Radiant energy – Ionic separation or analysis – Methods
Reexamination Certificate
1999-05-27
2003-01-07
Lee, John R. (Department: 2881)
Radiant energy
Ionic separation or analysis
Methods
C250S281000, C250S287000, C250S288000, C250S292000, C250S299000, C250S42300F
Reexamination Certificate
active
06504148
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of and apparatus for enhancing the performance of MS/MS mass spectrometers that involve two sequential mass analyzing steps. This invention more particularly relates to such a technique effective in a mass spectrometer with axial ejection from a linear ion trap with axial ejection.
BACKGROUND OF THE INVENTION
It is common in mass spectrometry to use at least two mass spectrometers in series separated by a gas filled collision cell. In triple quadrupole instruments the first mass spectrometer, often designated as MS1, is a resolving quadrupole followed by a collision cell operated in total ion mode and finally a second mass resolving quadrupole, often designated as MS2. The collision cell, in known manner includes another quadrupole rod set. These quadrupole rod sets are commonly referred to as Q1, Q2 and Q3 respectively and the ion path is often referred to as QqQ, where Q denotes a quadrupole rod set that can be operated in a mass resolving mode, and q a rod set used for collision induced dissociation and fragmentation. Such a configuration will often include a further upstream rod set, commonly denoted Q0, which is operated just as an ion guide. It serves to focus the ions and further eliminate gas from the ion stream, usually generated by an atmospheric source.
MS/MS experiments, as they are usually known, can be carried out in such instruments and involve choosing specific precursor ions with Q1, fragmenting the precursor ions in a pressurized Q2 via collisions with neutral gas molecules to produce fragment or product ions, and mass resolving the product ions with Q3. This technique has proven to be very valuable for identifying compounds in complex mixtures and in determining structures of unknown substances. Several possible scanning modes of MS/MS operation are well known and these are:
(1) setting MS1 (Q1) at a particular precursor ion m/z value to transmit a small range of mass resolved ions into the collision cell (Q2), while (Q3) is scanned to provide a product ion spectrum;
(2) setting MS2 (Q3) at a particular product ion m/z value and then scanning MS1 (Q1) to provide a precursor ion spectrum; and
(3) scanning both MS1 (Q1) and MS2 (Q3) simultaneously with a fixed m/z difference between them, to provide a neutral loss spectrum.
Thus the m/z value of a precursor ion, a product ion, or an ion generating a given neutral fragment ion can be determined using MS/MS techniques.
MS/MS techniques generally provide better detection limits than a single stage of mass analysis due to the reduction of chemical noise which is the signal due to generation of ions from other components within the sample, the solute, or the environment surrounding the ion source or within the mass spectrometer itself. MS/MS reduces this nonspecific ion signal and results in better signal-to-noise even though there are two stages of mass resolution which reduce the total number of ions at the detector.
MS/MS instruments based on scanning mass spectrometers, such as quadrupoles, reject the majority of ions formed at any given time within the scan cycle; the essence of scanning is to select a narrow m/z range for further analysis and reject all other ions. Thus, these instruments have inherently poor duty cycles.
Triple quadrupole mass spectrometers are often referred to as “tandem in space” devices since the precursor ion isolation, fragmentation, and fragment ion mass resolution are effected with different ion optical elements located at physically different locations in the ion path. Ion trap mass spectrometers have potentially much greater duty cycles than such tandem in space quadrupole mass spectrometers since all of the ions within the mass spectrometer can be scanned out and detected. The origin of this duty cycle enhancement arises from the fact that ion trap mass spectrometers are typically filled with a short pulse (typically 5-25 ms) of ions from which a complete mass spectrum is generated. On the other hand, in the time required to fill and scan an ion trap, a conventional beam type or tandem is space quadrupole mass spectrometer can only acquire mass spectral information over a very small mass range.
Hybrid MS/MS instruments such as QqTOF instruments, in which the final stage of mass analysis (MS2) is accomplished via a non-scanning time of flight (TOF) mass spectrometer have a duty cycle advantage over QqQ instruments in that the TOF section is not a scanning mass spectrometer, and all of the ions in the product ion mode are collected within a few hundred microseconds. These instruments are typically 10-100 times more sensitive than conventional QqQ instruments in the product ion scan mode of operation.
However in the precursor ion or neutral loss scan modes, in which Q1 is scanned and the ion signal of a particular product ion is measured, the problem of the low duty cycle of a scanning mass spectrometer reappears. In other words, while the TOF section can indeed measure ions over a wide range, in these experiments, one is only interested in an ion of particular m/z value. Additionally, there is an inherent incompatibility between quadrupole stages, which operate in a continuous flow mode, and a TOF stage with intermittent or pulsed operation. For the QqTOF instruments, the overall ion path transmission is considerably less than that of a QqQ instrument (typically ~1% as efficient as a QqQ due largely to this incompatibility). This is exacerbated by the low duty cycle that reappears in the precursor ion and neutral loss scan modes. Consequently many TOF scans must be acquired at each parent ion mass to generate a precursor ion scan with reasonable signal-to-noise and this also applies for the neutral loss scan. This can increase the time acquired for each such experiment to tens of minutes.
In applicant's U.S. Pat. No. 6,177,668 and also in published international application WO 97/47025, there is disclosed a multipole mass spectrometer provided with an ion trap and an axial ejection technique from the ion trap. The contents of these applications are hereby incorporated by reference.
The technique relies upon emitting ions into the entrance of a rod set, for example a quadrupole rod set, and trapping the ions at the far end by producing a barrier field at an exit member. An RF field is applied to the rods, at least adjacent to the barrier member. The barrier member is supplied with a barrier field to trap ions, and the barrier and RF fields interact in an extraction region adjacent to the exit end of the rod set and the barrier member, to produce a fringing field. Ions in the extraction region are energized, to eject, mass selectively, at least some ions of a selected mass-to-charge ratio axially from the rod set and past the barrier field. The ejected ions can then be detected. Various techniques are taught for ejecting the ions axially, namely scanning the frequency of an auxiliary AC field applied to the end lens or barrier, scanning the amplitude of an RF voltage applied to the rod set while applying a fixed frequency auxiliary voltage to the end barrier and applying an auxiliary AC voltage to the rod set (again scanned in frequency) in addition to, or instead of, that on the lens and the RF on the rods.
It has now been realized that this technique can be used to enhance the performance of a triple quadrupole or QqTOF instrument, or indeed in general any tandem in space MS/MS instrument including a collision cell between two mass analyzers.
SUMMARY OF THE INVENTION
In accordance with a first aspect of the present invention, there is provided a method of mass analyzing a stream of ions, the method comprising the steps of:
(1) passing the ions through a first mass analyzer to select a precursor ion;
(2) subsequently passing the precursor ions into a collision cell containing a gas, to cause dissociation of the precursor ions and the formation of fragment ions, for subsequent analysis, wherein the method includes trapping the fragment ions in the collision cell by means of a potential barrier, and scanning the fragment i
Bereskin & Parr
Lee John R.
MDS Inc.
Wells Nikita
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