In-situ determination of crystallization kinetics in ASDs via water sorption experiments.

Amorphous solid dispersions (ASD) are intended to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients. However, the development of long-term stable ASDs is often limited by the unwanted crystallization of the incorporated active pharmaceutical ingredient. Robust detection and quantification of crystal formation - especially at temperatures and humidites relevant for long-term storage tests - are essential for understanding crystallization phenomena. In this work, the crystallization kinetics in spray-dried nifedipine/poly (vinyl acetate) ASDs was investigated by measuring the time-dependent water sorption behavior at constant storage conditions. By coupling these experiments with thermodynamic predictions of the water sorption in amorphous and crystallized ASDs using the Perturbed-Chain Statistical Associating Fluid Theory, the amount of crystallized nifedipine as function of time could be determined in-situ just by weighing the ASD samples and without any calibration. The experimental findings were validated by X-ray diffraction measurements. Metastable ASDs with nifedipine contents between 70 wt% and 90 wt% were investigated at relative humidities between 60% RH and 90% RH and in a temperature range between 30 °C and 40 °C. Storage at high temperature and at high RH, and high nifedipine contents dramatically increased the crystallization rates.