Abstract
Novel crystalline forms of febuxostat (HFEB) salts were synthesized by liquid-assisted cogrinding with 2-methylimidazole (2MI) and di-2-pyridylamine (DPA) and characterized by Hirshfeld surface analysis, IR, 1H NMR, single crystal and powder X-ray diffractions, TGA and DSC. Two new HFEB salts featured different stoichiometries: 2:1 molecular ratio in HFEB-2MI and 1:1 molecular ratio in HFEB-DPA. For HFEB-2MI salt, two HFEB molecules lost one proton forming a singly charged hydrogen carboxylate anion H(FEB)2−, which interacted with the disordered 2MI cation via the N3H3A⋯O1i (i: −x, −y, −z+1) and N4H4B⋯O1ii (ii: x, y+1, z−1) hydrogen bonds to form one-dimensional structure. For HFEB-DPA salt, one proton transferred from one HFEB to DPA, which were further connected by N4H1⋯O1 and N3H2⋯O2 hydrogen bonds to form an R22(8) ring motif. HFEB-2MI and HFEB-DPA salts exhibited increased equilibrium solubilities and intrinsic dissolution rates compared to those of HFEB in aqueous medium.
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