Quality analysis apparatus and quality analysis method

Abstract

A mass spectrometry device (1) comprises a reaction chamber (26), a radical generation chamber (310), a radical generation unit (30) that generates radicals from plasma of a starting material gas supplied to the radical generation chamber, high-frequency power supply units (34, 43), a plasma detection unit (317) that detects light emitted from plasma of the starting material gas in the radical generation chamber, control units (42–45) that supply high-frequency power to the radical generation unit while supplying the starting material gas to the radical generation chamber and varying the frequency in a predetermined band but that fix the frequency of the high-frequency power supplied to the radical generation unit upon detection of light emitted from plasma of the starting material gas by the plasma detection unit, a radical introduction unit (31) that introduces radicals into the reaction chamber, a mass separation unit (28) that separates product ions generated from precursor ions in the reaction chamber in accordance with mass-to-charge ratio, and an ion detection unit (29) that detects product ions separated by the mass separation unit.

Description

Technical Field

[0001] The present invention relates to a mass spectrometer and a mass spectrometry method. In particular, it relates to a mass spectrometer and a mass spectrometry method for performing an operation of dissociating ions using radicals generated from a raw material gas.

Background Art

[0002] Among the ions generated from a sample, those having a specific mass-to-charge ratio are selected as precursor ions, and product ions are generated by attaching and dissociating specific types of radicals such as hydrogen radicals, oxygen radicals, and nitrogen radicals to the precursor ions, followed by mass spectrometry. A mass spectrometer is known (for example, Patent Documents 1 to 3, Non-Patent Document 1). For example, Patent Document 3 describes that by attaching hydrogen radicals to ions derived from a peptide, the ions derived from the peptide are dissociated at the position of the N-Cα bond, and c-series fragment ions reflecting the amino acid sequence of the peptide are generated to estimate the structure of the peptide.

[0003] Patent Documents 1 and 2 and Non-Patent Document 1 describe a mass spectrometer including a radical generation unit having a capillary tube made of a dielectric such as quartz, an antenna (helical antenna) made of a conductor wound in a three-dimensional spiral around the capillary tube, a power supply for supplying high-frequency power to the helical antenna, and a raw material gas supply unit for supplying a raw material gas into the capillary tube. In this mass spectrometer, while supplying a raw material gas into the capillary tube, high-frequency power having a predetermined frequency is supplied to the helical antenna to generate a plasma of the raw material gas in the capillary tube by eddy current and generate radicals.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

[0005] [Non-Patent Document 1] Hidenori Takahashi, Yuji Shimabukuro, Daiki Asakawa, Akihito Korenaga, Masaki Yamada, Shinichi Iwamoto, Motoi Wada, Koichi Tanaka, "Identifying Double Bond Positions in Phospholipids Using Liquid Chromatography-Triple Quadrupole Tandem Mass Spectrometry Based on Oxygen Attachment Dissociation", Mass Spedctrometry, Volume 8(2019), S0080 [Non-Patent Document 2] Keizo Endo, "Axial Radiation Helical Antenna," Television, 1957, Vol. 11, No. 12, pp. 544-548. [Non-Patent Document 3] Tomohiro Maruchi, "Theoretical Study on Vertical Helical Antennas," Nanzan University, 2007 Graduation Thesis [Non-Patent Document 4] Yoshio Ebine, Koichi Tsunekawa, "Antenna Technology Part 1: Antenna Basics", NTT DoCoMo Technical Journal, Vol. 5, No. 3, October 1997. [Non-Patent Document 5] "Solid State Microwave Oscillator TG-0002 / TG-0004", [online], Tokyo Keiki Co., Ltd., [Retrieved August 29, 2022], Internet<URL:https: / / www.tokyokeiki.jp / products / detail.html?pdid=261> [Non-Patent Document 6] "ZHL-2425-250X+ High Power Amplifier, 2400 - 2500 MHz, 50Ω Connector Type: MCX / N", [online], Mini-Circuits, [Retrieved October 5, 2022], Internet<URL:https: / / www.minicircuits.com / WebStore / dashboard.html?model=ZHL-2425-250X%2B> [Non-Patent Document 7] "13 MHz to 5.8 GHz | Up to 1.7 kW Solid State Power Amplifiers", [online], Mini-Circuits, [Retrieved October 5, 2022], Internet<URL: https: / / lp.minicircuits.com / en-us / ism-rf-energy-solutions> [Non-Patent Document 8] "Voltage-controlled crystal oscillator", [online], Kyocera Corporation, [Retrieved August 30, 2022], Internet<URL:https: / / ele.kyocera.com / assets / products / crystal-device / kv5032g_j.pdf> [Non-Patent Document 9] "Double-Balanced Mixer", [online], MACOM Technology Solutions Inc., [Retrieved August 30, 2022], Internet<URL:https: / / cdn.macom.com / datasheets / M76H.pdf> [Overview of the project] [Problems that the invention aims to solve]

[0006] In the mass spectrometer described above, the frequency and magnitude of the high-frequency power supplied to the helical antenna are determined based on the results of preliminary experiments. However, slight differences in the diameter, winding interval, and circumference of the helical antenna can cause different frequencies to resonate easily (see, for example, Non-Patent Documents 2-4). Therefore, if the mass spectrometer used for the preliminary experiments is different from the mass spectrometer used for the actual analysis, it may not be possible to generate plasma even if high-frequency power at the frequency determined in the preliminary experiments is supplied to the helical antenna. Although this explanation focuses on supplying high-frequency power to a helical antenna, similar problems exist when supplying high-frequency power to a radical generation unit that generates radicals from the plasma of the source gas, not limited to helical antennas.

