Development of new multicomponent crystals of the antifungal drug tioconazole and the assessment of their biopharmaceutical attributes

Abstract

Tioconazole is commonly used as a broad-spectrum topical antifungal. The poor aqueous solubility and toxicity are two major concerns for its use in oral dosage forms. We have tried to address some of these issues through new multicomponent crystal development. Five crystalline salt forms (with hydrochloric, oxalic, malonic, fumaric, and DL-tartaric acids) were reported previously for (±)-tioconazole. In the present study, we have obtained fourteen new multicomponent crystals identified with the help of a rational coformer screening performed using modified molecular electrostatic potential-based site-pair interaction energy computations, a ΔpK_a-based salt screening, and a few were isolated from solution-mediated phase transformations. The antimicrobial activities of the selected multicomponent crystals were determined against ESKAP pathogens followed by cytotoxicity studies. A low toxicity and high selectivity were observed for three of the (±)-tioconazole multicomponent forms and were attributed to the reduced (±)-tioconazole content in these forms. The physicochemical property assessment of the selected novel multicomponent forms has been performed to check their suitability in oral dosage forms. The (±)-tioconazole–L-tartaric acid salt cocrystal reported in this study shows low toxicity (at MIC of 2 μg mL⁻¹), the highest solubility, and improved dissolution behavior compared to the freebase. The water-mediated anhydrate–hydrate transformations noted for three of the multicomponent forms, a partial conversion to a phosphate salt in phosphate buffer and a rapid disproportionation observed for the case of the (±)-tioconazole–nicotinic acid cocrystal are also discussed in this study.