Time-of-flight mass spectrometer and adjustment method thereof

Abstract

To reduce variation of a measurement result by aligning a mass resolution of a plurality of devices.SOLUTION: In an embodiment of a TOFMS according to the present invention, the TOFMS includes a measurement part (1) containing: each flight magnetic field formation part that forms a magnetic field for flying an ion into a flight space (153, 154, and 155); and each ion acceleration part (151 and 152) that accelerates the ion as a measurement object and feeds it into the flight space. The TOFMS comprises: a control part (3) that repeatedly executes a measurement to a predetermined sample while changing a voltage applied to an electrode contained in the measurement part, and operates the measurement part so as to calculates a mass resolution on the basis of the measurement result in each measurement; an approximate calculation part (3) that calculates an approximate for approximating a relation of them on the basis of data of a plurality of pairs of an application voltage to the electrode and a resolution corresponded to them, obtained under a control by the control part; and a voltage determination part (3) that calculates a voltage value corresponded to a target value of the mass resolution by using the approximate, and determines the voltage value as an application voltage to the electrode in the device.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a time-of-flight mass spectrometer (TOFMS) and a method for adjusting the same. [Background technology]

[0002] Mass spectrometers have been frequently used in recent years to identify and quantify compounds contained in samples. In TOFMS, a type of mass spectrometer, ions from a sample are accelerated by imparting a certain amount of kinetic energy to them and then introduced into a flight space. The time of flight of the ions is measured after they have traveled a certain distance within the flight space. Because this time of flight depends on the mass-to-charge ratio (m / z) of the ions, converting the time of flight into an m / z value allows the creation of a mass spectrum that shows the relationship between the m / z value and the ion intensity (ion amount).

[0003] Generally, TOFMS is often used when high mass resolution and mass accuracy are required, such as when estimating the structure of unknown compounds from precise mass measurement results. Therefore, in addition to improving sensitivity, further improvements in mass resolution and mass accuracy are required for TOFMS.

[0004] Mass spectrometers are typically equipped with an autotuning function that automatically adjusts the voltage applied to the electrodes of each component that affects the behavior of ions in the instrument (see Patent Document 1, etc.). Generally, this autotuning adjusts parameter values, such as the voltage applied to each component, so that the top intensity of a mass peak corresponding to a specific compound obtained when a standard sample is measured is maximized. The height of the top intensity of a mass peak is generally related to mass resolution, and maximizing the top intensity of the mass peak can also bring mass resolution close to its maximum.

[0005] In orthogonal acceleration TOFMS, which is one type of TOFMS, as disclosed in Patent Document 2, the following electrodes affect the behavior of ions and determine the performance of the device, such as the detection sensitivity and mass resolution: a first acceleration electrode arranged in the orthogonal acceleration section; a second acceleration electrode that further accelerates ions ejected from the orthogonal acceleration section; a flight tube having an internal flight space; and a reflectron that forms an electric field in the flight space to reflect ions. The voltages applied to these electrodes can be adjusted by autotuning. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 2018-120804 [Patent Document 2] International Publication No. 2019 / 229950 Summary of the Invention [Problem to be solved by the invention]

[0007] In conventional TOFMS, autotuning can be performed to adjust the instrument to a state close to its maximum performance. However, this conventional autotuning method has the following problems:

[0008] In many cases, even when an instrument is almost unused—that is, when there is almost no contamination of the electrodes or other components due to use—there are differences in instrument performance. Therefore, when measuring the same sample using multiple instruments of the same model, each adjusted by autotuning, the measurement results may differ. Furthermore, even if the inter-instrument difference is small when the instrument is new (or after an overhaul), it may increase with use. Even if the measurement results meet the target resolution specified by the instrument itself, if the difference between the measurement results of the same sample using different instruments is large, it becomes difficult to compare the measurement results. Therefore, inter-instrument performance differences can lead to product complaints from users to manufacturers and potentially damage the reliability of the product itself.

[0009] The present invention has been made to solve these problems, and its main object is to provide a TOFMS and an adjustment method therefor that can reduce the variation in mass resolution between multiple instruments of the same model, that is, those having the same configuration and structure. [Means for solving the problem]

[0010] One aspect of the TOFMS according to the present invention, which has been made to solve the above problems, is a time-of-flight mass spectrometer equipped with a measurement unit including a flight electric field forming unit that forms an electric field for ions to fly in a flight space, and an ion acceleration unit that accelerates ions to be measured and sends them into the flight space, a control unit that operates the measurement unit to repeatedly perform measurements on a predetermined sample while changing the voltage applied to the electrodes included in the measurement unit, and calculate the mass resolution based on the measurement results of each measurement; an approximate function calculation unit that calculates an approximate function that approximates the relationship between the voltage applied to the electrode and the corresponding mass resolution based on a plurality of sets of data obtained under the control of the control unit; a voltage determination unit that uses the approximation function to determine a voltage value corresponding to a target value of mass resolution and determines the voltage value as a voltage to be applied to the electrodes in the apparatus; Equipped with.