[0007] The problem that the present invention aims to solve is to provide a technology that enables the generation of plasma regardless of the instrument's characteristics in a mass spectrometer equipped with a radical generation unit that generates radicals by generating plasma from a raw material gas supplied to a radical generation chamber when high-frequency power is supplied. [Means for solving the problem]

[0008] The present invention, made to solve the above problems, is a method for generating product ions by attaching radicals to precursor ions derived from sample molecules and then performing mass spectrometry, The raw material gas is supplied to the radical generation chamber. During the time period in which the raw material gas is supplied to the radical generation chamber, high-frequency power is supplied to the radical generation unit that generates radicals from the plasma of the raw material gas supplied to the radical generation chamber, while changing the frequency within a predetermined band. The plasma state of the raw material gas in the radical generation chamber is observed. When the plasma is lit, the frequency of the high-frequency power supplied to the radical generation unit is fixed. It is.

[0009] Furthermore, the mass spectrometer according to the present invention, which was developed to solve the above problems, A reaction chamber into which precursor ions derived from the sample molecule are introduced, Radical generation chamber, A radical generation unit that generates radicals from the plasma of the raw material gas supplied to the radical generation chamber, A high-frequency power supply unit configured to supply high-frequency power to the radical generation unit while changing the frequency within a predetermined bandwidth, A plasma detection unit for detecting the emission of light from the plasma of the raw material gas in the radical generation chamber, A control unit for controlling the operation of the raw material gas supply unit and the high-frequency power supply unit, comprising: a control unit that supplies the raw material gas to the radical generation chamber, supplies high-frequency power to the radical generation unit while changing the frequency in a predetermined band, and fixes the frequency of the high-frequency power supplied to the radical generation unit when the plasma detection unit detects the emission of plasma from the raw material gas; A radical introduction unit that introduces radicals generated in the radical generation chamber into the reaction chamber into which the precursor ion has been introduced, A mass separation unit separates the product ions generated from the precursor ions in the reaction chamber according to their mass-to-charge ratio, An ion detection unit for detecting product ions separated in the mass separation unit and It is equipped with. [Effects of the Invention]

[0010] In the present invention, when generating radicals to be attached to precursor ions derived from sample molecules, while supplying a source gas serving as a radical raw material to a radical generation chamber, high-frequency power is supplied to a radical generation unit that generates radicals from the plasma of the source gas supplied to the radical generation chamber while changing the frequency within a predetermined band. Then, when the plasma of the source gas in the radical generation chamber lights up (detecting the emission of plasma), the frequency of the high-frequency power supplied to the radical generation unit is fixed. This predetermined band may be set to include, for example, the frequency of the high-frequency power determined based on the results of preliminary experiments or the like. Alternatively, it may be the frequency at which the plasma lit up during the previous use. Also, the size of the band may be appropriately set in consideration of the assumed magnitude of instrumental differences and the like. In the present invention, even when there is an instrumental difference between the mass spectrometer used for preliminary experiments and the mass spectrometer used for actual analysis, high-frequency power at a frequency that is likely to resonate in the latter is supplied to the radical generation unit, so that radicals can be generated.

Brief Description of Drawings

[0011] [Figure 1] Schematic diagram of the main part configuration of an embodiment of the mass spectrometer according to the present invention. [Figure 2] Cross-sectional view of the main part of the plasma generation unit in the mass spectrometer of this embodiment. [Figure 3] Graph showing an example of the relationship between the frequency control voltage and the oscillation frequency for the oscillator used in the mass spectrometer of this embodiment. [Figure 4] Flowchart of the processing at the start of plasma lighting in an embodiment of the mass spectrometry method according to the present invention. [Figure 5] Flowchart of the processing after plasma lighting in the mass spectrometry method of this embodiment. [Figure 6] Example of another microwave power source that can be used in the mass spectrometer of this embodiment.

Embodiments for Carrying Out the Invention

[0012] Hereinafter, an embodiment of the mass spectrometry method and mass spectrometer according to the present invention will be described with reference to the drawings.

[0013] Figure 1 is a diagram showing the main components of the mass spectrometer 1 of this embodiment. This mass spectrometer 1 is a triple quadrupole mass spectrometer equipped with an atmospheric pressure ion source. With this mass spectrometer 1, it is possible to perform mass analysis by directly introducing a liquid sample into the ion source, or to connect the column outlet of a liquid chromatograph (LC) to the ion source and perform mass analysis on the sample components separated by the column.

[0014] As shown in Figure 1, the mass spectrometer 1 has an ionization chamber 11 and a vacuum chamber 10. The ionization chamber 11 is in an atmosphere of approximately atmospheric pressure. The inside of the vacuum chamber 10 is divided by a partition into a first intermediate vacuum chamber 12, a second intermediate vacuum chamber 13, and an analysis chamber 14, in order from the side closest to the ionization chamber 11. Each chamber is evacuated by a vacuum pump (rotary pump and / or turbomolecular pump) not shown. The inside of the vacuum chamber 10 is configured as a multi-stage differential pumping system in which the vacuum level increases sequentially from the first intermediate vacuum chamber 12, located on the side of the ionization chamber 11 which is in an atmosphere of approximately atmospheric pressure, to the analysis chamber 14 which is in a high vacuum atmosphere.

[0015] An electrospray ionization (ESI) probe 20 is installed in the ionization chamber 11. For example, an eluate (sample solution) eluted from an LC column is introduced into the ESI probe 20. The ionization chamber 11 and the first intermediate vacuum chamber 12 are connected through a small-diameter desolvation tube 21. An ion guide 22 called a Q array is located inside the first intermediate vacuum chamber 12. The first intermediate vacuum chamber 12 and the second intermediate vacuum chamber 13 are connected through a small hole formed at the top of the skimmer 23. A multi-pole ion guide 24 is located inside the second intermediate vacuum chamber 13.

