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WO2025083550A1 - Spectromètre de masse à temps de vol - Google Patents

Spectromètre de masse à temps de vol Download PDF

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Publication number
WO2025083550A1
WO2025083550A1 PCT/IB2024/060100 IB2024060100W WO2025083550A1 WO 2025083550 A1 WO2025083550 A1 WO 2025083550A1 IB 2024060100 W IB2024060100 W IB 2024060100W WO 2025083550 A1 WO2025083550 A1 WO 2025083550A1
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Prior art keywords
ion
field
mass analyzer
region
ions
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Robert HAUFLER
Aaron BOOY
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DH Technologies Development Pte Ltd
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DH Technologies Development Pte Ltd
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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
    • H01J49/40—Time-of-flight spectrometers
    • H01J49/401—Time-of-flight spectrometers characterised by orthogonal acceleration, e.g. focusing or selecting the ions, pusher electrode
    • 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
    • H01J49/40—Time-of-flight spectrometers
    • H01J49/403—Time-of-flight spectrometers characterised by the acceleration optics and/or the extraction fields

Definitions

  • the present disclosure relates generally to systems and methods for performing mass spectrometry, and more particularly to such systems and methods that utilize time-of-flight (ToF) mass analyzers.
  • ToF time-of-flight
  • the present disclosure provides systems and methods for performing mass spectrometry, and particularly such systems and methods that allow faster data acquisition with adequate mass resolution.
  • Mass spectrometry is an analytical technique for determining the structure of test chemical substances with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the composition of atomic elements in a molecule, determining the structure of a compound by observing its fragmentation, and quantifying the amount of a particular chemical compound in a mixed sample. Mass spectrometers detect chemical entities as ions such that a conversion of the analytes to charged ions must occur.
  • Time-of-flight mass spectrometry relies on different detection times to separate ions having different m/z ratios.
  • the mass analyzer accelerates ions via their passage through a region in which an electric field imparts kinetic energy to the ions.
  • the accelerated ions enter a field-free ion drift region in which they travel to reach an ion detector that detects the ions.
  • the time required for the ions to pass through the drift region to reach the detector depends on their m/z ratios, thereby allowing the ions to be separated based on their m/z ratios.
  • the longer the time required for the ions to pass through the drift region to reach the ion detector the higher is the resolution of the mass measurements.
  • the longer time for each measurement translates into acquisition of fewer mass spectra per unit time, e.g., fewer mass spectra per second. In other words, a higher mass resolution can lead to a lower duty cycle.
  • a time-of-flight (TOF) mass analyzer which includes an inlet for receiving ions, a first ion acceleration region in which at least a portion of the received ions is accelerated to a first energy, a first field-free ion drift region positioned downstream of the first ion acceleration region for receiving the accelerated ions, a second ion acceleration region that is positioned downstream of the first field-free ion drift region for receiving ions exiting the first field-free ion drift region and accelerating the ions to a second energy, a second field-free ion drift region positioned downstream of the second ion acceleration region for receiving the ions exiting the second ion acceleration region, and an ion detector for receiving ions passing through the second field-free ion drift region and generating ion detection data.
  • TOF time-of-flight
  • the TOF mass analyzer can include a first pair of electrodes across which a first voltage differential (VI) is applied to generate an electric field (El) in the first ion acceleration region. Further, the TOF mass analyzer can include a second pair of electrodes across which a second voltage differential (V3) is applied to generate an electric field (E2) in the second ion acceleration region. Further, the voltages applied to at least one of the electrodes of the first pair and at least one of the electrodes of the second pair are selected to result in a vanishing electric field in the first field-free ion drift region. In other words, no electric field is present in the first field-free ion drift region. Similarly, no electric field is present in the second field-free ion drift region.
  • an electric field may be present in any of the first and the second field-free ion drift region, but at such a low level that it would not cause any substantial change in the trajectories of ions passing through those field-free ion drift regions.
  • the magnitude of such an electric field can be less than about lOV/mm.
  • the TOF mass analyzer exhibits a mass resolution of at least about 3000.
  • the mass resolution exhibited by the TOF mass analyzer can be in a range of about 3000 to about 20,000.
  • the first voltage differential (VI) can be in a range of about 500 volts to about 3000 volts.
  • the second voltage differential (V3) can be in a range of about 100 volts to about 20 kilovolts.
