The application of gas chromatography/atmospheric pressure chemical ionisation time-of-flight mass spectrometry to impurity identification in Pharmaceutical Development
The application of gas chromatography/atmospheric pressure chemical ionisation time-of-flight mass spectrometry to impurity identification in Pharmaceutical Development
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DOI：
10.1002/rcm.4557
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发表时间：
2010-06-01
影响因子：
2
通讯作者：
Sims, Martin
中科院分区：
文献类型：
--
作者：
Bristow, Tony;Harrison, Mark;Sims, Martin
精确的质量测量（用于确定元素公式）是药物开发中杂质鉴定的重要工具，用于工艺理解。准确的质量液相色谱/质谱法（LC/MS）广泛用于这些类型的分析;然而，在许多情况下，气相色谱（GC）/MS仍然是合适的技术。因此，必须提供可靠的技术，为这类活动提供准确的质量GC/MS（和GC/MS/MS）。在这份报告中，我们描述了一个新的可用的大气压化学电离（APCI）接口耦合GC飞行时间（TOF）MS的优化和应用。为了充分测试新接口的潜力的APCI源条件进行了优化，使用了一些标准化合物，具有各种结构，在阿斯利康合成中使用。随后通过GC/APCI-TOF MS分析这些化合物。进行本研究以评估适合使用该技术分析的化合物的范围。发现使用该技术可以检测和表征的化合物的范围非常广泛，包括非极性烃，如甲苯。在APCI产生的质谱中观察到质子化分子（[M + H]（+））和自由基阳离子（M+中心点），沿着出现额外的离子信号如[M + H + O]（+）。实现了1-2 mm/z单位（m/z 80-500）的典型质量准确度，允许基于其元素式鉴别反应杂质。这些结果清楚地表明了该技术作为药物开发中解决问题和理解过程的工具的潜力。还通过GC/电子电离（EI）-MS和GC/化学电离（CI）-MS分析了反应混合物，以了解GC/APCI-MS相对于这两种成熟技术的能力。版权所有（C）2010约翰威利父子有限公司
Accurate mass measurement (used to determine elemental formulae) is an essential tool for impurity identification in pharmaceutical development for process understanding. Accurate mass liquid chromatography/mass spectrometry (LC/MS) is used widely for these types of analyses; however, there are still many occasions when gas chromatography (GC)/MS is the appropriate technique. Therefore, the provision of robust technology to provide accurate mass GC/MS (and GC/MS/MS) for this type of activity is essential. In this report we describe the optimisation and application of a newly available atmospheric pressure chemical ionisation (APCI) interface to couple GC to time-of-flight (TOF) MS.To fully test the potential of the new interface the APCI source conditions were optimised, using a number of standard compounds, with a variety of structures, as used in synthesis at AstraZeneca. These compounds were subsequently analysed by GC/APCI-TOF MS. This study was carried out to evaluate the range of compounds that are amenable to analysis using this technique. The range of compounds that can be detected and characterised using the technique was found to be extremely broad and include apolar hydrocarbons such as toluene. Both protonated molecules ([M + H](+)) and radical cations (M+center dot) were observed in the mass spectra produced by APCI, along with additional ion signals such as [M + H + O](+).The technique has been successfully applied to the identification of impurities in reaction mixtures from organic synthesis in process development. A typical mass accuracy of 1-2 mm/zunits (m/z 80-500) was achieved allowing the reaction impurities to be identified based on their elemental formulae. These results clearly demonstrate the potential of the technique as a tool for problem solving and process understanding in pharmaceutical development. The reaction mixtures were also analysed by GC/electron ionisation (EI)-MS and GC/chemical ionisation (CI)-MS to understand the capability of GC/APCI-MS relative to these two firmly established techniques. Copyright (C) 2010 John Wiley & Sons, Ltd.