Structure–interaction–performance relationships in quercetin-based co-amorphous systems: insights from molecular simulations and experimental characterization

Quercetin (QUE) has recently attracted increasing interest as a co-former in co-amorphous systems owing to its multiple hydrogen-bonding functionalities. However, the relationship between its intermolecular interactions and co-amorphous performance remains poorly understood. This study investigated the influence of co-former chemistry on the molecular interactions, stability, and aqueous performance of quercetin-based co-amorphous systems using arginine (ARG) and glutamic acid (GLU) as model amino acid co-formers. Co-amorphous formulations were prepared by spray drying and characterized using molecular modelling, solution-state 1H NMR titration, FTIR spectroscopy, PXRD, mDSC, dynamic vapour sorption, solubility, and dissolution studies. Molecular simulations predicted stronger miscibility and intermolecular interactions in the QUE-ARG systems than in the corresponding QUE-GLU systems, which was supported by NMR and FTIR analyses. Although all formulations were initially amorphous, the QUE-GLU systems crystallized within one week of storage, whereas the QUE-ARG systems remained amorphous for at least three months. Notably, the QUE-GLU formulations exhibited comparable or higher glass-transition temperatures, indicating that Tg alone was not predictive of physical stability. The stronger interactions observed in the QUE-ARG systems were also associated with substantially improved saturated solubility and dissolution performance. These findings demonstrate that the effectiveness of quercetin as a co-former depends on the nature and specificity of intermolecular interactions and highlight their importance in the rational design of quercetin-based co-amorphous systems.