Unraveling the competitive cocrystallization behavior of natural products and impact of intermolecular interactions on their stability

Design of natural product cocrystals and its formation mechanism are of great significance importance to the development of fields such as medicine, food, cosmetics, and agriculture. In this research, alkaloids (theophylline, theobromine) and polyhydroxy natural products (quercetin, resveratrol, naringin) were selected as the research subjects. Through competitive cocrystal experiments, the study explored the stability differences among different cocrystals. Based on theoretical calculations, the study determined the hydrogen bonds and π-π bonds within the crystals were identified. Combined with cocrystal structure analysis, we discussed the influence of hydrogen bonding networks and π-π stacking modes on cocrystal stability. According to these results, the study correlated the cocrystal stability with void level, establishing the void formula to predict the stability between different cocrystals. Additionally, it summarized the structural unit cell model of natural product cocrystals, revealing formation mechanism of cocrystals, and intuitively demonstrating effect of intermolecular interactions on stability of crystal. Finally, we proposed the stability law, establishing a close connection between intermolecular interactions, void level, and cocrystal stability, providing a theoretical basis for exploring relationship between cocrystal microstructure and stability.