Solubility and permeability enhancement of BCS class IV drug ribociclib through cocrystallization

Abstract

Ribociclib (RBC) is an antineoplastic agent and a Biopharmaceutics Classification System (BCS) class IV drug with poor solubility and low permeability. A novel salt form of RBC with vanillic acid (VA) and a cocrystal with resorcinol (RES) were successfully synthesized and, for the first time, the crystal structure of RBC as its hydrate (RBC–HYD) is reported. The synthesized salt hydrate, RBC–VA–HYD, and cocrystal, RBC–RES, were satisfactorily characterized by single crystal X-ray diffraction to show that the two components in 1 : 1 stoichiometry exist in both salt and cocrystal forms, respectively. The dominant hydrogen bonds between RBC and VA are the charge-assisted O–H⋯O⁻ and N⁺–H⋯O⁻, whereas in the RBC–RES cocrystal O–H⋯O and O–H⋯N hydrogen bonds are present. The solubility, dissolution rate and permeability of the salt and cocrystal were studied under physiological pH environments. RBC in the cocrystal form exhibited 2-fold enhancement in permeability compared to pure RBC. The present investigation not only provides a promising candidate for improved therapeutic activity against cancer, but also provides a direction for selecting between salt or cocrystal forms for a high bioavailability drug formulation.