Fast, Sustainable Methods for Volatiles Analysis: Automated SIFT-MS

Selected ion flow tube mass spectrometry (SIFT-MS) is a direct-analysis technique that uses soft chemical ionization to quantify volatile compounds in the gas phase in real time. In its automated form—using “xyz” robotic autosamplers—SIFT-MS provides high sample throughputs for diverse functionalities on a single instrument configuration, which maximizes flexibility while reducing calibration frequency. The unique ionization approach used in SIFT-MS underpins these characteristics, significantly reducing sample preparation through sensitive and stable analyte ionization. In this article, a high-level assessment of the sustainability of the SIFT-MS technique and its automated variant is conducted using White Analytical Chemistry (WAC) principles. Reevaluation of selected headspace methods suggests that greenness is enhanced for some procedures compared to chromatographic techniques. Alongside sustainability benefits, automated headspace-SIFT-MS workflows save time and money, improves data quality through greater automation, and can also be better for the planet.

Achieving sustainable development is a focus of modern society. Since the 1990s, it has been recognized that chemists play an important role in this (so-called green chemistry), with a focus on transforming traditional practices into more sustainable ones. In the early 2000s, Green Analytical Chemistry (GAC) was identified as a necessary component of green chemistry (1). GAC can be regarded as a necessary development of more conventional analytical chemistry rather than a new discipline (2).

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GAC has 12 oft-repeated principles (1) that—while unnecessary to repeat in full here—broadly comprise (i) minimization of sample size, preparation, derivatization, and waste, (ii) adoption of procedures that are automated, integrated, more portable (ideally in situ/online), and use less energy, and (iii) reduce direct impact on operators and the environment. While seeking to address these goals is important, Nowak, Wietecha-Posłuszny, and Pawliszyn (3) have noted that they do not give a balanced perspective of an analytical procedure. These authors, therefore, proposed White Analytical Chemistry (WAC) in 2021, which also evaluates important analytical and practical performance criteria of the method (designated “red” and “blue,” respectively). The degree of “whiteness” achieved in this approach is determined by blending scores for these criteria according to the RGB color model, giving a very balanced view of the sustainability and functionality of the analytical method.

Both GAC and WAC approaches have been applied broadly to methods that utilize various forms of chromatographic analysis (4), while very little attention has been paid to the chromatography-free direct mass spectrometry (DMS) methods, such as proton transfer reaction mass spectrometry (PTR-MS) and selected ion flow tube mass spectrometry (SIFT-MS). These techniques have been developed over the past 30 years primarily for analysis of volatile organic compounds (VOCs) in the gas phase (5). Biasioli and coworkers (6) very favorably assessed PTR-MS as a green approach for food applications, and commented that, as a related technique, SIFT-MS would perform similarly. However, neither GAC nor WAC principles have been evaluated explicitly for SIFT-MS.

This article represents the first step toward filling this significant gap by using a qualitative approach to assessing the principles of WAC. By reviewing the existing literature, the SIFT-MS technique is shown to have inherent characteristics that fulfil most principles of both sustainable and practicable chemical analysis. As SIFT-MS only analyzes gas-phase samples, comparisons are made primarily with gas chromatography (GC)-based techniques. Practical, sustainable workflows for routine laboratory analysis are illustrated using several brief case studies. Finally, emerging strategies that further reduce the environmental impact of laboratory analysis using SIFT-MS are discussed. The resulting picture is one with significant promise but in need of more research.

Principles and Sustainability of the SIFT-MS Technique

The SIFT-MS technique has been described in detail elsewhere (7) and its diverse applications in gas analysis have been reviewed recently (8). Briefly, SIFT-MS uses soft chemical ionization (CI) in the form of highly controlled ion-molecule reactions (IMRs) to quantify a very wide range of VOCs—and certain inorganic gases—directly in the gas phase with high sensitivity. Up to eight standard ions (so-called “reagent ions” [9]) are available on commercial instruments, providing both broad-spectrum and high-specificity real-time analysis (10) because they have multiple ionization mechanisms and are very rapidly switched (9).

Figure 1: Schematic diagram of the layout of modern SIFT-MS instruments. Adapted and reproduced from reference 9 under the terms and conditions of the Creative Commons Attribution (CC-BY 4.0) license (https://creativecommons.org/licenses/by/4.0/).

