Patent Application
20090090853
The present invention relates generally to hybrid mass spectrometers and more specifically to guiding ions to a plurality of mass analyzers in hybrid mass spectrometers.
Triple stage quadrupole mass spectrometers (triple quads) have been in use for many years. These instruments include a quadrupole mass filter Q1 into which ions are guided, a collision cell q downstream from the mass filter Q1, and another quadrupole mass filter Q2 downstream from the collision cell q. A quadrupole mass filter may be operated as a mass filter or as an RF only ion guide. A collision cell may also be operated as an ion guide when collision gas is not present. When both quadrupoles are operated as mass filters, and q is operated as a collision cell, a triple quad may be operated in any of a variety of MS/MS or tandem mass spectrometry modes including precursor ion scan, product ion scan, neutral loss scan, and selected reaction monitoring modes.
Quadrupole mass filters specifically and triple quads in general have several strengths among which are selectability and adjustability of resolution. Ions of one or a range of m/z values may be selected and transmitted from the first quadrupole mass filter Q1 to the collision cell q by suitable adjustment of the amplitude of the RF and DC drive voltages applied to first quadrupole mass filter Q1. Then fragmentation can be caused in the collision cell q, and analysis may be performed in the quadrupole mass filter Q2 to yield greater details about the ions of the m/z or range of m/z values selected for analysis. Also, triple quads are operated by sending an ion beam through the quadrupole devices. Beam instruments operate in space by passing or rejecting or modifying the ion signal as it physically passes through each sequential device. These beam instruments have relatively good resolution and mass accuracy capabilities. However, triple quads have certain limitations including limitations on the number of additional stages of selection and fragmentation that can be performed practically, due to the time required for each step and the less than unity ion transmission of each step. The amount of useful information or specificity increases with each stage, while the amount of useful signal that can be obtained with additional stages of fragmentation and analysis diminishes with each additional stage. Also, since only a single m/z window is transmitted at any given time, in order to obtain information about ions having a broad range of m/z values, such as in a full scan spectrum, additional runs or scans of Q1 and/or Q2 will be required with associated time and duty cycle penalties.
Ion traps have the advantage of being capable of analyzing a whole spectrum in a very short time. They operate by accumulating ion signal in one step and analyze that ion signal rapidly in a subsequent step. MS/MS is accomplished by isolating selected precursor ions in a step subsequent to accumulation, and by fragmenting those ions in a step subsequent to isolation. These steps of isolation and fragmentation can be repeated “n” number of times producing MSn data, another advantage of ion trap mass analyzers. Other ion manipulation operations are also possible. For example, ion traps may be operated in any of a variety of fragmentation modes including collision induced dissociation (CID), electron transfer dissociation (ETD) and pulsed q dissociation (PQD). Many combinations of multiple ion manipulation steps may be concatenated prior to a single analysis step, which consumes the ion population. Each step, however, consumes time, and only the ion accumulation step contributes to sensitivity. The steps other than accumulation contribute to specificity. As a result, since ion signal is not being accumulated during these non-accumulation steps, sensitivity is decreased as the number of these steps increases.
The U.S. Pat. No. 6,177,668 to Hager describes in one of several embodiments a variation on the triple quad in which the third quadrupole, Q2, of the spectrometer can be selectively operated as an ion trap. The spectrometers disclosed in this patent combine some of the advantages of an ion trap with the strengths of a beam type instrument. However, the devices of the Hager spectrometer are operated in both filtering and trapping modes at different times or at different positions in an ion train for generally trapping or triple quad modes of operation.
There is a need for a mass spectrometer with full triple quad capabilities while at the same time providing ion trapping capabilities with attendant ion trapping strengths. There is a need for an instrument that enables both triple quad operation and ion trap operation in such a way that ions may be analyzed in the triple quad at the same time that other ions that have been sent to the trap are being stored and/or analyzed. Furthermore there is a need, such as in drug screening applications, in which more than one stage of fragmentation and analysis is available. That is, three or four stages including the traditional triple quad stages or the triple quad stages in combination with the trap would enable improved identification of ions as well as structural details of the compositions of the samples.
