EP2001039B1 - Spectromètre de masse - Google Patents

Spectromètre de masse Download PDF

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Publication number
EP2001039B1
EP2001039B1 EP08013533A EP08013533A EP2001039B1 EP 2001039 B1 EP2001039 B1 EP 2001039B1 EP 08013533 A EP08013533 A EP 08013533A EP 08013533 A EP08013533 A EP 08013533A EP 2001039 B1 EP2001039 B1 EP 2001039B1
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Prior art keywords
ions
mass
fragment
ion
ion trap
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German (de)
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EP2001039A1 (fr
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John Brian Hoyes
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Micromass UK Ltd
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Micromass UK Ltd
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Priority claimed from GBGB0211373.6A external-priority patent/GB0211373D0/en
Priority claimed from GB0222055A external-priority patent/GB2389704B/en
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    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/26—Mass spectrometers or separator tubes
    • H01J49/34—Dynamic spectrometers
    • H01J49/42—Stability-of-path spectrometers, e.g. monopole, quadrupole, multipole, farvitrons
    • H01J49/4205—Device types
    • H01J49/421—Mass filters, i.e. deviating unwanted ions without trapping
    • H01J49/4215—Quadrupole mass filters
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/26—Mass spectrometers or separator tubes
    • H01J49/34—Dynamic spectrometers
    • H01J49/42—Stability-of-path spectrometers, e.g. monopole, quadrupole, multipole, farvitrons
    • H01J49/426—Methods for controlling ions

Definitions

  • the present invention relates to a mass spectrometer and method of mass spectrometry.
  • Mass spectrometry has firmly established itself as the primary technique for identifying proteins due to its unparalleled speed, sensitivity and specificity. Strategies can involve either analysis of the intact protein, or more commonly digestion of the protein using a specific protease that cleaves at predictable residues along the peptide backbone. This provides smaller stretches of peptide sequence that are more amenable to analysis via mass spectrometry.
  • the mass spectrometry technique providing the highest degree of specificity and sensitivity is Electrospray ionisation ("ESI”) interfaced to a tandem mass spectrometer.
  • EI Electrospray ionisation
  • These experiments involve separation of the complex digest mixture by microcapillary liquid chromatography with on-line mass spectral detection using automated acquisition modes whereby conventional MS and MS/MS spectra are collected in a data dependant manner.
  • This information can be used directly to search databases for matching sequences leading to identification of the parent protein.
  • This approach can be used to identify proteins that are present at low endogenous concentrations.
  • the limiting factor for identification of the protein is not the quality of the MS/MS spectrum produced but is the initial discovery of the multiply charged peptide precursor ion in the MS mode.
  • Fig. 1 shows a typical conventional mass spectrum and illustrates how doubly charged species may be obscured amongst a singly charged background. A method whereby the chemical noise is reduced so that the mass spectrometer can more easily target peptide related ions would be highly advantageous for the study of protein digests.
  • a known method used to favour the detection of multiply charged species over singly charged-species is to use an Electrospray ionisation orthogonal acceleration time of flight mass analyser ("ESI-oaTOF").
  • the orthogonal acceleration time of flight mass analyser counts the arrival of ions using a Time to Digital Converter ("TDC") which has a discriminator threshold.
  • TDC Time to Digital Converter
  • the voltage pulse of a single ion must be high enough to trigger the discriminator and so register the arrival of an ion.
  • the detector producing the voltage may be an electron multiplier or a Microchannel Plate detector (“MCP"). These detectors are charge sensitive so the size of signal they produce increases with increasing charge state. Discrimination in favour of higher charge states can be accomplished by increasing the discriminator voltage level, lowering the detector gain, or a combination of both.
  • Fig. 2(a) shows a mass spectrum obtained with normal detector gain
  • Fig. 2(b) shows a comparable mass spectrum obtained with a reduced detector gain.
  • An important disadvantage of lowering the detector gain (or of increasing the discriminator level) is that the sensitivity is lowered.
  • the sensitivity is reduced by a factor of approximately x4 when a lower detector gain is employed. Using this method it is also impossible to pick out an individual charge state. Instead, the best that can be achieved is a reduction of the efficiency of detection of lower charge states with respect to higher charge states.
  • MALDI Matrix Assisted Laser Desorption Ionisation
  • WO 02/07185 discloses an instrument for use in providing rapid and sensitive analysis of organic and inorganic molecules.
  • ions are fragmented or reacted within the (first) ion trap. Therefore, once the ions have been fragmented or reacted in the (first) ion trap the ions present in the (first) ion trap (gas cell) will have a wide range of mass to charge ratios.
  • the first ion trap (gas cell) comprises an ion tunnel ion trap/collision cell which is not mass selective. Therefore, it is not possible to simply optimise the ejection of fragment or product ions from the first ion trap with, for example, a TOF mass analyser and hence a high duty cycle across the mass range can not be achieved.
  • fragment or product ions can then be passed through the ion mobility spectrometer which separates the fragment or product ions according to their ion mobility.
  • the fragment or product ions can then be trapped in the first ion trap and the pusher electrode of the TOF mass analyser can be arranged to be energised a predetermined period of time after fragment or product ions have been released from the first ion trap so as to optimise the duty cycle.
  • the delay time of the pusher electrode can be progressively increased.
  • the fragment or product ions can be mass analysed with a very high (approximately 100%) duty cycle. This represents a further significant advance in the art.
  • the fragment or product ions which are sent upstream preferably pass through the second device and/or the first device.
  • the second device is arranged to transmit the fragment or product ions without substantially mass filtering them.
  • the fragment or product ions are then preferably trapped in a second ion trap upstream of the first device.
  • multiply charged ions (which may include doubly, triply and quadruply charged ions and ions having five or more charges) are preferentially selected and transmitted whilst the intensity of singly charged ions may be reduced.
  • any desired charged state or states may be selected. For example, two or more multiply charged states may be transmitted.
  • the second device comprises a quadrupole rod set mass filter.
  • the quadrupole mass filter is operated as a high pass mass to charge ratio filter so as to transmit substantially only ions having a mass to charge ratio greater than a minimum value. Multiply charged ions are therefore preferentially transmitted compared to singly charged ions i.e. doubly, triply, quadruply and ions having five or more charges may be transmitted whilst singly charged ions are attenuated.
