Ion source and automatic analyzer provided with ion source

Abstract

In order to provide an ion source in which the stability of an ion source is improved, and an automatic analyzer provided with the ion source, the following configuration is employed.　An ion source in which, with a probe having a first flow path through which a sample-containing liquid is channeled and a second flow path through which a gas is channeled, the liquid discharged from the first flow path and the gas discharged from the second flow path are mixed at the distal end of the probe to ionize the sample, the ion source comprising an adjustment mechanism capable of adjusting the relative positional relationship between the distal end of the first flow path and the distal end of the second flow path on the basis of a control signal received from outside of the ion source.

Description

Ion source and automatic analyzer equipped with ion source

[0001] The present invention relates to an ion source and an automatic analyzer equipped with the ion source.

[0002] In mass spectrometry, which measures the mass-to-charge ratio (m / z) of a sample to identify the sample substance, the sample to be measured is ionized and measured. The mechanism that ionizes the sample solution is called an ion source. One of the ionization methods used in ion sources is the electrospray method (hereinafter referred to as the "ESI method"). In the ESI method, in order to improve ionization efficiency, the sample solution sprayed from a capillary is vaporized using heated gas. In such ion sources, it is desirable to stabilize the ionization efficiency.

[0003] Patent Document 1 discloses a technology in which a gas inlet is provided within a probe holder that holds an ion probe, and the heating section that increases the temperature of the heated gas is connected to the gas inlet by a plurality of independent pipes that extend along the extension direction of the ion probe, thereby homogenizing the temperature distribution and flow rate distribution of the heated gas and stabilizing the ionization efficiency.

[0004] Japanese Patent Application Laid-Open No. 2020-77537

[0005] The following factors are generally considered to cause changes in ionization efficiency at the ion source: (1) fluctuations in LC performance (signal suppression due to background ions eluting from the LC), (2) fluctuations in the electrospray process (continuous delivery of mobile phase organic solvent to the ion source, fluctuations in electrospray ionization (ESI) current, spray stability), (3) changes in ion movement due to contamination or moving optics (transmission through the ion optics from the air-vacuum interface to the mass detector), (4) fluctuations in ion source performance (signal suppression due to background ions eluting from the ion source), and (5) changes in detector sensitivity (detector sensitivity fluctuations due to contaminants). Factors (1) to (5) change over time, resulting in changes in ionization efficiency. In the technology described in Patent Document 1, the structure of the ion probe is fixed, so if the ionization efficiency changes due to the factors described above, there may be limitations to the adjustment of stabilization.

[0006] The present invention has been made in view of the above-mentioned problems, and has an object to provide an ion source with improved stability, and an automatic analyzer equipped with the ion source.

[0007] The present invention provides a solution to the above problems as follows: A probe having a first flow path through which a liquid containing a sample flows and a second flow path through which a gas flows, and an ion source that ionizes the sample at the tip of the probe by mixing a liquid discharged from the first flow path with a gas discharged from the second flow path, the ion source including an adjustment mechanism that can adjust the relative positional relationship between the tip of the first flow path and the tip of the second flow path based on a control signal received from outside the ion source.

[0008] The automatic analyzer also includes a detection unit that detects ions generated by the ion source, and a control unit that adjusts the adjustment mechanism based on a detection signal of the ions detected by the detection unit.

[0009] According to the present invention, it is possible to provide an ion source with improved stability, and an automatic analyzer equipped with the ion source.

[0010] FIG. 1 is a diagram showing a schematic configuration of a mass spectrometer. FIG. 2 is a diagram showing changes in IS signal values ​​during testosterone measurement. FIG. 3 is a schematic diagram showing the tip positions of the first flow channel and the second flow channel as viewed from above. FIG. 4 is a diagram showing an example of a spray state of gas spray. FIG. 5 is a diagram showing an example of a spray state of gas spray. FIG. 6 is a diagram showing a schematic configuration of an adjustment mechanism for the tip of an ion probe. FIG. 7 is a diagram showing a schematic configuration of an adjustment mechanism for the tip of an ion probe. FIG. 8 is a diagram showing a schematic configuration of an adjustment mechanism for the tip of an ion probe. FIG. 9 is a diagram showing a flowchart for adjusting the relative positional relationship between the tip of the capillary and the tip of the gas flow channel.

