Clearing an ion mobility separation cell between ion mobility separation cycles

Abstract

A device arranged and designed to separate ions in time according to their ionic mobility or their differential ionic mobility, comprising: an ion guide with several electrodes (2) and a first device arranged and designed to remove unwanted ions remaining within the ion guide after ions of interest have exited the ion guide, wherein the device comprises a control system arranged and designed to carry out the following: (i) causing the device to operate in a first mode of operation in which ions are separated in time according to their ion mobility or differential ion mobility during a first period T1, and then (ii) switching the device to operate in a second mode of operation in which unwanted ions are ejected from the ion guide during a second period T2, the control system being further arranged and designed to (i) applying one or more first transient DC voltages with a first amplitude and / or a first transient velocity to the electrodes (2) during the first operating mode within or along the ion guide, such that during the first operating mode, ions within the ion guide are temporally separated according to their ion mobility or differential ion mobility, and applying one or more transient second DC voltages with a second amplitude that is greater than the first amplitude and / or with a second transient velocity that is lower than the first transient velocity to the electrodes (2) during the second operating mode within or along the ion guide, such that during the second operating mode, ions are ejected from the ion guide, and / or (ii) applying one or more first DC voltages to the electrodes (2) to generate a first DC voltage gradient within or along the ion guide during the first operating mode, such that during the first operating mode ions are caused to be separated in time within the ion guide according to their ion mobility or differential ion mobility, and applying one or more second DC voltages to the electrodes (2) to generate a second DC voltage gradient, which has a higher magnitude than the first DC voltage gradient, within or along the ion guide during the second operating mode, such that during the second operating mode ions are caused to be ejected from the ion guide.

Description

BACKGROUND OF THE PRESENT INVENTION

[0001] The present invention relates to a device arranged and designed to separate ions temporally according to a physico-chemical property such as ion mobility, and to a method for separating ions temporally according to a physico-chemical property such as ion mobility.

[0002] In many analyses involving separation, particularly targeted analysis where the mass / charge ratio and / or drift time of analytes of interest is known, the maximum ion mobility drift time of a target analyte at a given chromatographic retention time is generally known.

[0003] To improve the duty cycle of an ion mobility separator, it is known to collect ions in an ion trap before the ions are released into the ion mobility separator, allowing the ions to be separated according to their ion mobility. It is advantageous to operate with the shortest practically possible ion mobility separation cycle time.

[0004] By using the shortest practically possible ion mobility separation cycle time, the amount of charge accumulated in the upstream ion trap prior to ion mobility separation is reduced. This limits ion losses and the loss of performance of the ion mobility separation device due to space charge effects prior to separation.

[0005] Additionally, relatively short ion mobility separation cycle times (and thus short collection times) advantageously limit the amount of charge for a given analyte within the ion mobility separation device during separation. It is known that space charge effects within ion mobility separation devices can lead to distortion of ion mobility separation peak widths and also to shifts in measured ion mobility separation drift times.

[0006] Furthermore, reducing the number of ions exiting the ion mobility separation device per ion mobility separation cycle reduces the need for ion detectors and high dynamic range recording electronics downstream of the ion mobility separation device.

[0007] It is therefore advantageous to analyze an ion population eluting from a chromatography device (such as a liquid chromatography separation device) using a relatively large number of sequential short ion mobility separation cycles with short collection times, rather than analyzing the ions eluting from the chromatography device using only a relatively small number of ion mobility separation cycles with longer collection times. This maximizes the dynamic range over which the entire ion population can be recorded.

[0008] In many cases, however, ions of matrix species or other non-targeted analyte species that have relatively low ion mobility and therefore a longer drift time than the analyte ions of interest are still present in the ion mobility separation device after the analyte ions of interest have exited the ion mobility separation device. Accordingly, if a second ion population is introduced into the ion mobility separation device before ions of non-interest that have relatively low ion mobilities have exited the ion mobility separation device, the ions of non-interest that have relatively low ion mobilities will still be present in the ion mobility separation device when the second ion population is introduced.Accordingly, unwanted ions with relatively low ion mobilities appear undesirable in the second ion mobility separation cycle and appear to have relatively short ion mobility separation drift times. Accordingly, unwanted ions remaining in the ion mobility separation device after analyte ions of interest have left the ion mobility separation device cause contamination or recirculation effects. The resulting contamination or recirculation effects can lead to interference and / or misassignment of ion mobility or calculated collision cross section ("CCS") values.

[0009] The problem of falsification or circulation effects is in a high definition MS e -("HDMS e“) experiment, where fragment ions resulting from fragmentation of parent or precursor ions and exiting an ion mobility separation device can disrupt the mass / charge ratio and ion mobility.

[0010] US 2010 / 0032561 A1 (Micromass) discloses an ion tunneling device that can be operated in a first mode in which ions are separated in time according to their ion mobility, and in a second mode in which ions are separated in time according to their mass / charge ratio.

[0011] US 2010 / 108879 A1 (Micromass) discloses a mass spectrometer comprising an ion mobility separation device. In one arrangement, once ions with a desired charge state have exited the ion mobility separation device, the AC or RF voltage applied to the ion mobility separation device can be removed, so that unwanted ions still within the device are no longer radially confined and can therefore disperse.

[0012] WO 02 / 071439 A2 (Tanner) discloses a mass spectrometer with a processing section such as a collision cell. An axial field and a DC free-clearing pulse can be applied to the collision cell to influence the charge distribution within the collision cell.

[0013] It is desirable to provide an improved mass spectrometer and an improved method for mass spectrometry. SUMMARY OF THE PRESENT INVENTION

[0014] According to one aspect of the present invention, there is provided a device adapted and configured to temporally separate ions according to their ion mobility or differential ion mobility, comprising: an ion guide with several electrodes and a first device arranged and designed to remove unwanted ions remaining within the ion guide after ions of interest have exited the ion guide, wherein the device comprises a control system arranged and designed to carry out the following: (i) causing the device to operate in a first mode of operation in which ions are separated in time according to their ion mobility or differential ion mobility during a first period T1, and then (ii) switching the device to operate in a second mode of operation in which unwanted ions are substantially ejected from the ion guide during a second period T2, wherein the control system is further arranged and designed to either apply one or more first transient DC voltages having a first amplitude and / or a first transient velocity to the electrodes or to apply one or more first DC voltages to the electrodes to generate a first DC voltage gradient within or along the ion guide during the first operating mode, such that during the first operating mode, ions within the ion guide are caused to be separated in time according to their ion mobility or differential ion mobility, and wherein the control system is further configured and adapted to either apply one or more second transient DC voltages having a second amplitude and / or a second transient velocity to the electrodes or apply one or more second DC voltages to the electrodes to generate a second DC voltage gradient within or along the ion guide during the second mode of operation, thereby causing ions to be ejected from the ion guide during the second mode of operation.

[0015] The present invention solves the problem of falsification of ion mobility separation peaks and enables optimization of the ion mobility separation cycle time for a given experiment.

[0016] To prevent unwanted contamination effects, according to the preferred embodiment, any remaining unwanted ions are preferably removed from the ion mobility separation device or cell once ions of interest have been eluted from the ion mobility separation device or cell. Any unwanted ions remaining or otherwise still present in the ion mobility separation device or cell are preferably removed or otherwise ejected from the ion mobility separation device or cell before a next or subsequent ion pulse is introduced into the ion mobility separation device.Ions to be subsequently separated in the ion mobility separation device are preferably collected in an upstream collection device or ion trap during the removal time or period, while unwanted ions are preferably ejected from the ion mobility separation device or cell.

[0017] The preferred embodiment advantageously enables ion mobility separation analysis of analyte ions within a defined ion mobility range without being affected by interference or corruption effects resulting from ions with relatively low ion mobilities.

