Crystallization process improvement driven by dynochem process modeling. Flavien Susanne.
 

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Crystallization process improvement driven by dynochem process modeling. Flavien Susanne. Presentation Transcript

  • 1. Crystallisation improvement driven by Dynochem process modelling Flavien Susanne Chemical Engineer Moussa Boukerche, Thomas DupontPfizer Confidential
  • 2. Introduction Crystallisation is a critical stage in the manufacture of an Active Pharmaceutical Ingredient (API) where key attributes such as purity together with physical and mechanical properties of the crystals are set. Particle size distribution, polymorphic form and crystal habit, have a direct impact on downstream processing (e.g. filtration, drying and powder processing) and ultimately on the performance of the drug productPfizer Confidential
  • 3. Outline2 case studies to illustrate the use of Dynochem toImprove API crystallisation1. Distillation/crystallisation process by constant anti-solvent addition Original process performed by strip and replace cycles Limitation and physical property issues Improvement by control of crystallisation parameters2. Continuous crystallisation by distillation and anti-solvent addition Original process performed by anti-solvent crystallisation Limitation and physical property issues Principle, Advantage and ImprovementPfizer Confidential
  • 4. Case study 1: original process Main issue: reliability of particle size distribution Multiple Strip and Replace cycles (7-9 cycles) 80:20 % w/w THF:water to >95% acetonitrile Large volume of solvent required Long cycle time, potential decomposition of API Concentration Addition of by distillation anti-solventPfizer Confidential
  • 5. Limitation of the process For each addition Variation of composition and temperature Sudden drop of solubility and increase of supersaturation when addition is done Uncontrolled increased of number of particle = uncontrolled crystallisationPfizer Confidential
  • 6. Results Batch to batch variability Crystallisation highly dependant to the process variability Different particle size distribution and physical propertyPfizer Confidential
  • 7. Crystallisation by continuous distillation/addition Transfer from Strip and Replace addition to constant addition Control of solubility evolution by avoiding sudden changes 80 g/L 701st event of crystallisationtriggered by aliquot addition 60 batch Solubility g/L 50 cst Solubility g/L 402nd event of crystallisation 30triggered by aliquot addition 20 10 0 0 100 200 300 400 500 mins Pfizer Confidential
  • 8. Approach and principal Addition of Addition of Concentration anti-solvent anti-solvent distillation by distillation Improve efficiency Better control of anti-solvent addition, less disruption of temperature and composition Better control of solubility and supersaturation Benefit Improvement of physical property Additional benefit Minimise solvent use Cycle timePfizer Confidential
  • 9. Equipment for POC: RC1-MP06 RC1MP06: Reactor for distillation Constant feed Weight of distillate recorded Weight of solvent measured Concentration of solvents and component monitored by IRPfizer Confidential
  • 10. RC1-MP06 Characterisation Specific to reactor Geometry, material of construction, HTF used (flow rate, Cp) First use of the UA Dynochem estimation Series of calibration run at different volume followed by heat up, cool down and distillation experiments for validation Prediction based on heat transfer and heat loss of the reactor used 90 35 80 30 % resistance 70 Temperature 25 60 50 20 0.085 40 15 30 10 20 10 5 0 0 Wall Process Lining fouling Outside Outside Inside Service Inside fouling film fluid fluid film Height (m) 0.035 10 8 UA (W/K) 6 4 -0.1 -0.05 0 0.05 0.1 2 0 0 0.5 1 1.5 Volume (user units)Pfizer Confidential
  • 11. Model in Dynochem and prediction Temperature prediction Liquid phase Composition prediction gas phase composition predictionPfizer Confidential
  • 12. Control of crystallisation parameters Calculation and prediction of solubility and supersaturation The solubility of the mixture THF:water:acetonitrile as a function of temperature was determined experimentally using 13-run D- optimal design The supersaturation was calculated from the solubilityPfizer Confidential
  • 13. POC Results Prediction of solvent evolution Validation of the Proof Of ConceptPfizer Confidential
  • 14. POC Results Repeatability from batch to batch Similar mono modal 1.40 1.35 1.30 1.25 1.20 1.15 1.10 1.05 1.00 0.95 0.90 Density distribution q3* 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0.4 0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100 200 particle size / µmPfizer Confidential
  • 15. Transfer to Large Scale POC demonstrated in the lab using the RC1 reactor automated 0.8L calorimeter reactor Transfer to the Pilot Plant reactor, conical 250L type reactor with twin jacket. Transfer to manufacture reactor, 1500L bottom dish reactorPfizer Confidential
