Improved quadrupole resistance

Abstract

Device for filtering ions, comprising: a separation unit for the temporal separation of ions according to a first physicochemical property; a first quadrupole rod assembly (1) for filtering the ions according to their mass-to-charge ratio, wherein the first quadrupole rod assembly (1) comprises a plurality of rods, and wherein the first quadrupole rod assembly (1) is arranged downstream of the separation unit; and a control system that is designed and configured to perform a single separation cycle of the separation unit: (i) Operating the first quadrupole stage (1) in a first operating mode of resolving at separation times when ions of interest are expected to exit the separation unit, so that the ions of interest are selected or filtered by the first quadrupole stage (1) according to their mass-to-charge ratio; and (ii) Operating the first quadrupole rod assembly (1) in a second non-resolving operating mode at separation times when substantially no ions of interest are expected to escape from the separation unit, so that substantially no ions will collide with the rods of the first quadrupole rod assembly (1).

Description

FIELD OF THE INVENTION

[0001] The present invention relates generally to mass spectrometry and, more particularly, to an apparatus for filtering ions and to quadrupole rod set mass filters. BACKGROUND

[0002] Quadrupole rod mass filters are well known and comprise four rod electrodes. Fig. Figure 1 shows a typical arrangement of a quadrupole rod set mass filter. An analytical quadrupole 1 is preceded by a prefilter quadrupole 2 and followed by a postfilter quadrupole 3. In operation, an RF voltage and a resolving DC voltage are applied simultaneously to the rod electrodes of the analytical quadrupole 1, so that the quadrupole rod set operates in a mass or mass-to-charge ratio resolution mode.

[0003] As will be understood by those skilled in the art, when the quadrupole rod set is operated in a mass-resolving mode of operation, ions having a mass-to-charge ratio within a desired mass-to-charge ratio range are transmitted by the mass filter, while unwanted ions having mass-to-charge ratio values ​​outside the mass-to-charge ratio range are substantially attenuated.

[0004] Ions that are not desired to be transmitted by the mass filter are attenuated by causing the ions to adopt unstable trajectories in analytical quadrupole 1. Consequently, at least some of the ions impact the rod electrodes of analytical quadrupole 1.

[0005] With increasingly powerful ion sources, instrument resilience due to ion beam-related contamination becomes a serious concern. This is particularly true for quadrupole-based instruments, where ions entering the mass filter are lost to the analytical quadrupole rods over most of the mass-to-charge ratio range during ion isolation. The ions lost to the analytical quadrupole rods build up and can eventually form non-conductive layers on the rods that comprise the quadrupole rod set. The non-conductive layers that can form on the rods can alter the fields within the quadrupole rod set, which can affect analytical performance.

[0006] Fig. Figure 2 of GB-2443952 A discloses an arrangement wherein a mass spectrometer is provided comprising an ion mobility spectrometer 8 and a mass filter 4. Ions exiting the ion mobility spectrometer 8 are selectively transmitted or rejected using an ion gate 9.

[0007] US-5572022 A discloses a mass spectrometer comprising a quadrupole filter.

[0008] WO 2004 / 068523 A2 discloses a mass spectrometer comprising a quadrupole ion accumulator.

[0009] It is desirable to provide an improved apparatus for filtering ions and an improved method for filtering ions. SUMMARY

[0010] According to one aspect, there is provided an apparatus for filtering ions, comprising: a separation unit for temporally separating ions according to a first physico-chemical property; a first set of quadrupole rods for filtering the ions according to their mass-to-charge ratio, wherein the first set of quadrupole rods comprises a plurality of rods, and wherein the first set of quadrupole rods is arranged downstream of the separation unit; and a control system which, during a single separation cycle of the separation unit, is designed and constructed to: (i) operating the first set of quadrupole rods in a first operating mode of substantially dissolving at separation times when ions of interest are expected to exit the separation unit, such that the ions of interest are selected or filtered by the first set of quadrupole rods according to their mass-to-charge ratio; and (ii) operating the first set of quadrupole rods in a second mode of operation of substantially non-resolving or transferring at separation times when substantially no ions of interest are expected to exit the separation unit, such that substantially no ions impact the rods of the first set of quadrupole rods.

[0011] According to one aspect, there is provided an apparatus for filtering ions, comprising: a separation unit for temporally separating ions according to a first physico-chemical property; a filter unit for filtering ions according to their mass-to-charge ratio, wherein the filter unit is arranged downstream of the separation unit, and wherein the filter unit comprises an analytical quadrupole rod set and a pre-filter quadrupole rod set arranged upstream of the analytical quadrupole rod set; and a control system which, during a single separation cycle of the separation unit, is designed and constructed to: (i) operating the filter unit in a first operating mode, wherein the pre-filter quadrupole rod set is operated in a transmitting operating mode, and wherein ions of interest are selected from the analytical quadrupole rod set; and (ii) operating the filter unit in a second operating mode at separation times when substantially no ions of interest are present, wherein the pre-filter quadrupole rod set is operated in a non-transmitting operating mode such that substantially no ions impinge on the rods of the analytical quadrupole rod set.

[0012] According to one embodiment, a separation unit is provided that temporally separates ions according to a first physicochemical property (e.g., a mass-to-charge ratio or ion mobility). The separation unit can be arranged upstream of a filter unit. The filter unit can comprise at least a first quadrupole rod set, which can comprise an analytical quadrupole rod set.

