Tween 80 Loading Nonmonotonically Modulates Curcumin Oral Exposure from Piperine-Containing TPGS-Based Amorphous Solid Dispersions

Objectives: This study investigated how polysorbate 80 (Tween 80; TW80) loading affects the biopharmaceutical performance of curcumin (CUR) amorphous solid dispersions (ASDs), focusing on the relationship between apparent dissolution and oral exposure. Methods: ASDs were prepared by rotary evaporation with piperine (PIP) as a bioenhancer and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an amphiphilic carrier. The CUR/PIP/TPGS mass ratio was fixed at 1:0.25:8, with 0, 1, 2, or 4 mass equivalents of TW80, yielding CPT, CPT-TW1, CPT-TW2, and CPT-TW4, respectively. CUR-excipient interactions and excipient self-assembly were examined using FT-IR, NMR, and pyrene fluorescence spectroscopy. Non-sink dissolution in water, PXRD of recovered precipitates, colloidal characterization, cell-associated CUR in MDCK cells, and rat pharmacokinetics were evaluated to assess relationships between in vitro performance and systemic exposure. Results: Spectroscopic findings supported noncovalent CUR-excipient interactions, while fluorescence measurements suggested mixed-excipient aggregation. Combining TPGS and TW80 markedly increased apparent CUR solubility. Higher TW80 loadings enhanced apparent dissolution, whereas colloidal size changed nonmonotonically. TW80-containing formulations yielded recovered solids with lower relative crystallinity indices than TW80-free CPT. ASDs increased cell-associated CUR relative to crystalline and amorphous CUR. However, oral exposure did not follow the dissolution ranking. CPT-TW1 produced the highest AUC0-t (281.2 ± 33.9 ng·h/mL), approximately 1.8-fold that of CPT (p < 0.01). Despite greater apparent solubilization, CPT-TW2 and CPT-TW4 yielded lower AUC0-t of 157.4 ± 17.2 and 109.2 ± 24.7 ng·h/mL, respectively. Conclusions: TW80 loading nonmonotonically affected oral CUR exposure. Higher apparent dissolution in water did not predict higher systemic exposure. Altered colloidal partitioning is a possible explanation requiring direct validation under biorelevant conditions. Surfactant loading should be optimized based on absorption-relevant performance rather than maximized solely to enhance apparent dissolution.