New Miconazole Salts with Heterocyclic Carboxylic Acids with Improved Water Solubility and Enhanced Antifungal Activity

Miconazole is a commonly used imidazole antifungal drug with a broad spectrum of activity against Candida strains and other microorganisms. However, its poor solubility and low bioavailability have limited its use to topical infections. To overcome this limitation through the use of cocrystalization techniques, the present work focuses on the relatively less explored class of heterocyclic carboxylic acid coformers, containing two nitrogen atoms in the ring, aimed at developing alternative multicomponent forms of miconazole. Five new forms of miconazole were subjected to in-depth structural analysis, including an evaluation of the effect of hydrate formation. Furthermore, layered motifs in the supramolecular crystal architectures were subjected to qualitative and quantitative surface analysis using CSD-Particle. All new forms of miconazole were also characterized by FT-IR spectroscopy and thermogravimetric analysis. Water solubility was identified as the most important physicochemical property, and significant improvements were obtained for four of the five salts studied. Notably, the newly synthesized miconazole salts with heterocyclic (di)carboxylic acids exhibited high antifungal activity. The tested compounds effectively inhibited the growth of C. albicans and C. parapsilosis at concentrations several times lower than the parent drug and also showed activity against the important C. auris strain. Therefore, the obtained salts may constitute attractive alternatives to currently used antifungal therapies.