[0013] In one embodiment, during each separation cycle of the separation unit, an ion packet is pulsed into the separation unit and separated temporally according to the first physicochemical property. The filter unit can be operated in at least two operating modes during the separation cycle of the separation unit.

[0014] At separation times when ions of interest are present in the filter unit, the filter unit may be operated in a first operating mode such that ions of interest are mass-selected by the first set of quadrupole rods, i.e., the first set of quadrupole rods may be operated in a resolving operating mode to preferentially transfer ions with a desired mass-to-charge ratio.

[0015] In this first mode of operation, the first set of quadrupole rods can be operated with a (relatively narrow) mass-to-charge ratio transfer window that is centered with respect to the mass-to-charge ratio value of the ions of interest, so that ions with mass-to-charge ratio values ​​within the window are transferred from the first set of quadrupole rods.

[0016] As can be understood, ions other than the ions of interest (i.e., ions with mass-to-charge ratio values ​​outside the mass-to-charge ratio transfer window) are attenuated in this first mode of operation, so that at least some of these ions impact the rods of the first set of quadrupole rods.

[0017] At separation times when no ions of interest are present in the filter unit, the filter unit can be operated in a second operating mode, with no ions impacting the rods of the first set of quadrupole rods.

[0018] The first quadrupole rod set can be operated in a non-resolution or transfer mode in the second operating mode, so that all ions captured by the quadrupole rod set are transferred onward. As can be understood, by operating the quadrupole rod set in this way, so that all ions are transferred onward, no ions will subsequently impact the rods of the quadrupole rod set.

[0019] Thus, it is understood that in the second mode of operation, when no ions of interest are present, no ions impact the rods of the quadrupole rod set.

[0020] According to an alternative embodiment, the same result can be achieved by filtering ions upstream of the first quadrupole rod set. According to one embodiment, the pre-filter quadrupole of a quadrupole mass filter array can be operated in a non-transmission mode of operation at separation times when essentially no ions of interest are present. As can be understood, if ions are prevented from reaching the first quadrupole rod set, no ions will impact the rods of the analytical quadrupole rod set. Furthermore, the use of the pre-filter quadrupole of a quadrupole mass filter array provides a particularly simple and efficient mechanism for preventing ions from reaching the first quadrupole rod set, since it does not require, for example, additional hardware elements such as a separate upstream filter or gate.

[0021] It is understood that a particularly advantageous aspect of the various embodiments is that the amount of ions that build up on the rods of the first quadrupole rod set is minimized compared to conventional arrangements. Accordingly, the accuracy of the quadrupole rod set according to various embodiments is increased, and the lifetime and durability of the quadrupole rod set are advantageously extended.

[0022] Fig. 2 of GB 2 443 952 A (Micromass) discloses an arrangement wherein a mass spectrometer is provided comprising an ion mobility spectrometer 8 and a mass filter 4. Ions emerging from the ion mobility spectrometer 8 are selectively transmitted or rejected using an ion gate 9. GB 2 443 952 (Micromass) does not disclose an arrangement wherein a set of quadrupole rods is operated in a non-resolution or transmission mode of operation during a single separation cycle of an ion mobility spectrometer at separation times when substantially no ions of interest are present, to prevent ions from impacting the rods of the quadrupole rod set.

[0023] Similarly, GB 2 443 952 A (Micromass) does not disclose an arrangement in which a pre-filter quadrupole of a quadrupole mass filter assembly is operated in a non-transfer mode of operation during a single separation cycle of an ion mobility spectrometer at separation times in which substantially no ions of interest are present, in order to prevent ions from impinging on the rods of the analytical quadrupole rod set.

[0024] It is therefore understood that the various embodiments provide an improved apparatus for filtering ions and an improved method for filtering ions.

[0025] In one embodiment, the control system is constructed and arranged to operate the analytical quadrupole rod set in the first operating mode with a first mass-to-charge ratio transfer window and to operate the pre-filter quadrupole rod set with a second mass-to-charge ratio transfer window, wherein the second mass-to-charge ratio transfer window is greater than or equal to and includes the first mass-to-charge ratio transfer window.

[0026] In one embodiment, the filter unit comprises a post-filter quadrupole rod set arranged downstream of the analytical quadrupole rod set.

[0027] In one embodiment, the control system is further constructed and arranged to determine the position of ions of interest in or from an examination scan.

[0028] In one embodiment, the examination scan comprises a multi-dimensional examination scan.

[0029] In one embodiment, the first physicochemical property is either: (i) not correlated with a mass-to-charge ratio; or (ii) at least partially correlated with a mass-to-charge ratio.

[0030] In one embodiment, the first physicochemical property includes mass, mass-to-charge ratio, or time of flight.

[0031] In one embodiment, the separation unit comprises a time-of-flight separation unit and / or an ion trap.

[0032] In one embodiment, the first physicochemical property comprises ion mobility or differential ion mobility.

[0033] In one embodiment, the separation unit comprises an ion mobility separator or a differential ion mobility separator.

[0034] In one embodiment, the control system is constructed and arranged to select a plurality of different ions of interest during the single separation cycle.

[0035] In one embodiment, in the first mode of operation, the control system is constructed and arranged to operate the first or analytical quadrupole rod set with a first mass-to-charge ratio transfer window such that at least some ions having mass-to-charge ratio values ​​outside the first mass-to-charge ratio transfer window are caused to impact the rods of the first or analytical quadrupole rod set.

