easily via a pycnometer, whereas particle size distribution in suspension can be determined by methods like sedimentation method, Coulter counter method, etc. η᾿ 5 η᾿ 0 ð1 1 2:5ϴÞ (17.10) where, η᾿ 5 is viscosity of suspension η᾿ o 5 viscosity of dispersion medium ϴ 5 volume of fraction of dispersed medium The reduction in particle size enhances the stability of suspension as well as the therapeutic efficiency of the formulation because as the particle size reduces, the intrinsic dissolution rate increases which leads to quicker and better absorption of drug in systemic circulation. Experimentally, it has been demonstrated that the reduction in particle size of spironolactone micropowders elicits higher level of plasma concentration as compared to powdered formulation (Dave et al., 2017). Therefore, such information based on density of continuous phase and dispersed phase enables vital information about the suspension stability. This also guides the formulator to adjust the parameters according to the desired quality parameters. The particle size analysis can be done using sedimentation rate and Coulter counter method, discussed below (Parikh, 2016). 17.7 EMULSIONS The methods which are usually applied for the determination of size distribution of suspension and emulsions are almost similar. In thecase of emulsion, it comprises of a dispersion phase (liquid) and a continuous phase (liquid), wherein both are immiscible with each other. The latest technologies like laser diffraction method and Coulter counter method could be employed to calculate size, as well as size distribution for the emulsions, as size plays a decisive role in determining and estimating the stability of emulsion (Salvia-Trujillo et al., 2013). Laser diffraction (LD) technique involves a laser beam which is transmitted through the emulsion and the pattern of diffraction is determined using a series of light-sensitive detectors as schematically shown in Fig. 17.13. DOSAGE FORM DESIGN CONSIDERATIONS 628 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 17.13 Schematic representation of laser diffraction technique. Firstly, the laser beam is directed on to the cuvette containing the emulsion sample, which diffracts the beam which is collected by the detectors, which then, using a sophisticated system, convert the diffraction data into size distribution data. The diffraction pattern depends directly on the scattering of the beam due to the droplets formed in the emulsion. Theory of light scattering assumes that each droplet scatters one photon of light, thus dilution of emulsion or disaggregation of droplets must be done so as to avoid false results. However, the accuracy, as well as the precision of estimating the droplet size in emulsion via DL method, greatly depends on the design of the optical system employed for measuring the diffraction pattern through the cuvette and the mathematical model which is employed to convert the diffraction signal pattern to an understandable droplet size distribution. Also, the number of detectors used for diffraction analysis also determines the accuracy and sensitivity as the higher the number of detectors, the wider the angles covered, and the more accurately the diffraction pattern can be determined (Saberi et al., 2013). Generally, the commercially available instruments have a tendency to measure droplets with diameter ranging from 0.1 and 1000 µm, even though some instruments have special additional features or capabilities which enable them to investigate even smaller droplets. The complete analysis of the system requires no more than 3 min right from putting the sample into the system and getting the full particle size distribution (Saberi et al., 2013). Therefore, DL methods are considered to be the latest technology in determining the size distribution in emulsions as well as in suspension or, as a matter of fact, size distribution of any solution with materials that can scatter light could be determined using DL method with a very short span of time with reliable results. 17.8 NOVEL DRUG DELIVERY SYSTEMS In case of drug delivery system, micrometrics plays a crucial role right from its optimization until it forms a fully developed final product (Sharma et al., 2015; DOSAGE FORM DESIGN CONSIDERATIONS 17.8 NOVEL DRUG DELIVERY SYSTEMS 629 TABLE 17.9 Material Parameter That Influences Certain Process Parameters and Properties Related to Drug Delivery Systems Influential Material Parameters Properties Governed by Parameters Particle size Flow of powder, degree of compaction, compression, blend uniformity, dosage uniformity, dissolution and ultimately bioavailability Particle shape It influences the degree of compaction, critical element in solid and liquid dispersion processing, and also the bioavailability Surface area It majorly influences surface area, solubility, compaction, and stability of products. These all mention parameters eventually govern the bioavailability of the drug Density It influences the process of roller compaction, crystallinity, tableting, lubrication, segregation, and compaction Porosity It influences the process variables for roller compaction, tableting, compaction, segregation, and also influences the shelf life Note: The parameters of the particulate system which effects via process parameters and properties interrelated to drug delivery systems. Affected factors, viz, particle size; particle shape; surface area; density; porosity. Tekade et al., 2015; Maheshwari et al., 2015a). There are several material characteristics that influence one or the other properties which eventually determine the final product attributes which are mentioned below in Table 17.9. The particle size is considered to be the crucial factor in case of NDDS, especially in the field of nanoparticles targeted towards cancer. There are nanoparticles like polymeric nanoparticles, self-assembled nanoparticles, etc., which are expected to show tumorspecific drug delivery via enhanced permeation and retention (EPR) effect which completely depends on size and such targeting is called passive targeting. For the formulation to show EPR effect the size range of the particles should fall within a size range of 10 100 nm, as particles larger than this are unable to pass through the leaky fenestrations of the poorly developed blood vessels of tumor. In case of transdermal delivery systems the average size range to get optimum penetration is 100 200 nm but rather than size, the nature and molecular weight of the drug molecule along with the nature of formulation used play more crucial roles in delivering the payload. Another important factor is macrophage uptake which also shows a sizedependent effect. When the particle size ranges lie within 0.5 4.6 µm range, maximal phagocytosis is observed, thus it is generally recommended to keep the particle size below the mentioned range. Thus, several properties associated with the material or particulate material are essential to be understood so as to get an estimate for the desired attributes for the dosage form designed (Maheshwari et al., 2017; Soni et al., 2017). Micrometrics play a crucial role in formulating drug delivery formulations to get optimum target profile and therapeutic range (Tekade et al., 2017a,b,c). Thus, in the above section, we have discussed in detail about the effect of the micromeritics in the development of novel drug delivery systems. It was very clear that the particle size along with its distribution have prodigious roles in deciding the dosage form DOSAGE FORM DESIGN CONSIDERATIONS 630 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT parameters. Taking a lead from that, another parameter which could affect the dosage is the crystalline habit as it will eventually determine the size of the drug molecule and its distribution which is discussed in the subsequent section. 17.9 RELATION BETWEEN CRYSTALLIZATION AND MICROMERITICS OF DRUG SUBSTANCES Crystals are nothing but the ordered arrays of molecules and atoms held together by noncovalent interactions. Within a specific crystal, each unit cell (the smallest repetitive unit) is usually of the same size and contains the same number of molecules or ions arranged in a specific array (Patil et al., 2014). In each single unit cell, the sides and angles are arranged at a specific distance and angle, respectively, so as to form different unit cell. There are a total of seven different primitive unit cells termed as cubic, trigonal, hexagonal, tetragonal, orthorhombic, monoclinic, and triclinic. However, depending upon the unit cells present in a primitive unit cell type there could be three different types of variations expected, like face-centered, body-centered, and end-centered. Generally, the drug molecule has triclinic, monoclinic, and orthorhombic as the unit cell and this unit cell repeats in a specific pattern so as to form a crystal habit (prismatic, pyramidal, tabular, etc.). Sometimes the same compound can crystallize out in different crystal habits, such a phenomenon is called polymorphism. It has been understood that different crystal habits can influence properties like particle size, filtration process, bulk powder flow, compressibility, dissolution rates, and also the bioavailability (Abioye et al., 2014). In the case of spironolactone, a steroidal aldosterone agonist chemical structure shown in Fig. 17.14A that is used as a diuretic, it can crystallize in two polymorphic forms and also as four solvated crystalline forms depending on the solvents and methods used for crystallization. Both the unit cells are orthorhombic but possess different dimensions and also the melting point of form-1 is 205 C and of form-2 it is 210 C. Out of the two crystalline forms, form-1 is produced when spironolactone powder is dissolved in acetone at a temperature very close to the boiling point and the solution is then cooled within a few hours down to 0 C. Similarly, form-2 can be formed when the powder is dissolved in acetone, dioxane, or chloroform at room temperature and the solvent is allowed to evaporate spontaneously over a period of several weeks. The packing of two molecules of both the forms are depicted in Fig. 17.14B, and it explains that form-1 would have good bulk volume compared to form-2, thereby good flow properties can be expected in case of form-1. Paracetamol exists in two different forms: form-1 which is monoclinic and form-2 which is orthorhombic. The scanning electron microscopic (SEM) images shown in Fig. 17.14C and D, and form-1 is more stable at room temperature as compared to form-2 (Nichols and Frampton, 1998). Even though form-1 of paracetamol is more stable, it is not suitable for direct compression into tablets. Hence, it has to be mixed with binding agents before tableting, which is considered to be a time-consuming process and thus not favored for industrial operations. In the case of form-2, it can easily undergo plastic deformation upon compaction and it has been suggested that this form may have distinct processing advantages over the form-1. Thus, even though the form-1 can be DOSAGE FORM DESIGN CONSIDERATIONS 17.10 CONCLUSION 631 FIGURE 17.14 Chemical structures of spironolactone and paracetamol and their crystal arrangements. (A) and (C) chemical structures of spironolactone and paracetamol respectively. (B) Packing arrangements of two molecules of spironolactone of form-1 and form-2. (D) SEM images of form-1 and form-2 of paracetamol. Adapted with permission from Nichols, G., Frampton, C.S., 1998. Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J. Pharm. Sci., 87 (6), 684 693. formed easily as compared to form-2, it is difficult to obtain. But, it could be obtained on the lab scale by the process of nucleation of the supersaturated solution of form-2 to get the desired form. Sometimes polymorphs can show transition from form-1 to form-2 upon reaching a particular temperature called the transition temperature. Such changes in polymorphic forms of vehicles, such as Theobroma oil used to make suppositories, could cause products with different and unacceptable melting characteristics (Thalluri, 2015). Thus, the crystallization process affects the shape of crystals formed thereby affecting the size distribution, bulk properties, flow properties, compression ability, and other physical properties (Sowa et al., 2017). 17.10 CONCLUSION Knowledge and control of the size and the size range of particles are of profound importance in pharmacy. At this point, you should understand that particle size is related in a significant way to the physical, chemical, and pharmacologic properties of a drug. DOSAGE FORM DESIGN CONSIDERATIONS 632 17. MICROMERITICS IN PHARMACEUTICAL PRODUCT DEVELOPMENT Clinically, the particle size of a drug can affect its release from dosage forms that are administered orally, parenterally, rectally, and topically. The successful formulation of suspensions, emulsions, and tablets, from the viewpoints of both physical stability and pharmacologic response, also depends on the particle size achieved in the product. The student should have an understanding of the common particle sizes of pharmaceutical preparations and their impact on pharmaceutical processing/preparation; be familiar with the units for particle size, area, and volume and typical calculations; and be able to describe how particles can be characterized and why these methods are important. In the area of tablet and capsule manufacture, control of the particle size is essential in achieving the necessary flow properties and proper mixing of granules and powders. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant (Grant #ECR/2016/001964) allocated to Dr Tekade for research work on gene delivery and N-PDF funding to Dr. Maheshwari (PDF/2016/003329) for work on targeted cancer therapy in Dr. Tekade’s Laboaratory. The authors also acknowledge the support by Fundamental Research Grant (FRGS/1/2015/TK05/IMU/03/1) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. The authors would also like to thank Dr. Vimukta Sharma; Director, BM College of Pharmacy, Indore, India for her critical reading and suggestions on this manuscript. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. 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Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. J. Thromb. Haemost. 12 (7), 1182 1192. Polakowski, C., Sochan, A., Bieganowski, A., Ryzak, M., Földényi, R., Tóth, J., 2014. Influence of the sand particle shape on particle size distribution measured by laser diffraction method. Int. Agrophys. 28 (2), 195 200. Power, R., Simpson, S., Reid, J., Hudson, A., 2013. The transition from liquid to solid-like behaviour in ultrahigh viscosity aerosol particles. Chem. Sci. 4 (6), 2597 2604. Rahul, M., Piyoosh, S., Tekade, M., Atneriya, U., Dua, K., Hansbroe, P.M., et al., 2017. Microsponge embedded tablet for sustained delivery of nifedipine. Pharm. Nanotechnol. Richard, S., Rajadurai, J.S., Manikandan, V., 2016. Influence of particle size and particle loading on mechanical and dielectric properties of biochar particulate-reinforced polymer nanocomposites. Int. 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Powder Technol. 289, 104 108. Sun, C.C., 2017. Microstructure of tablet—pharmaceutical significance, assessment, and engineering. Pharm. Res. 34 (5), 918 928. Sun, J., Wang, F., Sui, Y., She, Z., Zhai, W., Wang, C., et al., 2012. Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q10 as naked nanocrystals. Int. J. Nanomed. 7, 5733. Tekade, R.K., Maheshwari, R.G.S., Sharma, P.A., Tekade, M., Singh Chauhan, A., 2015. siRNA therapy, challenges and underlying perspectives of dendrimer as delivery vector. Curr. Pharm. Des. 21 (31), 4614 4636. Tekade, R.K., Maheshwari, R., Soni, N., Tekade, M., 2017a. Chapter 12 - Carbon nanotubes in targeting and delivery of drugs A2 - Mishra, Vijay. In: Kesharwani, P., Amin, M.C.I.M., Iyer, A. (Eds.), Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes. Academic Press. Tekade, R.K., Maheshwari, R., Soni, N., Tekade, M., Chougule, M.B., 2017b. Chapter 1 - Nanotechnology for the development of nanomedicine A2 - Mishra, Vijay. In: Kesharwani, P., Amin, M.C.I.M., Iyer, A. (Eds.), Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes. Academic Press. Tekade, R.K., Maheshwari, R., Tekade, M., 2017c. 4 - Biopolymer-based nanocomposites for transdermal drug delivery. Biopolymer-Based Composites. Woodhead Publishing. Thalluri, C.S., 2015. Enhancement of micromeritic compressional properties and bioavailability of some insoluble drugs by polymorphism. Tinkle, S., McNeil, S.E., Mühlebach, S., Bawa, R., Borchard, G., Barenholz, Y.C., et al., 2014. Nanomedicines: addressing the scientific and regulatory gap. Ann. N. Y. Acad. Sci. 1313 (1), 35 56. Wan, L.S., Heng, P.W., Muhuri, G., 1992. Incorporation and distribution of a low dose drug in granules. Int. J. Pharm. 88 (1-3), 159 163. Wang, F., Liu, Y., Zhang, Y., Hu, S., 2012. Experimental study on the stability of asphalt emulsion for CA mortar by laser diffraction technique. Constr. Build. Mater. 28 (1), 117 121. Xu, R., 2015. Light scattering: a review of particle characterization applications. Particuology 18, 11 21. Further Reading Patil, B.A., Jain, A., Mane, A., Sharma, B., 2016. Spherical crystallization: a novel particle design technique. J. Biomed. Pharm. Res. 5 (4). DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 18 Four Stages of Pharmaceutical Product Development: Preformulation, Prototype Development and Scale-Up, Biological Aspects, and Commercialization Basant Amarji1, Sara Nidal Abed2, Ujjawal Bairagi1, Pran Kishore Deb2, Omar Al-Attraqchi2, Anup Avijit Choudhury1 and Rakesh K. Tekade3 1 Dr. Reddy’s Laboratories Limited, Hyderabad, Telangana, India 2Faculty of Pharmacy, Philadelphia University, Amman, Jordan 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 18.1 Introduction 638 18.2 Preformulation Aspects in Pharmaceutical Product Development 640 18.2.1 The Sphere of Preformulation Studies 640 18.2.2 Major Disciplines of Preformulation Studies 640 Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00018-6 18.3 Prototype Development 18.3.1 Considerations to Ideate/ Conceptualize a Product 18.3.2 Experimental Design and Product Optimization 642 642 645 18.4 Biological Aspects in Pharmaceutical Product Development 650 637 © 2018 Elsevier Inc. All rights reserved. 638 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT 18.4.1 The Preclinical Tenure and Strategies 18.4.2 The Clinical Cycle Development 18.4.3 Emerging Trends 18.5 Commercialization Aspects in Pharmaceutical Products Development 18.5.1 Patents, Exclusivity, and Evergreening Strategies 18.5.2 The Product Life Cycle 18.5.3 Commercialization Realities 18.5.4 Factors Affecting Commercialization 650 652 653 658 658 659 660 662 18.6 Conclusion 663 Abbreviations 663 References 664 Further Reading 667 18.1 INTRODUCTION The preformulation studies refer to the studies done at the early stages of the development process of drug candidates into different dosage forms. Investigation of both the physical and chemical properties of these candidates are achieved during the preformulation stage in order to identify the critical features that affect the selection of the most appropriate candidate (Nyqvist, 1986). Preformulation studies have been reported to act as accurate predictors that effectively predict the changes that may be associated with the combination process of the active pharmaceutical ingredient (API) with a suitable delivery system that is intended to safely and effectively deliver the active ingredient to the patient (Bynum, 2011). Preformulation studies are usually classified into three main phases, as shown in Fig. 18.1 (Nyqvist, 1986). FIGURE 18.1 The three phases of preformulation studies. DOSAGE FORM DESIGN CONSIDERATIONS 18.1 INTRODUCTION 639 Preformulation studies have been shown to play an important role during processes of drug discovery and development since these studies are usually relied on when valuable information is needed regarding stages of lead identification and optimization. The role of the data collected during the preformulation studies varies as shown in Fig. 18.2 based on the different groups involved in the discovery and development stages (Bharate and Vishwakarma, 2013). Potential new drugs are known to extensively undergo studies of pharmacological and toxicological purposes before starting with the human trials. The outcomes resulting from the preformulation studies determine whether further development of the drug is going to be done or not. However, other factors were reported to have a role in the continuation of the development process, for example, the shelf life in various environments, the absorption reproducibility, as well as the dosage form’s economical manufacturing. Therefore, it is essential to have adequate knowledge regarding the physicochemical, physicomechanical, as well as biopharmaceutical properties (Graffner et al., 1985). Additionally, various regulatory processes are followed after the process of identifying the development candidates, these processes include the investigational new drug (IND) application, new drug application (NDA), and abbreviated new drug application (ANDA). Despite the great financial reward of a successful product, the failure rate of product marketing is extremely high (Lau, 2001). The importance of preformulation studies is directly connected to their role in the determination of the important characteristics of the tested compound. Data obtained at the preformulation stage are considered to be prerequisite during the development process of new drug candidates, FIGURE 18.2 Different groups in a drug’s discovery and development stages. DOSAGE FORM DESIGN CONSIDERATIONS 640 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT needed for submitting the chemistry manufacturing and control (CMC) section of the investigational new drug (IND) application (Tilak et al., 2015). Preformulation studies strengthen the scientific foundation of the guidance, provide regulatory relief, conserve resources in the drug development and evaluation process, and improve and enhance product quality and public safety standards (Sathish Kumar et al., 2016). 18.2 PREFORMULATION ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT In this section, more detailed information regarding the preformulation stages of drug development is going to be discussed. Bulk characterization and the analysis of solubility and stability parameters are also covered as they represent the major disciplines of preformulation studies. 18.2.1 The Sphere of Preformulation Studies The process of preformulation can be referred to as the development stage in which characterization, as well as establishment of the physicochemical properties of the drug, are taking place. An appropriate characterization of the physicochemical properties of the drug has been shown to effectively enable the determination of the suitable formulation process and delivery method of the developed drug. It has been reported that the main objective of preformulation studies is to develop drugs with the desired stability, efficacy, and safety (Kulkarni et al., 2015). The term preformulation comprises the applications of the principles of biopharmaceutics to the physicochemical properties of the drug substance. Preformulation studies have been reported to be done for the sake of designing new delivery systems with the optimum characteristics (Vilegave et al., 2013). During the early stages of new drug development, synthetic chemists and specialists from other disciplines are known to collect the preformulation data in order to help know the important properties of the drug before starting with the preformulation studies. Such data usually include information about the potency of the drug, the dosage form, the stability, routes of administration, the bioavailability, as well as the pharmacokinetic properties of the drug (Chaurasia, 2016). 18.2.2 Major Disciplines of Preformulation Studies Preformulation studies comprise various aspects that are going to be briefly covered under this section. Powders that are dealt with in the pharmaceutical industry have to be well characterized, therefore, the powders’ physical, mechanical, and physicomechanical properties and their characterization are the focus of this section. 18.2.2.1 Bulk Characterization Bulk characterization studies are required for the identification of every solid form existing as an outcome of the synthetic stage (i.e., polymorphs present). During the process DOSAGE FORM DESIGN CONSIDERATIONS 18.2 PREFORMULATION ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 641 of development, various properties of the solid bulk, such as the particle size, surface morphology, as well as the bulk density, were shown to have a possibility to be changed. A number of aspects were shown to be involved in the bulk characterization testing (Chaurasia, 2016). The following points represent some of the aspects that are taken into consideration when testing bulk solids for drugs development. a. Particle size: Experimentally, it has been proven by many researchers that particle size and particle size distribution were shown to significantly influence various characteristics of the drug such as their dissolution rate, bioavailability, taste, color, content uniformity, stability, and others. Additionally, other properties including the flow characteristics and rates of sedimentation have been reported to be observably affected by the particle size (Chaurasia, 2016). Particle size distribution has an impact on the physicochemical properties of the drug substances, and in many cases, an enhancement of the drug’s bioavailability has been achieved by administering the drug substance in the fine form rather than the coarse form. This technique has proved its efficiency especially in the case of drug substances showing poor water solubility (Ozioko, 2017). b. Powder flow properties: Powder flow behavior is a very important issue that has to be taken into consideration when formulating pharmaceutical dosage forms (i.e., tablets). During the evaluation of drug substances in the preformulation stage of drug development, it is shown to be essential to study the flowability of the drug substances and more importantly in the case of formulating large anticipated dose of the drug. Powders can exist in either two forms based on their flow characteristics, where the first form is referred to as the freely-flowing powder and the other form is the cohesive powder (Chaurasia, 2016). Particles properties including their size, shape, density, electrostatic charge, as well as the adsorbed moisture were shown to have an influence on the flow behavior of powder. In addition, forces between particles that can be either frictional or cohesive have been also reported to affect powder flowability (Ozioko, 2017). c. Crystallinity and polymorphism: Crystallinity as a term represents the structure of solids which tends to disappear in both states of liquid and vapor. Crystallinity usually describes the unique arrangement of solid molecules in a regular and periodic pattern (Ozioko, 2017). Since most drugs are marketed as solid dosage forms that may contain drugs in the crystalline form, the crystal habit is therefore considered as an important issue during drugs manufacturing. There are various physicochemical properties of drugs such as the solubility, rate of dissolution, melting behavior, mechanical strength, compressibility, as well as their flowability, which are shown to be dependent on a drug’s crystal habit (Chadha et al., 2011). 18.2.2.2 Solubility Analysis Drug solubility is considered as a fundamental property that has to be evaluated in the early stages of drug discovery. Due to the considerably complicated procedures for the detection of aqueous solubility and the chemistry of the solid-phase, the prediction of a drug candidate’s solubility is therefore considered to be difficult (Bharate and Vishwakarma, 2013). Various parameters will have an effect, such as the polarity of both DOSAGE FORM DESIGN CONSIDERATIONS 642 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT the drug and the solvent, drug particle size, in addition to the parameters associated with the solution process, such as the temperature and agitation. Such parameters have been reported to significantly affect the solubility of the drug substance (Garg et al., 2003). One of the most important objectives of preformulation studies is to invent a technique that provides solutions of the drug substances. And it has been proven that in order for a drug to exert the desired therapeutic activity, it has to exhibit a respectable aqueous solubility (Chaurasia, 2016). Various approaches have been used at different stages of drug discovery and development processes such as in silico approaches and kinetic and equilibrium approaches of solubility assessment (Bharate and Vishwakarma, 2013). 18.2.2.3 Stability Analysis Screening of a drug candidates’ stability is shown to have a significant role in the process of drugs discovery since it gives an overview of the compounds’ stability at various pharmaceutical situations, which in turn aids in the identification of the potential liabilities that may have an influence on the development of new drugs. Data collected by stability screening studies can be employed to modify some of the labile groups and hence improve their stability. Additionally, such data can also be applied to determine whether a certain compound has the ability to develop or not, not to mention the guidelines they provide for handling, storage, and solubilization strategies of the developed compounds (Bharate and Vishwakarma, 2013). The official definition of stability can be described as the time lapse when the pharmaceutical product is shown to preserve the same properties given by the manufacturer. In other words, stability is expressed in terms of expiry period or technically shelf life. The main purpose for stability screening studies is to ensure the most efficient, safest, and most qualified active dosage form, in addition to other objectives such as supporting labile claims, gaining information regarding the product’s packaging, and determining the compatibility between the drug substance and other additives (Chaurasia, 2016). 18.3 PROTOTYPE DEVELOPMENT Ideas are the descriptive statements that can either be written or verbalized. Ideas are usually converted into a concept that in the case of pharmaceutical products includes the product’s benefits and features. Like a seed, this concept is further germinated by wet lab work into a prototype. The prototype development is an important stage during the development of a new product that represents the primary working model of the product which will then be perfected in the form of the final product. Basically, there are four phases of prototype development as shown in Fig. 18.3 (Sathish Kumar et al., 2016). 18.3.1 Considerations to Ideate/Conceptualize a Product In this section, some of the considerations needed to be taken into account during the preformulation stage of drug development are discussed. Aspects regarding the active pharmaceutical ingredients (APIs) and their chemical nature are covered. Safety and efficacy concerns during the preclinical and the clinical stages of drug developments are also discussed in addition to the issues of regulation and intellectual property. DOSAGE FORM DESIGN CONSIDERATIONS 18.3 PROTOTYPE DEVELOPMENT 643 FIGURE 18.3 Phases of prototype development. 18.3.1.1 API Chemistry and Preformulation It is well known that the majority of drug substances in use nowadays are at the solid state of pure chemical composition of either crystalline or amorphous forms. Hence, it is essential to understand the characteristics of these substances before the development of the final dosage forms. Selecting the most appropriate form of the drug, for example, whether it should be a base, salt, anhydrous, or hydrate form, is a critical process that ensures the best solubility, absorption, and stability of the formulated drug product (Allen, 2008). Pharmaceutical chemists and formulators typically tend to modify the drug’s chemical, physical, economic, and biological characteristics by following the technique of salt conversion of drug substances. This technique has proven its efficiency in developing drugs having good bioavailability, stability, manufacturability, in addition to patients’ compliance. Cocrystals are another approach that have been used for the modification of the physicochemical characteristics of drugs (Bica et al., 2011). Tsutsumi et al. have studied the salts and cocrystals of miconazole as methods to improve the physicochemical properties of the pharmaceutical agent miconazole. Their results have shown a novel cocrystal form of miconazole known as hemisuccinate, this new form of the drug has been associated with an improvement in the rate of dissolution along with a superior stability, which has made it an efficient alternative for the nitrate salt of the drug (Tsutsumi et al., 2011). Fini et al. have prepared diclofenac salt using different agents for salt formation, so that they can compare between the resultant salt forms and choose the one with the optimal stability. Diclofenac salts with cyclic aliphatic amines, namely, pyrrolidine, piperidine, morpholine, piperazine, in addition to their Nhydroxyethyl analogs, have been prepared. However, results have shown that these salts are poorly soluble in aqueous media in comparison with sodium-salt of diclofenac (Fini et al., 2012). Hence, every pharmaceutical substance has to undergo preformulation studies to determine its expected stability and availability upon administration. DOSAGE FORM DESIGN CONSIDERATIONS 644 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT 18.3.1.2 Biological Considerations (Preclinical and Clinical Activity) w.r.t. Safety and Efficacy At the preclinical stage of drug development, biopharmaceutical and physicochemical properties including the solubility, cellular activity, selectivity, as well as the ADMET properties are optimized in order to make it possible to reduce the rate of failure during the clinical trials (Hann and Keserü, 2012). Drug substances with poor solubility and or substances having poor bioavailability have to undergo additional efforts during formulation at the developmental stage (Parrott and Lavé, 2002). Several in silico and in vitro models are applied for screening and assessing the potential of these substances to be used as lead candidates. It is becoming increasingly important to predict the potency of drugs at the desired target, their toxicity with the predicted potency at the possible sites of action, as well as the prediction of the pharmacokinetic properties early in drug discovery research (Devadasu et al., 2012). Several drugs have been withdrawn from the market because of safety and efficacy concerns in addition to economic factors (Preziosi, 2004). Numerous aspects have to be taken into account when taking a new lead candidate through the process of preclinical development. Such aspects include the synthesis of sufficient compounds to assess the safety, formulating as well as characterizing the drug product, determining both the bioavailability and the metabolic profile of the drug product, and finally determining the toxicity of the drug based on the safety data conducted. Sufficient characterization of the chemical and pharmaceutical properties can lead to the development of a new drug product with better pharmacokinetic properties, which may also reduce the rate of drugs’ failure during the preclinical and early clinical stages (Clark, 2007). 18.3.1.3 Intellectual Property Intellectual property (IP) can be referred to as anything that is originally created by the human intellect. Intellectual property rights (IPR) can be defined as the legal rights provided to an inventor in order to put his invention under protection for a specific period of time (Bhattacharya and Saha, 2011). IPR have an observable role in a countries’ economy since they promote healthy competition and encourage the economic growth (Angell, 2000). Numerous increases in the costs of the pharmaceutical research and development (R&D) along with an increase in the investments required for putting new technologies in the market have been observed. Therefore, the need for a protection right of the knowledge from unauthorized use has become necessary for a period that ensures R&D cost recovery in addition to other costs associated and sufficient profits that ensure continuous investment in research and development (Bhattacharya and Saha, 2011). As compared to other industrial fields, the field of drugs and pharmaceuticals necessitates the protection by a very strong IP system. Since the costs needed for a drug to access the market range between US$300 million to US$1000 million, taking into account all the risks that could be associated during the developmental stage, no company will take the risk to make its intellectual property a public property without guaranteed adequate returns (Bhattacharya and Saha, 2011). The creation, obtaining, protection, and management of the intellectual property have to become as important as the raising of the resources and funds (Angell, 2000). DOSAGE FORM DESIGN CONSIDERATIONS 18.3 PROTOTYPE DEVELOPMENT 645 18.3.2 Experimental Design and Product Optimization Experimental design is an essential part of the pharmaceutical product development process because experiments are required in order to ensure that the product has the desired characteristics. Experimental design can be defined as the process of strategic planning to conduct an experiment that can be used to obtain the required information in a precise and efficient manner. Experiments are generally costly, time-consuming, and require many resources, thus, it is important to make experiments more efficient to reduce the time and costs required. Experiments are used to investigate a defined area using various tools to obtain information that can be analyzed to draw conclusions. Generally, in experiments one or more factors are varied and the change in response is monitored to see the effect of these factors’ variations on the outcome, the varied factors are called the independent variables, and the response is called the dependent variable (Ziegel et al., 2000; Armstrong and James, 2002). Generally, each experiment involves the following steps as shown in Fig. 18.4. The first step is to clearly define the problem being investigated because it is important to know the purpose of the experiment to be conducted and what data are required to be obtained from the experiment. The second step is the selection of factors that are required to be investigated by the experiment. The third step is the selection of the response to be measured and what methods are used to measure this response. The fourth step is the experimental design, which involves the design of the experiment which requires considerations of different factors, such as the degree of accuracy required; in general, the more the experiment is replicated, the more statistical validity the results have, but at the same FIGURE 18.4 The general steps involved in the experiment process. DOSAGE FORM DESIGN CONSIDERATIONS 646 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT time, replication of the experiments increases the costs, thus, it is important for the investigator to find the correct balance between the costs and the accuracy required. The fifth step involves the conduction of the experiment and obtaining the data from the experiment’s results. The sixth step is the analysis of the data obtained from the experiment and, in the seventh step, a conclusion is drawn based on the analysis of the data obtained (Armstrong and James, 2002). The product optimization process is required in the development of pharmaceutical products in order to ensure that the product fulfills the specified requirements of the regularity authorities and complies with the quality standards. The general outputs that should be attained from the optimization step are mainly a defined active ingredient, excipients, pack and product specifications, in addition to a quantitatively defined formula of the active ingredients and the excipients amounts used (Gibson, 2016). 18.3.2.1 Parenteral Dosage Forms Parenteral dosage forms in the pharmaceutical products context can be defined as the dosage forms that are administrated by injection, these include mainly the intravenous injections (IV), intramuscular injections (IM), and subcutaneous injections (SC), although there are other parenteral routes of administration that are used to a lesser extent, such as the intraarterial injections. The parenteral routes of administrations offer considerable advantages in comparison with other routes of administration, for example, parenteral administration of drugs avoids the problems associated with the oral route of administration, such as the low bioavailability rate and the stability issues of many drugs, and in particular, the biopharmaceutical products, such as peptide and protein therapeutics (Pawer et al., 2004). Parenteral formulations are also useful in patients who are unable to take oral medications and also who require immediate treatment (e.g., epilepsy, etc.). The parenteral dosage forms currently available in the market can be broadly classified into simple injections and complex injections (Fig. 18.5). Simple injections are mostly true solutions mainly containing the active pharmaceutical ingredient, vehicle (water for Injection), pH adjusting agent, tonicity adjusting agents, and buffers etc. Depending upon the need for multiple uses, some formulations contain a preservative to keep the product free from microorganisms during the administration period. Besides chemical parameters (assay and related substances), other physical parameters (pH, osmolality, fill volume, particulate matter, etc.) and microbiological parameters (sterility, bacterial endotoxin, preservative efficacy) are important for the simple injections. Complex injection is another category of parenteral dosage form. It includes surfactantbased drug delivery systems (emulsion, microemulsion, etc.) (Maheshwari et al., 2015a), vesicle-based formulations (liposomes, nanosomes etc.) (Maheshwari et al., 2012; Maheshwari et al., 2015b), and particulate drug delivery systems (suspensions, microspheres, depot, nanoparticles etc.) (Lalu et al., 2017; Sharma et al., 2015; Tekade et al., 2017b). The key advantages offered by complex dosage forms include reduction in dosing frequency, reduction in side effects, increasing the solubility and/or bioavailability, etc. (Tekade et al., 2017a). In complex types of parenteral systems, in addition to the parameters given in simple injections, certain other physicochemical quality attributes are critical. Those attributes (e.g., particle size distribution, percent in vitro drug release, entrapment efficiency, drug loading, zeta potential) play critical roles in defining the efficacy and safety profile of DOSAGE FORM DESIGN CONSIDERATIONS 18.3 PROTOTYPE DEVELOPMENT 647 FIGURE 18.5 Classification of parenteral dosage form. the finished product. To achieve these critical attributes (CQAs), critical material attributes and critical process parameters (e.g., sequence of addition, mixing type-time-temperature, etc.) must be studied and optimized. Lyophilized dosage forms are also intended the for the parenteral dosage forms. These are the freeze-dried powder for injection, required to be reconstituted with water or certain diluents such as 5% dextrose or saline before administration. These types of dosage forms are advantageous specifically for the molecules which have limited chemical stability in aqueous media. Since parenteral dosage forms are intended to be injected directly into systemic circulation, they must be free from foreign particulate matter. Besides this, there are various other quality factors that need to be carefully considered. The sterility of the product is one of the critical quality parameters. Sterility has prime importance because the administrated drug formulation must be instantly bioavailable. The sterility of solutions is usually achieved by heating with pressure using the autoclave, however, there are many heatsensitive drugs that can be degraded by the excessive heat or pressure which is the case for most peptide and protein therapeutics; in this case, sterilization by filtration can be used to achieve sterility at the same time as avoiding drug degradation. Another factor that is required to be adjusted is the pH of the solution. In general, the pH of the solution should be as close as possible to the physiological pH, however, the pH can also influence the stability and solubility of the drug in the solution, and in many cases the optimum pH for stability and the solubility does not coincide with the physiological pH (Strickley, 1999); thus, the pH of the solution must be adjusted to a value that maintains the stability and adequate solubility of the drug, while at the same time not differing considerably with the physiologic pH in order to avoid problems associated with solutions of highly different pH in comparison with the physiologic pH, for example, solutions with pH values higher than 9 can cause tissue necrosis (DeLuca and Boylan, 1992). DOSAGE FORM DESIGN CONSIDERATIONS 648 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT Another important factor in parenteral dosage form optimization is the solubility of the drug in the solution, as usually the products of parenteral admiration are required to be soluble in the amount of submicrograms per milliliter, which imposes a problem for poorly soluble drug substances. There are various strategies and techniques that can be used to enhance the solubility of drug substances, for example, the control of the pH value of the solution, the use of solubilizing agents such as surfactants, the use of a cosolvent, and converting the drug substance into a soluble complex (Parve et al., 2014). Other factors required to be considered include the proper choice of excipients in order to avoid any incompatibility which may arise from a drug excipient interactions or excipient excipient interactions in the formulation and the volume of the solution of injection (Niazi, 2004) 18.3.2.2 Oral Solid Dosage Forms The oral administration of drugs represents the most popular route of administration in patients because of the attractive characteristics it has which include mainly the ease of use by the patients. Also, from the manufacturer’s point of view, oral solid dosage forms, such as tablets and capsules, are cheap to produce and offer greater stability in comparison with other dosage forms, such as liquid and semisolid dosage forms; the tablets and capsules can be made in many different types based on the required therapeutic purposes and the desired characteristics (Florence, 2013). Since the solid dosage forms, such as tablets and capsules, are generally manufactured from powder substances, a thorough characterization and understanding of the powder’s properties and effects on various manufacturing processes are required, as the powder properties not only affect manufacturing process, but also affect the biopharmaceutical characteristics of the drug, such as the dissolution in the gastrointestinal tract. The shape and size of the particles of the powder substance can influence the powder flow, which is an important factor in the tableting process since improper flow can lead to a variation in the filling of the tablets, which in turn can cause variability in the content of the tablet produced. Other processes affected by the particle size and shape are the mixing and the compaction processes. Thus, careful consideration of particle size selection is required in order to ensure proper formulation manufacturing (Aulton, 2013). 18.3.2.3 Topical/Dermal/Transdermal Dosage Forms Pharmaceutical formulations intended for application on the skin whether for local treatment (by topical formulation) or systemic treatment (by transdermal formulation) require careful adjustments of various factors to ensure proper drug penetration and to attain the desired outcome . The skin is composed mainly of four layers, namely, the stratum corneum layer, which is the outmost layer, followed by the epidermis and dermis layers, and then the subcutaneous tissue. The stratum corneum represents a barrier that prevents the penetration of foreign materials into the skin. Drugs applied to the skin are required to penetrate to the stratum corneum first in order exhibit their action or to penetrate further for systemic delivery. The main factors that determine the penetration of the drug into the stratum corneum are the concentration of the drug substance, the ability of the drug substance to diffuse across the stratum corneum and the partition coefficient of the drug substance between the stratum corneum and its vehicle (Allen and Ansel, 2013). The absorption process across the skin is also affected by biological factors such as DOSAGE FORM DESIGN CONSIDERATIONS 18.3 PROTOTYPE DEVELOPMENT 649 age, sex, and the ability of the skin for metabolism. The absorption can be enhanced by using a penetration enhancer such as phospholipids and urea which can increase the ability of the drug to penetrate in the skin (Smith and Maibach, 2006). Some other enhancers are azones (e.g., laurocapram), sulfoxides (e.g., dimethylsulfoxide, DMSO), glycols (e.g., propylene glycol, PG, a common excipient in topically applied dosage forms), alcohols and alkanols (e.g., ethanol, or decanol), surfactants (also common in dosage forms), and terpenes (Williams and Barry, 2004). 18.3.2.4 Inhalational Formulations The inhalation dosage forms are important in the treatment of the respiratory tract diseases such as asthma and bronchitis because these diseases are usually treated by topical application of the drug into the lung. The inhalational formulations hold the advantage of direct application of the drug to the lung which reduces the systemic side effects that are encountered in the systemic administration of drugs. The drug delivery systems/device are of particular importance in the inhalational formulations and can highly impact the decision of the physician and the acceptance of the patient for a particular formulation. There are various devices that are used in delivering inhalational formulations, these mainly include dry powder inhalers, metered dose inhalers, and nebulizers. The choice of inhalers varies according to different factors, for example, nebulizers are preferred for pediatrics (Gibson, 2016). An important factor to be considered in the inhalational formulations is the particle size of the inhaled powder because it is the particle size of the powder that determines whether the powder will reach the lung and to what extent it can go in the respiratory tract. Generally, particles with size between 5 and 7 µm can reach the lung while very large particles are removed from the respiratory tract. In order to achieve penetration of the alveoli, usually a particle size of about 3 µm is required, but it should be noted that very fine particles, for example, particles smaller than 1 µm are usually exhaled from the respiratory tract. Thus, particle size is critical in the inhalation formulations and should be carefully optimized to obtain a formulation with the desired characteristics (Chew and Chan, 2002; Gibson, 2016). 18.3.2.5 Nasal Solutions/Suspensions The nasal route of administration can be used for both local treatment and for systemic treatment, the local treatment is important in treating various nasal conditions such as rhinitis. The nasal route of administration can also be used to deliver drugs to the systemic circulation, because it has many advantages in comparison with other route of administrations, for example, it avoids the first-pass metabolism associated with the oral route of administration, which is important for drugs with low metabolic stability. In addition, the nasal route has rapid absorption and provides an easy way of administration (Gibson, 2016). Nasal formulations require a proper choice of excipients used, administration device, and avoidance of any incompatibilities in the formulation. Other important factors include the selection of proper preservative in the solutions and suspensions to prevent the microbial growth, e.g., benzalkonium chloride (BKC) is usually used as a preservative in nasal formulations. In cases where a poor penetration is observed, such as with proteins or peptides, a penetration enhancer may be used to increase the nasal absorption, DOSAGE FORM DESIGN CONSIDERATIONS 650 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT examples of penetration enhancers are cyclodextrins and liposomes. It is also important to ensure the stability and compatibility of the substances used in the formulation (Davis and Illum, 2003; Bernstein, 2000). 18.3.2.6 Ophthalmic Formulations Ophthalmic formulations are used to topically treat various eye diseases. The ophthalmic formulations have many advantages in treating diseases associated with the eye when compared with the systemic administration of drugs to treat diseases of the eye, for example, the ophthalmic formulations avoid the systemic side effects associated with the drugs administrated systemically, also, in general, drugs cannot penetrate the eye efficiently from the systemic circulation, thus better amounts of drug can reach the eye by topically applying ophthalmic formulations (Conway, 2008; Chrai and Robinson, 1974). Considerations in the optimization of ophthalmic formulations include the adjustment of the pH value and the osmolarity of the solution, ensuring the sterility of the formulation and solubility of the drug in the solution. In general, the pH of the solution needs to be as close as possible to the physiologic pH, although there is a close range of acceptable pH values that are close to the physiologic pH. The osmolarity of the solution also requires adjustment in order to ensure that the solution is isotonic with the tears, in order to avoid any irritation. The sterility of the ophthalmic formulations is also of prime importance, usually a preservative is used to prevent microbial growth in the product, examples of preservatives used in ophthalmic formulations are BKC and methylparaben (Wade and Weller, 1994). Since there is a chance of suck-back of formulation drops, the role of preservative becomes critical and the selection of the proper preservative is essential, e.g., long-term use of BKC is not recommended. The proper selection of preservative depends on formulation pH, presence of surfactant, type of API/excipients, etc. Besides, pH adjusting agents, tonicity adjusting agent, buffer and preservative, some ophthalmic dosage forms contain a viscosity modifier also. The role of the viscosity modifier (polymer) is to retain the drug molecule on the ocular surface for a longer duration to increase retention time and thereby bioavailability. Some of the formulations may include solubilizers and/or penetration enhancers such as polysorbates, cremophor. These components increase the solubility of the molecule in aqueous media and may increase the penetration, thereby reducing the drug required to achieve the therapeutic efficacy and increasing bioavailability. 18.4 BIOLOGICAL ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 18.4.1 The Preclinical Tenure and Strategies In this section, three essential parts are involved in the preclinical stage of drug development. The first part focuses on the in vitro models and their importance in the preclinical stage, whereas the second part provides a brief discussion about the application of new in silico models and how simulation prediction has aided in the efficiency of the drug development process, and the last part covers the issue of using animals as models for testing some properties of the newly-synthesized drugs. DOSAGE FORM DESIGN CONSIDERATIONS 18.4 BIOLOGICAL ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 651 18.4.1.1 In Vitro Screenings and Importance In vitro models, intended to be applied for the assumption of different aspects associated with the biological fate of a drug product, are commonly used in the pharmaceutical industry as well as in academic research. The use of in vitro models usually provides information in the early stage of preclinical development regarding probable biological performance of the drug product. It is known that the use of in vitro studies and the experiments done for humans are not easy to integrate. Nevertheless, in vitro screening models are known to be mostly used for the understanding of drug product behavior. However, whatever the purpose of in vitro models employment, it is proven that data obtained by these models provide very useful information to be further used for in vivo testing (Almeida and Souto, 2007). In the early stages of the drug development process, the use of in vitro models is considered more useful than precise, because, at these stages, absolute precision is not required until validation is recommended. In the case of using in vitro methods for regulatory purposes, these in vitro methods have to be validated. This is shown to have a role in speeding up the process of development and hence aid in the characterization of the drug formulation more properly before the drug is given to humans (Treadway, 2006). 18.4.1.2 In Silico Models and Simulation Predictions Computational prediction models are shown to have an observable role in modern medicinal chemistry since these models offer a high potential to transform the drugs’ early research phases, in terms of saving both time and cost (Andricopulo et al., 2008). In silico methods of prediction and assessment are of a noticeable importance because the lack of such models would make it very difficult and even impossible to assume all factors affecting the prediction by in vitro/in vivo models (Treadway, 2006). However, due to the continuously increased pressure for reducing the time and costs of the process of drug development, researchers are shifting from applying principles of random screening into methods that are more rational. This has shown to have a direct effect on the rate of success of a new chemical entity (NCE) development and, hence, improve the productivity of the pharmaceutical research and development (R&D) (Overington et al., 2006). Nowadays, virtual screening models are considered as essential components in the modern process of drug discovery (Oprea et al., 2007). Computational tools are also playing a critical role in the programs of medicinal chemistry programs (Overington et al., 2006). Similarly, various computational tools are available to predict API’s solubility/miscibility/or possible reaction with single or mixture of raw materials. With time such tools will become necessary to develop a drug product to save resources, like time and money. 18.4.1.3 The Use of Animal Models It is known that testing pharmaceutical formulations directly in humans is an unaffordable and unethical process. Thus, the establishment of in vivo in vitro correlation (IVIVC) is essential for the prediction of the performance of such formulations in humans, which may, therefore, minimize the risk of failure in the first-in-human (FIH) studies. Animal models that are commonly used in the pharmaceutical field include rats, mini-pigs, dogs, and monkeys. These animal models are used for the evaluation of the performance of the DOSAGE FORM DESIGN CONSIDERATIONS 652 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT newly-formulated drug product before testing in humans. Each model has advantages and limitations regarding its capability to predict the behavior of the new formulation in humans (Ayad, 2014). Nowadays, it is becoming essential to improve animal models’ authenticity and the therapeutic approaches designs applied in the preclinical stage of drug development (Ludolph et al., 2010). In contrast, many new pharmacokinetic software designed on physiologic bases, such as GastroPlus and PK-SIM, are being applied for testing the behavior of new formulations. The quality of such software is dependent on how precise the input data is (Ayad, 2014). However, the awareness regarding the inability of animal models to reliably predict formulations’ behavior in clinical trials is increasing. Despite the wide use of mice, they are still considered as poor models for most human diseases (Mak et al., 2014). 18.4.2 The Clinical Cycle Development 18.4.2.1 Safety and Efficacy Investigators and physicians working on clinical trials for the development of pharmaceutical products, refer to the two concepts “safety” and “efficacy” as mutually exclusive concepts (Talbot, 2008). While designing a product, evaluation of safety is to be the central component at every stage of the drug development process. Before a newly-formulated drug product enters the market, monitoring and evaluating its safety in all stages of the preclinical phase is required. It is a mandatory activity of pharmaceutical sponsors before they apply for the approval to introduce the drug product to the market. Even after the market release of the product, it is a sincere responsibility of manufacturer and regulatory agency to continuously watch the product since more data will be gathered from patient population after usage of drug product (Yao et al., 2013). 18.4.2.2 Different Phases The in-human clinical trials are basically classified into four main phases as per the following: Phase I studies: during this phase, assessment of drugs or devices’ safety takes place. This testing phase can take up to several months to be completed. Typically, during this phase, a few volunteers (usually around 20 to 100 healthy volunteers) are paid to participate in this study. The purpose of this stage testing is to assess the drug’s or device’s effect on humans. This assessment includes its absorption, metabolism, and excretion. This phase also comprises testing of the possible side effects when the levels of doses increase (Umscheid et al., 2011). Phase II studies: during this phase, assessment of the drug’s or device’s effectiveness takes place. This phase usually takes from several months to approximately two years to be completed and is usually done on hundreds on participating patients. Most studies involved in this phase are done by random trials by which patients are grouped into two or more groups represent control group and patients will takes standard treatment. Rest groups represents test group and takes the experimental drug. These studies allow the investigators to make a comparison regarding the safety and efficacy of the drug. Phase III studies: this phase of clinical trials involves random testing of the experimental drug on hundreds to thousands patients. This phase can take several years to be DOSAGE FORM DESIGN CONSIDERATIONS 18.4 BIOLOGICAL ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 653 completed and provides both the pharmaceutical company as well as the regulatory agency with thorough understanding of the experimental drug’s or device’s effectiveness, intended benefits, and the possible adverse reactions (Cahana and Romagnioli, 2007). Phase IV studies: this phase is most commonly referred to as the post-marketing surveillance trials. These trials are known to be conducted after approving the drug or the device to be used by consumers. This phase may lead to the withdrawal of a drug or device from the market or in some cases the use of these drugs or devices might be restricted (Fontanarosa, 2004). 18.4.2.3 Regulatory Requirements Comparing Different Countries In present scenario, drug development is not centric to a specific part of world, it has become globalized to develop new good pharmaceutical products that fulfill the demands of patients around the world. With the said aim of drug globalization, it has become important to generate clinical data across the world. Currently, it is challenging both operationally and scientifically to set up a global program for drug development, in part due to distinct and sometimes conflicting requirements from different countries’ different regulatory authorities. Since there is no harmonization between the regulation of different countries it is a challenge for reviewing authorities to check and verify the generated data from multiregional clinical trials (MRCTs) for the approval of new drug products. In order to overcome the current challenges, the International Council for Harmonization (ICH) published a document in June 2016 containing a number of guidelines related to the planning and design of MRCTs. Presently it is a draft guidance, entitled “E17 General Principles for Planning and Design of Multi-Regional Clinical Trials.” The environments of clinical trial were found in surveys to be less mature in Asia, Latin America, the Middle East, and Africa, as compared to North America and Western Europe. The results of these surveys were shown to provide evidence of the local medical practices and care standards that vary among the different regions (Shenoy, 2016). Table 18.1 represents different countries with the regulatory authorities found in each. 18.4.3 Emerging Trends In this section four emerging trends are briefly discussed, namely, the pharmacovigilance trend, the pharmacogenomics and its clinical applications, drug repositioning and repurposing, as well as the use of cell lines from human origins. 18.4.3.1 Pharmacovigilance Pharmacovigilance, as defined by the World Health Organization (WHO), refers to the science and activities associated with the operations of detection, understanding, assessment, and prevention of drugs’ adverse effects and the other expected problems. Pharmacovigilance as a systematic process involves several steps, as shown in Fig. 18.6 (Kumar, 2017). Pharmacovigilance has been reported to have a significant role to ensure that both the doctor and the patient have sufficient information regarding a certain treatment which aids in the decision-making when choosing the most suitable drug (Jeetu and Anusha, 2010). A new medicinal product’s approval depends basically on the results of the efficacy DOSAGE FORM DESIGN CONSIDERATIONS 654 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 18.1 Regulatory Authorities in Different Countries Around the World Name of Country/ Group Regulatory Authority Australia TGA—Therapeutic Goods Administration Brazil ANVISA—National Health Surveillance Agency or Agência Nacional de Vigilância Sanitária Canada HPFB—Health Products and Food Branch China CFDA—China Food and Drug Administration European Union EMA—European Medicines Agency India CDSCO—Central Drugs Standard Control Organization Japan PMDA—Pharmaceuticals and Medical Devices Agency New Zealand MEDSAFE—New Zealand Medicines and Medical Devices Safety Authority Russia ROSZDRAVNADZOR—Federal Service for Surveillance in Healthcare South Africa MCC—Medicines Control Council Switzerland SWISSMEDIC—Swiss Agency for Therapeutic Products Tanzania TFDA—Tanzania Food and Drugs Authority United Kingdom MHRA—Medicines and Healthcare Products Regulatory Agency USA FDA—Food and Drug Administration FIGURE 18.6 Systematic process steps of pharmacovigilance. DOSAGE FORM DESIGN CONSIDERATIONS 18.4 BIOLOGICAL ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 655 and safety that are obtained during the clinical trials. Nevertheless, some aspects regarding the safety of a medicinal product might not be determined during the clinical trials for different reasons, such as the relatively small sizes of samples used in the clinical trials, the inadequate safety data, and the broad safety aspects as well (Kumar, 2017). Nowadays, pharmacovigilance is challenged to provide global systems for better health care. Examples of the major challenges are the globalization, web-based information and sales, safety concerns, monitoring of the established products, as well as the emerging countries and various other challenges (Jeetu and Anusha, 2010). Pharmacovigilance is considered as a continuous process that requires the participation of the patient, the pharmacist, the drug manufacturer, as well as the regulatory authorities. Pharmacovigilance has to be a part of the educational process for both the pharmacy students and the professional pharmacists as a way to increase their active participation in this important process (Kumar, 2017). 18.4.3.2 Pharmacogenomics and Its Clinical Applications Pharmacogenetics refers to the study of the way the genetic variations might affect the drugs’ or classes of drugs’ response in patients. It is becoming highly requested to have knowledge regarding pharmacogenetics. Therefore, skillful clinicians are needed for the interpretation and translation of clinical pharmacogenetic research, in order to optimize drug therapies (Chang et al., 2015). Drugs have to exhibit an appropriate safety as well as efficacy in order to be approved for patient use. Anyhow, it is not common for drugs to be effective or safe for all patients. Significant effects on the quality and the cost of healthcare were reported as a result of the inherent variabilities found among individuals. Clinical pharmacogenetic assay has been established to distinguish between different individual patients who were found to be more or less responsive to a certain drug, or for patients who are more or less at risk for adverse effects. Better therapies can be chosen based on the previous information provided by the clinical pharmacogenetic assay which in turn facilitates the manufacturing of more efficacious and less risky therapies (Spear et al., 2001). Massive interindividual variability has been observed in clinical drug response, as shown in Fig. 18.7. This variability has led to treatment failure, and in rare cases, severe adverse reactions. The variability in drug response is typically due to two major factors, namely, the genetic and nongenetic factors. Factors of nongenetic sources are often taken into consideration when adjusting the dose of the drug or when electing alternative therapies for the optimization of patients’ outcomes as ways to prevent the adverse reactions associated with the drug. Inherent genetic variants can also have a clinically significant effect on drug response (Chang et al., 2015). The evaluation of patients’ responses to drug therapies usually takes years. Consented samples of DNA are required for genetic testing, which should also be gathered across the whole study. Actually, collecting DNA from all participants has to be planned for in order to take into consideration the approval of patients (Roses et al., 2014). 18.4.3.3 Drug Repositioning and Repurposing The definition of drug repositioning can be given as the systematic or targeted-based evaluation of pharmaceutically-synthesized compounds that were originally indicated for certain diseases for the identification of new (different) disease indications (Dudley et al., 2010). Compounds at any stage of drug development cycle can be considered as drug DOSAGE FORM DESIGN CONSIDERATIONS 656 FIGURE 18.7 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT The clinical application of pharmacogenomics. repositioning candidates for the identification of new indications (Jung et al., 2014). During clinical trials compounds might fail due to efficacy/toxicity concerns, such compounds might then be used as candidates for drug repositioning. Drug repositioning provides an effective, accelerated, and cost-effective technique for pharmaceutical companies (Shameer et al., 2015). Drug repositioning methods are variable according to the bases they rely on, as shown in Fig. 18.8 (Quinn et al., 2013). Drug repurposing is a strategy that comprises drug repositioning and drug combination (when two or more drug components are combined) (Murteira et al., 2013). Before starting with the strategy of drug repurposing, validation and locking of three elements have to be done by the developer as follows: 1. The regulatory path for target indication. 2. The protection by the intellectual property (IP). 3. The premium price opportunity with the desirable reimbursements (Murteira et al., 2014). Drug repositioning has a promising future for all of the patient communities, translational researchers, and the pharmaceutical industry. Drug repositioning will offer accelerated treatments with the minimum side effects in a considerably short time (Shameer et al., 2015). DOSAGE FORM DESIGN CONSIDERATIONS 18.4 BIOLOGICAL ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT 657 FIGURE 18.8 Methods of drug repositioning. 18.4.3.4 Use of Cell Lines and Cultures of Human Origin The human tissue’s relevant material can be considered as the material that might either consist of human cells or include human cells. Human tissues include blood, tissues, or organs. Some human-relevant materials cannot be considered as human tissue, such as acellular materials, e.g., urine, plasma or serum, gametes, and material created in vitro, including the embryos and cell lines. The development of cell lines might occur in-house, taken from other reliable laboratories (in instances where no other reliable sources are available), or bought from a cell bank. Table 18.2 represents a number of cell banks (Geraghty et al., 2014). Protein therapeutics, such as monoclonal antibodies, peptides, and recombinant proteins, have accounted for the majority of the new products developed by the biopharmaceutical industry. Various platforms of protein therapeutics are available, including nonmammalian expression systems and mammalian expression systems. Mammalian expression systems are considered to be the most preferred platform for biopharmaceuticals manufacturing because these cell lines are capable of producing large, complex proteins including post-translational modifications which are nearly similar to proteins produced in humans (Dumont et al., 2015). Most glycoproteins intended to be used as biopharmaceuticals were manufactured by using mammalian cell lines due to the similar glycan profile as compared to that of humans. Chinese hamster ovary (CHO) cell line is considered as the predominant mammalian cell host that has been used widely for the commercial production (Butler and Spearman, 2014). DOSAGE FORM DESIGN CONSIDERATIONS 658 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 18.2 A Selection of Cell Banks Cell Banks Website American Type Culture Collection (ATCC) www.atcc.org CellBank Australia www.cellbankaustralia.com Coriell Cell Repository http://ccr.coriell.org Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) www.dsmz.de European Collection of Animal Cell Cultures (ECACC) www.phe-culturecollections.org.uk/ Health Science Research Resources Bank (HSRRB), Japan www.jhsf.or.jp/English/index_e.html Japanese Collection of Research Bioresources (JCRB http://cellbank.nihs.go.jp NIH Stem Cell Unit http://stemcells.nih.gov/research/nihresearch/ scunit/ RIKEN Gene Bank http://en.brc.riken.jp UK Stem Cell Bank (UKSCB) www.ukstemcellbank.org.uk/ WiCell www.wicell.org There are some problems that might be associated with cell culture operation, such as contamination with microorganisms especially mycoplasma, misidentification of the cell line, and the phenotypic and genotypic instability. Such problems are being ignored in the research community. These problems can be encountered regardless the nature of cell culturing, small or large, and the purpose, whether it is intended for academic or commercial benefit (Geraghty et al., 2014). 