Time-of-flight mass spectrometer and method for adjusting the same

Abstract

To present an evaluation result obtained by more surely reflecting a bilateral symmetry of a real peak profile to a user.SOLUTION: In an embodiment of a TOFMS according to the present invention, the TOFMS contains a measurement part including: a flight magnetic field formation part that forms a magnetic field for flying an ion into a flight space; and an ion accumulation part that accumulates the ion and feeds them into the flight space. The TOFMS comprises: an analysis processing part (33) of generating a spectrum indicating a relation between a flight time or m / z and an ion strength on the basis of data obtained by the measurement part; an index value calculation part (34) that calculates a difference between a middle point of a first peak width in the strength obtained by multiplying a first ratio with a top strength in a peak observed in the spectrum and a middle point of a second peak width in the strength obtained by multiplying a second ratio smaller than the first ratio to the top strength as an index value; and an evaluation result storage part (35) that stores by evaluating a bilateral symmetry of the peak from the index value.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 constant 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, the parameter values such as the applied voltage to each part are adjusted so that the top intensity of a mass peak (hereinafter simply referred to as "peak") corresponding to a specific compound obtained when measuring a standard sample becomes maximum, or so that the mass resolution calculated from the peak becomes maximum.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] [Non-Patent Document 1] "2.00 General Principles of Chromatography," Pharmaceuticals and Medical Devices Agency, [Online], [Accessed May 10, 2022], Internet<URL: https: / / www.pmda.go.jp / files / 000242610.pdf> [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] However, even with high sensitivity and mass resolution, peak shape distortion can occur, such as large peak leading or tailing, and it is undesirable to use the appropriate voltage value in such situations. For example, if the left-right symmetry of the peak is compromised, there is a possibility that another peak with a similar m / z value is superimposed. If the peak area differs from the original value due to such peak overlap, the intensity error will be large, for example, when the peak area value is used as the intensity of the centroid peak after centroid processing. Also, if the left-right asymmetry of the peak is large, the centroid position will be shifted significantly when centroid processing is performed, resulting in a large error in the m / z value. For these reasons, the degree of left-right symmetry of the peak is useful information for understanding the adjustment status of the instrument.

[0008] Conventionally, the asymmetry coefficient (or symmetry coefficient) described in Patent Document 2 and Non-Patent Document 1 has been known as an index value indicating the left-right symmetry of the peak. In Patent Document 2, the asymmetry coefficient is calculated as follows.

[0009] First, using the height h of the peak top P as a reference, for example, a height h1 that is 1 / 10 of the peak top height h is identified. Next, two points Pa and Pb with height h1 are identified in the leading and tailing portions of the peak. Then, when a is the distance from the perpendicular line passing through point P at the peak top to point Pa, and b is the distance from the perpendicular line to point Pb, the asymmetry coefficient As is defined as As = b / a. In the case of perfect left-right symmetry, As = 1, and As increases as the degree of tailing increases. The definition of the symmetry coefficient (tailing coefficient) described in Non-Patent Literature 2 is similar to this.

[0010] These conventional index values ​​accurately represent the bilateral symmetry of a peak when there are many discrete measurement points (i.e., many data points) that make up a single peak profile, meaning that the shape of the peak profile can be reproduced with almost exact accuracy by these data points. However, when there are few discrete measurement points that make up a single peak, the above index values ​​may not adequately represent the true bilateral symmetry of the peak profile. The index values ​​described in Patent Document 2 and Non-Patent Document 1 are primarily intended for peaks observed in chromatograms. Generally, chromatograms have a relatively large number of discrete measurement points that make up a single peak. In contrast, mass spectra, especially TOFMS mass spectra, often have a small number of discrete measurement points that make up a single peak. Therefore, it is difficult to evaluate the bilateral symmetry of a peak with sufficient accuracy using the above conventional index values.

[0011] This invention was made to solve these problems, and its main objective is to provide a TOFMS that can provide an index value for accurately evaluating the left-right symmetry of a peak, even when the number of measurement points constituting a single peak is small, and a method for adjusting the TOFMS using such an index value. [Means for solving the problem]

[0012] To solve the above problems, one embodiment of the TOFMS according to the present invention comprises a measuring unit including 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, An analysis processing unit, which creates a spectrum showing the relationship between time of flight or mass-to-charge ratio and ionic intensity based on the data obtained by the measurement unit, An index value calculation unit calculates, as an index value, the difference between the time of flight or mass-to-charge ratio between the midpoint of the first peak width at an intensity obtained by multiplying the peak's top intensity by a first ratio and the midpoint of the second peak width at an intensity obtained by multiplying the peak's top intensity by a second ratio smaller than the first ratio, for the peaks observed in the spectrum. An evaluation result storage unit that evaluates and stores the left-right symmetry of the peak from the aforementioned index value, It is equipped with.

