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EXPLOITATION OF QBD ELEMENTS FOR A BATCH/CONTINUOUS PROCESS

EXPLOITATION OF QBD ELEMENTS FOR A BATCH/CONTINUOUS PROCESS. Girish MALHOTRA, PE EPCOT International Quality By Design International Pharmaceutical Academy October 19-20, 2009 Somerset, New Jersey. My perspective. MY DEFINITION OF API:.

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EXPLOITATION OF QBD ELEMENTS FOR A BATCH/CONTINUOUS PROCESS

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  1. EXPLOITATION OF QBD ELEMENTSFOR A BATCH/CONTINUOUS PROCESS Girish MALHOTRA, PE EPCOT International Quality By Design International Pharmaceutical Academy October 19-20, 2009 Somerset, New Jersey EPCOT International

  2. My perspective EPCOT International

  3. MY DEFINITION OF API: It is a specialty chemical that has a disease curing value. EPCOT International

  4. GOAL QUALITY AND PROFITABILITY EPCOT International

  5. QUALITY AND PROFITABILITY Good Process High on-stream-time (high equipment utilization) Green and Safe Quality first and all the time (QBD) Easier Regulatory compliance Better “Total Business Process” EPCOT International

  6. LABORATORY LEARNING • HOW CHEMICALS INTERACT? • GENERAL PROCESS CONDITIONS. • BASIC PROCESSING METHODS. • ESTABLISH BASIC SPECS. • WHICH ANALYTICAL TOOLS NEEDED. EPCOT International

  7. LABORATORY LEARNING ABSOLUTELY NOTHING WRONG WITH LAB PROCESSES. THEY ARE A ROAD MAP. EPCOT International

  8. LABORATORY LEARNING • GENERALLY ON SMALL SCALE. • LABORATORY METHODS CAN NOT SIMULATE COMMERCIAL EQUIPMENT. • WHAT WORKS IN THE LAB DOES NOT WORK IN THE PLANT. EPCOT International

  9. LABORATORY LEARNING • SHOULD NOT COMMERCIALIZE AN “AS IS” LAB PROCESS. • GENERALLY NOT REPRODUCIBLE. • REPEATED ANALYSIS  PARALYSIS. EPCOT International

  10. OUR NEED • PROCESS: PRODUCES QUALITY PRODUCT. • FIRST TIME AND ALL THE TIME. • SIMPLIFY “TOTAL BUSINESS PROCESS”. • MIN. IN-PROCESS INVENTORIES. EPCOT International

  11. PHYSICAL PROPERTIES • REACTION MECHANISM • CHEMISTRY/MASS BALANCE QBD ELEMENTS UNDERSTAND AND MANIPULATE FOR A SAFE AND ECONOMIC PROCESS EPCOT International

  12. OUR GOAL WE HAVE TO HAVE TOTAL COMMAND. COMMAND ON PROCESS ONLY “IF WE UNDERSTAND” QBD ELEMENTS. EPCOT International

  13. TEST OFCOMMAND ON THE PROCESS WILL BE: ”IN-PROCESS SAMPLING” DELIVER ALL TIME QUALITY EPCOT International

  14. ? EPCOT International

  15. COMMAND OF QBD ELEMENTS • FEASIBLE. • CONTINUOUS IMPROVEMENT EASY. • IT WILL MAKE DEVELOPMENT OF A BATCH OR A CONTINUOUS PROCESS EASY. • SIMPLER REGULATORY PROCESS. EPCOT International

  16. COMMAND OF QBD ELEMENTS CHEMISTS/ ENGINEERS HAVE TO OPTIMIZE THE ROAD MAP. EPCOT International

  17. PHYSICAL PROPERTIES: • PHYSICAL STATE • BOILING POINT/ MELTING POINT • AZEOTROPE • VISCOSITY • DENSITY • THERMODYNAMIC PROPERTIES • SOLUBILITY EPCOT International

  18. REACTION CHEMISTRY & MECHANISM: • HOW THE COMPONENTS REACT? • YIELD/ STOICHIOMETRY EPCOT International

  19. QBD ELEMENTS DEFINE AND ESTABLISH PROCESS AND OPERATINGPARAMETERS EPCOT International

  20. COMMAND OF QBD ELEMENTS • HOW • EXAMPLES EPCOT International

  21. USP 7,109,203 NOVARTISPREPARATION OF 2-CHLORO-4 BROMOBENZENESUFONYL CHLORIDE EPCOT International

  22. USP 7,109,203 NOVARTISPREPARATION OF 2-CHLORO-4 BROMOBENZENESUFONYL CHLORIDE • Laboratory process: • 4-bromo-2-chloroaniline is a solid @ RT. • Slurried in Acetic acid [high use of acid] • Hydrochloric acid • Sodium nitrite EPCOT International

