阅读说明：本技术 离子过滤装置 (Ion filtering device ) 是由 大卫·J.·兰格里奇 詹森·李·维尔德古斯 马丁·雷蒙德·格林 丹尼尔·詹姆斯·肯尼 凯文· 于 2019-09-10 设计创作，主要内容包括：公开了一种使用装置根据离子的离子迁移率来过滤所述离子的方法,所述方法包括多个电极和被布置成并且适于向所述多个电极施加电压的一个或多个电压源,所述方法包括：使用所述一个或多个电压源生成一个或多个局部分离区域,其中离子可根据其离子迁移率在每个局部分离区域内分离；以及使每个局部分离区域以一定速度沿所述装置轴向移动,使得对于每个局部分离区域,具有处于选定范围内的离子迁移率值的所述离子与所述局部分离区域一起沿所述装置轴向传输,而具有超出所述范围的较高和/或较低离子迁移率的离子脱离所述局部分离区域,其中脱离所述局部分离区域的任何离子从所述装置内被去除和/或以其它方式与处于所述选定范围内的那些离子保持分开。(Disclosed is a method of filtering ions according to their ion mobility using an apparatus, the method comprising a plurality of electrodes and one or more voltage sources arranged and adapted to apply voltages to the plurality of electrodes, the method comprising: generating one or more local separation regions using the one or more voltage sources, wherein ions can be separated within each local separation region according to their ion mobility; and moving each local separation region axially along the device at a speed such that for each local separation region, ions having an ion mobility value within a selected range are transported axially along the device with the local separation region, whilst ions having higher and/or lower ion mobilities outside said range exit the local separation region, wherein any ions exiting the local separation region are removed from the device and/or otherwise remain separated from those ions within the selected range.)

1. A method of filtering ions according to physicochemical properties using an apparatus comprising a plurality of electrodes and one or more voltage sources arranged and adapted to apply voltages to the plurality of electrodes, the method comprising:

generating one or more local separation regions using the one or more voltage sources, wherein ions can be separated within each local separation region according to the physicochemical properties; and

moving each local separation region axially along the device at a speed such that for each local separation region ions having a physicochemical value within a selected range are transported axially along the device with the local separation region, whilst ions having higher and/or lower physicochemical values outside said range exit the local separation region,

wherein any ions that exit the local separation region are removed from within the device and/or otherwise remain separated from those ions within the selected range.

2. The method of claim 1, wherein for each local separation region, ions having values of the physicochemical property within the selected range are transmitted axially through the device towards an ion outlet, while ions having values outside the selected range of the physicochemical property are not transmitted through the device and are lost.

3. A method according to claim 2, wherein ions exiting the localised region of separation are driven out of the device and/or towards the electrode.

4. A method according to claim 1, wherein for each local separation region, ions having a physicochemical property value within the selected range are transmitted axially through the device towards an ion outlet as a first ion packet, whilst any ions having a higher and/or lower physicochemical property value and exiting the local separation region are transmitted towards the ion outlet as one or more separate ion packets.

5. The method of claim 5, comprising generating one or more DC potential wells or barriers adjacent to the local separation region using the voltage source, wherein any ions exiting a local separation region are captured by the one or more DC potential wells or barriers and transmitted as corresponding one or more ion packets towards the ion outlet.

6. The method of claim 4 or 5, wherein the ions exiting the local separation region are discarded at the exit of the device.

7. The method of claim 1, wherein for each local separation region, ions having values of a physicochemical property within the selected range are axially transportable along the device, while ions having values outside the selected range of the physicochemical property are radially ejected from the device for onward transport.

8. The method of any preceding claim, wherein the physicochemical property is ion mobility.

9. A method according to any preceding claim, wherein each local separation region comprises an axial DC gradient for separating ions according to their ion mobility.

10. A method according to any preceding claim, wherein ions are radially confined within the device.

11. A method according to any preceding claim, comprising applying a mass or mass to charge ratio filtering field to at least the localised region of separation within the device such that only ions having a mass to charge ratio or range of mass to charge ratios are transmitted through the device.

12. A method as claimed in any preceding claim, comprising generating a plurality of local separation regions, wherein each local separation region is for axial transport of ions having a physicochemical property value within a respective range of the physicochemical property.

13. The method of claim 12, wherein different localized separation regions are used to filter different ranges of the physicochemical properties.

14. The method of any preceding claim, comprising: when a local separation region coincides with an ion inlet, packet ions are injected through the ion inlet of the device such that ions within the packet having values of a physicochemical property within a selected range are transported along the device with the local separation region, while ions having values outside the selected range exit the local separation region.

15. An apparatus for filtering ions according to physicochemical properties, the apparatus comprising:

a plurality of electrodes; and

one or more voltage sources arranged and adapted to apply voltages to the plurality of electrodes to generate, in use, one or more local separation regions in which ions can be separated according to the physicochemical properties within each local separation region, and

wherein each local separation region is moved axially along the device at a speed such that for each local separation region ions having a physicochemical value within a selected range are transported axially along the device with the local separation region, whereas ions having higher and/or lower physicochemical values outside said range exit the local separation region,

wherein any ions that exit the local separation region are removed from within the device and/or otherwise remain separated from those ions within the selected range.

