In Situ Characterization of Waters of Hydration in a Variable-Hydrate Active Pharmaceutical Ingredient Using 35Cl Solid-State NMR and X-ray Diffraction

Abstract

Variable-hydrate active pharmaceutical ingredients (APIs) are known to form thermodynamically and kinetically stabilized solid phases over a continuous range of nonstoichiometric hydration levels. Some of these forms can be problematic in the production of solid dosage forms (e.g., tablets and capsules), where manufacturing processes can induce changes in the hydration level of the API, resulting in transformations to undesirable solid phases that may affect product quality. In order to improve the development of variable-hydrate APIs for commercial use, reliable methods must be developed to not only measure the hydration levels, but also to probe the influences of water molecules on the molecular-level structures of APIs within dosage formulations. In this study, we examine a Genentech development compound, GNE-A, which is a hydrochloride (HCl) salt of an API that exhibits variable-hydrate behavior. Using a combination of 35Cl solid-state NMR (SSNMR), variable-relative humidity (RH) powder X-ray diffract...