18.5 COMMERCIALIZATION ASPECTS IN PHARMACEUTICAL PRODUCTS DEVELOPMENT 18.5.1 Patents, Exclusivity, and Evergreening Strategies 18.5.1.1 Patent Listing With Different World Body A patent is an authority given by government or a kind of license for the applicant to manufacture, sell, and take all kind of financial benefit out of an invention/product for a set period. The awarded patent by the government of a country is valid only within its territorial boundaries. To get a patent for particular territory, a request must be made in that territory’s patent office. Some territories have various administrative arrangements with regional patent offices, such as the European Patent Office (EPO). By law, it is mandatory for all countries that belong to the WTO (World Trade Organization) to take authorization from a current patent-holder, not only to use the patented knowledge but also to trade products embodying or produced by the patented technology across the territorial DOSAGE FORM DESIGN CONSIDERATIONS 18.5 COMMERCIALIZATION ASPECTS IN PHARMACEUTICAL PRODUCTS DEVELOPMENT 659 boundaries. The WIPO Convention is the constituent instrument of the World Intellectual Property Organization (WIPO). It has two major objectives, the first is to encourage the safeguarding of intellectual property worldwide; and the second is to ensure administrative support among the intellectual property unions recognized by the treaties that WIPO administers. Currently, WIPO has 191 member states. 18.5.1.2 Evergreening Strategies The word green is considered as a symbolic representation of proliferation/growth. Similarly, evergreening in a general sense refers to something that is growing without being affected by external factors. Particularly in the field of commercialization, irrespective of pharmaceutical products development or any kind of engineering development, evergreening simply is a way of continuous extension of an existing monopolistic or market dominant position by various strategies. In other words, evergreening can be understand as a tactic of patent extension or extension of market exclusivity period. Evergreening is also considered as a part of product’s life cycle management. Experts have been defining evergreening for very long time; recently Alkhafaji, Trinquart et al. (2012) defined evergreening as a way that allows “owners of pharmaceutical products using numerous strategies, such as patent laws and minor drug modifications, to extend their monopoly privileges with their products.” Rathod (2010) also defined evergreening in a meaningful way as a “strategy by which technology producers, using serial secondary patents and other mechanisms, keep their product sales protected for longer periods of time than would normally be permissible under the law.” Persons are continuously using newer ways of evergreening. A few commonly used ways are: 1. Business strategy: a. Collaboration with other business units to gain legal leverage of market exclusivity. b. The use of aggressive litigation to fend off or delay entries. 2. Technical strategy: a. Minor improvement in the current form of product by reformulation and repackaging. b. Development of a successor product as an alternate product with an overlapping technology base. c. Use of multiple trademark protection (like brand name, appearance, color, etc.) and then aggressive marketing of the successor product. 18.5.2 The Product Life Cycle Product life cycle (PLC) includes the milestones of the entire life cycle of a product from its conception, through designing strategy and manufacture, to marketing and removal from the market. 18.5.2.1 Management of Product Life Cycle The average costs required for introducing a new drug into the market have risen since 1970s from US$54 million to US$800 million (Spruill and Cunningham, 2005). Approximately, it may take around 12 15 years for the process of drug development DOSAGE FORM DESIGN CONSIDERATIONS 660 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT (Barak and Wilson, 2003). The concept of PLC has been covered by many researchers during the early 1960s, nevertheless, recently, employment of life cycle management (LCM) strategies has taken place in the pharmaceutical industry. Companies of pharmaceutical research have been noted to be increasingly dependent on LCM strategies as a new approach for profitability maximization. The most successful strategies for LCM have been developed by the companies having close interaction with their customers as well as a good market insight (Kvesic, 2008). 18.5.2.2 Brands and Generics Some pharmaceutical companies have protected their market share after patent expiration by benefiting from their insight position in the market and hence increasing their brand loyalty. Companies seek to maximize their brand name during the exclusivity period in order to create and acquire long-term brand loyalty. A strong brand name makes it hard sometimes for other generic drugs to competitively access the market (Kvesic, 2008). The issue of marketing standardization rather than customization is being recently discussed (Viswanathan and Dickson, 2007). A global marketing standardization has been shown to be more suitable and can also extend across national borders. By applying this strategy, the costs of brand development are shown to be reduced, messaging is more consistent and has better control, as compared to the customization strategy of marketing campaigns; global marketing standardization is therefore considered to be ideal to globally build a strong brand identity (Kvesic, 2008). 18.5.2.3 Competitive Advantage The theory of product life cycle reflects the intersection between the supply instability and the instabilities associated with a products’ demand. Demand instability is usually related to the factors driving consumers for products in and out of the market (Nadeau and Casselman, 2008). On the other hand, the supply instability is shown to be related to the reason behind the different numbers of firms providing a certain product in the same market, which can be referred to as monopolistic (Onkvisit and Shaw, 1986). However, in the growth phase of any product entering the market, the competition between firms is taking place, but still many products are considered as substitutions for each other. At the phase of maturity, the market will start to act like an oligopoly, where barriers are put up to prevent any new firms entering the market at that phase (Christensen, 2001). 18.5.3 Commercialization Realities In this section, some of the aspects related to newly-synthesized drugs reaching the market are discussed. Topics of the patents and the problems associated, in addition to the strategies that companies follow to maintain viable products and business are covered. Other topics including access to medicine, the commercial pressure in the market, and the environmental challenges facing the introduction of a new drug to the market are focused on. 18.5.3.1 Problems and Litigations Around Patents Ensuring long-term profitability after introducing a new drug to market is now raising serious problems for the associated parties in the pharmaceutical industry. As in any other industry, the loss of patent protection is shown to be result in serious losses in both sales DOSAGE FORM DESIGN CONSIDERATIONS 18.5 COMMERCIALIZATION ASPECTS IN PHARMACEUTICAL PRODUCTS DEVELOPMENT 661 and profits. After the expiry of the protection by patents, drugs of equivalent features start to enter the market from generic manufacturers at considerably lower price as compared to the original inventor (Pearce, 2006). The immediate fall in revenue that follows the patent expiration is usually described as a “patent cliff.” Patent cliffs are considered as one of the serious issues that face firms in the pharmaceutical industry. The loss of exclusivity to important products is typically followed by a seriously negative impact on the performance of the pharmaceutical company (Mittra, 2007). The productivity of pharmaceutical R&D has shown a continuous decline over the past few decades associated with an increase in the costs needed to bring a new drug to the market (Pammolli et al., 2011). 18.5.3.2 Maintaining a Viable Product and Business The pharmaceutical industry comprises sets of businesses where shareholders are persuaded to invest with high expectations of receiving a return for these investments. However, the pharmaceutical industry is considered to be a highly risky business (Taylor, 2015). Because of the very large investment required, in addition to its long-term nature and the high risks associated, the returns provided for such investments have to be considerably high. Despite the drawbacks of this business model, it is still considered to be very attractive to investors looking to develop a very successful industry (Kessel and Frank, 2007). However, some people believe that making very high profits out of developing essential medicines is unethical and that such tasks should be undertaken by nonprofit organizations. However, it is highly risky for governments or nonprofit organizations to handle this task. It is very clear that although pharmaceutical companies are large, they do not yet have enough resources to fulfill all medical needs, due to the need to work on several drug candidates at a time which increases the investment risk (Taylor, 2015). In order to take such decisions, large numbers of patients able to pay for drugs have to be available. Therefore, it should not be surprising that pharmaceutical companies tend to heavily invest in research of chronic illnesses such as cancer, dementia, diabetes, and hypertension, whereas less attention is paid for diseases affecting small numbers of patients (Kessel and Frank, 2007). 18.5.3.3 Access to Medicine It is shown that pharmaceutical companies more often accused of not investing in some medical areas since low profits are expected from such investments. Antibiotics are the commonly used treatment for infectious diseases and are used by most of the population. However, the pharmaceutical industry has now reached a stage where the development of antibiotics has shrunk. The reason behind this is related to the difficulties associated with the processes of identifying compounds to effectively as well as rapidly kill pathogens in a relatively short period of time. Another concern preventing such investments is the economic regulations that necessitate that newly synthesized drugs have to be harmless to any cell other than the infected cell, which is a difficult duty that developers have to take into account (Taylor, 2015). However, in most countries including the developing countries, the pricing of pharmaceutical drugs is controlled partially by the state. An increase in the downward pressure on pharmaceutical products’ prices are caused by increasing the pressure on national health services and companies with private health insurance, which may lead in some cases to a complete rejection of allowing the prescription of a new pharmaceutical drug (Hughes and Doheny, 2011). DOSAGE FORM DESIGN CONSIDERATIONS 662 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT 18.5.3.4 Environmental Challenges Recently, many suggestions regarding discovering green pharmaceuticals have been arising. Despite the very low risk caused by drugs to the environment, many pharmaceutical residues are still being detected in the environment. Consequently, many people are still continuously putting pressure on the pharmaceutical industry to start paying more attention to develop “greener drugs” (Daughton, 2003). The principle regarding the development of green drugs stands for the production of pharmaceuticals that are expected to leave the minimum amount of residues in the environment. Additionally, several environmental scientists are continuously assuming that pharmaceutical products have to be biodegradable (Taylor, 2015). The effects of pharmaceutical products on the environment are difficult to assess when using a single product and can be overlooked. Additionally, it is also difficult to pose a visible effect of a certain pharmaceutical substance incorporated in a product. Consequently, assessing the environmental risks that might be caused by any newly-synthesized pharmaceutical compound has to be validated in the preapproval stage of drug development. Antibiotics have been specifically discussed due to their tendency to accumulate in soil, and hence reach the groundwater, in addition to their contribution to the microbial resistance associated with many antibiotics (Kuster and Adler, 2014). 18.5.4 Factors Affecting Commercialization Commercial success of pharmaceutical companies is widely dependent on the activities during the stages of research and development. These activities usually provide information regarding the efficacy, safety, as well as the tolerability of drugs to the regulatory agencies. After regulatory approval, drugs are marketed to certain doctors and pharmacists. Therefore, market accessibility typically involves a set of stakeholders (Kumar et al., 2014). Additionally, the variations between the regulatory requirements among countries is shown to make it difficult for a drug to access the market, and hence, providing healthcare services has been changed, and patients are increasingly provided with information regarding their health conditions in addition to the possible treatments available, and then their perspectives are taken into consideration during the early stages of drugs development. On the other hand, doctors may be less free to choose the medications for their patients due to the national prescribing guidelines they must follow (Eichler et al., 2008). Personalized treatments are the new approach applied recently, which have led to an increase in the need for a superior description of market access (Qattan et al., 2012). This approach aims to develop an appropriate treatment that suits each patient’s needs, not to mention the importance of taking into consideration the genetic, clinical, biological, and environmental aspects and lifestyles. Ideally, such information is expected to allow the predictions of the susceptibility to disease and the patient’s response to the given treatment, which will, therefore, minimize the possibility of failure and toxicity of therapeutic agents (Sendyona et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS ABBREVIATIONS 663 18.6 CONCLUSION The discovery and development of new pharmaceutical products is a process that involves multiple steps. Pharmaceutical product development basically comprises four main stages, namely, the preformulation stage, the prototype development, scale-up, and commercialization. Preformulation studies are very important because drug developers rely on the data obtained by these studies for further processes. Preformulation studies comprise three major disciplines: the bulk characterization, the solubility analysis, and the stability analysis. During the process of drug discovery and development, certain aspects need to be considered regarding the conception of the active pharmaceutical ingredients (APIs), the disease to be treated, the proper route of administration, the biological aspects during the preclinical and clinical trials including safety and efficacy of the drug, in addition to the intellectual property. During the development stages of pharmaceutical products, the optimization of the product and the experimental design of the dosage forms play important roles in the efficiency of the final product. In the preclinical stage of drug development, strategies such as in vitro screening, in silico prediction, as well as the use of animal models are broadly relied on. There are a number of emerging trends in the field of pharmaceutical industry development, such as the pharmacovigilance, pharmacogenomics, drug repositioning, and the use of cell lines and cultures of human origins. Drug commercialization and the challenges facing the pharmaceutical companies are now focused on the field of pharmaceutical research and development. ABBREVIATIONS ANDA APIs CHO CMC IND NDA VS IP IPR R&D PLC LCM WHO IV IM SI IVIVC FIH FDA NCE MRCTs abbreviated new drug application active pharmaceutical ingredients Chinese hamster ovary chemistry manufacturing and control investigational new drug new drug application visual screening intellectual property intellectual property right research and development product life cycle life cycle Management World Health Organization intravenous intramuscular subcutaneous injection in vitro/ in vivo correlation first-in-human Food and Drug Administration new chemical entity Medical Research Council Technology DOSAGE FORM DESIGN CONSIDERATIONS 664 18. FOUR STAGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT Disclosures: The authors of Dr. Reddy’s Laboratories Limited (Basant Amarji, Ujjawal Bairangi, and Anup Avijit Choudhury) would like to acknowledge that the views, thoughts, and opinions expressed by them in the text belong solely to the authors, and not necessarily to the author’s employer, organization, committee or other group or individual. References Almeida, A., Souto, E., 2007. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv. Drug Deliv. Rev. 59 (6), 478 490. Alkhafaji, A.A., Trinquart, L., Baron, G., Desvarieux, M., Ravaud, P., 2012. Impact of evergreening on patients and health insurance: a meta-analysis and reimbursement cost analysis of citalopram/escitalopram antidepressants. BMC Med. 10, 142. Allen, L., 2008. Dosage form design and development. NCBI 30 (11), 2102 2111. Allen, L., Ansel, H.C., 2013. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. 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Importance of preformulation studies in designing formulations for sustained release dosage forms. Int. J. Pharm. Technol. 4 (4), 2311 2331. Scannell, J., Blanckley, A., Boldon, H., Warrington, B., 2012. Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discov. 11 (3), 191 200. Song, C., Han, J., 2016. Patent cliff and strategic switch: exploring strategic design possibilities in the pharmaceutical industry. SpringerPlus 5 (1), 1 14. DOSAGE FORM DESIGN CONSIDERATIONS C H A P T E R 19 Scale-Up Studies in Pharmaceutical Products Development Nidhi Raval1, Vishakha Tambe1, Rahul Maheshwari1, Pran Kishore Deb2 and Rakesh K. Tekade1,3 1 National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 2Faculty of Pharmacy, Philadelphia University, Amman, Jordan 3 Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 19.1 Introduction 670 19.2 Solid Dosage Forms 19.2.1 Scale-Up in Dry Blending, Mixing, and Granulation 19.2.2 Common Mixing Guidance 19.2.3 Granulation and Drying 19.2.4 Compaction and Tableting 670 19.3 Parenteral Dosage Forms 19.3.1 Mixing and Agitation 685 685 671 671 675 681 19.4 Semisolid Dosage Forms 686 19.4.1 Material Transfer Rate 687 19.4.2 Mixing 688 19.4.3 Heating and Cooling Rates 689 19.4.4 Viscous and Non-Newtonian Liquids 689 Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00019-8 19.5 Scale-Up of Nanoformulations: Case Studies 691 19.6 Quality by Design (QbD) for Scale-Up 692 19.7 Problems Encountered During Scale-Up 693 19.8 Conclusions 694 Acknowledgments 695 References 695 Further Reading 699 669 © 2018 Elsevier Inc. All rights reserved. 670 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT 19.1 INTRODUCTION The traditional process of pharmaceutical product development until it reaches the global market involves a long journey of many experiments, observations, challenges, and resolutions. During the initial formulation stage, certain physicochemical parameters are considered to convert the raw materials into a drug formulation with an aim to maintain the required quality attributes such as potency, release time, etc. However, at the initial level, these investigations are performed at a small scale by using small-output equipment, where the methods and results observed from these investigations are pertinent to that scale only (Amirkia and Heinrich, 2015). Transformation of these small-scale observations into the large-scale development mostly requires entirely varied design strategies and equipment which may result in differences in quality (Vladisavljević et al., 2013). Producing materials at larger scale without performing small-scale experimentation is unreasonable as an overall tactic for modern pharmaceutical product development. However, there are large differences persisting between small scale and large scale due to the lack of proper scale-up methodologies. This is true particularly in the context of modern pharmaceutical formulations, such as liposomes, dendrimers, polymeric nanomaterials, and many of these types (Lalu et al., 2017; Maheshwari et al., 2012, 2015b; Sharma et al., 2015; Tekade et al., 2017b). Maintaining the quality of a product at the scale-up level is never done by accident, nor is it admissible under recent regulatory laws to employ final product estimation to get excellence by scrapping a product that does not meet norms. Alternatively, quality must be developed through the proper processing techniques, and this can be achieved only when there is a wide technical understanding of the physicochemical properties and the techniques that translate the incoming materials into the final drug product (Santos and Laczniak, 2015). In recent time, regulatory bodies are considered to be more efficient at predicting the influence of scale-up of a product as an area that requires the development in the recent state of pharmaceutical manufacturing (Strovel et al., 2016). 19.2 SOLID DOSAGE FORMS The solid dosage form is the most preferred and explored formulation for the human use and are mostly available as tablets, capsules, powders, granules, lozenges, and suppositories containing a mixture of active pharmaceutical ingredient/s (drugs) and nondrug components (excipients) (York, 2013). The large-scale production of a solid dosage form requires well-proven and documented formula and equipments. Any substantial alteration in the procedure of producing and developing pharmaceutical products is a matter of regulatory legislation. Scale-Up and Postapproval Changes (SUPAC) are the superior interest of the Food and Drug Administration (FDA) (Diaz et al., 2016; Khatri et al., 2017). Associations among the FDA, the pharmaceutical industry, and academia for the purpose of scale-up of pharmaceuticals have been launched under the framework of the Product Quality Research Institute (PQRI). Problems associated with scale-up might require DOSAGE FORM DESIGN CONSIDERATIONS 19.2 SOLID DOSAGE FORMS 671 changes in post-approval that would affect the final formulation composition, site change, and manufacturing process or equipment changes (Strovel et al., 2016). Additionally, from the regulatory standpoint, scale-up and scale-down are preserved with the similar degree of examination. 19.2.1 Scale-Up in Dry Blending, Mixing, and Granulation Dry powder blending and mixing is usually a crucial step in the manufacturing of solid oral dosage forms, particularly tablets and capsules, that have direct impact on the uniformity of content. For instance, tumbling blenders are used for mixing purpose. A tumbling mixer is a container with several holes attached to a rotating shaft, where the material to be mixed is loaded in a vessel that rotates for several revolutions (Barling et al., 2015). With higher capacity, less shear stress, and a smooth container, they come in different sizes and geometries from lab scale of fewer than 16 quarts to massive production or industry scale of .500 feet3. The most common geometric patterns used in tumbling mixers include V-shaped or twin shall blender, double cone blender, in-bin blender, and rotating blender. Without prior experimental work, none of the mathematical methods are able to predict the impact or behavior of the granule (Lawrence et al., 2014). There is a typical problem regarding mixing by tumble blenders having 5-ft3-capacity, occupied to 50% of volume and operated for 15 minutes at 15 rpm in order to obtain the desired mixture homogeneity. Some questions would arise, i.e., what results can be obtained by using a 25 feet3 blender? There is a lack of an exact accepted procedure available to solve this problem.(Pandey and Badawy, 2016). 19.2.2 Common Mixing Guidance 19.2.2.1 Describing Mixing Phenomenon Understanding of critical issues and common guidelines regarding the mixing process of API and excipients to obtain homogeneous blend are discussed under this section. Determination of mixing composition is considered as a crucial part before carrying out the mixing process. Still, there is no method available for online mixing component evaluation, however, quantification of samples by intermediate removal can be monitored online. For intermediate sampling, the blender must stop in at predefined intervals, but the interruption of the blending cycle may affect mixing of the blend (Lee et al., 2015). Based on the mixing index, the mean value and coefficient of variances are determined for collected mixing samples. Several mixing indices are available but still, there is no mixing index that would act as a general mixing index. Therefore, it is entirely up to the investigator to choose what he refers to. As the definition of mixedness, tracking of mixing samples continues until the mixing homogeneousness is attained (Alizadeh et al., 2014). Apparent variability is shown to fundamentally rely on the size of the sample. In the case of a very small quantity of the sample, variations can be aggravated, however, a more substantial amount of a sample can distort the concentration gradients (Shenoy et al., 2015). Granule beds require energy to mix samples, whereas miscible fluids do not and are usually mixed through diffusion and undergo repeated mixing on a micro-scale. DOSAGE FORM DESIGN CONSIDERATIONS 672 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT Henceforth, it is necessary to take a sufficiently large quantity of the representative sample of the blender volume. In scale-up and during the mixing process, standard samples are taken as representative of the local concentration at a particular site. Sampling instruments must be designed in such a way that they avoid sampling errors occurring due to any reason, such as poor flow of powders or granules, or sample contamination when samples are transferred between different zones of the blender during the thief cavity (Romañach, 2015). The degree of mixedness indicates homogeneity in sampling and is an important parameter that must be maintained in dosage formulation. Numerous mixtures of granules can unexpectedly segregate into regions of unlike composition when disturbed by shear, vibration flow, etc. As soon as a good blend of powders mixture is attained, the mixture should be handled carefully during analysis, transfer, or storage to avoid any “demixing”. Many of these steps play an important role during scale-up of powders flowing from bins, blenders, and hoppers due to the high tendency of segregation. The coming section focuses on all such issues in order to ensure proper handling of powders or granules during mixing to prevent powder segregation. 19.2.2.2 Issues Related to Mixing Moreover, the process of blending is explained by three fundamentally independent mechanisms, namely, convection, shear, and dispersion mechanisms. Conventional blending involves the movement of large groups of particles in the direction of flow, i.e., orthogonal to the axis of rotation as a consequence of vessel rotation (Carvalho et al., 2015). Random motion of particles in the dispersion happens due to impacts or interparticle action basically orthogonally to the direction of flow, i.e., parallel to the rotation axis. Particles separated by the shear mechanism caused by the accumulation of particles or cohesion forces between them would require high shear forces (Domike and Cooney, 2015). Thus, one must take into consideration all such factors while selecting a specific type of blender for mixing. A homogeneous mixing relying on the symmetrical design of a tumbling blender rate of mixing is inadequate because of the amount of material that can cross from one side of the symmetry plane to the other. Asymmetric blenders include offset V-blenders and slant cone, which display higher mixing efficiency. The rate of mixing depends on the rotational speed of the blender (Sen et al., 2017). Another critical factor is loading of multiple ingredients in a blender. Loading of less than 1% component requires a lot of care in order to avoid slowness of mixing procedure (Hassoun et al., 2015). 19.2.2.3 Process Parameters In the scale-up using tumbling blenders, rotation rate as well as variations in the size play a crucial role and may affect the scale-up production of pharmaceutical goods. Investigations performed on V-blenders and double cone blenders revealed no significant effect on the rate of mixing when rotation rate was less than the critical speed of the blender. Additionally, critical speed signifies the speed at which tangential acceleration resulting from revolution matches the acceleration caused by gravity. Further, in some other findings, it was suggested that the number of revolutions was the vital restriction governing the mixing rate (Baxter and Prescott, 2017). DOSAGE FORM DESIGN CONSIDERATIONS 19.2 SOLID DOSAGE FORMS 673 During scale-up to geometrically comparable mixing of blend, mixture composition and fill level must be kept at a constant level of scale. Conversely, if an improvement is made to the size of the vessel provided, the fill level must be same to that of the relative volume of particles at the dropping layer (Thiry et al., 2015). After comparing it to the bulk, it has been accompanied with a large decrease in the mixing rate. It was observed that a 1-pint V-blender running at 40% fill carries a mixing rate which is nearly three times quicker than at 60% fill. Therefore, occupancy level has to be maintained at a constant for geometric correspondence. If the flowing layer depth is a critical step then it may not be possible to counterpart mixing rate per revolution across changes in scale. 19.2.2.4 Scale-Up Approaches Scaling up of pharmaceutical formulations is the activity of expanding an intervention or program from initial facilities that serve a small proportion of the population to facilities that serve a significantly larger population (such as an entire region or country) and there are several approaches. The Froude number as shown in Eq. (19.1); Fr 5 Ω2 R=g (19.1) where Ω stands for the rotation rate, Fr are the dimensionless number, R is the radius of the vessel, and g is denoted as the acceleration from gravity. The equation balances inertial forces and gravitational forces. It can result from the standard calculations of motion for a general fluid (Pandey and Badawy, 2016). Unfortunately, no experimental data have been offered to support the validity of this approach. The continuum method may propose other dimensionless groups if a relation between powder flow and powder stress can be determined. Furthermore, Froude number refers to the resultant data based on continuum mechanics, but the scale of the physical system for the blending of granular materials is on the order of the mean free path of individual particles, which may invalidate the continuum hypothesis (Feehan and Salganik, 2016). During scaling of 5 feet3, Fr is utilized as the scaling parameter. Further, prerequisites are intended to confirm geometric resemblance, i.e., total number of revolutions, all angles, and ratios of lengths are reserved constant. For geometric equalities, the 25 feet3 blender may be used due to its similarity to the expansion of the 5 feet3 blender. In this situation, the linear increment is 71%. The occupancy level must remain the same. Further, to conserve the same Fr, R must be enhanced by 71%, the rpm should be decreased by 0.76 factor concerning 11.5 rpm. Practically, not all blends are sensitive to speed, and mostly accessible blenders are usually used at a preferable stable speed, i.e., nearer to 11.5 rpm (Parikh, 2016). Consistent scale-up criteria have influences foremost on the development period and costs. Nonsystematic scale-up techniques mostly lead to extremely lengthy processing times and incompetent application of existing capacity. Increase in processing time might result in undesirable side effects, such as sintering of particles, heat generation, attrition, or extreme agglomeration (Conder et al., 2017). One of the benefits of labor-intensive scale-up is the decrement in process uncertainty. Experiments are completed in a generalized manner which reduces the development time and investigational disappointments (Wang et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 674 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT FIGURE 19.1 Involved major product development stages. A complete schematic showing different stages of formulation development starting from raw material level to product in hand level. Segregation is another powder blending effect that is typically known as a comparison between the standard deviation of samples of the final product (dosage form) to those collected from the blender or upon release of material from the blender. Segregation often has consequences in different tendencies along the path of formulation development. Different steps of mixing must be properly interconnected with a sequence of powder flow from the blender to the dosage formulation, like tablets or capsules, and the likely segregation mechanisms to diagnose the problem (Alizadeh et al., 2014). Powder might transfer from one blender into other containers and then be transferred into a small press hopper (Oka, 2016). Certain common strategies that may assist the experts during the scale-up process are shown in Fig. 19.1. Firstly, one needs to confirm whether a simple alteration in the capacity of blender would lead to changes in the main mixing mechanism of the blender, i.e., convective to dispersive. As a result, it would lead to asymmetry in the loading situations. For DOSAGE FORM DESIGN CONSIDERATIONS 19.2 SOLID DOSAGE FORMS 675 FIGURE 19.2 Representation of different type of tumbling mixer used in the scale-up batch formulation. (A) Double cone mixer; (B) rotating cube mixer; (C) Y-cone mixer; (D) twin shell mixer with its agitator. completely freely flowable powders, number of revolutions is considered an important factor, while rates of rotation are irrelevant. In the case of cohesive powders, the mixing process relies on both shear rate and rotation rates (Gao et al., 2013). During scale-up tests, sufficient samples are taken for an accurate explanation of the mixture state in the vessel. Additionally, one should be cautious about the interpretation of samples, regarding the mixing index means and confidence levels. Mixing rate increases owing to decrement in the occupancy level are not desirable. Further decreases in the occupancy level will also lessen the probability of the occurrence of dead zones (Lawrence et al., 2014). Asymmetry in the vessel results from the addition of baffles and has a tremendous impact on the mixing rate as shown in Fig. 19.2. 19.2.3 Granulation and Drying Production of granules is still based on the perception of the batch of intended formulation. During the initial dosage form development, such as in case of a clinical study, a smaller batch size is usually preferred. However, in a later phase, a batch size used for the large-scale manufacturing of the dosage form will be up to 100 times greater. This is where scale-up process is of extreme importance to achieve similar characteristics of products even at larger manufacturing scales than are achieved during the initial development phase. (Shanmugam, 2015). Variation in the equipment is one of the major tasks involved during the scale-up process. The quality of the granules might change during the scale-up process, in addition to final moisture content, friability, granule size distribution, compressibility and compatibility of the granules, all of which in turn significantly affect the final tablet properties like tablet hardness, the dissolution rate of the active substance, tablet friability, disintegration time, aging of the tablet, etc. (Pandey et al., 2017). Mathematical considerations of the scale-up theory, in-process control methods, scale-up DOSAGE FORM DESIGN CONSIDERATIONS 676 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT invariants, and design of robust dosage forms are various approaches used for analyzing the scale-up process (Clancy, 2017). For instance, percolation theory plays an important role. A quasi-continuous construction line of granules is presented in the following section wherein small-scale batches for clinical studies and production sets can be made using similar equipment. An elegant and cost-efficient method helps to evade problems regarding scale-ups (Nekkanti et al., 2015). Scale-up performed through a conventional fluidized bed spray granulation process is discussed below, as the process instruments are frequently used in spray granulation and drying of granules prepared by wet granulation. The amalgamation of reproducibility and batch size flexibility results in a highly efficient manufacturing method. The dry-blending step is a crucial step during mixing of low-dosage formulations. Cohesive powder components have to be dis-agglomerated to obtain a high degree of mixing. Further, the shear forces during the step of sieving results in dis-agglomeration of cohesive material and lead to contact between finer and coarser particles. The content uniformity of a low-dose formulation may depend on established theoretical considerations, such as Poisson statistics, particle size of the active substance, etc. (Gao et al., 2013). In the case of wet granulation, the procedure for scale-up cannot be defined efficiently through mathematical equations, although dimensionless groups could be determined through dimension analysis. Theoretically, dimension analysis is done through Buckingham’s theorem to identify dimensionless groups, such as powder number, a specific amount of granulation fluid, a fraction of volume loaded with the particle, centrifugal/gravitational energy determined through Froude number, geometric number as the ratio of characteristic lengths, etc. (Levin, 2015). In a mixer/kneader or mixers of the planetary type (e.g., Dominici, Glen, and Molteni), the wet granulation process can be simply supervised by the determination of the power intake. A linear relationship exists between liquid used for granulation and the batch size. For the scale-up process, the rate of addition of granulation liquid is larger in amount for larger batch size (Meena et al., 2017). A well-soluble binder can be added in the dry state or dissolved in the granulating liquid with a low viscosity. Demineralized water is the top choice as granulating liquid due to its high interfacial tension, easily distillable property, and cost-effectiveness (Järvinen et al., 2015). Models which are described by Newitt, Rumpf, and Conway-Jones depict that during the moist agglomeration process, cohesive forces may lead to the formation of liquid bridges in the voids between solid particles (Quaicoe et al., 2015). In a faultless situation with a 5 0 (contact) and d 5 0 , the cohesive stress σc of the powder bed, comprising of identical spherical particles with diameter x, void space is somewhat filled up with granulating liquid (Eq. (19.2)). ε AΠγ (19.2) σc 5 1 2 ε x 1 1 tg 2θ where ε 5 powder mass porosity, A 5 proportionality constant, based on the geometry of packing of the particles packing. The robustness of the scale-up process is of paramount importance for any dosage formulation. Granule size distributions should not vary among different batches. The decrement in product properties and variability are considered as major problems of FDA DOSAGE FORM DESIGN CONSIDERATIONS 19.2 SOLID DOSAGE FORMS 677 process analytical technology (PAT). Although it is also found as a greatly challenging task for both academia and industry (Gibson, 2016). The significant parameters of the granulation procedure in a high-shear mixer are the amount and the form of granulating liquid. For an optimum selection of the granulating liquid, power consumption method interpretation can be very vital. During the in-process control method, possible variation of the initial particle size distribution of the API and excipients can be recompensed (Fonteyne et al., 2013). Sometimes it is essential to match the enactment of two different granule formulations. Although two formulations are varying in composition and also in the amount of granulating liquid needed, the quantity of granulating liquid could be adjusted to achieve a correct comparison. Dissolution process of the active material in the final granules or tablet is affected by not only the type of excipients but also by the amount of granulating liquid added during formulation of tablet granules. Granules manufacturing or the granulation procedure are still not clearly understood, particularly where the essential boundary circumstances for an optimal granulation process are not satisfied. Difficulties could arise when the granulating liquid is nonNewtonian, during a hydration process, or under a higher temperature, if a gelation process occurs, or if granulating liquid itself dissolves an important amount of the powder formulation. In a perfect scenario, the only role of the granulating liquid is to produce liquid bonds among the powder particles to produce efficient granules (Beer et al., 2014). Recently a quasi-continuous granulation and drying process (QCGDP) has been described to evade scale-up problems as a batch concept and continuous process. Production by continuous process has a vital role in food and chemical production, while pharmaceutical industry manufacturing is mostly grounded in a batch-type process technique. The batch notion is very appropriate regarding the dosage form safety and quality assurance. Thus, a definite batch can be accepted or excluded (Cahyadi et al., 2015). In the circumstance of a continuous procedure, a batch should be distinct in some way at an artificial level. Alternatively, continuous processes propose two crucial benefits such as no problematic scale-up implementation is essential for larger batches and an automatic production line up to 24 hours could be possible (Meier, 2016). Quasi-continuous production line principle is centered on a semicontinuous production of minibatches with the help of a specifically premeditated high-shear mixer/granulator. It is associated with a continuous multicell-fluidized bed dryer, e.g., Glatt Multicell bed dryer (Fig. 19.3). Various formulations were tested on the semicontinuous production line and compared with a conventional batch process. A universal target of quasi-continuous granulation and fluid-bed drying is an important parameter in the production of many dosage forms. A small-scale component of 7 9 kg production, as a substitute for a whole batch, permits an automatized, continuous granulation and drying technique (Werani et al., 2004). Reproducibility of each subunit can be assured by separating techniques into several compartments such as mixing, sieving, and drying compartments. Utilization of the same plant in research, development, and production will reduce the time to release new solids formulations to the market. This could be taken up by applying common existing manufacturing techniques that avoid altering the mixture’s constituents. The produced granules’ quality and tablets fulfill all product specifications. The resultant quasi-continuous DOSAGE FORM DESIGN CONSIDERATIONS 678 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT FIGURE 19.3 (A) Diagrammatic representation of Glatt Multicell Equipment. Granules are produced in quasicontinuous production which looks like a train of minibatches passing through the instrument for drying, and granulation. Glatt Multicell Equipment is generally comprised of three types of cells with different temperatures of air. Granules were dried in the first cell at 80 C and the last compartment for maintenance of temperature and humidity in the granules. Subsequently, there are three drying cells comprised Glatt Multicell production line for granules production. (1) Transportation and drug dosage form for mixer/granulator filling; (2) High-speed plough share mixer horizontal; (3) Rotary sieving technologies for misty and last sieving; (4) Three chambered fluid-bed dryer; (5) The pneumatic transport system. (B) Image of production plant situated at Pfizer Goedecke, Freiburg, Germany. (A) Adapted with permission from Leuenberger, H., 2003. Scale-up in the 4th dimension in the field of granulation and drying or how to avoid classical scale-up. Powder Technol. 130 (1), 225 230; (B) Adapted with permission from Werani, J., Grünberg, M., Ober, C., Leuenberger, H., 2004. Semicontinuous granulation—the process of choice for the production of pharmaceutical granules? Powder Technol. 140 (3), 163 168. granulation is found as a continuous and reproducible process. With comparison to commonly used granulation equipment, viz., DiosnaBP-600 high-speed granulator, quasi-continuous granulation demonstrates the equal or improved superiority of granules and tablets (Arkenau-Marić et al., 2014). For quasi-continuous granulation and fluid-bed drying, the Glatt-Multicell unit consists of the subsequent essential steps for a transport and dosage system for mixer filling (layout of Glatt-Multicell as shown in Fig. 19.3). Fluidized bed dryer is utilized in the pharmaceutical industry for spray granulation and drying as a step after wet granulation (Liu et al., 2014), whereas batch production in high- or low-shear granulators, or by the fluidized bed spray granulation method could dry the granules quickly and its related parameters as depicted in Fig. 19.4. The heat transport to the bed of fluidizing granules comes from a mixture of inlet air temperature and volume (Suresh et al., 2017). Therefore, regardless of the technique employed to manufacture the granules and the subsequent batch size, a significant factor in scale-up is the enhancement in drying size in major equipment. Numerous kinds of spraying patterns are followed for fluidized bed dryer, i.e., top spray, bottom spray, and tangential spray as shown in Fig. 19.5. Scaling up to production scale is a challenging task. As in the production scale batch size increases drastically so a mass effect predominates. Granules produced by the process DOSAGE FORM DESIGN CONSIDERATIONS 19.2 SOLID DOSAGE FORMS 679 FIGURE 19.4 Critical process parameters to be considered in fluidized bed drying during dosage formulation. FIGURE 19.5 Pictorial representation of type of spray mechanism involved in fluidized-bed dryer and batch fluid beds. (A) In top spray, powder which is intended to be granulation would be suspended in the hot air of fluid bed and liquid binder sprayed from through nozzle situated above. (B) In case of bottom spray, air would pass through fluidized bed and particulate material is lifted up due to the air stream and solution is sprayed from bottom for granulation. (C) Here with tangential spray nozzle situated at side of contained as well as three main force as particle movement, mixing and granulating are affecting. DOSAGE FORM DESIGN CONSIDERATIONS 680 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT of fluidization are porous in nature with the presence of pores at the surface as well as in the interstitial space. A property like this enhances compressibility, distentrgation, and dissolution properties of granules. However, porosity and tensile strength are inversely related and the influence of mass concerning the larger batch size is such that compaction may reduce porosity and enhance attrition (loss of granule structure). Granules in a batch of 500 kg are exposed to considerably more force than those in a laboratory scale batch of 5 kg. Although the magnitude of the impact is probably not predictable, in general, an increase in bulk density of approximately 20% as a function of scale-up in large machines may be expected. It is understandable that a larger batch size and increased bed depth influence the granules (Pandey and Bharadwaj, 2016). Other key granule properties are particle size and distribution, which are related to droplet size, and as long as this is preserved in scale-up, the granule size and distribution of the larger batch should be comparable. Size of granule is connected to the size of a droplet of the binder which is sprayed into the fluidizing substrate particles. In industries, automated instruments enable the delivery of liquid to the bed. It is utilized at available drying capacity, and at a droplet size which is essentially equivalent to that used in the laboratory. For example, the laboratory spray rate was 100 g/min at 200m3/h process air volume, and the manufacturing equipment functioned at 4000 m3/h, for spraying in the production equipment the initial point would be 2000 g/min, or equal to 20 times of that applied in the laboratory machine, regardless of the size of the batch (Levin, 2015). In the production machine, the size of the spray nozzle would increase the spray rate inside its performance envelope, which has uniform droplet size and uniformity in distribution or correspondence in granule size would be not possible. Mostly two approaches are available to determine spray rates. If the air volume can be evaluated directly from the apparatus, then the calculation of the spray rate can be done by applying the following Eq. (19.3): S2 5 S1 X V2 V1 (19.3) where S1 is spray rate in the laboratory measure equipment, S2 is spray rate in the larger batch scaled-up equipment, V1 is denoted as the air volume in the laboratory scale equipment, and V2 as the air volume in the scaled-up equipment. In the case of no direct air volume in the equipment, for approximation cross-sectional areas of the product bowl screens can be used as depicted in the Eq. (19.4): S2 5 S1 X A2 A1 (19.4) where A1 is the cross-sectional area of the laboratory scale equipment, and A2 is the crosssectional area of the scaled-up equipment (Lawrence et al., 2014). Similarly, in a scale-up process, the driving force should be maintained, which is directly affected by spray rate, binder concentration, droplet size, and then regularized by using batch size. The growth rate of the granule is compared to the driving force which is calculated by the following Eq. (19.5): Driving force 5 spray rate 3 Binder concentration 3 Droplet size=Batch size DOSAGE FORM DESIGN CONSIDERATIONS (19.5) 19.2 SOLID DOSAGE FORMS 681 19.2.3.1 Continuous Models There are numerous continuous fluid-bed models of Glatt GF and AGT. In the Glatt GF model, the inlet air plenum is separated into many chambers, with variable temperature and airflow control. In this manner, a single unit could perform spray agglomeration, drying, and cooling. Through air flow regulation, the overall powder would flow in a plug fashion near the liberation port. Commercialization of Glatt AGT machinery starts in the 1980s, and it consist of discharge tube right midway of the bottommost screen. The velocity of air in the pipe regulates the size of particles (Ghijs et al., 2016) and greater particles with dropping velocity greater than the air velocity are discharged from the inner side of the pipe. On the other hand, smaller particles are driven back to the fluid-bed and are again exposed to the layer. These continuous models are mostly preferred in agriculture, food, and chemical industry. So with the aid of proper equipment, operating settings, and appropriate excipients, they could be used in scale-up from the laboratory scale to commercial production scale and the wet-granulation process could be optimized from formulation to formulation. Therefore, it is necessary to recognize the simple perceptions behind equipment design and central granulation theory, with the intention to develop robust and scalable formulations and processes (Yamamoto and Shao, 2017). Additionally, utilization of PAT and DOE can aid in the formulation of a design space for the fluid-bed granulation and can help as great tools for scale-up and technology transfer. Besides formulations and procedures are optimally established via fluid-bed technology, the granules will eventually impart excellent superiority to the pharmaceutical end product such as in a tablet, capsule, etc. (Sen et al., 2014). 19.2.4 Compaction and Tableting Compaction and tableting are associated with scale-up issues despite the availability of other good technologies. One needs to focus on the molecular mechanisms taking place and evolve from the pilot plant to the manufacturing technical operations center. Scale-up guidance for immediate-release solid dosage forms (SUPAC-IR) and post-approval changes have been published by USFDA (Boersen et al., 2016). Generally, tablets are made up of compressed powder in a die by punches in a rotary tablet press. During this process the die table, along with punches, rotates and pushes each set of upper and lower punches between compression rollers (Yamamoto and Shao, 2017). This results in he punches traveling inside the die and bringing about the compression of powder. Thus the process of production of tablets briefly involves two processes: compaction and compression (Fig. 19.6). During compaction flow, the pattern or behavior in the blender or hopper could be predicted through mathematical approaches, whereas powder flow analysis in a hopper is achieved through dimensionless relations and it can be redundant. To prevent arching, a minimum outlet size is required in case of gravity discharge and it is also based on the type of flow pattern of powder. Irrespective of the flow pattern of the powders the outlet size of the hopper is determined by the powder’s flow function which is reflected by measuring the cohesive strength tests. The size of the outlet required to overcome no-flow conditions is merely based on the flow pattern. In order to overcome arching in the funnel, DOSAGE FORM DESIGN CONSIDERATIONS 682 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT FIGURE 19.6 Compression and compaction processes involved in tablet manufacturing. Compression is intended to reduce bulk volume which has a direct effect on porosity of tablet formulation and its dissolution pattern. Compaction is used to apply mechanical strength toward particles and is directly proportional to the hardness of tablet which is a critical parameter for absorption. Adapted with permission from Yamamoto, K., Shao, Z.J., 2017. Process development, optimization, and scale-up: fluid-bed granulation. Developing Solid Oral Dosage Forms (second ed.). Elsevier. flow develops in place of mass flow and thus the minimum diameter of the outlet is given through the propensity for a stable rathole to the formation, due to a larger diameter that is required for arching (Natoli et al., 2017). Hopper angle basically depends on two factors namely wall friction angle and internal friction of the material. Proper angle of hopper is required for mass flow and also determines the level of powder within the hopper or the diameter or height of the bin, especially for minimum outlet size. With lower normal pressure the wall friction increases and if the outlet size is larger, it discharges and exhibits a mass flow pattern. Additionally, the mass flow of powder is highly reliant on conditions beneath the hopper which are the presence of a throttled valve, a lip or other protrusion, or anything that can dose a zone of stationary powder into funnel flow, irrespective of the angle of the hopper or surface finish (Mitra et al., 2016b). Earlier a bench-scale compression model was developed by Gereg and Capolla which is able to translate parameters to scale compactors. The objectives of this study were to characterize the ingredients as per their properties and categorize the process parameters in order to attain the essential particle size and density using the dry granulation process (Mitra et al., 2016a). Powder granules formed by a roller compactor are similar to those obtained from the Carver press. Lactose monohydrate or spray-dried lactose monohydrate were utilized as the model compounds. Authors observed that parametric association exists between the laboratory bench Carver press and the production-scale compactor and thus several process parameters can be shifted directly (Singh et al., 2015). The compact which has been milled generated slightly larger particles and the associated round slugs that have been formed by the Carver press produced a greater number of fines. Further, in the case of roller compacted material, flow rate was twice as fast as that for the Carver press’ granules, although both flow rates were thought to be satisfactory (Shah and Stagner, 2016). DOSAGE FORM DESIGN CONSIDERATIONS 19.2 SOLID DOSAGE FORMS 683 The authors have also used the wet granulation procedure but it was not feasible due to the high solubility of the active bulk molecules. Further, it was observed that the granulating pockets had highly wetted areas preventing uniform moisture distribution and granule formation. To solve these problems, it was possible to carry out granulation with a solution of drug. However, this is not a standard protocol as it results in the formation of an amorphous form of the compound after drying. Another method was to perform a dry slugging granulation procedure to overcome the problems that arise in wet granulation (Shanmugam, 2015). Slugging was a good alternative but it had limitations, like difficulty in compressing slugs owing to low bulk density and poor blend flow properties. From batch to batch, weight and hardness variation of the slugs vary in a wide range during the slugging process. Furthermore, nonconsistency in particle size distribution, bulk, and tap densities make it difficult to compress slugs (Pandey et al., 2017). The compaction procedure was scaled-up to a rate of 100 150 kg/h using the same parameters as set at the pilot scale. Granules made from the compactor scale-up created a tablet with excellent physical properties paralleled to the slugging process. This demonstrated that the roller compaction method maintained predictable powder properties and consistency with a slugging process. 19.2.4.1 Roller Compactor: Use From Pilot to Scale-Up Roller compaction is most frequently used in the dry granulation process, as shown in Figs. 19.7 and 19.8. Over the last few years, there has been an increase in the utilization of roller compaction in the pharmaceutical industry. It is used to study the effect of the scale-up process on tablet robustness. Roller compaction is indeed a one-step process providing advantages including flexibility for continuous manufacturing and higher production amount as compared to other granulation techniques. Model drug theophylline and hydroxyl-propyl methylcellulose are examples of actives prepared by this method (Allesø et al., 2016). Many regulatory authorities have provided in-depth guidelines for scaling up of oral solids. During the scale-up process, API loss is the most common problem due to larger equipment setup. Some other difficulties involve the prediction of postcompacted ribbon, granule properties of the tablet, and the complexity of the excipient interaction with the operating factors of the equipment. Several examples can be given for the roller compaction development (Fonteyne et al., 2015). It comprises theoretical models such as finite element methods, neural networks, quadratic regression, multilinear stepwise regression, thin layer, and polynomials. Roller compaction, as well as milling studies, indicate that there are insignificant differences between the pilot and plant scaling (Singh et al., 2014). Boersen et al. investigated a comparison of scale-up, and transfer of roller compacted formulations. They utilized dimensionless variables for scale-up and transferability and focused on ribbon porosity as the factor of central interest. They compared the ribbons of the similar porosity from different equipment with comparable properties. Additionally, ribbon porosity and dimensionless variable combination provides amalgamation of different parameters, and raw materials, it could be possible to use the similar relationship for different pieces of roller compaction equipment. In order to validate the relationships between porosity of the ribbon and variables which were used to create the dimensionless relationship multivariate relationships were established (Boersen et al., 2015). DOSAGE FORM DESIGN CONSIDERATIONS 684 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT FIGURE 19.7 Diagrammatic representation of process occurring in roller compaction (in roller compaction injected material is broken, sized, and lubricated and compression is performed to formulate the tablet as the final dosage form). FIGURE 19.8 Enlarged representation of mechanism of roller. Here, A represents slip region or entry region where material is starting to rotate and speed is lower than actual roller speed; B depicts the Nip region where velocity of roll become equal to the rolls; C represents the release region starting where the gap between the rolls increases again. DOSAGE FORM DESIGN CONSIDERATIONS 19.3 PARENTERAL DOSAGE FORMS 685 Tablets from roller compacted granulations have demonstrated greater physical properties, which include no breaking, minimal chipping, and no physical defects. Moreover, no significant variances were observed in the drug release among direct compression of the ANDA product and the laboratory scaled roller compactor product and pilot roller compactor product. Moreover, in vitro drug release results were unaffected by roll compaction scaling (Heiman et al., 2015). In another investigation by Boersen et al., roller compaction was used for scale-up of the batches with the aid of roll width as a scaling factor and ribbon porosity as critical material qualities. Because of the complexity and problems regarding the mechanical modeling used for scale-up through roller compaction for production of tablets, they introduced an inventive equipment in which the diameter of the roll was kept fixed between scales despite diverging the roll width. They used nondestructive laser-based method to evaluate the porosity of the ribbon at-line with greater precision and accuracy. It was compared with a recognized volume dislodgment oil intrusion method. Based on the results, it was found that ribbon porosity is scale-independent once matching the average porosity. Ribbon samples were produced from the small scale with the use of Mini-Pactor to the large scale with the aid of Macro-Pactor. For reproduction purposes, ribbon porosity from small scale to larger scale could be adjusted. Moreover, it was found to be directly transferrable to batch-scale production on the Macro-Pactor. This creates a better link between formulation development and tech-transfer (Boersen et al., 2016). 19.3 PARENTERAL DOSAGE FORMS 19.3.1 Mixing and Agitation The term “parenteral” is referred to the preparations which are administered through an injection via skin tissue. Injections require circumventing the firstmost defensive layers of the human body like the skin and the mucous membranes. Quality of the product is usually fulfilled via close operation of good manufacturing practices (GMP). It could be sterile and nonsterile in liquid preparations (Gibson, 2016). A high degree of accuracy is needed during the scale-up of parenteral dosage formulations which indeed becomes a liquid scale-up assignment. The method is grounded on the measure of agitation method. The primary scale-up measurement is an equivalent liquid signal at the time of comparison of pilot-size batches to larger production-size batches in the case of single phase liquid systems. Mixing is the most important procedure included in the parenteral scale-up process (Tabora and Domagalski, 2017). Mixing of liquid material is achieved through transport procedures that could be attained in three different scales. Among them, one material as solute attains uniform concentration in solvent. In the scale-up method, bulk diffusion technique is utilized, and other remaining elements were mixed through impeller. However, mixing on a larger scale depends on the flow of material inside the vessel. There are numerous methods involved in the scale-up of mixing process. The geometric mixing process involves mixing of liquid through geometric factors. As a geometric parameter the ratio of the diameter of the impeller to tank diameter must be taken into consideration. Additionally, the height of the liquid in the tank to tank diameter ratio is DOSAGE FORM DESIGN CONSIDERATIONS 686 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT also measured for larger scale mixing in the case of parenteral dosage forms (Aulton, 2017). Another rotational speed parameter, N could be considered, and it is calculated by using the following Eq. (19.6), where N1 and N2 are two different rotational speeds. 2 1 N2 5 N1 (19.6) R Another method is the dimensionless parameter method that is used for the prediction of scale-up parameters. The dimensionless number method is used to calculate the heat transfer and at some level in mass transfer or gas dispersion for scale-up of mixing process. The above mentioned methods are related to the traditional fluid automated methodology that is identified as dimensional analysis. However, results could not be always accomplished in various manufacturing environments. Another specific technique is presented below and it can be simply applied to various research and production situations and actually represents a mixture of the above two methods (Chen, 2017). The scale-up of the agitation process is a part of geometric scale-up process. It requires an equal fluid velocity in both large and small apparatus. This method is mostly applied to the turbulent flow agitation process, in which the tank is assumed as a vertical cylinder, even though great success has been gained by using marine-type propeller systems, lowrpm, axial, or radial impeller measures. Additionally mixing was mostly and initially taking place nearer to the impeller. Physical properties of the two different materials should be the same such as viscosity and density. Most available parenteral formulations are found to be in the liquid form and would follow Newtonian flow as well. In such cases, the Reynolds number should be more than 2000. Moreover, if the Reynolds number of the fluid tank is less than 2000, it is found to be a viscous material. This agitation scale parameter provides qualitative data during the different mixing types (Niazi, 2016). The scale of agitation could be easily adjusted through the number of revolutions per minute of the impeller in the tank. These scale-up methodologies enable exact transfer of liquid parenteral solutions for the production scale at a large level. Appropriate agitation is required during mixing of injectable formulations. Several equipments are utilized during the manufacturing process of parenteral drugs, viz., sterilization instruments, filtration assembly, pumps, and packaging equipment. These parameters should all be geometrically scalable and easily denominated for the variability (Karode et al., 2015). SUPAC guidelines must be followed for suitable stability studies and for proper compliance to the agency. 19.4 SEMISOLID DOSAGE FORMS Semisolid dosage forms include ointments, creams, or gels. A wide variety of materials are available to prepare semisolid dosage forms including preservatives and antioxidants. Particular materials are selected to prepare semisolids depending upon the nature of the drug delivery system and as per the required emollient (Mishra et al., 2014). Briefly, any semisolid dosage form consists of two phases, namely, the external continuous phase and the internal discontinuous phase. Active ingredients based on the solubility can be added DOSAGE FORM DESIGN CONSIDERATIONS 19.4 SEMISOLID DOSAGE FORMS 687 to any of these two phases. During scale-up of semisolid dosage forms, one needs to consider various important factors that are of critical importance to obtain a uniform semisolid dosage form at a large scale (Allen and Ansel, 2013). 19.4.1 Material Transfer Rate Transfer of semisolids from one location (production tank) to another location (filling tank) is achieved through pipes by inducing flow with the aid of pumps. Induction of flow occurs by one or more mechanisms, including gravity, electromagnetic force, mechanical impulse, centrifugal force, displacement, or momentum transfer. Transfer of semisolid materials from holding tanks to the mixing or filling equipment either by gravity or pump feeding is considered to be problematic. A change in the shear stress or shear rate or rate of transfer during transfer may lead to instability of the resultant products. Moreover, particle size of the product tends to increase during such transfer. These all factors should be considered during scale-up of semisolids to production or pilot scale as these problems are not much evident during formulating of semisolids at the laboratory scale (Sowden et al., 2014). Other essential factors in the scale-up of liquid formulations include the mixing of two solutions at different pH simultaneously to obtain one single homogeneous solution. In this case, at the laboratory scale, the quantities are small and therefore can be easily mixed with each other. However, during scale-up, the solution needs to be pumped and since the quantity is large, the time required for pumping the entire solution will be greater. Thus during the initial period and due to the large pumping time pH will vary as compared to the final pH when the entire solution is pumped. This variation in pH can bring about precipitation or increase in the particle size (Mascia et al., 2013). Materials transfer during mixing can occur by two mechanisms, either diffusion or bulk flow. Bulk flow involves motion induced either artificially by mechanical agitation or naturally by density variation. Diffusion involves the movement of heat or mass from a region of higher concentration to the region of lower concentration. In the case of low viscosity systems, transfer of unmixed components via bulk or convective flow to mixing zones depends on the presence of either laminar or turbulent flow in these regions. Generally, in regions near the impeller, the flow is turbulent, whereas towards the wall of the mixing tank the flow may be at times laminar (Niazi, 2016). Thus one needs a proper understanding of these flow patterns at various regions in the mixing equipment to determine the material transfer rates. Thus the flow changes from laminar to turbulent are characterized by one dimensionless quantity that is referred to as the Reynolds number (Eqs. (19.7) and (19.8)). NRe 5 NRe1 5 Lυρ η (19.7) D2 Nρ η (19.8) where ρ is density, υ is velocity, L is a characteristic length, and η is the Newtonian viscosity; which is referred to as the impeller Reynolds number, since D is the impeller diameter and N is the rotational speed of the impeller. NRe represents the ratio of the inertia forces DOSAGE FORM DESIGN CONSIDERATIONS 688 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT to the viscous forces in a flow. Mass transfer occurs more efficiently in the turbulent regions as the eddy moves rapidly here. Thus all these factors play an essential role while scaling up the semisolids formulations (Pandey et al., 2017). 