Fast Modulation with Downstream Homogenisation

Abstract

A method of mass spectrometry is disclosed involving scanning a parameter of a first device through which a mixture of components is passed. Different components are transmitted through or produced in the first device at different values of the parameter and hence scanning the device parameter introduces a temporal modulation or profile to the components. This temporal variation is then removed prior to mass analysing the components through a process of homogenisation.

Claims

1. A method of mass spectrometry comprising: passing an ion beam containing a mixture of components through a first device; recording a mass spectrum of at least some of said components with a single spectrum production time Ts; during a single spectrum production cycle, scanning a parameter of said first device over a range of values with a cycle time T1<Ts, wherein different components are transmitted through or produced in the first device at different values of the parameter such that scanning said parameter introduces a temporal modulation or profile to said components; and prior to recording said mass spectrum, substantially removing or altering said temporal modulation or profile by converting the temporally modulated components into a substantially continuous or pseudo-continuous ion beam or by converting the temporally modulated components into a substantially homogeneous ion packet.

2. A method as claimed in claim 1, comprising converting the temporally modulated components into a substantially continuous or pseudo-continuous ion beam by passing the components through or along a gas-filled homogenisation device.

3. A method as claimed in claim 2, wherein said gas-filled homogenisation device comprises: (i) a gas cell; (ii) a gas-filled RF or AC device; (iii) an ion guide, ion guiding region or ion funnel; or (iv) a fragmentation or reaction cell.

4. A method as claimed in claim 2, wherein said gas-filled device: (i) constitutes or is said first device; (ii) is disposed downstream of said first device and/or between said first device and an ion detection or acquisition system or mass analyser; or (iii) constitutes or is an ion detection or acquisition system or mass analyser.

5. (canceled)

6. A method of mass spectrometry as claimed in claim 1, wherein said components are converted into a substantially homogeneous ion packet by passing the components into or through an ion trap or ion accumulation device.

7. A method as claimed in claim 1, wherein said cycle time T1 is less than: (i) 10 ms; (ii) 5 ms; (iii) 2 ms; or (iv) 1 ms.

8. A method as claimed in claim 1, comprising: passing the ion beam to a mass analyser for recording said mass spectrum; and wherein said temporally modulated components are converted into a substantially continuous or pseudo-continuous ion beam and/or a substantially homogeneous ion packet before the ion beam is passed to the mass analyser.

9. A method as claimed in claim 1, further comprising matching said cycle time T1 to a transmission window, extraction window or fill time, Tf, of a second device disposed downstream of said first device, so that T1≦Tf<Ts.

10. A method as claimed in claim 1, further comprising scanning said parameter of said first device multiple times during said single spectrum production cycle.

11. A method as claimed in claim 1, wherein said first device comprises: (i) a collision cell wherein the parameter is collision energy; (ii) a fragmentation or reaction cell wherein the parameter is a fragmentation or reaction parameter; (iii) an ion guide wherein the parameter is a DC, AC or RF potential that controls or changes ion transmission through the ion guide; or (iv) an ion filter wherein the parameter is a DC or RF potential that controls or changes ion transmission through the ion filter.

12. A method as claimed in claim 1, further comprising passing said components from said first device onwards to a mass analyser for recording the mass spectrum, wherein said mass analyser is optionally selected from the group comprising: (i) a quadrupole mass analyser; (ii) a 2D or linear quadrupole mass analyser; (iii) a Paul or 3D quadrupole mass analyser; (iv) a Penning trap mass analyser; (v) an ion trap mass analyser; (vi) a magnetic sector mass analyser; (vii) Ion Cyclotron Resonance (“ICR”) mass analyser; (viii) a Fourier Transform Ion Cyclotron Resonance (“FTICR”) mass analyser; (ix) an electrostatic mass analyser arranged to generate an electrostatic field having a quadro-logarithmic potential distribution; (x) a Fourier Transform electrostatic mass analyser; (xi) a Fourier Transform mass analyser; (xii) a Time of Flight mass analyser; (xiii) an orthogonal acceleration Time of Flight mass analyser; and (xiv) a linear acceleration Time of Flight mass analyser.

13. A method as claimed in claim 1, wherein the step of scanning said parameter comprises increasing, decreasing or varying said operating parameter in a linear, non-linear, or stepped manner.

