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

Abstract

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 4hydroxybenzoic 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.

Rational Design of the Carbamazepine Ternary Cocrystals

“…In the present work, the Gibbs energy of formation (Δ G f 0 ) values for [CBZ + MlnAc + BZA] (1:1:1) and [CBZ + MlnAc + PAM] (1:1:1) were experimentally estimated using the cocrystal solubility method, which is systematically applied to binary cocrystals. ,,, In brief, this method entails measuring the thermodynamic solubility of the parent and cocrystal components in a specific solvent at a predetermined temperature. The primary requirement is to use a solvent, in which the cocrystal dissolves congruently.…”

“…The negative values of the Gibbs energy, enthalpy, and entropy indicate that the formation of both ternary cocrystals from the corresponding equimolar physical mixtures of the parent compounds is a thermodynamically favorable process driven by enthalpy. Previously, a relation between the driving forces of cocrystallization (enthalpy or entropy) and the crystal packing features of the CBZ binary cocrystals was identified . According to it, the enthalpically favored CBZ cocrystals are characterized by the presence of strong hydrogen bonds between the main structural motifs, such as dimers, rings, and chains, in contrast to the entropically favored cocrystals.…”