Solubility prediction, solvate and cocrystal screening as tools for rational crystal engineering

Abstract

COSMO-RS theory can be applied to a range of physico-chemical properties, which are of interest in rational crystal engineering. Most notably, in combination with experimental reference data, accurate quantitative solubility predictions in any solvent or solvent mixture are possible. Additionally, COSMO-RS can be extended to the prediction of cocrystal formation, which results in considerable predictive accuracy concerning coformer screening. In a recent variant costly quantum chemical calculations are avoided resulting in a significant speed-up and ease-of-use.

Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

“…This approach was successfully applied to a variety of systems including cocrystals [44][45][46]. It assumes that the miscibility of supercooled liquids is also associated with miscibility in the solid state.…”

“…All systems were mixed with unimolar proportions. It is worth mentioning that the highest probability of cocrystallization is assumed for cases with negative enough H mix values [45,52]. Here this threshold was set to -1.30 kcal/mol.…”

“…One can, however, raise the question about the quantification of the similarities between distinct molecules. Since mixing enthalpy is often used as a first sign of potential stability of molecular complexes [45,52], its value seems to be a quite natural index of similarity of compounds affinities in the context of homogeneity of condensed phases. For verification of this hypothesis, series of pairs involving amides and other coformers were considered, for which H mix values were computed and used as a quantitative measure of likenesses between different compounds.…”

“…A virtual cocrystal screening method [43] was successfully validated against experimental cocrystals. Besides, the mixing enthalpy of supercooled liquid coformers with a given stoichiometry can be used for screening of cocrystallization potential [44][45][46]. Besides, the supramolecular phenomena expressed in terms of homo-or heterosynthons proved to be valuable guidance for practical applications [47][48][49].…”

In silico screening of dicarboxylic acids for cocrystallization with phenylpiperazine derivatives based on both cocrystallization propensity and solubility advantage

“…Alternatively, some methods that consider the electrostatic potential surface of the molecule have been used to identify the most likely contacts between components [24, 34, 35]. In particular, comparing values of the excess enthalpy of mixing ( H mix ) of coformers under supercooled conditions [36–38] has been found to be a very efficient way to screen for APIs that have a propensity to cocrystallize [25, 39–41]. Indeed, it has become possible to use this particular methodology [40] to rationalize the selection of pairs of coformers based on similarities in their affinities and cocrystallization landscapes.…”