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 Cl-35 solid-state NMR (SSNMR), variable-relative humidity (RH) powder X-ray diffraction (PXRD), thermogravimetric analysis, and dispersion-corrected plane-wave density functional theory (DFT-D2*) calculations, we reveal the local and long-range structural effects of water under different storage and processing conditions. Cl-35 SSNMR spectra are particularly sensitive to the presence of water and reveal distinct anionic Cl- environments in the hydrated and dehydrated forms of the HCl API. Our data demonstrate that complete dehydration of the material is surprisingly difficult, even with repeated drying cycles. Finally, Cl-35 SSSNMR is shown to be very useful for probing the local structural environments of Cl- ions in tablets processed using either wet or dry granulation, since there are no interfering signals from the complex array of excipient molecules present in the formulation.

• University of Windsor
• Florida State University
• Genentech Inc; Boehringer Ingelheim Pharmaceuticals Inc

• API
• PAT

1. API
2. API hydrate form
3. crystal structure
4. pat
5. PXRD
6. Research Article
7. Solid state NMR
8. solvates