Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients
Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients
复制标题
DOI：
10.1016/j.ejpb.2012.07.003
复制
发表时间：
2012-10-01
影响因子：
4.9
通讯作者：
Taylor, Lynne S.
中科院分区：
文献类型：
--
作者：
Christensen, Niels Peter Aae;Rantanen, Jukka;Taylor, Lynne S.
本研究的目的是结合振动光谱和化学计量学来研究赋形剂诱导阿托伐他汀钙盐在与固体制剂的制造和储存相关的环境中转化为相应的游离酸形式。在所研究的辅料中，柠檬酸和聚丙烯酸被发现能引起歧化。此外，还观察到暴露在高相对湿度、高温和研磨都会促进歧化。结果表明，粉末中药物盐的歧化是通过溶液介导的机制发生的，赋形剂的选择对观察到的歧化程度有相当大的影响。因此，在药物开发过程中必须仔细注意赋形剂的选择，并应最大限度地减少暴露在高湿度和机械活化等压力下。(C)2012爱思唯尔B.V.保留所有权利。
The aim of the present study was to combine vibrational spectroscopy and chemometrics for investigating excipient-induced disproportionation of the calcium salt of atorvastatin into the corresponding free acid form in environments relevant to manufacturing and storage of solid dosage formulations. Of the excipients investigated, citric acid and polyacrylic acid were found to induce disproportionation. Moreover, it was also observed that exposure to high relative humidity, elevated temperatures, and milling all promoted disproportionation. The results suggest that disproportionation of drug salts in powders happens via a solution-mediated mechanism and that the choice of excipient has a considerable impact on the extent of disproportionation observed. Thus, careful attention must be paid to excipient selection during pharmaceutical development and exposure to stresses such as high humidity and mechanical activation should be minimized. (C) 2012 Elsevier B.V. All rights reserved.