[0013] To solve the above problems, one embodiment of the TOFMS adjustment method according to the present invention is a measurement unit comprising: 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; Based on the data obtained by the measurement unit, an analysis processing step is performed to create a spectrum showing the relationship between time of flight or mass-to-charge ratio and ionic intensity. An index value calculation step in which, for the peak observed in the spectrum, the difference between the time of flight or the mass-to-charge ratio between the midpoint of the first peak width at an intensity obtained by multiplying the peak's top intensity by a first ratio and the midpoint of the second peak width at an intensity obtained by multiplying the peak's top intensity by a second ratio smaller than the first ratio is calculated as an index value, An adjustment step of adjusting the voltage applied to the electrodes included in the measuring unit using at least the index value or another numerical value obtained from the index value, It has. [Effects of the Invention]

[0014] According to the above aspect of the TOFMS according to the present invention, even when the number of discrete measurement points (data points) constituting the peaks observed in the spectrum is small, compared with the conventionally used index values such as the asymmetry coefficient, it is possible to present to the user an evaluation result that more accurately reflects the left-right symmetry of the true peak profile. Further, according to the above aspect of the adjustment method of the TOFMS according to the present invention, it is possible to accurately adjust the applied voltage to the electrodes included in the measurement unit so that the left-right symmetry of the peak profile is improved.

Brief Description of the Drawings

[0015] [Figure 1] Configuration diagram of the main part of a quadrupole-time-of-flight mass spectrometer which is an embodiment of the present invention. [Figure 2] Flowchart showing the flow of the auto-tuning operation in the quadrupole-time-of-flight mass spectrometer of the present embodiment. [Figure 3] Conceptual diagram for explaining the method of calculating the evaluation value of the peak left-right symmetry in the present embodiment. [Figure 4] Conceptual diagram for explaining the comparison between the conventional asymmetry coefficient and the evaluation value of the peak left-right symmetry which is an aspect of the present invention when the number of measurement points constituting one peak is small. [Figure 5] Flowchart showing the flow of the auto-tuning operation in one modification.

Modes for Carrying Out the Invention

[0016] A quadrupole-time-of-flight mass spectrometer (hereinafter sometimes referred to as "Q-TOFMS") which is an embodiment of the 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 and MS / MS analysis in which specific ions are dissociated.

[0017] Figure 1 is a diagram showing the main components of the Q-TOFMS of this embodiment. As shown in Figure 1, this Q-TOFMS comprises a measurement unit 1, a voltage source 2, a control / processing unit 3, an input unit 4, and a display unit 5.

[0018] The measurement unit 1 performs measurements on a sample (liquid sample) and includes 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 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 under approximately atmospheric pressure, and the system is configured as a multi-stage differential pumping system in which the vacuum level 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.

[0019] Although Figure 1 omits the description of the vacuum pumps used to evacuate each chamber, generally, the first intermediate vacuum chamber 12, which is the next stage after the ionization chamber 11, is evacuated by a rotary pump, and each subsequent chamber is evacuated by a turbomolecular pump that uses a rotary pump as a roughing pump.

[0020] An electrospray ion (ESI) source 111 is located in the ionization chamber 11, and the ionization chamber 11 and the first intermediate vacuum chamber 12 are connected through a small-diameter desolvation tube 112. A multipole ion guide 121 is located 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 with an opening at the top. A multipole ion guide 131 is also located in the second intermediate vacuum chamber 13. The first analysis chamber 14 contains a quadrupole mass filter 141, a collision cell 142 having a multipole ion guide 143 inside, and the front half of a transfer electrode 144. The second analysis chamber 15 contains the rear half of the transfer electrode 144, the orthogonal acceleration section 151 including the extrusion electrode 1511 and the retraction electrode 1512, the second acceleration electrode section 152, the flight tube 153, the reflectron 154, the back plate 155, and the ion detector 156.

