New Pharmaceutical Cocrystal Forms of Flurbiprofen: Structural, Physicochemical, and Thermodynamic Characterization

In this work, three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide, and picolinamide have been discovered using thermodynamic analysis of solid–liquid binary phase diagrams, and their crystal structures have been determined from the high-resolution synchrotron powder diffraction data. Periodic density functional theory calculations have been carried out to gain additional insight into energy differences between the cocrystal structures. The pH–solubility behavior and solubility advantage of the cocrystals have been examined via eutectic concentrations of the components, and the thermodynamic stability relationships between different solid phases have been rationalized in terms of Gibbs energies of the formation reactions. In addition, a new model has been proposed for estimating the solubility product ( K sp ) of a cocrystal, based on the experimental intrinsic solubility of the drug and coformer complemented by calculated physicochemical HYBOT descriptors. The relationship between the change in Gibbs free energy and the molecular volume of cocrystal formation has been observed and discussed.