Hydrogen Bonds, Topologies, Energy Frameworks and Solubilities of Five Sorafenib Salts

Sorafenib (Sor) is an oral multi-kinase inhibitor, but its water solubility is very low. To improve its solubility, sorafenib hydrochloride hydrate, sorafenib hydrobromide and sorafenib hydrobromide hydrate were prepared in the mixed solvent of the corresponding acid solution, and tetrahydrofuran (THF). The crystal structures of sorafenib hydrochloride trihydrate (Sor center dot HCl.3H(2)O), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrochloride trihydrate, C21H17ClF3N4O3+center dot Cl-.3H(2)O (I), sorafenib hydrochloride monohydrate (Sor center dot HCl.H2O), C21H17ClF3N4O3+center dot Cl-.H2O (II), its solvated form (sorafenib hydrochloride monohydrate monotetrahydrofuran (Sor center dot HCl.H2O.THF), C21H17ClF3N4O3+center dot Cl-.H2O.C4H8O (III)), sorafenib hydrobromide (Sor center dot HBr), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrobromide, C21H17ClF3N4O3+center dot Br- (IV) and sorafenib hydrobromide monohydrate (Sor center dot HBr.H2O), C21H17ClF3N4O3+center dot Br-.H2O (V) were analysed. Their hydrogen bond systems and topologies were investigated. The results showed the distinct roles of water molecules in stabilizing their crystal structures. Moreover, (II) and (V) were isomorphous crystal structures with the same space group P2(1)/n, and similar unit cell dimensions. The predicted morphologies of these forms based on the BFDH model matched well with experimental morphologies. The energy frameworks showed that (I), and (IV) might have better tabletability than (II) and (V). Moreover, the solubility and dissolution rate data exhibited an improvement in the solubility of these salts compared with the free drug.

Automated summary

Sorafenib and its salts were prepared to improve solubility, and the distinct roles of water molecules in stabilizing crystal structures were investigated. The crystal structures of sorafenib hydrochloride monohydrate and sorafenib hydrobromide monohydrate were found to be isomorphous, with similar unit cell dimensions. The tabletability and solubility of these salts were shown to be improved compared to the free drug.