Figure 1 shows a schematic diagram of a modern commercial instrument, and will help to aid the discussion as we follow the analytical process from top left to bottom right. See reference 9 for full details of instrument operation.

Ion Source

Reagent ions (H₃O⁺, NO⁺, and O₂^+• as standard; OH⁻, O^−•, O₂^−•, NO₂⁻, and NO₃⁻ are optional) are generated from humidified or dry air (9) using a microwave discharge. Hence the ion source uses sustainable, readily available, low-cost consumables, rather than compressed gas supplies. This also reduces the logistics carbon footprint and improves safety. Furthermore, the ion source is free of radioactive isotopes.

The absence of carbon-containing reagent ions in SIFT-MS means that maintenance procedures are infrequent for the ion source (replacement of quartz discharge tube; six monthly). The adjacent ion lenses and quadrupole mass filter (QMF), which are used to select the reagent ions, require very infrequent cleaning, with typical usage giving years of maintenance-free operation. In addition, the carbon-free reagent ions reduce VOC usage both in ion generation and cleaning operations. Vacuum in this region is achieved and maintained by a small turbomolecular pump, backed by a scroll pump that is also used to back the larger split-flow turbomolecular pump (SF-TMP;see below). These pumps all have a six- or 12-month service cycle, as specified by the manufacturer.

Carrier Gases

Conventional SIFT-MS analysis has used helium carrier gas, though nitrogen is increasingly used (7,9)—especially for 24/7 monitoring (11). Several points of difference exist for SIFT-MS compared to GC usage of carrier gas; in SIFT-MS it is not used for temporal separation of analytes. Carrier gas is:

1. Used to (i) cool reagent ions prior to introduction of sample, and (ii) carry reagent and product ions along the flow tube with minimal acceleration by electric field. It ensures that CI is conducted under very soft conditions.

2. Only consumed when the instrument is analyzing samples. For helium carrier gas, SIFT-MS usage is similar to GC on a per-sample basis.

3. More readily switched than in GC methods. In SIFT-MS method development, the primary concern is to ensure that the enhanced interaction of ions with water in nitrogen carrier gas is understood and can be accommodated with the analytes and matrix.

Sample Introduction and Analysis (Flow Tube)

As mentioned above, SIFT-MS is a gas-phase analytical technique, so method compatibility relies upon the ability of analytes to partition to the gas phase from the condensed phase, if appropriate. Furthermore, because there is no chromatographic separation, the total load of reactive compounds needs to be considered (12). Where these basic suitability requirements are met, SIFT-MS may provide significantly greener analysis because:

1. Analysis can be conducted continuously—even online—if the application benefits from it (7,11).

2. A very diverse range of functional groups are detected simultaneously with high sensitivity via the IMRs applied in SIFT-MS (10).

3. SIFT-MS handles humidity very well and drying of samples is eliminated. For headspace analysis specifically, aqueous solution is preferred (13), in contrast to most GC and MS analyses.

4. There is no need to solvent extract or otherwise preconcentrate samples (14).

Finally, unless there is a gross contamination event, maintenance of the flow tube is unnecessary; the IMR-based sample ionization is very soft, so does not result in deposition of carbonaceous(or other) materials.

Gas Standard

A certified gas standard (several VOCs at low part-per-million concentration by volume [ppmV] in a balance of nitrogen or air) is utilized to align mass-to-charge ratios (m/z) and account for the different transmission of ions through the flow tube and quadrupole mass spectrometer (QMS) (9). Typically, this is a 48-L compressed gas standard that lasts at least one year, so the environmental impact is minimal for the benefit it provides—including supporting the stability that reduces calibration demand.

Quadrupole Mass Spectrometer and Detector

Only a small proportion of the total gas flow is passed to the detection region with product ions and unreacted reagent ions, resulting in very low maintenance requirements. Compared to the MS in a GC–MS system, cleaning procedures are essentially eliminated. The high vacuum in this region is achieved using the SF-TMP.

