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 DTU Chemical Engineering Department of Chemical and Biochemical Engineering
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 2 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
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 ) Major drivers Goals cheaper processes smaller equipment/plants Selectivity, Costs, safer processes Competitiveness, Sustainability less energy consumption Safety, Reliability shorter time to market Energy savings less waste/by-products better company image Moulijn, J. A.; Stankiewicz, A. I. Re-engineering the Dechema. European Roadmap for Process chemical processing plant: process intensification . Intensification. Creative Energy - Energy Transition. Marcel Dekker, Inc.: New York, USA, Vol. 982003. 3 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Process intensification • Small scale pharmaceutical production Mesoscale flow chemistry Exothermic (fast) chemical reactions Endothermic (slow) chemical reactions Substrates Batch processes Products Microreactor technology Ultrasounds Chemical catalysis and Supportive operations (mechanical or sonochemical) biocatalysis Microwave assisted organic Changes / Modifications synthesis (MAOS) of synthetic routes 4 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Process intensification • Cooperation with other disciplines important for the pharmaceutical industry Goals: Goals: Deeper understanding of Efficient usage of resources Process Intensification process New simulation methods and (PI) Higher production quality decision making tools Lower production costs Functional, integrated design of product and processes Self-adjusting production Optimization of performance processes ... ... Process Analytical Process Systems Technology (PAT) Engineering (PSE) Tools: Tools: Process analyzers Numerical analyses, optimization methods Process chemometrics Informatics and intelligent Real time process systems monitoring and control ... Automation 5 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 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 H O N N OH N H H N Cl Cl S S 6 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Synthetic route towards Clopenthixol O OMgCl OH Cl Cl Cl Mg salts THF, 25 - 30 °C THF, acid + + MgCl S Grignard alkylation Hydrolysis S S H H OH Cl Cl Cl THF/Toluene, acid + Slow chemical reactions Dehydration S S S OH H OH N Cl N H N + Cl Hydroamination S N H S H O N OH H N Cl H N + Cl Hydroamination S N H S 7 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Manufacturing route towards Clopenthixol Water By-products Grignard Grignard reagent “Alkoxide” “N714-Allylcarbinol” Hydrolysis Separation L-L Alkylation (Step 2) (Step 3) CTX, THF THF THF, Water, By-products (Step 1) Water “N714-Allylcarbinol” Acetic acid THF Crystallization “N714-Allylcarbinol” “N714-Allylcarbinol” Water Drying Distillation Filtration (Step 6) (Step 4) (wet) Water, Ethanol Ethanol (Step 5) “N714-Allylcarbinol” Water (dry) Ethanol Toluene, Acetyl chloride Acetic acid Distillation Toluene “N746-Butadienes” Clopenthixol Dehydration Hydroamination (Step 7) Toluene HEP (Step 8) HEP Acetyl chloride Acetic acid anhydride 8 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Manufacturing route towards Clopenthixol Water By-products Grignard Grignard reagent “Alkoxide” “N714-Allylcarbinol” Hydrolysis Separation L-L Alkylation (Step 2) (Step 3) CTX, THF THF THF, Water, By-products (Step 1) Water “N714-Allylcarbinol” Acetic acid THF THF Distillation “N746-Butadienes” Clopenthixol Dehydration Hydroamination (Step 7) THF HEP (Step 8) HEP 10 M Sulfuric acid 9 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Manufacturing route towards Clopenthixol Water By-products Grignard Grignard reagent “Alkoxide” “N714-Allylcarbinol” Hydrolysis Separation L-L Alkylation (Step 2) (Step 3) CTX, THF THF THF, Water, By-products (Step 1) Water “N714-Allylcarbinol” Acetic acid THF THF Distillation “N746-Butadienes” Clopenthixol Dehydration Hydroamination (Step 7) THF HEP (Step 8) HEP 10 M Sulfuric acid 10 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Grignard alkylation • Action plan • Batch mode • Filter reactor • Filter reactor and mesoscale • Mesoscale tubular reactor tubular reactor • Room temperature • Room temperature • Room temperature • Room temperature • Solubility of CTX in THF • Solubility of CTX • Solubility of CTX • Solubility of CTX in THF is regulated with a filter in THF in THF issue again • Good dosage of Grignard reag. • Inadequate dosage • Inadequate dosage • Inadequate dosage of Grignard of Grignard reag. of Grignard reag. reagent Grignard reagent THF, CTX, Grignard reagent THF, CTX, THF, CTX, Grignard reagent Grignard reagent Heat exchanger Heat exchanger Heat exchanger Heat exchanger THF, CTX, Alkoxide, THF, Alkoxide, THF, Mg salts Alkoxide, THF, Mg salts ”Alkoxide”, Mg salts Mg salts THF, CTX, Alkoxide, THF, Mg salts 11 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 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.; Mu ̈ ller 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 12 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Grignard alkylation • Switch from batch mode to the CSTR with side entry tubular reactor 13 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Manufacturing route towards Clopenthixol Water By-products Grignard Grignard reagent “Alkoxide” “N714-Allylcarbinol” Hydrolysis Separation L-L Alkylation (Step 2) (Step 3) CTX, THF THF THF, Water, By-products (Step 1) Water “N714-Allylcarbinol” Acetic acid THF THF Distillation “N746-Butadienes” Clopenthixol Dehydration Hydroamination (Step 7) THF HEP (Step 8) HEP 10 M Sulfuric acid 14 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
Hydrolysis and separation L-L • 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 of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator . Organic Process Research & Development 2012 , 16 (5), 888-900 15 DTU Chemical Engineering, Process Intensification in Small Scale Pharmaceutical Production 09 April, 2014 Technical University of Denmark
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