19.4.2 Mixing Semisolids are prepared by mixing the aqueous and the oily phase in mixing tanks with different designs of impellers. Generally, to prepare semisolids preparations like ointments and creams, either agitator mixers or shear mixers are used (Fernández-Campos et al., 2017). Agitator mixers include sigma mixers and planetary mixers. Shear mixers include colloidal mills and triple roller mills as shown in Fig. 19.9. Mixing is one common step involved in the preparation of semisolids. While considering mixing of discontinuous phase with the continuous phase, one needs to determine the optimum amount of shear and optimal mixing methods and whether the speed is sufficient to obtain a uniform semisolid product at larger scale (Kumar et al., 2014). Creams (o/w emulsions or w/o emulsions) require higher shear to obtain uniform droplet size and dispersion. On the contrary, gel requires low shear to preserve physical characteristics such as viscosity. Thus, mixing speed needs to be optimized at each batch scale (Ramanauskiene et al., 2016). As per the SUPAC guidelines for nonsterile semisolid dosage forms, minimum batch size for the NDA pivotal clinical trial batch or the ANDA/AADA biobatch should be at least 100 kg or 10% of a production batch, whichever is larger. Further, any deviations FIGURE 19.9 Mixers used in preparation of semisolids. Sigma mixers and planetary mixers are agitator mixers, and triple roller mills and colloid mills are shear mixers used for mixing the ointment base with the actives and other constituents for large-scale production of semisolids preparation. The mixing mechanism, speed, and time needs to be optimized during scale-up to obtain uniform ointments or creams. DOSAGE FORM DESIGN CONSIDERATIONS 19.4 SEMISOLID DOSAGE FORMS 689 from this recommendation should be properly discussed with the appropriate agency review division. Additionally, all scale changes should be properly validated and inspected by appropriate agency personnel (Shah et al., 2015). Briefly while scaling up or scaling down the batch size of nonsterile semisolid dosage forms SUPAC guidelines have defined two level changes, namely level 1 change, and level 2 change. Level 2 change refers to a change in batch size up to and including 10 times the size of the pivotal clinical trial or biobatch, wherein firstly the equipment used to produce the test batches are of the same design and same operating principles. Secondly, the test batches are manufactured in compliance with the cGMP, and lastly the same standard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures are used on the test batches and full-scale production batches (Prabu et al., 2016). In vitro release documentation and in vivo bioequivalence are only needed in case of level 2 changes. Documentation of the long-term stability data on the first production batch is described in the annual report for level 1 change. On the contrary, along with this, for level 2 change, additional documentation of one batch with three months accelerated stability data is reported with changes being effected. Thus one needs to take into consideration this guideline while scaling up or down the semisolid dosage forms (Yacobi et al., 2014). 19.4.3 Heating and Cooling Rates Semisolids have the property of melting at a moderate temperature and solidifying if cooled at room temperature. Semisolid preparations involve phase transition in which melting results in an absorption of the heat and cooling which releases heat. Cooling rates have a significant effect on the initial as well as the final consistency of creams prepared with fatty alcohol or nonionic polyoxyethylene surfactants. Sudden cooling of emulsion creams result in a very mobile emulsion which tends be converted to a gel on storage (Tran and Wang, 2014). 19.4.4 Viscous and Non-Newtonian Liquids Viscous liquid generally shows a tendency to undergo improper mixing by conventional impellers. Non-Newtonian liquids exhibit variability in the viscosity due to the shear imparted by the impeller. This gradual change in viscosity affects the mixing efficiency (Alkhatib, 2015). In the case of high viscosity liquids, the Reynolds number is below 100. Thus laminar flow shows dominance over turbulent flow. Also, eddy formation and diffusion are virtually absent. Basically, the initial forces imparted to the viscous system during the mixing process tend to dissipate quickly. Hence adequately designed mixing equipment are needed for efficient mixing of highly viscous liquids (Yang et al., 2014). Briefly, paddles, anchors, screws, and kneading mixers are used in order to increase in the viscosity. The Z blade or sigma blades are specialized impellers used to promote mixing in the region closer to the wall of the mixing tank along with the narrow clearance between the impeller DOSAGE FORM DESIGN CONSIDERATIONS 690 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT FIGURE 19.10 Different designs of impellers used in semisolids manufacturing equipment depending upon the viscosity. For lower viscosity semisolid bases paddle blades are used, followed by the screw blade, anchor blade, sigma blade, and lastly kneading blades are used for highly viscous semisolids bases. blades and the wall of the mixing tank to obtain maximum mixing efficiency Fig. 19.10 (Dickey, 2015). Despite all these modifications to enhance the mixing of viscous liquids, stagnant layers are sometimes formed near the shaft of the impellers. Based on the principles of rheology, flow of non-Newtonian materials is characterized by the Ostwald de Waele equation as described below in Eq. (19.9). τ 5 Kϒ α or log τ 5 K0 1 a log ϒ Y (19.9) where τ is the shear stress, log τ 5 K’ 1 a (log ϒ Y) is the rate of shear, K’ is the logarithmically transformed proportionality constant K with dimensions dependent upon a the so-called flow behavior index. For pseudoplastic or shear-thinning materials, a , 1; for dilatant or shear-thickening materials, a . 1; for Newtonian fluids, a 5 1. For a power-law fluid, the average apparent viscosity η can be related to the average shear rate by the following equation: n21 dv η5K (19.10) dy avg In the case of Bingham plastic materials, the minimum shear stress yield value needs to be exceeded for proper flow to occur. In the circumstances wherein the yield value is not exceeded it results in the absence or presence of flow in some region of the mixing tank resulting in channel or cavity formation along with a reduction in the mixing efficiency. Thus, for Bingham plastic fluid, helical ribbon or screw impellers are preferred over conventional propeller or turbine impeller as shown in Fig. 19.11. For pseudoplastic fluids of high viscosity, helical ribbon impellers are used, the design of which is based on an assumed linear relationship between the shear rate and rotation speed of the impeller (Jegatheeswaran et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 19.5 SCALE-UP OF NANOFORMULATIONS: CASE STUDIES 691 FIGURE 19.11 Equipment’s used for non-Newtonian materials in semisolids preparation: Helical ribbon impeller is used for designing plastic and pseudoplastic materials. Double planetary mixers are used for dilatant materials comprised of any one of the three types of blades to provide sufficient torque for uniform dispersions of materials, the viscosity of which tends to increase with the increase in the shearing stress. Dilatant fluids are shear thickening systems that increase the rate of shear and hence the viscosity. Thus to mix such systems efficiently, one needs mixing tanks to be designed with an impeller which moves through the batch regardless of the product flow. In other words, the equipment should be able to bear shear thickening effects of the dilatant fluids and bring about efficient mixing. Double planetary mixers are designed for efficient mixing of dilatant fluids. The principle involves the rotation of two identical blades on their own axis as they orbit on a common axis moving the dilatant material (Marriott, 2013). Planetary blades are operating at low speed but impart a thorough folding action bringing about efficient mixing of dilatant materials. 19.5 SCALE-UP OF NANOFORMULATIONS: CASE STUDIES Major categories of nanoformulations include liposomes (Maheshwari et al., 2015b; Maheshwari et al., 2012), polymeric nanoparticles (Sharma et al., 2015; Maheshwari et al., 2015a), lipidic nanoparticles (Tekade et al., 2017c; Soni et al., 2016), carbon nanotubes (Tekade et al., 2017a), and genetic material-based formulations (Maheshwari et al., 2017; Kumar Tekade et al., 2015), which are in the nanometer range. Nanotechnology has made revolutionary changes in the field of drug delivery (Tekade et al., 2017b; Lalu et al., 2017). The basic aim of nanotherapy is to increase the effective surface area by reduction in size and thereby to increase the rate of dissolution. Nanocrystals are one such approach used to increase the solubility of Biopharmaceutical classification system (BCS) Class II and class IV drugs having low solubility (Khan et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS 692 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT Many researchers have tried to scale-up nanoformulations prepared by different techniques. A pilot plant scheme to prepare nanocapsules by the emulsification-solvent diffusion techniques is discussed here. Suppose the reservoir of lower capacity A is placed at the top, whereas the reservoir of highest capacity C is placed at the bottom, the reservoir B is an intermediate capacity placed at an intermediate level. Positions of the three reactors allow the transfer of the solution by gravity from A to B and B to C. Reservoir A contains water and partially miscible organic phase which are mixed and allowed to reach thermodynamic equilibrium to allow the formation of mutually saturated liquids. Furthermore, after separation the lower phase water saturated with organic solvents is transferred in the reactor B through the valve V1 while the organic solvent saturated with water is retained in the reactor A. After this various ingredients can be added to the organic as well as the aqueous phase as per the solubility of the individual formulation components. Later the organic phase in reactor A is transferred to the aqueous phase in reactor B under vigorous stirring to form an emulsion in reactor B. Reactor B was optimized for the required fluid motions as obtained during the lab scale. The reactor B has also been designed in such a way to obtain the desired emulsion. Agitation was provided for 30 min, and then the emulsion was transferred to reactor C through valve V2 for further dilution with the aqueous phase (Heo et al., 2014). The pilot plant set up for the reverse salting out technique was slightly different than other available technique for nanoparticle preparation. Reactor A and C were placed at the same level, whereas reactor B was connected to both these reactors and was placed at the lowest level. The aqueous phase 1000 g was prepared in reactor A, added to the organic phase 600 g prepared in reactor B. Emulsion was formed by controlling designed parameters of reactor B. Pure water from the reactor C was added to emulsion already present in the reactor B for the dilution step (Crucho and Barros, 2017). Nanoprecipitation is another technique used for the preparation of nanoparticles which involves precipitation of the polymer under vigorous mixing of the organic phase with the aqueous phase. The key role is to control the mixing of these two phases to obtain the desired precipitation of the polymer. At larger scale, this is achieved with the T-shaped mixing device attached to the two reactors containing the aqueous and organic phase via peristaltic pumps. Further, the T-shaped device outlet is connected to the third reactor where the obtained nanoparticles are purified (Rivas et al., 2017). The only drawback inherent to the method is related to the low polymer concentration in the organic phase which needs to be maintained to obtain diluted polymer solution. However, this significantly limits the number of nanoparticles recovered in the final raw dispersion (Heo et al., 2014). Thus, nowadays scale-up of nanoparticles to pilot scale has been achieved. How to control the levels of permissible organic solvent while scaling up nanoformulations is an important factor to be considered. 19.6 QUALITY BY DESIGN (QBD) FOR SCALE-UP Statistical designs ensure the development of the proper relationship between the process parameters. Nowadays, many of the pharmaceutical processes have shifted from a trial and error design approach towards quality by design approaches for scaling up. QbD DOSAGE FORM DESIGN CONSIDERATIONS 19.7 PROBLEMS ENCOUNTERED DURING SCALE-UP 693 involves identifying broadly two parameters, i.e. the critical process parameters and critical product attributes, significantly affecting the desired characteristics of the final product. Key elements of QbD involve target product quality profile, critical quality attributes, risk assessment, design space, product life cycle management control strategy, and continual improvement to understand the performance of any product within the design space (Jameel et al., 2015). Naproxen enteric-coated pellets were prepared in a fluidized-bed coater based on the QbD principle. Initially, the significant factors like TEC percentage, GMS percentage, spray rate, atomizing pressure, batch size, coating aqueous dispersion solid content, coating weight gain, and curing time affecting the characteristics of enteric-coated pellets were screened by Plackett Burman design. Box Behnken design was used to study the impact of significant variables of triethyl citrate (TEC) percentage, GMS (Glycerol monostearate) percentage, and coating weight gain on the response to acid drug resistance and cumulative drug release. The main effects, as well as interaction effects, were also studied (Kan et al., 2014). A drug product consisting of a wax matrix microsphere is loaded with drug and prepared by using a melt spray congeal process. The drug was released from this microsphere either through channels formed as a result of solubilization of drug or by pores formed due to the dissolution of soluble additives. The rate of dissolution was correlated directly to a particle size of the drug. Thus during scale-up, it is impossible to control process parameters optimized by a trial and error method to obtain proper particle size for a good rate of dissolution. Thus, the authors identified key parameters influencing microsphere particle sizes, like the speed of the spinning disk, temperature of the operating system, and viscosity of drug melt suspension, and utilized two to the power three factorial design and developed a predictive model for melt rheology and microsphere size. This reduces the time and number of experiments to obtain the desired size spray congeal mass (Jameel and Wolfrum, 2015). The International Conference on Harmonization and United States Food and Drug Administration (USFDA) emphasized the application of Qbd in the pharmaceutical industry. Also, it is required by regulatory authorities for approval of the pharmaceutical product. During scale-up, the parameters may differ, but the attributes responsible for quality remain the same. QbD application during scale-up will help to control the parameters to obtain the desired quality product. It ensures product safety and efficacy during scale-up and also helps to understand the pharmaceutical processes and methods more effectively. Risk-based analysis by QbD enhances the quality of the final product (Jameel, 2015). The variability in scale-up is reduced by application of QbD. 19.7 PROBLEMS ENCOUNTERED DURING SCALE-UP Incompletely characterized equipment, like multishaft mixers or homogenizers, results in improper mixing or nonuniform particle size reduction, respectively. During small-scale mixing laminar flow may not be predominant, however, during the scale-up it may show dominance (Stefansson et al., 2011). Thus, if scaling of the process is solely done by turbulent flow without considering the effect of laminar flow, it will significantly affect the process at the production scale. DOSAGE FORM DESIGN CONSIDERATIONS 694 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT Knowledge of process with detailed information about all the processes and product variables need to be noted and identified to predict the changes that may occur during scaling to pilot or production scale. Thorough knowledge of the manufacturing process or purification procedure, along with the various factors that can significantly affect the process, is of utmost importance for successful scale-up. At lab scale, many small factors are unidentified as their impact on the final product is low, however, when we scale it up to production scale these factors turn out to be significant and thus hamper the final product (Heider et al., 2014). Size exclusion chromatography was used in the purification of oligonucleotide drug product. It was observed that at laboratory scale and pilot scale, this product had 99.5% purity. However, the purity of compound after scale-up to production scale was reduced to 94% along with a change in impurity profile. After an investigation, it was found out that problem was due to column overloading and the regeneration of column resins from production run to run (Pandey et al., 2017). This factor affected the purification process but if it had been identified earlier it could have helped to save cost and time and would have resulted in a more efficient scale-up of the purification process of the oligonucleotide (Lee et al., 2015). For tablet manufacturing processes, if it is changed from a single station press to multistation rotary press then there are effects on powder feed rate and compression profile, e.g., one sided or double sided, precompression or compression time, or tablet ejection speed or force. Thus, the more similar the geometry of the equipment used at laboratory scale, the easier it is to scale up to production scale. In tablet compaction, studying the effects of the changes in compaction profile are used to predict the scale-up modifications (Singh et al., 2013). Flowability of powders is not an issue during laboratory scale, however, during the scale-up to production scale rathole formation or arching or erratic flow can occur. During scaling up of emulsions or suspensions coalescence or change in particle size occurs (Aulton, 2013). 19.8 CONCLUSIONS The traditional process of pharmaceutical product development involves a long journey of many experiments, observations, challenges, and resolutions before the drug reaches the global market. Most available dosage forms, such as tablets, capsules, powders, granules, lozenges, and suppositories, are solid dosage forms containing both the mixture of drugs and excipients. The large-scale production of solid dosage forms requires well proven and documented formulae for production. Dry powder blending and mixing is a crucial step in the manufacturing of many pharmaceutical products, particularly tablets and capsules, that directly have an impact on the uniformity of content. Determination of mixing composition is a crucial part of the mixing process. Still, there is not any method available for online mixing component evaluation, although quantification of samples can be done through intermediate removal. In scale-up using a tumbling blender, rotation rate plays a crucial role and may change scale-up with variations in size. Investigations regarding the use of V-blenders and double cone blenders have shown that when rotation rate DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES 695 was less than the critical speed of the blender no significant effect on the mixing rate was noted. The amalgamation of reproducibility and batch size flexibility results in a highly efficient manufacturing method. Parenteral dosage form (parenteral solution) scale-up is subject to a liquid scale-up assignment which requires a high degree of accuracy. The method is grounded on the measurement of the agitation method. The primary scale-up measure is an equivalent liquid signal at the time of comparison of pilot-size batches to larger production-size batches in the case of single-phase liquid systems. Mixing is the most important procedure regarding parenteral scale-up process. Statistical designs ensure the development of the proper relationship between the process parameters. Nowadays, many of the pharmaceutical processes have shifted from a trial and error design approach towards quality by design approaches for scaling up. QbD involves identifying the critical process parameters and critical product attributes that significantly affect the desired characteristics of the final product. Acknowledgments The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology (DST), Government of India for grant (#ECR/2016/001964) allocated to Dr Tekade for research work on drug and gene delivery. The author also acknowledges DST-SERB for N-PDF funding (PDF/2016/003329) to Dr. Rahul Maheshwari in Dr Tekade’s lab for work on targeted cancer therapy. Authors would also like to acknowledge Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India, for supporting research on cancer and diabetes at NIPER- Ahmedabad. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. References Alizadeh, E., Bertrand, F., Chaouki, J., 2014. 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Multivariate analysis and statistics in pharmaceutical process research and development. Annu. Rev. Chem. Biomol. Eng. 0, pp. Tekade, R.K., Maheshwari, R., Soni, N., Tekade, M., 2017a. Chapter 12 - Carbon nanotubes in targeting and delivery of drugs A2 - Mishra, Vijay. In: Kesharwani, P., Amin, M.C.I.M., Iyer, A. (Eds.), Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes. Academic Press. Tekade, R.K., Maheshwari, R., Soni, N., Tekade, M., Chougule, M.B., 2017b. Chapter 1 - Nanotechnology for the development of nanomedicine A2 - Mishra, Vijay. In: Kesharwani, P., Amin, M.C.I.M., Iyer, A. (Eds.), Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes. Academic Press. Tekade, R.K., Maheshwari, R., Tekade, M., Chougule, M.B., 2017c. Chapter 8 - Solid lipid nanoparticles for targeting and delivery of drugs and genes A2 - Mishra, Vijay. In: Kesharwani, P., Amin, M.C.I.M., Iyer, A. 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Validation: significance of a documented development stage in process validation. Pharma Science Monitor 3 (3). Asfaram, A., Ghaedi, M., Azqhandi, M.A., Goudarzi, A., Dastkhoon, M., 2016. Statistical experimental design, least squares-support vector machine (LS-SVM) and artificial neural network (ANN) methods for modeling the facilitated adsorption of methylene blue dye. RSC Adv. 6 (46), 40502 40516. DOSAGE FORM DESIGN CONSIDERATIONS 700 19. SCALE-UP STUDIES IN PHARMACEUTICAL PRODUCTS DEVELOPMENT Changi, S.M., Yokozawa, T., Yamamoto, T., Nakajima, H., Embry, M.C., Vaid, R., et al., 2017. Mechanistic investigation of a Ru-catalyzed direct asymmetric reductive amination reaction for a batch or continuous process scale-up: an industrial perspective. React. Chem. Eng. 2 (5), 720 739. Chen, M., Bisgin, H., Tong, L., Hong, H., Fang, H., Borlak, J., et al., 2014. Toward predictive models for druginduced liver injury in humans: are we there yet? Biomarkers 8 (2), 201 213. Chen, W., Chen, X., Gandhi, R., Mantri, R.V., Sadineni, V., Saluja, A., 2016. Application of mechanistic models for process design and development of biologic drug products. J. Pharm. Innov. 11 (3), 200 213. Duan, C.-L., Zhu, P.-H., Deng, Z., Li, Y., Shan, B., Fang, H.-S., et al., 2017. Mechanistic modeling study of atomic layer deposition process optimization in a fluidized bed reactor. J. Vacuum Sci. Technol. A: Vacuum Surf. Films 35 (1), 01B102. Dunlap, D., McDonough, E.F., Mudambi, R., Swift, T., 2016. Making up is hard to do: knowledge acquisition strategies and the nature of new product innovation. J. Product Innov. Manage. 33 (4), 472 491. Duygu Yilmazer, N., Korth, M., 2016. Prospects of applying enhanced semi-empirical QM methods for 2101 virtual drug design. Curr. Med. Chem. 23 (20), 2101 2111. Fonteyne, M., Gildemyn, D., Peeters, E., Mortier, S.T.F., Vercruysse, J., Gernaey, K.V., et al., 2014. 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Martin, J.W., Benoit, G., Mann, R., 2016. Method and apparatus to condition polymers utilizing multiple processing systems. Google Patents. Morkhade, D.M., 2017. Comparative impact of different binder addition methods, binders and diluents on resulting granule and tablet attributes via high shear wet granulation. Powder Technol. 320, 114 124. Omrani, H., Tayyebi, A., Pijanowski, B., 2015. Integrating the Multi-Label Land Use Concept and Cellular Automata with the ANN-Based Land Transformation Model. Geocomputing Conference. 208 210. O’Brien, E.J., Monk, J.M., Palsson, B.O., 2015. Using genome-scale models to predict biological capabilities. Cell 161 (5), 971 987. Peppas, N.A., Narasimhan, B., 2014. Mathematical models in drug delivery: How modeling has shaped the way we design new drug delivery systems. J. Controlled Release 190, 75 81. Purohit, P., Shah, K., 2013. Quality by design (QBD): new parameter for quality improvement & pharmaceutical drug development. Pharma Sci. Monitor 3 (3). Qiu, Y., Chen, Y., Zhang, G.G., Yu, L., Mantri, R.V., 2016. Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice. Academic press. San-Valero, P., Dorado, A.D., Martı́nez-Soria, V., Gabaldón, C., 2018. Biotrickling filter modeling for styrene abatement. Part 1: Model development, calibration and validation on an industrial scale. Chemosphere 191, 1066 1074. Shaikh, H.K., Kshirsagar, R., Patil, S., 2015. Mathematical models for drug release characterization: a review. Wjpps 4, 324 338. Stark, J., 2015. Product lifecycle management. Product Lifecycle Management (Volume 1). Springer. Taylor, D., 2015. The Pharmaceutical Industry and the Future of Drug Development. Tsamandouras, N., Rostami-Hodjegan, A., Aarons, L., 2015. Combining the ‘bottom up’and ‘top down’approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data. Br. J. Clin. Pharmacol. 79 (1), 48 55. Wieringa, R., 2014. Empirical research methods for technology validation: scaling up to practice. J. Syst. Softw. 95, 19 31. DOSAGE FORM DESIGN CONSIDERATIONS C H A P T E R 20 Manipulation of Physiological Processes for Pharmaceutical Product Development Rahul Maheshwari1, Kaushik Kuche1, Ankita Mane2, Yashu Chourasiya3, Muktika Tekade4 and Rakesh K. Tekade1,5 1 National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India 2Acropolis Institute of Pharmaceutical Education and Research, Indore, Madhya Pradesh, India 3Shri Bherulal Pharmacy Institute, Indore, Madhya Pradesh, India 4TIT College of Pharmacy, Technocrats Institute of Technology Campus, Bhopal, Madhya Pradesh, India 5Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia O U T L I N E 20.1 Introduction 702 20.2 Various Physiological Factors Affecting Product Development 703 20.2.1 Route of Administration 703 20.2.2 Environmental pH 704 20.2.3 Gastric Emptying 705 20.2.4 Small and Large Bowel Transit Time 706 20.2.5 Active Transport and Efflux 706 20.2.6 Gut Wall Metabolism 708 20.2.7 First-Pass Excretion 710 20.2.8 Liver Metabolism 711 Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00020-4 20.2.9 Carrier-Mediated Transport 20.2.10 Enhanced Permeation and Retention (EPR) Effect 20.2.11 Mucosal Layer and Bioadhesion 20.2.12 Blood Supply Sublingual 20.2.13 Skin Permeation 20.2.14 Macrophage Uptake and Spleen/Lymph Node Targeting 20.3 Modeling Procedures for Transport, Metabolism, and Efflux of Drug 701 713 713 714 715 715 716 718 © 2018 Elsevier Inc. All rights reserved. 702 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT 20.3.1 Gastrointestinal Drug Absorption Model and Elimination Model 20.3.2 Liver Metabolism Model 20.3.3 Intestinal Metabolism Model 20.3.4 Efflux and Transport Model 20.3.5 Pharmacokinetics Modeling 20.3.6 Numerical Integration of the Model 20.4 Bioavailability: The Ultimate Goal to Achieve 718 719 720 721 721 722 722 20.5 Role of Computer in Physiological Process Manipulations 723 20.6 Conclusion 723 Acknowledgments 724 References 724 20.1 INTRODUCTION In the recent era of pharmaceutical formulation development where the formulation technology and formulation additives are getting increasingly more advanced regarding the development of more patient compliant products, a physiological process associated with product development is even more challenging (Ashford, 2017b). Physiological processes are those which affect the absorption, metabolism, elimination, permeation, solubility, and bioavailability of the administered drug by any direct or indirect means (Cardoso et al., 2016). The internalization of the drug inside the body by any available route of administration to achieving complete pharmacological action, involves many basic physiological factors (Wickens et al., 2017). The onset of action and pharmacological potential of a drug candidate largely depend on the administration route used (Lalu et al., 2017; Tekade et al., 2017b). For example, oral route involves the whole length of the gastrointestinal tract (GIT) for the absorption of the drug, whereas buccal or sublingual route avoids the first-pass metabolism and are suitable for the delivery of drugs which are lipophilic in nature (Mansuri et al., 2016b). Similarly, absorption of the drug through the nasal membrane is a characteristic feature of the nasal route of administration. The majority of pharmaceutical products belong to the oral route of administration and therefore each factor that may critically affect the physiological process is of significant consideration (Tekade et al., 2017c; Dua et al., 2017). Some of these factors include pH, which varies from the oral cavity to the colon and the whole GIT, gastric emptying, gastric motility, and stability in gastrointestinal (GI) fluids. Absorption also depends on the physicochemical properties of the drug (pKa, log P), nature of drug (hydrophilic, lipophilic), and anatomy and physiology of absorption site (pH, surface charge) (Mansuri et al., 2016a; Tekade et al., 2017a; Tekade et al., 2017c). Membrane physiology also plays an important role in the absorption process; for example, if the drug is administered through the oral route, the drug must cross the intestinal epithelium either by the transcellular pathway or paracellular pathway. The permeability of drug candidates into systemic circulation through absorption sites mostly depends on molecular properties of drug and physical and biochemical properties of the cellular membrane (Carpenter et al., 2016). If it is a parenteral administration, the pH of formulation plays an essential role and decides whether the formulation will produce irritation at the injection site or not (Tekade et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT 703 The ultimate goal of every pharmaceutical product is to achieve the desired bioavailability to get the desired clinical effects (Maheshwari et al., 2012; Maheshwari et al., 2015b; Soni et al., 2016). The overall objective of different physiological processes are to enhance ultimately or add-on to the bioavailability (fraction of administered drug that reaches to blood) (Kumar Tekade et al., 2015; Maheshwari et al., 2015a; Soni et al., 2017). Any processes (environmental pH, membrane physiology at absorption site) that result in the loss of bioavailability must be considered during product development (Maheshwari et al., 2017). Based on the extensive knowledge of these physiologic processes their manipulation can be used further to meet the specific requirement for the formulation of the suitable product. In this book chapter, apart from an extensive discussion about physiological processes and factors we also included some mathematical models for the prediction of physiological processes at many organs. Considering the evolutionary role of computers in the drug discovery and drug design, we also added a note on the use of computerbased manipulation of physiological processes. This section gives basic information on various physiological processes which influence the absorption, metabolism, elimination, permeation, solubility, and bioavailability of the administered drug directly or indirectly. However, it is important to read and learn the physiological factors which affect the product development. Therefore, the next section is written to elaborate and enlist various factors affecting formulation development. 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT Depending upon the intended use of the formulation or the product the factors vary, because the desired action varies. For example, in the case of a drug with systemic activity, it must get absorbed entirely from the applied site, whereas a drug intended for local activity should show little systemic absorption; similarly for extended release it is expected that a drug would remain at the site of application and get released slowly or at a predetermined rate (Sharma et al., 2015; Gorain et al., 2017). Thus, there are multiple factors which are mentioned below that usually govern such desired release parameters and absorption that must be taken care of while designing and developing a product. 20.2.1 Route of Administration Drugs can be administered via several routes like enteral route (which includes oral, sublingual, and rectal), parenteral route (which includes intravenous, intravenous, and subcutaneous), topical, inhalational, intranasal, and transdermal route (Dwivedi et al., 2016). However, there are two major factors that control the selection of the route, i.e., the desired therapeutic issues and properties related to the drug (Gibson, 2016). The therapeutic issues include rate of onset of action, duration of action, whether the target site for drug is readily accessible or not, and the patient compliance, whereas the properties related to drug which governs the route of administration is the physicochemical properties which include molecular size, ionization status, lipid solubility, etc. and the plasma concentration time profile (Wang et al., 2016a). DOSAGE FORM DESIGN CONSIDERATIONS 704 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT Also depending upon the disease condition whether the condition is acute or chronic the formulation and the route of administration must be modified. Like, in the case of acute or emergency conditions, parenteral injections are the most preferred route, although there are other routes, like the intrathecal route in the case of amphotericin B for treating cryptococcal meningitis. Also, inhalational route and sublingual route can also be employed for acute conditions. In the case of chronic diseased conditions, e.g., rheumatoid arthritis (RA), a study was carried out by Fautrel et al. wherein they determined the factors that were responsible for poor compliance with drugs related to RA. Although the study showed that the compliance rates were broadly similar for I.V, S.C, and oral route, compliance could be enhanced by informing patients or by improving the formulation aspect (Fautrel et al., 2016). Generally, in the case of chronic conditions, the most preferred routes are oral, topical, and transdermal. In such situations formulation is demanded to show an extended release which would be more beneficial for patients, thus improving patient compliance (Augsburger and Hoag, 2016). 20.2.2 Environmental pH The environmental pH of the site from where the drug is being absorbed is a very critical factor as it governs the degree of ionization of the drug (Dressman and Reppas, 2016). The drug can be absorbed easily via passive diffusion through the absorption membrane only if the drug is unionized; if the drug is ionized, then passive diffusion across the biological membrane is difficult as the biological membrane is hydrophobic in nature. Therefore, it does not favor any charged or hydrophilic species to penetrate through it (Bergström et al., 2014). Probably that is the reason why all the drugs are either weakly acidic or weakly basic in nature, as the chances of such molecules to be unionized are high. The degree of ionization of a drug can be estimated well by using the Henderson Hasselbalch equation if we know the pKa of drug and the pH of the environment from which it is being absorbed (Eq. (20.1) and (20.2)). ionized drug ðfor weak acidÞ (20.1) pH 5 pKa 1 log unionized drug unionized drug ðfor weak baseÞ (20.2) pH 5 pKa 1 log ionized drug Thus, the drugs which are weakly acidic in nature are absorbed more from stomach where the pH is low, wherein weakly basic drugs can be absorbed from intestine as the pH is slightly alkaline (Chillistone and Hardman, 2017a). This effect of pH on absorption is applied in case of poisoning cases, e.g., when there is acidic drug poisoning alkalinization is done to decrease its absorption by making the drug ionized and making it hydrophilic thereby increasing its excretion, similarly in case of basic drug poisoning acidification is done to promote its excretion (Sim, 2015). Also, the percentage of the drug in the ionized form can be identified using Eq. (20.3) for weak acids and Eq. (20.4) for the weak base. %Ionization 5 10ðpH2pKaÞ 100 ðfor weak acidsÞ 1 2 10ðpH2pKaÞ DOSAGE FORM DESIGN CONSIDERATIONS (20.3) 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT %Ionization 5 10ðpKa2pHÞ 100 ðfor weak baseÞ 1 2 10ðpKa2pHÞ 705 (20.4) Hence, it is vital to know the pKa of the drug and the pH of the environment from where it is supposed to be absorbed as these parameters governs the degree of ionization, wherein maximum efforts should be made to keep the drug in unionized form (Taniguchi et al., 2014). However, such environmental changes in pH, especially in GIT, could be utilized for enhanced absorption, like the work by Horava et al., where a pH-sensitive hydrogel network loaded with acid-sensitive hematological factor IX (FIX) was administered orally and showed enhanced delivery profile (Horava and Peppas, 2016). As FIX has higher absorption from the intestinal region and the hydrogel network gets disrupted and releases content in the intestine, thus environmental pH could be utilized for targeted release purposes too. 20.2.3 Gastric Emptying The stomach has the primary function of mixing and churning food, wherein the distal region of the stomach, called the antrum, is responsible for mixing and delivering it into the duodenum (Ashford, 2017a). This process of passing of the churning, mixed, and digested food by stomach enzymes into the intestinal region for further processing is termed as gastric emptying (Kar et al., 2015). However, this gastric emptying can be influenced by the therapeutics which can act either locally or on long neuronal reflexes. Also, the food’s energy density also controls the gastric emptying. It has been studied and understood that gastric emptying is altered by factors like the volume content, acidity, osmolarity, and fat content (Kar et al., 2015). Thus drugs affecting any of these parameters can lead to altering of the gastric emptying (Fig. 20.1). FIGURE 20.1 Enlisting factors governing gastric emptying. Several factors like viscosity, the physical state of food, therapeutic actions of the drug on gastric receptors, pathological conditions of the gastric system, body posture, the concentration of ions, and type of meal govern the gastric emptying. DOSAGE FORM DESIGN CONSIDERATIONS 706 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT One such study by Ikumi Ishibashi-Shiraishi et al. studied the effect of amino acid on gastric emptying (Ishibashi-Shiraishi et al., 2016). For this study L-arginine L-glutamate (ArgGlu)—already available in the market in I.V form—was administered orally and its effect on gastric emptying was determined using a barometer. A dose-dependent increase in L-arginine L-glutamate (ArgGlu) showed an improvement in gastric emptying in rats and the assumed mechanism was the vagus nerve activation. Another investigation with an attempt to decrease the undesired action of delayed gastric emptying upon administration of clonidine was successfully done by administration of L-arginine L-glutamate (ArgGlu) in dogs (Ishibashi-Shiraishi et al., 2016) (Fig. 20.2). Depending upon the physicochemical parameters of the drug being developed and depending upon its absorption site, we can alter the gastric emptying to enhance or sustain its absorption depending upon the desired intent. 20.2.4 Small and Large Bowel Transit Time As the intestine is the largest section of the alimentary canal, it has various favorable regions throughout its length which can favor absorption for various drugs (Kim and Pritts, 2017). Such absorption sites are called absorption windows, hence for those drugs which have their absorption window in the small intestine, it is desired to have a long transit time in the intestine—ideally the small intestine has a transit time of 3 to 4 h (Ringel-Kulka et al., 2015). Enteric coated tablets are generally those that have their absorption window in the intestine, thus desiring longer intestinal transit (Rahul et al., 2017). Similarly the drugs which are aimed at certain colon-related disease conditions like inflammatory bowel disease (IBD) (e.g., olsalazine, mesalazine etc.), colonic cancer (e.g, doxorubicin, methotrexate, 5-fluorouracil), for amebiasis (e.g., metronidazole, albendazole, etc), and for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, etc., are desired to show longer colonic transit time (Abuhelwa et al., 2016). Thus this could be achieved via the colon targeting approach where several techniques have been employed to improve colonic transit so that drug would be released in the colon, hence showing maximum transit and most therapeutic effect. In one such study, the authors developed cyclodextrin mesoporous silica particles (CDMSP) for controlled release of antibiotics in the colonic region (Abuhelwa et al., 2016). The authors used two drugs, one hydrophobic (clofazimine) and one hydrophilic (metronidazole), and successfully formed the CD-MSP, and showed that such particles are capable of loading both hydrophobic and hydrophilic antibiotics with a potential for colon targeting for lower intestinal bacterial infections. 20.2.5 Active Transport and Efflux Active transport is a mechanism that involves the expenditure of energy in the form of ATP, and this generally happens when either the compound is charged or being transported across the concentration gradient, or is facing some resistivity towards its absorption (Chillistone and Hardman, 2017a). There are many receptors that have been identified to be present on the intestinal layer which can be broadly divided into two classes and DOSAGE FORM DESIGN CONSIDERATIONS 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT 707 FIGURE 20.2 Effect of L-arginine L-glutamate (ArgGlu) on gastric emptying of a liquid meal in normal rats. Gastric emptying rate (%) of a liquid test meal was evaluated 60 minutes after administration using the phenol-red method in freely fed rats. (A) Dose dependency of the accelerating effect of L-arginine L-glutamate on gastric emptying. ArgGlu (0.3 30 mg/kg) was dissolved in the test meal and administered simultaneously. (B) Dose dependency of the accelerating effect of mosapride, a 5-HT4 agonist. Mosapride (0.1 10 mg/kg) was administered orally 60 minutes before the test meal. N 5 10; versus vehicle (parametric Dunnett’s test). (C) The effect of i.v. administration of L-arginine L-glutamate on gastric emptying. ArgGlu (10 mg/kg) was i.v. administrated just before the test meal. N 5 8, P 5 0.825; versus vehicle (two-sided t-test). (D) The vagotomy of gastric branches canceled the accelerating effect of L-arginine L-glutamate on gastric emptying. ArgGlu (10 mg/kg) was dissolved in the test meal and administered simultaneously to rats receiving gastric vagotomy. N 5 10, P 5 0.926; versus vehicle (two-sided t-test). (E) Dose dependency of the accelerating effect of L-glutamate on gastric emptying. N 5 8; versus vehicle (parametric Dunnett’s test). (F) The effect of L-arginine on gastric emptying. N 5 8, P 5 0.594 (analysis of variance). Adapted with permission from Ishibashi-Shiraishi, I., Shiraishi, S., Fujita, S., Ogawa, S., Kaneko, M., Suzuki, M. et al., 2016. L-arginine L-glutamate enhances gastric motor function in rats and dogs and improves delayed gastric emptying in dogs. J. Pharmacol. Exp. Ther. 359 (2), 238 246. DOSAGE FORM DESIGN CONSIDERATIONS 708 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT TABLE 20.1 Major Human SLC Drug Transporters Expressed in Intestine Protein Membrane Tissue Mechanism Distribution Localization Examples of Drug Substrates PEPT1 H1/peptide Intestine symporter Kidney BBM Ampicillin, amoxicillin, bestatin, cefaclor, cefadroxil, cefixime, enalapril, temocapril, temocaprilat, midodrine, valacyclovir, valganciclovir OCT1 OC uniporter Intestine Liver BLM SM Acyclovir, ganciclovir, metformin, cimetidine, quinine, quinidine, zidovudine OCTN1 H1 or OC antiporter Intestine Kidney BBM Mepyramine, quinidine, verapamil, ergothioneine, gabapentin OCTN2 OC antiporter Na1 symporter (carnitine Intestine Kidney BBM Mepyramine, quinidine, verapamil, valproate, cephaloridine, emetine OATP1A2 OA antiporter Intestine Kidney (DT) BBM BBM Fexofenadine, indomethacin, ouabain, rocuronium, enalapril, temocaprilat, rosuvastatin, pitavastatin, levofloxacin, methotrexate, imatinib, saquinavir OATP2B1 OA antiporter Liver Intestine SM BBM Benzylpenicillin, bosentan, atorvastatin, pravastatin, pitavastatin, fluvastatin, rosuvastatin, glibenclamide Here, BBM, brush border membrane; BLM, basolateral membrane; SM, sinusoidal membrane; CM, canalicular membrane; PT, proximal tubule; DT, distal tubule; OA, organic anion; OC, organic cation. Adapted with permission from Russel, F.G., 2010. Transporters: importance in drug absorption, distribution, and removal. Enzyme-and Transporter-Based Drug-Drug Interactions. Springer. they are ATP-binding cassette (ABC)-type transporters and solute carrier (SLC)-type transporters. Wherein the ABC is involved in efflux of substrates and SLC are involved in influx or bi-directional transport of drugs across the cell membrane (van Leeuwen et al., 2014). Tables 20.1 and 20.2 enlist the available receptors in the intestine that are involved in active transport. If the drug’s structural moiety resembles the substrate, the chances are that it can be transported across the membrane and depending upon the mechanism either via exchange of some anions or cations, which will involve consumption of ATP. Thus while developing such a molecule, a special attention towards its affinity for certain efflux or influx receptors must be studied to avoid undesired or substandard therapeutic action. For example, Ghadiri et al. formed drug loaded dextran-spermine nanoparticles that were conjugated with transferrin. This formulation enhanced the Capecitabine transport across the BBB as transferrin acts as a necessary ligand for active transport, thereby creating a nanoformulation that can be used for brain targeting (Ghadiri et al., 2017). 20.2.6 Gut Wall Metabolism Every xenobiotic which is ingested undergoes gut wall metabolism, also termed as hepatic metabolism, which greatly reduces the amount reaching the systemic circulation DOSAGE FORM DESIGN CONSIDERATIONS 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT TABLE 20.2 Protein 709 Major Human ABC Drug Transporters Expressed in Small Intestine Membrane Tissue Mechanism Distribution Localization Examples of Drug Substrates Primary MDR1/Pglycoprotein Active Intestine Liver Kidney BBM CM BBM Vinblastine, vincristine, daunorubicin, doxorubicin, colchicine, docetaxel, paclitaxel, ortataxel, etoposide, imatinib, methotrexate, bisantrene, mitoxantrone, paclitaxel, topotecan, digoxin, digitoxin, celiprolol, talinolol, indinavir, nelfinavir, ritonavir, saquinavir, levofloxacin, grepafloxacin, sparfloxacin, erythromycin, ivermectin, chloroquine, amiodarone, lidocaine, losartan, lovastatin, mibefradil, fexofenadine, terfenadine, carbamazepine, desipramine, loperamide, methadone, morphine, sumatriptan, vecuronium, cyclosporine A, tacrolimus, sirolimus MRP2 Primary Active Intestine Liver Kidney BBM CM BBM Vinblastine, vincristine, doxorubicin, etoposide, cisplatin, methotrexate, indinavir, ritonavir, saquinavir, grepafloxacin, glutathione conjugates, PAH. MRP3 Primary Active Intestine Liver Kidney BLM SM BLM (CCD) Glucuronide conjugates (morphine, acetaminophen, etoposide, ethinylestradiol), methotrexate MRP4 Primary Active Intestine Liver Kidney BBM SM BBM Methotrexate, leucovorin, topotecan, 6-mercaptopurine, 6-thioguanine, adefovir, tenofovir, ceftizoxime, cefazolin, cefotaxime, cefmetazole, hydrochlorothiazide, furosemide, olmesartan, edaravone glucuronide, PAH. BCRP Primary Active Intestine Liver Kidney BLM CM BBM Mitoxantrone, flavopiridol, topotecan, SN-38, camptothecin, methotrexate, imatinib, gefitinib, erlotinib, abacavir, lamivudine, zidovudine, nelfinavir, cerivastatin, pitavastatin, rosuvastatin, glibenclamide, olmesartan, dipyridamole, cimetidine, edaravone sulfate, albendazole sulfoxide, oxfendazole, ciprofloxacin, norfloxacin, ofloxacin, sulfasalazine, nitrofurantoin, Here, BBM, brush border membrane; BLM, basolateral membrane; SM, sinusoidal membrane; CM, canalicular membrane; CCD, cortical collecting duct; PAH, p-amino hippuric acid; SN-38, active metabolite of irinotecan. Adapted with permission from Russel, F.G., 2010. Transporters: importance in drug absorption, distribution, and removal. Enzyme-and Transporter-Based Drug-Drug Interactions. Springer. (Jones et al., 2016). This is due to the presence of several enzymes present in the liver, e.g., microsomal and nonmicrosomal degradation, that are responsible for metabolism; also there are several enzymes and gut microbes present throughout the intestine which are responsible for chemical modification of drugs (Hatley et al., 2017). The extrahepatic metabolism, i.e., intestinal metabolism, is carried out by CYP3A family of iso-enzymes which are present in the mucosa. Similar to isoproterenol which undergoes metabolism via sulfate conjugation, other drugs like chlorpromazine, levodopa, and diethylstilbestrol are also reported to undergo metabolism in the gut (Paine, 2016). Drugs which have certain hydrolysis prone regions are also metabolized by esterases and lipases—enzymes present in the gut wall. However, DOSAGE FORM DESIGN CONSIDERATIONS 710 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT FIGURE 20.3 Regulation of the ASBT and treatment of relevant diseases. The enterohepatic circulation of BAs is associated with the following processes: (1) biosynthesis from cholesterol in hepatocytes; (2) secretion from hepatocytes into intestinal epithelial cells by the ASBT; and (3) entering the hepatic portal and reabsorption into liver sinusoids. Low levels of cholesterol and some transcription factors (HNF1-alpha, PPAR-alpha, GR, VAD, and RAR) increase the expression of the ASBT, whereas high levels of cholesterol, Bas, and SHP decrease ASBT expression. Inhibition of the ASBT could improve some diseases, including hypercholesterolemia, cholestasis, and diabetes mellitus, and induction of the ASBT might facilitate remission of Crohn’s disease. Adapted with permission from Xiao, L., Pan, G., 2017. An important intestinal transporter that regulates the enterohepatic circulation of bile acids and cholesterol homeostasis: the apical sodium-dependent bile acid transporter (SLC10A2/ASBT). Clin. Res. Hepatol. Gastroenterol. such a metabolizing mechanism can be used as a strategy for targeted action, e.g., sulfasalazine which is reduced to azo and nitro drugs by the bacterial flora present in the gut (Chillistone and Hardman, 2017b). Another phenomenon of reabsorption occurs in the case of drugs which are exported out into gut after glucuronidation, as the presence of intestinal β-glucuronidase cleaves off the glucuronide moiety thus making the drug free to be reabsorbed, and this cycle is termed as enterohepatic circulation or recycling (Fig. 20.3) (Xiao and Pan, 2017). 20.2.7 First-Pass Excretion The first-pass metabolism or the first-pass effect or presystemic metabolism is the phenomenon which occurs whenever the drug is administered orally, enters the liver, and suffers extensive biotransformation to such an extent that the bioavailability is drastically reduced, thus showing subtherapeutic action (Chordiya et al., 2017). It happens when the drug is absorbed through GIT and then via the enterohepatic circulation the drug is absorbed directly into the liver where it undergoes metabolism before being released into the systemic circulation. Generally while designing a drug, some candidates may show good “drug-likeness” but fail due to their biochemical sensitivity towards metabolizing enzymes (Kashyap et al., 2017). Hence, to counteract this first-pass effect the total quantity DOSAGE FORM DESIGN CONSIDERATIONS 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT 711 of metabolized drug is to be calculated and an equivalent amount of excess drug is added to the oral formulation, or an alternative route for administration is recommended to bypass the first-pass metabolism. 20.2.8 Liver Metabolism The liver is considered to the main metabolizing site in the body, and hepatocytes are functional cells of the liver which carry out such activities. They are involved in several critical syntheses of certain molecules which would be employed elsewhere in the body for homeostasis. They are also involved in converting one form of a chemical moiety to another form that is therapeutically useful (e.g., prodrugs) (Madrigal-Matute and Cuervo, 2016). Various drugs along with their active metabolites are listed in Table 20.3. Within the hepatocytes, the majority of drug metabolism activity is carried out in smooth endoplasmic reticulum and cytosol, also metabolism can occur in mitochondria and in the plasma membrane. The best example is atracurium, a neuromuscular blocker, that undergoes TABLE 20.3 Representation of Active Metabolites of Various Drugs With Their Respective Category Drug Category of Drug Active Metabolite Allopurinol Xanthine oxidase inhibitors Alloxanthin Amitriptyline Tricyclic antidepressants Nortriptyline Acetylsalicylic acid Nonsteroidal anti-inflammatory drug Salicylic acid Butadion Nonsteroidal anti-inflammatory drug Oxyphenbutazone Diazepam Antianxiety Dismethyldiazepam Digitoxin Cardioprotective Digoxin Codeine Opiate (narcotic) analgesics Morphine Crtizol Steroid hormone Hydrocortisone Methyldopa Antiadrenergic Levodopa Prednisone Corticosteroids Prednisolone Novocainamid Class 1A antiarrhythmic N-acetylnovocainamid Propranolol β blocker N-oxypropranolol Alprenolol β blocker 4-hydroxyprenolol Buspirone Anxiolytic 1-Pyrimidinylpiperazine Desipramine Tricyclic antidepressants 10-hydroxydesipramine Dextropropoxyphene Opioid analgesic Norpropoxyphene Dihydroergotamine Ergot alkaloids 8-Hydroxydilhydroergotamine Note: Many drugs administered into body through either route of administration first metabolized into their active form which is actually responsible for the clinical effects. DOSAGE FORM DESIGN CONSIDERATIONS 712 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT nonenzymatic degradation, actually Hoffman elimination, along with pseudocholinesterase action in plasma (Billat et al., 2017). It is also the fact that if the drug will not metabolize, it may produce toxicity (Tekade et al., 2018). The enzymes which are responsible for metabolizing xenobiotic are either microsomal and found in smooth endoplasmic reticulum (SER), or nonmicrosomal enzymes and found elsewhere than the SER (Srinivas et al., 2017). The whole process of metabolism is divided into two phases, i.e., phase I and phase II (Fig. 20.4). In phase I, also termed as nonsynthetic phase, there is the addition of a functional group via oxidation, reduction, or hydrolysis, thus improving the hydrophilicity of the molecule. In phase II, conjugation occurs on the newly added functional group on the drug from the phase 1 reaction which further increases the polarity of the molecule (den Braver-Sewradj et al., 2016). Reactions like glucuronidation, sulfonation, glutathione-conjugation, acetylation, methylation, and amino acid conjugation are the reactions that are known as phase II reactions. Thus a drug designed with a pharmacophore showing any functional groups sensitive to the mentioned reactions would show low half-life. In some cases, there is strategic designing of a prodrug with metabolism sensitive region, where the drug undergoes metabolism and forms active moieties (Titchenell et al., 2017). FIGURE 20.4 Hepatic metabolizing enzymes. Liver is the primary site for metabolism, and the process of metabolism is classified into phase I and II. Thus, the major enzymes involved in biotransformation in phases I and II are listed. DOSAGE FORM DESIGN CONSIDERATIONS 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT 713 20.2.9 Carrier-Mediated Transport Carrier-mediated transport is a process which includes the movement of glucose, amino acid, and other polar molecules across the cell membrane, which is mediated by certain carrier proteins. This kind of movement exhibits several kinds of properties, like competitive binding, substrate specificity, and also carrier saturation (León, 2016). Considering the drug molecules specifically, drugs which are lipophilic in nature can easily pass through a cell membrane either by absorption, diffusion, or a carrier-mediated route, but if lipophilicity is low then carrier-mediated delivery across the membrane is the only option (Yusof et al., 2017). The carrier transport system can be classified as an active transport, passive diffusion, facilitated diffusion, vesicular transport, carrier-mediated intestinal transport, and ion pair transport (Li et al., 2017). Active transport as the name suggests involves energy in the form of ATP being spent to cart the molecule across the membrane. This kind of transport is seen when the molecule is to be transported against the concentration gradient (Vapurcuyan et al., 2017). Further active transporters are classified as a primary active carrier (PAC), which involves consumption of ATP, and secondary active carrier (SAC), which further employs an electrochemical gradient as a source of energy to move the molecules across. There are two types of SACs, i.e., symports, which port two molecules across the membrane in the same direction, and antiports, which port two molecules across the membrane in opposite directions (Lagarce and Roger, 2016). Passive diffusion is the type of diffusion which is based on a concentration gradient, thus it doesn’t require ATP for carting the molecules across (Cocucci et al., 2017). The four main kinds of passive transports are filtration, osmosis, diffusion, and facilitated diffusion. In the case of facilitated diffusion, there are certain integral transmembrane substratespecific receptors, which upon binding with substrate drug undergo internalization, thus carting it across the membrane along the concentration gradient (Timney et al., 2016). The carrier-mediated intestinal transports include carrier receptors which are located in the basolateral and brush border membrane of intestine and are specific for certain ions and nutrients which are essential for the body. The vesicular transport system is where the molecule, particles, or dissolved material is engulfed inside the cell; this is once again classified further as either pinocytosis, referred to as cell drinking, or phagocytosis, referred to as cell eating (Pichardo et al., 2017). In the case of ion-pair formation, the charged molecules or drugs undergo linking with endogenously present oppositely charged ions like mucin thereby forming an ion pair, thus the overall charge of the pair is neutral and can be diffused easily across the cell membrane (Incecayir et al., 2016). Hence, design-specific docking studies of the drug with specific receptors should be done to attain a good proof of concept about the target and delivery of the drug into the targeted cells (Sassoon et al., 2016). 20.2.10 Enhanced Permeation and Retention (EPR) Effect EPR effect is generally dependent on the size of the drug or the formulation, generally passive targeting of cancerous cells is done by employing drug-loaded nanoformulations (Tekade and Sun, 2017). This effect is observed in cancerous cells, as the tumor cells desire DOSAGE FORM DESIGN CONSIDERATIONS 714 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT to proliferate and grow as rapidly as they can, so there is angiogenesis where the developed vessels are poorly formed with comparatively wider fenestrations, which allow easy flow of nutrients to the tumors cells (Dwivedi et al., 2016). Such poorly developed vessels also show a poorly developed lymphatic system (analogous to draining system), thus such a phenomenon of enhanced permeability along with slower rate of elimination through the cancer tissues serves as a good phenomenon to be taken advantage of for delivering anticancer drugs specifically towards tumor cells by adjusting their formulation size in the nm range (Ghanghoria et al., 2016; Choudhury et al., 2017). Thus majorly the nanoformulations in the size range of 100 to 200 nm are observed to permeate through highly fenestrated vessels around a tumor. Thus if the intended drug is designed specifically for cancer targeting then its size should be controlled well within the nm range or else could be loaded into several nanoformulations 20.2.11 Mucosal Layer and Bioadhesion 20.2.11.1 Mucus Membrane The mucus membrane, also known as mucosae, is the moist surface which lines the walls of various body cavities. For example, the walls of the gastrointestinal and respiratory tract. In the last few years, mucosal drug delivery has received much attention as it can be designed for enabling prolonged retention at the application site. Due to prolonged retention time, a controlled rate of drug release can be obtained (Gloster et al., 2016). 20.2.11.2 Bioadhesion Bioadhesion is defined as a state in which two materials are held together by interfacial forces for an extended period (Hannig et al., 2016). One of the two materials must be biological in nature. Regarding drug delivery, bioadhesion refers to the attachment of a drug carrier system to a specific biological location. It can either be an epithelium tissue or a mucus coat over the tissue surface. If the adhesive attaches to a mucus coat, the phenomenon is called mucoadhesion (Tonkin et al., 2016). The mucosal layer is relatively permeable and hence allows fast drug absorption. However, the mucociliary clearance system, which is a natural defensive mechanism of the body, can remove the applied formulation from the mucous membrane assuming it is an impurity. To eliminate this problem bioadhesive molecules can be used which retain the formulation at the application sites which may be the oral cavity, conjunctiva, nasal cavity, gastrointestinal tract, and vagina. Bioadhesion/mucoadhesion may be affected by various factors like molecular weight, hydrophilicity, swelling, pH cross-linking, and concentration of active polymer (Tekade and Tekade, 2016). Among various physiological factors that affect mucoadhesion, the rate of mucus turnover, nature of surface available to bioadhesive formulation, and presence of local or systemic disease are prominent. Therefore, the dosage forms should possess a few features allowing it to be delivered through the mucosal membrane, such as flexible and small in size, high drug loading capacity, and excellent mucoadhesive properties. Erodible formulations can play a significant role here as system retrieval is not required at the end of the desired dosing interval. DOSAGE FORM DESIGN CONSIDERATIONS 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT 20.2.12 Blood Supply 715 Sublingual The sublingual mucosa is the membrane of the ventral surface of the tongue. Sublingual administration of drug refers to the placement of drug under the tongue (Rehfeld et al., 2017). The sublingual route bypasses the first-pass metabolism and hence facilitates rapid absorption of the drug into the systemic circulation. Drug directly reaches the systemic circulation using blood vessels. The sublingual region holds a rich source of blood vessels which are routed parallel to the mucosal surface (Yin et al., 2016). The sublingual artery supplies blood to the salivary glands. It branches in surrounding muscles and mucous membranes of mouth, tongue, and gums. The sublingual artery originates from the lingual artery which constitutes the primary blood supply to the tongue and mouth floor region (Harki et al., 2016). The lingual artery stems from the external carotid artery. Blood vessels present in the carotid artery region split into smaller blood vessels which in turn join the adjoining vessels creating an extensive blood supply network. This blood vessel network facilitates more profusion through the sublingual region as compared to the skin (Masui et al., 2016). The sublingual mucosa contains high amounts of polar lipids. This polar nature of sublingual mucosa facilitates increased membrane fluidity along with higher permeation of water and hydrophilic compounds (dos Santos Chaves et al., 2017). Two major pathways responsible for drug transport across the submucosal membrane are lipoidal and aqueous routes. The lipoidal route, i.e., the intercellular route filled with 50% polar lipids, permits passage of drug through transcellular and intercellular pathways. The aqueous route, in turn, is a paracellular pathway with the presence of water molecules trapped by the polar head of intercellular lipids in-between cells. Permeation of drug through submucosal membrane takes place by one of these pathways, hence understanding the permeation pathway of the drug is necessary for designing of the dosage form (Meltzer, 2017). Experiments by Lesch et al. with the porcine oral mucosa suggested that the permeability of water is greater in the sublingual area than in the gingival, palatal, buccal mucosa, and epidermis. Hence drug should be highly soluble in aqueous fluids (Lesch et al., 1989). Based on pH partition hypothesis, pKa of a drug needs to be stated. Unionized species of the drug can pass the lipid biological membrane more profusely than the ionized species. Hence the pH of the drug should be in favor of increased concentration of unionized species of the drug. 20.2.13 Skin Permeation Skin, the largest organ of the human body, covers 1.7 m2 and accounts for more than 10% of total mass of an average person (Tekade et al., 2017b). Stratum corneum together with epidermis, dermis, and subcutaneous tissue composes the human skin. It also contains hair follicles, apocrine, eccrine, sweat glands, and nails as appendages. The epidermis is avascular as it is composed of keratinocytes which constantly proliferate, differentiate, and keratinize. The epidermis is divided into (1) stratum basale, (2) stratum spinosum, (3) stratum granulosum, and (4) stratum lucidum. The outermost layer of the skin, stratum corneum, is also known as the horny layer. The stratum corneum possesses a unique combination of intercellular lipids arranged as multiple stacked membrane layers in an intercellular DOSAGE FORM DESIGN CONSIDERATIONS 716 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT lipid lamellae (Russo et al., 2016). This represents a critical permeability barrier function of stratum corneum. The dermis is composed of dense and irregular connective tissue along with collagen fibrils. Both provide support and elasticity to the skin. The dermis provides a highly vascularized network which facilitates passage of drug molecules from the dermoepidermal junction to the bloodstream. Lymph vessels present in the dermis also remove permeated drug molecules from the skin. The hypodermis is a loose connective tissue layer consisting of lipocytes with interconnecting collagen and elastin fibers. It protects the body from physical shock, heat insulation, and energy storage (Lodise et al., 2016). Drug transport through skin occurs mainly by two different pathways: transappendageal route (sweat ducts, hair follicles, and associated sebaceous gland), transepidermal route (across stratum corneum). As for the stratum corneum, two routes may exist for the drug transport in it: intercellular lipid route between the corneocytes and the transcellular route through the corneocyte and interleaving lipids (Maheshwari et al., 2015b). Since the corneocytes contain an intercellular keratin matrix which is hydrated and polar in nature, the transcellular route is regarded as a polar route. For drug permeation, consecutive partitioning between this polar environment and the lipophilic domains involving the corneocytes is required. Hydrophilic compounds prefer this route for permeation (Talbi et al., 2017). The drug transport predominantly occurs through the intercellular route, i.e., through the stratum corneum. Various factors that affect permeation through the skin are categorized into two types: physiological factors and properties of the drug. Physiological factors include age, anatomical site, ethnicity, gender, and skin diseases. Properties of the drug also affect permeation through skin. The drug should be able to penetrate both hydrophilic and hydrophobic domains of skin to be efficiently permeated. For this, the drug is required to have a high and balanced partition coefficient in between (Prausnitz, 2017). Unionized drugs are more permeable across the skin as compared to their ionized counterparts. The drug should have low molecular weight to be permeable across skin as the size of the drug affects the diffusivity through the stratum corneum. Other than these properties drugs should also possess high therapeutic potency, short biological life, and poor bioavailability so that the maximum advantage of the transdermal administration can be acquired (Tonkin et al., 2016). 20.2.14 Macrophage Uptake and Spleen/Lymph Node Targeting 20.2.14.1 Macrophages Mononuclear phagocyte system present in bone marrow consists of various forms of monocytes and macrophages. Monocytes are the large mononuclear cells that originate in red bone marrow, are actively motile, phagocytic, and develop into macrophages when they migrate to other tissues. Macrophages perform various major functions like phagocytosis, destruction, clearance of microorganisms and apoptotic cells, chemotaxis, secretion of enzymes, antigen processing, and destruction of tumor cells. Macrophages are mainly found in liver, lungs, spleen, and lymph nodes, thymus and gut, bone marrow, connective tissue, and serous cavity (Ufuk et al., 2017). Mononuclear cells play an effective role in therapeutic drug delivery provided that the drugs are delivered as a particulate carrier system. This targeted drug delivery DOSAGE FORM DESIGN CONSIDERATIONS 20.2 VARIOUS PHYSIOLOGICAL FACTORS AFFECTING PRODUCT DEVELOPMENT 717 FIGURE 20.5 Types of macrophages with location in body. Mononuclear phagocyte system present in bone marrow consists of various forms of monocytes and macrophages which perform various major functions like phagocytosis, destruction, clearance of microorganisms and apoptotic cells, chemotaxis, secretion of enzymes, antigen processing, and destruction of tumor cells. becomes more pertinent in cases where macrophages provide shelter to certain organisms (Komin et al., 2017). Macrophages ingest exogenous antigens, i.e., whole microorganisms, insoluble particles, and endogenous matters (dead host cells, cellular debris). First, macrophages undergo chemotaxis, i.e., they respond to a variety of substances, which is a result of immune response (Ozcelikkale et al., 2017). Next, macrophages attach the antigen to its membrane utilizing membrane protrusions, called pseudopodia. This pseudopodia enfolds the material in a membrane-bounded structure called a phagosome. Phagosomes move towards the cell interior and fuses with a lysosome and forms a phagolysosome. These phagolysosomes are then eliminated through exocytosis (BinnemarsPostma et al., 2016). Different types of macrophages based on their location in the body are shown in Fig. 20.5. 20.2.14.2 Spleen/Lymph Node Targeting For treating diseases which involve the lymphatic system, the development of approaches for delivery of drug to the lymph nodes is required. The lymphatic system is a complex network consisting of lymphatic vessels, lymph nodes, spleen, thymus, Peyer’ patches, and tonsils (Meijer et al., 2017). The lymphatic system plays an important role in recognition and response of the immune system. Numerous dosage forms have been developed which can specifically deliver entrapped material, particularly, a therapeutic drug to the lymph nodes via macrophages. This includes microspheres, liposomes, nanoparticles, polymeric micelles nanoemulsion, activated carbon, and silicon. The drugs can be targeted to the reticuloendothelial system by developing them in these forms. The size DOSAGE FORM DESIGN CONSIDERATIONS 718 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT of the drug delivery system should be less than 100 nm to be transported through the lymphatic vasculature. Drugs should be targeted passively to improve bioavailability and to reduce side effects (Yu et al., 2016). 20.3 MODELING PROCEDURES FOR TRANSPORT, METABOLISM, AND EFFLUX OF DRUG The gastrointestinal absorption process coupled with efflux and transport processes along with liver metabolism and pharmacokinetics can be studied in detail using mathematical models. This scientific model includes all the nonlinear progressions and hence helps in the estimate of dose-response relations and scheming of optimal dosage regimes of drugs extracted nonlinearly. Here, a scientific model of nonlinear liver metabolism and gut metabolism has been developed along with the development of a nonlinear transport model of drug efflux and drug influx in the gut. This model has been incorporated into the existing ACAT model, i.e., Advanced Compartmental Absorption, and Transit model (Wang et al., 2016b). 20.3.1 Gastrointestinal Drug Absorption Model and Elimination Model In this, the ACAT model was improved so as the intestinal wall elimination of drugs can be included via the inclusion of a sequence of enterocyte partitions that correspond to every luminal partition (Gobeau et al., 2016). In this new modified model, the drug absorbs by two processes, namely passive diffusion and carrier-mediated transport through the apical membrane of the enterocyte. The concentration gradient of the drug makes passive diffusion follow linear kinetics whereas it makes carrier-mediated transport follow Michaelis Menten kinetics (Fowler et al., 2017). A saturable efflux process going- on inside an enterocyte transports the drug back to the lumen. Diffusional clearance across the basolateral membrane competes with the metabolism for enzymes for the elimination of the drug from the enterocyte section. Sink conditions generated through blood circulation lead to much less diffusional resistance (in vivo) to the drug transfer across the basolateral membrane than across the apical membrane. Hence, the gut barrier is generally designed using the “thin wall” assumption (Almukainzi et al., 2016). Drugs that accumulate in intestinal wall tissue alter the drug appearance rate into circulation as compared to elimination rate from the lumen. The diffusional resistance from all barriers (except the apical membrane of enterocytes) leads to the proposal of an “Absorptive clearance” model to justify the presence of the drug in the blood circulation (Rygg and Longest, 2016). As for carrier-mediated transport, noteworthy concentration gradients occur within the enterocytes owing to lower diffusion coefficients along with low protein binding in the cytoplasm. A basic understanding of drug absorption via passive diffusion and active transport is shown in Fig. 20.6. DOSAGE FORM DESIGN CONSIDERATIONS 20.3 MODELING PROCEDURES FOR TRANSPORT, METABOLISM, AND EFFLUX OF DRUG 719 FIGURE 20.6 Gastrointestinal drug absorption model and elimination model. Efflux process in the enterocytes explains the absorption and metabolism of drug and mechanisms involved in the processes. 