Continuous Plug Flow Crystallization of Pharmaceutical Compounds
Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. In th...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society
2012
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| Online Access: | http://hdl.handle.net/1721.1/68690 |
| _version_ | 1811072129026752512 |
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| author | Alvarez, Alejandro J. Myerson, Allan S. |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Alvarez, Alejandro J. Myerson, Allan S. |
| author_sort | Alvarez, Alejandro J. |
| collection | MIT |
| description | Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. In this work, continuous crystallization of ketoconazole, flufenamic acid, and l-glutamic acid in a nonconventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent. A strategy of multiple points of addition of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with an increased number of antisolvent addition points, depending on the kinetics of the system. It was also found that smaller crystals with a narrower size distribution can be obtained with the static mixers. A model to describe the continuous crystallization process was developed through the simultaneous solution of a population balance equation, kinetics expressions for crystal growth and nucleation, and a mass balance. The comparison of experimental and calculated values for crystal size distribution revealed that a growth rate dispersion model could describe accurately the continuous crystallization process. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the nonconventional plug flow crystallizer with static mixers. |
| first_indexed | 2024-09-23T09:01:22Z |
| format | Article |
| id | mit-1721.1/68690 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:01:22Z |
| publishDate | 2012 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | mit-1721.1/686902022-09-26T09:54:09Z Continuous Plug Flow Crystallization of Pharmaceutical Compounds Alvarez, Alejandro J. Myerson, Allan S. Massachusetts Institute of Technology. Department of Chemical Engineering Myerson, Allan S. Myerson, Allan S. Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. In this work, continuous crystallization of ketoconazole, flufenamic acid, and l-glutamic acid in a nonconventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent. A strategy of multiple points of addition of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with an increased number of antisolvent addition points, depending on the kinetics of the system. It was also found that smaller crystals with a narrower size distribution can be obtained with the static mixers. A model to describe the continuous crystallization process was developed through the simultaneous solution of a population balance equation, kinetics expressions for crystal growth and nucleation, and a mass balance. The comparison of experimental and calculated values for crystal size distribution revealed that a growth rate dispersion model could describe accurately the continuous crystallization process. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the nonconventional plug flow crystallizer with static mixers. Johnson & Johnson. Pharmaceutical Research & Development 2012-01-30T14:58:26Z 2012-01-30T14:58:26Z 2010-03 2010-03 Article http://purl.org/eprint/type/JournalArticle 1528-7483 1528-7505 http://hdl.handle.net/1721.1/68690 Alvarez, Alejandro J., and Allan S. Myerson. “Continuous Plug Flow Crystallization of Pharmaceutical Compounds.” Crystal Growth & Design 10.5 (2010): 2219-2228. en_US http://dx.doi.org/10.1021/cg901496s Crystal Growth and Design Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society Prof. Meyerson via Erja Kajosalo |
| spellingShingle | Alvarez, Alejandro J. Myerson, Allan S. Continuous Plug Flow Crystallization of Pharmaceutical Compounds |
| title | Continuous Plug Flow Crystallization of Pharmaceutical Compounds |
| title_full | Continuous Plug Flow Crystallization of Pharmaceutical Compounds |
| title_fullStr | Continuous Plug Flow Crystallization of Pharmaceutical Compounds |
| title_full_unstemmed | Continuous Plug Flow Crystallization of Pharmaceutical Compounds |
| title_short | Continuous Plug Flow Crystallization of Pharmaceutical Compounds |
| title_sort | continuous plug flow crystallization of pharmaceutical compounds |
| url | http://hdl.handle.net/1721.1/68690 |
| work_keys_str_mv | AT alvarezalejandroj continuousplugflowcrystallizationofpharmaceuticalcompounds AT myersonallans continuousplugflowcrystallizationofpharmaceuticalcompounds |