[0036] In one embodiment, the device further comprises an ion trap arranged upstream of the separation unit.

[0037] In one embodiment, the ion trap is constructed and designed to pulse one or more packets or ions into the separation unit.

[0038] According to one aspect, there is provided a method for filtering ions, comprising: temporally separating ions according to a first physico-chemical property using a separation unit; Filtering the ions according to their mass-to-charge ratio using a first quadrupole rod set, wherein the first quadrupole rod set comprises a plurality of rods, and wherein the first quadrupole rod set is arranged downstream of the separation unit; and during a single separation cycle of the separation unit: Operating the first set of quadrupole rods in a first operating mode of substantially dissolving at separation times when ions of interest are expected to exit the separation unit, such that the ions of interest are selected or filtered by the first set of quadrupole rods according to their mass-to-charge ratio; and

[0039] Operating the first set of quadrupole rods in a second operating mode of substantially non-resolving or transferring at separation times when ions of interest are expected to exit the separation unit, such that substantially no ions impact the rods of the first set of quadrupole rods.

[0040] According to one aspect, there is provided a method for filtering ions, comprising: temporally separating ions according to a first physico-chemical property using a separation unit; Filtering ions according to their mass-to-charge ratio using a filter unit, wherein the filter unit is arranged downstream of the separation unit, and wherein the filter unit comprises an analytical quadrupole rod set and a pre-filter quadrupole rod set arranged upstream of the analytical quadrupole rod set; and during a single separation cycle of the separation unit: Operating the filter unit in a first operating mode, wherein the pre-filter quadrupole rod set is operated in a transmitting operating mode, and wherein ions of interest are selected from the analytical quadrupole rod set; and

[0041] Operating the filter unit in a second operating mode at separation times when substantially no ions of interest are present, wherein the pre-filter quadrupole rod set is operated in a non-transmitting operating mode such that substantially no ions impinge on the rods of the analytical quadrupole rod set.

[0042] According to one aspect, there is provided an apparatus for filtering ions, comprising: a separation unit for temporally separating ions according to a first physico-chemical property; a filter unit for filtering the ions according to a second physico-chemical property, wherein the filter unit is arranged downstream of the separation unit and wherein the filter unit comprises a first filter; and a control system which, during a single separation cycle of the separation unit, is designed and constructed to: (i) operating the filter unit in a first resolution mode of operation, wherein ions of interest are selected by the first filter; and (ii) operating the filter unit in a second non-resolution or transfer mode of operation at separation times when substantially no ions of interest are present, such that substantially no ions are lost to the first filter.

[0043] In one embodiment, the first filter comprises a mass-to-charge ratio filter, an ion mobility filter, or a differential ion mobility filter.

[0044] According to one aspect, there is provided a method for filtering ions, comprising: temporally separating ions according to a first physico-chemical property using a separation unit; Filtering the ions according to a second physico-chemical property using a filter unit, the filter unit comprising a first filter; and during a single separation cycle of the separation unit: Operating the filter unit in a first resolution mode of operation, wherein ions of interest are selected by the first filter; and Operating the filter unit in a second non-resolution or transfer mode of operation at separation times when substantially no ions of interest are present such that substantially no ions are lost to the first filter.

[0045] In one embodiment, the first filter comprises a mass-to-charge ratio filter, an ion mobility filter, or a differential ion mobility filter.

[0046] According to one aspect, a mass spectrometer is provided comprising a device for filtering ions as described above.

[0047] According to one aspect, a mass spectrometric method is provided comprising a method for filtering ions as described above.

[0048] According to one aspect, there is provided an apparatus for filtering ions, comprising: a separation unit for temporally separating ions according to a first physico-chemical property; a filter unit for filtering ions according to their mass-to-charge ratio downstream of the separation unit, the filter unit comprising a first set of quadrupole rods; and a control system which, during a single separation cycle of the separation unit, is designed and constructed to: Operating the filter unit in a first operating mode, wherein ions of interest are selected from the first set of quadrupole rods; and Operating the filter unit in a second operating mode where no ions of interest impact the rods of the first set of quadrupole rods. In one embodiment, the control system is designed and configured to: Operating the filter unit in the first operating mode when ions of interest are present; and Operating the filter unit in the second operating mode when no ions of interest are present.

[0049] In one embodiment, the first physicochemical property is either (i) not correlated with a mass-to-charge ratio or (ii) at least partially correlated with a mass-to-charge ratio.

[0050] In one embodiment, the first physicochemical property includes mass, mass-to-charge ratio, or time of flight.

[0051] In one embodiment, the separation unit comprises a time-of-flight separation unit and / or an ion trap.

[0052] In one embodiment, the first physicochemical property comprises ion mobility or differential ion mobility.

[0053] In one embodiment, the separation unit comprises an ion mobility separator or a differential ion mobility separator.

[0054] In one embodiment, the first quadrupole rod set comprises an analytical quadrupole rod set.

[0055] In one embodiment, the control system is constructed and arranged to operate the first quadrupole rod set in a non-resolution or transmission mode of operation in the second mode of operation.

[0056] In one embodiment, the filter unit comprises a first filter upstream of the first quadrupole rod set.

[0057] In one embodiment, the first filter comprises a second quadrupole rod set, a pre-filter quadrupole, a gate electrode, a deflector lens, a defocusing lens, and / or a Bradbury-Neilson gate.

