Tailoring aqueous solubility of a highly soluble compound viacocrystallization: effect of coformer ionization, pHmax and solute–solvent interactions

Abstract

Cocrystals of a nonionizable, water soluble compound (gababentin lactam (GBPL)) with less soluble coformers, are shown to be 2 to 17 times less soluble than GBPL. Cocrystals of GBPL with gentisic acid, 4-hydroxybenzoic acid, 4-aminobenzoic acid and fumaric acid are characterized by carboxylic acid---amide hydrogen bonds between coformer and GBPL, consistent with a previously reported structure of a benzoic acid cocrystal. The lattice and solvation contributions to cocrystal aqueous solubility were evaluated and solvation was found to be the main contribution to solubilization. Cocrystals exhibited pH-dependent solubility and pH_max, both of which are described by coformer pK_a and cocrystal K_sp values. These findings have important implications for the characterization and selection of cocrystals for desired drug delivery behavior.