Drug-dependent modulation of micelle morphology and encapsulation in Triton X-100 systems

Micelle-based drug delivery systems offer a promising strategy for enhancing the solubility and bioavailability of poorly water-soluble therapeutics. Among these, nonionic surfactants such as Triton X-100 are particularly attractive due to their biocompatibility and capacity to encapsulate structurally diverse small molecules. In this work, all-atom molecular dynamics simulations were employed to investigate the encapsulation of three drugs (aspirin, atenolol, and felodipine) within Triton X-100 micelles. The selected molecules span a broad range of hydrophobicities and hydrogen-bonding capabilities, enabling a systematic comparison of how physicochemical properties influence solubilisation behaviour and micelle morphology. The simulations reveal that drug-micelle interactions are dominated by the hydrophilic ethylene-oxide headgroups, with limited penetration into the hydrophobic core. Hydrophobicity correlates positively with total drug loading; however, deviations from this trend highlight the competing roles of polarity and conformational flexibility. Atenolol, the most polar compound, penetrates deepest into the micelle core and induces the greatest deformation, whereas felodipine's extended aromatic surface stabilises more spherical aggregates. Overall, this work demonstrates that Triton X-100 micelles adapt dynamically to chemically diverse guest molecules. The results establish quantitative structure-property relationships linking molecular features, including hydrophobicity, polarity and topology, to encapsulation efficiency and micelle shape. These insights provide molecular-level understanding of the physicochemical principles governing solubilisation in nonionic micellar systems and support the broader application of molecular simulation as a predictive tool for micelle-based drug delivery formulations.