[0018] Because the maximum ion mobility separation drift time required for an analysis preferably changes during the elution of analytes from an upstream chromatographic separation device (such as a liquid chromatography device), the duration of the ion mobility separation cycle preferably changes during the analysis to maintain the optimal ion mobility separation cycle time based on the different target compounds of interest present in the sample being analyzed.

[0019] It is known to remove ions from a collision gas cell during a period between scans to minimize crosstalk between different ion populations when the instrument state is changed. However, gas cells are not separation devices, and known arrangements do not progressively adjust the time at which removal of unwanted ions occurs based on the specific analyte ions.

[0020] In this regard, it should be understood that the present invention is different from the arrangement described in WO 02 / 071439 A2 (Tanner), in which a DC clearing pulse can be used to remove ions from a collision cell (which is not a separation device). In contrast, the present invention relates to the removal of unwanted ions from an ion guide in a second mode of operation, wherein, in a preceding first mode of operation, ions are temporally separated according to their ion mobility or differential ion mobility within or along the ion guide.

[0021] The control system according to the present invention is arranged and designed to apply one or more DC voltages to the electrodes of the ion guide to cause ions within the ion guide to be temporally separated according to their ion mobility or their differential ion mobility during a first operating mode. According to a particularly preferred embodiment, the one or more DC voltages applied to the electrodes during the first operating mode comprise transient DC voltages having a first amplitude and preferably a first transient speed or first switching time. According to less preferred embodiments, the one or more DC voltages applied to the electrodes during the first operating mode may comprise one or more DC voltages that generate a first DC voltage gradient within or along the ion guide.

[0022] The control system according to the present invention is further configured and adapted to apply one or more DC voltages to the electrodes of the ion guide to cause ions to be ejected from the ion guide during a second operating mode. According to a particularly preferred embodiment, the one or more DC voltages applied to the electrodes during the second operating mode comprise transient DC voltages having a second amplitude and preferably a second transient speed or second switching time. According to less preferred embodiments, the one or more DC voltages applied to the electrodes during the second operating mode comprise one or more DC voltages that generate a second DC voltage gradient within or along the ion guide.

[0023] Therefore, according to the present invention, during the second operating mode, ions are actively ejected from the ion guide by applying DC voltages to the electrodes of the ion guide. Actively ejecting ions in this manner is particularly advantageous because it allows these unwanted ions to be removed from the ion guide over a shorter period of time than with other methods. Accordingly, the present invention differs, for example, from the method of US 2010 / 108879 A1 (Micromass), which does not disclose applying DC voltages to the electrodes of the ion guide to eject ions, but instead allows ions to spread radially from the ion guide over a longer period of time by switching off the radially confining RF electric fields.

[0024] The device preferably comprises a second device which is arranged and designed to introduce ions into the ion guide in a pulsed manner.

[0025] The second device preferably comprises an ion trap or an ion gate.

[0026] The second device is preferably arranged and designed to introduce a first group of ions into the ion guide in a pulsed manner, and the first device is arranged and designed to remove the unwanted ions from the ion guide before introducing a second or subsequent ion pulse into the ion guide.

[0027] According to a less preferred embodiment, substantially all ions can never be removed from a section at the front of the ion guide during use. According to this less preferred embodiment, unwanted ions are caused to pass into a second section of the ion guide after the time at which ions of interest have eluted. Ions can then be eliminated or removed from the second section of the ion guide at substantially the same time as a second ion pulse is introduced into the front of the ion guide. According to this less preferred embodiment, the clearing pulse is preferably over before ions having the highest ion mobility reach the second part of the ion guide.

[0028] The control system is preferably arranged and designed to set the first period T1 and the second period T2 such that T2 < T1.

[0029] The control system is preferably arranged and designed to switch repeatedly between at least the first operating mode and the second operating mode several times during a single detection.

[0030] The control system is preferably arranged and designed to progressively change, shorten or lengthen the first period T1 during the course of a recording.

[0031] The control system may be arranged and designed to progressively change, shorten or lengthen the second period T2 during the course of a survey.

[0032] The control system is preferably arranged and designed to keep the second period T2 substantially constant over the course of a detection.

[0033] The first amplitude is preferably selected from the group consisting of: (i) < 5 V, (ii) 5 - 10 V, (iii) 10 - 15 V, (iv) 15 - 20 V, (v) 20 - 25 V, (vi) 25 - 30 V, (vii) 30 - 35 V, (viii) 35 - 40 V, (ix) 40 - 45 V, (x) 45 - 50 V and (xi) > 50 V.

[0034] The control system may be arranged and designed to keep the first amplitude substantially constant during the first mode of operation.

[0035] The control system is preferably arranged and designed to change, decrease or increase the first amplitude during the first operating mode.

[0036] The control system is preferably arranged and designed to apply the one or more first transient DC voltages to the electrodes at a first rate or a first speed during the first mode of operation to cause ions to be temporally separated within the ion guide according to their ion mobility or differential ion mobility during the first mode of operation.

[0037] The first rate or speed is preferably selected from the group consisting of: (i) < 50 m / s, (ii) 50 - 100 m / s, (iii) 100 - 150 m / s, (iv) 150 - 200 m / s, (v) 200 - 250 m / s, (vi) 250 - 300 m / s, (vii) 300 - 350 m / s, (viii) 350 - 400 m / s, (ix) 400 - 450 m / s, (x) 450 - 500 m / s, (xi) 500 - 550 m / s, (xii) 550 - 600 m / s, (xiii) 600 - 650 m / s, (xiv) 650 - 700 m / s, (xv) 700 - 750 m / s, (xvi) 750 - 800 m / s, (xvii) 800 - 850 m / s, (xviii) 850 - 900 m / s, (xix) 900 - 950 m / s, (xx) 950 - 1000 m / s and (xxi) > 1000 m / s.

[0038] The control system is preferably arranged and designed to maintain the first rate or the first speed substantially constant during the first mode of operation.

[0039] The control system may be arranged and designed to change, increase, or decrease the first rate or the first speed during the first mode of operation.

[0040] According to one embodiment, in the first operating mode, the ion guide is maintained at a pressure selected from the group consisting of: (i) < 0.0001 mbar, (ii) 0.0001 - 0.001 mbar, (iii) 0.001 - 0.01 mbar, (iv) 0.01 - 0.1 mbar, (v) 0.1 - 1 mbar, (vi) 1 - 10 mbar, (vii) 10 - 100 mbar, (viii) 100 - 1000 mbar and (ix) > 1000 mbar.

[0041] The second amplitude is preferably selected from the group consisting of: (i) < 5 V, (ii) 5 - 10 V, (iii) 10 - 15 V, (iv) 15 - 20 V, (v) 20 - 25 V, (vi) 25 - 30 V, (vii) 30 - 35 V, (viii) 35 - 40 V, (ix) 40 - 45 V, (x) 45 - 50 V and (xi) > 50 V.

[0042] The second amplitude is preferably greater than (or less than or equal to) the first amplitude.

[0043] The magnitude of the second DC voltage gradient is preferably greater than (or less than or equal to) the magnitude of the first DC voltage gradient.

[0044] The control system is preferably arranged and designed to apply the one or more second transient DC voltages to the electrodes at a second rate or a second speed during the second mode of operation to cause ions to be ejected from the ion guide during the second mode of operation.

[0045] The second rate or speed is preferably selected from the group consisting of: (i) < 50 m / s, (ii) 50 - 100 m / s, (iii) 100 - 150 m / s, (iv) 150 - 200 m / s, (v) 200 - 250 m / s, (vi) 250 - 300 m / s, (vii) 300 - 350 m / s, (viii) 350 - 400 m / s, (ix) 400 - 450 m / s, (x) 450 - 500 m / s, (xi) 500 - 550 m / s, (xii) 550 - 600 m / s, (xiii) 600 - 650 m / s, (xiv) 650 - 700 m / s, (xv) 700 - 750 m / s, (xvi) 750 - 800 m / s, (xvii) 800 - 850 m / s, (xviii) 850 - 900 m / s, (xix) 900 - 950 m / s, (xx) 950 - 1000 m / s and (xxi) > 1000 m / s.