  23. COMPARISON OF TWO SIMILAR REACTIONS EPCOT International epcot international

  24. Commercial process: (batch/continuous) • 4-bromo-2-chloroaniline MP = about 70°C Explore use as a melt or water slurry. • Consider no acetic acid. • Reduce Hydrochloric acid • Sodium nitrite USP 7,109,203 NOVARTISPREPARATION OF 2-CHLORO-4 BROMOBENZENESUFONYL CHLORIDE EPCOT International

  25. COMPARISON OF TWO SIMILAR REACTIONS BOTH CHEMISTRIES ARE “ZERO” ORDER REACTIONS I.E. INSTANTANEOUS CHEMISTRY IN PATENT > 16 HRS. THIS IS DUE TO LAB EQUIPMENT LIMITATIONS. PRODUCT “X” PROCESSED CONTINUOUSLY. EPCOT International

  26. Continuous process for Product “X” Decanter CuCl2 Solvent E D Decanter Catalyst Recovery HE Rx 1 Heat exchanger (HE) Rx 3 Rx 2 HE Pump HE B C A Pump Pump Flow rate of B & C is dependent on flow A. Pump Decanter Acid Precipitation Rx 4 HE Solvent recovery Finished product Carbon Treatment Pump Crystallization Dissolution Filtration EPCOT International

  27. Continuous process for Product “X” Decanter CuCl2 Solvent D HE Rx 1 Heat exchanger (HE) Rx 2 Pump HE B C A Pump Pump Flow rate of B & C is dependent on flow A. Pump EPCOT International

  28. RAW MATERIAL FINESSE PRODUCT “XYZ” REACTANTS “A” + “B” + “C” WITH WATER (SOLVENT) A, B AND C ALL LIQUIDS ORDER OF ADDITION WATER + A + B + C (CONTROLLED RATE) BATCH PROCESS OVER 8-10 HOURS. PRODUCT VARIABILITY. EPCOT International

  29. RAW MATERIAL FINESSE PRODUCT “XYZ” COMMERCIAL PROCESS IS SAME AS THE LAB PROCESS EPCOT International

  30. RAW MATERIAL FINESSE PRODUCT “XYZ” REACTANTS “A” AND “C” INERT TO EACH OTHER. REACTANT “B” AND WATER INERT TO EACH OTHER. TWO SOLUTIONS OF PREPARED OF THE DESIRED STOICHIOMETRY. PRECISELY CONTROLLED ADDITION OF TWO LIQUIDS RESULTED IN A ”CONTINUOUS PROCESS” WITH IMPROVED YIELD AND HIGHER PRODUCTIVITY. MEETS STRINGENT SPEC. THAN BATCH PROCESS. EPCOT International

  31. PREPARATION OF PHTHALIMIDE: PHYSICAL STATE REACT PHTHALIC ANHYDRIDE WITH AMMONIA STOICHIOMETRIC SINGLE STEP REACTION FEED LIQUID PHTHALIC ANHYDRIDE AND LIQUID NH3 CONTROL PRESSURE WITH THE GENERATED STEAM QUALITY PRODUCT. EPCOT International

  32. PREPARATION OF METFORMIN HYDROCHLORIDE: PHYSICAL STATE REACT DIMETHYL AMINE HYDROCHLORIDE WITH DICYANDIAMIDE STOICHIOMETRIC SINGLE STEP REACTION FEED LIQUIDDIMETHYL AMINE HYDROCHLORIDE ANDLIQUID DICYANDIAMIDE CONTROL RESIDENCE TIME AND FEED RATES EPCOT International

  33. PREPARATION OF METFORMIN HYDROCHLORIDE: PHYSICAL STATE QUALITY PRODUCT. CONTINUOUS PROCESS YIELD > 95% WITH CONSISTENT QUALITY BATCH PROCESSES YIELD 65- 69% EPCOT International