20.3.2 Liver Metabolism Model For describing drug concentration in liver, a venous equilibrium model is used. The blood flow portal veins carry the absorbed drug to the liver (Robles et al., 2014). Here the consumed drug mixes with blood flow from the hepatic artery which contains drug at its systemic concentration. The mixing equation can be given by Eq. (20.5): Cliv 5 Rabs 1 Cp QH (20.5) where Cliv 5 liver concentration Rabs 5 drug absorption rate from gastrointestinal tract QH 5 hepatic flow rate CP 5 plasma concentration Drug elimination rate from liver follows Michaelis Menten kinetics, i.e., Xn Vmax;i Cliv tRmetabolism 5 i51 Km;i ð fP 1 Cliv Þ DOSAGE FORM DESIGN CONSIDERATIONS (20.6) 720 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT where Vmax,I 5 maximum velocity constant of ith metabolic enzyme Km, i 5 concentration at which half of the maximum velocity is reached. FP 5 part of unbound drug present in plasma n 5 total enzyme no. Involved in clearance of the drug Vmax If we assume the quantity Km 1 C to be rapid unbound intrinsic clearance (CLint) of fP liv the drug from liver, then the the the total clearance rate from liver (CLh) can be given as Eq. (20.7); ! CLtotal int (20.7) QH eCLh 5 QH 1 CLtotal int Here, CLtotal int is the summation of the rapid intrinsic clearance of total enzymes. The drugs which escape hepatic removal are subjected to systemic metabolism through passage via the liver. Therefore, the degree of the first-pass metabolism is imitated by subtracting the metabolism rate created by systemic circulation from the total amount of drug metabolized via the liver. It is assumed that this difference corresponds to the drug elimination rate before attaining systemic circulation and therefore, is a degree of rapid bioavailability (Meacham and Burkhead, 2016). CLPlasma 5 int Vmax 1 CP Km fP (20.8) In vitro experiments gave values of (Vmax ; Km ), i.e., Michaelis Menten kinetic constants, and was used for in vivo conditions. In some cases data for in vitro enzyme kinetics was not available, here a solitary set of Vmax andKm data was optimized for predicting bioavailability and pharmacokinetics for multiple drug doses or dosage forms by means of GastroPlus. 20.3.3 Intestinal Metabolism Model The liver is the principal organ of metabolic drug clearance in human, but a few drugs undergo intestinal first-pass extraction as well. Examples of these kinds of drugs include cyclosporine and midazolam. The isoforms P-450 are found in the liver as well as in intestine, but the quantity of P-450 in the liver is 1 70-fold higher than that in the intestine. It is already stated that intestinal first-pass is higher due to the exposure of the drug to the metabolizing enzymes during the passage of the drug via enterocytes (Jones et al., 2015). This exposure of drug to the metabolizing enzymes occurs due to the efflux proteins present in the enterocytes. The most studied P-450 isoform is CYP3A4 which is present in both liver and intestine. The quantity of 3A4 present in the gut is 70 times less than that present in the liver. In these representations, the amount of in vitro Vmax of drug obtained from the liver microsomes was scaled to the in vivo Vmax of the drug. If the in vitro Vmax of drug DOSAGE FORM DESIGN CONSIDERATIONS 20.3 MODELING PROCEDURES FOR TRANSPORT, METABOLISM, AND EFFLUX OF DRUG 721 obtained from liver microsomal developments is Vliv, the amount of enzyme in the liver is Alive, and the amount of the same enzyme in a gastrointestinal section is AGIC, then Vmax for biotransformation in gastrointestinal tract section, VGIC, for enzyme was calculated as Eq. (20.9): VGIC 5 Vliv AGIC Aliv (20.9) 20.3.4 Efflux and Transport Model In the intestine, the membrane-bound active efflux protein, P-glycoprotein, i.e., P-gp is stated in the apical membrane of enterocytes. It works as a barrier to absorption of the drug by secreting drug from cell to lumen. Various forms of P-glycoprotein are found in all barrier tissues including blood brain barrier, lungs, liver, and kidneys. Many models had been proposed for explanation of in vitro saturable efflux (Bernd et al., 2015). To simplify a P-glycoprotein distribution in the gastrointestinal tract, an assumption was made that P-glycoprotein appears in the same arrangement and at the same intrinsic action in all sections of the gastrointestinal tract. This will explain the alteration in the flux rate in basolateral to apical direction owing to the change in P-glycoprotein quantity in the compartment (Chen et al., 2014). It was stated that efflux ratio ranges between 1.4 19.8 with the highest ratio in the ileum. Another assumption made was that the densities of Pgp in colon and duodenum are same. Under these assumptions, a solitary set of efflux Vmax and Km data was optimized for each drug that can be used in all progressions. It was stated that the Km data of various drugs for P-glycoprotein ranged between 1 300 µm (Stott et al., 2015). As far as carrier-mediated transport is considered, it was assumed that the transport proteins were found at luminal sides of enterocytes. As the sectional distribution of these transport proteins is unknown, an assumption is made that the distribution of these proteins along the small intestine is constant. Due to little information about basolateral transporters, basolateral membrane transport is neglected. In all the models, drug molecules are cleared from the enterocytes via diffusion into the bloodstream (Kalvass et al., 2013). 20.3.5 Pharmacokinetics Modeling Once a drug reaches systemic circulation, it gets distributed to one or more than one peripheral section followed by systemic clearance, hepatic clearance, kidney clearance, and other clearance organs. Considerations required for distributing the drug to peripheral sections can be gained from the literature using the PKPlus module (GastroPlus) (Xia et al., 2014). Availability of plasma concentration levels following an intravenous dose of the drug can be used to optimize microconstants like intersectional rates of mass transfer and sectional values using PKPlus module. Subjects used for obtaining oral absorption data were used as well for obtaining pharmacokinetic parameters in this module. Other important DOSAGE FORM DESIGN CONSIDERATIONS 722 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT assumptions that were made for this pharmacokinetic modeling included linear plasma protein binding, linear hepatic clearance, and linear nonhepatic clearance (Hénin et al., 2016). 20.3.6 Numerical Integration of the Model The type of the ACAT model that was applied in GastroPlus described the release, dissolution, luminal degradation, metabolism, and absorption of the medication during its transition via sequential sections (Herceg et al., 2017). A system of combined linear and nonlinear rate equations was used for modeling the kinetics associated with these processes. The resulting set of equations is integrated numerically in GastroPlus by the use of 4th/5th order Rungekutta numerical integration order. A 24-hour simulation was solved in 1 5 seconds. If a high degree of nonlinearity arises owing to various contending saturable progressions, the numerical integrator takes 20 seconds for imitations (Bulik et al., 2017). 20.4 BIOAVAILABILITY: THE ULTIMATE GOAL TO ACHIEVE Bioavailability can be stated as that part of the administered drug which goes to the blood circulation. Loss of drug, if any, can be due to processes explained above, i.e., due to gut metabolism, liver metabolism, etc. (Hartlieb et al., 2017). Overall bioavailability can be given as Eq. (20.10): n F 5 Li51 Fi (20.10) Here, Fi 5 Fraction of drug that escapes extraction at any organ/process, i 5 Process, F 5 Total bioavailability Practically, bioavailability is well-defined as the proportion of the Area under Curves (AUCs) following extravascular and intravascular administration. It assumed that the difference between AUCs is a measure of the first-pass metabolism. Hence Eq. 20.11: F5 AUCoral Doseiv AUCiv Doseiv (20.11) According to the definition, intravenous bioavailability is supposed to be more than 99%. Since intravenous doses are less compared to oral doses, AUCoral is alleviated with AUCiv via dose ration. The mass action laws rule the collaboration of the medicament with metabolic enzyme owing to which the dosage AUC association does not appear linear for many drugs (Janga et al., 2013). During intravenous dosing, the dose is instantaneously disseminated all through the distribution volume owing to the occurrence of higher systemic concentrations of the drug as compared to oral dosing. Due to this, the concentration after an intravenous dose saturates the enzymes involved leading to a disproportionate increase in AUC with dose. In such case, bioavailability becomes underpredicted (Shivaprasad et al., 2014). DOSAGE FORM DESIGN CONSIDERATIONS 20.6 CONCLUSION 723 Other important considerations for bioavailability determination are needed to be studied. One such consideration is different dosage forms of the same drug. In this case, the same drug dose may show a three-fold variance in bioavailability depending on the drug release rate. Another consideration is the site of release. In the case of drug metabolism, this factor needs to be considered because the dispersal of metabolizing enzymes differs across the gastrointestinal area (Shivaprasad et al., 2014). 20.5 ROLE OF COMPUTER IN PHYSIOLOGICAL PROCESS MANIPULATIONS Prevailing data had been utilized for building computational representations of octanol and water partition coefficient (log P), effective human jejunal permeability (Peff), aqueous solubility, permeability of cell culture, and molecular diffusivity so that the expense can be lessened and time required for investigational determination of biopharmaceutical properties (in vitro) can be decreased (Carson and Cramp, 2013). Various statistical methods, such as partial and linear least squares and artificial neural network, have been applied to the sets of molecular descriptors which are derived from 2D and 3D molecular structures for the development of these models (Esch et al., 2015). When these models are coupled with physiologically centered simulations of dissolution, GI transit, absorption and metabolism, the in vitro data and in silico properties are obtained which in turn allows estimation of oral dose fraction that is absorbed and bioavailability of drug (Carson and Cramp, 2013). Some of these models include single tank mixing, macroscopic/microscopic mass balance models, CAT model, and heterogenous tube model. CAT model has been one of the more versatile models amongst the given models. This model explained the oral plasma concentration profiles along with a simulation of degree and extent of absorption of the drug. The CAT model was further modified in the ACAT model, i.e., Advanced CAT model which included GastroPlus—a simulation software (Parrott and Lave, 2016). The ACAT model was preferred over the original CAT model due to various aspects. ACAT model used an assumption that a drug which passes through the small intestine will require equal transit time in all compartments. Moreover, the luminal wall used in the CAT model was modified by adding compartments which correspond to the enterocytes and the surrounding tissues. The CAT model presumed that drug transfer should be unidirectional, i.e., it should be transferred from lumen to the central compartment, but ACAT model presumed that the concentration gradient of the drug across the apical and basolateral membranes should be considered. ACAT model explains the release of drug, dissolution of the drug, luminal degradation of drug, metabolism, and absorption of a drug during its transition via consecutive compartments (Zhang et al., 2014). 20.6 CONCLUSION The chapter explains various physiological factors that can be considered as essential for the development of a drug product. It summarizes the distinct characteristics of different biological membranes which a drug must pass to produce a therapeutic effect. It DOSAGE FORM DESIGN CONSIDERATIONS 724 20. MANIPULATION OF PHYSIOLOGICAL PROCESSES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT explains what properties a drug should possess to be able to cross this membrane and produce therapeutic results. The chapter also summarizes the mechanisms through which a drug can pass these membranes. It is also briefly described here how the absorption, transition, metabolism, and distribution of a drug could be studied using various physiological and computational models. Computational models include single tank mixing, macroscopic or microscopic mass balance models, CAT model, and heterogenous tube model. Various physiological models like liver metabolism model, gut metabolism models, efflux and transport models are used for computing drug concentration at the liver, small intestine, and apical and basolateral membranes as well. The data obtained from these models can used for pharmacokinetic modeling. This explanation can be beneficial in the development of various new dosage forms of drugs in the future. Moreover, the models can be used for establishing the octanol water partition coefficient (log P), effective human jejunal permeability (Peff), aqueous solubility, cell culture permeability, and molecular diffusivity data for the newly developed drugs that will be designed in new dosage forms. Acknowledgments The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology (DST), Government of India for grant (#ECR/2016/001964) allocated to Dr Tekade for research work on drug and gene delivery. The author also acknowledges DST-SERB for N-PDF funding (PDF/2016/003329) to Dr. Rahul Maheshwari in Dr Tekade’s lab for work on targeted cancer therapy. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There are no conflicts of interest and disclosures associated with the manuscript References Abuhelwa, A.Y., Foster, D.J., Upton, R.N., 2016. A quantitative review and meta-models of the variability and factors affecting oral drug absorption—Part II: gastrointestinal transit time. AAPS. J. 18 (5), 1322 1333. 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Zhang, H., Xia, B., Sheng, J., Heimbach, T., Lin, T.-H., He, H., et al., 2014. Application of physiologically based absorption modeling to formulation development of a low solubility, low permeability weak base: mechanistic investigation of food effect. AAPS PharmSciTech. 15 (2), 400 406. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 21 Impact of Pharmaceutical Product Quality on Clinical Efficacy Vandana Soni1, Vikas Pandey1, Saket Asati1 and Rakesh K. Tekade2,3 1 Department of Pharmaceutical Sciences, Dr. H.S. Gour Central University, Sagar, Madhya Pradesh, India 2Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 21.1 Introduction 21.2 Risk Assessment and Management of Medicine 21.2.1 Product Quality Defects 21.2.2 Medication Errors 21.2.3 Known Side Effects 21.3 Elements of Pharmaceutical Development 21.3.1 Quality Target Product Profile 21.3.2 Critical Quality Attributes 21.3.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00021-6 732 734 734 735 739 743 744 745 746 21.3.4 Design Space and Control Strategy 747 21.4 Factors Affecting Drug Product Performance 748 21.4.1 Physicochemical Properties of Drug Substance 748 21.4.2 Differences in Manufacturing Processes 752 21.4.3 Differences in Excipients, Excipient Selection, and Quality Control 754 21.5 Drug Product Quality and Drug Product Performance 759 21.6 Scale-Up and Postapproval Changes 760 731 © 2018 Elsevier Inc. All rights reserved. 732 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY 21.6.1 FDA Level of Changes 21.6.2 Assessment of the Effects of the Changes 21.6.3 Critical Manufacturing Variables 21.6.4 Bulk Active Postapproval Changes 21.7 Postmarketing Surveillance 760 761 761 762 21.8 Conclusion 764 Acknowledgment 764 Abbreviations 764 References 765 Further Reading 771 763 21.1 INTRODUCTION The quality of a pharmaceutical product is the major criterion for the better clinical efficacy in the human body. The quality of pharmaceutical product development is a vital part for the different regulatory authorities and the pharmaceutical industry to meet the requirement of the swift growing demand. To maintain the quality of pharmaceutical product, there is the requirement for the suitable processes, pharmaceutical tests, and apparatus. The following advantages are important which are accomplished by proper development of a pharmaceutical product (Pramod et al., 2016): • • • • successful product development; subsequent rapid regulatory approval; reduce extensive validation load; considerably lessen postapproval changes. Product safety is the main criterion focused by all regulatory agencies as well as drug manufacturers. The formed product should be safe and effective to establish standards of quality and should be manufactured according to current Good Manufacturing Practices (cGMPs) requirements. The entire batches of drug products released by a company must follow the standards and specifications along with the company requirements. Failure in these specifications of a marketed drug product must be recorded and reported to the regulatory agencies for their immediate corrective and preventive measures (Patel and Chotai, 2011). Various parameters affect the product quality in the manufacturing industries. In the 21st century, the Food and Drug Administration’s (FDA) primary objective is to encourage a high-quality product with the help of competent, active, and high quality manufacturing technologies in the pharmaceutical industry (FDA, 2004). The product quality has been enhanced with the better understanding of cGMPs, process analytical technology, and quality by design (QbD) approaches. There have been disputes regarding the increase in drug recalls and shortages which show the failure of the product quality in pharmaceutical industry over the same period (Nagaich and Sadhna, 2015). DOSAGE FORM DESIGN CONSIDERATIONS 21.1 INTRODUCTION 733 Most of the pharmaceutical drug product shortages and their recalls may be due to poor product quality during the product fabrication process (FDA, 2013). These types of recall and shortages of the pharmaceutical product are responsible for the long-term improvement of the industrial parameters which are needed for the development of a high-quality drug product. Therefore, the industries are continuously trying to enhance the product quality for the manufacturing of better and safer drug products. A highquality product is principally related to safety and efficacy, thus, it must be ensured that the drug product has suitable quality standards or specifications during the manufacturing process. The different regulatory agencies are regularizing the manufacturing industries to make high-quality product because the consumers or patients are unaware about product quality until they face any serious problem related to the product (Stegemann, 2016). The pharmaceuticals have a direct impact on the human body. Thus, their regulation is very essential for the purpose of safety. The quality of products should show better performance with a high level of safety. So, the manufacturers are trying to develop high-quality products with regard to the clinical efficacy and safety of the drug product. The manufacturers have only a few economic benefits related to the quality. The FDA needs to simplify their regulatory requirements related to the manufacturing, so that the manufacturers can get the higher economic incentive (Woodcock and Wosinska, 2013). For the development of a high-quality product, various methods have been utilized. The identification and determination of different sources of risk from medicine and pharmaceutical development techniques are very useful for the development of quality product. There are various risk factors which affect the quality of the product. They include product quality defects, medication errors, and known side effects. These factors should be identified and corrected prior to the product development so as to improve the quality of product. The QbD is one of the most common approaches commonly used for the optimization and manufacturing of high-quality products. The design includes various quality related parameters like quality target product profile (QTPP), critical quality attributes (CQAs), risk assessment of factors, and elements associated with the QbD (Sangshetti et al., 2017). From the beginning of the 21st century, various initiatives have been taken for the improvement of the product quality with the modernization of technology and equipment used in the manufacturing processes. These initiatives help in the acceptance of modern techniques by the following steps: 1. 2. 3. 4. Set up the relationship between public and private research institutions; Advancement in manufacturing process regulations; Maintain drug quality standards; Provide good funding for the new and safe technology in the field of manufacturing of quality product; 5. Maintain the harmonization of emerging and new technology throughout the world and provide wider and broader applicability of these techniques, which can be used globally (O’Connor et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 734 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY 21.2 RISK ASSESSMENT AND MANAGEMENT OF MEDICINE There are various risk factors which affect the clinical efficacy of the product. These risk factors are associated with the product quality defects, medication administration errors, and adverse drug reactions (ADRs) or known side effects. These risk sources are the major factors which affect the clinical safety and efficacy of the product. The marketed products that are used in hospitals or general practices may not show the same effect as they showed in the clinical trial study (Poeran et al., 2014; Naci and Ioannidis, 2015). This difference in the effect may be due to the fact that in a clinical trial study, only a few numbers of patients use the medicine for a short period, but when studies are carried out in large populations, some ADRs may be observed. Thus, the complete safety and effectiveness of the product can be predicted by determining product’s overall marketing life and their recalls from the market (Eichler et al., 2011). To consider these effects, a branch called pharmacovigilance plays an important role. It is the branch of pharmacy that deals with the safety and efficacy of the drugs from the research time to their marketed period; hence, it determines and includes all the risk factors associated with the drug during clinical studies. There are various steps undertaken for pharmacovigilance purposes, like determining the unknown side effects of drugs of daily use, evaluating their effects with risk factors, and fixing the effective and safe dose of the drugs to the patient (Edwards and Bencheikh, 2016). The drug is believed to be safe when it is expected to show greater effects than the adverse effects or risks associated with them. The quality of the product should be maintained throughout the storage period, and remain constant in all respects when it is used in order to minimize the product recalls and shortage from the market. Some of the sources of risks from medicine are discussed below: 21.2.1 Product Quality Defects The product quality, safety, and efficacy are affected by several undesirable factors which are present in the product itself and responsible for the product or quality defects (Lipsitz et al., 2016). Most of the product recalls, and reduction in supply may be due to these quality defects. Therefore, the sources of the quality defects need to be identified (Kweder and Dill, 2013; Ebbers et al., 2016) and reported to the manufacturer and regulatory authority, so that the necessary actions can be taken for the protection of human health from the suspicious medicines. Various authorities have been appointed for the detection of these product quality defects. The health product quality regulatory authority quality defects and recall group or FDA are the authorities for the product quality management system and maintain the product quality as per the guidelines (HPRA, 2017). The severity of the medicinal products on the human health, and hence the product quality defects or recalls may be classified into three types (FDA, 2017): DOSAGE FORM DESIGN CONSIDERATIONS 21.2 RISK ASSESSMENT AND MANAGEMENT OF MEDICINE 735 21.2.1.1 Critical Quality Defects or Class I Recall These defects may lead to very dangerous and life-threatening effects which will cause death or other serious permanent damage to the human body. The defects are responsible for the class I recall of the product from the market. For example, defective artificial heart valve, defective catheter, incorrect information of dose strength, dosing information, etc. (FDA, 2017; HSA, 2017). 21.2.1.2 Major Quality Defects or Class II Recall These defects may be responsible for the temporary damage or illness to the human body, which are reversible. Thus, these lead to the class II recall of the product. For example, contamination in medical device and package defects (FDA, 2017). 21.2.1.3 Minor Quality Defects or Class III Recall These defects are not very harmful to human health and do not have any adverse effect consequences. Class III recalls may be used for these types of defects. For example, in 2010 children’s medicines were contaminated with plastic materials and thus were recalled from the market (http://www.alllaw.com/articles/nolo/personal-injury/fda-class-i-ii-iiirecalls.html). Some of the product recalls with their appropriate reasons and manufacturers are given in Table 21.1. 21.2.2 Medication Errors Medication errors are general and can cause appreciably harm to patients. Medication errors are caused by incorporating wrong and inaccurate doses in the product development which cause discomfort leading to severe problems for patients. Medication errors may be defined as the failure in the treatment of any disease which may cause either preventable adverse effects or serious effects leading to death or permanent injury to the patient or consumers (Aronson, 2009). The word failure means the effect of the medication is not up to the standard level, which has been set up previously by some experiments. These errors are present due to various reasons, like prescription errors, dispensing of the formulation, administration, product name, labeling, packaging, miscommunication, monitoring failure, etc. (Mohammadi et al., 2015). The medication errors may lead to different adverse effects on the human being. The adverse effects are defined as the any abnormal or unplanned effects of the medicine that could be responsible for the ADRs. An ADR is the objectionable and harmful reaction which influences the safety and efficacy of a medication and/or drug product (Alomar, 2014). Some medication errors may also cause an adverse event that is not classified under the category of ADRs, e.g., when a cannula penetrates a blood vessel causing temporary swelling of a blood vessel, known as hepatoma. One incident of ADR of medication errors happened in 1985: some patients, mostly children, were seriously affected with spinal injections that contained harmful vinca alkaloids that lead to paralysis or death of some of the patients (Arcangelo and Peterson, 2006). Therefore, medication errors are not always responsible for causing serious adverse reactions, but sometimes these errors may be free DOSAGE FORM DESIGN CONSIDERATIONS TABLE 21.1 List of Products Recalled With Their Associated Reasons Product Brand Name With Description Types of Recalling Manufacturer Country Reasons/Defects Official Recall Date All unexpired sterile drug syringes and IV bags Voluntary (hospital and user level) Cantrell Drug Company USA Lack of sterility assurance 25-07-2017 Ultra-Sten capsules (dietary supplement) Voluntary (consumer level) Hardcore Formulations USA 05-07-2017 Presence of unapproved drugs (Methylstenbolone, an anabolic steroid) Serious liver injury, Increased risk of heart attack and stroke, kidney injury, etc. D-Zine capsules (dietary supplement) Voluntary (consumer level) Hardcore Formulations USA Presence of unapproved drugs (Dymethazine, an anabolic steroid) 05-07-2017 Serious liver injury, Increased risk of heart attack and stroke, kidney injury, etc. Succinylcholine chloride 20 mg/mL Voluntary (hospital/clinic level) Fagron Sterile Services USA Short of sterility assurance and presence of microbial growth 23-06-2017 Systemic invasive mycoses and systemic bacterial sepsis Eliquis (apixaban) 5 mg Tablets Voluntary (consumer level) Bristol-Myers Squibb USA Tablet Mix-Up (Bottle labeled as Eliquis 5 mg was found to contain Eliquis 2.5 mg tablets) 10-06-2017 Increased probability of stroke, blood clot and pulmonary embolism Clindamycin Injection USP Voluntary (hospital/retail level) Alvogen South Korea Lack of sterility assurance and presence of microbial growth 16-06-2017 Systemic invasive mycoses and systemic bacterial sepsis Nitroglycerin products Voluntary (hospital/user level) Advanced Pharma, Inc. d/b/a Avella of Houston USA Potential problem with 15-06-2017 product potency (lower than expected potency) Interruption in patient’s treatment Paliperidone ExtendedRelease Tablets, 3 mg Voluntary (consumer/user level) Teva Pharmaceuticals, Inc. USA Failed dissolution test 31-05-2017 causing less drug absorption Treatment failure Tetracycline-ABC and Dibecline topical products Voluntary (retail level) Phillips Company USA Due to incorrect processing procedure 14-06-2017 Affect safety and efficacy of the product posing a risk to patients BRILINTA (ticagrelor) 90 mg tablets Voluntary (physician and consumer level) AstraZeneca UK Mixing of BRILINTA (ticagrelor) and ZURAMPIC (Lesinurad) 25-05-2017 Acute renal failure, risk of heart attack and stroke Lupin Pharmaceuticals Inc. USA Out of sequence tablets and Expiry/Lot information was not printed on the package 25-05-2017 Risk of contraceptive failure and unintended pregnancy Mibelas 24 Fe (Norethindrone Voluntary Acetate and Ethinyl Estradiol (consumer level) 1 mg/0.02 mg chewable and ferrous fumarate 75 mg) Oral contraceptive Risk Statements Serious life-threatening infections Amitriptyline HCl Tablets, Voluntary USP 50 mg and Phenobarbital (consumer/user Tablets, USP 15, 30, 60, level) 100 mg C.O. Truxton, Inc. USA Lack of proper labeling 08-05-2017 Overdose of Amitryptiline may cause uneven heartbeats, extreme drowsiness, seizures, etc. Overdose of Phenobarbital may cause cardigenic shock, coma, renal failure, etc. 25% Dextrose Injection, USP (Infant) Voluntary (hospital/user level) Hospira, Inc. USA Presence of particulate matter (human hair) Baby teething tablets and Nighttime teething tablets Voluntary (consumer level) Standard Homeopathic Company USA Contains variable amounts 13-04-2017 of belladonna alkaloids from the calculated amounts Serious health hazard Multiple compounded sterile products Voluntary (hospital/user level) Isomeric Pharmacy Solutions USA Possible lack of sterility 06-04-2017 Systemic invasive mycoses and systemic bacterial sepsis EpiPen (epinephrine injection, Voluntary USP) and EpiPen Jr (epinephrine injection, USP) Auto-Injectors Mylan N.V. USA Failure to activate the device 31-03-2017 due to a potential defect Significant health consequences All unexpired sterile injectable products labeled “latex free” Voluntary (user level) Avella Specialty Pharmacy USA Products may contain synthetic latex and natural latex 23-02-2017 Allergy, swelling, and inflammation Ibuprofen Lysine Injection, (20 mg/2 mL) Voluntary (hospital/user level) Exela Pharma Sciences, LLC USA Found to contain particulate matter 08-02-2017 Blood vessel blockage, provoke immune response, microinfarcts lead to lifethreatening side effect Duravet (Duramycin-10 Soluble Powder) Voluntary (consumer level) Huvepharma, Inc Bulgaria Possible undetermined hazard 28-12-2016 Significant health consequences Megajex; Tadalafil and Sildenafil capsules (Male Sex Enhancer Dietary Supplement) Voluntary MS Bionic, Inc USA 29-11-2016 May cause lowered blood pressure to the dangerous level Unapproved new drug 21-04-2017 Local swelling, blockage of blood vessels and systemic allergic response 738 FIGURE 21.1 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY Venn diagram illustrating the relationship between medication errors and ADRs and adverse events. from any type of adverse events. The Venn diagram in Fig. 21.1 shows the relationship between medication errors and adverse events (Ferner and Aronson, 2006). 21.2.2.1 Classification of Medication Errors The medication errors may present due to mistakes that occur in the planning and processing during the manufacturing and dispensing time. These errors can be broadly categorized as mistakes and skill-based errors. Then, these errors may be further classified into the four classes, i.e., action-based errors, knowledge-based errors, memory-based errors, and rule-based errors. The knowledge-based errors and rule-based errors are categorized into the mistakes class while action-based errors and memory-based errors fall under the skill-based category (Aronson, 2009). 1. Knowledge-based errors: These errors are present due to lack of complete knowledge about the medication, e.g., when penicillin is given to an allergic patient without prior knowledge about the patient history. Communication problems between the health professionals and consumers that may lead to misinterpretations in the drug dosing and dispensing of the medication can fall under this category (Evans and Swan, 2015). These errors can be minimized by providing the full knowledge about the medication to the consumers. Some other methods or technologies, like, computer- and bar-coded prescription system and cross-verification of prescriptions by health professionals, can also reduce the errors (Keers et al., 2013). 2. Rule-based errors: Two types of medication rules, i.e., good rules and bad rules, are available. When bad rules are applied, or good rules are misapplied or not applied, rulebased errors are present, e.g., diclofenac injection injected into the thigh muscle instead of buttock leads to intense pain. Therefore, good rules and better knowledge reduce these types of errors (Kim, 2011; Keers et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS 21.2 RISK ASSESSMENT AND MANAGEMENT OF MEDICINE 739 3. Action-based errors: These are the technical type errors. Wrong labeling on the drug product or misinterpretation in reading of a prescription may lead to action-based errors e.g., diltiazem is given in place diazepam due to misreading of labels. This error may lead to serious harmful effects on the human being due to administration of an inappropriate medicine (Grissinger, 2012). These errors can be reduced with proper labeling and prescribing the medication in the correct format (Filik et al., 2006). 4. Memory-based errors: The errors are present due to forgetting about the proper dose, or allergic or harmful drugs are prescribed, e.g., forgetting the allergic reaction of a patient to penicillin. The errors can be minimized with the help of the computer-based prescription system, in which the patient history is saved, including all the allergic reactions (Macy, 2014). All these errors can occur due to various factors that depend upon the working conditions of the individual. For example, increased medication errors by the nursing staff and doctors due to poor support, depression, overtime working with insufficient resources, and job security stress. The errors are minimized through proper knowledge and improvement of working conditions of the health professional staff (Shanafelt et al., 2002; Fahrenkopf et al., 2008; Wilkins and Shields, 2008). 21.2.3 Known Side Effects The major function of the FDA is to approve the safety and efficacy of drugs to be sold in the US market. Drugs are to be considered safe when they show high efficacy with lowrisk factors or side effects. Side effects (adverse events) are the unwanted signs and symptoms due to medicaments or drug products during the treatment (Kuhn et al., 2015). Various factors which affect the intensity and incidence of side effects depend upon the gender, age, individual pharmacokinetic parameters, races, metabolic enzyme activity, etc. It may be noted that some side effects may happen when: • The new drug is administered as the complementary medicines; or • Withdrawal of some drugs may lead to side effects like withdrawal syndromes; or • Increasing or decreasing the dose amount for long-term medicines. All medicines and drug products are responsible for some common side effects. These drug products cover all types of medicines like prescription or over-the-counter (OTC) drugs, vitamins, herbal preparations, etc. For example, β-lactam antibiotics, like penicillin, and other antibiotics, and other drugs like sulfonamides, cause allergic reactions and skin rashes in the majority of the population (Kuyucu et al., 2014). Complementary medicines are the medicines which are given along with the standard or primary treatment, like herbal medicines, vitamins. These herbal medicines or vitamin preparations may also be responsible for the side effects (Shirzad and Nasri, 2014). Some side effects of the prescription, OTC, or complementary medicines are given in Table 21.2. The side effects may be present in the range of mild to very serious effects. Some critical side effects lead to hospitalization or in some cases death may also occur. The side effects may also be responsible for some allergic or anaphylactic reactions. In an analysis from 1992 to 2012 in the United Kingdom, there was an increase in the anaphylaxis-related hospitalization cases due to the drug or food allergic reactions (Turner et al., 2015). Therefore, it DOSAGE FORM DESIGN CONSIDERATIONS TABLE 21.2 List of Drugs and Their Reported Side Effects Disease Category First-Line Drugs Leading Brand Name Reported Side Effects Reference Cancer Imatinib mesylate Glivec (Novartis, India) Muscle cramps and bone pain, hypophosphatemia Caldemeyer et al. (2016) Imalek (Sun Pharma) Lupinib (Lupin) Cetuximab Erbitux (Eli Lilly and Company) Sore throat, weight loss, cutaneous side effect Vinod and Diaz (2015) Bevacizumab Avastin (Roche) Jaw pain, gum infection, age-related macular degeneration Schmid et al. (2014) Pemetrexed Alimta (Eli Lilly and Company) Anemia, myelosuppression, hepatotoxicity Zattera et al. (2017) Pemanat (Natco) Pemex (United Biotech) Rituximab Ikgdar (Emcure) Mabthera (Roche), Reditux (Dr. Reddy’s) Myelosuppression, inflammatory syndrome (tumor flare) Ruan et al. (2015) 5-Fluorouracil (5-FU) 5-Flucel (Celon) Leukopenia, diarrhea, stomatitis, and nausea Focaccetti et al. (2015) Idarubicin Zavedos (Pharmacia) Cardiovascular side effect, testicular damage Langer (2014), Deihimi et al. (2017) Vincristine Alcrist (Alkem) Biocristin (Biochem) Motor delay, bacteremia with anemia, peripheral neuropathy Wang et al. (2016) Aceten (Wockhardt), Angiopril-DU (Torrent), Capotril (Lupin) Cardiac side effects, dry mouth, elevation of creatinine level Zaher et al. (2016) Atenolol A-Card (Race Pharma), Abiten (Alpic Biotech), Acord Plus (Invision) Hypotension, sleep disturbance, cold extremities Raphael et al. (2016) Timolol Brimolol (Sun Pharma), Ganfort (Allergan) Chest pain, cardiac arrest, cerebral ischemia, asthenia, respiratory problems Raphael et al. (2016) Dizziness, abnormal weight gain, stomach cramps, diarrhea Angelakis et al. (2014), Srinivasa et al. (2017) Hypertension Captopril Bone-related disorders Adrucil (Sun Pharma) Hydroxychloroquine Arthoquin (Acekinetic), Hcqs (IPCA) Methotrexate Alltrex (Miracalus), Biotrexate (Biochem), Mucosal, hematologic, hepatic and Caditrex (Cadila) gastrointestinal side effects Shea et al. (2014) Malaria Sulfasalazine Iwata (Cadila), Saaz (IPCA), Salazar-DS (Zydus) Blood dyscrasias, Yellowing of skin and eyes Chester Wasko et al. (2016) Alendronate Denfos (Dr. Reddy’s), Alenost (Macleods) Atypical femoral fractures (AFF) and Osteonecrosis of the jaw (ONJ) Ishtiaq et al. (2015) Chloroquine Cadiquin (Zydus Cadila) Gastrointestinal intolerance, aquagenic pruritus, retinal toxicity, blurred vision, paresthesia, insomnia, “stings” into the skin Goodman et al. (2001), Costedoat-Chalumeau et al. (2015), Martins et al. (2015) Brainstem neurotoxic encephalopathy, bone marrow suppression, nausea, vomiting, anorexia, and dizziness, mild blood abnormalities Ho et al. (2014), Lai et al. (2014) Aralen Maliago (Cipla) Artemisinin Alaxin (GVS Labs) Arte Plus (Zydus Cadila) Combither (Aristo) Atovaquoneproguanil Malarone (GlaxoSmithKline) Stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes) WHO (2015), CDC (2017) Quinine Qualaquin Tinnitus, slight impairment of hearing, headache, hypoglycemia, asthma, thrombocytopenia, hepatic injury, and psychosis Achan et al. (2011) Hepatotoxicity, neurotoxicity, Peripheral neuropathy, Lupus-like syndrome Jnawali and Ryoo (2013), WHO (2010), Falzon et al. (2017) Gastrointestinal upset, hepatotoxicity, exanthema, immunological reactions Jnawali and Ryoo (2013), Falzon et al. (2017) Hypersensitivity reactions, gastrointestinal upset Jnawali and Ryoo (2013), Falzon et al. (2017) Dizziness, blurred vision, color blindness, nausea, vomiting, stomach pain, loss of appetite, headache, rash, itching, breathlessness, swelling of the face, lips or eyes Jnawali and Ryoo (2013), Falzon et al. (2017) Cinkona (IPCA) Qinarsol (Cipla) Tuberculosis Isoniazid ISOKIN (Pfizer - Warner) CX-3 (Zydus- Cadila) Rifampin RIMACTANE (Novartis) CX-3 (Zydus- Cadila) Pyrazinamide Ethambutol P-ZIDE (Cadila) (Continued) TABLE 21.2 (Continued) Disease Category Diabetes First-Line Drugs Leading Brand Name Reported Side Effects Reference Streptomycin AMBISTRYN-S INJ (Sarabhai) Ototoxicity, nephrotoxicity, vestibular dysfunction Jnawali and Ryoo (2013), Falzon et al. (2017) Metformin (I Line) Gluconorm-SR (Lupin) Gastrointestinal side effects, slow/irregular Raz (2013), Abdulheartbeat, stomach pain with nausea, Ghani et al. (2017) vomiting, or diarrhea Glumet (Cipla) Insulin (II Line) Bovine Fastact (USV) Humalog (Eli Lily) Sulfonylureas (II Line) Glimepiride (Amaryl) Glyburide (DiaBeta; Micronase) Hypoglycemia, fast heartbeat, fainting, or seizure, sudden sweating Abdul-Ghani et al. (2017) Hypoglycemia, gastrointestinal upset, weight gain Karagiannis et al. (2012), Sola et al. (2015), Abdul-Ghani et al. (2017) Sore throat, muscle pain, weight gain, tooth problems Abdul-Ghani et al. (2017) Glipizide (Glucotrol) Glitazones (III Line) Pioglitazone (Actos) Rosiglitazone (Avandia) 21.3 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT 743 becomes necessary to take medicines carefully under the supervision of medical professionals. There are some steps which could be helpful in the duration of any adverse event or before drug administration and thus can reduce the risk of experiencing the side effects. These steps may be as follows: • Asking for the prescribing information about the drug, so that the written side effect can be understood carefully before taking the medicine. For example, taking a nasal decongestant by a person suffering from hypertension would lead to unwanted reactions (FDA, 2017). • If any information is written on the label or packing of the container it needs to be read very carefully. The information may contain the proper administrative procedure or possible side effects. For example, store in a cool place, shake the bottle, do not use after a certain date, discard 28 days after opening, for topical use only, etc. • If any side effects are present after the administration of the drug, there is a need to seek the help from health professionals, so that he or she can suggest the correct remedy for the side effects. For example, during chemotherapy the proper diagnosis should be performed for the normal functioning of liver, if not so further treatment may be unsuitable unless the liver recovers (Sharma et al., 2014). 21.3 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT The elements of pharmaceutical development are used to design and develop a product which would maintain the quality to show better performance of the drug. This could be achieved by gathering the information and knowledge from the scientific understanding and then incorporating them in research. The principle of pharmaceutical development is to develop an efficient manufacturing process for designing high-quality product. QbD is a systematic approach for the development of a pharmaceutical product which tries to meet the predefined quality standard of the product with high clinical efficacy. The QbD concept was first used and reviewed by Joseph Moses Juran. The QbD helps to understand risk factors with the scientific and hands-on techniques to enhance the drug product quality. The International Conference on Harmonization (ICH) has also approved these methods for the pharmaceutical development, pharmaceutical quality system, and quality risk management under the ICH Q8, ICH Q9, and ICH Q10 sections, respectively (FDA, 2006, 2009a,b). QbD techniques are based on the identification of CQAs which are required for the development and manufacturing of good quality product. The CQAs are the factors which select the appropriate critical process parameters (CPPs) by using QbD methods on the basis of their efficacy. These selected CPPs are helpful in the development of effective, robust, and flexible methods to produce high-quality product for the long duration of time (Lawrence et al., 2014). QbD-based approaches function as major processes for running any pharmaceutical industry effectively as these methods are related to developing a safe and effective product. There are various advantages of QbD methods, which are given below (Sangshetti et al., 2017); • Safety and efficacy of the products to the patient and consumers. DOSAGE FORM DESIGN CONSIDERATIONS 744 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY • The method develops an effective, flexible, and robust process for better designing of the product. • Various CPPs and material attributes are optimized with scientific knowledge. • Risk assessments of the various factors may be done by providing better solutions to problems. • The developed product with QbD technique shows predefined quality standard and uniformity during the manufacturing process. • The design also reduces the cost of the product during scale-up and postapproval changes (SUPAC). The pharmaceutical developmental stage may follow different steps or elements of QbD techniques: • Step-I: The targeted product profile will be chosen and well defined on the basis of safety, use, and efficacy of the product. • Step-II: The risk factors will be indicated which affect the product quality and are related to the drugs, excipients, and other ingredients used in the formulation. • Step-III: The CQAs and CPPs will be selected with the help of various experimental works to optimize the product quality and efficacy. • Step-IV: The manufacturing method will also be developed by designing and changing the strategy and leads to product quality improvement. 21.3.1 Quality Target Product Profile The predefined standards of product quality, which should be followed during the manufacturing and optimization process, are considered to be the target product profile. When QbD methods are used to fulfill the targeted profile of the product then they are known as the QTPP. The QTPP is very important for the development of an optimized process. It also helps in the development of product having high-quality and efficacy with the help of CQAs, such as drug and dosage form characteristics, in the product development process (Lawrence and Kopcha, 2017; Sangshetti et al., 2017). ICH guidelines define the quality product profile under the section of ICH Q8 R2 on the grounds of designing and development of high-quality product. Factors influencing the quality target profile of the product are given below: • Route of administration, dose strength, and type of dosage forms, e.g., drugs which are degraded by acidic medium should not be administered by oral route or if administered they must be in a modified form, such as a coating concept can be used for maintaining their efficacy. • Drug release kinetics from the dosage form and their pharmacokinetic parameters such as modified-release drug products includes extended or modified release of active moiety. • Drug excipients interaction may be physical (between primary amine drugs and microcrystalline cellulose) and chemical (primary and secondary amines interact with reducing sugars) and may change the original form of the drug to affect its quality and efficacy. DOSAGE FORM DESIGN CONSIDERATIONS 21.3 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT 745 • Product purity, sterility, stability, and dosage form appearance. • Pharmacological and therapeutic effects produced by the drug from the final drug product. 21.3.2 Critical Quality Attributes CQAs are defined under the ICH Q8 R2 guidelines as, “physical, chemical, microbiological or biological properties which should be required within the certain range or limit to confirm the predefined quality standard product”. They are considered to be foremost factors for the development of any dosage form while maintaining quality. If variations are present in the range of these attributes, they show low or no risk to the quality of the product. The CQAs depend upon the type of dosage forms, drug substances, and excipients used in the formulation (Lawrence et al., 2014). For example, a controlled drug release formulation strongly depends upon the dissolution test; hence, it is a critical parameter for these formulations, while a dissolution test is not critical for an immediate drug release formulation due to high solubility of the drug (Sangshetti et al., 2017). The drug substance and excipients are used as raw materials for the manufacturing of any dosage form. The quality and quantity of these substances are referred to as the main attributes for the product development. CQAs may be different for the different formulations, e.g., dose strength, purity, release kinetics, and product stability are the main factors which affect the CQAs for the solid oral dosage forms. Similarly, the sterility and clarity are the major parameters for the parenteral dosage forms. The CQAs are obtained from the QTPP with the FIGURE 21.2 Example of CQAs for nanoparticle preparation. DOSAGE FORM DESIGN CONSIDERATIONS 746 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY prior knowledge about various attributes for the development of optimized process and product. Along with the materials attributes of the drug and excipients, some process parameters also strongly affect the CQAs, these parameters are known as CPPs (Lawrence et al., 2014). These CPPs may include operating conditions (like stirring speed, sonication time, temperature, pH), method of preparation, batch size, equipment type, and environmental factors (like moisture, aseptic condition). For example, nanoparticles formulation method may depend upon the various material attributes and process parameters and may be categorized as the CQAs, as shown in Fig. 21.2 (Li et al., 2017). Thus, the main objective of QbD method is to identify and define CQAs with the appropriate material attributes and CPPs. Process capability is a statistical term for the measurement of process robustness and reproducibility. Robustness means the consistency of product quality and performance with the tolerable limits of process variables. The most common formula for the process capability is six standard deviation approaches. The process capability index (CpK) is the ratio of tolerable limit of any character and the six sigma, i.e., process capability. The CpK formula is given below (Roy, 2012); CpK 5 Upper limit of specification 2 Lower limit of specification 6 Standard deviation If the value of CpK is more than 1, then the process is robust and reproducible, hence, it is said to be a capable process (Glodek et al., 2006; Roy, 2012). 21.3.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs The CQAs cover both material attributes and process parameters. The design space defines the relationship or connection between CQAs and CPPs. The design space is the region where the predefined standard quality product may be produced by using these linkage relationships. Hence, design space provides the region for the development of a FIGURE 21.3 Relationship between the knowledge space, design space, and operating range. DOSAGE FORM DESIGN CONSIDERATIONS 21.3 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT 747 high efficacy quality product with the help of optimized process and prevents the product failure loss during the manufacturing process (Kelley et al., 2016). The knowledge space is a broad region, which includes all the critical and noncritical parameters during the process of product development. This region has critical attributes, which cover the design space and operating ranges, where the products are produced within a range of certain quality attributes maintaining quality for their effectiveness. Knowledge space provides the specific area of research in the field of product development, beyond the boundary of that there is no requirement of research (Kelley et al., 2016). Fig. 21.3 explains the relationship between the knowledge space, design space, and operating ranges of product development. Risk assessment is the method to determine the CQAs associated with the process and quality of product. The risk assessment functions as the assistive tool for the communication between the industry and FDA as well as manufacturing and research and development departments within the company (Patricia, 2007). There are various regulatory authorities providing different validation guidelines for bioanalytical methods during the manufacturing process. It may lead to confusion for the manufacturer and thus is not suitable for process and product development. The risk of the confusion is assessed by the risk management method, hence this reduces the risk of the wrong decision being made during the process and helps to develop a high-quality product (Rozet et al., 2011). ICH Q9 guidelines describe the different methods of risk assessment. These methods may include fault tree analysis (FTA); failure mode effects analysis (FMEA); failure mode, effects and criticality analysis (FMECA); preliminary hazard analysis (PHA); hazard operability analysis (HAZOP); hazard analysis and critical control points (HACCP); quality function deployment; supporting statistical tools; risk ranking and filtering. Scientific knowledge about the risk and sufficient efforts for the solution of those risk factors are the main principles of the risk management of the process. Risk management is the collective duty of all the departments of the clinical, manufacturing, and sales unit (Ribeiro, 2013). 21.3.4 Design Space and Control Strategy The ICH Q8 defines the design space. Design space is the region where the material attributes and process parameters interact to assure quality. Hence, it explains the connection between CQAs and CPPs and determines the required operating ranges for product development. It is the region where a standard product can be produced (Bhatia et al., 2016). To ensure the consistency of the product quality, properties such as chemical, physical, and/or microbiological must be defined properly. The product would be achieving the required quality when all the operations are carried out within the design space. Thus, it describes a recognized choice of material attributes and/or process parameters that generate the product of desired quality. To achieve this, it is always advisable to choose a design space which could cover the entire process by providing improved flexibility in the design. Data from the previous studies of the product development stages will be very helpful when considering the construction of a design space in order to achieve the DOSAGE FORM DESIGN CONSIDERATIONS 748 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY efficacy of the product by proper formulation based on the design and involvement of different parameters. Control strategy is the method which controls various parameters obtained from the current product development process to confirm the high efficacy of the process and produce high-quality product. The control strategy is defined by the QbD methodology where the CQAs and process capability parameters are taken into consideration. Generally, the control strategy includes all the parameters during the manufacturing process, such as raw material control, facility control, process control, in-process quality assurance, drug release testing, characterization method control, comparative study, and stability study (Gawade et al., 2013; Sk et al., 2013). 21.4 FACTORS AFFECTING DRUG PRODUCT PERFORMANCE Factors influencing the design and performance play a vital role in the drug product development and its performance. Therefore, they must be considered in manufacturing and clinical performance. These unique physicochemical factors show some applications in synthesis, and modifications which help principally to develop suitable candidates (Tekade et al., 2014). While developing the formulations, a predictable therapeutic response is required to be achieved by the developed candidate and should possess the ability to convert it into large-scale manufacture with reproducible product quality. To ensure product quality, various factors are to be considered to achieve the required quality and therapeutic response of the drug. These factors are discussed below: 21.4.1 Physicochemical Properties of Drug Substance The physical and chemical properties of active drug moiety are the pioneered concerned area in the product development. The scientists in the middle of the 20th century study their effects on the biological performance and clinical efficacy of the developed drug product (Barbour and Lipper, 2008). Many drug candidates are not able to maintain the pharmacokinetics and failure to do so will lead to rejection, as they would be unsuitable in terms of quality. The poor physicochemical properties of a potent drug during discovery and development would affect the costs of bringing it to a product stage by formulation. 21.4.1.1 Chemical Factors The different chemical options are available and used to enhance the stability and systemic availability of drugs. For example, esters produce the more stable derivatives of both acids and bases to prevent hydrolysis and become more stable. The stability, as well as solubility of both acids and bases, tends to rise when they are in the salt forms. Penicillin in the form of salt is more soluble, hence on administration, it shows higher blood concentration as compared to its acid form (Haveles, 2014). Thus, these will produce a proper response of the administered dose and will maintain the quality of the product by becoming stable or showing some other effects like solving solubility problems. The chemical degradation of the drug in the formulation may raise the impurity intensity and DOSAGE FORM DESIGN CONSIDERATIONS 21.4 FACTORS AFFECTING DRUG PRODUCT PERFORMANCE 749 FIGURE 21.4 Crossing of different moieties across biological barrier. FIGURE 21.5 Dynamic relationship in drug, drug product and pharmacologic effect. thus decrease the potency of the drug whereas physical transformation would cause the product to be unsuccessful in the dissolution testing (one of the key CQAs). 21.4.1.2 Molecular Size and Diffusivity The diffusion of small drug molecules across the biological membrane is possible through the glycerol and water-filled free volume. The molecules which are larger than the membrane-pores do not cross the membrane and are retained on the sample side of the membrane. The small molecules and their buffer salts can cross biomembranes. Gases, DOSAGE FORM DESIGN CONSIDERATIONS 750 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY hydrophobic molecules, and small polar uncharged molecules are candidates of interest which diffuse across phospholipid bilayers, but larger polar and charged molecules cannot cross the biomembranes (Maheshwari et al., 2012, 2015b). So, only small and relatively hydrophobic molecules can diffuse across a phospholipid bilayer at significant rates (Fig. 21.4). The ability of a drug to cross the membrane is considered as diffusivity. The molecular weight greater than 500 Da produces many difficulties to cross the membranes (Halligudi et al., 2012; Schalk and Mislin, 2017). 21.4.1.3 Aqueous Solubility and Dissolution Rate Solubility, a thermodynamic property of a compound, controls the fraction of drug being absorbed by passing the barriers of the gastrointestinal tract and reaching the systemic circulation (Fig. 21.5). The rate determining steps in the absorption of orally administered drugs are rate of dissolution (for lipophilic drugs, e.g., Griseofulvin) and rate of drug permeation through the biomembrane (for hydrophilic drugs, e.g., Neomycin). A preliminary requirement for the absorption of a drug is that it must be present in aqueous solution which depends on a drug’s aqueous solubility and dissolution rate. The drug having low aqueous solubility shows low dissolution rate hence it suffers from bioavailability (BA) problems (Savjani et al., 2012). The proper solubility and dissolution rate will enable the dosage form to deliver the proper amount of drug to maintain the proper therapeutic effects. 21.4.1.4 Amorphous and Crystalline Form The crystalline form has lower energy as compared to the amorphous form, hence it is more stable than the amorphous form. Hence, the crystalline form is explained in terms of the requirement of energy at the molecular level to break the stronger bonding. Solubility of compounds is dependent on the intermolecular hydrogen bonds between solute molecules and solvent molecules. Higher solubility correlates with higher dissolution rate and better BA of the compound. The amorphous form has higher dissolution rate than the crystal form as the crystal form has greater intermolecular forces (Yadav et al., 2009). An important factor for consistent therapeutic action is the drug product quality itself and the drug should be able to show a sufficient solubility profile which is better obtained in the amorphous form to maintain the quality. 21.4.1.5 Particle Size and Effective Surface Area Micronization produces smaller particles by size thus creating a greater effective surface area for the intimate contact between solid surface and aqueous solvent, thus causing higher dissolution rate. This finally leads to enhanced absorption efficiency. So, a reduction in particle size is used to boost the absorption of various poor water-soluble drugs, like digoxin, bishydroxycoumarin, nitrofurantoin, tolbutamide, and griseofulvin (Lancaster, 2013; Dizaj et al., 2015). Many of the newly developed and reported drug delivery carriers basically function via reduction of particle size down to the nanoscale (Tekade et al., 2017; Sharma et al., 2015; Maheshwari et al., 2015a). Maheshwari et al. formulated sustained release nifedipine tablets by making use of micronization technique. They prepared microsponge which was further granulated to form tablets of nifedipine (calcium channel blocker with poor water solubility) (Rahul et al., 2017). DOSAGE FORM DESIGN CONSIDERATIONS 21.4 FACTORS AFFECTING DRUG PRODUCT PERFORMANCE 751 TABLE 21.3 Comparison of Stable and Metastable Form (Prasanthi et al., 2016) Stable Form • • • • • Metastable Form Lowest energy state More stable form Highest melting point Least aqueous solubility Dissolution rate limited • • • • • Highest energy state Less stable form Lowest melting point Higher aqueous solubility Better absorption and bioavailability 21.4.1.6 Polymorphism and Amorphism When a substance occurs in more than one crystalline form it is designated as a polymorph, whereas amorphous form explains the quality of being amorphous or formless. In amorphous forms, no energy is considered to be necessary to break up the crystal lattice leading to faster dissolution of the drug moiety from drug product. So, the amorphous form is often selected over the crystalline form, and numerous drugs, including prednisolone and hydrocortisone, are marketed in the amorphic form (Censi and Di Martino 2015). The comparison between the stable and metastable form are given in Table 21.3. Polymorphic forms possess different chemical and physical properties such as chemical reactivity, melting point, apparent solubility, dissolution rate, vapor pressure, optical and mechanical properties, and density. These properties affect the process and manufacturing of drug product by affecting dissolution, bioavailability, and finally stability. So, polymorphism can influence the quality, safety, and efficacy of the formed drug product. 21.4.1.7 Partition Coefficient Partition coefficient (PC) gives the value of the drug partitioned between aqueous phase and nonaqueous phase. Ideally, for best possible absorption, a drug should have sufficient aqueous solubility to help it to dissolve in fluids at the absorption site and lipid solubility (Ko/w) good enough to facilitate the partitioning of the drug in the lipoidal biomembranes. So, as the PC (lipid solubility) increases, the percentage of drug absorbed also increases (Chillistone and Hardman, 2017). A special focus on the optimum region of lipophilicity and supervision of lipophilic efficiency indices will help significantly to improve overall quality of drugs at several stages of discovery. 21.4.1.8 pKa Ionization Constant pKa measures the strength of an acid or base determining the charge on the molecules at a given pH. Only undissociated and unionized molecules can cross the lipoidal membrane as compared to ionized molecules. Hence, the amount of the drug that exists in unionized form is a function of the dissociation constant of a drug and pH at the absorption site. Drugs existing in unionized form at the absorption site are good candidates for absorption while some drugs that exist in ionized form are poor candidates for absorption (Ashford, 2013). The performance of the acidic and basic drug molecules depends on the pKa and thus this is a very essential factor while considering the quality of the product. DOSAGE FORM DESIGN CONSIDERATIONS 752 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY 21.4.1.9 Solvates/Hydrates Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. The most common solvate is water. If water is incorporated as a solvent, then solvates are commonly known as hydrates. If water molecules are already present in a crystal structure as in hydrates form, the tendency of the crystal to attract additional water to initiate the dissolution process is reduced, and solvated (hydrated) crystals tend to dissolve more slowly than anhydrous forms, e.g., hydrous and anhydrous forms of caffeine, ampicillin, theophylline, mercaptopurine, and glutethimide. They are indirectly involving in affecting the clinical significance of the drug product (Savjani et al., 2012; Florence and Attwood, 2015). In case of solvates like theophylline monohydrate, water molecule acts as a bridge that links two molecules of theophylline which consequently requires breakage during the dissolution process. So, we can find that anhydrous theophylline is more soluble than its monohydrate form. However, in some cases, solvates may have elevated solubility as compared to the anhydrous form that reduces the affinity of the drug towards water which in turn reduces the solubility and dissolution. Thus, hydrates are less soluble than the amorphous forms. For example, the anhydrous form ampicillin is more soluble than the trihydrate form of ampicillin (Lee, 2014; Santos et al., 2014). As the formation of hydrates affects the solubility and stability of the product at different conditions, a careful and cautious choice of the specific form of cocrystals is essential to maintain the quality of a pharmaceutical product within particular standards. 21.4.2 Differences in Manufacturing Processes The competition and market pressures among the fast-growing industries for improved quality and better therapeutic effect have resulted in improved measurement and maintenance of product development record and different process involved throughout the product life cycle (Shahbaz et al., 2006). The manufacturing industries have collected and retained huge amounts of comprehensive data which could be related to designs, manufacture, operation and scheduling, processes achievement, and performance, as well as the use of specific machinery and other related resources, such as their sales, inventory control, and finally marketing. The basic idea of production or manufacturing is to generate (or produce) something that has a functional and useful structure. This structure (or form) is most probably predetermined and calculated using physical geometry and chemical nature (Duardo et al., 2015). The manufacturing progress or process improvement program should recognize all the critical development parameters, and they should be considered, monitored, or controlled to guarantee the product that is being produced has all the desired qualities. Significant variations between the manufacturing processes used to produce batches for pivotal clinical trials (safety, efficacy, BA, bioequivalence (BE)) or primary stability studies should be summarized to explain the effect of the differences on the manufacturability, performance, and quality achievement of the product. These data so obtained, should be represented in a way which facilitates comparison of the processes and the corresponding DOSAGE FORM DESIGN CONSIDERATIONS 21.4 FACTORS AFFECTING DRUG PRODUCT PERFORMANCE 753 batch analyses information (Lawrence et al., 2014). The following information should be included: • • • • • the identity of the product, e.g., batch number; utility of the produced batches, e.g., BE study batch number; the product development and manufacturing site; the product batch size; and any significant and relevant equipment differences, e.g., different design, operating principle, size. The following manufacturing processes/phases are involved in the product development from start to finish of the product to maintain the quality of product (Kin et al., 2014). 21.4.2.1 Initial Planning Stage It is the first stages which depend on the specifications from the customer regarding the product plans and quality. These proposals estimate a rough cost which is calculated on the basis of the manufacturing method and overall schedule. Hence, it becomes necessary to consider the feasibility of manufacturing and its processes for the proposed product on a commercial scale. The initial planning stage of a product is helpful for proper designing that will help to ensure and meet the required cost, timeline, and quality targets. 21.4.2.2 Product Development Phase After establishing the feasibility of the project and its process, it becomes important to determine and explore the specifications of the drug product in more detail through working on the design and manufacture by selecting and obtaining the necessary processing data. This phase is helpful as it is important to maintain and achieve the specification planned in the earlier phase, i.e., initial planning stage. 21.4.2.3 Prototype Production/Evaluation The product plans and its quality specifications established from the customer through the use of product are used for the product manufacturing plans to determine the product development phase. It should follow the customer’s needs and specifications to establish the required quality standards. Its evaluation should be repeated during the process of product development, prototype production, and prototype until the prototype reaches the standard of quality required. Every batch’s products may have some defects, so manufacturers should concern the quality control department to reduce the defects to an acceptable point. Inspectors should have a regular inspection during this phase and quality product is allowed to be released for the next stage process. 21.4.2.4 Commercial Prototype Production Planning To build up a efficient manufacturing process line leading to the production of highquality products, a process should be adopted in such as a way that it supports the design of a core technique to fulfill the proposed pertinent manufacturing design and its layout. This phase is necessary and guarantees the commercial success of the high-quality DOSAGE FORM DESIGN CONSIDERATIONS 754 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY product. It will help to cultivate, maintain, and increase a company’s market contribution by fulfilling a consumer requirement. 21.4.2.5 Commercial Prototype Production/Evaluation Depending on the manufacturing design and proposed layout in the commercial prototype production planning stage, the manufacturing line is built, and produces a commercial prototype. 