This study employed advanced computational methods, including semi-empirical parametric method 3 (PM3) and density functional theory (DFT), to investigate the host/guest inclusion complexes of β-cyclodextrin (β-CD) with homovanilic acid (HVA). Utilizing B3LYP, M08HX, and PW6B95 approaches, global minima were optimized in both vacuum and aqueous phases. The focus spanned complexation, interaction, and deformation energies, as well as the geometry, electronic structure, and chemical reactivity of HVA during encapsulation.

Natural-bonding orbital (NBO) simulations highlighted the significant role of intermolecular hydrogen interactions in the stability of HVA/β-CD complexes. The study, employing the Global-hybrid meta-GGA functional methodology (PW6B95/6-31G(d)), shed light on energetically favored molecules, emphasizing superior results in orientation A. The Gauge-Including Atomic Orbital (GIAO) method has been used to study 1H nuclear magnetic resonance (NMR) complexes. These insights contribute to advancing host-guest systems and drug delivery applications.