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Process Intensification in Small Scale Pharmaceutical Production - - PowerPoint PPT Presentation

Mar 21, 2023 257 likes •695 views

Process Intensification in Small Scale Pharmaceutical Production Aleksandar Mitic Prof. Krist V. Gernaey (PROCESS-CAPEC, DTU Chemical Engineering) Prof. Kim-Dam Johansen (CHEC, DTU Chemical Engineering) MS Tommy Skovby (H. Lundbeck A/S) April

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DTU Chemical Engineering Department of Chemical and Biochemical Engineering

Process Intensification in Small Scale Pharmaceutical Production

Aleksandar Mitic

  • Prof. Krist V. Gernaey (PROCESS-CAPEC, DTU Chemical Engineering)
  • Prof. Kim-Dam Johansen (CHEC, DTU Chemical Engineering)

MS Tommy Skovby (H. Lundbeck A/S) April 09, 2014 NL GUTS & PIN-NL Separation and Process Intensification Bronswerk Heat Transfer Nijkerk The Netherlands

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 2 DTU Chemical Engineering, Technical University of Denmark

Outline

  • Process intensification
  • Example process
  • Synthetic route towards Clopenthixol
  • Manufacturing route towards Clopenthixol

– Grignard alkylation – Hydrolysis and separation L-L – Dehydration reaction – Hydroamination reactions

  • Conclusions and future perspectives
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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 3 DTU Chemical Engineering, Technical University of Denmark

Energy savings Safety, Reliability

Process intensification

  • Definition:

– “PI provides radically innovative principles (‘paradigm shift’) in process and equipment design which can benefit (often with more than a factor two) process and chain efficiency, capital and operating expenses, quality, wastes, process safety and more” (EFCE in European Roadmap for Process Intensification)

Dechema. European Roadmap for Process

  • Intensification. Creative Energy - Energy Transition.

Selectivity, Costs, Competitiveness, Sustainability Major drivers Goals  cheaper processes  smaller equipment/plants  safer processes  less energy consumption  shorter time to market  less waste/by-products  better company image

Moulijn, J. A.; Stankiewicz, A. I. Re-engineering the chemical processing plant: process intensification. Marcel Dekker, Inc.: New York, USA, Vol. 982003.

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 4 DTU Chemical Engineering, Technical University of Denmark

Process intensification

  • Small scale pharmaceutical production

Substrates Products Mesoscale flow chemistry Batch processes Microreactor technology Microwave assisted organic synthesis (MAOS) Ultrasounds (mechanical or sonochemical) Chemical catalysis and biocatalysis Changes / Modifications

  • f synthetic routes

Supportive

  • perations

Exothermic (fast) chemical reactions Endothermic (slow) chemical reactions

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 5 DTU Chemical Engineering, Technical University of Denmark

Process intensification

Process Intensification (PI) Process Systems Engineering (PSE) Process Analytical Technology (PAT)

  • Cooperation with other disciplines important for the pharmaceutical industry

 Process analyzers  Process chemometrics  Real time process monitoring and control  Automation  Deeper understanding of process  Higher production quality  Lower production costs  Self-adjusting production processes  ...

Goals: Tools: Goals:

 Efficient usage of resources  New simulation methods and decision making tools  Functional, integrated design

  • f product and processes

 Optimization of performance  ...

Tools:

 Numerical analyses,

  • ptimization methods

 Informatics and intelligent systems  ...

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 6 DTU Chemical Engineering, Technical University of Denmark

Example process

  • Clopenthixol

– a product of H. Lundbeck A/S – thioxanthene compound as a mixture of two geometrical isomers – cis-isomer (API) – Zuclopenthixol – treating schizophrenia and mania S Cl H N N O H

S Cl H N N OH

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 7 DTU Chemical Engineering, Technical University of Denmark

S O Cl + MgCl S Cl OMgCl S Cl OH + Mg salts

THF, 25 - 30 °C Grignard alkylation THF, acid Hydrolysis

S Cl OH S Cl H S Cl H +

THF/Toluene, acid Dehydration

S Cl H S Cl H N N O H + N N H OH

Hydroamination

S Cl H + N N H OH S Cl H N N OH

Hydroamination

Slow chemical reactions

Synthetic route towards Clopenthixol

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 8 DTU Chemical Engineering, Technical University of Denmark

