Patent Grant
11810773
The present invention relates generally to mass spectrometry and mass spectrometers and, more particularly, relates to operation of electrostatic trap mass analyzers and to operation of mass spectrometer systems employing electrostatic trap mass analyzers.
Electrostatic traps are a class of ion optical devices where moving ions experience multiple reflections or deflections in substantially electrostatic fields. Unlike trapping in RF field ion traps, trapping in electrostatic traps is possible only for moving ions. Thus, a high vacuum is required to ensure that this movement takes place with minimal loss of ion energy due to collisions over a data acquisition time Tm. Since its commercial introduction in 2005, the ORBITRAP™ mass analyzer, which belongs to the class of electrostatic trap mass analyzers, has become widely recognized as a useful tool for mass spectrometric analysis. In brief, the ORBITRAP™ mass analyzer, which is commercially available from Thermo Fisher Scientific of Waltham Massachusetts USA, is a type of electrostatic trap mass analyzer that is substantially modified from the earlier Kingdon ion trap.
In both FT-ICR and ORBITRAP™ mass analyzers, ions are compelled to undergo collective oscillatory motion within the analyzer that induces a correspondingly oscillatory image charge in neighboring detection electrodes, thereby enabling detection of the ions. The oscillatory motion used for detection may be of various forms including, for example, circular oscillatory motion in the case of FT-ICR and axial oscillatory motion while orbiting about a central electrode in the case of a mass spectrometer system or mass analyzer of the type schematically illustrated in
The oscillating ions induce oscillatory image charge and oscillatory current at frequencies which are related to the mass-to-charge (m/z) values of the ions. Each ion of a given mass to charge (m/z) value will oscillate at a corresponding given frequency such that it contributes a signal to the collective ion image current which is generally in the form of a periodic wave at the given frequency. The total detected image current of the transient is then the resultant sum of the image currents at all the frequencies present (i.e., a sum of periodic signals). Frequency spectrum analysis (such as Fourier transformation) of the transient yields the oscillation frequencies associated with the particular detected oscillating ions; from the frequencies, the m/z values of the ions can be determined (i.e. the mass spectrum) by known equations with parameters determined by prior calibration experiments.
More specifically, an ORBITRAP™ mass analyzer includes an outer barrel-like electrode and a central spindle-like electrode along the axis. Referring to
Other types of ion storage apparatuses may be employed in place of the C-trap. For example, the aforementioned U.S. Pat. No. 6,872,938 teaches the use of an injection assembly comprising a segmented quadrupole linear ion trap having an entrance segment, an exit segment, an entrance lens adjacent to the entrance segment and an exit lens adjacent to the exit segment. By appropriate application of “direct-current” (DC) voltages on the two lenses as well as on the rods of each segment, a temporary axial potential well may be created in the axial direction within the exit segment. The pressure inside the trap is chosen in such a way that ions lose sufficient kinetic energy during their first pass through the trap such that they accumulate near the bottom of the axial potential well. Subsequent application of an appropriate voltage pulse to the exit lens combined with ramping of the voltage on a central spindle electrode causes the ions to be emptied from the trap axially through the exit lens electrode and to pass into the electrostatic orbital trapping mass analyzer 4.
The electrostatic orbital trapping mass analyzer 4 comprises a central spindle shaped electrode 6 and a surrounding outer electrode which is separated into two halves 8a and 8b.
where a, b, c, and d are constants determined by the dimensions of and the voltage applied to the orbital trapping analyzer electrodes, and where z=0 is taken at the axial position corresponding to the equatorial plane of symmetry 7 of the electrode structure. The “bottom” or zero axial gradient point of the portion of “quadro-logarithmic potential” dependent on the axial displacement (i.e. the portion which determines motion in the axial dimension, z, along the longitudinal axis 9) occurs at the equatorial plane 7. This potential field has a harmonic potential well along the axial (Z) direction which allows an ion to be trapped axially within the potential well if it does not have enough kinetic energy to escape. It should be noted that Eq. 1 represents an ideal functional form of the electrical potential and that the actual potential in any particular physical apparatus will include higher-order terms in both z and r.