[0011] One aspect of the TOFMS adjustment method according to the present invention, which has been made to solve the above problems, is a method for adjusting a plurality of time-of-flight mass spectrometers each having a measurement unit including a flight electric field forming unit that forms an electric field in a flight space for ions to fly, and an ion acceleration unit that accelerates ions to be measured and sends them into the flight space, comprising: a target setting step of setting a target value of mass resolution common to the plurality of time-of-flight mass spectrometers; In each of the plurality of time-of-flight mass spectrometers, a measuring step in which measurements are repeatedly performed on a predetermined sample while changing a voltage applied to an electrode included in the measurement unit, and mass resolution is calculated based on the measurement results of each measurement; a voltage determination step of determining a voltage value corresponding to the target value based on a plurality of sets of data of the voltage applied to the electrode and the corresponding mass resolution obtained in the measurement step, and determining the voltage value as the voltage applied to the electrode in the device; Execute. [Effects of the Invention]

[0012] The above-described aspects of the TOFMS and adjustment method thereof according to the present invention can roughly align the mass resolutions of multiple instruments of the same model, thereby reducing the differences in mass resolution between the instruments, thereby reducing the variability in measurement results when the same sample is measured using multiple different instruments. [Brief explanation of the drawings]

[0013] [Figure 1] 1 is a configuration diagram of the main parts of a quadrupole time-of-flight mass spectrometer according to one embodiment of the present invention. [Figure 2] FIG. 2 is a functional block diagram of a control and processing unit in the quadrupole time-of-flight mass spectrometer of the present embodiment. [Figure 3]4 is a flowchart showing the flow of processing operations for autotuning in the quadrupole time-of-flight mass spectrometer of the present embodiment. [Figure 4] FIG. 2 is a diagram showing an example of the relationship between the applied voltage and the mass resolution in the quadrupole time-of-flight mass spectrometer of the present embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0014] A quadrupole time-of-flight mass spectrometer (hereinafter sometimes referred to as "Q-TOFMS"), which is one embodiment of a TOFMS according to the present invention, will be described with reference to the accompanying drawings. This Q-TOFMS is a tandem mass spectrometer that combines a quadrupole mass filter and an orthogonal acceleration TOFMS, and can selectively perform general mass analysis without ion dissociation, or MS / MS analysis in which specific ions are dissociated.

[0015] Fig. 1 is a configuration diagram of the main parts of the Q-TOFMS of this embodiment, and Fig. 2 is a functional block configuration diagram of the control and processing parts of the Q-TOFMS of this embodiment. As shown in FIG. 1, this Q-TOFMS comprises a measurement unit 1 , a voltage source 2 , a control and processing unit 3 , an input unit 4 , and a display unit 5 .

[0016] The measurement unit 1 performs measurements on a sample (liquid sample) and has a vacuum chamber 10 and an ionization chamber 11 connected to the front of the vacuum chamber 10. The interior of the vacuum chamber 10 is roughly divided into four chambers: a first intermediate vacuum chamber 12, a second intermediate vacuum chamber 13, a first analysis chamber 14, and a second analysis chamber 15. The ionization chamber 11 is in a substantially atmospheric pressure atmosphere, and is configured as a multi-stage differential pumping system in which the degree of vacuum increases in stages from the ionization chamber 11 to the first intermediate vacuum chamber 12, the second intermediate vacuum chamber 13, the first analysis chamber 14, and the second analysis chamber 15 in that order.

[0017] Although the vacuum pumps used to evacuate each chamber are not shown in FIG. 1, the first intermediate vacuum chamber 12, which is the next chamber after the ionization chamber 11, is generally evacuated by a rotary pump, and each subsequent chamber is evacuated by a turbomolecular pump that uses a rotary pump as a roughing pump.

[0018] An electrospray ion source (ESI source) 111 is disposed in the ionization chamber 11, and the ionization chamber 11 and first intermediate vacuum chamber 12 are connected via a thin-diameter desolvation tube 112. A multipole ion guide 121 is disposed in the first intermediate vacuum chamber 12, and the first intermediate vacuum chamber 12 and second intermediate vacuum chamber 13 are separated by a skimmer 122 having an opening at the top. A multipole ion guide 131 is also disposed in the second intermediate vacuum chamber 13. A quadrupole mass filter 141, a collision cell 142 having a multipole ion guide 143 therein, and the front half of a transfer electrode 144 are disposed in the first analysis chamber 14. The second analysis chamber 15 is equipped with the rear half of the transfer electrode 144, an orthogonal acceleration section 151 including a push electrode 1511 and a pull electrode 1512, a second acceleration electrode section 152, a flight tube 153, a reflectron 154, a back plate 155, and an ion detector 156.

[0019] In accordance with the control of the control and processing unit 3, the voltage source 2 applies a predetermined voltage to each of the electrodes in the measurement unit 1, specifically to the electrodes included in, for example, the ESI source 111, ion guides 121, 131, 143, quadrupole mass filter 141, transfer electrode 144, orthogonal acceleration unit 151, second acceleration electrode unit 152, flight tube 153, reflectron 154, backplate 155, ion detector 156, etc.

[0020] The control and processing unit 3 controls the measurement unit 1 directly or via the voltage source 2, and receives and processes the detection signal obtained by the measurement unit 1. As shown in Fig. 2, the control and processing unit 3 includes, as functional blocks, a measurement control unit 31, a data processing unit 32, a tuning execution unit 33, and a parameter storage unit 34. The tuning execution unit 33 includes, as lower-level functional blocks, a parameter search unit 331, and a parameter readjustment unit 332 including a readjustment control unit 3321, an approximate function calculation unit 3322, and a parameter determination unit 3323.

[0021] Generally, the control / processing unit 3 is actually a personal computer (PC), and the functions in the functional blocks can be realized by executing dedicated control / processing software installed on the PC. In this case, the input unit 4 is a pointing device such as a keyboard or mouse attached to the PC, and the display unit 5 is a monitor display attached to the PC.