14. A method as claimed in claim 1, further comprising scanning a second parameter of said first device and/or of a further device through which the ion beam passes with a cycle time T2, wherein T2≠T1.

15. A mass spectrometer comprising: a first device having a variable operating parameter; a mass analyser that records a mass spectrum of ions after they have passed through said first device with a single spectrum production time Ts; a control system arranged and adapted to scan said parameter of said first device with a cycle time T1<Ts during a single spectrum production cycle, wherein different components are transmitted through or produced in the first device at different values of the parameter such that scanning said parameter introduces a temporal modulation or profile to said components; and one or more homogenisation devices for substantially removing or altering said temporal modulation or profile from said components prior to their mass analysis.

16. (canceled)

17. A method of mass spectrometry comprising: passing an ion beam through a first device; during a single spectrum production cycle, scanning a parameter of said first device multiple times over a range of values with a cycle time T1, wherein different components are transmitted through or produced in the first device at different values of the parameter such that scanning said parameter introduces a temporal modulation or profile to said components; passing the temporally modulated components through or along a gas-filled homogenisation device to substantially remove or alter said temporal modulation or profile; and then recording a mass spectrum of at least some of said components.

18. A method as claimed in claim 17, wherein said homogenisation device converts said temporally modulated components into a substantially continuous or pseudo-continuous ion beam.

19. (canceled)

20. A mass spectrometer as claimed in claim 15 wherein said control system is arranged and adapted to during a single spectrum production cycle, scan said parameter of said first device multiple times with said cycle time T1.

21. A mass spectrometer as claimed in claim 15 wherein said one or more homogenisation devices are arranged and adapted to convert the temporally modulated components into a substantially continuous or pseudo-continuous ion beam.

22. A mass spectrometer as claimed in claim 15 wherein said one or more homogenisation devices are arranged and adapted to convert the temporally modulated components into a substantially homogenous ion packet.

23. A method as claimed in claim 17, wherein said homogenisation device converts said temporally modulated components into a substantially homogenous ion packet.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0188] 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:

[0189] FIG. 1 shows schematically a mass spectrometer being operated in a conventional manner;

[0190] FIG. 2 shows schematically a mass spectrometer being operated in accordance with an embodiment;

[0191] FIG. 3 shows schematically a mass spectrometer being operated in accordance with another embodiment;

[0192] FIG. 4 shows schematically an ion trap mass spectrometer being operated in a conventional manner;

[0193] FIG. 5 shows schematically an ion trap mass spectrometer being operated in accordance with an embodiment;

[0194] FIG. 6 shows schematically an ion trap mass spectrometer being operated in accordance with another embodiment;

[0195] FIG. 7 shows schematically a further embodiment using an ion trap with a relatively long fill time; and

[0196] FIG. 8 shows schematically a further embodiment using an ion trap with a relatively short fill time.

DETAILED DESCRIPTION

[0197] A conventional arrangement will first be described with reference to FIG. 1.

[0198] FIG. 1 shows schematically an experiment in accordance with a conventional arrangement in which the collision energy of a fragmentation cell 2 is ramped. In the conventional experiment shown in FIG. 1, the collision energy is linearly ramped over the period of a spectral acquisition time Ts (i.e. the time to produce a single spectrum). This is shown in the uppermost graph.

[0199] In the instrument depicted in FIG. 1, ions generated by an ion source 1 are accelerated through a number of lenses 5 into the fragmentation cell 2. The fragmentation cell 2 is filled with gas and is maintained at a high enough pressure such that ions accelerated into or through the fragmentation cell 2 may undergo collisional-induced dissociation (“CID”). The collision energy is determined by the accelerating potential between the lenses 5 and the fragmentation cell 2. By increasing this accelerating voltage the collision energy can be ramped. The resulting fragment ions are then passed through ion optics 6 into a mass analyser 3.

[0200] Different ions may start to fragment at different collision energies such that the result of scanning the collision energy is that fragment ions are generated in the gas cell 2 with different temporal profiles. The temporal intensity profiles resulting from scanning the collision energy over the period of the acquisition time for two different fragment ions 7,8 are illustrated in the lower left graph of FIG. 1. It can be seen that the fragment ion with intensity profile 7 (the dashed line) is produced at relatively low collision energies whilst the fragment ion with intensity profile 8 (the solid line) only starts to be produced at higher collision energies.

