Mass filter

Abstract

A mass filtering apparatus comprising: a mass filter (3) having an analytical section (5) for mass filtering ions and a pre-filter arranged (4) upstream of the analytical section for guiding ions into the analytical section; an extraction electrode (7) arranged upstream of the pre-filter (4) for extracting ions from within the pre-filter; and voltage supplies configured to apply different DC voltages to the extraction electrode (7) and pre-filter (4) so as to maintain a DC potential profile within the pre-filter for urging ions out of the pre-filter in the upstream direction towards the extraction electrode.

Description

[0001] 173606-02v1 (M-4737)

[0002] MASS FILTER

[0003] CROSS-REFERENCE TO RELATED APPLICATION

[0004] This application claims priority from and the benefit of United Kingdom patent application No. 2417752.9 filed on 3 December 2024, the entire contents of which are incorporated herein by reference.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates generally to a method of mass spectrometry and a mass spectrometer configured to perform the method. More specifically, the present invention relates a mass filter, such as a quadrupole mass filter, for filtering ions according to mass to charge ratio

[0007] BACKGROUND

[0008] Quadrupole mass filters typically comprise a main, analytical section for performing mass filtering of ions and an upstream pre-filter section, known as a Brubaker lens, for improving the transmission of the ions into the analytical section. Due to the DC potentials required to be applied to various components of the mass spectrometer, ions become trapped in the pre-filter section. This affects the transmission of other ions through the mass filter, which has negative consequences.

[0009] SUMMARY

[0010] The present invention provides a mass filtering apparatus comprising: a mass filter having an analytical section for mass filtering ions and a pre-filter arranged upstream of the analytical section for guiding ions into the analytical section; an extraction electrode arranged upstream of the pre-filter for extracting ions from within the pre-filter; and voltage supplies configured to apply different DC voltages to the extraction electrode and pre-filter so as to maintain a DC potential profile within the pre-filter for urging ions out of the prefilter in the upstream direction towards the extraction electrode.

[0011] The voltage supplies are configured to provide the DC potential profile in the prefilter for urging ions, that are reflected at a boundary between the pre-filter and the analytical section, out of the pre-filter in the upstream direction towards the extraction electrode. The present invention substantially prevents ions being trapped in the pre-filter, which may otherwise affect the transmission of other ions through the mass filter.

[0012] The DC potential profile may be the DC potential profile along a central axis extending through the mass filter. The pre-filter may be the ion-optical element closest, in the upstream direction, to the analytical section.

[0013] The voltage supplies may be configured to apply DC voltages to the extraction electrode, pre-filter and analytical section such that said DC potential profile is provided throughout the pre-filter.

[0014] The voltage supplies may be configured to apply said DC voltages such that said DC potential profile is maintained throughout the pre-filter so that substantially no ions are able to be trapped in the pre-filter.

[0015] The voltage supplies may be configured to apply said DC voltages such that said DC potential profile has no DC potential well within the pre-filter.

[0016] The voltage supplies may be configured to apply said DC voltages such that the DC potential profile continuously and / or monotonically decreases from a downstream end of the pre-filter to the upstream end of the pre-filter.

[0017] The voltage supplies may be configured to apply DC voltages to the extraction electrode, pre-filter and analytical section such that the electrodes of the pre-filter are maintained at a lower DC electric potential than any electrodes of the analytical section, and such that the extraction electrode is maintained at a lower DC electric potential than the electrodes of the pre-filter.

[0018] The apparatus may comprise an ion-optical component upstream of the extraction electrode and a DC voltage supply configured to maintain that ion-optical component at a DC electric potential that is higher than the DC electric potential applied to the extraction electrode.

[0019] The DC voltage supply may be configured to maintain the ion-optical component at a DC electric potential that is substantially the same as, or higher than, the DC potential at which at least some of the electrodes of analytical section are maintained. This enables ions to be transmitted from the ion-optical component into the analytical section of the mass filter, although as described above, some ions are reflected back and urged out of the pre-filter in the upstream direction.

[0020] The extraction electrode may be arranged immediately upstream of the pre-filter. By this it is meant that the extraction electrode is the ion-optical component closest, in the upstream direction, to the pre-filter. The extraction electrode may however be spaced apart from the pre-filter.

[0021] The voltage supplies may be configured to apply said DC voltages such that the DC potential profile includes a potential well proximate to the extraction electrode. As such, ions that enter the pre-filter and are reflected at a boundary between the pre-filter and the analytical section will be accelerated back upstream towards the extraction electrode.

[0022] The voltage supplies may be configured to apply said DC voltages such that the DC potential profile is arranged for accelerating ions out of the pre-filter in the upstream direction so as to strike the extraction electrode and / or another ion-optical component of the apparatus that is upstream of the pre-filter. The apparatus may comprise a heater for heating the extraction electrode and / or said another ion-optical component, for burning off contamination thereon due to the ions striking these components.

[0023] The apparatus may comprise more than one extraction electrode upstream of the pre-filter, and voltages may be applied to these extraction electrodes so as to guide the ions that are accelerated out of the pre-filter in the upstream direction to impact on an electrode in the apparatus.

[0024] The ion extraction electrode may define an aperture through which ions are transmitted to the pre-filter, where the aperture is substantially the same size or larger than the ion entrance to the pre-filter. This ensures that the ion entrance conditions into the mass filter are not significantly affected by the ion extraction electrode.

[0025] The mass filter may be a quadrupole mass filter.

[0026] The pre-filter may comprise a quadrupole rod set having four elongated rod electrodes.

[0027] The analytical section may comprise a quadrupole rod set having four elongated rod electrodes.