  • the quadrupole mass filter is scanned so that the minimum mass to charge ratio cut-off is progressively increased during a cycle (which is defined as the period between consecutive pulses of ions being admitted into the ion mobility spectrometer).
  • the quadrupole mass filter is scanned in a substantially continuous (i.e. smooth) manner.
  • the ion source may be a pulsed ion source such as a Matrix Assisted Laser Desorption Ionisation ("MALDI") ion source.
  • the pulsed ion source may alternatively comprise a Laser Desorption Ionisation ion source which is not matrix assisted.
  • a continuous ion source may be used in which case an ion trap for storing ions and periodically releasing ions is also preferably provided.
  • Continuous ion sources which may be used include Electrospray, Atmospheric Pressure Chemical Ionisation (“APCI”), Electron Impact (“EI”), Atmospheric Pressure Photon Ionisation (“APPI”) and Chemical Ionisation (“CI”) ion sources.
  • APCI Electrospray
  • EI Electron Impact
  • APPI Atmospheric Pressure Photon Ionisation
  • CI Chemical Ionisation
  • Other continuous or pseudo-continuous ion sources may also be used.
  • the mass spectrometer may be a Fourier Transform mass spectrometer or a Fourier Transform Ion Cyclotron Resonance mass spectrometer.
  • the method of mass spectrometry further comprises the steps of:
  • fragment or product ions can be mass analysed with a very high (approximately 100%) duty cycle.
  • the mass to charge ratio of (product or fragments) ions exiting the combination of the ion mobility spectrometer and the quadrupole mass filter can be predicted. Therefore, the mass to charge ratio of ions present in the first ion trap at any instance can be predicted.
  • a group of ions having a relatively narrow spread of mass to charge ratios can be pulsed or otherwise ejected from the first ion trap and a predetermined time later the pusher/puller electrode of a TOF mass analyser can be energised so as to orthogonally accelerate the ions into the drift region of the TOF mass analyser.
  • the predetermined time can be optimised to that of the mass to charge ratios of the ions present and hence ejected from the first ion trap at any point in time. Accordingly, the ions released from the first ion trap are orthogonally accelerated with a very high (approximately 100%) duty cycle (as will be appreciated by those skilled in the art, if ions having a wide range of mass to charge ratios were to be simultaneously ejected from the first ion trap then only a small percentage (typically ⁇ 25%) of those ions would then be orthogonally accelerated).
  • the first device comprises an ion mobility spectrometer or other ion mobility device.
  • Ions in an ion mobility spectrometer may be subjected to an electric field in the presence of a buffer gas so that different species of ion acquire different velocities and are temporally separated according to their ion mobility.
  • the mobility of an ion in an ion mobility spectrometer typically depends inter alia upon its mass and its charge. Heavy ions with one charge tend to have lower mobilities than light ions with one charge. Also an ion of a particular mass to charge ratio with one charge tends to have a lower mobility than an ion with the same mass to charge ratio but carrying two (or more) charges.
  • the ion mobility spectrometer may comprise a drift tube together with one or more electrodes for maintaining an axial DC voltage gradient along at least a portion of the drift tube.
  • the ion mobility spectrometer may comprise a Field Asymmetric Ion Mobility Spectrometer ("FAIMS").
  • the FAIMS may comprise two parallel plates.
  • the FAIMS may comprise two axially aligned inner cylinders surrounded by a long outer cylinder.
  • the outer cylinder and a shorter inner cylinder are preferably held at the same electrical potential.
  • a longer inner cylinder may have a high frequency high voltage asymmetric waveform applied to it, thereby establishing an electric field between the inner and outer cylinders.
  • a compensation DC voltage is also applied to the longer inner cylinder.
  • a FAIMS acts like a mobility filter and may operate at atmospheric pressure.
  • the ion mobility spectrometer may comprise a plurality of electrodes having apertures wherein a DC voltage gradient is maintained across at least a portion of the ion mobility spectrometer and at least some of the electrodes are connected to an AC or RF voltage supply.
  • the ion mobility spectrometer is particularly advantageous in that the addition of an AC or RF voltage to the electrodes (which may be ring like or otherwise annular) results in radial confinement of the ions passing through the ion mobility spectrometer. Radial confinement of the ions results in higher ion transmission compared with ion mobility spectrometers of the drift tube type.
  • the ion mobility spectrometer preferably extends between two vacuum chambers so that an upstream section comprising a first plurality of electrodes having apertures is arranged in a vacuum chamber and a downstream section comprising a second plurality of electrodes having apertures is arranged in a further vacuum chamber, the vacuum chambers being separated by a differential pumping aperture.
  • At least some of the electrodes in the upstream section are preferably supplied with an AC or RF voltage having a frequency within the range 0.1-3.0 MHz.
  • a frequency of 0.5-1.1 MHz is preferred and a frequency of 780 kHz is particularly preferred.
  • the upstream section is preferably arranged to be maintained at a pressure within the range 0.1-10 mbar, preferably approximately 1 mbar.
  • At least some of the electrodes in the downstream section are preferably supplied with an AC or RF voltage having a frequency within the range 0.1-3.0 MHz.
  • a frequency of 1.8-2.4 MHz is preferred and a frequency of 2.1 MHz is particularly preferred.
  • the downstream section is preferably arranged to be maintained at a pressure within the range 10 -3 -10 -2 mbar.
  • the voltages applied to the electrodes in the upstream section may be such that a first DC voltage gradient is maintained in use across at least a portion of the upstream section and a second different DC voltage gradient may be maintained in use across at least a portion of the downstream section.
  • the first DC voltage gradient is preferably greater than the second DC voltage gradient. Both voltage gradients do not necessarily need to be linear and indeed a stepped voltage gradient is particularly preferred.
  • the ion mobility spectrometer comprises at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 electrodes.
  • at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the electrodes forming the ion mobility spectrometer have apertures which are of substantially the same size or area.
  • the ion mobility spectrometer comprises an ion tunnel comprising a plurality of electrodes all having substantially similar sized apertures through which ions are transmitted.
  • An orthogonal acceleration time of flight mass analyser is particularly preferred although other types of mass analysers such as a quadrupole mass analysers or 2D or 3D ion traps may be used according to less preferred embodiments.
