Mass spectrometer with interleaved acquisition

Abstract

A method of mass spectrometry is disclosed comprising passing ions through a first stage and a second stage of a mass spectrometer and monitoring a first ion acquisition for a first dwell time extending from a time T.sub.1 to a time T.sub.1+T.sub.dwell1. The method further comprises reconfiguring the mass spectrometer or one or more components of the mass spectrometer to monitor a second ion acquisition and setting the first stage to transmit ions of the second ion acquisition at a time T, wherein T<T.sub.1+T.sub.dwell1. The method further comprises monitoring the second ion acquisition for a second dwell time starting at a time T.sub.2, wherein T.sub.2>T.sub.1+T.sub.dwell1 and determining the time T based on a known or calculated ion transit time through one or more regions or components of the mass spectrometer disposed downstream of the first stage.

Claims

1. A method of mass spectrometry comprising: passing ions through a first stage and a second stage of a mass spectrometer; monitoring a first ion acquisition for a first dwell time extending from a time T.sub.1 to a time T.sub.1+T.sub.dwell1; reconfiguring said mass spectrometer or one or more components of said mass spectrometer to monitor a second ion acquisition; and setting said first stage to transmit ions of the second ion acquisition at a time T, wherein T<T.sub.1+T.sub.dwell1; and monitoring the second ion acquisition for a second dwell time starting at a time T.sub.2, wherein T.sub.2>T.sub.1+T.sub.dwell1 so that there is a non-zero interscan time T.sub.2T.sub.1+T.sub.dwell1; the method further comprising determining said time T based on a known or calculated ion transit time through one or more regions or components of said mass spectrometer disposed downstream of said first stage.

2. A method as claimed in claim 1, wherein said second stage comprises an ion detector or is arranged to transmit ions to an ion detector.

3. A method as claimed in claim 2, wherein said one or more regions or components of the mass spectrometer are disposed upstream of said second stage or said ion detector.

4. A method as claimed in claim 1, wherein said first stage and/or said second stage are selected from the group comprising: (i) a quadrupole mass filter or analyser; (ii) an ion mobility separation or differential ion mobility separation device; (iii) a Time of Flight mass analyser or other mass analyser; (iv) an ion trap; and (v) an ion guide or ion transfer device.

5. A method as claimed in claim 1, wherein said mass spectrometer further comprises a fragmentation or reaction device disposed between said first and second stages so that said first stage transmits parent or precursor ions and said second stage transmits fragment, daughter or product ions.

6. A method as claimed in claim 5, wherein said fragmentation or reaction device comprises a collision or reaction cell or device.

7. A method as claimed in claim 5, wherein said first stage comprises a first quadrupole mass filter or analyser and said second stage comprises a second quadrupole mass filter or analyser and wherein monitoring said first and second ion acquisitions comprises measuring first and second precursor-fragment or MRM transitions.

8. A method as claimed in claim 5, further comprising clearing said fragmentation or reaction device of ions between the first and second ion acquisitions.

9. A method as claimed in claim 8, further comprising clearing said fragmentation or reaction device is cleared using an AC or DC driving force, travelling wave or axial field.

10. A method as claimed in claim 1, wherein the step of reconfiguring the mass spectrometer or one or more components of the mass spectrometer comprises changing: (i) the mass to charge ratio of ions transmitted through a quadrupole mass filter or analyser; (ii) a collision energy or other fragmentation or reaction parameter; (iii) the polarity of the instrument; (iv) a RF voltage applied to an ion guide; (v) a DC axial field or voltage applied to a component of the mass spectrometer; or (vi) a de-clustering or cone voltage.

11. A method as claimed in claim 1, wherein an interscan time is less than 0.2 ms, 0.3 ms, 0.4 ms, 0.5 ms, 0.6 ms, 0.8 ms, 1 ms, 2 ms, 3 ms, 4 ms, 5 ms, 10 ms or 20 ms.