[0016] Inside the analysis chamber 14, which is maintained at a high vacuum, a pre-stage quadrupole mass filter 25, a collision cell 26, a post-stage quadrupole mass filter 28, and an ion detector 29 are arranged along the linear ion optical axis C, which is the central axis of the ion flight path. Both the pre-stage quadrupole mass filter 25 and the post-stage quadrupole mass filter 28 have four rod electrodes arranged parallel to the ion optical axis C so as to surround the ion optical axis C. The pre-stage quadrupole mass filter 25 and the post-stage quadrupole mass filter 28 each have the function of selecting ions according to the mass-to-charge ratio. A radical generation unit 30 is connected to the collision cell 26, and in the collision cell 26, ions are dissociated by radical species such as oxygen radicals supplied from the radical generation unit 30. Inside the collision cell 26, a multi-pole type ion guide 27 is arranged so as to surround the ion optical axis C. The detection signal from the ion detector 29 is transmitted to the control / processing unit 4.

[0017] As shown in Figure 1, the radical generation unit 30 comprises a plasma generation unit 31, a raw material gas supply source 32, a cooling gas supply source 33, and a microwave power supply 34. A flow rate adjustment unit (MFC) 35 is provided in the flow path from the raw material gas supply source 32 to the plasma generation unit 31.

[0018] Figure 2 is a schematic cross-sectional view of the main part showing the structure of the plasma generation section 31 in the radical generation section 30.

[0019] The plasma generation unit 31 generates plasma based on the raw material gas supplied from the raw material gas supply source 32, and introduces the radicals generated in the plasma into the collision cell 26. Examples of raw material gases include water vapor, oxygen gas, nitrogen gas, dry air, and hydrogen gas. The cooling gas supply source 33 supplies appropriately pressurized cooling gas. The microwave power supply 34 supplies power for generating the plasma. The microwave power supply 34 in this embodiment includes an oscillator 341 and an amplifier 342. The oscillator 341 used is one in which the relationship between the magnitude of the frequency control voltage input based on a control signal from an external source (the frequency change unit 43 described later) and the oscillation frequency is known. For example, those described in Non-Patent Documents 5 to 7 can be used as such oscillators 341. Figure 3 shows an example of the relationship between the frequency control voltage and the oscillation frequency. In this embodiment, microwaves in the band from 2.4 GHz to 2.5 GHz (the hatched area in Figure 3) are used.

[0020] The plasma generation unit 31 includes a central cylindrical tube 310 made of quartz or aluminum oxide (or other dielectric material), which is both an insulator and a dielectric; a helical antenna 311, which is a strip-shaped conductor (usually made of a metal such as copper) spirally wound around the central cylindrical tube 310; an outer conductor portion 312 made of a conductor, which is coaxial with the central cylindrical tube 310 and has a cylindrical opening whose inner diameter is slightly larger than the outer diameter of the central cylindrical tube 310; a permanent magnet 313 embedded in the outer conductor portion 312; and a casing 314 that holds the outer conductor portion 312. For the helical antenna 311, for example, a material close to pure copper with high conductivity and formability (such as oxygen-free copper or tough pitch copper) is used. Furthermore, it is preferable that its surface be gold-plated to prevent oxidation.

[0021] The casing 314 is provided with a microwave supply connector 316 and a cooling gas introduction section (not shown). The casing 314 is also fitted with a light source 315 that emits ultraviolet light inside the central cylindrical tube 310 and a photodetector 317 that detects the emission of plasma generated inside the central cylindrical tube 310. The light source 315 is turned on / off based on a control signal transmitted from the control / processing unit 4. In this embodiment, for example, a light source 315 that emits deep ultraviolet light with a wavelength of 275 nm or less is used. When light in this wavelength range is irradiated onto the central cylindrical tube 310 made of quartz or aluminum oxide, electrons are emitted from the wall surface of the central cylindrical tube 310. These electrons induce the illumination of the plasma. For example, a UV-LED can be used as the light source 315. The photodetector 317 used is one that is not sensitive to the wavelength range of light emitted from the light source 315, but is sensitive only to the wavelength range of light emitted from the plasma inside the central cylindrical tube 310. For example, a photodiode can be used as the photodetector 317. The detection signal from the photodetector 317 is transmitted to the control / processing unit 4.

[0022] The central cylindrical tube 310 is a raw material introduction tube through which raw material gas is introduced from the raw material gas supply source 32, and its interior becomes a plasma generation chamber. The microwave supply connector 316 is a coaxial connector and is connected to the microwave power supply 34 via a coaxial cable. The conductive wire of the coaxial connector is connected to one end of the helical antenna 311. The outer conductor portion 312 is also grounded. A part of the helical antenna 311 and the outer conductor portion 312 are electrically connected via a resonator adjustment mechanism 320, and the helical antenna 311 is grounded at the connection point. The helical antenna 311, the outer conductor portion 312, the resonator adjustment mechanism 320, etc. constitute the resonator of the electron cyclotron resonance (ECR). The resonator adjustment mechanism 320 is used to adjust the ECR resonator. Since the resonator adjustment mechanism 320 has the same configuration as described in Patent Document 2, a detailed explanation of its configuration and operation is omitted. The microwave power supply 34 supplies power to the resonator via a coaxial cable and a microwave supply connector 316.

[0023] The plasma generation unit 31 of this embodiment has a configuration called ECR-LICP (Electron Cyclotron Resonance-Localized Inductively Coupled Plasma) type, which utilizes localized inductive discharge and electron cyclotron resonance for plasma generation and maintenance. In the ECR-LICP type plasma generation unit 31, the plasma density can be increased and stabilized by ECR.

