Flight time type mass spectrometer and adjustment method

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 an adjustment method thereof.

Background Art

[0002] In recent years, mass spectrometers have been frequently used for the identification and quantification of compounds contained in samples. In TOFMS, which is one type of mass spectrometer, ions derived from a sample are accelerated by imparting a certain kinetic energy and introduced into a flight space, and the flight time of the ions that have flown a predetermined distance within the flight space is measured. Since this flight time depends on the mass-to-charge ratio (m / z) of the ions, a mass spectrum showing the relationship between the m / z value and the ion intensity (ion amount) can be created by converting the flight time into an m / z value.

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

[0004] Normally, a mass spectrometer is equipped with an auto-tuning function that automatically adjusts the applied voltage to each electrode of each part that affects the behavior of ions in the device (see Patent Document 1, etc.). Generally, in such auto-tuning, parameter values such as the applied voltage to each part are adjusted so that the peak intensity of a mass peak corresponding to a specific compound obtained when measuring a standard sample becomes maximum. The height of the peak intensity of the mass peak is generally related to the mass resolution, and by maximizing the peak intensity of the mass peak, the mass resolution can be brought into a state close to the maximum.

[0005] In orthogonal acceleration TOFMS, a type of TOFMS, as disclosed in Patent Document 2, a first accelerating electrode arranged in the orthogonal acceleration section, a second accelerating electrode that further accelerates ions ejected from the orthogonal acceleration section, a flight tube having a flight space inside, and a reflectron that forms an electric field in the flight space to reflect ions are electrodes that affect the behavior of ions and influence the performance of the device, such as detection sensitivity and mass resolution, and the voltage applied to these electrodes can be adjusted in auto-tuning. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2018-120804 [Patent Document 2] International Publication No. 2019 / 229950 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Conventional TOFMS systems allow for auto-tuning, which adjusts the device to a state close to its best performance. However, this conventional auto-tuning method has the following problems:

[0008] In many cases, even when a device is almost unused, meaning there is little contamination of electrodes and other components from use, there are differences in the performance of the devices. Therefore, when measuring the same sample using multiple devices of the same model but different models, each adjusted by auto-tuning, differences in measurement results may occur. Furthermore, even if the differences between devices are small when the device is new (or after an overhaul), these differences may increase with use. Even if the measurement results meet the target resolution specified by the device itself, if there are large differences in measurement results between different devices for the same sample, it becomes difficult to compare the measurement results. Therefore, differences in performance between devices can lead to product complaints from users to manufacturers and may undermine the reliability of the product itself.

[0009] This invention was made to solve these problems, and its main objective is to provide a TOFMS and a method for adjusting the same that can reduce variations in mass resolution between multiple devices of the same model, that is, devices having the same configuration and structure. [Means for solving the problem]

[0010] To solve the above problems, one aspect of the TOFMS according to the present invention is a time-of-flight mass spectrometer comprising a measuring unit that includes a flight electric field forming unit that forms an electric field in the flight space for ions to fly, and an ion acceleration unit that accelerates the ions to be measured and sends them into the flight space, A control unit 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 to calculate the mass resolution based on the measurement results of each measurement. An approximation function calculation unit obtains, under the control of the control unit, a plurality of sets of data of the voltage applied to the electrode and the corresponding mass resolution, and determines an approximation function that approximates the relationship between the two. A voltage determination unit that uses the aforementioned approximation function to determine a voltage value corresponding to the target value of mass resolution and determines this voltage value as the voltage applied to the electrode in the device, It is equipped with.

[0011] One aspect of the TOFMS adjustment method according to the present invention, which was developed to solve the above problems, is a method for adjusting multiple time-of-flight mass spectrometers, each comprising a measurement unit that includes a flight electric field forming unit that forms an electric field in the flight space for ions to fly, and an ion acceleration unit that accelerates the ions to be measured and sends them into the flight space, A target setting step is performed in which a target value for the mass resolution common to the multiple time-of-flight mass spectrometers is set. In each of the aforementioned multiple time-of-flight mass spectrometers, A measurement step in which measurements are repeatedly performed on a predetermined sample while changing the voltage applied to the electrodes included in the measurement unit, and the mass resolution is calculated based on the measurement results in each measurement, A voltage determination step in which, based on the data of multiple sets of applied voltages to the electrodes and their corresponding mass resolutions obtained in the measurement step, a voltage value corresponding to the target value is determined, and this voltage value is determined as the applied voltage to the electrodes in the apparatus; Execute this. [Effects of the Invention]

