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EP-4740237-A1 - IMPROVED SIGNAL TO NOISE RATIO AT THE LLOQ THROUGH THE REDUCTION OF CHEMICAL NOISE

EP4740237A1EP 4740237 A1EP4740237 A1EP 4740237A1EP-4740237-A1

Abstract

Various embodiments relate to the reduction of chemical noise at or near the mass of an analyte of interest prior to selection by a mass filter. The use of a narrow bandpass in the ion optics removes chemical noise that can repopulate ions at or near the mass of an analyte of interest by removing other chemical noise ions that can fragment into the same or similar mass as the mass of an analyte of interest through collision induced dissociation.

Inventors

  • COLLINGS, BRUCE

Assignees

  • DH Technologies Development Pte. Ltd.

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A method of performing mass spectrometry, the method comprising: introducing a plurality of ions, including one or more analyte ions and one or more chemical noise ions, into a first mass filter to select ions having m/z ratios within a specific range for passage through the first mass filter; accelerating the selected ions; introducing the accelerated ions into an ion trap containing a background gas for causing preferential collision induced dissociation (CID) of chemical noise ions passing through the first mass filter while substantially retaining the one or more analyte ions undissociated; allowing at least a portion of ions to exit the ion trap; and introducing at least a portion of the ions exiting the ion trap into a second mass filter configured to allow passage of the undissociated analyte ions.
  2. 2. The method of Claim 1 , wherein the ions exiting the ion trap comprise undissociated analyte ions, fragment ions generated via dissociation of the analyte ions, undissociated chemical noise ions, and fragment ions generated via dissociation of the chemical noise ions.
  3. 3. The method of Claim 1 or Claim 2, wherein said first mass filter is configured to block passage of chemical noise ions having m/z ratios that are separated from an m/z ratio of the analyte ion by at least a specific m/z value.
  4. 4. The method of Claim 3, wherein the specific m/z value is in a range of about +/-5 Da to about +/- 15 Da.
  5. 5. The method of any one of Claims 1-2 and 4, further comprising causing dissociation of the analyte ions passing through the second mass filter to generate a plurality of analyte product ions.
  6. 6. The method of Claim 5, further comprising determining a mass spectrum of said analyte product ions by introducing said analyte product ions to a third mass filter and utilizing a detector downstream of the third mass filter to monitor an intensity of product ions passing through the third mass filter.
  7. 7. The method of Claim 6, wherein the utilized detector is selected from the group consisting of a channeltron ion detector, a discrete dynode detector, a multi-channel plate detector, and an optical detector.
  8. 8. The method of any one of Claims 1-2, 4, and 6-7, wherein said first mass filter and said ion trap are disposed in a common first chamber.
  9. 9. The method of Claim 8, wherein said second mass filter is disposed in a second chamber positioned downstream from said common first chamber.
  10. 10. The method of Claim 1, further comprising applying a DC offset voltage between said first mass filter and said ion trap for accelerating the selected ions.
  11. 11. The method of Claim 10, wherein said DC offset voltage is selected such that said accelerated ions acquire a kinetic energy at which the chemical noise ions are more likely to dissociate than the analyte ions.
  12. 12. The method of Claim 10, wherein said first mass filter comprises a first plurality of rods arranged in a multipole configuration.
  13. 13. The method of Claim 12, wherein said ion trap comprises a second plurality of rods arranged in a multipole configuration.
  14. 14. The method of Claim 13, wherein said DC offset voltage is applied between at least one of said first plurality of rods and at least one of said second plurality of rods.
  15. 15. The method of Claim 14, wherein said DC offset voltage is in a range of about 2 eV to about 200 eV .
  16. 16. The method of any one of Claims 12-15, further comprising applying an RF voltage and a DC resolving voltage to said first plurality of multipole rods of the first mass filter to generate a bandpass filter.
  17. 17. The method of Claim 16, wherein said RF voltage and said DC resolving voltage are selected such that the bandpass filter exhibits a bandpass in a range of about 10 Da to about 30 Da.
  18. 18. The method of any one of Claims 1-2, 4, 6-7, and 9-15, further comprising maintaining a pressure within said ion trap in the range of about 1 mTorr to about 30 mTorr.
  19. 19. The method of Claim 1-2, 4, 6-7, and 9-15, further comprising applying a DC gating voltage between the ion trap and a downstream component of the mass spectrometer.
  20. 20. The method of Claim 19, further comprising modulating the DC gating voltage between a trapping voltage at which ions are trapped within the ion trap and a release voltage at which ions can exit the ion trap to enter the downstream component.