The motions of trapped ions are associated with three characteristic oscillation frequencies: a frequency of rotation around the central electrode 6, an orbital frequency about a nominal rotational radius and a frequency of axial oscillations along the z axis. In order to detect the frequencies of oscillations, the motion of ions of a given m/z need to be coherent. The radial and rotational oscillations are only partially coherent for ions of the same m/z as differences in average orbital radius and size of radial oscillations correspond to different orbital and radial frequencies. It is easiest to induce coherence in the axial oscillations as ions move in an axial harmonic potential so axial oscillation frequency is independent of oscillation amplitude and depends only on m/z. Therefore, the axial oscillation frequencies are the only ones used for mass-to-charge ratio determinations. The outer electrode is formed in two parts 8a, 8b as described above and is shown in
Ions having various m/z values which are trapped within the C-trap are preferentially injected from the C-trap into the electrostatic orbital trapping mass analyzer 4 in a temporally and spatially short packet through an ion inlet aperture 5 that is located at an axial position that is offset from the equatorial plane 7 of the analyzer. This off-center ion injection geometry enables so-called “excitation by injection” whereby the ions of the ion packet immediately commence orbital motions about the central electrode 6 as well as other oscillations within the mass analyzer in the quadro-logarithmic potential. The ions of the packet are injected into the ion inlet aperture 5 along an initial injection trajectory that is essentially tangential to the stable orbital trajectories within the mass analyzer. The ions oscillate axially between the two outer electrodes 8a and 8b while also orbiting around the inner electrode 6. The axial oscillation frequency of an ion is dependent on the m/z values of the ions contained within the ion packet so that ions in the packet with different m/z begin to oscillate at different frequencies.
The two outer electrodes 8a and 8b serve as detection electrodes. The oscillation of the ions in the mass analyzer causes an image charge to be induced in the electrodes 8a and 8b and the resulting image current in the connected circuitry is sensed as a signal that is amplified by an amplifier 10 (
The information processor 14 performs a Fourier transformation (or other mathematical transformation) on the data of the received transient. For example, the mathematical method of discrete Fourier transformation may be employed to convert the transient in the time domain, which comprises the mixture of periodic transient signals which result from the mixture of m/z present among the measured ions, into a spectrum in the frequency domain. If desired, at this stage or later, the frequency domain spectrum can be converted into the m/z domain by straightforward calculation. The discrete Fourier transformation produces a spectrum which has a profile point for each frequency or m/z value, and these profile points form a peak at those frequency or m/z positions where an ion signal is detected (i.e. where an ion of corresponding m/z is present in the analyzer).
The mass spectrometer system 1 also includes one or more power supplies 18 that provide(s) appropriate oscillatory radio frequency (RF) and non-oscillatory (DC) voltages to electrodes of the ion source 3, the ion storage apparatus 2, the electrostatic orbital trapping mass analyzer 4 and other not-illustrated mass spectrometer components through various electrical lines or cables such as the lines or cables 27a, 27b and 27c, such voltages being necessary for the proper operation of the mass spectrometer. The electrodes to which voltages are provided include various electrostatic lenses and ion guides, some of which are illustrated in this document. The information processor 14, which may comprise one or more computers and/or logic controllers, provides control signals to the one or more power supplies 18 which control the timing and magnitude of voltages provided over the electrical lines or cables 27a-27c by the one or more power supplies 18. The timing of the controlled application of the various voltages may be controlled algorithmically by computer-readable instructions that are embedded within or are otherwise accessible by the information processor 14. Such instructions may be generally adaptable to the analytical requirements of various users and/or various samples. As is generally understood, the mass spectrometer system 1 also includes various not-illustrated vacuum pumps and associated evacuation lines and may comprise various other not-illustrated mass filtering, ion trapping and/or ion reaction components.