  • 16. Model in Dynochem and predictionPfizer Confidential
  • 17. Large scale reactor Characterisation Extract mathematical description of heat transfer using Dynochem 1 1 1 1 1 1 1       U hi hif hl hw ho f hoTC Jacket wall Reactor r (m) outside film lining inside filmPfizer Confidential
  • 18. Large scale reactor Characterisation Measure heat up and cool down curves for different volumes and stirring speeds Analyze dynamics of reactors with respect to heat transfer Calculation of resistance contribution for different reactors From lab to large scalePfizer Confidential
  • 19. Large scale reactor Characterisation Prediction heat transfer model specific to Pilot Plant reactor Geometry, material of construction, HTF (flow rate and Cp) Heat up and cool down experiment  UA and Ulossexp1 95kg Tj=60°C 70.0 exp5 130.4kg DT=30°C Jacket.Temperature (Imp) (C) Bulk liquid.Temperature (Exp) (C) Jacket.Temperature (Imp) (C) 150.0 Bulk liquid.Temperature (C) Bulk liquid.Temperature (Exp) (C) Bulk liquid.Temperature (C) 56.0 120.0 Process profile (see legend) exp4 130.4kg Tj=20°C Jacket.Temperature (Imp) (C) Bulk liquid.Temperature (Exp) (C) 42.0 70.0 Bulk liquid.Temperature (C) 90.0 28.0 56.0 60.0 Process profile (see legend) 42.0 30.0 14.0 28.0 0.0 0.0 0.0 21.97 43.94 65.91 87.88 109.85 0.0 43.527 87.053 130.58 174.107 217.633 exp6 166.2kg Tj=60°CTime (mins) Jacket.Temperature (Imp) (C) Bulk liquid.Temperature (Exp) (C) exp7 166.2kg Tj=20°CTime (mins) Jacket.Temperature (Imp) (C) Bulk liquid.Temperature (Exp) (C) 75.0 Bulk liquid.Temperature (C) 70.0 Bulk liquid.Temperature (C) 14.0 60.0 56.0 0.0 Process profile (see legend) 0.0 41.03 82.06 123.09 164.12 205.15 Time (mins) 45.0 42.0 30.0 28.0 15.0 14.0 0.0 0.0 33.873 67.747 101.62 135.493 169.367 0.0 0.0 35.707 71.413 107.12 142.827 178.533 Time (mins) Time (mins) Pfizer Confidential
  • 20. Large scale reactor Characterisation Predictive model specific to the Pilot Plant reactor Distillation trials  partial reflux and N2 sweep effectconstant level trial 150.0 sumof f gasv olume (Exp) (L) Bulk liquid.Temperature (Exp) (C) Jacket.Temperature (Exp) (C) v apour.THF (kg) 120.0 Jacket.Temperature (C) Bulk liquid.Temperature (C) sumof f gasv olume (L) 90.0 exp11 distillation from batch exp 150.0 sumof f gas (Exp) (kg) Bulk liquid.Temperature (Exp) (C) 60.0 Jacket.Temperature (Exp) (C) sumof f gas (kg) 120.0 Jacket.Temperature (C) Process profile (see legend) Bulk liquid.Temperature (C) 30.0 90.0 0.0 0.0 30.0 60.0 90.0 120.0 150.0 exp10 distillation test 60.0 250.0 Time (mins) sumof f gas (Exp) (kg) Bulk liquid.Temperature (Exp) (C) Jacket.Temperature (Exp) (C) sumof f gas (kg) 30.0 200.0 Jacket.Temperature (C) Process profile (see legend) Bulk liquid.Temperature (C) 150.0 0.0 0.0 24.347 48.693 73.04 97.387 121.733 Time (mins) 100.0 Different distillation conditions 50.0 Match between experimental data and prediction 0.0 0.0 32.0 64.0 96.0 128.0 160.0 Time (mins) Pfizer Confidential
  • 21. Process transfer Constant feed of MeCN : Flow rate between 32L/hour Volume contained at 150L ± 10% Variation of Cp and density affecting variation of volume Distillation time 13h 10h time saving compare to batch for same end point >10% solvent saving More accurate control of solubility and supersaturationPfizer Confidential
  • 22. Case study 1: Results and Conclusions Prediction of solvent evolution Validation of the model on large scale t 100 n d e e t v l a l l o i t s s i s d s e a m m 80 u l o % v 60 THFmassratio (Exp) watermassratio (Exp) acetonitrilemassratio 40 (Exp) watermassratio acetonitrilemassratio THFmassratio 20 sumoffgasvolume sumoffgasvolume (Exp) 0 0 200 400 600 800 minsPfizer Confidential
  • 23. Case study 1: Results and Conclusions Repeatability from batch to batch Process conducted in 250L and 1500L reactorsPfizer Confidential
  • 24. Outline2 case studies to illustrate the use of Dynochem toImprove API crystallisation1. Distillation/crystallisation process by constant anti-solvent addition Original process performed by strip and replace cycles Limitation and physical property issues Improvement by control of crystallisation parameters2. Continuous crystallisation by distillation and anti-solvent addition Original process performed by anti-solvent crystallisation Limitation and physical property issues Principle, Advantage and ImprovementPfizer Confidential
  • 25. Case study 2: original process Main issue: reliability of particle size distribution Anti-solvent crystallisation 65:35 % w/w heptanes:IPAc, 11mL/g Long cycle time, low throughput Physical property issues (high degree of secondary nucleation)Addition ofanti-solventPfizer Confidential
