Density Functional Theory Analysis of β‐Blocker–Surfactant Interactions in a Vesicle‐Forming System

Theoretical investigation on the interaction between a cationic, double‐tailed vesicle‐forming surfactant dioctadecyldimethylammonium bromide (DDOAB) and three non‐selective β‐blocker drugs: propranolol (PPL), atenolol (ATL), and metoprolol (MPL) have been carried out using density functional theory (DFT). Among the systems studied, the PPL–DDOAB complex exhibited the highest stability, followed by ATL–DDOAB and MPL–DDOAB, as indicated by their relative stabilization energies. Frontier molecular orbital (FMO) analysis revealed noticeable changes in highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) energy levels after complex formation. In all cases, the HOMO–LUMO energy gap (ΔE) decreased compared with the isolated drugs, suggesting stronger electronic interaction and modified reactivity. The PPL–DDOAB complex displayed the smallest energy gap (4.67 eV), indicating enhanced electron mobility and greater charge‐transfer capability. Quantum molecular descriptors derived from HOMO and LUMO energies further supported these observations. Chemical hardness ( η ) decreased upon complexation, particularly in the PPL–DDOAB system, implying increased reactivity. Variations in electrophilicity (ω) and softness (S) also reflected differences in chemical behavior. Non‐covalent interaction (NCI) and reduced density gradient (RDG) analyses confirmed that non‐covalent interactions govern complex stabilization. Overall, these findings highlight the importance of non‐covalent interactions in drug–surfactant association and their implications for optimizing vesicle‐based drug delivery systems.