High-field asymmetric waveform ion mobility spectrometry: A new tool for mass spectrometry

General principles are reviewed for ion mobility spectrometry including new methods for ion separation through field dependent mobilities in strong electric fields with high frequency asymmetric waveform. Additionally, recent advances in the instrumentation for the characterization of ion mobilities in air at ambient pressure are described and critically reviewed. Advances in instrumentation, understanding of principles of measurements by IMS, and the development of hyphenated technologies have resulted in an increase in the number of applications in recent years.

Ion Mobility Spectrometry: Principles and Applications

High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) and Differential Mobility Spectrometry (DMS) harness differences in ion mobility in low and high electric fields to achieve a gas-phase separation of ions at atmospheric pressure. This separation is orthogonal to either chromatographic or mass spectrometric separation, thereby increasing the selectivity and specificity of analysis. The orthogonality of separation, which in some cases may obviate chromatographic separation, can be used to differentiate isomers, to reduce background, to resolve isobaric species, and to improve signal-to-noise ratios by selective ion transmission. This review will focus on the applications of these techniques to the separation of various classes of analytes, including chemical weapons, explosives, biologically active molecules, pharmaceuticals and pollutants. These papers cover the period up to January 2007.

Review of applications of high-field asymmetric waveform ion mobility spectrometry (FAIMS) and differential mobility spectrometry (DMS).

A non-radioactive atmospheric pressure device for ionization of analytes comprises an atmospheric pressure chamber having an inlet for carrier gas, a first electrode (31) at one end, and a counter-electrode (32) at the other end of the chamber for creating an electrical discharge in the carrier gas thus creating metastable neutral excited-state species. Optionally, a grid (14) is provided to generate electrons or ions by contact with the excited-state species. The carrier gas containing the excited-state species or the electrons generated therefrom is directed at an analyte at atmospheric pressure near ground potential to form analyte ions.

Atmospheric pressure ion source

The phenomenon of ion mobility (IM), the movement/transport of charged particles under the influence of an electric field, was first observed in the early 20th Century and harnessed later in ion mobility spectrometry (IMS). There have been rapid advances in instrumental design, experimental methods, and theory together with contributions from computational chemistry and gas-phase ion chemistry, which have diversified the range of potential applications of contemporary IMS techniques. Whilst IMS-mass spectrometry (IMS-MS) has recently been recognized for having significant research/applied industrial potential and encompasses multi-/cross-disciplinary areas of science, the applications and impact from decades of research are only now beginning to be utilized for “small molecule” species. This review focuses on the application of IMS-MS to “small molecule” species typically used in drug discovery (100-500 Da) including an assessment of the limitations and possibilities of the technique. Potential future developments in instrumental design, experimental methods, and applications are addressed. The typical application of IMS-MS in relation to small molecules has been to separate species in fairly uniform molecular classes such as mixture analysis, including metabolites. Separation of similar species has historically been challenging using IMS as the resolving power, R, has been low (3-100) and the differences in collision cross-sections that could be measured have been relatively small, so instrument and method development has often focused on increasing resolving power. However, IMS-MS has a range of other potential applications that are examined in this review where it displays unique advantages, including: determination of small molecule structure from drift time, “small molecule” separation in achiral and chiral mixtures, improvement in selectivity, identification of carbohydrate isomers, metabonomics, and for understanding the size and shape of small molecules. This review provides a broad but selective overview of current literature, concentrating on IMS-MS, not solely IMS, and small molecule applications (review).

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Ion mobility spectrometry-mass spectrometry (IMS-MS) of small molecules: Separating and assigning structures to ions.

A pulsed corona discharge ionisation source, a candidate replacement for 63Ni ionisation sources for ion mobility spectrometry, is described along with a new design of ion mobility spectrometer-mass spectrometer. Preliminary research on the characterisation of the reactant ion peaks associated with the use of this ionisation source was undertaken by assembling a pulsed corona discharge ionisation switchable high-resolution ion mobility spectrometer-mass spectrometer to enable the mobility spectra, atmospheric chemical ionisation mass spectra and selected-mass mobility spectra to be obtained. With ammonia doping at 2.39 mg m−3 in air and a water content of approximately 80 mg m−3 in the positive mode the observed response was attributable to the formation of [(H2O)nNH4]+ and [(H2O)n(NH3)NH4]+ in the reaction region. The observed responses in the negative mode were more complex with evidence for the formation [(H2O)nO2]−, [(H2O)nCO3]−, [(H2O)nHCO3]−, [(H2O)nCO4]− and [(H2O)nNO3]−. The responses due to these species were clearly discernible in the resultant mobility spectra, with enough oxygen-based species formed to support analytically useful responses.

A pulsed corona discharge switchable high resolution ion mobility spectrometer-mass spectrometer.

