Cocrystals of Caffeine and Hydroxybenzoic Acids Composed of Multiple Supramolecular Heterosynthons: Screening via Solution-Mediated Phase Transformation and Structural Characterization

Abstract

Caffeine, a pharmaceutical model compound, generally forms cocrystals with carboxylic acids that involve an O-H • • • N hydrogen bond between the carboxylic acid group of the acid and the caffeine imidazole moiety. Such solids are typically based on a single heterosynthon. To examine the facility of introducing additional supramolecular heterosynthons to the caffeine-carboxylicacid cocrystal system, structural isomers of aromatic carboxylic acids (i.e., hydroxy-and dihydroxybenzoic acids) with additional hydrogen-bonding functional groups (i.e., hydroxy group) were screened for cocrystal formation. For this purpose, a highly efficient screening method based on thermodynamically driven solution-mediated phase transformation was utilized. This method enabled the rapid discovery of nine new solid phases involving caffeine. These caffeine phases were identified using single-crystal X-ray diffraction and FT-IR spectroscopy as cocrystals based on 2-, 3-, 4-hydroxybenzoic-and 2,3-, 2,4-, 2,5-, 3,4-, and 3,5-dihydroxybenzoic acids. Structural analyses of the cocrystals revealed solids composed of up to three caffeine-carboxylic acid heterosynthons.

Stability Order of Caffeine Co-crystals Determined by Co-crystal Former Exchange Reaction and Its Application for the Validation of in Silico Models

“…It was also known that CA-HY existed as 1 : 2 and 2 : 1 co-crystallization systems. 29) According to the previous report, the lattice energy of CA-HY (1 : 2) was lower than that of CA-HY (2 : 1), 30) suggesting that CA-HY (1 : 2) was more stable than CA-HY (2 : 1). Therefore, CA-HY (1 : 2) was used in the following study.…”

“…The PXRD patterns of the co-crystals obtained in this study were identical to those reported previously. [26][27][28][29] It was previously reported that CA-MA existed as 1 : 1 and 2 : 1 co-crystallization systems. 28,29) However, we found that CA-MA (2 : 1) changed to CA-MA (1 : 1) upon the presence of equimolar MA, suggesting that CA-MA (1 : 1) is more stable than CA-MA (2 : 1).…”

“…The π-π stacking in the CA-HY co-crystal system, 29) which is not accounted in ΔE, could be a possible reason for this discrepancy. Previously, Moribe et al reported the stability order of carbamazepine co-crystals as glutaric acid>succinic acid>malonic acid, 25) whereas the order of the ΔE is opposite, i.e., malonic acid (−12 kJ mol ).…”

Molecular recognition of caffeine in solution and solid state

“…The Zhang's group [171,172] described nine cocrystals involving caffeine and structural isomers of (di)hydroxybenzoic acids. The cocrystals are studied using a new technique which is based on thermodynamically driven solution-mediated phase transformation (SMPT).…”

Cocrystal Systems of Pharmaceutical Interest: 2009

“…The latter finding led the authors to speculate on the proper nomenclature that would be suitable for crystal systems containing neutral and charged organic compounds contained in the same structure. Nine cocrystal products have been obtained by the interaction of caffeine with 2-hydroxy, 3-hydroxy, and 4-hydroxybenzoic acids, and also with 2,3-dihydroxy, 2,4-dihydroxy, 2,5-dihydroxy, 3,4-dihydroxy, and 3,5-dihydroxybenzoic acids [40]. The existence of OÀH(carboxyl)Á Á ÁN (imidazole), OÀH(hydroxyl)Á Á ÁO(urea), and OÀH(hydroxyl)Á Á ÁO(amide) heterosynthons was reported in the structurally diverse cocrystals, which were produced using a thermodynamically driven, solution-mediated, phase transformation process.…”