[0012] According to the above embodiment of the TOFMS and its adjustment method of the present invention, the mass resolution of multiple devices of the same model can be made roughly the same, and the difference in mass resolution between devices can be reduced. This reduces the variability in measurement results when the same sample is measured with multiple different devices. [Brief explanation of the drawing]

[0013] [Figure 1] A diagram showing the main components of a quadrupole time-of-flight mass spectrometer, which is one embodiment of the present invention. [Figure 2] Functional block diagram of the control and processing unit in the quadrupole-time-of-flight mass spectrometer of this embodiment. [Figure 3]Flowchart showing the processing operation of auto-tuning in the quadrupole-time-of-flight mass spectrometer of the present embodiment. [Figure 4] 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.

Mode for Carrying Out the Invention

[0014] A quadrupole-time-of-flight mass spectrometer (hereinafter sometimes referred to as "Q-TOFMS"), which is an embodiment of 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 spectrometry without ion dissociation operation, MS / MS analysis in which specific ions are dissociated, and the like.

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

[0016] The measurement unit 1 executes measurement 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 inside of the vacuum chamber 10 is generally partitioned 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 from this ionization chamber 11, the first intermediate vacuum chamber 12, the second intermediate vacuum chamber 13, the first analysis chamber 14, and the second analysis chamber 15 are arranged in order, and it has a configuration of a multi-stage differential exhaust system with gradually increasing vacuum degree.

[0017] In FIG. 1, the description of the vacuum pump for evacuating each chamber is omitted. Generally, the interior of the first intermediate vacuum chamber 12 at the subsequent stage of the ionization chamber 11 is evacuated by a rotary pump, and the interiors of the subsequent chambers are evacuated by a turbomolecular pump using a rotary pump as a roughing pump.

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

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

[0020] The control and processing unit 3 controls the measurement unit 1 either through the voltage source 2 or directly, and receives and processes the detection signal obtained by the measurement unit 1. As shown in Figure 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 functional blocks, a parameter search unit 331, a parameter readjustment unit 3321, an approximate function calculation unit 3322, and a parameter determination unit 3323, which are included in the parameter readjustment unit 3322.

[0021] Generally, the control / processing unit 3 is a personal computer (PC), and each function in the above-mentioned functional block is realized by running 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 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 part of the measurement unit 1.

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

[0024] In the ionization chamber 11, ions derived from the sample components and fine charged droplets of solvent that have not yet fully vaporized are drawn into the desolvation tube 112, primarily by the gas flow formed by the pressure difference between the ionization chamber 11 (approximately atmospheric pressure) and the first intermediate vacuum chamber 12. The desolvation tube 112 is heated to a suitable temperature, and as the charged droplets pass through the inside of the desolvation tube 112, the vaporization of the solvent in the droplets is promoted, further stimulating 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 high-frequency electric field formed by the ion guide 121. The focused ions enter the second intermediate vacuum chamber 13 through the opening at the top of the skimmer 122. Ions that enter the second intermediate vacuum chamber 13 are focused by the high-frequency electric field formed by the ion guide 131 and sent to the first analysis chamber 14.

[0026] Ions incident on the first analysis chamber 14 are introduced into a 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. Collision gases such as argon and nitrogen are continuously or intermittently supplied to the inside of the collision cell 142. Ions (precursor ions) that pass through the quadrupole mass filter 141 and are incident on 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 focused 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 narrow, highly parallel ion stream by the transfer electrode 144 are then ejected in pulses in the orthogonal acceleration section 151 in a direction approximately perpendicular to the incident direction of the ion stream (a direction parallel to the ion optical axis C1), that is, as roughly a single ion packet.

[0028] Each ion constituting this ion packet is further accelerated by the second accelerating electrode section 152 and introduced into the flight space inside the flight tube 153. In the flight space, an electric field is formed by the flight tube 153, reflectron 154, and backplate 155, causing the ions to fold back along the path shown as C2 in Figure 1. As a result, after folding back, the ions fly again inside 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 corresponding to the number of incident ions and sends it to the control / processing unit 3.

