Optimised ion mobility separation timescales for targeted ions

Abstract

An analytical device for analyzing ions is provided comprising a separator 2 for separating ions according to a physico-chemical property and an interface 3 comprising one or more ion guides. A quadrupole rod set mass filter 4 is arranged downstream of the interface 3. A control system is arranged and adapted: (i) to transmit a first group of ions which emerges from the separator 2 through the interface 3 with a first transit time t1; and (ii) to transmit a second group of ions which subsequently emerges from the separator 2 through the interface 3 with a second different transit time t2.

Claims

1. An analytical device for analyzing ions comprising: a separator for separating ions according to a physico-chemical property and comprising a transfer region, said transfer region comprising a plurality of electrodes; a quadrupole rod set mass or mass to charge ratio filter arranged downstream of said transfer region; and a control system arranged and adapted: (i) to transmit a first group of ions through said transfer region with a first transit time t1; and (ii) to transmit a second group of ions through said transfer region with a second different transit time t2, wherein said control systems is further arranged and adapted to: maintain at a first time a first DC voltage or potential gradient along said transfer region so that said first group of ions are urged along said transfer region with the first transit time t1, and maintain at a second later time a second DC voltage or potential gradient along said transfer region so that said second group of ions are urged said transfer region with the second, different transit time t2.

2. An analytical device as claimed in claim 1, wherein said physico-chemical property comprises ion mobility or differential ion mobility.

3. An analytical device as claimed in claim 2, wherein said separator comprises an ion mobility separator or a differential ion mobility separator.

4. An analytical device as claimed in claim 1, wherein said physico-chemical property comprises mass or mass to charge ratio.

5. An analytical device as claimed in claim 4, wherein said separator comprises a time of flight region.

6. An analytical device as claimed in claim 1, wherein said control system is arranged and adapted to apply a shift or increase in transit time for the second group of ions through said transfer region.

7. An analytical device as claimed in claim 6, wherein said shift or increase in transit time is introduced by altering the parameters of said separator.

8. An analytical device as claimed in claim 1, wherein said control system is further arranged and adapted to apply one or more transient DC voltages or potentials to said plurality of electrodes so that said first group of ions are translated along said transfer region with a first velocity.

9. An analytical device as claimed in claim 8, wherein said control system is further arranged and adapted to apply one or more transient DC voltages or potentials to said plurality of electrodes so that said second group of ions are translated along said transfer region with a second different velocity.

10. An analytical device as claimed in claim 9, wherein said second velocity is slower than said first velocity.

11. An analytical device as claimed in claim 8, wherein said physico-chemical property comprises ion mobility, and said separator comprises an ion mobility separator.

12. An analytical device as claimed in claim 1, wherein said second DC voltage or potential gradient is less than said first DC voltage or potential gradient.

13. An analytical device as claimed in claim 1, wherein said control system is further arranged and adjusted: (i) to cause said mass or mass to charge ratio filter to transmit ions having masses or mass to charge ratios within a first mass or mass to charge ratio range; and then (ii) to cause said mass or mass to charge ratio filter to transmit ions having masses or mass to charge ratios within a second different mass or mass to charge ratio range.

14. An analytical device as claimed in claim 1, wherein said control system is arranged and adapted to transmit said first group of ions through said transfer region with a first transit time t1 and to transmit said second group of ions through said transfer region with a second different transit time t2 within or during a single cycle of separation of ions within said separator.

15. A mass spectrometer comprising an analytical device as claimed in claim 1.

16. An analytical device as claimed in claim 1, wherein said control system is arranged and adapted to transmit said second group of ions through said transfer region with a transit time t2, wherein t2>t1.

17. A method of analysing ions comprising: separating ions according to a physico-chemical property in a separator comprising a transfer region comprising a plurality of electrodes; providing a quadrupole rod set mass or mass to charge ratio filter arranged downstream of said transfer region; transmitting a first group of ions through said transfer region with a first transit time t1; transmitting a second group of ions through said transfer region with a second different transit time t2; maintaining at a first time a first DC voltage or potential gradient along said transfer region so that said first group of ions are urged along said transfer region with the first transit time t1; and maintaining at a second later time a second DC voltage or potential gradient along said transfer region so that said second group of ions are urged along said transfer region with the second, different transit time t2.