[0022] An example of the MS / MS analysis operation performed in the Q-TOFMS of this embodiment will now be briefly described. In this operation, the measurement control unit 31 controls the voltage source 2 based on various parameter values ​​stored in the parameter storage unit 34, and the voltage source 2 applies a predetermined voltage to each component of the measurement unit 1.

[0023] A liquid sample containing compounds separated by, for example, a liquid chromatograph (not shown) is continuously supplied to the ESI source 111. The ESI source 111 ionizes the compounds in the sample by spraying the supplied liquid sample into the ionization chamber 11 while imparting an electric charge to the sample. However, the ionization method is not limited to ESI, and ion sources using other methods such as atmospheric pressure chemical ionization and atmospheric pressure photoionization may also be used. Furthermore, an ion source that ionizes a gas sample or a solid sample instead of a liquid sample may also be used.

[0024] Ions derived from the sample components generated in the ionization chamber 11 and fine charged droplets from which the solvent has not yet been fully vaporized are mainly carried by a gas flow formed by the difference between the pressure inside the ionization chamber 11 (approximately atmospheric pressure) and the pressure inside the first intermediate vacuum chamber 12, and are drawn into the desolvation tube 112. The desolvation tube 112 is heated to an appropriate temperature, and the passage of the charged droplets through the inside of the desolvation tube 112 promotes the vaporization of the solvent in the droplets, further facilitating the generation of ions derived from the sample components.

[0025] Ions discharged from the outlet end of the desolvation tube 112 into the first intermediate vacuum chamber 12 are focused near the ion optical axis C1 by the action of the radio frequency electric field formed by the ion guide 121. The focused ions pass through an opening at the top of the skimmer 122 and enter the second intermediate vacuum chamber 13. The ions that have entered the second intermediate vacuum chamber 13 are focused by the radio frequency electric field formed by the ion guide 131 and are sent to the first analysis chamber 14.

[0026] Ions that enter the first analysis chamber 14 are introduced into the quadrupole mass filter 141, and only ions with a specific m / z value corresponding to the voltage applied to the quadrupole mass filter 141 pass through the quadrupole mass filter 141. A collision gas such as argon or nitrogen is continuously or intermittently supplied into the collision cell 142. Ions (precursor ions) that pass through the quadrupole mass filter 141 and enter the collision cell 142 with a predetermined energy come into contact with the collision gas and are dissociated by collision-induced dissociation, generating various product ions.

[0027] Various product ions emitted from the collision cell 142 are converged by a transfer electrode 144 consisting of multiple annular electrodes and sent to the second analysis chamber 15. The ions introduced into the second analysis chamber 15 as a thin, highly parallel ion flow by the transfer electrode 144 are emitted in a pulsed manner, that is, as a roughly single ion packet, from the orthogonal acceleration section 151 in a direction substantially perpendicular to the incident direction of the ion flow (a direction parallel to the ion optical axis C1).

[0028] Each ion constituting this ion packet is further accelerated by the second acceleration electrode unit 152 and introduced into a flight space inside the flight tube 153. In the flight space, an electric field that causes the ions to fly in a turning manner along a path indicated by C2 in FIG. 1 is formed by the flight tube 153, reflectron 154, and back plate 155. As a result, the ions are turned back and fly again within the flight tube 153, and finally reach the ion detector 156. The ion detector 156 includes, for example, a microchannel plate, and generates a detection signal according to the number of incident ions and sends it to the control and processing unit 3.

[0029] Ideally, the kinetic energy imparted to each ion in the orthogonal acceleration unit 151 and the second acceleration electrode unit 152 is constant. Therefore, each ion flies at a speed according to the m / z value of the ion, specifically, the smaller the m / z value, the faster the speed, and reaches the ion detector 156. Therefore, the various ions contained in the ion packet that are introduced into the flight space almost simultaneously are spatially separated as they fly according to their m / z values, and enter the ion detector 156 with a time difference.

[0030] The orthogonal acceleration section 151 and the second acceleration electrode section 152 correspond to the ion acceleration section in this invention. The flight tube 153, the reflectron 154, and the back plate 155 correspond to the flight electric field forming section in this invention. Therefore, the electrodes included in the ion acceleration section are the pusher electrode 1511, the puller electrode 1512, and the multiple annular electrodes that make up the second acceleration electrode section 152. Furthermore, the electrodes included in the flight electric field forming section are the flight tube 153, the multiple annular electrodes that make up the reflectron 154, and the back plate 155. Furthermore, the transfer electrode 144 corresponds to the ion introduction section in this invention, and the electrodes included in the ion introduction section are the multiple annular electrodes that make up the transfer electrode 144.

[0031] In the control and processing unit 3, the data processing unit 32 receives the detection signal output from the ion detector 156, converts the signal into digital data, and stores the data. The data processing unit 32 also converts the time of flight of each ion, starting from the point in time when the ion packet is ejected from the orthogonal acceleration unit 151, into an m / z value, and creates a mass spectrum (product ion spectrum) that shows the relationship between the m / z value and the ion intensity. The created mass spectrum is displayed on the display unit 5 in response to a user instruction given via the input unit 4.

[0032] The above explanation is about the operation during MS / MS analysis, and it is possible to obtain a mass spectrum by performing normal mass analysis instead of MS / MS analysis by allowing all ions to pass through the quadrupole mass filter 141 without selecting ions and not dissociating ions in the collision cell 142. Even in this case, mass separation of ions is performed by the orthogonal acceleration TOFMS, so a mass spectrum with high mass resolution and mass accuracy can be obtained.

