Piperine as a molecular bridge mediates a ternary coamorphous system of polyphenols with enhanced pharmaceutical properties

The coamorphous formulations have attracted increasing interest due to enhanced solubility and bioavailability, together with synergistic pharmacological effects. In this study, a ternary coamorphous system of polyphenols was successfully prepared, wherein baicalein (Bai) and resveratrol (Res) were constructed into a single-phase coamorphous system mediated by piperine (Pip). FTIR and ss ¹³C NMR spectra together with quantum chemical calculation and molecular dynamics simulation suggested Pip as a molecular bridge connected Bai and Res molecules through π-π stacking and hydrogen bonding interactions. The configuration of coamorphous Bai-Pip-Res could minimize the system energy to facilitate its formation and enhance the stability. The ternary system showed 3.2, 4.3 and 5.3-fold increase in apparent solubilities of Bai, Res and Pip, and maintained the peak concentrations for at least 24 h. Compared to binary coamorphous systems, the ternary system exhibited superior physical stability under temperature and humidity conditions. Furthermore, coamorphous Bai-Pip-Res exhibited enhanced antibacterial activity, significant antioxidant ability and synergistic anti-inflammatory effect. This work offers a promising strategy to construct a ternary coamorphous delivery system with enhanced pharmaceutical properties by incorporating a molecular bridge, especially for components with the lack of intermolecular interactions.