The application of gas chromatography/atmospheric pressure chemical ionisation time‐of‐flight mass spectrometry to impurity identification in Pharmaceutical Development

Abstract

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.

Gas chromatography coupled to atmospheric pressure ionization mass spectrometry (GC-API-MS): Review

“…Orbitrap-MS is not as fast as with TOF, but it is comparable to qMS and provides sufficient data points for each chromatographic peak. The accurate mass measurement is crucial for the identification of unknowns, as discussed above and emphasized in the identification of impurities in pharmaceutical development [91].…”

“…The combination of the accurate mass data produced by GC/APCI-TOF MS and the structural information from GC/EI-MS can provide a very powerful tool for impurity identification [91]. But two drawbacks in comparison with GC-EI-MS are worth to be discussed.…”

Comparison of Atmospheric Pressure Ionization Gas Chromatography-Triple Quadrupole Mass Spectrometry to Traditional High-Resolution Mass Spectrometry for the Identification and Quantification of Halogenated Dioxins and Furans

“…22 In addition, tandem mass spectrometry (MS/MS) has been applied to dioxin analysis using both triple quadrupole and quadrupole ion trap instruments and has proven to be valid a technique for the analysis. 23,24 In 2014, the European Union created EU 589 as a validated method for the analysis of dioxins in food, which included GC-MS/MS as a confirmatory method.…”

Application of gas chromatography–(triple quadrupole) mass spectrometry with atmospheric pressure chemical ionization for the determination of multiclass pesticides in fruits and vegetables

“…Application studies including pharmaceutical development [18], profiling of phenolic compounds in oil [19], metabolic profiling [20] and pesticide residue analysis [21], most of them using GC-(APCI) TOF MS, can be found since 2009. Recently, we investigated the potential of APCI in GC-triple quadrupole MS for wide-scope pesticide residue analysis [22] and [23].…”