Orthogonal extraction ion mobility spectrometry

Ion Mobility Spectrometry is a powerful tool for the study of molecular conformations, separation of mass isomers, and analysis of complex mixtures and suppression of chemical background. The factors that limit the capabilities of the technique include its relatively low resolving power and duty cycle. New principle of gas-phase ion separation, based on ion focusing under the influence of electrostatic field and stationary in time gas flow, is proposed. Both analytical calculations and a numerical simulation show that a diffusion-limited resolution of several hundred can be achieved. The new type of ion mobility analyzer is called orthogonal extraction IMS. The proposed ortho-IMS can be interfaced with commercial mass spectrometers and offers the theoretical resolution of several hundred and ion transmission close to 100%.     

Liquid phase ion mobility spectrometry

A novel analytical method, called Liquid Phase Ion Mobility Spectrometry (LiPIMS) was demonstrated, where aqueous phase analytes were ionized and introduced into non-aqueous liquids, transported by an external electric field from the point of generation to a collection electrode. Ions were produced from a unique liquid phase ionization process, called Electrodispersion Ionization. Spectra of analyte ions illustrated the potential of LiPIMS as a new separation technique. Experimental data showed that electrodispersion ionization was effective in generating nanoampere level of ion current in hexane and benzene from aqueous samples. By controlling the ionization voltage in relation to the sample flow rate, it was possible to operate the electrodispersion ionization source in both continuous and pulsed ionization modes. Unique LiPIMS spectra of aqueous samples of tetramethylammonium bromide, tetrabutylammonium bromide and bradykinin were presented and their respected liquid phase ion mobility values were determined.     

A study of focusing effect in the variable DC electric fields Ion mobility spectrometry

Drift tube Ion Mobility Spectrometry (IMS) is an atmospheric analysis technology which was developed in the 1970s. It has been widely used in the detection of drugs, explosives and environmental monitoring. IMS has characteristics of high sensitivity, portability and quick detection. In addition, it has a focusing effect for the ions passed by. In the work reported in this paper, a variable DC electric fields Ion Mobility Spectrometry was constructed, and the characteristic of focusing was studied by simulation and experiments. The results showed that the focusing effect had a strong correlation with the field distribution. With the increasing of the additional voltage δv, the focusing effect enhanced. The peak intensity of the IMS increases, and the drift time increases firstly and then decreases. The good agreements between simulation and experiment show that the simulation has predictive power for ion motion in IMS. This study can serve as visual aids for intuitively understanding the factors that determine ion transport.     

Compensation voltage shifting in high-field asymmetric waveform ion mobility spectrometry-mass spectrometry

The separation and ion focusing properties of High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) depend on desolvated ions entering the device, leading to a compound-specific, reproducible compensation voltage (CV) for each ion. This study shows that the conditions identified for stable spray and satisfactory ion desolvation in normal electrospray ionization mass spectrometry (ESI-MS) operation might significantly differ from those required for FAIMS-MS. In a typical setup with high-flow electrospray conditions, ions could be incompletely desolvated, resulting in the formation of unidentified clusters with differing behavior in a FAIMS environment. This causes compound-specific shifts of as much as 10 V in CV values when the mobile phase composition and/or flow rate are varied. The shifts diminish and finally disappear when the flow rate of methanol, used as mobile phase, is reduced to 40 microL/min and that of acetonitrile to 20 microL/min. The reproducibility of the observed CV was determined by scanning the CV while infusing a five-component mixture into a 400 microL/min flow of methanol or 50:50 acetonitrile/water. The relative standard deviation (RSD) for these multiple scans ranged from 0.7% to 6%. Therefore, under a constant set of experimental parameters, the CV does not shift appreciably. These observations have an impact on method development strategies. High flow rates can be used with the FAIMS device, since the CV values are reproducible, but it is likely that clusters are forming. Therefore, CV scans should be performed under conditions which mimic the chromatographic elution or flow injection analysis conditions, including matrix composition, to minimize errors in CV determination. An alternative approach is to determine the liquid flow rate at which the CV becomes compound-specific and to split the mobile phase stream accordingly. These experimental results may be specific to the setup used for this study and may not be directly applicable to other instrument FAIMS devices.     