It is to be understood that the more general terms “ion beam device” and “beam device” may be substituted for the more specific terms “quadrupole mass filter” and “quadrupole” as they are described below with reference to a mass analyzer downstream of the ion path switch. These ion beam devices may include, but are not limited to, quadrupole filters, ion mobility spectrometry devices, high field asymmetric ion mobility spectrometry (FAIMS) devices, and drift tubes, for example. It is further to be understood that the more general term “non-beam device” may be substituted for the more specific terms “ion trap mass analyzer” and “trap”, as described with reference to a mass analyzer downstream of the ion path switch. Non-ion beam devices may include, but are not limited to, two dimensional traps, three dimensional traps, electrostatic traps, and time-of-flight mass spectrometers, for example. It is also to be understood that beam devices may be operated as non-beam devices such as when a quadrupole is operated as a linear trap. Non-beam devices may be operated as beam devices such as when a trap is operated to eject a stream or beam of ions.
In a simple form, the mass spectrometer of the present invention may include a mass selection device in an ion path, at least one collision cell downstream of the mass selection device in the ion path, and a beam switch that is also downstream of the mass selection device. The beam switch may have at least a first outlet and a second outlet. At least a first mass analyzer including a beam device and a second mass analyzer including non-beam device may be respectively coupled to the first and second outlets. The first and second mass analyzers are to be located downstream of the mass selection device, the at least one collision cell, and the at least one beam switch. As such, the beam switch can direct an ion beam to a selected one of the first and second mass analyzers.
In an embodiment, the mass selection device may include a quadrupole mass filter. The at least one collision cell may be a single collision cell located upstream in the ion path relative to the beam switch. Alternatively, first and second collision cells may be located downstream in the ion path relative to the beam switch. The first and second collision cells may be located upstream of the first and second mass analyzers, respectively.
The mass spectrometer may include first and second ion paths within the more general ion path described above. In one embodiment, the beam switch has an ion gate with a junction and a valve at the junction. In this embodiment, the valve is switchable between a first switching configuration corresponding to guiding ions along the first ion path toward the first outlet and a second switching configuration corresponding to guiding ions along the second ion path toward the second outlet.
The mass spectrometer in accordance with an embodiment of the present invention includes a controller operably connected to the mass selection device and the first mass analyzer. Under user, software, and/or firmware control, the controller initiates a mode of operation including, but not limited to, one or more of a product ion scan mode, precursor ion scan mode, neutral loss scan mode, and selected reaction monitoring (SRM) mode.
The mass spectrometer in accordance with an embodiment of the present invention may include a controller and a detector in which the controller changes the ion path and directs the ion beam into the second mass analyzer in response to detection of a triggering event by the detector. For example, the triggering event may be an occurrence of an m/z peak in the first mass analyzer.
In another simple form, a mass spectrometer in accordance with the present invention may include a mass selection device in an upstream portion of a branched ion path, at least one collision cell in the branched ion path downstream of the mass selection device, and at least one ion path switch in the branched ion path downstream of the mass selection device. In an embodiment of the invention, the ion path switch is configured to alternatively guide ions toward one of first and second branches of the branched ion path. The mass spectrometer may include at least a first mass analyzer including a beam device and a second mass analyzer including a non-beam device. The first and second mass analyzers in this embodiment are to be respectively located in the first and second branches of the branched ion path downstream of the mass selection device, the at least one collision cell, and the at least one ion path switch. The ion path switch is configured to selectively direct ions along the respective branches of the branched ion path to one of the first and second mass analyzers.
In still another simple form, the present invention includes a method of analyzing samples by tandem mass spectrometry. The method may include generating ions from a sample, selecting precursor ions having mass-to-charge ratios within a range of values, and fragmenting the precursor ions to produce product ions. Subsequent to the step of selecting, the method may include directing the precursor ions or the product ions to a selected one of a first mass analyzer including a beam device and a second mass analyzer of a different type than the first mass analyzer.
The method may include controlling an ion path for the precursor ions or the product ions in which the step of directing further comprises changing the ion path from a first path through the first mass analyzer to a second path through the second mass analyzer. The method may further include changing the ion path in response to a triggering event, such as detecting an m/z ratio peak in the first mass analyzer.
