An Unconventional Plasticizer Strategy for Stabilizing Ternary Coamorphous Polyphenol Systems: Mechanistic Insight into Dynamic Hydrogen Bonding

Abstract Coamorphous formulations have emerged as a promising strategy to improve the solubility and bioavailability of poorly soluble drugs, but their application is often limited by inherent thermodynamic instability. Herein, we propose an unconventional plasticizer strategy to stabilize coamorphous systems. The ternary coamorphous systems of baicalein (Bai), piperine (Pip), and resveratrol (Res) at 1:1:1, 1:2:1, 1:3:1, and 1:4:1 molar ratios were successfully prepared and exhibited enhanced supersaturated dissolution profiles, with approximately 3.4-, 5.3-, and 4.6-fold increases in the apparent solubilities of Bai, Pip, and Res, respectively. Pip as a plasticizer increased molecular mobility and lowered Tg from 107.5 to 52.3, 45.7, and 37.5 °C with increasing Pip content. Unexpectedly, coamorphous systems with higher Pip ratios exhibited enhanced physical stability. Fourier-transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance spectroscopy, molecular dynamics simulations, and quantum chemical calculations revealed a composition-dependent redistribution of intermolecular interactions. With increasing Pip content, Pip preferentially associated with Res and subsequently interacted with Bai, progressively disrupting the pre-existing Res−Bai hydrogen bond (HB). Meanwhile, the normalized HB numbers decreased, while the normalized binding energies remained nearly unchanged. Furthermore, the systems with a higher Pip ratio prolonged the intermittent HB lifetime with fast HB breaking and reformation (i.e., dynamic hydrogen bonding). Pip-mediated interaction reorganization and dynamic HB jointly contributed to the improved stability. This work provides a promising strategy for stabilizing coamorphous systems via plasticizers capable of establishing reorganized heteromolecular interactions and dynamic hydrogen bonding.