Synthonic modelling of quercetin and its hydrates: explaining crystallization behaviour in terms of molecular conformation and crystal packing

Hydrated structures of a specific compound can often have different physiochemical properties compared to the anhydrous form. Therefore, being able to predict and understand these properties, especially the stability, is critical. In this study quercetin, a flavonoid molecule, is modelled in three different states of hydration to gain an understanding of the effect of water molecules on the structure, packing and conformation energetics of the three forms. Conformational analysis and modelling of intermolecular interactions (synthonic modelling) have been performed. It was found that in the anhydrous form hydrogen bonding is the strongest type of interaction while in the two hydrate structures, the incorporation of water within the lattice leads to the formation of hydrogen bonds between the quercetin and water molecules. Within hydrates quercetin molecules adopt a more planar conformation which allows them to pack more closely by strong π-π stacking interactions, thus resulting in a higher relative stability. The modelling results highlight the importance of water in the stabilization of the lattice and explain the preferential nucleation of the dihydrate form. It is further demonstrated how synthonic modelling can be a predictive tool for the product’s properties, leading to more efficient product design and faster development.