Direct Observation of Nanostructures during Aqueous Dissolution of Polymer/Drug Particles

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 ∼10 and ∼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 °C, potentially inducing the polymer to associate with itself or other hydrophobic species in solution. During <i>in vitro</i> dissolution of HPMCAS SDscontaining either phenytoin or probucol as the APIthe polymer and hydrophobic drug formed