The present teachings are generally related to methods and systems for efficient transfer of ions having a range of m/z ratios into an ion trap, e.g., a linear ion trap (LIT), in a mass spectrometer.
Mass spectrometry (MS) is an analytical technique for measuring mass-to-charge ratios of molecules, with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the structure of a particular compound by observing its fragmentation, and quantifying the amount of a particular compound in a sample. Mass spectrometers detect chemical entities as ions such that a conversion of the analytes to charged ions must occur during sample processing.
In tandem mass spectrometry (MS/MS), ions generated from an ion source can be mass selected in a first stage of mass spectrometry (precursor ions), and the precursor ions can be fragmented in a second stage to generate product ions. The product ions can then be detected and analyzed.
In some cases, precursor ions selected by an upstream mass filter can be introduced into an RF ion trap functioning as a collision cell in which they undergo fragmentation. The fragmented ions can then be received by a downstream LIT and released according to their m/z ratios, e.g., via mass selective axial ejection (MSAE), to be detected by a downstream detector.
Conventional linear ion traps can, however, exhibit poor trapping efficiency for large m/z ions at low applied RF voltage(s), due to low effective trapping potential. Increasing the applied RF voltage(s) can increase the trapping efficiency of large m/z ions but could adversely affect the trapping of low m/z ions because at higher applied RF voltage(s) the motion of the low m/z ions can become unstable. As a result, the mass range of linear ion traps is typically parsed using separate sample runs and pieced back together to be able to process ions having a wide range of m/z ratios. Such parsing of the mass range can, however, decrease the duty cycle and sensitivity.
Accordingly, there is a need for improved linear ion traps for use in mass spectrometry.
In one aspect, a method of processing ions in a mass spectrometer is disclosed, which comprises trapping a plurality of ions having different mass-to-charge (m/z) ratios in a collision cell, releasing said ions from the collision cell in a descending order in m/z ratio, and receiving the ions in a mass analyzer having a plurality of rods to at least one of which an RF (radiofrequency) voltage is applied, where the RF voltage is varied from a first value to a lower second value as the released ions are received by the mass analyzer.
The change in the RF voltage from the first value to the second value is configured to ensure that efficient trapping of ions within the mass analyzer is achieved as the ions are released in a descending order in m/z ratio from the upstream collision cell to be received by the mass analyzer. While in some embodiments the variation of the RF voltage applied to the mass analyzer, as the analyzer receives ions from the collision cell, can be linear, in other embodiments such variation can be nonlinear. In some embodiments, the variation of the RF voltage as a function of time can be characterized by decreasing portions separated by plateaus. In some embodiments, the RF voltage applied to the mass analyzer is decreased by at least about 80% as the ions having m/z ratios in a range of about 50 to about 1000 are received by the analyzer.
The ions received by the mass analyzer can then be released, e.g., via mass selective axial ejection (MSAE), to be detected by a downstream detector. For example, the ions contained in the mass analyzer can be released via MSAE in an ascending order in m/z ratio, i.e., from low m/z to high m/z ratio.
In some embodiments, the collision cell can comprise a plurality of rods arranged in a quadrupole configuration. One or more RF voltages can be applied to one or more rods of the collision cell to generate an electromagnetic field for radially confining ions within the collision cell. In some embodiments, one or more electrodes disposed in the proximity of the entrance and/or exit of the collision cell can be employed to apply an axial electric field to the collision cell for providing axial confinement of ions.
In some embodiments, the release of ions from the collision cell can be achieved via mass selective axial ejection (MSAE). By way of example, MSAE can be achieved via application of an AC excitation voltage to at least one rod of the collision cell to radially excite a subset of ions such that the interaction between the excited ions and the fringing fields at the distal end of the collision cell can cause the ejection of the ions from the collision cell. In some embodiments, the amplitude of the excitation voltage can be ramped from a first value to a second value, where the first value is lower than the second value. By way of example, the amplitude of the excitation voltage can be varied from about 0.2 volts to about 5 volts. In some embodiments, the excitation voltage is a dipolar voltage that is applied to a pair of the rods of the collision cell. In some embodiments, MSAE is performed by applying an excitation voltage to a lens disposed between the collision cell and the mass analyzer.
In some embodiments, ions are released from the collision cell by varying the amplitude of an AC voltage applied to the rods of a quadrupole rod set of the collision cell from a first value to a second value.
In some embodiments, a gas pressure pulse can be applied to the mass analyzer, in conjunction with the reduction of the RF voltage applied thereto, as ions are received by the mass analyzer. Such a pressure pulse can advantageously facilitate the cooling of the ions received by the mass analyzer, and enhance efficient trapping of ions having a large range of m/z ratios, e.g., in a range of about 30 to about 4000, in the mass analyzer.
In some embodiments, an ion source positioned upstream of the collision cell generates a plurality of ions and a filter, e.g., an RF/DC filter, disposed between the ion source and the collision cell is employed to select a subset of those ions for introduction into the collision cell.
