Insight into the Phase Inversion of Myristic Acid In Situ Gels for Drug Delivery Applications.

In situ gels (ISGs) are well-known as smart drug delivery systems due to their inherent gel-forming ability and controlled drug release properties. This study presents comprehensive molecular-level insights into the physical properties and phase transformation processes of the formulation of 10 to 60% w/w myristic acid (MYR)-based ISGs using ethanol (EtOH), -methyl-2-pyrrolidone (NMP), and dimethyl sulfoxide (DMSO) as solvents, investigated using conventional experimental techniques, molecular dynamics (MD) simulations, and density functional theory (DFT). The results showed that 40% w/w myristic acid in NMP (NM40) exhibited swift gel formation with low water tolerance to induce phase inversion into the matrix. Scanning electron microscopy revealed that NM40 had multilayer, sheet-like structures, in which NM40 displayed a denser and less porous topography than 40% w/w myristic acid in DMSO (DM40). NM40 also had efficient antimicrobial efficacy against various microbes; thus, NM40 was the appropriate ISG as an antimicrobial drug delivery system. Moreover, MD simulation demonstrated that during the initial stage of gel formation, MYR began to agglomerate and arrange in an orderly manner, resembling crystallization. A higher concentration of MYR promoted a higher compactness of the MYR structure and the lower solvent exchange rate. Additionally, DFT calculations demonstrate that hydrogen bonding is the key interaction, contributing to the orderly arrangement of molecules. These significant findings pave the way for the tailoring and optimization of ISG formulations in drug delivery systems.