[0033] In order to achieve high sensitivity, high mass resolution, and high mass accuracy in the Q-TOFMS of this embodiment, it is necessary to appropriately adjust the voltages applied to the electrodes of each component included in the measurement unit 1. This Q-TOFMS has an autotuning function to automatically and appropriately adjust these applied voltages. Next, we will explain the operation during autotuning, which is a characteristic of the Q-TOFMS of this embodiment.

[0034] Conventional tuning methods for orthogonal acceleration TOFMS involve sequentially adjusting the voltage applied to each electrode to maximize sensitivity when measuring a standard sample, specifically, to maximize the top intensity of a mass peak for a specific compound. Another known tuning method involves sequentially adjusting the voltage applied to each electrode to maximize the mass resolution of that mass peak. Mass resolution is a key performance factor for mass spectrometers, and instrument manufacturers only ship instruments that, when properly tuned, can achieve a mass resolution exceeding a specified target value. However, as mentioned above, differences between instruments are inevitable, even for the same model, and the maximum mass resolution each instrument can achieve varies from instrument to instrument. Therefore, tuning to maximize or nearly maximize mass resolution results in differences in the achievable mass resolution between instruments.

[0035] For example, for a user who owns only one instrument, the difference in mass resolution between instruments described above is often not a problem. On the other hand, for a user who owns multiple instruments of the same model, the difference in mass resolution between instruments may be a problem because they often compare measurement results such as mass spectra obtained with different instruments. Therefore, the Q-TOFMS of this embodiment performs a unique tuning to make the mass resolutions of the different instruments as uniform as possible.

[0036] Fig. 3 is a flowchart showing the flow of the autotuning process in the Q-TOFMS of this embodiment. Fig. 4 is a diagram showing an example of the relationship between the applied voltage and the mass resolution in the Q-TOFMS of this embodiment.

[0037] For example, when a user performs a predetermined operation on the input unit 4, the tuning execution unit 33 in the control and processing unit 3 executes auto-tuning according to a predetermined program. When auto-tuning starts, the parameter search unit 331 first repeats measurements of the same standard sample while sequentially changing the voltage applied to the electrodes of each unit, and searches for the voltage value at which the mass resolution is at or near maximum based on the measurement results (step S1).

[0038] The standard sample contains one or more known compounds at known concentrations, and can be introduced into the ESI source 111 instead of a normal liquid sample. Alternatively, a dedicated ionization probe that ionizes the standard sample by electrospraying may be provided separately from the ESI source 11. Furthermore, measurement of the standard sample is performed by normal mass spectrometry without ion dissociation.

[0039] Mass resolution can be determined from the peak of the target compound observed in the mass spectrum, which is the measurement result. Typically, mass resolution R can be calculated from the m / z value M of the peak and the full width at half maximum (FWHM) Δm at 50% of the peak top intensity, using the formula R=M / Δm. However, the method for calculating mass resolution is not limited to this.

[0040] Mass resolution and mass accuracy, which are performance characteristics of the Q-TOFMS of this embodiment, depend on the voltages applied to the multiple electrodes subsequent to the transfer electrode 144. For example, changing the voltages applied to the multiple annular electrodes constituting the transfer electrode 144 changes the degree of divergence of ions that leave the transfer electrode 144 and enter the orthogonal acceleration unit 151. As the ion divergence increases, the initial position of ions along the ion path C2 increases when a pulse voltage is applied to the pusher electrode 1511, resulting in a decrease in mass resolution. Furthermore, changing the pulse voltage applied to the pusher electrode 1511, the DC voltage applied to the puller electrode 1512, the DC voltages applied to each of the multiple annular electrodes included in the second acceleration electrode unit 152, the DC voltage applied to the flight tube 153, the DC voltages applied to each of the multiple annular electrodes included in the reflectron 154, and the DC voltage applied to the backplate 155 also changes the behavior of ions, resulting in a change in mass resolution. Therefore, in step S1, the voltages applied to a plurality of these electrodes are sequentially adjusted to search for the voltage conditions that maximize the mass resolution.

[0041] However, in step S1, voltage conditions that improve overall performance may be searched for in combination with other factors related to the performance of the mass spectrometer, such as mass resolution, sensitivity, and the waveform shape of the mass peak. For example, in Patent Application No. 2022-074176 previously filed by the present applicant, a score value is calculated based on a predetermined formula from the top intensity of the mass peak and the mass resolution, and voltage conditions that maximize this score value are searched for. This is because, in orthogonal acceleration TOFMS, the voltage conditions that maximize sensitivity and the voltage conditions that maximize mass resolution may not match. Therefore, it is possible to find voltage conditions that maximize mass resolution while balancing sensitivity and mass resolution. Therefore, voltage conditions that maximize mass resolution may be searched for in this way.

[0042] Furthermore, an index value indicating the quality of the waveform shape of the mass peaks, as disclosed in Patent Document 2, may also be used to calculate a score value based on a predetermined formula from this index value and the mass resolution, and voltage conditions that maximize this score may be searched for. This makes it possible to search for voltage conditions that result in a reasonably good waveform shape of the mass peaks and a mass resolution that is close to maximum.

[0043] In conventional autotuning, the voltage values ​​applied to each electrode determined in step S1 are stored as optimal parameter values, and these parameter values ​​are used to measure the target sample.In contrast, in the Q-TOFMS of this embodiment, the parameters are readjusted by executing the processes from step S2 onwards.

