Correctly Measuring and Predicting Solubilities of Solvates, Hydrates, and Polymorphs

Abstract

The formation of solvates, hydrates, or different polymorphs significantly alters the physicochemical properties of a target component (TC) (e.g., active pharmaceutical or agrochemical active ingredient), such as solubility and dissolution behavior. Thus, it is very important to know under which conditions a certain solvate, hydrate, or polymorph is formed. This information can be obtained from phase diagrams, which are usually based on solubility measurements. Possible pitfalls in measuring the solubility of TC hydrates or solvates in pure solvents and solvent mixtures are discussed, and strategies for obtaining reliable solubility data are proposed. To substantiate the proposed solubility-measurement strategies, a thermodynamic approach based on the Perturbed-Chain Statistical Associating Fluid Theory for modeling solvate/hydrate solubilities was developed. This approach allows identifying stability regions of solvates/hydrates and predicting solubilities of solvates/hydrates or of polymorphs in pure solvents and solvent mixtures. It was successfully verified for modeling the solubility of the indomethacin-methanol solvate in methanol and of the carbamazepine dihydrate in water. Furthermore, the solubility of carbamazepine dihydrate and theophylline monohydrate in water/ethanol mixtures was predicted in excellent agreement with experimental data.