Ion injection into an ORBITRAP™ electrostatic trap mass analyzer and other electrostatic trap mass analyzers is a complex process compared to other mass spectrometry ion manipulations. The complexity arises as a result of the requirement to set the initial conditions of injected ions relatively far away from where they are detected. Ions that are to be injected are allowed to come to their thermal velocities in about 1 mtorr pressure of nitrogen within the C-trap or other ion storage apparatus 2. Subsequently, in practice, the electrical potential of the C-trap is raised from ground potential to an appropriate voltage (e.g., about 2400 V if the central spindle electrode 6 is at a voltage of about −5 kV) that causes the ejection of ions towards the ORBITRAP™ ion entrance slot 5. En-route to the electrostatic trap mass analyzer, the ions pass through several electrostatic lenses, some of which are necessary for differential pumping concerns, while others attempt to shape the beam itself.
As shown in
The above-described ion injection mechanism works quite well, at least for “first-order” effects like capture of ions and observation of accurate mass assignments and ion abundances. However, for “second-order” effects, such as ion-ion interactions, and long-term ion cloud stability, the details of the injection process may become important. In particular, if the beam is spatially very small upon injection, then the possibility of ion-ion interactions is greater, and this condition improves long term ion cloud stability. Conversely, if the beam is more spread upon injection, ion-ion interactions are reduced, and highest mass resolutions are more difficult to achieve. The principal of ion-ion interaction affecting electrostatic trap mass spectrometry is ion cloud coupling, in which two clouds closely spaced in frequency of motion tend to acquire the same frequency, leading to observation of one mass spectral peak where there should be two. This phenomenon is known as peak coalescence.
In general, subtle change in mass analysis performance characteristics can result when injection conditions are varied slightly. In particular, if the beam is focused tightly, then the ion cloud may become compressed, leading to stronger ion-ion interactions. Strong interactions between different ion species having different mass-to-charge ratio (m/z) values produce negative consequences for ion cloud coupling and its mass spectral representation, peak coalescence. Conversely, if the beam is spread spatially upon entering the trap, ion-ion interactions are weaker, leading to improved resolution of closely spaced peaks, such as isotopic variant peaks.
Reduction of peak coalescence can be achieved through changing specific injection and transfer voltages, but these changes can potentially adversely affect other mass spectral characteristics, such as differential ion cloud loss of coherence, resulting in loss of isotope ratio fidelity.
This disclosure describes methods for exploiting ion optical lens aberrations in order to spread ion packets upon their entrance into an electrostatic trap, therefore leading to better space-charge tolerance without affecting other important performance characteristics. The novel methods in accordance with the present teachings exploit transfer-lens aberrations in order to control the degree of ion packet spreading at an injection slot of the electrostatic trap. According to one aspect of the present teachings, if the ion packet is directed slightly away from the central axis of a focusing lens, then ion optical geometrical aberrations will come into effect, and not all portions of an ion packet will have the same focal point at the slot. Stated differently, each ion packet will be spatially spread out at the injection slot. Directing the ion packets as described herein can be accomplished by changing the field strength of one or more transfer lenses upstream from the focusing lens, thereby inducing a lens asymmetry. In such an asymmetric configuration, ions may exit a transfer lens at a trajectory that is at an angle from that at which the ions entered the transfer lens. The ions traversing the resulting partially deflected trajectory will then enter the focusing lens along a line that is displaced from the central axis of the focusing lens. As a result, a focal region may be slightly shifted either upstream or downstream from an ion entrance aperture of the electrostatic trap and the ions of each packet will be spatially dispersed upon entrance into the trap.
In accordance with some embodiments of the present teachings, a method of operating a mass spectrometer system comprising an electrostatic trap mass analyzer, comprises:
In accordance with some other embodiments of the present teachings, a mass spectrometer system is provided, the system comprising:
The first and second ion packets may be derived from a single sample or from separate samples. The use of a first and a second mode of operation of the electrostatic lenses that are used to transfer the ions of the first and second packets, respectively, or the application of first and second injection voltages during the transfer of the first ion packet and the second ion packet, respectively, can enable different mass spectral characteristics to be separately optimized during the first and second mass analyses, respectively. For example, during one of the mass analyses, the mode of operation or the injection voltage may be chosen so that the introduced packet of ions is brought to a line focus or otherwise diffuse focal region upon entrance into the electrostatic trap, thereby reducing charge density within the trap during the analysis. Such reduced charge density can reduce undesirable peak coalescence within a mass spectrum that results from the mass analysis but may adversely affect other mass spectral characteristics, such as overall resolving power and isotope ratio fidelity.