[0021] The voltage source 2 applies a predetermined voltage to each electrode in the measurement unit 1, specifically to electrodes in 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., in accordance with the control of the control / processing unit 3. The predetermined voltage here is a DC voltage, pulse voltage, high-frequency voltage (RF voltage), AC voltage with a frequency lower than the RF voltage, or a combination of several of these.

[0022] 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. 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, a peak symmetry evaluation value calculation unit 34, and a storage unit 35.

[0023] 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.

[0024] An example of the MS / MS analysis operation performed in the Q-TOFMS of this embodiment will be briefly described. During normal mass spectrometry and MS / MS analysis, the measurement control unit 31 controls the voltage source 2 based on various parameter values ​​stored in the memory unit 35, and accordingly the voltage source 2 applies a predetermined voltage to each part of the measurement unit 1.

[0025] The ESI source 111 is continuously supplied with a liquid sample containing compounds separated by, for example, a liquid chromatograph (LC) (not shown). 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; other ion sources, such as atmospheric pressure chemical ion sources, can also be used. Furthermore, ion sources that ionize gaseous or solid samples instead of liquid samples can also be used.

[0026] 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.

[0027] 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.

[0028] Ions incident on the first analysis chamber 14 are introduced into the quadrupole mass filter 141, and only ions with a specific m / z depending on 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. The product ions are ion guides.143 The high-frequency electric field formed by this process converges the light, and the light is emitted from the collision cell 142.

[0029] 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.

[0030] Each ion contained in 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.

[0031] In the orthogonal acceleration section 151 and the second acceleration electrode section 152, the kinetic energy imparted to each ion is ideally the same. 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 (various product ions generated from a single precursor ion) introduced into the flight space almost simultaneously are spatially separated according to their m / z values ​​during flight and incident on the ion detector 156 with a time difference.

[0032] Furthermore, the orthogonal acceleration section 151 and the second acceleration electrode section 152 correspond to the ion acceleration section in the present invention. Also, the flight tube 153, reflectron 154, and backplate 155 correspond to the flight electric field forming section in the present invention.

[0033] 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.

[0034] The above description explains the operation of 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.

[0035] 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 each electrode in the measurement unit 1. This Q-TOFMS has an auto-tuning function to automatically and appropriately adjust such voltages.

[0036] In general, with 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 peak intensity for a particular compound is maximized. Alternatively, a tuning method is known in which the voltage applied to each electrode is sequentially adjusted so that the mass resolution of the peak for a particular compound is maximized. Furthermore, in Japanese Patent Publication No. 6989008, proposed by the present applicant, as an example, the voltage applied to the electrodes is adjusted using two peak widths: one at 50% peak intensity and another at 10% peak intensity. In this way, by using not only the peak width at 50% peak intensity but also the peak width at lower intensities, it is possible to determine the voltage conditions so that peak distortion is minimized.

[0037] However, even with the method described in the above-mentioned Japanese Patent Publication No. 6989008, it is not possible to determine the left-right asymmetry of the peak waveform, so the voltage may be adjusted so that only the leading or tailing of the peak is large. In contrast, in the Q-TOFMS of this embodiment, when auto-tuning is performed, measurements are taken on a standard sample while changing the voltage applied to the electrodes, and when determining sensitivity, mass resolution, etc. based on the measurement results, in addition to these existing index values, the peak symmetry evaluation value calculation unit 34 calculates an evaluation value indicating the left-right symmetry of the peak. An example of the method for calculating this evaluation value indicating the left-right symmetry of the peak is illustrated in Figure 3. Figure 3 is a conceptual diagram for illustrating the method for calculating the peak symmetry evaluation value.

[0038] As shown in Figure 3, the peak symmetry evaluation value calculation unit 34 determines points P1 and P2 at 50% intensity (0.5 × Ia) and points P3 and P4 at 10% intensity (0.1 × Ia) when the intensity of the peak top P0 of the peak profile 100 is Ia. Then, it determines the midpoint 102 of the first peak width 101 between points P1 and P2 and the midpoint 104 of the second peak width 103 between points P3 and P4, and calculates the distance 105 between these two midpoints 102 and 104. This distance 105 is a value with positive or negative polarity based on either midpoint 102 or 104, and if the position of midpoint 102 is m / z A and the position of midpoint 104 is m / z B, the distance L = BA. For example, if the midpoint 102 is at m / z 200 and the midpoint 104 is at m / z 190, then the distance L = -10.

