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Ion Mobility-MassSpectrometry

Wentao Jiang and Rena A.S. RobinsonUniversity of Pittsburgh, Pittsburgh, PA, USA

1 Introduction 12 Principles of Ion Mobility Spectrometry 2

2.1 Drift-Time Ion Mobility Spectrometry 22.2 High-Field-Asymmetric Waveform Ion

Mobility Spectrometry 42.3 Traveling Wave Ion Mobility

Spectrometry 43 Ion Mobility Spectrometry–Mass

Spectrometry Instrumentation 43.1 Sources 53.2 Hybrid Instruments 6

4 Multidimensional Ion MobilitySpectrometry–Mass Spectrometry 104.1 Liquid Chromatography-Ion Mobility

Spectrometry-Mass Spectrometry 104.2 Capillary Electrophoresis-Ion Mobility

Spectrometry-Mass Spectrometry 114.3 Ion Mobility Spectrometry-Ion Mobility

Spectrometry-Mass Spectrometry 114.4 Ion Mobility Spectrometry-Ion Mobility

Spctrometry-Ion Mobility Spectrometry-Mass Spectrometry 13

5 Applications of Ion MobilitySpectrometry–Mass Spectrometry 135.1 Proteomics 145.2 Probing Structural Information 145.3 Lipidomics 145.4 Metabolomics 145.5 Chiral Species 155.6 Chemical Warfare Agents 155.7 Pharmaceuticals 155.8 Environmental 15

6 Conclusions and Future Outlook 16Acknowledgments 16Abbreviations and Acronyms 16Further Reading 16References 16

Ion mobility spectrometry (IMS) separates ions based ontheir mobility in an inert buffer gas in the presence of an

electric field. The mobility of ions is based on their size,shape, and charge, thus IMS provides insights into struc-ture. In addition to being used for structural information,IMS can also be used as a separation device for complexmixtures. When coupled with mass spectrometry (MS),IMS–MS offers a powerful hybrid analytical techniquethat has many biological, pharmaceutical, structural, envi-ronmental, and other applications. This article providesan overview of IMS–MS, which focuses on principlesof drift-time ion mobility spectrometry (DTIMS), high-field-asymmetric ion mobility spectrometry (FAIMS),and traveling wave ion mobility spectrometry (TWIMS)methods. Several IMS–MS instruments are discussed andexamples of the current applications of the technology areprovided.

1 INTRODUCTION

IMS is a powerful analytical technique that has becomemore widespread in the last 40–50 years. IMS has severalcapabilities as a stand-alone instrument and has been usedto monitor the detection of atmospheric compounds,(1 – 3)

explosives,(4 – 6) chemical warfare agents (CWAs),(7,8) andpetrochemical reagents.(3) In recent years, IMS tech-nology has been used to detect explosives and narcoticsin airport scanner devices. While it has been extremelyeffective in field applications as a stand-alone or portabledevice, the coupling of IMS with MS extends the capabil-ities and applications of the technique tremendously.IMS–MS is extremely useful for obtaining structuralinformation on small polyatomic ions(9,10) to macromolec-ular ions, such as proteins(11 – 13) and even viruses.(12)

IMS–MS instruments can be operated in modes whichtake advantage of IMS as a separation device allowingcomplex mixtures to be investigated and low-abundancespecies to be detected owing to the removal of chemicalnoise. Furthermore, IMS–MS provides fast measure-ments which allow it to be compatible with other front-endanalytical separations, such as liquid chromatography andcapillary electrophoresis.

Owing to the growing interest in IMS–MS, thisarticle seeks to provide a general overview of IMS–MStechnology. There have been several notable advances inIMS–MS instrumentation which have led to a plethoraof interesting applications. The reader will be introducedto the basic principles surrounding three of the mostcommonly employed types of IMS separations. Currentapplications of IMS–MS have only been made possibledue to the many advances that have taken place ininstrumentation development and technology. Thus, anoverview of several IMS–MS instrumentation setups isalso provided. Finally, examples of several applications

Encyclopedia of Analytical Chemistry, Online © 2006–2013 John Wiley & Sons, Ltd.This article is © 2013 John Wiley & Sons, Ltd.This article was published in the Encyclopedia of Analytical Chemistry in 2013 by John Wiley & Sons, Ltd.DOI: 10.1002/9780470027318.a9292

2 MASS SPECTROMETRY

that stem from IMS–MS are discussed and this articleconcludes with a future outlook on potential applicationsand advancements of IMS–MS.

2 PRINCIPLES OF ION MOBILITYSPECTROMETRY

The basic principle of ion mobility separation canbe simply described as a gas-phase electrophoresistechnique, whereby gaseous ions are separated accordingto their size, shape, and charge in the presence of aweak electric field. The drift tube is filled with an inertbuffer gas (i.e. argon, helium, and nitrogen) at either lowvacuum pressures or at atmospheric pressure conditions.Ions move according to diffusion processes through thedrift tube as the energies of the ions are similar to thethermal energy of the buffer gas. Various ions will havedifferent mobilities in a given drift tube device whichallows the separation of mixtures of ions and structuralinformation to be obtained. The simplest configurationof a drift tube is one in which a series of stacked ringelectrodes have a static direct current (DC) field appliedacross the electrodes and the tube is filled with an inertbuffer gas. As ions move under the influence of thisweakly applied electric field, they have a velocity, νD ,which is governed by the electric field, E, and mobility ofthe ion, K , in a specific buffer gas.

νD = KE (1)

K is measured experimentally based on the time it takesan ion to traverse the drift tube of length, L.

K = L

tDE(2)

Comparisons of reduced ion mobilities, K0, acrosslaboratories can be obtained by normalizing for buffergas pressure, P , and temperature, T , as follows:

K0 = L

EtD

273T

P

760(3)

It is often useful to deduce information about thestructure (i.e. the size and shape) of specific ions basedon a mobility experiment. This is possible using anexperimentally derived collision cross-section, �, for anion, which represents the average area of the moleculethat interacts with the buffer gas over a range of three-dimensional orientations.

� = (18π)1/2

16ze

(kBT )1/2

[1mI

+ 1mB

]1/2tDE

L

760P

T

2731N(4)

In the above expression, ze refers to the charge onthe ion, kB is Boltzmann’s constant, mI and mB are themasses of the ion and buffer gas, respectively, and N isthe number density of the buffer gas.(14) Because IMS canbe coupled with MS the mass and charge of an ion canbe readily deduced. By operating at specific fields (i.e.low or high) or with different pressure regimes, differentIMS methods can be developed. Here we discuss threecommon approaches: DTIMS, FAIMS, and TWIMS.