12. A method as claimed in claim 1, wherein said ions are passed through said first stage and/or are passed through said one or more components or regions and/or are passed to said second stage as a substantially continuous, pseudo-continuous or extended stream.

13. A mass spectrometer comprising: a first stage; a second stage; and a control system arranged and adapted: (i) to monitor a first ion acquisition for a first dwell time extending from a time T1 to a time T1+T.sub.dwell; (ii) to reconfigure said mass spectrometer or one or more components of said mass spectrometer to monitor a second ion acquisition; (iii) to set said first stage to transmit ions of the second ion acquisition at a time T, wherein T<T1+T.sub.dwell so that there is a non-zero interscan time; (iv) to monitor a second ion acquisition for a second dwell time starting at a time T.sub.2, wherein T.sub.2>T1+T.sub.dwell; and wherein the non-zero interscan time equals T2T1+T.sub.dwell.

14. A method as claimed in claim 1 comprising: passing a beam of ions through a tandem mass spectrometer comprising a collision cell, a first quadrupole mass filter or analyser disposed upstream of said collision cell arranged to transmit parent or precursor ions, and a second quadrupole mass filter or analyser disposed downstream of said collision cell arranged to transmit fragment or product ions; monitoring a first precursor-fragment transition for said first dwell time extending from said time T.sub.1 to said time T.sub.1+T.sub.dwell1; setting said first quadrupole mass analyser to transmit parent or precursor ions of the second transition at said time T, wherein T<T.sub.1+T.sub.dwell1; and monitoring a second precursor-fragment transition for said second dwell time starting at said time T.sub.2, wherein T.sub.2>T.sub.1+T.sub.dwell1; the method further comprising determining said time T based on a known or calculated ion transit time through said collision cell and/or through an ion guide disposed upstream of said second quadrupole mass filter or analyser.

15. A method as claimed in claim 14, further comprising transmitting fragment or product ions from said second quadrupole mass analyser to an ion detector.

16. A method as claimed in claim 14, wherein an interscan time is less than 0.2 ms, 0.3 ms, 0.4 ms, 0.5 ms, 0.6 ms, 0.8 ms, 1 ms, 2 ms, 3 ms, 4 ms, 5 ms, 10 ms or 20 ms.

17. A mass spectrometer as claimed in claim 13 comprising: a first quadrupole mass filter or analyser; a second quadrupole mass filter or analyser; a collision cell disposed between said first and second quadrupole mass filters or analysers; and wherein said control system is arranged and adapted: (i) to monitor a first precursor-fragment transition for said first dwell time extending from said time T.sub.1 to said time T.sub.1+T.sub.dwell1; (ii) to set said first quadrupole mass filter or analyser to transmit parent or precursor ions of the second transition at said time T, wherein T<T.sub.1+T.sub.dwell1; and (iii) to monitor a second precursor-fragment transition for said second dwell time starting at said time T.sub.2, wherein T.sub.2>T.sub.1+T.sub.dwell1; wherein said time T is based on a known or calculated ion transit time through said collision cell and/or through an ion guide disposed upstream of said second quadrupole mass filter or analyser.

18. A method of mass spectrometry comprising: passing ions through a first stage and a second stage of a mass spectrometer; monitoring a first ion acquisition for a first dwell time extending from a time T.sub.1 to a time T.sub.1+T.sub.dwell1; reconfiguring said mass spectrometer or one or more components of said mass spectrometer to monitor a second ion acquisition; and setting said first stage to transmit ions of the second ion acquisition at a time T, wherein T<T.sub.1+T.sub.dwell1 so that there is a non-zero interscan time T.sub.2T.sub.1+T.sub.dwell1; and monitoring the second ion acquisition for a second dwell time starting at a time T.sub.2, wherein T.sub.2>T.sub.1+T.sub.dwell1.