[0058] In one embodiment, the control system is constructed and arranged to operate the first filter in a non-transmission mode of operation in the second mode of operation.

[0059] In one embodiment, the control system is configured and arranged to operate the first filter in a transmission mode of operation in the first mode of operation.

[0060] In one embodiment, the control system is constructed and arranged to operate the first quadrupole rod set in the first operating mode with a first mass-to-charge ratio transmission window and to operate the first filter with a second mass-to-charge ratio transmission window, wherein the second mass-to-charge ratio transmission window is greater than or equal to and includes the first mass-to-charge ratio transmission window.

[0061] In one embodiment, the filter unit comprises a second filter downstream of the first quadrupole rod set.

[0062] In one embodiment, the second filter comprises a third quadrupole rod set and / or a post-filter quadrupole.

[0063] In one embodiment, the control system is constructed and arranged to select a plurality of different ions of interest during the single separation cycle.

[0064] In one embodiment, in the first mode of operation, the control system is configured and arranged to operate the first quadrupole mass filter with a first mass-to-charge ratio transfer window such that at least some ions having mass-to-charge ratio values ​​outside the first mass-to-charge ratio transfer window are caused to impact the rods of the first quadrupole rod set.

[0065] In one embodiment, the device further comprises an ion trap arranged upstream of the separation unit.

[0066] In one embodiment, the ion trap is constructed and designed to pulse one or more packets or ions into the separation unit.

[0067] According to one aspect, there is provided a method for filtering ions, comprising: temporally separating ions according to a first physico-chemical property using a separation unit; Filtering the ions according to their mass-to-charge ratio using a filter unit, the filter unit comprising a first set of quadrupole rods; and during a single separation cycle of the separation unit: Operating the filter unit in a first operating mode, wherein ions of interest are selected from the first set of quadrupole rods; and Operating the filter unit in a second operating mode where no ions of interest impact the rods of the first set of quadrupole rods.

[0068] According to one aspect, there is provided an apparatus for filtering ions, comprising: a separation unit for temporally separating ions according to a first physico-chemical property; a filter unit for filtering ions according to a second physico-chemical property, arranged downstream of the separation unit, the filter unit comprising a first filter; and a control system which, during a single separation cycle of the separation unit, is designed and constructed to: Operating the filter unit in a first operating mode, wherein ions of interest are selected by the first filter; and Operating the filter unit in a second operating mode, whereby no ions are lost to the first filter.

[0069] In one embodiment, the first filter comprises a mass-to-charge ratio filter, an ion mobility filter, or a differential ion mobility filter.

[0070] According to one aspect, there is provided a method for filtering ions, comprising: temporally separating ions according to a first physico-chemical property using a separation unit; Filtering the ions according to a second physico-chemical property using a filter unit, the filter unit comprising a first filter; and during a single separation cycle of the separation unit: Operating the filter unit in a first operating mode, wherein ions of interest are selected by the first filter; and Operating the filter unit in a second operating mode, whereby no ions are lost to the first filter. In one embodiment, the first filter comprises a mass-to-charge ratio filter, an ion mobility filter, or a differential ion mobility filter.

[0071] According to one aspect, a mass spectrometer is provided comprising a device for filtering ions as described above.

[0072] According to one aspect, a mass spectrometric method is provided comprising a method for filtering ions as described above.

[0073] According to one aspect, there is provided a mass spectrometer device comprising: a separation unit upstream of an analytical quadrupole; wherein the prefilter of the quadrupole unit is designed to alternate between zero transmission and transmission of precursors of interest one or more times within the separation cycle.

[0074] In one embodiment, the separation unit is based on mass-to-charge ratio, mass, or ion mobility.

[0075] 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 (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 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 mica discharge ionization (ASGDI) ion source; (xx) a mica discharge (GD) ion source; (xxi) an impactor ion source; (xxii) a direct analysis in real-time (DART) ion source; (xxiii) 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 units and / or one or more field asymmetric ion mobility spectrometer units; and / or (e) one or more ion traps or one or more ion capture 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 collision or electron impact dissociation fragmentation device; (vi) a photo-induced dissociation (PID) fragmentation device; (vii) a laser-induced dissociation fragmentation device; (viii) an infrared-ray-induced dissociation device; (ix) a UV-radiation-induced dissociation device; (x) a nozzle-skimmer interface fragmentation device; (xi) a fragmentation device in the source;(xii) a collision-induced dissociation fragmentation device in the source; (xiii) a heat or temperature source fragmentation device; (xiv) an electric field induction fragmentation device; (xv) a magnetic field induction 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 adduct or product ions; (xxvi) an ion-metastable ion reaction device for reacting ions to form adduct or product ions; (xxvii) an ion-metastable molecule reaction device for reacting ions to form adduct or product ions; (xxviii) an ion-metastable atom reaction device for reacting ions to form adduct 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 2D or linear quadrupole mass analyzer; (iii) a 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 analyzer configured to generate an electrostatic field having a quadrolologarithmic 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 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 analyzer; (ii) a 2D or linear quadrupole ion trap; (iii) a Paul or 3D 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.

[0076] The mass spectrometer can further comprise either: (i) a C-trap and a mass analyzer comprising a cylinder-like outer electrode and a coaxial spindle-like inner electrode generating an electrostatic field with a quadrolologarithmic potential distribution, wherein ions are conveyed to the C-trap in a first operating mode and thereafter injected into the mass analyzer, and wherein ions are conveyed to the C-trap in a second operating mode and thereafter to a collision cell or electron transfer dissociation device, wherein at least some of the ions are fragmented into fragment ions, and wherein the fragment ions are then conveyed to the C-trap before being injected into the mass analyzer; and / or (ii) a stacked ring ion guide comprising a plurality of electrodes each having an aperture through which ions are conveyed in use, and wherein the spacing of the electrodes increases along the length of 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.

