Continuous Crystallization of Pharmaceuticals Allan S. Myerson Dept. of Chemical Engineering Novartis-MIT Center for Continuous Manufacturing Massachusetts Institute of Technology
Crystallization Process Development Process Goals Purity Yield Average Size and Size Distribution Correct Polymorph or Pseudopolymorph Shape
Technological Approaches and Innovation Crystallizer Process Design and Attainable Regions New Operational Approaches and Configurations of MSMPR Crystallizer Cascades New Crystallizer Designs Crystallization for Process Intensification
Work flow for MSMPR design MSMPR cascade design Given: API, solvent system Experimental validation API characterization Dynamic simulation Process Optimization Determine analytics & calibration Solubility measurement Conduct steady state MSMPR experiments Estimate kinetic parameters Run simulation, track control variables Set control objectives & limitations Operational window Conduct experiments to validate dynamic model prediction Verify feasibility Determine the optimal operating conditions
Case study: operation window The case of p-aminobenzoic acid in water Control objective: yield > 0.9, polymorph purity > 0.95 Constraints: Two stage MSMPR τ total =120 mins T 2 =5 C Operating variables: T 1, τ 1 (contour: yield, white lines: polymorph purity)
Barriers to Implementation Significant Amounts of Kinetic Data required with long experimental times if steady state experiments are performed Minimum amount of API needed is typically above 20grams Knowledge of population balance modeling and parameter estimation required 6
New Operational Approaches and Configurations Using MSMPR Cascades Crystallization with Solution Concentration and Recycle Crystallization with Solid Recycle Crystallization with Impurity Removal and Solute Concentration Using Nanofiltration Membrances for Solution Recycle Crystallization with Impurity Complexation for Purity Improvement
Continuous Single Stage MSMPR with Recycle for Cooling Crystallization Feed Crude MSMPR Separator solution 155mL (mother liquor only) Pure API (solid only) Vac. Evaporation Acetone Concentrated Mother liquor Waste Condensation Evaporation Acetone Removal Filter unit Feed Waste Filter unit Waste Crystallizer Recycle
Crystallization with Solid Recycle Objectives Improve yield with a short residence time Control crystal size and purity Supersaturation Crystal surfaces Nucleation Crystal growth Solids recycle Higher suspension density Larger surface area More crystal mass deposition Higher yield Cooling crystallization of cyclosporine 9
MSMPR with Membrane Concentration Additional Purgestream? Depleted API Concentrated Impurity Membrane Module Permeate: Ideally Solvent And Impurity
MSMPR with Membrane Filter Unit Feed Membrane Unit Antisolvent FBRM (for CLD) Crystallizer, RT = 1 h
Combined MSMPR with Membrane Recycle % w/w % w/w 4 3.5 3 2.5 2 1.5 1 0.5 0 Without Membrane 24-P84-1:2-PP-X 24-P84-1:3-PP-X 0 2 4 6 8 10 Time, h Crystallizer Recycle Purge 4 3.5 3 2.5 2 1.5 1 0.5 0 0 2 4 6 8 10 Time, h % w/w Crystallizer Retentate Permeate 4 3.5 3 2.5 2 1.5 1 0.5 0 0 2 4 6 8 10 Time, h Crystallizer Retentate Permeate Batch MSMPR, no Membrane MSMPR with 1:2-PP-X MSMPR with 1:3-PP-X Yield* 89.22% 70.29% 98.03% 98.71% 4HBA in crystals, ppm*,** 0.32 0.13 0.15 0.22 *Novartis process (batch): Yield = 92%, limit of 4HBA in crystals = 3 ppm ** values below reporting limit (defined by HPLC method)
New Crystallizer Designs Oscillatory Baffled Crystallizer Continuous Flow Tubular Crystallization in Slugs Pressure Driven Mini MSMPR 13
COBR (Continuous Oscillatory Baffled Reactors) Series of periodically spaced orifice baffles, superimposed oscillatory motion of a fluid (with a net flow) Decouples mixing from net flow thus reduced processing time Reduced average shear (when compared to localized shear from impellers) Enhancement in processes such as rapid heat transfer, particle mixing and mass transfer. Plug flow reactor Fig 1. Example of a typical COBR set-up Net flow Eddies Oscillation Fig 2. Various baffle types: single orifice, multiple orifice, smooth constrictions. Back stroke Forward stroke Fig 3. Flow interaction with baffles
Nucleation method: Indirect ultrasonication Sonication probe Air Hot solution Sonication bath Air Slurry Air Slurry Air Slurry Nucleation Slug formation Growth Sonication converter Sonication probe Silicone tubing Water bath 15
Pressure-driven flow crystallizer (PDFC) Reagent Stream 1 Reagent Stream 2 Pressure Release Opening No Pump 1 Nc TV-1 No Transfer Line 1 Transfer Line 2 L2a L1a L2b L1b No Nc TV-2 No Vacuum Stage 1 Stage 2 Collection Vessel
Crystallization For Process Intensification Combined Salt Formation and Crystallization Crystallization of Crystalline Excipients Crystallization of Polymer Excipients. 17
C13 concnetration in the mother liquor, mass/mass Salt Formation and Crystallization in a Single Step O O OH H N NH2 + a) HCl-gas, ipr 2 O b) NaOH, Me-THF O O O NH 2 OH O H N NH 2 O O NH 2 O O C11 92% C11 92%. 1/2 C11 (SPP-100 FREE BASE) C12(FUMARIC ACID) ALISKIREN (SPP-100) SALT 6.00% 5.00% 4.00% 3.00% 2.00% 1.00% 0.00% 0.3 0.5 0.7 0.9 1.1 1.3 Molar Ratio of fumaric acid/c11 Ratio of Fumeric Acid to Free Base Crucial Parameter
Continuous Crystallization of On Excipients Excipient API Solid Excipient Feed D-mannitol Inlet Solution Acetaminophen Ethanol M Feed Solution Acetaminophen Ethanol D-mannitol P1 M Product To Filter TC TT Acetaminophen Ethanol D-mannitol P2 TC TT Feed Vessel MSMPR Crystallizer
From Films to Tablets