Cocrystals of Lenvatinib with Sulfamerazine and Salicylic Acid: Crystal Structure, Equilibrium Solubility, Stability Study, and Anti-Hepatoma Activity

The purpose of this study was to investigate the effect of cocrystal formation of lenvatinib on the drug's properties, including solubility, stability, and anti-hepatoma activity. Lenvatinib (LEN) is a multitargeted tyrosine kinase inhibitor with poor aqueous solubility. In this work, cocrystals of LEN with sulfamerazine and salicylic acid were synthesized via slurry reactive crystallization. The corresponding single crystals were obtained by a slow evaporation method. The crystal structures and intermolecular interactions were characterized by single-crystal X-ray diffraction techniques, Hirshfeld surface analysis, and molecular electrostatic potential analysis. These two cocrystals crystallized in the monoclinic space group, and the structures are maintained by hydrogen-bonding interactions. The synthesized cocrystals were further characterized by powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy, and proton nuclear magnetic resonance spectrometer techniques. The solubility of LEN cocrystals was determined in four dissolution media. The results demonstrated that both LEN cocrystals showed improved solubility compared to LEN free base. Stability studies through dynamic vapor sorption analysis, stress testing, and accelerated testing corroborated that the synthesized LEN cocrystals were stable and exhibited lower hygroscopicity than LEN free base and commercially available LEN mesylate. Moreover, the in vitro cytotoxicity assay showed a decreased IC50 value of the LEN-SMR cocrystal, suggesting improved anti-hepatoma activity.