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  • 15 Volumes, 4/1 MeOH/ water Dissolution at 69-70 C Seed at 60 C with 1% seed Cool to 20 C ( 0 C ) Isolate 72% yield ( 80% yield )
  • Facss Presentation

    1. 1. In Process Monitoring of Polymorphic Form Conversion by Raman Spectroscopy S Barnes, J Anderson, J Chen, D Ertl, J Rydzak
    2. 2. Outline <ul><li>Background / Introduction </li></ul><ul><ul><li>Crystallization and crystal form </li></ul></ul><ul><ul><li>In-situ techniques to monitor form conversion </li></ul></ul><ul><ul><ul><li>In-line versus traditional off-line measurements </li></ul></ul></ul><ul><li>In-situ Raman spectroscopy to monitor solvent mediated form conversion </li></ul><ul><ul><li>In-situ measurements of reaction kinetics and Induction times </li></ul></ul><ul><ul><li>Data analysis approaches – Multivariate Curve Resolution (MCR) </li></ul></ul><ul><ul><li>Comparison of Raman spectroscopy and turbidity measurements </li></ul></ul><ul><li>Conclusion </li></ul>
    3. 3. Introduction; Crystallization <ul><li>Pharmaceutical crystallization is a common unit operation to stabilise and purify process intermediates and finished products. </li></ul><ul><li>Crystallization can separate very similar molecules relatively cheaply and easily. </li></ul><ul><li>Can control crystal size distribution, crystal morphology and polymorphic form </li></ul><ul><li>Particle size and shape affect down stream formulation and bioavailability </li></ul>Solubility curve for a typical cooling crystallization
    4. 4. Introduction; Crystal Form <ul><li>Active Pharmaceutical Ingredients (APIs) are found in different polymorphic forms </li></ul><ul><li>Polymorphs have different properties: solubility, dissolution, stability, bioavailability. </li></ul><ul><li>Develop robust process to consistently make desired form for secondary processing </li></ul><ul><li>Full characterization of phase diagram identifies most stable crystal form at any operating condition </li></ul><ul><ul><li>Thermodynamic </li></ul></ul><ul><ul><ul><li>Temperature </li></ul></ul></ul><ul><ul><ul><li>Solvent concentration </li></ul></ul></ul><ul><ul><ul><li>Purity </li></ul></ul></ul><ul><ul><li>Kinetic </li></ul></ul><ul><ul><ul><li>Hold time at isolation temperature </li></ul></ul></ul><ul><ul><ul><li>Cooling rate </li></ul></ul></ul><ul><ul><ul><li>Equipment; mixing, heat transfer </li></ul></ul></ul><ul><ul><ul><li>Seed </li></ul></ul></ul>
    5. 5. Off-line Measurement of Polymorphic Form <ul><li>Different polymorphs identified by a number of off-line analytical methods </li></ul><ul><ul><li>FTIR </li></ul></ul><ul><ul><li>Raman </li></ul></ul><ul><ul><li>XRPD </li></ul></ul><ul><ul><li>DSC </li></ul></ul><ul><li>Off-line techniques provide no continuous information </li></ul><ul><ul><li>Sampling delay </li></ul></ul><ul><ul><li>Form can be very fast or can occur over night to days </li></ul></ul><ul><li>Change in processing history </li></ul><ul><ul><li>isolation, drying </li></ul></ul>Monohydrate Anhydrate Methanol solvate 1 Methanol solvate 2 XRPD traces; all four forms
    6. 6. In-Situ Spectroscopic Analysis of Crystal Form <ul><li>In-line monitoring techniques can be applied for analysis of: </li></ul><ul><ul><li>De-super saturation (ATR-FTIR) </li></ul></ul><ul><ul><li>Particle size (FBRM) </li></ul></ul><ul><ul><li>Particle shape (lasentec PVM) </li></ul></ul><ul><ul><li>Polymorphic form (Raman, NIR) </li></ul></ul><ul><li>In-situ Raman spectroscopy can be applied to monitor form transformations </li></ul><ul><ul><li>Rapid sampling; no delay </li></ul></ul><ul><ul><li>No sample preparation </li></ul></ul><ul><ul><li>Non-destructive measurements. </li></ul></ul><ul><ul><li>Kinetic and thermodynamic information </li></ul></ul><ul><ul><li>Versatile sampling interface </li></ul></ul><ul><li>Raman data provides molecular specific data </li></ul><ul><ul><li>Turbidity </li></ul></ul><ul><ul><li>Lasentec / FBRM </li></ul></ul><ul><li>  </li></ul>
