Febuxostat-aloperine co-amorphous drug delivery system with enhanced water solubility and binding affinity to xanthine oxidase

Febuxostat (FEB), a primary long-term therapy for managing gout and chronic hyperuricaemia, has limited clinical application primarily due to its low aqueous solubility. This limitation necessitates high-dose administration, thereby increasing the risk of cardiovascular mortality. To address the solubility challenge, a natural bioactive alkaloid aloperine (ALO) was used as a co-former to form FEB-ALO, a co-amorphous system of FEB and ALO at a 1:1 molar ratio using both solvent evaporation and the liquid-assisted grinding method. Structural characterisation was performed using powder X-ray diffraction, Fourier transform infrared spectroscopy (IR), differential scanning calorimetry, and nuclear magnetic resonance spectroscopy (NMR). Dissolution behaviours, such as equilibrium solubility and the intrinsic dissolution rate, were also investigated. FEB-ALO showed a greatly enhanced intrinsic dissolution rate (145-fold) and water solubility (>10,000-fold) compared to those with the crystalline form A of FEB. Integrating IR, NMR and molecular electrostatic potential surface analysis revealed that robust ionic and hydrogen-bonding interactions within the FEB-ALO co-amorphous system explained the enhanced dissolution performance.Molecular docking and dynamic simulations further demonstrated the strong affinity and binding stability of FEB-ALO to xanthine oxidase, suggesting its promising efficacy in the treatment of hyperuricaemia and gout. The findings presented herein indicate that the drug-drug co-amorphous system holds promise for optimising the FEB dosage and proposing a synergistic drug combination approach.