Crystallization and Phase Behavior: Polymorphism Case Study

A pharmaceutical compound displaying complex thermodynamic properties was investigated. Details of the discovery and characterization of multiple true polymorphic forms will be presented with crystallographic data. The molecular conformation in these polymorphs was examined to understand the relationship between the intrinsic nature of a crystal form and its solid state properties. Because of the minute solubility differences between the polymorphs and rapid inter-conversions, attempts to establish the phase diagram based on solubility measurements and van't Hoff's plot were unsuccessful. Application of the eutectic-melting method allowed better determination of the relative stability and monotropic/enantiotropic relationship among the forms of this multi-polymorphic system. In addition, the integrated Raman-DSC technology proved to be a helpful tool for the thermal property characterization of different forms. A detailed understanding of the polymorphs and phase behavior enabled by various techniques is valuable in shaping the development of the API synthesis and crystallization process.