  • the mass analyzer can have an effective length equal to or less than about 2 meters.
  • the effective length of the mass analyzer can be in a range of about 200 mm to about 2 meters.
  • the first acceleration region can have an effective length ( ⁇ 7/) such that the first voltage differential (VI) generates an electric field having a magnitude in a range of about lOV/mm to about 250V/mm in the first ion acceleration region.
  • the direction of the electric field in each of the ion acceleration regions is along a longitudinal axis of the linear TOF mass analyzer, e.g., along a direction that is orthogonal to the surface of the deflector electrode.
  • the second voltage differential (V3) can be in a range of about 100 volts to about 20,000 volts (20 kV).
  • the second ion acceleration region can have a length (d3) such that the second voltage differential (V3) generates an electric field in a range of about lOOV/mm to 850V/mm in the second ion acceleration region.
  • the mass analyzer can include at least one voltage source for applying any of said first and second voltage differentials to the first pair and the second pair of electrodes, respectively.
  • the at least one voltage source can be configured to apply the first voltage as a DC voltage on which a plurality of temporally separate voltage pulses is superimposed.
  • the voltage pulses can be applied at a frequency in a range of about 1000 Hz to about 200 kHz, by way of example.
  • Such voltage pulses can periodically direct ions (or at least a portion of ions) entering the mass analyzer into the first acceleration region.
  • an effective length ( ⁇ 72) of the first field-free ion drift region and an effective length (d-l) of the second field-free ion drift region satisfy the following relations concurrently: wherein, dl denotes a length of the first ion acceleration region, dl denotes a length of the first field-free ion drift region, d3 denotes a length of the second ion acceleration region, d4 denotes a length of the second field-free ion drift region,
  • E/ denotes the voltage across the first ion acceleration region
  • V3 denotes the voltage across the second ion acceleration region, and wherein, d2 and d4 have real (non-imaginary) and positive values.
  • a length ( ⁇ 72) of the first field-free ion drift region and alength ( ⁇ 77) of the second field-free ion drift region can be defined in terms of the magnitudes of the electric fields in the first and the second ion acceleration regions as well as the lengths of the ion acceleration regions.
  • the lengths ( ⁇ 72) and d4) can satisfy the following relations concurrently: wherein, dl denotes a length of the first ion acceleration region, d2 denotes a length of the first field-free ion drift region, d3 denotes a length of the second ion acceleration region, d4 denotes a length of the second field-free ion drift region,
  • El denotes a magnitude of an electric field established across the first ion acceleration region
  • E3 denotes a magnitude of an electric field established across the second ion acceleration region, wherein, d2 and d4 have real (non-imaginary) and positive values.
  • the first ion acceleration region can have a length in a range of about 2 mm to about 25 mm.
  • the first field-free ion drift region can have a length in a range of about 0.5 mm to about 20 mm
  • the second ion acceleration region can have a length in a range of about 0.5 mm to about 20 mm
  • the second field-free ion drift region can have a length in a range of about 200 mm to about 2 meters.
  • a linear time-of-fight (TOF) mass analyzer which includes an inlet for receiving ions, at least two ion acceleration regions, at least two field- free ion drift regions, and an ion detector.
  • One of the field-free ion drift regions is positioned between the two ion acceleration regions and another one of the field-free ion drift regions is positioned between one of the acceleration regions and the ion detector.
  • the TOF mass analyzer can provide a mass resolution of at least about 3000, e.g., in a range of about 3000 to about 20,000.
  • the field-free ion drift region that is positioned between one of the ion acceleration regions and the ion detector can have a length that is equal to or less than about 2 meters.
  • a combined length associated with the at least two ion acceleration regions and the at least two field- free ion drift regions is equal to or less than about 2 meters, e.g., in a range of about 200 mm to about 2 meters.
  • the TOF mass analyzer can include a first pair of electrodes across which a first differential voltage can be applied to generate one of the at least two ion acceleration regions and a second pair of electrodes across which a second differential voltage can be applied to generate another one of the at least two ion acceleration regions.
  • a mass spectrometer which includes a mass filter for receiving a plurality of ions and allowing passage of ions having m/z ratios within a bandpass window thereof, an ion dissociation device for receiving the ions passing through the mass filter and causing dissociation of at least a portion thereof to generate a plurality of product ions, and a linear time-of-flight (TOF) mass analyzer positioned downstream of the ion dissociation device for receiving the product ions and having an ion detector for detecting at least a portion of the product ions to generate ion detection data.
