Techniques for Enabling the Continuous Manufacturing of APIs Vijay Kirpalani CEO : Pi – PROCESS Intensification Exp. LLP President : Flow Chemistry Society – India Chapter Copyright Pi-Process Intensification Exp. LLP
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Applicability of Process Intensification Flow Chemistry
of e n o b back
Reactions Other Platforms Extraction
Process Intensification
Distillation Crystallization Unit Operations
Filtration Drying
Defining Tenets of Flow : A clean, product-specific, atom-efficient reaction; requiring minimal downstream processing
Air Pollution Control - Absorption Effluent Treatment Copyright Pi-Process Intensification Experts LLP
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FLOW REACTOR types - Static & Dynamic - Examples PASSIVELY mixed reactors = STATIC
ACTIVELY mixed reactors = DYNAMIC
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Dynamic Flow Reactor Solutions (1) SynthetronTM Solution to handle solid-precipitates / crystals in flow
“FUMI” Spinning Disk Reactor
Forced Uniform Molecular Interdiffusion
Lab to Mini-plant - mg to Kg / hour
Turn-down ratio : 1/800
Appln: BuLi, Li-Halex, Dibal-H, Grignards, 2 -10 µ particle-size, polymorph-selectivity Copyright Pi-Process Intensification Experts LLP
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Dynamic Flow Reactor Solutions (1)
SynthetronTM
TM
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Dynamic Flow Reactor Solutions (1) SynthetronTM
n-BuLi Halex : API intermediate Cetrizine Intermediate Synthesis – 2 Step Reaction Step 1: Generation of p-chlorophenyl lithium with n-BuLi Step 2: Trapping with benzaldehyde to afford the benzhydrol (Cetrizine Intermediate)
Lab to Plant in the same equipment
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o” m e p-D o h rks o “W
Dynamic Flow Reactor Solutions
n-BuLi Halex : API intermediate
2.8 Kgs/hr in a Fume hood
Synthetrons
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TM
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Dynamic Flow Reactor Solutions (2) CofloreÂŽ
Scalable Platform (for 30-50 % solids as slurry) Industrial
Development
Coflore ACR (Agitated Cell Reactor) 30 to 85 ml flexible vol.
Coflore
Industrial
ATR
(Agitated Tube Reactor) 0.35 to 10 L in same System
Coflore
RTR
100 L
Mixing independent of flow rate
Slow reactions, multi-phase reactions
Solid/liquid/gas handling
Suitable for slurry processing and formation
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Dynamic Flow Reactor Solutions (2) Coflore速
Scalable Platform (for 30-50 % solids as slurry)
Coflore速 RTR 100L
7000 L Batch Reactor
Size comparison: Coflore速 RTR vs 7000 L batch reactor. For a 20 min residence time, the Coflore速 100L RTR can process > 7000 L in 24 h Copyright Pi-Process Intensification Exp. LLP
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Dynamic Flow Reactor Solutions (2) CofloreÂŽ
Residence Time Distribution true Plug Flow i.e. Dispersion number ( D/ÂľL < 0.01 ) achieved at all RTs , viz., 7, 14, 28 & 55 minutes. Conclusion : Radial mechanical agitation decouples Plug Flow from Residence Time (and Flow Velocity).
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Dynamic Flow Reactor Solutions (2) CofloreÂŽ
Biocatalysis (S/L)
36 tonne/annum
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Dynamic Flow Reactor Solutions (2) CofloreÂŽ
@ 120 t/a API (beta-Blocker) Intermediate
Drivers: High atom efficiency, time & energy conservation, high selectivity & no degradation prod. Copyright Pi-Process Intensification Exp. LLP
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Dynamic Flow Reactor Solutions (2) CofloreÂŽ Hydrogenation
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FUJI Techno “Super Metering Pumps” are Pulse-Free & Accurate Operating Principle :
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Accurate
Pulse-Free
Inert Gas Purge
Liq.Flush Copyright Pi-Process Intensification Experts LLP
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Pump â&#x20AC;&#x201C; Design Principle (Fuji Techno)
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DOWNSTREAM Unit Ops – L/L Extraction
10 ml/min
200 ml/min
3000 ml/min
• • • •
Continuous operation Scalable Separation of liquids with same density Multistage extraction
Scale
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DOWNSTREAM Unit Ops â&#x20AC;&#x201C; L/L Extraction In-line work-up is essential to link the reactive steps:
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DOWNSTREAM Unit Ops â&#x20AC;&#x201C; L/L Extraction
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DOWNSTREAM Unit Ops â&#x20AC;&#x201C; G/L Extraction ( HiGee) Dr. C. Ramshaw invented (1979) Rotating Packed Beds ( HiGee ) to intensify mass transfer for G-L separation process
POTTERS & POTTERS
Drivers: v. high vapour-liquid forced regenerated contact surfaces v. high number theoretical plates v. low space requirements Copyright Pi-Process Intensification Exp. LLP
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Unit-Ops -- Intensified HiGee Distillation
Liq flows from topto-bottom at 1 g acceleration
Liq flows from inside to outside at > 100 g 30 mt column replaced by a 1.5 mt column for MeOH Distn. acceleration
Drivers: v. high vapour-liquid forced regenerated contact surfaces v. Low reflux ratios (hence, v. low energy consumption) v. low space requirements
HiGee Distillation
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DOWNSTREAM Unit Ops â&#x20AC;&#x201C; Continuous Filtration
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DOWNSTREAM Unit Ops â&#x20AC;&#x201C; Continuous Drying
Fluidized Bed Dryer-Cooler
Multi-stacked Rotating Disk Air/Vac DRYER-cum-Cooler
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Benefits of PI for APIâ&#x20AC;&#x2122;s
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