AstraZeneca, Pharmaceutical Development, Silk Road Business Park, Charter Way, Macclesfield SK10 2NA, UK.
Rapid Commun Mass Spectrom. 2010 Jun 15;24(11):1673-81. doi: 10.1002/rcm.4557.
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(+.)) 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.
准确质量测量（用于确定元素配方）是药物开发过程理解中杂质鉴定的重要工具。准确质量液相色谱/质谱（LC/MS）广泛用于此类分析；然而，在许多情况下，气相色谱（GC）/MS 仍是合适的技术。因此，提供强大的技术来为这种类型的活动提供准确质量 GC/MS（和 GC/MS/MS）是必不可少的。在本报告中，我们描述了一种新的大气压化学电离（APCI）接口与飞行时间（TOF）MS 耦合的优化和应用。为了充分测试新接口的潜力，使用了许多标准化合物（如阿斯利康合成中使用的各种结构的化合物）优化了 APCI 源条件。随后使用 GC/APCI-TOF MS 对这些化合物进行了分析。这项研究旨在评估使用该技术可分析的化合物范围。发现该技术可检测和表征的化合物范围非常广泛，包括甲苯等非极性烃类。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(+.))，以及其他离子信号，如 M+H+O。该技术已成功应用于有机合成过程开发中反应混合物中杂质的鉴定。实现了 1-2mm/z 单位（m/z 80-500）的典型质量精度，允许根据其元素配方鉴定反应杂质。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过程理解工具的潜力。还使用 GC/电子电离（EI）-MS 和 GC/化学电离（CI）-MS 对反应混合物进行了分析，以了解 GC/APCI-MS 相对于这两种成熟技术的能力。