  • TOF linear time-of-flight
  • the TOF mass analyzer can include a first and a second ion acceleration region, and a first and a second field-free ion drift regions, wherein the first field-free ion drift region is positioned between the first and the second ion acceleration regions and the second field-free ion drift region is positioned between the second ion acceleration region and the detector of the TOF mass analyzer.
  • the mass spectrometer can further include an RF voltage source and a DC voltage source for applying RF and DC voltages to the mass filter for adjusting the bandpass window of the mass filter.
  • the mass spectrometer can further include a controller for controlling the DC and RF voltage sources.
  • the controller can be configured to send control signals to the DC and RF voltage sources for adjusting the bandpass window of the mass filter so as to operate the mass spectrometer in a data independent acquisition (DIA) mode.
  • DIA data independent acquisition
  • the mass spectrometer can further include a data processing module that is configured to receive ion detection data generated by the ion detector of the TOF mass analyzer and process the ion detection data to generate a mass spectrum of the product ions.
  • FIG. 1A schematically depicts various steps in an embodiment of a method according to the present teachings for performing mass spectrometry
  • FIG. IB is a schematic view of a ToF mass analyzer according to an embodiment of the present teachings.
  • FIG. 1C is a schematic view of another implementation of the ToF mass analyzer illustrated in FIG. IB,
  • FIG. ID schematically depicts an example of implementation of a ToF mass analyzer according to an embodiment of the present teachings
  • FIG. IE is a partial expanded view of the ToF mass analyzer for better illustration of grid electrodes employed therein.
  • FIG. 2 shows a simulated mass resolution as a function of the ion path length associated with the last field-free ion drift region in an embodiment of a ToF mass analyzer according to the present teachings
  • FIG. 3 shows the expected potential difference in the first acceleration region as a function of the length of the second field-free region, in a simulated implementation of the mass analyzer according to an embodiment of the present teachings
  • FIG. 4 schematically depicts a mass spectrometer according to an embodiment of the present teachings
  • FIG. 5 shows a simulated mass peak for an ion with an m/z of 829.5 generated using a simulated ToF mass analyzer according to an embodiment where the liner had a length of 200mm,
  • FIG. 6 shows another simulated peak for the ion with an m/z of 829.5 generated using a simulated ToF mass analyzer according to another embodiment where the liner had a length of 500 mm,
  • FIG. 7B shows a narrower mass range of the spectrum depicted in FIG. 7A, and the isotopic peaks of the ALILTLVS peptide (m/z 829.539 amu) are displayed.
  • FIG. 8A shows a mass spectrum of a set of ions having a range of m/z from 118 amu to 829.5 amu acquired using a mass spectrometer having a TOF mass analyzer according to another embodiment, which had a second field- free region with a of 500 mm,
  • FIG. 8B shows isotopic peaks of the ALILTLVS peptide
  • FIG. 9 presents theoretical ion utilization data for three types of TOF mass analyzers.
  • the terms “about” and “substantially equal” refer to variations in a numerical quantity that can occur, for example, through measuring or handling procedures in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of compositions or reagents; and the like.
  • the terms “about” and “substantially” as used herein means 10% greater or less than the value or range of values stated or the complete condition or state. For instance, a concentration value of about 30% or substantially equal to 30% can mean a concentration between 27% and 33%.
  • the terms also refer to variations that would be recognized by one skilled in the art as being equivalent so long as such variations do not encompass known values practiced by the prior art.
  • mass resolution refers to a measure of the ability of a mass spectrometer to distinguish between ions of different mass-to-charge ratios (m/z) having very similar masses.
  • mass resolution can be expressed as a ratio (R) defined by the following relation:
  • R represents the mass resolution, in represents the mass of the ion of interest, and /?/ represents the minimum difference in mass that can be detected or resolved by the mass spectrometer.
  • sensitivity in the context of an analytical device, including a mass spectrometer, refers to the ability of the device to detect small changes or variations in the quantity or concentration of an analyte in a sample under analysis.
  • sensitivity can be defined as the ratio of the change in the device’s response (e.g., a detection signal generated by the device) to a corresponding change in the quantity or concentration of the analyte being measured.
