Structural Analysis of Anhydrate Salt Cocrystal of Ibuprofen and Loxoprofen Sodium with Fructose by Single-Crystal X-ray Diffraction and Solid-State NMR

Sodium salt formation is widely selected to improve the solubility of acidic drugs, while it also often undergoes a hydrate–anhydrate transition due to humidity change. In this study, ibuprofen sodium (IbuNa) dihydrate was selected as a model drug to investigate the potential use of sugar as a coformer for salt cocrystallization and inhibit the hydration tendency. In the screening test, fructose (Fru), ribose (Rib), and xylitol formed new multicomponent solid forms with IbuNa. IbuNa-Fru and IbuNa-Rib salt cocrystals were characterized by water vapor adsorption/desorption and stability tests. It was revealed that IbuNa-Fru and IbuNa-Rib were anhydrate and monohydrate, respectively. Structural characterization by single-crystal X-ray diffraction (SC-XRD) measurement revealed that IbuNa-Fru formed a two-dimensional sheet-like structure similar to previously reported loxoprofen sodium (LoxNa)-Fru. Solid-state NMR measurement with multiple nuclei (1H, 13C, 23Na) demonstrated similar molecular-level changes of Fru carbons and Na cations between IbuNa-Fru and LoxNa-Fru, which could be correlated to their similar anhydrate nature. Comparing the present result with other reported salt cocrystals, it was suggested that the stability of salt cocrystals against hydrate formation is contributed by the number of oxygen atoms available in the coformer and its structure. The results showed that SC-XRD and solid-state NMR measurements aided in establishing the structure–property relationship at the molecular level in the case of salt cocrystals.