[0039] Note that in Figure 3, the distance 105 is calculated for peaks on the mass spectrum, so the unit of distance 105 is, for example, Da or u, but it is not converted to m / z values ​​in the time-of-flight spectrum. of Alternatively, the distance 105 can be calculated relative to the peak, in which case the unit would be, for example, μsec (or nsec).

[0040] Here, the values ​​of 50% and 10% used to determine the intensity for finding the peak width are just examples and can be changed as appropriate. Specifically, 50% can be appropriately selected within the range of approximately 40-60%, and 10% can be appropriately selected within the range of approximately 5-30%. The lower limit of the ratio, 5%, is determined by the noise level of the mass spectrum (or time-of-flight spectrum). If the noise is relatively high, the lower limit needs to be higher, and conversely, if the noise is low, the lower limit can be lower than 5%.

[0041] Furthermore, the two points used to calculate the distance may not be the midpoint of the first and second peak widths, but rather points obtained by dividing each peak width into a predetermined number of parts. For example, the first and second peak widths may each be divided into three parts, and the first division point from the left may be used instead of the midpoint, and the distance between these division points may be calculated. Alternatively, the first and second peak widths may each be divided into three parts, and the first division point from the left in the first peak width and the first division point from the right in the second peak width may be used instead of the midpoint, and the distance between these division points may be calculated. In other words, the distance 105 can be the distance between points selected according to a predetermined rule for each peak width.

[0042] Figure 4 is a conceptual diagram illustrating a comparison between the conventional asymmetry coefficient and the peak symmetry evaluation value in this embodiment when the number of measurement points constituting a single peak is small. In this example, one peak profile is composed of five measurement points. In this case, there is a large difference between the measured peak created by connecting these measurement points with straight lines (hereinafter referred to as the "actual measured peak") and the true peak profile shown by the dashed line in the figure. As shown in Figure 4(A), the asymmetry coefficient is b1 / a1 in the actual measured peak, while the asymmetry coefficient is b / a in the true peak profile. The difference between these two asymmetry coefficients is large, and one of the main reasons for this is that the position on the horizontal axis indicating the peak top is significantly shifted due to the small number of measurement points.

[0043] In contrast, when calculating the peak symmetry evaluation value described above, the peak top intensity is used to identify the intensity for determining the peak width, but the position on the horizontal axis indicating the peak top is not used. As shown in Figure 4(B), there is a large difference in peak top intensity between the measured peak and the true peak profile, but since the intensity for determining the peak width is at 50% and 10% of the peak top intensity, the effect of the difference in peak top intensity is considerably reduced. Therefore, the difference in peak width at 50% and 10% intensity between the measured peak and the true peak profile can be small. As a result, the peak symmetry evaluation value described above more accurately represents the left-right asymmetry of the peak compared to the conventional asymmetry coefficient, even when the number of measurement points constituting a single peak is small.

[0044] Next, we will describe the operation of the Q-TOFMS in this embodiment during auto-tuning execution. Figure 2 is a flowchart showing an example of the auto-tuning operation flow. 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. In auto-tuning, the voltages applied to multiple electrodes included in the measurement unit 1 are adjusted sequentially. Figure 2 shows the flow when adjusting the voltage applied to one of these electrodes. As an example, the case of adjusting the voltage applied to the orthogonal acceleration unit 151 will be explained.

[0045] First, the tuning execution unit 33 initializes the voltage applied to the orthogonal acceleration unit 151 (step S1). That is, it reads the most recently set voltage value stored in the memory unit 35 or a default voltage value, and controls the voltage source 2 to apply the voltage corresponding to that voltage value to the extrusion electrode 1511 and the retraction electrode 1512 of the orthogonal acceleration unit 151, respectively. The voltage applied to each electrode other than the orthogonal acceleration unit 151 is set to a previously adjusted voltage value or a predetermined default value.

[0046] Under the control of the tuning execution unit 33, the measurement unit 1 performs normal mass spectrometry over a predetermined m / z value range on the standard sample (step S2). The standard sample contains one or more known compounds at known concentrations and can be introduced into the ESI source 111, for example, instead of a normal liquid sample. Alternatively, a dedicated ionization probe may be provided separately from the ESI source 111 to ionize the standard sample by electrospraying.

[0047] The data processing unit 32 collects the data obtained from the measurement in step S2 and creates a mass spectrum near a predetermined m / z value. It then extracts the peak corresponding to a known compound from the mass spectrum, calculates the mass resolution from the peak height and peak width, and stores the mass resolution in the storage unit 35 in association with the voltage value applied to the orthogonal acceleration unit 151 (step S3). The peak symmetry evaluation value calculation unit 34 calculates the peak symmetry evaluation value for the same peak according to the procedure described above, and also stores this value in the storage unit 35 in association with the voltage value (step S4).

