Patent Grant
8415617
The present invention relates generally to mass spectrometers, and more particularly to a two-dimensional radial-ejection ion trap mass analyzer.
Two-dimensional radial-ejection ion traps have been described extensively in the literature (see, e.g., Schwartz et al., “A Two-Dimensional Quadrupole Ion Trap Mass Spectrometer”, J. Am. Soc. Mass Spectrometry, 13: 659-669 (2002)) and are widely used for mass spectrometric analysis of a variety of substances, including small molecules such as pharmaceutical agents and their metabolites, as well as large biomolecules such as peptides and proteins. Generally described, such traps consist of four elongated electrodes, each electrode having a hyperbolic-shaped surface, arranged in two electrode pairs aligned with and opposed across the trap centerline. At least one of the electrodes of an electrode pair is adapted with an aperture (slot) extending through the thickness of the electrode in order to permit ejected ions to travel through the aperture to an adjacently located detector. Ions are radially confined within the ion trap interior by applying opposite phases of a radio-frequency (RF) trapping voltage to the electrode pairs, and may be axially confined by applying appropriate DC offsets to end sections or lenses located axially outward of the electrodes or central sections thereof. To perform an analytical scan, a dipole resonant excitation voltage is applied across the electrodes of the apertured electrode pair (often referred to as the X-electrodes because they are aligned with the X-axis of a Cartesian coordinate system, which is oriented such that X and Y are the radial axes of the trap and Z is the longitudinal axis extending along the trap centerline) while the amplitude of the RF trapping voltage is ramped. This causes the trapped ions to come into resonance with the applied excitation voltage in order of their mass-to-charge ratios (m/z's). The resonantly excited ions develop unstable trajectories and are ejected from the trap through the aperture(s) of the X-electrodes to the detectors, which generate signals representative of the number of ejected ions. The detector signals are conveyed to a data and control system for processing and generation of a mass spectrum.
It has long been recognized that the presence of the aperture(s) in the X-electrodes causes distortion in the desired quadrupolar trapping field, in particular adding negative octopolar (where both X-electrodes are apertured) and other higher even-order field components. These field distortions have been found to have operationally significant effects when the ion trap is employed for analytical scanning, including but not limited to ion frequency shifting and degradation of mass accuracy. One way in which ion trap designers have attempted to compensate for aperture-caused field distortions and minimize the associated adverse effects is by outwardly displacing the apertured electrodes (the X-electrodes), such that the apertured electrodes are positioned at a slightly greater distance from the trap centerline relative to the un-apertured electrodes. This outward displacement helps cancel (or can invert) the field distortions caused by the apertures in the electrodes. A drawback to this approach (commonly referred to as “stretching” the trap) is that when RF voltages are applied to the electrodes in the normal manner (whereby electrodes of one electrode pair receive a voltage equal in amplitude and opposite in polarity to the electrodes of the other electrode pair), the resultant electric field is not balanced, causing the centerline of the device to exhibit a significant RF potential. When ions are then introduced into the trap interior along the centerline, for a given RF amplitude the acceptance of the ions can be significantly m/z-dependent, which is an undesired behavior. Furthermore, ions in a misbalanced field can effectively oscillate with different frequencies in the X- and Y-dimensions, which eliminates the possibility of conducting phase-locked resonance experiments in both dimensions. In addition, due to the octopolar field component, the oscillation frequency shifts associated with a changing ion trajectory amplitude are in opposite directions for ion motion in the X and Y-dimensions.
Various approaches to balancing the RF field in a radial-ejection two-dimensional ion trap have been proposed in the prior art, including altering the hyperbolic surface profiles of the apertured electrodes to reduce their radii of curvature relative to the non-apertured electrodes (see U.S. patent application Ser. No. 11/437,038 by Senko, entitled “System and Method for Implementing Balanced RF Fields in an Ion Trap Device”), and applying RF voltages of different amplitudes to the apertured and non-apertured electrodes (see U.S. patent application Ser. No. 11/437,087 by Schwartz, also entitled “System and Method for Implementing Balanced RF Fields in an Ion Trap Device”). However, the implementation of these approaches may be difficult in practice and may significantly increase the cost and/or complexity of manufacturing and operating the mass spectrometer instrument.