16. The apparatus of claim 15, wherein for each local separation region:

(a) ions having values of the physicochemical property within the selected range are transmitted axially through the device towards an ion outlet, whilst ions having values outside the selected range of the physicochemical property are not transmitted through the device and are lost;

(b) ions having a physicochemical property value within the selected range are transmitted axially through the device towards an ion outlet as a first ion packet, whilst any ions having a higher and/or lower physicochemical property value and exiting the local separation region are transmitted towards the ion outlet as one or more separate ion packets; or

(c) Ions having values of the physicochemical property within the selected range are axially transportable along the device, while ions having values outside the selected range of the physicochemical property are radially ejected from the device for onward transport.

17. A method according to any one of claims 1 to 14, or apparatus according to claim 15 or 16, wherein the apparatus is operable to switch between a filtration mode of operation and a second mode of operation in which ions are separated according to the physicochemical properties.

18. The method of any one of claims 1 to 14, or the device of any one of claims 15, 16 or 17, wherein the device is a linear or axial device, wherein the ions pass from an ion inlet at one end of the device to an ion outlet at the other end of the device.

19. The method of any one of claims 1 to 14, or the device of any one of claims 15, 16, 17, or 18, wherein the device comprises a stacked annular ion guide, or wherein the device comprises a segmented multipole ion guide.

20. A method of filtering ions according to ion mobility using an apparatus comprising a plurality of electrodes and one or more voltage sources arranged and adapted to apply voltages to the plurality of electrodes, the method comprising:

generating a plurality of local separation regions using the one or more voltage sources, wherein ions can be separated within each local separation region according to their ion mobility; and

moving each local separation region axially along the device at a velocity such that for each local separation region ions having an ion mobility value within a selected range are transported axially along the device with the local separation region, while ions having higher and/or lower ion mobility values of the physicochemical property outside said range exit the local separation region,

wherein any ions that exit the local separation region are removed from within the device and/or otherwise remain separated from those ions within the selected range.

Technical Field

The present invention relates generally to methods and devices for filtering ions according to physicochemical properties such as ion mobility, and in particular to methods of mass spectrometry and mass spectrometers including such devices.

Background

It is known to analyze ions by the following methods: ions are separated according to physicochemical properties such as ion mobility, and then the separated ions are detected so that ions of different species can be distinguished based on their different detection times. Conventional linear field or traveling wave ion mobility separator devices operate in a pulsed manner in which ions are released into the device in discrete packets and then separated along the device according to their ion mobility. Ions will thus exit the device at a particular drift time (measured from packet release) which is related to their ion mobility, and it is therefore possible to generate drift time (ion mobility) mass spectra for these ions by recording the ions which exit the device. The frequency of the pulses in such devices is limited by the time required for the slowest ion species to exit the device, which may result in a relatively low duty cycle (e.g., 1% or less). The duty cycle can be boosted by trapping ions before they are released into the device, but this can then introduce space charge issues.

Multiplexed ion mobility separators are also known in which ions are pulsed into the device at a higher pulse frequency so that ions from different pulses can overlap or overtake one another within the device. Higher pulse frequencies can help to increase duty cycle (and/or reduce space charge effects with trapping). However, since ions from successive pulses are allowed to overlap, the recorded signals produced by ions exiting the device may then require additional processing (deconvolution) to obtain meaningful drift time (ion mobility) mass spectra.

In some cases, only a single ion species or a relatively narrow range of ion mobility may be of interest, in which case it may be relatively inefficient to separate all ions using a conventional ion mobility separator as described above. It is therefore also known to perform ion mobility filtration, in which only ions having a mobility within a certain range are transported by the device. In this case, the output is limited to the ion species of interest. Filters can typically operate using continuous beams or shorter trapping/release periods, and thus can operate at higher duty cycles without the need for ion trapping or the introduction of space charge effects. Furthermore, the packing (packetized) of the output of the filter over time is typically significantly less than the output of the separator.

Currently available ion mobility filters include field-assisted ion mobility separation ("FAIMS") or differential mobility separation ("DMS") devices. However, it will be appreciated that these devices separate based on differential mobility under high and low field conditions, rather than being true ion mobility filters, and thus may be somewhat inaccurate when used for ion mobility based filtering. Furthermore, current FAIMS and DMS devices typically have relatively low sensitivity. Also, the DMS device requires a laminar gas flow orthogonal to the drive electric field, which can be difficult to maintain, so that implementations of the DMS device can be relatively complex.

Accordingly, it would be desirable to provide improved devices for filtering ions according to their mobility and/or other physicochemical properties.

Disclosure of Invention

From a first aspect, there is provided a method of filtering ions according to physicochemical properties using an apparatus comprising a plurality of electrodes and one or more voltage sources arranged and adapted to apply voltages to the plurality of electrodes, the method comprising:

generating one or more local separation regions using one or more voltage sources, wherein ions can be separated within each local separation region according to a physicochemical property; and

moving each local separation region axially along the device at a speed such that for each local separation region ions having a physicochemical value within a selected range are transported axially along the device with said local separation region, whereas ions having higher and/or lower physicochemical values outside said range exit the local separation region,

wherein any ions that exit the localized separation region are removed from the device and/or otherwise kept separate from those ions within the selected range.