[0028] The elongated rod electrodes of the pre-filter may be shorter than the elongated rod electrodes of the analytical section.

[0029] The apparatus may comprise an ion guide upstream of the extraction electrode for guiding ions to the mass filter; and optionally the apparatus may comprise a wall between the ion guide and the extraction electrode, wherein the wall comprises an aperture that is aligned with the ion guide such that ions are able to be transmitted from the ion guide, through the aperture to the mass filter.

[0030] The apparatus may comprise voltage supplies connected to electrodes of the analytical section of the mass filter, and a controller configured to control the voltage supplies so as to apply RF and DC voltages to the electrodes such that only ions having a restricted range of mass to charge ratios are able to be transmitted through the analytical section and ions having other mass to charge ratios are filtered out, optionally wherein the controller is configured to vary the RF and DC voltages with time such that the range of mass to charge ratios that are able to be transmitted by the analytical section varies with time.

[0031] Where the mass filter is a quadrupole mass filter, the apparatus may comprise an RF voltage supply that is connected to the rod electrodes of the analytical section such that one phase of the voltage supply is applied to one of the pairs of opposing rod electrodes and an opposite phase of the voltage supply is applied to the other pair of opposing rod electrodes. The apparatus may also comprise a DC voltage supply connected to at least two of the electrodes of the analytical section so as to apply a DC resolving voltage between the electrodes. The apparatus may comprise an RF voltage supply that is connected to the rod electrodes of the pre-filter such that one phase of the voltage supply is applied to one of the pairs of opposing rod electrodes and an opposite phase of the voltage supply is applied to the other pair of opposing rod electrodes. Each rod electrode of the pre-filter may be colinear with a rod electrode of the analytical section. These axially adjacent electrodes may be maintained at RF voltages having the same phase and frequency, but optionally different amplitudes. For example, the amplitude of the RF voltage applied to the electrodes of the pre-filter may be lower than the amplitude of the RF voltage applied to the electrodes of the analytical section.

[0032] It is contemplated that the mass filter may be a digital mass filter.

[0033] The present invention provides a mass spectrometer comprising an apparatus as described above.

[0034] The mass spectrometer may be a tandem mass spectrometer comprising: a first mass filtering apparatus for mass filtering precursor ions; a fragmentation or reaction device downstream of the first mass filtering apparatus for fragmenting or reacting precursor ions transmitted by the first mass filter so as to produce fragment or other product ions; and a second mass filtering apparatus for mass filtering said fragment or other product ions; where the first and / or second mass filtering apparatus is a mass filtering apparatus as described above.

[0035] The tandem mass spectrometer may have control circuitry configured to control the first and second mass filtering apparatus so as to monitor for one or more pre-selected multiple reaction monitoring (MRM) transition.

[0036] Accordingly, the tandem mass spectrometer may have control circuitry configured to control the first mass filtering apparatus so that at a first time it is only capable of transmitting a first pre-selected range of mass to charge ratios corresponding to a first precursor ion species of interest, and to control the second mass filtering apparatus so that at the first time it is only capable of transmitting a second pre-selected range of mass to charge ratios corresponding to a fragment or other product ion species of the first precursor ion species of interest.

[0037] The mass spectrometer may comprise an ion detector downstream of the second mass filtering apparatus. When the detector detects an ion then the occurrence of the MRM transition being monitored for is confirmed by the spectrometer.

[0038] The control circuitry may be configured to control the first mass filtering apparatus so that at a second different time it is only capable of transmitting said first pre-selected range of mass to charge ratios, and to control the second mass filtering apparatus so that at the second time it is only capable of transmitting a third pre-selected range of mass to charge ratios corresponding to a different fragment or other product ion species of said first precursor ion species of interest.

[0039] The control circuitry may be configured to control the first mass filtering apparatus so that at a further time it is only capable of transmitting a further pre-selected range of mass to charge ratios corresponding to a second, different precursor ion species of interest, and to control the second mass filtering apparatus so that at the further time it is only capable of transmitting a fourth pre-selected range of mass to charge ratios corresponding to a fragment or other product ion species of the second precursor ion species of interest.

[0040] The present invention also provides a method of mass filtering ions using the mass filtering apparatus described above. Accordingly, the present invention provides a method of mass filtering ions comprising: providing a mass filtering apparatus as described above; and transmitting ions into said mass filter whilst applying different DC voltages to the extraction electrode and pre-filter so as to maintain said DC potential profile within the pre-filter that urges ions out of the pre-filter in the upstream direction towards the extraction electrode.

[0041] Some of the ions transmitted into the mass filter are reflected between the pre-filter and analytical section of the mass filter, and are urged out of the pre-filter in the upstream direction towards the extraction electrode by the DC potential profile, whereas others of the ions transmitted into the mass filter pass through the pre-filter and into the analytical section; and voltages may be applied to electrodes of the analytical section so as to mass filter the ions passing therethrough.

[0042] The present invention also provides a method of mass spectrometry comprising the method of mass filtering ions.

[0043] Although embodiments have been described in which the extraction electrode is arranged upstream of the pre-filter, it may alternatively be arranged between the pre-filter and the analytical section.

[0044] Accordingly, the present invention provides a mass filtering apparatus comprising: a mass filter having an analytical section for mass filtering ions and a pre-filter arranged upstream of the analytical section for guiding ions into the analytical section; an extraction electrode arranged between the pre-filter and the analytical section, for extracting ions from within the pre-filter; and voltage supplies configured to apply different DC voltages to the extraction electrode and pre-filter so as to maintain a DC potential profile within the prefilter for urging ions out of the pre-filter in the downstream direction towards the extraction electrode.