[0077] According to one embodiment, the mass spectrometer further comprises a device configured and adapted to supply an alternating (AC) or RF voltage to the electrodes. The AC or RF voltage optionally has an amplitude selected from the group consisting of: (i) approximately <50 V peak to peak; (ii) approximately 50-100 V peak to peak; (iii) approximately 100-150 V peak to peak; (iv) approximately 150-200 V peak to peak; (v) approximately 200-250 V peak to peak; (vi) approximately 250-300 V peak to peak; (vii) approximately 300-350 V peak to peak; (viii) approximately 350-400 V peak to peak; (ix) approximately 400-450 V peak to peak; (x) approximately 450-500 V peak to peak; and (xi) > approximately 500 V peak to peak.

[0078] The AC or RF voltage may have a frequency selected from the group consisting of: (i) < about 100 kHz; (ii) about 100-200 kHz; (iii) about 200-300 kHz; (iv) about 300-400 kHz; (v) about 400-500 kHz; (vi) about 0.5-1.0 MHz; (vii) about 1.0-1.5 MHz; (viii) about 1.5-2.0 MHz; (ix) about 2.0-2.5 MHz; (x) about 2.5-3.0 MHz; (xi) about 3.0-3.5 MHz; (xii) about 3.5-4.0 MHz; (xiii) about 4.0-4.5 MHz; (xiv) about 4.5-5.0 MHz; (xv) approximately 5.0-5.5 MHz; (xvi) approximately 5.5-6.0 MHz; (xvii) approximately 6.0-6.5 MHz; (xviii) approximately 6.5-7.0 MHz; (xix) approximately 7.0-7.5 MHz; (xx) approximately 7.5-8.0 MHz; (xxi) approximately 8.0-8.5 MHz; (xxii) approximately 8.5-9.0 MHz; (xxiii) approximately 9.0-9.5 MHz; (xxiv) approximately 9.5-10.0 MHz; and (xxv) > approximately 10.0 MHz.

[0079] The mass spectrometer may further comprise a chromatography or other separation unit upstream of an ion source. According to one embodiment, the chromatography separation unit comprises a liquid chromatography or gas chromatography device. According to another embodiment, the separation unit may comprise: (i) a capillary electrophoresis (CE) separation unit; (ii) a capillary electrochromatography (CEC) separation unit; (iii) a multilayer microfluidic substrate separation unit based on substantially rigid ceramic (ceramic tiles); or (vi) a supercritical fluid chromatography separation unit.

[0080] The ion guide may be maintained at a pressure selected from the group consisting of: (i) < about 0.0001 mbar; (ii) about 0.0001-0.001 mbar; (iii) about 0.001-0.01 mbar; (iv) about 0.01-0.1 mbar; (v) about 0.1-1 mbar; (vi) about 1-10 mbar; (vii) about 10-100 mbar; (viii) about 100-1000 mbar; and (ix) > about 1000 mbar.

[0081] According to one embodiment, analyte ions can be subjected to electron transfer dissociation (ETD) fragmentation in an electron transfer dissociation fragmentation device. Analyte ions can be caused to interact with ETD reagents within an ion guide or fragmentation device.

[0082] According to one embodiment, to effect electron transfer dissociation, either: (a) analyte ions are fragmented or induced to dissociate and form product or fragment ions after reacting 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, thereafter inducing at least some of the multiply charged analyte ions or positively charged ions to dissociate and form product or fragment ions; and / or (c) analyte ions are fragmented or induced to dissociate and form product or fragment ions after reacting with neutral reagent gas molecules or atoms or a non-ionic reagent gas;and / or (d) electrons are transported from one or more neutral, non-ionic, or uncharged basic gases or vapors to one or more multiply charged analyte cations or positively charged ions, thereafter inducing at least some of the multiply charged analyte cations or positively charged ions to dissociate and form product or fragment ions; and / or (e) electrons are transported 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, thereafter inducing at least some of the multiply charged analyte cations or positively charged ions to dissociate and form product or fragment ions;and / or (f) electrons are transported 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, thereafter inducing at least some of the multiply charged analyte cations or positively charged ions to dissociate and form product or fragment ions; and / or (g) electrons are transported 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, thereafter inducing at least some of the multiply charged analyte cations or positively charged ions 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) frankium vapor or atoms; (vii) C; 60 vapor or atoms; and (viii) magnesium vapor or atoms.

[0083] The multiply charged analyte cations or positively charged ions can include peptides, polypeptides, proteins or biomolecules.

[0084] 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.