Ion mobility spectrometry: a personal retrospective

With a background in mass spectrometric studies of gas-phase ion chemistry the atmospheric pressure technology of ion mobility spectrometry (IMS) presented me with challenges and opportunities. Fundamental studies of the parameters that influence the mobility of ions in a low electric field yielded insights about the effects of temperature, drift gas composition and the conformation of ions on the collision cross section. The inadequacy of current rigid-sphere, polarization limit and hard-core models to predict the mobility of ions particularly at low temperature and in heavy drift gases, led to inclusion of additional terms to the hard-core model to account for these effects. These studies eventually resulted in the two monographs entitled “Ion Mobility Spectrometry” and “Ion Mobility Spectrometry –Second Edition” co-authored with Prof. Gary Eiceman and published by Taylor & Francis, CRC Press in 1994 and 2005, respectively. Novel applications for biological and medical applications were developed on the basis of measurement of biogenic amines by IMS, in particular the rapid, accurate and inexpensive diagnosis of vaginal infections.     

Characterization of a miniature, ultra-high-field, ion mobility spectrometer

By combining a multiple micron-gap ion separator with a novel high-frequency separation waveform drive topology, it has been possible to considerably extend the separation field limits employed in Field Asymmetric Ion Mobility Spectrometry (FAIMS)/Differential Mobility Spectrometry (DMS); giving rise to an Ultra-High-Field operational domain. A miniature spectrometer, based around the multi-micron-gap ion separator and ultra-high-field drivers, has been developed to meet the continuing industrial need for sensitive (sub-ppm), broadband and fast (second timescale) response volatile chemical detection. The packaged miniature spectrometer measures 12?×?12?×?15?cm, weighs 1.2?kg and is fully standalone; consisting of the core multi-micron gap ion separator assembly and RF/DC electronic drivers integrated with pneumatic handling/sample conditioning elements, together with ancillary temperature, flow and humidity sensing for stable closed loop operation (under local microprocessor control). The combination of multiple micron-gap ion separators with the novel high-frequency separation waveform drive topology enables ion separations to be performed over scanning electric field ranges of 0 to >75?kV·cm^?1 (0 to >??320 Td at 101?kPa), offering a potential solution to trace and ultra-trace chemical detection/monitoring problems, that conventional IMS and DMS/FAIMS may otherwise find challenging. In this ultra-high field operational regime effective ion temperatures may be ??swept?? from ambient to >1000 K because critically, the effective ion temperature scales to at least the square of the applied field. With this field induced ion heating a controlled manipulation (or switching) of the ion chemistry within the separation channel (the ion drift region) may be invoked. For example, ion fragmentation via thermal dissociation can be induced. Chemical separation and identification is thus derived from the unique kinetic and thermodynamic behavior of ions assessed over a very broad effective temperature range. In addition to describing the novel miniature spectrometer, this paper addresses key aspects of ultra-high-field operation, which render it distinct from traditional ion mobility technologies and principles. In particular, this paper essays a model of ultra-high-field operation and highlights model deviations, whilst providing clear theoretical explanation backed up with experimental evidence.     

Using probabilistic relational learning to support bronchial carcinoma diagnosis based on ion mobility spectrometry

Ion Mobility Spectrometry (IMS) provides a means for analyzing the substances a person exhales. In this paper, we report on an approach to support early diagnosis of bronchial carcinoma based on such IMS measurements. Given the peaks in a set of ion mobility spectra, we first cluster these peaks with a modified k-means algorithm. We then apply probabilistic relational modelling and learning methods to a logical representation of the data obtained from the ion mobility spectra and the peak clusters. Markov Logic Networks and the MLN system Alchemy are employed for various modelling and learning scenarios. These scenarios are evaluated with respect to ease of use, classification accuracy, and knowledge representation aspects.     