[0045] The voltage supplies are configured to provide the DC potential profile in the prefilter for urging ions, that are reflected at a boundary between the pre-filter and the analytical section, out of the pre-filter in the downstream direction towards the extraction electrode. The present invention substantially prevents ions being trapped in the pre-filter, which may otherwise affect the transmission of other ions through the mass filter.

[0046] The DC potential profile may be the DC potential profile along a central axis extending through the mass filter.

[0047] The extraction electrode may be the only ion-optical element between the pre-filter and the analytical section.

[0048] The voltage supplies may be configured to apply DC voltages to the extraction electrode, pre-filter and analytical section such that said DC potential profile is provided throughout the pre-filter.

[0049] The voltage supplies may be configured to apply said DC voltages such that said DC potential profile is maintained throughout the pre-filter so that substantially no ions are able to be trapped in the pre-filter.

[0050] The voltage supplies may be configured to apply said DC voltages such that said DC potential profile has no DC potential well within the pre-filter. The voltage supplies may be configured to apply said DC voltages such that the DC potential profile continuously and / or monotonically decreases from an upstream end of the pre-filter to the downstream end of the pre-filter.

[0051] Said voltage supplies may be configured to apply DC voltages to the extraction electrode, pre-filter and analytical section such that the electrodes of the pre-filter are maintained at a lower DC electric potential than any electrodes of the analytical section, and such that the extraction electrode is maintained at a lower DC electric potential than the electrodes of the pre-filter.

[0052] The apparatus may comprise an ion-optical component upstream of the pre-filter and a DC voltage supply configured to maintain that ion-optical component at a DC electric potential that is higher than the DC electric potential applied to the extraction electrode and / or to the pre-filter.

[0053] The DC voltage supply may be configured to maintain the ion-optical component at a DC electric potential that is substantially the same as, or higher than, the DC potential at which at least some of the electrodes of analytical section are maintained. This enables ions to be transmitted from the ion-optical component into the analytical section of the mass filter, although as described above, some ions are reflected back and urged out of the pre-filter in the upstream direction.

[0054] The extraction electrode ay be arranged immediately downstream of the pre-filter. By this it is meant that the extraction electrode is the ion-optical component closest, in the downstream direction, to the pre-filter. The extraction electrode may however be spaced apart from the pre-filter.

[0055] The voltage supplies may be configured to apply said DC voltages such that the DC potential profile includes a potential well proximate to the extraction electrode. As such, ions that enter the pre-filter and are reflected at a boundary between the pre-filter and the analytical section will be accelerated downstream towards the extraction electrode.

[0056] The voltage supplies may be configured to apply said DC voltages such that the DC potential profile is arranged for accelerating ions out of the pre-filter in the downstream direction so as to strike the extraction electrode and / or an electrode of the analytical section.

[0057] The apparatus may comprise a heater for heating the extraction electrode and / or said analytical section, for burning off contamination thereon due to the ions striking these components.

[0058] The apparatus may comprise more than one extraction electrode downstream of the pre-filter, and voltages may be applied to these extraction electrodes so as to guide the ions that are accelerated out of the pre-filter in the downstream direction to impact on an electrode in the apparatus.

[0059] The ion extraction electrode may define an aperture through which ions are transmitted to the analytical section, where the aperture is substantially the same size or larger than the ion entrance to the analytical section. This ensures that the ion entrance conditions into the analytical section are not significantly affected by the ion extraction electrode. The mass filter may be a quadrupole mass filter.

[0060] The pre-filter may comprise a quadrupole rod set having four elongated rod electrodes.

[0061] The analytical section may comprise a quadrupole rod set having four elongated rod electrodes.

[0062] The elongated rod electrodes of the pre-filter may be shorter than the elongated rod electrodes of the analytical section.

[0063] The apparatus may comprise an ion guide upstream of the pre-filter for guiding ions to the mass filter; and optionally comprising a wall between the ion guide and the pre-filter, wherein the wall comprises an aperture that is aligned with the ion guide such that ions are able to be transmitted from the ion guide, through the aperture to the mass filter.

[0064] The apparatus may comprise voltage supplies connected to electrodes of the analytical section of the mass filter, and a controller configured to control the voltage supplies so as to apply RF and DC voltages to the electrodes such that only ions having a restricted range of mass to charge ratios are able to be transmitted through the analytical section and ions having other mass to charge ratios are filtered out, optionally wherein the controller is configured to vary the RF and DC voltages with time such that the range of mass to charge ratios that are able to be transmitted by the analytical section varies with time.

[0065] Where the mass filter is a quadrupole mass filter, the apparatus may comprise an RF voltage supply that is connected to the rod electrodes of the analytical section such that one phase of the voltage supply is applied to one of the pairs of opposing rod electrodes and an opposite phase of the voltage supply is applied to the other pair of opposing rod electrodes. The apparatus may also comprise a DC voltage supply connected to at least two of the electrodes of the analytical section so as to apply a DC resolving voltage between the electrodes. The apparatus may comprise an RF voltage supply that is connected to the rod electrodes of the pre-filter such that one phase of the voltage supply is applied to one of the pairs of opposing rod electrodes and an opposite phase of the voltage supply is applied to the other pair of opposing rod electrodes. Each rod electrode of the pre-filter may be colinear with a rod electrode of the analytical section. These axially adjacent electrodes may be maintained at RF voltages having the same phase and frequency, but optionally different amplitudes. For example, the amplitude of the RF voltage applied to the electrodes of the pre-filter may be lower than the amplitude of the RF voltage applied to the electrodes of the analytical section.

[0066] It is contemplated that the mass filter may be a digital mass filter.

[0067] The present invention also provides a mass spectrometer comprising the apparatus described above.