2.1 Drift-Time Ion Mobility Spectrometry

DTIMS–MS is the most widespread developed andemployed approach. DTIMS is the only IMS methodwhich provides a direct measure of collision cross-sectionbased on an ion’s mobility. Figure 1(a) shows a simpledrift tube instrument that is filled with inert buffer gasin a counter direction of the ion motion. The weak elec-tric field applied to the drift tube is generated usinga series of resistors and a DC potential. The electricfield applied is generally around 2.5–20 V cm−1(15,16) inreduced-pressure IMS (i.e. the drift pressure ranges from1 to 15 mbar). Higher voltages are applied across the drifttube when higher pressures, such as atmospheric pres-sures, are used.(17,18) Regardless of the pressure regimeused, it is important that the voltages applied do not causethe potential breakdown of the buffer gas. Traditionallyused buffer gases are helium, nitrogen, and argon, ormixtures thereof.(19 – 24)

DTIMS does not work with continuous injection ofions, therefore packets of ions are introduced into thedrift tube using an ion gate(17,25) or ion funnel.(15,26) Ionpackets can range in width from 100 to 200 μs. Because ofthe use of ion packets, the overall sensitivity of the methodis reduced(27) such that only 0.1–1% of ions generated aresent to the IMS. After the ions are injected into the drifttube, the species begin to separate based on their mobilitythrough the buffer gas. For example, doubly-chargedspecies experience the force of the electric field twice asmuch as singly-charged ions, therefore for ions of the sameshape the doubly-charged ion will have a higher mobilitythrough the tube and thus a shorter drift time. Also, ionswhich have more elongated conformations will undergomore collisions with buffer gas atoms and thus take alonger time to drift through the tube than more compactstructures. These concepts are illustrated in Figure 1(a).

Typically, ions travel through the drift tube on theorder of milliseconds(28) which makes for a relativelyfast separation. As can be inferred from the mobilityequations described, the length of the drift tube caninfluence the transient time and mobility of an ion. Thedrift resolving power (t/�t) at full-width half maximum


ION MOBILITY-MASS SPECTROMETRY 3

(a)

(b)

(c)

Drift time

Inte

nsity

Traveling wave potential

Ionsource

Time

Driftgas

t1

t2

tn

Driftgas

Drift tube

Electric field

Drift time

Inte

nsity

Ionsource

CV

~V(t)

Carriergas

Ionsource

CV1

CV2

CV2

CV3

CV

Inte

nsity

Figure 1 Illustration of drift tube separation principles. (a) Principle of DTIMS. Packets of ions are injected into a drift tube filledwith an inert buffer gas. Under the influence of a weak electric field, ions are separated by charge, size, and shape. (b) Principlesof FAIMS separation. An asymmetric waveform is applied to two cylindrical plates such that ions experience alternating high andlow electric fields. Ions traverse the region between the plates moving in a perpendicular direction to the buffer gas and with theinfluence of a DC potential, termed the compensation voltage (CV). Only selected ions at a given CV will make it through the driftregion. (c) Principles of TWIMS separation. An alternating phase radio-frequency (RF) potential is applied to a series of stackedring ion guides (SRIGs). Ions are pushed through the drift region with a traveling potential wave and become mobility separated ashigher mobility ions are able to ‘roll-over’ the traveling waves generated and exit the SRIG region.

is approximated as follows:

t

�t≈

(LEze

16kBT ln 2

)1/2

(5)

This theoretical resolving power approximation(29)

shows that increasing the length of the drift tube orapplied electric fields, or decreasing the buffer gastemperature can increase the resolving power. A typical

length for an in-house-built IMS drift tube is ∼1 m.Clemmer et al.(30) and Bowers et al.(31) have shownthat increasing the tube length to 2 m or greater cansignificantly improve the resolving power. A circulardrift tube design, which has effectively infinite length,can extend the drift resolving powers of small peptidesto >300.(32) At higher electric fields, the buffer gasstarts to break down, therefore higher electric fieldsare employed only with higher pressure drift tubes


4 MASS SPECTROMETRY

as mentioned earlier.(33,34) Cryogenically cooled drifttubes with subambient temperatures have been recentlydemonstrated.(35) The ability to work with higherresolution drift instruments allows greater separationpower for complex mixtures or isomeric and isobaricspecies with closely related mobilities and can give betterinsight into structural transitions in the gas phase.

It is worth briefly mentioning, as are further discussedsubsequently, that the IMS and MS separations using thisapproach are not completely orthogonal. Because themass and shape of ions strongly influence ion mobility,there is a mass correlation observed in a two-dimensional(2D) IMS–MS experiment.

2.2 High-Field-Asymmetric Waveform Ion MobilitySpectrometry

At extremely high electric fields (i.e. >104 V cm−1), thevelocity of ions does not follow the relationship shownin Equation (1).(36,37) The mobility of the ions is depen-dent on the strength of the electric field which changesthroughout the course of the experiment. As shown inFigure 1(b), there are two closely spaced (∼2 mm) cylin-drical or planar plates in which an asymmetric field isapplied.(38) As ions move toward each of the plates, theyexperience different field strengths and form an oscil-lating motion between the plates. For example, the fieldon one plate is twice the electric field that ions experienceon the second plate. In contrast to DTIMS, the buffer gasis flowing in the direction of the ion motion which causesthe path of the ions to be perpendicular to that of theelectric field. In order for ions to traverse down the courseof the electrodes and avoid hitting the electrode walls, acompensation voltage (CV) is applied to the plates. Undera given CV, only a specific ion is able to exit the end ofthe drift field. Therefore, a scan of increasing CVs allowsa range of ions with different mobilities to be measured.FAIMS acts similar to a quadrupole mass analyzer in thisway which is in contrast to DTIMS whereby all ions aretransmitted simultaneously. Ion abundances are reportedas a function of CVs as opposed to drift times. FAIMSalso allows a continuous beam of ions to be introducedinto the drift tube as opposed to a small packet of ions inDTIMS.(7,38)

The exact mechanisms of FAIMS separation are notclearly understood and thus it becomes very difficult todeduce structural information from this IMS method.However, there are examples whereby FAIMS hasbeen useful for obtaining conformations of well-studiedsystems.(39 – 41) In addition, because the field strengthemployed is in the high-field limit the nature of the bathgas can greatly influence the ion energy and mobility.(38)

2.3 Traveling Wave Ion Mobility Spectrometry

TWIMS has its origins in the commercialization ofIMS–MS technology by Waters Corporation (see Section3.2.1).(42,43) The drift tube instrument in this case consistsof a series of three stacked ring ion guides (SRIG) inwhich an radio frequency (RF) voltage is applied acrossconsecutive electrodes and used to stop the radial spreadof ions. Superimposed on top of the radio frequency (RF)fields is a DC voltage which is used to move ions down theaxial direction of the tube. As illustrated in Figure 1(c),the DC is pulsed so that in time ions begin to ride along thewells created by the potential field. Ions continue to moveforward and are separated as higher mobility ions are alsoable to ride over the wave. The highest mobility ions ‘roll-over’ the waves less times and have a faster transit throughthe SRIG.(43,44) The wave amplitude, velocity and buffergas pressure can be altered in order to optimize iontransmission through the SRIG.(43) For specific applica-tions, the SRIG can be used as a transmission device,storage device, or collision cell.(43) Conformational infor-mation can be obtained from TWIMS by using carefulcalibrations to well-studied systems.(45)

3 ION MOBILITY SPECTROMETRY–MASSSPECTROMETRY INSTRUMENTATION

IMS–MS began with the work performed by McDanielet al.(46) in the late 1950s and 1960s when he developedan IMS–MS instrument to study ion molecule reactionsof noble gases and pure hydrogen. His instrumentdesign was a low-pressure drift device that was coupledto a magnetic sector mass spectrometer. Kebarleand Hogg(47) also created an early IMS–MS devicefor measuring ethylene gaseous ions. Over the last40–50 years, there have been numerous developmentsin IMS–MS devices. The basic components found inany IMS–MS instrument include the source, drift tube,mass analyzer, focusing elements, and ion detector.Technological advances in each of these componentshave greatly added to the overall improvement ofIMS–MS instruments. Different combinations of IMSand MS instruments have been realized, includingIMS-time-of-flight mass spectrometers (TOF-MS), IMS-quadrupole mass spectrometers (qMS), IMS-ion trapmass spectrometers (IT-MS), IMS-Fourier transformmass spectrometers (FTMS), and IMS-magnetic sectormass spectrometers. We provide a brief overview ofionization sources and discuss the features of commonlyused IMS–MS instruments in the following sections.



