Investigation into the structures and physicochemical properties of multi-component crystals of voriconazole

Voriconazole (VZL) is a second-generation and broad-spectrum triazole against fungal infections. Being a BCS (biopharmaceutics classification system) class II compound, the poor aqueous solubility has limited its bioavailability and clinical efficacy. Aims to overcome this disadvantage, a cocrystallization strategy based on crystal engineering principles has resulted in five new multi-component crystals of VZL with maleic acid, L-tartaric, protocatechuic, gallic, and 3,5-dinitrobenzoic acids. Structure analysis revealed that the hydroxyl/carboxylic acid center dot center dot center dot triazole N-3 hydrogen bonding interaction appears as a main supramolecular heterosynthon in the VZL multi-component crystals with organic acids. And VZL molecule has a flexible conformation in each of the five multi-component structures. The newly synthesized multi-component crystals showed impressive solubility improvement compared to that of the raw material of VZL. Molecular electrostatic potential surfaces (MEPS) analysis based on density functional (DFT) calculations revealed that hydrogen bond interactions in cocrystals mainly involved pairwise interactions in the global maxima and minima sites, but this rule is not always followed. This study indicates the potential of cocrystals to improve the solubility and dissolution rate of VZL (c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

Voriconazole (VZL), a second-generation triazole, has limited bioavailability and clinical efficacy due to its poor aqueous solubility. A cocrystallization strategy based on crystal engineering principles has resulted in five new multi-component crystals of VZL, which showed impressive solubility improvement compared to the raw material.