Augmentative molecular aspect for phase inversion of vancomycin hydrochloride-loaded fatty acid in situ forming matrices

Highlights: • Molecular dynamic indicated step of fatty acid in situ matrix formation and movement of loaded vancomycin HCl • Fatty acid chain length and temperature influenced drug release pattern and molecular in situ matrix formation • Interior matrix structure depended on fatty acid crystallization and influenced drug release character • Invert in situ matrix formation produced swelling-gel-like fatty matrix resulting in freer drug diffusion Fatty acid-based in situ forming systems that carry vancomycin HCl (VCM) have been developed to treat local Gram-positive infections. However, little is known about mechanistic formation of fat-based in situ forming matrices. In this study, VCM-loaded fatty acid (C₈–C₁₆)-based in situ forming matrices and their computational model were investigated. Molecular dynamics (MD) simulations at various conditions confirmed the steps of the fatty acid-based in situ formation process and the movement/location of VCM. The MD simulation, topography of dried matrix and model fitting of VCM release profile indicated the movement of VCM through a complex/non-complex interior matrix structure of fatty acids where the low-molecular-weight fatty acid showed a more tangled passage than the high-molecular-weight fatty acid. The release pattern/mechanism were influenced by the aliphatic chain length and the environmental temperature. A sustained drug release was attained in the C₁₂-C₁₄ fatty acid-based system. However, the temperature affected the C₁₂ fatty acid-based structure in which the invert in situ formation process was revealed, and its ability to sustain drug release subsequently diminished. Hence, the mechanistic formation of VCM-loaded fatty acid-based in situ forming matrix and drug release were revealed for further development of in situ forming systems based on fatty acid.