Selective Stabilization of β-Blockers within Cationic Vesicles: A DFT Study of Propranolol, Atenolol, and Metoprolol

Abstract 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). The primary aim is to elucidate the molecular mechanisms governing drug-surfactant complex formation, stability, and electronic behaviour in gas phase, thereby providing foundational insights into their potential relevance in drug delivery systems. PPL-DDOAB system exhibited the most stable complex, followed by ATL-DDOAB and MPL-DDOAB, based on relative stabilization energies. Frontier Molecular Orbital (FMO) analysis revealed significant changes in the HOMO–LUMO energy levels upon complex formation. The energy gap (ΔE) decreased for all drug-surfactant complexes compared to the isolated drugs, indicating enhanced electronic interaction and altered reactivity. Notably, the PPL-DDOAB complex showed the lowest energy gap (4.67 eV), suggesting improved electron mobility and the highest charge transfer potential among the studied systems. Quantum molecular descriptors (QMDs), calculated from HOMO and LUMO energies, further supported these findings. The chemical hardness (η) of DDOAB decreased upon complexation, with the lowest value in the PPL-DDOAB complex, implying increased reactivity and stabilization. Electrophilicity (ω) and softness values (S) also varied among the complexes, highlighting subtle differences in chemical behaviour. Non-Covalent Interaction (NCI) analysis, combined with Reduced Density Gradient (RDG) plots, visually and quantitatively identified van der Waals forces, steric repulsions, and hydrogen bonding as the main contributors to complex stabilization. Overall, the findings underscore the critical role of non-covalent interactions in the formation and stability of drug-surfactant complexes. These insights are vital for the rational design of vesicle-based drug delivery systems, where optimized molecular interactions can significantly influence drug loading, release, and bioavailability.