21.4.2.6 Commercial Production Commercial production will start only on completion of all the necessary preparation. But modifications and improvements can be performed for the manufacturing line, making and encouraging the staff to improve their work continually. So, it is the effort of whole team which is actively cooperating to develop high-quality products as efficiently as possible. When the efforts of all the teammates are put together, then it will help to achieve the high-quality products by considering and strictly following the finalized protocol. 21.4.2.7 Inspection, Shipment, and Delivery The final developed products are closely evaluated and inspected both manually and by machine to ensure that there are no shortcoming, flaws, or defects. The goods that are approved by the inspection processes are ready to be used. For this, they are packed carefully to prevent contamination or damage and finally released into the market to be utilized by the customer. The inspection and quality control before shipment and delivery is necessary due to the following advantages: ensures accuracy, reduces the costs, protects the company name and its reputation, ensures the delivery of the right products, receives fewer complaints from customers, gathers data to improve efficiency, establishes a superior relationship with market, allows a justification to elevate their prices by maintaining and ensuring high-quality control, and helps to reduce marketing costs over time. 21.4.3 Differences in Excipients, Excipient Selection, and Quality Control Pharmaceutical inactive ingredients, commonly called excipients, are crucial to a drug product’s quality and its efficacy; hence they play a key function in formulation development. The pharmaceutical industries are focused on fulfilling a patient’s therapeutic needs by understanding the key features of active ingredients and inactive excipients in formulation progress, and they are evaluated for safety (Alsante et al., 2014). Excipients help in the manufacturing, administration, or absorption of dose to achieve the therapeutic response. Excipients, pharmacologically inert, can initiate, propagate, or take part in physical or chemical interactions with drug compounds, which may affect the success and quality of a medication. Excipients can show incompatibility and interactions with APIs. Hence, their selection and the understanding of drug excipients interactions is to be considered critically as they can influence the effectiveness and safety of the active moiety depending upon the administration route, e.g., excipients in solid dosage form can influence effectiveness and safety by enhancing or delaying gastrointestinal release. DOSAGE FORM DESIGN CONSIDERATIONS 755 21.4 FACTORS AFFECTING DRUG PRODUCT PERFORMANCE TABLE 21.4 Overview of Pharmaceutical Excipients Category Examples Acidifying agent Phosphoric acid, malic acid, fumaric acid, citric acid, succinic acid Adsorbent Colloidal silicon dioxide, cellulose, microcrystalline cellulose (MCC), silica gel Alkalizing agent Potassium bicarbonate, sodium citrate dehydrate, ammonium carbonate Anionic surfactant Sodium lauryl sulfate (SLS) and other alkyl sulfates and alkyl ethoxylate sulfates Anticaking agent Talc, calcium silicate, starch, magnesium carbonate, colloidal silicon dioxide, cellulose, calcium phosphate di or tri basic Antifoaming agent Dimethicone, insoluble oils, certain alcohols, stearates, glycols Antimicrobial preservative Benzyl alcohol, butyl paraben, glycerin, methyl paraben, propylene glycol, propylene paraben, potassium sorbate, sodium benzoate, sorbic acid, sodium propionate Antioxidant Butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), sodium metabisulfite Antiseptic Aluminum acetate, benzethonium chloride, hydrogen peroxide, iodophors, chlorhexidine gluconate, iodine, ethyl alcohol Base for medicated confectionery Sucrose, glucose Binder Alginate, candelilla wax, carnaubawax, cornstarch, lactose hydrous or anhydrous or monohydrate or spray dried, potato starch, sodium starch Buffering agent Calcium phosphate di or tri-basic, disodium hydrogen phosphate, sodium citrate dehydrate Carbonating agent Sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate Cationic surfactant Cetylpyridine chloride, cetrimide, benzalkonium chloride Chelating agent/sequestering agent Ethylene diamine tetra acetic acid (EDTA), monoisoamyl dimercaptosuccinic acid (MiADMSA), dimercaptosuccinic acid (DMSA) Coating agent Ethyl cellulose, gelatin, glyceryl behenate, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose (HPMC), hypromellose, HPMC phthalate, methylcellulose, methacrylic acid copolymer, sodium carboxymethyl cellulose (Na-CMC), titanium dioxide Coloring agent Erythrosine sodium, iron oxides red or ferric oxide, iron oxide yellow Detergent SLS, tweens, spans Diluent for dry-powder inhalers Lactose hydrous or anhydrous or monohydrate or spray dried Disinfectant Benzyl alcohol, cetylpyridine chloride, propylene glycol Disintegrant Citric acid, MCC (Avicel), cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate (Continued) DOSAGE FORM DESIGN CONSIDERATIONS 756 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY TABLE 21.4 (Continued) Category Examples Dispersing agent Poloxamer 407 or 188 or plain, soap powder, turkey red oil, alkali sulfates, alkyl aryl sulfonates Emollient Dimethicone, glycerin, glyceryl monostearate, mineral oil Emulsifying agent Acacia, glyceryl monostearate, hydroxypropyl cellulose, methylcellulose, poloxamer 407 or 188 or plain, polyoxy140 stearate, SLS, stearic acid, sodium citrate dehydrate, colloidal silicon dioxide Film-former Copolyvidone, gelatin, HPMC, hypromellose Flavoring fixative Ethyl cellulose, gum arabic, monosodium glutamate (MSG) Gelling agent Gelatin, polyacrylamides, sodium alginate, magnesium aluminum silicate (veegum), poloxamers (pluronics), carbopols (carbomers), bentonite Glidant Colloidal silicon dioxide, cellulose, starch pregelatinized, starch, talc Granulating agent Copolyvidone, base for medicated confectionery Humectants Glycerin, propylene glycol, triacetin Lubricant Hydrogenated vegetable oil, mineral oil, polyethylene glycol (PEG), stearic acid, magnesium stearate, SLS Lyophilization aid Lactose hydrous or anhydrous or monohydrate or spray dried Mucoadhesive Polyethylene oxide, Acacia, chitosan, tragacanth Nonionic surfactant Glyceryl monooleate, tweens, spans Nutrient and dietary supplementary Calcium phosphate di or tribasic, minerals, fiber, fatty acids, or amino acids Ointment base PEG, white petrolatum, anhydrous lanolin, hydrophilic petrolatum Oleaginous vehicle Mineral oil, cocoa butter, white petrolatum Opacifier Titanium dioxide, ethylene glycol mono- and distearates, Cetyl alcohol, stearyl alcohol Plasticizer Glycerin, propylene glycol, triacetin, triethyl citrate, PEG Rate-controlling polymer for sustained release HPMC, hypromellose Reducing agent Cysteine HCl, copper hydride, ascorbic acid, alcohol dehydrogenase Skin penetrant SLS, dimethyl sulfoxide (DMSO) Solubilizing agent Cetylpyridine chloride, glyceryl monostearate, polysorbate 80, poloxamer 407 or 188 or plain, polyoxy140 stearate, stearic acid, sorbitan monooleate Solvent Benzyl alcohol, glycerin, mineral oil, PEG, propylene glycol, triacetin Stabilizer for vitamins Propylene glycol, disodium edetate, cysteine, thiourea, nicotinic acid Stabilizing agent Acacia, alginate, CMC, glyceryl monostearate, hydroxy propyl cellulose (HPC), HPMC, hypromellose, sodium alginate, Na-CMC (Continued) DOSAGE FORM DESIGN CONSIDERATIONS 21.4 FACTORS AFFECTING DRUG PRODUCT PERFORMANCE TABLE 21.4 757 (Continued) Category Examples Suppository base PEG, cocoa butter (Theobroma oil) Suspending agent Acacia, alginate, colloidal silicon dioxide, cellulose, CMC, gelatin, HPC, HPMC, hypromellose, MCC, methyl cellulose, polyvinylpyrrolidone (PVP), sucrose, sodium alginate, Na-CMC Sustained-release ingredient Glyceryl monostearate, carbopol, polyvinyl acetate (PVA), poly (ε-caprolactone) (PCL), poly (lactic-co-glycolic acid) (PLGA), poly (lactide acid) (PLA) Sweetening agent Confectioner sugar, glycerin, mannitol, sucrose, saccharin sodium Tablet and capsule diluents Calcium carbonate, confectioner sugar, cellulose, plain or anhydrous calcium phosphate, calcium hydrogen phosphate dehydrate, calcium phosphate di or tri basic, dibasic calcium phosphate, lactose hydrous or anhydrous or monohydrate or spray dried, MCC, mannitol, magnesium carbonate, magnesium oxide, sodium starch glycolate (SSG), starch pregelatinized, starch, sucrose, sodium chloride, talc Tablet and capsule disintegrant Croscarmellose sodium, CMC, MCC, methyl cellulose, PVP, SSG, starch pregelatinized, starch, sodium alginate, Na-CMC Tablet and capsule lubricant Calcium stearate, castor oil hydrogenated, glyceryl monostearate, glyceryl behenate, magnesium stearate, PEG, poloxamer 407 or 188 or plain, SLS, sodium benzoate, stearic acid, sodium stearyl fumarate, talc Tablet binder Acacia, alginic acid, copolyvidone, ethyl cellulose, gelatin, glyceryl behenate, HPC, HPMC, hypromellose, lactose hydrous or anhydrous or monohydrate or spray dried, methylcellulose, PVP, polyethylene oxide, starch pregelatinized (starch, potato, corn, wheat, rice), sodium alginate, Na-CMC Tablet disintegrant Alginic acid, colloidal silicon dioxide, crospovidone, sodium croscarmellose Tablet filler Sucrose, HPC, ethyl cellulose, sorbitol, starches, xylitol, lactose Therapeutic agent Calcium carbonate, sodium carbonate, magnesium hydroxide, aluminum hydroxide Thickening agent HPC, polyethylene oxide, Acacia, tragacanth, carbopol Tonicity agent Glycerin, glycine, mannitol, sodium chloride Vehicle (bulking agent) for lyophilized preparations Sucrose mannitol, dextran, sodium gluconate, lactose Viscosity-increasing agent Acacia, alginic acid, colloidal silicon dioxide, CMC, ethyl cellulose, gelatin, HPC, HPMC, hypromellose, methyl cellulose, sucrose, sodium alginate, Na-CMC Water-absorbing agent CMC, Na-CMC Water-miscible cosolvent Propylene glycol, alcohol, acetic acid, formic acid, pyridine, 1,4-dioxane Wetting agents Cetylpyridine chloride, poloxamer 407 or 188 or plain, polyoxy140 stearate, SLS DOSAGE FORM DESIGN CONSIDERATIONS 758 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY An excipient is the substance additionally used in the manufacturing process apart from the active drug(s) or prodrug present in a finished pharmaceutical dosage form and is purposely incorporated in a drug delivery system. Commercially, they are being used for increasing the bulkiness, lubrication, flowability, compressibility, and compatibility that can provide the specific and desired properties to the finishing product, such as modifying drug release, controlling the drug release process in the case where quick assimilation could lead to gastric exasperation or stomach distress. They are categorized as binders, disintegrants, diluents, glidants, lubricants, emulsifying solubilizing agents, coating agents, sweetening agents, antimicrobial preservatives, etc. (Table 21.4). They have been categorized into two categories (1) compendial excipients (2) noncompendial excipients. The composition consistency of compendial excipients are detailed in monographs such as the United States Pharmacopeia (USP), National Formulary (NF), Indian Pharmacopoeia (IP), British Pharmacopoeia (BP), etc. Hence, they are the better-characterized excipients and possess the required qualities. They are preferred over the noncompendial excipients for pharmaceutical formulations, although noncompendial excipients can also be used in pharmaceutical formulations (Chang et al., 2013). These excipients should be selected so as to provide compatible and toxicity-free excipients which can be linked to various unit processes in product development. The functional and performance characteristics of an excipient significantly depend on its quality in the development and manufacturing. The performance of any dosage form is based on the physical and chemical properties of the excipient used. To achieve the required specification, it becomes necessary to select the specific tests and specifications to ensure the performance of excipient, which can be achieved by a complete understanding of the physical and chemical properties of each excipient in the final drug product (Lawrence et al., 2014). Hence, both pharmaceutical users and excipient suppliers should identify and control excipient critical material attributes for the proposed drug application use. Factors such as the concentration, the type, and characteristics of excipients that can affect the performance of the drug product (such as stability, BA, etc.) or manufacturing should be consulted relative to the respective role of each excipient. The trace levels of impurities in some cases in the excipient could have high impact on product performance. For example, for a drug which is prone to oxidation, their oxidative product should be considered as they may significantly affect drug product stability and, subsequently, its purity/impurity profile could be affected (Kristensen, 2007; Wu et al., 2011). With the escalating globalization of the pharmaceutical industry, numerous challenges arise with the sourcing of excipients available from multiple manufacturers and suppliers. This could lead to variation in batch-to-batch, lot-to-lot, or supplier-to-supplier material that could create issues with performance in equivalence and efficacy. Manufacturing a quality pharmaceutical product requires well-defined excipients and processes that yield consistent results (Thacker et al., 2010; Van Buskirk et al., 2014). Some of the excipients are used to enhance the product taste and improve appearance along with the improvement in the patient compliance, especially in the case of children. Although technically “inactive” from a therapeutic point, they are critical and fundamental components which are providing the gear to the modern drug product development (Daniels et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 21.5 DRUG PRODUCT QUALITY AND DRUG PRODUCT PERFORMANCE 759 21.5 DRUG PRODUCT QUALITY AND DRUG PRODUCT PERFORMANCE Drug product quality includes the different analytical procedures and tests which will give the values in the acceptance criteria. These tests are responsible for confirmation of the quality of drug products, substances, any intermediate(s), raw material involved, containers, and any other material or components of the production process. Hence, they act as regular and predictable methods to measure the safety of the product development, thus helping the organization to surmount any science and technology issues. Product performance and attributes are significant factors that affect product quality (Thoorens et al., 2014). Quality must be maintained throughout the different development stages starting from the initial, i.e., research, until the final development. This is achieved by practicing procedures and systems that are followed during the development and manufacture of the drug product. These procedures and methods adopted for the purpose must be able to evaluate the effect of the physical and chemical properties of the drug, drug stability, and its production at a large-scale for the aforesaid biologic performance of the drug (Du et al., 2011). Drug product performance means how and in what quantity the drug is reaching systemic circulation is dependent upon the drug release from the drug product. Hence, its performance depends upon the BA which is related to pharmacodynamic effects whether favorable or unfavorable. Hence, drug product quality is of great concern for the clinical efficacy which is responsible for the drug product performance. BA, the amount of active drug available in the systemic circulation, is an important feature of drug product quality and is affected by the different factors (Savjani et al., 2012; Kollipara and Gandhi, 2014). It provides the information of in vivo performance of a new drug product. This will help to setup the safety of the product and can be used in clinical safety and efficacy studies. Another study for the drug product performance includes the BE studies which compare the BA of the drug in one product with the other drug products. Thus, for the in vivo performance, BA and BE are considered to be very important (Zaman et al., 2016). Quality assurance and quality control (QA/QC) are responsible for all aspects related to product QA/QC and the completion of necessary documentation to verify the work performed and its authenticity. The results so produced will be able to judge whether to approve or reject the different parameters used in the product development, such as chemicals, process or process variables, packaging material, and labeling. Hence, it is involved in ensuring that all test reports are verified to meet the contract requirements, and all the documentation has been compiled in a final presentable manner, in harmony with the conditions of the contract. QA/QC department is accountable for approving or disapproving drug product, processing, and packaging for the product which are held under contract by the company. The pharmacodynamic, pharmacokinetic, and in-vitro in-vivo correlation (IVIVC) models are used to study the effect of manufacturing differences and variability on clinical performance/efficacy of a developed dosage system (Munoz, 2013; Kaur et al., 2015). DOSAGE FORM DESIGN CONSIDERATIONS 760 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY 21.6 SCALE-UP AND POSTAPPROVAL CHANGES SUPAC is the method of developing the new product and scaling up the batch size of the developed and manufactured goods. It includes the changes and scale-up in the composition, manufacturing process, batch size, manufacturing apparatus and equipment, and change of manufacturing location. The FDA has published various guidelines for SUPAC. They are designated as (1) Supac-IR (for immediate drug release solid oral dosage form; (2) Supac-MR (for modified drug release solid oral dosage form); and (3) SUPAC-SS (for nonsterile semisolid dosage form including lotions, creams, ointments, and gel) (FDA, 2014). These guidelines provide recommendations for postapproval changes in component or composition, location of manufacturing, scale-up of manufacture, and the manufacturing variables. It includes the process and equipment (from nonautomated to automated or vice versa moving of ingredients, or use of some alternative and optional equipment of same design and operating on same principle with similar or dissimilar capacity) (FDA, 1997). While following the FDA guidelines, the focus must be on modification in the number of excipients in the formulation without changing the amount of the drug material (Van Buskirk et al., 2014). The FDA is playing a greater effort to check their feasibility and approaches to be concurrent with the modern manufacturing practices. 21.6.1 FDA Level of Changes The FDA has recommended several steps that will lessen the regulatory burden related to the retaining of approved status of existing drug products when they undergo changes in their content and/or their manufacture. The FDA does this by making the companies and organization follow the SUPAC guidelines (Khetani and Bhatia, 2008; Anand et al., 2011). For that they have used the certain levels which are as follows: Level 1: Includes the changes which can have any detectable effect on formulation quality, value, and performance. It includes the examples such as changes in the flavors, color, excipients which are expressed as the percentage (w/w) of entire formulation. The changes should also be reported in the final annual statement and report. It includes the requirements related to the documentation application and/or compendial release requirements, announcement of changes and submission of updated batch records in annual report, report of one batch kept for long-term stability in yearly report, no dissolution or in vivo testing, and filing documentation with yearly report (long-term stability commitment). Level 2: Includes the changes which could have considerable effects on the formulation quality and performance. It includes changes in the different technical grade of excipient (such as Avicel PH-102 and Avicel PH-200), changes expressed in terms of percent (w/w of total formulation). The requirements of level 2 includes stability testing, such as one batch with 3 months accelerated stability data and one batch on long-term stability and dissolution documentation maintenance, such as case B testing, filing documentation with earlier approved supplement and its annual report. Level 3: Includes the changes which have significant effects on formulation quality, value, and performance. It includes qualitative or quantitative chemical excipient DOSAGE FORM DESIGN CONSIDERATIONS 21.6 SCALE-UP AND POSTAPPROVAL CHANGES 761 changes to a narrow therapeutic drug beyond the range for level 1. All other drugs which are not meeting the dissolution criteria are considered as level 2. Changes in the process or formulation may require costly clinical and bioclinical studies to establish safety and efficacy and an earlier approval declaration from the FDA, which provides the information that the changes made by you have been accepted. This process can take about 6 or more months; hence it may lead to delay in process validation of stability studies and delay in time for the commercial launch of the product. 21.6.2 Assessment of the Effects of the Changes One of the major challenges to the pharmaceutical industries is constantly varying requirements and changes in the initial stage of product development cycle due to the unavailability of proper and adequate information. Numerous tools, process, and methods address how changes affect additional and essential product components (Stark, 2015). Thus, they may result in changes of the development cost and time. Hence, additional effort should be performed, and estimation of its impact on development must be correlated. ICH Guideline Q5 provides principles to compare and correlate biological/biotechnological products before and after changes performed in the development and manufacturing process for the drug product or drug substance (Guideline, 2013). 21.6.3 Critical Manufacturing Variables Critical manufacturing variables are the key variables in the pharmaceutical manufacturing affecting the production progression and related to the quality of the product development. These are the attributes to be monitored to spot deflections in standardized and uniform production operations and product output worth or variations in CQAs. These FIGURE 21.6 Linking Patient to Product to Process. DOSAGE FORM DESIGN CONSIDERATIONS 762 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY variables affect a quality of the product. Hence, they should be controlled or monitored to guarantee the process to produce the desired quality. For example, in pharmaceutical tablet manufacturing processes, the most important and major source of trouble is the (lot-to-lot) variability and inconsistency of the incoming raw materials which affect the drug product quality (Mitchell, 2014). To overcome and minimize the undesired effect, novel modeling, and process optimization policies are designed and opted to compensate raw material variability and their proper utilization. The effectiveness of the methodologies could be successfully achieved by obtaining interrelationships among the three sources of variability, i.e., attributes, parameters, materials, as defined by the ICH-Q8 guideline. CPPs are the process parameters whose variability has an impact on a CQAs and therefore should be monitored or controlled to ensure the process produces the desired quality (FDA, 2006; Short et al., 2011) (Fig. 21.6). The different process variables which could affect the product quality and its efficacy for the proper disease management include particle size distribution, loading level, blending, type and geometry of mixer, number of revolutions including time and speed, order of addition, holding time, etc. 21.6.4 Bulk Active Postapproval Changes The FDA has issued a Guideline for Industry entitled “BACPAC I: Intermediates in Drug Substance Synthesis” in 2001 that offers clarification as well as regulatory relief for late-stage active pharmaceutical ingredient (API) postapproval changes. Bulk active postapproval changes (BACPAC) I covers all processes and the different steps involved along with the intermediates. BACPAC helps in successful reviewing of the postapproval arena of SUPAC which helps in covering the documents for the complete scope of API used in the processes (Nusim, 2016). Supporting and assisting data should be incorporated in the regulatory submissions. Manufacturing changes of the API may result in the change in its quality attributes. These quality attributes include solid-state properties, chemical purity, and residual solvents. They provide the guidance for the development of bulk active product manufacturing and its synthesis along with the API and their benefits for the design and development of new drug product (Van Buskirk et al., 2014). The difference in the solid-state properties of the API may alter and affect the manufacture of the dosage form or/and product performance. One of such factors includes change in particle size resulting in the difference and altering the API bulk density or/and tablet hardness, whereas API solubility and stability may be affected by different polymorphs of the API used. Changes in particle size and polymorph may affect the drug’s BA in vivo. Moreover, the pharmacologic properties of the excipient(s) and vehicle used may influence product quality and performance rate (Nusim, 2016). After the issues of BACPAC I, FDA has released the BACPAC II for controlling and observation of the post changes. FDA also warned that BACPAC II would not achieve regulatory relief. So BACPAC II was subsequently withdrawn and in 2006 BACPAC I DOSAGE FORM DESIGN CONSIDERATIONS 21.7 POSTMARKETING SURVEILLANCE 763 guidance was withdrawn officially. So, at present no postapproval guidance for APIs has been issued (Nusim, 2016). 21.7 POSTMARKETING SURVEILLANCE The consumption of the drugs in the today’s world is increasing at higher rates as compared to the 1950s and 1960s. According to the FDA, a new and novel drug should be “safe and efficacious for its intended use” when it is to be released in the market, providing positive benefit to harm balance, and showing its beneficial and positive effects. The randomized clinical trials by the regulatory authorities before drug approvals provide the information regarding the favorable effects which can overcome any potential (Furberg, 2011). It becomes necessary to monitor the approved drugs by collecting information regarding medication problems to maintain the quality of marketed pharmaceutical products. This monitoring of marketed product after the approval by the FDA is called postmarketing surveillance (PMS). It is an important part of product development that is necessary to observe the safety and assurance of a pharmaceutical drug or medical device (Waning et al., 2001). This will help in perceiving the negative or positive effects over an extended period and provide the evaluation and monitoring information of the ADRs. PMS requires special attention in case of pediatric pharmacovigilance as the disorders and diseases of childhood vary quantitatively and qualitatively. It starts immediately after the marketing of the product. In these cases, the safety of medicine and its monitoring is of paramount importance when the drug is under the clinical development. Different cases have been reported where the different medicines were withdrawn from the market because of ADRs and these are considered as postmarketing withdrawal (Onakpoya et al., 2016a, 2016b). Thus, it becomes significant to be very attentive for ADRs-related spontaneous problems and the ways to crack them. The attentive measures taken by the authorities thus have shortened the period between launch date and reports of ADRs in the past few decades. Different approaches used by PMS to monitor the safety of licensed drugs are (1) spontaneous reporting, (2) databases, (3) prescription even monitoring, (4) electronic health records, (5) patient registries, and (6) record linkage between health databases. The evidences such as observational studies, systematic reviews, anecdotal reports, animal data, or clinical trials provide the ADRs knowledge and thus speed up the postapproval withdrawal of medicinal products from the market. Thus, this removal of formerly approved products from the market can lead to the loss of trust in medicinal product by the public which ultimately leads to the loss of profit for drug manufacturers. Challenge - dechallenge- rechallenge (CDR) is a method which is providing the protocol for testing the medicinal products and kits for their ADRs at each stage. Challenge is the drug administration to the patient for the period of the treatment. The response observed for the reduction or removal of ADRs on withdrawal or removal of a drug from a patient is commonly known as dechallenge and is crucial for proper prescription. DOSAGE FORM DESIGN CONSIDERATIONS 764 21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY Dechallenge is the stopping of the drug, generally after an adverse incident or as the last part of a designed treatment. It may be a positive dechallenge (adverse event disappearing after the stopping of the drug) or a negative dechallenge (adverse event not disappearing after the stopping of the drug). Rechallenge is the restarting of the same drug after being stopped; generally for an adverse event it is necessary to authenticate the cause and link of ADRs. It may be a positive rechallenge (adverse event repeating after restarting the drug) or a negative rechallenge (the adverse event does not repeat after the drug is restarted) (Meyboom, 2013; Banu et al., 2014). There are many drugs which have been banned by the FDA in many countries due to their serious toxic effects. Nimesulide is a common example which has been banned in many countries like Japan, Spain, India, Israel, Finland, Turkey, and Sri Lanka as it is responsible for increased chances of hepatotoxicity. Hence, Nimesulide has not yet been approved by FDA (Ahmad et al., 2014). 21.8 CONCLUSION The quality of the production process influences the development of a drug product. The maintenance of the quality and safety of a product during the production process and postproduction process is the key consideration and will assist industry for a booming product development and to expedite regulatory approval. This chapter provides the information and understanding of the correlation between the drug product development and its efficacy for the formulated dosage form of active moiety. The topics discussed in this chapter help the formulators to move with the required demand of the market regarding its market value and availability in the product. The clinical efficacies should be achieved by applying the biopharmaceutics information for the design of the new product and are important to be considered during the product development process. It should be kept in consideration that for the high-quality product therapeutics, the objectives are to achieve maximum BA and to minimize adverse effects. Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant allocated to Dr. Tekade for research work on gene delivery and N-PDF funding (PDF/2016/003329) for work on targeted cancer therapy. RT would also like to thank NIPER-Ahmedabad for providing research support for research on cancer and diabetes. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There are no conflicts of interest and disclosures associated with the manuscript. ABBREVIATIONS ADRs API BA Adverse drug reactions Active pharmaceutical ingredient Bioavailability DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES BACPAC BE BHA BHT CDR cGMPs CpK CPPs CQAs DMSA DMSO EDTA FDA FMEA FMECA FTA HACCP HAZOP HPC HPMC ICH IVIVC MCC MiADMSA MSG Na-CMC PC PCL PEG PHA PLA PLGA PMS PVA PVP QA/QC QbD QTPP SLS SSG SUPAC 765 Bulk active postapproval changes Bioequivalence Butylated hydroxy anisole Butylated hydroxy toluene Challenge - dechallenge - rechallenge Current good manufacturing practices Process capability index Critical process parameters Critical quality attributes Dimercaptosuccinic acid Dimethyl sulfoxide Ethylene diamine tetraacetic acid US Food and Drug Administration Failure mode effects analysis Failure mode, effects, and criticality analysis Fault tree analysis Hazard analysis and critical control points Hazard operability analysis Hydroxypropyl cellulose Hydroxyl propyl methyl cellulose International Conference on Harmonization In-vitro in-vivo correlation Microcrystalline cellulose Monoisoamyl dimercaptosuccinic acid Monosodium glutamate Sodium carboxy methyl cellulose Partition coefficient Poly ε-caprolactone Polyethylene glycol Preliminary hazard analysis Poly (lactide acid) Polylactic-co-glycolic acid Postmarketing surveillance Polyvinyl acetate Polyvinylpyrrolidone Quality assurance and quality control Quality by design Quality target product profile Sodium lauryl sulfate Sodium starch glycolate Scale-up and postapproval changes References Abdul-Ghani, M., Migahid, O., Megahed, A., Adams, J., Triplitt, C., DeFronzo, R.A., et al., 2017. 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Springer Berlin Heidelberg, pp. 339 351. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank C H A P T E R 22 Formulation Additives Used in Pharmaceutical Products: Emphasis on Regulatory Perspectives and GRAS Satish Manchanda1, Akhilesh Chandra1, Shantanu Bandopadhyay2, Pran Kishore Deb3 and Rakesh K. Tekade4 1 Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research (DIPSAR), New Delhi, India 2Department of Pharmacy, Saroj Institute of Technology & Management, Lucknow, Uttar Pradesh, India 3Faculty of Pharmacy, Philadelphia University, Amman, Jordan 4National Institute of Pharmaceutical Education and Research (NIPER)Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 22.1 Introduction: Background of Additives 775 22.2 Role of Additives in Pharmaceutical Formulation 776 22.3 Classification and Sources of Formulation Additives 22.3.1 Additives Based on Their Origin 22.3.2 Classification of Additives Based on Their Functions Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00022-8 777 778 778 773 22.3.3 Classification of Additives Based on Their Therapeutic Values 778 22.4 Processing of Additives as per Good Manufacturing Practice 779 22.4.1 Processing 779 22.4.2 Production Records 780 22.4.3 Training of Employees 780 22.4.4 Control of Raw Materials 780 22.4.5 Preventing Contamination 781 22.4.6 Qualification of Manufacturing Equipment 781 © 2018 Elsevier Inc. All rights reserved. 774 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS 22.4.7 Process Validation 22.4.8 Cleaning Validation 22.4.9 Process Monitoring and Control 22.4.10 Sampling and Testing 22.4.11 Packaging and Labeling 22.4.12 Quality Release 22.4.13 Storage 22.5 Additives Interaction in Pharmaceutical Products 782 782 783 783 784 784 785 785 22.6 Formulation Additives for Designing of Solid Dosage Forms 786 22.6.1 Additives in Spray-Dried Powders 788 22.6.2 Additives in Controlled Release Solid Dosage Forms 789 22.11.2 Regulatory Perspectives: GRAS, IIG 799 22.12 WHO Perspectives 22.12.1 Documentation 802 803 22.13 Study of Different Types of Additives 22.13.1 Antioxidant 22.13.2 Preservatives 22.13.3 Colors 22.13.4 Flavoring Agents 22.13.5 Emulsifying Agent 22.13.6 Suspending Agent 805 805 808 809 809 810 811 22.14 Functional and Coprocessed Additives 812 22.14.1 Approaches for Development of Coprocessed Additives 813 22.14.2 Properties and Advantages of the Coprocessed Additives 814 22.7 Formulation Additives for Designing of Semisolid Dosage Forms 789 22.8 Formulation Additives for Designing of Liquid Dosage Forms 791 22.15 Classification of Pharmaceutical Diluents 815 22.15.1 Organic Diluents 815 22.15.2 Inorganic Diluents 816 22.15.3 Coprocessed Diluents 816 792 22.16 Pharmaceutical Solvents 22.16.1 Inorganic Solvents 22.16.2 Organic Solvent 22.9 Current Guidelines for Pharmaceutical Additives (FDA, EU, Japan) 22.10 Regulatory Aspects of Additives Approval 22.10.1 Current Regulatory Status of New Additives 22.10.2 The IPEC Procedure 22.10.3 Additive Master Files and Other Filings 22.10.4 Recommended Strategies to Support Marketing of New Additives in Drug Products 22.11 Regulatory Perspectives of Formulation Additives 22.11.1 IPEC Perspectives 796 796 796 796 797 798 799 816 818 819 22.17 Evaluation and Quality Testing of Pharmaceutical Additives 820 22.17.1 Additive Specifications 820 22.17.2 Additive Stability 821 22.17.3 Receipt, Sampling, Testing, and Approval of Raw Materials 821 22.17.4 Packaging and Labeling Control 822 22.17.5 Analytical Procedures 822 22.18 Current Developments in Additive Science 823 22.19 International Patented Additives 824 DOSAGE FORM DESIGN CONSIDERATIONS 22.1 INTRODUCTION: BACKGROUND OF ADDITIVES 22.19.1 Sustained Release Excipient and Tablet Formulation (US5128143 A) 22.19.2 Cross-Linked Cellulose as Some Tablet Excipients (US5989589 A) 22.19.3 Low-Melting Moldable Pharmaceutical Excipient and Dosage Forms Prepared Therewith (US5004601 A) 22.19.4 Pharmaceutical Excipient Having Improved Compressibility (US5585115 A) 22.19.5 Trehalose as Stabilizer and Tableting Excipients (US4762857 A) 22.19.6 Coprocessed Tablet Excipient Composition Its Preparation and Use (US20130177649 A1) 824 824 825 825 825 826 775 22.19.7 Chemical Additives to Make Polymeric Materials Biodegradable (US8513329 B2) 826 22.19.8 Coprocessed Microcrystalline Cellulose and Sugar Alcohol as an Excipient for Tablet Formulations (US 8932629 B2) 826 22.20 FDA GRAS Additives 22.20.1 Substances That Are Generally Recognized as Safe 22.20.2 Examples of GRAS Additives 826 22.21 Conclusion 828 Abbreviations 828 References 829 Further Reading 831 827 827 22.1 INTRODUCTION: BACKGROUND OF ADDITIVES Drugs are always administered in the form of a dosage form that consists of two basic parts: the active pharmaceutical ingredient (API) and different fraction and changeable figure of the additive. Additives are pharmacologically inactive supplies from a different genesis (biological, minerals, chemical, or synthesis-based, etc.). Most pharmaceutical dosage forms could not be finished without the use of additives. The quantity of additives in the formulation can be superior to API and depending on whether they are organic or inorganic molecules may be of different character, up to highly complex materials. Initially, the safety of additives was ignored and no distinct safety evaluation was usually performed because they were deemed as inactive. But they are not dormant; they have considerable impact on the drug substance safety and effectiveness (bioavailability and stability) and also on a dosage form. Several exemplars have demonstrated that partial understanding of additives functionality can directly affect process control and final product eminence. Some additives are inert in nature but some can form toxic reactions in the concentrations used in dosage form. The Federal Food, Drug, and Cosmetic Act of 1938 (the Act) was sanctioned after the disaster of sulfanilamide in 1937 in which an additive which was not tested for effectiveness was accountable for the casualty of several children who taken the formulation (U.S. Department of Health and Human Services, Administration, 2005). Earlier it was DOSAGE FORM DESIGN CONSIDERATIONS 776 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS considered that additives, or their impurities, can be linked with unfavorable events, either by direct action or by creation of undesirable adducts. However this fact has been distorted over times and at present it is accepted that the added substances’ lethality is not immaterial and should not be disregarded, because it could directly interact with the pharmaceutical ingredient, with the body or with other additives, which may lead to a potential change in the connection between toxicity and effectiveness (Tekade et al., 2018). The hazard and advantage of using additives should always be assessed on the basis of not merely their manufacturing and quality but also of their safety and toxicity. Good Manufacturing Practices (GMPs), Toxicology Assessment, Good Laboratory Practices, and Good Distribution Practices requirements are needed for additives also like API or dosage form those pretense exceptional challenges in terms of attaining pharmaceutical grade material and in regulatory control. As added substances are an indispensable piece of every single pharmaceutical plan it is significant for the pharmaceutical researcher to perceive the distinctive sorts/evaluations of added substances that are accessible. It is further fundamental to perceive whether new added substances will be necessary (understanding the cost, accessibility, and biopharmaceuticals) inside the definition and how these new added substances can get administrative approval. There are about 8000 nondynamic fixings being utilized as a part of food, makeup, and pharmaceuticals (de Jong, 1999). Added substances makers, for the most part, supply their material to various end clients, i.e., pharmaceuticals, nourishment, corrective, and so forth. Henceforth, providers of added substances don’t really know the last utilization of their items, i.e., it is regularly troublesome helping end clients select fitting evaluations and grades are frequently not between variable. However, added substances for pharmaceutical use may require additional quality, usefulness, and safety requirements. There are no controls in most developed countries that address the enrollment of added substances as a different element. Presently, the Food and Drug Administration (FDA) investigates and facilitates the utilization of additives under same process as that of New Drug Application (NDA) process. Drug master file (DMF) for an additive is checked on just as a component of the NDA procedure. The FDA obviously supports the utilization of financially settled additives, nourishment added substances, and substances that have been assigned “Generally Recognized As Safe (GRAS).” The current regulatory methodology does not give a prepared procedure for picking up endorsement of new additives that are not as of now allowed in approved drugs (Steinberg et al., 1996). Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act) state that any substance that is deliberately added to food as a food additive, is obligated to premarket evaluation and guaranteeing by FDA unless the substance is recognized, as having been acceptably appeared to be safe under the circumstance of its planned use, or unless the use of the substance is generally excepted from the meaning of a food additive (Generally Recognized as Safe (GRAS) FDA, 2016). 22.2 ROLE OF ADDITIVES IN PHARMACEUTICAL FORMULATION Pharmaceutical additives are secondary constituents present in both pharmaceutical formulation and over-the-counter (OTC) drug formulations. Additives are classified on the DOSAGE FORM DESIGN CONSIDERATIONS 22.3 CLASSIFICATION AND SOURCES OF FORMULATION ADDITIVES 777 bases of their function and interactions influencing drug administration due to their chemical and physicochemical properties. The major classes are the coating additives, emulgents, taste and smell-improvers, ointment bases, antioxidants, consistency or viscosity enhancers, and disintegrating materials. Few additives have more than one function, e.g., methylcellulose works as both coating material, viscosity enhancer, disintegrating agent, or binder in tablets (Kalász and Antal, 2006). Additives carry out a key function in drug development operation in the formulation of stable dosage forms and in their administration. Their work is to take delivery of the dosage form with ease, to escalate the stability of active ingredients, to be used as filler so that it can properly fill a dosage form, or to serve as preservatives for enhancing the shelf life of the product or API A direct selection of additive can even lead to harsh intoxications, as experienced by epileptic patients in Australia in the late 1960s who were using phenytoin capsules. The calcium sulfate that served as a diluent in the capsule had been substituted with lactose and this substitution was believed to be harmless. However, lactose aggravated an abrupt and massive release of phenytoin higher than the toxic threshold (Furrer, 2013). Additive’s functional roles in dosage form and on drug substance consist of: • Influence on solubility and bioavailability of the active ingredient(s). • Improving stability of the API in finished products and also inside the subject after administration. • Preserve physiochemical property of drug substance. • Work as preservatives, lubricant, adhesives, propellants, glidants, flavors, colors, disintegrant, diluents and bulking agents, fragrances, coating agents, sweetening agents, polishing agents etc. • Protecting physical and chemical entity of dosage form. • Amending predetermined physiological or immunogenic response toward API. • Maintenance of the formulation for long period: Additives are incorporated in formulations which aid in the stability or enhance the time of the product in its original form for its shelf life period. • To form bulk of content if API does not have required concentration for making a dosage. • Get better patient acceptance. • Helps in improving bioavailability of active constituents: In most of the cases, an API for, e.g., aspirin is poorly absorbed or soluble in body fluid easily. In these instances, additives are incorporated which support the absorption of the drug from the external environment to inside the body. • Increase the safety and stability throughout the product shelf life. 22.3 CLASSIFICATION AND SOURCES OF FORMULATION ADDITIVES The natural world has offered us an extensive assortment of substances to aid, improve, and maintain the health of patients. It can be direct or indirect. Mucilage and gums are naturally obtained for both new and old dosage forms. Natural substance have advantages over synthetic because of their chemically stability, nontoxicity, low price, DOSAGE FORM DESIGN CONSIDERATIONS 778 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS TABLE 22.1 Additives Classification on the Basis of Their Origin Animal Origin • • • • • • Vegetable Origin Stearic acid Honey Lactose Gelatin Musk Lanolin, etc. • • • • • Turmeric Guar gum Acacia Starch Peppermint, etc. Mineral Origin • • • • • • Synthetic Talc Asbestos Kaolin Calcium phosphate Silica Paraffin, etc. • • • • • • • Polyethylene glycols Boric acid Saccharin Polyethylene glycols Polysorbates Boric acid Saccharin, etc. TABLE 22.2 Additives Classification on the Basis of Their Therapeutic Value Anesthetics Laxatives • Chloroform, etc. • • • • pH Modifiers Bentonite • Citric acid Psyllium Xanthan gum Guar-gum, etc. Astringent Carminative Nutrient Sources • Cinnamon • Cinnamon water • Agar • Alum • Dill water • Lactose, etc. • Zinc sulfate • Anise water biodegradability, and they are commonly obtainable (Ramesh Kumar and Mohan, 2014). Categorization of additives can be done based on their source or the function they perform as: 22.3.1 Additives Based on Their Origin Table 22.1 show different additives classified on the basis of their origin. 22.3.2 Classification of Additives Based on Their Functions 1. Additives for solid dosage forms: disintegrating agent, binders, plasticizers, etc., e.g., 5% starch paste acts as a binder in solid formulations, in dry form it works as disintegrant. 2. Additives for liquid dosage forms: solvents, antimicrobial agents, emulsifying agents, cosolvents, flavor, buffers, sweetening agents etc. 3. Additives for semisolid dosage form: gelling agent, preservative, emollients, suppository bases, solubilizing agents, etc. 22.3.3 Classification of Additives Based on Their Therapeutic Values Table 22.2 shows different additives classified on the basis of their therapeutic value (Chaudhari and Patil, 2012). DOSAGE FORM DESIGN CONSIDERATIONS 22.4 PROCESSING OF ADDITIVES AS PER GOOD MANUFACTURING PRACTICE 779 22.4 PROCESSING OF ADDITIVES AS PER GOOD MANUFACTURING PRACTICE GMP is that piece of value certification which guarantees that things are always conveyed and controlled to the quality standards apropos to their normal use. GMP is aimed chiefly to protect pharmaceutical production and human health from hazards, e.g., cross contamination and mix-ups of material due to false labeling. Under recent GMP rules and regulations, it is the pharmaceutical manufacturer who is accountable for the whole operations including the quality of material: API, the active, the additives, and the packaging materials ( Ptael and Chotal, 2010). Various regulatory agencies provide GMP guidelines for APIs. Unlike APIs, additives receive the slightest oversight from regulatory authorities. WHO published GMP Guidelines exclusively for additive manufacturers in 1999 and as a consequence of which the industry has to follow the guidelines which were not there in the past (Silverstein, 2002). UK based Pharmaceutical Quality Group (PQG) built “PS 9100:2002 Pharmaceutical Excipients” which includes both a GMP guide and an audit standard based on ISO 9001:2000 for additive regulatory and safety. In 2006, the International Pharmaceutical Excipient Council (IPEC) of Europe and America mutually published “Good Manufacturing Practices Guide for Pharmaceutical Excipients” (IPEC, 2006). U.S. Pharmacopeia 31-NF 26 also cited a distinct chapter for GMP for Bulk Pharmaceutical Excipients (Ptael and Chotal, 2010). The regulatory process for additives was subject to enhancement in Europe by the introduction of new pharmaceutical laws in 2005. According to which the manufacturer has to go through GMP requirements for approval of new or novel material. Directive 2004/27/EC implements the follow-up of GMP for “certain additives” including: • Additives from a Transmissible Spongiform Encephalopathy relevant animal species, with the exception of lactose. • Additives resourced from animal or human which have contamination risk. • Sterile additives. • Additives without pyrogen and endotoxin. • Specific additives like propylene glycol and glycerol. Implementation of Additive GMPs to the manufacturing process initiated with an assurance concerning when full added substance GMP requirement must be connected. This starts with the review of the process involved. Working back from the packaging of finished additive, the manufacturer must decide at which step the final molecule is formed or where the last purification occurs. For polymeric additives, full GMPs are connected at the polymerization step on the grounds that after the polymer is formed there is no decontamination or reformulation technique to make it useful for work (Katdare, 2006). 22.4.1 Processing An operation methodology normally can be categorized as one of two general categories: first is batch process, second one is continuous processing. There ought to be clear DOSAGE FORM DESIGN CONSIDERATIONS 780 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS and complete manufacturing guidance for the laborers to follow. There ought to be record generation which gives assurance that the work is done under guidelines. Added substance creation premises ought to be kept in a decent condition of repair and with incredible housekeeping in order to display a respectable appearance to administrative inspector, e.g., no peeling paint, loose insulation, rust, and so on. Premises should be inaccessible for insects and flies. Apparatus and equipment should be appropriately stored and cleaned on a regular basis. Pharmaceutical additives must be operated under appropriate instructions, equipment, base materials, quality test procedures, and records. Records and documents should be well maintained for the inspecting team whether all the instructions of GMP were followed or not. 22.4.2 Production Records All records related to production are official reports. Each batch or product is mentioned with its barcode for ease of access with records of the date and time the testing was done. Individual pages of the records ought to contain numbering alongside the aggregate page number in the document. Blank production records should be issued to the production unit only as needed to control the number of copies, which will ease migration to a newer version when the production record is updated. Records ought to be archived with the finish of each progression. Records ought to never be closed until the errand has been executed nor should assignments be finished with the sections still to be completed. All notations expected on the production record must be either finished or the record should indicate why no entry was necessary. Finished generation records ought to be checked by a senior person to affirm that the record is done with no unfilled spaces and those reasonable entries have been added with a signature and date of checking. 22.4.3 Training of Employees Workers ought to be capable of the employment they execute with training for their work and function. For work preparation, the coach should finish an agenda affirming that important training has been given to employees. At regular intervals, the trainer should convey the rules of GMP that are applicable to their process. Finally, they ought to be educated that it is important to inform their manager of any sickness, particularly open sores, that they have, which may contaminate the added substance and effect directly or indirectly the execution of its function. 22.4.4 Control of Raw Materials Raw materials quality and processing should be done in a GMP consistent way. Crude materials ought to be acquired just from providers acknowledged by the Quality Unit. For raw commodities whose feature is vital to conformance of the added substance to compendia or particular necessities, or to execution desires, the provider endorsement methodology ought to be an amalgamation of a visit to the site and an appraisal of quality of the crude material. For other crude materials, it should be of prediscussed specification and DOSAGE FORM DESIGN CONSIDERATIONS 22.4 PROCESSING OF ADDITIVES AS PER GOOD MANUFACTURING PRACTICE 781 quality. GMP implementation and quality testing prevent the product from adulteration and significant substances causing impurities that might be there in the crude material. Labeling of raw material should be adequate to prevent the mix up of materials in processing. Each part of a crude material ought to be inspected and the research facility should do no less than a personal investigation notwithstanding confirmation from the providing Certificate of Analysis (COA) to verify the added additives from any supplier. Consumable water is imperative wherever water makes contact with the materials amid handling, specifically the completed added substance atom. It is desirable to acquire consumable water from a municipal corporation, which can give a certificate for the water regarding the Environmental Protection Agency (EPA) requirement for consumable drinking water. 22.4.5 Preventing Contamination During the production of pharmaceutical additives contamination must be prevented, starting with the packaging of crude materials of the additive through to the final container. In general, problems emerge for two reasons: introduction of the additives to the outside environment during production and defects in the machine. For the most part amid the synthesis of additives, the danger of environmental contamination just arises during the charging of crude materials, additives, or preparing aids, or whilst filling the final container. So special care and measures should be adopted to prevent contamination of the additive at all phases of production caused by environmental factors. Sources of contamination arise from dust or other chemical processing, nearby fields, flying insects, and processing fumes. Mainly environmental contamination occurs in the packaging room so the packaging process should be done under a enclosed air-filtered room. The enclosed packaging room must be built of washable walls, floor, and ceiling. It is recommended that rooms have an air filtering system in which air is passing through a 2 mm filter operating at 95% efficiency with about 20 air changes per hour and there must be an uncontaminated indefinite interval of time before every packaging operation. The second risk or source of contamination is “operating equipment.” Equipment leads to additive contamination by two means: cross-contamination due to use of the other processing machine, or due to the equipment itself, e.g., corrosion or damage. It can be possible for the same equipment to be used for different chemical moieties, so the manufacturer should take care of cross-contamination by cleaning the equipment at every change of product processing of a new chemical moiety. Maintenance like greasing, oil changing, adding lubricant should also be done regularly to prevent both equipment working problems and processing contamination problems. 22.4.6 Qualification of Manufacturing Equipment At the first stage from where the procedure of overall GMP conformity commences, the additive has to be processed in validated apparatus by means of a validated production method. Testing and cleaning must be completed using a validated method. The qualification activity for equipment will be described by a protocol used in the process. Qualification of DOSAGE FORM DESIGN CONSIDERATIONS 782 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS apparatus starts with an installation qualification (IQ), which is followed by an operation qualification (OQ) and wrapped up with performance qualification (PQ). In IQ, equipment has been introduced legitimately, as specific either to the equipment producer or by the buyer. OQ shows that the apparatus works as anticipated. The capacity of the apparatus is contrasted with the apparatus maker’s specification or as indicated by the additives producer’s outline design. At last, the PQ demonstrates that the equipment performs and works as proposed. In processing, PQ includes running a test substance, e.g., water or a production batch. So additives production should use a qualified and an approved procedure. For IQ and OQ, an approved technique is readied that shows how maintenance and generation records will be utilized to give confirmation that the equipment was introduced appropriately and is in action as planned. At that point, the technique/convention is implemented by investigating the maintenance and production paperwork for the supporting information. At last, information is framed stating that establishment and operation of the equipment conforms to protocol necessities. 22.4.7 Process Validation After working on IQ, OQ, and PQ of equipment, process validation can proceed. There should be creation of a master validation plan (MVP) that will describe the validation method like retrospective, concurrent, or perspective which will show the preparing stages that need validation, and establishes an arrangement for implementation of every validation. For the most part, the MVP covers the preparing steps that affect additives quality for the purpose of the start of full GMP consistency. The most settled validation strategy is perspective. This validation approach takes a shot at the finishing of the validation before production starts and the item marketed so the maker requires no less than three back to back batches amid protocol execution. The groups are assessed and affirmed by the protocol needs; a report is arranged and endorsed. At that point, the finished batch is freely available to be purchased and generation is initiated utilizing the approved procedure. Concurrent validation is another typical way to deal with beginning the protocol. However, the testing prerequisites for concurrent validation are ordinarily harsher than for prospective validation so it will limit the danger of discharging a batch whose execution may be unsatisfactory. Testing in concurrent validation is undertaken parallel to the finished product analysis. 22.4.8 Cleaning Validation Final quality validation program in production is cleaning. The reason for cleaning validation is to verify the theory that the cleaning strategy is successful in expelling contamination deposits from the chosen apparatus. In cleaning, validation specialists need to clean the apparatus in a standard and regular protocol and in this manner, there ought to be detailed command and guidelines with reference to how to clean the equipment, in addition to looking after the paperwork to authenticate that the protocol were followed. Cleaning validation description involves: • Cleaned equipment, • Procedure to be followed for cleaning, DOSAGE FORM DESIGN CONSIDERATIONS 22.4 PROCESSING OF ADDITIVES AS PER GOOD MANUFACTURING PRACTICE • • • • • 783 Material use for cleaning, Evaluation of cleaning, Limit of acceptance for cleaning, Recognizable proof of the complicated area of the apparatus to clean, Number of duplicates to demonstrate the cleaning system has been validated. Cleanliness validation of the equipment includes determining the deposits remaining on a recognized range of the apparatus. This is done by swabbing the checked range with a decent solvent for the deposit. Laboratory testing evaluates various remains in the swabbed range after cleaning operation to determine if any deposit left in the equipment can be assessed. If the test consequence of the deposit is beneath the limit points from the risk analysis above, at that point the apparatus has been acceptably cleaned. 22.4.9 Process Monitoring and Control In-process monitoring is typically an amalgamation of online estimations and sampling. Individual measuring devices either show the quality of the manufacturing level or are utilized to direct processing factors for the purpose of affecting product quality must be made using a calibrated instrument. The calibration process necessitates that for all apparatus there is: • • • • • • Separate assessment; Establishment of due date for calibration; Validated calibration process; Calibration against NIST traceable calibration standards; Calibration operators should be qualified; and Evidence of every calibration that incorporates, in addition to the information indicated, the discoveries of the calibration. Tagging of instrument has to be done so that it can be labeled with the next due calibration. It causes the administrator to make sure that the apparatus is inside its calibration period. 22.4.10 Sampling and Testing An in-process sampling includes a composed procedure which ought to be taken after. The Standard Operating Procedure (SOP) or generation direction ought to represent when and how and from where in the production, an example is to be taken, from where the specimen is to be taken, e.g., taking an amount of a sampling point or distribution through an sampling loop for a fixed interval before taking the specimen, which sampling apparatus is to be utilized for taking the specimen and how it is to be cleaned, amount of test to be taken, a depiction of the storing container into which the specimen is gathered, and labeling of item. The consequences of in-process testing are key to verifying the best possible working of the hardware. In this manner, it is important to give affirmation of cleaning the equipment according to protocol. DOSAGE FORM DESIGN CONSIDERATIONS 784 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS In the event that the testing is performed via a prepared workforce, the accompanying prerequisites ought to be met: There ought to be the preparation of faculty with direction. Preparing of assembling staff ought to be finished by qualified mentors. Testing instructions ought to be promptly accessible. Test records should be appropriately reported. Periodic evaluation by the trained personnel has to be done using techniques, such as inspection, performing the test or measurement, and comparing the sample with reference standard. Sample planning should be done on finished additives. The arrangement ought to be as per the in-process sampling rules. COA: When a single sample indicating an additive lot is utilized for quality checking, the records of those investigations are accounted for by the COA. When a number of specimens from the completed item are taken and exclusively tried for quality, the matter of reporting results on the COA must be addressed. 22.4.11 Packaging and Labeling Packaging and labeling operations will add up the risk of quality and regulatory compliance. The risk is due to the experience of finished additives to airborne contamination and humidity. To guard the additive, a positive pressure area using filtered/purified air should be used for filling of additives containers. This area should be cleaned on a regular basis to avoid contamination. Therefore, a manufacturing unit should be built according to the GMP so that the walls, floor, and roof ought to be launderable to permit cleaning. Packaging which could get in contact with additives must not be unfastened until the time they are passed to the packaging area. Received containers ought not to be unfastened until the time they are in the enclosed wrapping area; or else they will be presented to contamination. Filling, closing, and sealing should be done while in the packaging controlled environment. Faculty engaged in packaging operations should wear proper clothing and ought to be prepared for the operation. Packaging and labeling operation guarantees administrative consistency to GMP necessities. It is imperative to pack in a similar are for each one in turn and the room ought to be utilized for a single batch/group of the additive. This is to prevent mix-ups of multiple batches. Additive marks might be either printed or obtained preprinted. Where labels are purchased, the Quality Unit should approve their receipt by matching the incoming label content against an approved reference label. Weight adjustment must be done in the same controlled environment. Weight adjustments should be done with the same additive lot in order to prevent contamination and adulteration. A tamper evident device should be affixed which gives evidence of final sealing. 22.4.12 Quality Release Last Quality Release includes the validation that every single required record is appropriately finished and incorporated for the batch being referred to. After finishing the quality release task, a lot of finished additives are appropriate for sale. DOSAGE FORM DESIGN CONSIDERATIONS 22.5 ADDITIVES INTERACTION IN PHARMACEUTICAL PRODUCTS 785 The Quality Unit should check the records of the following operations: • • • • Record and documentation of batch operation. Packaging document. Labeling record. The quality control (QC) record. The above task should be properly signed with date and time which is then reviewed by supervision as required. 22.4.13 Storage At last the finished product is stored in the facility. The storage area should be properly maintained so to prevent the additives’ packaging and label from deterioration by water or sunlight. The lot should be kept in predefined manner and precise location written in records so that searching is easy and the storeroom should be well lighted. Like all facilities, the warehouse also should be cleaned on a regular basis. The manufacturer should provide the storing conditions to warehouse controller. Insect and rodent control program should also be done with occasional inspection by a quality team or supervisor. If somehow quality department wants sample from finished product then sampling should be done in the same controlled environment as the packaging area and then the packaging of product resealed well. 22.5 ADDITIVES INTERACTION IN PHARMACEUTICAL PRODUCTS Additives interaction involves kinetics principals and occurs frequently. These may be additive drug, additive additive interactions. These interactions are either due to physical interaction (i.e., modification of the dissolution speed or uniformity of the dosage) or chemical interaction (i.e., drug degradation and/or the formation of degraded products) (Katdare, 2006). Additives even though considered inert substance, have the tendency to react with drug components, other additives, and also the packaging system. Impurities present in additives can also lead to deterioration of API. Fig. 22.1 shows different types of interactions. FIGURE 22.1 Different types of interactions. DOSAGE FORM DESIGN CONSIDERATIONS 786 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS Drug Additive interaction: In pharmaceutical formulations, the API are in close contact with the additives which are present in larger quantities than the drug. Incompatibilities between both may lead to drug additive interaction. Additive interactions are classified as physical, chemical, and physiological/biopharmaceutical (Katdare, 2006). Physical interactions are different from chemical interactions because the components retain their molecular entity. Chemical interactions involve chemical reactions leading to the formation of a different molecule(s). The crucial variation between physical and chemical interactions is that in physical interactions the molecules are not chemically modified or changed by any means. Example of chemical interaction: esters are susceptible to pH change and also the presence of alkaline earth metal and salts. The Milliard reaction occurs in primary amines due to reducing sugar. Physiological interactions involve interactions between the additive(s) and the body fluids after administration. For example, change of dissolution time, Ph, disintegration time, etc. This interaction is beneficial in control release formulation (Katdare, 2006). Additive Additive interactions: Additive Additive interactions occurs very rarely, but, it is very important to establish the stability of additives used in a formulation before the operation begin. Additive Additive interactions can be undesirable or sometimes they are desired to contribute to the formulations to get the required product attributes. An example is coprocessed additives. 22.6 FORMULATION ADDITIVES FOR DESIGNING OF SOLID DOSAGE FORMS Solid dosage forms contribute a lot for the treatment of patients and a large population depends upon the solid dosage forms for their wellness. Broadly, solid dosage forms include but are not limited to tablets, capsules, freeze-dried (lyophilized) powders, powder aerosol formulations, spray-dried powders, etc. Solid dosage forms, such as tablets, granules, and powders, have lots of advantages for both patients and medical practitioners. All the solid dosage forms utilize a number of additives which may include diluents, binders, lubricants, etc. Depending upon their use in solid dosage forms additives are classified as follows: Diluents/fillers: These additives increase the bulk content of the dosage form whenever the active constituent in the formulation is of less quantity. Example: lactose, lactose anhydrous, lactose spray dried, directly compressible starch, hydrolyzed starch, MCC, other cellulose derivatives, dibasic calcium phosphate dihydrate, mannitol, sorbitol, sucrose, etc. Binders: These may be dry powders or liquid, they are added at a specific stage in wet granulation to promote formation of granules or to provide cohesive force between particles during direct compression for mechanical strength. Example: cellulose, methyl cellulose, polyvinyl pyrrolidine, polyethylene glycol (PEG), gelatin, polyvinylpyrrolidone, hydroxypropyl methylcellulose, sucrose, starch, etc. Disintegrants: Disintegrants are added to the formulation to facilitate the fragmentation of the tablet and capsule into smaller particles that will provide increased surface area and DOSAGE FORM DESIGN CONSIDERATIONS 22.6 FORMULATION ADDITIVES FOR DESIGNING OF SOLID DOSAGE FORMS 787 thus aid a quick release of the API from formulation. Example: starch, starch derivatives, clay, cellulose, alginates, Polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (NaCMC), etc. Wetting Agents: In solid dosage form wetting agents aid water uptake by reducing surface tension and thereby enhancing disintegration and dissolution. Example: Sodium lauryl sulfate. Chelating Agents: Chelating agents tend to respond with overwhelming metal particles inactivating their synergist action in the oxidation of medicaments by forming soluble complexes. Example: ethylenediaminetetraacetic acid, glycine, citric acid, or tartaric acid, etc. Lubricants: Lubricants are intended to decrease the friction between surfaces in mutual contact like tablets and die cavity. It works to make efficient ejection of tablet from die cavity. Example: stearic acid salt, surfactants, waxes, etc. Glidants: Glidants are used to improve the flowability of granular mixture by reducing interparticle friction and that is used in the pharmaceutical production of tablets and capsules. Actually, glidants, lubricant, and antiadherent have a close relationship because in different concentration glidants work as lubricants and antiadherents. Example: talc, corn starch, etc. Film Former: Coating is a process in which coating material is spread over a surface of a dosage form like tablet and capsule in order to remove disadvantages of uncoated tablet like taste and odor. Example: ethylcellulose, PG, cellulose acetate phthalate, HPMCP, etc. Plasticizer: Glycerine and Sorbitol are the two most common plasticizers. Glycerine is in general used with oil-based fills. Sorbitol is not soluble in PEG and therefore will not leach out of the shell into the PEG based fill like Glycerin would (Raj, 2015). Opacifier: Titanium dioxide is used as opacifier to produce an opaque shell to avoid photodegradation of light sensitive components and also to hide the content color or appearance. Stabilizer: It is a chemical that is used to prevent degradation by environmental stresses, and physical and chemical stress during manufacturing. These may contribute to changes that affect quality of product. These additives play a vital role in turning an unstable drug or formulation into an acceptable one. Example: saccharides work to stabilize lyophilized protein formulation (Chan and Chew, 2007). Miscellaneous • Adsorbent: In solid dosage form if there is a requirement to add a liquid or semisolid material in the formulation; adsorbents absorb or adsorb the liquid part on to the dry powder. Example: magnesium oxide, bentonite, etc. • Flavors: Used to improve the flavor, mask the taste and give a pleasant and acceptable taste to the formulation. • Colorants: Colorants used in the formulation to increase the patient compliance like formulation for pediatric patient. Example: food-drug and cosmetics and drug and cosmetics approved dyes and lakes. • Sweeteners: lactose, saccharine, etc. DOSAGE FORM DESIGN CONSIDERATIONS 788 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS • Preservatives: Preservatives are an important part of formulation, they prevent the development of microorganisms. E.g., benzoate derivatives like methyl and propyl are used as preservatives Some of the commonly utilized additives are examined below along with their numerous utilizations in the strong dose frames: • Lactose hydrous or anhydrous or monohydrate or spray dried: work as binding agent, function as diluent for dry-powder inhalers, tablet, and capsule, lyophilization aid. Also, lactose was reported to help to deliver carrier-based protein dry powder aerosols. Lactose carrier produced a higher fine particle fraction. • Starch: diluent for tablet and capsule. Retain water quickly for proper disintegration. • MCC (Microcrystalline cellulose): suspending agent, tablet and capsule diluents, adsorbent. • Calcium phosphate di or tri: anticaking agent, diluent, buffer, dietary supplement; glidant; nutrient. • Mannitol: sweetening agent, tablet and capsule diluent, tonicity agent, vehicle. • Sucrose: suspending agent, sugar coating adjunct, binder, diluent, viscosity-increasing agent, sweetening agent. • Polyvinylpyrrolidone: disintegrant, adhesive, emulsifier. • PEG: plasticizer, solvent, surfactant, base, and tablet, and lubricant, etc. • Alginate: tablet binder, tablet disintegrant. • NaCMC: tablet and capsule disintegrant, adhesive. • Talc: anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant. • Stearic acid and derivatives: tablet and capsule lubricant, softening and thickening agent. • Silicone dioxide: anticaking agent; adsorbent; glidant; suspending agent, emulsion stabilizer. • MgO: tablet and capsule diluent, absorbent. • Kaoline: absorbs some active drugs when used in tablet formulations at very low concentrations • Gelatin: coating agent, film-former, gelling agent, suspending agent, tablet binder. It is a translucent, colorless, brittle (when dry), flavorless food derived from collagen obtained from various animal body parts. Hard-shelled capsules are generally made up of gelatine base and contain dry powdered material mix. TYPE A Derived from acid treated precursor. It is extract out from pork skin. Type B Derived from alkali treated precursor. It is extract out mainly from animal bones (Raj, 2015). 