Salt formation of cabozantinib with hydrochloric and hydrobromic acids – influence on the in vitro dissolution behavior and food effect

Abstract

The aim of this study was to prepare stable novel crystalline salts of cabozantinib, a tyrosine kinase inhibitor used to treat medullary thyroid cancer, to improve its dissolution properties and thereby reduce the positive food effect associated with its marketed salt form (L-malate). Five novel multi-component solid forms were obtained. In addition to the detailed physicochemical characterization, we report the crystal structures of the saccharinate, hydrochloride, and hydrobromide salts. The hydrobromide and hydrochloride salts of cabozantinib were chosen for further studies based on promising preliminary results from dissolution rate measurements. The potential of the hydrochloride and hydrobromide salts to be used for drug formulation was determined by testing their physical stability using hygroscopicity tests and by observing their melting properties. To investigate the impact of these salts on reducing the patient-relevant food effect, in vitro dissolution studies in stimulated fed and fasted states using biorelevant media were performed and compared to the marketed form of the drug.