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

Abstract

Surveys of crystal form diversity of two test compounds, 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 diverse solvents, compared with nine forms originally reported from a traditional screening effort. The efficiency of screening in HT mode is estimated to be about 2 orders of magnitude greater than traditional bench-scale approaches. The multiple patented forms of 2 have been summarized and evaluated based on published information, which is found to include several transient species and at least one mixture of known phases. A comparison between results of HT experiments and data on the disclosed forms shows that the HT effort generates the viable crystal forms; highly unstable hydrates and one metastable polymorph IV were not observed. In attempting to recover form IV, a novel acetic acid solvate was discovered and characterized by single crystal X-ray diffraction. Additionally, a previously undisclosed ethyl acetate hemisolvate of 2 was identified as an intermediate en route to form T1. The study demonstrates 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 of crystal forms.