[0024] The control and processing unit 4 controls the operation of each of the above-mentioned parts and processes the detection signals input from the ion detector 29. The control and processing unit 4 is equipped with a memory unit 41. The memory unit 41 stores a compound database containing measurement conditions and analysis parameters for various known compounds. In addition, as will be described later, it stores conditions used at the start of plasma ignition and after plasma ignition (frequency and magnitude of high-frequency power supplied to the helical antenna 311, gas supply amount, etc.) and various information necessary to determine whether or not the plasma has been ignited. This information will be described later.

[0025] The control and processing unit 4 also includes, as functional blocks, a measurement control unit 42, a frequency changing unit 43, a plasma determination unit 44, a condition changing unit 45, and an analysis processing unit 46. The control and processing unit 4 is, for example, a general-purpose personal computer, and these functional blocks are realized by executing a pre-installed mass spectrometry program on the processor.

[0026] Here, a typical MS / MS measurement in the mass spectrometer 1 of this embodiment will be briefly described. The measurement control unit 42 controls the operation of each part of the mass spectrometer 1 according to the measurement conditions recorded in the compound database for the compound to be analyzed, and performs MS / MS analysis.

[0027] The ESI probe 20 imparts an electric charge to the supplied sample solution and sprays the sample solution as charged droplets into the ionization chamber 11. The sample components in the sprayed charged droplets are ionized as the droplets are atomized and the solvent vaporizes. The ions generated from the sample components are introduced into the desolvation tube 21 by the gas flow formed by the pressure difference at both ends of the desolvation tube 21 and sent to the first intermediate vacuum chamber 12. The ions that enter the first intermediate vacuum chamber 12 are focused along the ion optical axis C and proceed through the ion guide 22, the orifice of the skimmer 23, and the multi-pole ion guide 24 before being sent to the analysis chamber 14.

[0028] In the analysis chamber 14, a voltage obtained by superimposing a DC voltage and a high-frequency voltage is applied to multiple rod electrodes constituting the pre-stage quadrupole mass filter 25 from a power supply (not shown). Ions having a specific mass-to-charge ratio corresponding to this voltage are selected as precursor ions, pass through the pre-stage quadrupole mass filter 25, and are introduced into the collision cell 26. A predetermined type of radical is supplied into the collision cell 26 from the radical generation unit 30, and the precursor ions introduced into the collision cell 26 react with the radicals and dissociate. The mechanism of ion dissociation utilizing the reactions of various radicals and precursor ions that occur in the collision cell 26 is the same as that conventionally known, as described in Patent Document 1, etc., so an explanation is omitted here. The various product ions generated by dissociation are focused by the electric field formed by the ion guide 27, exit the collision cell 26, and are introduced into the subsequent quadrupole mass filter 28.

[0029] Similar to the preceding quadrupole mass filter 25, a voltage obtained by superimposing a DC voltage and a high-frequency voltage is applied to the multiple rod electrodes constituting the downstream quadrupole mass filter 28. Only product ions having a specific mass-to-charge ratio corresponding to this voltage selectively pass through the downstream quadrupole mass filter 28 and reach the ion detector 29. The ion detector 29 outputs a detection signal corresponding to the amount of incident ions to the control and processing unit 4.

[0030] For example, when performing quantitative analysis of a known compound, the mass-to-charge ratio of the precursor ion selected by the pre-stage quadrupole mass filter 25 and the product ion selected by the post-stage quadrupole mass filter 28 are fixed based on the measurement conditions of the compound recorded in the compound database. During the retention time of the compound (the time period from elution from the LC column to introduction into the ESI probe 20), product ions with a specific mass-to-charge ratio, generated from precursor ions with that specific mass-to-charge ratio, are repeatedly detected. In other words, multiple reaction monitoring (MRM) measurements targeting specific combinations of mass-to-charge ratios (MRM transitions) are repeated. The analysis processing unit 46 creates a chromatogram (extracted ion current chromatogram) based on the detection signals obtained by the repeated MRM measurements, and calculates the concentration (content) of the target sample component from the area and height of the peaks observed in the chromatogram.

[0031] The mass spectrometry method and mass spectrometer 1 of this embodiment are characterized by the process used to generate radicals that react with precursor ions in the MS / MS measurement described above. This point will be explained below with reference to the flowcharts in Figures 4 and 5. Figure 4 is a flowchart relating to the process of generating plasma in the source gas (igniting the plasma), and Figure 5 is a flowchart relating to the process after the plasma has been ignited.

[0032] After the start of measurement and before the introduction of the sample, the measurement control unit 42 starts supplying raw material gas from the raw material gas supply source 32 to the internal space (radical generation chamber) of the central cylindrical tube 310 according to the conditions for plasma ignition start stored in the memory unit 41 (Step 1). In this embodiment, the flow rate of the raw material gas at the start of plasma ignition is, for example, 0.5 sccm. -1 (Standard Cubic Centimeter per Minute. Flow rate (cc) normalized at a constant temperature such as 1 atm (atmospheric pressure 1013 hPa), 0°C, or 25°C). The measurement control unit 42 also turns on the light source 315 and irradiates the inside of the central cylindrical tube 310 (radical generation chamber) with deep ultraviolet light (Step 2).

[0033] Next, the measurement control unit 42 sets the magnitude of the high-frequency power output from the microwave power supply 34 according to the conditions at the start of plasma ignition. In this embodiment, the power output at the start of plasma ignition is, for example, 100W.

