Theobromine cocrystals with monohydroxybenzoic acids – synthesis, X-ray structural analysis, solubility and thermal properties.
Theobromine, an organic compound from the purine alkaloids group, is much less soluble in polar solvents than its analogues, i.e. caffeine and theophylline, that is why it has been used as an active pharmaceutical ingredient (API) model in cocrystals preparation. A series of theobromine (TBR) cocrystallizations from the solution with such coformers as 2-hydroxybenzoic acid (2HBA), 3-hydroxybenzoic acid (3HBA) and 4-hydroxybenzoic acid (4HBA) were carried out. In addition, neat grinding and liquid-assisted grinding were performed. Obtained cocrystals of TBR·2HBA, TBR·3HBA, as well as TBR·2(4HBA)·H2O cocrystal monohydrate have been characterized by single crystal X-ray diffraction (SXRD), PXRD, UV-vis and STA (TGA/DSC) analyses. In all cases no proton transfer from the acid molecule to the imidazole nitrogen atom in theobromine was observed. TBR-ACID heterosynthons are sustained by N∙∙∙H-O interactions, where proton donors in TBR·2HBA and TBR·3HBA are carboxylic group, and in TBR·2(4HBA)·H2O it is hydroxyl group of acid molecule. In each cocrystal TBR-TBR homosynthons R(_2^2)(8) formation by N-H∙∙∙O hydrogen bonds were observed. Acid-acid dimers are created only in crystal lattice of TBR·2(4HBA)·H2O. C-H∙∙∙O and π···π forces present in described structures are responsible for 2D and 3D structure stabilization.
- This article is part of the themed collection: 1st International Conference on Noncovalent Interactions