18. A method as claimed in claim 17, wherein the steps of transmitting said first group of ions through said transfer region with a first transit time t1 and transmitting said second group of ions through said transfer region with a second different transit time t2 are performed within or during a single cycle of separation of ions within said separator.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

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

(2) FIG. 1 shows a mass spectrometer according to an embodiment of the present invention comprising an ion mobility spectrometer or separator device, an interface or transfer device, a quadrupole rod set mass filter, a gas cell and an orthogonal acceleration Time of Flight mass analyser;

(3) FIG. 2 shows the temporal separation of two ions of interest with respect to the start of an ion mobility experiment at positions A, B and D as shown in FIG. 1;

(4) FIG. 3 shows how the difference in timescale between the separation of ions using an ion mobility spectrometer or separator device and the ability to switch a quadrupole mass filter can limit the effectiveness of the isolation stage;

(5) FIG. 4 illustrates the effect of increasing the transit time of ions through an interface or transfer region in accordance with a preferred embodiment of the present invention;

(6) FIG. 5 shows two components separated at the exit of the gas cell;

(7) FIG. 6 shows how according to an embodiment the gas cell may be configured to allow some loss of fidelity of the IMS peaks in order to improve dynamic range; and

(8) FIG. 7 shows a further embodiment wherein an ion gate is provided upstream of the interface or transfer device.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

(9) FIG. 1 shows a simplified schematic of a IMS-Q-ToF mass spectrometer according to an embodiment of the present invention. The mass spectrometer comprises an ion mobility separator (IMS) 2, an interface or transfer device 3, a quadrupole rod set mass filter 4, a gas or reaction cell 5 and an orthogonal acceleration Time of Flight mass analyser 6. Various different types of experiments may be performed utilising this instrument geometry. In particular, the quadrupole mass filter 4 which is preferably arranged downstream of the ion mobility spectrometer or separator device 2 may be utilised to select specific parent or precursor ions.

(10) According to an embodiment ions may be separated according to their ion mobility in the ion mobility spectrometer or separator device 2. The ions are then preferably transported through the interface, transfer device or transfer region 3 to the quadrupole mass filter 4 which is preferably arranged to operate in a resolving mode. The quadrupole mass filter 4 preferably switches between components of interest which elute from the ion mobility spectrometer or separator device 2 within a single ion mobility spectrometer or separator cycle or single cycle of separation thereby providing both improved selectivity (due to the partially orthogonal nature of ion mobility and mass to charge ratio separations) and also improved duty cycle (due to the temporal pre-separation of the ions before quadrupole filtering). This approach provides significant improvements over standard MSMS approaches for both targeted experiments where the mass to charge ratio and ion mobility of components of interest are derived from a library/method development stage and also for Data Dependent Acquisitions (DDA) where the mass to charge ratio and ion mobility are derived from an initial survey scan.

(11) FIG. 2 shows the temporal separation of two ions of interest with respect to the start of an ion mobility experiment at positions A, B and D within a mass spectrometer as shown in FIG. 1 during a single cycle of separation.

(12) In FIG. 2 the time taken by ions to reach position A is dominated by the mobility of the ions. The ion mobility provides a mechanism of separation as shown by the temporal separation of the two components. The two components of interest also have different mass to charge ratio values as shown in FIG. 2 although, at position A, no mass to charge ratio based separation has yet occurred.

(13) On exiting the ion mobility spectrometer or separator region 2 the ions preferably enter an interface or transfer region 3 which according to an embodiment may comprise a travelling wave ion guide (TWIG). The interface or transfer region 3 is preferably maintained at an intermediate pressure between that of the ion mobility spectrometer or separator device 2 and the quadrupole mass filter 4. The travelling wave ion guide preferably transports ions at a fixed velocity such that the times at position B are further increased by a value TB-TA which is related to the length of the travelling wave ion guide and the speed of the travelling wave. For example, a 50 mm long travelling wave ion guide operated with a travelling wave speed of 300 m/s would introduce a temporal shift of approximately 167 s. Again, at this position within the instrument no mass to charge separation has yet occurred.

