Structural features, dissolution performance and anthelmintic efficacy of multicomponent solid forms of fenbendazole with maleic and oxalic acids

Abstract

Two new multicomponent crystalline phases of fenbendazole (FNB), a benzimidazole anthelmintic agent, with maleic and oxalic acids have been prepared, and their structural and physicochemical properties carefully investigated. The crystal structures of the solid forms have been determined from powder X-ray diffraction data. The positions of dynamic hydrogen atoms have been further refined via dispersion-corrected density functional theory calculations, which validated the salt nature of the resulting solid forms by demonstrating proton transport from the corresponding acids to the FNB molecule. The in vitro dissolution performance of the solid forms in aqueous media at different pH values, as well as the in vivo anthelmintic efficacy of fenbendazole on the laboratory model of Trichinella spiralis infection in mice have been evaluated and compared to that of the previously reported salt of FNB with p-toluenesulfonic acid. A relationship between the in vitro dissolution characteristics and the in vivo therapeutic action has been revealed and discussed.