[0029] In the orthogonal acceleration section 151 and the second acceleration electrode section 152, the kinetic energy imparted to each ion is ideally constant. Therefore, each ion flies at a velocity corresponding to its m / z value; specifically, the smaller the m / z value, the greater the velocity, and reaches the ion detector 156. Consequently, the various ions contained in the ion packet, introduced into the flight space almost simultaneously, are spatially separated during their flight 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 the present invention. The flight tube 153, reflectron 154, and back plate 155 correspond to the flight electric field forming section in the present invention. Therefore, the electrodes included in the ion acceleration section are the extrusion electrode 1511, the retraction electrode 1512, and the multiple annular electrodes that constitute the second acceleration electrode section 152. The electrodes included in the flight electric field forming section are the multiple annular electrodes that constitute the flight tube 153 and reflectron 154, and the back plate 155. The transfer electrode 144 corresponds to the ion introduction section in the present invention, and the electrodes included in the ion introduction section are the multiple annular electrodes that constitute 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 flight time of each ion, starting from the time the ion packet is ejected from the orthogonal acceleration unit 151, into m / z values ​​and creates a mass spectrum (product ion spectrum) showing the relationship between the m / z values ​​and ion intensity. The created mass spectrum is displayed on the display unit 5 according to the user's instructions given from the input unit 4.

[0032] The above description describes the operation during MS / MS analysis. By allowing all ions to pass through the quadrupole mass filter 141 without ion selection and by not performing ion dissociation in the collision cell 142, it is possible to perform normal mass spectrometry instead of MS / MS analysis and obtain a mass spectrum. Even in this case, since ion mass separation is performed by orthogonal accelerated TOFMS, a mass spectrum with high mass resolution and mass accuracy can be obtained.

[0033] In the Q-TOFMS of this embodiment, in order to achieve high sensitivity, high mass resolution, and high mass accuracy, it is necessary to appropriately adjust the voltage applied to the electrodes of each part included in the measurement unit 1. This Q-TOFMS has an auto-tuning function to automatically and appropriately adjust such applied voltages. Next, the operation during auto-tuning, which is characteristic of the Q-TOFMS of this embodiment, will be described.

[0034] In orthogonal accelerated TOFMS, a tuning method is known in which the voltage applied to each electrode is sequentially adjusted so that, for example, sensitivity is maximized when measuring a standard sample, specifically so that the top intensity of the mass peak for a particular compound is maximized. Another tuning method is known in which the voltage applied to each electrode is sequentially adjusted so that the mass resolution of that mass peak is maximized. In particular, mass resolution is one of the important performance characteristics of a mass spectrometer, and instrument manufacturers ship only instruments that can achieve a mass resolution exceeding a specified target value when properly tuned. However, as mentioned above, differences between instruments are unavoidable even among the same model, and the maximum mass resolution that each instrument can achieve differs from instrument to instrument. Therefore, when tuning is performed to achieve the maximum or near-maximum mass resolution, differences in the achievable mass resolution will occur from instrument to instrument.

[0035] For example, for a user who owns only one instrument, the differences in mass resolution between instruments, as described above, are often not a problem. On the other hand, for a user who owns multiple instruments of the same model, they often compare measurement results such as mass spectra obtained from different instruments, so differences in mass resolution between instruments can become a problem. Therefore, in the Q-TOFMS of this embodiment, a distinctive tuning is performed to make the mass resolution of different instruments as uniform as possible.

[0036] Figure 3 is a flowchart showing the process flow of auto-tuning in the Q-TOFMS of this embodiment. Figure 4 is a diagram showing an example of the relationship between applied voltage and 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 performs auto-tuning according to a predetermined program. When auto-tuning starts, the parameter search unit 331 first repeatedly measures the same standard sample while sequentially changing the voltage applied to the electrodes of each part, and searches for a voltage value that maximizes or comes close to it based on the measurement results (step S1).

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

[0039] The mass resolution can be determined from the peak of the target compound observed in the mass spectrum obtained from the measurement. Typically, the mass resolution R can be determined 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, this is not the only method for calculating the mass resolution.

