Comparative study of the cocrystals with layered/cavity structure in regulating in vitro pharmaceutical properties of diuretic acetazolamide

Abstract

To optimize in vitro pharmaceutical properties of the classical diuretic acetazolamide (ACZ) and probe the roles of N-containing compounds on adjusting crystal structures and properties through cocrystallization technique, two novel cocrystals of ACZ formed with two bipyridine compounds 4,4′-bipyridine-N,N'-dioxide (BPYO) and 4,4′-bipyridine (BPY), namely ACZ-BPYO (1) and ACZ-BPY (2), are successfully prepared and characterized by single-crystal/powder X-ray diffraction, and other techniques. Single-crystal X-ray diffraction reveals that the two cocrystals 1 and 2 are consisted of ACZ respectively in 1:1 and 2:1 ratios with BPYO/BPY, and the three-dimensional hydrogen bonding networks in the cocrystal of 1 can be divided to two interpenetrating individuals with plenty of cavities, while layered structure is observed in the crystal lattice of 2. In addition, the theoretical and experimental evaluations on physicochemical properties suggest that both of the cocrystals outperform synchronous hoisting in dissolubility and permeability, in which the cocrystal 1 is comparatively more advantageous due to its unique cavity structure which can provide more help than layer structure of 2 in improving ACZ's properties. This study provides two novel cocrystals as chemical basis for developing ACZ crystalline solids with pharmaceutical advantages, and also some new insights for the application of N-containing compounds in cocrystallization.