    7. 7. Experimental Details <ul><li>Raman data acquired using a Kaiser Rxn-1 system </li></ul><ul><ul><li>785 nm laser </li></ul></ul><ul><ul><li>Short focus immersion probe, 18” long, ½ “ dim </li></ul></ul><ul><ul><li>Data acquisition time of 10 seconds (10 sec exposure 1 accumulation) </li></ul></ul><ul><li>In-situ data obtained from slurry samples in 1L JLR </li></ul><ul><ul><li>Methanol / water solvent system </li></ul></ul><ul><ul><li>Rapid agitation of slurry with temperatures ranging from 0 – 70 o C </li></ul></ul><ul><li>Data analyzed in real-time </li></ul><ul><ul><li>Real-time analysis in HoloReact </li></ul></ul><ul><ul><li>Trending of peak areas / derivatives </li></ul></ul><ul><ul><li>Application of MCR </li></ul></ul><ul><li>Results supported by off-line analysis of grab samples </li></ul><ul><ul><li>FTIR </li></ul></ul><ul><ul><li>XRPD </li></ul></ul><ul><ul><li>Optical Microscopy </li></ul></ul>Raman probe
    8. 8. Off-line Data; Four Crystal Forms Anhydrate Monohydrate Methanolate 1 Methanolate 2 <ul><li>Four polymorphic forms identified </li></ul><ul><ul><li>Anhydrate, monohydrate, 2 methanolate forms </li></ul></ul><ul><li>Form obtained dependant on a number of factors </li></ul><ul><ul><li>Solids added </li></ul></ul><ul><ul><li>Slurry temperature </li></ul></ul><ul><ul><li>Solvent content </li></ul></ul><ul><ul><li>Hold time before isolation </li></ul></ul><ul><li>Optical microscopy </li></ul><ul><ul><li>Standard method form identification </li></ul></ul><ul><li>Change in crystal structure and particle size observed between forms </li></ul><ul><ul><li>Physical properties </li></ul></ul><ul><ul><li>Processability </li></ul></ul>
    9. 9. Off-line Raman Spectra of Crystal Forms Off-line Raman spectra of the monohydrate, anhydrate and methanolate in powder form <ul><li>Distinct differences in spectral features of the three forms in solid state </li></ul>Raman shift (cm -1 ) HYDRATE METHANOLATE (M1) ANHYDRATE
    10. 10. Off-line Raman Spectra of Methanol Solvates Spectral differences for two methanolate forms (M1 and M2) METHANOLATE (M1) METHANOLATE (M2) <ul><li>Strong differences in spectral data of solid samples </li></ul><ul><li>Differences in in-line data more subtle due to strong solvent bands </li></ul><ul><ul><li>Identification of isolated features ascribed to each form </li></ul></ul>
    11. 11. In-line Raman Data of Form Conversion at 25 C Methanolate (M1) Anhydrate Time (days) <ul><li>Waterfall plots of in-situ Raman data acquired over time during form conversion from anhydrate to methanolate at 25 C </li></ul><ul><ul><li>Data acquired over 2 days </li></ul></ul><ul><ul><li>Induction time 12 hours </li></ul></ul><ul><ul><li>First methanolate form observed </li></ul></ul><ul><ul><li>Wavenumber shifts </li></ul></ul><ul><ul><li>Appearance of new features </li></ul></ul>1148 cm -1
    12. 12. Emergence of peak at 1148 cm -1 on formation of the methanolate Change in baseline integrated peak area over time used to map form change in real-time Methanolate Anhydrate Anhydrate Methanolate (M1) Real-time Data Analysis: HoloReact