22.6.1 Additives in Spray-Dried Powders Spray drying is a process where a drug solution is sprayed through a nozzle into a chamber that simultaneously has hot air blown into it for evaporating the moisture content of formulation to convert a mixture from its liquid form to a powder. Trehalose is used to prevent denaturation of protein in dry powder formulation; polysorbate 20 to stabilize aggregation of proteins; silica to increase the flow of powder; polyvinylpyrrolidone prevented the sublimation of salicylic acid during spray-drying; dibutyl phthalate were used DOSAGE FORM DESIGN CONSIDERATIONS 22.7 FORMULATION ADDITIVES FOR DESIGNING OF SEMISOLID DOSAGE FORMS 789 as plasticizers for controlled-release microspheres of theophylline and sulfamethazine prepared by spray drying. 22.6.2 Additives in Controlled Release Solid Dosage Forms Controlled release dosage is formed by using polymeric additives which coat around a drug core by microencapsulation or as a matrix in which the drug is embedded. It includes water-soluble resins (e.g., gelatin, starch, polyvinylpyrrolidone, and water-soluble celluloses), water-insoluble resins (e.g., polymethacrylate, silicones, and water-insoluble celluloses), waxes and lipids (e.g., paraffin, beeswax, stearic acid), enteric resins (e.g., shellac cellulose acetate phthalate). Surfactant like tween 20 and PEG additives have been used in microencapsulation of macromolecules for various effects (Chan and Chew, 2007). 22.7 FORMULATION ADDITIVES FOR DESIGNING OF SEMISOLID DOSAGE FORMS It contains a major portion of pharmaceutical formulations. It is used to deliver a drug by way of skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining. But topically applied drugs have some problems in their permeation, but to minimize this issue additives play a vital role in delivering the drug in an efficient manner (Barry, 1983). Additives work on the physical properties of the vehicle, which make them capable to change the stratum corneum property, e.g., alcohol, or the mucosa to deliver the drug effectively. Semisolid dosage forms usually are intended for localized drug delivery. Semisolids have rheological properties in which they impart solid-like properties until they are disturbed; disturbance easily breaks down particle forces. Semisolids includes creams, ointments, pastes, and gels (Katdare, 2006). Bases: The base is the central ingredient used in semisolid dosage formulation. Base of ointment does not merely act as the transporter of the drug but influences the absorption of drug. Bases are categorized as follows: Water-soluble base: They are mixtures of high and low MW PEG which have the general formula CHCH2 CH2OCH2 CH2OH. The CH2OH. The characteristics of these bases are: • Low molecular weight as liquids; those with moderately higher molecular weight are unctuous and the high molecular weight are solids. • No water is required for their preparation. • Suitable combination of high and low molecular weight PEG yield material having ointment-like consistency. It melts when applied to the skin. • Presence of many polar groups make it water soluble. • Also called greaseless ointment bases. The macrogols or carbowax are polycondensate mix materials of ethylene oxide and water and they are denoted by their average molecular weights, e.g., microgel 1500 (semisolid), 200, 300 (viscous), 3000, 4000 (waxy), etc. DOSAGE FORM DESIGN CONSIDERATIONS 790 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS PEG: Like paraffine, their consistency differs from viscous liquids to waxy solids, e.g., PEG 200, PEG 400, PEG 1000, PEG 1540, and PEG 6000. Different grade of PEGs are mixed together to get desired consistency of formulation. Water-miscible bases: Excess of water is used to make them soluble, that is why formulation using these bases can be removed after use or application, e.g., cetrimide, cetomacrogol. For o/w type, e.g., antifungal benzoic acid ointment. Importance of water-miscible bases: Promptly miscible with the exudates. Reduced impedance with ordinary skin functioning. Effective in touch with the skin, in view of their surfactant content. Elevated corrective agreeableness, and it makes less probability of the patients discontinuing treatment. • Easy expulsion from the hair. • • • • Absorption base: The absorption bases have absorbing or emulsifying property. The name does not express their action on the skin. These bases absorb considerable amounts of water but their consistency will not change (sometimes called emulsifiable ointment bases) Preparations of these bases not contain any water but if water may be used then it converts to w/o type emulsion. Some commonly used bases are discussed below: • Wool Fat (Anhydrous Lanolin): Fat obtained from the wool of sheep. Water solubility is very poor but can absorb water of about 50%. Hence, preparation using wool fat can hold the water in a large amount. It is used with other bases for better consistency. • Hydrous Wool Fat (Lanolin): It is a mix of wool fat and water (70:30%). It is a w/o emulsion. It can be incorporated as an emollient. • Wool Alcohol: It is emulsified part wool fat. Wool fat is alkaline treated from which cholesterol and alcohol is separated. It has around 30% cholesterol. It absorbs water to maximum extent in w/o formulation (emulsifying agent). • Beeswax: It is purified wax obtained from honeycomb of honey bees, contains very low quantity of cholesterols and acts as a stiffening agent in preparation. It is available in two types yellow and white. • Cholesterol: Widely available from animal sources. Source of cholesterol is wool fat. It helps in absorbing water in preparation. • Oleaginous Base: These are mixture of oils and fats. Important one is hydrocarbons, i.e., petrolatum, paraffin, and mineral oils. • Petrolatum (Yellow Soft paraffin) MP 38 56 C: It is a mixture of hydrocarbons obtained from heavy lubricating oil. Antioxidants, e.g., butylated hydroxytoluene (BHT), etc. may also be used with this base to make the formulation stable. • White Soft Paraffin (White Petroleum Jelly, White Petrolatum): It is a mix of semisolid hydrocarbons, also known as white petroleum jelly. It is decolorized by percolating yellow paraffin. When you apply it to the skin it leaves a layer of oil on the surface of the skin that prevents water evaporating from the skin surface. • Hard Paraffin (Paraffin): It colorless, odorless wax type mix of solid hydrocarbons obtained from petroleum. Above 50 C it solidifies. It is used as a stiffening agent. DOSAGE FORM DESIGN CONSIDERATIONS 22.8 FORMULATION ADDITIVES FOR DESIGNING OF LIQUID DOSAGE FORMS 791 • Liquid Paraffin (Liquid Petrolatum/White Mineral Oil): It is transparent, colorless refined mineral oil which is a mix of liquid hydrocarbons obtained from petroleum used in cosmetics. On long storage, it may oxidize, therefore antioxidant like tocopherol or BHT incorporated in preparation. It may combine with other bases for desired consistency. Other additives used in semisolid dosage forms include the following: • Antioxidant: free radical which is very highly reactive, if formed in formulation may cause damaging effect to product stability and shelf life. So, antioxidant is a molecule that inhibits the oxidation of other molecules or prevents formation of free radical. E.g., butylated hydroxyanisole (BHA), BHT. • Antioxidant Synergist: tartaric acid, etc. • Antioxidants: BHA, BHT, etc. • Reducing Agents: potassium and sodium metabisulfite, thiosulfite, etc. • Humectants: glycerine, etc. • Gelling Agent: tragacanth, pectin, gelatin, etc. • Emulsifiers: • Anionic: soaps, sulfonates, sulfosuccinates, etc. • Cationic: quaternary ammonium compounds, etc. • Nonionic: alkyl-aryl ethers, sorbitan esters, glyceryl fatty acid esters, etc. • Buffers: sodium citrate, potassium meta phosphate, etc. 22.8 FORMULATION ADDITIVES FOR DESIGNING OF LIQUID DOSAGE FORMS Compared to solid dosage form, liquids are processed and formulated as solutions, suspensions, and emulsions according to the dosage form required or API solubility and stability. Powder may also be delivered as syrups, solutions, suspensions, and emulsions by reconstitution in which powder and vehicle are combined prior to delivery. Liquid formulation (LDF) requires various additives (Fig. 22.2) which are elaborated as follow: Vehicles: That carry drug APIs and other additives in dissolved or dispersed state. • Aqueous Vehicles: water (SWFI, WFI, USP purified water), propylene glycol, ethyl alcohol, glycerine. • Oily Vehicle: Vegetable oils, mineral oils, organic oily bases or emulsified bases. Solubilizers: Breaking the hydrogen bond between the particles so they get soluble in water. Solubility can be modified by use of cosolvent, pH change, complex formation, or the use of surfactants. Example of solubilizers in LDF are ethanol, PEGs such as PEG-400, etc. (Katdare, 2006). Sweeteners: Generally, sweeteners are used in between 30% and 50% of the total formulation concentration except for cold syrups that contain 80% of sweetener. • Natural Sweeteners: Sucrose, lactose, mannitol, etc. • Artificial Sweetener: Aspartame, saccharin, etc. pH Modifiers and Buffering Agents: Buffers used to control or prevent changes in the formulation pH which could prevent and increase the stability. DOSAGE FORM DESIGN CONSIDERATIONS 792 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS FIGURE 22.2 Different additives used in liquid dosage forms. Antimicrobial Preservatives: Preservative used in preparation to prevent the growth of microbes so it should be of wide spectrum. It should be nontoxic, nonsensitizing, compatible with other additives, and have no taste and odor, e.g., parabens (0.015% 0.2% w/v.), Phenol, benzyl alcohol (2%), chlorocresol, etc. (AULTON pharmaceutics). Surfactant: Anionic Sodium lauryl sulfate (SLS), 2-naphthalene sulfonate sodium, docusate sodium. • Cationic: cetylpyridinium chloride. • Nonionic: poloxamer, polysorbate. Suspending Agent and Viscosity Modifying Agent: Cellulose derivatives: MCC (and derivatives such as carboxymethylcellulose (CMC)); Clays: magnesium aluminum silicate; sodium alginate, xanthan gum, carbomer povidone, tragacanth, guar gum; colloidal silicon dioxide; BHA, BHT, EDTA; fumaric acid tartaric acid, ascorbic acid, alpha tocopherol, citric acid (Katdare, 2006). Color: Different colorants are frequently used in the liquid dosage forms and most of the time the purpose is to enhance the elegance of the formulation and thereby the acceptability of the dosage forms, e.g., food, drug, and cosmetic colors 22.9 CURRENT GUIDELINES FOR PHARMACEUTICAL ADDITIVES (FDA, EU, JAPAN) Sources of additives vary according to their origin like animal, plants, minerals and synthetic but they have to go through the quality check and control for assurance of safety DOSAGE FORM DESIGN CONSIDERATIONS 22.9 CURRENT GUIDELINES FOR PHARMACEUTICAL ADDITIVES (FDA, EU, JAPAN) 793 and stability. The new technology in pharmaceutical formulation additives has to be also modified for better functioning like coprocessed additives which can be a new entity or combination of old additives. Currently, thousands of additives are in use in manufacturing. In the past, additives were recognized as an inactive part of the formulation but with new trends, these assumptions are changed because additives also have function, like API which interact with the other ingredient and also effect the ADME of dosage form, plus they also have toxicity effects. The safety assessment of pharmaceutical additives is the major issues in different countries. To popularize additives there is no regulatory prerequisite to demonstrate that there ought to be a monograph of this substance. If there is an additive monograph in a pharmacopeia, the additive should be complemented with the monograph because the regulatory authorities require conformity. For the supplier, it is always preferable to present an additive with a monograph or a complementary document about it that is relevant, because it means that this additive has quality for pharmaceutical use. National pharmacopeias depict quality prerequisites for pharmaceutical additives and these get priority over the three main pharmacopeia (USPNF, Ph. Eur., and JP). The US FDA describes a new additive as any inactive fixings that are purposefully added to the therapeutic and diagnostic items, however that are not anticipated that would apply remedial impacts at the planned dosage, regardless of the way that they may act to improve item delivery that present well-being data concerning the correct now proposed level of introduction, exposure time, or route of administration. As per Japan, a substance which has no prior record as additives in overseas or in Japan qualifies to be new additives if, additives are administrated orally, have cosmetic use in pharmaceutical formulation. If the route of administration is newer than the marketed formulation then it is treated as a new additive (Uchiyama, 1999). Responsibilities for regulating additives approval and safety are divided among MHW (Ministry of Health and Welfare) and National Institutes for Hygienic Sciences (NHS) and Central Pharmaceutical Affairs Council (CPAC). Monograph for additives approval is given in Pharmacopeia of Japan (JP) and Japanese Standards of Pharma Ingredients (JSPI) (Uchiyama, 1999). The European Union regulatory authority, EMEA, defines novel additives as new additives which are in first-time use in a drug product or have new route of administration in EU and outside EU for human administration. New additives are treated as a new entity or drug in the EU. European commission released recently guidelines on additive labels and packaging information for all market authorization applications for additives used in pharmaceutical formulation. And for other products, if any additives show some effect then it should be mentioned on the label (Guideline on Excipients in the Dossier for Application for Marketing Authorization of a Medicinal Product, June 2007). United States of America: The US FDA has issued guidelines for new additives to establish the safety of dosage forms entitled “Non-Clinical Studies for the Safety Evaluation of Pharmaceutical Excipients.” It will help in QC and safety assessment of formulation intended for use in human. New additives manufacturers should clearly mention and document the safety profile to support the use of novel additives. OTC Products: 21 CFR 330.1(e) section for OTC requires the following condition to be fulfilled: “The additives used in formulation have to be used in safe concentration and do DOSAGE FORM DESIGN CONSIDERATIONS 794 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS not interfere with effectiveness and quality tests which can decide whether the item meets its maintained models of character, quality, quality, and purity. Guidance for Color additives are given in section 721/subchapter A of this chapter.” Generic Products: The USFDA requires that the generic formulation planned for parenteral, ophthalmic, or optic use ought to contain an indistinguishable added substances in similar concentration from the reference standard, except for buffer, preservative, and antioxidant. However, for this, the condition is that the applicant distinguishes and characterize the difference and gives data showing that the changes doesn’t influence the safety of product. For different courses of administration, there is no necessity that the added substances in the final formulation are the same as those in the reference, but they do not influence the safety, efficacy, and quality of the planned product. The European Union: The IPEC Europe has in print a parallel guideline for the evaluation of safety of the potential novel additives. In Europe, the information about the novel additive to be used in the dosage form is to be provided in the application for marketing authorization application by the applicant. The information to be included by the applicant is according to the guidance entitled “Guideline on additives in the dossier for application for marketing authorization of a medicinal product” (Bajaj and Budhwar, 2012). The following data are to be submitted: • Full particulars of manufacturer, characterization, and controls with safety data according to the guideline. • Detail about the functioning and condition for use of additives. For mixture of additives quality and quantity, data should be provided. • For mixture of additives chemistry and toxicology and the field in which the product is already used should be mentioned. • Document related to the international specifications of additives according to (FAO/ WHO/JECFA), and other publications, like Food Chemical Codex. • Safety data for cosmetic additives used for topical formulation. • Data concerning the toxicology of the new additive according to the dosage form and the route of administration of the medicinal product in Module 4, which is the safety section of the dossier. Documentation on science of additives is required for every single novel additives, on the principle of the CPMP Guideline (Chemistry of New Active Substances) including: Origin, name and manufacturer details. Process of manufacturing and purification. Chemistry. Identification and purity test procedure. Validation method for operation and equipment. Miscellaneous information (microbiological tests, etc). Test result for contamination and impurity presence. Novel additives having mixture of numerous components, properties of all the content should be described. • Stability data and document. • • • • • • • • DOSAGE FORM DESIGN CONSIDERATIONS 22.9 CURRENT GUIDELINES FOR PHARMACEUTICAL ADDITIVES (FDA, EU, JAPAN) 795 Japan: There are a few reference materials that have to be attached to an application for endorsement of another pharmaceutical substance containing an added substance. All applications require data concerning the explanations behind the added substance’s consideration in the planning, points of reference of utilization, and a suitable quality model. For things with recently added substances, it is vital to give information on the beginning and change of the additional substance, including a depiction of its uses abroad and its qualities, and in addition a correlation with different additives. Stability and safety information are likewise required and submitted for new additives (Uchiyama, 1999). The regulation for additives in Japan is the same as for other countries. Guidelines are issued by Pharmacopoeia of Japan (JP) and the Japanese Standard of Pharmaceutical Ingredient (JSPI). Japanese Pharmacopoeia states that: “Additives are incorporated for giving indicated properties and quality amid capacity or upgrade the efficacy of medication product yet it ought not to meddle with the therapeutic efficacy or the testing of the product.” On regulatory provision on additives, JP resides in the pharmaceutical affair bureau of the Ministry of Health, Labor and Welfare organization (MHLW). Monographs of JP contained mandatory standards for the most broadly used excipients. Quality and safety is evaluated by a subcommittee designated by Central Pharmaceutical Affair Council (CPAC) and approval process by pharmaceuticals and Medical Devices Evaluation Center (PMDE). NEW RULE: In July of 1997 new evaluation system was put in effect by the Ministry of Health and Welfare (MHW), application for affirming pharmaceutical substance is made through a prefectural office of the Pharmaceuticals and Medical Devices Evaluation Center (PMDE Center). In the event that application for new item contains an added substance with no past use as added substance in Japan then the quality and safety of the additives must be tested by the Subcommittee on Pharmaceutical Additives of the Central Pharmaceutical Affairs Council (CPAC) and PMDE. The duty of the drug regulatory agency is to verify all documents attached with NDAs. All applications require to submit the data for additives including why it is incorporated in the preparation, past use, and quality standards. For new additives, the origin, manufacturing operation of the additive, overseas use, and its property are to be submitted, as well as a comparison with other additives (Uchiyama, 1999). It is imperative to perform chance benefit testing on new additives to set up passable and permitted limit for these substances. This requires proper planning with possible toxicology test of an additive in a relatively efficient manner. The centers perceive that current human information for a few additives can substitute with documented earlier human presentation and not require assessment in the full set of toxicology studies given in the rules. Under some situations (e.g., similar route, height, and length of exposure, patient population) prior use may effectively qualify an additive. Note that the consideration of an additive in a USP/NF monograph or other non-FDA archive isn’t an indication that the substance has been investigated by the FDA and discovered safe for utilize (Verma et al., 2016). DOSAGE FORM DESIGN CONSIDERATIONS 796 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS 22.10 REGULATORY ASPECTS OF ADDITIVES APPROVAL 22.10.1 Current Regulatory Status of New Additives In the United States, specific requirements for “new” additives are given in the US FDA Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, May 2005. Overall, the International Conference on Harmonization (ICH) has not given additives rules, but rather the FDA takes ICH safety testing direction papers for leading safety tests. However, these guidelines address only one aspect of the approval process leaving a major gap i.e., the precise definition of “newness”. As per the ICH, “new” or novel additives are define by the use for the first time for a pharmaceutical drug product or have a new route of administration. US FDA document the Inactive Ingredient Database (IID) has lists of approved products, administration routes, and dosage concentration. The definition does not separate between totally new chemical elements and previously approved additives that have been changed, different routes of administration, or coprocessed material. Supporting data for other new additives can be given in an application which is comparative and have similar detail like new drug substance e.g. chemical properties, all the data of quality and safety, etc. 22.10.2 The IPEC Procedure According to the IPEC, the manufacturer has to submit all relevant data and records in the DMF to propose a new additive for safety and quality assurance. An expert panel, having highly experienced persons from academia, industry, and regulatory, evaluates the information of the additive in the DMF considering guidelines proposed by FDA and ICH. This panel will conclude the conformance to the sponsor if they find all the data relevant. Applications for global acceptance is a work under process If the panel concludes that the data submitted to the FDA do not meet the specifications, then it recommends particular steps to pass the dossier application information into conformity. That allows the resubmission of the dossier document with the asked for changes. The expert report is possessed by the sponsor and discharged at their discretion. The additive manufacturer can consult the summary and table of content of studies with cost-based consultants before submission. The consultant provides the candidate with a report with the DMF needed pattern for drug product application. IPEC only reviews the application but does not play any role in this process or evaluation. The evaluation of the application procedure is kept private between the panel and sponsor which is not known by IPEC. 22.10.3 Additive Master Files and Other Filings DMF is an accumulation of specialized understated elements identified with the manufacture of the added inactive substance and is arranged according to or similar to Common Technical Document (CTD) format for effortless upcoming submission. DMF ordinarily incorporates particulars and test techniques for crude substances, testing in DOSAGE FORM DESIGN CONSIDERATIONS 22.10 REGULATORY ASPECTS OF ADDITIVES APPROVAL 797 between processing, and the completed added substance item, an entire depiction of the assembling procedure, safety information, packaging information, and information printed on the label. In the United States, an added substance provider will frequently present a DMF to the FDA to give classified data in respect to the added substance, safety data, and certificate for processing as per GMP necessities. Both Canada and Japan follow the identical or similar rules. In Europe, compilation of drug product information by a pharmaceutical producer should be provided specifically to the client for consideration for their approval, utilizing secrecy understandings where important. 22.10.4 Recommended Strategies to Support Marketing of New Additives in Drug Products 22.10.4.1 Safety Pharmacology All novel or effective new excipients are fittingly assessed for pharmacological effect utilizing a run of standard tests as indicated by ICH direction for industry S7A Safety Pharmacology Studies for Human Pharmaceuticals. Pharmacology studies are valuable for this information to be gotten at an early level amid the safety assessment of additives, since, if additives are pharmacologically dynamic, this data can impact results and the development process. 22.10.4.2 Potential Additives Intended for Short-Term Use Newer additives that are intended for use in products that are limited by labeling to clinical use of 14 or fewer consecutive days per treatment episode and are infrequently used include at least the following: • Toxicity studies. • Pharmacokinetics studies of an additive with toxicokinetics. • 1-month toxicity studies are performed in first rodent animal types and second mammalian nonrodent animal groups by the course of treatment planned for clinical use with an assessment of clinical pathology, toxicokinetics, and histopathology analysis. • Toxicity in reproductive stage. 22.10.4.3 Potential Additives Intended for Intermediate Use New added substances that are expected for use in a drug product that is labeled for clinical utilization of over 2 weeks yet not exactly or equivalent to 3 months for each treatment episode require: • All trial of safe pharmacology and in-between use aside from 1-month repeated dose toxicity trial. • 3-month repeat-dose toxicity studies are processed in which studies include assessment of clinical pathology, toxicokinetic, and histopathology analysis in both rodent and nonrodent animal. • Other study (e.g., studies for Parenteral administration). DOSAGE FORM DESIGN CONSIDERATIONS 798 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS 22.10.4.4 Potential Additives Intended for Long-Term Use New ingredient that is expected for use in a drug product named for clinical utilization of above 3 months in a specified patient (either a single treatment scene or because of different courses of treatment to treat an incessant or chronic condition) requires: • All tests have to be done like safety, pharmacology, short-term and intermediate use test. One or three-month test is not essential or may be done for better safety assessment. • 6-month repeat-dose toxicology study on rodent including full assessment of clinical pathology, toxicokinetic, and histopathology analysis. FDA recommends that less toxic additives are tested in their higher concentration. • If no toxicity and pharmacologic effect were found then 6-month study is sufficient. But when toxic effect is shown in small duration of test than chronic study should be conducted in nonrodent of 9 to 12 months. • Carcinogenicity study according to ICH(S1A). 22.10.4.5 Potential Additives for Use in Pulmonary, Injectable, or Topical Products • Have to perform all required studies like Safety assessment, Pharmacology test, for concluding its duration (short, long, intermediate) of safe exposer and administration route. • Sensitization study (e.g., guinea pig maximization study or murine local lymph node assay) with respect to CDER guidance. Immunotoxicology evaluation of IND for more information can be done. • Things to be considered for additives used in injectable: • Hemolytic study (IV bolus and/or infusion). • The plasma creatinine kinase determination for I.M. or S.C. injectable can provide study data on potential muscle injury. • Protein binding test. • Additives expected for topical administration may involve support from toxicology determination by both the planned clinical course and the oral or parenteral course. • For topical and ophthalmic formulation, ocular irritation study should be conducted. Photostability Testing: FDA suggests that additives be assessed with respect to the requirement for photo testing given in the CDER guidelines. Either the added substance or the entire medication item could be tried. 22.11 REGULATORY PERSPECTIVES OF FORMULATION ADDITIVES Regulatory perspectives of the United States, Europe, and Japan have already been discussed in this chapter earlier. Now here we will discuss IPEC, GRAS, and Inactive Ingredient Guide (IIG) regulatory perspectives. DOSAGE FORM DESIGN CONSIDERATIONS 22.11 REGULATORY PERSPECTIVES OF FORMULATION ADDITIVES 799 22.11.1 IPEC Perspectives The IPEC Federation, a worldwide association comprising of local affiliations sorted out to advance quality in pharmaceutical added substances, was formally made in January 2010 at a meeting in Cannes, France. IPEC Europe right now holds the Presidency of the IPEC Federation, and IPEC-Americas and IPEC Japan fill in as Vice-President and Treasurer separately. The purpose of IPEC is to encourage the harmonization of different standards for manufacturing and use of pharmaceutical additive, develop improved consumer safety in the manufacture and use of pharmaceutical additive, and introduce new pharmaceutical additives. There are various national additive regulation registration systems that have yet to be internationally harmonized. The lack of regulatory provision is to be identified by IPEC. The IPEC Federation is a worldwide association that advances quality in pharmaceutical added substances. The IPEC Federation speaks to the five-existing provincial International Pharmaceutical Excipient Councils (IPECs)—IPEC-Americas, IPEC Europe, IPEC Japan, IPEC China and IPEC India—and gives a bound together voice to advance the best utilization of added substances in drugs as a method for enhancing persistent treatment and well-being. IPEC has objectives with respect to the International Harmonization of Excipient Standards. The IPEC’s principal work is introduction of novel added substance with commercial center and advancement of well-being assessment guidelines. The Safety Committee of IPEC (SCIPEC) incorporates qualified researchers and creates security testing of the added substances. The guidelines depend on chemical and physical properties of the added substance, survey of the logical writing, presentation, condition (Including measurement, dosage length, recurrence, course and client populace), and nonattendance or nearness of pharmacological activity. The IPEC recommended the guidelines for the safety assessment of new added substances and good manufacturing guides for mass pharmaceutical additives. The guidelines give adequate information to characterize the safe state of utilization of new additives. The additive poisonous quality guidelines are compressed, which were created with reference to the FDA proposed usage archive (Steinberg et al., 1996). ICH has affirmed direction archives on specialized prerequisites for medicate products containing new fixings. Additives are controlled intently by characterized detail, or monographs, accumulated in three noteworthy Pharmacopoeias in the United States, Japan, and Europe. Pharmacopoeial Harmonization likewise maintains a strategic distance from superfluous deferrals in the administrative procedure, while guaranteeing their quality, safety, and viability. Pharmacopoeial Discussion Group (PDG) was set up in 1989, and harmonization might be done reflectively to existing monographs or sections or tentatively for new monographs. So far 25 of the 35 general sections and 39 of the 62 additive monographs have been harmonized (IPEC Federation, 2017). 22.11.2 Regulatory Perspectives: GRAS, IIG 22.11.2.1 Generally Recognized As Safe Food Status GRAS is an American Food and Drug Administration (FDA) assignment that a concoction or substance added to food is viewed as protected by specialists, and is exempted DOSAGE FORM DESIGN CONSIDERATIONS 800 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS from the typical Federal Food, Drug, and Cosmetic Act (FFDCA) food additive resistance prerequisites. Food Additives Amendment of 1958 firstly explained the concept of GRAS for food additives and entire additives introduced after this concept were required to be analyzed by new standards. Under this provision, different data like testing, exposure, manufacture, etc. were supposed to be evaluated by a GRAS specialist panel. After approval by GRAS experts, the approved additive can be used only with those food products and within that concentration for which approval was taken. Though it is not a mandatory procedure but some manufacturers opt for GRAS notification steps just to cross-check whether FDA is also in consent with the GRAS findings or not. More than 3000 additives have been endorsed by this strategy to date and this speaks to a model of industry and regulator participation (Burdock et al., 2006). Substances which go under GRAS status and which are formally seen by the FDA are recorded in the regulations at 21C.F.R. 182, 184, and 186. FDA notes in its direction, “it is unfeasible to list every single such substance that are GRAS.” It is improbable that an ingredient that does not have some formal position with the FDA will be acknowledged by the office as safe for use in a different medication without the full investigations that are essential for novel additives, in particular for pharmaceutical additives. The GRAS procedure is an open rulemaking technique where the information supporting the GRAS status is set in an open docket for input. At the point when all comments are evaluated, the FDA will make a confirmation on whether the additive should be seen as GRAS. The GRAS confirmation process requires a impressive effort regarding an organization to procure toxicological information (frequently long-haul information) that is adequate to the FDA. The FDA at that point frequently takes a long time to survey the information and issue the direction. Subsequently, this procedure is occasionally utilized. GRAS Notification: Rather than the formal GRAS confirmation request, the FDA started another methodology for GRAS ingredients, the GRAS notice. Under the notice procedure, a producer makes an assurance that an ingredient is GRAS and notice to the FDA to take additive data it in consideration for GRAS assurance. Inside 90 days, the FDA reacts to the producer that either the office does not scrutinize the reason for the maker’s GRAS assurance, or that FDA presumes that the notice does not give an adequate premise to a GRAS assurance. In any occasion, the FDA does not formally perceive the GRAS status of the ingredient as it did under the certification procedure. The notification procedure has been profitable to food and food ingredient makers, as it is significantly quicker and less oppressive than the GRAS affirmation process; in any case, its utility for pharmaceutical added substance producers is less certain. Under the affirmation process, the component had an official acknowledgment as GRAS in FDA regulations. Under the notice procedure, no finding is made by FDA regarding ingredient’s GRAS status and therefore, ingredients under notification process consideration are possibly less worthy to the FDA as pharmaceutical additives. For a long time, chemical makers and pharmaceutical firms (clients) and additionally FDA commentators casually utilized these FDA food freedom components to give new drug analysts (e.g., toxicologists and pharmacologists) a level of solace about the safety of an additive contained in a finished pharmaceutical formulation. At the point when a utilization of a substance does not meet all requirements for the GRAS exception, that utilization of the substance is liable to the premarket endorsement ordered by the Federal Food, DOSAGE FORM DESIGN CONSIDERATIONS 22.11 REGULATORY PERSPECTIVES OF FORMULATION ADDITIVES 801 Drug, and Cosmetic Act. Under these conditions, the FDA can make authorization move to stop dissemination of the food substance and foods containing it in light of the fact that such foods are unlawful or these food items contain a few unlawful food additives (Generally Recognized as Safe (GRAS) FDA, 2016). IIG: IIG is a piece of FOI Special Topics, which goes under Drug Information division of CDER. IIG comprise of all the dormant ingredient introduce in endorsed drug item or restrictively affirmed drug items right now marketed for human utilize. IIG is prepared by DDIR (Division of Drug Information Resources). IIG does not show contaminant found in affirmed drug items. DDIR does not generally incorporate Proprietary names of Ingredient in IIG. In such circumstances, one needs to scan information for such ingredient under individual segment passages. The IID contains idle ingredients particularly proposed in their original form by the producer. Inert ingredients can likewise be viewed as dynamic ingredients in specific situations, as per the meaning of an active ingredient given in 21 CFR 210.3(b) e.g., Alcohol. IID gives data on inert additives available in FDA-affirmed drug items. Industry can be utilized the data as a guide in creating drug items. For new drug advancement purposes, if additive is get listed in approved drug product for a specific course of organization, the idle ingredient is not viewed as new and may require a less broad examination whenever it is incorporated into another drug product. It has turned out to be normal practice in creating drug products to counsel the FDA’s IIG to acquire data on “satisfactory levels” of additives utilized as a part of already affirmed items. The FDA likewise considers whether the states of use of the latent additive in the already affirmed item are similar to (or more prominent than) those of the proposed new item. Other factors that the FDA considers in this investigation are • Administration route, • Level and duration of exposure, • Population of patient Administration Route—This foundation is the one for which the FDA permits the best adaptability. Information on levels of inactive additive can, by and large, be utilized conversely when the course of organization of the drug item is the same (e.g., information from oral tablet details can be utilized for oral containers, information from topical gel definitions can be utilized for topical creams). Besides this, an additive utilized as a part of a topical formulation like cream might not have a similar safety profile if utilized as a part of an occlusive topical PATCH. In this way, extra safety data might be expected to qualify the utilization of the additive in an alternate detailing regardless of the possibility that the course of organization and every other factor influencing use are the same. Level and Duration of Exposure—In considering related knowledge with a inactive additive, the FDA assesses whether the earlier use in the affirmed item is in any event of a comparable length as the utilization of the proposed formulation. Despite the fact that the IIG gives data on the level of an additive present for each measurement unit, it doesn’t give data on the level of presentation of the patient who utilizes the item. Day by day measurements considered by the FDA while assessing the sufficiency of the IIG data. The rate of administration is especially imperative in considering parenteral formulations. DOSAGE FORM DESIGN CONSIDERATIONS 802 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS A inactive additives considered safe when implanted gradually may not be considered similarly safe when infused quickly. IIG description includes Name, Route/Dosage Form, CAS No., NDA Count, Last NDA Approval Date and Potency Range. Numerous inactive ingredients have CAS Registry Numbers, which are helpful in looking different databases for chemical. FDA refreshes the database quarterly, in April, July, October, and January tenth working day. The IID Download is given as delimited content and Excel documents (US Food and Drug Administration, 2017). Patient Population—The patient populace is additionally a critical factor that is considered while surveying whether earlier presentation at a level referred to in the IIG is sufficient to qualify that idle ingredient in a planned formulation. Additives essential for the conveyance of lifesaving treatments might be satisfactory to the FDA at larger amounts or with to a lesser extent a safety database than if the additives are utilized as a part of items planned for patients with more considerate conditions. Additionally, quiet populaces contrasting in age or malady status may likewise vary in their capacity to endure certain additives (e.g., benzyl liquor, an antimicrobial additive, is not endured in neonates on the grounds that their capacity to utilize the additive is not completely created). 22.12 WHO PERSPECTIVES These guidelines supplement the specific GMP guidelines for pharmaceutical formulation in print by WHO which are similar like GMP guidelines for additives. Additives essentially influence the completed product value, in few cases making up nearly the whole formulation. Numerous additives are utilized as a part of substantially more prominent amounts in different industries like the food, cosmetic or industrial chemical industry. In pharmaceuticals formulation there are so many additives are in use. That’s why a program must be set up which will screen these added substances and give the essential confirmation that they conform to the quality parameters for pharmaceutical production operations. Equivalence (“biobatch”) production and commercial scale-up batches to give satisfactory confirmation of product performance in-vivo, the additives used to produce business batches ought not to contrast differ from that utilized as a part of biobatches. Where critical difference might be normal, extra testing by the completed measurements maker might be required to build up the bioequivalence of the final product. It remains similarly imperative to guarantee that the bioequivalence of ensuing, post-approval batch of product is not unfavorably affected after some time. Generally, added substances are utilized as acquired, with no additional alteration or purification. Thusly, impurity influences exhibit in the added substance will be extended to the completed measurements shape. While dosage form makers may have a constrained control over added substance quality acquiring testaments of investigation and testing reference sample. The added substance producer has more prominent control over physical attributes, quality, and the existence of trace contamination in the additives. The manufacturer must execute evaluation and testing in regular basis. DOSAGE FORM DESIGN CONSIDERATIONS 22.12 WHO PERSPECTIVES 803 Some additives manufacturing operation may require recognition of GMP appropriate to completed product or bulk active ingredient in light of the added substance’s use. It may not be necessary but the necessities increase as the process progresses. GMP should be maintained before finishing step or operation. Application of GMP in which step is done by the qualified personnel which have thorough knowledge of production. ISO “certification” for additive manufacturing is more and more being required by manufacturer of USA, Europe, and Japan. International Standards of ISO 9000 series, in particular to ISO 9002, help in supporting suitability of additive in world market. This system will enhance the quality standard of additive use with GMP guidance. Self-inspection and quality audits An assessment group comprising of correct personnel (e.g., reviewers, engineers, research center examiners, acquiring operators, PC specialists) who should take an interest in examinations. The operational confinements and endorsement of the essential preparing steps of an era procedure should be inspected, to ensure that the maker is finding a way to watch that the procedure works reliably. Use of equipment: Multipurpose equipment is used to manufacture additives. Fermentation tanks, reactors, dryers, grinders, centrifuges and some others type are gladly used or modified for a variety of products. Equipment use for multiple processing of substance should be adequately cleaned according to written procedures. Falter or sticky residues present in equipment that can’t be removed easily ought to be dedicated for use with these items as it were. Cleaning program where multipurpose equipment is being used, it is vital to be able to determine previous usage when investigating cross-contamination or the likelihood of such impurity or contamination, equipment cleaning and use log, while desirable and perhaps preferable, is by all account, not the only method of determining earlier use. Any documentation system which clearly identifies the previous bunch and demonstrates that the equipment was cleaned is acceptable. Materials: On account of labile items that might be touchy to natural factors, e.g., air, light, water, hot or cool, suitable assembling and capacity conditions must be utilized to guarantee substance quality all through the procedure. The added substance producer ought to check that the provider of beginning materials and parts can meet the settled upon necessities. Any beginning material or completed additives not consenting to particulars must be obviously recognized and isolated to avoid coincidental use or discharge available to be purchased. In the event that returned additives containers are reused, all past label ought to be evacuated or ruined. In the event that the container is utilized over and again exclusively for a similar additive, all past label should totally be destroyed. Pharmaceutical added substances ought to be put away under conditions set up by the manufacturer on the grounds of stability data. 22.12.1 Documentation General: The added substance maker ought to have a framework to cover all records and information that identify with the necessities of the quality framework. Records and consequent changes to the reports have to be looked into and endorsed by assigned supervisor before being issued to the fitting zones distinguished in the archives. Beginning DOSAGE FORM DESIGN CONSIDERATIONS 804 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS material particulars ought to be sorted out to isolate those tests that are standard from those that are performed rarely or just for new providers. All this can be done easily by using computer system monitoring and documentation. Preventing contamination: The manufacturer of additives must be shield the additives contamination from starting point like raw material container opening to final marketed container filling. In general contamination sources: introduction of the added substance to environment or open air amid the production procedure and defects in the equipment. For the most part amid the blend of additives, the danger of natural contamination just emerges during the changing of crude materials, added substances, or preparing helps, or during the packaging of the finished product in container. Prevented steps ought to be taken to shield the additive from environmental contamination in all phases of production. The operation of packaging and manufacturing should be performed in an enclosed room with good or efficient air flow system. It should be cleaned on regular basis and record should also be maintained. The other critical risk of additives contamination originates from the working equipment. Whatever equipment is utilized to deliver or manufacture numerous substance moieties with same equipment, the producer must have satisfactory techniques for cleaning the equipment in regular change in moiety. The cleaning of equipment is additionally examined under cleaning validation. The devices must be traps, seals, and preventive maintenance procedure should be employed. Process validation: After working on IQ, OQ, and PQ of equipment, process validation can proceed. There should be creation of MVP that will describe the validation method like retrospective, concurrent, or perspective which will show the preparing steps that need validation, and Establishes an arrangement for implementation of every validation. For the most part, the MVP covers the preparing steps that effect additives quality from the purpose of a start of full GMP consistency. Cleaning validation: The reason for cleaning validation is to affirm the theory that the cleaning method is powerful in expelling production deposit from the assigned apparatus. It needs that laborers sanitized the apparatus in a tedious way. There should be detailed instruction with reference to how they should clean the equipment and in addition records to affirm the guidelines were taken after. Water system and quality: While drinking water is utilized for some additives forms refined water is utilized broadly. Due to impurities, deionizers and ultra-filtration or RO framework were utilized to deliver cleansed water. Appropriate QC technique ought to be built up which legitimately validate and check the security and nature of water utilized. Packaging and labeling: Packaging and labeling operations will add up the risk of quality and regulatory compliance. The risk is due to the experience of finished additives to airborne contamination and humidity. To guard the additive, positive pressure area using filtered/purified air should be used for filling of additives containers. This area should be clean on a regular basis so to avoid from becoming contaminated. Therefore, manufacturing unit should be built according to the GMP like the walls, floor, and roof ought to be launderable to permit cleaning. Packaging which could get in contact with additives should not be unlocked till the time they are transferred to the packaging area. Received containers ought not to be unfastened till the time they are in the enclosed wrapping space; or else they will be presented to contamination. Filling, closing and sealing should DOSAGE FORM DESIGN CONSIDERATIONS 22.13 STUDY OF DIFFERENT TYPES OF ADDITIVES 805 be done while in packaging control environment. Faculty engaged in packaging operations should wear proper clothing and it ought to be prepared for the operation. Good practices in QC: The QC unit having the duties and expert to affirm and dismiss all parts, in-process material, packaging material, and completed product. Starting material: Starting material must be verified and tested prior to use. In process testing: examination and testing should be performed by testing which should give the result in limit. Quality records: the manufacturer ought to build up and kept up methodology for ID, collecting, ordering, documenting and maintaining and accessibility of record. Calibration testing of equipment: All equipment uses for measurement and testing distinguished as being a piece of quality framework ought to be appropriately calibrated and kept clean. Reagent, instruments, apparatus, gauges and measuring gadgets not meeting determination ought not be utilized (Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipient, 1999). 22.13 STUDY OF DIFFERENT TYPES OF ADDITIVES 22.13.1 Antioxidant The efficacy and safety of drugs administered are in close proximity with different problems like permeability, solubility, and stability. The stability of the drugs may be compromised due to different physical factors like temperature, light, etc. which ultimately results in the aggravation of different chemical reactions, e.g., oxidation, reduction, hydrolysis, etc. Antioxidants are added in the formulations with an objective to enhance the stability as well as shelf life of the formulations (Celestino et al., 2012). Antioxidants are the chemicals which are when added in the formulations, even in the minute concentrations, having chemicals which are prone to oxidation, significantly interrupt or stop the oxidation. A variety of substances are included in this category, e.g., peroxide inactivators, metal chelators, free radical scavengers, etc. The chemical category of antioxidants includes two types of chemical, firstly those which are added in products to increase the stability and secondly those which are present in food articles and body and are supposed to have good effects on health (Shahidi, 2000). The intention of inclusion of antioxidants in pharmaceutical several formulations is to exclude the oxidation reaction. Oxidation responses don’t really require atomic oxygen. For instance, the oxidation of cytidine analogs to the proportional uridine analogs can happen within the sight of water even without oxygen (Remington et al., 2006). These materials are balanced out, amid fabrication, by assembling under a nitrogen cover to reject oxygen or by inclusion of antioxidants. It is imperative to know which material is balanced out, in light of the fact that an adjustment in the source may prompt sudden stability issues due to the nearness or nonattendance of the antioxidant agent, and along these lines changes in the potential for interaction. Most antioxidant agent work by giving electron or labile H1 which will be acknowledged by any free radical to end the chain response. A large number of the lipid solvent antioxidant goes about as scavengers. DOSAGE FORM DESIGN CONSIDERATIONS 806 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS Antioxidants can likewise go about as chain eliminators, responding with free radicals in answer for stopping the free-radical propagation cycle (Decker et al., 1998). 22.13.1.1 Synthetic Antioxidants As free radicals were observed to be in charge of lipid oxidation, several natural and manufactured mixes have been assessed for their adequacy as radical scavengers or for their other inhibitory impacts. Among synthetics, just four antioxidants are generally utilized; to be specific, BHA, BHT, propyl gallate (PG), and tert-butyl hydro-quinone (TBHQ). All antioxidants have purposes of qualities and shortcomings. In this manner, certain focuses, e.g., thermal stability, concentration required, and synergism, ought to be thought about while choosing antioxidants for use specifically in food products. Administrative (regulatory) status is another factor that can’t be overlooked, particularly for a few antioxidants that have been accounted to indicate potential unfriendly well-being impacts. Synthetic antioxidants have been tested for safety and approval for use in food at low concentrations on the basis of complex toxicity studies. Reasonable breaking points for utilization of antioxidants shift extraordinarily from nation to nation and rely upon the nourishment item underthought. 22.13.1.2 Butylated Hydroxyanisole and Butylated Hydroxytoluene BHA is an antioxidant comprising of a blend of two isomeric natural mixes, 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole. It is formed from 4-methoxyphenol and isobutylene. Since 1947, BHA has been added to palatable fats and fatcontaining nourishments for its antioxidant properties as it avoids rancidification of food which makes offensive smells. BHA is a white, waxy solid that is sold as flake or tablet. It is a very fat-dissolvable monophenolic antioxidant that is widely utilized as a part of mass oils and additionally oil-in-water emulsions. BHT (3,5-di-tert-butyl-4-hydroxytoluene) is a white crystalline structure with traits like BHA. It is proper for thermal treatment, however not as steady as BHA. BHT does not have an ideal fixation; more often than not, BHA/BHT blends are added at levels of up to 0.02%. Albeit engineered antioxidants have broadly been utilized as a part of the food business, there are a few contentions about their well-being. Notwithstanding the cancer-causing nature of BHA in the forestomach of rodents, BHA and BHT have been accounted for to be cytotoxic. In spite of positive and negative reports of these manufactured antioxidants on human well-being, their utilization is liable to the direction of different regulatory bodies. As per the current food added substance controls distributed by the FDA, BHA and BHT are legitimate for use separately or in a mix at a most extreme level of 0.02%, or 200 ppm. TBHQ: It is an aromatic compound which is a sort of phenol. It is a subordinate of hydroquinone, substituted with a tert-butyl gathering. Both the EFSA and the USFDA have evaluated TBHQ and determined that it is safe to consume at the concentration allowed in foods. The FDA sets a highest level of 0.02% of the oil or fat substance in nourishment. At high measurements, it has some negative well-being consequences for lab creatures, e.g., leading to precursors of stomach tumors and harm to DNA. Various investigations have demonstrated that drawn-out presentation to high measurements of TBHQ might be cancer-causing, particularly for stomach tumors. TBHQ displayed a nontypical method of cell demise and demonstrated cytotoxicity toward human monocytic leukemia DOSAGE FORM DESIGN CONSIDERATIONS 22.13 STUDY OF DIFFERENT TYPES OF ADDITIVES 807 cells. As per directions concerning the utilization of antioxidants in nourishments, TBHQ is allowed for food use by the FDA and the USDA at under 0.02% and 0.01%, separately. At levels higher than 0.02%, TBHQ may apply an expert oxidant impact. In Japan and Europe, the expansion of TBHQ in nourishment is not permitted. 22.13.1.3 Gallates Three esters of gallic acid are affirmed for use in nourishment, in particular, PG, octyl gallate, and dodecyl gallate. PG is a white crystalline powder that is somewhat soluble in both water and fat. Although the higher octyl and dodecyl gallate are for all intents and purposes insoluble in water, they get solubilized effortlessly in fats and oils. PG is generally utilized as a part of foods where lipid-solvent antioxidants, e.g., BHA, BHT, and TBHQ are not appropriate. They prevent autooxidation of oils and peroxide development in ether and display synergistic impacts with different antioxidants, e.g., BHA. 22.13.1.4 Natural Antioxidants Worries about the security of engineered antioxidants have led to the increased research on characteristic wellsprings of antioxidants. They bring less thorough weight of security confirmation than that required for engineered ones. Be that as it may, natural antioxidants may have a few disadvantages, including high use levels, low antioxidant productivity, undesirable flavor or smell, and conceivable misfortune amid preparation. Ascorbic acid and tocopherols are the most critical business normal antioxidants. 22.13.1.5 Tocopherols and Tocotrienols Tocopherols and tocotrienols, on the whole, known as tocols, are monophenolic and lipophilic compounds that are broadly dispersed in plant tissues. When all is said in done, tocotrienols have a more grounded antioxidant impact on lipid oxidation than tocopherols. Tocols are solvent in vegetable oils but insoluble in water. They work as a free radical eliminator in autooxidation responses. As common antioxidants, tocopherols have GRAS status, and they are viewed as safe food added substances. In the United States, common tocopherols are constrained to 0.03%, i.e., 300 ppm in animal fats, and 0.02% in blend with BHA, BHT, and PG. 22.13.1.6 Ascorbic Acid L-Ascorbic acid (Vitamin C) and its salts (sodium ascorbate and calcium ascorbate) are extensive in plant tissues or are created artificially in huge amounts. Ascorbic acid is a white or somewhat yellow crystalline powder. It is an antioxidant with numerous capacities, including extinguishing different types of oxygen, diminishment of free radicals, and regeneration of essential antioxidants. Ascorbic acid and ascorbate salts have GRAS status with no usage limits. As indicated by the literature, vitamin C is protected at supplementation levels of up to 600 mg/day, and larger amounts of up to 2000 mg/day are without the chance. As common or characteristic indistinguishable items, they are much perceived as antioxidant supplements by customers. DOSAGE FORM DESIGN CONSIDERATIONS 808 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS 22.13.2 Preservatives In the pharmaceutical business, a significant number of the components utilized as a part of the formulation can advance microbial development. Such formulations are subsequently powerless to undesirable tainting. To keep this from happening, antimicrobial agents or preservatives should be added to the formulation. Theoretically, such preservatives protect the product against microbial proliferation but should not compromise product performance. Preservatives are substances added to different pharmaceutical dose structures and cosmetics to anticipate or hinder microbial development. A perfect preservative would be compelling at low concentration against all conceivable microorganism, be nonlethal and good with different constituents of the formulation, and be steady for the life span of the formulation. In practice, this means that any preservative or antimicrobial agent should: • Apply a wide range of antimicrobial action against all microorganisms at low consideration levels. • Maintain effectiveness all through item fabrication, the time span of usability and utilization. • Be nontoxic and compatible with other constituents of the preparation. • Not bargain the quality or execution of formulation, package or delivery system. • Not unfavorably influence patient well-being or resistance of the formulation. Criteria for choosing antimicrobial preservatives include: • Preservative dose. • Effects on the active ingredient. • Antimicrobial functionality. Classification of Preservatives Based on their source of origin preservatives are classified as: Natural Preservatives: These drugs are obtained by natural sources that are plant, mineral sources, animal, etc., e.g., neem oil, salt (sodium chloride), lemon, honey, etc. Artificial Preservatives: These preservatives are man-made by chemical synthesis and active against various microorganisms in small concentration, e.g., benzoates, sodium benzoate, sorbates, propionates, nitrites, etc. (Shaikh et al., 2016). Preservatives may be categorized based on their chemical nature as: Acids: e.g., benzoic acid, sorbic acids, boric acids. Esters: e.g., parabens, sodium propionate, potassium sorbate. Alcohols: e.g., chlorobutanol, benzyl alcohol, phenyl ethyl alcohol. Phenols: e.g., phenol, chlorocresol, O-phenyl phenol. Mercurial compounds: e.g., thiomersal, nitromersol, phenylmercuric nitrate, phenylmercuric acetate. 6. Quaternary ammonium compounds: e.g., cetyl pyridinium chloride, benzalkonium chloride. 1. 2. 3. 4. 5. DOSAGE FORM DESIGN CONSIDERATIONS 22.13 STUDY OF DIFFERENT TYPES OF ADDITIVES 809 22.13.3 Colors Colorants or shading specialists are for the most part used to bestow a particular appearance to the pharmaceutical dosage forms. We can likewise say that the colorants are the beautifying agents for the pharmaceutical formulations in light of the fact that the stylish appearance of dose structures can be improved by utilizing appropriate colorants. The fundamental classes of formulations that are shaded are tablets (either the center itself or the covering.), capsules, oral fluids, topical creams, toothpaste, balms, etc. The elegance and eye interest of a hued item are important. Pharmaceutical products are hued essentially to: • Augment suitability. • For detection. • Amplify stability. 22.13.3.1 Classification 1. Organic Dyes and Lakes Dyes: these are manufactured, chemical compounds that show their shading power or tinctorial quality when solubilized in a solvent. They are normally 80% 93% (infrequently 94% 99%) unadulterated colorant material. Dyes are likewise soluble in propylene glycol and glycerin. They are accessible at less expensive cost. E.g., tartrazine, sunset yellow patent blue V, erythrosine (Kanekar et al., 2014). Lakes: They have been characterized by the FDA as the “Aluminum salts of FD&C water-dissolvable dyes stretched out on a substratum of alumina.” Lakes arranged by expanding the calcium salts of the FD&C colors are likewise allowed, however to date, none has been made. Lakes likewise should be confirmed by the FDA. Lakes, dissimilar to dyes, are insoluble, e.g., Sunset yellow lake, Indigo carmine lake (Allam and Kumar, 2011). 2. Inorganic or mineral colors: Light stability is a vital trademark showed by these materials, some of which have a valuable opacifying capability, e.g., TiO2 (Allam and Kumar, 2011). 3. Natural colors or vegetable and animal color: This is an artificially and physically assorted gathering of materials. Some of these hues are the results of substance amalgamation as opposed to extraction processes, like beta-carotene. Examples of natural colorants include anthocyanins, curcumin, beetroot red, etc. (Kanekar et al., 2014). 22.13.4 Flavoring Agents Flavor alludes to a blended vibe of taste, touch, notice, sight, and sound, all of which include a mix of physiochemical and physiological activities that impact the view of substances. With the extension of innovation in the flavor business, numerous artificial or impersonation flavors have been made. Pediatric and geriatric products now are accessible in an assortment of flavors which effectively cover unpalatable tastes without influencing the physical and chemical stabilization (Sharma and Sharma, 1988). Flavor acknowledgment is likewise influenced by age. As a rule, youngsters like organic product seasoned DOSAGE FORM DESIGN CONSIDERATIONS 810 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS syrup; grown-ups incline toward a more acidic taste, while numerous old individuals discover mint or wine enhancers more pleasing. Reaction to the flavor may not be the same as well-being and infection while a flavor satisfactory for a brief timeframe may end up noticeably questionable if the treatment is drawn out. Flavors are likewise chosen on the premise of the essence of the medication to be joined. For example, to mask the salty taste butterscotch flavor is added, whereas for acidic taste citrus flours are added. A portion of the flavors are favored for specific sorts of pharmaceuticals relying on their peculiar taste. For example, for antibiotics orange, vanilla, butterscotch, etc. are used, while on the other hand for decongestants and expectorants apricot, cherry vanilla, raspberry, etc. are preferred (Sharma and Sharma, 1988). 22.13.5 Emulsifying Agent Emulsions are balanced out by including an emulsifier or emulsifying agents. These agents have both a hydrophilic and a lipophilic part in their substance structure. All emulsifying agents aggregate at and are adsorbed onto the oil: water interface to give a defensive obstruction around the scattered droplets. Notwithstanding this defensive boundary, emulsifiers settle the emulsion by lessening the interfacial strain of the framework. A few agents improve stability by giving a charge on the droplet surface consequently lessening the physical contact between the drops and diminishing the potential for coalescence. Some ordinarily utilized emulsifying agents incorporate SLS, Spans and Tween, sodium dioctyl sulfosuccinate, etc. Emulsifying agents can be grouped by (1) structure; or (2) mode of action. Classes, as indicated by structure are synthetic, natural, finely dispersed solids and auxiliary agents. Classes, as indicated by mode of action, are monomolecular, multimolecular, and particle films. Notwithstanding their grouping, all emulsifying specialists must be steady in the framework, dormant and chemically nonresponsive with other emulsion parts, and nontoxic and nonirritant. They ought to likewise be sensibly scentless. Natural Emulsifying Agents: They are gotten from plant and animal tissues and for the most part as hydrated lipophilic colloids. These emulsifiers influence the defensive sheath around the droplets, to render droplets a charge with the goal that they repulse each other and swell to boost up the consistency of the fluid. Albeit natural emulsifiers are modest, safe, and nonlethal, yet they are moderate in action in real life. So, the vast amount of emulsifier is required for legitimate activity. Additionally, the natural emulsifiers require preservatives as these are subjected to microbial development. The animal subordinates are more grounded than the plant ones. The best case of this is lecithin and cholesterol. A few people are hypersensitive to these so should be used in the wake of knowing the derivatives. Both semisynthetic and synthetic emulsifying agents require no preservative as these are not inclined to microbial development. They support the emulsion preparation by different mechanisms like interfacial tension reduction, interfacial film formation, and electrical double layer formation. Categorization of emulsifiers can also be done as: • Surfactants of synthetic origin. • Hydrophilic colloids (natural and semisynthetic). • Solid particles (finely divided). DOSAGE FORM DESIGN CONSIDERATIONS 22.13 STUDY OF DIFFERENT TYPES OF ADDITIVES 811 Examples of Emulsifiers: soap, diacetyl tartaric acid esters, gum, lecithin, cetyl alcohol, methylcellulose, stearic acid, sodium carboxymethylcellulose, etc. Soaps: Soaps or detergents may be anionic, cationic, and nonionic. They are amphipathic. One end sticks to oil (hydrophobic) and one end sticks to water (hydrophilic). Soap or synthetic detergent contains a long nonpolar tail and a polar or ionic head. The nonpolar end of the molecule dissolves well in nonpolar grease and oil while the polar or ionic head dissolves in water. The tail of soap molecule penetrates into oil or grease and breaks it up into tiny micelles. Gum: Gum may be cationic, nonionic, or anionic, e.g., xanthan gum is anionic (natural), cationic guar gum (seminatural) is cationic, and guar gum is nonionic (natural). Gums are hydrocolloidals that bind, thicken, and emulsify gluten-free ingredients. Guar gum is an emulsifier, thickener, and stabilizer endorsed for use in an extensive variety of food, beauty care products, and pharmaceuticals. It thickens without application of heat. It can act as a light emulsifier as it prevents oil droplets from coalescing. It can be easily solubilized in hot as well as cold water, has resistance to oil, greases, and solvents, with high viscosity, is functional at low temperature, and a better thickening agent. In baking it increases dough yield, in dairy products it thickens milk, yogurt, and liquid cheese products, for meat, it functions as a binder. Lecithin: It is a sort of phosphoglyceride present in a variety of plant and animal substances, e.g., egg yolk. Naturally occurring phospholipids are derived from soybean. Both oil and water loving, lecithin is a vitamin supplement and a dietary supplement. An important component of cells, it can help nourish damaged cells and tissues and also helps in keeping skin soft and supple. Used in making surfactant, to improve flow property of chocolate, to reduce cholesterol level, and helps keep our blood’s cholesterol circulating freely. Methylcellulose: Series of methyl ethers of cellulose. Hydrophilic thickening agent and stabilizer for o/w emulsion; weak o/w emulsifier. Stearic acid: An assortment of solid acid from fat, primarily stearic and palmitic. It is a lipophilic thickening agent and stabilizer for o/w lotion. Sodium carboxymethylcellulose: Sodium salt of carboxymethyl ester of cellulose, hydrophilic thickening agent, and stabilizer for o/w emulsion 22.13.6 Suspending Agent The particles in suspensions are encounter each other in a form of Brownian motion and the particles may overcome the repulsive power between them and shape bigger particles which will then settle quickly. Suspending agents decrease this development of the particles by expanding the consistency of the medium. As per Stoke’s law, the rate of sedimentation is inversely related to the thickness of the medium. So, the settling of the particles, either in flocculated or deflocculated framework, can be reduced by expanding the drag drive on the moving particles by increasing the consistency of the medium. A number of suspending agents perform two capacities. Other than going about as a suspending specialist they likewise confer thickness to the arrangement. Suspending DOSAGE FORM DESIGN CONSIDERATIONS 812 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS agents shape film around particle and lessening interparticle fascination. Suspending agents likewise go about as thickening agents. They increment thickness of the arrangement, which is important to counteract sedimentation of the suspended particles according to Stoke’s law. A decent suspension ought to have very much created thixotropy. The arrangement is adequately gooey when it avoids sedimentation and consequent accumulation or building up of the particles. At the point when fomentation is connected the thickness is diminished and gives great stream flow from the mouth of the container. Example: methylcellulose, carboxymethylcellulose, bentonite, gelatin, etc. Examples of Suspending Agents: methylcellulose, hydroxyethylcellulose (HEC), acacia, carboxymethylcellulose, tragacanth, etc. Methylcellulose: Methylcellulose is accessible in a few thickness grades, differences in methylation, and polymer chain length. Methylcellulose is more solubilized in chilly water than high-temperature water. Including methylcellulose in boiling water and cooling it with consistent blending gives a clear or opalescent gooey arrangement. Methylcellulose is steady at pH range of 3 11. As methylcellulose is nonionic, it is good with numerous ionic adjuvants. On warming to 50 C, the arrangement of methylcellulose is changed over to gel form and on cooling, it is again changed over to the arrangement of a solution. Hydroxyethylcellulose: HEC has to some degree comparative attributes to methylcellulose. In HEC hydroxyethyl groups are connected to a cellulose chain. Not at all like methylcellulose, HEC is soluble in both hot and icy water and does not form gel on warming. CMC: Carboxymethylcellulose is available at various consistency grades i.e., low, medium, and high. The choice of proper grade of CMC is dependent on the viscosity and stability of the suspension. If there should be an occurrence of HV-CMC, the thickness essentially diminishes when temperature increases to 40 C from 25 C. This may turn into a formulation stability concern. In this manner to enhance consistency and stability of suspension, MV-CMC is generally recommended. Acacia: Acacia is not a decent thickening agent but rather generally utilized as a part of the unpremeditated suspension product. For thick powder, acacia alone is not fit for giving suspending activity; for this manner, it is blended with tragacanth, starch, and sucrose which are together known as Compound Tragacanth Powder BP. Tragacanth: Tragacanth solution is gooey in nature, it gives thixotropy to the solution. It is a superior thickening agent than acacia. The greatest thickness of the arrangement of Tragacanth is accomplished after a few days, in light of the fact that it takes a few days to hydrate totally. 