[0011] 1 is a schematic diagram of a mass spectrometer. The mass spectrometer 1 is mainly composed of an ion source 104 and a vacuum vessel 105. The vacuum vessel 105 houses a mass analysis unit 107 and other components. The ion source 104 includes an ion source chamber (ion generation unit) 103.

[0012] Ions generated by the ion source 104 are introduced into the vacuum vessel 105 through a hole 106 in the introduction electrode 118, and the mass analysis unit 107 analyzes the ions. The space between the ion source chamber 103 and the vacuum vessel 105 may be sealed (or nearly sealed) to prevent components such as gas and droplets not introduced into the vacuum vessel 105 from leaking outside the device. Furthermore, an exhaust port 123 for exhausting the excess gas and droplets may be provided. The ion source chamber 103 may also have an imaging unit 109 to observe the spray state at the tip of the capillary 101. A voltage is applied between the capillary 101 and the introduction electrode 118 by a power supply 114, and ions generated in the ion source chamber are introduced into the mass analysis unit 107 via the vacuum vessel 105. The timing and voltage value of the voltage application by the power supply 114 are controlled by a control unit 130.

[0013] The mass analysis unit 107 is composed of an ion analysis unit and a detector (neither of which are shown). The ion analysis unit separates and dissociates ions. The ion analysis unit may be an ion trap, a quadrupole filter electrode, a collision cell, a time-of-flight mass spectrometer (TOF), or a combination of these.

[0014] The detector detects ions that have passed through the ion analysis unit. An electron multiplier tube, a multichannel plate (MCP), or the like can be used as the detector. The ions detected by the detector are converted into electrical signals, etc. The control unit 130 uses these signals to perform detailed analysis of information such as the mass and intensity of the ions. The control unit 130 includes an input / output unit 131 that accepts user input instructions, a display unit 132 that displays analysis results, etc., and a memory (not shown) that stores data for controlling voltage, etc. It also includes software necessary for controlling the power supply, etc.

[0015] The ion analysis section is configured to apply a high frequency voltage, a direct current voltage, an alternating current voltage, or a combination of these voltages to perform the desired analysis.

[0016] The vacuum vessel 105 is divided by a plurality of partition walls 140, and each vacuum chamber is connected by a small diameter hole. The small diameter holes are passageways for ions, and a voltage may be applied to the member having each hole. In this case, insulation between the vacuum vessel 105 and the housing parts is required via an insulator (not shown). The number of vacuum chambers may be more or less than that shown in FIG. 1. Each vacuum vessel 105 is evacuated by a vacuum pump, and generally, the vacuum levels are maintained at approximately several hundred Pa, several Pa, and 0.1 Pa or less from the side closest to the ion source.

[0017] In the ion source 104, a sample in a sample container 110 and a solvent from a solvent container 111 containing a solvent for diluting the sample are sent to a mixer 141 by pumps 112 and 113, respectively, and the solvents are mixed in the mixer 141. The purpose of mixing multiple solvents is to separate impurities from the sample separated in a separation column mounted in the LC unit 152. It is preferable to change the mixing ratio of the multiple solvents depending on the type of impurity to be separated.

[0018] The sample to be ionized is injected into a sample loop in an injection valve 151 from an injection port of a liquid chromatograph (LC section) 152, and the injection valve 151 is switched to inject the sample into a mixed solvent. The sample diluted with the mixed solvent is sprayed from a capillary (first flow path) 101. Simultaneously with the spraying of the diluted sample from the capillary 101, heated gas is released from a gas flow path (second flow path) 102 that releases heated gas, thereby ionizing the diluted sample sprayed from the capillary 101 (the capillary 101 and the gas flow path 102 that releases heated gas are sometimes referred to as an ion probe).

[0019] An adjustment mechanism 150 having an adjustment part 108 for adjusting the relative positional relationship with the tip position of the gas flow channel 102 is provided near the tip of the capillary 101. Details of the adjustment mechanism 150 will be described later.

[0020] Figure 2 shows the results of measuring testosterone as a sample using the mass spectrometer shown in Figure 1. The vertical axis of Figure 2 shows the signal value of the IS (Internal Standard), and the horizontal axis shows the number of measurements (measurement points). Also, circles and triangles in the graph indicate differences in the measurement devices. That is, Figure 2 shows the results of measuring the same concentration of testosterone internal standard solution at different times using eight measurement devices.

