New Approach for Estimation of Two-component Crystals Cocrystallization Thermodynamics

Based on a literature analysis, we have compiled a database of fusion temperatures and enthalpies for two-component molecular cocrystals and their pure components (3032 occurrences). To estimate the formation thermodynamics of two-component crystals, we have developed a database on the basis of the values reported in the literature from 1900 to 2024, inclusive. The database comprises the enthalpy and Gibbs energy values of individual molecular crystals obtained by various methods. An equation that allows for the estimation of the Gibbs free energy of formation of a two-component molecular crystal from the Gibbs free energy of sublimation of its coformers has been proposed. An approach has been developed to evaluate all cocrystallization/formation thermodynamic functions for two-component crystals. This approach is based on the sublimation Gibbs energy, enthalpy, and melting points of the individual coformers as well as the melting point of the resulting cocrystal/salt. Using this approach, we evaluated and analyzed the formation thermodynamic functions for 934 two-component crystals from a total database of 3032 occurrences. It is shown that for all stoichiometric compositions, the formation processes for 22.8% of the systems studied are entropy-driven. Using the example of Carbamazepine (CBZ) based two-component crystals (for which all cocrystallization thermodynamic functions were calculated), we analyzed the molecular packing in crystals located in different sectors of the diagram characterizing the main driving forces of cocrystallization. It was found that for cocrystals/salts located in sectors with entropy-driven processes, the molecular packing forms agglomerates in the shape of tetramers, which are packed into columns. Within these columns, the tetramers interact with each other through either van der Waals forces or hydrogen bonding. All columns interact with each other via van der Waals forces. In contrast for cocrystals/salts with enthalpy-driven processes, the molecular packing forms agglomerates (tetramers, hexamers), which are packed into layers and interconnected by hydrogen bonds. Within the layers, a two-dimensional network of hydrogen bonds is formed. These layers interact with each other via van der Waals forces.