High-Throughput Surveys of Crystal Form Diversity of Highly Polymorphic Pharmaceutical Compounds

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• 作者：Ö ; rn Almarsson ; Magali B. Hickey ; Matthew L. Peterson ; Sherry L. Morissette ; Stephen Soukasene ; Chris McNulty ; Mark Tawa ; J. Michael MacPhee ; and Julius F. Remenar
• 刊名：Crystal Growth & Design
• 出版年：2003
• 出版时间：November 2003
• 年：2003
• 卷：3
• 期：6
• 页码：927 - 933
• 全文大小：242K
• 年卷期：v.3,no.6(November 2003)
• ISSN：1528-7505

文摘

Surveys of crystal form diversity of two test compounds, <B>1 (an experimental angiotensin II antagonist)and 2 (sertraline HCl, the active drug in Zoloft), have been performed with high-throughput (HT) crystallization.Compound 1 was found to have at least 18 crystal forms based on a HT recrystallization experiment using diversesolvents, compared with nine forms originally reported from a traditional screening effort. The efficiency of screeningin HT mode is estimated to be about 2 orders of magnitude greater than traditional bench-scale approaches. Themultiple patented forms of 2 have been summarized and evaluated based on published information, which is foundto include several transient species and at least one mixture of known phases. A comparison between results of HTexperiments and data on the disclosed forms shows that the HT effort generates the viable crystal forms; highlyunstable hydrates and one metastable polymorph IV were not observed. In attempting to recover form IV, a novelacetic acid solvate was discovered and characterized by single crystal X-ray diffraction. Additionally, a previouslyundisclosed ethyl acetate hemisolvate of 2 was identified as an intermediate en route to form T1. The studydemonstrates that highly polymorphic pharmaceutical compounds can be surveyed by HT form experimentation,and that an HT strategy coupled with critical analysis of reported form diversity can be used to rank the utility ofcrystal forms.