Accelerated predictive stability (APS) strategies applied to screening pharmaceutical formulations: A comparison of spray dried and hot melt extruded nifedipine amorphous solid dispersions

Abstract

This study addresses the challenges in designing stable amorphous solid dispersions (ASDs) for pharmaceutical applications, focusing on nifedipine ASDs. The research involved manufacturing four different nifedipine ASDs using scalable pharmaceutical techniques-hot melt extrusion (HME) and spray drying (SD). Two pharmaceutical grade polymers, Soluplus® and poly-vinylpyrrolidone vinyl acetate (PVPVA, Kollidon® VA64), were used as carriers. The study employed an Accelerated Predictive Stability (APS) approach to assess the stability of these formulations. This included High-Performance Liquid Chromatography (HPLC) for quantifying nifedipine degradation, Powder X-Ray Diffraction (PXRD), and Differential Scanning Calorimetry (DSC) for measuring crystallisation kinetics. Additionally, Near-Infrared (NIR) spectroscopy was utilised to develop Partial Least Squares (PLS) regression models, providing a cost-effective and non-destructive method to quantify physicochemical changes. The results revealed that all four ASDs significantly improved the dissolution rate of nifedipine compared to its crystalline form. However, notable differences in stability among the formulations were observed through APS. The SD powders demonstrated greater physical stability, evidenced by a single glass transition temperature, in contrast to the extrudates, which showed dual glass transition temperatures indicating phase separation. Conversely, the HME formulations exhibited superior chemical stability compared to their SD counterparts, with the latter showing increased moisture sensitivity. Additionally, the degradation kinetics of the SD formulations were more complex than those of the extruded materials. Under less extreme conditions, SD systems followed Avrami-type kinetics, whereas more extreme conditions led to a shift from Avrami to diffusion kinetics, likely due to the miscibility of degradation products with polymer chains. In conclusion, the SD-PVPVA64 ASD was identified as the most balanced formulation in terms of physical and chemical stability, making it a prime candidate for further development. The study underscores the effectiveness of the APS approach, combined with chemometrics, as a robust methodology for guiding decision-making in the development of pharmaceutical amorphous formulations.

Keywords: Accelerated predictive stability, APS; Amorphous solid dispersions; Hot melt extrusion; NIR modelling; Nifedipine; Physical stability; Spray-drying.