  • 26. Results: standard crystallisation • Varying composition/volume/supersaturation • Deliver small primary particles(<20m) that are prone to agglomeration • 92% yield of recovery in >600min • Throughput ~9kg/m3.hour 0.925 0.900 0.875 0.850 Pfizer, Materials Science, Sympatec HELOS (H1258) Primary particles UK-453061 0.825 0.800 Batch No. % < 21.5 µm D[v,0.1] D[v,0.5] D[v,0.9] D[4,3] agglomeration 0.775 % 703611/30 65.47 µm 1.61 µm 7.06 µm 328.29 µm 84.38 primary particles 0.750 0.725 703611/26 75.93 703611/27 80.31 1.43 1.53 5.38 6.11 357.17 107.04 73.46 43.41 agglomerated 0.700 0.675 Neil Dawson 21 JUL 2010 during drying 0.650 0.625 0.600 0.575 0.550 0.525 Density distribution q3* 0.500 0.475 0.450 0.425 0.400 0.375 0.350 0.325 0.300 0.275 0.250 0.225 0.200 Primary particles 0.175 Controlled by 0.150 0.125 crystallization 0.100 0.075 0.050 0.025 0.000 1 2 4 6 8 10 20 40 60 80 100 200 400 600 800 particle size / µmPfizer Confidential
  • 27. Continuous crystallisation Concept Design new process to enable better crystallisation Increase the seed surface to promote rate of growth Control the rate of nucleation Vs rate of growth Starting volume with high seed concentration The crystallisation is generated by addition of anti-solvent and distillation to the right concentration solvent/anti-solvent Continuous distillation of azeotropic solutionPfizer Confidential
  • 28. Model in Dynochem and predictionPfizer Confidential
  • 29. Continuous crystallisation P-8 Start +++++++++++++++++++++++++++++++ No flow Heptane P-10 E-6 Preparation of seed bed 13g API in 65g heptanes and 32g IPAc solubility ~6g/L IPAc Composition and concentration stay constant Continuous Distillation/crystallisation Large surface of seed Promote growth LiquorsPfizer Confidential
  • 30. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 31. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 32. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 33. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min P-9 T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 34. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min P-9 T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 35. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min P-9 T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 36. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min P-9 T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 37. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min P-9 T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 38. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min P-9 T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 39. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min P-9 T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 40. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min LiquorsPfizer Confidential
  • 41. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min API LiquorsPfizer Confidential
  • 42. Continuous crystallisation P-8 Flow in +++++++++++++++++++++++++++++++ Start of flow in 7.5g/min Heptane heptanes P-10 E-6 0.5g/min API 6g/min IPAc 7.5g/min heptanes Solution of IPAc Start of vacuum at 80mbar 0.5g/min T= 25.5C 6g/min IPAC Continuous Distillation/crystallisation Distillation rate controlled by T Heptanes: 4.1 – 6 g/min IPAc: 3.65 – 5.3 g/min API LiquorsPfizer Confidential
  • 43. Continuous crystallisationUse of Dynochem prediction for distillation API API Pfizer Confidential
  • 44. Continuous crystallisationAdvantage P-8 4 plates columns to recycle the +++++++++++++++++++++++++++++++ Control of the crystallisation by modelling Heptane Heptane Only one reactor required for the P-10 E-6 crystallisation Only half Heptane required for same conditions Green Chemistry approach API in IPAc No additional investment solution existing batch reactor can be used Solid out Continuous Distillation/crystallisation Liquors Pfizer Confidential
  • 45. Results: continuous crystallisation •Constant supersaturation and composition: optimisation of crystal growth •Bigger particles (~25m) than typical batch size •Particles can be grown bigger if processed longer •Particles are not prone to agglomeration •>90%yield of recovery •Throughput : 36kg/m3.hour 1.25 UK-453,061 API - Particle size distribution 1.20 Comparison of continuous crystallisation batches isolated in an AFD 1.15 Batch No. D[v,0.1] D[v,0.5] D[v,0.9] D[4,3] 1.10 µm µm µm µm 1.05 120782/109/1 2.24 9.06 21.95 10.96 120782/103/3 2.71 9.84 25.31 12.97 1.00 0.95 Neil Dawson 0.90 0.85 0.80 0.75 Density distribution q3* 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100 200 400 particle size / µmPfizer Confidential
  • 46. Conclusion Alternative to standard crystallisation process can be developed Dynochem was a fantastic tool to enable new process crystallisation development Dynochem makes innovative thinking possible and easy!!!Pfizer Confidential
  • 47. Acknowledgment Thomas Dupont Moussa Boukerche Andrew Derrick Julian Smith Wilfried Hoffmann Garry O’ConnorPfizer Confidential