Accordingly, there remains a need in the mass spectrometry art for a two-dimensional radial ejection ion trap which minimizes or eliminates the adverse performance effects of field distortion arising from the presence of the ejection apertures while maintaining a balanced RF electric field.
In accordance with an illustrative embodiment, a two-dimensional radial-ejection ion trap is constructed from four elongated electrodes arranged about the trap centerline. Each of the electrodes has an inwardly directed hyperbolic surface defining a hyperbolic radius r0 and a longitudinally extending aperture. The four electrodes are equally spaced from the centerline by a distance r, wherein r is greater than r0, such that both electrode pairs are stretched by equal amounts relative to the “normal” spacing. When a trapping RF voltage is applied to the electrodes in the conventional manner, with one electrode pair receiving an oscillatory voltage that is equal in amplitude and opposite in polarity to the voltage applied to the other electrode pair, a balanced RF field is generated. This balanced field significantly reduces the m/z dependence of the ion injection process and allows ions having a wide m/z range to be injected at the same RF amplitude. In addition, it allows ion injection to be performed at high RF amplitudes (corresponding to high values of the Mathieu parameter q) relative to injection into a conventional unbalanced field, which has advantages relating to space charge capacity, elimination of unwanted low m/z ions, and higher ion frequency dispersion (facilitating higher resolution isolation or ejection of ions during ion injection). A further advantage of an ion trap of the foregoing construction is that the RF field produced thereby does not possess a significant octopolar field component; instead, the principal higher order field component is dodecapolar or icosapolar, which has advantages including that any ion frequency shifting is the same in both radial (X and Y) dimensions. This permits, for example, phase-locked resonance excitation to be performed between the X and Y dimensions.
Another potentially advantageous aspect of an ion trap constructed in accordance with an embodiment of the invention is that its field is symmetrical and more closely approximates that of a conventional round-rod quadrupole mass filter. Thus, the ion trap (alternatively referred to as a multipole structure) may be configured to be selectably operable as a radial-ejection ion trap mass analyzer or (by removing the DC potential well and adding a resolving DC component to the applied RF voltage) as a quadrupole mass filter analyzer. Thus, in another illustrative embodiment, a mass spectrometer is provided having an ion source for generating ions from a sample, a set of ion optics for guiding the ions from the ion source, a multipole device comprising four apertured elongated electrodes having hyperbolic surfaces arranged around the centerline such that each electrode is spaced at a stretched distance r from the centerline, and a controller, coupled to the multipole device, for applying RF and DC voltages to the electrodes to selectively operate the multipole device as a quadrupole mass filter or a two-dimensional radial-ejection ion trap mass analyzer. One specific implementation of this embodiment includes a quadrupole mass filter and a collision cell located upstream in the ion path from the multipole device, so that the mass spectrometer is operable (by adjustment of the RF and DC voltages applied to the multipole device) as a triple quadrupole mass spectrometer or as a hybrid Q-trap mass spectrometer.
