The Challenges of Developing an API Crystallization Process for a Complex Polymorphic and Highly Solvating System. Part I

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• 作者：Brian P. Chekal ; Anthony M. Campeta ; Yuriy A. Abramov ; Neil Feeder ; Paul P. Glynn ; Robert W. McLaughlin ; Paul A. Meenan ; Robert A. Singer
• 刊名：Organic Process Research & Development
• 出版年：2009
• 出版时间：November 20, 2009
• 年：2009
• 卷：13
• 期：6
• 页码：1327-1337
• 全文大小：285K
• 年卷期：v.13,no.6(November 20, 2009)
• ISSN：1520-586X

文摘

Developing a robust crystallization process for an active pharmaceutical ingredient (API) molecule with a complex polymorphic profile can present a significant challenge. The presented case illustrates an unusual crystallization development problem where a polymorphically complex API has the additional obstacles of poor solubility in standard crystallization solvents as well as a propensity for forming solvates. After early polymorph screening of this candidate highlighted the potential for a complex solid form profile, a variety of experimental approaches was utilized to determine the low-energy polymorph and characterize the various solvates formed. Characterization of the API crystallization process identified a critical solvent composition range for the transformation from a metastable solvate form to the desired polymorph. During subsequent crystallization process development studies, a new lower-energy polymorph was discovered. Examination of the crystal structures led to a rationale for the formation of solvates and the existence of a new lower-energy form.