The architecture of a mass analysis instrument in accordance with embodiments of the present invention enables users to obtain valuable additional details including structural information about samples and components of samples that are not readily available with conventional instruments. The architecture is that of a hybrid with a branched ion path in which a particular m/z or range of m/z can be isolated in a first branch and then ions having the same m/z as the isolated ions can be automatically diverted and analyzed in an ion trap in a second branch, for example. Thus, details only available in an ion trap along with details for specific m/z values or ranges of m/z that are only available with mass filters are now made available in the same instrument. The result is increased resolution, selectivity, and/or increased sensitivity for various analyses with a single instrument. As such, additional structural detail regarding a particular precursor or product ion may be obtained immediately by switching the ion beam path from the first path to the second path. In one embodiment the first path may extend through a triple quadrupole portion of the instrument, and the second path may extend into an ion trap portion of the instrument. As may be appreciated, a high sensitivity full scan spectrum can be obtained in the trap. At the same time a second group of ions can be analyzed in the triple stage quadrupole portion while the trap is being operated with ions previously collected. Thus, the instruments in accordance with the embodiments of the present invention also improve duty cycle relative to that which is available in performing two separate experiments in conventional instruments, for example.
Accordingly,
It is to be understood that a first subscript in the description and accompanying figures represents the stage. A second subscript, when present, represents the branch among a plurality of branches. Thus, in the first branch the subscripts for stages three and four of the mass spectrometry would be 3,1 and 4,1, for example. The abbreviations for the various devices in the illustrated examples of instruments use conventional and otherwise easily correlated letters with subscripts to identify the stage and branch. For example, a mass filter has the designation “Q”, an ion guide or collision cell has the designation “q”, and an ion trap has the designation “IT”. Thus, an ion trap forming a fourth stage on a second branch will have the designation IT4,2.
The mass selection device 18, which may take the form of a first quadrupole mass filter Q1, is configured to select (either in a fixed or scanned mode of operation) ions having mass-to-charge ratios (m/z's) within a narrow range of values. Alternatively, the mass selection device may include a Wein filter, momentum analyzer, or some other selection device. The selected ions flow to an entrance end of a branched ion transfer device 15, which includes a trunk corresponding to ion guide 12 joined to first and second branches 40, 41 corresponding to respective ion guides 13 and 14. These ion guides 12, 13, and 14 are also generally labeled q2 since they provide the second stage corresponding to a branched ion transfer device 15 from the mass filter Q1. In the embodiment depicted in
A branched ion path 19 within mass spectrometer 20 is composed of the first and second ion paths 40 and 41 having common and divergent portions. The first ion path 40 extends from the source 1 through first quadrupole mass filter or mass filter 18, branched ion transfer device 15, the mass analyzer 30 in the first branch, and radially or axially to one or more ion detectors 36. If the mass analyzer 30 is a second quadrupole mass filter, then the detectors will be axially located. In any case, the ion detector(s) generate a signal representative of the abundance of ions transmitted through second quadrupole mass filter or mass analyzer 30 in the first ion path 40. Ions traveling along the first ion path 40 experience a first mass selection followed by fragmentation, and a second mass selection of product ions in a manner substantially identical to ions traveling through a conventional triple quad mass spectrometer. As is known in the art, the mass selection device 18 and the mass analyzer 30 may be operated as first and second quadrupole mass filters in prescribed combinations of scanned and fixed (parked) modes to acquire various types of mass spectra of the ions derived from the sample. These modes include, but are not limited to, modes for obtaining precursor ion spectra, product ion spectra, selected reaction monitoring (SRM) spectra, multiple reaction monitoring (MRM) spectra, and neutral loss spectra. Thus, by directing ions along first ion path 40, mass spectrometer 20 is capable of producing results substantially identical to those obtained by employing a conventional triple quad mass spectrometer.
The second ion path 41 extends from the ion source 1 through the first quadrupole mass filter or mass selection device 18, the branched ion transfer device 15, the ion trap 33 of the second ion path 41, and radially or axially into one or more ion detectors 36 (which generates a signal representative of the abundance of ions in the trap 33 and their m/z values). Ions traveling along second ion path 41 experience a first mass selection, followed by fragmentation, trapping, and detection of a spectrum of product and/or precursor ions. The first quadrupole mass filter or mass selection device 18 may be operated in prescribed combinations of scanned and fixed (parked) modes to acquire various types of mass spectra of the ions derived from the sample. The collision cell 42 and/or collision cell 48 may be operated to fragment the ions in any predetermined manner. Thus, the ions analyzed in the ion trap 33 may produce product ion spectra of the ions selected or scanned by the mass filter or mass selection device 18. Therefore, by directing ions along the second ion path 41, mass spectrometer 20 is capable of detecting more structural details and generating full spectra showing those details for a whole sample or a selected range of m/z values within the sample, as is only possible in an ion trap.