[0068] The mass spectrometer may be a tandem mass spectrometer comprising: a first mass filtering apparatus for mass filtering precursor ions; a fragmentation or reaction device downstream of the first mass filtering apparatus for fragmenting or reacting precursor ions transmitted by the first mass filter so as to produce fragment or other product ions; and a second mass filtering apparatus for mass filtering said fragment or other product ions; where the first and / or second mass filtering apparatus is a mass filtering apparatus as described above.

[0069] The tandem mass spectrometer may have control circuitry configured to control the first and second mass filtering apparatus so as to monitor for one or more pre-selected multiple reaction monitoring (MRM) transition.

[0070] Accordingly, the tandem mass spectrometer may have control circuitry configured to control the first mass filtering apparatus so that at a first time it is only capable of transmitting a first pre-selected range of mass to charge ratios corresponding to a first precursor ion species of interest, and to control the second mass filtering apparatus so that at the first time it is only capable of transmitting a second pre-selected range of mass to charge ratios corresponding to a fragment or other product ion species of the first precursor ion species of interest.

[0071] The mass spectrometer may comprise an ion detector downstream of the second mass filtering apparatus. When the detector detects an ion then the occurrence of the MRM transition being monitored for is confirmed by the spectrometer.

[0072] The control circuitry may be configured to control the first mass filtering apparatus so that at a second different time it is only capable of transmitting said first pre-selected range of mass to charge ratios, and to control the second mass filtering apparatus so that at the second time it is only capable of transmitting a third pre-selected range of mass to charge ratios corresponding to a different fragment or other product ion species of said first precursor ion species of interest.

[0073] The control circuitry may be configured to control the first mass filtering apparatus so that at a further time it is only capable of transmitting a further pre-selected range of mass to charge ratios corresponding to a second, different precursor ion species of interest, and to control the second mass filtering apparatus so that at the further time it is only capable of transmitting a fourth pre-selected range of mass to charge ratios corresponding to a fragment or other product ion species of the second precursor ion species of interest.

[0074] The present invention also provides a method of mass filtering ions using the mass filtering apparatus described above.

[0075] Accordingly, the present invention provides a method of mass filtering ions comprising: providing a mass filtering apparatus as described above; and transmitting ions into said mass filter whilst applying different DC voltages to the extraction electrode and pre-filter so as to maintain said DC potential profile within the pre-filter that urges ions out of the pre-filter in the downstream direction towards the extraction electrode.

[0076] Some of the ions transmitted into the mass filter are reflected between the pre-filter and analytical section of the mass filter, and are then urged out of the pre-filter in the downstream direction towards the extraction electrode by the DC potential profile. Others of the ions transmitted into the mass filter may not be reflected and pass through the prefilter and into the analytical section; and voltages may be applied to electrodes of the analytical section so as to mass filter the ions passing therethrough. The present invention also provides a method of mass spectrometry comprising the method of mass filtering ions.

[0077] BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Various embodiments of the present invention will now be described, by way of example only, and with reference to the accompanying drawings in which:

[0079] Fig. 1 shows a portion of a known mass spectrometer;

[0080] Fig. 2 illustrates an example of how MRM transitions may be monitored;

[0081] Fig. 3 shows a portion of a mass spectrometer according to an embodiment of the present invention; and

[0082] Figs. 4-7 show plots of the ion signal response detected for MRM transitions monitored by a conventional tandem quadrupole mass spectrometer or a tandem quadrupole mass spectrometer according to an embodiment of the present invention.

[0083] DETAILED DESCRIPTION

[0084] Quadrupole mass filters typically comprise a main, analytical section for performing mass filtering of ions and an upstream pre-filter section for improving the transmission of the ions into the analytical section. As is known in the art, the analytical section is formed from relatively long rod electrodes, to which opposite phases of an RF voltage are applied together with a resolving DC voltage for causing ions to be mass filtered. The pre-filter section has shorter rod electrodes, and the RF voltage is also applied to these electrodes, although at a lower amplitude than the amplitude applied to the analytical section. A resolving DC voltage is not applied between the electrodes of the pre-filter, but a DC voltage is applied to the electrodes of the pre-filter for maximising the transmission of ions through the mass filter. The pre-filter is often referred to as a Brubaker lens.

[0085] Fig. 1 shows a portion of a known mass spectrometer comprising an ion guide 1 , a wall 2 having a differential pumping aperture therein, and a quadrupole mass filter 3 comprising a pre-filter section 4 and an analytical section 5. Typically, the electrodes of the pre-filter 4 are maintained at a DC potential that is lower than the DC potentials at which the ion guide 1 and wall 2 are maintained, and that is lower than the DC potentials applied to the electrodes of the analytical section 5 of the mass filter. Fig. 1 also shows an example of the DC potential profile 6 that may be present along the central axis of this portion of the mass spectrometer.

[0086] As can be seen from the DC potential profile, the relatively low DC potential applied to the electrodes of the pre-filter 4 creates a DC potential well between the ion guide 1 and the analytical section 5 of the mass filter 3, where the pre-filter is located. It has been recognised that some ions are reflected at the electric field boundary between the pre-filter and the analytical section of the mass filter, and that some of these reflected ions can become trapped in the pre-filter due to the DC potential well. The presence of a significant number of ions in the pre-filter can lead to space-charge effects on the ions being transmitted through the pre-filter, which can cause an undesirable variation in the transmission of ions through the mass filter. For example, when there is a relatively high ion flux into the mass filter the DC potential well in the pre-filter fills with trapped ions relatively quickly, causing the ion signal that is able to be transmitted through the mass filter to vary with time until an equilibrium condition is established. The time it takes to fill the DC potential well is dependent on the depth of the DC potential well and the ion current passing into the mass filter, but it typically takes at least 500 ms for a stable signal to be transmitted by the mass filter.

