Multiple stage mass spectrometer

Details Multiple stage mass spectrometer Multiple stage mass spectrometer

2000-08-25

2002-11-19

Anderson, Bruce (Department: 2881)

Radiant energy

Ionic separation or analysis

Cyclically varying ion selecting field means

C250S282000, C250S287000

Reexamination Certificate

active

06483109

ABSTRACT:

FIELD OF THE INVENTION
The invention generally relates to mass spectrometers and specifically to tandem mass spectrometers. More specifically the invention is directed to a mass spectrometry apparatus and method that provides an effective solution for multiple stage mass spectrometric analysis and coupling of low resolution multiple stage mass spectrometry devices with external high-resolution mass spectrometers.
BACKGROUND OF THE INVENTION
Traditionally tandem mass spectrometers (MS-MS) have been employed to provide structural information for samples of interest. In MS-MS instruments, a first mass spectrometer is used to select a primary ion of interest, for example, a molecular ion of a particular biomolecular compound such as a peptide, and that ion is caused to fragment by increasing its internal energy, for example, by colliding the ion with a neutral molecule. A second mass spectrometer then analyzes the spectrum of fragment ions, and often the structure of the primary ion can be determined by interpreting the fragmentation pattern. The MS-MS instrument improves the recognition of a compound with a known pattern of fragmentation and also improves specificity of detection in complex mixtures, where different components give overlapping peaks in simple MS. In the majority of applications the detection limit is defined by the level of chemical noise. Drug metabolism studies and protein recognition in proteome studies are good examples. Frequently, MS-MS techniques can also improve the detection limit. When analyzing certain samples it is often desirable to conduct further analyses of fragments produced from the originally selected ion, and such further analyses consist of repeated sequences of mass to charge ratio (m/z) isolation and fragmentation. In some cases different m/z fragments derived from a single parent ion are further analyzed, and in other cases a single m/z fragment is subjected to a succession of “n” mass spectrometric steps to yield relevant information regarding the original parent ion. This continued mass spectrometric analyses is referred to in the art as MS
n
analyses. Various types of mass spectrometers have been employed to conduct MS
n
analysis as discussed below.
A three-dimensional ion trap (3-D IT) is one of the most flexible devices for MS-MS and multi-step (MS
n
) analysis. This trap is composed of a ring electrode and two end cap electrodes of special shape to create a quadrupolar distribution of potential. Radio frequency (RF) and DC offset electric potentials are applied between electrodes and cause ions to oscillate within the trap. By appropriately selecting voltage parameters, ions of a specific mass/charge ratio can be made to have stable or unstable trajectories. In another implementation an additional (auxiliary) AC voltage is applied to the end-caps to induce resonant excitation of selected ions either for the purpose of ejecting the selected ions or for the purpose of inducing collisional dissociation.
The 3-D ion trap is capable of single step mass spectrometric analysis. In such analysis ions are injected into the trap (or generated within the trap), confined to the center of trap because of low energy collisions with an inert gas such as helium (typically at 1 mtorr pressure) and then sequentially ejected through the apertures in the end cap electrodes onto an external detector by raising the amplitude of the RF field. The same device could be used for a multi-step, i.e. MS
n
, analysis. The ion trap isolates ions in a m/z window by rejecting other components, then fragments these isolated ions by AC excitation, then isolates resulting ion fragments in a m/z window and repeats such sequence (MS
n
operation) in a single cell. At the end of the sequence ions are resonantly ejected to acquire the mass spectrum of N-th generation fragments. The 3-D IT is vulnerable to sensitivity losses due to ion rejection and instability losses at the time of ion selection and fragmentation.
Fourier transform ion cyclotron resonance mass spectrometry (FTMS) currently provides the most accurate measurement of ion mass to charge ratios with a demonstrated resolution in excess of 100,000. In FTMS, ions are either injected from outside the cell or created inside the cell and confined in the cell by a combination of static magnetic and electric fields (Penning trap). The static magnetic and electric field define the mass dependent frequency of cyclotron motion. This motion is excited by an oscillating electric potential. After a short period the applied field is turned off. Amplifying and recording weak voltages induced on the cell plates by the ion's motion detects the frequency of ion motion and, thus, the m/z of the ion. Ions are selectively isolated or dissociated by varying the magnitude and frequency of the applied transverse RF electric potential and the background neutral gas pressure. Repeated sequences of ion isolation and fragmentation (MS
n
operation) can be performed in a single cell. An FIMS is a “bulky” device occupying a large footprint and is also expensive due to the costs of the magnetic field. Moreover, an FTMS exhibits poor ion retention in MS
n
operation (relative to the 3-D ion trap).
Currently, the most common form of tandem mass spectrometer is a triple quadrupole, where both mass spectrometers are quadrupoles and an RF only quadrupole functions as a collisional cell to enhance ion transport. Because of low scanning speed the instrument employs continuous ion sources like ESI and atmospheric pressure chemical ionization (APCI). Since scanning the second mass spectrometer would cause losses, the most effective way of using this instrument is monitoring of selected reactions. Drug metabolism studies are a good example where a known drug compound is measured in a rich biological matrix, like blood or urine. In those studies both parent and daughter fragment masses are known and the spectrometer is tuned on those specific masses. For more generic applications requiring scanning, the triple quadrupole instrument is a poor instrument choice because of its low speed, sensitivity, mass accuracy and resolution.
Recently hybrid instruments combining quadrupoles with time of flight analyzers (Q-TOF) have been described where the second quadrupole mass spectrometer is replaced by an orthogonal time of flight spectrometer (o-TOF). The o-TOF back end allows observation of all fragment ions at once and the acquisition of secondary spectra at high resolution and mass accuracy. In cases where the full mass range of daughter ions is required, for example, for peptide sequencing, the Q-TOF strongly surpasses the performance of the triple quadrupole. However, the Q-TOF suffers a 10 to a 100 fold loss in sensitivity as compared to a single quadrupole mass filter operating in selected reaction monitoring mode (monitoring single m/z). For the same reason the sensitivity of the Q-TOF is lower in the mode of “parent scan” where, again, the second MS is used to monitor a single m/z.
More recently, the quadrupole has been replaced by a linear ion trap (LIT). The quadrupole with electrostatic “plugs” is capable of trapping ions for long periods of time. The quadrupole field structure allows one to apply an arsenal of separation and excitation methods, developed in 3-D ion trap technology, combined with easy introduction and ejection of the ion beam out of the LIT. The LIT eliminates ion losses at selection and also can operate at poor vacuum conditions which reduces requirements on the pumping system. However, a limited resolution of ion selection, R<200, has been demonstrated thus far.
All of the existing MS
n
devices suffer from a common drawback in that they do not provide a capability for storing results of multiple MS steps with the concomitant capability to explore multiple branches of fragmentation using the same ion material. The current state of the art is that the sequence of functional steps (selection, cooling, fragmentation and analysis) is done either “in-time” while keeping results in the same cell, as in ion trap and FTMS devic

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