[0085] According to one embodiment, the electron transfer dissociation fragmentation process comprises interacting analyte ions with reagent ions, wherein the reagent ions comprise dicyanobenzene, 4-nitrotoluene, or azulene. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Various embodiments will now be described by way of example only and with reference to the accompanying drawings, in which: Fig. 1 schematically shows a quadrupole rod set mass filter arrangement operable in accordance with one embodiment; Fig. Figure 2A schematically shows an ion population obtained by temporally separating ions according to a physicochemical property that does not correlate with the mass-to-charge ratio (m / z), and Fig. 2B schematically shows the operation of the filter unit according to an embodiment; Fig. Figure 3 A schematically shows an ion population obtained by temporally separating ions according to a physicochemical property that correlates with the mass-to-charge ratio (m / z), and Fig. 3B schematically shows the operation of the filter unit according to an embodiment; Fig. 4 shows the operation of a prefilter quadrupole of a quadrupole mass filter arrangement according to one embodiment; and Fig. 5A schematically shows a quadrupole rod set mass filter arrangement including an ion gate operable according to an embodiment, and Fig. 5B schematically shows the operation of the ion gate according to one embodiment. DETAILED DESCRIPTION

[0087] An embodiment will now be described relating to a method of operating a quadrupole-based mass spectrometer wherein the ion population undergoes temporal separation before arriving at the quadrupole unit or the filter unit.

[0088] A pulsed temporal separation unit may be connected to a temporal gating unit. Ions may be pulsed into the separation unit, after which the ions are caused to separate according to a first physicochemical property. The first physicochemical property may include a mass-to-charge ratio or may include a physicochemical property related or correlated with a mass-to-charge ratio (e.g., ion mobility).

[0089] The separation unit can separate multiple parent or precursor ions before they arrive at the downstream quadrupole unit or filter unit. The downstream quadrupole unit or filter unit can include an analytical resolving quadrupole.

[0090] The quadrupole unit downstream of the separation unit can be switched between at least two operating modes during the separation cycle, ie as a function of the separation time.

[0091] In a first mode of operation, the analytical resolving quadrupole can be operated in a resolution mode to isolate ions of interest. The first mode can include a mode wherein the analytical resolving quadrupole operates in a mass-to-charge ratio filtering mode, such that at least some ions outside the mass-to-charge ratio range of interest are lost to the quadrupole rods. This mode of operation can be activated at times when ions of interest (e.g., precursor or parent ions of interest) are present.

[0092] In a second operating mode, the quadrupole unit can be configured such that essentially no ions are lost to the analytical quadrupole rods. This operating mode can be activated at times when no ions of interest (e.g., parent or precursor ions of interest) are present at the quadrupole.

[0093] The Fig. 2A and Fig. 2B illustrate the operation of a first embodiment. In this embodiment, the first physicochemical property is not correlated with the mass-to-charge ratio (i.e., the separation unit separates ions temporally according to a physicochemical property that is not correlated with a mass-to-charge ratio). The gray area in Fig. Figure 2A represents an ion population separated over time by the separation unit. The black line represents ions of interest present in the ion population.

[0094] As in Fig. As shown in Figure 2B, according to one embodiment, at separation times when ions of interest are present (i.e., at time 12), the filter unit is operated such that the analytical quadrupole selects (i.e., filters and transmits) the ions of interest. However, at separation times when no ions of interest are present (i.e., at times 10 and 11), the filter unit is operated such that no ions are lost to the rods of the analytical quadrupole.

[0095] This embodiment may include a step of determining where the ions of interest are located in an ion population (i.e., where the ions of interest are located in the two-dimensional mass-to-charge ratio separation-time space). This may be based, for example, on knowledge of the sample obtained, for example, from previous experiments, such as a previous multidimensional survey scan. This is necessary because the ions of interest (with the mass-to-charge ratio value of interest) can, in principle, elute from the separation unit over a wide time range (since the separation time does not correlate with the mass-to-charge ratio in this embodiment).

[0096] The Fig. 3A and Fig. 3B illustrate operation according to another embodiment. In this embodiment, the first physicochemical property is correlated with the mass-to-charge ratio (i.e., the separation unit separates ions temporally according to a physicochemical property that correlates with a mass-to-charge ratio). The first physicochemical property may include, for example, mass-to-charge ratio or ion mobility. As shown in the Fig. 2A and Fig. 2B, the grey area in Fig. Figure 3A shows an ion population separated over time by the separation unit. The black line represents ions of interest present in the ion population.

[0097] According to this embodiment, the relationship between separation time and mass-to-charge ratio means that the time at which the quadrupole should be switched between the two operating modes can be accurately determined based on the mass-to-charge ratio value of the ions of interest alone.

[0098] Furthermore, the relationship between time and mass-to-charge ratio restricts the charge ratio range of ions present at the quadrupole when it is switched to dissolution mode (i.e., during period 12), further reducing the number of ions lost to the quadrupole. This can be seen when Fig. 3A with Fig. 2A compares. In Fig. 3A, a relatively narrow range of ions is present at separation time 12, when the ions of interest are present. In contrast, the uncorrelated nature of the separation time with respect to the mass-to-charge ratio in Fig. 2A to a mass-to-charge ratio range of ions eluting from the separation unit at time 12 of interest. This increases the number of ions lost to the rods of the analytical quadrupole when the quadrupole is operated in resolution mode.

[0099] Embodiments can be implemented with a typical quadrupole geometry as described in Fig. 1. An analytical quadrupole rod set 1 can be preceded by a prefilter quadrupole rod set 2 and can be followed by a postfilter quadrupole rod set 3. Even if Fig. 1 shows a quadrupole assembly including both a pre-filter 2 and a post-filter 3, it will be understood that the unit can operate without a post-filter 3. Advantageously, this approach does not require the provision of any hardware in addition to a typical quadrupole mass filter arrangement.