From a second aspect, there is provided an apparatus for filtering ions according to physicochemical properties, the apparatus comprising:

a plurality of electrodes; and

one or more voltage sources arranged and adapted to apply voltages to the plurality of electrodes to generate, in use, one or more local separation regions in which ions can be separated according to physicochemical properties within each local separation region, and

wherein each local separation region is moved axially along the device at a speed such that for each local separation region ions having a physicochemical value within a selected range are transported axially along the device with said local separation region, whereas ions having higher and/or lower physicochemical values outside said range exit the local separation region,

wherein any ions that exit the localized separation region are removed from the device and/or otherwise kept separate from those ions within the selected range.

The embodiments described herein provide for efficient filtering of ions, for example, with higher sensitivity and/or duty cycle, while still allowing for relatively low complexity implementations (such that relatively simple device structures may be provided). This is achieved by generating one or more local separation regions which translate axially along the device and each of which is used to filter out ions having a particular range of physicochemical properties of interest.

Specifically, the speed at which each local separation region translates axially along the device is selected so that ions having a certain value (or range of values) of the physicochemical property are carried along with the local separation region. Thus, ions within the selected range of physicochemical properties are transported with the local separation region as the local separation region is translated axially along the device.

However, for each local separation region, ions outside the selected range will either exit the local separation region by traveling faster than the local separation region (and thus moving in front of and 'falling' from the front) or by traveling slower than the local separation region (and thus 'falling' from the back of the local separation region).

Any ions that exit the local separation region are then kept separate from the ions having the desired values of the physicochemical properties and are thus transported with the local separation region.

In particular, regions of the device adjacent to the local separation regions, or regions between local separation regions in which a plurality of local separation regions are provided, may be arranged to keep any ions that are disassociated from the local separation regions separate from ions transmitted by the local separation regions. For example, the regions may be configured to remove those ions from the device and/or otherwise separate those ions from ions having the desired physicochemical property values. In this way, ions having a desired physicochemical property value can be efficiently filtered (filtered out). These regions therefore also keep ions transmitted with each local separation region separate, for example from ions transmitted by other local separation regions in which a plurality of local separation regions are provided.

For example, in embodiments, ions may be filtered within the device such that only ions having a selected physicochemical property value or range of values are transmitted onwards by the device (e.g., for subsequent analysis and/or detection). Thus, in an embodiment, for each local separation region, ions having a value of the physicochemical property within a selected range are transmitted axially through the device towards the ion outlet, whereas ions having a value outside the selected range of the physicochemical property are not transmitted through the device and are lost.

In this case, the region of the device adjacent to the local region of separation may be arranged such that ions exiting the local region of separation are removed from the device. For example, ions may be driven toward the electrode (and thus lost), or driven out of the device (e.g., radially). This can be achieved in various possible ways. For example, limiting RF voltages may be disabled in these regions and/or a DC field may be applied to drive ions toward the electrodes or through the exit aperture.

In other embodiments, for each local separation region, ions having a physicochemical value within a selected range are transmitted axially through the device towards the ion outlet as a first ion packet, whilst any ions having a higher and/or lower physicochemical value and exiting the local separation region are transmitted towards the ion outlet as one or more separate ion packets.

For example, the voltage source may be used to generate one or more DC potential wells adjacent to the local separation region, or one or more DC potential barriers at the edge of the local separation region, such that any ions exiting the local separation region are then captured and transmitted as corresponding one or more ion packets towards the ion outlet.

In this case, ions exiting the local separation region and being transported separately towards the ion outlet may be discarded at the device outlet. Alternatively, these ions may be transmitted onwards (to the filtered ions as separate ion packets).

In another embodiment, ions exiting the localized separation region may be ejected radially from the device. These ions can then be transported onwards. For example, ions may be ejected into a radially adjacent ion guide and then transported onward for detection and/or analysis. Slots or gaps may be provided along the device to allow radial ejection of ions. Also, ions may be ejected between adjacent electrodes.

Thus, for each local region of separation, ions having values of the physicochemical property within a selected range may be transported axially along the device, while ions having values outside the selected range of the physicochemical property are ejected radially from the device for onward transport. In this case, the axially transmitted ions may be lost (so that the device acts as a reverse filter to remove ions within a selected range), or may also be transmitted onwards through the axial ion outlet (so that all ions are transmitted, but they follow a different path).

In an embodiment, the physicochemical property is ion mobility. That is, in embodiments, ions are separated in each local separation region based on their ion mobility, and are therefore filtered. It will be appreciated, however, that by appropriately configuring the local separation regions to separate ions based on different ion characteristics, the ions may be filtered as desired according to any suitable physicochemical properties, including, for example, mass-to-charge ratio, time-of-flight, mixed mass-to-charge ratio and ion mobility, poor ion mobility (e.g., as in a FAIMS device).

Each local separation region serves to separate ions locally (rather than globally along the device as in more conventional ion mobility separator devices). I.e. ions are locally separated in each local separation region, each local separation region having a limited axial extent. Generally, a given ion will be separated in only a single localized separation region. Thus, for example, once an ion has exited a local region of separation, it is no longer separated (e.g., in a subsequent local region of separation, where multiple are provided), but rather is removed from the device and/or kept separate from the ions transported along with the local region of separation.

Each local separation region may, for example, comprise an axial DC gradient for separating ions according to their ion mobility. An axial DC gradient may, for example, cause ions to separate in a local separation region according to their ion mobility. Where an axial DC gradient is provided, this may generally result in separation of ions in the same direction as the movement of the local separation region.