3.1 Sources

3.1.1 Electrospray Ionization

Electrospray ionization (ESI) is one of the most popularion sources used in IMS–MS and MS since its discoveryand application in biological molecules from the workof Nobel laureate John Fenn et al.(48) ESI is a soft andcontinuous ionization method that is nondestructive toanalytes and generates multiply-charged ions.(48) Theassociation of multiple charges on analytes extends theeffective mass range of species that can be detected,thereby making molecules such as DNA and virusesaccessible.(49 – 51) In addition, other types of nonvolatileand thermally labile compounds, such as polymers andsmall polar molecules, are accessible with ESI.

The ESI source consists of a glass, metal, or fused-silica sample capillary which contains liquid solutions ofthe analyte of interest flowing at rates of 0.1–1 mL min−1

or higher. There is a potential drop (∼several kilovolts)that is created between the capillary and source of theinstrument (in this case the drift tube, see Figure 2a).The distance between the capillary tip and the instrumentsource is 0.3–2 cm creating a ‘Taylor Cone’ which containscharged droplets of the analyte. As these droplets migratetoward the entrance of the instrument, the droplets shrinkin size as the solvent evaporates. At a given point, theCoulombic repulsion in the droplet exceeds the surfacetension and the droplets disperse into smaller droplets.This process continues until protonated analyte ions areleft in the gas phase. Nebulizer and drying gases are oftenused in order to assist with desolvation and aid in thetransfer of ions to the source. For IMS–MS instruments,such as those encountered in DTIMS and TWIMS, an iongate is located following the ESI source.

3.1.2 Matrix-Assisted Laser Desorption/Ionization

Matrix-assisted laser desorption/ionization (MALDI) isanother attractive source for the study of large molecules.

MALDI is a soft ionization method and unlike ESI, it isa pulsed source and primarily generates singly-chargedions.(52,53) The sample preparation procedure is simple,making it a good choice for imaging MS applications.(54)

In addition, MALDI has better tolerance to salts anddetergents within samples. Analytes of interest aremixed with selected small organic matrix compounds(e.g. 3,5-dimethoxy-4-hydroxycinnamic acid, α-cyano-4-hydroxycinnamic acid, and 2,5-dihydroxybenzoic acid).After solvent evaporation, the matrix and analyte cocrys-tallize on the surface of a 96-well metal plate. The matriceshave been selectively chosen so that they can absorb theradiation emitted by the laser (e.g. Nd:YAG or CO2).Spots are bombarded with laser pulses either undervacuum source conditions, as in traditional MALDI,(52,53)

or at atmospheric conditions for atmosphere pres-sure matrix-assisted laser desorption/ionization (AP-MALDI).(55,56) As shown in Figure 2(b), charged analyteand matrix ions are irradiated from the surface of thespot and are accelerated toward the IMS source. BecauseMALDI is a pulsed ionization technique, it works wellwith DTIMS as each laser shot generates a packet of ionswhich can be injected into the drift tube without the useof an ion gate. Several groups have employed MALDI asan ion source before IMS–MS.(21,31,57 – 59)

3.1.3 Laserspray Ionization

Laserspray ionization (LSI) is a newly developed ioniza-tion technique that resembles AP-MALDI, howeverresults in multiply-charged ions similar to those producedin ESI.(60,61) The setup is slightly different from that ofAP-MALDI, as shown in Figure 2(c). The major differ-ences are that a transparent slide is used to house theanalyte/matrix crystals, no voltage is applied to the plateto accelerate ions into the source, and the laser beam istransmitted through the bottom portion of the glass slideas opposed to directly ablating the surface of the plate.(62)

The distance of the sample plate to the inlet (∼1 mm) is

M

M

M

M

M

MM

M

M

M

M

M

Capillary

Taylor cone

V+ −

+

+

+

++

+

+

++

+

+

++

+

+

++

Matrixmolecules

Analytemolecules

V+ −

Met

al p

late

(a)

ESI

(b)

MALDI

(c)

LSI

+

++

++

+

+

++

+Laser beam

+

++

+

+

++

Matrixmolecules

Analytemolecules

+

++

+

Met

al p

late

Lase

r bea

m

Figure 2 Schematic diagram showing the mechanisms of (a) ESI, (b) MALDI, and (c) LSI.


6 MASS SPECTROMETRY

important for minimizing sample loss. Matrices used byLSI are similar to those used with MALDI.

LSI features high sensitivity, easy sample prepa-ration, simple laser focusing, and simple sourceinstrumentation.(61) The combination of LSI withIMS–MS provides a solvent-free ionization and analysisplatform. Recently, Inutan and Trimpin(63) validated thiscoupling with a commercial Waters Synapt G2 IMS–MSinstrument on peptides and proteins ranging in molecularweight (MW) from 5.7 to 17 kDa.

3.1.4 Others

While we highlight three ionization sources which areused for a range of higher MW compounds, thereare other ion sources which have been applied inIMS–MS. Early studies of small gas-phase ions andmolecules also applied corona ion discharge(19,64) andradioactive ion sources.(65) Laser desorption ionizationis useful for the ionization of solid samples and hasbeen demonstrated on carbon clusters, silicon clusters,and fullerenes.(66 – 68) Other examples of sources includeultraviolet (UV) photoionization,(69) secondary ESI,(70)

desorption electrospray ionization (DESI),(71) and directanalysis in real time.(72) For more detailed information onsources compatible with IMS, we refer readers to a recentreview on the subject.(73)

3.2 Hybrid Instruments

3.2.1 Ion Mobility Spectrometry–Time-Of-Flight-MassSpectrometry

Since the principles of TOF-MS have been proposed in the1940s,(74,75) DTIMS-TOF-MS has attracted considerableattention and undergone continuous development andimprovement. McAfee et al.(19) constructed the first IMS-TOF-MS in 1967 to study the mobilities and reactionsof small ions in the presence of argon gas. IMS is anexcellent match for TOF-MS analyzers owing to thetimescales of each technique. The scan time of TOF isthe order of microseconds, which is much faster than theIMS separation that occurs on the order of milliseconds.Thus a ‘nested’ IMS-TOF measurement is obtained(25)

and hundreds to thousands of MS spectra are acquiredfor a single IMS pulse (Figure 3a).