If the two packets of ions are derived from a single sample, then the mode of lens operation or the applied injection voltage during the injection of the other packet may be chosen so as to optimize these other mass spectral characteristics. If the two packets of ions comprise different ion population sizes, either because they are derived from different samples or else from different portions or fractions of a same sample, then the change from a first to a second mode of lens operation or the change from a first to a second injection voltage may be made based on and in response to the different ion population sizes. For example, lens operating modes and/or injection voltages that disperse the focus and the ion cloud within the mas analyzer may be employed for large ion populations (i.e., ion packets having a large number of ions), whereas lens operating modes and/or injection voltages that maintain a tight focus and compact ion cloud within the mass analyzer may be employed for analyses of small ion populations.
The computer instructions of the information processor of the mass spectrometer system may be further operable to digitally analyze a mass spectrum generated by the mass analysis of the first packet of ions and to automatically, in response to the digital analysis of the mass spectrum, cause a change of the mode of operation of the electrostatic lenses from the first to the second mode of operation or a change of the injection voltage from the first to the second pre-determined magnitude. For example, if the digital analysis detects an undesirable level of peak coalescence within the mass spectrum, the computer instructions may automatically cause a change of either the mode of operation of the electrostatic lenses from the first to the second mode of operation or a change of the injection voltage from the first to the second pre-determined magnitude in response to the detected level of peak coalescence, whereby the change or changes are such as to reduce the level of peak coalescence in the subsequent mass analysis of the second packet of ions. On the other hand, if the digital analysis detects an acceptably low level of peak coalescence within the mass spectrum, the computer instructions may automatically cause a change of either the mode of operation of the electrostatic lenses from the first to the second mode of operation or a change of the injection voltage from the first to the second pre-determined magnitude, whereby the change or changes are such as to improve overall resolving power or to improve isotope ratio fidelity in the subsequent mass analysis of the second packet of ions.
The above noted and various other aspects of the present invention will become apparent from the following description which is given by way of example only and with reference to the accompanying drawings, not drawn to scale, in which:
The following description is presented to enable any person skilled in the art to make and use the invention, and is provided in the context of a particular application and its requirements. Various modifications to the described embodiments will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiments and examples shown but is to be accorded the widest possible scope in accordance with the features and principles shown and described. The particular features and advantages of the invention will become more apparent with reference to the appended figures taken in conjunction with the following description.
In the description of the invention herein, it is understood that a word appearing in the singular encompasses its plural counterpart, and a word appearing in the plural encompasses its singular counterpart, unless implicitly or explicitly understood or stated otherwise. Furthermore, it is understood that, for any given component or embodiment described herein, any of the possible candidates or alternatives listed for that component may generally be used individually or in combination with one another, unless implicitly or explicitly understood or stated otherwise. Additionally, it will be understood that any list of such candidates or alternatives is merely illustrative, not limiting, unless implicitly or explicitly understood or stated otherwise. Moreover, it is to be appreciated that the figures, as shown herein, are not necessarily drawn to scale, wherein some of the elements may be drawn merely for clarity of the invention. In addition, reference numerals may be repeated among the various figures to show corresponding or analogous elements.
Unless otherwise defined, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. It will be appreciated that there is an implied “about” prior to the quantitative terms mentioned in the present description, such that slight and insubstantial deviations are within the scope of the present teachings. In this application, the use of the singular includes the plural unless specifically stated otherwise. In addition, the use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. As used herein, “a” or “an” also may refer to “at least one” or “one or more.” Also, the use of “or” is inclusive, such that the phrase “A or B” is true when “A” is true, “B” is true, or both “A” and “B” are true.
