Computational and Experimental Approaches for HPMCAS-Based Solid Dispersions of Abiraterone Acetate: Formulation, Characterization, and Biopharmaceutical Enhancement Evaluation.
OBJECTIVE To enhance the solubility, dissolution rate, and permeability of poorly water-soluble drug Abiraterone Acetate (ABA) by developing solid dispersions using hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF). SIGNIFICANCE Enhancing the biopharmaceutical performance of ABA is crucial due to its extremely poor solubility and dissolution characteristics. The present study demonstrates that HPMCAS-LF-based solid dispersion effectively improves the physicochemical performance of ABA through enhanced solubility, dissolution, and in vitro drug diffusion. METHODS Molecular dynamics (MD) simulations were conducted over 100 ns to evaluate the stability and structural behavior of the ABA-HPMCAS-LF complex, with analyses including root mean square deviation (RMSD), radius of gyration and solvent-accessible surface area . Binding free energy was measured using MM-GBSA calculations. Solid dispersions were prepared using co-grinding and solvent assisted cogrinding techniques and characterized by FTIR, PXRD, thermal analysis (TGA/DTG-DTA), SEM, and solid-state13C NMR. Solubility, in vitro dissolution, in vitro drug diffusion, hygroscopicity, and anticancer activity were assessed. RESULTS The ABA-HPMCAS-LF complex exhibited dynamic stability, with RMSD stabilization at 6-7 Å and a binding free energy of -33.45 kcal/mol, indicating strong van der Waals, lipophilic, and Coulombic interactions. Solid dispersions demonstrated a 1.07 to 16.72-fold increase in solubility compared to pure ABA, and in vitro release enhanced drug dissolution across different media. Diffusion increased by 6.36-fold in simulated gastric fluid (SGF 1.2) and 2.55-fold in phosphate buffer (pH 6.8) relative to pure ABA. CONCLUSION The solid dispersion of ABA with HPMCAS-LF significantly improved solubility, dissolution, and diffusion, highlighting its potential for enhanced oral bioavailability and improved therapeutic outcomes.