  • the sensitivity can be determined by the limit-of-detection (LoD) of the analytical device, which is based on the minimum amount of an analyte that is detectable (identifiable) by the device.
  • LiD limit-of-detection
  • a measurement cycle in the context of an analytical device, refers to a series of steps or processes that the device follows to generate analytical data for a sample (or sample portion) introduced into the device.
  • a measurement cycle can include the introduction of an eluate exiting the LC column to an ion source to generate precursor ions, the passage of the precursor ions through a mass filter to select precursor ion(s) of interest, the dissociation of the selected precursor ions to generate product ions and using a mass analyzer (e.g., a TOF mass analyzer) to generate ion detection signals corresponding to the product ions.
  • the “measurement cycle time” refers to the time required for the device to perform a measurement cycle.
  • measurement cycle frequency and “cycle frequency,” are used interchangeably to refer to the number of measurement cycles that are performed per unit time (e.g., the number of measurement cycles per second).
  • duty cycle is the ratio of the number of ions detected to the total number of ions injected into the time-of-flight mass analyzer. “Duty-cycle” is mass dependent in time- of-flight mass spectrometry. The lower mass-to-charge ions will have a lower duty cycle. Some high mass-to-charge ions can have a duty cycle of 100%.
  • a physical path length of the mass analyzer can be measured as the physical distance between the ion start location, e.g., the position of the deflector electrode, and the ion detector.
  • an effective length associated with the final field-free ion drift region e.g., the second field-free ion drift region in various embodiments discussed herein, where the effective path length can be computed by multiplying the ion flight time by ion velocity within the final field-free ion drift region.
  • an effective length may be used as a metric for comparing TOF mass analyzer that include ion mirrors.
  • field-free indicates that no electric field is present in a region or any electric field that may be present is not sufficiently strong to cause any substantial change in the trajectory of ions passing through the field-free region.
  • any electric field that may be present in the field- free region would have a magnitude less than about lOV/mm.
  • the present disclosure provides systems and methods for performing high-resolution mass spectrometry that can acquire spectra at a high rate, e.g., at a rate of at least about 1000 spectra per second (e.g., in a range of about 1000 to about 100,000 spectra per second), at an acceptable level of mass resolution (e.g., 10,000).
  • a high rate e.g., at a rate of at least about 1000 spectra per second (e.g., in a range of about 1000 to about 100,000 spectra per second), at an acceptable level of mass resolution (e.g., 10,000).
  • a time-of-flight (TOF) mass analyzer that includes at least two acceleration regions and at least two field-free ion drift regions that are disposed relative to one another such that ions received by the TOF mass analyzer pass alternatively through an ion acceleration region and a field-free ion drift region to reach an ion detector after passage through the final field-free ion drift region.
  • TOF mass analyzers according to the present teachings are linear mass analyzers that do not include any ion mirrors.
  • FIG. 1A is a flow chart depicting various steps of a method according to an embodiment for performing mass spectrometry, in which a plurality of ions is introduced into a time-of-flight (ToF) mass analyzer.
  • the ions are accelerated in a first ion acceleration region of the ToF mass analyzer to achieve a first kinetic energy.
  • the accelerated ions are then introduced into a first field-free ion drift region.
  • the ions are accelerated in a second ion acceleration region to achieve a second kinetic energy. Subsequently, the ions are introduced into a second field-free ion drift region.
  • the ions After passage through the second field-free ion drift region, the ions are detected via an ion detector of the mass analyzer, which generates ion detection data.
  • the ion detection data can be processed to generate a mass spectrum of the ions.
  • the lengths of the ion acceleration regions and the field-free ion drift regions are selected so as to achieve a desired mass resolution while allowing fast acquisition of ion detection data.
  • FIG. IB schematically depicts a linear ToF mass analyzer 100 according to an embodiment of the present teachings, which includes an inlet 101 for receiving a plurality of ions propagating along a transverse axis (TA) and a deflector electrode 102 to which voltage pulses can be applied.
  • Each voltage pulse can cause the deflection of a portion of ions arrived at the TOF mass analyzer into an orthogonal direction along a longitudinal axis (LA) into a first ion acceleration region 104 established between the deflector electrode 102 and a downstream grid electrode 106.
  • a voltage differential (VI) applied via a pulsed voltage source 105 operating under control of a controller 107 between the deflector electrode 102 and the downstream grid electrode 106 can generate an electric field El in the region between the deflector electrode 102 and the grid electrode 106, thereby establishing a first ion acceleration region 104 in which ions can be accelerated under the influence of the electric field El to a first kinetic energy (KE1).
