Quality by design (QbD) development of a Soluplus/TPGS-based ternary amorphous solid dispersion for enhanced oral...

Acacetin, a natural flavonoid with high-melting-point (> 200 °C) and poorly aqueous solubility, presents significant challenges in oral bioavailability due to its low dissolution rate. To address this limitation, acacetin-loaded amorphous solid dispersion (ASD) were developed via a quality-by-design (QbD) framework and manufactured using solvent-free hot-melt extrusion (HME). The formulation incorporated Soluplus as the polymeric matrix and d-a-tocopherol polyethylene glycol succinate (TPGS) as multifunctional plasticizer. The amorphization of acacetin was confirmed by differential scanning calorimetry (DSC) and Powder X-ray diffraction (PXRD). The optimized ternary system Aca-Soluplus-TPGS (2:6:2, w/w/w) achieved solubility 32.5 ± 11.5 μg/mL in simulated gastric fluid (SGF, pH 1.2), 180.5 ± 1.5 μg/mL in simulated intestinal fluid (SIF, pH 6.8), and 211.5 ± 6.3 μg/mL in water, respectively, 2203- to 3142-fold improvements over Aca. In single-pass intestinal perfusion (SPIP) studies, the optimized formulation exhibited 23.7 μg/cm² intestinal absorption per unit area, a 1.2-fold increase compared to Aca. The pharmacokinetic of Aca-Soluplus (2:8), Aca-Soluplus-TPGS (2:6:2), and Aca-Soluplus-TPGS (2:2:6) showed relative bioavailability of 698.0%, 725.2%, and 1456.3%, respectively, compared to Aca. Stability testing (40 °C/75% RH, 6 months) confirmed no recrystallization, indicating the robustness of the HME-based ASD strategy. These findings highlight HME as a scalable, solvent-free and continuous approach to enhance the biopharmaceutical performance of high-melting-point compound Aca.