A substantially uniform DC gradient may be provided. However, this need not be the case, and in embodiments the field may vary over the length of the localised separation region, for example to alter the characteristics of the device. For example, the field may be lower at the leading edge of the local separation region and higher at the trailing edge, which tends to increase the range of ions transported with the local separation region and may also provide additional focusing of ions of interest (e.g., by reducing diffusion propagation). Alternatively, the opposite configuration may be used to increase resolution and transmit a narrower range of ions.

In general, any suitable and desired field may be provided within each of the locally separated regions to achieve the desired separation.

For example, an axial DC gradient need not be provided, and various other suitable separation techniques may be used, e.g., depending on the desired separation. For example, rather than using an axial DC gradient to separate ions according to ion mobility, each local separation region may include a plurality of traveling waves (i.e., moving DC barriers or potential wells). In a travelling wave system, a given ion will still travel at a certain average drift velocity in relation to its ion mobility, so in that case the operation of the device is substantially the same.

Furthermore, by increasing the travelling wave velocity (using a "fast travelling wave") within each local separation region, it is possible to enter an operating state in which ions are separated based on both their mass-to-charge ratio and their ion mobility (such that the physicochemical properties on which the ions are separated are mixed mass-to-charge ratio and ion mobility). By further increasing the traveling wave speed, a state may be reached in which ions are separated substantially based on mass-to-charge ratio (substantially independent of ion mobility).

The apparatus is typically a gas cell containing a suitable drift gas to achieve the desired separation. In an embodiment, a (counter-) flow of air may also be used to enhance the resolution of the device. In other embodiments, a gas flow may be used to drive ions through the device and cause the ions to be separated in a local separation region.

In an embodiment, the ions are radially confined within the device. For example, in an embodiment, ions may be radially confined using RF potentials or some combination of RF and DC potentials. However, it is also possible to not confine or periodically (re-) confine ions within the device.

In an embodiment, the method comprises applying a resolving field (e.g. a quadrupole resolving field) to at least a local separation region within the device such that only ions having a mass to charge ratio or range of mass to charge ratios are transmitted through the device. Similarly, other mass or mass-to-charge ratio filtering (e.g., resonant radial injection, quadrupole excitation, low mass cutoff) can be applied to the top of the filtering caused by the local separation region. In these cases, the device can be used to filter simultaneously by physicochemical properties (e.g., ion mobility) and mass or mass-to-charge ratio.

In an embodiment, the method may comprise generating a plurality of local separation regions, wherein each local separation region is for axially transporting ions having a physicochemical property value within a respective range of physicochemical properties. Thus, at any one time, a plurality of local separation regions may be present simultaneously within the apparatus for filtering a corresponding plurality of ion packets.

Each of the plurality of locally separated regions can be used to filter out the same range. However, it is also contemplated that different local separation regions may be used to filter different ranges of physicochemical properties (by providing different separation fields to different local separation regions, and/or by moving different local separation regions at different axial velocities).

In embodiments where multiple local separation regions are provided, the speed of these regions and their spacing may be selected to ensure that the local separation regions do not overrun each other. However, it is also possible to allow the local separation regions to pass each other (although this may require additional processing to track this).

The method may generally include: ions of the implant packet are injected through the ion inlet of the device when the local separation region coincides with the ion inlet such that ions within the packet having values of the physicochemical property within the selected range are transported along the device with the local separation region, while ions having values outside the selected range exit the local separation region. Thus, the timing of injection of ion packets to be filtered into the device may be selected or set according to the rate at which the local separation region moves along the device.

The device may be used to switch between a filtration mode of operation and a second mode of operation in which ions are separated according to a physicochemical property, for example in the case where the device is operated as an ion mobility separator. For example, in the second mode of operation, a substantially linear drift field may be applied across the device to cause ions to be separated according to ion mobility. Similarly, in the second mode of operation, the traveling wave and/or the gas flow may be used to separate ions according to ion mobility. In the second mode of operation, substantially all ions may be transmitted through the device.

The device may thus comprise a controller or other switching means for switching between these modes of operation. The method may include selecting a filtering mode of operation and/or switching between these modes.

The device may be a linear device in which ions pass axially from an ion inlet at one end of the device to an ion outlet at the other end of the device. However, it is also contemplated that the device may be a circulation device.

The apparatus may comprise a stacked annular ion guide comprising a plurality of electrodes, each electrode having an aperture through which ions are transmitted in use. The size of each electrode (and aperture) may be substantially the same. However, it is also contemplated that the size of the electrodes (apertures) may vary along the length of the device, for example to define an ion funnel. In use, opposite phases of AC or RF voltage may be applied to successive electrodes (or groups of electrodes) to radially confine ions within the device.

However, various other arrangements are of course possible. For example, in other embodiments, the device may comprise a segmented multipole ion guide, such as a segmented quadrupole, hexapole, octopole or other higher order multipole ion guide. As another example, the device may alternatively comprise a plurality of substrates, wherein the electrodes are patterned (printed) onto the substrates.

The apparatus may comprise means arranged and adapted to supply an AC or RF voltage to the electrodes. The AC or RF voltage optionally has an amplitude selected from the group consisting of: (i) about <50V peak-to-peak; (ii) about 50 to 100V peak-to-peak; (iii) about 100 to 150V peak-to-peak; (iv) about 150 to 200V peak-to-peak; (v) about 200 to 250V peak-to-peak; (vi) about 250 to 300V peak-to-peak; (vii) about 300 to 350V peak-to-peak; (viii) about 350 to 400V peak-to-peak; (ix) about 400 to 450V peak-to-peak; (x) About 450 to 500V peak-to-peak; and (xi) > about 500V peak-to-peak.