[0044] The mass resolution achievable by the voltage condition search in step S1 can vary considerably between instruments, even for the same model. Of course, if the instrument is in good condition, the mass resolution will typically be equal to or greater than the target value U for all instruments when step S1 is completed. However, because performance such as mass resolution depends on factors such as mechanical precision during assembly, differences in performance between instruments are unavoidable, and the mass resolution value itself often varies. From step S2 onward, the voltage value is readjusted to bring the mass resolution close to the predetermined target value U. Here, as an example, we show how to readjust the voltage applied to the second accelerating electrode 152, which has a significant impact on mass resolution. However, the target for readjustment of the applied voltage is not limited to the second accelerating electrode 152, as long as it is an electrode that affects mass resolution.

[0045] The target mass resolution value U can be predetermined by the instrument manufacturer and stored in the parameter storage unit 34. In this case, the instrument manufacturer can determine an appropriate target value for each instrument model, which is a common target value for all instruments of the same model regardless of the user. Therefore, the mass resolution of all instruments of the same model can be roughly matched regardless of the user. However, even if the instrument hardware itself is the same, if the mass resolution changes depending on the control and processing software, the mass resolution may change depending on the version of that software. In such cases, the target mass resolution value can be updated with software updates. Furthermore, if a user owns multiple instruments of the same model, the user may be able to change the target mass resolution value so that the mass resolutions of those multiple instruments can be matched. In this case, the target mass resolution U is a common target value for all instruments owned by that user.

[0046] When the device is shipped from the manufacturer, it may be adjusted to a value with a certain margin over the mass resolution guaranteed in the catalog specifications, taking into account measurement errors, and the target value U may be that value, or it may be the mass resolution value guaranteed in the catalog specifications itself. In addition, the target value U may be set in various ways, as long as it is achievable by each of multiple devices and is a common value.

[0047] In the parameter readjustment unit 332, the readjustment control unit 3321 sets the voltage applied to the electrodes of each unit, including the second accelerating electrode unit 152, to the voltage value (initial voltage value) determined in the processing of step S1, and then controls each unit to perform measurement on the standard sample. At this time, the initial voltage value applied to the second accelerating electrode unit 152 is set to Vp. Then, based on the data obtained by the measurement, the readjustment control unit 3321 calculates the mass resolution from the peak as described above (step S2).

[0048] Next, the readjustment control unit 3321 changes the voltage value by a predetermined step width in the direction of decreasing the voltage value (reducing the absolute value of the voltage) from the current voltage, and controls each unit to perform measurement on the standard sample at that voltage value.The readjustment control unit 3321 then calculates the mass resolution based on the data obtained by the measurement (step S3).

[0049] In step S3, instead of decreasing the voltage from the initial voltage value Vp, the voltage may be increased from the initial voltage value Vp (to increase the absolute value of the voltage). However, experiments by the inventors have confirmed that increasing the voltage value of the second accelerating electrode 152 from the initial voltage value (the voltage value at which mass resolution is maximized) not only reduces mass resolution but also worsens the waveform shape of the mass peaks (leading or trailing edges become longer). For this reason, the voltage is decreased here, which does not (or is unlikely to) cause deterioration in the waveform shape of the mass peaks. If such a phenomenon as deterioration of the waveform shape of the mass peaks does not occur, the voltage may be increased from the initial voltage value.

[0050] After executing step S3, the readjustment control unit 3321 determines whether the calculated mass resolution is below the target value U of the resolution (step S4). If it is not below the target value U, the process returns from step S4 to S3. Accordingly, by repeating steps S3 and S4, measurements of the standard sample are repeated while changing the voltage applied to the second accelerating electrode 152 by a predetermined step width until the mass resolution falls below the target value U. If the mass resolution falls below the target value U, the process proceeds from step S4 to S5, where it is determined whether the number of measurement points up to that point is equal to or greater than a predetermined number. This predetermined number can be set appropriately to a value equal to or greater than three, such as 3 or 5. The determination process in step S5 is performed to avoid situations in which the accuracy of the approximation function, described below, cannot be ensured.

[0051] If it is determined in step S5 that the number of measurement points has not reached the predetermined number, the step width for changing the voltage value is narrowed (step S6), and the process returns to step S2, where readjustment is started over again.

[0052] On the other hand, if it is determined in step S5 that the number of measurement points is equal to or greater than the predetermined number, the approximate function calculation unit 3322 calculates an approximate function indicating the relationship between voltage value and mass resolution by performing a regression analysis based on the multiple combinations of voltage value and mass resolution obtained in the processing of steps S2 to S4 (step S7). The regression analysis can use the least squares method, which is a relatively simple calculation and can produce good results. Furthermore, a cubic or higher order function can be used as the approximate function, but a quadratic function is usually sufficient.

[0053] Figure 4 shows an example of actual measurements, where the voltage step width is narrowed and the number of measurement points is increased considerably. The mass resolution fluctuates with each change in applied voltage, but from multiple pairs of voltage values ​​and mass resolutions, a sufficiently reliable approximation function y = Ax, as shown by the dotted line in the figure, can be obtained. 2 +-Bx-C can be found.

[0054] Next, the parameter determination unit 3323 uses the approximation function calculated in step S7 to determine the voltage Vq corresponding to the target value U of the mass resolution, as shown in Fig. 4 (step S8). Then, the parameter determination unit 3323 determines this voltage Vq as the voltage value after readjustment to be applied to the second accelerating electrode 152 (step S9). Then, this determined voltage value is stored in the parameter storage unit 34 and used in subsequent measurements.

