The comparison researches of cis/trans-butenedioic acids in regulating solid crystalline forms and improving pharmaceutical properties of antifungal drug econazole

Abstract

To highlight the preponderance of excipients maleic acid (MA) and fumaric acid (FA) in perfecting physicochemical peculiarities of antifungal drug econazole (ENZ), furthermore get some innovative cognitions on the regulation of solid crystalline form and antifungal activity of ENZ through regioisomers of unsaturated aliphatic dicarboxylic acids, two novice crystalline complexes of ENZ involving one cocrystal with FA, ENZ-FA (1), and one molecular salt with MA, ENZ-MA (2), are gained and structurally identified. The single-crystal X-ray diffraction analysis confirms that the component ratios of 2:1 and 1:1 for ENZ and corresponding acid molecules severally in 1 and 2. Both the cocrystallized solids have sandwich layer structures with hydrophobic surfaces and hydrophilic inner supramolecular networks with varied supramolecular aggregates, resulting in the simultaneous increasement in their dissolubility and permeability, thereinto, 1 owns higher permeability, while 2 is more ascendent in dissolubility, which are demonstrated by the combination of theory with experiment approaches. Specifically, compared with parent drug ENZ, the optimized physicochemical properties have endowed these cocrystallized complexes with strengthened in vitro antifungal activities, displaying larger inhibition rings and smaller MIC values, comparatively, 2 showcases stronger antifungal ability than that of 1. All the outcomes supply different molecular crystalline solids for ENZ, and fill the gap of its cocrystal investigations.