Surfactants Significantly Improved the Oral Bioavailability of Curcumin Amorphous Solid Dispersions and Its Underlying Mechanism

<b>Background/Objectives:</b> Surfactants are commonly used in amorphous solid dispersions (ASDs) to improve drug dissolution. A mechanistic understanding of their impact on in vitro dissolution and in vivo pharmacokinetics is essential for rational ASD design and for establishing predictive in vitro-in vivo correlation (IVIVC). <b>Methods:</b> Binary (Cur/P188) and ternary (Cur/P188/TW80, Cur/P188/SLS) ASDs were prepared by rotary evaporation. Drug-polymer-surfactant interactions were characterized by ¹H NMR and FT-IR spectroscopy. To elucidate the bioavailability enhancement mechanism, we performed (i) in vitro non-sink dissolution to assess dissolution kinetics, nanostructure formation, and precipitate transformation; (ii) cellular uptake assays; and (iii) in vivo pharmacokinetic studies. <b>Results:</b> Cur self-associates via hydrogen bonding and π-π stacking, limiting its solubility. Polymer carrier P188 disrupts these interactions and forms stronger drug-polymer bonding. Surfactants TW80 and SLS exhibited distinct interaction profiles: TW80 competitively disrupted Cur-P188 bonding, whereas SLS integrated into the Cur-P188 assembly to form stable ternary nanostructures. The Cur/P188/SLS ASD achieved the highest and most sustained supersaturation, maintained amorphous precipitates, and enhanced cellular uptake, leading to significantly improved oral bioavailability. <b>Conclusions:</b> Surfactants critically influence ASD performance by preserving high-energy drug states through three key mechanisms: (1) generating and maintaining supersaturation, (2) facilitating nanostructure formation, and (3) stabilizing amorphous precipitates. These mechanisms collectively enhance cellular uptake and bioavailability. Our findings demonstrate that both dissolution and in vivo performance are governed by multifaceted drug-polymer-surfactant interactions, providing critical insights into surfactant functionality and IVIVC to guide rational ASD formulation.