Role of the Strength of Drug–Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions

The effects of specific drug–polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly­(acrylic acid) (PAA), poly­(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP) were prepared. Drug–polymer interactions in the ASDs were evaluated by infrared and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy, and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA, and weaker dipole–dipole interactions with PVP. On the basis of dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. On the basis of both DSC and VTXRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug–polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.