Role of Molecular Packing in Solvent-Mediated Ellagic Acid·Phenazine Co-Crystals Toward Biological Activity Enhancement and Rational Drug Design

Ellagic acid (EA), a biologically active polyphenol abundant in various natural plants, has been widely applied in diverse pharmacological systems. This study investigates cocrystals formed by EA with common pharmaceutical intermediates, yielding crucial insights into their atomic-level biological performance. Three novel cocrystals of EA·Phenazine were synthesized in different solvents (cocrystal 1: EA·Phenazine; cocrystal 2: EA·Phenazine·2MeOH; cocrystal 3: EA·Phenazine·2H 2 O). In addition, their structures are characterized using single-crystal X-ray diffraction. Co-crystal 1 without lattice solvent and cocrystal 3 containing lattice H 2 O, exhibited intriguing EA–EA and phenazine–phenazine π–π stacking interactions. Conversely, cocrystal 2 bearing methanol can illustrate robust interligand EA/phenazine π–π stacking interactions. Thus, cocrystal 2 displayed a wider absorption range and a more negative oxidation potential, indicative of enhanced functional performance. The superior properties of cocrystal 2 were attributed to the lower energy level of the lowest unoccupied molecular orbital, particularly the p−π* antibonding orbitals of phenazine, owing to the potent π–π interactions, as unveiled by theoretical calculations. In summary, the presence of interligand interactions emerges as a pivotal factor in augmenting the biological activities of cocrystals, with the extent of enhancement contingent on specific packing modes. This structure–property relationship allows a profound understanding of the polymorphism observed in drug molecules.