[0201] Although some of the fidelity of the modulation may be lost during the ion transit and acquisition process, because the ramp duration in FIG. 1 is relatively long, the temporal intensity profiles of the fragment ions 7,8 are at least partially maintained as the ions arrive at the mass analyser 3. Ions thus arrive at the mass analyser 3 over the period of the acquisition time in a temporally modulated manner. The ion arrival profiles in FIG. 1 are illustrated in the lower right graph.

[0202] This temporal modulation leads to various problems. For instance, the mass analyser 3 may comprise a Time of Flight (“TOF”) mass analyser e.g. an orthogonal acceleration Time of Flight mass analyser. In Time of Flight detection or acquisition systems, ions are repeatedly pushed into the Time of Flight region during the course of an acquisition. The ions separate according to mass in the Time of Flight region and a mass spectrum is then recorded based on the arrival times of ions at a detector component. In the situation illustrated in FIG. 1, the ions arrive at the push region of the Time of Flight system concentrated in time. This has a detrimental effect on the dynamic range of the instrument because full use is not made of all of the available pushes.

[0203] FIG. 2 illustrates the improvements made possible through the techniques described herein according to various embodiments. The instrument geometry is similar to that shown and described above with reference to FIG. 1 except that an additional homogenisation device 4 is disposed between the fragmentation cell 2 and the mass analyser 3.

[0204] In the embodiment illustrated by FIG. 2 the collision energy is scanned with a cycle time short enough to allow downstream homogenisation of the components being analysed. The collision energy ramping is illustrated in the uppermost graph of FIG. 2. The collision energy is ramped multiple times during the course of the spectral cycle time. It is noted that the spectral cycle times (i.e. the timescales on the graphs) are the same in each of the figures. The result of the repeated collision energy ramping/cycling is that the intensity profiles of fragment ions exiting the fragmentation cell 2 are temporally modulated at a relatively high frequency. The intensity profiles 7,8 for the same two fragment ions illustrated above resulting from this fast modulation are shown in the lower left graph.

[0205] The modulated ions are then passed to a homogenisation device 4 which converts or smoothes the temporally modulated ion beam components into a substantially continuous or pseudo-continuous ion beam before being presented to the mass analyser 3. The intensity profiles of the two fragment ions arriving at the mass analyser 3 are illustrated in the lower right graph. It can be seen that the result of the homogenisation process is that a continuous beam of ions for each mass to charge value or component enters the mass analyser 3. The problems described above can thus be alleviated. For instance, where the mass analyser 3 is a Time of Flight mass analyser, because ions are continuously provided to the extraction region full use can be made of each push and the dynamic range can be maximised or enhanced.

[0206] The homogenisation device 4 can take a variety of forms so long as it is capable of removing a temporal profile resulting from the parameter scan prior to the ions being recorded by the mass analyser 3. For instance, the homogenisation device 4 may comprise a relatively high pressure ion guide or gas collision cell. In this case collisions with the background gas cause ions to scatter and diffusively spread. The diffusive spreading of ions within the homogenisation device 4 smoothes out or removes any temporal variation so that the fidelity of the temporal modulation is removed or altered. Gas cells or gas-filled RF devices may be particularly useful for beam-based instruments such a quadrupole Time of Flight or tandem quadrupole mass spectrometers. The time required to homogenise an ion beam generally depends on the extent or width of the temporal modulation and on the conditions within the homogenisation device 4.

[0207] The width of the total temporal intensity profile of the ion beam (i.e. of all of the components) resulting from each parameter scan will be determined by the cycle time i.e. the duration of the ramp for which the parameter (e.g. collision energy) is scanned for. A relatively short scan cycle time will result in a relatively narrow intensity profile and where the scan cycle is repeated multiple times, a relatively short scan cycle time will result in a relatively high frequency temporal modulation. To allow the ion beam to be homogenised downstream of the device that is being scanned (e.g. collision cell 2) it is important that a sufficiently short or fast scan cycle time is used.

[0208] The time required to homogenise the ion beam, which determines the upper limit for the parameter scan cycle time, will depend on the conditions in the homogenisation device 4. For instance, the nature of and the pressure of the gas within the homogenisation device 4 as well as any applied electrostatic confining or driving forces may affect the ion-gas interactions in the homogenisation device 4. The ions must be present in the homogenisation device 4 long enough to ensure that they can sufficiently diffusively spread.