Manufacturing route towards Clopenthixol

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Distillation (Step 4) Water Ethanol Crystallization Filtration (Step 5) “N714-Allylcarbinol” Water, Ethanol Water Ethanol Drying (Step 6) “N714-Allylcarbinol” (wet) “N714-Allylcarbinol” (dry) Water By-products Dehydration (Step 7) “N746-Butadienes” Toluene Toluene Acetyl chloride Acetic acid anhydride Distillation Hydroamination (Step 8) Clopenthixol HEP HEP Toluene, Acetyl chloride Acetic acid

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 9 DTU Chemical Engineering, Technical University of Denmark

Manufacturing route towards Clopenthixol

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Water By-products Dehydration (Step 7) “N746-Butadienes” THF 10 M Sulfuric acid Distillation Hydroamination (Step 8) Clopenthixol HEP HEP THF

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 10 DTU Chemical Engineering, Technical University of Denmark

Manufacturing route towards Clopenthixol

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Water By-products Dehydration (Step 7) “N746-Butadienes” THF 10 M Sulfuric acid Distillation Hydroamination (Step 8) Clopenthixol HEP HEP THF

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 11 DTU Chemical Engineering, Technical University of Denmark

Grignard alkylation

  • Action plan

Heat exchanger Heat exchanger

THF, CTX, Alkoxide, THF, Mg salts Grignard reagent THF, CTX, Alkoxide, THF, Mg salts Grignard reagent THF, CTX, Grignard reagent Alkoxide, THF, Mg salts THF, CTX, THF, CTX, ”Alkoxide”, Mg salts Grignard reagent

Heat exchanger Heat exchanger

Alkoxide, THF, Mg salts

  • Batch mode
  • Room temperature
  • Solubility of CTX

in THF

  • Inadequate dosage
  • f Grignard reag.
  • Filter reactor
  • Room temperature
  • Solubility of CTX

in THF

  • Inadequate dosage
  • f Grignard reag.
  • Filter reactor and mesoscale

tubular reactor

  • Room temperature
  • Solubility of CTX in THF

regulated with a filter

  • Good dosage of Grignard reag.
  • Mesoscale tubular reactor
  • Room temperature
  • Solubility of CTX in THF is

issue again

  • Inadequate dosage of Grignard

reagent

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 12 DTU Chemical Engineering, Technical University of Denmark

Grignard alkylation

  • Switch from batch mode to the CSTR with side entry tubular reactor

Cervera-Padrell, A. E.; Nielsen, J. P.; Jønch Pedersen, M.; Müller Christensen, K.; Mortensen, A. R.; Skovby, T.; Dam-Johansen, K.; Kiil, S.; Gernaey, K. V. Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy. Organic Process Research & Development 2012, 16 (5), 901-914

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 13 DTU Chemical Engineering, Technical University of Denmark

  • Switch from batch mode to the CSTR with side entry tubular reactor

Grignard alkylation

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 14 DTU Chemical Engineering, Technical University of Denmark

Manufacturing route towards Clopenthixol

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Water By-products Dehydration (Step 7) “N746-Butadienes” THF 10 M Sulfuric acid Distillation Hydroamination (Step 8) Clopenthixol HEP HEP THF

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 15 DTU Chemical Engineering, Technical University of Denmark

  • Switch from batch mode to tubular laminar reactor with consequent L-L sepration with

miniscale hydrophobic PTFE membrane separator

Cervera-Padrell, A. E.; Morthensen, S. T.; Lewandowski, D. J.; Skovby, T.; Kiil, S.; Gernaey, K. V. Continuous Hydrolysis and Liquid–Liquid Phase Separation

  • f

an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator. Organic Process Research & Development 2012, 16 (5), 888-900

Hydrolysis and separation L-L

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 16 DTU Chemical Engineering, Technical University of Denmark

Manufacturing route towards Clopenthixol

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Water By-products Dehydration (Step 7) “N746-Butadienes” THF 10 M Sulfuric acid Distillation Hydroamination (Step 8) Clopenthixol HEP HEP THF

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 17 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

  • 2 h for complete conversion
  • Reflux conditions in batch

mode

  • Acetic acid anhydride and

acetyl chloride – catalytic system

  • Toluene as a solvent
  • 3 h for complete

conversion

  • Reflux conditions in batch

mode

  • Sulphuric acid used as a

chemical catalyst

  • THF used as a solvent
  • 3 min for complete

conversion

  • Increased pressure in the

system

  • Sulphuric acid used as a

chemical catalyst

  • THF used as a solvent

Heat exchanger Heat exchanger

Toluene, Acetic Acid Anhydride, Acetyl Chlorie, ”N714-Allylcarbinol” THF, Sulphuric acid, ”N714-Allylcarbinol” Toluene, Acetic Acid, Acetyl Chlorie, ”N746-Butadienes” THF, Sulphuric acid, ”N746-Butadienes” THF, Sulphuric acid, ”N714-Allylcarbinol” THF, Sulphuric acid, ”N746-Butadienes”