  • VI voltage differential
  • the linear TOF mass analyzer 100 further includes another grid electrode 110 that is positioned downstream from the grid electrode 106 and is held at the same electrical potential as the grid electrode 106 (in this embodiment, both grid electrodes 106 and 110 are maintained at the ground electric potential) so as to establish a first field-free ion drift region 108 between the two grid electrodes 106 and 110.
  • a first field-free ion drift region 108 between the two grid electrodes 106 and 110.
  • ions having the same electric charge, but different masses undergo some degree of spatial separation before exiting the first field- free ion drift region.
  • KE1 kinetic energy
  • the ions exiting the field-free drift region 108 enter the second ion acceleration region 112 established between the grid electrodes 110 and 114 and are accelerated under the influence of the electric field in this region to achieve a kinetic energy KE2, which is greater than the kinetic energy KE1.
  • the linear TOF mass analyzer further includes a second field-free ion drift region 116 that is positioned downstream of the second ion acceleration region 112 and is enclosed within a shell 117 (herein also referred to as a liner) that is maintained at the same electric potential as the grid electrode 114. More specifically, the second field- free ion drift region 116 extends from the grid electrode 114 to an ion detector 118 that can detect ions passing through the second field- free ion drift region 116 and generate ion detection data.
  • a shell 117 herein also referred to as a liner
  • the ion detection data can in turn be received by a digital data processing module 120 (herein also referred to as the computer data system) that can operate on the ion detection data to generate a mass spectrum associated with the ions detected by the mass analyzer.
  • a digital data processing module 120 herein also referred to as the computer data system
  • FIG. 1C schematically depicts another implementation of the ToF mass analyzer 100 (herein referred to as ToF mass analyzer 100’) in which the grid electrodes 106/110, which are electrically connected, are in electrical communication with a pulsed voltage source 105’a (herein also referred to as the primary pulser) and the deflector electrode 102 is in electrical communication with a pulsed voltage source 105’ b (herein also referred to as the floated pulser) such that electric field pulses can be generated within the first ion acceleration region while the region between the grid electrodes 106/108 remains field-free. Further, in this implementation, the liner 117 is maintained at the electric ground.
  • a pulsed voltage source 105’a herein also referred to as the primary pulser
  • the deflector electrode 102 is in electrical communication with a pulsed voltage source 105’ b (herein also referred to as the floated pulser) such that electric field pulses can be generated within the first ion acceleration region while the region between the grid electrode
  • an ion detector 118 receives the ions passing through the second field-free ion drift region and generates ion detection data (herein also referred to as ion detection signals) in response to the detection of the ions.
  • the ion detection data can be analyzed via a computer data system 120 to generate a mass spectrum of the ions.
  • the first ion acceleration region ( ⁇ 77) of the ToF mass analyzer 200 includes a pulser electrode 202, e.g., in the form of a solid conductive planar element, for deflecting the ions received by the ToF mass analyzer in an orthogonal direction and a pair of stacked electrodes 204, 206, e.g., in the form of solid conductive planar elements having central openings through which ions can pass.
  • Various voltages can be applied to electrodes 204 and 206 to establish a desired electric field within the first acceleration region ( ⁇ 77).
  • a plurality of spacers 203a and 203b separate, respectively, the electrodes 202/204 and 204/206 from one another.
  • the thickness of the spacers can be chosen to achieve a desired length of the first acceleration region ( ⁇ 77).
  • the mass analyzer 200 further includes a second ion acceleration region ( ⁇ 73) and a first field-free ion drift region ( ⁇ 72) that separates the first and the second ion acceleration regions.
  • the second ion acceleration region ( ⁇ 73) includes electrically conductive electrodes 208, 210, 212, 214, 216, 218 and 220, for example, each in the form of a planar surface having a central opening through which ions can pass, which are stacked relative to one another and are pairwise separated via a plurality of electrically insulating separators 207, 209, 211, and 213. Voltages applied to the electrically conductive electrodes can establish an electric field within the second ion acceleration region.
  • the thickness of the insulating separators can be selected to achieve a desired effective length for the second ion acceleration region.