[0034] The frequency changing unit 43 applies a predetermined voltage (frequency control voltage) to the oscillator 341 under the control of the measurement control unit 42. The oscillator 341 oscillates microwaves at a frequency corresponding to the magnitude of the applied voltage. The amplifier 342 amplifies these microwaves to a magnitude set by the measurement control unit 42 and outputs them. The high-frequency power output from the microwave power supply 34 is supplied to the helical antenna 311 through the microwave supply connector 316 (step 3). In this embodiment, the value of the frequency control voltage applied from the frequency changing unit 43 to the microwave power supply 34 is set so that high-frequency power of 2.45 GHz is output from the microwave power supply 34 when the voltage application from the frequency changing unit 43 to the microwave power supply 34 begins. Therefore, at this point, 100 W of high-frequency power of 2.45 GHz is supplied to the helical antenna 311.

[0035] When the supply of high-frequency power from the microwave power supply 34 to the helical antenna 311 begins, the plasma determination unit 44 compares the magnitude of the detection signal from the photodetector 317 with a predetermined threshold and determines whether the plasma has been lit based on whether the magnitude of the detection signal exceeds the threshold (step 4). If plasma lit is confirmed (YES in step 4), the light source 315 is turned off (step 10), and the process proceeds to the post-plasma lit processing (Figure 5). At the same time, the introduction of the sample into the ESI probe 20 (or the LC connected to the ESI probe 20) begins.

[0036] If the magnitude of the detection signal from the photodetector 317 does not exceed a predetermined threshold, and the plasma determination unit 44 determines that the plasma is not lit (NO in step 4), the frequency change unit 43 determines whether a predetermined time (e.g., 20 minutes) has elapsed since the start of the plasma ignition process (step 5). This predetermined time is set to be longer than the time required to apply high-frequency power of different frequencies within a predetermined bandwidth (e.g., 2.4 GHz or more to 2.5 GHz) to the helical antenna 311. This is done by increasing the frequency by predetermined values ​​from a predetermined initial value (e.g., 2.45 GHz) up to the upper limit, and then reversing the direction of frequency change to decrease and decreasing the frequency by predetermined values ​​up to the lower limit. At this point, the plasma ignition process has just started, and the predetermined time has not yet elapsed (NO in step 5).

[0037] If a predetermined time has not elapsed since the start of the plasma ignition process (NO in step 5), it is determined whether the magnitude of the voltage applied to the microwave power supply 34 has reached the upper or lower limit of a predetermined range (step 6). In this embodiment, the range of the voltage applied to the microwave power supply 34 from the frequency changing unit 43 is set so that the frequency of the high-frequency power output from the microwave power supply 34 is within a predetermined range (2.4 GHz or more, 2.5 GHz or less). Specifically, based on the relationship shown in Figure 3, the range of the frequency control voltage applied to the oscillator 341 is set to 1.6 V or more, 4.6 V or less. The value of this frequency control voltage varies depending on the characteristics of the microwave power supply actually used, so it is changed as appropriate so that high-frequency power with a frequency within the predetermined range (2.4 GHz or more, 2.5 GHz or less) is output. If the magnitude of the voltage applied to the microwave power supply 34 has not reached this upper or lower limit (NO in step 6), the voltage is changed by a predetermined amount. In this embodiment, during the plasma ignition start process, the frequency control voltage is initially set to be increased by a predetermined amount (for example, by 0.1V each time). This changes (in this case increases) the frequency of the high-frequency power output from the microwave power supply 34 by a predetermined value (step 7).

[0038] When the frequency change unit 43 changes the voltage value applied to the microwave power supply 34, thereby changing (increasing) the frequency of the high-frequency power supplied from the microwave power supply 34 to the helical antenna 311, the process returns to step 4, and the plasma determination unit 44 determines again whether or not the plasma has been lit. If the plasma has still not been lit at this point (NO in step 4), the frequency change unit 43 repeats the process in steps 5 to 7.

[0039] When the frequency control voltage continues to increase and reaches its upper limit (YES in step 6), the condition change unit 45 reverses the direction of voltage change (step 8). Up to this point, the frequency control voltage had been set to increase, so the condition change unit 45 changes the setting to decrease the frequency control voltage by a predetermined amount (for example, by -0.1V). Then, it returns to step 4 and repeats the process in steps 4 to 7. When the frequency control voltage continues to decrease and reaches its lower limit (YES in step 6), the condition change unit 45 reverses the direction of voltage change again (step 8) and repeats the process in steps 4 to 7 again.

[0040] If the plasma does not light up even after a predetermined time has elapsed that is longer than the time required to supply high-frequency power across the entire range of frequencies predetermined (2.4 GHz and above, 2.5 GHz and below) (YES in step 5), it is considered that there is a problem with the settings for the conditions at the start of plasma lighting (magnitude of high-frequency power, flow rate of source gas, etc.) or the condition of the hardware (e.g., helical antenna 311), so the system switches to safe mode and terminates the measurement (step 9).

[0041] If the plasma determination unit 44 determines that the plasma has been lit (YES in step 4), the process proceeds to the post-plasma lit-up process shown in Figure 5.

[0042] After the plasma is lit, the measurement control unit 42 fixes the value of the frequency control voltage applied to the microwave power supply 34 from the frequency change unit 43 at the time the plasma is lit, thereby fixing the frequency of the high-frequency power output from the microwave power supply 34. It also reads the measurement conditions after plasma lit from the memory unit 41 and changes the magnitude of the high-frequency power output from the microwave power supply 34 (step 11). In this embodiment, the magnitude of the high-frequency power after plasma lit is, for example, 26W. The measurement control unit 42 also changes the supply amount of raw material gas based on the measurement conditions after plasma lit (step 12). In this embodiment, the flow rate of raw material gas after plasma lit is, for example, 0.25 sccm. -1In general, once the plasma is lit, it can be maintained with lower high-frequency power and lower raw gas flow rates compared to when the plasma was first lit. In this embodiment, by reducing the amount of high-frequency power and the gas flow rate after the plasma is lit, power consumption and gas consumption can be suppressed.