[0048] Next, the tuning execution unit 33 determines whether the voltage value applied to the orthogonal acceleration unit 151 immediately beforehand exceeds a predetermined adjustment range (step S5). If the voltage value is within the adjustment range, it changes the voltage value by a predetermined step width (step S6) and returns to step S2. Returning to step S2, the measurement unit 1 performs a measurement on the standard sample under the changed voltage value. Thus, by repeating steps S2 to S6, the voltage value applied to the orthogonal acceleration unit 151 is changed by a predetermined step width starting from the initial value until it exceeds the preset adjustment range, and the measurement on the same standard sample is repeated. During this repeated measurement, the mass resolution and peak symmetry evaluation value are stored in the storage unit 35 as log information for auto-tuning, corresponding to the voltage value.

[0049] When the voltage applied to the orthogonal acceleration unit 151 exceeds the adjustment range, the process proceeds from step S5 to S7. The tuning execution unit 33 compares the mass resolution stored in the memory unit 35 and identifies the voltage value that maximizes the mass resolution (step S7). The identified voltage value is then stored in the memory unit 35 as the adjusted voltage parameter applied to the orthogonal acceleration unit 151 (step S8).

[0050] In this way, in the Q-TOFMS of this embodiment, the voltage applied to the orthogonal acceleration unit 151 is adjusted so that the mass resolution is maximized. Here, the peak symmetry evaluation value is not used during voltage adjustment, but its value is stored in the storage unit 35 as log information. Therefore, at an appropriate time, for example, immediately after the completion of auto-tuning, or if there are doubts about the measurement results, the user can retrieve the log information by performing a predetermined operation from the input unit 4 and display it on the display unit 5. This allows the user to check the peak symmetry evaluation value at the end of auto-tuning and during auto-tuning. Furthermore, when maintenance service personnel perform maintenance work on the device, they can understand the past state of the device by checking the peak symmetry evaluation value at the end of auto-tuning and during auto-tuning, and perform appropriate troubleshooting.

[0051] Even with high mass resolution, the symmetry of the peak may be disrupted due to large peak leading or tailing. Such distortion of the peak waveform shape can lead to errors in peak intensity and m / z value, especially when centroid processing is performed. Therefore, if a user complains about a decrease in mass accuracy, for example, maintenance service personnel can check the peak symmetry evaluation value in the log information to determine whether the left-right asymmetry of the peak is the cause of the decrease in mass accuracy.

[0052] This log information is data stored in the memory unit 35. Therefore, if the PC implementing the control / processing unit 3 can connect to an external server via the internet or the like, maintenance service personnel can check the log information remotely, away from the device's installation location, and perform at least some troubleshooting.

[0053] In the above explanation, the distance 105 explained in Figure 3 was used directly as the peak symmetry evaluation value. However, the evaluation value may also be obtained by normalizing the distance by the observed m / z value. For example, the evaluation value can be calculated by finding the m / z value corresponding to the midpoint of the peak width at 50% intensity and dividing the distance by this m / z value. The evaluation value obtained in this way does not depend on the m / z value, so it may be more preferable as an index value indicating the asymmetry of the peak shape. Alternatively, instead of a specific numerical value like the peak symmetry evaluation value, an evaluation result indicating the left-right symmetry of the peak may be obtained by determining, for example, which of several predetermined levels it falls into.

[0054] Furthermore, while the above description described adjusting the voltage applied to the orthogonal acceleration unit 151 to maximize mass resolution, the applied voltage may also be adjusted to maximize sensitivity, that is, to maximize the intensity of a specific peak, rather than mass resolution. Alternatively, as described in Japanese Patent Publication No. 6989008, the applied voltage may be adjusted using multiple peak widths at different intensities. Furthermore, instead of focusing on a single indicator value such as mass resolution or sensitivity, the system may explore voltage conditions that comprehensively improve performance by considering a combination of multiple factors related to the performance of the mass spectrometer, such as mass resolution, sensitivity, and peak waveform shape.

