Multiple approaches to pharmaceutical polymorphism investigation—A case study

Polymorph screening of Compound A, an investigational drug, revealed two anhydrous polymorphs (Forms I and II) and two monohydrates (Forms III and IV) of this pharmaceutical solid. The physiochemical properties of the four forms were characterized by thermal analysis, hot-stage microscopy, equilibrium solubility and intrinsic dissolution rate measurements, and X-ray powder diffraction. Inter-conversion relationship of the four forms was fully elucidated. Thermodynamic stability relationship was inferred from melting data for Form I and Form II and evaluated by van’t Hoff plot for Form III and Form IV. Form I and Form III were found to be the more stable anhydrous and hydrate form, respectively. Anhydrous Form I was selected for further pharmaceutical development.