  • Action plan
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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 18 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

  • Switch from batch towards mesoscale tubular reactor

dz r z φ Rr Dr L

dz Q Fρh Fρ(h+dh) r z

  • λS
  • λS ( dz)

Rr

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 19 DTU Chemical Engineering, Technical University of Denmark

  • Constraints:

1. Low boiling point of THF 2. High molar concentration of sulphuric acid cause formation of impurities 3. Limited solubility of water in THF

Dehydration reaction

40 80 120 160 200 1 2 3 4 5 6 7 8 9 10 11 12 Temperature [⁰C] Pressure [bar]

Boiling point of THF vs. pressure

Below 12 M of H2SO4 Below 1.4 M of H2O

  

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 20 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

  • Switch from batch towards mesoscale tubular reactor

B1 B2 T1 V1 T2 V3 V2 M1 M2 Data Analysis FT-NIR T3 FC BPR P1

Mitic, A.; Cervera-Padrell, A., E.; Mortensen, A., R.; Skovby, T.; Dam-Johansen, K.; Javakhishvili, I.; Gernaey, K. V. Application of a Mesoscale Laminar Tubular Reactor in the Manufacturing of an Active Pharmaceutical Ingredient (API) Intermediate. Organic Process Research & Development (in preparation)

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 21 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

  • Switch from batch towards mesoscale tubular reactor
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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 22 DTU Chemical Engineering, Technical University of Denmark

Extracted raw data set Select wavelength regions Build PLS model Mathematical Pretreatments Optimize No. of LVs 0.8 < RMSECV / RMSEC <1.2 Yes External validation Independent Samples Yes Initialize No. of LVs RMSEP~ RMSECV No No PLS model Remove outliers

Dehydration reaction

  • Process Chemometrics
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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 23 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

  • Constituents

1. THF 2. H2O 3. “N714-Allylcabinol” 4. “N746-Butadienes”

S Cl OH S Cl H S Cl H

O

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 24 DTU Chemical Engineering, Technical University of Denmark

No. Pre-treatment At-Line In-Line f RMSECV RMSEC RMSEP f RMSECV RMSEC RMSEP

1.

  • 4

0.0250 0.0237 0.0430 4 0.0196 0.0198 0.0161 2. BLC 4 0.0370 0.0345 0.0340 4 0.0197 0.0199 0.0154 3. MC 4 0.0253 0.0225 0.0409 4 0.0206 0.0197 0.0159 4. SG1+7p 2 0.0967 0.0950 0.0785 3 0.0620 0.0634 0.0696 5. SG1+11p 3 0.0571 0.0667 0.0697 3 0.0924 0.0668 0.0920 6. SG1+15p 4 0.0552 0.0667 0.0697 5 0.0438 0.0668 0.0920 7. SG2+7p 2 0.0664 0.0760 0.0944 4 0.0245 0.0228 0.0226 8. SG2+11p 4 0.0572 0.0477 0.0426 5 0.0272 0.0211 0.0377 9. SG2+15p 4 0.0381 0.034 0.0148 7 0.0770 0.0313 0.0755 10. MC+SG1+15p 3 0.0473 0.0508 0.0411 7 0.0235 0.0134 0.0351 11. MC+SG2+15p 3 0.0892 0.0921 0.0895 7 0.0865 0.0308 0.0873 12. MC+BLC 3 0.0385 0.0392 0.0312 3 0.0239 0.0244 0.0085

Dehydration reaction

  • Choice of the best pre-treatment for “N714-Allylcarbinol”
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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 25 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 Molar Concetrations (off-line mode) [M] Molar Concetrations (at-line mode) [M] Molar Concetrations (in-line mode) [M]

"N714-Allylcarbinol"

at-line ext_val_at-line

  • ff-line

ext_val_off-line Ideal

  • Validation of the calibration model for “N714-Allylcarbinol”

 High accuracy of experimental data (R2 > 0.992)  Robust calibration model for FT-NIR  Issue with high molar concentrations (1.4 M and above)

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 26 DTU Chemical Engineering, Technical University of Denmark

0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 Molar Concetrations (off-line mode) [M] Molar Concetrations (at-line mode) [M] Molar Concetrations (in-line mode) [M]

"N746-Butadienes"

at-line ext_val_at-line

  • ff-line

ext_val_off-line Ideal 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 Molar Concetrations (at-line mode) [M] Molar Concetrations (in-line mode) [M]

