Journal Articles Crystal Growth & Design Year : 2025

Cocrystallization of Caffeine and Gallic Acid in Water and Methanol: Solid-State Landscape Using Ternary Diagrams

Abstract

Crystal engineering is increasingly focused on the systematic search for all possible cocrystalline forms of an API–coformer system. Constructing a ternary phase diagram for the system is beneficial to gain insights into the phase behavior to control the crystalline form obtained from solution-based approaches. In this work, the goal is to construct a phase diagram for the caffeine–gallic acid system in a mixture of two solvents (water and methanol). This involves the construction of three ternary isothermal or isoplethal sections of the quaternary phase diagram caffeine–gallic acid_water_methanol at 296 K. One diagram is built by varying the caffeine and gallic acid proportions in pure water. The two others are constructed at a fixed caffeine/gallic acid ratio by varying the water/methanol ratio (v/v). Powder X-ray diffraction (PXRD) is employed to identify the different solid phases and high-performance liquid chromatography (HPLC) to determine the concentration of the solutes in the saturated solutions of each sample. Three cocrystals (CAF-GAL·1.5H2O, 3CAF-GAL·6H2O, and CAF-GAL·1H2O·1MeOH) are identified, and their existence domain is determined. Other cocrystals crystallized by slow evaporation (CAF-GAL·0.75H2O) or by coprecipitation (CAF-GAL·0.5H2O form II) are metastable forms. Therefore, nonphotochemical laser-induced nucleation (NPLIN) is able to crystallize stable and metastable forms, and the cocrystal reported in the literature, CAF-GAL·0.5H2O form I, is not observed under thermodynamic equilibrium conditions; indeed, these latter ones are metastable phases.

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Dates and versions

hal-05112047 , version 1 (13-06-2025)

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Dania Mellah-Hammouni, Yohann Cartigny, François-Xavier Legrand, Nicolas Guiblin, Bertrand Fournier, et al.. Cocrystallization of Caffeine and Gallic Acid in Water and Methanol: Solid-State Landscape Using Ternary Diagrams. Crystal Growth & Design, 2025, 25 (13), pp.4705-4712. ⟨10.1021/acs.cgd.5c00195⟩. ⟨hal-05112047⟩
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