The basic components of an IMS-TOF-MS instrumentinclude an ion source, a drift region, a TOF analyzer,focusing elements, and a detector. The layout of theinstrument can be similar to that shown in Figure 3(b),which is a design by Baker et al.,(76) in which the TOFanalyzer is orthogonal to the drift tube. Ions generated inthe ion source are injected into the drift region in packets.If a continuous ion source is used, such as ESI, an ion

gate with a grid is used to pulse ion packets into the drifttube. Figure 3(a) shows an example of a typical pulsingdiagram that may be used in an IMS-TOF-MS setup (seeFigure 3b). A packet of ions (100-μs wide) is injectedinto the drift tube and mobility separated for a definedperiod (e.g. ∼50 ms). The mobility period is selected tocorrespond with the drift time of the lowest mobilityspecies of interest. During mobility separation, TOFspectra are collected in a 50-μs window correspondingto the desired m/z range which generally spans up to2000 m/z; although with the TOF analyzer, theoretically,there is no upper limit on the m/z to be measured.Hundreds to thousands of TOF spectra are nested withineach IMS measurement.

Data generated from this experiment can be displayedin a 2D plot of flight time (or m/z) as a function of drifttime, similar to that shown in Figure 4(a), for a mixtureof tryptic peptides. The axes can also be switched forthese plots. It can be observed from the plot that thereis a mobility–mass correlation(77,78) which demonstratesthat the two techniques are not completely orthogonal.Specific trend lines appear in the spectrum, which corre-late with different charge-state families, allowing forseparation of multiply-charged ions generated during ESIor LSI. In cases where the TOF resolution is limited, thesetrend lines would allow charge-states to be assigned.Mobility–mass behavior is not limited to peptides butalso occurs for proteins and can be used to distinguishdifferent classes of compounds such as proteins, lipids,DNA, and glycans.(11,58)

A few points should be noted regarding the IMS-TOF-MS designs. Because the drift gas pressure (e.g.0.5–15 Torr)(15,16,26,31) is generally much higher than thelow vacuum necessary for TOF detection (i.e. 10−6 Torr),a differential pumping region is necessary to couple thedevices. This can be done through designing an inter-mediate vacuum stage consisting of multipoles or otherfocusing lenses. Due to the differences in pressure that canoccur between the ESI source and drift tube, consider-able ion loss can occur because of diffusional losses.(46) Amajor contribution to improve ion transmission efficiencyin DTIMS-TOF-MS is the ion funnel designed and intro-duced by Smith et al.(26,80) Two ion funnels are present inthe instrument shown in Figure 3(b): an hourglass-shapedion funnel after the source capillary and a second funnellocated after the drift region. The design is based on astacked ring RF ion guide, which is composed of a setof ring electrodes with opposite RF phases applied toevery other electrode (Figure 3b inset). The ring elec-trodes have orifices with gradual decreasing diametersthat focus the ions into a collimated beam at pressuresup to 30 Torr.(76) A DC gradient is also applied alongthe funnel to push the ions in the z-direction. The hour-glass funnel is similar except for its geometry that allows



100 µs

Mobility separation

Ion injection

50 ms

IMS scan cycle

TOF detection

50-µs TOF scan

2 µs

(a)

Figure 3 (a) Example of a pulsing diagram for a DTIMS-TOF-MS experiment. The upper trace shows that an ion packet (100 μswidth) is injected into the drift tube and mobility separated over the course of 50 ms. After a variable delay following ion injection,TOF scans of the order of 50 μs for a typical size m/z range, are acquired. Hundreds to thousands of TOF spectra are acquiredwithin a single mobility experiment. (b) A schematic diagram of ESI-DTIMS-TOF-MS reprinted from Ref. 76. (Reproduced withpermission from Ref. 76. Copyright 2007, Springer.) The inset shows a zoom-in of a typical ion funnel geometry.

ions to be trapped for ion injection to the drift tube. Ionfunnel functions include accumulating and focusing ions,increasing ion transmission efficiency, and collisionallyactivating ions.(16,26)

Ions can also be collisionally activated in the IMS-TOF-MS design at regions located after the drift tubebefore entering the TOF analyzer.(42,81 – 87) Activationis possible with skimmer cones,(81) octopole collisioncells,(82) Triwave cells,(42) split-fields,(83) surface-induced

dissociation,(84) and other methods.(85 – 87) Due to thetimescale of the mobility separations and the short timeof ion activation, the drift times of fragment ions arevery similar to that of the precursor ions from which theyarose. Figure 4(b) gives an example of fragmentationspectra for a tryptic peptide that was isolated using aquadrupole mass filter and fragmented in a collisioncell. The b- and y-fragment ions detected for thispeptide all have similar drift times. One advantage of


8 MASS SPECTROMETRY

(a) (b) 46

44

42

40

38

36

34

32

30

28

26

24

22

201 2 3 4 5 6 7 8

250

500

750

1000

1250

46

44

42

40

38

36

34

32

30

28

26

24

22

201 2 3 4 5 6 7 8

250

500

750

1000

1250

m/z

m/z

Drift time (ms)Drift time (ms)

Flig

ht ti

me

(μs)

Flig

ht ti

me

(μs)

IntensityIntensity

y12

y10

y9

y8

b7 or y142+

b7–H2O orLEVEPSD+

IQDK+

LR+

TLTGK+

LIFAGK+

ESTLHLVLR+

[M + 2H]2+ [M + H]+

TLSDYNIQK+

EGIPPDQQR+

MQIFVK+

QLEDGR+

AKIQDK+

TITLEVEPSDTIENVK2+TITLEVEPSDTIENVK2+

ESTLHLVLR2+

EGIPPDQQR2+

MH–H2O2+

y11

Figure 4 (a) Nested drift (flight) time distribution for an electrosprayed mixture of tryptic peptides of ubiquitin. The octopolecollision cell was evacuated during the collection of these data, and the quadrupole was set to transmit all ions. The solidlines provide visual guides corresponding to the [M + H]+ and [M + 2H]2+ charge-state families. (b) Nested drift (flight) timedistribution for ubiquitin tryptic mixture. The quadrupole was used to select the [TITLEVEPDTIENVK + 2H]2+ ion (m/z = 849)and 3.8 × 10−4 Torr of argon was added to the octopole collision cell. Fragmentation of the [TITLEVEPSDTIENVK + 2H]2+ ionas well as the [TLTGK + H]+ ion is apparent. (Reproduced with permission from Ref. 79. Copyright 2000, American ChemicalSociety.)

Intelli Start.

TRI WAVE.

QUANTOF.STEP

Stepwave ion guide QuadrupoleTrap

Helium cell

Dual-stage reflectron

Transfer

High-fieldpusher Ion

mirror

Ion detectionsystem

Ion mobilitysperation

WAVE

Analyte spray Lockmass spray

Air-cooled turbomolecular pumpsRotary pump

21 3 4 5

6

Figure 5 Schematic of Waters Synapt G2-STM HDMS instrument. It features a Stepwave ion guide, a quadrupole, a TriwaveTWIMS, and a QuanTOF MS. (Image used with permission from Waters Corp.)

IMS-TOF-MS fragmentation is that without quadrupoleselection, all ions are simultaneously fragmented. This‘parallel fragmentation’(79,81) can increase the throughputof Tandem mass spectrometry (MS/MS) experiments.

FAIMS(41,88,89) and TWIMS(42) devices have also beencoupled to TOF-MS analyzers. Waters Corporationcommercialized the TWIMS-TOF-MS design in 2006(42)

in which the first instrument design was called a Synapt. In



LC pump

Electrosprayionization source

Chiral ion mobility spectrometer

Quadrupole mass spectrometer

Drift gasheater

Desolvationregion

Drift gas

Diffusion pump #1 Diffusion pump #2

Drift region

Chiral modifier infusion

Figure 6 A simplified drawing of DTIMS–qMS instrument. A heated desolvation region was designed to help in desolvating thesolvent. (Reproduced with permission from Ref. 91. Copyright 2006, American Chemical Society.)

