Enhancing Febuxostat Solubility Through Cocrystal Formation: Role of Substrate Selection and Amide Coformers

Solubility plays a crucial role in drug bioavailability and therapeutic efficacy. Febuxostat (FEB), a BCS Class II drug used to treat hyperuricemia and gout, has low solubility, limiting its effectiveness. Cocrystallization offers a strategy to enhance solubility without modifying the drug's chemical structure. While FEB exhibits multiple polymorphic forms, no prior studies have explored cocrystal formation from its commercially available hemihydrate. This study examines whether FEB's initial form-hemihydrate or anhydrous-affects cocrystal formation. We investigated cocrystals with aromatic amides (nicotinamide, isonicotinamide, and picolinamide) and explored new FEB cocrystals with aliphatic amides (diacetamide, malonamide, and D,L-lactamide) to assess solubility enhancement. Our results show that anhydrous FEB cocrystals reliably form with both aromatic and aliphatic amides, regardless of the starting material. However, the aliphatic coformers lead to thermally unstable cocrystals. Nevertheless, the new cocrystals significantly improved FEB's solubility, with FEBH-LAC (13.9 mg/L) being the most soluble, but thermally unstable. FEBH-DIA showed the best balance, with 12.2 mg/L solubility and the fastest dissolution rate. These findings highlight cocrystallization with aliphatic amides as a promising approach for enhancing FEB's solubility and therapeutic potential; however, they may pose problems with stability and reproducibility.