Density functional theory investigation of hydroxyzine adsorption on silver clusters: implications for SERS-based sensing and interfacial stability

Hydroxyzine is a first-generation piperazine antihistamine with established antipruritic, anxiolytic, and sedative uses, and emerging evidence suggests additional anti-inflammatory and anticancer potential. In this study, the interaction of hydroxyzine (A4) with a small silver cluster (Ag4) is investigated using density functional theory (DFT) to evaluate its suitability for sensing and possible drug-delivery related applications. Geometry optimizations and vibrational frequency analyses are performed at the B3LYP/LANL2DZ level. Four adsorption configurations are examined based on reactive regions identified from MEP analysis: Ag4 positioned near the Cl-substituted phenyl ring (AC1), the OH group (AC2), the C-O-C region (AC3), and the mono substituted phenyl ring (AC4). Adsorption energies, dipole moments, polarizabilities, frontier-orbital descriptors, thermodynamic parameters (∆E, ∆H, ∆G, ∆S), and Mulliken charges are evaluated in both vacuum (air) and aqueous environments, showing that solvation significantly stabilizes the complexes and increases polarity. The strongest interaction is observed for oxygen-coordinated arrangements (particularly AC2/AC3), with AC3 emerging as the most stable in water. Predicted Raman/IR shifts and appearance of new modes indicate polarizability changes upon adsorption. Sensor recovery time estimates suggest very fast regeneration in air, while stronger binding in water slows recovery. Complementary molecular dynamics (Forcite/Materials Studio, COMPASSIII) on an Ag (1 1 1) slab indicates strong adsorption energetics and stable trajectories; NCI and RDG analyses support predominantly dispersion-driven (physisorptive) interactions at the interface.