As used herein, the term “DC” (for “Direct Current”) is used only for the purpose of designating a non-oscillatory voltage or non-oscillatory electrical potential applied to an electrode and does not necessarily imply the existence of a current that is carried by the movement of electrons through wires, electrodes or other conductors. The term “DC” is thus used herein to distinguish the referred-to voltage(s) from applied periodic oscillatory voltages, which themselves may be referred to as either “RF” (radio frequency) or “AC” voltages.
In the following discussion, the electrodes 33a and 33b of the lens 33 are referred to as entrance electrodes of the lens because ions that arrive from the ion storage apparatus 2 first enter the lens between these two electrodes. Similarly, the electrodes 33c and 33d are referred to as exit electrodes because ions exit the lens 33 between this latter pair of electrodes. The electrodes 33b and 33c are herein referred to as being “diametrically-opposed to one another” or as a “pair of diametrically-opposed electrodes” because they are disposed both at opposite ends of the lens 33 relative to one another and are also disposed on opposite sides of an ion pathway (31, 32, 39) through the lens 33. For a similar reason, the electrodes 33a and 33d are also herein referred to as being “diametrically-opposed to one another” or as a “pair of diametrically-opposed electrodes.”
The nominal operation of the transfer lens 33 is achieved when the ion path into the lens is precisely midway between the pair of entrance electrodes 33a, 33b and the pair of exit electrodes 33c, 33d and when the electric field between electrodes 33c, 33d is precisely reversed (i.e., same magnitude and opposite direction) relative to the electric field between the electrodes 33a, 33b. Accordingly, the direction of motion of the exiting ions may be caused to be non-parallel to the direction of motion of the incoming ions by either manipulation of the electric fields between the entrance and exit electrode pairs and/or by manipulation of the positions of the electrodes. Such latter operation in which the trajectories of ions entering and exiting the ion transfer lens 33 are not parallel to one another is herein referred to as a perturbed or non-nominal operation of the lens.
As shown in
The ion trajectory calculations that are schematically depicted in
The inventors theorize that the greater calculated width w32 of ion packets that enter the electrostatic trap from the perturbed lens system, as compared to the calculated width w31 of ions packets that enter the trap from the nominal lens system arises from the combined aberrational effects of focus shifting and astigmatism that are introduced by the controlled perturbation. The greater initial spatial spread of ions that are introduced from the perturbed lens system is theorized to be able to reduce undesirable coupled ion-ion interactions between ion species having differing mass-to-charge ratios within the electrostatic trap, thereby reducing peak coalescence. This idea was tested in the laboratory using a nominally symmetric transfer lens 33. Data were taken using the lens in its nominal (symmetric, unperturbed) state, as well as with 50 μm shims inserted near the entrance aperture, similar to the depiction of
The above discussion relates to increasing the spatial spread of ion packets entering an electrostatic trap mass analyzer by introducing a perturbation into an ion transfer lens that guides the ion packets from an ion storage apparatus into the mass analyzer. Similar effects may be achieved by introducing perturbations into a focusing upstream from an ion injection aperture of the mass analyzer. Accordingly,
In accordance with some methods of the present teachings, the entire lens 36, comprising apertured plate electrodes 37a, 37b and 37c, may be translated, as a unit, relative to its nominal position. The shaded electrodes in
Simple translations of the ion focusing lens 36 parallel to only the x-axis cause the focus of the lens to shift parallel to the same axis either upstream or downstream from the ion inlet aperture 5 relative to the nominal focal point within the ion inlet aperture. In each instance, the focal point moves the same distance, Δx36, as the lens is moved. Movement of the lens focal point upstream from the ion inlet aperture (such as to the vicinity of point f32 in
Simple translations of the ion focusing lens 36 parallel to only the y-axis cause a shift of the lens central axis 41 so that it no longer coincides with the center of the pathway 39 of incoming ions (the pathway assumed here to be fixed by the ion transfer lens 33). In this case, ions that traverse the pathway 39 experience unbalanced repulsive forces from the electric field produced by the energized central plate electrode 37b. Such a shift can thus perturb the lens focusing properties of the lens 36 in a fashion similar to that previously described in reference to perturbation of the ion transfer lens 33. Specifically, the lens focal point will move upstream from its nominal position, thereby enlarging the spatial spread of ion packets as they enter the electrostatic trap mass analyzer.