[0040] One of the performance characteristics of the Q-TOFMS in this embodiment, namely mass resolution and mass accuracy, depends on the voltages applied to the multiple electrodes after the transfer electrode 144. For example, changing the voltage applied to the multiple annular electrodes constituting the transfer electrode 144 changes the degree of ion spread as they exit the transfer electrode 144 and enter the orthogonal acceleration section 151. When the ion spread increases, the variation in the initial position of ions in the ion path C2 direction when a pulse voltage is applied to the extrusion electrode 1511 increases, thus reducing the mass resolution. Furthermore, changing the pulse voltage applied to the extrusion electrode 1511, the DC voltage applied to the retraction electrode 1512, the DC voltages applied to each of the multiple annular electrodes included in the second acceleration electrode section 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, thus changing the mass resolution. Therefore, in step S1 above, the voltage conditions that maximize mass resolution are searched for by sequentially adjusting the voltage applied to several of these electrodes.

[0041] However, in step S1, it is also possible to search for voltage conditions that result in high overall performance in combination with other elements related to the performance of the mass spectrometer, such as sensitivity and mass peak waveform shape, in addition to mass resolution. For example, in Japanese 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 accelerated TOFMS, the voltage conditions that maximize sensitivity and the voltage conditions that maximize mass resolution may not coincide, and it is possible to find voltage conditions that are close to the maximum mass resolution while balancing sensitivity and mass resolution. Therefore, voltage conditions that are close to the maximum mass resolution may be searched for in this manner.

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

[0043] In conventional auto-tuning, the voltage values ​​applied to each electrode obtained in step S1 are stored as optimal parameter values, and these parameter values ​​are used for measuring the target sample. In contrast, the Q-TOFMS of this embodiment readjusts the parameters by executing the processes from step S2 onward.

[0044] The mass resolution that can be achieved by exploring the voltage conditions in step S1 above can vary considerably from device to device, even within the same model. Of course, if the device is in good condition, the mass resolution will usually be equal to or greater than the target value U at the end of step S1. However, since performance such as mass resolution also depends on the mechanical precision of the assembly, differences in performance between devices are unavoidable, and the value itself often varies. In step S2 and beyond, the voltage value is readjusted to bring the mass resolution close to the predetermined target value U. Here, as an example, we show an example of readjusting the applied voltage to the second accelerating electrode section 152, which has a large impact on the mass resolution, but the target of readjusting the applied voltage is not limited to the second accelerating electrode section 152, as long as it is an electrode that affects the mass resolution.

[0045] The target value U for mass resolution described above can be predetermined by the equipment manufacturer and stored in the parameter storage unit 34. In this case, the equipment manufacturer can determine an appropriate target value for each model, so that it is a common target value for equipment of the same model regardless of the user, and the mass resolution of all equipment of the same model can be roughly standardized regardless of which user owns it. However, even if the hardware of the equipment itself is the same, if the mass resolution changes due to the control and processing software, the mass resolution may change depending on the version of that software. In that case, the target value of mass resolution can be updated along with the software update. Also, if a user owns multiple units of the same model, the user may be allowed to change the target value of mass resolution so that the mass resolution can be standardized only among those multiple units. In that case, the target value U is a common target value only for the multiple units owned by that user.

[0046] When a device is shipped from the manufacturer, it may be adjusted to a value that allows for a certain margin of error compared to the mass resolution guaranteed in the catalog specifications, taking measurement errors into consideration. 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 can be set in various ways, as long as it is achievable for each of the 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 acceleration electrode unit 152, to the voltage value (initial voltage value) obtained in the process of step S1, and then controls each unit to perform a measurement on a standard sample. At this time, the initial voltage value applied to the second acceleration electrode unit 152 is denoted as Vp. Then, based on the data obtained from 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 voltage at that time, and controls each part to perform the measurement on the standard sample under that voltage value. Then, the readjustment control unit 3321 calculates the mass resolution based on the data obtained from the measurement (step S3).