  • the mass spectrometer further comprises:
  • Fig. 6 illustrates the general principle of selecting ions having a specific charge state according to a preferred embodiment
  • Fig. 7 shows a preferred embodiment of the present invention
  • Fig. 8(a) illustrates a preferred embodiment of an ion trap, ion gate and ion mobility spectrometer
  • Fig. 8(b) illustrates the various DC voltages which may be applied to the ion trap, ion gate and ion mobility spectrometer
  • Fig. 8(c) illustrates how the DC voltage applied to the ion gate may vary as a function of time
  • Fig. 8(d) illustrates how a quadrupole mass filter may be scanned according to a preferred embodiment
  • Fig. 9 illustrates how the duty cycle of an ion trap-time of flight mass analyser increases to approximately 100% for a relatively narrow mass to charge ratio range compared with a typical maximum duty cycle of approximately 25% obtained by operating the time of flight mass analyser in a conventional manner;
  • Fig. 10 illustrates a first mode of operation according to a preferred embodiment wherein precursor ions having a particular desired charge state(s) are selected and subsequently mass analysed with a 100% duty cycle;
  • Fig. 11 illustrates a second mode of operation according to the preferred embodiment wherein precursor ions having a desired charge state(s) are fragmented or reacted and stored in a first ion trap;
  • Fig. 12 illustrates a third mode of operation according to the preferred embodiment wherein fragment or product ions which have been accumulated in the first ion trap are sent back to an upstream ion trap whilst ions continue to be accumulated from the ion source;
  • Fig. 13 illustrates a fourth mode of operation according to the preferred embodiment wherein fragment or product ions are separated according to their ion mobility and are subsequently mass analysed with a 100% duty cycle;
  • Fig. 14 shows a typical experimental cycling of modes of operation.
  • Fig. 3 shows the known relationship of flight time in a drift region of a time of flight mass analyser versus drift time in an ion mobility spectrometer for various singly and doubly charged ions.
  • An experimentally determined relationship between the mass to charge ratio of ions and their drift time through an ion mobility spectrometer is shown in Fig. 4 .
  • This relationship can be represented by an empirically derived polynomial expression.
  • a doubly charged ion having the same mass to charge ratio as a singly charged ion will take less time to drift through an ion mobility spectrometer compared with a singly charged ion.
  • the ordinate axis of Fig. 3 is given as the flight time through the drift region of a time of flight mass analyser, it will be appreciated that this correlates directly with the mass to charge ratio of the ion.
  • a mass filter is provided in combination with an ion mobility spectrometer, and if the mass filter is scanned (i.e. the transmitted range of mass to charge ratios is varied) in synchronisation with the drift of ions through the ion mobility spectrometer, then it is possible to arrange that only ions having a particular charge state (e.g. multiply charged ions) will be transmitted onwardly e.g. to a mass analyser.
  • ions having a particular charge state e.g. multiply charged ions
  • Fig. 5 illustrates the principle of charge state selection.
  • the known data of Fig. 3 and the experimentally derived data of Fig. 4 can be interpreted such that all ions having the same charge state can be considered to fall within a distinct region or band of a 2D plot of mass to charge ratio versus drift time through an ion mobility spectrometer.
  • singly and doubly charged ions are shown as falling within distinct bands with an intermediate region therebetween where very few ions of interest are to be found.
  • Triply and quadruply charged ions etc. are not shown for ease of illustration only.
  • the large area below the "scan line" can be considered to represent singly charged ions and the other area can be considered to represent doubly charged ions.
  • a mass filter is provided which is synchronised with the operation of an ion mobility spectrometer.
  • ions may be emerging from the ion mobility spectrometer with various different mass to charge ratios. Those ions which emerge with a mass to charge ratio of approximately 1-790 are most likely to be singly charged ions whereas those ions emerging with a mass to charge ratio of approximately 1070-1800 are most likely to be doubly charged ions.
  • the mass filter may track the lower predetermined mass to charge ratio for doubly charged ions.
  • the cut-off mass to charge ratio may also lie for at least a portion of a cycle within the intermediate region which separates the regions comprising singly and doubly charged ions.
  • the minimum cut-off mass to charge ratio of the mass filter may also vary in a predetermined or random manner between the upper threshold of the singly charged ion region, the intermediate region and the lower threshold of the doubly charged ion region. It will also be appreciated that according to less preferred embodiments, the minimum cut-off mass to charge ratio may fall for at least a portion of time within the region considered to comprise either singly or doubly charged ions. In such circumstances, ions of a potentially unwanted charge state may still be transmitted, but the intensity of such ions will nonetheless be reduced.
  • the minimum cut-off mass to charge ratio is varied smoothly, and is preferably increased with time.
  • the minimum cut-off mass to charge ratio may be increased in a stepped manner.
  • Fig. 6 illustrates how the basic arrangement described in relation to Fig. 5 may be extended so that ions of a specific charge state(s) may be selected.
  • the mass filter is operated as a band pass mass to charge ratio filter so as to select ions of a specific charge state (in this case triply charged ions) in preference to ions having any other charge state.
  • the mass filter being operated in a band pass mode, is set so as to transmit ions having a mass to charge ratio > P and ⁇ Q, wherein P preferably lies on the upper threshold of the region containing doubly charged ions and Q preferably lies on the lower threshold of the region containing quadruply charged ions.
  • the upper and lower mass cut-offs P,Q are preferably smoothly increased with time so that at a later time T', the lower mass to charge ratio cut-off of the band pass mass to charge ratio filter has been increased from P to P' and the upper mass to charge ratio cut-off of the band pass mass to charge ratio filter has been increased from Q to Q'.
  • the upper and lower mass to charge ratio cut-offs do not need to follow the lower and upper thresholds of any particular charge state region, and the upper and lower cut-offs may fall within one or more intermediate regions and/or one or more of the bands in which ions having a particular charge state are to be found.
  • the lower and upper mass to charge ratio cut-offs may simply follow the thresholds of the region comprising doubly, triply, quadruply etc. charged ions.
  • Two, three, four or more charge states may be selected in preference to any other charge state (e.g. doubly and triply charged ions may be transmitted).
  • Arrangements are also contemplated wherein non-neighbouring charge states (e.g. doubly and quadruply charged ions) are transmitted but not any other charge states.