[0055] For example, in Japanese Patent Application No. 2022-074176, filed earlier by the present applicant, a score value is calculated based on a predetermined formula using the peak top intensity and mass resolution, and the 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 coincide. Therefore, it is possible to find voltage conditions that balance sensitivity and mass resolution while maximizing the mass resolution. In other words, in the Q-TOFMS of this embodiment, the index value representing the device performance for voltage adjustment in auto-tuning is not particularly limited; it is sufficient to calculate and save the peak symmetry evaluation value along with such index values.

[0056] Furthermore, while the above explanation describes the adjustment of the voltage applied to the orthogonal acceleration unit 151 during autotuning, the voltages applied to the electrodes of other parts, such as the flight tube 153, reflectron 154, and transfer electrode 144, can be adjusted in the same manner. In addition, instead of individually adjusting the voltage applied to the electrodes of each part, multiple electrodes can be grouped together, and the voltage applied to each group can be adjusted.

[0057] As described above, in the Q-TOFMS of this embodiment, the user or maintenance service personnel can check the peak symmetry evaluation value in the log information. For example, instead of the voltage value that maximizes the mass resolution, they can re-select the voltage value that brings the peak symmetry evaluation value closest to zero (i.e., when leading and tailing are of similar magnitude) as the adjusted voltage parameter.

[0058] Furthermore, it is possible to manually readjust the voltage value using the peak symmetry evaluation value. Specifically, adjustments can be made as follows:

[0059] The peak symmetry evaluation value indicates whether leading or tailing is greater, and the extent of the difference between them. Voltage source 2 applies the same DC voltage to the extrusion electrode 1511 and the retraction electrode 1512 of the orthogonal acceleration unit 151 during the period when ions are received from the transfer electrode 144, and during the period when ions are ejected from the orthogonal acceleration unit 151, it applies a pulse voltage to push ions only to the extrusion electrode 1511, or it applies a pulse voltage to push ions to the extrusion electrode 1511 while applying a pulse voltage to retract ions to the retraction electrode 1512. When the DC voltage applied to the extrusion electrode 1511 and the retraction electrode 1512 is the same during the period when ions are received, the ions incident on the orthogonal acceleration unit 151 travel along the ion optical axis C1.

[0060] In contrast, if a difference is made in the DC voltage applied to the extrusion electrode 1511 and the retraction electrode 1512, the ions incident on the orthogonal acceleration unit 151 will travel while curving upward or downward relative to the ion optical axis C1 as shown in Figure 1. When a pulse voltage is applied to eject ions in the orthogonal acceleration unit 151 while the ions are moving upward from the ion optical axis C1, the ion flight distance becomes substantially longer, and tailing increases. Conversely, when a pulse voltage is applied to eject ions in the orthogonal acceleration unit 151 while the ions are moving downward from the ion optical axis C1, the ion flight distance becomes substantially shorter, and leading increases. In other words, if the peak symmetry evaluation value can be used to determine which is greater, leading or tailing, and what the difference between them is, the user or maintenance service personnel can recognize which electrode's voltage should be changed and by how much to reduce the peak symmetry evaluation value, and can quickly adjust the voltage accordingly.

[0061] In the above embodiment of Q-TOFMS, the peak symmetry evaluation value is not directly used for automatic adjustment of auto-tuning, but the peak symmetry evaluation value may be used for automatic adjustment. Figure 5 is a flowchart showing the flow of auto-tuning operation in one modified example of Q-TOFMS. Steps that perform substantially the same processing operations as in the flowchart shown in Figure 2 are given the same step numbers.

[0062] The measurement is performed while changing the voltage applied to the orthogonal acceleration unit 151, and the mass resolution and peak symmetry evaluation value corresponding to each voltage value are calculated and stored, just as in the above embodiment. In this modified Q-TOFMS, if Yes is determined in step S5, the tuning execution unit 33 uses both the mass resolution and the peak symmetry evaluation value, or even adds an index value indicating sensitivity, to comprehensively select an appropriate voltage (step S17). For example, a score value is calculated from the mass resolution and the peak symmetry evaluation value based on a predetermined calculation formula, and the voltage that maximizes this score value is selected. By appropriately defining the calculation formula, it is possible to find a voltage in which the mass resolution is not at its maximum but is high enough to a certain extent and the asymmetry of the peak shape is small.

[0063] Furthermore, as described above, the system may automatically perform adjustments similar to those manually performed to reduce leading and tailing based on the peak symmetry evaluation value. That is, the tuning execution unit 33 may monitor the peak symmetry evaluation value obtained from the measurement results and adjust the voltage so that the evaluation value approaches zero or falls below a predetermined value.

