Enhanced Dissolution and Diffusion of Ribociclib by Salt Formation with Fluorobenzoic Acid Coformers

Ribociclib (RBC) is an anticancer drug of poor aqueous solubility and low permeability. In this study, we report the improvement in the physicochemical properties of RBC, such as dissolution, solubility, diffusion, permeability, and bioavailability, through cocrystal/salt formation. Novel multicomponent cocrystal salt (MCCS) forms of RBC were obtained by liquid-assisted grinding (LAG) with pharmaceutically acceptable fluorobenzoic acid coformers such as 4-fluorobenzoic acid (4-FBA), 2,3-difluorobenzoic acid (23-DFBA), 2,4,5-trifluorobenzoic acid (245-TFBA), 2,3,5,6-tetrafluorobenzoic acid (2356-TFBA), and 4-fluoro-2-hydroxy benzoic acid (4F2-HBA). A new dihydrate of the drug (RBC–H2O, 1:2), one salt (RBCH+–4F2HBA–, 1:1), and four salt hydrates of RBC [RBCH+–4FBA––H2O (1:1:3), RBCH+–23DFBA––H2O (1:1:2), RBCH+–245TFBA––H2O (1:1:∼2), and RBCH+–2356TFBA––H2O (1:1:1)] are reported in this paper. The multicomponent phases were characterized by infrared spectroscopy, 1H NMR, differential scanning calorimetry, thermogravimetric analysis, and powder X-ray diffraction (PXRD), and their crystal structures were determined by single crystal XRD. The drug–coformer hydrate structures stabilized by ionic N+–H···O– hydrogen bonds were analyzed by Hirshfeld surface analysis. These novel salts exhibit improved solubility, permeability, dissolution, diffusion, and bioavailability in comparison to RBC. The normalized enhancement in the diffusion of the cocrystal/salt is calculated using the equation diffnorm = diffusion/dissolution. Finally, this study alerts to that fact that a novel and more stable hydrate form of the drug may appear during salt/cocrystal screening experiments, e.g., a dihydrate of RBC was discovered in this study compared to the monohydrate reported by us previously, leading to a revision in the calculations for dissolution and diffusion compared to that of the reference drug crystal form.