  • Fig. 7 shows a preferred embodiment of the present invention.
  • An ion mobility spectrometer 4 is provided.
  • a pulse of ions is admitted to the ion mobility spectrometer 4.
  • a continuous ion source e.g. an electrospray ion source, preferably generates a beam of ions 1 which are trapped in an upstream ion trap 2 upstream of the ion mobility spectrometer 4.
  • ions are then pulsed out of the upstream ion trap 2 by the application of an extraction voltage to an ion gate 3 at the exit of the upstream ion trap 2.
  • the upstream ion trap 2 may comprise a quadrupole rod set having a length of approximately 75 mm.
  • the upstream ion trap 2 comprises an ion tunnel ion trap comprising a plurality of electrodes having apertures therein through which ions are transmitted.
  • a separate ion gate 3 does not need to be provided.
  • the apertures are preferably all the same size or area. In other embodiments at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the electrodes have apertures which are substantially the same size or area.
  • the ion tunnel ion trap 2 may preferably comprise at least 20, 30, 40 or 50 electrodes.
  • Adjacent electrodes are preferably connected to opposite phases of an AC or RF voltage supply so that ions are radially confined in use within the ion tunnel ion trap 2.
  • the voltages applied to at least some of the electrodes forming the upstream ion trap 2 can be independently controlled.
  • a "V" shaped axial DC potential profile may be created so that a single trapping region is formed within the ion trap 2.
  • the voltage applied to the ion gate 3 and/or to a region of the ion trap 2 may be dropped for a short period of time thereby causing ions to be ejected from the ion trap 2 in a substantially pulsed manner into the ion mobility spectrometer 4.
  • a pulsed ion source such as a Matrix Assisted Laser Desorption Ionisation (“MALDI”) ion source or a Laser Desorption Ionisation ion source may be used instead of a continuous ion source. If a pulsed ion source is used, then ion trap 2 and ion gate 3 may be omitted in some modes of operation.
  • MALDI Matrix Assisted Laser Desorption Ionisation
  • ion trap 2 and ion gate 3 may be omitted in some modes of operation.
  • the ion mobility spectrometer 4 is a device which causes ions to become temporally separated based upon their ion mobility. A number of different forms of ion mobility spectrometer may be used.
  • the ion mobility spectrometer 4 may comprise an ion mobility spectrometer consisting of a drift tube having a number of guard rings distributed within the drift tube.
  • the guard rings may be interconnected by equivalent valued resistors and connected to a DC voltage source. A linear DC voltage gradient is generated along the length of the drift tube.
  • the guard rings are not connected to an AC or RF voltage source.
  • the ion mobility spectrometer 4 may comprise a Field Asymmetric Ion Mobility Spectrometer ("FAIMS").
  • FIMS Field Asymmetric Ion Mobility Spectrometer
  • the ion mobility spectrometer 4 comprises an ion tunnel arrangement comprising a number of ring, annular or plate electrodes, or more generally electrodes having an aperture therein through which ions are transmitted.
  • the apertures are preferably all the same size or area and are preferably circular. In other less preferred embodiments at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the electrodes have apertures which are substantially the same size or area.
  • a schematic example of a preferred ion mobility spectrometer 4 is shown in Fig. 8(a) .
  • the ion mobility spectrometer 4 may comprise a plurality of electrodes 4a,4b which are either arranged in a single vacuum chamber or, as shown in Fig.
  • the portion of the ion mobility spectrometer 4a in an upstream vacuum chamber may have a length of approximately 100 mm, and the portion of the ion mobility spectrometer 4b in a downstream vacuum chamber may-have a length of approximately 85 mm.
  • the ion trap 2, ion gate 3 and upstream portion 4a of the ion mobility spectrometer 4 are all preferably provided in the same vacuum chamber which is preferably maintained, in use, at a pressure within the range 0.1-10 mbar.
  • the vacuum chamber housing the upstream portion 4a may be maintained at a pressure greater than 10 mbar up to a pressure at or near atmospheric pressure. Also, according to less preferred embodiments, the vacuum chamber may alternatively be maintained at a pressure below 0.1 mbar.
  • the electrodes comprising the ion trap 2 are maintained at a DC voltage V rf1 .
  • Ion gate 3 may be held normally at a higher DC voltage V trap than V rf1 , but the voltage applied to the ion gate 3 may be periodically dropped to a voltage V extract which is preferably lower than V rf1 thereby causing ions to be accelerated out of the ion trap 2 and to be admitted into the ion mobility spectrometer 4.
  • ion trap 2 may comprise an ion tunnel ion trap 2 preferably having a V-shaped axial DC potential profile in a mode of operation.
  • the DC voltage gradient on the second. (downstream) half of the ion trap 2 may be lowered or otherwise reduced or varied so as to accelerate ions out of the ion trap 2.
  • Adjacent electrodes which form part of the ion trap 2 are preferably connected to opposite phases of a first AC or RF voltage supply.
  • the first AC or RF voltage supply preferably has a frequency within the range 0.1-3.0 MHz, preferably 0.5-1.1 MHz, further preferably 780 kHz.
  • Alternate electrodes forming the upstream section 4a of the ion mobility spectrometer 4 are preferably capacitively coupled to opposite phases of the first AC or RF voltage supply.
  • the electrodes comprising the ion trap 2, the electrodes comprising the upstream portion 4a of the ion mobility spectrometer 4 and the differential pumping aperture Ap1 separating the upstream portion 4a from the downstream portion 4b of the ion mobility spectrometer 4 are preferably interconnected via resistors to a DC voltage supply which in one embodiment comprises a 400 V supply.
  • the resistors interconnecting electrodes forming the upstream portion 4a of the ion mobility spectrometer 4 may be substantially equal in value in which case an axial DC voltage gradient is obtained similar to that shown in Fig. 8(b) .
  • the DC voltage gradient is shown for ease of illustration as being linear, but may more preferably be stepped.
  • the applied AC or RF voltage is superimposed upon the DC voltage and serves to radially confine ions within the ion mobility spectrometer 4.
  • the DC voltage V trap or V extract applied to the ion gate 3 preferably floats on the DC voltage supply.
  • the first AC or RF voltage supply is preferably isolated from the DC voltage supply by a capacitor.