Ion mobility spectrometry detection for gas chromatography

The hyphenated analytical method in which ion mobility spectrometry (IMS) is coupled to gas chromatography (GC) provides a versatile alternative for the sensitive and selective detection of compounds after chromatographic separation. Providing compound selectivity by measuring unique gas phase mobilities of characteristic analyte ions, the separation and detection process of gas chromatography-ion mobility spectrometry (GC-IMS) can be divided into five individual steps: sample introduction, compound separation, ion generation, ion separation and ion detection. The significant advantage of a GC-IMS detection is that the resulting interface can be tuned to monitor drift times/ion mobilities (as a mass spectrometer (MS) can be tuned to monitor ion masses) of interest, thereby tailoring response characteristics to fit the need of a given separation problem. Because IMS separates ions based on mobilities rather than mass, selective detection among compounds of the same mass but different structures are possible. The most successful application of GC-IMS to date has been in the international space station. With the introduction of two-dimensional gas chromatography (2D-GC), and a second type of mobility detector, namely differential mobility spectrometry (DMS), GC prior to mobility measurements can now produce four-dimensional analytical information. Complex mixtures in difficult matrices can now be analyzed. This review article is intended to provide an overview of the GC-IMS/DMS technique, recent developments, significant applications, and future directions of the technique.     

Removal of metabolite interference during liquid chromatography/tandem mass spectrometry using high‐field asymmetric waveform ion mobility spectrometry

The effect of metabolite interference during liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis of an amine drug was investigated using FAIMS (high‐Field Asymmetric waveform Ion Mobility Spectrometry). The selected reaction monitoring (SRM) transition used for the drug exhibited an interference due to in‐source conversion of the N‐oxide metabolite to generate an ion isobaric with the drug. The on‐line FAIMS device removed the metabolite interference before entrance to the mass spectrometer. FAIMS was used to demonstrate the relative accuracy and precision of drug analysis even in the presence of a co‐eluting metabolite that may undergo in‐source conversion. Copyright © 2005 John Wiley & Sons, Ltd.     

Electrospray ionization-voltage sweep-Ion mobility spectrometry for biomolecules and complex samples

Voltage Sweep Ion Mobility Spectrometry (VSIMS) has been applied to complex samples using electrospray ionization (ESI). The usable range of VSIMS has been extended from that obtained in previous studies where only volatile compounds were investigated. Using ESI, VSIMS was evaluated with compounds with reduced mobility values as low as 0.3 V²cm^?1 s^?1. The primary advantage of VSIMS is to enable a drift time ion mobility spectrometer (DTIMS) to detect both fast and slow moving ions at optimal resolving power, thus improving the peak capacity. In this work ESI-VSIMS was applied to a series of small peptides and drugs spanning a large range of reduced mobility values in order to demonstrate ESI-VSIMS to separation. To demonstrate improved peak capacity of IMS with voltage scan operation, oligomers of silicone oil provided a series of evenly-spaced peaks, ranging in reduced mobility values from 0.85 to 0.3 V²cm^?1 s^?1. The peak capacity of 61 for a standard IMS was improved to 102 when voltage sweep operation was employed. In addition, VSIMS increased the average resolving power of the DTIMS from 66 to 106 for silicone oil.     

Fourier transform ion mobility spectrometry of barbiturates after capillary gas chromatography

This paper demonstrates a novel operating mode of an ion mobility detector (IMD) for obtaining both qualitative and quantitative data after capillary gas chromatographic separation of 5,5′-disubstituted barbiturates. Using a recently developed time dispersive Fourier transform method for ion mobility spectrometry, complete ion mobility spectra could be obtained for each component in the chromatogram. This type of spectra can be used for providing qualitative information on unknown compounds or for selecting the proper detector conditions needed when operating in the continuous mobility monitoring mode. In this study each of the five barbiturates investigated produced a Fourier transformed ion mobility spectrum containing one major product ion. When drift times corresponding to those of the product ions measured in the FT mode were monitored continuously, selective chromatographic detection of the barbiturates was achieved. In one case even isomers could be differentiated based on mobility characteristics.     

Rapid and sensitive differentiation of anomers,linkage, and position isomers of disaccharides using High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS)

A challenging aspect of structural elucidation of carbohydrates is gaining unambiguous information for anomers, linkage, and position isomers. Such isomers with identical mass can't be easily distinguished in mass spectrometry and a separation step is required prior to mass spectrometry identification. In our laboratory, gas-phase separation and differentiation of anomers, linkage, and position isomers of disaccharides was achieved using High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS). The FAIMS method responds to changes in ion mobility at high field rather than absolute values of ion mobility, and was shown to provide efficient separation and identification of disaccharide isomers at high sensitivity. Separation of analyzed disaccharide isomers can be accomplished at low nM level in a matter of seconds without sample purification or fractionation. Capability for examining a large population of ionic species of disaccharides by this method allowed for correlating structural details of disaccharide isomers with their separation properties in FAIMS. Results for disaccharide isomers indicate that this method could be applied to a larger group of carbohydrates.     

