(196x) Direct Observation of Remarkable Nanoparticle Evolution during Aqueous Dissolution of Polymer/Drug Particles

Amorphous solid dispersions (SDs), metastable blends of an active pharmaceutical ingredient and a polymer excipient, can significantly enhance the aqueous solubility of hydrophobic drugs, but the mechanism is not well understood. To resolve this ambiguity, we explored the dissolution of hydroxypropyl methylcellulose acetate succinate (HPMCAS) SDs in phosphate buffered saline (PBS). Light scattering measurements of HPMCAS solutions showed the polymer forms a mixture of ~10 and ~100 nm sized structures (assigned to linear and covalently coupled polymer chains, respectively) in both PBS and tetrahydrofuran. The measurements also demonstrated that PBS is a poor solvent for HPMCAS at and below 37 °C, suggesting the solvent induces the polymer to associate with itself or other hydrophobic species in solution. In vitro dissolution of HPMCAS SDs – containing either phenytoin or probucol as the encapsulated hydrophobic drug – in PBS was studied using a combination of cryogenic transmission electron microscopy (both bright-field imaging and electron diffraction) and small-angle X-ray scattering. These tools revealed that HPMCAS and drug form <100 nm amorphous nanoparticles in solution. A direct correlation between the SD dissolution profiles and nanostructure evolution was uncovered for both drugs, implying that a significant portion of the drug measured in the supernatant during the dissolution assay is retained in the form of nanoparticles. Drug identity, loading, and targeted concentration influenced nanoparticle size, shape, and lifespan. These discoveries confirm that persistent nanostructures are important for enhancing drug supersaturation during SD dissolution.