[0055] In this way, in the Q-TOFMS of this embodiment, the voltage conditions are set so that the mass resolution is at or near maximum, and then the applied voltage can be readjusted so that the mass resolution is near the target value U that is common to multiple instruments. Such tuning has the following advantages:

[0056] (1) The mass resolution of multiple instruments can be aligned to the target value U. This reduces the variability in measurement results when measuring the same sample using multiple instruments. (2) Even when multiple measurements are performed under certain voltage conditions on a single device, the measurement results will vary to some extent. Therefore, in order to calculate the average value of this variation, it is necessary to perform multiple measurements under the same voltage conditions. This not only takes time for tuning, but also increases the amount of standard sample used, leading to increased costs. In contrast, the above method makes it possible to reduce the influence of variation in the measurement results from multiple measurements without performing multiple measurements under the same voltage conditions, thereby determining a voltage value with high accuracy (i.e., one that makes it easier to bring the mass resolution close to the target value U). This shortens the time required for tuning. It also reduces the amount of standard sample used, thereby reducing costs.

[0057] As mentioned above, the example in Figure 4 shows a case where the number of measurement points is quite large, but when a quadratic function is used as the approximation function, fairly accurate approximation is possible even with 3 to 5 measurement points, which is sufficient for practical purposes.

[0058] As mentioned above, in the above explanation, the mass resolution was adjusted by changing the voltage applied to the second acceleration electrode section 152, but the mass resolution may also be adjusted by changing the voltage applied to each electrode included in the transfer electrode 144, the orthogonal acceleration section 151, the flight tube 153, the reflectron 154, and the backplate 155.

[0059] Furthermore, in the Q-TOFMS of the above embodiment, autotuning results in a mass resolution close to the target value U. However, some users may wish to adjust the mass resolution to obtain the highest possible mass resolution achievable with the instrument. While such adjustments can be made manually, the process is quite tedious. Therefore, in the Q-TOFMS of this embodiment, the user may be given the option of ending tuning after step S1 of the flowchart shown in FIG. 2 is completed, or of completing steps S2 through S9 following step S1. By allowing such a choice, the user can perform measurements at or near the highest mass resolution achievable by the instrument, as needed.

[0060] While the above embodiment is an example in which the present invention is applied to a reflectron-type orthogonal acceleration TOFMS, the present invention is not limited to reflectron-type TOFMS, but can also be applied to other TOFMS with different flight path configurations, such as linear and multi-turn types. In a linear type, the flight electric field generator includes only the flight tube. On the other hand, in a multi-turn type, the flight electric field generator includes electrodes that cause ions to fly in a circular path (or in a spiral path, etc.), and electrodes that introduce ions into and / or remove ions from such a path.

[0061] Furthermore, the present invention is not limited to the orthogonal acceleration method, but can also be applied to an ion trap TOFMS in which, for example, ions to be measured are temporarily held in a linear ion trap or a three-dimensional quadrupole ion trap, and then an acceleration voltage is applied to the electrodes that make up the ion trap, causing the ions to be ejected from the ion trap and sent into flight space. In this case, the electrodes included in the ion acceleration unit are the electrodes that make up the ion trap.

[0062] The present invention can also be applied to a TOFMS that uses a matrix-assisted laser desorption / ionization (MALDI) source, in which ions are extracted from the vicinity of the sample immediately after being generated in the ion source, accelerated, and sent into a flight space, such as a MALDI-TOFMS. In this case, the electrodes included in the ion acceleration section are an extraction electrode that extracts ions from the vicinity of the sample, and an acceleration electrode that accelerates the extracted ions.

[0063] Furthermore, the above-described embodiment and the various modified examples are examples of the present invention, and it is clear that any modifications, changes, or additions made within the spirit of the present invention will also be encompassed within the scope of the claims of the present application.

[0064] [Various aspects] It will be apparent to those skilled in the art that the above-described exemplary embodiments are examples of the following aspects.

[0065] (Item 1) One aspect of the TOFMS according to the present invention is a time-of-flight mass spectrometer equipped with a measurement unit including a flight electric field forming unit that forms an electric field in a flight space for ions to fly, and an ion acceleration unit that accelerates ions to be measured and sends them into the flight space, a control unit that operates the measurement unit to repeatedly perform measurements on a predetermined sample while changing the voltage applied to the electrodes included in the measurement unit, and calculate the mass resolution based on the measurement results of each measurement; an approximate function calculation unit that calculates an approximate function that approximates the relationship between the voltage applied to the electrode and the corresponding mass resolution based on a plurality of sets of data obtained under the control of the control unit; a voltage determination unit that uses the approximation function to determine a voltage value corresponding to a target value of mass resolution and determines the voltage value as a voltage to be applied to the electrodes in the apparatus; Equipped with.

[0066] (Item 2) In the TOFMS described in item 1, the target value can be set in common for a plurality of instruments that are to share the same mass resolution.