  • two grid electrodes 300 and 302 are in electrical contact with electrodes 206 and 208, respectively. These grid electrodes provide openings through which ions can pass. To establish the field-free ion drift region, the electrodes 206 and 208 and the respective grid electrodes 300 and 302 are maintained at the same voltage. In various embodiments, the grid electrodes can facilitate the formation of sharp transitions in the magnitude of the electric field between the ion acceleration regions and the adjacent field-free ion drift regions.
  • a second field-free ion drift region (d4) extends from the second ion acceleration region (d3) to an ion detector 118.
  • the ions exiting the second ion acceleration region (d3) pass through a grid electrode 304 to propagate through the final field-free ion drift region to reach the ion detector 118.
  • the voltage applied to the grid electrode positioned between the second ion acceleration region (d3) and the second field-free ion drift region (d4) is the same as the voltage applied to the liner of the second field-free ion drift region and in various embodiments, it can create a distinct and sharp transition between the second ion acceleration region and the second field-free ion drift region.
  • the second field-free ion drift region is surrounded by a liner, which can be maintained, for example, at the ground electric potential or at a floated voltage.
  • the flight time (FT) of an ion having a mass-to-charge ratio denoted by m/z through the mass analyzer can be obtained using the following relation:
  • dl denotes the length of the first ion acceleration region
  • d2 denotes the length of the first field- free ion drift region
  • d3 denotes the length of the second ion acceleration region
  • d4 denotes the length of the second field- free ion drift region
  • VI denotes the voltage applied across the first ion acceleration region
  • V3 denotes the voltage applied across the second ion acceleration region.
  • the values of the ion path length associated with the first ion acceleration region, namely, (dl), and the ion path length associated with the second ion acceleration region, namely, (d3), as well as the voltages VI and V3 to be applied across the first and the second ion acceleration regions can be obtained using the above relations, which are derived by solving for (d2) and (d4) in the above Eqs. (3) and (4).
  • the dimensions of various regions of the mass analyzer 100 can be determined by selecting the dimensions of two regions of the mass analyzer and the voltages applied across the two ion acceleration regions and using in the above relations.
  • the ion path length through the mass analyzer i.e., the path length of an ion from the deflector electrode 102 to the ion detector 118
  • the voltages applied across the two ion acceleration regions can be chosen to obtain a desired resolution
  • the rate of the pulser i.e., the rate at which voltages are applied to the deflector electrode
  • the choice of the dl-d4 lengths and the voltages can affect the overall resolution and the limits of the maximum pulser frequency that can be utilized, but it does not directly change the pulser frequency.
  • the acquisition rate be changed. More generally, by selecting the values of four of the above parameters, the values for the other two parameters can be derived from the above relations (Eqs. (3) and (4)).
  • FIG. 2 shows a simulated mass resolution as a function of the ion path length associated with the last field-free ion drift region in the above mass analyzer 100.
  • the mass resolution data shows an increasing mass resolution as the length of the last field-free ion drift region increases, albeit at a decreasing rate of change.
  • the m/z of the ion employed for the simulation was 829.5 amu.
  • Table 1 below provides the voltages applied across the first and the second ion acceleration regions as well as the lengths of the ion acceleration and the field-free ion drift regions together with the resultant simulated mass resolutions and time-of-flight of the ions through TOF mass analyzer.
  • FIG. 3 shows the expected potential difference in the first acceleration region as a function of the length of the second field-free region of the mass analyzer 100 in which the above values for the other parameters were employed.
  • the trend shown in FIG. 3 illustrates that an optimized analyzer, as defined by the solutions for d2 and d4. will require a vanishingly small potential difference in the first acceleration region, as the length of the second field-free region is increased beyond a certain threshold.
  • FIG. 4 schematically depicts such an LC-MS spectrometric system 400 that includes a liquid chromatography (LC) column (not shown in the figure) that can receive a sample and an ion source (not shown in the figure) that is in communication with the LC column to receive an eluate exiting the LC column.
  • LC liquid chromatography
  • the ion source can ionize one or more analytes within the received eluate to generate a plurality of ions that can be received by an ion guide Q Jet via an orifice 402 of the mass spectrometer, where the Q Jet ion guide includes a set of rods 401 arranged in a quadrupole configuration, two of which 401a/401b are visible in the figure, and employs a combination of gas dynamics and radio frequency fields to cause focusing of the ions.
