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American Pharmaceutical Review Barnes Et Al

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American Pharmaceutical Review, March / April 2008, 11, 3, 80–89.

American Pharmaceutical Review, March / April 2008, 11, 3, 80–89.


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  • 1. In Process Monitoring of Polymorphic Form Conversion by Raman Spectroscopy and Turbidity Measurements Susan Barnes, Jason Gillian, Ann Diederich, Delphi Burton, Darryl Ertl Foreword The aim of pharmaceutical development is to design superior active pharmaceutical ingredients (APIs) with robust manufacturing processes that consistently deliver product of pre-defined quality and performance. Quality cannot be tested into products; it should be built-in or should be by design.1 The information and knowledge gained from research and development studies as well as manufacturing experience, provide scientific understanding to enable determination of the design space, product specifications, and manufacturing controls.2 Process Analytical Technologies (PAT) are systems for designing, analyzing, and controlling pharmaceutical manufacturing processes allowing timely measurements of critical quality and performance attributes of raw and in-process materials. Incorporating PAT into quality by design (QbD) encompasses the use of scientifically based process optimization, appropriate sensor technologies, statistical tools (chemometrics), feedback process control strategies and knowledge management tools to ensure production of final high quality products at manufacturing. Introduction Crystallization of APIs is a common unit operation used to stabilise and purify process intermediates and finished products. This procedure allows firm control of crystal size distribution, morphology and polymorphic form, which are often critical quality attributes of a drug substance. 3 Taking a QbD approach to producing the final particle forming step is central to form control and critical to ensure product stability, safety, efficacy and performance at secondary manufacturing. Historically, form identification has been achieved using off-line techniques such as XRPD, NMR, DSC and FTIR. 3, 4 Off-line methods provide no continuous information on the process, often involve sampling delays and can alter the processing history. More recently process analytical technologies (PAT) such as near infrared (NIR) spectroscopy 5, 6 and Raman spectroscopy7-9 have been realized as techniques for characterization of crystal form and conversion kinetics. Tools, such as FBRM, are also being utilized for monitoring of particle size distribution. 10-12 This article details the application of fiber-optic Raman spectroscopy for in-situ measurement of a form transformation during a final crystallization and isolation step. Data were acquired in order to develop an understanding of the design space for the process over a range of operating conditions. In alignment with the goals of the PAT framework and the quality by design tenet, this knowledge has enabled scale-up of a robust crystallization that consistently ensures a pre-defined form and product quality.
  • 2. Case Study The desired form of the API is an anhydrate (Form A). Research has been conducted to develop a cooled seeded crystallization intended to isolate the anhydrate form of the API in a methanol-water solvent system. During this work, a monohydrate and two distinct methanol solvate forms (M1 and M2) were also identified. Distinct differences in crystal size and morphology were observed between the four forms (Figure 1). These differences can affect processability at secondary manufacturing and product bioavailability. Each crystal form was found to have a very distinctive powder X-ray diffraction pattern and off-line FTIR and Raman spectra. Preliminary work indicated that the final form recovered from this process was governed by the methanol-water solvent ratio, batch isolation temperature and hold time after seeding. Induction of a form conversion from the anhydrate to the methanol solvate was seen in batches with extended holds over a range of isolation temperatures. Consequently, determination of the maximum hold time before occurrence of an undesirable form conversion was paramount to the design of a robust process. Figure 1: Optical microscope images of the monohydrous, anhydrous and methanol solvate forms of the API In-situ Raman spectroscopy was utilized to develop a phase diagram for identification of the most stable form over a wide range of operating conditions. Other additional experiments involving in-situ monitoring were designed to determine form and induction time as a function of isolation temperature, cooling rate and solvent ratio. All in-situ data was supported by optical microscopy, XRPD and DATR. One major advantage of utilizing Raman for this application was the low sensitivity of the technique to water. Spectra of slurries of all four crystal forms showed very distinct features with good separation from the solvent bands, making Raman an excellent qualitative technique for form discrimination. In-situ data were acquired from slurries of the API in methanol-water with an 18” long, ½ diameter short focus immersion optic, interfaced with a port in the top of a 1 L JLR. Initial data analysis was conducted by simple integration of bands associated with each form, allowing mapping of the transformation kinetics and end point determination.