    13. 13. MCR Analysis of Raman Data <ul><li>Data analyzed in real-time using HoloReact </li></ul><ul><ul><li>Data clipped (1100 – 1500 cm -1 ) </li></ul></ul><ul><ul><li>Persons Baseline correction </li></ul></ul><ul><ul><li>1 st derivative </li></ul></ul><ul><li>2 Principal components </li></ul><ul><li>Excellent agreement between trend plots and PCs from MCR </li></ul><ul><ul><li>MCR for form change profiles </li></ul></ul><ul><ul><li>Real-time kinetics information </li></ul></ul>Anhydrate Methanolate (M1)
    14. 14. Raman Data for Form Conversion at 0 C In-situ Raman data acquired during form conversion from anhydrate to methanolate 2 at 0 C Spectrum no. Anhydrate Methanolate 2 <ul><li>Integrated area of feature at 1200 cm -1 used to map form </li></ul><ul><li>Conversion confirmed by XRPD and FTIR </li></ul>
    15. 15. <ul><li>Excellent correlation between data from turbidity and Raman measurements </li></ul><ul><li>Both techniques sensitive to change in form from anhydrate to M1 at 25 C </li></ul><ul><li>Turbidity sensitive to change in particle size during form conversion </li></ul>Raman and Turbidity Data for Form Conversion Seeding Anhydrate at 0C Methanolate 2, 0C Dissolution
    16. 16. Raman Data of Transformation kinetics Raman measurements of form change induction time as a function of isolation temperature Lower temperature reduces induction time for conversion to solvate Data shows a decrease in the time for isolation and recovery of the API at lower temperatures Determination of induction time and form change kinetics M2 9 hr 3 C M2 7 hr 0 C M2 12 hr 10 C M1 25 hrs 20 C Solvate form produced on holding Induction time for 1st Trace of Solvate Temp of Isolation (C)
    17. 17. Raman Data; Phase Diagram Phase diagram showing stability of all four forms as a function of temperature and water content Raman data used to gain knowledge of the process over range of solvent compositions and temperatures Removes / reduces need for off-line samples Data acquisition less labor intensive Develop understanding of the design space for a cooled seeded crystallization in this solvent system Hydrate Anhydrate Methanolate 1 Methanolate 2
    18. 18. Summary <ul><li>Raman is an effective technique for in-situ identification of polymorphic form </li></ul><ul><ul><li>Kinetic measurements of form transformation </li></ul></ul><ul><ul><li>No sample preparation </li></ul></ul><ul><ul><li>Less labor / time intensive </li></ul></ul><ul><li>Application of in-situ Raman allowed process understanding of the final crystallization step </li></ul><ul><ul><li>Affect in solvent composition and temperature on form </li></ul></ul><ul><ul><li>Time for API isolation before form conversion at each temperature </li></ul></ul><ul><li>Excellent agreement between Raman and turbidity measurements for measurement of form transformation </li></ul><ul><ul><li>Raman molecular specific but more expensive </li></ul></ul><ul><ul><li>Turbidity – inferential measurement but simple to implement </li></ul></ul><ul><li>Software interface allows Raman to be used extensively in the lab as an in-situ diagnostic tool </li></ul><ul><ul><li>MCR and peak integration methods developed for simplified routine analysis </li></ul></ul>
    19. 19. Acknowledgments <ul><li>Jason Gillian </li></ul><ul><li>Delphi Burton </li></ul><ul><li>Ann Diedrich </li></ul><ul><li>Duncan Thompson </li></ul><ul><li>Colleagues in US PAT&C </li></ul><ul><li>FACSS organization for the opportunity to present </li></ul><ul><ul><ul><li>Thank you for your attention </li></ul></ul></ul><ul><ul><ul><li>Questions? </li></ul></ul></ul>