According to an alternative mode of operation of the ion focusing lens 36, the lens assembly remains in a fixed position and, instead of moving the lens, the focal length of the lens is perturbed by means of adjustment of the voltage that is applied to the center plate electrode 37b of the lens. Increasing this voltage relative to its nominal value decreases the focal length, thereby causing the ion pathway 39 to come to a focus upstream from the ion injection aperture 5 of the electrostatic trap apparatus 4. Subsequently, the voltage applied to the center plate electrode may be reduced so as to cause the focus to move in the opposite direction back towards, and perhaps beyond the ion injection aperture. As noted above, the adjustment of the focal position can increase the spatial spread of ion packets entering the electrostatic trap, relative to nominal operating conditions and this increased spatial spread can reduce mass spectral peak coalescence.
Arrow 46 in
The application of the first and second voltages to the lens 43, as described above in accordance with the first mode of operation, causes the ion trajectories to converge to a focal line 45 instead of converging to a point-like focus f31, f32, as would otherwise occur using the Einzel focusing lens 36 (
According to a second mode of operation of the quadrupole lens 43, which is not specifically illustrated in the drawings, voltages of V0+ΔV (where may be either negative or positive) are applied to both of the pairs of electrodes of the lens such that the ion trajectories converge to a point-like focus, similar to the to a point-like foci 131, 132 that are depicted in
Diagrams 72, 74 and 76 of
Increasing ellipticity of orbits about the central electrode can lead, in many measurement situations, to one or more of the disadvantageous effects of: diminished overall resolving power, lower signal-to-noise ratio, reduced dynamic range and reduced isotope ratio fidelity. (Note that the term “isotope ratio fidelity” refers to the degree to which an experimentally observed isotope abundance ratio matches an expected isotope abundance ratio.) Nonetheless, the same phenomenon may provide beneficial effects in some other measurement situations. In particular, increasing orbital ellipticity causes each introduced packet of ions to occupy a larger proportion of the measurement chamber 17 of an electrostatic trap, as shown in
From the above considerations, the inventors have realized that it is advantageous for operators of electrostatic trap mass analyzers to be able to control ion injection conditions into the electrostatic trap so as to balance tradeoffs between frequently beneficial metrics like signal-to-noise ratio and isotopic ratio fidelity, and, at other times, beneficial increased ion-ion separation. In some instances, the changing of ion injection conditions may occur between analyses of different samples in response to different analytical needs between samples. In other instances, the changing of ion injection conditions may occur during repeated analyses of a single sample or even of a single analyte in order to maximize the types and/or quality of information obtained about the analyte. Accordingly,
In step 51 of the method 50 (
After a certain pre-determined quantity of ions have been stored in the ion storage apparatus or, equivalently, after having accumulated ions for a certain pre-determined duration of time, the next step 53 is executed. In this step, the ion transfer and focusing lens system is configured so as to cause the accumulated packet of ions to exit the ion storage apparatus towards the mass analyzer. The release of the ion packet from the ion storage apparatus occurs under the impetus of an electrical potential difference applied between the lens system and the ion storage apparatus.
During the transfer of the ion packet in step 53, the ion transfer and focusing lens system may, in some instances, be configured in a first configuration so as to cause the packet of ions to enter an ion inlet aperture of the mass analyzer in a spatial configuration that causes the mass analyzer to yield mass spectra in accordance with a first desired performance characteristic or desired set of performance characteristics. In other instances of execution of step 53, a voltage of a first pre-determined magnitude may be applied to an electrode of the mass analyzer so as to yield mass spectra in accordance with the first desired performance characteristic or characteristics. In yet other instances of execution of step 53 both the ion transfer and lens system and the mass analyzer injection voltage may be configured in accordance with the desired performance characteristic(s). As but one example, a first desired performance characteristic may relate to reduction of coalescence of mass spectral peaks that correspond to separate ion species, such as isotopic variants of a single species of molecular ion, that have closely similar m/z values.
