Cocrystallization studies were undertaken to improve the solubility of a highly water-insoluble drug, febuxostat (FXT), used in the treatment of gout and hyperuricemia. A liquid-assisted grinding (LAG) method was successfully employed, starting with the screening of various coformers for obtaining cocrystals. However, in this process, three eutectic systems with coformers (probenecid, adipic acid, and α-ketoglutaric acid) were formed. Affinities of the different functional groups to form a hydrogen bond and ΔpK a differences, leading to the eutectic formation, were discussed. The eutectic systems thus formed were further characterized and analyzed using a differential scanning calorimeter (DSC) and powder X-ray diffraction (PXRD). Binary thermal phase diagrams were plotted using different ratios of the systems to confirm the formation of eutectics, and pH-dependent solubility studies exhibited a significant decrease in the solubility in comparison to that of the drug for all three eutectic systems. The solubility of FXT reduced from 46.53 μg/mL (pH 5.63) to 46.03 μg/mL, 28.53 μg/mL, and 18.88 μg/mL; 770.58 μg/mL (pH 8.21) to 307.574 μg/mL, 116.63 μg/mL, 113.40 μg/mL; and from 13165.97 μg/mL (pH 10.13) to 1409.737 μg/mL, 854.51 μg/mL, and 1218.99 μg/mL for FXT-probenecid, FXT-adipic acid, and FXT-α-ketoglutaric acid eutectic systems, respectively. Furthermore, the microenvironmental pH studies were carried out to understand the effect of the microenvironment on the solubility of these eutectic systems. The contribution to solubility from lattice and nonlattice forces considering the microenvironment was also discussed.

The present study was carried out with an aim to improve dissolution rate of febuxostat (FBX, BCSclass II) drug. Spherical agglomerates were prepared by hybrid technique of spherical crystallization and solid dispersion using different ratios of FBX and polymer (PVP K30, HPMC E3LV and chitosan). Drug excipient compatibility study was evaluated by Fourier transform infrared spectroscopy and X-ray diffractometry. Scanning electron microscopy was used for measurement of size of agglomerate. In vitro dissolution study of prepared spherical agglomerates was compared with untreated FBX and marketed formulation in phosphate buffer pH 6.8. The ratio of drug to polymer also affected the drug dissolution results. Drug excipient compatibility study showed no interaction between FBX and PVP K30 (1:5) polymer. The use of PVP K30 (1:5) resulted in partial amorphization and improved drug dissolution. Direct compression method can be adopted in manufacturing to simplify the validation efforts. The performance of the formulated product was superior to the marketed product in the in vitro dissolution test.