Simultaneous enhancements of solubility and dissolution rate of poorly water-soluble febuxostat via salts

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, H-1 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) over bar, which interacted with the disordered 2MI cation via the N3-H3A center dot center dot center dot O1(i) (i:-x,-y,-z+1) and N4-H4B center dot center dot center dot O1(ii)(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 N4-H1 center dot center dot center dot O1 and N3-H2 center dot center dot center dot O2 hydrogen bonds to form an R-2 (2)(8) ring motif. HFEB-2M1 and HFEB-DPA salts exhibited increased equilibrium solubilities and intrinsic dissolution rates compared to those of HFEB in aqueous medium. (C) 2017 Elsevier B.V. All rights reserved.