  • 3. Figure 2: MCR analysis of in-situ Raman data acquired from conversion of the anhydrate to the methanol solvate form of an API in methanol at 25 o C A B 80 80000 70 Anhydrate, 25 C 70000 PC 1 PC 2 Peak area 60000 60 50000 Integrated peal area (arb) 50 40000 Integrated area (au) PC (arb) 40 arb units 30000 C Methanolate 1, 25C 30 20000 15 10 10000 20 5 0 0 10 -10000 -5 0 -20000 -10 0 500 1000 1500 2000 -10 -30000 -15 1100 1150 1200 1250 1300 Time (minutes) Time (minutes) Raman Shift (1/cm) Figure 2A shows a waterfall plot of in-situ Raman data acquired from the anhydrate slurried in methanol at 25 o C. The objective of the experiment was to determine an induction time for conversion of the batch to the solvate during an extended hold at a 25 o C isolation temperature. The waterfall plot, presented as a function of hold time, shows notable changes in the spectral features in the fingerprint region (1250 – 1080 cm-1). The integrated area of the feature at 1148 cm-1, ascribed to the first methanolate form (M1), was used to map the form conversion over time (Figure 2B). Data were acquired over a 2 day period and showed a form conversion induction time of 13.5 hours and a total conversion time of 10 hours. A subsequent approach to analyzing the spectral data, which moves away from relying on the presence of isolated bands to profile kinetics, is the application of Multivariate Curve Resolution (MCR).13, 14 Figure 2B is an overlay of the integrated peak area plot with the profiles of first two MCR components calculated from analysis of the spectral region (1250 – 1080 cm-1). Data were pre-processed by baseline correction and calculation of the 1st derivative. Excellent agreement can be observed between the peak area profile and the component profiles. Analysis of the estimated spectral profiles (Figure 2C) showed strong similarities with the 1st derivative spectra of the anhydrate and M1 respectively which gives confidence that the correct profiles were extracted from the data. A further range of experiments were conducted to determine the effect of isolation temperature and hold time on final form. Figure 3 presents results from four such experiments in a 4:1 methanol-water solvent system. The anhydrate was slurried and held for extended periods of time Methanol-water at four different isolation temperatures (0, 2, 10 and 20 o C). Figure 3: Form conversion induction time for as a function of isolation temperature
  • 4. Raman data from each experiment were used to identify form, induction time and total conversion time (Shown in Table). The data showed that lowering the temperature had the effect of significantly reducing the time at which the slurries could be held before isolation. Raman data showed that the first methanolate form was the more stable form at 20 o C, whereas M2 was more stable between 0-10 o C. In-situ monitoring proved to be an invaluable tool for acquiring continuous process data and removed the need for laborious off-line testing over long periods of time (up to 25 hours). Real-time identification of form by Raman was confirmed by off-line analysis of the isolated material. Figure 4: Phase diagram showing thermodynamic stability of each form of the API as a function of solvent composition and slurry temperature Figure 4 is an experimental phase diagram showing the thermodynamic stability of each form of the API as a function of solvent composition and slurry temperature. Full development of the phase diagram led to selection of an operating region where the desired form is the most stable allowing development of a cooled seeded crystallization to reproducibly produce the desired form. Combined with kinetic data on the form change induction times over a range of temperatures, the data set allowed selection of an acceptable temperature for material to be isolated following the crystallization. This information is invaluable, especially at scale-up, where hold times before material isolation can become much longer than those typically seen in the laboratory. Scale-up to Pilot Plant