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

The device may typically comprise a gas chamber. The device may be maintained at a pressure selected from the group consisting of: (i) < about 0.0001 mbar; (ii) about 0.0001 to 0.001 mbar; (iii) about 0.001 to 0.01 mbar; (iv) about 0.01 to 0.1 mbar; (v) about 0.1 to 1 mbar; (vi) about 1 to 10 mbar; (vii) about 10 to 100 mbar; (viii) about 100 to 1000 mbar; and (ix) > about 1000 mbar.

The devices described herein may be provided as part of a mass spectrometer and/or an ion mobility mass spectrometer. Similarly, the methods disclosed herein may include methods of mass and/or ion mobility. Accordingly, from a further aspect there is provided a mass spectrometer and/or an ion mobility mass spectrometer comprising apparatus substantially as described herein.

The mass spectrometer disclosed herein may comprise 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 ("EI") ion source; (ix) a chemical ionization ("CI") 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 high-speed 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 source of nickel-63 radioactive ions; (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 real-time direct analysis ("DART") ion source; (xxiii) A laser spray ionization ("LSI") ion source; (xxiv) An ultrasonic 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; (xxviii) A laser ablation electrospray ionization ("LAESI") ion source; and (xxix) a surface assisted laser desorption ionization ("SALDI") ion source. The mass spectrometer may comprise one or more continuous or pulsed ion sources.

The mass spectrometer may comprise one or more collision, fragmentation or reaction chambers 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) electron impact or impact dissociation fragmentation devices; (vi) a light-induced dissociation ("PID") fragmentation device; (vii) a laser-induced dissociation fragmentation device; (viii) an infrared radiation induced dissociation device; (ix) an 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 heat source or temperature source fragmentation device; (xiv) An electric field induced fragmentation device; (xv) A magnetic field induced fragmentation device; (xvi) An enzymatic digestion or degradation fragmentation device; (xvii) An ion-ion reactive fragmentation device; (xviii) An ion-molecule reaction fragmentation device; (xix) An ion-atom reaction fragmentation device; (xx) An ion-metastable ion reactive fragmentation device; (xxi) An ion-metastable molecule reaction fragmentation device; (xxii) An ion-metastable atom reaction fragmentation device; (xxiii) Ion-ion reaction means for reacting ions to form an adduct or product ions; (xxiv) An ion-molecule reaction device for reacting ions to form an adduct or product ions; (xxv) Ion-atom reaction means for reacting ions to form an adduct or product ion; (xxvi) Ion-metastable ion reaction means for reacting ions to form an adduct or product ion; (xxvii) Ion-metastable molecular reaction means for reacting ions to form an adduct or product ion; (xxviii) Ion-metastable atom reaction means for reacting the ions to form an adduct or product ion; and (xxix) electron ionization dissociation ("EID") fragmentation devices.

The mass spectrometer may comprise one or more mass filters selected from the group consisting of: (i) a quadrupole mass filter; (ii)2D or linear quadrupole ion traps; (iii) paul or 3D quadrupole ion traps; (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.

Mass spectrometers may include a device or ion gate for pulsing ions; and/or means for converting the substantially continuous ion beam to a pulsed ion beam.

The mass spectrometer may comprise a mass analyser selected from the group consisting of: (i) a quadrupole mass analyzer; (ii)2D or linear quadrupole mass analyzers; (iii) paul or 3D 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 analyser arranged to generate an electrostatic field having a quartic logarithmic potential distribution; (x) A Fourier transform electrostatic 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 analyser.

From a third aspect, there is provided a method of filtering ions according to ion mobility using an apparatus comprising a plurality of electrodes and one or more voltage sources arranged and adapted to apply voltages to the plurality of electrodes, the method comprising:

generating a plurality of local separation regions using one or more voltage sources, wherein ions can be separated within each local separation region according to their ion mobility; and

moving each local separation region axially along the device at a velocity such that for each local separation region ions having an ion mobility value within a selected range are transported axially along the device with said local separation region, while ions having higher and/or lower ion mobility values of a physicochemical property outside said range exit the local separation region,

wherein any ions that exit the localized separation region are removed from the device and/or otherwise kept separate from those ions within the selected range.

Drawings

Various embodiments will now be described, by way of example only, with reference to the accompanying drawings, in which:

FIG. 1 schematically illustrates the principle of operation behind a conventional linear field ion mobility separation device;

figure 2 schematically illustrates the principle of operation behind a conventional travelling wave ion mobility separation device;

fig. 3 schematically illustrates the principle of operation behind an ion filtering device including a local separation region for filtering ions having a selected range of ion mobilities, in accordance with an embodiment;

FIG. 4 illustrates another embodiment of an ion filtering device similar to that shown in FIG. 3, but including a plurality of localized separation regions for filtering a plurality of ion packets simultaneously;

FIG. 5 is a graph showing the ion position distribution of three ions at the end of the device; and

fig. 6 illustrates an example of a mass spectrometer within which the ion filtration device described herein may be employed.