Formation of multimeric steroid metal adducts and implications for isomer mixture separation by traveling wave ion mobility spectrometry

Steroid analysis is essential to the fields of medicine and forensics, but such analyses can present some complex analytical challenges. While chromatographic methods require long acquisition times and often provide incomplete separation, ion mobility spectrometry (IMS) as coupled to mass spectrometry (MS) has demonstrated significant promise for the separation of steroids, particularly in concert with metal adduction and multimerization. In this study, traveling wave ion mobility spectrometry (TWIMS) was employed to separate multimer steroid metal adducts of isomers in mixtures. The results show the ability to separate steroid isomers with a decrease in resolution compared with single component standards because of the formation of heteromultimers. Additionally, ion‐neutral collision cross sections (CCS) of the species studied were measured in the mixtures and compared with CCSs obtained in single component standards. Good agreement between these values suggests that the CCS may aid in identification of unknowns. Furthermore, a complex mixture composed of five sets of steroid isomers were analyzed, and distinct features for each steroid component were identified. This study further demonstrated the potential of TWIMS‐MS methods for the rapid and isomer‐specific study of steroids in biological samples for use either in tandem with or without chromatographic separation.     

Optimum waveforms for differential ion mobility spectrometry (FAIMS)

Differential mobility spectrometry or field asymmetric waveform ion mobility spectrometry (FAIMS) is a new tool for separation and identification of gas-phase ions, particularly in conjunction with mass spectrometry. In FAIMS, ions are filtered by the difference between mobilities in gases (K) at high and low electric field intensity (E) using asymmetric waveforms. An infinite number of possible waveform profiles make maximizing the performance within engineering constraints a major issue for FAIMS technology refinement. Earlier optimizations assumed the non-constant component of mobility to scale as E(2), producing the same result for all ions. Here we show that the optimum profiles are defined by the full series expansion of K(E) that includes terms beyond the first that is proportional to E(2). For many ion/gas pairs, the first two terms have different signs, and the optimum profiles at sufficiently high E in FAIMS may differ substantially from those previously reported, improving the resolving power by up to 2.2 times. This situation arises for some ions in all FAIMS systems, but becomes more common in recent miniaturized devices that employ higher E. With realistic K(E) dependences, the maximum waveform amplitude is not necessarily optimum, and reducing it by up to approximately 20% to 30% is beneficial in some cases. The present findings are particularly relevant to targeted analyses where separation depends on the difference between K(E) functions for specific ions.     

Novel design for drift tubes in ion mobility spectrometry for optimised resolution of peak clusters

In the past decade, Ion Mobility Spectrometry has established a very strong foot hold in medical and biological applications due to its numerous advantages including sensitivity, ruggedness and reproducibility. During the analysis of complex samples such as human breath, it is very probable that two or more analytes form peak clusters due to similar drift times and pre-separation times, thus hindering the identification of the analytes. Furthermore, such overlapping of signal makes quantification very difficult or even impossible. Resolving these peak clusters is important to enable proper identification and quantification of analytes detected for diagnosis. Hence, we designed a drift tube with variable length for investigating the influence of varying drift lengths and electric field on resolution. Peak cluster formations usually seen between acetone and the reactant ion peak, between the dimer peaks of 2-Heptanone and 4-Heptanone have been resolved with the new drift tube after optimisation. These novel drift tubes could easily negate the peak clusters often encountered when complex medical and biological samples are measured with the ion mobility spectrometer. Furthermore, the fact that these drift tubes can be altered in length thereby providing a wide range of electric fields (from 50 to 3300 V.cm⁻¹), opens up new research options in ion motions in an electric field.     

