# US 12,191,132 B2 · Method for mass spectrometry > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,191,132 B2 - Document ID: US12191132B2 - Status: Granted - Kind: B2 - Application number: 17/753,035 - Filed: 2020-08-22 - Published: 2022-11-10 - Granted: 2025-01-07 - Earliest claimed: 2019-08-30 - Assignees: DH Technologies Development Pte. Ltd. - Applicants: Dh Technologies Development Pte. Ltd. - Inventors: Yves Le Blanc; David M. Cox - Web page: https://patentgrep.com/patent/US12191132B2 ## CPC - H01J 49/0431: {for liquid samples (interfaces to liquid chromatographs G01N30/7233)} - H01J 49/0072: {by ion/ion reaction, e.g. electron transfer dissociation, proton transfer dissociation} - H01J 49/165: {Electrospray ionisation} - H01J: ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS (spark-gaps H01T; electric arc lamps H05B31/00; particle accelerators H05H) ## Abstract Before a sample is introduced into a liquid sample delivery device, an ion source device receives aqueous mobile phase solution from the liquid sample delivery device and ionizes compounds of the aqueous mobile phase solution, producing an ion beam. A tandem mass spectrometer performs a first neutral loss scan of the ion beam with a first neutral loss value set to a molecular weight of a first known solvent, producing a first intensity, and performs a second neutral loss scan of the ion beam with a second neutral loss value set to a molecular weight of a second known solvent, producing a second intensity. A ratio of the first intensity to the second intensity is calculated. It is determined if the aqueous mobile phase solution is properly being delivered by the liquid sample delivery device based on the ratio. ## Claims ### Claim 1 Apparatus for determining if an aqueous mobile phase solution is properly being delivered by a mass spectrometry liquid sample delivery device, comprising: an ion source device that, before a sample is introduced into a liquid sample delivery device, receives the aqueous mobile phase solution from the liquid sample delivery device and ionizes compounds of the aqueous mobile phase solution, producing an ion beam of aqueous mobile phase solution compounds; a tandem mass spectrometer that, before the sample is introduced into a liquid sample delivery device, or after analysis of the sample but before another sample is introduced into the liquid sample delivery device, receives the ion beam of aqueous mobile phase solution compounds from the ion source device, performs a first neutral loss scan of the ion beam with a first neutral loss value set to a molecular weight of a first known solvent, producing a first intensity, and performs a second neutral loss scan of the ion beam with a second neutral loss value set to a molecular weight of a second known solvent, producing a second intensity; and a controller that calculates a ratio of the first intensity to the second intensity, and determines, based on the calculated ratio being constant for intensity measurements from first and second neutral loss scans, performed at different time periods using respective first and second neutral loss values, that the aqueous mobile phase solution reached steady state conditions. ### Claim 2 (depends on 1) The apparatus of claim 1, further comprising a display device, wherein upon determination that the aqueous mobile phase solution reached steady state conditions, the display device displays information describing that the aqueous mobile phase solution is properly being delivered by the liquid sample delivery device. ### Claim 3 (depends on 2) The apparatus of claim 2, wherein, before the sample is introduced into the liquid sample delivery device, the tandem mass spectrometer performs the first neutral loss scan and the second neutral loss scan at two or more time periods until the rate of change in both the first intensity and the second intensity decreases below a threshold rate of change and, when the rate of change in both the first intensity and the second intensity decreases below the threshold rate of change, the display device displays information on describing that the liquid sample delivery device has reached a steady state. ### Claim 4 (depends on 2) The apparatus of claim 2, further includes a memory device, wherein, each time the controller calculates the ratio, the the controller stores the ratio in the memory device. ### Claim 5 (depends on 4) The apparatus of claim 4, wherein, between sample introductions into the liquid sample delivery device and after the tandem mass spectrometer calculates the ratio, the tandem mass spectrometer compares the ratio to a ratio previously stored in the memory device, and, if the ratio differs by more than a threshold difference from the ratio previously stored in the memory device, the display device displays information on the display device describing that the aqueous mobile phase solution has changed. ### Claim 6 (depends on 2) The apparatus of claim 2, wherein tandem mass spectrometer, before the sample is introduced into the liquid sample delivery device, or after analysis of the sample but before the other sample is introduced into the liquid sample delivery device, further performs a third neutral loss scan of the ion beam with a third neutral loss value set to a molecular weight of a first known mobile phase additive, producing a third intensity, performs a fourth neutral loss scan of the ion beam with a fourth neutral loss value set to a molecular weight of a second known mobile phase additive, producing a fourth intensity, and wherein the controller calculates a second ratio of the third intensity to the fourth ion current, and determines if that an additive, in combination with the aqueous mobile phase solution, reached steady state conditions based on the second ratio. ### Claim 7 (depends on 6) The apparatus of claim 6, further includes a memory device, wherein, each time the controller calculates the second ratio, the controller stores the second ratio in the memory device. ### Claim 8 (depends on 7) The apparatus of claim 7, wherein, between sample introductions into the liquid sample delivery device and after the controller calculates the second ratio, the controller compares the second ratio to a second ratio previously stored in the memory device, and, if the second ratio differs by more than a threshold difference from the ratio previously stored in the memory device, the display device displays information on the display device describing that the mobile phase additive has changed. ### Claim 9 (depends on 6) The apparatus of claim 6, wherein the first known mobile phase additive comprises formic acid and the second known mobile phase additive comprises acetic acid. ### Claim 10 (depends on 1) The apparatus of claim 1, wherein the first known solvent comprises methanol and the second known solvent comprises one of acetonitrile, isopropyl alcohol (IPA), or acetone. ### Claim 11 (depends on 1) The apparatus of claim 1, wherein the first known solvent comprises acetonitrile and the second known solvent comprises one of methanol, isopropyl alcohol (LPA), or acetone. ### Claim 12 (depends on 1) The apparatus of claim 1, wherein the tandem mass spectrometer, before the sample is introduced into the liquid sample delivery device, or after analysis of the sample but before the other sample is introduced into the liquid sample delivery device, further performs a third neutral loss scan of the ion beam with a third neutral loss value set to a molecular weight of a third known solvent, producing a third intensity, and wherein the controller further calculates a second ratio of the first intensity to the third ion current, calculates a third ratio of the second intensity to the third ion current, and determines that the aqueous mobile phase solution reached steady state conditions based on the ratio, the second ratio, or the third ratio. ### Claim 13 (depends on 1) The apparatus of claim 1, wherein the ion source device comprises an electrospray ionization (ESI) ion source device or an atmospheric pressure chemical ionization (APCI) ion source device and the tandem mass spectrometer comprises a triple quadrupole (QqQ) device or a quadrupole linear ion trap (QqLIT) device. ### Claim 14 A method for determining if an aqueous mobile phase solution is properly being delivered by a mass spectrometry liquid sample delivery device, comprising: Instructing, using a processor, an ion source device, before a sample is introduced into a liquid sample delivery device, to receive the aqueous mobile phase solution from the liquid sample delivery device and ionize compounds of the aqueous mobile phase solution, producing an ion beam of aqueous mobile phase solution compounds; instructing using the processor a tandem mass spectrometer, before the sample is introduced into a liquid sample delivery device, or after analysis of the sample but before another sample is introduced into the liquid sample delivery device, to receive the ion beam of aqueous mobile phase solution compounds from the ion source device, perform a first neutral loss scan of the ion beam with a first neutral loss value set to a molecular weight of a first known solvent, producing a first intensity, and perform a second neutral loss scan of the ion beam with a second neutral loss value set to a molecular weight of a second known solvent, producing a second intensity; calculating a ratio of the first intensity to the second intensity using the processor; and determining using the processor, based on the calculated ratio being constant for intensity measurements from first and second neutral loss scans, performed at different time periods using respective first and second neutral loss values, that the aqueous mobile phase solution reached steady state conditions. ### Claim 15 (depends on 14) The method apparatus of claim 14, further comprising: displaying upon determination that the aqueous mobile phase solution reached steady state conditions, information describing that the aqueous mobile phase solution is properly being delivered by the liquid sample delivery device. ### Claim 16 (depends on 15) The method of claim 15, further comprising: performing, before a sample is introduced into the liquid sample delivery device, the first neutral loss scan and the second neutral loss scan at two or more time periods until the rate of change in both the first intensity and the second intensity decreases below a threshold rate of change and; displaying, when the rate of change in both the first intensity and the second intensity decreases below the threshold rate of change, information describing that the liquid sample delivery device has reached a steady state. ### Claim 17 (depends on 14) The method of claim 14, wherein the first known solvent comprises methanol and the second known solvent comprises one of acetonitrile, isopropyl alcohol (IPA), or acetone. ### Claim 18 (depends on 14) The method of claim 14, wherein the first known solvent comprises acetonitrile and the second known solvent comprises one of methanol, isopropyl alcohol (LPA), or acetone. ### Claim 19 (depends on 14) The method of claim 14, further comprising: performing, before the sample is introduced into the liquid sample delivery device, or after analysis of the sample but before the other sample is introduced into the liquid sample delivery device, a third neutral loss scan of the ion beam with a third neutral loss value set to a molecular weight of a third known solvent, producing a third intensity; and calculating a second ratio of the first intensity to the third ion current, calculating a third ratio of the second intensity to the third ion current, and determining that the aqueous mobile phase solution reached steady state conditions based on the ratio, the second ratio, or the third ratio. ### Claim 20 A computer program product, comprising a non-transitory and tangible computer-readable storage medium whose contents include a program with instructions being executed on a processor to perform a method for determining if an aqueous mobile phase solution is properly being delivered by a mass spectrometry liquid sample delivery device, the method comprising: providing a system, wherein the system comprises one or more distinct software modules, and wherein the distinct software modules comprise a control module and an analysis module; instructing an ion source device, before a sample is introduced into a liquid sample delivery device, to receive the aqueous mobile phase solution from the liquid sample delivery device and ionize compounds of the aqueous mobile phase solution, producing an ion beam of aqueous mobile phase solution compounds, using the control module; instructing a tandem mass spectrometer, before the sample is introduced into a liquid sample delivery device, or after analysis of the sample but before another sample is introduced into the liquid sample delivery device, to receive the ion beam of aqueous mobile phase solution compounds from the ion source device, perform a first neutral loss scan of the ion beam with a first neutral loss value set to a molecular weight of a first known solvent, producing a first intensity, and perform a second neutral loss scan of the ion beam with a second neutral loss value set to a molecular weight of a second known solvent, producing a second intensity, using the control module; calculating a ratio of the first intensity to the second intensity using the analysis module; and determining using the analysis module, based on the calculated ratio being constant for intensity measurements from first and second neutral loss scans, performed at different time periods using respective first and second neutral loss values, that the aqueous mobile phase solution reached steady state conditions.