  • alternate electrodes forming the downstream portion 4b of the ion mobility spectrometer 4 are preferably capacitively coupled to opposite phases of a second AC or RF voltage supply.
  • the second AC or RF voltage supply preferably has a frequency in the range 0.1-3.0 MHz, preferably 1.8-2.4 MHz, further preferably 2.1 MHz.
  • a substantially linear or stepped axial DC voltage gradient is maintained along the length of the downstream portion 4b of the ion mobility spectrometer 4.
  • the applied AC or RF voltage is superimposed upon the DC voltage and serves to radially confine ions within the ion mobility spectrometer 4.
  • the DC voltage gradient maintained across the upstream portion 4a is preferably not the same as the DC voltage gradient maintained across the downstream portion 4b. According to a preferred embodiment, the DC voltage gradient maintained across the upstream portion 4a is greater than the DC voltage gradient maintained across the downstream portion 4b.
  • the pressure in the vacuum chamber housing the downstream portion 4b is preferably in the range 10 -3 to 10 -2 mbar. According to less preferred embodiments, the pressure may be above 10 -2 mbar, and could be similar in pressure to the pressure of the vacuum chamber housing the upstream portion 4a. It is believed that the greatest temporal separation of ions occurs in the upstream portion 4a due to the higher background gas pressure. If the pressure is too low then the ions will not make enough collisions with gas molecules for a noticeable temporal separation of the ions to occur.
  • the size of the orifice in the ion gate 3 is preferably of a similar size or is substantially the same internal diameter or size as the differential pumping aperture Ap1. Downstream of the ion mobility spectrometer 4 another differential pumping aperture Ap2 may be provided leading to a vacuum chamber housing a quadrupole mass filter 5. Pre- and post-filters 14a,14b may be provided.
  • the ion mobility spectrometer 4 may comprise an ion tunnel comprised of a plurality of segments.
  • 15 segments may be provided.
  • Each segment may comprise two electrodes having apertures interleaved with another two electrodes having apertures. All four electrodes in a segment are preferably maintained at the same DC voltage but adjacent electrodes are connected to opposite phases of the AC or RF supply. The DC and AC/RF voltage supplies are isolated from one another.
  • at least 90% of all the electrodes forming the ion tunnel comprised of multiple segments have apertures which are substantially similar or the same in size or area.
  • Typical drift times through the ion mobility spectrometer 4 are of the order of a few ms.
  • An important feature of the preferred embodiment is the provision of a mass filter 5 which is varied in a specified manner in conjunction with the operation of the ion mobility spectrometer 4. According to the preferred embodiment a quadrupole rod set mass filter 5 is used.
  • the mass filter 5 can be set to transmit (in conjunction with the operation of the ion mobility spectrometer 5) only those ions having a mass to charge ratio that corresponds at any particular point in time with the charge state of the ions of interest.
  • the mass filter 5 should be able to sweep the chosen mass to charge ratio range on at least the time scale of ions drifting through the drift region. In other words, the mass filter 5 should be able to be scanned across the desired mass to charge ratio range in a few milliseconds. Quadrupole mass filters 5 are capable of operating at this speed.
  • either the AC (or RF) voltage and/or the DC voltage applied to the quadrupole mass filter 5 may be swept in synchronisation with the pulsing of ions into the ion mobility spectrometer 4.
  • the quadrupole mass filter 5 may be operated in either a high pass or band pass mode depending on whether e.g. multiply charged ions are preferred in general, or whether ions having a specific charge state are preferred.
  • the varying of a mass filtering characteristic of the quadrupole mass filter 5 is such that ions having a favoured charge state (or states) are preferably onwardly transmitted, preferably to the at least near exclusion of other charge states, for at least part of the cycle time Tm between pulses of ions being injected into the ion mobility spectrometer 4.
  • Figs. 8(c) and (d) show the inter-relationship between ions being pulsed out of the ion trap 2 into the ion mobility spectrometer 4, and the scanning of the mass filter 5. Synchronisation of the operation of the mass filter 5 with the drift times of desired ions species through the ion mobility spectrometer 4 enables a duty cycle of approximately 100% to be obtained for ions having the charge state(s) of interest.
  • a downstream ion trap 6 is provided downstream of the ion mobility spectrometer 4 and the quadrupole mass filter 5.
  • the downstream ion trap 6 comprises a collision (or gas) cell 6. Ions may be arranged so that they are sufficiently energetic when they enter the collision cell 6 that they collide with gas molecules present in the gas cell 6 and fragment into daughter ions. Subsequent mass analysis of the daughter ions yields valuable mass spectral information about the parent ion(s). Ions may also be arranged so that they enter the gas or collision cell 6 with much less energy, in which case they may not substantially fragment. The energy of ions entering the collision cell 6 can be controlled by e.g.
  • the collision cell 6 can, in effect, be considered to be switchable between a relatively high fragmentation mode and a relatively low fragmentation mode.
  • ions can be arranged to react with a gas present in the gas cell 6 to form product ions.
  • the gas cell 6 may comprise an ion tunnel ion trap similar to the upstream ion trap 2 and the ion mobility spectrometer 4 according to the preferred embodiment.
  • the gas cell 6 may comprise a plurality of electrodes having apertures therein.
  • the electrodes may take the form of rings or other annular shapes or rectangular plates.
  • the apertures are preferably all the same size or area. In other embodiments at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the electrodes have apertures which are substantially the same size or area.
  • the gas cell 6 may comprise approximately,50 electrodes. Adjacent electrodes are preferably connected to opposite phases of an AC or RF voltage supply so that ions are radially confined in use within the ion tunnel ion trap 6. According to the preferred embodiment the voltages applied to at least some of the electrodes forming the gas cell 6 can be independently controlled.
  • V-shaped DC potential profile comprises an upstream portion having a negative DC voltage gradient and a downstream portion having a positive DC voltage gradient so that (positive) ions become trapped towards the centre of the ion trap 6. If the positive DC voltage gradient maintained across the downstream portion of the ion trap 6 is then changed to a zero gradient or more preferably to a negative gradient, then (positive) ions will be accelerated out the ion trap 6 as a pulse of ions.
  • the gas cell 6 may act both as an ion trap and as a collision cell.