[0021] 2, it can be seen that the IS signal value drifts as the number of measurement points increases. It can also be seen that there are differences in the IS signal value between instruments, with the signal value fluctuating between approximately 1,500,000 and approximately 4,700,000.

[0022] The signal value of an internal standard solution within a certain range indicates that the performance of the instrument system is consistent. For example, the following document states that variations in the IS signal response of a target sample can affect data accuracy, and that if the tolerance is exceeded, the operator must determine whether the observed difference affects the accuracy of the target sample data. In an instrument system, maintaining the signal value of an internal standard solution within a certain range is expected to alleviate such concerns. Reference: Evaluation of Internal Standard Responses During Chromatographic Bioanalysis: Questions and Answers, Guidance for Industry, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), September 2019, Biopharmaceutic. Therefore, in order to reduce this variability, the inventors thoroughly investigated the cause and came to believe that one of the causes of the variability in measurement values ​​is the variation in the relative positional relationship between the tip of the capillary 101 of the ion probe and the tip of the gas flow path 102 that emits heated gas, as shown in Figure 1, from instrument to instrument.

[0023] Figure 3 shows the tip of the ion probe viewed from the longitudinal direction. Figure 3(A) shows a state in which the central axis of the capillary 101 and the central axis of the gas flow channel 102 that emits the heated gas are aligned, while Figure 3(B) shows a state in which the central axes are misaligned. This misalignment between the tip positions of the capillary 101 and the gas flow channel 102 that emits the heated gas affects the measured values. It is expected that this misalignment in the tip positional relationship will increase or decrease as measurements are repeated due to deformation caused by thermal expansion of the flow channel tip.

[0024] 4 to 6 are diagrams that show the effect on measurement values ​​of such misalignment of the ion probe tip. 801 is a schematic diagram of the state of ion spray from the tip of the capillary 101, photographed by the photographing unit 109 in FIG. 1. The size of the circles indicates the size of the sprayed droplets. Since the droplets evaporate as they fly away, droplets sprayed further away become smaller. FIG. 4 shows the state of spraying when the central axis of the capillary 101 and the central axis of the gas flow path 102 that emits heated gas are aligned, as shown in FIG. 3(A). It can be seen that the sprayed droplets are neatly round.

[0025] In contrast, the shape of the sprayed droplets is biased to the right in Figure 5. Also, in Figure 6, the spray shape is symmetrical, but is not as circular as in Figure 4.

[0026] The relationship between the spray shape and the measurement conditions is considered to be, for example, as follows: When the organic solvent ratio is changed from low to high as the mixing ratio, the protrusion amount of the capillary 101 at the tip of the ion probe is changed from high to low. When the IS signal value is small, the nozzle tip is shortened to increase the sprayed mist. When the IS signal value is small, the voltage applied by the power supply 114 in Figure 1 is increased, and the nozzle is shortened to increase the mist sprayed from the capillary 101. In an actual device, such adjustments are made by trial and error, as shown in Figure 2, to adjust the tip of the ion probe in response to changes in the IS (Internal Standard) signal value due to the number of measurements (measurement points), and adjustment know-how for suppressing changes in the signal value is accumulated. In this case, by using well-known statistical methods such as machine learning and Mahalanobis distance, it is possible to learn the adjustment method more quickly.

[0027] A specific method for changing the relative positional relationship of the nozzle tips will be described below with reference to FIGS.

[0028] 7A shows a state in which the adjustment unit 108 is not in contact with the capillary 101. FIG. 7B shows a state in which the adjustment mechanism 150 moves the adjustment unit 108 to press against the capillary 101, and the adjustment unit 108 grips the capillary 101. FIG. 7C shows a state in which the adjustment mechanism 150 moves upward from the state in FIG. 7B, thereby shortening the length 151 between the tip of the capillary 101 and the tip of the gas flow path 102. That is, the capillary 101 is configured to be movable in the longitudinal direction relative to the gas flow path 102. Although not shown, an airtight sealing member such as an O-ring is provided at the upper end of the gas flow path 102. The O-ring slides against the capillary 101, allowing the tip of the capillary 101 to be extended or retracted from the tip position of the gas flow path 102.

