Role of Structure, Microenvironmental pH, and Speciation To Understand the Formation and Properties of Febuxostat Eutectics

Abstract

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 hydrogen bond, and ΔpKa differences leading to the eutectic formation were discussed. The eutectic systems thus formed were further characterized and analyzed using 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. pH dependent solubility studies exhibited a significant decrease in the solubility in comparison to that of the drug for all the three eutectic systems. 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 microenvironment on the solubility of these eutectic systems. Contribution to solubility from lattice and non-lattice forces considering microenvironment was also discussed.