Radiant energy – Ionic separation or analysis
Reexamination Certificate
2003-05-29
2004-08-24
Lee, John P. (Department: 2881)
Radiant energy
Ionic separation or analysis
C250S287000, C250S282000, C250S288000, C250S298000
Reexamination Certificate
active
06781117
ABSTRACT:
BACKGROUND
1. Field of Invention
This invention relates to the field of analytical mass spectrometry. Specifically it introduces a new apparatus and methods for the identification and quantification of target compounds in a mixture by means of accepting an ion beam composed of either a single mass or ion clusters from an ion source, and further analyzing the ion beam by a controlled collision in a collision cell operated with direct current (DC) potentials, followed by mass analysis of the resulting fragments or de-clustered ions. More specially, the invention relates to the method of utilizing the collision cell to fragment ions at either high or low collision energy. Furthermore, the invention relates to methods of ionizing neutral fragments inside the collision cell and; also reacting ionic components within the collision cell with externally introduced counter ions or electrons—then analyzing these newly formed ionic species.
2. Description of Prior Art
Collisional induced dissociation (CID) is employed in tandem mass spectrometry is elucidate structural information of gas-phase ions derived from the ionization of organic and inorganic ions. The use of mass spectrometry to select gas-phase ions (precursor ions) for CID and analysis of the resulting fragments (product ions), has been extensively described in various reviews (Hoffmann, E., “Tandem mass spectrometry: A Primer,” J. Mass Spectrom. 31, pages 129-137,1996; Busch, K. L., Glish, G. L., McLuckey, S. A., “Mass Spectrometry/Mass Spectrometry: Techniques and Applications of Tandem Mass Spectrometry,” VCH Publishers: New York (1988), Yost, R. A., Fetterolf, D. D., Tandem mass spectrometry (MS/MS) instrumentation,” Mass Spectrom. Rev. 2, pages 1-45, 1983).
The oldest mass spectrometric configuration for tandem mass spectrometry is the combination of magnetic mass (B) and an electrostatic energy (E) sectors. The energy sector produces an ion kinetic energy separation providing information on metastable or CID ions. If a ‘field-free’ area is interposed between sectors, high energy ions are injected into this ‘field-free’ collision area undergoing collisions with the background gases (such as, helium or argon). Due to the low gas pressure (10
−3
torr), and the high forward velocity of the ion, there are very few collisions with the background gas. A collision, if it occurs, primarily involves a transfer of energy to the electrons of the molecule—resulting in odd-electron product ions. Because there are few collisions, the MS/MS spectrum typically shows a prominent precursor ion and low ion abundance of product ions.
If sectors are configured with a quadrupole collision cell and a quadrupole mass analyzer, both high and low energy collisions are possible (such as EBqQ). For low energy collisions, precursor ions are first selected with magnetic and electrostatic sectors, decelerated, then injected into high pressure quadrupole collision cell where they undergo multiple collisions with the background gas, and then mass analyzed with the second quadrupole. This Leads to product ion mass spectra that are similar to product ion spectra as observed in triple quadrupole MS/MS instruments (see below).
Other configurations utilizing sector analyzers have been configured and commercialized. In one alternative a time-of-flight mass analyzer (TOF) is placed in tandem with the sector analyzers and a surface induced collision (SID) cell, with the TOF mass analyzer performing high-resolution mass analysis of the product ions resulting from high energy collisions from SID.
The use of 3-dimensional ion traps (3-D IT) for MSIMS analysis using low-energy collisions is typified by Syka et al. (U.S. Pat. No. 4,736,101), Bier et al (U.S. Pat. No. 5,420,425), and Scwartz et al (U.S. Pat. No. 5,572,002). MS/MS analysis with the use of the 3-D IT uses at least two distinct mass analysis steps. First, a desired m/z is isolated in the trap by ejecting undesired ions during an ion accumulation step. This is performed using one of several techniques, such as applying a DC potential to the ring electrode, applying selective RF (waveforms), or scanning the RF so the undesirable ions are pass through the trap and are not accumulated. After the undesired ions are ejected from the trap, fragments or product ions can be formed when the ions that have remained in the trap are excited by applying a RF potential causing the ions to resonate (referred to as resonance excitation) and experience multiple collisions (low-energy) with the background gas, usually helium, inside the ion trap. The RF voltage (and possibly DC) is then readjusted to contain these lower mass fragments. The second MS step is then performed by ejecting the fragment ions by using a mass selective instability scan, such as, manipulation of the radio frequency amplitude, RF frequency, supplemental AC field amplitude, supplemental AC field frequency, or a combination thereof to eject ions out of the trap and collection and detection by a electron multiplier—thus performing two mass spectrometry steps with one device (MS/MS in time). Additional steps of accumulation, ejection, and fragmentation can be performed leading to MS/MS
n
(MS/MS to the nth degree, n=1, 2, 3, . . . ).
Other configurations utilizing 3-D IT assemblies as MSIMS analyzers have been configured and commercialized. In one alternative a time-of-flight mass analyzer is placed in tandem with a 3-D IT, with the TOF mass analyzer performing high-resolution mass analysis of the product ions. In others, a 3-D IT or a 2-D linear IT (q) replaces the third quadrupole in a triple quad system (see below), allowing further fragmentation of the product ions, leading to MS/MS
n
(see Bier et al., U.S. Pat. No. 5,420,425 for a 2-D linear IT). Recently a 2-D linear IT has been combined with a fourier transform mass spectrometer (Qq-FTMS), resulting in high-resolution mass analysis of the product ions similar to 3-D IT-TOF and the Q-TOF (see below).
Enke et al (U.S. Pat. No. 4,234,791) have described a quadrupole mass spectrometer system-three quadrupoles in tandem, typically referred to as a triple quad (QqQ). The first quadrupole is operated in a mode where both RF and DC voltages are applied to the rods and a resolution is chosen (by choosing a ratio of RF/DC ratio) to select one ion mass (or mass range) from the first quadrupole and then introducing it into a second quadrupole. The second quadrupole is operated with no DC voltage and at elevated pressures (millitorr range) relative to the first and third quadrupole, and only a relatively small RF voltage (usually ⅓-½ of the Rf of the first quadrupole) is applied to the rods. In this mode, the second quadrupole acts as a ‘high pass mass filter’—rejecting the passage of all masses below a certain mass (commonly referred to as low mass cutoff) and passing all masses above this mass. Fragments, or product ions, can then be formed by passing (or injecting) the precursor ions from the first quadrupole into the second quadrupole at elevated pressures and colliding these ions with a neutral gas, such as argon, nitrogen, or just air in combination with a voltage difference (commonly referred to as in-lab collision energy, typically 10-100 ev) between the lens before the entrance to the first quadrupole and second quadrupole. The fragments in the second quadrupole are then passed to the third quadrupole.
The third quadrupole, operated in a similar manner to the first quadrupole, can pass one particular mass. This mode being commonly referred to SRM (selective reaction monitoring). Alternatively, the third quadrupole is scanned (varying the RF/DC ratio) and placing ions exiting the second quadrupole producing a mass spectrum of the collision fragment ions emerging from the second quadrupole. Other configurations utilizing quadrupole assemblies have been configured and commercialized. The third quadrupole has been replaced with a time-of-flight (TOF) mass analyzers, resulting in a Q-TOF instruments having the ability of producing high resolution mass spectra of product ion. A
Sheehan Edward W
Willoughby Ross C
Hashmi Zia R.
Lee John P.
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