Track: Formulation and Delivery - Chemical - Formulation - Amorphous and Co-crystal Systems
Category: Late Breaking Poster Abstract
Impact of Storage Conditions on the Physical Stability of Indomethacin-PVP Amorphous Solid Dispersions
Purpose: Various storage conditions have a large impact on the stability of a drug product. In particular, the growth in popularity of amorphous solid dispersions (ASDs) has led to an increased importance of maintaining physical stability in ASDs by preventing recrystallization. The impact of drug loading and storage temperature relative to the glass transition temperature (Tg) has been explored for their relative importance as the cause for crystallization in ASDs. Methods: Indomethacin (IND) and polyvinylpyrrolidone (PVP) K12 ASDs were formulated at varying drug loadings (65 – 100% w/w) via cryomilling and melt-quenching. The Tg for each dispersion was measured using differential scanning calorimetry (DSC), and storage temperatures were then assigned (40 – 100°C) to probe the design space both above and below the glass transition. Samples were stored over desiccant (approximately 0% RH) and monitored for the onset of crystallization and change in hydrogen bonds using powder X-ray diffractometry (PXRD) and Fourier-transform infrared spectroscopy, respectively. Results: All dispersions were initially confirmed as amorphous using modulated DSC and initial PXRD scans. Higher drug loading with IND resulted in increasingly lower Tg values and a faster onset of crystallization at all storage temperatures. A loss of IND-PVP hydrogen bonds and an exponential dependence of crystallization onset time was noted as a function of drug loading for all temperatures. As the Tg was approached, an increase in the rate of subsequent crystallization was observed, along with a change in crystallization activation energy, possibly indicating a switch to diffusionless crystallization. Conclusion: Maintaining the stability of the amorphous drug component is critically important for successful pharmaceutical formulations. Increased drug loading and temperature provide a larger thermodynamic driving force for crystallization from which the onset time may be able to be predicted as a function of drug loading in IND-PVP ASDs. A better understanding of the causes of destabilization and their relative significance towards causing crystallization will help to make better informed decisions during formulation and storage.