(14) A similar time shift is observed for ions transiting the gas cell 5 to reach position D although the ions at this point may comprise fragment ions related to components 1 and 2 and at a similar time to components 1 and 2. For illustrative purposes only the two components shown in FIG. 2 have not undergone fragmentation. As the ions transit between position B and position C they preferably pass through a resolving quadrupole mass filter 4 that preferably sequentially isolates the mass to charge ratios of components 1 and 2 at the appropriate times thereby improving selectivity and duty cycle.

(15) The above described approach affords significant advantages over conventional systems. However, it does nonetheless suffer from some limitations. The present invention seeks to address some of these limitations.

(16) One drawback with the approach described above with reference to FIG. 1 is that the ion mobility spectrometer or separator separation times between two closely eluting components may be significantly shorter than the speed at which the resolving quadrupole mass filter 4 can switch between two mass to charge ratio settings.

(17) The time taken to switch a quadrupole mass filter 4 between different mass to charge ratio settings depends on a number of parameters including the settling time of various electronic components and the time of flight through the resolving quadrupole mass filter 4. Typical values for this switching time are of the order of 1 ms. By contrast, two baseline resolved components with nominal transit times through a linear drift tube ion mobility spectrometer or separator device of 5 ms and which operates at a resolution of 50 might be separated in time by only 200 s. It will be apparent, therefore, that the quadrupole 4 may be unable to switch mass to charge ratio transmission windows on this timescale.

(18) FIG. 3 illustrates in more detail how the difference in timescale between the ion mobility spectrometer or separator device 2 and the switching of the quadrupole mass filter 4 can limit the effectiveness of the isolation stage. FIG. 3 shows a system operating at an approximate ion mobility spectrometer or separator resolution of 50 (FWHM) and shows two components arriving at position B (i.e. at the exit of the ion mobility spectrometer or separator device 2) with nominal transit times of 5 ms. However, the two components are actually separated by 0.4 ms and are therefore fully baseline resolved. The quadrupole mass filter 4 is switched at a time T.sub.s immediately after the last of component 1 has eluted from the ion mobility spectrometer or separator device 2. However, the time taken for the quadrupole mass filter 4 to switch mass to charge ratio transmission windows in order to select between these two components is T.sub.q and it is apparent from FIG. 3 that component 2 will arrive at the quadrupole mass filter 4 before time T.sub.s+T.sub.q. As a result, component 2 will arrive at the mass filter 4 before the mass filter 4 has had sufficient time to switch to transmit ions having mass to charge ratios corresponding with component 2. As a result, component 2 will not be onwardly transmitted by the mass filter 4. This effectively limits the resolution of the filtering or isolation stage.

(19) According to an embodiment of the present invention an improvement to this approach is to delay component 2 by introducing an interface or transfer device 3 between the ion mobility spectrometer or separator device 2 and the quadrupole mass filter 4 and by altering the transit time across or through the interface or transfer region 3 during a single cycle of separation. This may be achieved by, for example, altering (i.e. reducing) the speed of a travelling wave applied to the interface or transfer ion guide 3 after component 1 has exited or emerged from the interface or transfer device 3 during a single cycle of separation.

(20) FIG. 4 shows the effect of reducing the speed of the travelling wave applied to electrodes of the interface from 300 m/s to 60 m/s after component 1 has exited the interface or transfer travelling wave ion guide 3. For a transfer travelling wave ion guide 3 having a length of 50 mm the transit time for component 2 to traverse the interface or transfer travelling wave ion guide 3 is increased by 833 s. This shift or increase in transit time ensures that component 2 will now arrive at the quadrupole mass filter 4 after the quadrupole mass filter 4 has switched and has had sufficient time to settle thereby ensuring onward transmission of component 2. In this case the resolution of the isolation stage is now related to the transit time through the interface or transfer device 3.

