Characterization of the hydrochloride salt hemihydrate as a new salt of the antifungal agent tioconazole

Abstract

Tioconazole is an effective antifungal agent, which has a very low solubility in aqueous media, that limits its bioavailability and efficacy. In an effort to overcome the drug limitations by improving its solubility, the hydrochloride salt was prepared in methanolic 1 M HCl and obtained as the hemihydrate, as demonstrated by elemental analysis. Single crystals were grown by slow evaporation from an aqueous 1 M HCl solution and their structure was determined using single-crystal X-ray diffraction at 302 K. The structures resulting from dehydration and further rehydration were also assessed, at 333 and 283 K, respectively. The morphology of the crystal, which exhibited birefringence under polarized light, was verified by hot stage microscopy. The solid was characterized by additional means, including thermal analysis (melting point, differential scanning calorimetry and thermogravimetry), spectroscopic methods (mid infrared, near infrared, ¹H, ¹³C and ¹⁵N nuclear magnetic resonance in solution, as well as ¹³C and ¹⁵N solid state with spinning at the magic angle) and X-ray diffraction techniques. Functional evaluation tests, including the intrinsic dissolution rate and the dissolution of powders were also performed. In the intrinsic dissolution rate test, the salt proved to dissolve over 2000 times faster than tioconazole. The results suggest that the new salt has physicochemical and performance properties which may support its use as a replacement of the free base in certain applications, especially where improved dissolution rate, solubility or bioavailability of the drug would be desired.

Keywords: Intrinsic dissolution; Salt formation; Solid-state characterization; Thermal methods; Tioconazole hydrochloride hemihydrate; Vibrational and NMR spectroscopies; X-ray diffractometry and crystal structure.