[0046] The second rate or speed is preferably less than (or greater than or equal to) the first rate or speed.

[0047] According to one embodiment, in the second operating mode, the ion guide is preferably maintained at a pressure selected from the group consisting of: (i) < 0.0001 mbar, (ii) 0.0001 - 0.001 mbar, (iii) 0.001 - 0.01 mbar, (iv) 0.01 - 0.1 mbar, (v) 0.1 - 1 mbar, (vi) 1 - 10 mbar, (vii) 10 - 100 mbar, (viii) 100 - 1000 mbar and (ix) > 1000 mbar.

[0048] According to another aspect of the present invention, a mass spectrometer is provided which comprises a device as described above.

[0049] According to one aspect of the present invention, there is provided a method for temporally separating ions according to their ion mobility or their differential ion mobility, comprising: Providing an ion guide having a plurality of electrodes, and Removing unwanted ions remaining within the ion guide after ions of interest have exited the ion guide, the method further comprising: Applying either one or more first transient DC voltages to the electrodes having a first amplitude and / or a first transient velocity or one or more first DC voltages to the electrodes to generate a first DC voltage gradient within or along the ion guide during the first operating mode, so as to cause ions in a first operating mode to be temporally separated within the ion guide according to their ion mobility or their differential ion mobility during a first period T1, and then

[0050] Applying either one or more second transient DC voltages to the electrodes having a second amplitude and / or a second transient velocity or one or more second DC voltages to the electrodes to create a second DC voltage gradient within or along the ion guide during the second mode of operation, thereby causing ions to be ejected from the ion guide in a second mode of operation during a second time period T2.

[0051] The method further comprises the pulsed introduction of ions into the ion guide.

[0052] The method also uses an ion trap or ion gate to introduce pulsed ions into the ion guide.

[0053] In the method, a first group of ions is introduced into the ion guide in a pulsed manner and unwanted ions are removed from the ion guide before a second or subsequent ion pulse is introduced into the ion guide.

[0054] In the method, the first period T1 and the second period T2 are further defined such that T2 < T1.

[0055] The method further comprises repeatedly switching between the first operating mode and the second operating mode at least several times during a single acquisition.

[0056] In the method, the first period T1 is preferably progressively changed, shortened or extended during the course of a recording.

[0057] In the method, the second period T2 is preferably progressively changed, shortened or extended during the course of a recording.

[0058] In the method, the second period T2 is preferably kept substantially constant during the course of a detection.

[0059] The first amplitude is preferably selected from the group consisting of: (i) < 5 V, (ii) 5 - 10 V, (iii) 10 - 15 V, (iv) 15 - 20 V, (v) 20 - 25 V, (vi) 25 - 30 V, (vii) 30 - 35 V, (viii) 35 - 40 V, (ix) 40 - 45 V, (x) 45 - 50 V and (xi) > 50 V.

[0060] In the method, the first amplitude is further kept substantially constant during the first operating mode.

[0061] In the method, the first amplitude may further be changed, decreased or increased during the first operating mode.

[0062] The method preferably further comprises applying the one or more first transient DC voltages to the electrodes at a first rate or a first velocity during the first mode of operation to cause ions within the ion guide to be temporally separated according to their ion mobility or differential ion mobility during the first mode of operation.

[0063] The first rate or speed is preferably selected from the group consisting of: (i) < 50 m / s, (ii) 50 - 100 m / s, (iii) 100 - 150 m / s, (iv) 150 - 200 m / s, (v) 200 - 250 m / s, (vi) 250 - 300 m / s, (vii) 300 - 350 m / s, (viii) 350 - 400 m / s, (ix) 400 - 450 m / s, (x) 450 - 500 m / s, (xi) 500 - 550 m / s, (xii) 550 - 600 m / s, (xiii) 600 - 650 m / s, (xiv) 650 - 700 m / s, (xv) 700 - 750 m / s, (xvi) 750 - 800 m / s, (xvii) 800 - 850 m / s, (xviii) 850 - 900 m / s, (xix) 900 - 950 m / s, (xx) 950 - 1000 m / s and (xxi) > 1000 m / s.

[0064] The method further comprises maintaining the first rate or speed substantially constant during the first mode of operation.

[0065] In the method, preferably, the first rate or the first speed is further changed, increased or decreased during the first operating mode.

[0066] In the first mode of operation, the ion guide is preferably maintained at a pressure selected from the group consisting of: (i) < 0.0001 mbar, (ii) 0.0001 - 0.001 mbar, (iii) 0.001 - 0.01 mbar, (iv) 0.01 - 0.1 mbar, (v) 0.1 - 1 mbar, (vi) 1 - 10 mbar, (vii) 10 - 100 mbar, (viii) 100 - 1000 mbar and (ix) > 1000 mbar.

[0067] The second amplitude is preferably selected from the group consisting of: (i) < 5 V, (ii) 5 - 10 V, (iii) 10 - 15 V, (iv) 15 - 20 V, (v) 20 - 25 V, (vi) 25 - 30 V, (vii) 30 - 35 V, (viii) 35 - 40 V, (ix) 40 - 45 V, (x) 45 - 50 V and (xi) > 50 V.

[0068] The second amplitude is preferably larger than the first amplitude.

[0069] The second DC voltage gradient preferably has a higher magnitude than the first DC voltage gradient.

[0070] The one or more second transient DC voltages are preferably applied to the electrodes at a second rate or a second velocity during the second mode of operation to cause ions to be ejected from the ion guide during the second mode of operation.

[0071] The second rate or speed is preferably selected from the group consisting of: (i) < 50 m / s, (ii) 50 - 100 m / s, (iii) 100 - 150 m / s, (iv) 150 - 200 m / s, (v) 200 - 250 m / s, (vi) 250 - 300 m / s, (vii) 300 - 350 m / s, (viii) 350 - 400 m / s, (ix) 400 - 450 m / s, (x) 450 - 500 m / s, (xi) 500 - 550 m / s, (xii) 550 - 600 m / s, (xiii) 600 - 650 m / s, (xiv) 650 - 700 m / s, (xv) 700 - 750 m / s, (xvi) 750 - 800 m / s, (xvii) 800 - 850 m / s, (xviii) 850 - 900 m / s, (xix) 900 - 950 m / s, (xx) 950 - 1000 m / s and (xxi) > 1000 m / s.

[0072] The second rate or the second speed is preferably less than the first rate or the first speed.

[0073] In the second mode of operation, the ion guide is preferably maintained at a pressure selected from the group consisting of: (i) < 0.0001 mbar, (ii) 0.0001 - 0.001 mbar, (iii) 0.001 - 0.01 mbar, (iv) 0.01 - 0.1 mbar, (v) 0.1 - 1 mbar, (vi) 1 - 10 mbar, (vii) 10 - 100 mbar, (viii) 100 - 1000 mbar and (ix) > 1000 mbar.

[0074] According to another aspect of the present invention, there is provided a method of mass spectrometry comprising a method as described above.

[0075] According to one aspect of the present invention, a device is provided which is arranged and designed to separate ions in time according to a physico-chemical property comprising: an ion guide with several electrodes and a first device arranged and designed to remove unwanted ions remaining within the ion guide after ions of interest have exited the ion guide.

[0076] According to a less preferred embodiment, the physicochemical property comprises mass or mass / charge ratio.

[0077] The first device is preferably arranged and designed to remove unwanted ions remaining within the ion guide after ions of interest have exited the ion guide by changing, increasing or decreasing the amplitude and / or frequency and / or phase of one or more AC or RF potentials applied to the plurality of electrodes.