If, prior to the execution of step 53, the ion transfer and focusing lens system is not already in an appropriate operating configuration for producing mass spectra having the desired performance characteristic or characteristics, then the execution of step 53 includes reconfiguring the ion transfer and focusing lens system into the proper operating configuration. The reconfiguring may include mechanical displacement of one or more electrodes of the lens system, as indicated by the displacement, Δy33, as indicated in
Step 54 is executed once the packet of ions has been transferred from the ion storage apparatus to the electrostatic trap mass analyzer. In this step, the ion transfer and focusing lens system is reconfigured such that no additional ions are transferred out of the ion storage apparatus and such that the transferred packet of ions is trapped within the mass analyzer. During this step, mass analysis of the packet of ions is performed by the mass analyzer and mass spectral data is generated. Execution of the method 50 then returns to step 52 in which a new packet of ions is accumulated within the ion storage apparatus. All or a portion of the accumulation of the new packet of ions (step 52) in the ion storage apparatus may occur simultaneously with the mass analysis of the prior packet of ions (step 54) in the electrostatic trap mass analyzer. After the completion of the mass analysis, any remaining ions from the prior packet of ions are expelled from the mass analyzer and, once the new packet of accumulated ions is ready to be transferred from the ion storage apparatus, execution may optionally return to the step 52. Optionally, execution of the method 50 may repeatedly loop through the steps 52-54 a variable number of times. The exact number, m, of times that the loop is executed (where m≥1) depends on many experimental variables, such as the nature and concentration of compounds in the sample, the type of analysis being performed, etc.
After completion of the m iterations of the execution of steps 52-54, where m≥1, the execution of the method 50 branches to step 55. Steps 55, 56 and 57 are analogous to steps 52, 53 and 54, respectively. Specifically, ion storage step 55 and mass analysis step 57 are identical to steps 52 and 54, respectively. The intervening step 56 is similar to step 53 but differs from step 53 in that, in the step 56, either the ion transfer and focusing lens system or the mass analyzer electrode injection voltage (or both) is/are reconfigured so as to cause the mass analyzer to yield mass spectra in accordance with a second desired performance characteristic or a second desired set of performance characteristics. In some instances, the execution of step 56 may comprise reconfiguring the ion transfer and focusing lens system in a second configuration so as to cause the packet of ions to enter the ion inlet aperture of the mass analyzer in a second spatial configuration that causes the mass analyzer to exhibit the desired performance characteristic or characteristics. In other instances of execution of step 56, a voltage of a second pre-determined magnitude may be applied to an electrode of the mass analyzer so as to yield mass spectra in accordance with the first desired performance characteristic or characteristics. In yet other instances of execution of step 56 both the ion transfer and lens system and the mass analyzer injection voltage may be configured in accordance with the desired performance characteristic(s).
The steps 55-57 comprise a second set of steps that, optionally, may be repeated a variable number of times. In other words, the set of steps 55-57 may be executed at total of n times, where n≥1. Whereas the first set of possibly-iterated steps (steps 52-54) comprise a set of mass analyses during which the first desired mass spectral characteristic or first desired set of mass spectral characteristics is optimized, the second iterated set of steps (steps 55-57) comprise another set of mass analyses during which the second desired mass spectral characteristic(s) is/are optimized. For instance, a second desired performance characteristic may relate to improvement of mass spectral signal-to-noise ratio by permitting some level of coalescence of isotopic variant peaks.
