(224c) Predicting Multicomponent Crystal Formation: The Interplay Between Homomeric and Heteromeric Interactions

Current approaches to improving physicochemical properties without changing desirable therapeutic behaviour of active pharmaceutical ingredients include formation of multicomponent crystals such as salts and cocrystals. We report a method that can provide a priori prediction for multicomponent crystal formation based on intermolecular pair interactions characterised using pulsed gradient spin-echo nuclear magnetic resonance (PGSE NMR). The accuracy of our prediction method 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 6 solvents. The model systems chosen represent a complex situation where outcomes of solution crystallisation of the molecular pairs range from 7 salts, 13 cocrystals to pairs that do not form any multicomponent crystals. The results provide a new perspective of how the fundamentals of intermolecular interactions in solutions could be correlated with the solid formation of single- or multicomponent crystals if these solutions are supersaturated. While the ΔpKa rule results in numerous contradicting exceptions, our method robustly predicts multicomponent crystal formation. These results reveal that the application of PGSE NMR for determining the self diffusivity of molecules and subsequently the strength of intermolecular interactions has the potential to be developed into a standard and robust protocol for the study of multicomponent solution chemistry.