[0078] The first device is preferably arranged and designed to remove unwanted ions remaining within the ion guide after ions of interest have exited the ion guide by applying one or more deflection voltages to one or more sections of the ion guide.

[0079] The first device is preferably arranged and designed to remove unwanted ions remaining within the ion guide after ions of interest have exited the ion guide by applying one or more gas pulses or pulses of other substances to the ion guide.

[0080] According to another aspect of the present invention, there is provided a mass spectrometer comprising a device as described above.

[0081] According to another aspect of the present invention, there is provided a method for temporally separating ions according to a physico-chemical property, comprising: Providing an ion guide having a plurality of electrodes, and Removing unwanted ions that remain in the ion guide after ions of interest have exited the ion guide. According to another aspect of the present invention, there is provided a method of mass spectrometry comprising a method as described above.

[0082] According to one aspect of the present invention, there is provided a method for mass spectrometry comprising: Introducing an ion population into an ion mobility separation or mass / charge ratio separation device, Separating the ions according to their ion mobility and / or their mass / charge ratio during a period T1 after ions of interest have exited the device, preferably rapidly removing any ions still in the device after a period T1 during a subsequent period T2, where T2 < T1, and Introducing a second ion population into the device. The period T1 may vary.

[0083] According to one embodiment, the mass spectrometer may further comprise: (a) an ion source selected from the group consisting of: (i) an electrospray ionization (“ESI”) ion source, (ii) an atmospheric pressure photoionization (“APPI”) ion source, (iii) an atmospheric pressure chemical ionization (“APCI”) ion source, (iv) a matrix-assisted laser desorption ionization (“MALDI”) ion source, (v) a laser desorption ionization (“LDI”) ion source, (vi) an atmospheric pressure ionization (“API”) ion source, (vii) a desorption ionization on silicon (“DIOS”) ion source, (viii) an electron impact (“El”) ion source, (ix) a chemical ionization (“Cl”) ion source, (x) a field ionization (“Fi”) ion source, (xi) a field desorption (“FD”) ion source, (xii) an inductively coupled plasma (“ICP”) ion source, (xiii) a fast atom bombardment (“FAB”) ion source, (xiv) a liquid secondary ion mass spectrometry (“LSIMS”) ion source,(xv) a desorption electrospray ionization (“DESI”) ion source, (xvi) a radioactive nickel-63 ion source, (xvii) an atmospheric pressure matrix-assisted laser desorption ionization ion source, (xviii) a thermal spray ion source, (xix) an atmospheric sampling glow discharge ionization (“ASGDI”) ion source, (xx) a glow discharge (“GD”) ion source, (xxi) an impactor ion source, (xxii) a direct analysis in real-time (“DART”) ion source, (xxii) a laser spray ionization (“LSI”) ion source, (xxiv) a sonic spray ionization (“SSI”) ion source, (xxv) a matrix-assisted Inlet ionization (“MAII”) ion source, (xxvi) a solvent-assisted inlet ionization (“SAII”) ion source, (xxvii) a desorption electrospray ionization (“DESI”) ion source, and (xxviii) a laser ablation electrospray ionization (“LAESI”) ion source, and / or, (b) one or more continuous or pulsed ion sources and / or (c) one or more ion guides and / or (d) one or more ion mobility separation devices and / or one or more field asymmetric ion mobility spectrometer devices and / or (e) one or more ion traps or one or more ion confinement regions and / or (f) one or more collision, fragmentation or reaction cells selected from the group consisting of: (i) a collision-induced dissociation (“CID”) fragmentation device, (ii) a surface-induced dissociation (“SID”) fragmentation device, (iii) an electron transfer dissociation (“ETD”) fragmentation device, (iv) an electron capture dissociation (“ECD”) fragmentation device, (v) an electron impact or impact dissociation fragmentation device, (vi) a photo-induced dissociation (“PID”) fragmentation device, (vii) a laser-induced dissociation fragmentation device, (viii) an infrared radiation-induced dissociation device, (ix) a Ultraviolet radiation-induced dissociation device, (x) a nozzle-skimmer interface fragmentation device, (xi) an in-source fragmentation device,(xii) an in-source collision-induced dissociation fragmentation device, (xiii) a thermal or temperature source fragmentation device, (xiv) an electric field-induced fragmentation device, (xv) a magnetic field-induced fragmentation device, (xvi) an enzyme digestion or enzyme degradation fragmentation device, (xvii) an ion-ion reaction fragmentation device, (xviii) an ion-molecule reaction fragmentation device, (xix) an ion-atom reaction fragmentation device, (xx) an ion-metastable ion reaction fragmentation device, (xxi) an ion-metastable molecule reaction fragmentation device, (xxii) an ion-metastable atom reaction fragmentation device, (xxiii) an ion-ion reaction device for reacting ions to form adducts or product ions, (xxiv) an ion-molecule reaction device for reacting ions to form adducts or product ions,(xxv) an ion-atom reaction device for reacting ions to form adducts or product ions, (xxvi) an ion-metastable ion reaction device for reacting ions to form adducts or product ions, (xxvii) an ion-metastable molecule reaction device for reacting ions to form adducts or product ions, (xxviii) an ion-metastable atom reaction device for reacting ions to form adducts or product ions and (xxix) an electron ionization dissociation (“EID”) fragmentation device, and / or, (g) a mass analyzer selected from the group consisting of: (i) a quadrupole mass analyzer, (ii) a two-dimensional or linear quadrupole mass analyzer, (iii) a Paul or three-dimensional quadrupole mass analyzer, (iv) a Penning trap mass analyzer, (v) an ion trap mass analyzer, (vi) a magnetic sector mass analyzer, (vii) an ion cyclotron resonance (“ICR”) mass analyzer, (viii) a Fourier transform ion cyclotron resonance (“FTICR”) mass analyzer, (ix) an electrostatic mass analyzer arranged to generate an electrostatic field having a quadrolologarithmic potential distribution, (x) an electrostatic Fourier transform mass analyzer, (xi) a Fourier transform mass analyzer, (xii) a time-of-flight mass analyzer,(xiii) an orthogonal acceleration time-of-flight mass analyzer and (xiv) a linear acceleration time-of-flight mass analyzer and / or, (h) one or more energy analyzers or electrostatic energy analyzers and / or (i) one or more ion detectors and / or (j) one or more mass filters selected from the group consisting of: (i) a quadrupole mass filter, (ii) a two-dimensional or linear quadrupole ion trap, (iii) a Paul or three-dimensional quadrupole ion trap, (iv) a Penning ion trap, (v) an ion trap, (vi) a magnetic sector mass filter, (vii) a time-of-flight mass filter and (viii) a Wien filter and / or (k) a device or ion gate for pulsing ions and / or (l) an apparatus for converting a substantially continuous ion beam into a pulsed ion beam.

[0084] The mass spectrometer may further comprise one of the following: (i) a C-trap and a mass analyzer having an outer tubular electrode and a coaxial inner spindle-like electrode forming an electrostatic field with a quadrolologarithmic potential distribution, wherein in a first mode of operation, ions are transferred to the C-trap and then injected into the mass analyzer, and wherein in a second mode of operation, ions are transferred to the C-trap and then transferred to a collision cell or electron transfer dissociation device where at least some ions are fragmented into fragment ions, and wherein the fragment ions are then transferred to the C-trap before being injected into the mass analyzer, and / or (ii) a ring stack ion guide comprising a plurality of electrodes each having an aperture through which ions are passed in use, and wherein the distance between the electrodes increases along the ion path, and wherein the apertures in the electrodes in an upstream portion of the ion guide have a first diameter, and wherein the apertures in the electrodes in a downstream portion of the ion guide have a second diameter smaller than the first diameter, and wherein opposite phases of an AC or RF voltage are applied in use to successive electrodes.