[0087] The above problem is particularly problematic, for example, in multiple reaction monitoring (MRM) experiments. As is well known in the art, typically a MRM experiment is performed using a tandem quadrupole mass spectrometer having an upstream quadrupole mass filter for selectively transmitting precursor ion species, a fragmentation cell for fragmenting the precursor ion species, and a downstream quadrupole mass filter for transmitting the resulting fragment ions. In a MRM experiment the mass spectrometer is controlled so as to monitor certain precursor-fragment transitions. This is performed by controlling the upstream mass filter so that it is only capable of transmitting a mass to charge ratio for a precursor ion species of interest and controlling the downstream mass filter so that it is only capable of transmitting a mass to charge ratio corresponding to a fragment ion species of that precursor ion species of interest. Precursor ions are then supplied to the upstream mass filter and an ion detector monitors for any ions that are transmitted by the downstream mass filter. If an ion is detected at the detector then the occurrence of the precursor-fragment transition being monitored for is confirmed.

[0088] The downstream mass filter may be controlled so that it is capable of transmitting mass to charge ratios corresponding to different fragment ion species of the precursor ion species of interest at different times, so as to monitor for multiple precursor-fragment transitions for the same precursor ion species. Typically, precursor-fragment transitions are monitored for multiple different precursor ion species. These different precursor ion species tend to arrive at the upstream mass filter during partially overlapping time periods, e.g. due to the analytical sample being separated upstream of the mass filter by a liquid chromatography. As such, the mass spectrometer may repeatedly perform a cycle, during each of which the mass spectrometer sequentially monitors MRM transitions for different precursor ion species, as described in relation to Fig. 2.

[0089] Fig. 2 schematically illustrates an example in which one or more MRM transitions for precursor ion species having mass to charge ratios of 100 Da, 200 Da, 300 Da and 2000 Da are monitored. In this example, the 100 Da precursor ion species arrives at the mass filter over time periods 1-4, the 200 Da precursor ion species arrives at the mass filter over time periods 3-5, the 300 Da precursor ion species arrives at the mass filter over time periods 4-7, and the 2000 Da precursor ion species arrives at the mass filter over time periods 2-6. The mass spectrometer switches between monitoring MRM transitions for these precursor ion species during each of the time periods. For example, during time period 4 the mass spectrometer controls the mass filters so as to first monitor for one or more MRM transitions for the 100 Da precursor ions, then switches to monitor for one or more MRM transitions for the 200 Da precursor ions, then switches to monitor for one or more MRM transitions for the 300 Da precursor ions, and then switches to monitor for one or more MRM transitions for the 2000 Da precursor ions.

[0090] However, 100 Da ions do not reach the mass filter during time period 5 and so after the MRM transitions for the 2000 Da ions are monitored for in time period 4, the next ions to reach the upstream mass filter in time period 5 are the 200 Da precursor ions. Similarly, 200 Da ions do not reach the mass filter during time period 6 and so after the MRM transitions for the 2000 Da ions are monitored for in time period 5, the next ions to reach the upstream mass filter in time period 6 are the 300 Da precursor ions.

[0091] As described above, ions become trapped in the pre-filter of each of the mass filters. As such, each time the mass spectrometer begins monitoring an MRM transition for a particular precursor ion species, the pre-filter will be filled with ions that were transmitted to it in the immediately preceding time period. As the different precursor ion species arrive at the upstream mass filter during different, partially overlapping durations, the species and possibly number of ions trapped in the pre-filter for the upstream mass filter may be different for the different instances that any given precursor ion species is subjected to MRM monitoring. Similarly, the species and possibly number of ions trapped in the prefilter for the downstream mass filter may be different for the different instances that any given precursor ion species is subjected to MRM monitoring. The effect on ion transmission to the ion detector that is caused by the ions being trapped in the pre-filters may therefore be different for the different instances that the precursor ion species is subjected to MRM monitoring.

[0092] For example, referring again to Fig. 2, the monitoring of a MRM transition for the 300 Da precursor ion species during time period 5 is preceded by the monitoring of a MRM transition for the 200 Da precursor ion species, whereas the monitoring of the MRM transition for the 300 Da precursor ion species in time period 6 is preceded by the monitoring of a MRM transition for the 2000 Da precursor ion species in time period 5. As such, the ion transmission for the MRM transition for the 300 Da ions may be affected differently when it is monitored for in time periods 5 and 6, leading to different initial ion signals being detected in these time periods. In contrast, the monitoring of the MRM transition for the 300 Da precursor ion species during time period 7 is preceded by the monitoring of the MRM transition for the 2000 Da precursor ion species in time period 6. As such, the ion transmission for the MRM transition for the 300 Da ions will be affected in substantially the same manner in time periods 6 and 7, leading to substantially the same initial ion signals being detected in these time periods.

[0093] As the DC voltages applied to the pre-filters are selected so as to maximise ion transmission into the analytical section and through the mass filter, these voltages cannot be changed significantly in order to prevent the ion trapping in the pre-filters and overcome the above problem, without reducing the performance of the mass filter. Therefore, in order to avoid the above problem it is known to apply pulsed DC voltages to the electrodes of the pre-filters between monitoring for different MRM transitions, so as to empty the prefilters of trapped ions. However, this requires a relatively complex and expensive voltage source in order to provide the voltage pulse within the required timescale. Also, when using this pulsed technique, each time the mass spectrometer begins monitoring a new MRM transition the pre-filters begin filling with trapped ions again, and as the charge density of the trapped ions increases during filling this affects the transmission of ions through the pre-filters in a time varying manner. Also, the duration taken to fill the DC potential wells in the pre-filters depends on the incoming ion current, which may be nonlinear and so may cause non-linear affects on the ion signal transmitted by the mass filters. Also, if the initial part of the ion signal detected by the detector is used in a process for determining the cleanliness of the ion optics in the mass spectrometer, the above issues may affect this process.

