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Classification of the Crystallization Behavior of Amorphous Active Pharmaceutical Ingredients in Aqueous Environments

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ABSTRACT

Purpose

To classify the crystallization behavior of amorphous active pharmaceutical ingredients (API) exposed to aqueous environments.

Methods

A set of approximately 50 chemically and physically diverse active pharmaceutical ingredients (APIs) was selected for this study. Two experimental setups were employed to characterize the crystallization behavior of the amorphous API in an aqueous environment. For the first approach, precipitation, as evidenced by the development of turbidity, was induced using the solvent shift method, by mixing concentrated API solutions in DMSO with an aqueous buffer in a capillary. Subsequently, crystallization was monitored in situ over time using synchrotron radiation (simultaneous SAXS/WAXS beamline 12-ID-B at the Advanced Photon Source, Argonne National Laboratories, Argonne, IL). In the second approach, amorphous films were prepared by melt quenching; after adding buffer, crystallization was monitored with time using polarized light microscopy.

Results

In general, the crystallization behavior of a given compound was similar irrespective of the experimental method employed. However, the crystallization behavior among different compounds varied significantly, ranging from immediate and complete crystallization to no observable crystallization over biorelevant time scales. Comparison of the observed behavior with previous studies of crystallization tendency in non-aqueous environments revealed that the crystallization tendency of individual APIs was somewhat similar regardless of the crystallization environment.

Conclusions

API properties, rather than the method by which amorphous materials are generated, tend to dictate crystallization behavior in aqueous media.

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ACKNOWLEDGMENTS AND DISCLOSURES

Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02- 06CH11357. Dr. Byeongdu Lee and Dr. Xiaobing Zuo (12-ID-B beamline, Advanced Photon Source, Argonne, IL) are acknowledged for their help with the XRPD experiments. B.V.E. is a Postdoctoral Researcher of the “Fonds voor Wetenschappelijk Onderzoek”, Flanders, Belgium. The authors would like to thank the National Science Foundation Engineering Research Center for Structured Organic Particulate Systems for financial support (NSF ERC-SOPS)(EEC-0540855).

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA

    Bernard Van Eerdenbrugh, Shweta Raina, Yi-Ling Hsieh & Lynne S. Taylor

  2. Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N2 Herestraat 49, Box 921, 3000, Leuven, Belgium

    Bernard Van Eerdenbrugh & Patrick Augustijns

  3. Formulation Sciences, Allergan, Inc., Irvine, California, 92612, USA

    Yi-Ling Hsieh

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  1. Bernard Van Eerdenbrugh
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  2. Shweta Raina
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  3. Yi-Ling Hsieh
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  4. Patrick Augustijns
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  5. Lynne S. Taylor
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Correspondence to Lynne S. Taylor.

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Van Eerdenbrugh, B., Raina, S., Hsieh, YL. et al. Classification of the Crystallization Behavior of Amorphous Active Pharmaceutical Ingredients in Aqueous Environments. Pharm Res 31, 969–982 (2014). https://doi.org/10.1007/s11095-013-1216-z

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  • DOI: https://doi.org/10.1007/s11095-013-1216-z

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