Jenapharm GmbH & Co. KG, Otto-Schott-Str. 15, 07745 Jena, Germany; University of Leipzig, Pharmaceutical Technology, Institute of Pharmacy, Eilenburger Str. 15A, 04317 Leipzig, Germany.
Jenapharm GmbH & Co. KG, Otto-Schott-Str. 15, 07745 Jena, Germany.
Int J Pharm. 2015 Dec 30;496(2):751-8. doi: 10.1016/j.ijpharm.2015.10.074. Epub 2015 Nov 2.
Ethinylestradiol (EE) as a highly active and low dosed compound is prone to oxidative degradation. The stability of the drug substance is therefore a critical parameter that has to be considered during drug formulation. Beside the stability of the drug substance, granule particle size and moisture are critical quality attributes (CQA) of the fluid bed granulation process which influence the tableting ability of the resulting granules. Both CQA should therefore be monitored during the production process by process analytic technology (PAT) according to ICH Q8. This work focusses on the effects of drying conditions on the stability of EE in a fluid-bed granulation process. We quantified EE degradation products 6-alpha-hydroxy-EE, 6-beta-hydroxy-EE, 9(11)-dehydro-EE and 6-oxo-EE during long time storage and accelerated conditions. PAT-tools that monitor granule particle size (Spatial filtering technology) and granule moisture (Microwave resonance technology) were applied and compared with off-line methods. We found a relevant influence of residual granule moisture and thermic stress applied during granulation on the storage stability of EE, whereas no degradation was found immediately after processing. Hence we conclude that drying parameters have a relevant influence on long term EE stability.
炔雌醇（EE）是一种高效低剂量的化合物，容易发生氧化降解。因此，药物的稳定性是药物制剂过程中必须考虑的关键参数。除了药物的稳定性之外，颗粒粒径和水分是流化床造粒过程的关键质量属性（CQA），会影响所得颗粒的压片能力。ICH Q8 规定，这两个 CQA 都应通过过程分析技术（PAT）在生产过程中进行监测。这项工作重点研究了干燥条件对流化床造粒过程中 EE 稳定性的影响。我们在长时间储存和加速条件下定量了 EE 降解产物 6-α-羟基-EE、6-β-羟基-EE、9（11）-脱氢-EE 和 6-酮-EE。应用了监测颗粒粒径（空间滤波技术）和颗粒水分（微波共振技术）的 PAT 工具，并与离线方法进行了比较。我们发现，颗粒残余水分和造粒过程中施加的热应力对 EE 的储存稳定性有很大的影响，而在加工后立即没有发现降解。因此，我们得出结论，干燥参数对 EE 的长期稳定性有很大的影响。