In the accompanying drawings:
The operation of the various components of mass spectrometer 100 is directed by a control and data system (not depicted in
While mass spectrometer 100 is depicted as being configured for an electrospray ion source, it should be noted that the ion trap 140 may be employed in connection with any number of pulsed or continuous ion sources (or combinations thereof), including without limitation a matrix assisted laser desorption/ionization (MALDI) source, an atmospheric pressure chemical ionization (APCI) source, an atmospheric pressure photo-ionization (APPI) source, an electron ionization (EI) source, or a chemical ionization (CI) ion source. Furthermore, although
Electrodes 205a,b,c,d (or a portion thereof) are coupled to an RF trapping voltage source 240, excitation voltage source 245, and DC voltage source 250, all of which communicate with and operate under the control of controller 255, which forms part of the control and data system. RF trapping voltage source is configured to apply RF voltages of adjustable amplitude in a prescribed phase relationship to pairs of electrodes 205a,b,c,d to generate a trapping field that radially confines ions within the interior of ion trap 140. Excitation voltage source 245 applies an oscillatory excitation voltage of adjustable amplitude and frequency across at least one pair of opposed electrodes to create a dipolar excitation field that resonantly excites ions for the purposes of isolation of selected species, collision induced dissociation, and mass-sequential analytical scanning. During a mass-sequential analytical scan, the excitation and RF trapping voltage amplitudes may be temporally varied in accordance with calibrated relationships experimentally determined by known techniques, or by the technique described in the U.S. patent application by Philip M. Remes et al. entitled “Methods Of Calibrating And Operating An Ion Trap Mass Analyzer To Optimize Mass Spectral Peak Characteristics” and filed on even date herewith, the disclosure of which is incorporated by reference. DC voltage source is operable to apply DC potentials to electrodes 205a,b,c,d or sections thereof to, for example, generate a potential well that axially confines ions within ion trap 140. In an alternative configuration, axial confinement is achieved by applying an oscillatory voltage across the electrode end sections or electrodes positioned axially outward of electrodes 205a,b,c,d to generate an axial pseudo-potential well. This alternative configuration provides the capability of simultaneous axial confinement of ions of opposite polarities, which is useful for certain ion trap functions, such as electron transfer dissociation (ETD) in which positive analyte ions are reacted with negative reagent ions to yield product ions.
x2−y2=r02
for the X-electrode pair 310, and
x2−y2=−r02
for the Y-electrodes 320. Stretching X-electrodes 310 and Y-electrodes 320 by equal amounts produces an RF field (upon application of the RF voltages) that possesses X-Y (i.e., four-fold rotational) symmetry and has a zero RF potential at centerline 305. The elimination of the centerline RF potential substantially reduces the m/z dependence of the ion injection process and enables injection of ions having a wide range of m/z's at the same RF trapping voltage amplitude. In addition, the balanced RF field allows ion injection to be conducted at relatively high trapping RF voltage amplitudes (and correspondingly high values of the Mathieu parameter q), which possesses advantages of higher space charge capacity, elimination of unwanted low m/z ions, and higher ion frequency dispersion (which facilitates higher-resolution mass selection during ion injection). In a typical construction, each electrode 205a,b,c,d is spaced from the centerline by a distance r equal to at least 1.01*r0, and preferably in the range of 1.07*r0 to 1.2*r0.
The RF field produced within ion trap 140 has a higher-order field component (alternatively referred to as a field distortion) that is primarily dodecapolar with a smaller icosapolar (20-pole) component. As is known in the art, a two-dimensional electric potential Φ(x,y,t) may be expanded in multipoles ΦN(x,y) as follows:
where V(t) is the voltage applied between an electrode and ground, and AN is the dimensionless amplitude of the multipole ΦN(x,y). Conventional radial-ejection two-dimensional ion traps, as well as the axial-ejection round-rod two-dimensional ion traps and multipoles described by Soudakov et al. in U.S. Pat. No. 6,897,438 (“Geometry of Generating a Two-Dimensional Substantially Quadrupolar Field”) produce RF fields that exhibit a relatively high octopole amplitude A4; Soudakov et al. prescribe the deliberate introduction of an octopole field component that has an amplitude A4 in the range of 1-4% of the quadrupole field amplitude A2. In contradistinction, the RF field generated by ion trap 140 theoretically has no octopole field component, amplitude A4, but a relatively large dodecapole amplitude A6 and smaller icosapole A10 amplitude respectively. The dodecapole field amplitude (and icosapole field) will depend on the degree of stretching of electrode pairs 310 and 320. Typically, the electrodes will be positioned to produce a dodecapole field amplitude of at least 0.2%, and preferably between 0.5 and 0.9% of the quadrupole field amplitude, and an octopole field amplitude of less than 0.001% of the quadrupole field amplitude (which may arise from imprecision in the electrode symmetry). In some cases, the stretch may be such that the dodecapole field is minimized (ideally to zero) while the icosapole (20-pole) field remains.