19. A mass spectrometer as claimed in claim 13, wherein the time T is determined based on a known or calculated ion transit time through one or more regions or components of said mass spectrometer disposed downstream of said first stage.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Various embodiments together with other arrangements given for illustrative purposes only will now be described, by way of example only, and with reference to the accompanying drawings in which:

(2) FIG. 1 illustrates a conventional MRM acquisition method;

(3) FIG. 2 shows the measured ion current for the two transitions illustrated in FIG. 1;

(4) FIG. 3 depicts an interleaved MRM acquisition according to an embodiment; and

(5) FIG. 4 represents the measured ion current for the two transitions shown in FIG. 3.

DETAILED DESCRIPTION

(6) A conventional MRM method will first be described.

(7) In tandem or multi-stage mass spectrometry, an ion acquisition is monitored for a certain dwell time. In order to monitor a different ion acquisition it is generally necessary to reconfigure the instrument. For example, the mass to charge ratio of ions transmitted by one or more quadrupole mass filters may be changed. Other reconfigurations include changing the polarity of the instrument, changing a collision energy, changing the RF voltages applied to an ion guide, changing a DC axial field or voltage and changing a de-clustering or cone voltage. These reconfigurations generally have an associated settling or stabilisation time. To measure the second acquisition with sufficient accuracy, the mass spectrometer should be reconfigured and the ion beam should be allowed to stabilise before the start of the second dwell time.

(8) FIG. 1 shows a conventional tandem quadrupole mass spectrometer comprising a first resolving quadrupole mass filter Q1, a collision cell 2 for fragmenting ions transmitted by the first quadrupole mass filter Q1, and a second resolving quadrupole mass filter Q2. The second quadrupole mass filter Q2 transmits fragment ions received from the collision cell 2 to an ion detection system 3. Representations of the ion current for the first transition 5 and the ion current for the second transition 6 are schematically shown at five evenly spaced time intervals t1, . . . , t5.

(9) Between times t1 and t3, the ion detection system 3 monitors ions of the first MRM transition 5. The instrument is then reconfigured to monitor a second MRM transition, for example, by changing the resolving RF and DC voltages applied to the first quadrupole mass filter Q1 and/or to the second quadrupole mass filter Q2 so that the transition between a different precursor-fragment pair is monitored. After the instrument has been re-configured, at time t4, the first quadrupole mass filter Q1 is set to transmit ions corresponding to the second MRM transition 6. These ions are then fragmented in the collision cell 2 and the resulting fragment ions are eventually transmitted to the ion detection system 3 at a time t5.

(10) FIG. 2 represents the measured ion current associated with monitoring the first and second transitions depicted in FIG. 1. It can be seen that the interscan time is t5t3.

(11) In a conventional MRM operation such as that depicted in FIGS. 1 and 2, the instrument is reconfigured for a second measurement only after a first measurement is made. The acquisition is, therefore, inherently of a serial nature and the interscan time is at least as long as the time corresponding to the transit time of ions through the device. The transit time for ions through different regions of the mass spectrometer will vary depending upon the pressure in the region and the forces applied to the ions. For example, it can take many milliseconds for an ion to traverse a collision cell if no driving force such as a travelling wave or an axial field is applied to speed or accelerate the ions through the device.

(12) Applying a driving force such as a travelling wave or an axial field to the collision cell reduces the ion transit time and may also advantageously clear out any undesired fragment ions that are within the collision cell. By clearing out the collision cell in this way, fragments of the first transition are not transmitted during the measurement of the second transition (this effect being known as cross-talk).

(13) However, even when driven with a 300 m/s travelling wave it will typically take 0.6 ms for an ion to transit through a 180 mm collision cell. The time of flight through a quadrupole of length 130 mm for a 1 eV ion of mass to charge ratio 200 is 132 s. Using these values for the arrangement depicted in FIG. 1, the total time of flight through the first quadrupole mass filter Q1, the collision cell 2 and the second quadrupole mass filter Q2 would be 864 s. This leaves very little overhead in which to actually configure the instrument to transmit these ions when trying to achieve 1 ms or lower interscan times.

