Relationship between synthesis method-crystal structure-melting properties in cocrystals: the case of caffeine-citric acid

The influence of the crystal synthesis method on the crystallographic structure of caffeine-citric acid cocrystals was analyzed thanks to the synthesis of a new polymorphic form of the cocrystal. In order to compare the new form to the already known forms, the crystal structure of the new cocrystal (C8H10N4O2·C6H8O7) was solved by powder X-ray diffraction thanks to synchrotron experiments. The structure determination was performed using 'GALLOP', a recently developed hybrid approach based on a local optimization with a particle swarm optimizer, particularly powerful when applied to the structure resolution of materials of pharmaceutical interest, compared to classical Monte-Carlo simulated annealing. The final structure was obtained through Rietveld refinement, and first-principles density functional theory (DFT) calculations were used to locate the H atoms. The symmetry is triclinic with the space group P1 and contains one molecule of caffeine and one molecule of citric acid per asymmetric unit. The crystallographic structure of this cocrystal involves different hydrogen-bond associations compared to the already known structures. The analysis of these hydrogen bonds indicates that the cocrystal obtained here is less stable than the cocrystals already identified in the literature. This analysis is confirmed by the determination of the melting point of this cocrystal, which is lower than that of the previously known cocrystals. © 2024 International Union of Crystallography. All rights reserved.