  • the ion tunnel ion trap/collision cell 6 may comprise a plurality of segments (e.g. 15 segments), each segment comprising four electrodes interleaved with another four electrodes. All eight electrodes in a segment are preferably maintained at the same DC voltage, but adjacent electrodes are preferably supplied with opposite phases of an AC or RF voltage supply.
  • a collision gas preferably nitrogen or argon may be supplied to the collision cell 6 at a pressure preferably of 10 -3 -10 -2 mbar. Ions may be trapped and/or fragmented in the ion trap/collision cell by appropriate setting of the DC voltages applied to the electrodes and the energy that ions are arranged to have upon entering the ion trap/collision cell 6.
  • Ion optical lenses 7 may be provided downstream of the collision cell 6 to help guide ions through a further differential pumping aperture Ap3 and into an analyser chamber containing a mass analyser.
  • the mass analyser comprises an orthogonal acceleration time of flight mass analyser 11 having a pusher and/or puller electrode 8 for injecting ions or otherwise orthogonally accelerating them into an orthogonal drift region.
  • a reflectron 9 is preferably provided for reflecting ions travelling through the orthogonal drift region back towards a detector 10.
  • at least some of the ions in a packet of ions entering an orthogonal acceleration time of flight mass analyser will be-orthogonally accelerated into the orthogonal drift region.
  • Ions will become temporally separated in the orthogonal drift region in a manner dependent upon their mass to charge ratio. Ions having a lower mass to charge ratio will travel faster in the drift region and will reach the detector 10 prior to ions having a higher mass to charge ratio. The time it takes an ion to drift-through the drift region and to reach the detector 10 can be used to accurately determine the mass to charge ratio of the ion in question. The intensity of ions and their mass to charge ratios can be used to produce a mass spectrum.
  • the downstream ion trap (gas cell) 6 may comprise a 3D-quadrupole ion trap comprising a central doughnut shaped electrode together with two endcap electrodes or a 2D ion trap.
  • the downstream ion trap 6 may comprise a hexapole ion guide.
  • this embodiment is less preferred since no axial DC voltage gradient is present to urge ions out of the hexapole ion guide. It is for this reason that an ion tunnel ion trap is particularly preferred.
  • a first mode of operation will now be described in relation to Fig. 10 .
  • the ion source can remain permanently on.
  • a single upstream ion trap 2 is used and ions from the ion source are trapped in a "V" shaped potential in the upstream ion trap 2.
  • the voltage applied across the second (downstream) half of the ion trap 2 is periodically dropped so that the "V" shaped potential is changed to a preferably linear potential gradient which causes ions to be accelerated out of the ion trap 2 and into the ion mobility spectrometer 4 which according to the preferred embodiment comprises an upstream portion 4a and a downstream portion 4b.
  • the ions become temporally separated as they pass through the ion mobility spectrometer 4.
  • the ions then pass to a quadrupole mass filter 5 which is swept across the mass scale in a synchronised manner with the ion mobility spectrometer 4.
  • a quadrupole mass filter 5 which is swept across the mass scale in a synchronised manner with the ion mobility spectrometer 4.
  • the precursor ions are then trapped and periodically released from a downstream ion trap 6 which according to the preferred embodiment is a fragmentation or collision cell 6. Due to the dispersion afforded by the ion mobility spectrometer 4, lighter ions of the selected charge state arrive in the gas cell 6 first.
  • the precursor ions are released or pulsed out of the downstream ion trap 6.
  • a predetermined period of time later the ions are orthogonally accelerated by energising a pusher electrode 8 of the oa-TOF mass analyser 11.
  • Substantially all the ions arriving at the pusher electrode 8 will be orthogonally accelerated into the drift region of the mass analyser 11.
  • This process can, if desired, be repeated a number of times (for example 4-5 packets of ions can be sent to the mass analyser 11 without changing the delay time of the pusher electrode 8 relative to the release of ions from the ion trap 6).
  • the ions arriving in the ion trap.6 will have a relatively higher average mass to charge ratio (but the spread of mass to charge ratios of the ions present in the ion trap 6 at any instance remain relatively low).
  • the delay time before the pusher electrode 8 is energised is increased so as to ensure that these ions are also orthogonally accelerated with a near 100% duty cycle.
  • the predetermined time delay of the pusher electrode 8 it is also possible to adjust the length of the extraction pulse from the ion trap 6 such that the size of the packet of ions released from the ion trap 6 exactly fills the pusher electrode 8.
  • a second mode of operation will now be described in relation to Fig. 11 .
  • the first mode of operation it was possible to mass analyse multiply charged precursor ions with a high duty cycle having removed, for example, singly charged background ions. It order to help identify the precursor ions, the precursor ions can be fragmented (or reacted) and the fragment (or product) ions mass analysed.
  • Fig. 11 shows how fragment ions are generated and accumulated from precursor ions of the chosen charge state.
  • the first stages i.e. upstream ion trap 2, ion mobility spectrometer 4 and quadrupole mass filter 5 are operated in a similar manner to the first mode of operation except that the ions exiting the quadrupole mass filter 5 are arranged to be accelerated by a collision voltage into the gas cell 6 so as to induce fragmentation in the gas cell 6.
  • the gas cell 6 is also operated as an ion trap to accumulate ions. Fragment ions are not then pulsed out of the ion trap 6 directly into the TOF mass analyser 11.
  • the fragment ions are sent back upstream of the ion trap 6.
  • a collision voltage may not be provided and precursor ions may instead be passed to the gas cell 6 to react with a gas to form product ions.
  • a second trapping stage 2b is preferably created in a downstream region of the upstream ion trap 2. This is preferably achieved by providing a "W" shaped potential profile across the ion tunnel ion trap 2. However, according to less preferred embodiments two discrete ion traps may be provided.
  • the upstream region 2a of the upstream ion trap 2 may continue to accumulate ions generated by the ion source 1.
  • the fragment (or product) ions present in the downstream ion trap 6 are accelerated out of the collision cell 6 and pass back through the quadrupole mass filter 5 and the ion mobility spectrometer 4a,4b.
  • the mass filter 5 in this mode of operation is preferably operated in a wide band pass mode so that the fragment (or product) ions are not substantially mass filtered. As such, the mass filter 5 operates as an RF-only ion guide with a high transmission for all ions.