In a related aspect, a mass spectrometer is disclosed, which comprises a source for generating a plurality of ions having different mass-to-charge (m/z) ratios, an ion trap for receiving and trapping at least a subset of said plurality of ions, where said subset comprises ions having different m/z ratios. A mass analyzer is positioned downstream of the ion trap. The mass analyzer can comprise a plurality of rods to at least one of which an RF voltage can be applied, and a controller for effecting release of the trapped ions from the ion trap in a descending order in m/z ratio and varying the RF voltage applied to at least one rod of the mass analyzer as the released ions are received by said mass analyzer.
In some embodiments, the ion trap can include four rods arranged in a quadrupole configuration. In some such embodiments, the ion trap can be configured as a collision cell.
In some of the above embodiments, the mass spectrometer can further include one RF voltage source for applying an RF voltage to at least one rod of the mass analyzer and a second RF voltage source for applying an RF voltage to at least one rod of the ion trap. Further, the mass spectrometer can include an excitation voltage source operating under the control of the controller for applying an excitation voltage across two rods of the ion trap for causing mass selective axial ejection (MSAE) of the ions from the ion trap.
In addition, the controller can control the RF voltage source supplying RF voltage to the mass analyzer to vary the amplitude of the RF voltage applied to at least one rod for the mass analyzer, e.g., to decrease the RF voltage, as the ions released from the ion trap are received by the mass analyzer.
Further understanding of various aspects of the present teachings can be obtained by reference to the following detailed description in conjunction with the associated drawings, which are described briefly below.
The present teachings relate generally to methods and systems for efficiently loading a mass analyzer ion trap. As discussed in more detail, in some embodiments, the mass analyzer ion trap can receive ions from an upstream collision cell. The amplitude of an RF confining voltage applied to the rods, e.g., quadrupole rod set, of the mass analyzer ion trap is reduced, e.g., in a linear or non-linear fashion, as ions are received by the mass analyzer. In this manner, the mass analyzer can be efficiently loaded with ions having a wide range of m/z ratios, e.g., m/z ratios in a range of about 30 to about 4000. As discussed in more detail below, in some embodiments, in addition to reducing the amplitude of the RF voltage applied to the rods of the mass analyzer, a gas pressure pulse can be applied to the mass analyzer to expedite cooling of the ions received thereby.
With reference to the flow chart of
Subsequently, the ions collected in the mass analyzer can be released, e.g., via MSAE, and the released ions can then be detected by a downstream detector.
The RF voltage applied to the mass analyzer can be varied (decreased) as the ions released from the collision cell are received by the mass analyzer in a variety of different ways. By way of example, as shown in
Alternatively, as shown in
In many embodiments, the variation of the RF voltage applied to the mass analyzer as the analyzer receives the ions released from the collision cell can allow effectively trapping ions having m/z ratios spanning a large range, e.g., ions having m/z ratios in a range of about 50 to about 1000, in the mass analyzer.
The present teachings can be implemented in a variety of different mass spectrometers. By way of example and with reference to
As will be appreciated by a person of skill in the art, the quadrupole rod set Q1 can be operated as a conventional transmission RF/DC quadrupole mass filter that can be operated to select an ion type of interest and/or a range of ion types of interest. By way of example, the quadrupole rod set Q1 can be provided with RF/DC voltages suitable for operation in a mass-resolving mode. As should be appreciated, taking the physical and electrical properties of Q1 into account, parameters for an applied RF and DC voltage can be selected so that Q1 establishes a transmission window of chosen m/z ratios, such that these ions can traverse Q1 largely unperturbed. Ions having m/z ratios falling outside the window, however, do not attain stable trajectories within the quadrupole and can be prevented from traversing the quadrupole rod set Q1. It should be appreciated that this mode of operation is but one possible mode of operation for Q1. By way of example, in some embodiments, the quadrupole rod set Q1 is operated in RF only mode thus acting as an ion guide for ions received from Q0.
Ions passing through the quadrupole rod set Q1 can pass through the stubby ST2, also a Brubaker lens, to enter a collision cell 1304 in which at least a portion of the ions undergo fragmentation to generate ion fragments. In this embodiment, the collision cell includes a quadrupole rod set, though other multi-pole rod sets can also be employed in other embodiments. An RF voltage source 1310a operating under the control of a controller 1312 applies RF voltages to the rods of the collision cell to radially confine ions within the collision cell. Further, in this embodiment, IQ2 and IQ3 lenses are disposed in proximity of the inlet and outlet ports of the collision cell. By applying DC voltages to the IQ2 and IQ3 lenses that are higher than the collision cell's rod offset, axial trapping of the ions can be achieved.
In some embodiments, the collision cell is maintained at a high pressure, e.g., at a pressure in a range of about 2 mTorr to about 15 mTorr, to ensure efficient cooling of ions contained therein.
