The application of gas chromatography/atmospheric pressure chemical ionisation time-of-flight mass spectrometry to impurity identification in Pharmaceutical Development
Article first published online: 10 MAY 2010
Copyright © 2010 John Wiley & Sons, Ltd.
Rapid Communications in Mass Spectrometry
Volume 24, Issue 11, pages 1673–1681, 15 June 2010
How to Cite
Bristow, T., Harrison, M. and Sims, M. (2010), The application of gas chromatography/atmospheric pressure chemical ionisation time-of-flight mass spectrometry to impurity identification in Pharmaceutical Development. Rapid Commun. Mass Spectrom., 24: 1673–1681. doi: 10.1002/rcm.4557
- Issue published online: 10 MAY 2010
- Article first published online: 10 MAY 2010
- Manuscript Revised: 23 MAR 2010
- Manuscript Accepted: 23 MAR 2010
- Manuscript Received: 31 JAN 2010
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. Copyright © 2010 John Wiley & Sons, Ltd.