[0043] Next, the measurement control unit 42 checks whether the detection signal from the photodetector 317 exceeds a threshold at predetermined time intervals (step 13). If the plasma determination unit 44 determines that the plasma is lit (YES in step 13), it then determines whether the end time for measuring the sample has been reached (step 16). If that time has not yet been reached (NO in step 16), it returns to step 13 and repeats the determination of the plasma's lit state. If the end time for measuring the sample has been reached (YES in step 16), the measurement control unit 42 stops the introduction of the raw material gas and the supply of high-frequency power (step 17).

[0044] If the plasma determination unit 44 does not determine that the plasma is lit (even though it was confirmed that the plasma was lit in step 4, it was determined that it subsequently turned off) (NO in step 13), then step 13 is also NO, and it is determined whether the plasma ignition start process has been performed a predetermined number of times (for example, 5 times) (step 14). If this number has reached the predetermined number (YES in step 14), it is considered that there is a problem with the setting values ​​of the setting conditions after plasma ignition (such as the magnitude of high-frequency power and the flow rate of the raw material gas) or the state of the hardware (for example, the helical antenna 311), so the system switches to safe mode and terminates the measurement (step 15).

[0045] If the plasma ignition start process has not reached a predetermined number of times (NO in step 14), the measurement control unit 42 returns to step 1 of the plasma ignition start process.

[0046] After returning to step 1, the plasma ignition start process described above with reference to Figure 4 is performed again. If the plasma determination unit 44 determines that the plasma has been ignited (YES in step 4), the steps described above are executed again starting from step 11 of the post-plasma ignition process.

[0047] In conventional mass spectrometry, high-frequency power fixed to a frequency determined based on preliminary experiment results is supplied to the helical antenna. However, slight differences in the diameter, winding interval, and circumference of the helical antenna can cause different frequencies to resonate (see, for example, Non-Patent Documents 2-4). If the mass spectrometer used for preliminary experiments is different from the mass spectrometer used for actual analysis, the plasma may not ignite because the frequencies at which the helical antenna resonates differ.

[0048] In contrast, the mass spectrometry method and mass spectrometer 1 of this embodiment change the frequency of the high-frequency power supplied to the helical antenna 311 within a predetermined band when igniting the plasma, as described above. In this embodiment, even if there is a difference between the mass spectrometer used for the preliminary experiment and the mass spectrometer used for the actual analysis, the latter helical antenna 311 is supplied with high-frequency power at a frequency that is easily resonant, so radicals can be easily generated without increasing power consumption. Furthermore, the state of the helical antenna may change over time after the preliminary experiment, but even if the state of the helical antenna changes after the preliminary experiment, the mass spectrometry method and mass spectrometer 1 of this embodiment can easily generate radicals by supplying high-frequency power at a frequency that is easily resonant to the helical antenna 311 after the state change.

[0049] The above embodiments are examples and can be modified as appropriate in accordance with the spirit of the present invention.

[0050] In the above embodiment, a microwave power supply 34 is used, which includes an oscillator 341 and an amplifier 342 that generate microwaves of different frequencies according to a frequency control voltage input from an external source. The frequency of the high-frequency voltage is changed by a control signal transmitted from a frequency change unit 43, which is a functional block implemented by software. However, other configurations can also be adopted.

[0051] For example, as shown in Figure 6, a configuration can be adopted in which a microwave whose frequency changes within a predetermined bandwidth (for example, a bandwidth of 2.4 GHz to 2.5 GHz) is generated using a fixed oscillator 361 that generates a microwave of a predetermined fixed frequency (for example, 2.45 GHz), a modulation oscillator 362 that generates a waveform that modulates the frequency of the microwave in the range of 0 to 0.05 GHz, and a mixer 363 that mixes the waveforms generated by these oscillators, and high-frequency power is supplied to the helical antenna 311 by amplifying it with an amplifier 364. For example, the fixed oscillator 361 can be the one described in Non-Patent Document 5. For example, the modulation oscillator 362 can be the one described in Non-Patent Document 8. Furthermore, for example, the mixer 363 can be the one described in Non-Patent Document 9.

[0052] In the above embodiment, high-frequency power was supplied to a helical antenna 311 wound around the outer circumference of a dielectric tube to generate plasma of the raw material gas. However, plasma of the raw material gas may be generated using other configurations. For example, plasma of the raw material gas can also be generated by supplying high-frequency power to a two-dimensionally wound coil (such as a spiral antenna) located outside a part of the wall surface of a chamber containing a radical generation chamber, where the wall surface is made of dielectric material.

[0053] In the above embodiment, a mass spectrometer 1 equipped with a triple quadrupole mass separation unit was used, but any mass separation unit can be used. Also, in the above embodiment, an ion source equipped with an ESI probe 20 that generates ions from a liquid sample was used, but other atmospheric pressure ion sources can also be used. Alternatively, an ion source that generates ions in a vacuum atmosphere may be used. Furthermore, an ion source that generates ions from gaseous or solid samples can also be used. In addition, in the above embodiment, a collision cell 26 was used to react precursor ions with radicals, but other reaction chambers such as a three-dimensional ion trap may be used.

