Strength of Drug–Polymer Interactions: Implications for Crystallization in Dispersions

We investigated the influence of the strength of drug–polymer interactions on the crystallization behavior of a model drug in amorphous solid dispersions (ASDs). Ketoconazole ASDs were prepared with each poly­(acrylic acid), poly­(2-hydroxyethyl methacrylate), and polyvinylpyrrolidone. Over a wide temperature range in the supercooled region, the α-relaxation time was obtained, which provided a measure of molecular mobility. Isothermal crystallization studies were performed in the same temperature interval using either a synchrotron (for low levels of crystallinity) or a laboratory X-ray (for crystallization kinetics) source. The stronger the drug–polymer interaction, the longer was the delay in crystallization onset time, indicating an increase in physical stability. Stronger drug–polymer interactions also translated to a decrease in the magnitude of the crystallization rate constant. In amorphous ketoconazole as well as in the dispersions, the coupling coefficient, a measure of the extent of coupling between relaxation and crystallization times was ∼0.5. This value was unaffected by the strength of drug–polymer interactions. On the basis of these results, the crystallization times in ASDs were predicted at temperatures very close to T g, using the coupling coefficient experimentally determined for amorphous ketoconazole. The predicted and experimental crystallization times were in good agreement, indicating the usefulness of the model.