Charge-assisted bond and molecular self-assembly drive the gelation of lenvatinib mesylate

Abstract

Lenvatinib mesylate (LM) is a first-line anticancer agent for the treatment of unresectable hepatocellular carcinoma, while it formed viscoelastic hydrogel when contacting with aqueous medium, which would significantly hinder its in vitro dissolution. The aim of this study was to systematicly explore the gelation mechanism and gel properties via thermal analysis, rheology, morphology and spectroscopy studies. The formed hydrogel was found to be composed of a new polymorph of crystalline LM, and its mechanical strength depended on the cross-linking degree of the fibrillar network structure. Spectroscopy analyses revealed that the intermolecular hydrogen bonds (the bifurcated hydrogen bond between the adjacent urea groups and the NH⋯OC hydrogen bond between the primary amide groups) as well as π-π stacking interactions (between the benzene ring and the quinoline ring) were suggested to be the driving forces for the self-assembly of LM during gelation process. Additionally, no gelation phenomenon was observed when suspending the base form lenvatinib in water, while it could form gel in various acidic solutions (e.g. hydrochloric acid, phosphoric acid and methanesulfonic acid) because the regenerated N+-H group increased the solubility of lenvatinib and promoted the balance between the dissolution or aggregation of LX (X: acid radical ion) molecules in solutions. In conclusion, the charge-assisted bond N+-H in LM molecule and intermolecular non-covalent interactions drived the hydrogel formation of LM in aqueous media. This study elucidates the gelation mechanism and gel properties of LM hydrogel, which would be helpful to figure out strategy to eliminate its gelation fundamentally and pave the way for its further formulation development in future.