[0209] The homogenisation device 4 may rely solely on passive diffusion or spreading of the temporally modulated components into a substantially continuous beam. Additionally, or alternatively, time and/or position varying electric fields may be applied to the homogenisation device 4 in order to actively homogenise the beam. The time and/or position varying fields may comprise transient DC voltages or voltage waveforms or travelling waves. Travelling waves can be used to control or manipulate the residence times, velocities and/or position of ions within the homogenisation device 4. In this way, the components can be actively converted into a substantially continuous beam. Active homogenisation may allow a greater degree of control over the extent of homogenisation or the time required to homogenise an ion beam. Practical cycle times can be determined, for example, using calibration experiments or by extrapolating from programmable dynamic range enhancement (“pDRE”) data. The pDRE technique is described in U.S. Pat. No. 7,683,314 (MICROMASS). For instance, a practical cycle time can be determined by alternately attenuating an ion beam for a time t1 and transmitting ions through the homogenisation device 4 (or a testing device having the same characteristics as the homogenisation device) for a time t2 and monitoring the output. Where the output is a continuous beam it can be seen that the ion beam has spread sufficiently within the homogenisation device 4 to remove the attenuation. By varying the attenuation time period t1, the temporal width that can be homogenised in the homogenisation device 4 (and hence suitable ramp cycle times) can be determined.

[0210] It may be desirable to drive ions through the homogenisation device 4 in order to reduce the overall transit time of ions. Ions may be driven or urged along the homogenisation device 4 for instance using axial fields or by applying one or more transient DC potentials or potential waveforms (travelling waves) although it is noted that any other means for driving ions known in the art may also be used. In these cases, the characteristics of the driving means e.g. the travelling waves or axial field should be arranged to ensure that the desired loss of temporal modulation occurs. This may typically involve operating the devices with relatively low axial fields or travelling wave heights or high travelling wave velocities. Typically, to ensure homogenisation within a travelling wave or axial field driven gas cell, cycle times of less than 10 ms may be appropriate. For fast instruments with relatively short spectral production and inter scan times, experiments have found that cycle times less than 2 ms, or less than 1 ms, provide better results i.e. dynamic range enhancements.

[0211] In the embodiment illustrated in FIG. 2 a separate homogenisation device 4 downstream of the collision cell 2 is used.

[0212] In other embodiments, the fragmentation cell 2 being a gas-filled device may itself act to homogenise the ion beam in a similar manner to that described above. This is schematically illustrated in FIG. 3.

[0213] Again, the ramp cycle times and the conditions within the fragmentation cell 2 should be selected to ensure that the temporal profile can be sufficiently homogenised.

[0214] Whilst certain improvements have been described above specifically in relation to time of flight mass analysers, the various embodiments are not limited to any particular type of ion detection or acquisition system. Similar improvements may be achieved for other mass analysers which may advantageously be provided with a homogenised or continuous ion beam.

[0215] In particular, the techniques described herein may provide improvements in instruments employing a device having a relatively small transmission window or fill time downstream of the device that is being scanned. In these cases the downstream device effectively samples only a portion of the ion beam. Accordingly, where the ion beam is temporally modulated or uneven, the transmission window may not overlap with the temporal profile of some of the components. These components would not then be sampled. This may inadvertently introduce a bias into the measurement.

[0216] To illustrate this effect, FIG. 4 schematically shows a mass spectrometer where the mass analyser comprises an ion trap 3 operating with automatic gain control (“AGC”) being operated in accordance with a known arrangement. In AGC ion traps the fill time of the ion trap is often a relatively short portion of the overall experimental cycle. The fill time of the ion trap is controlled by a transmission gate 6 disposed adjacently upstream of the ion trap 3.

[0217] In FIG. 4, like FIG. 1, the collision energy in the fragmentation cell 2 is ramped over the full period of a spectral acquisition as shown in the uppermost graph. This results in ions arriving at the ion trap 3 with temporally modulated intensity profiles as shown in the lower right graph. The transmission time window 9 of the ion trap is shown superimposed onto the intensity profiles.