It is to be understood that Q1 may be operated in RF only mode and there may be no collision gas in a subsequent stage. In this way the ions may be introduced without having been filtered or fragmented into the ion trap, and the trap may be operated as a regular trap. When operated in this way, a collision gas in the trap may be used to cause collision induced dissociation at resonant frequencies for ions of particular m/z value(s) for MSn. Alternatively, Q1 may be operated as a filter to mass select a particular m/z or range of m/z with no collision gas in a subsequent stage. Then the ions may be introduced into the trap for regular operation of the trap including collision induced dissociation for MSn. Implementing mass selection in Q1 may provide the benefits of reducing space charge effects and increasing mass resolution in the subsequent ion trap, or to reduce the time for ion selection and thereby increase duty cycle. Further alternatively, Q1 may be operated as a filter, a subsequent stage may include a collision cell q2, and the trap may be operated for MSn where n is equal to 3 or more.
To enable the selective operation of the mass spectrometer 20 as a triple quad or an ion trap, the branched ion transfer device 15 may have a downstream end that includes two or more outlets connected to respective downstream portions of the branched ion path 19. Each of the trunk and branches correspond to respective ion guides 12, 13, and 14 and may be integral with the rest of the branched ion transfer device 15 (as shown in the embodiment of
The embodiment of
In
Embodiments of the invention are not limited to an architecture having a beam device in one branch and a non-beam device in another branch. Rather, embodiments may include a system having two beam devices in respective branches. In one case, the mass analyzer 33 may have a magnetic sector device instead of the trap IT3,2, and additional stages may or may not be added downstream. Alternatively, the system may have two non-beam devices such as a quadrupole ion trap, and a TOF (or orbitrap), for example. Any combination of beam and non-beam devices may be incorporated in any number of branches without limitation.
During use of the illustrated embodiments, when additional structural information yielding identification or verification of ions is a goal, a path of the ions can be switched to enter the second mass selection device 33 of ion path 41 in
The controller 51 is also configured to select a mode of operation. The controller 51 is operably connected to the first mass selection device 18 and the mass analyzer 30 downstream of the branched ion transfer device 15/29 in the first ion path 40. The controller 51 initiates an analysis mode of operation from among several modes. For example, the controller can select a product ion scan mode and cause the mass selection device 18 to operate as a mass filter to select ions of a predetermined m/z. In this mode, the controller 51 further causes the mass analyzer 30 (also labeled Q3,1) in the first ion path 40 to scan product ions received from the collision cell 42/45 in the product ion scan mode. The controller 51 can alternatively or additionally select one or more other modes including, but not limited to, a precursor ion scan mode, a neutral loss scan mode, a selected reaction monitoring (SRM) mode, and a multiple reaction monitoring (MRM) mode. For each of these modes, the controller initiates the mode, causes the mass selection device 18 to scan ions through a predetermined range of m/z values or to select ions by filtering all ions but those having a predetermined range of m/z. Then the controller causes the mass analyzer 30 (also labeled Q3,1) to operate as a mass filter or scanning device to select ions having a predetermined m/z ratio received from the collision cell 42/45 or to scan them. Additional information about the ions can be obtained by switching the path of the ions such that they enter the mass analyzer 33 (also labeled IT3,2 or Trap) of the second ion path 41 for additional or alternate analysis.
When energized with an appropriate RF voltage and placed in a position that forms a continuous space within the branched quadrupole ion guide 52, the flipper 81 helps to form an ion gate or an ion beam gate that inhibits passage along one path and facilitates passage of ions along another path. The ion path switch 83 is actually an ion beam switch that includes an ion gate with a junction and a valve at the junction. The flipper 81 is analogous to a movable shutter in a mechanical valve. However, as will be described below, the valve or gate need not be mechanical or electromechanical.
The ion gates need not include specific structure having first and second branch sections. It is also to be understood that electromechanical ion gates are not limited to the specifics of a “flipper” like that disclosed above and in U.S. patent application Ser. No. 11/542,076, entitled SWITCHABLE BRANCHED ION GUIDE, filed Oct. 2, 2006, and Provisional Patent Application Ser. No. 60/799,813, entitled SWITCHABLE BRANCHED ION GUIDE, filed May 5, 2006, both by Alan E. Schoen, both of which are incorporated herein by reference in their entirety. While the flippers 81/107 together with internal structural features of the branched ion guides at respective junctions help to form ion gates or ion beam gates with valves, many other switching mechanisms and movements may be incorporated without limitation. For example, devices that are moveable or rotatable in other ways or about other axes such as the movable guide of U.S. Pat. No. 5,825,026 to Baykut, incorporated herein by reference, may be substituted for the switches or ion gates disclosed herein without departing from the spirit and scope of the present invention.