Detailed Description

Fig. 1 shows a potential energy diagram of a typical linear field IMS cell. The potential across the device drops linearly, which produces a constant axial field E. The drift velocity of an ion in a constant field is related to its mobility K, and the formula is:

v_d＝K E

in fig. 1, at time t1, three ions (K1, K2, K3) having different ion mobilities are injected into the cell at the same initial position at the cell entrance. According to the above equation, ions move with a drift velocity proportional to their mobility. Thus, at time t2, the ions are spatially separated, with the higher mobility ions (K1) traversing the largest axial distance and the lower mobility ions (K2, K3) traversing shorter distances. At time t3, the highest mobility ion K1 has now reached the end of the device and exited the device, while the other two ions are still passing through the device.

The output of this device is therefore a series of ion packets separated in drift time according to mobility. Thus, individual ion species are compressed into relatively narrow peaks in the drift time mass spectrum, depending on the resolving power of the device.

Figure 2 then shows a typical operation of a travelling wave IMS unit. In this case, rather than applying a constant axial field along the length of the device as in fig. 1, there are now multiple DC barriers moving along the device at a velocity that produces a set of traveling waves that push ions towards the ion exit. The pulses or waves periodically overtake the ions, with less mobile species being overtaken more frequently than more mobile species, so that the ions are thus separated according to their ion mobility. In conventional IMS, whether linear or traveling wave fields are used, it is often necessary to wait until the slowest ion has passed through the device before introducing a new ion packet to prevent potential interference between high and low mobility ions from adjacent packets. Since the gate time for the incoming ions is typically only a small fraction of the drift time, the device can have a low duty cycle. The duty cycle may be boosted by trapping ions upstream of the IMS device. However, this introduces space charge effects due to the limited capacity of the ion trap. Furthermore, the output from IMS devices is highly packed over time, by nature, which can have deleterious effects on downstream analyzers and detection systems.

Multiplexed IMS is also known, in which ions are pulsed (gated) into the IMS device at a higher frequency, so that ions from different packets are allowed to interfere. This increases the duty cycle, but the resulting signal then requires additional processing (deconvolution) to obtain the IMS mass spectrum.

Furthermore, in some cases, it is not necessary to obtain a complete IMS mass spectrum, but only a single species or a relatively narrow range of ions is of interest. In this case, conventional IMS devices may not be efficient.

Thus, in an embodiment, there is provided an apparatus that may be similar in structure to a conventional IMS apparatus, but may operate in an ion filtration mode at a relatively high duty cycle. In use, a plurality of localized separation regions are generated, each comprising an axial DC field, and each traveling axially along the device at some given speed. Ions can then be implanted into the device when these regions coincide with the entrance end of the device. When the drift velocity of the ions in the DC field matches the velocity of the DC drive region, the ions will then remain in the DC drive region as the device is moved down in the DC drive region and thus be transported to the exit end of the device. On the other hand, ions of higher mobility will be overtaken by the region of the DC drive field, and ions of lower mobility will be overtaken by the DC drive field. These ions will thus be detached from the local separation region.

Fig. 3 shows an example of an embodiment in which a local separation region 30 is generated along a portion of the apparatus. In fig. 3, the local separation region 30 is a small region over which a linear DC voltage drop (and hence constant field E) is applied, while in the rest of the apparatus the ions are not confined. The local separation region 30 moves across the device at some selected velocity selected to filter ions of a particular mobility (in this example, the region moves at the drift velocity of the intermediate mobility ion (K2), i.e., at the velocity v ═ K2. e). As shown in fig. 1, at time t1, at device start-up, three ions (K1, K2, K3) are injected into the local isolation region 30. At time t2, since the DC region 30 and the selected ion (K2) are moving at the same average velocity, the ion (K2) remains in the center of the local separation region 30, while the higher and lower mobility ions (K1, K3) separate toward the front and back of the region, respectively. At time t3, the high and low mobility ions have exceeded the spatial extent of the local separation region 30 and are therefore detached from the local separation region 30 and lost from the device. When the local separation region 30 reaches the exit of the device at time t4, only the selected ions (K2) remain in the region and are then transmitted. Thus, the original ion packet has been filtered to transmit only selected ions (K2).

Fig. 4 shows a similar system to that of fig. 3, but now with multiple locally separated regions that simultaneously traverse the drift cells. The local separation zones are created periodically at device start-up, filled with ions, and the device is moved downward at the selected velocity described above. If the local separation regions all have the same velocity, they will not catch up with or be exceeded by other regions, and the separation of ions in each region is independent of the other regions, since the local separation regions are separated by regions where ions are lost to the device.

Thus, in contrast to conventional linear field IMS devices (as shown in FIG. 1) or traveling wave IMS devices (as shown in FIG. 2), in the present device there is a local separation within each DC-driven region (rather than ions being separated along the length of the device).

Thus, fig. 4 illustrates a snapshot of a single time instance in which a device is populated with multiple regions having different ion populations that evolve along the device in accordance therewith. As described above, only the intermediate mobility ion (K2) is transmitted at the exit of the device because the velocity of the region is selected to match the drift velocity of this ion.

It will be appreciated that this system is somewhat similar to multiplexed IMS, as we have a potentially higher pulse frequency than conventional IMS. However, although multiplexed IMS allows ion packets to overlap and thus requires deconvolution to obtain an IMS mass spectrum, in the present system, ions carried by each DC-driven region are prevented from overlapping (by the intermediate regions).