[0100] Fig. Figure 4 illustrates a method of operating the unit of Fig. 1. It is understood that the illustrated voltage waveforms in Fig. 4 are not quantitative and are intended only to represent the direction of change (e.g. for positive ions) when switching between modes.

[0101] In the first operating mode (during period 12), both an RF voltage and a resolving DC voltage are applied to pre-filter 2, such that ions within a mass-to-charge ratio range greater than or equal to the mass-to-charge ratio range of ions of interest are further transmitted from pre-filter 2. In one embodiment, the magnitude of the resolving DC current in the first operating mode may be equal to or close to zero, thereby enabling stable trajectories of ions of interest along the entire ion path.

[0102] In the second operating mode (during periods 10 and 11), an RF voltage and a resolving DC voltage are applied to the pre-filter 2 so that all ions within the pre-filter 2 are unstable and no ions are transmitted to the analytical quadrupole 1.

[0103] With reference to the Fig. In the arrangement shown in Figure 4, the DC bias of the prefilter 2 is also switched at times 12 when ions of interest are present, to ensure that unwanted ions are slowed down and have sufficient time to be ejected, while desired ions experience optimized transmission conditions. In one embodiment, this DC bias switching is not used.

[0104] In the case of the above-mentioned with reference to the Fig. 1 and Fig. 4, the transmission characteristics of the analytical quadrupole 1 and a post-filter 3 (if present) can remain static for the entire separation time or can change synchronously with the pre-filter 2.

[0105] In some embodiments, multiple ions of interest (e.g., parent or precursor ions of interest) can elute from the separation unit and be sequentially selected by the resolving quadrupole. In these embodiments, the analytical quadrupole 1 can be synchronously switched with the prefilter 2. Accordingly, in one embodiment, one or more ions (e.g., parent or precursor ions) of interest are selected per separation cycle.

[0106] In various embodiments, the analytical quadrupole 1 may be preceded by a range of known ion sources and / or ion guides and / or followed by a range of known analytical units, including fragmentation devices and / or mass spectrometers.

[0107] Thus, according to one embodiment, a mass spectrometer device is provided comprising a separation unit arranged upstream of an analytical quadrupole, wherein the prefilter of the quadrupole unit is configured to alternate between zero transmission and transmission of ions (e.g., parent or precursor ions) of interest one or more times within a separation cycle. The separation unit can be based on the mass-to-charge ratio, mass, or ion mobility.

[0108] In various other embodiments, gating electrodes may be used upstream of the analytical quadrupole 1 instead of or in addition to the prefilter quadrupole 2. Gating electrodes such as those used in deflector lenses or defocusing lenses may be used, or a Bradbury-Neilson (BN) gate may be used. These embodiments require additional hardware compared to other embodiments that use the prefilter quadrupole 2 of a quadrupole mass filter array.

[0109] Fig. Figure 5A shows an embodiment wherein a Bradbury-Neilson gate 4 is provided and used as the first filter. The Bradbury-Neilson gate 4 can be operated to alternate between maximum transmission and zero transmission at the appropriate times. This prevents ions from being lost to the rods of the analytical quadrupole 1 by preventing the ions from reaching the quadrupole assembly. Fig. In the arrangement shown in Figure 5A, the Bradbury-Neilson gate 4 is shown arranged between the prefilter 2 and the analytical quadrupole 1. The Bradbury-Neilson gate 4 can be placed anywhere between the upstream separation unit and the analytical quadrupole 1.

[0110] Fig. 5B shows the transmission of the Bradbury-Neilson gate 4 according to one embodiment.

[0111] Other embodiments are contemplated that include providing and using one or more downstream units such as one or more post-filters 3 or gates.

[0112] In one embodiment, synchronized data acquisition may be performed in combination with switching the analytical quadrupole 1 between resolution and non-resolution modes.

[0113] In various embodiments, other mass spectrometers or filters may be provided and used, including time-of-flight instruments, electrostatic traps, and / or mass analyzers that utilize inductive detection. In one embodiment, time-domain signal processing is used that converts time-domain signals to mass-to-charge ratio domain signals or spectra. In various embodiments, the processing includes (but is not limited to) Fourier transform, probabilistic analysis, filter diagonalization, forward fitting, and least-squares fitting.

[0114] In various embodiments, the approach disclosed above can be applied to non-mass-based filters, including differential mobility separation (DMS), field asymmetric ion mobility spectrometry (FAIMS), and / or differential mobility analysis (DMA) filters. These embodiments involve temporally separating ions according to a first physicochemical property, filtering the ions according to a second physicochemical property, and during a single separation cycle of the separation unit: (i) operating the filter unit in a first mode of operation, wherein ions of interest are selected by the filter; and (ii) operating the filter unit in a second mode of operation, wherein no ions are lost to the first filter.

[0115] In various embodiments, the approach disclosed above can be applied to tandem mass spectrometers and / or ion mobility spectrometry-capable instruments.

[0116] It is understood that one embodiment provided an apparatus for filtering ions while improving the robustness and lifetime of the resolving quadrupole.

