(252b) Strategies and Challenges for Making a Metastable Polymorph of a Pharmaceutical API

A pharmaceutical compound has three known polymorphs that were discovered at different stages of development. Polymorph I, a metastable form, was chosen for development due to its superior biopharmaceutical properties. A controlled crystallization process to isolate the meta-stable form was developed and practiced at industrial scale despite the significant challenges in producing the desired form. Through experimental studies, a key aspect of the polymorph control was found to be the presence of certain impurities. Using this information, various options to control the polymorph have been investigated. Multiple processing methods were also developed based on impurity and supersaturation control.