22.14 FUNCTIONAL AND COPROCESSED ADDITIVES Inventions occur in the pharmaceutical industry on a regular basis to cope with the latest problems arising all around the globe. Besides all the advancement in novel drug delivery systems, unit dosage forms like tablets are still a priority for researchers due to the several advantages provided by the tablets, e.g., easy manufacturing, patient compliance, etc. (Patel and Pingale, 2014). Along with the advancement in the formulations DOSAGE FORM DESIGN CONSIDERATIONS 22.14 FUNCTIONAL AND COPROCESSED ADDITIVES 813 formulation, scientists have also focused on the manufacturing and development of multipurpose additives with improved attributes in order to have better product quality. Emergence of new APIs having a variety of physical and chemical properties has also forced researchers to focus on the development of new additives to match the properties of new drug molecules. There are other factors too which have led to the development of new additives: • Demand of direct compression methods. • Need of multifunctional additives to substitute two or more additives during process. • Enhanced production capacity of manufacturing machines which require additives also to maintain the quality of the product. • Demand of patient specific products, e.g., hypertensive patients, diabetic patients, etc. • Requirement to amend the attributes of the drug molecules, e.g., solubility, etc. (Babu et al., 2013). Due to the excess utilization of additives for a variety of intentions, they have been treated as “functional ingredients” rather than “inactive ingredients.” A desirable property of an additive is the one which can upgrade the level of manufacturing or which can perk up the quality and thereby the performance of the formulation when utilized. The additives may be utilized to aid in the manufacturing process e.g., with compression, flow, ejection, etc. or to aid the product quality e.g., better dissolution, etc. (Katdare, 2006). Coprocessing is a fresh notion of varying additive attributes by the addition of new attributes with the aid of a second additive by keeping the needed properties of the parent additive untouched (Bansal and Nachaegari, 2002; Nachaegari and Bansal, 2004). A coprocessed additive is any combination of two or more additives obtained by physical coprocessing that does not lead to the formation of covalent bonds. Coprocessed additives have functionalities that are not achievable through sample blending. 22.14.1 Approaches for Development of Coprocessed Additives Characteristics of the additives can be altered easily and on a large scale with the aid of either coprocessing or particle engineering. Earlier coprocessing was adopted in the food industry only to overcome some issues like solubility, stability, etc. For example, glucomannan and galactomannan were used to enhance the gelling traits of food products. In the pharmaceutical world, coprocessing was introduced in the late 1980s in the coprocessing of MCC with calcium carbonate followed by the coprocessing of cellulose and lactose (Cellactose) in the year 1990. Coprocessing: In this process additives interact at subparticle level with an objective to provide the enhanced and improved synergistic traits of both the additives and at the same time mask the undesired characteristics of each additive. Generally, it is done with the aid of codrying and coprecipitation. Both the additives are dispersed in a solvent followed by drying, resulting into a physical mixture which is brought to a desired size range. While making a coprocessed additive the selection of components should be done wisely in such a manner that the properties of each component should complement each other. DOSAGE FORM DESIGN CONSIDERATIONS 814 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS A typical process of coprocessing may involve the following steps: • • • • • Selection and identification of group of additives to be co-processed. Selection of different ratio of the additives. Determination of particle size of coprocessed additives. Finalization of proper drying process. Process optimization. Particle engineering as a source of new additives: This is a technique where the alteration of different properties of particles such as size, shape, etc. is involved. These alterations result in the transformation of the bulk properties, e.g., flow, compression, etc. Characterization of solids can be done at three different levels, i.e., molecular level, particle level, and bulk level. These three levels are interrelated in such a way that minute changes in a single level will result in alterations in other levels. As stated earlier modulation in particle level will alter the traits at bulk level too. This interrelation provides the scientific basis for development of new additives. The formulation of the new additive must start at the particle design. The crystal lattice modulation can be easily done by altering the conditions of crystallization, drying, etc. It is also possible to engineer particles without affecting the preceding molecular level. The modulation of single additive provides limited improvement in the functional traits, therefore, to have the improved traits at a larger scale coprocessing of multiple additives is needed. 22.14.2 Properties and Advantages of the Coprocessed Additives No chemical modification: A number of studies on coprocessed additives have shown that no chemical modulation happens after coprocessing. This helps in reducing regulatory compliance. 22.14.2.1 Alteration in Physicomechanical Traits Better flow properties: Alteration in the size and size distribution results in excellent flowability which excludes the addition of glidants. Improved compressibility: Quasi-hornification is a phenomenon where an additive loses the compressibility on water addition which can be regained after coprocessing, e.g., MCC regains its compressibility when coprocessed to SMCC. Improved dilution capacity: It is an attribute where additives compressibility remains unaltered even after dilution with others, e.g., Cellactose. Fill weight variation: Bad flowability results in the higher fill weight variations but this doesn’t occur with coprocessed additives which may be due to the particle to particle matrix impregnation. Reduced lubricant sensitivity: Coprocessed additives are made of two opposite behavior materials which complement each other, e.g., brittle material (lactose monohydrate) and plastic substance (cellulose). In the mentioned combination cellulose offers better bonding, whereas lactose monohydrate gives low lubricant sensitivity (Tatavarti et al., 2005). DOSAGE FORM DESIGN CONSIDERATIONS 22.15 CLASSIFICATION OF PHARMACEUTICAL DILUENTS 815 22.15 CLASSIFICATION OF PHARMACEUTICAL DILUENTS Pharmaceutical diluents which are also termed as filler or thinner are diluting substances. These are static materials which serve as fillers in different formulations during their manufacturing processes, e.g., tablet and capsule, etc. These make up the major portion of a tablet or capsule. Lactose is used often because it is inexpensive, stable, and does not react with other medicinal substances. Furthermore, lactose has rapid solubility in water which is an advantage for the quick release of a drug substance. Other diluents used are starch (from wheat, corn, rice, and potato) sucrose, mannitol, avicel, and celutab, etc. Some fluids are unable to flow properly due to their higher viscosity which can cause a serious financial problem as it is costlier to transport such liquids. But this problem can be easily solved by the use of diluents which can decrease the viscosity and thereby the carrying costs of the viscous liquids. Tablets are designed in a manner so that the possible punchable sized tablet can be manufactured. Where the dose is very small, a large quantity of diluents are added to prepare the tablets of desired size, whereas for higher dose drugs fewer diluents are needed. The addition of diluents may induce physical or chemical changes which can result in unstable product hence the choice of diluents should be made wisely. The intention of addition of diluents to different formulations is to have some advantages like: • • • • Better cohesion. Enabling direct compression. Improved flow properties. Weight adjustment as per die/machine capacity. Categorization of tablet diluents can be done as follows: • Organic diluents—e.g., Carbohydrate and tailored carbohydrates. • Inorganic diluents—e.g., Calcium phosphates and others. • Coprocessed Diluents. During wet granulation process, carbohydrate, e.g., sugars, starches, and celluloses, can also serve as binders but they can also serve as diluents if utilized during direct compression process, unlike inorganic diluents. Also, solubility can be used as criteria to classify the diluents. Sugars, e.g., sucrose, mannitol, etc., are in the insoluble diluent category, whereas MCC, starch, etc. are in the insoluble category. 22.15.1 Organic Diluents Lactose Monohydrate (Hydrous): This is utilized in wet granulation as it is not directly compressible. Also, it is water soluble, economic, doesn’t affect drug release, has poor flow attributes and results in hard tablets which continue hardening during storage. Lactose monohydrate containing formulations are more prone to instability as it includes 5% of hydrous composition. DOSAGE FORM DESIGN CONSIDERATIONS 816 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS Spray-Dried Lactose: This diluent is also utilized in the pharmaceutical industry due to its inherited attributes like direct compressibility, free-flowing, etc. But it is costlier when compared to hydrous and anhydrous lactose. Also, it gets darker in color with amines and similar compounds and due to excess moisture which may be attributed to furaldehyde. Lactose Anhydrous: Unlike hydrous lactose, it is directly compressible. It has poor flow characteristics, undergoes Maillard reaction to very little extent, is cheap, and can absorb moisture under high humidity conditions. Mannitol: It is water soluble, costly, has bad flowability, less hygroscopic, noncarcinogenic, and inherited with low caloric value and popularly used in chewable tablets. MCC: It has good compressibility and is popularly used as tablet diluent and results in good hardness of tablets even at low pressure. Also, it has satisfactory flowability and is comparatively pricey. It also exhibits binding and disintegrant properties. During compression of tablets, it may face plastic deformation and thereby is more susceptible to lubricants. Variants of MCC, i.e., silicified MCC, provide some advantages over MCC, e.g., augmented compactibility, improved flowability, etc. 22.15.2 Inorganic Diluents Calcium Phosphates: Calcium phosphates are low priced have good flow attributes, nonhygroscopic, compressible, and result in hard tablets, while at the same time their abrasive behavior causes machine wear and tear and the alkaline pH results in instability. They include hydrated and anhydrous variants of dibasic and tribasic calcium phosphate. They have found their wide application in both direct compression as well as in wet granulation. A variant of dicalcium phosphate, i.e., spherically granulated dicalcium phosphate anhydrous has found good flowability, good compressibility, and increased moisture uptake under high humid conditions as a contrast to dicalcium phosphate dihydrate (DCPD). 22.15.3 Coprocessed Diluents Cal-Tab: It is a combination of Calcium sulfate and vegetable gum (93:7). Sugartab: It is a blend of Sucrose (90% 93%) and invert sugar (7% 10%). Emdex: It is an intermingle of Dextrose (93% 99%) and maltose (1% 7%). 22.16 PHARMACEUTICAL SOLVENTS Solvents are chemical substances that can dissolve, suspend, or separate different substances more often than not without chemically changing either the solvents or alternate materials. Solvents can be organic, which means the solvent contains carbon as a major aspect of its constitution, or inorganic, which means the solvent does not contain carbon. For example, hydrocarbon and oxygenated solvents are organic solvents that can adequately dissolve numerous materials. DOSAGE FORM DESIGN CONSIDERATIONS 22.16 PHARMACEUTICAL SOLVENTS 817 Viable synthesis of an API is, as a rule, a multilevel and confounded process. Generally, chemical synthesis comprises of four stages: reaction, separation, purification, and drying. Regularly employments of solvents in the union are solubilization (reaction medium), extraction, and crystallization. They may likewise participate in reactions, as reactants or catalysts and furthermore partake in azeotropic or extractive refining processes as entrainers. The principle capacity of solvents in a reaction step is solubilization. Solvents make solutes more responsive by breaking strong bonds that hold crystalline and fluid solutes together. An assortment of solvents are utilized as a part of the extraction process, e.g., chlorinated solvents, e.g., chloroform as well as ketones, ethers, esters, and alcohols. In numerous crystallizations the control of properties, e.g., size and shape, is an imperative factor (Grodowska and Parczewski, 2010). Organic solvents can also be utilized as a segment of the last product and don’t need to be evacuated. Generally, they satisfy the capacity of diluents or solubilizers, primarily in fluid and semisolid dosage forms when water can’t be utilized. Fluid production comprises of dissolving the dynamic pharmaceutical ingredient in a proper solvent, regularly with different preservatives and different additives, and blending the ingredients totally. The most famous and the most alluring solvent for these medications is water. The most up to date innovations effectively maintain a strategic distance from organic solvents for water. Nonetheless, here and there the utilization of nonaqueous solvents is fundamental. In such cases, they can be utilized independently or in blends of at least two solvents (cosolvents). In the wet granulation procedure of tablet generation, solvent (granulation liquid) causes massing of a dry blend powder. Solvents for granulation might be utilized alone or with the expansion of different substances that enhance the adhesive properties of particles. Much of the time, water is utilized for the granulation procedure. Previously, the pharmaceutical business expected to bring together regulations and breaking points for residual solvents (RSs). For a long time, the United States Pharmacopeia was the main pharmacopeia setting limits for RSs in pharmaceutical items. In 1990, limits for RS were recommended in Pharmeuropa and, all the more as of late, in the second International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) rule draft. The ICH distributed its Guidance for Industry Q3C, in December 1997. ICH guideline traded off regulatory specialists from Europe, Japan, and the United States, and also agents of the researchbased pharmaceutical companies. As per Q3C guideline, solvents are isolated into four groups. The primary gathering (Class 1) contains known human cancer-causing agents, compounds emphatically associated with being human cancer-causing agents, and natural risks, e.g., 1, 2-dichloroethane, carbon tetrachloride, benzene, etc. Class 2 comprises of solvents which should be constrained in light of the fact that they are nongenotoxic animal cancer-causing agents or conceivable causative specialists of irreversible toxicity, e.g., neurotoxicity or teratogenicity. They are additionally associated with other huge, reversible toxicities, e.g., chlorobenzene, cyclohexane, 1,2-dichloroethene, etc. Class 3 solvents have authorizations of day by day exposures of 50 mg (0.5%) or less on per day basis. DOSAGE FORM DESIGN CONSIDERATIONS 818 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS Class 4 solvents. For this group, there is no sufficient toxicological information empowering a plan of satisfactory limits. On the off chance that makers need to utilize Class 4 solvents, they should make available advocation for residual levels of this class of solvents in a formulation (ICH-Q3C(R6), 2016). The solvents are classified as inorganic solvents and organic solvents 22.16.1 Inorganic Solvents Water: It is polar in nature and considered as a universal solvent. Like other pharmaceutical substances, water must affirm to GMP standards. It must be versatile and consent to WHO rules for drinking water quality. Types of pharmaceutical water: Bulk form: • Purified water. • Water for injection (WFI). Packaged form: • • • • • Bacteriostatic water for injection. Sterile water for inhalation. Sterile water for injection. Sterile water for irrigation. Sterile purified water. Purified Water: It is a sort of water that has been mechanically separated or handled to expel debasements and make it appropriate for utilization. It may come from either a spring or surface or groundwater source or straightforwardly from the tap. Since the cleaning procedure is intended to expel practically a wide range of polluting influences, the nature of the source water has small bearing on the nature of the last item. Purified water is typically created by the cleansing of potable water. The contaminations that may be required to be separated out are organic compounds, inorganic ions, bacteria, endotoxins, and nucleases. WFI: This is pyrogen-free water, purified by distillation for the manufacturing of parenteral formulations. It is intended for use as solvent only in solution, i.e., to be sterilized after preparation and endotoxin content must be controlled. Water for injection can be prepared under aseptic conditions. It does not contain any additive. It must meet the standards of pyrogen test and sterility test for purified water. Types of WFI • Potable Water: Utilized in early stages of chemical synthesis. • Purified Water: Utilized as additives in production of pharmaceuticals. • Bacteriostatic Water for injections (USP): Contains added antimicrobial preservatives which prevent the growth of microorganisms. Sterile Water for Injection (USP): It is a nonpyrogenic and sterile form of water for infusion which contains no bacteriostat, antimicrobial, or included buffer and is provided just DOSAGE FORM DESIGN CONSIDERATIONS 22.16 PHARMACEUTICAL SOLVENTS 819 in the single-measurement container to dilute or solubilize drugs for the parenteral purpose. For I.V. products, an adequate solute is added to make an isotonic arrangement. This parenteral formulation is demonstrated just to dilute or dissolve drugs for intravenous, intramuscular, or subcutaneous products, as indicated by guidelines of the producer of the medication to be administered. Bacteriostatic Water for Injection (USP): It is a nonpyrogenic, sterile form of water for injection containing 0.9% (9 mg/mL) of benzyl alcohol included as a bacteriostatic additive. Bacteriostatic water for injection is made up from WFI that is disinfected and reasonably bundled, containing at least one appropriate antimicrobial specialist. Sterile Water for Irrigation (USP): It is a hypotonic, nonpyrogenic, sterile irrigating liquid or pharmaceutical aid completely made out of Sterile Water for Injection USP. It is made up by distillation and contains no antimicrobial or bacteriostatic additives or included buffer and have pH 5.7 (5.0 7.0). Sterile Water for Inhalation Injection: It is packed and made sterile and is planned for application and preparation of inhalational formulations. It conveys less stringent particulars for bacterial endotoxins than sterile water for injection, and in this way, is not appropriate for parenteral products. 22.16.2 Organic Solvent Organic solvents are always present in the pharmaceutical manufacturing procedures. The pharmaceutical business is one of the biggest clients of organic solvents per measure of the final formulation. For toxicological causes, makers try to limit the number and measure of solvents connected in a drug manufacturing process. Due to some physical and chemical hindrances, organic solvents can’t be totally disposed of from the item by manufacturing processes, e.g., by drying in a raised temperature under diminished pressure or by lyophilization. Normally some little measures of solvents may stay in the final product. They are called RSs, additionally regularly known as organic volatile impurities. Extraordinary headings distributed in pharmacopeias and ICH guidelines decide the greatest reasonable measures of RS in pharmaceutical products. If the measures of RS are beneath the limits the examined product is cleared as available to be purchased. Organic solvent use in pharmaceutical drug manufacturing processes (Bauer and Barthélémy, 2001): • Alcoholic solvents: ethanol, butanol, 2-ethylhexanol, isobutanol, isopropanol propanol, etc. • Ketones: methyl ethyl ketone, acetone, methyl isopropyl ketone, etc. • Halogenated solvents: Chloroform, etc. • Amides: dimethylformamide, etc. • Ethers: ethyl ether, etc. • Sulfur containing: DMSO, etc. • Nitriles: acetonitrile, etc. DOSAGE FORM DESIGN CONSIDERATIONS 820 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS 22.17 EVALUATION AND QUALITY TESTING OF PHARMACEUTICAL ADDITIVES The FDA’s key role is to verify safety issues for drug items and additives because the pharmacologically inactive additives make up the majority of a drug product. Shockingly, there are some outstanding cases of patient mischief that came about because of additive impurity influences. This section concentrates on the issues expected to guarantee that the additives utilized as a part of drug product fabrication are truly what they are proposed to be. They should meet manufacturing determinations and regulatory prerequisites (Petersen et al., 2004). In the blend with the extension of reasonable manufacturing procedures, the additive maker ought to create suitable Quality test techniques, where the additive is marked as meeting the requirements of a monograph. Test techniques that don’t take the majority of the points of interest portrayed in the monograph ought to be invalidated. This involves recorded logical proof demonstrating additive meets the assigned monograph determination parameter. In the event that different strategies are created and considered more agreeable, they should be validated against the detailed techniques or strategy and observed to be proportionate to or superior to the compendial technique. Their utilization ought to be legitimized. If there is an irregularity between the outcomes accomplished utilizing the compendia strategy and the manufacturer’s technique, the compendia technique is considered the official outcome. Frequently an additive manufacturer will build up its own test technique for different processes, e.g., to give affirmation the additive meets the planned execution necessities or to screen or manage the existence of different ingredients. These noncompendial systems must match the necessities for a reasonable test procedure as ordered in the compendia. Test procedures fall into two characterizations; those which can and those which can’t be approved. Instances of systems which can’t be approved include estimations, ordinarily including physical procedures, e.g., bulk density and refractive index which rely upon organizing estimation using adjusted instruments. Such techniques can’t be validated in the classical manner. Another characterization is for procedures which can be approved. There should be a validation rule and report for the entirety of procedures that are noncompendial. The validation protocol ought to depict the examination with a specific end goal to demonstrate the strategy is proper, including such points of interest as a portrayal of the test technique, reagents, standards, and so on. The protocol ought to likewise depict the test outcomes that must be accomplished keeping in mind the end goal to consider the technique validated. After commencement of validation has been coordinated, there should be a report filing the test results and conclusion. Test strategy approval may consolidate appraisal of things, e.g., exactness, specificity, linearity, etc. ICH Q2 validation direction gives extra points of interest on validation (ICH-Q2(R1), 2005). 22.17.1 Additive Specifications A specification should be in accordance with the established material monograph. Draft or conditional specifications ought to be produced that are as per acknowledged standards DOSAGE FORM DESIGN CONSIDERATIONS 22.17 EVALUATION AND QUALITY TESTING OF PHARMACEUTICAL ADDITIVES 821 and are reliable with the manufacturing procedure and its procedure ability. The additives end use (oral, sterile, dermal) should moreover be considered in building up these specifications. The specifications ought to incorporate control of the composition (e.g., RSs) identified with both the crude materials and the manufacturing procedure. It is essential that proper cutoff points for the addition of microbial tallies and compendial marker organisms ought to be built up in light of the probability for microbial contamination and the capacity of the additive to help microbial development. If the additive is planned for use in parenteral drug items, proper points of confinement ought to likewise be built up for endotoxins. The draft specification for compendial additives ought to contain determined extents for all results that guarantee the additive meets the compendial prerequisites. If the additive is not compendial, at that point the predetermined extents ought to guarantee the additive matches the specialized and regulatory prerequisites fitting the utilization and route of administration. 22.17.2 Additive Stability The additive stability should be sufficient that the additive stays within sales specification until past its expiration period. The additive provider ought to give information to demonstrate soundness in the commercial packs and characterized stockpiling conditions that are expected to shield the additive from spoilage all through the inventory network. If stability information is not accessible; the additive client may need to create it themselves. Preliminary data can be created utilizing accelerated stability studies and conditions portrayed in the ICH guideline Q1A. This guideline was created for drug substances (APIs) and drug formulations, so assessment of additive stability is done under the guidance of these guidelines. Preferably, tests of three commercial batches of the additive ought to be utilized to set up the stability of the additive in the commercial pack. Tests of the additive from these batches ought to be put away in commercial conditions or in the most pessimistic scenario of packing material under the prescribed stockpiling conditions. Occasionally, additives ought to be examined from the three batches and tested to ensure they exhibit conformance of stability through the expressed expiry time frame (Katdare, 2006). 22.17.3 Receipt, Sampling, Testing, and Approval of Raw Materials The COA is the additive manufacturer’s duty: to check the item and guarantee that it is legitimately tested, handled, and stocked after production. Upon supply of a shipment, each batch of additive should be withheld from use until the point that the parcel is inspected, tried, or analyzed by the specified methodology. The QC workforce will inspect every package for the manufacturer’s name, the lot number, any kind of leakage, contamination, infringed containers, packaging and labeling, and Material safety data sheet. Samples of every shipment must be gathered for testing. The quantity of containers to be examined relies upon the component inconstancy, confidence level, level of precision, past quality history of the provider, and the amount required for investigation and reserve DOSAGE FORM DESIGN CONSIDERATIONS 822 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS stock. For dangerous or profoundly toxic crude materials, in which on-site testing might be unreasonable, providers’ COA ought to be gotten, demonstrating that the raw materials conform to specifications by examining its labeling and packaging. The absence of on-site testing for perilous raw materials ought to be reported. Each sack or container of raw materials ought to be related to a special code, lot, or receipt number which is utilized as a part of recording the disposition of each parcel. Crude materials should be put in custody under isolated conditions until the point when they are inspected, tested, and discharged. Raw materials ought to be deliberately handled and put away to maintain a strategic distance from any contamination or cross-contamination. When sacked and boxed crude materials are secured, it must be done as such in enough cleaned structures that are free of invasion by rodents, fowls, creepy crawlies, and other vermin, and the building ought to be maintained. A controlled environment might be important to maintain a strategic distance from microbial contamination or degradation caused by the introduction of temperature, air, or light. When the crude materials are secured outside, the container should be acceptable for the outdoors stockpiling. A sample of each package will be assembled for testing according to the developed technique. A number of compartments to test and the illustration measure should be established on indicated criteria as required (Tatavarti et al., 2005). Test containers ought to be appropriately labeled. The label ought to incorporate information about the example name, manufacturer name, test size, and date and hour of examining. Raw material containers chosen for examining ought to be opened, sampled, and resealed in a control condition to protect from contamination of the crude materials themselves or other material. After QC controller stamp is endorsed, the material is discharged and the item is exchanged from quarantine to the accessible stock range to be used. If QC lab rejects the material, it will be moved into a different region. Raw materials ought to be reevaluated, as fundamental, to decide their reasonableness for utilization (e.g., after prolonged stockpiling or after introduction to temperature or high mugginess). 22.17.4 Packaging and Labeling Control Stockpiling conditions ought to be mentioned on the label of containers. Point by point composed strategies clarifying the accepting, handling, recognizing, putting away, and testing of the crude materials ought to be set up. Crude material container names ought to contain the material name, provider’s name, lot number, stockpiling conditions, retesting date, and some other notices or risks. Named stockpiling conditions should be according to standard definitions for “Controlled Room Temperature,” “Cold,” or “Freezer,” as characterized in the USP or guidelines of the ICH. The label on every container ought to likewise involve any notices to watch the contents from unjustifiable warmth, light, dampness, or freezing. Any labeling or packing substances that don’t meet the specifications ought to be disposed of properly. 22.17.5 Analytical Procedures Analytical techniques and references ought to be open if the systematic strategy utilized is in the present revision of another FDA-perceived standard reference (e.g., AOAC DOSAGE FORM DESIGN CONSIDERATIONS 22.18 CURRENT DEVELOPMENTS IN ADDITIVE SCIENCE 823 International Book of Methods), and the referenced expository methodology is not adjusted. In any case, the validated systematic methodology for novel additives ought to be given. The ICH guidelines (Q2A, Q6B) can be used to facilitate. 22.18 CURRENT DEVELOPMENTS IN ADDITIVE SCIENCE With the progress from basic formulations to drug delivery frameworks, the interest in synthetic or semi-engineered utilitarian polymers, e.g., acrylates, has increased colossally. In the current scenario, as the pharmaceutical business needs to manage the patent cliff, reduced healthcare spending, and more thorough regulations, drug advancement has turned out to be muddled. In any case, new additives offer open doors. A novel additive could reformulate endorsed drugs to show signs of improving quality and safety of the pharmaceutical or to trim down its assembling costs. Regardless of the quantity of modulated and coprocessed additives to have gone to the market as of late, all producers avoid their advancement in light of the fact that the procedure is time-consuming, requires assets, and is related with high disappointment risks. There’s a formulation change in many aspects. First of all, the API is coming up in many novel formats. For biologics, we’ve seen changes in the regime from monoclonal antibodies to multivariations of antibody formats. In formulation research, people are looking for further stable formulations with extended life cycles and longer shelf life. Aside from dependable qualities, the progression and assessment of new additives involve a multidisciplinary comprehension of technical, safety, quality, and regulatory perspectives. The technical complexities linked with drug development have amplified over the years. This is mainly due to the challenges associated with the drug solubility problems, complex drug actives, and stability of the drugs. More often than not, the present arrangement of additives in endorsed products is not sufficient to plan challenging molecules, compelling pharmaceutical researchers to explore new additives. International pharmacopeias had defined the list of purposes for which certain additives are used. Many additives have more than one use, which can be a plus since it shrinks the number of additives needed and minimizes the risk of interactions between them (Steinberg et al., 1996). Right now, it is expected that an additive is “accepted” when a novel formulation, of which it is an ingredient, gets regulatory acknowledgment. Existing regulations and guidelines demonstrate that the latest additives ought to be tested for full toxicological assessment like a new chemical entity. No authority is accessible for possibly valuable materials (basically new additives) available from different businesses, e.g., established additives with another application, e.g., route of administration change. Be that as it may, regardless of this state, drug organizations are effectively assessing new materials or applying new uses to existing additives (Baldrick, 2000). In spite of the absence of regulatory direction, the advancement of new or change of existing additives has been growing as of late. What’s more, the use of new additives in old drug formulations for a variety of pharmaceutical classes is being researched, e.g., • Different applications are being examined for the polysaccharide chitosan which is an acknowledged nourishment additive. These look at the use in controlled-discharge DOSAGE FORM DESIGN CONSIDERATIONS 824 • • • • • 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS matrix tablets, in novel formulation (e.g., for hormone discharge) in transmucosal drug delivery and in wound recovering. Preclinical assessment to date has demonstrated no unfavorable toxicity (Illum, 1998). Aquateric watery enteric coating in solid dose forms has as of late experienced subchronic and formative toxicity examinations in light of IPEC proposals with no antagonistic impacts or genotoxicity found (Batt and Kotkoskie, 1999). PEGs are recognized as a settled part of protected pharmaceutical additives. The protection of these substances as enhancers has been evaluated in different toxicity quality investigations with just mellow local toxicity observed (Hjortkjaer et al., 1999). PEG 400 exhibited no unfavorable impacts on the morphology and respectability of the nasal mucosa when tried as an enhancer (Rahman and Lau-Cam, 1999). A variety of distributed information exists for the utilization of liposomes (phospholipid-based vesicles) or smaller particles (micro/nano) having additives to advance the delivery of applicant drugs. It has improved stability and toxicity with a sustained life span of activity and has a part in particular site delivery. No unfriendly impacts have been accounted for liposomes (Maheshwari et al., 2012, 2015). Microspheres/nanospheres prepared from polymer-like PLGA are right now being assessed for an assortment of controlled-discharge drug delivery applications. A humanized monoclonal antibody administered intravitreally of PLGA microspheres demonstrated no unfavorable impacts with the additive from its toxicology and pharmacokinetics data (Tekade et al., 2017). The polyol erythritol has been assessed for metabolic and toxicological evaluation in animal and tests with human has been appeared to be very much endured with no toxicological reporting (Munro et al., 1998). 22.19 INTERNATIONAL PATENTED ADDITIVES 22.19.1 Sustained Release Excipient and Tablet Formulation (US5128143 A) The present invention relates to a sustained release pharmaceutical excipients product that may be intermingled with a variety of therapeutically active agents and tableted. A controlled-released additive embraced of hydrophilic gum matrix having combination of two gums, i.e., xanthan and galactomannan gum proficient of cross-linking under the environment of gastric fluid with xanthan gum. The proportion of said xanthan to said galactomannan gum being from in regards to 3:1 to question 1:3, and a dormant diluent, the proportion of said idle diluent to said hydrophilic gum grid being from around 4:1 to around 0.67:1, and a productive amount of a medicament to render a therapeutic impact, the proportion of said medicament to said hydrophilic gum framework being from around 1:3 to around 1:10 (Baichwal and Staniforth, 1990). 22.19.2 Cross-Linked Cellulose as Some Tablet Excipients (US5989589 A) Cross-linked cellulose is a magnificent binder disintegrant that can be utilized as a part of the formulation of pharmaceutical tablets. The tablets that are so arranged are made of DOSAGE FORM DESIGN CONSIDERATIONS 22.19 INTERNATIONAL PATENTED ADDITIVES 825 a compacted blend of a powder of a pharmaceutically dynamic ingredient with a powder of a pharmaceutical additive including a pharmaceutically worthy type of cross-linked cellulose in an amount up to 35% by weight of the aggregate weight of the tablet. The crosslinked cellulose is detailed by cross-linking microcrystalline or fibrous cellulose with a cross-linking mediator. Tests have exhibited that cross-linked cellulose is anything but difficult to integrate and has low binding/disintegrating which is determined by the degree of cross-linking degree. At low cross-linking degree, cross-linked cellulose is more a binder than a disintegrant although at a degree of high cross-linking, it is more a disintegrant than a binder (Cartilier and Chebli, 1997). 22.19.3 Low-Melting Moldable Pharmaceutical Excipient and Dosage Forms Prepared Therewith (US5004601 A) An additive for a pharmaceutical compound dissolving at body temperature but that won’t immediately distort at higher temperatures experienced in shipment was readied. A low-melting pharmaceutical additive consisting essentially of low MW PEG 75% 90% (M.P. about 37 C), medium to high MW PEG 0% 4%, long-chain saturated carboxylic acid 0% 4%, polyethylene oxide 0% 4%, and (MW 100,000 5,000,000) colloidal silica 10% 20% (Snipes, 1988). 22.19.4 Pharmaceutical Excipient Having Improved Compressibility (US5585115 A) An additive based on MCC having improved compressibility, regardless of whether used in direct compression, dry granulation, or wet granulation formulations, was readied. The additive is the blend of MCC particles and silicon dioxide particles (0.1% 20% by weight of the MCC), wherein the MCC and silicon dioxide were in suggested association with each other. The silicon dioxide used in the novel additive has a molecule estimate from around 1 nm to around 100µm (Sherwood et al., 1995). 22.19.5 Trehalose as Stabilizer and Tableting Excipients (US4762857 A) An improved method for preparing tablets useful in diagnostic and therapeutic applications, utilizing trehalose as an additive and stabilizer, was provided. In the method of tableting powders for therapeutic applications, wherein the powders were the product of an spray freezing process, for obtaining frozen droplets by spraying an aqueous solution of ingredients useful in therapeutic applications onto the surface of a moving bath of boiling perfluorocarbon liquid, followed by lyophilization of the droplets to dried powders suitable for tableting, the improvement comprising tableting the dried powders with the use of trehalose as tableting additive and stabilizer (Ernest Bollin and Fletcher, 1987). DOSAGE FORM DESIGN CONSIDERATIONS 826 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS 22.19.6 Coprocessed Tablet Excipient Composition Its Preparation and Use (US20130177649 A1) The development relates to a coprocessed additive piece reasonable for tableting, said creation involving no less than one filler-binder, no less than one disintegrant and no less than one lubricant which has been subjected to granulation mutually, and said arrangement to some degree or entirely covered with lactose, ideally in crystalline form. The creators defeated the bias contrary to the utilization of lubricants in tableting additive structures right on time in the tableting procedure. It was discovered that the claimed negative impacts of the lubricant as far as binding and disintegration could promptly be controlled in an additive arrangement wherein the lubricant is coprocessed in the matrix, and the composition is furnished with a lactose coat. The coprocessed additive comprising 40% 70% lactose, 20% 50%, MCC, 10% 10% cross-linked sodium starch glycolate and 0.2% 1% lubricant, based on total dry weight of the composition (Gessel, 2010). 22.19.7 Chemical Additives to Make Polymeric Materials Biodegradable (US8513329 B2) In the present development another additive material that was physically mixed with polymeric material to make no less than a mostly biodegradable product, was prepared. An admixture which was used for enhancing biodegradation of polymeric material when added thereto comprising a furanone; a glutaric acid; a carboxylic acid compound comprising a chain length from about 2 to about 36 carbons; a polymer chosen from the cluster of poly-caprolactone, polycaprolactone, poly(lactic acid), poly (glycolic acid), and poly(lactic-co-glycolic acid); and a carrier resin selected from the collection consisting of polydivinyl benzene, ethylene vinyl acetate, polyethylene, polypropylene, polystyrene, polyethylene terephthalate, polyvinyl chloride, methyl methacrylate, polycarbonate, polyamide, poly olefins and any copolymers of said polymers (Lake and Adams, 2008). 22.19.8 Coprocessed Microcrystalline Cellulose and Sugar Alcohol as an Excipient for Tablet Formulations (US 8932629 B2) A particulate coprocessed synthesis containing MCC and no less than one sugar alcohol was formulated. The flavored sugar alcohol was mannitol. The structure had a better compressibility profile, lubricant affectability, and ejection profile than MCC and the no less than one sugar alcohol, either alone or in a blend as a simple dry mix, in the development of solid dose formulations, e.g., tablets. The composition of said additive was MCC and at least one sugar alcohol in ration 70:30 to 95:5 (Li et al., 2007). 22.20 FDA GRAS ADDITIVES Under the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act, any substance purposely added to food is a food additive and is liable to premarket DOSAGE FORM DESIGN CONSIDERATIONS 22.20 FDA GRAS ADDITIVES 827 endorsement by FDA unless the utilization of the material is GRAS (the GRAS arrangement) (or generally excepted from the meaning of food additive, e.g., color additive). By 1961, FDA had revised its regulations to incorporate a rundown of food substances that are GRAS under specific states of utilization (“the GRAS list”). In the 1960s, numerous producers asked for FDA’s judgment on whether their decisions of GRAS status were advocated and received “opinion letters.” In 1969, FDA expelled cyclamate salts from its GRAS list because of safety inquiries, and afterward, President Nixon guided FDA to reexamine the safety of GRAS substances. In the 1970s, FDA announced that it was leading a “comprehensive review” of assumed GRAS substances and built up rulemaking methods to affirm the GRAS status of substances that were either on the GRAS list or the subject of an appeal (“GRAS affirmation”). To remove the rulemaking methodology, in 1997, FDA proposed to supplant the GRAS affirmation to process with a notice strategy (“GRAS notification”) (Burdock et al., 2006). 22.20.1 Substances That Are Generally Recognized as Safe 1. It is not reasonable to list all material that is GRAS for their proposed utilization. Be that as it may, basic food ingredients, such as pepper, vinegar, monosodium glutamate, etc., are viewed as safe for their proposed utilization. Extra substances are incorporated here that, when utilized for the reasons showed, as per GMP, are viewed as GRAS for such employment. 2. For the motivations behind this segment, GMP should be characterized to incorporate the accompanying limitations: a. The measure of a substance added to food does not outperform the whole sensibly critical to finish its proposed physical, supporting, or other specific effect in nourishment; and b. The measure of a substance that turns into a constituent of food because of its utilization in the manufacturing, preparing, or packaging, and this is not planned to achieve any physical or other specialized impact in the food itself, might be diminished to the degree reasonably conceivable. c. The substance is of proper food grade and is arranged and dealt with as a food ingredient. Based on specification and expected use, it is viewed as safe for the reason proposed, by specialists qualified to assess its safety. 3. The consideration of substances in the rundown of nutrients does not constitute a finding with respect to the Department that the substance is valuable as a supplement to the eating regimen for people. 4. Substances that are GRAS for their proposed use inside the importance of segment 409 of the act, but when status of additive or ingredient is revised, it will be erased from this part, and will be issued as another control under the suitable part. 22.20.2 Examples of GRAS Additives Spices and Other Natural Seasonings and Flavorings: e.g., angostura (cusparia bark), anise, capsicum, caraway, cardamom, spearmint, turmeric, vanilla, etc. DOSAGE FORM DESIGN CONSIDERATIONS 828 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS Multiple Purpose GRAS Food Substances: aluminum sodium sulfate, caffeine, calcium phosphate, caramel, glycerin, methylcellulose, monoammonium glutamate, monopotassium glutamate, sodium carboxymethylcellulose, etc. Anticaking Agents: calcium silicate, etc. Chemical Preservatives: sorbic acid, calcium ascorbate, potassium bisulfite, sodium bisulfite, sodium sorbate, tocopherols, etc. Stabilizers: Chondrus extract. Nutrients: ascorbic acid, calcium pyrophosphate, choline bitartrate, etc. 22.21 CONCLUSION The pharmaceutical additives are being used in each and every formulation, but due to the lack of awareness as well as regulations regarding the additives, patients, being the end consumers, may have to suffer the serious side effects. A few countries like the United States, China, Japan, and India have put the efforts into developing the regulations for the additives along with FDA but still their implementation during the manufacturing process of additives as well as formulations is still in doubt. All the additives should be manufactured, tested, stored, and utilized according to the specific guidelines. The GRAS status to different additives has sorted a variety of problems related to additives but still the GRAS additives should be utilized within the specified limits as per the guidelines. The mere GRAS status to different additives doesn’t justify the irrational utilization of the additives. As discussed, different countries and regulatory bodies have focused on framing the regulations but the implementations of those regulations should also be considered for the well-being of human society. Disclosures: There is no conflict of interest and disclosures associated with the manuscript. ABBREVIATIONS API BHA BHT CAS CFCs CMC COA CPAC CTD DMF EEC EFSA EPA FDA GMP GRAS HFA Active pharmaceutical ingredient Butylated hydroxyanisole Butylated hydroxy tocopherols Chemical Abstracts Service Chlorofluorocarbons Carboxy methyl cellulose Certificate of Analysis Central Pharmaceutical Affairs Council Common Technical Document Drug master file European Economic Community European Food Safety Authority Environmental Protection Agency Food and Drug Administration Good manufacturing practice Generally Recognized As Safe Hydrofluoroalkanes DOSAGE FORM DESIGN CONSIDERATIONS REFERENCES I.M. ICH IPEC M.P. MCC mg MHW mL MW NaCMC NDA PEG PMDE ppm PQG QC RS S.C. SLS SOP WFI WHO W/O 829 Intramuscular International Conference on Harmonization International Pharmaceutical Excipient Council Melting point Microcrystalline cellulose Milligram Ministry of Health and Welfare Milliliter Molecular weight Sodium carboxymethylcellulose New Drug Application Polyethylene glycols Pharmaceuticals and Medical Devices Evaluation Parts per million Pharmaceutical Quality Group Quality control Residual solvents Subcutaneous Sodium lauryl sulfate Standard Operating Procedure Water For Injection World Health Organization Water in oil References Allam, K.V., Kumar, G.P., 2011. Colorants the cosmetics for the pharmaceutical dosage forms. Int. J. Pharm. Pharm. Sci. 3, 13 21. Babu, S.S., Kumar, A.A., Suman, D.R., 2013. Co-processed excipients: A review. Int. J. Curr. Trends Pharm. Res. 1, 205 214. Baichwal, A.R., Staniforth, J.N., 1990. Sustained Release Excipient and Tablet Formulation. US5128143 A. Bajaj, S., Budhwar, V., 2012. Review of regulations for novel pharmaceutical excipients. Int. J. Pharm. Sci. Res. 3, 15 20. Baldrick, P., 2000. Pharmaceutical excipient development: the need for preclinical guidance. Regul. Toxicol. Pharmacol. 32, 210 218. Bansal, A.K., Nachaegari, S., 2002. High-functionality excipients for solid dosage forms, Bus. Briefing Pharmagenerics. Business Briefings Limited, London, pp. 38 44, ISBN:10:1903150698. Barry, B.W., 1983. Dermatological formulations: percutaneous absorption. Drugs and the Pharmaceutical Sciences: A Series of Textbooks and Monographs. Marcel Dekker, New York, NY, pp. 296 299. Batt, K.J., Kotkoskie, L.A., 1999. An evaluation of genotoxicity tests with Aquateric (R) Aqueous Enteric Coating. Int. J. Toxicol. 18, 117 122. Bauer, M., Barthélémy, C., 2001. Handbook of Solvents, first ed. ChemTec Publishing, Toronto, NY. Burdock, G.A., Carabin, I.G., Griffiths, J.C., 2006. The importance of GRAS to the functional food and nutraceutical industries. Toxicology 221, 17 27. Cartilier, L., Chebli, C., 1997. Cross-Linked Cellulose as a Tablet Excipient. US5989589 A. Celestino, M.T., Magalhães, U.D.O., Fraga, A.G.M., do Carmo, F.A., Lione, V., Castro, H.C., et al., 2012. Rational use of antioxidants in solid oral pharmaceutical preparations. Braz. J. Pharm. Sci. 48, 405 415. Chan, H., Chew, N.Y.K., 2007. Excipients: powders and solid dosage forms. Encyclopedia of Pharmaceutical Technology. Informa Healthcare Inc, New York, USA, pp. 1646 1656. Chaudhari, S.P., Patil, P.S., 2012. Pharmaceutical excipients: a review. Int. J. Adv. Pharm. Biol. Chem. 1, 21 34. de Jong, H.J., 1999. The safety of pharmaceutical excipients. Therapie 54, 11 14. Decker, E.A., Akoh, C.C., Min, D.B., 1998. Food Lipids: Chemistry, Nutrition and Biotechnology. Marcel Dekker, Inc, New York, NY, p. 394. DOSAGE FORM DESIGN CONSIDERATIONS 830 22. FORMULATION ADDITIVES USED IN PHARMACEUTICAL PRODUCTS Ernest Bollin, J., Fletcher, M.G., 1987. Trehalose as Stabilizer and Tableting Excipient. US4762857 A. Furrer, P., 2013. The central role of excipients in drug formulation. Eur. Pharm. Rev. 18, 67 70. Generally Recognized as Safe (GRAS) FDA, 2016. Gessel, A.W. Van, 2010. Co-Processed Tablet Excipient Composition Its Preparation and Use. US20130177649 A1. Good Manufacturing Practices: Supplementary Guidelines for the Manufacture of Pharmaceutical Excipient, 1999. Grodowska, K., Parczewski, A., 2010. Organic solvents in the pharmaceutical industry. Acta Pol. Pharm. 67, 3 12. Hjortkjaer, R.K., Bechgaard, E., Gizurarson, S., Suzdak, C., McDonald, P., Greenough, R.J., 1999. Single- and repeated-dose local toxicity in the nasal cavity of rabbits after intranasal administration of different glycols for formulations containing benzodiazepines. J. Pharm. Pharmacol. 51, 377 383. ICH-Q2(R1), 2005. ICHQ2(R1) Validation of Analytical Procedures: Text and Methodology. ICH-Q3C(R6), 2016. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH Harmonised Guideline Impurities: Guideline for Residual Solvents Q3C(R6). Illum, L., 1998. Chitosan and its use as a pharmaceutical excipient. Pharm. Res. 15, 1326 1331. IPEC, 2006. The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients 2006, IPEC. IPEC Federation [WWW Document], 2017. ,http://www.ipec.org/.. Kalász, H., Antal, I., 2006. Drug excipients. Curr. Med. Chem. 13, 2535 2563. Kanekar, M.H., Kanekar, H., Khale, A., 2014. Coloring agents: current regulatory perspective for coloring agents intended for pharmaceutical and cosmetic use. Int. J. Pharm. Phytopharm. Res 3, 365 373. Katdare, A., 2006. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. Informa Healthcare USA, Inc., New York, NY. Lake, J.A., Adams, S.D., 2008. Chemical Additives to Make Polymeric Materials Biodegradable. US8513329 B2. Li, J.-X., Carlin, B., Ruszkay, T., 2007. Co-Processed Microcrystalline Cellulose and Sugar Alcohol as an Excipient for Tablet Formulations. US 8932629 B2. Maheshwari, R.G., Tekade, R.K., Sharma, P.A., Darwhekar, G., Tyagi, A., Patel, R.P., et al., 2012. Ethosomes and ultradeformable liposomes for transdermal delivery of clotrimazole: a comparative assessment. Saudi Pharm. J. 20 (2), 161 170. Maheshwari, R.G., Thakur, S., Singhal, S., Patel, R.P., Tekade, M., Tekade, R.K., 2015. Chitosan encrusted nonionic surfactant based vesicular formulation for topical administration of ofloxacin. Sci. Adv. Mater. 7 (6), 1163 1176. Munro, I.C., Berndt, W.O., Borzelleca, J.F., Flamm, G., Lynch, B.S., Kennepohl, E., et al., 1998. Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data. Food Chem. Toxicol. 36, 1139 1174. Nachaegari, S.K., Bansal, A.K., 2004. Coprocessed excipients for solid dosage forms. Pharm. Technol. 28, 52 64. Patel, M.A., Pingale, P.L., 2014. High functionality coprocessed excipients: a review. World J. Pharm. Pharm. Sci. 3, 795 806. Petersen, L., Dahl, C.K., Esbensen, K.H., 2004. Representative mass reduction in sampling—a critical survey of techniques and hardware. Chemom. Intell. Lab. Syst. 74, 95 114. Ptael, K.T., Chotal, N.P., 2010. Vendor qualification for pharmaceutical excipients GMP requirements and approach. Pharmazie 65, 783 790. Rahman, M., Lau-Cam, C.A., 1999. Evaluation of the effect of polyethylene glycol 400 on the nasal absorption of nicardipine and verapamil in the rat. Pharmazie 54, 132 136. Raj, A., 2015. Soft gelatin capsules (softgels). Phamatutor 3, 16 18. Ramesh Kumar, S., Mohan, S.D., 2014. Pharmaceutical excipient development from natural source.compressed. Asian J. Pharm. Heal. Sci. 2, 620 626. Remington, J.P., Joseph, P., Beringer, P., 2006. Remington: the Science and Practice of Pharmacy. Lippincott Williams & Wilkins, Philadelphia, PA. Shahidi, F., 2000. Antioxidants in food and food antioxidants. Nahrung/Food 44, 158 163. Shaikh, S., Doijad, R., Shete, A., Sankpal, P., 2016. A review on: preservatives used in pharmaceuticals and impacts on health. PharmaTutor 4, 25 34. Sharma, A.V., Sharma, P.V., 1988. Flavouring agents in pharmaceutical formulations. Anc. Sci. Life 38 40. Sherwood, B.E., Hunter, E.A., Staniforth, J.H., 1995. Pharmaceutical Excipient Having Improved Compressability. US5585115 A. Silverstein, I., 2002. Excipient GMP quality standards one is enough. Pharm. Technol. 26, 46 52. DOSAGE FORM DESIGN CONSIDERATIONS FURTHER READING 831 Snipes, W.C., 1988. Low-Melting Moldable Pharmaceutical Excipient and Dosage Forms Prepared Therewith. US5004601 A. Steinberg, M., Borzelleca, J.F., Enters, E.K., Kinoshita, F.K., Loper, A., Mitchell, D.B., et al., 1996. A new approach to the safety assessment of pharmaceutical excipients. Regul. Toxicol. Pharmacol. 24, 149 154. Tatavarti, A.S., Fahmy, R., Wu, H., Hussain, A.S., Marnane, W., Bensley, D., et al., 2005. Assessment of NIR spectroscopy for nondestructive analysis of physical and chemical attributes of sulfamethazine bolus dosage forms. AAPS PharmSciTech 6, E91 E99. Tekade, R.K., Maheshwari, R., Tekade, M., 2017. 4 Biopolymer-based nanocomposites for transdermal drug delivery. Biopolymer-Based Composites. Woodhead Publishing, New York, UK. Tekade, R.K., Maheshwari, R., Jain, N.K., 2018. 9 Toxicity of nanostructured biomaterials A2 Narayan, Roger. Nanobiomaterials. Woodhead Publishing. Uchiyama, M., 1999. Regulatory Status of Excipients in Japan. Ther. Innov. Regul. Sci. 33, 27 32. U.S. Department of Health and Human Services, Administration, 2005. Guidance for Industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients. Pharmacol. Toxicol. 12. U S Food and Drug Administration [WWW Document], 2017. ,https://www.fda.gov/.. Verma, S., Baghotia, A., Singh, J., Saroha, K., 2016. Pharmaceutical excipients: a regulatory aspect. Pharm. Innov. J. 5, 124 127. Further Reading Cheng, L., Hostetler, K.Y., Chaidhawangul, S., Gardner, M.F., Beadle, J.R., Keefe, K.S., et al., 2000. Intravitreal toxicology and duration of efficacy of a novel antiviral lipid prodrug of ganciclovir in liposome formulation. Invest. Ophthalmol. Vis. Sci. 41, 1523 1532. Mordenti, J., Thomsen, K., Licko, V., Berleau, L., Kahn, J.W., Cuthbertson, R.A., et al., 1999. Intraocular pharmacokinetics and safety of a humanized monoclonal antibody in rabbits after intravitreal administration of a solution or a PLGA microsphere formulation. Toxicol. Sci. 52, 101 106. DOSAGE FORM DESIGN CONSIDERATIONS This page intentionally left blank Index Note: Page numbers followed by “f” and “t” refer to figures and tables, respectively. A A solubility profile, 492 495, 495f A1-acid glycoprotein (AAG), 361 Abbreviated new drug application (ANDA), 320 321 Absolute solubility, 289 Absolute surface area, 101 102, 159 Absorption, distribution, metabolism, and excretion (ADME), 260 and bioavailability, 462 in product development, 346 348 Absorption, distribution, metabolism, excretion, toxicity (ADMET), 35 36 Absorption. See Drug absorption Absorption base, 790 Absorption number, 310 “Absorptive clearance” model, 718 Acacia, 560, 812 Accelerated stability testing, 227 228 Acetaminophen, 68, 69f, 111, 111f, 325, 361 Achlorhydria, 136 137 Acid-labile compounds, 162 Acids, 157 158, 808 Acoustic spectroscopy, 619 620 Acquired immunodeficiency syndrome (AIDS), 173 Action-based errors, 739 Active diffusion, 122 concentration gradient, transport against, 122 Active pharmaceutical ingredient (API), 58, 67 68, 87, 183, 202, 236 238, 245, 402 403, 409, 420, 426, 436, 438 439, 446, 451, 461, 601, 642, 762 763 API chemistry and preformulation, 643 Active transport, 89, 122, 152, 706 708, 713 primary, 89 secondary, 89 Acyclovir ionic liquids, 537 Additives, 577 578, 785 786 additive additive interactions, 786 drug additive interaction, 786 Additives, types of, 805 812 antioxidant, 805 807 ascorbic acid, 807 butylated hydroxyanisole and butylated hydroxytoluene, 806 807 gallates, 807 natural antioxidants, 807 synthetic antioxidants, 806 tocopherols and tocotrienols, 807 colors, 809 classification, 809 emulsifying agent, 810 811 flavoring agents, 809 810 preservatives, 808 classification, 808 suspending agent, 811 812 Adenosine triphosphate (ATP) hydrolysis, 152 Adiponectin, 261 Adrenochrome, 232 Adsorbent, 787 Advanced Compartmental Absorption, and Transit model (ACAT), 718, 722 Adverse drug reactions (ADRs), 323, 734 738, 763 764 Adverse effects, defined, 735 738 Aeration, 570 571 Aerodynamic diameter, 426, 603t Aerosols, 204, 206 Agitating (stirring) element, eccentricity of, 299 Agitation, 298 Air-jet sieving, 611, 613f Albendazole, 462 463, 493t Albumin, 345, 377 379 Alcoholic solvents, 819 Alcohols, 45 46, 808 Aldehyde dehydrogenase, 204 Alendronate, 740t Alginate, 491 492, 575, 788 All-trans retinoic acid (ATRA), 202 Alpha-1-acid glycoprotein, 376 377, 379 380, 379f, 387 388 Amide functional group, 68, 69f Amides, 68, 819 Aminopenicillin, 72 73 polymerization reaction product of, 73f Aminopropyl(2-methyl)-gatifloxacin (APM-GFX) prodrug, 276 Amiodarone, 130, 380 381 5-Aminosalicylic acid, 172, 233 Amitriptyline, 194 Amlodipine, 94, 379, 524 525 Amorphism, 109, 160, 751 Amorphization, 527 528 Amorphous and crystalline form, 750 833 834 Amorphous form of a particular substance, 64 Amorphous solids, 63 64, 109 Amorphous solubility, 518 Amoxicillin, 152 Ampicillin, 106 107, 135, 160, 752 Andreasen pipette, 613 615, 614f Anhydrous, defined, 30 Anticholinergic drugs, 137 Antifungal ketoconazole, 173 Antimicrobial preservatives, 791 792, 808 Antioxidant synergist, 791 Antioxidants, 71, 791, 805 807 Anti-Parkinson’s disease drugs, 196 Antiport, 89, 122, 152 Antipyrine, 137 138 Antisecretory therapy, concomitant use of, 303 Antisolvent, 61 Antrum, 705 Aprotic ionic liquids, 535 Aqueous solubility, 15 16, 75 78, 189 of aspirin, 110 111 and dissolution rate, 750 of lipophilic drug, 109 in pharmaceutical products development, 75 78 cosolvent effect, 76 77 molecular modifications, 78 particle size reduction, 78 pH, effect of, 75 76 solubilizing agents, 77 78 Aqueous vehicles, 791 Arrhenius equation, 414 Artemisinin, 740t Artificial neural networks (ANNs), 43 44, 48 Artificial preservatives, 808 Artificial stomach duodenal model, 320 Artificial sweetener, 791 792 Arylamines, 133 ASBT, regulation of, 710f Ascorbic acid, 807 Aspirin, 15 16, 20f, 29, 99, 135, 138 Astellas Pharma (Tokyo), 210 Atenolol, 740t Atmospheric pollutants, 344 345 Atomization/spray drying technique, 483 Atovaquone-proguanil, 740t ATP-binding cassette (ABC) transporters, 128 132, 706 708 breast cancer resistance protein (BCRP), 131 132 multidrug resistance-associated proteins (MRPS), 131 P-glycoprotein (P-GP), 129 131 Atracurium, 711 712 INDEX B Bacterial enzymes, 172 Bacteriostatic water for injection, 819 Barbiturates, 69, 87, 161, 446 448 Barriers for drug absorption, 90 91 Batch extractive distillation (BED), 457 Beeswax, 790 Benazepril hydrochloride tablets, 297 298 Benserazide, 347 Benzalkonium chloride (BKC), 12 14, 392, 649 650 Benzimidazole 1, 527 Benzoic acid (BZA), 464 Benzylpenicillin, degradation reaction of, 68f Bepridil, 130 β-cyclodextrin (β-CD), 110f, 474 475 Beta-lactam ring, 69, 72 73 hydrolysis of, 70f β-methoxypsoralen, 201 6-β-naltrexol, 274, 274f Bevacizumab, 740t Bile extraction and drug metabolism, 91 Bile salts, 91, 171, 300 Binders, 166, 295, 778, 786 Binding system, solubility-permeability interplay from, 96 Bioadhesion, 203, 714 Bioavailability, 74 75, 108, 137, 163, 261, 263 264, 270, 272, 317, 322, 382 383, 495, 722 723, 759 Biofabrication, rheology in, 587 Biological aspects in pharmaceutical product development, 650 658 clinical cycle development, 652 653 different phases, 652 653 regulatory requirements comparing different countries, 653 safety and efficacy, 652 emerging trends, 653 658 cell lines and cultures of human origin, 657 658 drug repositioning and repurposing, 655 656 pharmacogenomics and its clinical applications, 655 pharmacovigilance, 653 655 preclinical tenure and strategies, 650 652 animal models use, 651 652 in silico models and simulation predictions, 651 in vitro screenings and importance, 651 Biological substance, defined, 238 Biopharmaceutical classification system (BCS), 9, 35, 90t, 92, 93f, 96, 156, 189, 309 311, 322, 348 349, 415, 415f, 521 in biowaiver of drugs, 349 Class I, 310, 349 Class II, 310 311, 349 INDEX Class III, 311, 349 Class IV, 349 relationship between solubility and, 521 522 Biopharmaceutical Drug Disposition Classification System (BDDCS), 309 311, 322 323 Biopolymers, application of rheology in, 584 Bioprinting, rheology in, 587 Biorelevant dissolution apparatus, 319 320 artificial stomach duodenal model, 320 dynamic gastric model (DGM), 320 Fed Stomach Model, 319 gastric digestion model (GDM), 320 TNO gastro-intestinal model (TIM), 320 Biorelevant dissolution testing, 317 318 limitations of, 320 need of, 317 Biotechnological product, stability testing of, 238 239 ICH guidelines for, 239t Biotherapeutics, 37 Biowaiver, 320 322, 349 data required for requesting, 322 definition and purpose of, 320 321 extension potential, 322 recommended by USFDA BCS guidance on biowaivers, 321 322 Blank fasted and fed (GF), 318 Blood flow through GIT, 138 Blood supply, sublingual, 715 Blood tissue barrier, 91 Blood brain barrier (BBB), 91 Bloodstream barriers, 91 Bolaamphiphiles, 565 Bracketing, 247 249 design instance, 249 factors related to design, 248 sizes of container closure and fills, 248 249 strength, 248 Breast cancer resistance protein (BCRP), 131 132 Broad-gap concentric cylinder viscometer, 580 581 Brønsted Lowry theory, 441 Brownian motion, 558, 563, 811 Brunner and Tolloczko, 293t B-type solubility profile, 495, 495f Buccal and sublingual routes of drug administration, 118 Buccal mucoadhesive formulations, 426 Buccal route, for of proteins and peptides, 426 Buccal/sublingual controlled release drug delivery systems, 197 198 Buffer capacity, 97, 301 Buffered solubility, 517 Buffering capacity, calculation of, 97 Buffers, 577 578, 791 835 Bulk active postapproval changes (BACPAC), 762 763 Bulk characterization, 14 15 Bulk characterization studies, 640 641 Bulk density, 409 Burst release, 184 Butylated hydroxyanisole and butylated hydroxytoluene, 806 807 Butylparaben (BP), 18 C C14mimBr, 536 537 Caco-2 cell lines, 356 Caco-2 monolayer permeability technique, 12 Caffeine, 95, 343 Caffeine monohydrate, 62 Calcium channel blockers, 182 Calcium phosphate, 788, 816 Cal-Tab, 816 Camptothecin, 132 Capillary viscometers, 556 557, 582 Captopril, 740t Carbamazepine, 31, 31f, 96, 160 Carbamazepine-succinic acid, 296 Carbon-based systems, 440 Carboplatin, 477f, 478 Carboxylesterase, 204 Carboxymethylcellulose (CMC), 576, 812 Carboxy-propylgatifloxacin (CP-GFX), 276 Cardiovascular diseases effect on drug disposition, 360 Carindacillin, 137 138 Carrier-mediated diffusion, 151 152, 168 Carrier-mediated transport, 128, 190 191, 713, 721 Carvedilol (CVD), 463 464, 493t, 496 Carver press, 682 Cascade impactor, 617, 618f CAT model, 723 Catechols, 71, 233 CD, 496 Cefadroxil, 272, 272f Celecoxib, 490, 493t, 518 519 Celiac disease, 137 Cell drinking, 124, 713 Cell eating, 713 Cell lines and cultures of human origin, 657 658 Cell membranes, 87 89, 120f, 153, 168, 345, 383, 713 Cellulose triacetate (CTA) II crystal dissolution, 325 Cephalexin, 272, 272f Cerebrospinal fluid, 91 Cetuximab, 740t Challenge-dechallenge-rechallenge (CDR) method, 763 764 836 Chelating agents, 478, 577, 787 Chemical degradation, 67 68, 226, 231 233 drug excipient and drug drug interactions, 233 hydrolysis, 232 233 oxidation, 233 Chemical nature of drug, 92 101 permeability, effect of, 94 96 permeability versus fraction absorbed, 96 solubility-permeability interplay from binding system, 96 solubility permeability interplay from nonbinding system, 96 pH, effect of, 97 buffering capacity, calculation of, 97 pH of gastrointestinal tract (GIT) & plasma fluid, 97 pH-Partition theory, 97 pKa and partition coefficient, concept and effect of, 98 101 apparent versus true partition coefficient, 101 effect of pKa on drug distribution between stomach and blood, 99 100 measurement of log P, 100 101 measurement of pKa, 100 pH pKa relationship with proportion unionized, 98 99 solubility, 92 94 estimation of, 93 influence of solubility on drug absorption, 93 modification of, 94 Chiral chromatography, 456 457 Chiral stationary phases (CSPs), 456 457 Chloramphenicol, 106, 135 136, 160, 232 233 Chloramphenicol palmitate, 30 31, 61 Chloroquine, 740t Chlorpromazine, 74, 137 138 Maillard reaction of, 74f Chlortetracycline suspension, 454 455 Cholesterol, 153, 790 Choline chloride, 463 Choline febuxostat (CXT), 463 Chronotherapeuticoral drug absorption system (CODAS), 327 Chylomicrons, 134, 380 Cimetidine, 95, 311 Cinchocaine, 68 Cinnarizine, 135 Ciprofloxacin, 478, 534 Cirrhosis, 261, 361 Cisplatin, 477 478, 477f, 499 501 Clausenamide (CLA) enantiomers, 264 Clinical efficacy, pharmaceutical product quality impact on, 731 INDEX drug product quality and drug product performance, 759 elements of pharmaceutical development, 743 748 critical quality attributes (CQAs), 745 746 design space and control strategy, 747 748 quality target product profile, 744 risk assessment, 746 747 factors affecting drug product performance, 748 758 differences in excipients, excipient selection, and quality control, 754 758 differences in manufacturing processes, 752 754 physicochemical properties of drug substance, 748 752 postmarketing surveillance (PMS), 763 764 risk assessment and management of medicine, 734 743 medication errors, 735 739 product quality defects, 734 735 scale-up and postapproval changes (SUPAC), 760 763 assessment of effects of changes, 761 bulk active postapproval changes (BACPAC), 762 763 critical manufacturing variables, 761 762 FDA level of changes, 760 761 Cloricromene, 275 Coacervation complexation, 491 492 Coated systems, dissolution of, 326 Cobalt ion complex, 478 Cocrystals, 63, 525 526 CODAS (Chronotherapeutic Oral Drug Absorption System) drug delivery system, 196 Colloid mills, 688f Colorants, 166, 787, 792, 809 Colors, 809 classification, 809 Combinatorial chemistry, 32 34, 419 Commercial production, 754 Commercial prototype production planning, 753 754 Commercial prototype production/evaluation, 754 Commercialization aspects in pharmaceutical product development, 658 662 evergreening strategies, 659 factors affecting, 662 patent listing with different world body, 658 659 