With continued reference to
Another RF voltage source 1310b operating under the control of the controller can apply RF voltages to the quadrupole rods of the analyzer ion trap. The controller can control the RF voltage source 1310b to reduce the amplitude of the RF voltage applied to the analyzer ion trap as ions are released from the collision cell and received by the analyzer ion trap. In some embodiments, the change in the amplitude of the RF voltage applied to the rods of the mass analyzer can be, for example, in a range of about 20% to about 90% The ions having higher m/z ratios received by the mass analyzer undergo collisional cooling while the amplitude of the applied RF voltage is decreased to accommodate the ions having lower m/z ratios. Such cooling of the higher m/z ions (e.g., ions having m/z ratios in a range of about 300 to about 1000) can facilitate the retention of those ions trapped in the mass analyzer despite the decrease in the amplitude of the applied RF voltage.
For example,
With reference to
In this embodiment, the fragment ions are axially trapped at the end of the collision cell by the DC voltage applied to the IQ3 lens. After a fill time that can vary from 1 ms to 200 ms, the DC voltage applied to the IQ2 is raised in order to prevent additional ions from entering the collision cell. In some embodiments, LINAC electrodes could be used to create an axial field across the collision cell in order to move the collisionally cooled ions toward the exit region of the collision cell.
Subsequently, the controller 1132 will increase the AC voltage of frequency Θ from zero voltage to a value large enough to create an effective potential between the collision cell rods and the IQ3 lens that would contain ions across the m/z window of interest even in the absence of a repulsive IQ3 voltage. After a short period, e.g., less than about 100 μs, the IQ3 DC voltage is changed to an attractive value relative to the RO2 rod offset. After an additional cooling period of less than about 1 ms, the AC amplitude is ramped down thus causing the release of ions contained within the collision cell in a descending m/z order. Such a mechanism for releasing ions from an ion trap, such as the collision cell 1304, is known in the art as “Zeno” pulsing.
In this embodiment, concurrent with the release of the ions from the collision cell, the controller can cause the RF source 1310b to decrease the amplitude of the RF voltage applied to the rods of the mass analyzer 1308. As discussed above, such a decrease can be achieved in a linear or a non-linear fashion. The total release time can vary from 1 to 20 ms depending on the m/z window. In some embodiments, the amplitude of the RF voltage applied to the rods of the mass analyzer can decrease by at least about 20%, e.g., in a range of about 20% to about 95%, from the start of the introduction of ions from the collision cell into the mass analyzer until the transfer of substantially all of the ions from the collision cell to the mass analyzer is accomplished. In some embodiments, the excitation voltage can be applied to the IQ3 lens.
In another embodiment, the fragment ions contained in the collision cell are released by applying a dipolar excitation voltage differential across two rods of the quadrupole rod set of the collision cell. For example,
With reference to
In this embodiment, concurrent with the release of the ions from the collision cell, the controller can cause the RF source 1310b to decrease the amplitude of the RF voltage applied to the rods of the mass analyzer 1308. As discussed above, such a decrease can be achieved in a linear or a non-linear fashion. In some embodiments, the amplitude of the RF voltage applied to the rods of the mass analyzer can decrease by at least about 20%, e.g., in a range of about 20% to about 95%, from the start of the introduction of ions from the collision cell into the mass analyzer until the transfer of substantially all of the ions from the collision cell to the mass analyzer is accomplished. In some embodiments, the excitation voltage can be applied to the IQ3 lens. In some embodiments, the amplitude of the excitation voltage can be ramped with m/z.
By way of further illustration,
By way of further illustration,
Optionally, in some embodiments, a gas pressure pulse can be applied to the mass analyzer as ions are released from the collision cell and are introduced into the mass analyzer. For example, as shown in
Subsequent to the collection of the ions in the mass analyzer, the ions can be released from the mass analyzer to be detected by a downstream ion detector 1314. By way of example, the release of the ions from the mass analyzer can be achieved via MSAE. The ions can be detected by the ion detector and the signals generated by the ion detector in response to the detection of the ions can be employed, e.g., via an analyzer (not shown), to form a mass spectrum.
The present teachings provide a number of advantages. For example, they allow for efficient trapping of both high m/z and low m/z ions. In other words, they allow for efficient trapping of ions having a wide range of m/z ratios, e.g., m/z ratios in a range of about 50 to about 2000. This can in turn enhance the duty cycle of mass analysis. For example, the implementation of the present teachings can result in at least a factor of 2 improvement in the duty cycle of mass analysis.
Those having ordinary skill in the art will appreciate that various changes can be made to the above embodiments without departing from the scope of the invention.
This application is a continuation of U.S. application Ser. No. 17/274,057 filed on Sep. 4, 2019, entitled, “RF Ion Trap Ion Loading Method,” which claims priority to U.S. provisional application No. 62/728,637 filed on Sep. 7, 2018, entitled “RF Ion Trap Ion Loading Method,” the disclosures of which are incorporated herein by reference in their entireties.
Number | Date | Country | |
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62728637 | Sep 2018 | US |
Number | Date | Country | |
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Parent | 17274057 | Mar 2021 | US |
Child | 17731684 | US |