How Molecular Packing Affects the Thermodynamic Parameters of Cocrystal Formation: The Case of Carbamazepine Cocrystals

In the present work, the thermodynamic aspects related to the driving force of cocrystal formation and their stability were studied for a series of 1:1 carbamazepine (CBZ) cocrystals. The formation thermodynamic parameters (Gibbs free energy, enthalpy, and entropy) for the CBZ cocrystals with cinnamic acid, salicylic acid, 2,4-dihydroxybenzoic acid, and 2,6-dihydroxybenzoic acid were determined from the solubilities of the parent compounds and cocrystals in acetonitrile at 293–313 K. The correlation between the solubility products of the CBZ cocrystals and the intrinsic solubility values of the coformers was used to estimate the standard Gibbs energy for the CBZ cocrystal with 4-hydroxybenzoic acid. The relation between the cocrystal molecular packing features and the thermodynamic parameters was observed. The crystal lattice energies of the CBZ cocrystals were calculated by PIXEL. The trend between the standard formation enthalpies and the calculated dispersion terms of the CBZ cocrystals was found. The competitive grinding reactions were used to evaluate the relative thermodynamic stability of the CBZ cocrystals. The results of the competitive grinding reactions were found to be in good agreement with the experimentally determined standard Gibbs energies of the CBZ cocrystal formation.