  • the ions exiting the QJet ion guide are focused by an ion lens IQ0 into an ion guide Q0, which includes a set of quadrupole rods 404, two of which 404a/404b are visible in the figure, to which RF voltages can be applied for causing radial confinement of the ions and generate an ion beam that is in turn received by an ion mass filter QI.
  • the ion guides QJet, Q0, and the mass filter QI are disposed in differentially-pumped chambers that are maintained at progressively lower pressures.
  • An ion lens IQ1 focuses the ions exiting the Q0 ion guide into the mass filter QI.
  • the mass filter QI includes a stubby lens 406 formed by a set of quadrupole rods (two of which 406a/406b are visible in the figure) to which RF voltages can be applied to cause focusing of the ions.
  • the mass filter QI further includes a set of quadrupole rods 410, two of which 410a/410b are visible in the figure, to which a combination of RF and DC voltages can be applied to allow the selection of one or more precursor ions, e.g., all precursor ions of interest when the mass spectrometer is operating in a DIA mode, having m/z ratios within a target m/z range for transmission to a downstream ion dissociation device Q2, e.g., a collision cell in this example via an ion lens IQ2
  • a DC voltage source 426 and an RF voltage source 428 operating under control of a controller 430 can apply RF and DC voltages to the mass filter QI in a manner known in the art and as informed by the present teachings to configure the bandpass window of mass filter.
  • the RF voltage applied to the rods of the QI mass filter can have a frequency in a range of about 200 kHz to about 12 MHz and a peak-to- peak amplitude (V pp ) in a range of about 100 volts to about 10 kilovolts (kV).
  • the collision cell Q2 includes a set of rods 417, two of which 417a/417b are visible in the figure, which are arranged in a quadrupole configuration and is pressurized via introduction of nitrogen gas to allow collisional fragmentation of the ions received by the collision cell Q2.
  • the RF frequency applied to the rods of the Q2 collision cell can be, for example, in a range of about 1 MHz to about 5 MHz.
  • the Q2 cell can be employed for collisional focusing, where higher RF frequencies, e.g., 5 MHz, can be employed.
  • the ions exiting the Q2 cell are focused by a set of ion focusing optics 415 into a time-of-flight (TOF) mass analyzer 418 according to various embodiments of the present teachings, such as the TOF mass analyzer 100 discussed above.
  • the mass analyzer 418 includes an ion detector 420, which generates ion detection data in response to the detection of ions incident thereon.
  • the ion detection signals generated by the ion detector can be processed using a data processing module 425 to generate the mass spectrum of the product ions.
  • a TOF mass analyzer can provide distinct advantages. As noted above, it can allow acquiring mass data at a high rate with high sensitivity. Further, it provides a much simpler geometry compared to TOF mass analyzers that utilize ion mirrors for extending the ion path length with subsequent increases in the focus of the ions. In various embodiments, the duty cycle can be sufficiently high so as to eliminate the need for using an ion trap upstream of the TOF mass analyzer. [0078] The following examples are provided for further elucidation of various aspects of the present teachings and are not provided to indicate necessarily optimal ways of practicing the present teachings and/or optimal results that can be obtained.
  • the m/z ratio of the ion was 829.5 amu.
  • the simulated mass peak depicted in FIG. 5 exhibits a mass resolution of about 6800.
  • the simulated flight time of the ion through the mass analyzer was 6.8 microseconds.
  • a lens was used to manipulate and prepare the ions for injection into the TOF accelerator. This lens was adjusted to minimize the base peak width to mid peak width ratio (5% peak height/50% peak height).
  • the peak shown was the result of simulating about 1 million different ion trajectories through the collision cell, transfer optics, and TOF analyzer.
  • the simulated data shows that even at an ion flight time of less than 7 ps (which corresponds to a measurement cycle frequency of more than 140 kHz), the computed mass resolution is greater than a typical mass resolution exhibited by a quadrupole mass filter.
  • the cycle frequency is greater than a cycle frequency that can be achieved via any TOF mass analyzer having an ion mirror (it is higher by a factor of about lOx).
  • the simulated mass peak depicted in FIG. 6 exhibits a greater mass resolution in comparison with the simulated mass peak depicted in FIG. 5, but at a longer flight time.
  • the measurement cycle frequency for this analyzer was computed to be about 76 kHz. Similar to the previous example, the FOR lens was chosen to minimize the width ratio.
