Design and characterization of lopinavir-loaded microspheres: linking drug-polymer interactions with sustained release and HIV-1 protease inhibition

This study aimed to develop a sustained-release drug delivery system for lopinavir (LPV) using cellulose acetate (CA)-based microspheres to enhance drug dissolution and physical stability. LPV-loaded microspheres were prepared via an oil-in-water (O/W) emulsion solvent evaporation method and characterized using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and near-infrared (NIR) chemical imaging. Solid-state characterization confirmed successful encapsulation and revealed that the crystalline drug was converted into a high-energy amorphous molecular dispersion within the CA polymeric matrix, showing excellent drug-polymer chemical compatibility. In vitro dissolution profiles demonstrated sustained drug release over 24 h, with formulations LPV-MCs (R4, R9, and R10, all prepared at a 1:1 drug-to-polymer ratio and a stirring speed of 1000 rpm, varying in surfactant concentration [0.1 to 0.5%] and stirring time [4 to 6 h]) showing the highest dissolution rates, achieving 75.82%, 62.40%, and 62.70% drug release after 24 h, respectively. Morphological analysis via SEM revealed regular spherical microspheres with progressive surface porosity that directly modulated the sustained drug release behavior through matrix diffusion. In silico molecular docking simulations predicted strong binding affinities and hydrogen-bonding networks between the active lopinavir molecules and the catalytic pocket of the target HIV-1 protease enzyme (yielding a free binding energy of - 7.064 kcal/mol). Furthermore, 3D pharmacophore modeling and matrix-docking evaluations supported a highly compatible host-guest relationship between the drug and the cellulose acetate subunits, explaining the high physical entrapment efficiency. These findings highlight the critical role of drug-polymer structural compatibility in modulating sustained drug release and maintaining the chemical integrity of the active pharmaceutical ingredient, validating LPV-loaded CA microspheres as a promising multiparticulate platform for optimized oral HIV therapy.