[0029] The adjustment mechanism 150 not only changes the distance between the tip of the capillary 101 and the tip of the gas flow path 102 as described in FIG. 7 , but also can position the tip of the capillary 101 in an oblique direction. FIG. 8 shows an example in which the tip of the capillary 101 is directed obliquely to the right by pressing the lower adjustment portion 108 of the adjustment mechanism 150 on the right side of the figure and the lower adjustment portion 108 of the adjustment mechanism 150 on the left side of the figure. Each adjustment portion 108 of the adjustment mechanism 150 can be independently extended or retracted, allowing the capillary tip to bend obliquely to the right or left in the figure. This bending occurs within the elastic deformation region of the metal material constituting the capillary 101, and when the pressure on the adjustment portion 108 is released, the capillary 101 returns to its straight state. The above-described adjustment of the adjustment mechanism 150 is controlled based on a control signal from the control unit 130.

[0030] 7 and 8 are explained by showing the capillary 101 bent to the right and left for ease of understanding, but in reality, the adjustment unit 108 is arranged so that the capillary 101 can be bent in any direction through 360 degrees. The structure will be described later.

[0031] Another configuration example of the adjustment unit 108 will be described with reference to FIG. 9 . FIG. 9 shows an example in which the adjustment unit 108 uses a roller-type protrusion 160 instead of the gripping unit shown in FIG. 7 . FIG. 9(A) shows a state in which the roller-type protrusion 160 is not in contact with the capillary 101, FIG. 9(B) shows a state in which the roller-type protrusion 160 grips the capillary 101 by pinching it, and FIG. 9(C) shows a state in which the roller of the roller-type protrusion 160 is rotated from the state shown in FIG. 9(B) to move the capillary 101 upward, shortening the length 151 between the tip of the capillary 101 and the tip of the gas flow path 102. By using a roller, the capillary 101 can be bent and stretched smoothly, and the mechanism for operating the adjustment unit 108 can be simplified, i.e., a mechanism that does not require much force for operation can be adopted.

[0032] The details of the adjustment mechanism 150 will be described with reference to FIG. 10 . FIG. 10(A) shows a mechanism for protruding or retracting the capillary 101 from the gas flow path 102, and FIG. 10(B) shows a top view of FIG. 10(A). The adjustment unit 108 is part of the adjustment unit support unit 170, has three or more parts that move in contact with the capillary 101, and is connected to the adjustment mechanism 150 that can move up and down and rotate. The adjustment mechanism 150 that can rotate up and down can change the vertical rotation position of the adjustment unit 108 by being rotated up and down by a motor or the like. The adjustment unit 108 can be protruded from the adjustment unit support unit 170 at an optimal position. Alternatively, the adjustment unit support unit 170 can be provided with a vertical rotation mechanism without being fixed to the adjustment mechanism 150.

[0033] FIG. 11 shows a flowchart for automatically adjusting the relative positional relationship between the tip of the capillary 101 and the tip of the gas flow path 102. S601: Start adjustment. S602: Check the tip positions of the capillary 101 and the gas flow path 102 using images captured by the imaging unit 109. This is because the ion probe is a mechanism that is periodically removed, cleaned, adjusted, etc., and therefore the capillary 101 may not be attached to the device in the ideal installation position when it is installed, and the operator may bend the capillary 101. Therefore, if the ion probe has already been used for measurements after cleaning and adjustment, this confirmation can be performed without using captured images by storing the position of the stepping motor that moves the adjustment mechanism by the number of movement pulses from the home position. S603: Monitor (confirm) the mixing ratio of multiple types of solvents. S604: Determine whether to move the relative positions. This determines whether the relative positions of the tip of the capillary 101 and the tip of the gas flow path 102 shown in FIG. 3 should be adjusted so that the center of the tip of the capillary 101 is coaxial with the center of the tip of the gas flow path 102, as shown in (A), or so that the central axis of the tip of the capillary 101 is offset from the central axis of the tip of the gas flow path 102, as shown in (B). If it is determined that the capillary 101 should be moved, the process proceeds to S605. If it is determined that the capillary 101 should not be moved, the process jumps to S606. Note that an allowable deviation range is set as a design value, and if it is within that range, the process jumps to S606 without moving the capillary 101. S605: Relative position movement. If the control unit 130 determines that the relative position should be moved, the control unit 130 sends a control signal to the adjustment mechanism 150, and moves the position of the adjustment mechanism 150 up, down, left, and right using a motor or the like, thereby changing the up, down, left, and right positions of the adjustment unit 108. S606: Measure IS signal value (the IS signal value measured here is also referred to as the "ion detection signal"). S607: If it is determined that relative movement is necessary as a result of the IS signal value measurement in S606, the process returns to S605. If it is determined that relative movement is unnecessary, the process jumps to S609. Note that a tolerance for deviation from the ideal value (design value) of the IS signal value is set as a design value, so if it is within that range, the process jumps to S609 without movement. S608: The voltage or current value applied to the ion source is monitored. This is done by feedback control based on the IS signal value, so that the IS signal falls within the target value range.Generally, it is confirmed that the voltage is within the target range to be set. S609: Determine whether to move the relative position again. S610: If it is determined in S609 that the relative position should be moved, move the relative position. S611: Measure the IS signal value again. S612: Determine whether to move the relative position again. S613: Photograph the spray state of the gas spray. S614: Determine whether to move the relative position again. S615: If it is determined in S614 that the relative position should be moved, move the relative position. S616: Measure the IS signal value again. S617: Determine whether to move the relative position again. S618: Measure the IS signal value again. S609: End.