[0049] In step S3, instead of decreasing the voltage value from the initial voltage value Vp, the voltage value may be changed in the opposite direction, increasing the voltage value from the initial voltage value Vp (increasing the absolute value of the voltage). However, according to the inventor's experiments, when the voltage value of the second accelerating electrode section 152 is changed in the direction of increasing the voltage value from the initial voltage value (the voltage value at which the mass resolution is maximized), not only does the mass resolution decrease, but the waveform shape of the mass peak deteriorates (tailing or leading becomes longer). For this reason, a voltage change in the direction of decreasing the voltage value is adopted here, as deterioration of the mass peak waveform shape does not occur (or is unlikely to occur). If there are no such phenomena as deterioration of the mass peak waveform shape, the voltage may be changed in the direction of increasing the voltage value from the initial voltage value.

[0050] After step S3 is executed, the readjustment control unit 3321 determines whether the calculated mass resolution is below the target resolution value U (step S4). If it is not below the target value U, the process returns from step S4 to S3. Thus, by repeating steps S3 and S4, the measurement on the standard sample is repeated while changing the voltage applied to the second accelerating electrode unit 152 by a predetermined step width until the mass resolution falls below the target value U. When 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 greater than or equal to a predetermined number. This predetermined number can be appropriately set to a value of 3 or more, such as 3 or 5. The determination process in step S5 is to avoid a situation where the accuracy of the approximation function, which will be described later, cannot be sufficiently ensured.

[0051] If it is determined in step S5 that the number of measurement points has not reached the predetermined number, the step size for changing the voltage value is narrowed (step S6), and the process returns to step S2 to readjust the settings from the beginning.

[0052] On the other hand, if it is determined in step S5 that the number of measurement points is greater than or equal to a predetermined number, the approximation function calculation unit 3322 calculates an approximation function showing the relationship between voltage value and mass resolution by performing regression analysis based on multiple combinations of voltage value and mass resolution obtained in steps S2 to S4 (step S7). In the regression analysis, the least squares method, which is relatively easy to calculate and can obtain good results, can be used. Furthermore, a function of degree 3 or higher may be used as the approximation function, but a quadratic function is usually sufficient.

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

[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 Figure 4 (step S8). The parameter determination unit 3323 then determines this voltage Vq as the readjusted voltage value to be applied to the second accelerating electrode unit 152 (step S9). This determined voltage value is then stored in the parameter storage unit 34 and used in subsequent measurements.

[0055] Thus, in the Q-TOFMS of this embodiment, after setting the voltage conditions so that the mass resolution is at or near its maximum, the applied voltage can be readjusted so that the mass resolution is near a target value U that is common to multiple devices. Performing this type of tuning offers the following advantages:

[0056] (1) The mass resolution of multiple instruments can be aligned to be near the target value U. Therefore, the variation in measurement results when measuring the same sample with multiple instruments can be reduced. (2) 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 increases the time required for tuning and the amount of standard samples used, leading to increased costs. In contrast, the above method makes it possible to obtain a voltage value that is highly accurate (i.e., one that makes it easier to bring the mass resolution close to the target value U) without performing multiple measurements under the same voltage conditions, thereby mitigating the effects of the variation in measurement results from those multiple measurements. This reduces the time required for tuning. It also reduces costs by reducing the amount of standard samples used.

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

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

[0059] Furthermore, in the Q-TOFMS of the above embodiment, the mass resolution will fall near the target value U after auto-tuning is performed. However, some users may want to adjust the system to obtain the highest possible mass resolution achievable by the device. Of course, such adjustments can be made manually, but the adjustment process is quite cumbersome. Therefore, in the Q-TOFMS of this embodiment, the user may be able to choose whether to end the tuning process when step S1 of the flowchart shown in Figure 2 is completed, or to continue the process from step S1 to steps S2 to S9 after step S1 and then end the tuning. By allowing such a choice, the user can perform measurements at the highest possible mass resolution achievable by the device, or close to it, as needed.

[0060] The above embodiment is an example of applying the present invention to a reflectron-type orthogonal acceleration TOFMS, but the present invention is not limited to the reflectron type, but can also be applied to other TOFMSs with different flight path configurations, such as linear type and multi-turn type. In the linear type, the electrodes included in the flight electric field forming section consist only of flight tubes. On the other hand, in the multi-turn type, the electrodes included in the flight electric field forming section include electrodes that cause ions to fly in a circular path (or in a spiral, etc.), and electrodes that introduce ions into such a trajectory and / or cause ions to deviate from such a trajectory.