[0085] According to one embodiment, the mass spectrometer further comprises a device configured and designed to supply an AC or RF voltage to the electrodes. The AC or RF voltage preferably has an amplitude selected from the group consisting of: (i) < 50 V peak-to-peak, (ii) 50 - 100 V peak-to-peak, (iii) 100 - 150 V peak-to-peak, (iv) 150 - 200 V peak-to-peak, (v) 200 - 250 V peak-to-peak, (vi) 250 - 300 V peak-to-peak, (vii) 300 - 350 V peak-to-peak, (viii) 350 - 400 V peak-to-peak, (ix) 400 - 450 V peak-to-peak, (x) 450 - 500 V peak-to-peak and (xi) > 500 V peak-to-peak.

[0086] The AC or RF voltage preferably has a frequency selected from the group consisting of: (i) < 100 kHz, (ii) 100 - 200 kHz, (iii) 200 - 300 kHz, (iv) 300 - 400 kHz, (v) 400 - 500 kHz, (vi) 0.5 - 1.0 MHz, (vii) 1.0 - 1.5 MHz, (viii) 1.5 - 2.0 MHz, (ix) 2.0 - 2.5 MHz, (x) 2.5 - 3.0 MHz, (xi) 3.0 - 3.5 MHz, (xii) 3.5 - 4.0 MHz, (xiii) 4.0 - 4.5 MHz, (xiv) 4.5 - 5.0 MHz, (xv) 5.0 - 5.5 MHz, (xvi) 5.5 - 6.0 MHz, (xvii) 6.0 - 6.5 MHz, (xviii) 6.5 - 7.0 MHz, (xix) 7.0 - 7.5 MHz, (xx) 7.5 - 8.0 MHz, (xxi) 8.0 - 8.5 MHz, (xxii) 8.5 - 9.0 MHz, (xxiii) 9.0 - 9.5 MHz, (xxiv) 9.5 - 10.0 MHz and (xxv) > 10.0 MHz.

[0087] The mass spectrometer may also comprise a chromatography or other separation device upstream of an ion source. According to one embodiment, the chromatography separation device comprises a liquid chromatography or gas chromatography device. According to another embodiment, the separation device may comprise: (i) a capillary electrophoresis ("CE") separation device, (ii) a capillary electrochromatography ("CEC") separation device, (iii) a separation device comprising a substantially rigid ceramic-based multilayer microfluidic substrate ("ceramic tile"), or (iv) a supercritical fluid chromatography separation device.

[0088] The mass spectrometer may include a chromatography detector.

[0089] The chromatography detector may comprise a destructive chromatography detector, preferably selected from the group consisting of: (i) a flame ionization detector (“FID”), (ii) an aerosol-based detector or a nanoquantity analyte detector (“NQAD”), (iii) a flame photometry detector (“FPD”), (iv) an atomic emission detector (“AED”), (v) a nitrogen phosphorus detector (“NPD”), and (vi) an evaporative light scattering detector (“ELSD”).Additionally or alternatively, the chromatography detector may comprise a non-destructive chromatography detector, preferably selected from the group consisting of: (i) a fixed or variable wavelength UV detector, (ii) a thermal conductivity detector (TCD), (iii) a fluorescence detector, (iv) an electron capture detector (ECD), (v) a conductivity monitor, (vi) a photoionization detector (PID), (vii) a refractive index detector (RID), (viii) a radio frequency detector, and (ix) a chiral detector.

[0090] The ion guide is preferably maintained at a pressure selected from the group consisting of: (i) < 0.0001 mbar, (ii) 0.0001 - 0.001 mbar, (iii) 0.001 - 0.01 mbar, (iv) 0.01 - 0.1 mbar, (v) 0.1 - 1 mbar, (vi) 1 - 10 mbar, (vii) 10 - 100 mbar, (viii) 100 - 1000 mbar and (ix) > 1000 mbar.

[0091] According to one embodiment, analyte ions can be subjected to electron transfer dissociation ("ETD") fragmentation in an electron transfer dissociation fragmentation device. Analyte ions are preferably caused to interact with ETD reagents within an ion guide or fragmentation device.

[0092] According to one embodiment, to effect electron transfer dissociation, either: (a) analyte ions are fragmented or caused to dissociate and form product or fragment ions after interacting with reagent ions and / or (b) electrons are transferred from one or more reagent anions or negatively charged ions to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (c) analyte ions are fragmented or caused to dissociate and form product or fragment ions after interacting with neutral reagent gas molecules or atoms or a non-ionic reagent gas,and / or (d) electrons are transferred from one or more neutral non-ionic or uncharged source gases or vapors to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (e) electrons are transferred from one or more neutral non-ionic or uncharged superbase reagent gases or vapors to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (f) electrons from one or more neutral,non-ionic or uncharged alkali metal gases or vapors to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (g) electrons are transferred from one or more neutral, non-ionic or uncharged gases, vapors or atoms to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, wherein the one or more neutral, non-ionic or uncharged gases, vapors or atoms are selected from the group consisting of: (i) sodium vapor or atoms, (ii) lithium vapor or atoms, (iii) potassium vapor or atoms,(iv) rubidium vapor or atoms, (v) caesium vapor or atoms, (vi) francium vapor or atoms, (vii) C, 60 vapor or atoms and (viii) magnesium vapor or atoms.

[0093] The multiply charged analyte cations or positively charged ions preferably include peptides, polypeptides, proteins or biomolecules.

[0094] According to one embodiment, to effect electron transfer dissociation: (a) the reagent anions or negatively charged ions are derived from a polyaromatic hydrocarbon or a substituted polyaromatic hydrocarbon and / or (b) the reagent anions or negatively charged ions are derived from the group consisting of: (i) anthracene, (ii) 9,10-diphenylanthracene, (iii) naphthalene, (iv) fluorine, (v) phenanthrene, (vi) pyrene, (vii) fluoranthene, (viii) chrysene, (ix) triphenylene, (x) perylene, (xi) acridine, (xii) 2,2'-dipyridyl, (xiii) 2,2'-biquinoline, (xiv) 9-anthracenecarbonitrile, (xv) dibenzothiophene, (xvi) 1,10'-phenanthroline, (xvii) 9'-anthracenecarbonitrile and (xviii) anthraquinone and / or (c) the reagent ions or negatively charged ions comprise azobenzene anions or azobenzene radical anions.

[0095] According to a particularly preferred embodiment, the electron transfer dissociation fragmentation process comprises the interaction of analyte ions with reagent ions, wherein the reagent ions comprise dicyanobenzene, 4-nitrotoluene or azulene. BRIEF DESCRIPTION OF THE DRAWING

[0096] Various embodiments of the present invention will now be described by way of example only and with reference to the accompanying drawings, in which: Fig. 1A an ion mobility separation device preferably used in the (y, z) dimension according to a preferred embodiment of the present invention, and Fig. 1B a ring electrode of the ion mobility separation device in the (x, y) dimension, Fig. Figure 2A shows an ion mobility separation spectrum related to the different fragment ions resulting from the fragmentation of doubly charged Glu-fibrinopeptide-[M+H] 2+-parent ions with a mass / charge ratio of 785.6 in a collision-induced dissociation (“CID”) cell and then separating the resulting fragment ions in a preferred ion mobility separation device, and Fig. 2B illustrates a preferred aspect of the present invention wherein, in one mode of operation, ions are substantially removed from the preferred ion mobility separation device in a relatively short period of time. Fig. 3 a fragment ion mass spectrum referring to the fragment ions resulting from the CID fragmentation of Glu-fibrinopeptide-[M+H] 2+ -parent ions with a mass / charge ratio of 785.6, and Fig. 4A a two-dimensional nested IMS-MS dataset and Fig. 4B the problem of falsification or circulation by using the same data as in Fig. 4A, but where the ion mobility separation drift time has been shortened and subsequent ion packets are pulsed into the ion mobility separation device while other ions are still present in the ion mobility separation device. DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

[0097] A preferred embodiment of the present invention will now be described with reference to Fig. 1A described.

