Novel pharmaceutical cocrystals of triflusal: crystal engineering and physicochemical characterization

Abstract

A platelet aggregation inhibitor, triflusal, is practically insoluble in water and rapidly converts to 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) in physiological systems. Six cocrystals of triflusal were discovered from a cocrystal screening with pharmaceutically acceptable coformers, namely, benzamide, isonicotinamide, picolinamide, propionamide, urea, and valpromide, in an attempt to find stable solid forms of triflusal. The choice of coformers was based on a crystal engineering strategy relying on the carboxylic acid group of the triflusal and the most prevalent supramolecular interactions that it can form with complementary functional groups. Crystal structure analysis revealed that all the cocrystals feature heterosynthons involving carboxylic acid group of triflusal and pyridine/amide group of the coformers. Except the cocrystals with propionamide and valpromide, all the cocrystals were found to be stable at accelerated storage condition (40 °C, 75% relative humidity). Under slurry conditions, cocrystals with benzamide, picolinamide, and valpromide were found stable, but the remaining cocrystals undergo dissociation and degration of triflusal to HTB. As triflusal is known to undergo degradation in the presence of pharmaceutical excipients, the stable triflusal cocrystals reported herein may serve as promising candidates for development of novel triflusal drug formulations.