[0054] In the above embodiment, an ECR-LICP type plasma generation unit 31 was used, but a plasma generation unit without an ECR resonator may also be used. Also, in the above embodiment, a light source 315 that irradiates a central cylindrical tube 310 made of quartz or aluminum oxide with ultraviolet light was used, but plasma may be generated without using the light source 315. In the above embodiment, the presence or absence of plasma generation was confirmed by measuring the emission of plasma light based on the output signal of the photodetector 317, but the presence or absence of plasma generation may be confirmed by the user visually observing the illumination of the plasma. Note that the light emitted from the plasma may include not only visible light but also invisible light such as ultraviolet light. Directly viewing ultraviolet light may have adverse effects on the user, so when the user checks the illumination of the plasma, it is advisable to use a photodetector such as a phototransistor to detect the emission of plasma light, or to view the plasma through a filter (such as a glass filter) that removes ultraviolet light.

[0055] In the above embodiment, radical generation was continued from the start to the end of the measurement. However, for each target compound, radical generation may be started in accordance with the start of the retention time of that target compound and stopped in accordance with the end of the retention time.

[0056] In the above embodiment, the frequency of the high-frequency power was changed by repeatedly increasing and decreasing the frequency. However, the manner in which the frequency is changed can be appropriately modified, such as increasing the frequency from the lower limit to the upper limit, and then increasing the frequency again from the lower limit to the upper limit after reaching the upper limit, or vice versa. Furthermore, in the above embodiment, the frequency was changed in the band of 2.4 GHz to 2.5 GHz. This is because it corresponds to the frequency band defined as the ISM band in the Radio Regulations stipulated in the International Telecommunication Union Constitution, and various commercially available power supplies can be used. Also, while obtaining a license or notifying the use may be required to use high-power high-frequency power in other frequency bands, obtaining a license or notifying the use is not required for the frequency band of 2.4 GHz to 2.5 GHz. Therefore, it is also possible to supply high-frequency power in other frequency bands to the helical antenna 311, etc. Furthermore, the specific shape of the radical generation unit 30, such as the helical antenna 311, in the above embodiment is merely an example and can be modified as appropriate, as long as it is capable of generating radicals from the raw material gas by supplying high-frequency power.

[0057] [Aspect] It will be obvious to those skilled in the art that the exemplary embodiments described above are specific examples of the following embodiments.

[0058] (Section 1) One aspect of the present invention is a method for generating product ions by attaching radicals to precursor ions derived from sample molecules and then performing mass spectrometry, The raw material gas is supplied to the radical generation chamber. During the time period in which the raw material gas is supplied to the radical generation chamber, high-frequency power is supplied to the radical generation unit that generates radicals from the plasma of the raw material gas supplied to the radical generation chamber, while changing the frequency within a predetermined band. The plasma state of the raw material gas in the radical generation chamber is observed. When the plasma is lit, the frequency of the high-frequency power supplied to the radical generation unit is fixed. It is.

[0059] (Section 5) A mass spectrometer according to another aspect of the present invention is: A reaction chamber into which precursor ions derived from the sample molecule are introduced, Radical generation chamber, A radical generation unit that generates radicals from the plasma of the raw material gas supplied to the radical generation chamber, A high-frequency power supply unit configured to supply high-frequency power to the radical generation unit while changing the frequency within a predetermined bandwidth, A plasma detection unit for detecting the emission of light from the plasma of the raw material gas in the radical generation chamber, A control unit for controlling the operation of the raw material gas supply unit and the high-frequency power supply unit, comprising: a control unit that supplies the raw material gas to the radical generation chamber, supplies high-frequency power to the radical generation unit while changing the frequency in a predetermined band, and fixes the frequency of the high-frequency power supplied to the radical generation unit when the plasma detection unit detects the emission of plasma from the raw material gas; A radical introduction unit that introduces radicals generated in the radical generation chamber into the reaction chamber into which the precursor ion has been introduced, A mass separation unit separates the product ions generated from the precursor ions in the reaction chamber according to their mass-to-charge ratio, An ion detection unit for detecting product ions separated in the mass separation unit and It is equipped with.

[0060] In the mass spectrometry method described in paragraph 1 and the mass spectrometer described in paragraph 5, when generating radicals to be attached to precursor ions derived from sample molecules, a raw material gas that serves as the raw material for radicals is supplied to the radical generation chamber, and high-frequency power is supplied to the radical generation unit, which generates radicals from the plasma of the raw material gas supplied to the radical generation chamber, while changing the frequency within a predetermined bandwidth. When the plasma of the raw material gas in the radical generation chamber lights up (detection of plasma emission), the frequency of the high-frequency power supplied to the radical generation unit is fixed. In the mass spectrometry method described in paragraph 1, plasma emission may be detected using a photodetector, or the user may observe the state of the plasma themselves. This predetermined bandwidth may be set to include the frequency of the high-frequency power determined based on the results of preliminary experiments, for example. Alternatively, it may be the frequency at which the plasma lit up during the previous use. The size of the bandwidth may be set appropriately considering the expected magnitude of instrumental differences. In the mass spectrometry method described in paragraph 1 and the mass spectrometer described in paragraph 5, even if there is a difference between the mass spectrometer used for the preliminary experiment and the mass spectrometer used for the actual analysis, high-frequency power at a frequency that is likely to resonate in the latter is supplied to the radical generation unit, thereby enabling the generation of plasma from the raw material gas. Furthermore, even if the state of the helical antenna changes after the preliminary experiment, high-frequency power at a frequency that is likely to resonate in the helical antenna after the state change is supplied to the radical generation unit, enabling the generation of plasma from the raw material gas.

[0061] (Section 2) The mass spectrometry method relating to paragraph 2 is, in the mass spectrometry method relating to paragraph 1, A high-frequency power at a predetermined starting frequency is supplied to the radical generation unit. If the plasma of the raw material gas does not light up even when high-frequency power at the predetermined starting frequency is supplied to the radical generation unit, high-frequency power is supplied to the radical generation unit while changing the frequency within the predetermined bandwidth. It is.

