Structural studies of a non-stoichiometric channel hydrate using high resolution X-ray powder diffraction, solid-state nuclear magnetic resonance, and moisture sorption methods

Structural investigations of a nonstoichiometric hydrate, AMG 222 tosylate, a DPP-IV inhibitor in clinical development for type II diabetes, were performed using a multitechnique approach. The Moisture sorption isotherm is in good agreement with a simple Langmuir model, suggesting that the hydrate water is located in well-defined crystallographic sites, which become vacant during dehydration. Crystal structures of AMG 222 tosylate at ambient and dry conditions were determined from high-resolution X-ray diffraction using the direct space method. On the basis of these crystal structures, hydrated water is located in channels formed by the drug framework. Upon dehydration, an isostructural dehydrate is formed with the channels remaining void and accessible to water for rehydration. Kitaigorodskii packing coefficients of the solid between relative humidity of 0% and 90% indicate that the equilibrium form of AMG 222 tosylate is the fully hydrated monohydrate.

X-ray powder diffractometry; crystal structure; hydrate; moisture sorption; solid state NMR.