Vacuum Pumps and Exhaust

The bulk of the gas passing through the flow tube is exhausted using the low-vacuum stage on the SF-TMP. The exhaust flow is only significant on instrument start-up and when samples are running because carrier gas flows only when samples are being analyzed. The concentrations of toxic analytes are typically low in the exhaust, but manufacturers recommend connecting the instrument exhaust to a reticulated exhaust system or into a fumehood.

Energy Consumption and General Consumables

SIFT-MS instruments operate from a standard mains power supply (1.4 kVA requirement at start-up, lasting 2 s, then 0.9 kVA running, including standby). It is generally recommended that instruments be left in “standby” mode for best performance, unless the instrument is not going to analyze samples for at least three days. Operation in an air-conditioned environment is also advised.

Other consumables include air and water for the ion source, and the certified gas standard. Additionally, specific analytical methods may require calibration standards (gas bottles, permeation tubes, or solutions). Overall, however, consumable demand is low for SIFT-MS compared to the chromatographic techniques.

Environmental and Operator Safety

In general, SIFT-MS reduces exposure of operators to hazardous substances, especially through reduction of sample preparation activities and hazardous waste. Coupled with automation technology, exposure risk is further reduced.

Flexibility and Usability

SIFT-MS is a flexible analytical technique for gas analysis, supporting multiple sample delivery options (12) and offering fixed and mobile laboratory installation options (11).

Commercial SIFT-MS instruments have been designed to make them usable by non-technical operators (assuming that appropriate method development has been conducted), so operation of routine methods by qualified technicians is readily accommodated (10).

In summary, the SIFT-MS technique supports sustainability initiatives through reduced usage of hazardous chemicals while meeting practical and analytical requirements for gas-phase analysis of VOCs.

Automated SIFT-MS in Routine Analysis

The practical benefits of integrating “xyz” robotic autosamplers with SIFT-MS instruments have been recently reviewed in detail (12). For the most common headspace analysis applications, these include:

• Straightforward automation using existing commercial “xyz” robotic autosamplers designed for coupling with chromatography instruments. The only custom product development required was a suitable sample inlet for SIFT-MS instrumentation.
• Higher sample throughputs because of faster runtimes. With SIFT-MS, incubation is the rate-limiting step in sample analysis, rather than runtime. Smart sequence scheduling by the autosampler software enables very efficient runs to be achieved for automated SIFT-MS across various headspace approaches.
• Multi-analyte methods are readily accommodated and can include very diverse chemical functionalities because of the gas-phase, soft CI utilized in SIFT-MS.
• Direct gas-phase analysis, which eliminates derivatization, preconcentration, and solvent extraction. This simplifies sample preparation, reduces the use of, and exposure to, harmful reagents and solvents, and creates more efficient workflows.
• Preference for aqueous solvent—when solvent is necessary—in contrast with GC where organic solvent is preferred. This reduces the use of, and potential exposure to, hazardous solvents. Note that when organic solvents are utilized with SIFT-MS (assuming compatibility [13]), then similar quantities to those used in the equivalent headspace-GC methods are typically required.
• Reduced calibration frequency as a result of the stability of the automated SIFT-MS platform (arising from the technology itself and the very reproducible IMRs it utilizes), and the ability to analyze diverse compounds across multiple methods using the same configuration. This reduces (i) standard preparation time for the analyst, (ii) exposure to hazardous compounds, and (iii) the time to process samples and report results. For multiple headspace extraction (MHE) and the method of standard additions (MoSA), which are expensive for GC as a result of repeat analyses, significant efficiencies are gained using SIFT-MS, making them more practical for routine analysis. Note that if conventional calibration approaches are retained for any headspace approach, these run faster for SIFT-MS as samples analyses do.

Additional considerations for sustainability of automated SIFT-MS methods that were not addressed in reference 12 are:

• Consumable usage (vials, caps, carrier gas) is very similar on a per-sample basis for SIFT-MS and the equivalent GC-based procedure. Note, however, that SIFT-MS may reduce the amount of waste generated in calibration for the reasons noted above, and with new developments (described in the last section).
• The ability to easily relocate automated SIFT-MS instruments.
• The flexibility of analysis; the same SIFT-MS instrument can be utilized for continuous in situ analysis of processes, if required.
• Elimination of solvent usage in some headspace methods, especially MHE.