[0218] The relatively long collision energy ramp again results in a wide temporal profile. The relatively short transmission window 9 only samples a portion of the ion beam i.e. only those components whose profiles overlap the window. The approach illustrated in FIG. 4 thus results in uneven sampling of the components of the ion beam. For instance, as shown in the lower right graph of FIG. 4, the fragment ion with intensity profile 7 (the dashed line) is not transmitted or sampled during the ion trap fill window 9. By scanning the collision energy in the fragmentation cell 2 a bias has been inadvertently introduced into the measurement. These problems can be avoided by the techniques described herein in accordance with various embodiments.

[0219] FIG. 5 shows a mass spectrometer employing an ion trap being operated in accordance with an embodiment.

[0220] In a similar manner to that described above, the collision energy in FIG. 5 is repeatedly ramped over a relatively short cycle time and the resulting temporal modulation is removed or homogenised within the gas-filled fragmentation cell 2. Each of the components of the ion beam are thus provided to the ion trap as a continuous beam and are all evenly sampled by the ion trap 3 within the transmitted time window 9 (the lower right graph). Because the ion beam is continuous, the transmitted time window 9 can be made as short as desired whilst still ensuring that each of the components is measured.

[0221] Although in the embodiment shown in FIG. 5 the fragmentation cell 2 acts to homogenise the beam, it is noted that a downstream homogenisation device (like that illustrated in FIG. 2) may equally be used.

[0222] Another embodiment is shown in FIG. 6. Here, the ion trap 3 forming the mass analyser acts as the homogenisation device.

[0223] Similarly, an additional ion accumulation device (not shown) may be disposed prior to the ion trap 3 or mass analyser and may be used to homogenise the beam.

[0224] In these cases, the parameter scan cycle time may be short enough to allow multiple ramps within the fill time or transmission window 9 of the ion trap 3 and/or ion accumulation device. For instance, as shown in the uppermost graph of FIG. 6 the parameter may be ramped or cycled multiple times within the fill time 9 of the ion trap 3. In this way, the full width of the temporal profile of the ion beam (i.e. of all of the components) can be sampled and each component of the ion beam measured. Any prior temporal profiles of the components will be lost once they are confined within a substantially homogeneous ion packet in the ion trap 3. The ions will tend to undergo collisional cooling within the ion trap 3 before they are mass analysed.

[0225] In embodiments, the ramp cycle time may be selected to match the fill time window 9 i.e. so that one or more complete ramps can be performed within the fill window 9 of the ion trap 3. This is illustrated in FIGS. 7 and 8 for relatively long and short trap fill times respectively. Where the ramp cycle is matched or synchronised with the transmission window or fill time of a downstream device it may be necessary to account for the transit times of ions through any devices interspersed between the device being ramped and the downstream device. Although FIGS. 7 and 8 illustrate only a single ramp, it will be appreciated that the parameter may be ramped multiple times. The fill time may thus be selected to match or synchronise with one or more complete ramps i.e. to select the modulated components resulting from only one or more of the ramps.

[0226] The techniques described herein may also provide advantages where multiple parameters are scanned during the course of an acquisition. These parameters may be scanned with substantially different cycle times to achieve an effective nested instrument control apparatus. In these cases it is not necessary that downstream homogenisation is combined with each of the multiple parameter scans. However, by homogenising the ion beam in combination with at least one of the parameter scans it is possible to remove any biases that may otherwise result from inadvertent synchronisation of two or more scans/ramps of different parameters over a single scan time. This is a problem of current instruments that employ multiple scans of e.g. mass to charge profile and collision energy.

[0227] The approaches described above can work in conjunction with nested separations and acquisitions. In this case, the spectral acquisition time may be the nested spectral acquisition time.

[0228] The modulation cycle (i.e. the ramp cycle time) may be synchronised with or matched to the spectra production cycle.

[0229] The instrument geometry and the nature and number of components described above are not intended to be limiting. For instance, although embodiments have been described which employ a CID fragmentation cell, the techniques may also apply to any device that may be scanned or varied in a similar manner. This may include any type of fragmentation or reaction device where scanning a fragmentation or reaction parameter introduces a temporal modulation such as those mentioned previously. The technique may also apply to RF ion guides or filtering devices in which case an RF and/or DC voltage may be scanned to vary the range of mass to charge values being transmitted. This results in a mass to charge range dependent temporal profile.

[0230] Although the present invention has been described with reference to particular 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.