[0094] Embodiments of the present invention seek to overcome the problems caused by ions being trapped in the pre-filter.

[0095] Fig. 3 shows a portion of a mass spectrometer according to an embodiment of the present invention. The mass spectrometer comprises an ion guide 1 , a wall 2 having a differential pumping aperture therein, an extraction electrode 7 and a quadrupole mass filter 3.

[0096] The quadrupole mass filter 3 comprises a main, analytical section 5 for performing mass filtering of ions and an upstream pre-filter section 4 for improving the transmission of the ions into the analytical section. The analytical section may be formed from a quadrupole rod set having four relatively long rod electrodes. An RF voltage supply is connected to the rod electrodes such that one phase of the voltage supply is applied to one of the pairs of opposing rod electrodes and an opposite phase of the voltage supply is applied to the other pair of opposing rod electrodes. A DC voltage supply is also connected to at least two of the electrodes so as to apply a DC resolving voltage between the electrodes. In operation, the RF and DC voltages are selected so as enable only ions having mass to charge ratios in a restricted range pass through the analytical section, whereas ions having other mass to charge ratios are filtered out and not transmitted. As is known in the art, the RF and DC voltages may be varied with time such that the range of mass to charge ratios that are able to be transmitted varies with time.

[0097] The pre-filter 4 may be formed from a quadrupole rod set having shorter electrodes than the analytical section. An RF voltage supply applies phases on an RF voltage to these electrodes in the same manner as described above in relation to the analytical section, i.e. with corresponding phases and frequencies. However, the amplitude of the RF voltage applied to the electrodes of the pre-filter may be lower than the amplitude of the RF voltage applied to the electrodes of the analytical section. A DC resolving voltage difference is not applied between the electrodes of the pre-filter, since it is not intended for the pre-filter to mass filter ions passing therethrough. Rather, the pre-filter is provided for increasing the ion transmission into the analytical section 5 of the mass filter. As such, a DC voltage is applied to at least some of the electrodes of the pre-filter for improving ion transmission into the analytical section. More specifically, the DC voltage is applied such that the electrodes of the pre-filter are at a lower DC electric potential than the DC potential at the electrodes of the analytical section. As described above, the ion-optical component immediately upstream of the quadruple mass filter 3 is conventionally maintained at substantially the same DC potential, or a slightly higher DC potential, than the mass filter such that ions travel downstream into the mass filter. For example, in the embodiment illustrated in Fig. 3 the exit of the ion guide 1 and / or the wall 2 may be maintained at a DC potential that is substantially the same, or slightly higher than, the DC potential applied to the analytical section 5 of the mass filter 3. This conventionally leads to the problem of ions becoming trapped in the prefilter 4, as has been described above.

[0098] According to embodiments of the present invention, an extraction electrode 7 is arranged upstream of the pre-filter 4 that is maintained at a DC potential, relative to that of the pre-filter, so that a DC potential well is not located in the pre-filter and ions substantially do not become trapped in the pre-filter. More specifically, the extraction electrode 7 arranged upstream of the pre-filter may be maintained at a DC potential such that a DC potential gradient is maintained along the pre-filter that urges ions out of the pre-filter. Preferably the DC potential gradient urges the ions out of the pre-filter in the upstream direction away from the analytical section 5. In the embodiment shown in Fig. 3, the extraction electrode is arranged immediately upstream of the pre-filter.

[0099] Fig. 3 shows a plot 8 of the DC potential present profile along the central axis of the portion of the mass spectrometer when the extraction electrode 7 is present, and a plot 9 of the DC potential profile present along the central axis when the extraction electrode is not present. When modelling the DC potential profiles the upstream end of the analytical quadrupole 5 was modelled as being at an axial position of 0 mm and the extraction electrode was modelled as being at an axial position of -17.5mm. The pre-filter electrodes were modelled as being maintained at -5 V and the extraction electrode was modelled as being an apertured electrode having an aperture diameter of 5mm and being maintained at -20 V. The relatively wide aperture of the extraction was chosen so as not to significantly change the entrance conditions into the quadrupole mass filter.

[0100] As can be seen from plot 9, when the extraction electrode is not provided the potential profile has a substantially symmetric DC potential well that is centred in the prefilter, in substantially the same manner as shown in Fig. 1. In contrast, as can be seen from plot 8, when the extraction electrode 7 is provided there is no DC potential well within the pre-filter 4. Instead, a DC potential profile is maintained through the pre-filter such that the DC potential profile continuously decreases through the pre-filter in the upstream direction. As such, any ions that are transmitted to the mass filter and get reflected at the boundary between the pre-filter and the analytical section of the mass filter will not become trapped in the pre-filter but will instead be urged in the upstream direction and out of the pre-filter.

[0101] Although a DC potential well is still present in plot 8, the potential well is asymmetric and may be such that its minimum is upstream of the pre-filter 4 and close to the position of the extraction electrode 7. As such, ions that enter the pre-filter and are reflected at the boundary between the pre-filter and the analytical section will be accelerated back upstream towards the extraction electrode. The voltages that are applied to the extraction electrode are such that these ions are not trapped upstream of the pre-filter. Rather, the ions may be accelerated back upstream such that they either strike the extraction electrode 7 or the wall 2 and are neutralised. However, it is contemplated that the DC potential minimum of the well need not be upstream of the pre-filter and may be within it. For example, the DC potentials applied to the various components may be such that the asymmetric DC potential well is arranged so that ions that have been reflected at the boundary between the pre-filter and the analytical section are accelerated back upstream by the portion of the DC potential well that is downstream of its minimum. This acceleration may cause the ions to gain sufficient energy to travel at least part way up the portion of the DC potential well that is upstream of its minimum such that they strike the extraction electrode 7 or wall 2.

