Two-Component Molecular Crystals: What Is the Difference between Drug–Drug, Drug–GRAS, and CF–CF Databases? Evaluation of Melting Points and Ideal Solubility of Unknown Co-crystals

Abstract

Based on literature analysis, we have built a database containing fusion temperatures and enthalpies of twocomponent molecular co-crystals and individual compounds (2170 co-crystals). The distribution functions of two-component crystals have been analyzed using their fusion temperatures, both for the database as a whole and separately for Drug−Drug, Drug− generally recognized as safe (GRAS), Drug−CF, and CF1−CF2 databases. A comparative analysis has been done of the co-crystal distribution by classes of compounds, I ("Between"), II ("Higher"), and III ("Low"), for the general database and six small databases. Correlation equations connecting the melting points of the co-crystals and individual components have been obtained, which has enabled us to design co-crystals with predictable melting temperatures. The effect of the difference between the melting temperatures of individual co-crystal components on the probability of formation of co-crystals of different groups (I−III) has been analyzed. An approach has been developed for evaluating the ideal solubility of co-crystals based on the knowledge of the ideal solubility of one of the co-crystal individual components only.

Prediction of solubility of two-component molecular crystals

“…The ideal solubilities of the individual compounds and co-crystals/salts thereof were obtained from the original literature and described in our previous work. 8 The values of the activity coefficients for the selected co-formers in various solvents at different temperatures and the calculated and experimental solubility values of the co-crystals are presented in Table S1† and Fig. 1.…”

“…Using the generated database of melting temperatures and enthalpies of two-component molecular crystals and their individual compounds, we tried to find a correlation between the ideal intrinsic solubility of the co-crystals/salts ( X CC i d ) and individual compounds ( X CF1/2 i d ). 8 To this end, we selected the co-crystals/salts from the database, in which one of the components remained unchanged, while the other could vary. Within each cluster, the values of the ideal intrinsic solubility of the co-crystals can be described by the following linear correlation equation:ln( X CC i d ) = C + D ·ln( X CF1/2 i d )where C and D (which will be referred to as the “slope”) are the correlation equation coefficients.…”

“…In our recent work, we have developed an approach for estimating the ideal solubility of two-component crystals based on the knowledge of only the ideal solubilities of the individual components included in the crystal. 8 However, there remains a significant problem associated with the assessment of the real solubility of a two-component system, without conducting solubility experiments with the co-crystal/ salt itself. In other words, it is still unclear whether it is possible to predict the solubility of a hypothetical co-crystal/ salt in any medium and at any temperature knowing only the solubility characteristics of the individual compounds in these media and at these temperatures.…”

“…In the present work, we propose an algorithm to solve this problem. The main idea of this algorithm is based on using the activity coefficients of the individual components (in the content of the co-crystal) in the investigation solutions (which have been applied recently by Rapeenun and co-workers 11 ) and on the regularities (obtained by us before 8 ) allowing the prediction of the ideal solubility of co-crystals based only on the ideal solubility of the individual components.…”

“…In our previous studies, we proposed an algorithm for estimating the melting temperatures of hypothetical co-crystals (not obtained experimentally yet) using the cluster partitioning of the database, which includes the melting temperatures of two-component molecular crystals and individual substances. 6,8 The term "cluster" means a group of known co-crystals with one particular coformer. It can be used to predict the melting point of hypothetical co-crystals/salts with adequate accuracy.…”