(441d) Direct Observation of Remarkable Nanostructure Evolution during Aqueous Dissolution of Polymer/Drug Blends

Authors: 
Ricarte, R., ESPCI Paris
Hillmyer, M. A., University of Minnesota
Lodge, T. P., University of Minnesota
Amorphous solid dispersions (SDs), metastable blends of an active pharmaceutical agent and a polymer excipient, can significantly enhance the aqueous solubility of hydrophobic drugs, but the mechanism is not well understood. To address this gap in knowledge, we investigated 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 indicated 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 hydrophobic drug – in PBS was studied using a combination of cryogenic transmission electron microscopy (both imaging and electron diffraction) and small-angle X-ray scattering. These techniques revealed that HPMCAS and drug form <100 nm amorphous nanoparticles in solution. A direct correlation between the SD dissolution profiles and nanostructure evolution was discovered for both drugs, suggesting a significant portion of the drug measured in the supernatant during the dissolution assay is retained in the form of nanoparticles. Nanoparticle size, shape, and lifespan were influenced by drug identity, loading, and targeted concentration. These observations establish that persistent nanostructures are important for maintaining drug supersaturation during SD dissolution.