(136f) Crystal Engineering Applications of COSMO-RS

Since its first introduction in 1995 COSMO-RS theory has become a standard tool for the prediction of molecular thermodynamic properties in pure liquids and mixtures, mainly due to its efficient and accurate treatment of intermolecular interactions in solution.[1]

Although COSMO-RS originally is a liquid phase thermodynamic theory, there are meanwhile many applications which are of relevance for crystal engineering and drug development in general. In addition to solubility prediction and the screening for suitable solvents, a rather recent application is the computational screening of cocrystal forming compounds (coformers).

Here, interactions within the cocrystal are approximated by assuming a hypothetical subcooled stoichiometric mixture of API and coformer. The resulting mixing enthalpy is a highly useful quantity giving the propensity of that mixture to form a cocrystal.[2]

Hence it is now possible to efficiently pre-select from thousands of potential coformers in order to focus experimentally only on the most promising candidates for co-crystallization.

A concise overview of this approach will be given including its strengths and weaknesses with a subsequent illustration of the latest COSMO-RS applications in the field of crystal engineering such as the prediction of solvates. Another potential area of interest is the discovery of co-amorphous materials by means of COSMO-RS which has been reported recently.[3] A further straight-forward application of COSMO-RS is the computational exploration of ternary phase diagrams for API, coformer and solvent or solvent mixtures.

1. Klamt A. The COSMO and COSMO-RS solvation models. WIREs: Comput. Mol. Sci. 2011;1:699–709.

2. Abramov YA, Loschen C, Klamt A. Rational coformer or solvent selection for pharmaceutical cocrystallization or desolvation. J. Pharm. Sci. 2012;101:3687.

3. Corner PA, Harburn JJ, Steed JW, McCabe JF, Berry DJ. Stabilisation of an amorphous form of ROY through a predicted co-former interaction. Chem. Commun. 2016;52:6537–40.