2010, the Synapt was upgraded to the Synapt G2-S HDMS(Figure 5) which features an improved performanceTOF analyzer, offline transfer lens design, and updatedsoftware. The major components are an ion source (ESI orMALDI), ion guides, a quadrupole, the TriWave whichincludes the TWIMS, and a reflectron TOF-MS. Theion beam generated is focused toward a ‘StepWave’ ionguide, in which neutral species are removed with anoffline lens design. After selection or all-ion transmissionin the quadrupole, ions are accumulated in a trap andejected into the TWIMS for mobility separation, andtransferred to an orthogonal dual-reflection TOF-MSanalyzer. Although the drift resolution of TWIMS islower than in-house-built DTIMS, the TWIMS offershigh transmission efficiency and sensitivity.(42)

3.2.2 Ion Mobility Spectrometry–Quadrupole MassSpectrometry

Quadrupole mass analyzers can filter ions with specificm/z ratios or allow all m/z ions to pass through thedetector. Although quadrupoles have slower scan speeds,lower resolutions, and mass accuracies than TOFs, theyare widely used mass analyzers because of their simplicity,inexpensive cost, and utility for targeted analyses. Thetime required for a qMS scan is on the scale of 100 ms,which is far slower than TOF-MS and is similar tothe timescales of DTIMS separations. Thus, it is morepractical to use single-ion monitoring instead of full m/z

scans in an IMS–qMS setup.The hybrid IMS–qMS instrument setup was introduced

in the 1970s(64) for monitoring ion–molecule reactionsof oxygen and nitrogen species. The instrument mainlyconsists of three parts (the ion source, a DTIMS, and a

qMS) located in separate chambers with small orifices tosustain the pressure differences. A DTIMS–qMS instru-ment with improved resolution has been reported(90) andis shown in Figure 6. The drift tube in this instrumentis operated under ambient pressure conditions and thebuffer gas can be manipulated with the addition of modi-fiers that help achieve chiral selectivity.(91) The ExcellimsCorporation offers a commercial atmospheric pressureDTIMS coupled to a qMS.(92) The drift tube in this config-uration is 10.85 cm. AB Sciex released an IMS–qMSinstrument with different IMS electrode geometries(93)

and a triple quadrupole/quadruple ion-trap MS.Wyttenbach et al.(15) implemented a funnel between

the ESI source and reduced-pressure drift tube to focusthe ion beam and prevent high-energy ion-neutral colli-sions. More recently, a DTIMS has been coupled to atriple qMS for explosive detection.(94) The triple qMSoffers additional scanning modes and greater sensitivitythan a single quadrupole analyzer. Cylindrical electrodeFAIMS designs, which offer higher sensitivity than flatplate electrodes, have also been coupled to qMS.(95)

Because FAIMS can act as a filter to eliminate chem-ical contaminants, the signal-to-noise (S/N) ratio can beimproved.(96,97)

3.2.3 Ion Mobility Spectrometry–Ion Trap MassSpectrometry

IMS-IT-MS with quadrupole ion traps (QITs, also knownas Paul ion trap) and linear ion traps (LITs) have beenreported.(18,98,99) The coupling of DTIMS-IT-MS requiresan ion gate at the IT-MS entrance to select a defined drift-time window. Clowers and Hill(18) have implemented adual-gate design. ESI-generated ions are pulsed into the


10 MASS SPECTROMETRY

Focusscreen inlet

Flared inletcapillary

Ion gate 1 Ion gate 2

Hexapole 1 Transfer optics7-T magnet

Hexapole 2

QuadrupoleSkimmers 1 and 2

Drift gas inlet

Nano-ESI Ion mobility spectrometer Ion transfer optics and Q-interface ICR cell

Figure 7 Schematic of ESI-DTIMS-FTICR MS instrument which consists of a drift tube, three multipole ion guides, and an ICRcell with 7-T magnetic field. (Reproduced with permission from Ref. 102. Copyright 2007, John Wiley & Sons, Ltd.)

drift region by the first ion gate, separated in the driftregion, selected by the second ion gate, focused throughthe ion guides, and mass scanned by the QIT. Recently,Zucker et al.(99) interfaced a DTIMS to a Thermo LTQVelos instrument which features a dual LIT design.Unique to this design is the introduction of a UV laser atthe back end of the second LIT for UV photodissociationexperiments. In this instrument, both UV photodisso-ciation and collision-induced dissociation (CID) can beemployed to fragment specific m/z ions that are isolatedin the LIT.

FAIMS coupled to a modified LTQ has beenreported(98) and commercialized by Thermo Fisher.(100)

Thermo Fisher provides the FAIMS interface in itstriple quadrupole instrument (i.e. TSQ Quantum) andwith LTQ and Orbitrap analyzers. The FAIMS is in aheated cube electrode design, in which selected ions cantravel through a gap between two electrodes and enterthe transfer capillary of the MS. This technology offersthe advantage of reduced chemical noise from ESI oratmospheric pressure chemical ionization (APCI) sourcesand complex samples before MS analysis.

3.2.4 Ion Mobility Spectrometry–Fourier TransformMass Spectrometry

The timescales of FT ion cyclotron resonance (ICR)MS do not make it the most attractive choice of massanalyzer for IMS coupling as scan times can be on theorder of seconds. However, because of the inherent highmass resolving powers attainable with FTICR-MS,(101)

a number of IMS applications can benefit from thishybrid setup. Coupling IMS to FTMS is similar to IMS-IT MS in which ion gates before and after the drifttube are required. Figure 7 shows an IMS-FTICR MSconstructed by Tang et al.(102) which is composed ofa nano-ESI ion source, a DTIMS, an interface region

containing ion transfer optics, and an ICR cell. Theinterface between the IMS and ICR cell serves as anintermediate pressure region before the high vacuumrequired in the ICR cell (i.e. 10−10 Torr). Althoughthe duty cycle (more than 99% of the ion signal iswasted) has a long way to be improved for this setup,there are sophisticated dynamic multiplexing approachesto combat these issues as has been recently presentedon Orbitrap FTMS instruments.(103 – 105) FAIMS-FTICR-MS(106) analysis on polymers has shown that this setupoffers the advantages of higher sensitivity, extendeddynamic range, high mass resolution and accuracy, andlower limits of detection due to the elimination ofchemical noise with FAIMS.

4 MULTIDIMENSIONAL ION MOBILITYSPECTROMETRY–MASSSPECTROMETRY

For the analysis of simple systems, DTIMS, TWIMS, orFAIMS may provide enough increased peak capacityand separation space to identify all components incombination with MS. However, for many applications(as discussed subsequently) of biological nature, thecomplexity of the system still requires increased dimen-sionality in order to detect more components, detectlow-abundance species, resolve isomeric and isobariccompounds, and extend dynamic range. To this end,IMS–MS can be connected with other front-end separa-tions.

4.1 Liquid Chromatography-Ion MobilitySpectrometry-Mass Spectrometry

Liquid Chromatography (LC)-IMS-MS has been previ-ously reported(107 – 113) and is one of the most straight-forward front-end separations to couple with IMS–MS.



