Pharmaceutical cocrystals and a nitrate salt of voriconazole

Abstract

Novel crystalline forms of voriconazole are identified with improved aqueous solubility. The dinitrate salt of voriconazole exhibited 10 fold higher solubility and 3 times faster dissolution rate in 0.1 N HCl medium compared to the reference drug.

Voriconazole ((2 R,3 S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1 H-1,2,4-triazol-1-yl)butan-2-ol, VZL) is an antifungal drug with low aqueous solubility of 0.71 mg mL ⁻¹ and a BCS class II drug (Biopharmaceutics Classification System) of the azole family. We have prepared a nitrate salt and three cocrystals of VZL with p-hydroxybenzoic acid, p-aminobenzoic acid (both are GRAS compounds) and m-nitrobenzoic acid coformers to improve the physicochemical properties. All four multi-component crystals of voriconazole were obtained by solution crystallization as well as solid-state grinding and their structures were confirmed by X-ray diffraction, FT-IR, Raman and NMR spectroscopy, and thermal techniques. VZL–PHBA and VZL–PABA are isostructural based on XPac calculations and molecular packing arrangement. A notable result from a crystal engineering viewpoint is that the supramolecular synthon between the basic drug and the acidic coformer undergoes a switch based on the p K _a of the acid.