(14) An embodiment will now be described.

(15) FIG. 3 shows a similar tandem quadrupole mass spectrometer to that depicted in FIG. 1 but operated in accordance with an embodiment. Like reference numerals represent like components.

(16) FIG. 4 represents the measured ion current corresponding to the embodiment shown in FIG. 3. Again, the ion current of the first MRM transition 5 is monitored for a first dwell time from t1 to t3. However, the first quadrupole Q1 is then reconfigured and set to transmit ions of second MRM transition 6 at an earlier time t2 i.e. before the end of the first dwell time (t3).

(17) As parts of the mass spectrometer are reconfigured for the second MRM transition whilst the first MRM transition is still being measured, the acquisitions are now parallel or interleaved. It can be seen from FIG. 4 that the reduced interscan time is now t4t3 (c.f. t5t3). Thus, the interscan time and hence overall cycle time is reduced compared to the conventional arrangement described in relation to FIGS. 1 and 2.

(18) In embodiments, one part of the mass spectrometer can monitor a first ion acquisition whilst another part of the mass spectrometer simultaneously transmits ions for the second acquisition. Such parallel or interleaved acquisition may be achieved by the fact that there is a known or calculable transit time through different regions of the mass spectrometer. As any given region or component of the mass spectrometer will contain a certain number of ions, ions will still exit the device for a period of time corresponding to the transit time through the device. The time at which the first quadrupole mass filter Q1 is set to start transmitting parent or precursor ions of the second MRM transition can be determined based on the ion transit times.

(19) For instance, as described above, it may take 0.6 ms for ions to transit the collision cell 2. The collision cell 2 therefore contains approximately 0.6 ms of ion current and the first quadrupole Q1 can be set to transmit ions for the second MRM transition 0.6 ms prior to the end of the first dwell time without affecting the first MRM measurement. Similarly, the ions subsequently transmitted through the first quadrupole mass filter Q1 for the second MRM transition will not reach the ion detector 3 before the end of the first dwell time so the ions of the first transition will not interfere with this measurement so that cross-talk with the previous transition may be avoided. The first quadrupole mass filter Q1, and the rest of the instrument downstream of the first quadrupole mass filter Q1, has already been configured by the start of the interscan period, so can be transmitting parent or precursor ions of the next transition into the collision cell 2. This allows a reduction in the time required to clear and re-fill the collision cell 2 and consequently a reduction in the interscan time by up to 0.6 ms.

(20) It will be readily apparent that since the current state of the art interscan time between monitoring MRM transitions is around 1.0 ms, a potential reduction of 0.6 ms represents a significant improvement.

(21) The advantages described in relation to the above embodiments may apply equally to other experiments where other reconfigurations are performed between the ion acquisitions. For instance, an MRM experiment in which the second MRM transition is of a different polarity may be performed. In this situation there are typically several gas-filled regions which will be populated with ions of the existing transition. There will be at least one ion guide at the entrance to the instrument in addition to the collision cell. Before the end of the first MRM transition dwell time the polarity of the electrospray ion source is changed. Because it can take several milliseconds to swap the polarity of the ion source, it is possible that the various ion guides have sufficient stored ion current for several first MRM transitions to be measured before measuring the first transition of opposite polarity. In this case, the polarity of the ion source could be swapped several transitions prior to the first transition of opposite polarity.

(22) The skilled person will recognise that the advantages discussed above are not confined to the specific quadrupole implementation shown in FIG. 3. Acquisitions can be temporally interleaved based on knowledge of the transit times through various regions or components of the mass spectrometer in a similar manner in any tandem or multi-stage mass spectrometer. For example, embodiments are contemplated comprising a quadrupole-Time of Flight mass spectrometer or an instrument containing an ion mobility separation stage.

(23) 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.