Flig

ht ti

me

(µs)

Flig

ht ti

me

(µs)

37

33

29

25

21

17

(a) (b)

Drift time (ms)1.5 2.0 2.5 3.0 3.5 4.0 4.5

1840

1440

1040

64020

22

24

26

28

30

32

34

36

y595+/ y35

3+/ b363+

y594+/ y44

3+/ b302+

y374+/ y66

7+

y635+/ y25

2+

y584+/ b72

5+

y585+/ b47

4+

y404+/ b41

4+

b636+

y605+

y615+

y625+

y645+

b655+

y444+/ b11

+

Drift time (ms)

1.5 2.0 2.5 3.0 3.5 4.0 4.5 640 1120

m /z

m/z

1600 2080

[M + 5H]5+

[M + 6H]6+

+4

+5

+6

+7

+8 – +13

Compact

ElongatedPartially folded

Compact

Ubiquitin

Ubiquitin

+13 – +10 +9 +8 +7 +6

Charge state fragment lanes

Figure 8 Illustration of multidimensional IMS separation spectra. (a) The nested drift (flight) time distributions for ubiquitintR = 38 min. ions with charge-states [M + 4H]4+ to [M + 13H]13+ are observed. In (b), the upper figure shows nested drift(flight)time distributions of the fragmentation patterns for ubiquitin, and the lower figure is an MS/MS spectrum integrated at tD = 2.96 mscorresponding to the fragmentation patterns observed for the [M + 7H]7+ charge-state of ubiquitin. (Reproduced with permissionfrom Ref. 111. Copyright 2004, Springer.)

This is primarily because of the timescale of the sepa-ration and the generation of ions using sources suchas ESI. In comparison to IMS, liquid LC separationsoccur on the order of hours with typical peak widthsranging from 15 to 45 s. This relatively long separa-tion allows the IMS–MS measurement to be introducedat no additional cost in experiment time. Essentially,a three-dimensional ‘nested’ experiment is performedparticularly if the IMS-TOF-MS platform is used. Thismultidimensional separation method can dramaticallyincrease the analytical peak capacity and reduce thechemical noise to benefit the analysis of complex samples,such as proteomes(114) or metabolomes.(110)

The inclusion of MS/MS is often necessary toconfidently identify biomolecules.(111,115,116) LC-IMS-MS/MS has been demonstrated in several applicationsof peptides and proteins(115,117) and generates a four- tofive-dimensional data set which is gigabits to terabitsin size. Sowell et al.(111) used nanoflow LC-DTIMS-MS/MS to separate mixtures of intact small MW proteins,demonstrating the effectiveness of this multidimensional

approach to characterize the overall shapes of proteinsand collisionally activate precursor ions on the timescaleof an LC separation (Figure 8).

4.2 Capillary Electrophoresis-Ion MobilitySpectrometry-Mass Spectrometry

Capillary electrophoresis (CE) was coupled to FAIMS-MS for the study of complex lipopolysaccharides.(118)

They used a microspray interface to connect the CEeluent to the front end of a FAIMS-triple qMS. Due thelimited number of reports using CE with IMS–MS, thereis opportunity to make this coupling more desirable.

4.3 Ion Mobility Spectrometry-Ion MobilitySpectrometry-Mass Spectrometry

A more straightforward approach to increase the dimen-sionality and peak capacity of IMS–MS technology isto exploit the mobility separation space. During thepast decade, ion mobility spectrometry-ion mobility



ESI emitter

FAIMS IMS drift tube Quadrupolestages

TOF MS

Carrier gasOuter electrode

Curtain gas

Manometer 1 Manometer 2

Hourglassion funnel

Edwards EIM18 mechanical pump

Alcatel 2033mechanical pump

Flow valveGas inflow

Regularion funnel

Q00 Q0 Q1 Q2

Inner electrode

Figure 9 Schematic of ESI-FAIMS-DTIMS-qTOF-MS instrumentation. (Reproduced with permission from Ref. 119. Copyright2005, American Chemical Society.)

(a) (b)

0 5 10 15 20

4.78 ms

4.78 ms

CID

[y6

–H2O]2+

[M + 2H]2+y

3y

4b

5

b6

y5

y6

b4

y2

y7

2+

b8

2+

y4

2+

y3

2+,y

y2

2+,F

R

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ESI

[M + 3H]3+

[M + 2H]2+

[M + H]+

C

C

B

A

D

E

22 25

Inte

nsity

TOF MSR = 3500–5000

F3 IA3G2 F2 IA2

F1/IA1/G1

D1

Sourcechamber

R(D2) = 40–80

R(D1 + D2) = 80–160Collision dynodel/MCP detector

a

b

c

Figure 10 (a) Schematic of DTIMS-DTIMS-TOF-MS instrument. (Reprinted with permission from Analytical Chemistry.)(b) Multidimensional DTIMS-MS spectra. DTIMS-DTIMS drift-time distributions of electrosprayed bradykinin ions shown on twotimescales: the total drift time (bottom) and the drift time observed after mobility selection (tD2), that is shifted by the selection time(as indicated by the dashed vertical line). Part (a) shows the distribution for all ions and includes an inset to show the low-intensityfeature that is often associated with [Mn + nH]n+ ions. Part (b) shows the feature-labeled C after it has been selected at G2. Part(c) shows the distribution of fragment ions that are observed when C is activated at IA2 using 126 V. (Reproduced with permissionfrom Ref. 16. Copyright 2006, American Chemical Society.)

spectrometry-mass spectrometry (IMS-IMS-MS) andFAIMS-IMS-MS instruments have been reported. Tanget al.(119) reported a FAIMS-IMS-TOF MS instrumentwhich is shown in Figure 9. Ions produced from the ESIemitter are filtered by the FAIMS, focused, and pulsedinto the DTIMS. The advantage of this approach is that

the separation principles of FAIMS and IMS are different,thus this coupling is completely orthogonal.

Koeniger et al.(16) also constructed a two-stage IMS-IMS-MS instrument using the DTIMS technology(Figure 10). Ion funnels connect the two drift tubesections which are ∼1 m in length and activation grids



are applied at each funnel to allow manipulation offields which can conformationally or collisionally activateions. The total drift resolving power of this instrumentis improved to R = 80–160.(16) One mode of operatingthis instrument is to select a small window of ions fromthe first IMS separation by applying a gate (G2) atthe second funnel which only allows specific mobility-selected ions to traverse to the second drift region.This mobility-selected window can be transmitted, acti-vated, or fragmented before separation in the second IMSregion. Figure 10(b) provides example data from such anexperiment performed on bradykinin ions. The spectrumon the bottom shows the drift distribution for the doubly-and triply-charged ions in which three and two conformerpeaks are detected, respectively. A second experimentwas initiated in which only the C conformer of the triply-charged bradykinin peak was isolated and detected. CIDwas carried out on this isolated C conformer in the secondfunnel and the fragments were allowed to mobility sepa-rate in the second drift region (D2), and are shown in thetop spectrum.

