Posaconazole-amino acid cocrystals for improving solubility and oral bioavailability while maintaining antifungal activity and low In vivo toxicity

Abstract

The present work contributes to modulate the biopharmaceutical parameters through co-crystallization of posaconazole. The cocrystals of posaconazole were fabricated with amino acids as co-formers, which are zwitterionic, GRAS status, and biological non-hazardous in nature using solvent evaporation and liquid assistant grinding. Preliminary screening was done by using DSC for the suitability of the co-former. Structural characterizations DSC, PXRD, FT-IT, SEM, 1H FT-NMR were conducted to identify cocrystal formation. The equilibrium solubility, % drug release, and stability of cocrystals were explored. Among the two novel cocrystals, posaconazole-l-glutamine cocrystal showed higher solubility (92.42-fold) and dissolution (7.72-fold) enhancement compared to that of the parent molecule. This may be due to the less enthalpy and weaker crystallinity reported in DSC and PXRD respectively. Moreover, both cocrystals maintained their integrity under different conditions of stability studies after 90 days. FT-NMR results revealed that the hydroxyl and triazole group of posaconazole and carboxyl and amino group of amino acids participated in intermolecular ionic interaction. Under bioavailability study, AUC0.24 of Posaconazole-glutamine cocrystals exhibited 13.14-fold and 2.34-fold enhancement than the pure drug and noxafil suspension respectively. Furthermore, In vitro antifungal activity and In vivo acute toxicity studies on novel cocrystal found to have high antifungal activity and no signs of toxicity even at 5000 mg/kg of body weight respectively. These results indicate that the co-crystallization technique has great potential in modulating the physicochemical properties of poorly water-soluble drugs like posaconazole.