Tony Bristow

The application of on‐line mass spectrometry for direct analysis of chemical and other types of process continues to grow in importance and impact. The ability of the technique to characterize many aspects of a chemical reaction such as product and impurity formation, along with reactant consumption in a single experiment is key to its adoption and development. Innovations in ionization techniques and mass spectrometry instrumentation are enabling this adoption. An increasing range of ambient ionization techniques make on‐line mass spectrometry applicable to a large range of chemistries. The academic development and commercialization of small footprint portable/transportable mass spectrometers is providing technology that can be positioned with any process under investigation. These developments, coupled with research into new ways of sampling representatively from both the condensed and gaseous phases, are positioning mass spectrometry as an essential technology for on‐line process optimization, understanding and intelligent control. It is recognized that quantitative capability of mass spectrometry in this application can cause some resistance to its adoption, but research activities to tackle this limitation are on‐going.

Real time online monitoring of chemical processes can be carried out by a number of analytical techniques, including optical and vibrational spectroscopies, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). As each technique has unique advantages and challenges, combinations are an attractive option. The combination of a 500‐MHz ¹H NMR and a small footprint mass spectrometer to monitor a batch reaction at process concentration was investigated. The mass spectrometer was coupled into the flow path of an online reaction monitoring NMR. Reaction mixture was pumped from a 100‐ml vessel to an NMR flow tube before returning to the vessel. Small aliquots were diverted into a sampling make‐up flow using an active flow splitter and passed to the mass spectrometer. Advantages of the combination were observed. ¹H NMR was ideal for quantitation of high level components, whereas MS showed a greater capability for detecting those at low level. In preliminary experiments MS produced a limited linear relationship with concentration (0.02% to 2% relative concentration, 0.01 mg/ml–1.25 mg/ml), because of signal saturation at the higher concentrations. NMR was unable to detect components below 0.1% relative to concentration maximum. Optimisation of sample transfer to the MS extended the linearity to 10% relative to the concentration maximum. Therefore, the combination of online NMR and MS allows both qualitative and quantitative analysis of reaction components over the full process range. The application of the combination was demonstrated by monitoring a batch chemical reaction and this is described. Copyright © 2016 John Wiley & Sons, Ltd.

For on-line monitoring of chemical reactions (batch or continuous flow), mass spectrometry (MS) can provide data to (1) determine the fate of starting materials and reagents, (2) confirm the presence of the desired product, (3) identify intermediates and impurities, (4) determine steady state conditions and point of completion, and (5) speed up process optimization. Recent developments in small footprint atmospheric pressure ionization portable mass spectrometers further enable this coupling, as the mass spectrometer can be easily positioned with the reaction system to be studied. A major issue for this combination is the transfer of a sample that is representative of the reaction and also compatible with the mass spectrometer. This is particularly challenging as high concentrations of reagents and products can be encountered in organic synthesis. The application of a portable mass spectrometer for on-line characterization of flow chemical synthesis has been evaluated by coupling a Microsaic 4000 MiD to the Future Chemistry Flow Start EVO chemistry system. Specifically, the Hofmann rearrangement has been studied using the on-line mass spectrometry approach. Sample transfer from the flow reactor is achieved using a mass rate attenuator (MRA) and a sampling make-up flow from a high pressure pump. This enables the appropriate sample dilution, transfer, and preparation for electrospray ionization. The capability of this approach to provide process understanding is described using an industrial pharmaceutical process that is currently under development. The effect of a number of key experimental parameters, such as the composition of the sampling make-up flow and the dilution factor on the mass spectrometry data, is also discussed. Figure

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 m m/z units ( 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.

Orthogonal‐acceleration quadrupole time‐of‐flight (oa‐QTOF) mass spectrometers, employed for accurate mass measurement, have been commercially available for well over a decade. A limitation of the early instruments of this type was the narrow ion abundance range over which accurate mass measurements could be made with a high degree of certainty. Recently, a new generation of oa‐QTOF mass spectrometers has been developed and these allow accurate mass measurements to be recorded over a much greater range of ion abundances. This development has resulted from new ion detection technology and improved electronic stability or by accurate control of the number of ions reaching the detector. In this report we describe the results from experiments performed to evaluate the mass measurement performance of the Bruker micrOTOF‐Q™, a member of the new‐generation oa‐QTOFs. The relationship between mass accuracy and ion abundance has been extensively evaluated and mass measurement accuracy remained stable (±1.5 m m/z units) over approximately 3–4 orders of magnitude of ion abundance. The second feature of the Bruker micrOTOF‐Q™ that was evaluated was the SigmaFit™ function of the software. This isotope pattern‐matching algorithm provides an exact numerical comparison of the theoretical and measured isotope patterns as an additional identification tool to accurate mass measurement. The smaller the value, the closer the match between theoretical and measured isotope patterns. This information is then employed to reduce the number of potential elemental formulae produced from the mass measurements. A relationship between the SigmaFit™ value and ion abundance has been established. The results from the study for both mass accuracy and SigmaFit™ were employed to define the performance criteria for the micrOTOF‐Q™. This provided increased confidence in the selection of elemental formulae resulting from accurate mass measurements. Copyright © 2008 John Wiley & Sons, Ltd.