Other examples of IMS-IMS-MS instruments includea recently reported DTIMS-FAIMS-qITMS hybridinstrument(120) and a 2D overtone mobility spectrom-eter (OMS) by Clemmer et al.(121) We refer the reader torecent reports of OMS which explain details of this IMSseparation method.(121 – 124)

4.4 Ion Mobility Spectrometry-Ion MobilitySpctrometry-Ion Mobility Spectrometry-MassSpectrometry

To date, the only IMS-IMS-IMS-MS instrument has beenreported by Merenbloom et al.(30) It is similar in principleto the DTIMS-DTIMS-MS discussed above; however,it provides more stages of separation and activation.Multidimensional IMS selection and activation makes itpossible to analyze more complex mixtures and extractlow-intensity features in the samples. Furthermore,this multiple mobility dimensionality is important forstudies that seek to characterize the nature of gas-phaseconformations of proteins.(125) Such insight would not beattainable without the high resolving powers and selectioncapabilities offered by IMS-IMS-MS or IMS-IMS-IMS-MS instruments.

5 APPLICATIONS OF ION MOBILITYSPECTROMETRY–MASSSPECTROMETRY

IMS–MS has been applied to a broad range ofapplications because of its ability to provide increasedseparation space, removal of chemical noise, andstructural insight into molecules. Here we only providea few examples as highlighted in Figure 11 to give thereader an insight into the advantages that can be gained

Chemical warfare

Environmentalanalysis

Proteomics

Applications of IMS-MS

R R

COOH COOH

C C HH

NH NH

Chiral species

Pharmaceuticals

Oxaloacetate Citrate

Isocitrate

α -Ketoglutarate

Succinyl-CoASuccinate

Sccinate

Malate

Acetyl-CoA

CO2

CO2

NADH + H+

NADH + H+

NADH + H+

GTP

FADH2

Metabolomics

HH

H

H

H

OO

OHCC

R2R1

CNN

Lipidomics

Figure 11 Overview of example research applications accessible with IMS–MS.



from using the combined IMS–MS approach. There areother reviews that may be helpful for obtaining an insightinto additional applications of IMS–MS.(3,126)

5.1 Proteomics

The complexity of mixtures encountered in proteomicsis enormous, such that multidimensional separationsbefore MS are necessary to obtain depth in proteomecoverage. It is clear that IMS has the capability todetect low-abundance species which would otherwisego undetected in an MS spectrum (see Figure 4a). Asmentioned earlier, the incorporation of IMS–MS into achromatographic separation occurs at no experimentalcost, therefore thousands of additional species can bedetected and/or identified with high throughput. In addi-tion, the drift times of peptides can be used along withthe chromatographic retention time to ‘map’ peptidesin multidimensional space.(127) Peptide mobilities havespecific signatures which can be correlated with chemicalcharacteristics such as hydrophobicity.(128) Several groupshave used IMS–MS for bottom-up proteomics analysis ofbiological samples such as human plasma,(104,129) mouseplasma,(112) Drosophila,(114,127,130) combinatorial peptidelibraries,(131 – 133) and other standard tryptic peptidemixtures.(78,104,119,134) Sowell et al.(111) reported on theuse of LC-IMS-MS for top-down proteomics analysis ofintact proteins; however, this is an area that could befurther explored. Biomarkers of disease, such as cancer,are also being explored using IMS–MS with MALDIimaging.(135,136)

5.2 Probing Structural Information

Early applications of IMS–MS probed structures of smallMW species, such as polyatomic ions and small inorganicclusters,(137 – 139) fullerenes,(140) and atomic cations.(141)

With the advent of ESI and MALDI, gas-phase confor-mations of higher MW species, such as proteins,(142 – 145)

DNA,(50,146,147) RNA,(148) and even viruses,(149 – 151) havebeen accessible with IMS–MS. Characterization ofgas-phase structures has relevance for understandingbiological pathways in diseases, such as Alzheimer’sdisease.(152 – 155) Since the commercialization of TWIMS,a number of groups have used IMS–MS to study biophys-ical parameters of proteins and protein complexes.(12,13)

These complexes have higher order tertiary and quater-nary structures and dynamic binding events which areonly partially understood with traditional biological andother analytical techniques, such as nuclear magneticresonance and X-ray crystallography. IMS–MS appli-cations of protein complexes have led to a betterunderstanding of oligomeric tryptophan RNA bindingattenuation protein complexes,(148) Hepatitis B virus

capsids which are 3–4 MDa in size,(149) and GroEL chap-erone systems in Escherichia coli,(156) to name a few.Much of the understanding of small inorganic systems tolarge biological systems with IMS–MS is made possiblethrough computer modeling algorithms which give insightinto shapes and sizes of molecules measured with experi-mental collision cross-sections.(12,13)

5.3 Lipidomics

Lipidomics research, which studies the pathways andnetworks of cellular lipids, is currently a rapidly growingarea in IMS–MS.(157) IMS–MS offers high-throughputanalysis, class identification, and structural informationof complex lipid samples, such as cellular membranesand phospholipids. One of the earliest studies of lipidswith IMS–MS reported on the ability of MALDI-IMS-TOF MS to distinguish sphingomyelin from peptides andoligonucleotides ionized from the same mixture.(58) Thespingomyelin ions had lower mobilities than the peptideand oligonucleotides and thus had a distinctive trend linein the 2D spectrum. Since these studies, other reportsinvestigating various classes of lipids were published.(157)

Generally, the separation of lipids in IMS–MS is due todifferences in the acyl chain length, degree of unsatura-tion, nature of the polar head group, and cationizationof individual species.(157) Different classes of phospho-lipids in complex tissue extracts and slices have beenstudied with IMS–MS.(89,158) The analysis of unsaturatedphosphatidylcholines (PCs) with TWIMS-TOF MS iden-tified a high mobility–mass correlation for saturated PCcations which was less significant for unsaturated PCcations.(159) Trimpin et al.(160) demonstrated the strengthsof multidimensional DTIMS-MS for reducing complexityof lipid samples, detecting low-abundance lipids, andelucidating structure in a global lipidomics analysis ofphospholipids.

5.4 Metabolomics

Metabolomics studies focus primarily on the analysis ofmetabolites for the purpose of early disease detectionand prevention.(161) Chemical properties of metabo-lites, such as polarity, solubility, and volatility, can varytremendously among different classes. IMS–MS has thecapability of analyzing complex and diverse samples withhigh accuracy, high peak capacity, and fast speed andhas been applied in target metabolomics analysis. Forexample, opiates and primary metabolites were analyzedby DTIMS-TOF MS such that metabolic isomers wereseparated based on mobility.(162) False-positive detec-tion of methamphetamine in hair by stand-alone MSwas improved with DTIMS–qMS analyses.(163) Further-more, the usage of IMS–MS has extended to metabolite



profiling. With IMS–MS, more than 200 intracellular E.coli metabolites containing lipids, inorganic ions, volatilealcohols and ketones, amino and nonamino organicacids, hydrophilic carbohydrates, etc. were tentativelyassigned.(164) Quantitative IMS–MS studies have beenused to monitor metabolic changes in rat lymph fluidcaused by dietary stresses.(165) Key to this work was the useof positive- and negative-mode ionization for the detec-tion of amino acids, sugars, triglycerides and diglyceridesin the presence of fatty acids and sugars, respectively.Pharmaceutical metabolite profiling of leflunomide andacetaminophen has been reported(166) and suggests thatIMS–MS is suitable for routine metabolomics analyses.