[0098] Fig. Figure 1A shows an ion mobility separation device according to a preferred embodiment of the present invention, wherein the ion mobility separation device comprises a plurality of electrodes, preferably comprising an RF-confined ring stack. The ion mobility separation device preferably comprises an entrance electrode 1, a series of ring electrodes 2, and an exit electrode 3. Opposite phases of an alternating voltage or potential, preferably oscillating at RF frequency, are preferably applied to alternating ring electrodes 2 to generate a radial RF confinement force such that ions within the ion mobility separation device are preferably radially confined by a radial pseudopotential barrier in the ion mobility separation device.

[0099] Fig. 1A shows the ion mobility separation device in the (y, z) dimension, and Fig. Figure 1B shows a single ring electrode 2 of the ion mobility separation device in the (x, y) dimension. In operation, ions are preferably introduced into the ion mobility separation device in a pulsed manner, and once the ions have entered the ion mobility separation device, they are then preferably forced from the ion mobility separation device's inlet 1 to its outlet 3 by applying one or more traveling DC voltage waves or DC potentials 4, preferably applied to the electrodes that are part of the ion mobility separation device. The one or more DC voltage waves preferably comprise one or more transient DC voltages, preferably applied at a first transient velocity to the ring electrodes 2, and preferably force ions from the inlet 1 to the outlet 3 of the ion mobility separation device.

[0100] Fig. Figure 2A shows an ion mobility separation spectrum of fragment ions resulting from the fragmentation of doubly charged Glu-fibrinopeptide-[M+H] 2+ -parent ions with a mass / charge ratio of 785.6 in a collision-induced dissociation (“CID”) fragmentation device and then passing the resulting fragment ions into the ion mobility separation device to separate the fragment ions in time. A corresponding mass spectrum of the fragment ions is shown in Fig. 3 shown.

[0101] The Fig. The ion mobility separation spectrum shown in Figure 2A was obtained by setting the speed of the traveling wave (i.e., the first transient speed or the effective speed or rate at which the one or more transient DC voltages were progressively applied to the ring electrodes 2 along the axial length of the ion mobility separation device) to 650 m / s and also by ramping the amplitude of the traveling wave (i.e., the amplitude of the one or more first transient DC voltages applied to the electrodes 2) from 22.2 V to 40 V over the course of the ion mobility separation time.

[0102] The ion mobility separation device was maintained at approximately 2.5 mbar nitrogen, and the length of the ion mobility separation device was 250 mm. Under these conditions, ions preferentially move along and through the ion mobility separation device at a velocity that is preferably related to their ion mobility, i.e., the ions are preferentially separated in time according to their ion mobility.

[0103] The longest drift time for the lowest-mobility ions generated was approximately 10 ms. Ions temporally separated within the preferred ion mobility separation device preferably travel along the axis of the ion mobility separation device or otherwise traverse it at a speed significantly lower than the speed of the traveling DC wave. This means that the ions can propagate along the ion mobility separation device at a speed of, for example, approximately 25 m / s, while the transient DC voltages can effectively be applied to or translated along the electrodes 2 at a significantly higher rate or speed, for example, 650 m / s. Accordingly, ions effectively pass over the DC wavefronts many times during the course of the ion mobility separation. This effect is fundamental to maintaining ion mobility separation.

[0104] To illustrate the utility of the present invention, consider a target ion of interest being pulsed into the ion mobility separation device described above, along with other ions of no interest. The target ion of interest may elute from the ion mobility separation device shortly before 3 ms. In this case, any ions exiting the cell after 3 ms are of no interest.

[0105] If the ion mobility separation cycle time—the time between successive releases of ion packets or ion pulses into the ion mobility separation device—is reduced to encompass only this drift time range, ions expected to elute after 3 ms would still be in the ion mobility separation device during the next ion mobility separation. As a result, these ions would appear at an apparently earlier drift time in the subsequent ion mobility separation spectrum. It is therefore clear that the ion mobility separation device would suffer from falsification or recirculation effects.

[0106] Falsification or circulation effects would cause significant problems. The possible falsification or circulation effects will now be discussed in more detail with reference to the Fig. 4A and Fig. 4B.

[0107] Fig. Figure 4A shows a two-dimensional nested IMS-MS data set showing the relationship between the ion mobility drift time of a group of ions and their mass / charge ratio. The region within the Fig. The ellipse shown in Figure 4A represents the IMS-MS space, which is filled with singly charged ions with different mass / charge values ​​such as fragment ions formed by fragmenting Glu-fibrinopeptide-[M+H] 2+ -Precursor ions with a mass / charge ratio of 785.6 could be generated in a collision-induced dissociation (“CID”) cell, as described in detail above with reference to the Fig. 2A and Fig. 3 has been explained.

[0108] During normal operation, multiple nested IMS-MS data sets can be summed to produce a summed two-dimensional nested IMS-MS plot such as the one shown in Fig. 4A shown.

[0109] Fig. 4B shows the same ions as in Fig. 4A, except that the maximum ion mobility drift time before the delivery of a subsequent ion packet into the ion mobility separation device has now been reduced. The drift time for each species is calculated relative to the injection of ions into the ion mobility separation device (T0).

[0110] It can be seen that if the ion mobility cycle time in the Fig. 4B, ions 11 with relatively high ion mobilities and thus relatively short drift times would emerge from the ion mobility separation device during the first cycle. During a second cycle, when a new ion pulse is admitted to the ion mobility separation device, ions 12 with intermediate ion mobilities and therefore intermediate drift times from the first cycle would still be present in the ion mobility separation device and would emerge during the second cycle. During a third cycle, when another ion pulse is admitted to the ion mobility separation device, ions 13 with relatively low ion mobilities and therefore relatively long drift times from the first cycle would still be present in the ion mobility separation device and would therefore emerge during the third cycle.

[0111] In summary, it should be noted that, as in Fig. 4B, ions with a relatively low ion mobility (and therefore a long drift time) and a relatively high mass-to-charge ratio have not exited an ion mobility separation device before a subsequent ion pulse is delivered into the ion mobility separation device. Accordingly, ions with a relatively low ion mobility and a relatively high mass-to-charge ratio appear in subsequent ion mobility separation spectra at short drift times.

[0112] It will be understood that this effect is particularly problematic if the ions exiting the ion mobility separation device are then subjected to fragmentation to produce multiple product or fragment ions, because the probability of interference and misalignment of fragment ions with corresponding parent or precursor ions is significantly increased.

[0113] The preferred embodiment seeks to prevent substantially all adulteration or recirculation effects, which are highly undesirable, by clearing or removing ions remaining in the ion mobility separation cell after the desired separation time and before a subsequent ion packet is introduced or pulsed into the ion mobility separation device.

[0114] According to one embodiment of the present invention, ions can be cleared or removed from the ion mobility separation device after a desired ion mobility separation time by adjusting a parameter of a traveling wave or one or more parameters of one or more (second) transient DC voltages, which are preferably applied to the electrodes 2.For example, if one or more transient DC voltages or one or more transient DC potentials are applied to the electrodes 2 forming the ion mobility separator such that the transient DC voltages are effectively shifted along the ion mobility separator at a relatively high speed, ions preferentially roll over the DC potentials as the transient DC voltages are shifted along the ion mobility separator such that ions are separated in time according to their ion mobility.However, if the effective speed or rate at which the one or more (second) transient DC voltages are translated along the ion mobility separator is slowed down, it can be ensured that substantially all ions within the ion mobility separator are driven or urged along the ion mobility separation cell at or near the speed of the (second) traveling DC voltage wave, i.e. at the speed at which the one or more transient DC voltages are effectively translated along the axis of the ion mobility separation device.

