High-resolution mass spectrometer and methods for determining the isotopic anatomy of organic and volatile molecules

Patent metadata

Field	Value
Publication number	US-10665329-B2
Application number	US-201715616533-A
Country	US
Kind code	B2
Filing date	Jun 7, 2017
Priority date	Oct 21, 2011
Publication date	May 26, 2020
Grant date	May 26, 2020

Abstract

A mass spectrometer including an entrance slit, an energy filter, a momentum filter and a detector array, the entrance slit, energy filter and momentum filter being configured to provide molecular analyte ions to the detector array at a mass resolution of about 20,000 or greater. A method for determining the isotopic composition of an analyte in a sample includes converting the analyte to molecular analyte ions, separating the molecular analyte ions using an entrance slit, separating the molecular analyte ions according to their energy levels, separating the molecular analyte ions according to their momenta, detecting two or more of the molecular analyte ions at a mass resolution of about 20,000 or greater to produce molecular analyte ion data; and analyzing the molecular analyte data to determine the isotopic composition of at least a portion of the analyte.

First claim

What is claimed is:

1. A method for determining the isotopic composition of an analyte in a sample, the method comprising:
converting the analyte to molecular analyte ions using an ion source in a mass spectrometer to produce a first output of the molecular analyte ions;
separating at least a portion of the molecular analyte ions of the first output using an entrance slit;
further separating at least a portion of the molecular analyte ions of the first output according to their energy levels using an energy filter to produce a second output of molecular analyte ions;
separating at least a portion of the molecular analyte ions of the second output according to their momenta using a momentum filter to produce a third output of molecular analyte ions, the third output of molecular analyte ions comprising two or more molecular analyte ion beams;
detecting the two or more molecular analyte ion beams of the third output at a mass resolution of about 20,000 or greater to produce molecular analyte ion data, the detecting the two or more molecular analyte ion beams comprising concurrently detecting at least two of the two or more molecular analyte ion beams using one detector; and
analyzing the molecular analyte ion data to determine the isotopic composition of at least a portion of the analyte.

2. The method of claim 1 , wherein the detecting the two or more molecular analyte ion beams comprises scanning at least two of the two or more molecular analyte ion beams across the one detector.

3. The method of claim 1 , further comprising introducing the analyte to the mass spectrometer as a continuous flow prior to converting the analyte to the molecular analyte ions.

4. The method of claim 1 , further comprising introducing the sample to the mass spectrometer as a time-resolved pulse prior to converting the analyte to the molecular analyte ions.

5. The method of claim 1 , wherein the analyzing comprises deconvolving the molecular analyte ion data to identify the relative contribution of each of the two or more molecular analyte ion beams to the molecular analyte ion data.

6. The method of claim 1 , wherein the analyte comprises two or more analyte isotopologues, analyte isotopomers or mixtures thereof.

7. The method of claim 1 , wherein the molecular analyte ions comprise intact molecular analyte ions and molecular analyte adduct ions, the intact molecular analyte ions being formed by ionizing an intact molecule of the analyte and the molecular analyte adduct ions being formed by combining one or more of the intact molecules of the analyte or the intact molecular analyte ions and a hydrogen atom or another material, the other material being the same as or different from the intact analyte molecules or the intact molecular analyte ions, and
wherein the molecular analyte ion data comprises an intact molecular analyte ion intensity I A-molecular corresponding to the intact molecular analyte ions and a molecular analyte adduct ion intensity I A′-adduct corresponding to the molecular analyte adduct ions, and the method further comprises:
determining a ratio of the molecular analyte adduct ions to the intact molecular analyte ions by calculating a constant of proportionality K adduct according to the Equation below:
I A′-adduct /I A-molecular =K adduct ; and

modifying the molecular analyte ion data using K adduct .

8. The method of claim 1 , wherein the molecular analyte ions comprise intact molecular analyte ions and molecular analyte fragment ions, the intact molecular analyte ions being formed by ionizing an intact molecule of the analyte and the molecular analyte fragment ions being formed by dissociating one or more of the intact molecules of the analyte or the intact molecular analyte ions, and
wherein the molecular analyte ion data comprises an intact molecular analyte ion intensity I A-molecular corresponding to the intact molecular analyte ions and a molecular analyte fragment ion intensity I FA corresponding to the molecular analyte fragment ions, and the method further comprises:
determining a ratio of the molecular analyte fragment ions to the intact molecular analyte ions by calculating a constant of proportionality K fragment according to the Equation below:
I FA /I A-molecular =K fragment ; and

modifying the molecular analyte ion data using K fragment .

9. A method of analyzing a drug or a drug metabolite, the method comprising:
determining the isotopic composition of at least a portion of an analyte of a drug or drug metabolite in a sample according to the method of claim 1 ; and
comparing the isotopic composition obtained for the drug or drug metabolite to a database of isotopic compositions.

10. A method of determining an amount of an anthropogenic contribution to an atmospheric concentration of an atmospheric gas, the method comprising:
determining the isotopic composition of at least a portion of an analyte in a sample according to the method of claim 1 ; and
comparing the isotopic composition obtained for the analyte to a database of isotopic compositions.

11. A method for the diagnosis or treatment of a disease, the method comprising:
determining the isotopic composition of at least a portion of an analyte in a sample from a patient according to the method of claim 1 ; and
comparing the isotopic composition obtained for the analyte to a database of isotopic compositions.

12. A method for determining a prior temperature of a sample, the method comprising:
determining the isotopic composition of at least a portion of an analyte in the sample according to the method of claim 1 ; and
comparing the isotopic composition obtained for the analyte to a database of isotopic compositions.

13. The method of claim 2 , wherein respective molecular analyte ions of the two or more molecular analyte ion beams have masses that differ from one another by less than about 1 atomic mass unit.

14. The method of claim 2 , further comprising introducing the analyte to the mass spectrometer as a continuous flow prior to converting the analyte to the molecular analyte ions.

15. The method of claim 6 , wherein the analyzing further comprises determining the molecular position of at least one isotope in at least one of the analyte isotopologues or the analyte isotopomers.

16. The method of claim 6 , further comprising:
obtaining mass discrimination reference data from a mass discrimination reference material comprising mass discrimination reference isotopologues or isotopomers A-MD and B-MD having respective mass discrimination reference concentrations [A-MD] and [B-MD], the mass discrimination reference data comprising mass discrimination reference ion intensities I A-MD and I B-MD corresponding to the respective mass discrimination reference isotopologues or isotopomers A-MD and B-MD;
determining the mass discrimination of the mass spectrometer by comparing a ratio of the mass discrimination reference ion intensities I A-MD and I B-MD to a ratio of the mass discrimination reference concentrations [A-MD] and [B-MD] using a constant of proportionality α IMF according to the Equation below:
I A-MD /I B-MD =([ A - MD ]/[ B - MD ])α IMF ; and

modifying the molecular analyte ion data using α IMF .

17. The method of claim 6 , further comprising:
obtaining first linearity reference data from a first linearity reference material comprising first linearity reference isotopologues or isotopomers A- 1 and B- 1 at a first linearity reference concentration ratio ([A- 1 ]/[B-1]) 1 , the first linearity reference data comprising

Assignees

• California Inst Of Techn
• Thermo Fisher Scient Bremen Gmbh

Inventors

• Eiler John M
• Schwieters Johannes

Classifications

• G16C20/20 Primary

  Identification of molecular entities, parts thereof or of chemical compositions · CPC title

• H01J49/326

  with magnetic and electrostatic sectors of 90 degrees · CPC title