Vijay Kirpalani of Pi-Process 'PI Techniques enabling advanced Continuous Manufacture of APIs'

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.

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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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