Formation Thermodynamics of Two-Component Molecular Crystals: Polymorphism, Stoichiometry, and Impact of Enantiomers

On the basis of literature analysis, we have built a database containing fusion temperatures of two-component molecular cocrystals and individual compounds (1947 cocrystals/salts). In order to estimate the thermodynamics of formation of two-component crystals, we have created a database on the basis of the values reported in the literature from 1900 until 2019 inclusive. The database includes the enthalpies and Gibbs energy values of individual molecular crystals obtained by various methods. A new algorithm for estimating the sublimation Gibbs energies of molecular crystals has been developed based on their sublimation enthalpies only. The algorithm divides the database into clusters including structurally related compounds. Using this approach, we have calculated the sublimation Gibbs energies for 269 crystals, whose sublimation enthalpies were obtained by the calorimetric method. The thermodynamic functions of the formation process of 509 cocrystals have been obtained and analyzed. The diagram method has been used to analyze the parameters under study. An analysis of the experimental data distribution in the diagram sectors has shown that the number of two-component crystals with enthalpy-driven processes of cocrystal formation corresponds to 70.8%, whereas of those with entropy-driven processes correspond to 29.2%. A detailed comparative analysis of the thermodynamic functions of cocrystal formation has been carried out for different monotropic polymorphic forms, two-component crystals with the same composition and different stoichiometries, and two-component crystals based on racemate and enantiomers.