The duty cycle of this system will depend on the on/off ratio (gate on/off). However, as an example, when a continuous beam is delivered to a device having multiple locally separated regions of a given length separated by non-transmissive regions of equal length, the duty cycle is about 50% (although it can be further improved, for example, by capturing before injecting or switching to a parallel device). The pulse frequency of the present invention is therefore a function of the drift velocity of the DC region. The output of this system will resemble a square wave, so the packetization is significantly less than that of a conventional IMS.

By considering such a device in the absence of diffusion, a simple calculation of the resolving power is possible. For example, there is a drift region of length Lr having a drift velocity vd, where the velocity matches the drift velocity of the selected ions, i.e., vd-K2E. The total length of the device is L, so the drift time td is L/vd.

The case of upstream trapping (where ions are released into the center of the drift region) or continuous beams (where they uniformly fill the initial drift region) can be considered separately.

For the case where ions are trapped and injected into the center of the region, we wish to find higher and lower mobility values just off the drift region as it reaches the ends of the device, this is then the range of mobilities transmitted by the filter. Thus, by equating the required drift distance to td drift velocity, it can be seen that:

L1＝L+Lr/2＝td*K1*E

L3＝L-Lr/2＝td*K3*E

these expressions can then be solved for K1 and K3 to yield:

K1＝(L+Lr/2)/td*E

K3＝(L-Lr/2)/td*E

and thus:

dK＝Lr/td*E

since vd — K2E, we can rearrange to arrive at:

K2＝L/td*E

and thus, the approximate resolving power K/dK is:

R＝L/Lr

thus, the resolving power in the absence of diffusion is simply the geometric factor of the total length divided by the region length. (for the continuous beam case, in the derivation above we replace Lr/2 with Lr, which doubles dK and halves the resolving power.) for a 200mm device with a 10mm drift region, the upper resolving power limit of the well filling is 20, and the continuous filling is 10.

In a real device, the peak will also widen due to diffusion, and thus the actual resolving power will be lower than the above analysis results. For example, consider the system described above, at a pressure of 2.25 torr, E-1000V/m, selected ion K2-0.0395 m2/Vs, L-0.2, Lr-0.01.

The RMS diffusion is given by the following equation:

where T is time, K is mobility, q is elementary charge, T is temperature and K_bIs the boltzmann constant.

To reach 3 x δ from the average of the faster/slower ion peaks to the edge of the drift region (i.e. 0.1% of the unwanted ions transported), the resolving power can be calculated to 6.7 for the trapping case. Figure 5 plots the ion position distribution of this system at the end of the device (where the K values for ion K1 and ion K3 were calculated to give a peak centre 3 x δ from the drift region).

Note that in conventional IMS, the resolution is defined as K/dK, where dK is the FWHM of the peak in K. To be used as a filter, a larger separation may be required, i.e., because the peak shape of the ion elution time is not retained. For example, overlapping peaks that would be sufficiently separated in an IMS mass spectrum may result in mixed transmissions in the case of a filter.

Another limitation with diffusion is that if the peak becomes wide enough for the edge of the peak to leave the drift region, transport losses of the ions of interest may arise. In the above example, ion K2 δ was 3.2mm, and therefore some loss was expected from the 10mm drift region of the trap fill system (as seen in fig. 5, ion K2 position distribution is greater than the DC region).

As can be seen from the above analytical expressions, in order to improve the resolving power, the length L of the entire cell may be increased, or the length Lr of the DC region may be decreased. It will also be appreciated that upstream acquisition may improve resolution compared to continuous beam input for a given system. The usual method of increasing the resolution of the IMS, i.e. increasing the length L or the field E, can be used to take into account the diffusion effect. Note that if Lr is too small, the transport of ions of interest may be reduced due to diffusion effects. There may be various practical considerations that will set a lower limit on Lr.

For the case of continuous beams, the duty cycle is substantially related to the ratio Lr/Lk of the size of the DC region to the termination region. With upstream trapping (periodically trapping ions and injecting them into the DC region), a 100% duty cycle can be achieved. Alternatively, multiple filters may be arranged to operate in parallel, then the timing of the DC regions is arranged so that ions will always (or more often) fill the DC region at the entrance end of one of the filters, thereby increasing the duty cycle in the case of a continuous beam.

The regions between the DC drive field local separation regions may be configured to remove ions from the system, as shown in fig. 3 above, so that ions not having the desired mobility are not transmitted. A "termination" region is required that separates the DC regions, otherwise high mobility ions will undershoot the front of the DC region, while low mobility ions may be swept away by the subsequent DC region.

Various practical embodiments of the termination region may be envisaged. For example, the limiting RF voltage may be disabled, and the DC field may drive ions toward the electrode. Alternatively, the ions may be driven through an exit aperture, such as a slot running down the device, which is typically protected by RF. Alternatively, ions may be dragged across the termination region by a larger traveling DC potential well, and these ions will be transported to the end of the device, but discarded at that point or subsequently discarded.

There is no need to remove ions from the device at the "stop" region. For example, the DC local separation region may have a potential barrier at each end, so that those ions that are filtered out will then accumulate at the front/back potential barriers. These ions may be discarded after leaving the device, or may be transmitted (the device filters out certain mobilities, but retains all other ions).

Likewise, a DC well may be provided in the center of the termination region, which will function in the same manner. Alternatively, if the ions can be filtered out of the device in the termination region, for example through an exit slot, a device that filters one mobility but retains the remaining range can also be used. These alternatives would allow operation as an inverse filter (i.e., transmitting everything except for a particular mobility), or could further manipulate the rest of the mobility range as needed (e.g., capture/activation, etc.) or analyzed in a downstream analyzer.