[0034] Through the steps described above, the relative positional relationship between the tip of the capillary 101 and the tip of the gas flow path is automatically adjusted.

[0035] The present invention is not limited to the above-described embodiments, and various combinations within the technical concept described are included in the present invention.

[0036] 1 Mass spectrometer, 101 Capillary (first flow path), 102 Gas flow path (second flow path), 103 Ion source chamber (ion generation section), 104 Ion source, 105 Vacuum vessel, 106 Hole, 107 Mass analysis section, 114 Power supply, 118 Introduction electrode, 130 Control section

Claims

1. An ion source comprising: a probe having a first flow path for flowing a liquid containing a sample and a second flow path for flowing a gas; and an ion source that ionizes the sample at the tip of the probe by mixing the liquid discharged from the first flow path with the gas discharged from the second flow path, and an adjustment mechanism that can adjust the relative positional relationship between the tip of the first flow path and the tip of the second flow path based on a control signal received from outside the ion source.

2. An ion source according to claim 1, wherein the adjustment mechanism moves the position of either the tip of the first flow path or the tip of the second flow path along the longitudinal direction of the probe.

3. An ion source according to claim 1, wherein the adjustment mechanism presses and moves either the tip of the first flow path or the tip of the second flow path in the short direction of the probe.

4. An automatic analyzer comprising: an ion source according to any one of claims 1 to 3; a detection unit that detects ions generated by the ion source; and a control unit that controls the adjustment mechanism by transmitting the control signal to the ion source based on a detection signal of the ions detected by the detection unit.

5. An automatic analyzer comprising: an ion source according to any one of claims 1 to 3; and an imaging unit that images the spray state of ions containing the sample sprayed from the probe, and a control unit that controls the adjustment mechanism by transmitting the control signal to the ion source based on the information imaged by the imaging unit.

6. An automatic analyzer comprising: an electrospray ion source according to any one of claims 1 to 3; and a control unit that controls the adjustment mechanism by transmitting a control signal to the ion source based on the voltage and / or current value applied to the probe.

7. An automatic analyzer comprising: an ion source according to any one of claims 1 to 3, wherein the first flow path is for flowing a mixed liquid of a plurality of types of solvents; and a control unit that controls the adjustment mechanism by sending the control signal to the ion source based on the mixing ratio of the solvents in the mixed liquid.

8. An automatic analyzer comprising: an ion source according to any one of claims 1 to 3; a detection unit that detects ions generated by the ion source; an imaging unit that images the spray state of ions containing the sample sprayed from the probe; and a control unit that controls the adjustment mechanism by transmitting the control signal to the ion source based on the detection signal of the ions detected by the detection unit and the information imaged by the imaging unit.

9. An automatic analyzer characterized in that the ion source according to claim 8 is an electrospray ion source, and the control unit controls the adjustment mechanism by transmitting the control signal to the ion source based on the voltage value and / or current value applied to the probe in addition to the detection signal of the ions detected by the detection unit and the information captured by the imaging unit.

10. An automatic analyzer according to claim 8, wherein the first flow path of the ion source is configured to pass a mixed liquid of multiple types of solvents, and the control unit controls the adjustment mechanism by transmitting the control signal to the ion source based on the mixture ratio of the solvents in the mixed liquid in addition to the detection signal of the ions detected by the detection unit, the information captured by the imaging unit, and the voltage value and / or current value applied to the probe.

Images