  • FIG. 7A shows an MS mass spectrum of an ion mixture covering masses between 100 and 1000 m/z obtained using a mass spectrometer with a TOF mass analyzer according to an embodiment of the present teachings. More specifically, the TOF mass analyzer included two ion acceleration regions separated by a field-free ion drift region. A second field-free ion drift region extended from the second ion acceleration region to an ion detector. The length of the second field- free ion drift region was 1000 mm and the data was acquired at 30 kHz.
  • FIG. 8A shows an MS mass spectrum of an ion mixture covering masses between 100 and 1000 m/z obtained using a mass spectrometer with a TOF mass analyzer according to an embodiment of the present teachings. More specifically, the TOF mass analyzer included two ion acceleration regions separated by a field-free ion drift region. A second field-free ion drift region extended from the second ion acceleration region to an ion detector. The length of the second field-free ion drift region was 500 mm and the data was acquired at 45kHz.
  • FIG. 9 provides theoretical ion utilization (duty cycle) for each of three types of TOF mass analyzers, based on certain operating voltage values and the analyzer’s dimensions, as a function of different m/z ratios in a range of about 50 to 1000. More specifically, FIG. 9 provides the duty cycle exhibited by a linear TOF mass analyzer (LTOF), a TOF mass analyzer having a single ion mirror (VTOF), and a TOF mass analyzer having two ion mirrors (NTOF).
  • LTOF linear TOF mass analyzer
  • VTOF TOF mass analyzer having a single ion mirror
  • NTOF TOF mass analyzer having two ion mirrors
  • a comparison of the pairwise ratios of the duty cycles at different masses shows these ratios to be constant, i.e., the ratios are independent of the mass-to-charge ratio.
  • the ratio of the duty cycle of the LTOF mass analyzer relative to that of the VTOF mass analyzer is about 4.3 irrespective of the mass-to-charge ratio
  • the respective ratio of the duty cycle of the LTOF mass analyzer to that of the NTOF mass analyzer is about 7.6.
  • the term "and/or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as "/".
  • a block or device corresponds to a method step or a feature of a method step.
  • aspects described in the context of a method step also represent description of a corresponding block or item or feature of a corresponding apparatus.
  • Some or all of the method steps may be executed by (or using) a hardware apparatus, like for example, a processor, a microprocessor, a programmable computer or an electronic circuit. In some embodiments, some one or more of the most important method steps may be executed by such an apparatus.
  • embodiments of the invention can be implemented in hardware and/or in software.
  • the implementation can be performed using a non- transitory storage medium such as a digital storage medium, for example a floppy disc, a DVD, a Blu-Ray, a CD, a ROM, a PROM, and EPROM, an EEPROM or a FLASH memory, having electronically readable control signals stored thereon, which cooperate (or are capable of cooperating) with a programmable computer system such that the respective method is performed. Therefore, the digital storage medium may be computer readable.

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Abstract

Selon un aspect, l'invention concerne un analyseur de masse à temps de vol (TOF), qui comprend une entrée pour recevoir des ions, une première région d'accélération d'ions dans laquelle au moins une partie des ions reçus est accélérée jusqu'à une première énergie, une première région de dérive d'ions sans champ positionnée en aval de la première région d'accélération d'ions pour recevoir les ions accélérés, une seconde région d'accélération d'ions positionnée en aval de la première région de dérive d'ions sans champ pour recevoir des ions sortant de la première région de dérive d'ions sans champ et accélérer les ions jusqu'à une seconde énergie, une seconde région de dérive d'ions sans champ positionnée en aval de la seconde région d'accélération d'ions pour recevoir les ions sortant de la seconde région d'accélération d'ions et un détecteur d'ions pour recevoir des ions passant à travers la seconde région de dérive d'ions sans champ et générer des données de détection d'ions. Les données de détection d'ions peuvent être analysées pour générer un spectre de masse des ions détectés.
PCT/IB2024/060100 2023-10-16 2024-10-15 Spectromètre de masse à temps de vol Pending WO2025083550A1 (fr)

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US20150014522A1 (en) * 2011-12-23 2015-01-15 Dh Technologies Development Pte. Ltd. First and second order focusing using field free regions in time-of-flight

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150014522A1 (en) * 2011-12-23 2015-01-15 Dh Technologies Development Pte. Ltd. First and second order focusing using field free regions in time-of-flight

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