Scale-up of an exothermic reaction from lab to production scale
Filipe AtaĂde October 2018
Agenda Context Batch exothermic reaction Microwave proof of concept Switch to flow chemistry Scale-up into commercial scale flow reactor
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Agenda Context Batch exothermic reaction Microwave proof of concept Switch to flow chemistry Scale-up into commercial scale flow reactor
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Objectives • Scale-up of an exothermic reaction step from lab to commercial scale • Conversion from batch to continuous mode of operation • Increase the intensification rate of the process • Make use of mechanistic modelling
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Context • Temperature: 125 ºC (exotherm above this temperature) • Total reaction step duration: 25-30 h (heat up + reaction + cool down) • 3 eq. of reagent (b.p. at Patm: 90ºC) Starting material + Reagent
Scale-up of an exothermic reaction from lab to production scale | October 2018
Product + Byproduct
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Context Demand for commercial scale • 2x 216 kg campaigns (2x4x 54 kg batch size) • 3x 441 kg campaigns (3x3x 147 kg batch size) • Total needs: 1754 kg Occupancy of large scale batch reactor • 8x 25-30h = 200-240h • 9x 25-30h = 225-270h • Total occupancy: 425-510 h ~ 18-21 days Scale-up of an exothermic reaction from lab to production scale | October 2018
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Agenda Context Batch exothermic reaction Microwave proof of concept Switch to flow chemistry Scale-up into commercial scale flow reactor
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Batch exothermic reaction Kinetic model fitting
10-pulses feed run at 135 ºC (40g scale)
Scale-up of an exothermic reaction from lab to production scale | October 2018
10-pulses feed run at 117 ºC (40g scale)
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Batch exothermic reaction Kinetic model validation
4 pulses feed run at 124ºC (40g)
1 pulse feed run at 134ºC (40g)
1 pulse feed run at 132ºC (400g)
1 pulse feed run at 125ºC (400g)
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Agenda Context Batch exothermic reaction Microwave proof of concept Switch to flow chemistry Scale-up into commercial scale flow reactor
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Microwave poof of concept Kinetic model fitting 5 min at 160ºC
10 min at 160ºC
15 min at 160ºC 2.5 min at 195ºC
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Microwave poof of concept Kinetic model validation 40 min at 195ºC
20 min at 195ºC (reaction with product)
60 min at 195ºC
Product concentration is not correctly represented by the model
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Microwave poof of concept Kinetic model validation
Starting material + Reagent Product + Reagent
Scale-up of an exothermic reaction from lab to production scale | October 2018
Product + By-product Impurity + By-product
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Microwave poof of concept Kinetic model validation 40 min at 195ºC
20 min at 195ºC (reaction with product)
60 min at 195ºC
Product concentration is fairly well represented by the model
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Agenda Context Batch exothermic reaction Microwave proof of concept Switch to flow chemistry Scale-up into commercial scale flow reactor
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Switch to flow chemistry Kinetic model fitting Lab flow reactor 1: flowrates from 4-36 µL/min
36 μL/min at 160ºC
12 μL/min at 160ºC
4 μL/min at 160ºC
36 μL/min at 195ºC
12 μL/min at 195ºC
4 μL/min at 195ºC
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Switch to flow chemistry Kinetic model validation Lab flow reactor 2: flowrates from 0.2-2 mL/min Scale-up 25-250x
1 mL/min at 200ºC
Scale-up of an exothermic reaction from lab to production scale | October 2018
1 mL/min at 210ºC
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Agenda Context Batch exothermic reaction Microwave proof of concept Switch to flow chemistry Scale-up into commercial scale flow reactor
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Scale-up to commercial scale flow reactor Commercial scale flow reactor • Temperature: -60 to 200ºC • Pressure: up to 18 bar • Flowrate: 1 – 10 L/min • Plate volume: 250 mL
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Scale-up to commercial scale flow reactor Theoretical scale-up
Reactor calculated parameters
Process conditions
• Characteristic dimension
• Residence time
• Heat transfer A/V
• Temperature: 200ºC
• U value
• Flowrate: 1L/min
Scale-up 25,000-250,000x
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Scale-up to commercial scale flow reactor Theoretical scale-up
Intensification • Increase mass of SM by up to 43% (Feed conc: 1.9 à 3.0 mol/L) • Increase yield from 76% to 87% • Increase throughput from 22.5 kg/h to 40.7 kg/h
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Scale-up to commercial scale flow reactor Demand for commercial scale • Total needs: 1754 kg Occupancy of large scale batch reactor • Total occupancy: 425-510 h ~ 18-21 days Occupancy of large scale flow reactor • Total occupancy: 1754 kg/40.7 kg/h = 43.1h = 1.8 days
Reduction of 90% of large scale reactor occupancy Scale-up of an exothermic reaction from lab to production scale | October 2018
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Conclusions • Conversion from batch to continuous flow successful • Scale-up to commercial scale of reaction step successful (up to 250x with experimental validation and 250,000x into a commercial scale flow reactor - theoretical) • Potential of 90% reduction in reactor uptime • Mechanistic modelling very useful guiding process development, by resorting to equipment characterization and kinetic modeling
Scale-up of an exothermic reaction from lab to production scale | October 2018
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Thank you for your attention Filipe AtaĂde fataide@hovione.com