Preparation and characterization of new salts of tioconazole. Comparison of their dissolution performance

Abstract

Tioconazole is an effective antifungal agent with very low solubility in aqueous media, which limits its bioavailability and efficacy. Aiming to overcome the drug limitations by improving the solubility of this active pharmaceutical ingredient, solution precipitation techniques were employed to prepare four new crystalline salts, namely the mesylate, tosylate, maleate (1:1), and fumarate (1:1) hemihydrate. The thermal stabilities, dissolution properties, and structural characteristics of the solids were determined, and the study was extended to compare their properties with the already-known oxalate salt.The structural characterization of the new phases was carried out using a multi-method approach, which included thermal (differential scanning calorimetry and thermogravimetry), diffractometric (powder X-ray diffraction), and spectroscopic (near-infrared and mid-infrared) methodologies. The determination of the melting point of the salts confirmed the findings made by thermal methods. Functional characteristics of the salts, involving their intrinsic dissolution rates were also determined.It was found that the salts exhibited improved thermal stability and that the nature of the counterion modulated their dissolution characteristics. The salts displayed better intrinsic dissolution rates than the free base, to the point of being “highly soluble” according to the Biopharmaceutical Classification System. At pH 4.3, the sulfonic acid derivatives exhibited better dissolution rates than their carboxylic acid-derived counterparts, greatly improved regarding bare tioconazole. The results suggest that the salts have great potential to be used as replacements for the free base; in principle, careful salt selection may help to fulfill each solubility need for the different scenarios where the drug may be used.