  • the fragment (or product) ions having passed through both the mass filter 5 and the ion mobility spectrometer 4a,4b then accumulate in the downstream region 2b of the upstream ion trap 2.
  • fragment (or product) ions can be orthogonally accelerated into the mass analyser with a near 100% duty cycle.
  • the fragment (or product) ions are released from the downstream region 2b of the upstream ion trap 2 and are temporally separated in the ion mobility spectrometer 4a,4b.
  • the quadrupole mass filter 5 is preferably not swept. Rather, the mass filter 5 is preferably operated in a wide bandpass mode so as not to mass filter the fragment (or product) ions. As such, the quadrupole mass filter 5 operates in an RF-only ion guide mode.
  • temporally separated fragment (or product) ions are received and trapped in the gas cell/ion trap 6.
  • the fragment (or product) ions are then periodically released from the ion trap 6 and are orthogonally accelerated in the drift region of the TOF mass analyser 11 after a predetermined time delay by energising the pusher electrode 8.
  • the delay time can be adjusted (i.e. increased) so that the fragment (or product) ions continue to be orthogonally accelerated into the TOF mass.analysisr 11 with a near 100% duty cycle.
  • the instrument After completion of the fourth mode of operation, the instrument preferably returns to the first mode of operation and the whole cycle may be repeated as shown in Fig. 14 .
  • the accumulation of the ions in the three trapping stages means that no ions are lost whilst other experiments are being performed. It should be noted that the proportion of time spent in each of the four modes shown in Fig. 14 can be varied according to the desired experiment e.g. it may be desirable to spend a large amount of time accumulating fragment (or product) ions so as to achieve good signal to noise.
  • the AC or RF voltage supplied to the electrode(s) in either the second ion trap 2, the ion mobility spectrometer 4 or the first ion trap/gas cell 6 may be non-sinusoidal and may, for example, take the form of a square wave.
  • mass filter 5 is used instead of (or in addition to) a quadrupole mass filter 5.
  • a RF ring set or a RF ion trap may be used.

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Claims (11)

  1. Procédé de spectrométrie de masse comprenant les étapes consistant à :
    - fournir un paquet ou une impulsion d'ions ;
    - séparer temporairement au moins certains des ions dans ledit paquet ou ladite impulsion en fonction de leur mobilité ionique dans un premier dispositif (4), lequel premier dispositif comprend un séparateur à mobilité ionique ; et
    - effectuer un filtrage de masse de certains au moins desdits ions en fonction de leur rapport masse-charge dans un second dispositif (5), lequel second dispositif comprend un filtre de masse comportant un ensemble de tiges de quadrupôle ;
    caractérisé en ce que ledit procédé consiste en outre à :
    - modifier progressivement une caractéristique de filtrage de masse dudit second dispositif (5) de sorte que les ions ayant un premier état de charge soient transmis vers l'avant de manière préférentielle aux ions ayant un second état de charge différent, lequel premier état de charge comprend des ions multichargés tandis que le second état de charge comprend des ions monochargés ;
    dans lequel ledit filtre de masse à quadrupôle (5) fonctionne comme un filtre à rapport masse-charge passe-haut de manière à ne transmettre essentiellement que les ions ayant un rapport masse-charge supérieur à une valeur minimale, et dans lequel ladite étape de modification progressive de la caractéristique de filtrage de masse dudit second dispositif consiste à balayer ledit filtre de masse à quadrupôle de manière à augmenter progressivement ladite valeur minimale, le filtre de masse à quadrupôle étant balayé de manière essentiellement continue ;
    lequel procédé consiste en outre à :
    - fragmenter ou faire réagir certains au moins desdits ions ayant ledit premier état de charge en des ions-fragments ou de manière à produire des ions-produits ;
    - piéger certains au moins desdits ions-fragments ou ions-produits dans un premier piège à ions (6) ; et
    - envoyer certains au moins desdits ions-fragments ou ions-produits en amont dudit premier piège à ions (6).
  2. Procédé selon la revendication 1, dans lequel ledit premier état de charge est choisi dans le groupe comprenant : (i) des ions à charge double ; (ii) des ions à charge triple ; (iii) des ions à charge quadruple ; et (iv) des ions possédant cinq charges ou plus.
  3. Procédé de spectrométrie de masse selon la revendication 1 ou 2, dans lequel ladite étape consistant à envoyer certains au moins desdits ions-fragments ou ions-produits en amont dudit premier piège à ions (6) consiste à envoyer certains au moins desdits ions-fragments ou ions-produits à travers ledit premier dispositif (4) et/ou ledit second dispositif (5).
  4. Procédé de spectrométrie de masse selon l'une quelconque des revendications précédentes, consistant en outre à piéger certains au moins desdits ions-fragments ou ions-produits envoyés en amont dans un second piège à ions (2) en amont dudit premier dispositif (4).
  5. Procédé de spectrométrie de masse selon la revendication 4, comprenant en outre les étapes consistant à :
    - libérer des ions-fragments ou ions-produits dudit second piège à ions (2) afin d'obtenir un paquet ou une impulsion d'ions-fragments ou d'ions-produits ;
    - séparer temporairement certains au moins des ions-fragments ou ions-produits dans ledit paquet ou ladite impulsion en fonction de leur mobilité ionique dans ledit premier dispositif (4) ;
    - piéger certains ions-fragments ou ions-produits ayant une première mobilité ionique dans ledit premier piège à ions (6) ;
    - libérer un premier groupe d'ions-fragments ou d'ions-produits dudit premier piège à ions (6) et accélérer orthogonalement ledit premier groupe d'ions au bout d'un premier moment prédéfini ;
    - effectuer une analyse de masse dudit premier groupe d'ions ;
    - piéger d'autres ions-fragments ou ions-produits ayant une seconde mobilité ionique différente dans ledit premier piège à ions (6) ;
    - libérer un second groupe d'ions-fragments ou d'ions-produits dudit premier piège à ions (6) et accélérer orthogonalement ledit second groupe d'ions au bout d'un second moment prédéfini différent ; et
    - effectuer une analyse de masse dudit second groupe d'ions.
