Radiant energy – Ionic separation or analysis – Methods
Reexamination Certificate
2002-04-01
2004-12-21
Lee, John R. (Department: 2881)
Radiant energy
Ionic separation or analysis
Methods
C250S281000, C250S284000, C250S288000, C250S290000, C250S42300F, C250S42300F
Reexamination Certificate
active
06833544
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to multiple stage mass spectrometers which have two mass analyzers, and this invention is more particularly concerned with both a method of and an apparatus for providing multiple stages of mass spectrometry (MS
n
) capabilities in such spectrometers.
BACKGROUND OF THE INVENTION
Tandem mass spectrometry is widely used for trace analysis and for the determination of the structures of ions. In tandem mass spectrometry a first mass analyzer selects ions of one particular mass to charge ratio (or range of mass to charge ratios) from ions supplied by an ion source, the ions are fragmented and a second mass analyzer records the mass spectrum of the fragment ions. In a triple quadrupole mass spectrometer system, this effects MS/MS. For example, ions produced in an atmospheric pressure source, pass through a region of dry nitrogen and then pass through a small orifice, into a region at a pressure of about 5 torr (0.7 kPa). Ions then pass through a quadrupole ion guide, operated at a pressure of about 7×10
−3
torr (9.1×10
−4
kPa) into a first quadrupole mass filter, operated at a pressure of about 2×10
−5
torr (2.6×10
−6
kPa). Precursor ions mass selected in the first quadrupole are injected into a collision cell filled with gas, such as argon, to a pressure of 10
−4
to 10
−2
torr (1.3×10
−5
to 1.3×10
−3
kPa). The collision cell contains a second quadrupole ion guide, to confine ions to the axis. Ions gain internal energy through collisions with the gas and then fragment. The fragment ions and any undissociated precursor ions then pass into a second mass analyzer, and then to a detector, where the mass spectrum is recorded.
Triple quadrupole systems are widely used for tandem mass spectrometry. One limitation is that recording a fragment mass spectrum can be time consuming because the second mass analyzer must step through many masses to record a complete spectrum. To overcome these limitations, QqTOF systems have been developed. This system is similar to the triple quadrupole system but the second mass analyzer is replaced by a time-of-flight mass analyzer, TOF. The advantage of the TOF is that it can record 10
4
or more complete mass spectra in one second. Thus for applications where a complete mass spectrum of fragment ions is desired the duty cycle is greatly improved with a TOF mass analyzer and spectra can be acquired more quickly. Alternatively for a given measurement time, spectra can be acquired on a smaller amount of sample.
A further known technique is the coupling of electrospray ionization (ESI) to time-of-flight mass spectrometers (TOFMS), and this is an attractive technique for mass spectrometry. ESI is a soft ionization technique capable of forming ions from a broad range of biomolecules, while TOFMS has the well known advantages of rapid mass scanning, high sensitivity, and a theoretically limitless mass range. However, ESI and TOFMS are, in one way, incompatible as a source/analyzer pair: ESI creates a continuous stream of ions and TOFMS requires pulsed operation. Thus in the simplest coupling of ESI to TOFMS there is a very poor duty cycle, with less than 1% of the ions formed being detected and early work in this field was predominantly concerned with increasing the duty cycle.
Within the past two years, literature on ESI-TOFMS has begun to focus on tandem mass spectrometry (MS/MS) with hybrid instruments. The fragmentation of ions in these systems is achieved via traditional methods for collision induced dissociation (CID). Tandem-in-space systems termed quadrupole-TOF's or “Qq-TOF's”, as noted above, are analogous to triple quadrupole mass spectrometers—the precursor ion is selected in a quadrupole mass filter, dissociated in a radiofrequency- (RF-) only multipole collision cell, and the resultant fragments are analyzed in a TOFMS. Tandem-in-time systems use a 3-D ion trap mass spectrometer (ITMS) for selecting and fragmenting the precursor ion, but pulse the fragment ions out of the trap and into a TOFMS for mass analysis.
It is sometimes desirable to perform multiple stages of tandem spectrometry termed MS
n
. In MS
3
for example, a precursor ion is selected in a first mass analyzer and dissociated to produce fragment ions. A fragment ion of a particular mass to charge ratio is then isolated and dissociated again to produce fragments of the fragment. The mass spectrum of these is then recorded. Multiple stages of MS are useful when insufficient dissociation can be produced in a first stage of MS/MS or to elucidate dissociation pathways of complex ions. The latter for example is especially useful to sequence peptides and other biomolecules by mass spectrometry.
The triple quadrupole system and QqTOF system described above provide only one stage of MS/MS and do not allow MS
n
. In particular such systems do not provide for trapping of ions.
In one known proposal, in PCT application WO 98/06481 from Analytica of Brantford, there is a described system including ion trapping. Ions from a source are injected into a multipole ion guide, and ions of one m/z or range of m/z are then isolated in the ion guide by applying resonant excitation or AC/DC voltages to the ion guide and trapping voltages at either end. The ion is then fragmented in the same ion guide, which can be operated as a linear ion trap (LM. No mass analyzer is placed before the ion guide. This is a distinct disadvantage, since a multipole ion guide used both for ion isolation and mass analysis has a relatively low resolution. For example, the present inventors have found that using a LIT as described by Analytica the resolution in isolating an ion is ca. 100. With a separate quadrupole mass filter or other mass analyzer before the ion trap the resolution can be many thousand. The relatively low resolution for ions introduced into the multipole ion trap may derive from at least two sources: (1) the pressure is relatively high (10
−3
-10
−1
torr (1.3×10
−4
to 1.3×10
−2
kPa) as described in the PCT application); and (2) in the system described in the PCT application the gas is either nitrogen or air that flows in from the ion source. This has a greater damping effect on ion motion in the LIT than lighter gases such as helium, and gives relatively poor resolution for resonant excitation of ions. Such a system does not readily enable the pressure and type of gas in the LIT to be adjusted to provide optimum conditions for MS
n
.
Additionally, there have been some recent examples of proposals using resonant excitation in RF-only quadrupoles for CID with fragment mass analysis by TOFMS. Dodonov et al (Rap. Comm. Mass Spectrometry 11, 1649-1656 (1997)) introduced a molecular ion reactor (MIR) consisting of a segmented RF-only quadrupole with a longitudinal electrical field which is operated at a high pressure. Depending on the mode of operation, CID was accomplished through either increasing the RF or DC voltages along the segments. However, no trapping of ions was demonstrated.
Loboda et al (proceedings of the 46th ASMS Conference on Mass Spectrometry and Allied Topics, Orlando, Fla., May 31-Jun. 4, 1998, MOD. 11: 55) modified the RF drive of the collision cell in a Q-TOFMS to apply quadrupolar excitation to ions flowing through the cell, inducing fragmentation. No trapping of ions was demonstrated. It was suggested that a 2D trap might be formed to isolate precursor ions, but it was not stated if this was to be done before or after a stage of mass analysis.
B. A. Thomson et al, in PCT application PCT/CA96/00541, describes a method and apparatus for speeding up the passage of ions through various stages of a mass spectrometer, such as the ion guide and the collision cell. The increase in ion speed is achieved via an axial DC field which can be created through various multipole rod configurations. The axial DC field also aids in the dissociation of ions in collision cells by oscillating the ions axially about their equilibrium
Campbell Jennifer
Collings Bruce
Douglas Donald J.
Abeles Daniel C.
Eckert Seamans Cherin & Mellott , LLC
University of British Columbia
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