[0067] (Item 11) One aspect of the TOFMS adjustment method according to the present invention is a method for adjusting a plurality of time-of-flight mass spectrometers each having a measurement unit including a flight electric field forming unit that forms an electric field in a flight space for ions to fly, and an ion acceleration unit that accelerates ions to be measured and sends them into the flight space, comprising: a target setting step of setting a target value of mass resolution common to the plurality of time-of-flight mass spectrometers; In each of the plurality of time-of-flight mass spectrometers, a measuring step in which measurements are repeatedly performed on a predetermined sample while changing a voltage applied to an electrode included in the measurement unit, and mass resolution is calculated based on the measurement results of each measurement; a voltage determination step of determining a voltage value corresponding to the target value based on a plurality of sets of data of the voltage applied to the electrode and the corresponding mass resolution obtained in the measurement step, and determining the voltage value as the voltage applied to the electrode in the device; Execute.

[0068] The "multiple devices for which mass resolution is to be shared" or "multiple time-of-flight mass spectrometers" referred to here generally refer to devices of the same model with the same configuration and structure, but devices that differ in some of their configuration or structure, or in the software that controls the devices, may also be devices that can achieve the same mass resolution.

[0069] According to the TOFMS described in paragraphs 1 and 2 and the TOFMS adjustment method described in paragraph 11, it is possible to roughly align the mass resolution of multiple instruments of the same model and reduce the difference in mass resolution between the instruments, thereby reducing the variation in measurement results when the same sample is measured using multiple different instruments.

[0070] Furthermore, even when measurements of the same sample are performed multiple times under the same voltage conditions, the measurement results will vary to some extent. Therefore, to obtain more accurate measurement results under a single voltage condition, it is necessary to perform an average of the measurements performed multiple times under the same voltage conditions. However, such a procedure takes time to perform the measurement, which in turn increases the time required for tuning. In contrast, the TOFMS described in paragraphs 1 and 2 and the TOFMS adjustment method described in paragraph 11 calculate an approximation function based on the results of measurements performed while varying the voltage, thereby reducing the impact of the variation in measurement results under a single voltage condition and reducing the number of measurements under the same voltage condition. This allows the mass resolution to be adjusted to or near the target value while shortening the time required for tuning.

[0071] (Item 3) In the TOFMS described in item 1, the approximate function calculation unit may calculate the approximate function by the least squares method.

[0072] Although regression analysis can be used to calculate an approximate function based on multiple sets of data on the applied voltage to the electrodes and the corresponding mass resolution, the least-squares method can be used to obtain an approximate function with high accuracy relatively easily. Therefore, the TOFMS described in Section 3 is more likely to achieve a mass resolution closer to the target value by performing tuning.

[0073] (Item 4) In the TOFMS according to item 3, approximation The function may be a quadratic function.

[0074] According to the inventors' investigations, the relationship between the voltage applied to the electrodes and the mass resolution can be adequately approximated by a relatively simple curve. Therefore, by using the TOFMS described in Section 4, it is possible to easily obtain a highly accurate approximate curve.

[0075] (Item 5) In the TOFMS described in any one of items 1 to 4, the control unit can operate the measurement unit to repeat the following measurement operation: measuring a predetermined sample by gradually changing the voltage applied to the electrodes included in the measurement unit from an initial voltage value that provides a mass resolution higher than the target value, and calculating the mass resolution based on the measurement results, at least until the mass resolution falls below the target value.

[0076] The TOFMS described in paragraph 5 makes it possible to more reliably find voltages that provide a mass resolution higher than the target value and voltages that provide a mass resolution lower than the target value with fewer measurements, thereby reducing tuning failures and shortening the time required for tuning.

[0077] (Item 6) In the TOFMS described in Item 5, the initial voltage value can be a voltage value that maximizes the mass resolution, or maximizes the mass resolution within an acceptable range for at least one of an index value that indicates the quality of the sensitivity or the waveform shape of the mass peak.

[0078] An example of an index value representing the quality of the waveform shape is the ratio of the peak widths at two intensities of a mass peak, as disclosed in Patent Document 2. Another example is the asymmetry coefficient, which is an index representing the symmetry (asymmetry) of a peak.

[0079] In the TOFMS described in Section 6, measurements are repeated while changing the voltage, starting from the voltage conditions that maximize the mass resolution, or the voltage conditions that maximize the mass resolution under conditions that do not necessarily maximize the mass resolution but that provide satisfactory sensitivity and good mass peak waveform shapes.

[0080] (Item 7) The TOFMS described in item 6 may further include a best state search unit that sequentially adjusts the voltages applied to the multiple electrodes included in the measurement unit to maximize the mass resolution, or to maximize the mass resolution within an acceptable range for at least one of index values ​​representing the quality of sensitivity or waveform shape, and after the adjustment by the best state search unit is completed, the control unit, the approximate function calculation unit, and the voltage determination unit adjust the voltages applied to a predetermined electrode or electrodes.

[0081] According to the TOFMS described in Section 7, the voltage conditions are set so that the mass resolution is at or near maximum, thereby avoiding a situation in which the mass resolution does not reach the target value due to inappropriate voltage conditions.

[0082] (Item 8) In the TOFMS described in any one of Items 1 to 7, the measurement unit includes an ion introduction unit that introduces ions into the ion acceleration unit, and the control unit can collect data that is a pair of voltage and mass resolution by repeating measurements while changing the voltage applied to electrodes included in either the ion introduction unit, the ion acceleration unit, or the flight electric field forming unit.

[0083] (Item 9) In the TOFMS described in item 8, the ion acceleration section can accelerate the ions introduced from the ion introduction section in a direction perpendicular to the ions.

[0084] According to the TOFMS described in item 9, ions derived from a sample supplied from, for example, a liquid chromatograph or a gas chromatograph can be measured almost continuously without being held in an ion trap or the like.