Table I

Table I summarizes the key criteria of WAC from reference 3 and provides a qualitative assessment of automated headspace-SIFT-MS performance against these criteria, together with supporting references (12–21).

Workflows for Automated SIFT-MS: Reassessing for Greenness

Table II

A recent detailed comparison of analytical workflows for SIFT-MS and GC (or liquid chromatography [LC]) (12) focused on the practical aspects (specifically B1 and B2 of Table I). In nearly all cases, SIFT-MS improved (i) throughput and (ii) time to first quantitative result, as shown in figure 7 of that work. Suitability from an analytical perspective (R1–R4) is method-dependent and determined prior to optimizing workflows. Therefore, in this section the green criteria (G1–G4) are briefly assessed for the six methods discussed in reference 12 relative to the incumbent method. The headspace methods in Table II use three approaches:

1. Static Headspace Analysis (SHA): SHA-1 is residual solvents analysis (19), SHA-2 is acetaldehyde and ethylene oxide analysis in relevant excipients (21), SHA-3 is VOC analysis in plasma (15).

2. Multiple Headspace Extraction: MHE-1 is N-nitrosodimethylamine (NDMA) in drug products (16), and MHE-2 is formaldehyde in Gelucire 44/14 excipient (22). Note that the comparison here is between MHE-SIFT-MS and LC dissolution methods, not MHE-GC, because the former approach is more common.

3. The Method of Standard Additions: MoSA-1 is toxic VOCs in personal care products (PCPs) (20).

Table II illustrates the importance of practical considerations (the blue parameters in Table I), in addition to the green parameters, because for some methods the benefit of adopting SIFT-MS is primarily improved workflows (12).

Emerging Strategies to Further Reduce Environmental Impact

As demonstrated in Table II, simply transferring a compatible method from GC or LC to SIFT-MS may not confer significant advantages when measured against greenness criteria. Several emerging strategies that offer potential benefits in reducing environmental impact are discussed here. In some cases, they also support more efficient workflows (B1 and B2 in Table I).

First, the high sensitivity of SIFT-MS analysis may enable reduction of the sample quantity used in the analysis (G2 in Table I). For example, in the method labelled SHA-2 in Table II, 10-fold less sample was readily accommodated for analysis of acetaldehyde and ethylene oxide while still easily meeting the regulatory limit for these impurities in Polysorbate 80 (P80). Moreover, dilution of the P80 matrix in water (a sustainable solvent) eliminated the existing method’s prolonged rotovap preparation of an impurity-free matrix blank, significantly reducing the energy consumption of the method. In this SIFT-MS method, significant workflow, analytical, and green benefits all converged.

Second, the use of aqueous solution for dissolution approaches—rather than organic solvent—with SIFT-MS reduces environmental impact, even if a small amount of organic solvent is still present (for example, to extract analyte from a water-insoluble matrix [13]). Solutions can be modified using salts or a small amount of biodegradable surfactant to help increase partitioning or solubilization, respectively.

Third, for suitable combinations of matrices and analytes, nitrogen carrier gas may be a viable alternative to helium. Use of a nitrogen generator rather than compressed nitrogen in cylinders would further enhance sustainability through a reduction in transportation carbon footprint.

Finally, utilization of the gas- and liquid-handling capabilities of the “xyz” robotic autosampler can further reduce the environmental impact of reduced-frequency SIFT-MS calibration procedures by leveraging high-precision flow control during syringe injection. Time efficiencies and data quality improvements are also obtained through reductions in user operations.

Figure 2: A sequence schedule (from Maestro software; Gerstel) for gas-phase calibration involving one-step dilution following 30-min incubation of pure analyte (23).

Very recent work has demonstrated that nine-point gas-phase VOC calibration can be conducted effectively from five or six headspace vials (23) depending on the volatility of the analyte and the concentration range over which calibration needs to be conducted (one-step or two-step preparation of stock vials, respectively). A sequence schedule for calibration following one-step dilution is shown in Figure 2. This approach reduces both chemical and physical waste.

Figure 3: Linearity of automated headspace-SIFT-MS calibration of toluene from (a) two and (b) one sample vials, by utilizing a variety of injection speeds to generate effective concentrations at the SIFT-MS instrument (24).

