Development and Characterization of a Cocrystal as a Viable Solid Form for an Active Pharmaceutical Ingredient

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• 作者：Soojin Kim ; Zhibin Li ; Yin-Chao Tseng ; Herbert Nar ; Earl Spinelli ; Richard Varsolona ; Jonathan T. Reeves ; Heewon Lee ; Jinhua J. Song ; John Smoliga ; Nathan Yee ; Chris Senanayake
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：March 15, 2013
• 年：2013
• 卷：17
• 期：3
• 页码：540-548
• 全文大小：511K
• 年卷期：v.17,no.3(March 15, 2013)
• ISSN：1520-586X

文摘

A phosphoric acid cocrystal of a drug substance candidate at Boehringer Ingelheim was identified from the standard salt form screen and was characterized and shown to have desirable physicochemical properties, stability characteristics, and improved solubility and bioavailability compared to those of the free form. The cocrystal structure was determined by single-crystal X-ray structure analysis and resolved hydrogen-bonding interactions between chains of phosphoric acid molecules and chains of molecules of the free base. Comparison of the key physicochemical properties and biopharmaceutical properties of the cocrystal against a salt form demonstrated the advantage of the cocrystal over the sulfate salt with its superior stability characteristics. The cocrystal was developed as a robust drug substance form for further development and scale-up. The crystallization of the cocrystal form from organic solutions exhibited a strong relationship between water content in the crystallization system and the crystallization kinetics. The effect on the kinetics was used for effective particle size control for the cocrystals, important for optimizing the surface area, dissolution rate, and thus, bioavailability of the drug substance.