Abstract
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·HCl.3H2O), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrochloride trihydrate, C21H17ClF3N4O3+·Cl−.3H2O (I), sorafenib hydrochloride monohydrate (Sor·HCl.H2O), C21H17ClF3N4O3+·Cl−.H2O (II), its solvated form (sorafenib hydrochloride monohydrate monotetrahydrofuran (Sor·HCl.H2O.THF), C21H17ClF3N4O3+·Cl−.H2O.C4H8O (III)), sorafenib hydrobromide (Sor·HBr), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrobromide, C21H17ClF3N4O3+·Br− (IV) and sorafenib hydrobromide monohydrate (Sor·HBr.H2O), C21H17ClF3N4O3+·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 P21/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.
Highlights
Sorafenib, an oral drug, is a multi-kinase inhibitor with anti-tumour activity against a large range of cancers [1]
To study sorafenib hydrochloride hydrate (Sor.HCl hydrate), Sor was crystallized from the mixed solvent of hydrochloric acid solution and THF with %THF of 45–55% and temperature at 0–5 ◦ C
To yield the high-quality crystals, we reduced the presence of concomitant phenomenon in the crystallization process and classified the crystals into three sets based on the morphologies and colours, which could be observed under a microscope
Summary
An oral drug, is a multi-kinase inhibitor with anti-tumour activity against a large range of cancers [1]. It is approved for the treatment of patients with advanced renal cell carcinoma, advanced hepatocellular carcinoma and thyroid carcinoma [2]. Sorafenib hydrobromide and its hydrated salts have been prepared and characterized in the literature [9,10]. Their crystal structures are not reported until now
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