(21) It is worth noting that the separation in time for a given ion mobility spectrometer or separator resolution can be significantly different for ion mobility spectrometer or separator instruments not using linear drift tubes such as T-Wave based ion mobility spectrometer or separator devices depending on the power term (X) in the relationship T=AK.sup.X where T is the drift time, K is the mobility and A is a constant. This difference can either aid or hinder the effects of previously described quadrupole switching limitation.

(22) A second drawback of the approach described above with reference to FIG. 3 is that the ion mobility separation also introduces significant restrictions to the dynamic range of the ion detecter system of an IMS-Q-ToF mass spectrometer due to the compression in time of any given component and the limited intensity scale of the ion detection system digitisation.

(23) FIG. 5 shows two components which are well separated and isolated in IMS-mass to charge ratio space at position D in FIG. 1 i.e. at the exit of the gas cell 5.

(24) According to a further embodiment the gas cell 5 may be configured to allow some loss of fidelity of the ion mobility spectrometer or separator peaks as shown in FIG. 6. As a result, a greater number of orthogonal acceleration Time of Flight pushes are now used to analyse the components. This advantageously increases the dynamic range of the system. The choice of the degree of loss of fidelity can be based on degree of separation of the two components.

(25) In both of the above examples the choice of two components is for descriptive purposes only. In practice, more than two components may be chosen depending on separations or resolution etc.

(26) Ions which are onwardly transmitted may be subjected to analytical techniques such as fragmentation, mass measurement or ion mobility measurement etc.

(27) Further embodiments are contemplated wherein the described approach is applied with other fast pre quadrupole separators such as ion traps and mass to charge ratio separators.

(28) According to another less preferred embodiment instead of switching the transit delay in time, ions may alternatively be switched in space into different transfer devices each having different effective transit times.

(29) According to another embodiment transfer devices 3 utilising approaches other than travelling waves such as axial fields may be used.

(30) Other instrument improvements can be accessed via the approach according to the preferred embodiment. For example, components can be pushed together in time if they are over separated allowing shorter ion mobility spectrometer or separator cycle times thereby ultimately reducing space charge effects in pre ion mobility spectrometer or separator accumulators.

(31) The delay shifts may be introduced by devices operating at the same pressure as the ion mobility spectrometer or separator device 2.

(32) The delay shifts can also be introduced by altering the parameters of the ion mobility spectrometer or separator device 2 itself.

(33) A continuous stretching of the time axis may be realised by continually and monotonically slowing the travelling wave speed so as to improve the ability of a scanning quadrupole mass filter 4 to track ions eluting from the ion mobility spectrometer or separator device 2 or to improve the digitisation of the ion mobility spectrometer or separator device 2 by, for example, the orthogonal acceleration Time of Flight mass analyser 6.

(34) Transfer devices 3 with transit speeds that vary as a function of length may be utilised as well as transfer devices with accumulation regions.

(35) The quadrupole mass filter 4 preferably provides isolation in both time and mass to charge ratio. However, in practice different devices may be used to provide time isolation (e.g. an ion gate 7) and mass to charge ratio isolation (e.g. a quadrupole mass filter 4). FIG. 7 shows a schematic of an example of this type of geometry.

(36) In the embodiment shown in FIG. 7 time regions corresponding to the regions containing components of interest are selected by the ion gate 7. The ion gate 7 may be part of the ion mobility spectrometer or separator device 2 or the transfer device 3 and is shown in FIG. 7 as a separate component for illustrative purpose only. The time selected regions may then be partitioned by the transfer travelling wave ion guide 3 and their temporal separations adjusted as they transit the transfer travelling wave ion guide 3 so as to allow efficient delivery to the resolving quadrupole mass filter 4. The previously described position dependent travelling wave speed travelling wave ion guide with accumulation regions is particularly beneficial for this approach.

(37) Although the present invention has been described with reference to preferred 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.