With further reference to
In the embodiment of
In an example of a method that may be implemented in accordance with an embodiment of the present invention, a mode of operation for a mass spectrometer may be selected under software or firmware control. The modes of operation may include, but are not limited to, product ion scan mode, precursor scan mode, neutral loss scan mode, selected reaction monitoring (SRM) mode, and multiple reaction monitoring (MRM). In another preliminary step of the method, an m/z ratio or range of ratios of interest may be selected in a mass filter. Ions may be generated from a sample in any manner including, but not limited to, electrospray ionization. One or more steps in the method may include fragmentation of the ions. Another step that may be implemented before or after the step of fragmentation is a step of determining an ion path or path branch for the precursor and/or product ions.
In accordance with the method, a mass spectrometer may be initially operated under software or firmware control to guide ions of an ion beam along a first portion of a branched path through a first mass analyzer, which may include a quadrupole or other multipole device. This may be considered a first mode of operation as indicated by block 221 in
It has been found that while additional information is made available by these hybrids, higher resolution and greater sensitivity to match or exceed that of respective portions of the instrument can result. For example, sensitivity to match that of the triple stage quadrupole is maintained when the method is carried out in the selected reaction monitoring (SRM) mode while enabling full spectrum information from the trap in a second portion of the instrument on the range of m/z selected in the mass analyzer of the first portion of the instrument. Furthermore, it is contemplated that for ions that fragment extensively, such as steroids and proteins, the collection of full scan MS/MS in these hybrids would likely provide additional ion current. Thus, monitoring multiple reaction pathways for these compounds would provide improved sensitivity over the triple stage quadrupole portion of the instrument, for example.
In accordance with embodiments of the present invention, ions can be fragmented prior to entering the ion trap. Because ions are fragmented prior to entering the ion trap, the time that would have been spent fragmenting them in the trap can be spent analyzing the ions. Therefore, duty cycle is improved. Furthermore, by fragmenting the ions prior to their entry into the ion trap, a problem of low mass cutoff is avoided. That is, when the ions are fragmented in the ion trap, the required frequency for fragmenting also eliminates ions at or below a particular threshold mass. Low mass cutoff is not a problem when the fragmentation is implemented prior to introduction of the ions into the trap.
To at least in part reiterate an advantage of embodiments of the present invention, mass spectrometers and associated methods in accordance with the embodiments of the present invention enable increased duty cycle. For example, after the ion path has been switched so that a first group of ions is being analyzed in the ion trap of the second mass analyzer, a second group of ions may be analyzed in the first mass analyzer while the first group of ions is being analyzed in the second analyzer. Similar advantages may be perpetuated in third, forth, and any number of additional stages of collision cells, beam or path switches, and mass analyzers. These stages may be added and interconnected in any combination without departing from the spirit and scope of the invention.
The architecture of the instrument in accordance with embodiments of the invention has been described in terms of first and second mass analyzers in first and second branches or ion paths, respectively. These mass analyzers have been shown and described as including a quadrupole mass filter or other beam device in the first branch or ion path and an ion trap or non-beam device in the second branch or ion path. It is to be understood, however, that any combination of mass analyzers may be placed in the first and second branches or ion paths. For example, the first mass analyzer in the first branch may be an ion trap or other non-beam device while the second analyzer in the second branch may be a time-of-flight (TOF) analyzer. Alternatively, the first and second mass analyzers in the first and second branches may be respective first and second ion trap mass analyzers or other devices. Still further, the branched path configuration with an ion beam or path switch at the junction of the branches may be implemented with a linear trap upstream of the switch and a variety of analyzers in the respective branches downstream of the switch. The downstream analyzers may include an electrostatic trap and a TOF, for example.
The embodiments and examples set forth herein were presented in order to best explain the present invention and its practical application and to thereby enable those of ordinary skill in the art to make and use the invention. However, those of ordinary skill in the art will recognize that the foregoing description and examples have been presented for the purposes of illustration and example only. The description as set forth is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the teachings above without departing from the spirit and scope of the forthcoming claims. For example, it is to be understood that features of any of the embodiments disclosed or incorporated herein may be applied to any other of the embodiments disclosed or incorporated herein without limitation. All such combinations are considered to be within the spirit and scope of the invention.