Still more dramatic reductions in waste can be achieved in calibration of headspace methods (24). By using variable, high-precision headspace injection, a 12-point calibration curve is readily generated from 4 ppb to 1000 ppb (equivalent) from two vials of standard in only 37 min analysis time (including incubation). If a narrower range suffices, then an eight-point calibration can be achieved using a single vial (for example, from 40 ppb to 2000 ppb [equivalent] in 30 min). Time efficiencies are also gained, with reductions from 75 min and 55 min for the multi-vial equivalents of the double and single vial approaches, respectively. The resulting calibration curves show excellent linearity (Figure 3). Clearly, this approach has significant benefits for both workflows and sustainability.

Conclusion

WAC takes a holistic approach to the evaluation of analytical methods, consolidating the greenness attributes of GAC and combining them with functional requirements: a method should also perform adequately (redness) and be practical (blueness). Previous studies have shown

that using SIFT-MS for automated headspace analysis of VOCs offers practical workflow advantages over GC as a result of its comprehensive analytical capabilities and rapid processing speed. Here, a high-level evaluation of SIFT-MS against the greenness criteria has been added, suggesting that for some methods there may be significant opportunities to reduce environmental impact—particularly those methods with significant sample prep requirements for GC or LC. Future research should quantitatively evaluate SIFT-MS methods against WAC criteria and ideally transition more methods from traditional helium carrier gas usage to nitrogen.

References

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(11) Langford, V. S.; Cha, M. Y.; Milligan, D. B.; Lee, J. H. Adoption of SIFT-MS for VOC Pollution Monitoring in South Korea. Environments 2023, 10, 201. DOI: 10.3390/Environments10120201

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(15) Hastie, C.; Thompson, A.; Perkins, M. J.; et al. [SIFT-MS] as an Alternative to Gas Chromatography/Mass Spectrometry (GC/MS) for the Analysis of Cyclohexanone and Cyclohexanol in Plasma. ACS Omega 2021, 6, 32818–32822. DOI: 10.1021/acsomega.1c03827

(16) Perkins, M. J.; Hastie, C. J.; Langford, V. S. Quantitative Analysis of NDMA in Drug Products: A Proposed High-Throughput Approach Using Headspace–SIFT-MS. AppliedChem 2024, 4, 107–121. DOI: 10.3390/appliedchem4010008

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(20) Perkins, M. J.; Hastie, C.J.; Langford, V. S. Headspace-[SIFT-MS] Workflows for Rapid Screening and Quantitation of Hazardous Volatile Impurities in Personal Care Products. Analytica 2024, 5, 153–169. DOI: 10.3390/analytica5020010

(21) Mathew, J.; Silva, L. P.; Bastian, K. C.; et al. Rapid Quantitative Analysis of Ethylene Oxide and 1,4-Dioxane in Polymeric Excipients Using SIFT-MS. The Column 2024, 20 (8), 17–22.

(22) Perkins, M. J.; Langford, V. S. Improved MHE-SIFT-MS Workflow: Even Faster Quantitation of Formaldehyde in Gelucire Excipient. Syft Technologies Application Note, 2023. Available online: http://bit.ly/431xTp2

(23) Perkins, M. J.; Langford, V. S. Optimized Calibration of Automated SIFT-MS Instrumentation: 1. Gas-Phase Analysis. Syft Technologies Technical Note, 2025.

(24) Perkins, M. J.; Langford, V. S. Leveraging Variable Sample Injection Speeds for Simplified Sensitivity Changes and Calibration. Syft Technologies Technical Note, 2025. Available online: https://bit.ly/4aJwurd

Vaughan Langford is a principal scientist at Syft Technologies in New Zealand. He joined Syft in late 2002 and has 43 peer-reviewed publications (including 10 book chapters and reviews) on a wide range of SIFT-MS applications. He has also contributed articles for industry publications and numerous conference papers.

Mark Perkins is a senior applications chemist and SIFT-MS automation expert at Element Lab Solutions (formerly Anatune Limited), based in Cambridge, United Kingdom. Mark graduated from the University of Southampton, UK, with a PhD in electrochemistry. Prior to joining Anatune/Element in early 2015, he was with the Malaysian Rubber Board’s UK research center for 12 years, first as a senior analyst and later as head of the analytical section.