Description

IMPROVED SIGNAL TO NOISE RATIO AT THE LLOQ THROUGH THE REDUCTION OF CHEMICAL NOISE Related Applications [0001] This application claims priority to U.S. Provisional Application No. 63/525,269 filed on July 6, 2023 and U.S. Provisional Application No. 63/585,763 filed on September 27, 2023, the contents of both of which are incorporated herein by reference in their entireties. Technical Field [0002] The present disclosure is generally directed to methods and systems for reducing chemical noise in mass spectrometry. Background [0003] The present disclosure is generally directed to methods and systems for performing mass spectrometry, and in particular, to such methods and systems for reducing, and preferably eliminating, chemical noise in mass spectra. [0004] Mass spectrometry (MS) 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. [0005] Multiple reaction monitoring (MRM) is a tandem mass spectrometry technique in which a precursor analyte ion is selected by a mass filter and dissociated, e.g., in a collision cell, to generate product ions, which can be selected by a second mass filter and analyzed. The presence of non-target ions, such as solvent and analyte/solvent clusters, having an m/z ratio that is the same as or close to the m/z ratio of the target ion can lead to the formation of non-target product ions having m/z ratios that are the same as or close to the m/z ratios of the target product ions. This can give rise to a chemical noise background that is often observed in MRM signals. [0006] The chemical noise spectrum is primarily due to solvent and analyte/solvent clusters and covers a wide m/z range with ions at nearly every m/z above about 50. Summary [0007] In one aspect, a method of performing mass spectrometry is disclosed, which comprises introducing a plurality of ions, including one or more analyte ions and one or more chemical noise ions, into a first mass filter to select ions having m/z ratios within a specific range for passage through the first mass filter, accelerating the selected ions, introducing the accelerated ions into an ion trap containing a background gas for causing preferential collision induced dissociation (CID) of chemical noise ions passing through the first mass filter while substantially retaining the one or more analyte ions undissociated, allowing at least a portion of ions to exit the ion trap, and introducing at least a portion of the ions exiting the ion trap into a second mass filter configured to allow passage of the undissociated analyte ions. [0008] The ions exiting the ion trap can include undissociated analyte ions, fragment ions generated via dissociation of the analyte ions, undissociated chemical noise ions, and fragment ions generated via dissociation of the chemical noise ions. The first mass filter is configured to block passage of chemical noise ions having m/z ratios that are separated from an m/z ratio of the analyte ion by a specific m/z value. By way of example, the specific m/z value can be in a range of about +/- 5 Da to about +/- 15 Da. [0009] The analyte ions passing through the second mass filter can be dissociated to generate a plurality of analyte product ions. A mass spectrum of the analyte product ions can be determined, e.g., using any suitable mass analyzer, such as a time-of-flight (ToF) mass analyzer, or a linear ion trap. [0010] In some embodiments, the first mass filter and the ion trap are disposed in a common first chamber. In such embodiments, the second mass filter can be disposed in a second chamber that is positioned downstream from the common chamber. In other embodiments, the first mass filter and the ion trap can be disposed in separate chambers, which can be, for example, maintained at different pressures. In various embodiments, the pressure within the ion trap can be maintained, e.g., in a range of about 1 mTorr to about 30 mTorr. [0011] A DC offset voltage can be applied between the first mass filter and the ion trap for accelerating the ions exiting the first mass filter as they transition from the first mass filter to the ion trap. The DC offset voltage can be selected such that the accelerated ions acquire a kinetic energy at which the chemical noise ions are more likely to dissociate than the analyte ions. By way of example, and without limitation, the DC offset voltage can be in a range of about 2 V to about 200 V, such as in a range of about 10 V to about 100 V. [0012] In various embodiments, the ion trap can include a plurality of rods that are arr