Development of Multicomponent Solid Forms of Miconazole: Improved Physicochemical and Antifungal Properties

Nine new multicomponent solid forms (one salt, five cocrystals, two salt-cocrystal intermediates, and one cocrystal polymorph) of the antifungal drug miconazole (MCZ) are reported with various coformers, such as sorbic acid (SOA), gallic acid (GAA), p-toluic acid (PTA), p-anisic acid (ANA), 2-chloro-4-nitrobenzoic acid (CNB), α-lipoic acid (LPA), syringic acid (SYA), and sinapic acid (SNP). All of the multicomponent solids crystallize as anhydrous in a 1:1 stoichiometric ratio, except for MCZ-GAA, MCZ-ANA, and MCZ-SNP, which crystallize as monohydrates. The crystal structures were established, and the material was produced in bulk quantities, except for MCZ-SYA F–II, and characterized using thermal (DSC, TGA), spectroscopic (FT-IR, 1 H NMR), and X-ray diffraction techniques. The formation of salt/cocrystal and salt-cocrystal intermediates was confirmed by difference Fourier map analysis, differences in C–O bond distances of coformers, and the bond angle of the imidazole ring of MCZ. Conformational flexibility was observed in the MCZ drug in the prepared multicomponent solids. The equilibrium solubility study of the developed multicomponent solids at pH 4.6 buffer and water medium showed significant improvement compared to the parent drug. Further, antifungal activity against four Candida strains was assessed using disc diffusion and minimum inhibitory concentration methods. The MCZ-GAA salt showed moderate efficacy, while MCZ cocrystals/salt-cocrystal intermediates significantly enhanced the antifungal activity (larger inhibition zones, lower MICs) compared to standard MCZ. These findings suggest the potential of MCZ cocrystals to improve antifungal therapy and combat drug resistance in Candida infections.