To elucidate the aqueous solubility enhancement mechanism of solid dispersions (SDs), metastable blends of an active pharmaceutical ingredient (API) and a polymer excipient, we investigated the dissolution of hydroxypropyl methylcellulose acetate succinate (HPMCAS) SDs in phosphate buffered saline (PBS). Two hydrophobic active pharmaceutical agents, phenytoin and probucol, were employed at loadings of 10, 25, and 50 wt % relative to polymer. Light scattering measurements of HPMCAS solutions showed that the polymer itself formed a mixture of similar to 10 and similar to 100 nm sized structures (attributed to linear and covalently coupled polymer chains, respectively) in both tetrahydrofuran and PBS. The measurements also revealed that PBS is a poor solvent for HPMCAS at and below 37 degrees C, potentially inducing the polymer to associate with itself or other hydrophobic species in solution. During in vitro dissolution of HPMCAS SDs containing either phenytoin or probucol as the API the polymer and hydrophobic drug formed <100 nm amorphous nanoparticles. Using a combination of cryogenic transmission electron microscopy (both imaging and electron diffraction) and small-angle X-ray scattering, a direct correlation between SD dissolution profiles and nanostructure evolution was discovered for both drugs. In other words, the drug that is measured in the dissolution assay is retained in the supernatant in the form of nanoparticles. The size, shape, and lifespan of the nanoparticles were a function of drug identity, loading, and targeted concentration. These findings confirm the importance of persistent nanostructures to SD dissolution and particularly to maintenance of supersaturation.