In additional embodiments, we apply quadrupole resolving DC to the DC region. In this case, the device will be configured as a segmented quadrupole. In the DC region, we will apply resolving DC to the relative segments of the quadrupoles in a conventional manner to obtain the desired m/z resolution. Although the analytical performance of quadrupoles decreases with increasing pressure, it is still possible to obtain relatively low m/z resolution filtering at high pressures. Resolving quadrupole DC may be disabled in the "termination" region, or may remain intact, or may increase (i.e., over-resolve). Applying an over-resolved DC to the "stop" regions is another possible method of eliminating ions moving into these regions.

In additional embodiments, the apparatus may be configured to apply quadrupole resolving DC to the DC region. This would allow for simultaneous filtration by, for example, mobility and mass-to-charge ratio.

While the method is applicable to unlimited systems or systems that are periodically re-limited, the device may be radially RF limited (e.g., SRIG or segmented multipole). The limit may be RF or some combination of RF and DC. The system may also be a single axis extension system, e.g. a slot instead of a tunnel. For example, multiple parallel filters may be created from an array of upper/lower RF/DC pads with appropriate voltage control.

The separation in the zones may be accomplished by other methods besides the DC ramp shown in fig. 3 and 4 above. For example, traveling waves ("T-waves") may be used to achieve separation. Although the relationship between drift velocity and mobility of a T-wave system is different compared to a linear field DC system, a given ion will still travel with an average drift velocity related to its mobility K, and thus the operation of the device is substantially the same.

For example, in a traveling wave device, ions with sufficiently high mobility are driven by a single traveling wave (e.g., DC potential barrier) to move efficiently at the velocity of the traveling wave. Thus, if the velocity of a local separation region is selected to match the traveling wave velocity within that local separation region, the device will act as a low mobility cut-off filter, where all ions not carried by a single traveling wave will have a lower drift velocity than the local region and are therefore filtered out.

In case a plurality of locally separated regions is provided, such as shown in fig. 4, the different regions may have different DC ramp gradients, so that the regions will be (individually) filtered for different mobilities. For MRM instruments, this may be particularly advantageous, for example, because the continuous DC region may be arranged to be filtered based on the mobility of the continuous MRM parent ions. The drift velocity of the continuous region may be the same, so the DC ramp gradient may be altered to filter for different mobilities. However, for significant mobility changes, this may require the application of non-ideal DC ramp gradients (low ramp gradients reduce resolution, high gradients may exceed low field limits/cause heating). It is therefore also possible to have different local separation regions travelling at different speeds (thereby allowing filtering with the same DC ramp gradient for different mobilities). In this case, the spacing between successive DC regions may be adjusted to ensure that the regions do not overtake each other (although the system may also be configured so that the regions can overtake each other).

The DC field (or equivalent separation field, e.g. T-wave) does not have to be kept constant over the whole local separation region. For example, varying fields may be used to alter the characteristics of the device. For example, if the field is lower at the leading edge of the region and higher at the trailing edge of the region, this tends to increase the mobility range transmitted by the region. This will also result in some focusing of the ions of interest, i.e. diffusion propagation will be reduced. Alternatively, the reverse configuration is possible, in which case ions tend to fall out of the region, which can be used to improve resolution at the expense of transmission. Note that in the conventional case, field relaxation tends to produce a non-constant field at the boundary of the DC region, this modification extending this characteristic over the entire region or a large portion thereof.

Although not as large as conventional IMS devices, the output of the devices will typically still be slightly packetized in time, for example about 50/50 for Lr — Lk. Thus, one or more downstream ion guides can be arranged to reduce or eliminate this packing, thereby providing advantages in terms of downstream analyzers/detectors.

Fig. 6 illustrates an example of a mass spectrometer incorporating an ion filtering device 4 according to an embodiment. As shown, a set of ions 1 is generated from an ion source (not shown) and passed to an ion filtering device 4. Optionally, the ions 1 may be stored in the upstream ion trap 2 and periodically released into the ion filtering device 4 for filtering before passing the ions 1 to the ion filtering device 4.

After filtering the ions in the manner described herein, the ions may then be passed through various additional ion guide and/or manipulation components 8, which may include, for example, one or more ion guides, collision cells, ion separators, further filtering devices, and the like. The ions are then fed to a mass analyser. For example, as shown in fig. 6, ions may be passed into a TOF mass analyser in which ions are orthogonally pulsed from a pusher electrode 10 into a TOF drift region 13 containing a repeller 11 and directed onto a suitable ion detector 12. However, although fig. 1 illustrates a TOF mass analyser, it will be appreciated that any suitable mass analyser may be employed.

Although various embodiments have been described above with respect to ion mobility separation, it should be understood that the same principles of operation may be applied to separation based on different ion characteristics (e.g., TOF, m/z, mixed m/z and mobility, FAIMS, etc.).

Similarly, although embodiments have been described above with respect to a linear field applied along the axis of the device, it will be appreciated that embodiments may also be implemented in a cyclic device.

The device can switch between operation as a filter and operation as a conventional IMS as disclosed herein.

The gas flow may also be used to separate ions along the device and/or to increase the effective resolution of the device.

Thus, while the invention has been described with reference to various embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as set forth in the appended claims.