Crystal Engineering of Tegafur Cocrystals: Structural Analysis and Physicochemical Properties

Tegafur (TG) is a chemotherapy agent and has been used in the treatment of several common cancerous tumors. Despite wide utility of TG as a main component of the TG-uracil combination drug, TG suffers severe drawbacks due to nonuniform oral absorption, a short biological half-life, and poor aqueous solubility. We report cocrystals of TG with pharmaceutically acceptable coformers such as nicotinamide, isonicotinamide, 4-hydroxybenzoic acid, pyrogallol, and an antiasthma drug theophylline. The selection of these coformers was made based on crystal engineering principles by analyzing the crystal structures in the Cambridge Structural Database. Cocrystals were prepared by conventional solvent evaporative crystallization and solid-state grinding techniques and characterized by Fourier transform infrared spectroscopy, thermal analysis, and X-ray diffraction techniques. Crystal structure analysis revealed heterosynthons between TG and the coformers in most of the cocrystals. Stability of the cocrystals was tested at accelerated conditions (40 °C, 75% relative humidity), slurry, and dynamic vapor sorption techniques that revealed greater stability of the cocrystals with isonicotinamide, 4-hydroxybenzoic acid, and theophylline. Solubility and dissolution rate of the TG-isonicotinamide cocrystal were found to be superior to the other cocrystals and TG, making it a promising cocrystal for development of novel TG formulations.