Simultaneously improving the physicochemical and pharmacokinetic properties of vemurafenib through cocrystallization strategy

Abstract

Vemurafenib (VEM) is a first-line drug for the treatment of metastatic melanoma with BRAFV600 mutation, which was developed in the form of amorphous solid dispersion to overcome the defects of poor aqueous solubility and oral absorption. However, the oral dose of VEM is still very high; besides, the poor stability of amorphous form may increase the risks in drug effectiveness and safety. Herein, we attempted to provide a solution to these issues based on cocrystallization strategy. Three cocrystalline forms involving VEM and D/L/dl-camphorsulfonic acid with stoichiometric ratio of 1:1 were synthesized and characterized by powder X-ray diffraction analysis, 1H nuclear magnetic resonance, thermal analyses and Fourier transform infrared spectroscopy. The in vitro evaluations show that all of the cocrystalline forms demonstrate improved hygroscopicity and stability compared to amorphous VEM; especially, the cocrystalline form with dl-camphorsulfonic acid exhibits much better tabletability and apparent solubility than all of other forms. Pharmacokinetic tests reveal that all the cocrystallized products show significantly enhanced Cmax and AUC0-t values compared to the amorphous form. Therefore, the newly discovered cocrystalline forms of VEM are expected to overcome the issues of poor solubility and oral absorption and provide great potential for the development of improved preparations of the drug.