Vanhoenacker Gerd, Dumont Emmie, David Frank, Baker Andrew, Sandra Pat
Research Institute for Chromatography, Kortrijk, Belgium.
J Chromatogr A. 2009 Apr 17;1216(16):3563-70. doi: 10.1016/j.chroma.2008.08.102. Epub 2008 Sep 3.
Arylamines and aminopyridines form a class of potentially genotoxic impurities (PGIs) that can be present at trace levels in active pharmaceutical ingredients (APIs). A generic method was developed that allows the analysis of a selected set of these solutes at sub-ppm level relative to the drug substance. A highly concentrated solution of the pharmaceutical compound is analyzed by LC-MS using a single quadrupole mass spectrometer in the selected ion monitoring (SIM) mode. Since a number of target compounds show little or no retention in the reversed-phase LC setup, a fast and simple derivatization procedure using hexylchloroformate was applied. The amide derivatives of the PGI result in a higher molecular weight (more specific ion for SIM) and better chromatographic behavior. The methodology, consisting of a dual run on respectively a non-derivatized and a derivatized sample, was validated and applied to a selection of pharmaceutical substances. The method was found to be sufficiently sensitive and robust and is applicable in a QA/QC environment.
芳胺和氨基吡啶构成一类潜在的基因毒性杂质（PGIs），它们可能以痕量水平存在于活性药物成分（APIs）中。开发了一种通用方法，该方法能够相对于原料药以亚ppm水平分析一组选定的这些溶质。通过液相色谱-质谱联用仪（LC-MS），使用单四极杆质谱仪在选择离子监测（SIM）模式下分析药物化合物的高浓度溶液。由于许多目标化合物在反相液相色谱设置中保留很少或没有保留，因此采用了使用氯甲酸己酯的快速简单衍生化程序。PGI的酰胺衍生物导致更高的分子量（用于SIM的更特异性离子）和更好的色谱行为。该方法包括分别对未衍生化和衍生化样品进行两次运行，经过验证并应用于多种药物物质。该方法被发现具有足够的灵敏度和稳健性，适用于质量保证/质量控制环境。