[0064] Furthermore, although the above embodiments and modifications are examples of applying the present invention to a reflectron-type orthogonal acceleration TOFMS, 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 and multi-turn types. 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.

[0065] 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.

[0066] 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.

[0067] Furthermore, it is clear that the above embodiments and the various modifications described above are merely examples of the present invention, and that any modifications, changes, or additions made within the scope of the present invention will still be included within the scope of the claims.

[0068] [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.

[0069] (Section 1) One embodiment of the TOFMS according to the present invention is a measuring unit comprising: 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, An analysis processing unit, which creates a spectrum showing the relationship between time of flight or mass-to-charge ratio and ionic intensity based on the data obtained by the measurement unit, An index value calculation unit calculates, as an index value, the difference between the time of flight or mass-to-charge ratio between the midpoint of the first peak width at an intensity obtained by multiplying the peak's top intensity by a first ratio and the midpoint of the second peak width at an intensity obtained by multiplying the peak's top intensity by a second ratio smaller than the first ratio, for the peaks observed in the spectrum. An evaluation result storage unit that evaluates and stores the left-right symmetry of the peak from the aforementioned index value, It is equipped with.

[0070] According to the TOFMS described in paragraph 1, even when the number of discrete measurement points (data points) constituting the peaks observed in the mass spectrum or time-of-flight spectrum is small, it is possible to present to the user with evaluation results that more accurately reflect the bilateral symmetry of the true peak profile compared to conventionally used index values ​​such as the asymmetry coefficient.

[0071] (Paragraph 2) In the TOFMS described in Paragraph 1, the above-mentioned ratio shall be 40% or more and 60% or more. below It can be considered to exist.

[0072] (Paragraph 3) In the TOFMS described in Paragraph 1 or Paragraph 2, the ratio of the second above shall be 5% or more and 30% or less. below It can be considered to exist.

[0073] According to the TOFMS described in paragraphs 2 and 3, it is possible to obtain evaluation results that accurately represent the degree of left-right symmetry of the peak.

[0074] (Article 4) The TOFMS described in any one of paragraphs 1 to 3 may further include a display processing unit that displays the evaluation results from the evaluation result storage unit.

[0075] According to the TOFMS described in Section 4, users or maintenance service personnel can easily check the peak symmetry evaluation results collected during past auto-tuning sessions, etc., to determine the status of the device, and manually adjust the voltage based on those evaluation results.

[0076] (Clause 5) The TOFMS described in any one of paragraphs 1 to 3 may be further provided with an adjustment unit that adjusts the voltage applied to at least one electrode in the measurement unit using the evaluation result from the evaluation result storage unit.

[0077] According to the TOFMS described in Section 5, the voltage applied to the electrodes can be appropriately and automatically adjusted so that the peaks are approximately symmetrical.

[0078] (Clause 6) The TOFMS described in any one of paragraphs 1 to 5 further comprises an adjustment unit that performs measurements in the measurement unit while changing the voltage applied to at least one electrode included in the measurement unit, and adjusts the voltage using one or more of the mass resolution, sensitivity, and mass peak waveform shape based on the measurement results, The index value calculation unit may calculate the index value based on the measurement result each time the voltage is changed in the adjustment unit and a measurement is performed.

[0079] According to TOSMS described in Section 6, for example, the voltage applied to the electrodes can be adjusted so that the mass resolution is maximized or close to it, and then evaluation results showing the left-right symmetry of the peak during the adjustment process can be obtained. This allows not only to understand the evaluation results corresponding to the adjusted voltage, but also to understand the evaluation results corresponding to each voltage during the adjustment process, for example, to find the voltage at which the left-right symmetry of the peak is best.

[0080] (Section 7) The TOFMS described in Section 6 further comprises an ion introduction section for introducing ions into the ion acceleration section, the ion acceleration section accelerating the introduced ions in a direction perpendicular thereto, and the flight electric field forming section includes a flight tube that forms a space for ions to fly freely, and a reflectron that forms an electric field that reflects ions, The adjustment unit may be configured to adjust the voltage applied to at least one electrode included in the ion acceleration unit, the flight tube, or the reflectron.

[0081] (Clause 8) In the TOFMS described in paragraph 7, 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 the ions accelerated by the first accelerating electrode is applied, and the adjustment unit may adjust the voltage applied to either the first accelerating electrode or the second accelerating electrode.