  • 5. Although shown to be a key tool for in-situ analysis of form on the laboratory scale, Raman spectroscopy is currently not available for analysis of the crystallization process at the pilot plant used for scale up of this particular process. Since in-situ analysis of this process on scale was desired because of concerns over the scale-up effect on induction time, an alternative PAT technique was assessed and pursued. Figure 5 shows results from the application of Raman spectroscopy and turbidity measurements to monitor a cooled, seeded crystallization of the anhydrate in 4:1, methanol-water (Figure 5A). Further data were collected to monitor the form change of the anhydrate to the methanol solvate on extended hold at an isolation temperature of 0 o C. Whilst Raman is sensitive to the change in the molecular structure of the API on form transformation, turbidity data is sensitive to alteration in light scattering properties of the slurry as result of the change in particle size, morphology and distribution during conversion. The profiles from both data sets determined that after an induction time of 9 hours the second methanolate was formed with a total conversion time of 8.5 hours. In the case of the Raman data, the integrated area of feature at 1200 cm-1 associated with the structure of M2 (Figure 5B) was used to profile the conversion kinetics. Excellent agreement was seen between the profiles of both data sets. Final form and complete conversion was confirmed by XRPD, FTIR and optical microscopy (Figure 5C). Figure 5: In-situ Raman and Turbidity data from analysis of a seeded cooled crystallization and subsequent form conversion on hold at isolation temperature Although not a molecular specific technique for form identification the sensitivity of the turbidity measurement makes it a powerful technique for in-situ detection of form transformation, especially when coupled with offline spectroscopic analysis. In-situ turbidity measurements were implemented as part of a 50 L pilot plant campaign to follow the crystallization of the API in the selected solvent system and to monitor for form transformation before isolation. Several batches on 50 L scale were run to test the edges of the design space using extended hold periods to determine the maximum induction times on scale. Induction times at isolation temperature were shown to be comparable to those determined at laboratory scale which provided promising data for further scale up of the process to pilot plant.
  • 6. Summary In summary, in-situ Raman spectroscopy is an effective technique for identification of polymorphic form and form conversion kinetics. In-line Raman was used extensively on the laboratory scale for development of the phase diagram the most stable form of the API as a function of solvent composition and slurry temperature. In-situ data acquisition reduced the requirement for off-line sampling which was time consuming, required sample preparation and ran the risk of altering the processing history of the material. On- scale, in-situ turbidity measurements were an effective tool for detection of form transformation during hold at batch isolation temperature. Turbidity is a technique which is simple and cost effective to implement on scale. Although turbidity is an inferential measurement, combined with one off-line sampling for confirmation of final form, it has been demonstrated to be a powerful technology for detection of form transformation in this system. Acknowledgements The Authors would like to acknowledge our colleagues Duncan Thompson and Thomas Thurston for their assistance with the MCR data analysis aspect of the work presented here. Thank you also to Charles Goss, Gregory Gervasio and the staff of the Process Engineering group at Upper providence for assistance with implementation of in-situ turbidity for measurement for form conversion on scale-up. References 1. Pharmaceutical cGMPs for the 21st Century – A Risk Based Approach, U.S Department of Health and Human Services, U.S Food and Drug Administration, September 2004. 2. Guidance for Industry Q8 Pharmaceutical Development, U.S Department of Health and Human Services, U.S Food and Drug Administration, May 2006. 3. Braatz, R, D., “Advanced Control of Crystallization Processes”, Annual Reviews in Control 26 (2002) 87-99 4. Yu, L, X., Lionberger R, A., Raw, A, S., D'Costa, R., Wu, H., and Hussain A, S., “Applications of Process Analytical Technology to Crystallization Processes,” Adv. Drug Delivery Rev. Vol. 56, 349–369. 5. Fevotte, G., Calas, J., Puel, F., and Hoff, C., “Applications of NIR Spectroscopy to Monitoring and Analyzing the Solid State during Industrial Crystallization Processes,” International Journal of Pharmaceutics, Vol. 273, 159-169, 2004 6. Kobayashi, R., FujiMaki, Y., Ukita, T., and Hiyama, Y., “Monitoring of Solvent-Mediated Polymorphic Transitions Using in-Situ Analysis Tools,” Organic Process Research and Development, Vol. 10, 1219-1226, 2006 7. Wang, F., Watcher, J.A., Antosz, F.J., and Berglund, K.A., "An Investigation of Solvent- Mediated Polymorphic Transformation of Progesterone Using In Situ Raman Spectroscopy," Organic Process Research & Development, Vol. 4, No. 5, 2000 8. Agarwal, P., and Berglund, K. A.,“In-situ Monitoring of Calcium Carbonate Polymorphs during Batch Crystallization in the Presence of Polymeric Additives Using Raman Spectroscopy.” Crystal Growth and Design, Vol. 3, No. 5, 941-946, 2003
