Development and Characterization of Amorphous PVP K30–Phosphatidylcholine Dispersions for the Fixed-Dose Co-Delivery of Hesperetin and Cannabidiol Prepared by Hot-Melt Extrusion

Hesperetin and cannabidiol (CBD) are promising plant-derived bioactives whose oral performance is limited by poor aqueous solubility. To address the shared biopharmaceutical limitations of both compounds, amorphous PVP K30–phosphatidylcholine dispersions were prepared via hot-melt extrusion (HME). A Box–Behnken design (DoE) was applied to investigate the impact of (i) total API load (hesperetin:CBD mass ratio 1:1), (ii) phospholipid content in the carrier, and (iii) extrusion temperature on the solubility of both actives. The resulting extrudates were characterized by XRPD, DSC, and FT-IR/ATR. Solubility and dissolution profiles were evaluated in phosphate buffer (pH 6.8). In vitro passive permeability was assessed using PAMPA GIT model. DoE indicated that API load and phospholipid content were statistically significant factors for solubility of both hesperetin and CBD, whereas extrusion temperature was not significant within the studied range. XRPD confirmed amorphization for all formulations except F6, which contained a minor residual crystalline fraction of hesperetin. DSC revealed single glass-transition events, supporting good miscibility. The best-performing formulation (F7; 15% APIs, 20% phospholipid, 165°C) achieved solubilities of 4.934 mg/mL (hesperetin; 987-fold increase) and 4.314 mg/mL (CBD; 66,369-fold increase) and showed the highest permeability in PAMPA GIT model. HME-produced PVP K30–phosphatidylcholine amorphous dispersions substantially improved the solubility, dissolution behavior, and in vitro permeability of hesperetin and CBD, highlighting polymer–phospholipid amorphous dispersions as a promising solubility-enhancing platform for delivery of poorly soluble. Graphical Abstract