Two-component molecular crystals: evaluation of the formation thermodynamics based on melting points and sublimation data

Abstract

Based on literature analysis, we have built up a database containing the fusion temperatures of two-component molecular co-crystals and individual compounds (1175 co-crystals/salts). In order to estimate the thermodynamics of two-component crystal formation, we have created a database on the basis of values reported in the literature from 1900 till 2016 inclusive. The database includes values of the enthalpies and Gibbs energies of individual molecular crystals obtained by various methods. The distribution functions of two-component crystals have been analysed using their fusion temperatures, both for the full sample and separately for the salts and the co-crystals. A comparative analysis was conducted to determine the differences in the melting temperatures of monotropic polymorphic forms, as well as a similar analysis of two-component crystals with the same composition and different stoichiometries. Correlation equations have been obtained, connecting the melting points of co-crystals/salts and individual components for 74 active pharmaceutical ingredients and coformers, which enabled us to design co-crystals with predictable melting temperatures. An approach to estimating co-crystal sublimation thermodynamic characteristics has been developed. The thermodynamic functions of the formation process of 281 co-crystals have been obtained and analyzed. The diagram method has been used to analyze the parameters under study. Analysis of experimental data distribution in the diagram sectors has shown that the number of two-component crystals with enthalpy determined processes of co-crystal/salt formation corresponds to 70.9%, whereas the number of those with entropy determined processes corresponds to 29.1%. A general algorithm for estimating the thermodynamics of the formation of two-component crystals is proposed.