Phase Transition and Permeability Behavior of Salicylic Acid Loaded Myristic Acid <i>In Situ</i> Gels: Insights from Molecular Dynamics and Confocal Imaging

A solvent-exchangeable <i>in situ</i> gel (ISG) system was developed for the localized and sustained delivery of salicylic acid (SAL) using a myristic acid (MYR) based lipid matrix. Upon exposure to aqueous environments, the ISG undergoes a sol-to-gel transition, forming a semisolid matrix that enables prolonged drug retention and controlled release. Confocal laser scanning microscopy demonstrated effective permeation, while powder X-ray diffraction confirmed a reduction in crystallinity following gelation, evidenced by broad peaks around 8° 2θ indicative of amorphous or semicrystalline transformation. Molecular dynamics (MD) simulations were employed to investigate the phase behavior, structural organization, and drug release mechanisms of SAL-loaded MYR-based ISGs, particularly in the SN30M25 system. MD simulations (0-200 ns) revealed early stage solvent migration and molecular rearrangement. MYR and <i>N</i>-methyl-2-pyrrolidone (NMP) reached equilibrium rapidly (∼20 ns), while water (WAT) and SAL equilibrated more slowly (30 and 60 ns, respectively), suggesting greater molecular mobility of SAL and WAT. This was supported by diffusion coefficients, where SAL (6.2357 m²/s) and WAT (20.8941 m²/s) exhibited higher values than MYR (3.2271 m²/s) and NMP (1.5345 m²/s). Radius of gyration (<i>R</i>_g) analysis showed more extended conformations for SAL and WAT, whereas MYR and NMP exhibited compact structures, implying stronger molecular aggregation. These findings suggest that SAL disrupts MYR packing, enhances solvent diffusion, and influences the gel matrix behavior. Overall, this study provides molecular-level insights into the structural dynamics of lipid-based ISGs and supports their potential for targeted and sustained drug delivery in oral applications.