  6. Procédé de spectrométrie de masse selon la revendication 1 ou 2, comprenant en outre les étapes consistant à :
    - séparer certains au moins desdits ions-fragments ou ions-produits envoyés en amont en fonction de leur mobilité ionique dans ledit premier dispositif (4) ;
    - piéger certains desdits ions-fragments ou ions-produits séparés dans ledit premier piège à ions (6) ; et
    - synchroniser la libération desdits ions-fragments ou ions-produits dudit premier piège à ions (6) avec le fonctionnement d'une électrode (8) afin d'accélérer orthogonalement les ions de sorte qu'au moins 70%, 80% ou 90% des ions-fragments ou ions-produits libérés dudit premier piège à ions soient accélérés orthogonalement par ladite électrode.
  7. Procédé selon l'une quelconque des revendications précédentes, consistant en outre à utiliser un analyseur de masse à temps de vol et à accélération orthogonale (11).
  8. Spectromètre de masse comprenant :
    - un premier dispositif (4) pour séparer temporairement une impulsion ou un paquet d'ions en fonction de leur mobilité ionique, lequel premier dispositif comprend un spectromètre à mobilité ionique ; et
    - un second dispositif (5) afin d'effectuer un filtrage de masse de certains au moins des ions dans ledit paquet ou ladite impulsion en fonction de leur rapport masse-charge, lequel second dispositif comprend un filtre de masse comportant un ensemble de tiges de quadripôle ;
    caractérisé en ce que :
    - lors de l'utilisation, une caractéristique de filtrage de masse dudit second dispositif (5) est modifiée progressivement de sorte que les ions ayant un premier état de charge soient transmis vers l'avant de manière préférentielle aux ions ayant un second état de charge, lequel premier état de charge comprend des ions multichargés tandis que le second état de charge comprend des ions monochargés ;
    dans lequel, lors de l'utilisation, ledit filtre de masse à quadrupôle (5) fonctionne comme un filtre à rapport masse-charge passe-haut de manière à ne transmettre essentiellement que les ions ayant un rapport masse-charge supérieur à une valeur minimale, et dans lequel ledit filtre de masse à quadrupôle est balayé de manière à augmenter progressivement ladite valeur minimale, ledit filtre de masse à quadrupôle étant balayé de manière essentiellement continue ; lequel spectromètre de masse comprend en outre :
    - un premier piège à ions (6) comprenant un gaz qui permet de fragmenter les ions en ions-fragments ou qui va réagir avec les ions de manière à former des ions-produits ;
    lequel premier piège à ions (6) est conçu pour piéger certains au moins des ions-fragments ou ions-produits, et pour envoyer lesdits ions-fragments ou ions-produits en amont dudit premier piège à ions.
  9. Spectromètre de masse selon la revendication 8, dans lequel ledit premier état de charge est choisi dans le groupe comprenant : (i) des ions à charge double ; (ii) des ions à charge triple ; (iii) des ions à charge quadruple ; et (iv) des ions possédant cinq charges ou plus.
  10. Spectromètre de masse selon la revendication 8 ou 9, comprenant en outre :
    - un second piège à ions (2) en amont dudit premier dispositif (4) ; et
    - un analyseur de masse (11) comprenant une électrode (8) afin d'accélérer orthogonalement les ions ;
    dans lequel ledit second piège à ions (2) est conçu pour piéger certains au moins desdits ions-fragments ou ions-produits envoyés en amont, et pour libérer un paquet ou une impulsion d'ions-fragments ou d'ions-produits de sorte que lesdits ions-fragments ou ions-produits soient temporairement séparés en fonction de leur mobilité ionique dans ledit premier dispositif (4) ;
    dans lequel ledit premier piège à ions (6), qui est en aval dudit premier dispositif (4), est conçu pour piéger certains des ions-fragments ou ions-produits ayant une première mobilité ionique, et pour ensuite libérer un premier groupe d'ions de sorte que ledit premier groupe d'ions soit accéléré orthogonalement par ladite électrode au bout d'un premier moment prédéfini, et soit ensuite soumis à une analyse de masse par ledit analyseur de masse ; et
    dans lequel ledit premier piège à ions (6) est en outre conçu pour piéger d'autres ions-fragments ou ions-produits ayant une seconde mobilité ionique différente, et pour ensuite libérer un second groupe d'ions de sorte que ledit second groupe d'ions soit accéléré orthogonalement par ladite électrode au bout d'un second moment prédéfini différent, et soit ensuite soumis à une analyse de masse par ledit analyseur de masse (11).
  11. Spectromètre de masse selon la revendication 8 ou 9, dans lequel
    - ledit premier dispositif (4) est en outre conçu pour séparer certains au moins desdits ions-fragments ou ions-produits envoyés en amont en fonction de leur mobilité ionique ; et
    - ledit premier piège à ions (6) est en outre conçu pour piéger certains desdits ions-fragments ou ions-produits séparés, et pour libérer les ions-fragments ou ions-produits en synchronisation avec le fonctionnement d'une électrode (8) afin d'accélérer orthogonalement les ions de sorte qu'au moins 70%, 80% ou 90% des ions-fragments ou ions-produits libérés dudit piège à ions soient accélérés orthogonalement par ladite électrode.
EP08013533A 2002-05-17 2002-10-14 Spectromètre de masse Expired - Lifetime EP2001039B1 (fr)

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GBGB0211373.6A GB0211373D0 (en) 2002-05-17 2002-05-17 Mass spectrometer
GBGB0212641.5A GB0212641D0 (en) 2002-05-17 2002-05-31 Mass spectrometer
GB0222055A GB2389704B (en) 2002-05-17 2002-09-23 Mass Spectrometer
EP02257117A EP1365438B1 (fr) 2002-05-17 2002-10-14 Spectromètre de masse comprenant un spectromètre à mobilité ionique et un filtre de masse

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EP3286557B1 (fr) * 2015-04-23 2021-09-01 Micromass UK Limited Séparation d'ions dans un piège à ions
US10832897B2 (en) 2018-10-19 2020-11-10 Thermo Finnigan Llc Methods and devices for high-throughput data independent analysis for mass spectrometry using parallel arrays of cells
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CA2407957A1 (fr) 2003-11-17
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EP1365438A3 (fr) 2006-04-12
GB2390478B (en) 2004-06-02
GB2390478A (en) 2004-01-07
EP1365438B1 (fr) 2010-09-08
GB0321698D0 (en) 2003-10-15
EP1365438A2 (fr) 2003-11-26

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