Water

at-line ext_val_at-line Ideal

Dehydration reaction

  • Validation of the calibration model for “N746-Butadienes” and water
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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 27 DTU Chemical Engineering, Technical University of Denmark

0,2 0,4 0,6 0,8 1 1,2 0,2 0,4 0,6 0,8 1 1,2 0,2 0,4 0,6 0,8 1 1,2 Molar Concetrations (off-line mode) [M] Molar Concetration (at-line mode) [M] Molar Concetration (in-line mode)[M]

"N714-Allylcarbinol"

at-line

  • ff-line

Ideal

Dehydration reaction

  • Real-time process monitoring of “N714-Allylcarbinol”

 High accuracy of experimental data (R2 > 0.993)  Precise data for kinetic model development  Easier process control and automation

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 28 DTU Chemical Engineering, Technical University of Denmark

0,2 0,4 0,6 0,8 1 1,2 0,2 0,4 0,6 0,8 1 1,2 Molar Concetration (at-line mode) [M] Molar Concetration (in-line mode)[M]

"Water"

at-line Ideal

Dehydration reaction

  • Real-time process monitoring of water

 High accuracy of experimental data (R2 > 0.998)  Operational window is respected  Robust calibration model for FT-NIR

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 29 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

  • Real-time process monitoring of “N746-Butadienes”

 High accuracy of experimental data if the molar concentration is lower than 0.8 M  Issues with side chemical reactions  Issues with real-time process monitoring

0,2 0,4 0,6 0,8 1 1,2 0,2 0,4 0,6 0,8 1 1,2 0,2 0,4 0,6 0,8 1 1,2 Molar Concetrations (off-line mode) [M] Molar Concetration (at-line mode) [M] Molar Concetration (in-line mode)[M]

"N746-Butadienes"

at-line

  • ff-line

Ideal

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 30 DTU Chemical Engineering, Technical University of Denmark

Dehydration reaction

  • Analysis of side reactions

347.22 360.48 373.74 387.01 400.27 413.53 426.79 440.05 453.31 466.57 479.83 Refractive Index (mV) Retention Volume (mL) 9.00 11.00 13.00 15.00 17.00 19.00 21.00 24.00

 Hydronium ions break THF ring  Polymerization of THF  Chemical reactions of open THF rings with carboctaion intermediate  Impurities with high Mw

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 31 DTU Chemical Engineering, Technical University of Denmark

Manufacturing route towards Clopenthixol

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Water By-products Dehydration (Step 7) “N746-Butadienes” THF 10 M Sulfuric acid Distillation Hydroamination (Step 8) Clopenthixol HEP HEP THF

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 32 DTU Chemical Engineering, Technical University of Denmark

Hydroamination reaction

  • 24 h for complete

conversion

  • 80⁰C in toluene
  • Excess of HEP
  • More than 24 h
  • THF as a solvent
  • Excess of HEP
  • Solvent evaporation
  • Excess of HEP
  • MAOS without evaporating solvent
  • Action plan

Microwave Microwave Microwave Microwave

THF HEP Clopenthixol THF, HEP ”N746-Butadiene” HEP ”N746-Butadiene” THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol Toluene, HEP ”N746-Butadiene” Toluene, HEP Clopenthixol THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol THF, HEP ”N746-Butadiene” HEP Clopenthixol THF (vapour) THF (liquid)

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 33 DTU Chemical Engineering, Technical University of Denmark

Hydroamination reaction

10 20 30 40 50 60 70 80 90 100 50 100 150 200 250 Converson [%] Time [min]

Microwave vs. Batch Hydroamination (Conversion of "N746-Butadiene")

Microwave Batch mode 10 20 30 40 50 60 70 80 90 100 50 100 150 200 250 Yield [%] Time [min]

Microwave vs. Batch Hydroamination (Yield of Clopenthixol)

Microwave Batch

  • Comparison between MAOS and solvent-free batch approaches
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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 34 DTU Chemical Engineering, Technical University of Denmark

10 20 30 40 50 60 70 80 90 100 20 40 60 Conversion [%] Time [min]

Conversion of "N746-Butadiene"

150⁰C 175⁰C 200⁰C 225⁰C 250⁰C 10 20 30 40 50 60 70 80 90 100 20 40 60 Yield [%] Time [min]

Yield of Clopenthixol [%]

150⁰C 175⁰C 200⁰C 225⁰C 250⁰C

Hydroamination reaction

  • Influence of the temperature increase on conversion of “N746-Butadienes” and yield of

Clopenthixol

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 35 DTU Chemical Engineering, Technical University of Denmark