FAIMS-MS-IR spectroscopy workflow: a multidimensional platform for the analysis of molecular isoforms

An original workflow allowing inline FAIMS separation, electrospray ionization, mass analysis and ion spectroscopy (IRMPD: InfraRed Multiple Photon Dissociation) is presented for multidimensional molecular analysis. This new instrument consists of an ultraFAIMS (Owlstone) device interfaced to a linear ion trap (LTQ XL Thermo Scientific) which was modified for IRMPD spectroscopy. Two modes of operation are demonstrated on an isomeric mixture of paracetamol and 2-phenylglycine. In the first mode a FAIMS (high-Field Asymmetric waveform Ion Mobility Spectrometry) separation of the isomers is performed with a static compensation field for mass- and isomer- selective ion spectroscopy. In the second mode, the compensation field is scanned while the ions are irradiated at a fixed wavenumber. The advantages of this workflow as compared to traditional FAIMS-MS and IRMPD spectroscopy are described. The potential of the two modes for molecular spectroscopy and analytical applications, in particular the new “omics” are discussed.     

Transport modeling of membrane extraction of chlorinated hydrocarbon from water for ion mobility spectrometry

Membrane-extraction Ion Mobility Spectrometry (ME-IMS) is a feasible technique for the continuous monitoring of chlorinated hydrocarbons in water. This work studies theoretically the time-dependent characteristics of sampling and detection of trichloroethylene (TCE). The sampling is configured so that aqueous contaminants permeate through a hollow polydimethylsiloxane (PDMS) membrane and are carried away by a transport gas flowing through the membrane tube into IMS analyzer. The theoretical study is based on a two-dimensional transient fluid flow and mass transport model. The model describes the TCE mixing in the water, permeation through the membrane layer, and convective diffusion in the air flow inside membrane tube. The effect of various transport gas flow rates on temporal profiles of IMS signal intensity is investigated. The results show that fast time response and high transport yield can be achieved for ME-IMS by controlling the flow rate in the extraction membrane tube. These modeled time-response profiles are important for determining duty cycles of field-deployable sensors for monitoring chlorinated hydrocarbons in water.     

Differentiation of chronic obstructive pulmonary disease (COPD) including lung cancer from healthy control group by breath analysis using ion mobility spectrometry

Non-invasive methods with potential for diagnosis of lung diseases gain increasing interest. Within the present study the exhaled breath of 132 persons (97 Chronic obstructive pulmonary disease (COPD) patients [35 COPD without lung cancer, 62 COPD with lung cancer] and 35 healthy volunteers) was investigated using an Ion Mobility Spectrometer (IMS) coupled to a Multi-Capillary Column (MCC) without any pre-separation or pre-enrichment. One hundred four different peaks were considered within the IMS-Chromatograms of the 10 mL breath samples of both groups. A principal component analysis (PCA) of these 104 peaks identified a single analyte, that allowed a separation of the healthy persons and the COPD patients (with and without lung cancer). The sensitivity obtained was 60%, the specificity 91%, the positive predictive value 95%. The peak was characterized as cyclohexanone (CAS 108-94-1). Subsequent studies must validate the identity of the peak used for separation of the two groups with a greater population and external standards. Breath gas analysis using ion mobility spectrometry offers a chance of separating healthy persons and COPD patients using a single analyte at a defined concentration.     

Validated quantitation method for a peptide in rat serum using liquid chromatography/high‐field asymmetric waveform ion mobility spectrometry

The analysis of peptides presents serious challenges for bioanalytical scientists including low total ion current and non‐selective fragmentation during tandem mass spectrometry (MS/MS). During method validation of a peptide in rat serum matrix some interferences could not be easily removed and thus prevented accurate and precise measurement. These problems associated with peptide quantitation were resolved by using FAIMS (high‐Field Asymmetric waveform Ion Mobility Spectrometry). This selectivity‐enhancing technique filters out matrix interferences, and the resulting pseudo‐selected reaction monitoring (pseudo‐SRM) chromatograms were nearly free from interferences. Control blank matrix samples contained an acceptable level of interference (only 7% signal as compared to the lower level of quantitation). Chromatographic peaks were easily, accurately and precisely integrated resulting in a validated liquid chromatography (LC)/FAIMS‐MS/MS method for the analysis of a peptide drug in rat serum according to United States Food and Drug Administration (US FDA) bioanalytical guidelines. These results confirm that new selectivity‐enhancing technologies aid the pharmaceutical industry in reliably producing acceptable pharmacokinetic data. Copyright © 2009 John Wiley & Sons, Ltd.