(700b) Establishing the Thermodynamic Relationship of Enantiotropic Polymorphs in Active Pharmaceutical Ingredients (APIs) with High-Throughput Methodology

Determining the most stable polymorph of APIs during pharmaceutical development is a necessity to ensure patient safety and long-term manufacturing reliability. Compounds with enantiotropically related polymorphs can generate complexity when the polymorphs are close in stability at ambient or process relevant conditions, or if impurities modify the relative stability. While competitive slurries are a commonly used technique to elucidate relationships between polymorphs, solubility data allows for a greater and faster understanding of the thermodynamic relationship. Moreover, systems with complex behavior can be studied more closely with solubility data.

In this work, an enantiotropically related polymorph system was investigated to determine the thermodynamic stability relationship between the two polymorphs. A large dataset of solubility samples for each polymorph was efficiently generated using automated lab technology in various solvent systems, temperatures, and impurity levels. The methodology to study this enantiotropic compound efficiently and the resulting trends discovered will be presented in addition to lessons learned along the way.