Predicting multicomponent crystal formation: The interplay between homomeric and heteromeric interactions

Abstract

Current approaches to improving physicochemical properties without changing desirable therapeutic behavior of active pharmaceutical ingredients include formation of multicomponent crystals such as salts and cocrystals. We report a technique that can provide a priori prediction for multicomponent crystal formation based on intermolecular pair interactions characterized using pulsed gradient spin-echo nuclear magnetic resonance (PGSE NMR). The accuracy of our prediction technique in comparison to the well-adopted ΔpKa rule of thumb is tested against 25 molecular pairs including protonated amines, nitrogen-protonated heterocyclic bases, phenols, and carboxylic acids dissolved in six solvents. While the ΔpKa rule results in numerous contradicting exceptions, our technique robustly predicts multicomponent crystal formation. These results reveal that the application of PGSE NMR for determining the self-diffusivities of molecules and subsequently the strengths of intermolecular interactions has the potential to be developed into a standard and robust protocol for the study of multicomponent solution chemistry. © 2009 American Chemical Society.