[0085] (Item 10) In the TOFMS described in Item 9, the ion acceleration section may include a first acceleration electrode to which a pulse voltage for accelerating ions is applied, and a second acceleration electrode to which a voltage for further accelerating the ions accelerated by the first acceleration electrode is applied, and the control section may adjust the voltage applied to either the first acceleration electrode or the second acceleration electrode when adjusting the mass resolution.

[0086] According to the TOFMS described in item 10, the mass resolution can be appropriately adjusted while suppressing the influence on other performances such as sensitivity. [Explanation of symbols]

[0087] 1...Measuring part 10...Vacuum chamber 11...Ionization chamber 111…ESI source 112...Desolvation tube 12...First intermediate vacuum chamber 121...Ion Guide 122...Skimmer 13...Second intermediate vacuum chamber 131...Ion Guide 14…1st analysis room 141...Quadrupole mass filter 142...Collision cell 143...Ion Guide 144...Transfer electrode 15…Second analysis room 151...Orthogonal acceleration section 1511...Extruded electrode 1512...Pull-in electrode 152...Second accelerating electrode section 153...Flight tube 154...Reflectron 155...Back plate 156...Ion detector 2...Voltage source 3...Control and processing section 31...Measurement control section 32...Data processing unit 33...Auto-tuning execution unit 331...Optimal parameter search unit 332...Parameter readjustment section 3321...Readjustment control section 3322... Approximation function calculation unit 3323...Parameter determination unit 34...Parameter storage section 4...Input section 5...Display section

Claims

1. A time-of-flight mass spectrometer having a measurement unit including a flight electric field forming unit that forms an electric field in a flight space for ions to fly, and an ion acceleration unit that accelerates ions to be measured and sends them into the flight space, a control unit that operates the measurement unit to repeatedly perform measurements on a predetermined sample while changing the voltage applied to the electrodes included in the measurement unit, and calculate the mass resolution based on the measurement results of each measurement; an approximate function calculation unit that calculates an approximate function that approximates the relationship between the voltage applied to the electrode and the corresponding mass resolution based on a plurality of sets of data obtained under the control of the control unit; a voltage determination unit that uses the approximation function to determine a voltage value corresponding to a target value of mass resolution and determines the voltage value as a voltage to be applied to the electrodes in the apparatus; wherein the target value is determined in common for a plurality of devices for which the mass resolution is to be shared.

2. The time-of-flight mass spectrometer according to claim 1 , wherein the approximate function calculation unit calculates the approximate function by a least squares method.

3. 3. The time-of-flight mass spectrometer according to claim 2, wherein the approximation function is a quadratic function.

4. 2. The time-of-flight mass spectrometer according to claim 1, wherein the control unit operates the measurement unit to repeat the following measurement operation: measuring a predetermined sample by gradually changing the voltage applied to the electrodes included in the measurement unit from an initial voltage value that provides a mass resolution higher than the target value, and calculating the mass resolution based on the measurement results, at least until the mass resolution falls below the target value.

5. 5. The time-of-flight mass spectrometer of claim 4, wherein the initial voltage value is a voltage value that maximizes mass resolution or maximizes mass resolution within an acceptable range for at least one of index values ​​representing the quality of sensitivity or waveform shape.

6. 6. The time-of-flight mass spectrometer of claim 5, further comprising a best state search unit that sequentially adjusts the voltages applied to the plurality of electrodes included in the measurement unit to maximize mass resolution or maximize mass resolution within an acceptable range for at least one of index values ​​representing the quality of sensitivity or waveform shape, and after adjustment by the best state search unit is completed, the control unit, the approximate function calculation unit, and the voltage determination unit adjust the voltages applied to a predetermined electrode or electrodes.

7. 2. The time-of-flight mass spectrometer according to claim 1, wherein the measurement unit includes an ion introduction unit that introduces ions into the ion acceleration unit, and the control unit collects data that is a pair of voltage and mass resolution by repeating measurements while changing a voltage applied to an electrode included in either the ion introduction unit, the ion acceleration unit, or the flight electric field forming unit.

8. 8. The time-of-flight mass spectrometer according to claim 7, wherein the ion acceleration section accelerates the ions introduced from the ion introduction section in a direction perpendicular to the direction of the ions.

9. 9. The time-of-flight mass spectrometer according to claim 8, wherein the ion acceleration unit includes a first acceleration electrode to which a pulse voltage for accelerating ions is applied, and a second acceleration electrode to which a voltage for further accelerating ions accelerated by the first acceleration electrode is applied, and the control unit adjusts the voltage applied to either the first acceleration electrode or the second acceleration electrode when adjusting the mass resolution.

10. A method for adjusting a plurality of time-of-flight mass spectrometers having a measurement unit including a flight electric field forming unit that forms an electric field in a flight space for ions to fly, and an ion acceleration unit that accelerates ions to be measured and sends them into the flight space, a target setting step of setting a target value of mass resolution common to the plurality of time-of-flight mass spectrometers; In each of the plurality of time-of-flight mass spectrometers, a measuring step in which measurements are repeatedly performed on a predetermined sample while changing a voltage applied to an electrode included in the measurement unit, and mass resolution is calculated based on the measurement results of each measurement; a voltage determination step of determining a voltage value corresponding to the target value based on a plurality of sets of data of the voltage applied to the electrode and the corresponding mass resolution obtained in the measurement step, and determining the voltage value as the voltage applied to the electrode in the device; A method for adjusting a time-of-flight mass spectrometer, comprising:

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