[0115] Fig. Figure 2B shows data related to the same fragment ions found in Fig. 2A, however, it shows a preferred embodiment of the present invention, wherein all fragment ions were removed from the ion mobility separation device in <0.5 ms, rather than being allowed to temporally separate and exit the ion mobility separation device over a period of 10 ms. The ions are preferably removed from the ion mobility separation device according to a preferred embodiment of the present invention by applying a (second) traveling DC voltage wave or one or more (second) transient DC voltages to the electrodes 2 comprising the ion mobility separation device, and setting the height or amplitude of the (second) traveling DC voltage wave or the amplitude of the one or more (second) transient DC voltages to 40 V.

[0116] Furthermore, the one or more (second) transient DC voltages were effectively applied to the electrodes 2 in such a way that the one or more (second) transient DC voltages were effectively shifted along the ion mobility separator at a reduced effective speed of 220 m / s. It will be understood that the speed at which the one or more (second) transient DC voltages are effectively shifted along the ion mobility separator is smaller than the speed at which the one or more (first) transient DC voltages are effectively shifted along the ion mobility separator to cause ions to be temporally separated according to their ion mobility.

[0117] As from Fig. 2B, when the ion mobility separation device is operated in a mode of operation in which ions are ejected from the ion mobility separation device, the ions can be driven out of the ion mobility separation device or cell in approximately 0.4 ms. According to the preferred embodiment, in order to remove all ions from the ion mobility separation device substantially simultaneously, the (second) transient DC voltages applied to the electrodes 2 forming the ion mobility separation device are preferably shifted along the ion mobility separation device at a significantly lower wave velocity. Thus, according to the preferred embodiment, in the mode of operation when ions are to be removed from the ion mobility separation device, preferably all ions travel at or close to the speed of the (second) traveling wave, i.e.the effective rate at which the transient DC voltages are applied along the ion mobility separation device to the electrodes 2. According to the preferred embodiment, as ions are removed from the ion mobility separation device, the transient DC voltages are applied at an amplitude and speed (or second switching time) such that very little, or effectively no, ion rollover occurs and therefore there is little or no ion mobility separation.

[0118] With regard to the example described, it should be noted that a packet of ions may be delivered into the ion mobility separation device or cell and preferably the ions are allowed to move under the same conditions as described above with respect to the Fig. 2A, to ensure that the target ions of interest have been eluted. According to the preferred embodiment, after 3 ms, the parameters of the traveling wave are then preferably adjusted to the conditions described above with respect to the operating mode for removing ions from the ion mobility separation device, as described above with respect to Fig. 2B. Therefore, any ions remaining within the ion mobility separation device are preferably expelled from the ion mobility separation device or cell within a period of about 0.4 ms.

[0119] During the removal period, when remaining ions are rapidly and effectively ejected from the ion mobility separation device, it is desirable, though not essential, to interrupt the acquisition of on-disk ion mobility separation data. It is also generally desirable, though not essential, to continue collecting ions in a pre-ion mobility separation collection device or ion trap during the removal period, with the ion trap preferably located upstream of the ion mobility separation device.

[0120] After 0.4 ms, when all ions have been effectively removed from the ion mobility separation device or otherwise ejected, the next ion packet is preferentially released into the ion mobility separation device. This process can be repeated until a different maximum drift time is required.

[0121] In the example given above, the total ion mobility separation cycle time required to avoid falsification advantageously decreases from approximately 10 ms to approximately 3.4 ms. The pre-ion mobility separation collection device, or ion trap, can continue to be filled with ions during the removal process, maintaining a 100% duty cycle for the target ions without any loss of duty cycle and therefore without any loss of sensitivity. This increases the dynamic range of the overall experiment and reduces any space charge by a factor of 3.

[0122] It should be noted that the ion mobility separation conditions do not need to be changed if the ion mobility separation cycle time is reduced to account for the maximum drift time of the target species. Accordingly, the ion mobility separation calibration parameters are preferably not changed, and the collision cross section can be calculated without recalibration when the ion mobility separation cycle is adjusted. Additionally, the total pre-ion mobility separation collection time is reduced to a minimum. This minimizes space charge distortion effects in the pre-ion mobility separation collection device or ion trap and in the ion mobility separation device itself.

[0123] For example, by drastically changing the ion mobility separation conditions and / or by changing the height or amplitude of the traveling wave and / or the effective velocity of the traveling DC wave and / or the buffer gas pressure, it is possible to achieve eluting all ions across the entire mobility range within 3 ms. However, this would not only change the calibration parameters but would also result in poor or substantially unoptimized resolution or separation capability of the ion mobility separation for the targeted analyte. In any case, it should be noted that this would be very difficult to achieve using an ion mobility separation employing a static DC field. To sufficiently extend the transit time, the potential would have to be impractically high.

[0124] The foregoing description refers to a preferred embodiment of the present invention, wherein transient DC voltages are applied to the electrodes of the ion guide to cause ions within the ion guide to be temporally separated according to their ion mobility or their differential ion mobility. However, according to less preferred embodiments, ions can be temporally separated according to their ion mobility or differential ion mobility using a DC voltage gradient generated within the ion guide and formed by applying potentials to the electrodes of the ion guide. This DC voltage gradient can, for example, be a static DC voltage gradient.

[0125] Similarly, according to the most preferred embodiment described above, transient DC voltages are applied to the electrodes of the ion guide to cause ions to be ejected from the ion guide. However, according to less preferred embodiments, ions can be ejected from the ion guide using a DC voltage gradient generated within the ion guide by applying potentials to the electrodes of the ion guide. This DC voltage gradient can, for example, be a static DC voltage gradient.

[0126] Accordingly, the present invention provides for separating ions according to their ion mobility or their differential ion mobility using DC potential waves or using a DC potential gradient, and further provides for removing ions from the ion mobility separation device using traveling DC waves or using a DC potential gradient.

[0127] According to embodiments in which a first DC voltage gradient is used for the separation of the ions and a second DC voltage gradient is used for the removal of the ions, the second DC voltage gradient preferably has a higher magnitude than the first DC voltage gradient.

[0128] According to various embodiments of the present invention, several different methods may be used to remove ions from an ion mobility separation device or cell.

[0129] For example, according to one embodiment, the RF amplitude of the RF voltage applied to the electrodes 2 forming the ion mobility separation device can be reduced to reduce the efficiency of radial confinement. As a result, the traveling wave potential applied to the electrodes 2 causes some ions to be pushed out of the ion mobility separation device or cell radially, or in a substantially radial direction. As a result, ions either escape radially from the ion mobility separation device or cell and are thereby lost to the system, or the ions may otherwise strike a side edge of one of the ring electrodes 2 and thus be annihilated.

[0130] According to one embodiment of the present invention, the ion tunneling or ion mobility separation device may be split longitudinally, thereby allowing a deflection voltage to be applied to all or part of the ion mobility separation device or cell. This may be used in conjunction with reduced confinement efficiency by reducing the RF amplitude. This embodiment preferably allows ions to be removed from a specific location within the device. According to a less preferred embodiment, the ion guide may be divided into two regions. In a first portion of the ion guide near the entrance of the device, preferably no removal pulse is applied after ions of interest have exited the device.In a second part near the exit of the device, a removal pulse or clearing pulse is preferably applied when ions of interest have left the device. Depending on the mobility range within the sample population, this embodiment allows a second ion packet to be introduced into the first part of the device while unwanted ions are removed from the second part of the device, thereby increasing the duty cycle.

[0131] According to another embodiment, a controlled gas pulse can be used to remove or assist in the removal of unwanted ions from the ion mobility separation device or cell. This method is particularly applicable to atmospheric pressure ion mobility separation devices or cells.