[0061] Furthermore, the present invention can be applied not only to orthogonal acceleration methods, but also to ion trap TOFMS, for example, in which the 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 constituting these ion traps to eject the ions from the ion traps and send them into the flight space. In this case, the electrodes included in the ion acceleration unit are the electrodes that constitute the ion trap.

[0062] Furthermore, the present invention is also applicable to TOFMS systems that accelerate ions extracted from the vicinity of the sample immediately after they are generated by the ion source, such as MALDI-TOFMS using a matrix-assisted laser desorption ionization source as the ion source, and then send them into the flight space. In this case, the electrodes included in the ion acceleration unit 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 embodiments and various modifications described above are merely examples of the present invention, and it is clear that any modifications, changes, or additions made within the scope of the present invention will be included within the scope of the claims of this patent application.

[0064] [Various forms] It will be obvious to those skilled in the art that the exemplary embodiments described above are specific examples of the following embodiments.

[0065] (Section 1) One aspect of the TOFMS according to the present invention is a time-of-flight mass spectrometer comprising a measuring unit that includes a flight electric field forming unit that forms an electric field in the flight space for ions to fly, and an ion accelerating unit that accelerates ions to be measured and sends them into the flight space, A control unit 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 to calculate the mass resolution based on the measurement results of each measurement. An approximation function calculation unit obtains, under the control of the control unit, a plurality of sets of data of the voltage applied to the electrode and the corresponding mass resolution, and determines an approximation function that approximates the relationship between the two. A voltage determination unit that uses the aforementioned approximation function to determine a voltage value corresponding to the target value of mass resolution and determines this voltage value as the voltage applied to the electrode in the device, It is equipped with.

[0066] (Paragraph 2) In the TOFMS described in Paragraph 1, the target value may be set in common for multiple devices whose mass resolution is to be standardized.

[0067] (Section 11) One aspect of the TOFMS adjustment method according to the present invention is a method for adjusting multiple time-of-flight mass spectrometers, each comprising a measurement unit that includes a flight electric field forming unit for forming an electric field in the flight space for ions to fly, and an ion acceleration unit for accelerating ions to be measured and sending them into the flight space, A target setting step is performed in which a target value for the mass resolution common to the multiple time-of-flight mass spectrometers is set. In each of the aforementioned multiple time-of-flight mass spectrometers, A measurement step in which measurements are repeatedly performed on a predetermined sample while changing the voltage applied to the electrodes included in the measurement unit, and the mass resolution is calculated based on the measurement results in each measurement, A voltage determination step in which, based on the data of multiple sets of applied voltages to the electrodes and their corresponding mass resolutions obtained in the measurement step, a voltage value corresponding to the target value is determined, and this voltage value is determined as the applied voltage to the electrodes in the apparatus; Execute this.

[0068] In this context, "multiple devices for which mass resolution is to be standardized" or "multiple time-of-flight mass spectrometers" generally refers to devices of the same model with identical configuration and structure. However, even if some components, structures, or the software controlling the device differ, it is acceptable as long as the devices 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, the mass resolution of multiple instruments of the same model can be roughly standardized, reducing the difference in mass resolution between instruments. This reduces the variability in measurement results when the same sample is measured with multiple different instruments.

[0070] Furthermore, even when multiple measurements are performed on the same sample 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 increase the number of measurements under the same voltage condition and take the average. However, performing such work increases the measurement time and the tuning time. In contrast, the TOFMS described in Sections 1 and 2, and the TOFMS tuning method described in Section 11, reduce the influence of variability in measurement results under a single voltage condition by obtaining an approximate function based on the results of measurements while varying the voltage, thus reducing the number of measurements under the same voltage condition. As a result, the mass resolution can be brought to the target value or its vicinity with good accuracy while shortening the tuning time.

[0071] (Clause 3) In the TOFMS described in paragraph 1, the approximation function calculation unit may determine the approximation function by the least squares method.

[0072] While regression analysis can be used to calculate an approximation function based on multiple sets of data representing the applied voltage to the electrodes and their corresponding mass resolution, employing the least squares method allows for a relatively simpler and more accurate approximation function. Therefore, according to the TOFMS described in Section 3, tuning increases the likelihood of achieving a mass resolution closer to the target value.