product life cycle (PLC), 659 660 brands and generics, 660 competitive advantage, 660 management of, 659 660 realities, 660 662 access to medicine, 661 environmental challenges, 662 maintaining viable product and business, 661 INDEX problems and litigations around patents, 660 661 Compaction and tableting, 681 685 roller compactor, 683 685 Complexation, 109 111, 295 cyclodextrin, 110 111 pi (π) donor or pi (π) acceptor complexes, 109 Complexation efficiency (CE), 533 Complexation in pharmaceutical products, 474 480 advantages and disadvantages of different methods employed in, 486t application of, 479 480, 499 503 cyclodextrin in drug delivery system, 501 503 metal ion complex in cancer, 499 501 polyelectrolyte complexation in drug delivery, 503 atomization/spray drying technique, 483 characterization of, 485 489 determination of guest content, 485 487 diffusion NMR studies, 489 infrared spectroscopy, 487 488 scanning electron microscopy, 488 489 thermo-analytical methods, 487 X-ray powder diffraction, 488 coprecipitation technique, 481 covalent and noncovalent interactions involved in, 476f effect of complexation on drug solubility and bioavailability, 492 496 extrusion, 485 factors influencing, 489 492 effect of coacervate on complex formation, 491 492 influence of chemical modification on complex formation, 490 influence of enzymatic modification on complex formation, 491 influence of temperature on complex formation, 489 490 kneading method, 481 lyophilization/freeze drying technique, 483 484 microwave irradiation method, 484 milling/cogrinding technique, 483 neutralization precipitation method, 483 physical blending method, 480 481 protein complex formation, 498 499 solution/solvent evaporation method, 481 482 supercritical antisolvent technique, 484 485 thermodynamics and kinetics of, 497 types of, 475 479 coordination complexes, 475 476 inclusion complexes, 478 479 metal ion coordinate complexes, 477 478 molecular complexes, 476 477 837 Complexing agents, 166, 489 490 Compound 1-(diphenylmethyl)-4-ethylpiperazine, 273 274 Compressibility, 410 Compression forces, 164, 296 types of, 555f Computational prediction models, 651 Computer’s role in physiological process manipulations, 723 Concentration gradient, transport against, 122 Concrete rheology, 585 586 Cone and plate viscometer, 581 Congestive heart failure (CHF), 136 137, 360 Contact angle, 65 66 Continuous fluid-bed models, 681 Controlled release formulations, current developments in, 209 211 Controlled release solid dosage forms, additives in, 789 Controlled release system (CRS), 179 180 controlled-release drug delivery systems (CRDDS), 197 208 buccal/sublingual, 197 198 intraarterial, 199 200 intramuscular, 200 intrauterine, 207 208 intravenous, 199 nasal, 203 205 ocular, 202 203 oral, 197 parenteral, 198 200 pulmonary, 205 206 rectal, 206 207 subcutaneous, 200 transdermal, 201 202 vaginal, 207 current developments, 209 211 current market share, 183 drug targeting using, 208 factors influencing, 186 188 patented controlled release drug delivery systems, 211 214 patient compliance, 196 pharmacodynamic factors influencing, 195 196 disease condition and the patient condition, 196 drug dose, 195 frequency of dosing, 195 margin of safety, 195 role of disease state, 195 side effects, 196 pharmacokinetic factors influencing the design of, 192 194 absorption, 192 193 distribution, 193 838 Controlled release system (CRS) (Continued) drug protein binding, 194 duration of action, 193 194 elimination half-life, 193 first-pass metabolism, 194 metabolism, 193 physiochemical properties of a drug influencing, 188 192 aqueous solubility, 189 drug stability, 191 ionization, 191 192 mechanism and site of absorption, 190 191 molecular weight and diffusivity, 188 189 partition coefficient, 190 permeability, 190 pH and pKa, 190 rationale for, 184 186 sustained and controlled release dosage forms advantages of, 182 limitations of, 182 183 objective of, 182 Controlled-release drug delivery systems (CRDDS), 181, 184, 197 208 buccal/sublingual, 197 198 intraarterial, 199 200 intramuscular, 200 intrauterine, 207 208 intravenous, 199 nasal, 203 205 ocular, 202 203 oral, 197 parenteral, 198 200 pulmonary, 205 206 rectal, 206 207 subcutaneous, 200 transdermal, 201 202 vaginal, 207 Coordination complexes, 109, 475 476 Coprecipitation technique, 481 Coprocessed additives, 812 814 development of, 813 814 properties and advantages of, 814 Coprocessing, 813 Corticosteroids, 201 Cosolvency, 530 531 Cosolvent effect, 76 77 COSRx, 327 Coulter counter method, 615 616, 627 Creep, 555 Critical manufacturing variables (CMVs), 761 762 identification of, 323 Critical process parameters (CPPs), 602, 694 695, 743 746 INDEX Critical quality attributes (CQAs), 43, 745 746 Critical quality defects, 735 Crohn’s disease, 136 137, 360 361 Cryoprotectants, 39 40 Crystal engineering, 451 Crystal habits, 30, 60, 405 Crystal lattice, 60, 60f, 62 63, 107 108, 294, 407, 516, 524 Crystal structure, 60, 62 63 disruption, 527 528 manipulation, 522 526 of potassium chloride, 60f Crystalline solid-state substances, 60 63 cocrystals, 63 hydrates, 62 polymorphism, 61 62 solvates, 62 63 Crystalline solubility, 518 Crystalline/amorphous form, 294 Crystallinity, 30, 641 and polymorphism, 30 31 Crystallization, 61, 456 of amorphous drugs, 234 and micromeritics, of drug substances, 630 631 CTLA-4 blocking antibody, 196 Cumulative dissolution profiles, analysis of, 306 Curcumin, 493t Current good manufacturing practice (cGMP), 238, 241 Cyanocobalamin, 476, 477f, 478 Cyclacillin, 152 Cyclic amides (lactams), 68 69 Cyclic temperature stress testing, 228 Cyclizine alkyl analogs, 273 274 Cyclodextrin, 96, 110 111, 294 295, 479f, 485 487, 501 503, 531 534 Cyclodextrin mesoporous silica particles (CDMSP), 706 CYP mapping, 355 CYP2D6 enzyme, 355 CYP3A4, 133, 261 265 Cysteamine gels, 45 Cytochrome c, 478 Cytochrome P (CYP)-dependent monooxygenases, 204 Cytochrome P450, 262 265, 343, 514 Cytochrome P450 3A4 (CYP3A4), 343, 351 353 Cytochromes P450 (CYPs), 132 133, 260 261 Cytosis, 152 D Dabigatran, 271 272 Danazol, 318 Dapsone, 133, 536 DDT, 354 INDEX Deamidation, 423 Deborah number, 554 Decarboxylation reactions, 73 74 Deflocculated suspensions, 558 559 Degradation reactions of drugs, 67 74 dehydration, 69 70 hydrolysis, 68 69 isomerization, 71 72 oxidation, 70 71 photochemical degradation, 71 polymerization, 72 73 Degradation studies of drug and drug products, 231 235 chemical degradation, 231 233 drug excipient and drug drug interactions, 233 hydrolysis, 232 233 oxidation, 233 photodegradation, 234 235 physical stability of drug substances, 233 234 crystallization of amorphous drugs, 234 Dehydration, 69 70, 70f Delavirdine mesylate, 29, 296 ∆9-Tetrahydrocannabinol (THC), 276 Densities, 408 409 Density functional theory (DFT), 325 326 basics of, 325 predict dissolution mechanisms, application to, 325 326 Design of experiment (DOE), 43 44, 681 Design space, 43 44 and control strategy, 747 748 Desmosomes, 154 155 Developability Classification System (DCS), 521 522 Dextrose, 74, 74f Maillard reaction of chlorpromazine with, 74f Diazepam, 378t Dicalcium phosphate, 165 166, 816 Diclofenac, 138, 461 Diclofenac salts, 461, 643 Diclofenac sodium, 200 Differential scanning calorimetry (DSC), 28, 407, 453 Differential thermal analysis (DTA), 28, 407 Differential thermogravimetry (DTG), 487 Diffusion coefficient, 103, 151 152 Diffusion NMR studies, 489 Diffusion rate of a drug, 87 Diffusivity, 188 189 Digoxin, 138, 159, 174, 310 311, 363 Di-hydrochloride (2*HCl) salt, 11 Dilation rheology, 583 Diltiazem, 130, 739 839 Diluents, 165 166, 646 647, 786 coprocessed diluents, 778 inorganic diluents, 816 organic diluents, 815 816 Dimethylamino-propyl-gatifloxacin (DMAP-GFX), 276 Dipeptides, 20 21 Dipeptidyl peptidase IV (DPP-IV) inhibitors, 211, 268 1-(Diphenylmethyl)-4-ethylpiperazine, 273 274, 274f Dipivefrin, 275, 275f Dipyridamole, 130, 522 Discovery pharmaceutics, 34 Disintegrants, 166, 786 787 Disintegration time, 163 Disodium cromoglycate, 15 16 Dispersant, 617 618, 627 DissoCubes, 327 Dissolution, 412 drug dissolution concept, 289 290 theories of, 290 293 Danckwerts model, 291 293 diffusion layer model, 291 interfacial barrier model, 291 Dissolution controlled drug delivery systems, 326 327 coated systems, dissolution of, 326 examples of, 327 matrix systems, dissolution of, 327 solid particles, dissolution of, 326 Dissolution mechanism, 325 326 density functional theory (DFT), 325 326 application to predict dissolution mechanisms, 325 326 basics of, 325 Dissolution number, 310 Dissolution profile, 306 analysis of cumulative dissolution profiles, 306 Dissolution rate, 163 164 Dissolution rate, factors affecting, 294 300 dissolution apparatus, 298 299 agitating (stirring) element, eccentricity of, 299 agitation, 298 flow pattern nonuniformities, 299 sampling probe position and filter, 299 vibration, 298 dissolution test parameters, 299 300 drug ionization, 294 drug product formulation related factors, 295 296 manufacturing/processing related factors, 296 298 compression force, 296 machine, 298 methods involve in manufacturing, 296 moisture content, 297 298 particle size, 294 840 INDEX Dissolution rate, factors affecting (Continued) solid state characteristics, 294 295 complexation, 295 crystalline/amorphous form, 294 polymorphism, 294 solvate formation, 295 solubility, 294 Dissolution testing, 303 305, 312 approaches for dissolution test method design, 303 design of dissolution method, 303 305 analytical methods associated with the dissolutions, 305 automation, 305 choice of dissolution equipment, 304 data simulation, 305 dissolution medium, 305 selection of agitation rate, 305 Dissolution testing in pharmaceutical product development, 311 325 biowaiver, 320 322 data required for requesting, 322 definition and purpose of, 320 321 extension potential, 322 recommended by USFDA BCS guidance on, 321 322 critical manufacturing variables (CMVs), identification of, 323 determination of the impact of concomitant use of other substances with drug product, 315 316 determining drug developability at preformulation stage, 314 dissolution as a key feature for biopharmaceutical approach in QbD, 316 drug disposition, prognosis of, 322 323 drug release mechanisms, investigation of, 325 food effects, simulation of, 314 315 in vivo dissolution, prediction of, 317 320 biorelevant dissolution apparatus, 319 320 biorelevant dissolution testing, limitations of, 320 bio-relevant dissolution testing, need of, 317 development of relevant dissolution test, 317 319 pharmaceutical product development phases, 312 314 drug product approval, 312 314 product storage stability, determination of, 324 quality control tool, 324 surrogate of bioequivalence study at postapproval changes of drug product (SUPAC), 323 324 Distribution of drug, 193 Diuretics, 182, 344 Donor acceptor method, 474 Dose number, 310 311 Dose-dependent first-pass metabolism, 269 270 Double mutant heat-labile toxin (DMH-LT), 40 41 Double reciprocal plot, 375, 376f Drug absorption, 18, 35, 63, 86 90, 118, 150, 192 193, 702 active transport, 89 primary, 89 secondary, 89 barriers, 90 91 blood brain barrier (BBB), 91 bloodstream barriers, 91 blood tissue barrier, 91 of intestine, 91 of kidneys, 91 of liver, 91 of mouth, 90 of stomach, 90 endocytosis, 89 90 phagocytosis, 90 pinocytosis, 89 events involved in, 119 physiology of membrane, 119 by facilitated diffusion, 123f indirect factors affecting physiological factors of, 135 139 age and gender, 135 136 blood flow through GIT, 138 diseased conditions, 136 137 food habit, 135 gastric emptying and motility, 137 gastrointestinal contents, 138 139 gastrointestinal pH, 137 138 influence of solubility on, 93 mechanism and site of, 88f, 190 191 metabolism as barrier to, 132 134 gut luminal enzymes, 132 gut wall metabolism by cytochrome P450, 132 133 metabolism in skin, 133 microbial metabolism, 133 134 passive diffusion, 87 facilitated, 88 89 pathways of, 121f role in product development, 346 347 Drug absorption, barriers to, 125 139 ATP-binding cassette (ABC) transporters, 128 132 such as breast cancer resistance protein (BCRP), 131 132 such as multidrug resistance-associated proteins (MRPS), 131 such as P-glycoprotein (P-GP), 129 131 indirect factors affecting physiological factors of drug absorption, 135 139 age and gender, 135 136 INDEX blood flow through GIT, 138 diseased conditions, 136 137 food habit, 135 gastric emptying and motility, 137 gastrointestinal contents, 138 139 gastrointestinal pH, 137 138 lymphatic absorption, 134 metabolism as barrier to drug absorption, 132 134 gut luminal enzymes, 132 gut wall metabolism by cytochrome P450, 132 133 metabolism in skin, 133 microbial metabolism, 133 134 mucus clearance, 126 mucus thickness, 126 nonmucosal barrier to drug absorption, 127 128 nail as barrier, 127 128 skin as barrier, 127 peristalsis, 127 unstirred water layer, 126 Drug absorption, drug transporters as determinants for, 128 132 ATP-binding cassette (ABC) transporters, 128 132 such as breast cancer resistance protein (BCRP), 131 132 such as multidrug resistance-associated proteins (MRPS), 131 such as P-glycoprotein (P-GP), 129 131 Drug absorption, effect of physicochemical parameters on, 92 107 chemical nature of drug, 92 101 concept and effect of pKa and partition coefficient, 98 101 effect of permeability, 94 96 effect of pH, 97 effect of solubility, 92 94 effect of dissolution rate, 102 104 diffusion gradient or concentration gradient, 102 103 effect of salt form on dissolution rate, 103 factors affecting drug dissolution, 104 Noyes Whitney equation, 103 sink condition, 103 104 effect of drug form, 104 106 clathrate forms, 106 complex form, 106 prodrugs and its implications, 106 effect of particles size & effective surface area, 101 102 ionization state, 107 solvates & hydrates, 106 107 Drug absorption, pathways of, 120 125 active diffusion, 122 841 transport against a concentration gradient, 122 facilitated drug absorption, 123 125 endocytosis, 124 125 passive diffusion, 120 122 facilitated diffusion, 120 122 simple diffusion, 120 Drug absorption through gastrointestinal tract (GIT), 107 111 complexation, 109 111 cyclodextrin, 110 111 pi (π) donor or pi (π) acceptor complexes, 109 polymorphism, 107 109 amorphism, 109 methods of polymorph preparation, 108 role of polymorphism in drug absorption, 108 surfactant based solubilization, 109 Drug additive interaction, 786 Drug cyclodextrin complexation, 532 533 Drug degradation, 67 Drug delivery system (DDS), 403 404, 418 Drug discovery process need for, 418 stages in, 418 420 candidate drug selection, 419 exploratory development, 419 exploratory research, 419 full development, 419 420 strategic research, 419 Drug disposition, 337 ADME in product development, 346 348 role of absorption, 346 347 role of distribution, 347 role of excretion, 348 role of metabolism, 347 348 biopharmaceutics classification system (BCS), 348 349 in biowaiver of drugs, 349 Class I (high solubility, high permeability), 349 Class II (high permeability, low solubility), 349 Class III (low permeability, high solubility), 349 Class IV (low solubility, low permeability), 349 effect of disease state on, 359 362 cardiovascular diseases, 360 gastrointestinal diseases, 360 361 kidney diseases, 361 362 liver diseases, 361 factors affecting distribution, 345 cell membrane composition, 345 molecular weight of drug, 345 factors affecting drug disposition, 349 354 drug dose frequency, 354 drug drug interactions, 350 effects of enzymes, 349 350 842 INDEX Drug disposition (Continued) food drug interactions, 352 353 genetic and environmental factors, 354 herb drug interactions, 351 352 polypharmacy, 353 factors affecting excretion, 346 enterohepatic circulation, 346 factors affecting the absorption, 341 342 pharmaceutical/dosage form related factors affecting absorption, 342 physicochemical properties of a drug, 341 342 physiological properties affecting drug absorption, 342 factors affecting the metabolism, 342 345 age, 343 environmental factors, 344 345 hormonal control of drug metabolism, 344 pathological status/diseased state, 344 sex, 344 species, 343 general principles, 338 in situ ex vivo models, 358 359 ex vivo models for induction and toxicity studies, 358 359 in situ models (perfusion), 358 in vitro metabolic models, 355 356 expressed enzymes, 355 subcellular fraction, 355 356 in vitro transporter models, 356 358 hepatocytes, 357 immortalized cell lines, 356 membrane vesicles, 357 358 transfected cell lines, 356 routes of administration, 338 341 intravenous route, 339 oral route, 338 339 subcutaneous route, 339 340 topical/local route of administration, 340 341 transporters in, 354 Drug dissolution concept, 289 290 Drug distribution, 345 role in product development, 347 Drug dose frequency, 354 Drug drug interactions, 233, 350 Drug excipient compatibility, 25 27, 414 Drug excipient interactions, 233 Drug latentiation, 278 Drug metabolism, 136 137 hormonal control of, 344 role in product development, 347 348 Drug-metabolizing enzymes in the small intestine, 261 262 Drug plasma concentration-time profile, 386 387 Drug product life cycle, 3f Drug product performance, factors affecting, 748 758 differences in excipients, excipient selection, and quality control, 754 758 differences in manufacturing processes, 752 754 commercial production, 754 commercial prototype production/evaluation, 754 commercial prototype production planning, 753 754 initial planning stage, 753 inspection, shipment, and delivery, 754 product development phase, 753 prototype production/evaluation, 753 physicochemical properties of drug substance, 748 752 amorphous and crystalline form, 750 aqueous solubility and dissolution rate, 750 chemical factors, 748 749 molecular size and diffusivity, 749 750 particle size and effective surface area, 750 partition coefficient (PC), 751 pKa ionization constant, 751 polymorphism and amorphism, 751 solvates/hydrates, 752 Drug product quality and drug product performance, 759 Drug protein binding, 194, 476 477, 498 Drug protein complex, 372, 383 Drug repositioning and repurposing, 655 656, 657f Drug solubility, 104, 158 159 effect of complexation on, 492 496 Drug stability, 191 Drug targeting using controlled release system, 208 Drugability, 32 35 Dry blending, mixing, and granulation scale-up in, 671 DuraSolv, 327 Dynamic gastric model (DGM), 320 Dynamic light scattering, 615 E Effective surface area, 159, 408, 750 Efflux and transport model, 721 Elastic recoil, 555 Electroacoustics, 619 620 Electrolytes, solubility of, 516 517 Electron microscopy, 610 611 Electronic scanning zone, 615 616 Elimination half-life, 193 Elutriation, 618 619 Emdex, 816 Emulsifiers, 791, 810 811 INDEX Emulsifying agent, 810 811 Emulsions, 627 628 rheology of, 563 Enalapril, 272 Enalapril maleate, 493t Enantiotropes, 406 Endocytosis, 89 90, 124 125, 125f classification of, 124 125 phagocytosis, 124 125 pinocytosis, 124 receptor-mediated endocytosis/clathrin-mediated endocytosis, 124 125 phagocytosis, 90 pinocytosis, 89 Energy of activation (Ea), 15 Enhanced permeation and retention (EPR) effect, 629, 713 714 Enteric coating, 171 Enterohepatic circulation, 346, 710f Environmental pH, 522, 704 705 Enzymatic modification, on complex formation, 491 Enzyme induction, 264 Enzymes affecting drug disposition, 349 350 Enzyme substrate interaction, 476 477 Epinephrine, 72 racemization reaction of under acidic conditions, 72f Epithelial cells, 154 Epoxide hydrolases, 204 Equilibrative nucleoside transporter (ENT), 124 Equilibrium dialysis method, 390 391, 390f Equilibrium solubility, 108, 517 518 Equivalent diameter, 65 Ergotamine tartrate caffeine complex, 166 Erythromycin, 69 70, 135, 137 139 dehydration reaction of, 70f Erythromycin estolate, 137 138, 294 Ester functional group, hydrolysis of in procaine structure, 69f Esters, 808 Estradiol, 201 Etexilate, 271 272 Ethambutol, 740t Ethers, 819 Ethyl cellulose, 23 Ethylene diaaminetetraaceticacid, 477f Ethylene vinyl acetate (EVA), 202 Ethylenediamine, 103, 474 475 Ethylenediamine tetraacetic acid (EDTA), 12 14, 166, 478 Ethylparaben (EP), 18 Etoricoxib-β-CD complex, 481 843 European Federation of Pharmaceutical Industries (EFPIA) Expert Working Group, 20 Evergreening strategies, 659 Excipient-based solubilization, 530 537 cosolvency, 530 531 cyclodextrin, 531 534 ionic liquids, 534 537 Excipients, 25 27, 754 758, 755t Excretion, role of in product development, 348 Exo- and endopeptidases, 204 Extended Clearance Classification System (ECCS), 322 Extrusion, 485 F Facilitated drug absorption, 123 125 endocytosis, 124 125 phagocytosis (cell eating), 124 125 pinocytosis (cell drinking), 124 receptor-mediated endocytosis/clathrin-mediated endocytosis, 124 125 Facilitated/carrier-mediated diffusion, 152 “Fail early fail cheap”, 35 Famotidine, 443f Fanconi syndrome, 232 Fasted State Simulated Intestinal Fluid (FaSSIF), 11, 318 Fasted-state simulated gastric fluid (FaSSGF), 318 Febuxostat (FXT), 463 Fed State Simulated Intestinal Fluid (FeSSIF), 11, 318 Fed Stomach Model, 319 Fed-state simulated gastric fluid (FeSSGF), 318 Felodipine, 353 Fentanyl, 274f Fenugreek osmopolymer, 212 Fick’s first law, 87, 293t, 521 Fick’s law, 151 Fick’s second law, 293t Filled polymer rheology, 586 Fillers, 165 166, 586 Film former, 787 Film theory, 102 103, 291 Filtration, 458 459 First-pass excretion, 710 711 First-pass metabolism, 172 173, 194, 259 considerations in pharmaceutical product development, 280 281 considerations in prodrug development, 278 280 role of liver and small intestine in, 260 278 effect of dose-dependent first-pass metabolism, 269 270 effect of gastrointestinal motility, 269 844 INDEX First-pass metabolism (Continued) effect of genetic polymorphism, 270 effect of hepatic blood supply, 268 effect of plasma protein binding, 268 269 hepatic and intestinal enzyme induction, 263 268 physiological and biochemical factors affecting intestinal metabolism, 261 263 route of administration and, 270 278 inhalation and buccal administration, 277 278 ocular drug delivery, 275 276 oral administration, 271 273 rectal administration, 278 subcutaneous and intramuscular administration, 276 277 transdermal delivery, 273 275 Flavin monooxygenases, 133 Flavoring agents, 809 810 Flavors, 787 Flecainide, 195 Flocculated suspensions, 558 559 Flow pattern nonuniformities, 299 5-Fluorouracil (5-FU), 152, 194, 564 565, 740t Flurbiprofen-methyl-β-CD complexes, 484 485 Food habit, 135 Food rheology, 585 Food drug interactions, 352 353 Forced degradation studies, 229, 231 Forced/stress degradation studies, 38 Formulation additives, 773 classification and sources of, 777 778 functions, additives based on, 778 origin, additives based on, 778 therapeutic values, additives based on, 778 current developments in additive science, 823 824 current guidelines for, 792 795 for designing of liquid dosage forms, 791 792 for designing of semisolid dosage forms, 789 791 for designing of solid dosage forms, 786 789 additives in controlled release solid dosage forms, 789 additives in spray-dried powders, 788 789 evaluation and quality testing of, 820 823 additive specifications, 820 821 additive stability, 821 analytical procedures, 822 823 packaging and labeling control, 822 receipt, sampling, testing, and approval of raw materials, 821 822 FDA GRAS additives, 826 828 examples of, 827 828 Generally Recognized As Safe (GRAS) substances, 827 functional and coprocessed additives, 812 814 interaction in pharmaceutical products, 785 786 additive additive interactions, 786 drug additive interaction, 786 international patented additives, 824 826 coprocessed microcrystalline cellulose and sugar alcohol as an excipient, 826 coprocessed tablet excipient composition, 826 cross-linked cellulose as some tablet excipients, 824 825 low-melting moldable pharmaceutical excipient and dosage forms, 825 to make polymeric materials biodegradable, 826 pharmaceutical excipient having improved compressibility, 825 sustained release excipient and tablet formulation, 824 trehalose as stabilizer and tableting excipients, 825 pharmaceutical additives, 776 777 pharmaceutical diluents, 815 816 coprocessed diluents, 816 inorganic diluents, 816 organic diluents, 815 816 pharmaceutical solvents, 816 819 inorganic solvents, 818 819 organic solvent, 819 processing as per good manufacturing practice, 779 785 cleaning validation, 782 783 control of raw materials, 780 781 packaging and labeling, 784 preventing contamination, 781 process monitoring and control, 783 process validation, 782 production records, 780 qualification of manufacturing equipment, 781 782 quality release, 784 785 sampling and testing, 783 784 storage, 785 training of employees, 780 regulatory aspects of additives approval, 796 798 additive master files and other filings, 796 797 current regulatory status of new additives, 796 IPEC procedure, 796 recommended strategies to support marketing of new additives in drug products, 797 798 regulatory perspectives of, 798 802 IPEC perspectives, 799 regulatory perspectives, 799 802 types of additives, 805 812 antioxidant, 805 807 colors, 809 emulsifying agent, 810 811 flavoring agents, 809 810 preservatives, 808 suspending agent, 811 812 WHO perspectives, 802 805 INDEX documentation, 803 805 Formulation development, first stage of, 4 5 Formulation life cycle and management, 2 4 Formulation strategy planning, 37 Fostamatinib, 133 134 Fourier-transform infrared spectroscopy (FT-IR), 487 488 Fraunhofer diffraction, 617 618 Freeze drying, 483 484 Froude number, 673 Fumaric acid (FUMA), 464 Functional additives, 812 814 G Gallates, 807 Gastric digestion model (GDM), 320 Gastric emptying, 705 706 and intestinal transit time, 170 and motility, 129t, 137 Gastric emptying time, 169 Gastric-emptying rate and forces, 303 Gastrointestinal contents, 138 139 Gastrointestinal drug absorption model and elimination model, 718 Gastrointestinal fluid, composition of, 300 Gastrointestinal motility effect on first-pass metabolism, 269 Gastrointestinal pH, 137 138 Gastrointestinal tract (GIT), 260 physiological conditions of, 119t Gastrointestinal tract (GIT), drug absorption through, 107 111, 149, 153f barriers in, 153 155 biological factors affecting, 167 174 age, 173 disease state, 173 gender, 173 presence of other drugs, 173 174 complexation, 109 111 cyclodextrin, 110 111 pi (π) donor or pi (π) acceptor complexes, 109 mechanism of, 150 153 membrane physiology, 167 168 nature of cell membrane, 168 transport processes, 168 pharmaceutical factors affecting, 163 167 disintegration time, 163 dissolution rate, 163 164 manufacturing variables, 164 nature and type of dosage form, 164 165 pharmaceutical ingredients, 165 167 product age and storage conditions, 167 physicochemical factors affecting, 155 162, 155f 845 chemical nature, 157 158 drug pKa, lipophilicity, and GI pH, 161 drug solubility and dissolution rate, 158 159 drug stability, 162 ionization state, 161 particles size and effective surface area, 159 160 pH partition hypothesis, 162 polymorphism and amorphism, 160 salt form of drug, 160 161 solvates and hydrates, 160 physiology, 168 173 drug stability in GIT, 171 effect of fluid, 171 effect of food, 171 effect of other normal GI contents, 171 gastric emptying time, 169 gastrointestinal contents, 171 gastrointestinal motility and intestinal transit time, 170 gastrointestinal pH, 169 presystemic metabolism, effect of, 172 173 surface area of GIT, 169 170 polymorphism, 107 109 amorphism, 109 methods of polymorph preparation, 108 role of polymorphism in drug absorption, 108 surfactant based solubilization, 109 Gastro-intestinal tract, barriers for drug absorption in, 90 91 intestine, 91 kidneys, 91 liver, 91 mouth, 90 stomach, 90 GastroPlus, 305, 652, 723 GastroPlus 8.0, 347 Gelatin, 788 Gellan gum, 577 Gelling agent, 791 Gels, 578 General solubility equation (GSE), 516 Generally Recognized As Safe (GRAS) food status, 799 802 Generic products, 794 Genetic polymorphism effect on first-pass metabolism, 270 Geophysics, application of rheology in, 584 Gibbs free energy, 107 108, 325 GI-Sim 4.1, 347 Glabridin/HP-β-CD inclusion complexes, 488 489 Glass, 109 Glass transition temperature, 527 528 Glatt AGT machinery, commercialization of, 681 Glatt Multicell Equipment, 678f 846 Glibenclamide, 63, 493t Glidants, 787 Glitazones (III Line), 740t Glivec (imatinib mesylate), 461 Glucocorticoids, 205 Glucose transporters, 124 Glucotrol XL, 210 Glutathione transferases, 204 Glycoproteins (GPs), 154 Gold complexes in cancer therapy, 501 Good manufacturing practices (GMP), 36 37 Granulation, method of, 164 Granulation and drying, 675 681 Granule density, 409 Graphical plots, to determine binding constants, 375 376 Griseofulvin, 64 65, 101 102, 104 105, 159, 164 165, 201, 310 311 Guanethidine, 15 16 Gum, 811 Gut luminal enzymes, 132 Gut microbiota, 133 134 Gut wall enzymes, 172 Gut wall integrity, 173 Gut wall metabolism, 708 710 by cytochrome P450, 132 133 H Half-life, 386, 395 Halogenated solvents, 819 Haloperidol, 94 Halothane, 261 HAMLET, 498 Hard paraffin, 790 Harvard Apparatus, 358 Heat shock protein 90 (HSP90), 498 499 Hemoglobin, 374, 477f, 478 Henderson Hasselbalch equations, 75, 98 100, 162, 410 411, 519 520, 704 Hepatic and intestinal enzyme induction, 263 268 cytochromes P-450, 263 265 p-glycoprotein, 266 268 UDP glucosyltransferases and sulfotransferases, 265 266 Hepatic blood supply effect on first-pass metabolism, 268 Hepatic clearance, 384 385 restrictive and nonrestrictive clearance, 385 Hepatic enzymes, 172 173, 357 Hepatic metabolism. See Gut wall metabolism Hepatic metabolizing enzymes, 712f Hepatocytes, 357 INDEX Herbal products, 239 240 requirements of stability testing of, 241 steps involved in development of, 240t Herb drug interactions, 351 352 pharmacodynamic interactions, 352 pharmacokinetic interactions, 351 Herschel Bulkley model, 553 High throughput screening (HTS), 32, 33f, 419 High-density lipoproteins (HDLs), 380 381 High-performance thin-layer chromatography (HPTLC), 456 457 High-pH alkaline solvents, 483 Higuchi equation, 293t Hixson and Crowell cube root equation, 293t HLB (Hydrophilic-Lipophilic balance) scale, 66 Hohenberg and Kohn theorem, 325 Hormonal control of drug metabolism, 344 Human peptide transporter 1 (hPEPT1), 272 Human serum albumin (HSA), 268, 377 Humectants, 791 Hyaluronic acid, 491 492 Hydralazine, 194 Hydrates, 30, 62, 523 Hydrochloride salts, 439, 454 455 Hydrocortisone, 109, 160 Hydrodynamic diameter, 603t Hydrodynamics, 302 303 Hydrogen bonds, 29, 521 Hydrolysis, 68 69, 232 233, 424 Hydrophilic colloids, 66 Hydrophilic diluents, 165 166 Hydrophilic moieties, 91 Hydrophilicity of a drug, 93 Hydroquinone digoxin complexes, 166 Hydrotropes, 531 Hydrotropy, 531 Hydrous wool fat, 790 5-Hydroxy-2-(di-n-propylamino) tetralin (5-OHDPAT), 274, 274f Hydroxychloroquine, 740t Hydroxyethylcellulose, 812 4-Hydroxyospemifene, 347 348 40 -Hydroxyospemifene, 347 348 Hydroxypropyl beta-cyclodextrin (HPβCD), 275 Hydroxypropyl methylcellulose acetate succinate (HPMCAS-HF), 316 Hydroxypropyl β-CD (HP-β-CD), 479, 490 Hygroscopicity, 28 29, 58 59, 63, 66 67, 408, 453 I Ibuprofen, 11, 109, 317, 378t, 493t, 622 Idarubicin, 740t INDEX Imatinib, 212 Imatinib mesylate, 461, 740t Immortalized cell lines, 356 Impeller Reynolds number, 687 688 In silico models, 347, 651 In situ ex vivo models, 358 359 ex vivo models for induction and toxicity studies, 358 359 in situ models (perfusion), 358 In vitro metabolic models, 355 356 expressed enzymes, 355 subcellular fraction, 355 356 In vitro transporter models, 356 358 hepatocytes, 357 immortalized cell lines, 356 membrane vesicles, 357 358 transfected cell lines, 356 In vitro in vivo correlation (IVIVC), 35, 306 309, 307f, 651 652 applications of, 308 309 in drug delivery system, 308 pharmaceutical product development, 309 definition, 306 levels of IVIVC correlation, 307 308 Level A correlation, 308 Level B correlation, 308 Level C correlation, 308 Level D correlation, 308 multiple level C correlations, 308 significance and purpose of, 306 307 In vivo drug dissolution rate, physiological factors affecting, 300 303 antisecretory therapy, concomitant use of, 303 buffer capacity, 301 gastric-emptying rate and forces, 303 gastrointestinal (GI) fluid, composition of, 300 hydrodynamics, 302 303 osmolality, 302 pH values, 300 surface tension, 302 temperature, 302 viscosity, 302 volume, 302 Inclusion complexes, 109, 476 479 Indomethacin, 296, 479, 528 albumin binding sites, 378t Indomethacin, 378t Industrial crystallization, 457 control of the crystallization, 457 filtration and drying, 458 459 solvent selection, 457 Infrared spectroscopy, 487 488 Inhalational formulations, 649 847 Inorganic solvents, 818 819 Inorganic/mineral colors, 809 Inspection, shipment, and delivery, 754 Institutional Review Board (IRB), 312 314 Insulin (II Line), 740t Integral membrane proteins, 120 Integral proteins, 154 Intellectual property (IP), 461, 644 Intellectual property rights (IPR), 644 Interferon α2a, 276 277 International patented additives, 824 826 coprocessed microcrystalline cellulose and sugar alcohol as an excipient, 826 coprocessed tablet excipient composition, 826 cross-linked cellulose as some tablet excipients, 824 825 low-melting moldable pharmaceutical excipient and dosage forms, 825 to make polymeric materials biodegradable, 826 pharmaceutical excipient having improved compressibility, 825 sustained release excipient and tablet formulation, 824 trehalose as stabilizer and tableting excipients, 825 Intestinal barriers present in absorption of drugs, 154f Intestinal metabolism, physiological and biochemical factors affecting, 261 263 cytochromes P-450, 262 263 drug-metabolizing enzymes in the small intestine, 261 262 mucosal blood flow, 261 Intestinal metabolism model, 720 721 Intestinal protective drug absorption system (IPDAS), 327 Intestine, barriers for drug absorption in, 91 Intraarterial controlled release drug delivery systems, 199 200 Intramuscular controlled release drug delivery systems, 200 Intrauterine controlled release drug delivery systems, 207 208 Intravenous controlled release drug delivery systems, 199 Intravenous route, 339 Intrinsic dissolution rate (IDR), 11 Intrinsic solubility, 517 Investigational new drug (IND), 3, 31 32 Investigational New Drug Application (IND), 312 Ioavailability, 492 496 effect of complexation on, 492 496 Ion trapping, 107 Ionic cocrystals (ICCs), 525 Ionic liquids, 534 537 848 Ionic strength, 19, 413 Ionicity, 537 Ionization, 99 100, 191 192 Ionization constant, 15 16, 410 411, 751 Ionization state, 107, 161 IPC testing, 241 Iron complexes, 478 Isomerization, 71 72 Isoniazid, 740t Isoprenaline lignocaine, 194 ITH12674, 484, 493t Itraconazole, 493t, 503 J Japan, 793, 795 K Kaoline, 788 Ketoconazole, 173, 300, 318 Ketones, 819 Ketoprofen, 317 Kidney diseases effect on drug disposition, 361 362 Kidneys, barriers for drug absorption in, 91 Kinetic solubility, 517 Kitazawa’s theory, 306 Kneading method, 481 Knowledge-based errors, 738 Krieger and Dougherty’s equation, 559 Kuhn Mark Houwink Sakurada equation, 557 L Lactose anhydrous, 816 Lactose hydrous, 788 Lactose monohydrate, 682, 814 815 LADMER, 150 Lamivudine, 171 Large-scale salt production, 455 457 chromatographic isolation, 456 457 crystallization, 456 distillation, 457 Laser diffraction (LD) technique, 617 618, 627 Latanoprost, 276f Law of mass-action, 372 373 L-dopa, 135, 279 280 Lead candidates, screening of, 35 Lecithin, 810 811 Levodopa, 138, 152, 213, 279 280 Levothyroxine, 303 Lewis acid base reaction, 474 475, 475f Light, effect on rheological properties, 571 572 Lincomycin, 173 INDEX Lipases, 172, 709 710 Lipid nanocapsules, 565 Lipid-based nanoformulations, 563 565 Lipid polymer-based nanoformulations, 566 Lipophilic compounds, 490 Lipophilic drugs, 87, 91, 96, 408 Lipophilicity, 15 18, 93, 98, 166 Lipoproteins, 377t, 380 381, 380f Liposomes, 45, 77, 440, 565 Liquid dosage forms, 166, 558 formulation additives for designing of, 791 792 Liquid paraffin, 791 Liver, barriers for drug absorption in, 91 Liver diseases effect on drug disposition, 361 Liver metabolism, 711 712 Liver metabolism model, 719 720 Liver perfusion model, 358 Log D, 15 16 Log P, 15 16 Lopinavir, 350 Lorcainide, 194 Lovastatin, 262 263 Low-density lipoproteins (LDLs), 380 381 Lubricants, 166, 787 Luminal enzymes, 172 Lymphatic absorption, 134 Lyophilization/freeze drying technique, 483 484 M Macro-Pactor, 685 Macrophages, 716 717 Macroscopic bulk properties and their techniques, 5t Magnetoelectric nanoparticles (MENs), 208 Maillard reaction, 74 of chlorpromazine with dextrose, 74f Major quality defects (class II recall), 735 Mandelic acid (MDA), 464 Mannitol, 788, 816 Manufacturing processes, differences in, 752 754 commercial production, 754 commercial prototype production/evaluation, 754 commercial prototype production planning, 753 754 initial planning stage, 753 inspection, shipment, and delivery, 754 product development phase, 753 prototype production/evaluation, 753 Manufacturing variables, 164 compression force, 164 granulation, method of, 164 Mark Houwink equation, 557 558 Material transfer rate, 687 688 Materials science, application of rheology in, 583 584 INDEX biopolymers, 584 polymer engineering, 583 584 Matrix systems, dissolution of, 327 Matrixing, 247 250 design examples, 250 design influences, 250 Maximum absorbable dose (MAD), 9, 158 159 Maximum length, 603t Means, types of, 606, 606t Median, 606 Medication errors, 735 739 classification of, 738 739 known side effects, 739 743 MEDIPAD (Elan Pharmaceutical Technologies), 200 Meloxicam-β-CD complex, 483 Membrane permeability, effect of electrostatic charges in, 417 418 Membrane vesicles, 357 358 Memory-based errors, 739 6-Mercaptopurine (6-MP), 356 Mercurial compounds, 808 Metabolism in skin, 133 Metabolism of drugs, 193 Metal ion complex in cancer, 499 501 gold and silver complexes, 501 platinum(IV) complexes, 500 platinum-based analogs, 499 500 ruthenium and copper complexes, 500 Metal ion coordinate complexes, 476 478 Metal ions salt complexes, 446 Metal-catalyzed oxidation, 20 21 Metaxalone, 135 Metformin (I Line), 740t Methotrexate, 740t Methyl parabens (MP), 18 Methylcellulose, 568, 811 812 Methyldopa, 70 71, 71f, 138, 152 Metoclopramide, 137, 174 Metoprolol, 160, 168, 194 Microbial metabolism, 133 134 Microcrystalline cellulose (MCC), 788, 816, 826 Microemulsions, 563 564 Micromeritics in pharmaceutical product development, 599 crystallization and micromeritics of drug substances, relation between, 630 631 emulsions, 627 628 methods to determine particle size distribution, 607 620 acoustic spectroscopy, 619 620 cascade impactor, 617 dynamic light scattering, 615 electronic scanning zone, 615 616 849 elutriation, 618 619 laser diffraction, 617 618 microscopy, 607 611 sieving method, 611 615 novel drug delivery systems, 628 630 particle size, effects of, 600 607 on dissolution, 602 604 on manufacturing processing parameters, 604 particle size distribution (PSD), 604 607 powders, 624 626 flow properties, 624 626 suspensions, 627 tablet and capsule, 620 624, 621t compressibility and compatibility or tablet strength, 623 624 content uniformity, 622 flow properties, 622 hardness, 623 particle arrangement and compaction, 622 segregation, 623 weight variation, 622 623 Micronization, 159 160, 529, 750 Microscopy, 607 611 electron microscopy, 610 611 optical microscopy, 607 610 Microvilli, 169 170 Microwave irradiation method, 484 Mie theory, 617 618 Milling techniques, 529 Milling/cogrinding technique, 483 Minimum effective concentration (MEC), 192 Minimum toxic concentration (MTC), 192 Mini-Pactor, 685 Minor quality defects (class III recall), 735 Mirodenafil, 270 Mitoxantrone-resistance protein (MXR), 131 132 Mixing, 671 672, 688 689 and agitation, 685 686 issues related to, 672 Mode, defined, 606 Modified starches, 491 Modulators, 268 Molecular cocrystals (MCCs), 525 Molecular complexes, 476 477 Molecular modifications, 78 Molecular size and diffusivity, 749 750 Molecular weight, 188 189 Molsidomine, 23 24, 26f Mono-6-deoxy-6-aminoethyl amino-β-cyclodextrin, 534 Monoclonal antibodies (MAbs), 570 Monohydrate, 62 Monotropes, 406 Morphine, 87, 194, 275 850 Mouth, barriers for drug absorption in, 90 Moxifloxacin, 12 14 Mucin, 125 126, 167 168, 171 Mucoadhesion, 714 Mucosal blood flow, 261 Mucus clearance, 126 Mucus membrane, 714 Mucus thickness, 126 Multidrug resistance-associated proteins (MRPS), 131 Multiple purpose GRAS food substances, 828 Multiregional clinical trials (MRCTs), 653 N Nadolol, 95 Nail as barrier to drug absorption, 127 128 Nano-based systems, rheology of, 563 566 lipid-based nanoformulations, 563 565 lipid polymer-based nanoformulations, 566 polymer-based nanoformulations, 566 surfactant-based nanoformulations, 565 566 NanoCrystals, 327, 602 603 Nanoedge technology, 529 530 Nanoemulsions, 564 Nanoformulations, scale-up of, 691 692 Nanonization, 529 530 Nanoprecipitation, 692 Nanosponges, 534 Nanostructured lipid carriers, 564 565 Naproxen, 302 303 Narrow-gap viscometers, 580 Nasal controlled release drug delivery systems, 203 205 Nasal route, for proteins and peptides, 426 Nasal solutions/suspensions, 649 650 Natural antioxidants, 807 Natural colors, 809 Natural Emulsifying Agents, 810 Natural preservatives, 808 Natural seasonings and flavorings, 827 Natural sweeteners, 791 Nature and type of dosage form, 164 165 N-cyclohexanecarbonyl-3-(4-morpholino)-sydnone imine hydrochloride (ciclosidomine), 19 Neostigmine, 194 Nernst Brunner equation, 293t Neutralization precipitation method, 483 New chemical entity (NCE), 3, 11, 31 32, 314, 459 New molecule entity (NME) output, 3 Newtonian systems, 552 Nicardipine, 130 Nifedipine, 22 23, 22f, 25f, 71, 72f, 94, 130, 194, 234 235 Nitriles, 819 INDEX Nitrofurantoin, 138 Nobex Technology, 421 Nonbinding system, solubility permeability interplay from, 96 Nonelectrolytes, solubility of, 516 517 Nonmucosal barrier to drug absorption, 127 128 nail as barrier, 127 128 skin as barrier, 127 Non-Newtonian systems, 552 555 time-dependent non-Newtonian flow, 554 555 time-independent non-Newtonian flow, 552 554 Nonreducing sugars, 39 40 Nonsteroidal antiinflammatory drug (NSAID), 135, 523 Nonsystematic scale-up techniques, 673 Nonthermodynamic solubility, 517 Norfloxacin, 481 482, 493t, 534 Novel drug delivery systems, 628 630 Noyes Whitney equation, 159, 163 164, 291, 293t, 412, 602 603 Noyes Whitney principle, 326 Noyes Whitney/Nernst Brunner equation, 520 Nucleotide-binding domains (NBD), 129 130 O Ocular controlled release drug delivery systems, 202 203 Ocular route, for proteins and peptides, 427 Oily vehicle, 791 Olanzapine-methyl-β-CD complexes, 484 485 Oleaginous base, 790 Oligopeptides, 402 403 Oligosaccharide, 125 One-way ANOVA, 607 Opacifier, 787 Ophthalmic formulations, 650 Ophthalmic inserts, 203 Optical microscopy, 607 610 Optimization of physicochemical properties, 342 Oral absorption of drug, 151f Oral bioavailability, 271 272, 496 Oral Controlled Absorption System (OCAS) technology, 210 211 Oral controlled release drug delivery systems, 197 Oral route, 338 339 of drug administration, 118 for proteins and peptides, 425 Oral solid dosage forms, 648 Organic cation/carnitine transporter 1 (OCTN1), 356 Organic dyes and lakes, 809 Organic molecular complexes, 109 Organic solvent, 817, 819 choice of, 449 Organoleptic test, 404 INDEX Organometallic complexes, 476 Osmolality, 302 Osmotically-controlled Release Oral Delivery System (OROS), 183, 210 Ostwald de Waele equation, 690 Ostwald Freundlich equation, 520 Over the counter (OTC) drugs, 181, 776 777 Oxalic acid (OXA), 464 Oxidation, 40t, 70 71, 233, 423 424, 805 mechanism, 39t P “P” scale, 15 Packaging components, preformulation studies of, 41 42 Paracetamol, 11, 12f, 138, 630 631 Parallel artificial membrane permeability assay (PAMPA), 12, 35 Parallel-plate viscometer, 581 582 Para-toluenesulfonic acid, 462 463 Parenteral controlled release drug delivery systems, 198 200 intraarterial controlled release drug delivery systems, 199 200 intramuscular controlled release drug delivery systems, 200 intravenous controlled release drug delivery systems, 199 subcutaneous controlled release drug delivery systems, 200 Parenteral dosage forms, 646 648, 685 686 mixing and agitation, 685 686 Parenteral route, drug administration through, 118 119 Parkinson’s disease (PD), 196 Particle size, 27 29, 64 65, 600 607, 641 effect on manufacturing processing parameters, 604 and effective surface area, 750 effects on dissolution, 602 604 reduction, 78 Particle size distribution (PSD), 604 607 acoustic spectroscopy, 619 620 analysis of data by statistics, 606 607 cascade impactor, 617 dynamic light scattering, 615 electronic scanning zone, 615 616 elutriation, 618 619 laser diffraction, 617 618 methods to determine, 607 620 electron microscopy, 610 611 microscopy, 607 611 851 optical microscopy, 607 610 PQRI recommended techniques for, 608t sieving method, 611 615 air-jet sieving, 611 sedimentation method, 612 615 types of, 605 606 intensity weighted distributions, 606 number weighted distributions, 605 volume weighted distributions, 605 606 Partition coefficient (PC), 98, 190, 411, 751 factors influencing, 417 Passive diffusion, 87, 120 122, 713 facilitated diffusion, 88 89, 120 122 simple diffusion, 120 Passive transport, 120, 151 Patent listing with different world body, 658 659 Patented controlled release drug delivery systems, 211 214 Pemetrexed, 740t Penetration theory, 291 Penicillin, 138 Penicillin G, 104, 137 138, 454 455 Pentazocin, 137 138 Pentazocine, 194 Pentobarbital, 15 16, 137 138 Pepsin, 168, 300 Peptidic/peptidomimetic drugs, 162 Percolation theory, 676 Peripheral type of proteins, 154 Peristalsis, 127 Permeability, 12 14, 94 96, 190 solubility-permeability interplay from binding system, 96 solubility permeability interplay from nonbinding system, 96 versus fraction absorbed, 96 Permeases, 152 Pethidine, 136, 194 Petrolatum, 790 p-Glycoprotein (P-gp), 129 130, 266 268, 721 ATP-binding cassette (ABC) transporters and, 129 131 efflux transporters, 12 pH, 75 76 effect of, 97 calculation of buffering capacity, 97 of gastrointestinal tract (GIT) & plasma fluid, 97 pH-Partition theory, 97 on rheological properties of suspensions, 574 575 pH modifiers and buffering agents, 791 792 pH profile, 15 pH stability study, 413 pH values, 191, 300 852 INDEX Phagocytosis, 90, 124 125, 152, 713 Phagosomes, 716 717 Pharmaceutical additives current guidelines for, 792 795 evaluation and quality testing of, 820 823 analytical procedures, 822 823 packaging and labeling control, 822 receipt, sampling, testing, and approval of raw materials, 821 822 specifications, 820 821 stability, 821 Pharmaceutical diluents, 815 816 coprocessed diluents, 816 inorganic diluents, 816 organic diluents, 815 816 Pharmaceutical inactive ingredients, 754 Pharmaceutical product development biological aspects, 650 658 clinical cycle development, 652 653 emerging trends, 653 658 preclinical tenure and strategies, 650 652 commercialization, 658 662 factors affecting, 662 patents, exclusivity, and evergreening strategies, 658 659 product life cycle (PLC), 659 660 realities, 660 662 preformulation aspects, 640 642 major disciplines of preformulation studies, 640 642 sphere of preformulation studies, 640 prototype development, 642 650 considerations to ideate/conceptualize product, 642 644 experimental design and product optimization, 645 650 scale-up, 637 Pharmaceutical salt characterization of, 451 459 assessment of the physicochemical properties, 452 453 assessment of the process impurities, 453 454 large-scale methods, 455 457 method optimization and large-scale production, 457 459 physical properties, 453 stability and preformulation assessments, 454 455 structure confirmation, 451 452 merits and demerits of, 438 439 preparations biological factors, 446 448 biopharmaceutical factors, 446 choice of organic solvent, 449 decision tree for salt selection, 449 451 dosage form and routes of administration, 448 449 ionic factors, 443 446 pKa rule for salt formation, 441 443 rationale of, 439 440 salt selection strategy, 440 441 selection of the API and counterions for, 440 451 regulatory requirements, 459 464 patenting prospective, 460 461 safety and efficacy, 461 464 Pharmaceutical solvents, 816 819 Pharmaceutical systems based on rheological behavior, 552 555 Newtonian systems, 552 non-Newtonian systems, 552 555 Pharmacodynamic interactions, 350, 352 Pharmacodynamics, defined, 338 Pharmacogenetics, defined, 655 Pharmacogenomics and its clinical applications, 655 Pharmacokinetic interactions, 350 351 Pharmacokinetics modeling, 347, 721 722 Pharmacovigilance, 653 655, 734 Phase I and Phase II enzymes, 262t Phase I reactions, 343, 712 Phase II reactions, 343, 712 Phase solubility profiles, 492 pH-dependent solubility, 522 Phenobarbital, 137 138 Phenolphthalein, 493t Phenols, 808 Phenylbutazone, 137 138, 378t, 388 389 Phenytoin, 137 138, 310 311, 361, 777 30 -Phosphoadenosine-5-phosphosulphate (PAPS), 266 Phospholipid bilayers, 120, 749 750 Photochemical degradation, 71 Photodecomposition, 23 Photodegradation, 234 235 Photon correlation spectroscopy. See Dynamic light scattering Photostability, 19 24, 234, 413 Physical blending method, 480 481 Physical characteristics of solid substances used in pharmaceutical product development, 58 67, 59f amorphous solids, 63 64 crystalline solid-state substances, 60 63 cocrystals, 63 hydrates, 62 polymorphism, 61 62 solvates, 62 63 hygroscopicity, 66 67 particle size, 64 65 INDEX wettability, 65 66 Physical stability of drug substances, 233 234 Physiological processes, manipulations of, 701 bioavailability, 722 723 computer’s role in, 723 modeling procedures for transport, metabolism, and efflux of drug, 718 722 efflux and transport model, 721 gastrointestinal drug absorption model and elimination model, 718 intestinal metabolism model, 720 721 liver metabolism model, 719 720 numerical integration of the model, 722 pharmacokinetics modeling, 721 722 physiological factors affecting product development, 703 718 active transport and efflux, 706 708 bioadhesion, 714 blood supply, sublingual, 715 carrier-mediated transport, 713 enhanced permeation and retention (EPR) effect, 713 714 environmental pH, 704 705 first-pass excretion, 710 711 gastric emptying, 705 706 gut wall metabolism, 708 710 liver metabolism, 711 712 macrophages, 716 717 mucus membrane, 714 route of administration, 703 704 skin permeation, 715 716 small and large bowel transit time, 706 spleen/lymph node targeting, 717 718 Phytopharmaceuticals, stability testing of, 239 242 protocol, 241 242 container closure system, 241 frequency of stability testing, 242 selection of batches, 241 specification, 242, 243t stress testing, 242 requirements of stability testing of herbal products, 241 Pi (π) donor/pi (π) acceptor complexes, 109 Pinocytosis, 89, 124, 152, 713 Piroxicam, 479 pKa and partition coefficient, concept and effect of, 98 101 apparent versus true partition coefficient, 101 effect of pKa on drug distribution between stomach and blood, 99 100 measurement of log P, 100 101 measurement of pKa, 100 853 pH pKa relationship with proportion unionized, 98 99 pKa of a drug, 15 16, 751 pKa rule for salt formation, 441 443 PK-SIM, 652 Placenta-specific ABC protein, 131 132 Planetary mixers, 688f Plasma and tissue protein binding implications on pharmacokinetics parameters, 382 387 bioavailability, 382 383 drug plasma concentration-time profile, 386 387 half-life, 386 hepatic clearance, 384 385 restrictive and nonrestrictive clearance, 385 renal clearance, 385 volume of distribution, 383 384 Plasma protein binding determination methods, 389 395 equilibrium dialysis method, 390 391 important considerations when using in vitro methods, 393 in silico methods, 394 395 in vivo methods, 394 ultracentrifugation method, 392 393 ultrafiltration method, 391 392 Plasma proteins, 372, 376 381 albumin, 377 379 alpha-1-acid glycoprotein, 379 380 lipoproteins, 380 381 Plastic systems, 553 554 Plasticizer, 64, 787 Platinum (II), 493t Platinum complexes, 478 Platinum(IV) complexes and anticancer activity, 500 Platinum-based analogs, 499 500 Plunkett Burman designs, 44 45 Poise, 551 Poly(lactic acid)-poly(ethylene)glycol (PLA)-PEG nanoparticles, 199 Polyacrylic acid, 575 Polychlorinated hydrocarbons, 354 Polyelectrolyte complexation in drug delivery, 503 Polyene antibiotics, 71 Polyethylene glycol (PEG), 39 40, 166 Polymer engineering, application of rheology in, 583 584 Polymer-based nanoformulations, 566 Polymeric nanoparticles, 440 Polymerization, 72 73 Polymorphism, 30 31, 61 62, 107 109, 160, 294, 406, 523, 641, 751 amorphism, 109 methods of polymorph preparation, 108 854 INDEX Polymorphism (Continued) role of polymorphism in drug absorption, 108 Polymorphs, 30 31, 61, 406, 523 524 Polypharmacy, 353 Polysorbates, 66 Polyvinyl alcohol (PVA), 202, 496 Polyvinyl pyrrolidone, 24, 166, 788 Postmarketing surveillance (PMS), 653, 763 764 Potassium chloride, crystal structure of, 60f Potassium salt, 454 455 Potential additives for intermediate use, 797 for long-term use, 798 for short-term use, 797 for use in pulmonary, injectable, or topical products, 798 Potentiometric titration, 100 Powder characterization, 14 15 Powder flow properties, 641 Powder X-ray diffraction (PXRD) technique, 488 Powders, 30, 624 626 flow properties, 624 626 angle of repose, 624 625 bulk and tapped density, 626 Pralidoxime, 232 Prandtl equation, 520 Prednisolone, 109, 133 134, 160, 167 Preformulation, 1 case studies on, 45 46 in drug development, 35 37 dosage form specific studies, 36 37 identification of challenges during formulation development, 36 in drug discovery, 31 35 “drugability” of new chemical entities, 32 34 material properties in lead selection, high throughput preformulation studies, 32 tools to assist in lead selection, 34 35 during product development, 7 8 formulation life cycle and management, 2 4 future remarks, 48 major hurdles impeding successful product development, 5 7 need of, 4 5 pharmacokinetics and, 46 47 in 21st century, 42 45 artificial neural network tool used in the factorial design, 43 45 computerization and aid of software, 42 43 in vaccine development, 40 41 Preformulation studies, 4, 7, 401, 638f, 640 642 biopharmaceutical factors, 415 computerization and aid of software in, 42 43 in drug discovery and pharmaceutical product development, 418 420 degradation pathways indicating instability of proteins and peptides, 421 425 factors causing problems in protein delivery, 428 429 influence of preformulation on the delivery of protein and peptides, 425 427 need for drug discovery, 418 preformulation as an aid in early product development, 420 prodrug approach, 420 421 stages in drug discovery process, 418 420 major disciplines of, 640 642 bulk characterization, 640 641 solubility analysis, 641 642 stability analysis, 642 of packaging components, 41 42 parameters of, 8 31 bulk characterization, 14 15 bulk properties, 30 crystallinity and polymorphism, 30 31 drug-excipient compatibility, 25 27 hygroscopicity, 28 29 inherent properties, 15 19 mechanical properties and compatibility, 30 particle size and distribution, 27 28 permeability of the drug, 12 14 solubility, 8 11 stability, 19 24 thermal properties, 28 physical factors, 404 414 bulk characteristics, 405 410 organoleptic properties, 404 solubility analysis, 410 412 stability analysis, 412 414 proteins and peptides, 37 40, 415 418 factors influencing preformulation studies, 416 418 types and structural considerations, 415 416 rules and regulations in, 47 48 sphere of, 640 vital concepts, 403 404 Preliminary preformulation, 34 35 Preservatives, 788, 808 classification, 808 Presystemic metabolism, 139, 172 effect of, 172 173 bacterial enzymes, 172 gut wall enzymes, 172 hepatic enzymes, 172 173 luminal enzymes, 172 Primary active carrier (PAC), 713 INDEX Primary active transporters, 128 129 Probenecid, 95 Procainamide, 68 Procaine, 68, 69f Procardia XL, 210 Process capability index, 746 Process-related impurities, 454 Prodrugs, 106, 134 definition, 260, 275 development, first-pass metabolism considerations in, 278 280 strategies, 526 527 Product age and storage conditions, 167 Product development, 311 312 major hurdles impeding successful product development, 5 7 role of preformulation during, 7 8 Product development phase, 753 Product life cycle (PLC), 659 660 brands and generics, 660 competitive advantage, 660 management of, 659 660 Product lifecycle and management, various stages of, 8f Product quality defects, 734 735 critical quality defects, 735 major quality defects, 735 minor quality defects, 735 Programmable oral drug absorption system (PRODAS), 327 Proinsulin, 261 Projected area diameter, 603t Promazine, 173 Propranolol, 130, 137 138, 172 173, 194 Propylparaben (PP), 18 Propylthiouracil, 138 Prostaglandin E2 and prostaglandin A2, 479 Proteases, 204 Protein binding, 387 drug-induced changes in, 388 389 pathologic factors influencing, 388 physiologic factors influencing, 387 388 Protein binding kinetics, 372 376 Protein complex formation, in oncology, 498 499 Protein delivery, factors causing problems in, 428 429 biochemical and biological factors, 428 selection of targeting ligands, 428 429 uptake of protein drugs, 429 Proteins and peptides, 402, 403f chemical stability of, 423 425 deamidation, 423 hydrolysis, 424 oxidation, 423 424 855 racemization, 424 reduction, 424 β-elimination, 425 degradation pathways indicating instability of, 421 425 influence of preformulation on the delivery of, 425 427 buccal route, 426 formulation design considerations, 425 nasal route, 426 ocular route, 427 oral route, 425 pulmonary route, 426 rectal route, 427 transdermal route, 426 427 vaginal route, 427 physical stability of, 422 423 aggregation or precipitation of misfolded species, 422 formation of stable misfolded species, 422 surface-induced structural changes/aggregation, 422 423 preformulation studies of, 37 40 Proteolysis, 39t, 424 Protic ionic liquids, 535 Prototype development, 642 650 considerations to ideate/conceptualize product, 642 644 API chemistry and preformulation, 643 biological considerations, 644 intellectual property (IP), 644 experimental design and product optimization, 645 650, 645f inhalational formulations, 649 nasal solutions/suspensions, 649 650 ophthalmic formulations, 650 oral solid dosage forms, 648 parenteral dosage forms, 646 648 topical/dermal/transdermal dosage forms, 648 649 Prototype production/evaluation, 753 Pseudoplastic systems, 553 554 Pseudopodia, 124, 716 717 Pseudopolymorphs, 160, 523 524 [PtIICl2(AcGlcpyta)], 493t Pulmonary controlled release drug delivery systems, 205 206 Pulmonary nanoparticles, 206 Pulmonary route, 205 for proteins and peptides, 426 Purified water, 818 Pyrazinamide, 740t 856 Q Q6B guideline, 239 Quality assurance and quality control (QA/QC), 759 Quality by design (QbD), 43, 733, 743 744 dissolution as a key feature for biopharmaceutical approach in, 316 for scale-up, 692 693 Quality Risk Assessment (QRA), 316 Quality target product profile (QTPP), 316, 744 Quantitative structure property relationship models (QSPRs), 395 Quasi-continuous granulation and drying process (QCGDP), 677 Quasi-elastic light scattering. See Dynamic light scattering Quaternary ammonium compounds, 808 Quinidine, 130 Quinine, 87, 740t R Racemization, 39t, 72f, 424 Randomized block designs (RBD), 44 45 Ranitidine bismuth citrate intragastric floating SR tablet, 211 Rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs), 356 Real-time stability testing, 227 228 Receptor-mediated endocytosis, 124 125, 152 Rectal controlled release drug delivery systems, 206 207 Rectal route of drug administration, 118 119 for proteins and peptides, 427 Reduced stability-testing plans, 247 250 bracketing, 248 249 design instance, 249 factors related to design, 248 sizes of container closure and fills, 248 249 strength, 248 bracketing and matrixing design, 247 248 matrixing, 249 250 design examples, 250 design influences, 250 Reducing agents, 791 Reference listed drug (RLD) product, 322 Relative humidity (RH), 28 29 Renal clearance, 385 Research and development (R&D) team, 2 3 Respiratory epithelial cells, 205 206 Response-surface-methodology (RSM), 43 45 Retained sample stability testing, 228 Reticuloendothelial system (RES), 199, 717 718 Reynolds number, 686 688 INDEX Rheology, 549 applications of, 583 588 concrete rheology, 585 586 filled polymer rheology, 586 food rheology, 585 in geophysics, 584 materials science, 583 584 pharmaceuticals, 586 588 physiology, 584 585 basic concepts, 550 558 deformation of liquids and deformation forces, 555 556 determination of molar weight by viscosity, 556 558 pharmaceutical systems based on rheological behavior, 552 555 shear viscosity, 551 552 viscoelasticity, 556 broad-gap concentric cylinder viscometer, 580 581 cone and plate viscometer, 581 dilation rheology, 583 of emulsions, 563 instruments for fluids and their limitations, 578 579 of nano-based systems, 563 566 parallel-plate viscometer, 581 582 pharmaceutical considerations, 567 578 chemical variables, 574 578 physical variables, 567 574 rheology modifiers, thickeners, and gels, 578 rotational-type rheometer, 579 580 of suspensions, 558 562 tube-type rheometers, 582 Rheumatoid arthritis (RA), 704 Rifampicin, 264 265 Rifampin, 740t RingCap, 327 Risk assessment, 734 743, 746 747 Risk management, 747 Ritonavir-boosted protease inhibitors, 350 Rituximab, 740t Roller compactor, 683 685 Rotational speed, 305 Rotational-type rheometer, 579 580 Routes of administration, 338 341, 703 704 and first-pass metabolism, 270 278 intravenous route, 339 oral route, 338 339 subcutaneous route, 339 340 topical/local route of administration, 340 341 Rule-based errors, 738 Ruthenium and copper complexes in cancer therapy, 500 INDEX S Saccharin, 296 Salicylates, 87 Salification, 524 Salmeterol, 277, 277f Salt defined, 436 formation, 524 525 merits and demerits of pharmaceutical salts, 438 439 salt preparation, fundamentals of, 437 Salt form of drug, 160 161 Salt selection decision tree for, 449 451 strategy, 440 441 Sampling probe position and filter, 299 Saquinavir, 350 Saturation concentration, 92 Saturation shake-flask method, 11 Scale-up and postapproval changes (SUPAC), 670 671, 760 763 assessment of effects of changes, 761 bulk active postapproval changes (BACPAC), 762 763 critical manufacturing variables, 761 762 FDA level of changes, 760 761 Scale-up guidance for immediate-release solid dosage forms (SUPAC-IR), 681 Scale-up studies, 669 common mixing guidance, 671 675 describing mixing phenomenon, 671 672 issues related to mixing, 672 process parameters, 672 673 scale-up approaches, 673 675 compaction and tableting, 681 685 roller compactor, 683 685 in dry blending, mixing, and granulation, 671 granulation and drying, 675 681 continuous models, 681 of nanoformulations, 691 692 parenteral dosage forms, 685 686 mixing and agitation, 685 686 problems encountered during, 693 694 quality by design (QbD) for, 692 693 semisolid dosage forms, 686 691 heating and cooling rates, 689 material transfer rate, 687 688 mixing, 688 689 viscous and non-Newtonian liquids, 689 691 solid dosage forms, 670 685 Scaling-up of salt formation, 458 459 Scanning electron microscopy (SEM), 488 489, 610 611 Scatchard plot, 375 376 SDS-PAGE, 239 Secondary active carrier (SAC), 713 Sedimentationof particles, 612 615 Semicrystalline state, 63 64 Semisolid dosage forms, 686 691 formulation additives for designing of, 789 791 heating and cooling rates, 689 material transfer rate, 687 688 mixing, 688 689 viscous and non-Newtonian liquids, 689 691 Sequestering agents, 577 578 Shake-flask method, 18 Shear rate, 567 568 Side effects, 739 743, 740t Sieve diameter, 603t Sieving method, 611 615 Sigma mixers, 688, 688f Silicone dioxide, 788 Silver complexes in cancer therapy, 501 Silymarin-β-CD, 481 Simcyp 13.1, 347 Simulated Gastric Fluid (SGF), 318 Simulated intestinal fluid (SIF), 318, 320 Simvastatin, 133 134, 262 263 SiRNA-loaded chitosan nanoparticles, 493t Size exclusion chromatography, 239, 694 Skin as barrier to drug absorption, 127 Skin permeation, 715 716 Small and large bowel transit time, 706 Smartrix tablet, 327 Smooth endoplasmic reticulum (SER), 712 Soaps, 811 Sodium carboxymethylcellulose, 811 Sodium hyaluronate, 45 Sodium hydroxide, 28 29 Sodium lauryl sulfate (SLS), 66, 96 Sodium starch glycolate, 295 Sodium taurocholate (STC), 96 Solid dosage forms, 462, 670 685 Solid lipid nanoparticles, 440, 564 Solid particles, dissolution of, 326 Solid-state NMR spectroscopy, 452 Solid-state properties, 405 compressibility, 410 crystalline and polymorphism, 405 407 densities, 408 409 flow properties, 409 hygroscopicity, 408 particle size and shape, 408 Solid-state stability, 414 Solubility, 11, 92 94, 181, 514 521 approaches to modulate, 522 530 857 858 Solubility (Continued) crystal structure disruption, 527 528 crystal structure manipulation, 522 526 pH modification, 522 prodrug strategies, 526 527 size reduction, 528 530 based on experimental setup, 517 518 equilibrium solubility, 517 518 kinetic solubility, 517 based on pH, 517 buffered solubility, 517 intrinsic solubility, 517 unbuffered solubility, 517 based on solid structure, 518 amorphous solubility, 518 crystalline solubility, 518 of electrolytes, weak electrolytes, and nonelectrolytes, 516 517 estimation of, 93 excipient-based solubilization, 530 537 cosolvency, 530 531 cyclodextrin, 531 534 ionic liquids, 534 537 factors influencing drug solubility, 518 520 crystal habit, 518 519 particle size, 520 pH, 519 520 influence of solubility on drug absorption, 93 modification of, 94 phenomenon of solubilization, 514 516 importance of solubility and solubilization in product development, 515 process of solubilization, 515, 516f solvent solute interactions, 515 516 in product development, 8 11 relationship between solubility and biopharmaceutical classification systems, 521 522 solute solvent interaction, 521 techniques to increase, 95f types of, 92t types of, 517 518 Solubility analysis, 410 412, 641 642 dissolution, 412 ionization constant, 410 411 partition coefficient, 411 solubilization, 411 412 Solubility aspects in pharmaceutical products development, 74 78 aqueous solubility, 75 78 cosolvent effect, 76 77 effect of pH, 75 76 molecular modifications, 78 INDEX particle size reduction, 78 solubilizing agents, 77 78 Solubility profile, factors influencing, 417 Solubility permeability interplay from binding system, 96 from nonbinding system, 96 Solubilization, 36, 411 412 excipient-based, 530 537 phenomenon of, 514 516 surfactant based, 109 Solubilizers, 791 Solubilizing agents, 77 78 Soluplus, 316 Solute carrier (SLC)-type transporters, 706 708 Solute solvent interaction, 521 Solution/solvent evaporation method, 481 482 Solution-state stability, 413 414 Solvate formation, 295 Solvates, 62 63 and hydrates, 160, 752 Solvent Evaporation Method, 108, 481 482 Solvent solute interactions, 515 516 Sorbitan esters, 66 Spheroidal oral drug absorption system (SODAS), 327 Spices, 827 Spironolactone, 15, 159, 630 Splanchnic circulation, 138, 170 Spleen/lymph node targeting, 717 718 Spray drying, 483, 490, 788 789 Spray-dried lactose, 816 Spray-dried powders, additives in, 788 789 Stability analysis, 412 414, 642 drug-excipients compatibility, 414 solid-state stability, 414 solution-state stability, 413 414 stability study in toxicological formulation, 413 Stability indicating assay method (SIAMS), 243 246 current updates in regulation of, 244 245 development of, 245 246 Step 1: Critical Study of the API Structure to Assess the Particular Degradation Pathway, 245 Step 2: Collection of Information on Physicochemical Properties of API, 245 Step 3: Forced Degradation Studies, 245 Step 4: Preliminary Separation Studies on Stressed Sample, 245 Step 5: Method Development and Optimization, 246 Step 6: Identification and Characterization of Decomposition Products, and Preparation of Standards, 246 Step 7: Validation of Stability Indicating Assay Method, 246 INDEX regulatory status of, 244 Stability indication assays, 238 Stability of drug, 19 24, 104 Stability studies for drug and drug product, 225 evaluation of stability data to determine retest period/shelf-life determination, 236 ICH guidelines for, 237t methods for, 227 228, 228f, 232t accelerated stability testing, 228 cyclic temperature stress testing, 228 real-time stability testing, 227 228 retained sample stability testing, 228 objectives of, 227f practical considerations during development of, 229 230 batches, 230 containers and closures, 230 orientation of storage of containers, 230 regulatory aspects and requirements for, 236 238 regulatory status of stability testing program, 237 requirements for a stability testing program, 238 significance of, 226 227 stability indicating assay method (SIAMS), 243 246 stability testing equipment, 230 231 steps of, 229, 229f Stability testing, 226 227 of biotechnological product, 238 239 of phytopharmaceuticals, 239 242 Stabilizer, 787, 825 Starch, 295, 788 Static light scattering, 617 618 Stearic acid, 788, 811 Sterile water for injection, 818 819 Sterile water for irrigation, 819 Sterilization, 572 574 Steroids, 71 Stoichiometric hydrates, 523 524 Stokes equation, 561 Stokes law, 613 Stokes’ diameter, 603t Stokes Einstein relationship, 615 Stomach, barriers for drug absorption in, 90 Stratum corneum, 127, 201 Streptomyces hygroscopicus, 45 46 Streptomycin, 740t Stress condition testing, 231 Stress testing, 242 Structure of drug and their physicochemical properties/biological properties, 111 Subcutaneous controlled release drug delivery systems, 200 859 Subcutaneous route, 339 340 Sublingual controlled release drug delivery systems, 197 198 Sublingual route of drug administration, 118, 197 198 Sucrose, 788 Sugartab, 816 Sulfamethoxazole, 133, 174 Sulfapyridine, 172 Sulfasalazine, 172, 740t Sulfonylureas (II Line), 740t Sulfotransferases, 265 266 Sulpiride, 95 Sulpyrine discoloration, 235 Supercritical antisolvent technique, 484 485, 485f Supersaturation, 61, 537 Surface diameter, 603t Surface Renewal theory, 291, 293t Surface science, 14 15 Surface tension, 302 Surfactant, 66, 77 78, 791 792 Surfactant based solubilization, 109 Surfactant-based nanoformulations, 565 566 Surfactants, 66, 66f, 96, 167, 577 578 Surrogate of bioequivalence study at postapproval changes of drug product (SUPAC), 323 324 Suspending agent, 811 812 and viscosity modifying agent, 792 Suspensions, 627 rheology of, 558 562 Sustained release (SR) systems, 188 189 Sweeteners, 787, 791 Sympathomimetic amines, 205 Symport, 122, 152 Synthetic antioxidants, 806 T Tablet and capsule manufacturing, significance of micrometrics in, 620 624, 621t compressibility and compatibility or tablet strength, 623 624 content uniformity, 622 flow properties, 622 hardness, 623 particle arrangement and compaction, 622 segregation, 623 weight variation, 622 623 Tablet coatings, 166 Tacrolimus, 133 134, 532 533 Taguchi designs, 44 45 Talc, 788 Tasosartan, 393, 393f Taxifolin, 481 482, 493t 860 INDEX Taxifolin-γ-cyclodextrin, preparing the inclusion complex of, 482f TBHQ, 806 807 Telmisartan, 481, 493t Temperature, 302 impact on rheological behavior of liquid-based systems, 568 570 influence on complex formation, 489 490 Ternary complexes, 534 Tertiary chlorpromazine chloride, 446 448 Tetrabutyl phosphonium (TBP), 537 Tetracycline, 69 72, 138, 165 166 dehydration reaction of, 70f racemization reaction of, 72f Tetradecyltrimethylammonium bromide (TTAB), 536 537 Tetrahydrofuran (THF), 462 463 Theophylline, 15 16, 103, 168, 302 303 Theory Limited Solvation, 293t Thermo-analytical methods, 487 Thermodynamic solubility, 517 518 Thermodynamic stability, 421 Thermogravimetric analysis (TGA), 407, 487 Thermoresponsive polymers, 568 569 Thickeners, 578 Thiopental anesthesia, 361 Thixotropy, 554 555 3D crystal structure, 394 Thyroxin, 201 TIMERx, 327 Timolol, 502, 740t Tissue binding, 381 measurement of, 381 TNO gastro-intestinal model (TIM), 320 Tocopherols and tocotrienols, 807 Tolbutamide, 137 138, 378t Topical/dermal/transdermal dosage forms, 648 649 Topical/local route of administration, 340 341 Total average steady-state concentration, 386 Toxic substances, 58 Toxicological formulation, stability study in, 413 Tragacanth, 812 Transdermal controlled release drug delivery systems, 201 202 Transdermal drug delivery, 273 275 Transdermal route, for of proteins and peptides, 426 427 Transfected cell lines, 356 Transmembrane domains (TMD), 129 130 Transmission electron microscopy (TEM), 610 611 Transporters in drug disposition, 354 Travoprost, 276f Trazodone hydrochloride, 462 Trifluoroacetyl chloride (TFA), 261 Tripeptide, 20 21 Triple roller mills, 688f True density, 409 Tube-type rheometers, 582 Tween 80, 392 Two-way ANOVA, 607 Tyrosine, 20 21 Tyrosyl photooxidation, 20 21 U UDP glucosyltransferases, 265 266 UDP-glucuronosyltransferases (UGTs), 350 UK-224 671, 273f Ultrafiltration method, 391 392, 391f Unbuffered solubility, 517 Unfolded α-lactalbumin, 493t Uniport, 122 Uniporter, 89 United States of America, 793 Unstirred water layer, 126 Uridine diphosphate (UDP)-glucoronyl transferase, 204 V Vaccine development, preformulation in, 40 41 Vaginal controlled release drug delivery systems, 207 Vaginal route, for of proteins and peptides, 427 Valacyclovir, 272 273, 272f Van der Waals interactions, 130 131 Vegetable and animal color, 809 Verapamil, 361 Very low-density lipoproteins (VLDLs), 380 Vibration, 298 Villi, 169 170 Vincristine, 740t Viscosity of GI, 302 Viscous and non-Newtonian liquids, 689 691 Vitamin B12, 190 191 Volume diameter, 603t Volume of distribution, 347, 383 384 Volume-surface diameter, 603t W Warfarin, 95, 137 138, 271 272, 361, 378t Water, 75, 818 Water for injection (WFI), 45, 818 Water-miscible bases, 790 Water-soluble base, 789 INDEX Weak acids, 99 dissociation of, 101f Weak Electrolytes, solubility of, 516 517 Wet granulation method, 164 Wettability, 65 66 Wetting agent, 66, 787 White soft paraffin, 790 Wool alcohol, 790 Wool fat, 790 World Intellectual Property Organization (WIPO), 658 659 X Xenobiotics, 262 263, 338, 342 343 X-ray diffraction (XRD), 461 X-ray powder diffraction, 407, 488 Xyloglucan, 569 Z Zidovudine, 171 Zinc, 478 Zydis, 327 861

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