Analytical Sciences, GlaxoSmithKline Pharmaceutical R&D, 709 Swedeland Road, King of Prussia, PA 19406, USA.
J Chromatogr A. 2010 Jan 15;1217(3):302-6. doi: 10.1016/j.chroma.2009.11.048. Epub 2009 Dec 1.
Many pharmaceutical genotoxic impurities are neutral molecules. Trace level analysis of these neutral analytes is hampered by their poor ionization efficiency in mass spectrometry (MS). Two analytical approaches including chemical derivatization and coordination ion spray-MS were developed to enhance neutral analyte detection sensitivity. The chemical derivatization approach converts analytes into highly ionizable or permanently charged derivatives, which become readily detectable by MS. The coordination ion spray-MS method, on the other hand, improves ionization by forming neutral-ion adducts with metal ions such as Na(+), K(+), or NH(4)(+) which are introduced into the electrospray ionization source. Both approaches have been proven to be able to enhance the detection sensitivity of neutral pharmaceuticals dramatically. This article demonstrates the successful applications of the two approaches in the analysis of four pharmaceutical genotoxic impurities identified in a single drug development program, of which two are non-volatile alkyl chlorides and the other two are epoxides.
许多药物遗传毒性杂质是中性分子。痕量水平分析这些中性分析物受到其在质谱（MS）中较差的电离效率的阻碍。开发了两种分析方法，包括化学衍生化和配位离子喷雾-MS，以提高中性分析物检测的灵敏度。化学衍生化方法将分析物转化为高电离或永久带电的衍生物，这些衍生物通过 MS 变得容易检测。另一方面，配位离子喷雾-MS 方法通过与引入电喷雾电离源的金属离子（例如 Na(+)、K(+)或 NH(4)(+)）形成中性离子加合物来改善电离。这两种方法都已被证明能够极大地提高中性药物的检测灵敏度。本文展示了这两种方法在单个药物开发计划中鉴定的四种药物遗传毒性杂质的分析中的成功应用，其中两种是非挥发性烷基氯，另外两种是环氧化物。
