(486a) Crystallinity Detection Methods for Polymer-Stabilized Solid Dispersion Formulations

Process technologies such as hot melt extrusion and spray drying can significantly enhance the bioavailability of low solubility drugs through creation of polymer-stabilized amorphous solid solutions. On the other hand, the inherent thermodynamic instability of the saturated amorphous state must be managed over the shelf-life of the product. Formulations, processes, and packaging configurations are typically designed to avoid conditions leading to recrystallization, but an accurate evaluation of these conditions depends on the availability of analytical techniques of sufficient sensitivity. Traditional approaches to detection of crystallinity in amorphous materials include XRPD and ssNMR, which typically have sensitivity ~1% crystallinity by weight in the drug product. After dilution with excipients, this may translate to far lower sensitivities for detection in the drug product on an API basis. This is perceived to be an area of concern for demonstration of adequate process control to Health Authorities.

We describe methods to address these regulatory concerns by characterization of products in development. Examples of quantitative limit methods for crystallinity detection via XRPD and FT-Raman are provided to show how sensitivity can be improved over typical levels by an order of magnitude in some cases. The enhanced sensitivity methods have a line of sight to potential use beyond development as validated release tests at commercial facilities, and compliment novel research techniques. Case studies illustrate contrasting characterization strategies for active-polymer mixtures with low and high crystallization tendency.