Generally, the first and second mass spectral characteristics or sets of characteristics described above correspond to different types of mass spectral information, the simultaneous optimization of which is difficult to achieve. For example, if the mass spectral resolution of closely-spaced isotopes of a given compound is an analytical goal, then it may be desirable to operate a mass spectrometer system having an electrostatic trap mass analyzer in a fashion so as so minimize peak coalescence as described above. Conversely, if it desired to use mass analysis to accurately quantify a low concentration of a known compound in a sample, then the lower limit of quantitation may be improved by taking advantage of signal-to-noise improvements that occur when isotopic variant peaks are allowed to coalesce. In the first example, ion transfer and focusing optics may be configured and/or operated such that the pathways of ion packets are de-focused or otherwise spatially spread as they enter the electrostatic trap mass analyzer at its ion inlet aperture. In the second example, the ion transfer and focusing optics may be configured and/or operated according to nominal operation, in which the ion pathways are tightly focused at the position of the ion inlet aperture.
The execution of steps 52-54 and the execution of the steps 55-57 of the method 50 may both pertain to a same sample composition, possibly as part of a single analysis. Such situations may apply when it is desired to obtain optimal measurements of both the first and second mass spectral characteristics pertaining to the single sample. Alternatively, the execution of steps 52-54 and the execution of the steps 55-57 may pertain to different sample compositions, derived from either different samples or from a single sample. In the latter case, the different sample compositions may be introduced in succession into the mass spectrometer as a result of separation of sample constituents by a separation or fractionation apparatus, such as a chromatograph, that provides sample material to the mass spectrometer system. In such instances, the change from execution of steps 52-54 (if repetitively executed) to execution of steps 55-57 may be made automatically in response to analysis of mass spectral data generated by the mass spectrometer. After completion of the possibly repeated execution of steps 55-57, execution of the method 50 may return, as a result of a decision made in decision step 58, to step 52, after which the set of steps 52-54 may again be executed, perhaps multiple times.
The discussion included in this application is intended to serve as a basic description. Although the invention has been described in accordance with the various embodiments shown and described, one of ordinary skill in the art will readily recognize that there could be variations to the embodiments and those variations would be within the spirit and scope of the present invention. The reader should be aware that the specific discussion may not explicitly describe all embodiments possible; many alternatives are implicit. Accordingly, many modifications may be made by one of ordinary skill in the art without departing from the scope and essence of the invention. Neither the description nor the terminology is intended to limit the scope of the invention. Any patents, patent applications, patent application publications or other literature mentioned herein are hereby incorporated by reference herein in their respective entirety as if fully set forth herein.
This application is a Continuation of and claims, under 35 USC § 120, the benefit of the filing date and the right of priority to co-pending and co-assigned U.S. application Ser. No. 17/355,958, now U.S. Pat. No. 11,581,180, which was filed on Jun. 23, 2021, the disclosure of which is hereby incorporated herein by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 5886346 | Makarov | Mar 1999 | A |
| 6872938 | Makarov et al. | Mar 2005 | B2 |
| 7714283 | Makarov et al. | May 2010 | B2 |
| 11581180 | Canterbury | Feb 2023 | B2 |
| 20120326023 | Kozole | Dec 2012 | A1 |
| 20130264474 | Kholomeev et al. | Oct 2013 | A1 |
| 20170352530 | Belov et al. | Dec 2017 | A1 |
| 20180144921 | Hoyes et al. | May 2018 | A1 |
| 20210242007 | Verenchikov | Aug 2021 | A1 |
| Number | Date | Country |
|---|---|---|
| WO-2020121168 | Jun 2020 | WO |
| Entry |
|---|
| EP Extended Search Report and Written Opinion dated Nov. 16, 2022, for EP Patent Application No. 22180646.6., 8 pages. |
| Perry et al., “Rephasing Ion Packets in the Orbitrap Mass Analyzer to Improve Resolution and Peak Shape”, JAm Soc Mass Spectrom 2009, 20, pp. 1397-1404. |
| Number | Date | Country | |
|---|---|---|---|
| 20230178356 A1 | Jun 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17355958 | Jun 2021 | US |
| Child | 18159040 | US |