[0073] (Paragraph 4) In the TOFMS described in Paragraph 3, the function may be a quadratic function.

[0074] According to the inventors' research, the relationship between the voltage applied to the electrode and the mass resolution can be sufficiently approximated by a relatively simple curve. Therefore, a highly accurate approximation curve can be easily obtained using the TOFMS described in Section 4.

[0075] (Clause 5) In the TOFMS described in any one of paragraphs 1 to 4, the control unit may operate the measuring unit to repeat the measurement operation, which involves gradually changing the voltage applied to the electrodes included in the measuring unit from an initial voltage value that yields a mass resolution higher than the target value, performing a measurement on a predetermined sample, and calculating the mass resolution based on the measurement results, until the mass resolution falls below the target value.

[0076] According to the TOFMS described in Section 5, it is possible to more reliably find, with fewer measurements, the voltages that yield a mass resolution higher than the target value and the voltages that yield a mass resolution lower than the target value. This reduces tuning failures and shortens the tuning time.

[0077] (Clause 6) In the TOFMS described in Clause 5, the initial voltage value may be such that the mass resolution is maximized, or such that the mass resolution is maximized within a range in which at least one of the index values ​​representing the quality of the sensitivity or the waveform shape of the mass peak is acceptable.

[0078] One 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 the peak.

[0079] In the TOFMS described in Section 6, measurements are repeated while varying the voltage, starting from a voltage condition that maximizes mass resolution, or a voltage condition that maximizes mass resolution under conditions where the sensitivity and the quality of the mass peak waveform are satisfactory, even if the mass resolution is not necessarily maximized.

[0080] (Clause 7) The TOFMS described in Clause 6 further comprises a best state search unit that sequentially adjusts the voltages applied to a plurality of electrodes included in the measurement unit so that the mass resolution is maximized, or so that the mass resolution is maximized within an acceptable range for at least one of the 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 approximation function calculation unit, and the voltage determination unit adjust the voltages applied to one or more predetermined electrodes.

[0081] According to the TOFMS described in Section 7, the voltage conditions are first set so that the mass resolution is at or near its maximum, thus avoiding situations where the mass resolution does not reach the target value due to inappropriate voltage condition settings.

[0082] (Clause 8) In the TOFMS described in any one of paragraphs 1 to 7, the measurement unit includes an ion introduction unit for introducing ions into the ion acceleration unit, and the control unit collects data in the form of a voltage-mass resolution pair by repeatedly performing measurements while changing the voltage applied to an electrode included in the ion introduction unit, the ion acceleration unit, or the flight electric field forming unit.

[0083] (Section 9) In the TOFMS described in Section 8, the ion acceleration unit may be configured to accelerate the ions introduced from the ion introduction unit in a direction perpendicular to it.

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

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

[0086] According to the TOFMS described in Section 10, the mass resolution can be appropriately adjusted while minimizing the impact on other performance aspects 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... Aeon Guide 122... Skimmer 13…Second Intermediate Vacuum Chamber 131... Aeon Guide 14…1st analysis room 141... Quadrupole mass filter 142...Collision cell 143… Aeon Guide 144... Transfer electrode 15…Second analysis room 151...Orthogonal acceleration section 1511...Extrusion electrode 1512...Incoming electrode 152…Second accelerating electrode section 153... Flight Tube 154...Reflectron 155...backplate 156... Ion detector 2…Voltage source 3…Control and Processing Unit 31...Measurement Control Unit 32...Data Processing Unit 33...Auto Tuning Execution Unit 331...Optimal parameter search unit 332...Parameter readjustment unit 3321... Readjustment Control Unit 3322... Approximation function calculation unit 3323...Parameter determination unit 34...Parameter storage unit 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; A time-of-flight mass spectrometer comprising:

2. 2. The time-of-flight mass spectrometer according to claim 1, wherein the target value is determined in common for a plurality of instruments that are to have a common mass resolution.

3. 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.

4. 4. The time-of-flight mass spectrometer of claim 3, wherein the function is a quadratic function.

5. 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.

6. 6. The time-of-flight mass spectrometer according to claim 5, 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.

7. 7. The time-of-flight mass spectrometer of claim 6, 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.

8. 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.

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

10. 10. The time-of-flight mass spectrometer according to claim 9, 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.

11. 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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