Radiant energy – Ionic separation or analysis
Reexamination Certificate
2002-05-31
2004-08-03
Lee, John R. (Department: 2881)
Radiant energy
Ionic separation or analysis
C250S282000, C250S288000
Reexamination Certificate
active
06770871
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to mass spectrometry apparatuses and methods for obtaining data which identify the mass to charge ratio of various parent ions in a sample as well as mass to charge ratio of daughter ions produced by fragmentation of the parent ions in the sample, such as to determine structural information about the parent ions, and to derive other information about relationships between the parent ions and daughter ions. More particularly, this invention relates to mass spectrometry systems which include tandem mass analyzers separated by an ion fragmentation cell to obtain multi-dimensional data about the parent ions and daughter ions of the sample.
BACKGROUND OF THE INVENTION
In simple mass spectrometers (MS), sample ions are formed in an ion source, such as by Electron Impact (EI), or by Atmosphere Pressure Ionization (API). The ions then pass through a mass analyzer, such as a quadrupole or time of flight device (TOF), for detection. The detected ions can be molecular ions (parent ions), fragment ions (daughter ions) of the molecular ions, or fragment ions of other daughter ions.
Quadrupole mass analyzers and magnetic sector mass analyzers, are mass filter type mass analyzers that allow only ions with specific mass/charge ratios (m/z) to pass through. Other ions are discarded during the scan. These type of mass analyzer is not non-destructive. This type of mass analyzer is thus not particularly effective for a full mass scan (also called full spectrum scan) where multiple ions of different m/z in a sample are to be detected and/or measured. Ion trap mass analyzers can trap ions and than analyze them sequentially based on the Fourier Transform Ion Cyclotron Resonance (FT-ICR) m/z. Mass analyzers can obtain similar full spectrum data, but in a different fashion by first measuring all of the ions and then performing a fourier transform analysis to measure the different ions in the sample. Therefore, the duty cycle and effectiveness of these types of non-destructive mass analyzers for full mass scans is higher than for mass filter type instruments. Time of flight mass analyzers sort ions based on flight time from an accelerator region to a detector spaced from the accelerator region. TOF mass analyzers can detect all ions, no matter what their mass to charge ratios are, and so they have very good sensitivity for a full mass scan spectrum.
Ion fragmentation mass spectrometers have been developed, characterized by having two or multiple sequential stages of mass analysis and an intermediate fragmentation region where parent ions from the first stage are fragmented into daughter ions for the second stage. Hence, these are generally termed “tandem” or “MS/MS” instruments. In such tandem mass spectrometers, sample ions are produced in an ion source, and the first stage of mass analysis analyzes selected parent ions of particular mass or m/z with a mass filter type mass analyzer. Then, some of the selected parent ions are fragmented or otherwise caused to dissociate, such as by metastable decomposition, collision induced dissociation (CID), or collisionally activated dissociation (CAD), to produce the daughter ions. Finally, the second stage of mass analysis sorts the daughter ions according to mass or m/z.
There are two styles of instruments in terms of “tandem” mass spectrometers, “tandem in space” and “tandem in time.” Tandem in space mass spectrometers, such as triple quadrupoles and quadrupole-time of flight (Q-TOF) devices, have two mass analyzers, one for parent ion selection and one for daughter ion detection and/or measurement. Two mass analyzers are separated by a fragmentation device. Tandem in time instruments, on the other hand, have one mass analyzer that analyses both parent ions and daughter ions, but sequentially in time. Ion trap and FT-ICR are two most common mass spectrometers that have tandem in time MS/MS. The parent ions first are selected in the analyzer cell then fragmented. Often fragmentation takes place inside the analyzer. Then the daughter ions are analyzed in the same cell. Alternatively, it is known to analyze the daughter ions in a downstream analyzer, such as a TOF analyzer.
Several MS/MS scan types are used based on the relationship between the parent ions and the daughter ions. “Daughter scan” is a method that involves a full scan of daughter ions while the parent ion from which the daughter ions originate is pre-selected and fixed. This method is useful if an analyst knows the molecular weight of the parent ion and wants to know structural information about the parent ion. For instance, two distinct parent ions of similar molecular weight, but different structure can be differentiated by what daughter ions they typically fragment into. The data dependent daughter scan is often used when combined with liquid chromatographs (LC-MS/MS). The mass spectrometer automatically selects a parent ion peak based on previous scans and the peak intensity, charge state and other considerations. The mass analyzer then makes a full scan of the daughter ions resulting from fragmentation of the parent ion of interest.
“Parent ion scan,” also known as “precursor scan,” is a method that has a fixed daughter ion selection for the second analysis stage, while using the first stage to scan all of the pre-fragmentation parent ions in the sample. Only those molecules/compounds in the sample are detected which produce a specific daughter ion when fragmented. If both parent ion selection and daughter ion selection are fixed, an analyst will get selected reaction monitoring (SRM). SRM has the best selectivity, and good signal to noise ratio for quantitation.
“Neutral loss scan” is a method that shows all parent ions that lose a particular mass during fragmentation. The second stage mass analyzer scans the ions together with the first stage mass analyzer but with a certain offset. Neutral loss scans are used for screening experiments where a group of compounds all give the same loss.
Magnetic and electrostatic sector (together referred to as “sector”) mass analyzers have relatively slow scan speed, so sector based MS/MS instruments including sector-sector, sector-quadrupole and sector-TOF are normally good for daughter scans which don't need high speed scanning of parent ions in the first stage. Tandem in time instruments select the parent ion first, then fragment and scan the daughter ions later. Normally this type of instrument can only perform full mass scan of the daughter ions.
Time of flight mass analyzers are known to have a number of advantages, including fast scanning rate, higher sensitivity, relatively high resolution and good mass accuracy. Q-TOF is a MS/MS instrument that combines quadrupole and TOF analyzers. It gives very good mass accuracy and sensitivity on full mass daughter scans but only filters a chosen parent ion with other parent ions being lost.
Triple quadrupole mass spectrometers can do all of the above scans. However, since both the first and second stages of mass analysis are of the mass filter type, triple quadrupole systems are generally less effective than ion trap for full scan MS/MS, and less accurate and sensitive than Q-TOF.
To solve modern analytical problems an analyst often needs to use more than one MS/MS scan method. For LC-MS/MS the parent ions duration time is limited because additional peaks elute from the LC device in a specified time period. Normally there is not enough time to do different types of scans in a single LC run. It is also not unusual that several parent ions co-elute at the same time. In many cases, data dependent scans do not have enough time to fully analyze all parent ions. A combined sector and TOF mass spectrometer is described in Enke at al U.S. Pat. No. 4,472,631. In Enke's method, a collision cell is placed before a magnetic sector. A pulsed ion source is also used, so that the flight time of the ion can be measured. The time resolution is used for parent ion information while a spatial resolution from a sector is used to give daughter ion information. By using
Nugent Kerry D.
Wang Houle
Gill Erin-Michael
Heisler & Associates
Lee John R.
Michrom BioResources, Inc.
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