Salt Selection and Simultaneous Polymorphism Assessment via High-Throughput Crystallization: The Case of Sertraline

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• 作者：Julius F. Remenar ; J. Michael MacPhee ; Bridget K. Larson ; Viraj A. Tyagi ; Jason H. Ho ; David A. McIlroy ; Magali B. Hickey ; Paul B. Shaw ; and Ö ; rn Almarsson
• 刊名：Organic Process Research & Development
• 出版年：2003
• 出版时间：November 2003
• 年：2003
• 卷：7
• 期：6
• 页码：990 - 996
• 全文大小：588K
• 年卷期：v.7,no.6(November 2003)
• ISSN：1520-586X

文摘

High-throughput (HT) crystallization experiments were conducted with sertraline free base in the presence of mono-, di-and triacidic salt formers. Over 3600 crystallization trials wereconducted, leading to the identification and characterizationof 18 crystalline salt forms. Due to the large number ofcrystallization conditions for a given salt type, it was possibleto gauge the propensity of a given salt form to exhibitpolymorphism. Four salt forms were found to exist (in thislimited screen) as monomorphic materials. Unlike the HCl saltin the marketed drug product, the HBr salt appears resistantto polymorphism, crystallizing as a single form from over 140discrete trials. This observation underscores the lack of predictability of polymorphic behavior of pharmaceuticals even whenseemingly minor changes to the composition are made. Theexperiments highlight the importance of coupling salt selectionstudies with simultaneous polymorph screening to gain a morecomprehensive understanding of solid form diversity as partof the form selection process for pharmaceutical development.