  34. PHYSICAL STATE FINESSE ALL LIQUID FEEDS BETTER CONTROL OF PROCESS. SAFE PROCESS. REDUCED CAPITAL INVESTMENT. EPCOT International

  35. FRIEDEL CRAFT REACTION: • CLASSICAL CHEMISTRY • SOLID ADDITION OF AlCl3. • NEUTRALIZE THE EXCESS. • BATCH PROCESS. PHYSICAL STATE EPCOT International

  36. FRIEDEL CRAFT REACTION: TWO POSSIBILITIES • DISPERSE ALCl3 IN A SOLVENT TO FORM A SUSPENDABLE SLURRY. • ITS FLOW RATE CAN BE CONTROLLED USING COMMERCIAL FLOW METERS. • NEUTRALIZE THE EXCESS. DISPERSING AGENT WATER SOLUBLE. PHYSICAL STATE FINESSE EPCOT International

  37. PHYSICAL STATE FRIEDEL CRAFT REACTION: BATCH SYNTHESIS  CONTINUOUS PROCESSES IBUPROFEN/NAPROXEN EPCOT International

  38. FRIEDEL CRAFT REACTION: • ZIPRASIDONE HYDROCHLORIDE (USP 4,831,031) • FIRST ISOLATED INTERMEDIATE 5-CHLOROACETYL-6-CHLORO 2-OXINDOLE • IT IS A SKIN SENSITIZER. • INVESTMENT NEEDED TO PROTECT PERSONNEL. PHYSICAL STATE EPCOT International

  39. FRIEDEL CRAFT REACTION: • ZIPRASIDONE HYDROCHLORIDE (USP 4,831,031) • PROPOSED ALTERNATE CHEMISTRY (1) • ISOLATION OF “HAZARDOUS INTERMEDIATES” • NADKARNI et. al. OPRD 2008, 12, 1142-1145 • GREAT BATCH  CONTINUOUS A POSSIBILITY PHYSICAL STATE EPCOT International

  40. SOLUBILITY AND TEMPERATURE • LABORATORY PROCESSES: • EFFORT TO SHOW “HOW” OF THE PROCESS. • MULTIPLE SOLVENTS. • DILUTION 10-30% KEY RAW CONCENTRATION. HIGH DILUTION YIELD LOSS: A POSSIBILITY. EPCOT International

  41. SOLUBILITY AND TEMPERATURE • LABORATORY PROCESSES: • LABORATORY EQUIPMENT LIMITATIONS. • COMMERCIALIZED “AS IS” VARIABLE RESULTS. • HIGH COST, HIGH WASTE, LOW PRODUCTIVITY. EPCOT International

  42. SOLUBILITY AND TEMPERATURE • HIGHER TEMPERATURE TO INCREASE SOLUBILITY. • SOLVENTS WITH HIGH SOLUBILITY. • MULTIPLE BENEFITS. EPCOT International

  43. RESULTS: • IMPROVED PRODUCTIVITY. • HIGHER YIELD. • BETTER PROCESS WITH CYCLE TIME. • LOWER INVESTMENT. SOLUBILITY AND TEMPERATURE EPCOT International

  44. ACETAMINOPHEN • A batch process [China and India]. • Use of acetic anhydride. • Other methods of acetylation. [acetic acid] • Simplification and can be a continuous process. • Mallinckrodt, Rhodia [CONTINUOUS] EPCOT International

  45. ALTERNATES METHODS:USP 7,399,870 (Wyeth) EPCOT International

  46. ALTERNATES METHODS:USP 7,399,870 (Wyeth) Yield (toluene) ~ 95% ALL LIQUID AND A CLEAN CONTINUOUS PROCESS Rx Rx EPCOT International

  47. ALTERNATES METHODS:USP 7,579,487 (MRK) O-FLUORO TOLUENE  4-Fluoro-3-methylbenzene sulfonamide THREE POTENTIAL ROUTES EPCOT International

  48. USP 7,579,487 (MRK) DIRECT CHLOROSULFONYLATION FOLLOWED BY AMINATION O-FLUORO TOLUENE SULFONYL CHLORIDE IS A LIQUID. Profitability through simplicity epcot international

  49. USP 7,579,487 (MRK) SULFONATION /CHLORINATION / AMINATION Profitability through simplicity epcot international

  50. USP 7,579,487 (MRK) DIAZOTIZATION/CHLOROSULFONYLATION/ AMINATION Profitability through simplicity epcot international

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