[0102] In order to demonstrate the effectiveness of an embodiment of the present invention, numerical simulations were performed using SIMION to model both a system as shown in Fig. 1 comprising the gas filled ion guide 1 , the wall 2, and the mass filter 3 having the pre-filter 4 and analytical section 5, and also a system as shown in Fig. 3 comprising the gas filled ion guide 1, the wall 2, the extraction electrode 7 and the mass filter 3 having the pre-filter 4 and analytical section 5. In the simulations the analytical section of the mass filter was modelled as being operated so as to have a narrow mass transmission window that is scanned across a mass peak having a mass to charge ratio of 556 and a peak width of 0.6 Da. In the arrangement according to Fig. 1 , which does not have the extraction electrode, 20.3% of the ions were transmitted by the mass filter, 73.5% of the ions were lost to electrodes, and 6.2% of the ions were trapped in the pre-filter. In contrast, in the embodiment according to Fig. 3 that has the extraction electrode (maintained at -20 V), 20.9% of the ions were transmitted by the mass filter, 79.1% of the ions were lost to electrodes, and 0.01 % of the ions were trapped in the pre-filter. This showed that the extraction electrode almost entirely eliminates ion trapping in the pre-filter.

[0103] In order to demonstrate the effectiveness of embodiments of the present invention, experiments were performed on a conventional tandem quadrupole mass spectrometer that did not have the extraction electrode in the mass filters (and which did not pulse the pre-filters in order to empty them of trapped ions) and a tandem quadrupole mass spectrometer according to an embodiment of the present invention that did have the extraction electrode (maintained at -25 V) in the mass filters. The results of the experiments are shown in Figs. 4-7.

[0104] Fig. 4 shows eleven plots of the normalised ion signal response detected in the conventional tandem quadrupole mass spectrometer as a function of time when monitoring an MRM transition for each of eleven different precursor ion species having the mass to charge ratios listed. The plot for each of the eleven precursors ion species shows the ion signal response detected from the time at which the upstream mass filter is switched to transmit that precursor ion species, where the mass filter had previously been set to transmit a lower mass to charge ratio. As can be seen, the ion signal in each plot tends to drop with time after the mass filter is switched to transmit the new mass to charge ratio. This effect is due to the pre-filter being filled with trapped ions, as has been described above. Fig. 5 shows eleven plots for the same experiments that were performed to obtain the data shown in Fig. 4, except using a tandem quadrupole mass spectrometer according to the embodiment of the present invention, i.e. having the extraction electrode. As can be seen, the ion signal in each plot is relatively constant with time, compared to Fig. 4, since substantially no ions are trapped in the pre-filter.

[0105] Fig. 6 shows eleven plots for the same experiments that were performed to obtain the data shown in Fig. 4, and using the same conventional tandem quadrupole mass spectrometer, except each plot shows the ion signal response detected from the time at which the upstream mass filter is switched to transmit that precursor ion species from having previously been set to transmit a higher mass to charge ratio.

[0106] Fig. 7 shows eleven plots for the same experiments that were performed to obtain the data shown in Fig. 5, and using the tandem quadrupole mass spectrometer according to the embodiment of the present invention, except each plot shows the ion signal response detected from the time at which the upstream mass filter is switched to transmit that precursor ion species from having previously been set to transmit a higher mass to charge ratio. As can be seen from comparing Figs. 6 and 7, the embodiment of the present invention reduces the variability of the ion signal over time, indicating that the extraction electrode is functioning to reduce ion trapping in the pre-filter.

[0107] Although the present 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 detail may be made without departing from the scope of the invention as set forth in the accompanying claims.

[0108] For example, the wall may be a wall 2 between different vacuum chambers of the mass spectrometer. Alternatively, the ion guide 1 and mass filter 3 may be located in the same vacuum chamber, but the ion guide or mass filter may be arranged in a gas cell located within the vacuum chamber and wherein the wall is a wall of the gas cell. Moreover, although the ion guide and wall are shown in Fig. 3, it will be appreciated that any other ion optical component may be provided instead, where that ion optical components is maintained at a potential higher than the extraction electrode.

[0109] Although embodiments have been described above in which the extraction electrode is an apertured plate electrode having a circular aperture, the extraction electrode may have a different configuration provided that it provides a DC potential profile that reduces ion trapping in the pre-filter.

[0110] It is contemplated that more than one extraction electrode may be provided upstream of the mass filter, and voltages may be applied to these electrodes so as to guide the ions that are accelerated upstream out of the pre-filter to impact on an electrode.

[0111] The one or more extraction electrode and / or wall described herein may be heated to temperature sufficient to burn off contamination due to ions striking these components.

[0112] Although embodiments have been described in which the extraction electrode is arranged upstream of the pre-filter, it is contemplated that the extraction electrode may instead be arranged between the pre-filter and the analytical section of the mass filter. An extraction electrode may also be arranged upstream of the pre-filter.

Claims

173606-02v1Claims:

1. A mass filtering apparatus comprising: a mass filter having an analytical section for mass filtering ions and a pre-filter arranged upstream of the analytical section for guiding ions into the analytical section; an extraction electrode arranged upstream of the pre-filter for extracting ions from within the pre-filter; and voltage supplies configured to apply different DC voltages to the extraction electrode and pre-filter so as to maintain a DC potential profile within the pre-filter for urging ions out of the pre-filter in the upstream direction towards the extraction electrode.

