Solvent-free aqueous spray drying of poorly soluble drugs enabled by hot-feed micellar solubilization and high-Tg...

Poor aqueous solubility limits the oral bioavailability of many BCS II drugs, while conventional spray drying of amorphous solid dispersions (ASDs) often relies on organic solvents. Here we develop an aqueous spray-drying (AQSD) strategy that couples temperature-boosted solubility with poloxamer-enabled micellar solubilization and a high-Tg polymer matrix. Using celecoxib (CEL) as a model drug, heating increased intrinsic solubility and poloxamer 407 (P407) further raised apparent solubility to a ≥ 1 mg·mL^-1 feed window suitable for atomization. Binary CEL-P407 produced wax-like solids, whereas adding soluble starch (SS) or polyvinylpyrrolidone (PVP) improved solidification and yielded powdery, amorphous products. PXRD and vibrational spectroscopy supported amorphization and a P407-rich hydrophobic microenvironment in the hot feed. Compared with the binary, ternary systems improved powderability/yield (e.g., ∼50% for CEL-P407-SS vs ∼40% for CEL-P407), maintained target drug loading with minimal net loss during drying, and enhanced non-sink dissolution, with CEL remaining amorphous after storage. The framework was further validated using indomethacin, sulfamerazine, and aripiprazole, while highlighting limitations for thermally labile compounds. Overall, AQSD provides a practical green rule-hot-feed micellar solubilization coupled with a Tg-raising matrix-for early ASD formulation screening and solvent-free manufacturing.