An adaptive sampler for collecting 2.5 dm3 samples of exhaled air from human subjects with an impaired respiratory function is described. Pressure in the upper respiratory tract is continuously monitored and the data used to control an automated system to collect select portions of the expired breathing cycle onto a mixed bed Tenax™ and Carbotrap™adsorbent trap for analysis by GC-MS. The sampling approach is intended for use in metabolomic profiling of volatiles in human breath at concentrations greater than µg m–3. The importance of experimental reproducibility in metabolomic data is emphasised and consequently a high purity air supply is used to maintain a stable exogenous volatile organic compound profile at concentrations in the range 5 to 30 µg m–3. The results of a 90 day stability study showed that exogenous VOCs were maintained at significantly lower levels (40 times lower for isopropyl alcohol) and with significantly higher reproducibility (80 times lower standard deviation for isopropyl alcohol) than would have been be the case if ambient air had been used. The sampling system was evaluated with healthy controls alongside subjects with chronic obstructive pulmonary disease. Subjects were able to breathe normally with control subjects observed to breathe at a rate of 9 to 17 breaths per minute, compared to 16 to 30 breaths per minute for subjects with COPD. This study presents, for the first time, observations and estimates of intra-subject breath sample reproducibility from human subjects. These reproducibility studies indicated that VOCs in exhaled breath exhibit a variety of dynamic behaviours, with some species recovered with a RSD <30%, while other species were observed to have significantly more variable concentrations, 30 to 130% RSD. The approach was also demonstrated to reliably differentiate the differences in the VOC profiles between alveolar and dead space air.

An adaptive breath sampler for use with human subjects with an impaired respiratory function

A chromatography-based method for producing mass flux-response surfaces for differential mobility spectrometers is described as a replacement for exponential dilution and mixing approaches. An exponential dilution or mixing experiment typically takes 150 min; while the exponential function in the Gaussian elution profile obtained from linear chromatography may be exploited in approximately 10 s. The approach was demonstrated with a gas chromatograph-mass spectrometer and the correlation of the calibration results to nominal on-column masses was within experimental error for 19 separate analyses. The method was then applied to a gas chromatographic (10.6 eV UV) differential mobility spectrometer. Mass fluxes in the range 10 pg s−1 to 250 ng s−1 were generated over the 5 s to 10 s associated with the elution of a chromatographic peak. The characterisations were repeated for a range of electrical field strengths from 10 kV cm−1 to 30 kV cm−1. Triplicate runs indicated that the approach was reproducible and that response surfaces could be generated rapidly from chromatographic data. The effects of trace impurities associated with the chromatographic eluent on the relationship between compensation voltage and electrical field strength was observed. This emphasised the importance of managing this aspect of the operation if reliable estimates of alpha functions for the compounds under study were to be obtained. Application of this approach to other detection systems with an 85% reduction in the analytical operations required to produce a reliable calibration function was also noted.

Fast quantitative characterisation of differential mobility responses.

The development of high-throughput environmental screening assays are needed to meet high-specification data quality objectives (DQOs) that require large numbers of samples to be taken and analysed rapidly. The acquisition and stabilisation of the sample is a key technical and operational challenge in analytical sequences associated with the determination of volatile organic compound (VOC) contamination of soils. Further the development of miniaturised and embedded analytical systems for environmental conditioning monitoring requires the development of new sampling techniques. A proof-of-concept study is described that shows how pressurised gas, in this case carbon dioxide, may be used to recover reversibly-bound VOCs from soil into an adsorbent sampler, and then analysed by thermal desorption-gas chromatography. The effects of the volume of the pressurised gas, the gas flow rate and the mass of the soil sample on the recovery efficiency and breakthrough from the adsorbent trap were investigated in a preliminary characterisation study. Two distinct approaches were identified. The first involved ventilation of the voids within the soil matrix to displace the soil–gas headspace, a rapid screening approach. The second involved a more prolonged purge of the matrix to strip reversibly bound species into the gas phase and hence pass them into the adsorbent trap, a purge and trap approach. The shortest possible sample processing time required to yield analytically useful responses was 5 s with the use of the headspace approach. In this case n-octane, benzene and toluene were recovered from conditioned spiked soil samples at concentrations in the range 42 to 1690 mg kg−1. The limit of detection for the system was estimated to be no greater than 1.2 mg kg−1. Using the purge and trap variant enabled recovery efficiencies greater than 93% to be achieved with liquid spikes of n-octane onto soil samples. These preliminary studies showed that a system based on this approach would need to balance recovery efficiency, time and analyte breakthrough from the adsorbent trap.

C. L. P. Thomas

Papers

A pulsed corona discharge switchable high resolution ion mobility spectrometer-mass spectrometer.

An adaptive breath sampler for use with human subjects with an impaired respiratory function

Fast quantitative characterisation of differential mobility responses.

Fast volatile organic compound recovery from soil standards for analysis by thermal desorption gas chromatography