[0082] According to the TOFMS described in paragraphs 7 and 8, the Q-TOFMS can be precisely adjusted to achieve high mass resolution.

[0083] (Section 9) One embodiment of the TOFMS adjustment method according to the present invention is a measurement unit comprising: 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 ions to be measured and sends them into the flight space, Based on the data obtained by the measurement unit, an analysis processing step is performed to create a spectrum showing the relationship between time of flight or mass-to-charge ratio and ionic intensity. An index value calculation step in which, for the peak observed in the spectrum, the difference between the time of flight or the mass-to-charge ratio between the midpoint of the first peak width at an intensity obtained by multiplying the peak's top intensity by a first ratio and the midpoint of the second peak width at an intensity obtained by multiplying the peak's top intensity by a second ratio smaller than the first ratio is calculated as an index value, An adjustment step of adjusting the voltage applied to the electrodes included in the measuring unit using at least the index value or another numerical value obtained from the index value, It has.

[0084] According to the TOFMS adjustment method described in Section 9, the voltage applied to the electrodes in the measurement unit can be accurately adjusted so that the left-right symmetry of the peak profile is good. [Explanation of Symbols]

[0085] 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 4...Input section 5...Display section

Claims

1. A time-of-flight mass spectrometer comprising a measuring unit including 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, An analysis processing unit, which creates a spectrum showing the relationship between time of flight or mass-to-charge ratio and ionic intensity based on the data obtained by the measurement unit, An index value calculation unit calculates, as an index value, the difference between the time of flight or mass-to-charge ratio between the midpoint of the first peak width at an intensity obtained by multiplying the peak's top intensity by a first ratio and the midpoint of the second peak width at an intensity obtained by multiplying the peak's top intensity by a second ratio smaller than the first ratio, for the peaks observed in the spectrum. An evaluation result storage unit that evaluates and stores the left-right symmetry of the peak from the aforementioned index value, A time-of-flight mass spectrometer equipped with the following features.

2. The time-of-flight mass spectrometer according to claim 1, wherein the first ratio is 40% or more and 60% or less.

3. The time-of-flight mass spectrometer according to claim 1, wherein the second ratio is 5% or more and 30% or less.

4. The time-of-flight mass spectrometer according to claim 1, further comprising a display processing unit for displaying the evaluation results from the evaluation result storage unit.

5. The time-of-flight mass spectrometer according to claim 1, further comprising an adjustment unit that adjusts the voltage applied to at least one electrode in the measuring unit using the evaluation results from the evaluation result storage unit.

6. The measurement unit further comprises an adjustment unit that performs a measurement in the measurement unit while changing the voltage applied to at least one electrode in the measurement unit, and adjusts the voltage using one or more of the mass resolution, sensitivity, and mass peak waveform shape based on the measurement results, The time-of-flight mass spectrometer according to claim 1, wherein the index value calculation unit calculates an index value based on the measurement result each time the voltage is changed in the adjustment unit and a measurement is performed.

7. The time-of-flight mass spectrometer according to claim 6, further comprising an ion introduction unit for introducing ions into the ion acceleration unit, the ion acceleration unit accelerating the introduced ions in a direction perpendicular thereto, the flight electric field forming unit including a flight tube that forms a space for ions to fly freely and a reflectron that forms an electric field that reflects ions, and the adjustment unit adjusting the voltage applied to at least one electrode included in the ion acceleration unit, the flight tube, or the reflectron.

8. The time-of-flight mass spectrometer according to claim 7, wherein 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 adjustment unit adjusts the voltage applied to either the first accelerating electrode or the second accelerating electrode.

9. A method for adjusting a time-of-flight mass spectrometer comprising a measuring unit including 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, Based on the data obtained by the measurement unit, an analysis processing step is performed to create a spectrum showing the relationship between time of flight or mass-to-charge ratio and ionic intensity. An index value calculation step in which, for the peak observed in the spectrum, the difference between the time of flight or the mass-to-charge ratio between the midpoint of the first peak width at an intensity obtained by multiplying the peak's top intensity by a first ratio and the midpoint of the second peak width at an intensity obtained by multiplying the peak's top intensity by a second ratio smaller than the first ratio is calculated as an index value, An adjustment step of adjusting the voltage applied to the electrodes included in the measuring unit using at least the index value or another numerical value obtained from the index value, A method for adjusting a time-of-flight mass spectrometer having the following characteristics.

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