2. The apparatus of claim 1, wherein the voltage supplies are configured to apply DC voltages to the extraction electrode, pre-filter and analytical section such that said DC potential profile is provided throughout the pre-filter.

3. The apparatus of claim 1 or 2, wherein the voltage supplies are configured to apply said DC voltages such that said DC potential profile is maintained throughout the pre-filter so that substantially no ions are able to be trapped in the pre-filter.

4. The apparatus of claim 1 , 2 or 3, wherein the voltage supplies are configured to apply said DC voltages such that said DC potential profile has no DC potential well within the pre-filter.

5. The apparatus of any preceding claim, wherein the voltage supplies are configured to apply said DC voltages such that the DC potential profile continuously and / or monotonically decreases from a downstream end of the pre-filter to the upstream end of the pre-filter.

6. The apparatus of any preceding claim, wherein said voltage supplies are configured to apply DC voltages to the extraction electrode, pre-filter and analytical section such that the electrodes of the pre-filter are maintained at a lower DC electric potential than any electrodes of the analytical section, and such that the extraction electrode is maintained at a lower DC electric potential than the electrodes of the pre-filter.

7. The apparatus of any preceding claim, comprising an ion-optical component upstream of the extraction electrode and a DC voltage supply configured to maintain that ion-optical component at a DC electric potential that is higher than the DC electric potential applied to the extraction electrode.

8. The apparatus of claim 7, wherein the DC voltage supply is configured to maintain the ion-optical component at a DC electric potential that is substantially the same as, or higher than, the DC potential at which at least some of the electrodes of analytical section are maintained.

9. The apparatus of any preceding claim, wherein the extraction electrode is arranged immediately upstream of the pre-filter.

10. The apparatus of any preceding claim, wherein the voltage supplies are configured to apply said DC voltages such that the DC potential profile includes a potential well proximate to the extraction electrode.

11. The apparatus of any preceding claim, wherein the voltage supplies are configured to apply said DC voltages such that the DC potential profile is arranged for accelerating ions out of the pre-filter in the upstream direction so as to strike the extraction electrode and / or another ion-optical component of the apparatus that is upstream of the pre-filter.

12. The apparatus of claim 11 , comprising a heater for heating the extraction electrode and / or said another ion-optical component, for burning off contamination thereon due to the ions striking these components.

13. The apparatus of any preceding claim, wherein the ion extraction electrode defines an aperture through which ions are transmitted to the pre-filter, where the aperture is substantially the same size or larger than the ion entrance to the pre-filter.

14. The apparatus of any preceding claim, wherein the mass filter is a quadrupole mass filter.

15. The apparatus of any preceding claim, comprising an ion guide upstream of the extraction electrode for guiding ions to the mass filter; and optionally comprising a wall between the ion guide and the extraction electrode, wherein the wall comprises an aperture that is aligned with the ion guide such that ions are able to be transmitted from the ion guide, through the aperture to the mass filter.

16. The apparatus of any preceding claim, comprising voltage supplies connected to electrodes of the analytical section of the mass filter, and a controller configured to control the voltage supplies so as to apply RF and DC voltages to the electrodes such that only ions having a restricted range of mass to charge ratios are able to be transmitted through the analytical section and ions having other mass to charge ratios are filtered out, optionally wherein the controller is configured to vary the RF and DC voltages with time such that the range of mass to charge ratios that are able to be transmitted by the analytical section varies with time.

17. A mass spectrometer comprising the apparatus of any preceding claim.

18. The mass spectrometer of claim 17, wherein the mass spectrometer is a tandem mass spectrometer comprising: a first mass filtering apparatus for mass filtering precursor ions; a fragmentation or reaction device downstream of the first mass filtering apparatus for fragmenting or reacting precursor ions transmitted by the first mass filter so as to produce fragment or other product ions; and a second mass filtering apparatus for mass filtering said fragment or other product ions; where the first and / or second mass filtering apparatus is a mass filtering apparatus as claimed in any one of claims 1-16.

19. A method of mass filtering ions comprising: providing a mass filtering apparatus as claimed in any one of claims 1-16; and transmitting ions into said mass filter whilst applying different DC voltages to the extraction electrode and pre-filter so as to maintain said DC potential profile within the prefilter that urges ions out of the pre-filter in the upstream direction towards the extraction electrode.

20. The method of claim 19, wherein some of the ions transmitted into the mass filter are reflected between the pre-filter and analytical section of the mass filter, and are urged out of the pre-filter in the upstream direction towards the extraction electrode by the DC potential profile, whereas others of the ions transmitted into the mass filter pass through the pre-filter and into the analytical section; and wherein voltages are applied to electrodes of the analytical section so as to mass filter the ions passing therethrough.21 . A mass filtering apparatus comprising: a mass filter having an analytical section for mass filtering ions and a pre-filter arranged upstream of the analytical section for guiding ions into the analytical section; an extraction electrode arranged between the pre-filter and the analytical section, for extracting ions from within the pre-filter; and voltage supplies configured to apply different DC voltages to the extraction electrode and pre-filter so as to maintain a DC potential profile within the pre-filter for urging ions out of the pre-filter in the downstream direction towards the extraction electrode.

22. A method of mass filtering ions comprising: providing a mass filtering apparatus as claimed in claim 21 ; and transmitting ions into said mass filter whilst applying different DC voltages to the extraction electrode and pre-filter so as to maintain said DC potential profile within the pre-filter that urges ions out of the pre-filter in the downstream direction towards the extraction electrode.

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