  • 7. 9. O’Brien, L. E., Timmins, P., Williams, A.C., and York, P., “Use of in situ Ft-Raman Spectroscopy to Study the Kinetics of the Transformation of Carbamazepine Polymorphs,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 36, No. 2, 335-340, 2004 10. Doki, N., Seki, H., Takano, K., Asatani, H., Yokota, M., and Kubota, N., “Process Control of Seeded Batch Cooling Crystallization of the Metastable -Form Glycine Using an In-Situ ATR-FTIR Spectrometer and an In-Situ FBRM Particle Counter,” Crystal Growth & Design, Vol. 4, 5, 949 -953, 2004 11. O’Sullivan, B., Barrett, P., Hsiao, G., Carr, A., and Glennon, B., “In-situ Monitoring of Polymorphic Transitions” Organic Process Research and Development, Vol. 7, 977-982, 2003 12. Barrett, P., Smith, B., Worlitschek, J., Bracken, V., O'Sullivan, B., and O'Grady, D., “A Review of the Use of Process Analytical Technology for the Understanding and Optimization of Production Batch Crystallization Processes,” ” Organic Process Research and Development, Vol. 9, 3, 348 -355, 2005 13. Cuesta Sanchez, F., Khots, M.S., and Massart. D.L., “Algorithm for the assessment of peak purity in liquid chromatography with photodiode-array detection,” Anal. Chim. Acta, Vol. 285, 181–192, 1994 14. Tauler, R., and Casassas, E., “Spectroscopic resolution of macromolecular complexes using factor analysis: Cu(II) -polyethyleneimine system,” Chemom. Intell. Lab. Syst.,Vol. 14, 305– 317, 1992 Author Biographies Dr Susan Barnes is a Principal Scientist at GlaxoSmithKline within the Process Analytical Technologies and chemometrics group. She received her BS in Chemistry and PhD in Mechanical Engineering from the University of Bradford in the UK. Prior to Joining GSK, she was a Guest Research Scientist in the Combinatorial Methods Group in the Polymers Division of the National Institute of Standards and Technologies. Her research interests include the implementation of in-situ spectroscopic techniques for process understanding and control. She has authored over 15 peer reviewed publications and conference proceedings. Dr Jason Gillian is a Principal Scientist at GlaxoSmithKline within the Particle Sciences Group in Chemical Development. Prior to joining GSK, he was a Senior Engineer within Merck Manufacturing Division for the commissioning, control and optimization of new processes in organic process development. Dr Gillian received his BS in Chemical Engineering from Virginia Tech, and was awarded his MS and PhD in Chemical Engineering from University of Virginia. Ann Diederich is an Investigator at GlaxoSmithKline within the Particle Sciences group in Chemical Development. She received her Bachelor degree in Chemistry from Ohio State University and her MS degree in Organic Chemistry from Texas A&M University. After spending the initial 9 years with the company in the Synthetic Chemistry, with an emphasis on process development and scale-up, Ann has
  • 8. been specializing in Particle Sciences for the last 8 years. Ann has 6 papers and 6 patents accredited to her name. Delphilia Burton is an Engineer at GlaxoSmithKline within the Process Engineering Group in Chemical Development. She received her BS and MS in Chemical and Biochemical Engineering from University of Maryland, Baltimore County, where her research primarily focused on small scale bioseparations, and down stream protein processing. Darryl Ertl is the manager of the Process Analytical Technology and Chemometrics group at GlaxoSmithKline in Chemical Development. Prior to joining GSK he worked at Bristol-Myers Squibb where he was responsible for implementing a world wide initiative for raw material identification using NIR spectroscopy and at Eastman Kodak where he applied numerous in-situ technologies to manufacturing processes for process control. Darryl received his BS degree in Chemistry from the University of Brockport.

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