Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
Eur J Pharm Biopharm. 2018 Jun;127:183-193. doi: 10.1016/j.ejpb.2018.02.028. Epub 2018 Feb 22.
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.
无定形固体分散体（ASD）旨在提高水溶性差的活性药物成分的生物利用度。然而，长期稳定 ASD 的开发通常受到掺入的活性药物成分不受欢迎的结晶的限制。在了解结晶现象时，对晶体形成的稳健检测和定量 - 特别是在与长期储存测试相关的温度和湿度下 - 是必不可少的。在这项工作中，通过在恒定储存条件下测量随时间变化的水分吸附行为，研究了喷雾干燥硝苯地平/聚（醋酸乙烯酯）ASD 中的结晶动力学。通过将这些实验与使用受扰链统计关联流体理论对无定形和结晶 ASD 中水分吸附的热力学预测相结合，可以原位确定随时间变化的结晶硝苯地平的量，而无需任何校准只需称量 ASD 样品即可。实验结果通过 X 射线衍射测量进行了验证。在相对湿度为 60%RH 至 90%RH 和温度范围为 30°C 至 40°C 下，研究了硝苯地平含量在 70wt%至 90wt%之间的亚稳 ASD。在高温和高 RH 下储存，以及高硝苯地平含量会显著提高结晶速率。