Claims

[1] Device for filtering ions, comprising: a separation unit for temporally separating ions according to a first physico-chemical property; a first quadrupole rod set (1) for filtering the ions according to their mass-to-charge ratio, wherein the first quadrupole rod set (1) comprises a plurality of rods, and wherein the first quadrupole rod set (1) is arranged downstream of the separation unit; and a control system which, during a single separation cycle of the separation unit, is designed and constructed to: (i) operating the first set of quadrupole rods (1) in a first operating mode of resolving at separation times when ions of interest are expected to exit the separation unit, such that the ions of interest are selected or filtered by the first set of quadrupole rods (1) according to their mass-to-charge ratio; and (ii) operating the first quadrupole rod set (1) in a second non-resolving mode of operation at separation times when substantially no ions of interest are expected to exit the separation unit, such that substantially no ions impact the rods of the first quadrupole rod set (1). [2] Device for filtering ions, comprising: a separation unit for temporally separating ions according to a first physico-chemical property; a filter unit for filtering ions according to their mass-to-charge ratio, wherein the filter unit is arranged downstream of the separation unit, and wherein the filter unit comprises a quadrupole mass filter having an analytical quadrupole rod set (1) and a pre-filter quadrupole rod set (2) arranged upstream of the analytical quadrupole rod set (1); and a control system which, during a single separation cycle of the separation unit, is designed and constructed to: (i) operating the filter unit in a first operating mode, wherein the pre-filter quadrupole rod set (2) is operated in a transmitting operating mode, and wherein ions of interest are selected from the analytical quadrupole rod set (1); and (ii) operating the filter unit in a second operating mode at separation times when substantially no ions of interest are present, wherein the pre-filter quadrupole rod set (2) is operated in a non-transmitting operating mode such that substantially no ions impact the rods of the analytical quadrupole rod set (1). [3] The apparatus of claim 2, wherein in the first operating mode the control system is constructed and arranged to operate the analytical quadrupole rod set (1) with a first mass-to-charge ratio transmission window and to operate the pre-filter quadrupole rod set (2) with a second mass-to-charge ratio transmission window, the second mass-to-charge ratio transmission window being greater than or equal to and including the first mass-to-charge ratio transmission window. [4] Device according to claim 2 or 3, wherein the filter unit comprises a post-filter quadrupole rod set (3) arranged downstream of the analytical quadrupole rod set (1). [5] Apparatus according to any preceding claim, wherein the control system is further constructed and arranged to determine the position of the ions of interest in or from an examination scan. [6] The apparatus of claim 5, wherein the examination scan comprises a multidimensional examination scan. [7] A device according to any one of the preceding claims, wherein the first physicochemical property is either: (i) not correlated with a mass-to-charge ratio; or (ii) at least partially correlated with a mass-to-charge ratio. [8] A device according to any one of the preceding claims, wherein the first physico-chemical property comprises mass-to-charge ratio or time of flight. [9] The apparatus of claim 8, wherein the separation unit comprises a time-of-flight separation unit and / or an ion trap. [10] A device according to any one of claims 1 to 7, wherein the first physico-chemical property comprises ion mobility or differential ion mobility. [11] The device according to claim 10, wherein the separation unit comprises an ion mobility separator or a differential ion mobility separator. [12] Apparatus according to any one of the preceding claims, wherein the control system is constructed and arranged to select a plurality of different ions of interest during the single separation cycle. [13] Apparatus according to any one of the preceding claims, wherein in the first mode of operation the control system is constructed and arranged to operate the first or analytical quadrupole rod set (1) with a first mass-to-charge ratio transfer window so as to cause at least some ions having mass-to-charge ratio values ​​outside the first mass-to-charge ratio transfer window to impact the rods of the first or analytical quadrupole rod set (1). [14] Apparatus according to any one of the preceding claims, further comprising an ion trap arranged upstream of the separation unit. [15] The apparatus of claim 14, wherein the ion trap is constructed and arranged to pulse one or more packets or ions into the separation unit. [16] A method for filtering ions, comprising: temporally separating ions according to a first physico-chemical property using a separation unit; Filtering the ions according to their mass-to-charge ratio using a first quadrupole rod set (1), wherein the first quadrupole rod set (1) comprises a plurality of rods, and wherein the first quadrupole rod set (1) is arranged downstream of the separation unit; and during a single separation cycle of the separation unit: Operating the first set of quadrupole rods (1) in a first operating mode of resolving at separation times when ions of interest are expected to exit the separation unit, such that the ions of interest are selected or filtered by the first set of quadrupole rods (1) according to their mass-to-charge ratio; and Operating the first quadrupole rod set (1) in a second non-resolving mode of operation at separation times when substantially no ions of interest are expected to exit the separation unit, such that substantially no ions impact the rods of the first quadrupole rod set (1). [17] A method for filtering ions, comprising: temporally separating ions according to a first physico-chemical property using a separation unit; Filtering ions according to their mass-to-charge ratio using a filter unit, wherein the filter unit is arranged downstream of the separation unit, and wherein the filter unit comprises a quadrupole mass filter having an analytical quadrupole rod set (1) and a pre-filter quadrupole rod set (2) arranged upstream of the analytical quadrupole rod set (1); and during a single separation cycle of the separation unit: Operating the filter unit in a first operating mode, wherein the pre-filter quadrupole rod set is operated in a transmitting operating mode, and wherein ions of interest are selected from the analytical quadrupole rod set (1); and Operating the filter unit in a second operating mode at separation times when substantially no ions of interest are present, wherein the pre-filter quadrupole rod set (2) is operated in a non-transmitting operating mode such that substantially no ions impact the rods of the analytical quadrupole rod set (1). [18] A mass spectrometer comprising an ion filtering device according to any one of claims 1 to 15. [19] A mass spectrometric method using a method for filtering ions according to any one of claims 16 and 17.

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