5.5 Chiral Species

In some instances, typical IMS–MS separations are ableto provide enough resolution so that isomeric and isobaricspecies are resolved.(167 – 169) However, in other cases thereare generally two IMS–MS strategies which are used toobtain enantiomeric separation.(91) The first is to add aselected chiral reference compound to the solution thatcontains analyte enantiomers. Diastereomeric complexesare formed by the chiral reference compound and analyteenantiomers, which can be physically separated in thedrift tube. For example, separation of D- and L-lacticacids was possible with FAIMS-MS by spiking theanalyte mixture solution with excess L-tryptophan.(88)

Also, six pairs of amino acid and terbutaline enantiomerswere characterized with IMS–MS through conversionof the enantiomers to metal-bound trimeric complexesof the form [MII(L-Ref)2(D/L-A)-H]+.(117,170) ESI is thepreferred ionization method with this chiral approach sothat the interactions between the enantiomers and chiralreference are not disrupted.

The second strategy of chiral separations, as mentionedearlier, is to dope the drift gas with a chiral modifier.For example, (S)- and (R)-atenolol enantiomers wereseparated with DTIMS-MS after the N2 drift gas wasdoped with (S)-(+)-2-butanol.(91) There are other reportsof IMS–MS being employed for chiral separation ofsmall molecules including amino acids, pharmaceuticals,and sugar enantiomers.(171) The reader is referred to arecent review of IMS–MS for chiral analyses.(172)

5.6 Chemical Warfare Agents

IMS is considered the most efficient technique for thedetection of CWA for its high speed, simplicity, low cost,and portability.(4,7) However, as a stand-alone techniqueit suffers from low resolving power, limited identificationability, existence of false-positive results, and samplematrix effects.(8) Most of these disadvantages can beovercomed when IMS is combined with MS.

Hill et al.(17,87,173 – 176) used DTIMS-qMS to test degra-dation products of common nerve agents and sulfurmustard gas in liquid samples. Different experimentalconditions were investigated to optimize the separationefficiency and sensitivity of CWAs’ detection includingthe ionization method (ESI, SESI, CI and Ni(63) radioac-tive ionization), ionization mode (positive/negative), driftvoltage, temperature, and matrices.(17,87,173 – 176) ACPIFAIMS-MS has been applied to detect nanogram permilliliter levels of CWAs in food and water samples.(177)

DESI with TWIMS-MS has also been applied in the detec-tion of common organophosphorus CWAs.(178) While thenumber of reports in this area is limited, it is clear that theuse of ambient ionization methods is critical for extendingCWA analysis to portable IMS–MS devices in the future.

5.7 Pharmaceuticals

IMS–MS is growing in use in pharmaceutical detectionfor its fast speed, low detection limit, and highaccuracy. However, it is unlikely that IMS–MS willbe used for online quality control in pharmaceuticalproduction processes owing to the relatively high costsof MS, however, it is a powerful technique for in-lab characterization and direct formulation analysis ofpharmaceuticals.(9)

Improvements in the accuracy of amine drug detec-tion are possible with IMS–MS over LC-MS techniquesbecause of the ability of IMS–MS to remove metabo-lite interferences.(116) The successful quantification ofamphetamine, methamphetamine, and methylenedioxyderivatives in human urine matrix demonstrated thepower of IMS–MS in the separation of rather complexpharmaceutical samples.(179) A strategy which can facil-itate the detection of active pharmaceutical ingredientsin complex matrices has also been reported by usingpolyethylene-based ‘shift reagents’ in IMS–MS analysis.These shift reagents can form noncovalent complexeswith the active pharmaceutical ingredients which movethem to different regions of the 2D mobility–massspace.(180) IMS–MS has been applied for the anal-ysis of benzodiazepine drugs(181,182) and a range ofover-the-counter and prescription tablets and creamformulations.(183)

5.8 Environmental

There are a very limited number of reports of IMS–MSuse for environmental analysis. For example, haloaceticacids were quantified from complex solutions withFAIMS-MS to obtain nanogram per milliliter detec-tion limits for samples without preconcentration orderivatization.(184) A class of important triazine pollu-tants were analyzed with FAIMS-MS.(185) Clearly, this



is an area which can be further explored with IMS–MStechnology.

6 CONCLUSIONS AND FUTURE OUTLOOK

IMS–MS represents a powerful coupling of analyticaltechnologies as demonstrated based on the numerousapplications and advantages discussed in this review.There is still room for instrumental improvements toadvance the technology further and make it moreaccessible to analytical, biological, industrial, and evenclinical laboratories. The availability of more commer-cial IMS–MS instruments will assist in this regard. Thepotential of IMS–MS for proteomics, metabolomics,lipidomics, pharmaceutical, and other applications is ofgreat interest and should be explored with this hybridapproach.

ACKNOWLEDGMENTS

The authors would like to acknowledge University ofPittsburgh Start-up Funds and the Society of AnalyticalChemists of Pittsburgh for funds to support thiswork.

ABBREVIATIONS AND ACRONYMS

2D Two-DimensionalAP-MALDI Atmosphere Pressure

Matrix-Assisted LaserDesorption/Ionization

APCI Atmospheric Pressure ChemicalIonization

CE Capillary ElectrophoresisCID Collision-Induced DissociationCV Compensation VoltageCWAs Chemical Warfare AgentsDC Direct CurrentDESI Desorption Electrospray

IonizationDTIMS Drift-Time Ion Mobility

SpectrometryESI Electrospray IonizationFAIMS High-Field-Asymmetric Ion

Mobility SpectrometryFTMS Fourier Transform Mass

SpectrometersICR Ion Cyclotron Resonance

IMS-IMS-IMS-MS Ion Mobility Spectrometry-IonMobility Spectrometry-IonMobility Spectrometry-MassSpectrometry

IMS-IMS-MS Ion Mobility Spectrometry-IonMobility Spectrometry-MassSpectrometry

IMS Ion Mobility SpectrometryIT-MS Ion Trap Mass SpectrometersLC Liquid ChromatographyLITs Linear Ion TrapsLSI Laserspray IonizationMALDI Matrix-Assisted Laser

Desorption/IonizationMS/MS Tandem Mass SpectrometryMS Mass SpectrometryMW Molecular WeightOMS Overtone Mobility SpectrometerPCs PhosphatidylcholinesQITs Quadrupole Ion TrapsqMS Quadrupole Mass SpectrometersRF Radio FrequencySESI Second Electrospray IonizationS/N Signal-to-NoiseSRIGs Stacked Ring Ion GuidesTOF-MS Time-Of-Flight Mass

SpectrometersTWIMS Traveling Wave Ion Mobility

SpectrometryUV Ultraviolet

FURTHER READING

A.B. Kanu, P. Dwivedi, M. Tam, L. Matz, H.H. Hill, J. MassSpectrom., 43, 1 (2008).

C. Uetrecht, R.J. Rose, E. van Duijn, K. Lorenzen, A.J.R. Heck,Chem. Soc. Rev., 39, 1633 (2010).

J.A. McLean, B.T. Ruotolo, K.J. Gillig, D.H. Russell, Int. J.Mass Spectrom., 240, 301 (2005).

R. Guevremont, J. Chromatogr., A, 1058, 3 (2004).

B.C. Bohrer, S.I. Merenbloom, S.L. Koeniger, A.E. Hilderbrand,D.E. Clemmer, Annu. Rev. Anal. Chem., 293, 1 (2008).

B.M. Kolakowski, Z. Mester, Analyst (Cambridge, U.K.), 132,842 (2007).

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