Pharmaceutical salts of azole anti-fungal drugs: physicochemical behaviour and activity studies

Abstract

Pharmaceutical cocrystal engineering is a potential and growing strategy for modulating the physicochemical and pharmacokinetic properties of drug molecules. This study aims to study the new solid forms of miconazole (MIC) and ketoconazole (KTC) prepared through the crystal engineering method of crystallization. Utilizing the understanding of the sulfonate-pyridinium synthon, molecular salts of MIC and KTC with naphthalene disulfonic acid (NDSA-2H) have been prepared and characterized through thermal, spectroscopic, microscopic, and diffraction methods. Both molecular salts, i.e., MIC-C and KTC-C, have been obtained as crystalline solids and their phase purity and formation have been established through diffraction studies. The new drug forms exhibit augmented thermal stability and aqueous solubility. Powder dissolution studies in an aqueous medium at pH 2 and pH 7 indicate a significant increase in thermal stability and aqueous solubility of the new drug forms compared to their drug precursors. Structural investigation of MIC-C validates the formation of the ionic sulfonate-pyridinium synthon involving proton transfer resulting in charge development, leading to enhancement in the physicochemical properties. In vitro studies show that KTC-C in addition to retaining most of the biological activities possesses antifungal potential comparable to that of the standard drug since it inhibited the growth of tested Candida strains without showing enhancement in host toxicity. Both the designed salts exhibit fluorescence properties inside Candida cells (in contrast to the standard drugs).