Six novel multicomponent systems of theobromine with carboxylic acids: crystallographic structures, solubility determination and DFT calculations

Abstract

A cocrystal screening of a series of theobromine (TBR) with five organic carboxylic acids (p-coumaric acid (p-COA), 2,4,6-trihydroxybenzoic acid monohydrate (2,4,6-TRM), gallic acid monohydrate (GAL), 1-hydroxy-2-naphthoic acid (1-H-2-NA) and citric acid monohydrate (CAM)) with 1 : 1 or 1 : 2 stoichiometry was performed in order to broaden its application in the food and pharmaceutical areas. Six novel multicomponent systems were identified, out of which two nonsolvated single crystals (TBR-2,4,6-TRM, TBR-p-COA) and two hydrated single crystals (TBR-GAL·2H₂O, TBR-GAL·4H₂O) except for TBR-GAL·2H₂O were first reported and the structures of four cocrystal or cocrystal hydrates were determined by SCXRD. The cocrystals of TBR were obtained by the solid-state mechanochemical grinding method and solution-state crystallization. The cocrystal structures were preliminarily determined directly from powder X-ray diffraction (PXRD) data, augmented by information from simultaneous thermal analysis (STA) and Fourier transform infrared spectroscopy (IR). Specifically, the four single crystals were successfully cultured in solution, the structures of which were characterized using the Shelxl method for structure refinement and meticulously searched in the Cambridge Structural Database (CSD). Moreover, the structure determination of the four single crystals was further confirmed by STA and IR assisted by Gaussian calculations. The results led us to the conclusion that TBR and four cocrystal formers (CCF) form a supramolecular system with lower energy. The hydrogen bonding network between TBR and CCF is mainly responsible for cocrystal formation, while TBR-GAL·2H₂O and TBR-GAL·4H₂O are mainly stabilized by water molecules. The solubilities of TBR, as well as that of cocrystals, were evaluated in two media: pure water and phosphate buffer solution (PBS) (pH 7.2–7.4). Solubilities in water and PBS of cocrystals of TBR-GAL·2H₂O and TBR-p-COA were improved by 1.59-fold and 2.98-fold, respectively. Thus, cocrystals significantly influence the solubility of TBR, which could be taken into account in enhancing solubility formulations.