Hydroamination reaction

  • Action plan
  • 24 h for complete

conversion

  • 80⁰C in toluene
  • Excess of HEP
  • More than 24 h
  • THF as a solvent
  • Excess of HEP
  • Solvent evaporation
  • Excess of HEP
  • MAOS without evaporating solvent

Microwave Microwave Microwave Microwave

THF HEP Clopenthixol THF, HEP ”N746-Butadiene” HEP ”N746-Butadiene” THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol Toluene, HEP ”N746-Butadiene” Toluene, HEP Clopenthixol THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol THF, HEP ”N746-Butadiene” HEP Clopenthixol THF (vapour) THF (liquid)

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SLIDE 36

09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 36 DTU Chemical Engineering, Technical University of Denmark

Hydroamination reaction

  • Comparison between MAOS and solvent-free batch approaches
  • 24 h for complete

conversion

  • 80⁰C in toluene
  • Excess of HEP
  • More than 24 h
  • THF as a solvent
  • Excess of HEP
  • Solvent evaporation
  • Excess of HEP
  • MAOS
  • MAOS with previously evaporated solvent

Microwave Microwave Microwave Microwave

THF HEP Clopenthixol THF, HEP ”N746-Butadiene” HEP ”N746-Butadiene” THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol Toluene, HEP ”N746-Butadiene” Toluene, HEP Clopenthixol THF, HEP ”N746-Butadiene” THF, HEP Clopenthixol THF, HEP ”N746-Butadiene” HEP Clopenthixol THF (vapour) THF (liquid) THF THF, HEP ”N746-Butadiene”

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 37 DTU Chemical Engineering, Technical University of Denmark

Conclusions and future perspectives

  • Overall manufacturing of Clopenthixol is accelerated

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Distillation (Step 4) Water Ethanol Crystallization Filtration (Step 5) “N714-Allylcarbinol” Water, Ethanol Water Ethanol Drying (Step 6) “N714-Allylcarbinol” (wet) “N714-Allylcarbinol” (dry) Water By-products Dehydration (Step 7) “N746-Butadienes” Toluene Toluene Acetyl chloride Acetic acid anhydride Distillation Hydroamination (Step 8) Clopenthixol HEP HEP Toluene, Acetyl chloride Acetic acid

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 38 DTU Chemical Engineering, Technical University of Denmark

  • Overall manufacturing of Clopenthixol is accelerated

Conclusions and future perspectives

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Water By-products Dehydration (Step 7) “N746-Butadienes” THF 10 M Sulfuric acid Distillation Hydroamination (Step 8) Clopenthixol HEP HEP THF

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 39 DTU Chemical Engineering, Technical University of Denmark

  • Overall manufacturing of Clopenthixol is accelerated

Conclusions and future perspectives

Grignard Alkylation (Step 1) Hydrolysis (Step 2) “Alkoxide” THF Separation L-L (Step 3) “N714-Allylcarbinol” THF, Water, By-products Water Acetic acid “N714-Allylcarbinol” THF Grignard reagent CTX, THF Water By-products Dehydration (Step 7) “N746-Butadienes” THF, Water, Salts 10 M H2SO4 Hydroamination (Step 8) Clopenthixol HEP HEP Neutralization Aqueous NaHCO3 “N746-Butadienes” Separation L-L Water By-products Evaporation “N746-Butadienes” THF “N746-Butadienes” THF

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 40 DTU Chemical Engineering, Technical University of Denmark

  • Slow chemical reactions are accelerated without using transition metals as chemical

catalysts

  • Transfer from batch to continuous processes is done together with satisfying PAT

requirements

  • Faster route from initial substrate to Clopenthixol is established with decreased number of

non-value added activities (intermediate storages, unnecessary purification steps)

  • Change from sulphuric acid to another dehydration agent should be done in the dehydration

step

  • Change of solvent in the dehydration step should be also considered
  • Combination of evaporation and MAOS should be performed as the most desired option for

the hydroamination reaction

Conclusions and future perspectives

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 41 DTU Chemical Engineering, Technical University of Denmark

Thanks for your attention.  ??? Questions ???

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09 April, 2014 Process Intensification in Small Scale Pharmaceutical Production 42 DTU Chemical Engineering, Technical University of Denmark

Department of Chemical and Biochemical Engineering Technical University of Denmark Building 229 DK-2800 Lyngby Denmark

  • Krist V. Gernaey

Email: kvg@kt.dtu.dk Phone: +45 45 25 29 70

  • Aleksandar Mitic

Email: asmi@kt.dtu.dk Phone: +45 45 25 29 49

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