While the ion trap electrodes are preferably formed with hyperbolic surfaces, other implementations may utilize electrodes having inwardly curved surfaces of different shapes, including “round rod” electrodes of generally cylindrical geometry.
In another embodiment of ion trap 140, only the electrodes of one opposed pair (e.g., X-electrodes 310) are adapted with apertures opening to the exterior of the ion trap. Each electrode of the other opposed pair (e.g., Y-electrodes 320) is instead adapted with a recess or indentation that extends radially outward from the hyperbolic surface but does not traverse the full thickness of the electrode. The recesses will typically have a length approximately equal to the length of the apertures. The cross-sectional geometry of the recesses is selected such that the recesses and apertures affect the RF field in substantially identical manners, i.e., the recesses produce field faults equivalent to those produced by the apertures. This embodiment may be favorable for applications where ions are to be ejected in only one dimension (e.g., the X-dimension).
The balanced, symmetric RF field established within ion trap 140, as well as the presence of apertures in both electrode pairs 310 and 320, enable the use of various techniques and modes of operation that are difficult or impossible to implement in conventional ion traps that have asymmetric trapping fields with a relatively high octopole field component. For example, ions may be resonantly excited in both the X-dimension and Y-dimension, for the purpose of producing ion fragmentation or ejection, by applying oscillatory excitation voltages of identical frequency across X-electrodes 310 and Y-electrodes 320 (in a conventional ion trap, the excitation voltage is applied across a single electrode pair.) Preferably, the excitation voltages are applied in a constant phase relationship of adjustable value. In another example, ions may be mass-sequentially ejected through the apertures of Y-electrodes in addition to the apertures of X-electrodes, and the ions ejected through the Y-electrodes may be detected by an second set of detectors (not depicted) located adjacent thereto. As is described in the aforementioned U.S. Pat. No. 6,797,950 to Schwartz et al., simultaneous analytical scans may be performed at different mass ranges by applying resonant excitation voltages of different frequencies across the X-electrodes and Y-electrodes; for example, an excitation voltage of relatively low frequency may be applied across Y-electrodes 320, resulting in the mass-sequential ejection through the Y-electrodes of ions in a range of fairly high m/z values (e.g., 2000-20,000) while an excitation voltage of fairly high frequency may be applied across X-electrodes 310 to effect mass-sequential ejection through the X-electrodes of ions in a range of fairly low m/z values (e.g., 200-2000). According to a variant of this technique, “artifact” peaks caused by the misassignment of m/z values to ions that are not ejected at the proper value of the Mathieu parameter q (which may occur, for example, if ions undergo fragmentation as they approach the resonance point, if the excitation voltage amplitude is inadequate to eject all ions at their resonance point, or by reformation of analyte ions from clusters) may be eliminated or substantially reduced by applying an excitation voltage across the Y-electrodes at reduced frequency relative to the excitation voltage applied across the X-electrodes (which places qy>qx). In this manner, ions that have “jumped” over the resonance point associated with ejection in the X-dimension do not reach the detectors located adjacent to X-electrodes 310 (which would result in the generation of an artifact peak), but are instead ejected in the Y-dimension through Y-electrodes 320.
