Improvement of humidity stability of ethyl gallate by the cocrystal strategy and study of dissolution behavior of the cocrystal†

Abstract

In this study, the humidity stability of ethyl gallate (EG) was improved by a co-crystallization method. Through a combination of COSMO-RS virtual screening and liquid-assisted grinding assay (LAG) screening, 14 new solid phases out of 25 candidate coformers were identified and a single crystal of the ethyl gallate (EG)-2-methylimidazole (2MIE) 1 : 1 cocrystal, EG-2MIE, was obtained. The cocrystal was characterized by single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared spectroscopy. The ternary phase diagram (TPD) of EG-2MIE in ethanol was constructed at 298.15 K, 303.15 K and 308.15 K. The dissolution behavior of EG-2MIE in ethanol was also investigated and the thermodynamic parameters of cocrystal formation were also estimated. The results showed that EG and 2MIE were congruently dissolved, which can provide a theoretical guide for the large-scale preparation of the EG-2MIE cocrystal. The accelerated stability tests showed that EG-2MIE exhibited better stability than the original EG at 40 °C and 75% relative humidity. The dissolution behavior and humidity stability were explained by comparing the strength of intermolecular interactions by calculating the Hirshfeld surface (HS), molecular electrostatic potential surface (MEPs), atoms in molecules (AIM) analysis, and lattice energy analysis.