[0132] Various other embodiments are also contemplated in which a combination of the above-described methods for removing ions from the ion mobility separation device or cell may be used to further reduce the removal time or the time required to eject unwanted ions from the ion mobility separation device.

[0133] The approach of removing unwanted ions from a device according to an embodiment of the present invention may also be applied to devices other than devices in which ions are temporally separated according to their ion mobility. For example, according to an embodiment of the present invention, the preferred method for clearing the device may also be applied to a traveling wave mass separator, as described in US 2010 / 0032561 (Micromass), the contents of which are incorporated herein by reference, in one mode of operation in which ions are temporally separated according to their mass-to-charge ratio rather than their ion mobility.

[0134] Further embodiments are contemplated in which a similar effect can be achieved by using a nonlinear or segmented amplitude and / or velocity ramp of a traveling wave rather than by using an abrupt change from optimal ion mobility separation conditions to maximum clearance conditions. However, the abrupt change from separation to clearance is preferred because it allows for optimization of the ion mobility separation conditions and minimizes the clearance time; however, it is not absolutely necessary that the conditions be changed abruptly.

[0135] The ion mobility separation conditions can be modified to optimize the separation conditions for each target analyte, and this modification should then be taken into account if collision cross section ("CCS") information is required. The various modes of removing ions from the preferred device described above can be used in conjunction with dynamic optimization of the ion mobility separation conditions for specific target ions.

[0136] The ion mobility separation device according to the preferred embodiment may be located before and / or after one or more mass analyzers and / or one or more fragmentation or activation devices.

Claims

[1] A device arranged and designed to separate ions in time according to their ionic mobility or their differential ionic mobility, comprising: an ion guide with several electrodes (2) and a first device arranged and designed to remove unwanted ions remaining within the ion guide after ions of interest have exited the ion guide, wherein the device comprises a control system arranged and designed to carry out the following: (i) causing the device to operate in a first mode of operation in which ions are separated in time according to their ion mobility or differential ion mobility during a first period T1, and then (ii) switching the device to operate in a second mode of operation in which unwanted ions are ejected from the ion guide during a second period T2, the control system being further arranged and designed to (i) applying one or more first transient DC voltages with a first amplitude and / or a first transient velocity to the electrodes (2) during the first operating mode within or along the ion guide, such that during the first operating mode, ions within the ion guide are temporally separated according to their ion mobility or differential ion mobility, and applying one or more transient second DC voltages with a second amplitude that is greater than the first amplitude and / or with a second transient velocity that is lower than the first transient velocity to the electrodes (2) during the second operating mode within or along the ion guide, such that during the second operating mode, ions are ejected from the ion guide, and / or (ii) applying one or more first DC voltages to the electrodes (2) to generate a first DC voltage gradient within or along the ion guide during the first operating mode, such that during the first operating mode ions are caused to be separated in time within the ion guide according to their ion mobility or differential ion mobility, and applying one or more second DC voltages to the electrodes (2) to generate a second DC voltage gradient, which has a higher magnitude than the first DC voltage gradient, within or along the ion guide during the second operating mode, such that during the second operating mode ions are caused to be ejected from the ion guide. [2] The device of claim 1, further comprising a second device configured and adapted to introduce ions into the ion guide in a pulsed manner. [3] The apparatus of claim 2, wherein the second device comprises an ion trap or an ion gate. [4] Apparatus according to claim 2 or 3, wherein the second device is arranged and designed to introduce a first group of ions into the ion guide in a pulsed manner, and the first device is arranged and designed to remove the unwanted ions from the ion guide before introducing a second or subsequent ion pulse into the ion guide. [5] Apparatus according to any one of the preceding claims, wherein the control system is arranged and designed to set the first period T1 and the second period T2 such that T2 < T1. [6] Apparatus according to any one of the preceding claims, wherein the control system is arranged and designed to repeatedly switch between at least the first operating mode and the second operating mode a plurality of times during a single detection. [7] Device according to one of the preceding claims, wherein the control system is arranged and designed to progressively change, shorten or lengthen the first time period T1 during the course of a detection. [8] Device according to one of the preceding claims, wherein the control system is arranged and designed to progressively change, shorten or lengthen the second period T2 during the course of a detection. [9] Apparatus according to any one of claims 1 to 7, wherein the control system is arranged and designed to keep the second period T2 substantially constant during a detection. [10] Apparatus according to any preceding claim, wherein the control system is arranged and designed to keep the first amplitude substantially constant during the first mode of operation. [11] Apparatus according to any one of claims 1 to 9, wherein the control system is arranged and designed to change, decrease or increase the first amplitude during the first mode of operation. [12] Apparatus according to any preceding claim, wherein the control system is arranged and designed to maintain the first speed substantially constant during the first mode of operation. [13] Apparatus according to any one of claims 1 to 11, wherein the control system is arranged and designed to change, increase or decrease the first speed during the first mode of operation. [14] Mass spectrometer comprising a device according to any one of the preceding claims. [15] A method for temporally separating ions according to their ion mobility or differential ion mobility, comprising: Providing an ion guide having a plurality of electrodes (2), and Removing unwanted ions remaining within the ion guide after ions of interest have exited the ion guide, the method further comprising: (i) applying one or more first transient DC voltages to the electrodes (2) with a first amplitude and / or a first transient velocity within or along the ion guide, such that ions are temporally separated in a first operating mode within the ion guide according to their ion mobility or their differential ion mobility during a first period T1, and then applying one or more second transient DC voltages with a second amplitude greater than the first amplitude and / or with a second transient velocity lower than the first transient velocity to the electrodes (2) during the second operating mode within or along the ion guide, such that ions are ejected from the ion guide during a second period T2 during the second operating mode, and / or (ii) applying one or more first DC voltages to the electrodes (2) to generate a first DC voltage gradient within or along the ion guide during the first operating mode, such that during the first operating mode, ions are caused to be separated in time within the ion guide according to their ion mobility or differential ion mobility during a first period of time T1, and then applying one or more second DC voltages to the electrodes (2) to generate a second DC voltage gradient, which has a higher magnitude than the first DC voltage gradient, within or along the ion guide during the second operating mode, such that ions are caused to be ejected from the ion guide in a second operating mode during a second period of time T2. [16] The method of claim 15, further comprising introducing ions into the ion guide in a pulsed manner. [17] The method of claim 16, further comprising using an ion trap or an ion gate to pulse ions into the ion guide. [18] The method of claim 16 or 17, further comprising introducing a first group of ions into the ion guide in a pulsed manner and removing unwanted ions from the ion guide before introducing a second or subsequent ion pulse into the ion guide. [19] The method according to any one of claims 15 to 18, further comprising setting the first period T1 and the second period T2 such that T2 < T1. [20] A method according to any one of claims 15 to 19, further comprising repeatedly switching between at least the first operating mode and the second operating mode a plurality of times during a single acquisition. [21] Method according to one of claims 19 to 20, wherein further in the course of a detection the first time period T1 is progressively changed, shortened or lengthened. [22] Method according to one of claims 19 to 21, wherein further in the course of a detection the second period T2 is progressively changed, shortened or lengthened. [23] Method according to one of claims 15 to 21, further comprising keeping the second period T2 substantially constant during a detection. [24] The method of any one of claims 15 to 23, further comprising maintaining the first amplitude substantially constant during the first mode of operation. [25] The method of any one of claims 15 to 23, further comprising changing, decreasing, or increasing the first amplitude during the first mode of operation. [26] The method of any one of claims 15 to 25, further comprising maintaining the first speed substantially constant during the first mode of operation. [27] The method of any one of claims 15 to 25, further comprising changing, increasing, or decreasing the first speed during the first mode of operation. [28] A method of mass spectrometry comprising a method according to any one of claims 15 to 27.

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