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

Objectives The fact that novel drug candidates are becoming increasingly insoluble is a major problem of current drug development. Computational tools may address this issue by screening for suitable solvents or by identifying potential novel cocrystal formers that increase bioavailability. In contrast to other more specialized methods, the fluid phase thermodynamics approach COSMO‐RS (conductor‐like screening model for real solvents) allows for a comprehensive treatment of drug solubility, solvate and cocrystal formation and many other thermodynamics properties in liquids. This article gives an overview of recent COSMO‐RS developments that are of interest for drug development and contains several new application examples for solubility prediction and solvate/cocrystal screening. Methods For all property predictions COSMO‐RS has been used. The basic concept of COSMO‐RS consists of using the screening charge density as computed from first principles calculations in combination with fast statistical thermodynamics to compute the chemical potential of a compound in solution. Key finding The fast and accurate assessment of drug solubility and the identification of suitable solvents, solvate or cocrystal formers is nowadays possible and may be used to complement modern drug development. Efficiency is increased by avoiding costly quantum‐chemical computations using a database of previously computed molecular fragments. Summary 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.