As depicted in
Another advantage of the symmetric construction of ion trap 140 is that it may be operated as a quadrupole mass filter (QMF) to provide m/z-filtering of a continuous or quasi-continuous ion beam. In contrast, a conventional radial ejection ion trap, in which only two of the four electrodes are apertured, is generally not suitable for use as a QMF due to its X-Y asymmetry. Operation of ion trap 140 in QMF mode requires the inclusion of a filtering DC component in the RF voltages applied to electrodes 205a,b,c,d, such that one electrode pair (e.g., X-electrode pair 310) receives a potential of +(U−V cos ωt) and the other electrode pair (e.g., Y-electrode pair 320) receives a potential of −(U−V cos ωt), where U is the filtering DC component, and V is the amplitude of the RF voltage. As is known in the art, the m/z range of the transmitted ions is determined by the values of U and V, and ions having a desired range of m/z values may be selected for transmission by appropriately adjusting the values of U and V. When operated in QMF mode, ion trap 140 may be “parked” by temporally fixing the values of U and V such that only a single ion species is transmitted, or may instead be “scanned” by progressively changing U and/or V such that the m/z of the transmitted ions varies in time. In order to improve the resolution of ion trap 140 when operated in QMF mode, electrodes 205a,b,c,d may be lengthened relative to a standard two-dimensional ion trap mass analyzer. Lengthening the electrodes would also provide increased ion storage capacity and hence improved sensitivity when operation in ion trap mode is desired.
When operation in ion trap mode is desirable, the filtering DC component is removed, and suitable DC offsets are applied to the end sections of electrodes 205a,b,c,d and/or to axial trapping electrodes 180 and 185 to establish a potential well that enables trapping of ions within the interior volume of multipole device 140. The ions may then be subjected to one or more stages of isolation and fragmentation, if desired, and the ions or their products may be mass analyzed by resonantly ejecting the ions to detectors 190, in accordance with known techniques. According to one preferred implementation, the frequency of the excitation voltage applied by excitation voltage source 250 during an analytical scan is equal to one-half or one-third of the frequency of the RF trapping voltage, and the phase of the excitation voltage is locked to the RF trapping voltage such that the phase relationship is maintained at a constant preselected value during the scan. Those skilled in the art will recognize that the value of the Mathieu parameter q at which ions are ejected will depend on the ratio of the frequencies of the excitation and RF trapping voltages. So as to provide extended mass operation, i.e., the ability to detect ions over a larger range of m/z's, the excitation voltage frequency may be set to a relatively small integer fraction, e.g. 1/7, of the trapping voltage frequency. In order to provide acceptable trapping efficiencies and to enable collision induced fragmentation during operation in the ion trap mode, a damping/collision gas may be added to the interior of multipole device 140 during its operation in ion trap mode. When multipole device 140 is switched to QMF mode, the damping/collision gas may be pumped away such that the interior volume is maintained at a low pressure conducive to good filtering performance.
In one particularly favorable implementation, multipole device 140 may be automatically switched between ion trap and QMF modes in a data-dependent manner, whereby the acquisition of mass spectral data that satisfies specified criteria triggers mode switching. For example, multipole device 140 may initially be operated in QMF mode to provide single ion monitoring (SIM) of an ion species of interest. When detector 410 generates a signal indicative of the presence of the ion species of interest, multipole device 140 may be automatically switched to operation in ion trap mode in order to perform MS/MS or MSn analysis for confirmation of the identification of the ion species of interest or to provide structural elucidation.
When multipole device 140 is operated in QMF mode, mass spectrometer 500 functions as a conventional triple quadrupole mass spectrometer, wherein ions are selectively transmitted by QMF 510, fragmented in collision cell 520, and the resultant product ions are selectively transmitted by multipole device 140 to detector 540. Samples may be analyzed using standard techniques employed in triple quadrupole mass spectrometry, such as precursor ion scanning, product ion scanning, single- or multiple reaction monitoring, and neutral loss monitoring, by applying (either in a fixed or temporally scanned manner) appropriately tuned RF and DC voltages to QMF 510 and multipole device 140.
Switching multipole device 140 to ion trap mode (which may be done in a data-dependent manner, as discussed above in connection with the
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
| Number | Name | Date | Kind |
|---|---|---|---|
| 7947948 | Schwartz | May 2011 | B2 |
| 8198580 | Schwartz et al. | Jun 2012 | B2 |
| 20040149903 | Wang | Aug 2004 | A1 |
| 20080210860 | Kovtoun | Sep 2008 | A1 |
| Number | Date | Country | |
|---|---|---|---|
| 20110186733 A1 | Aug 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12205750 | Sep 2008 | US |
| Child | 13085696 | US |
