Voriconazole-syringic acid co-crystals reduced voriconazole-induced hepatotoxicity: In vitro and in vivo studies

Voriconazole (VOR) is recommended for the management of Invasive Aspergillosis. However, hepatotoxicity is one of the most common adverse-effects of VOR. Therefore, the current study explored solid-phase modification of VOR by co-crystallization with hepatoprotective co-former, namely, syringic acid (SYR) to address hepatotoxicity concerns. The co-former was selected based on Molecular complementarity and Hydrogen bond propensity via the Mercury 2.0 software and based on Δpka rule. Consequently, the anti-solvent crystallization method was used to generate the VOR-SYR (2:1) co-crystals. Various analytical and spectral techniques were used to characterize co-crystals. The change in endotherm of VOR-SYR (2:1) co-crystal to the lower value (112.08 °C) than VOR (131.1 °C) and SYR (209 °C) indicated the possibility of a new solid form co-crystal. The alterations in characteristic peaks in the powder x-ray diffraction pattern confirmed the synthesis of VOR-SYR (2:1) co-crystals. The FT-IR (Fourier-Transform Infrared) spectroscopy results revealed the generation of a new peak at 3470 cm−1 and the reduced intensity of peak observed at 3197 cm−1 for VOR-SYR (2:1) co-crystals. This suggested the formation of inter molecular hydrogen bonds. The solubility of the VOR-SYR (2:1) co-crystals was similar to that of the pure drug. Dissolution of the VOR-SYR (2:1) co-crystals demonstrated 99.41% ± 2.58% release in 1 h, whereas the VOR displayed 100.28 ± 1.26% release in 4 h. The in vivo study revealed a significant decrease in hepatotoxicity in the C57bL/6 mice treated with VOR-SYR (2:1) co-crystals (∼40 mg kg−1/day) as compared to VOR (40 mg kg−1/day) treated mice. The reduction in hepatoxicity post administration of VOR-SYR (2:1) co-crystals may be attributed to slow down of metabolism owing to critical role of pyrimidine ring of VOR in co-crystal synthesis in addition to hepatoprotective, antioxidant and anti-inflammatory mechanisms of SYR. Thus, the VOR-SYR (2:1) co-crystals may be a potential dosage form for further pharmacodynamic analysis in experimental Invasive Aspergillosis infection. [Display omitted]