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.

Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

“…Also many other physicochemical properties can be modulated by cocrystallization including stability [21][22][23][24], hygroscopicity [25] and prolonged shelf life [26]. Among many drugs, aromatic amides acting either as APIs or as excipients attract nowadays substantial attention [27][28][29][30][31][32][33][34][35]. These compounds are known for their important roles in medical applications.…”

“…Although many pharmaceutical cocrystals containing amides have been studied [27][28][29][30][31][32][33][34][35], the data deposited in the Cambridge Structural Database (CSD) [41] are rather variable in the sense that many coformers were used for synthesis of diverse cocrystals. For example cocrystals of fumaric acid with benzamide, isonicotinamide or nicotinamide are known under refcodes YOPBUB, LUNNOX and EDAPOQ, respectively, but there is no information about solids of these coformers with temozolomide.…”

Hydrogen-bonded network in the salt 4-methyl-1H-imidazol-3-ium picrate

“…Co-crystallization, the crystallization of more than one solid component into a new compound, forming a new co-crystal or molecular salt, is a well known research field involving, for example, active pharmaceutical ingredients (Aitipamula et al, 2015;Weyna et al, 2012;Robinson, 2010;Arenas-García et al, 2010) and crystal engineering (Manoj et al, 2014). 4-Methylimidazole is an often used pharmaceutical intermediate (Shimpi et al, 2014).…”

Acid–ammonium heterodimer and N(ammonium)–H...N(pyridine) synthon preference in three salts of nicotinic acid with (1R,2R)-1,2-diphenylethylenediamine

“…The application of robust synthons (Aakerö y et al, 2001;Tothadi & Desiraju, 2013;Aitipamula et al, 2015;Banik et al, 2016;Saha & Desiraju, 2018) is considered to be effective in the design and synthesis of pharmaceutical solids. Nangia et al have designed pharmaceutical solids by the engineering of the robustness of synthons (Goud et al, 2011;Thakuria & Nangia, 2013;Sanphui et al, 2014), such as the cocrystals of the loop diuretic drug furosemide by the use of a sulfonamide-pyridine N-oxide synthon between aromatic primary sulfonamides and pyridine N-oxides.…”