Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
J Pharm Biomed Anal. 2012 Nov;70:111-6. doi: 10.1016/j.jpba.2012.06.002. Epub 2012 Jun 22.
During the stability evaluation of β-artemether containing finished drug products, a consistent and disproportional increase in the UV-peak areas of β-artemether degradation products, when compared to the peak area decline of β-artemether itself, was observed. This suggested that the response factors of the formed β-artemether degradants were significantly higher than β-artemether. Dry heat stressing of β-artemether powder, as a single compound, using different temperatures (125-150 °C), times (10-90 min) and environmental conditions (neutral, KMnO(4) and zinc), resulted in the formation of 17 degradants. The vast majority of degradants seen during the long-term and accelerated ICH stability study of the drug product, were also observed here. The obtained stress results allowed the calculation of the overall average relative response factor (RRF) of β-artemether degradants, i.e. 21.2, whereas the individual RRF values of the 9 most prominent selected degradants ranged from 4.9 to 42.4. Finally, Ames tests were performed on β-artemether as well as a representative stressed sample mixture, experimentally assessing their mutagenic properties. Both were found to be negative, suggesting no mutagenicity problems of the degradants at high concentrations. Our general approach and specific results solve the developmental quality issue of mass balance during stability studies and the related genotoxicity concerns of the key antimalarial drug β-artemether and its degradants.
在含有β-青蒿素的成品药物稳定性评估过程中，与β-青蒿素本身的峰面积下降相比，β-青蒿素降解产物的紫外峰面积持续且不成比例地增加。这表明形成的β-青蒿素降解产物的响应因子明显高于β-青蒿素。将β-青蒿素粉末（单一化合物）在不同温度（125-150°C）、时间（10-90 分钟）和环境条件（中性、KMnO4 和锌）下进行干热应激处理，导致形成了 17 种降解产物。在药物产品的长期和加速 ICH 稳定性研究中观察到的绝大多数降解产物也在这里观察到。获得的应激结果允许计算β-青蒿素降解产物的总体平均相对响应因子（RRF），即 21.2，而 9 种最突出的选定降解产物的个体 RRF 值范围为 4.9 至 42.4。最后，对β-青蒿素以及具有代表性的应激样品混合物进行了 Ames 测试，实验评估了它们的致突变性。两者均为阴性，表明在高浓度下降解产物没有致突变性问题。我们的一般方法和具体结果解决了在稳定性研究中质量平衡的开发质量问题以及关键抗疟药物β-青蒿素及其降解产物的相关遗传毒性问题。