[0062] (Section 6) The mass spectrometer relating to paragraph 6 is, in the mass spectrometer relating to paragraph 5, The control unit supplies high-frequency power at a predetermined starting frequency to the radical generation unit. If the emission of plasma from the raw material gas is not detected even after supplying high-frequency power at the predetermined starting frequency to the radical generation unit, the control unit supplies high-frequency power to the radical generation unit while changing the frequency within the predetermined bandwidth.

[0063] In the mass spectrometry method described in paragraph 2 and the mass spectrometer described in paragraph 6, first, high-frequency power at a predetermined starting frequency is applied to the radical generation unit. If the plasma does not ignite (no light emission is detected) at that frequency, the frequency is changed within a predetermined bandwidth. Therefore, in a mass spectrometer with no instrumental differences, the plasma is ignited immediately, and even in a mass spectrometer with instrumental differences, high-frequency power at a frequency that easily resonates can be supplied to the radical generation unit to ignite the plasma of the raw material gas. The predetermined starting frequency may be, for example, the frequency of the high-frequency power determined based on the results of preliminary experiments. Alternatively, it may be the frequency at which the plasma ignited during the previous use.

[0064] (Section 3) The mass spectrometry method relating to paragraph 3 is, in the mass spectrometry method relating to paragraph 1 or 2, After fixing the frequency of the high-frequency power supplied to the radical generation unit, if the plasma is turned off, the high-frequency power is supplied to the radical generation unit while changing the frequency within the predetermined bandwidth.

[0065] (Section 7) The mass spectrometer relating to paragraph 7 is, in the mass spectrometer relating to paragraph 5 or 6, After the control unit fixes the frequency of the high-frequency power supplied to the radical generation unit, if plasma emission is no longer detected, it supplies high-frequency power to the radical generation unit while changing the frequency within the predetermined bandwidth.

[0066] In the mass spectrometry method described in paragraph 3 and the mass spectrometer described in paragraph 7, even if the plasma light goes out, the plasma can be relit and the analysis can be continued.

[0067] (Section 4) The mass spectrometry method relating to paragraph 4 is a mass spectrometry method relating to any of paragraphs 1 to 3, After the plasma of the raw material gas is lit, the amount of raw material gas supplied to the radical generation chamber and / or the amount of high-frequency power supplied to the radical generation unit is reduced. It is.

[0068] (Section 8) The mass spectrometer relating to paragraph 8 is a mass spectrometer relating to any of paragraphs 5 to 7, The control unit reduces the amount of raw material gas supplied from the raw material gas supply unit to the radical generation chamber and / or the amount of high-frequency power supplied from the high-frequency power supply unit to the helical antenna after the plasma detection unit detects the emission of plasma from the raw material gas.

[0069] Generally, once the plasma is ignited, it can be maintained with lower high-frequency power and lower flow rates of the raw material gas compared to when the plasma was first ignited. In the mass spectrometry method described in paragraph 4 and the mass spectrometer described in paragraph 8, the consumption of gas and electricity can be reduced by decreasing the supply of raw material gas and / or high-frequency power after the plasma is ignited.

[0070] (Section 9) The mass spectrometer relating to paragraph 9 is a mass spectrometer relating to any of paragraphs 5 to 8, The aforementioned predetermined bandwidth is within the range of 2.4 GHz to 2.5 GHz.

[0071] The frequency band used in the mass spectrometer described in paragraph 9 corresponds to the frequency band defined as the ISM band in the Radio Regulations stipulated in the International Telecommunication Union Constitution, and various commercially available power supplies can be used. Furthermore, while obtaining a license or notifying the authorities of use may be required to use high-frequency power in other frequency bands at high output, obtaining a license or notifying the authorities of use is not required for the frequency band between 2.4 GHz and 2.5 GHz.

[0072] (Section 10) The mass spectrometer relating to paragraph 10 is a mass spectrometer relating to any of paragraphs 5 to 9, The aforementioned high-frequency power supply unit An oscillator that changes the frequency of the high-frequency power output based on a control signal input from an external source, A frequency control unit that transmits a control signal to the high-frequency power supply that changes the frequency within the predetermined bandwidth. It is equipped with.

[0073] In the mass spectrometer described in paragraph 10, the frequency of the high-frequency power can be changed via software.

[0074] (Section 11) The mass spectrometer relating to paragraph 11 is a mass spectrometer relating to any of paragraphs 5 to 9, The aforementioned high-frequency power supply unit A fixed oscillator that outputs a waveform signal of a predetermined fixed frequency, A modulation oscillator that outputs a waveform signal to modulate the frequency, A mixer that superimposes the waveform signal output from the second oscillator onto the waveform signal output from the first oscillator. It is equipped with.

[0075] In the mass spectrometer described in paragraph 11, the frequency of the high-frequency power can be changed in hardware. [Explanation of Symbols]

[0076] 1...Mass spectrometer 10… Vacuum Chamber 11…Ionization Chamber 12…First intermediate vacuum chamber 13…Second Intermediate Vacuum Chamber 14…Analysis room 20…ESI probe 21…Desolvation tube 22… Aeon Guide 23... Skimmer 24…Multipole type ion guide 25…Pre-stage quadrupole mass filter 26...Collision cell 27…Aeon Guide 28...Later stage quadrupole mass filter 29…Ion detector 30…Radical generation section 31…Plasma generation section 310...Central cylindrical tube 311... Helical antenna 312...Outer conductor part 313…Permanent magnet 314...Casing 315...Light source 316... Microwave supply connector 317... Photodetector 320…Resonator adjustment mechanism 32…Source of raw gas 33…Cooling gas supply source 34... Microwave power supply 341... Oscillator 342, 364… Amplifiers 361... Fixed oscillator 362... Modulation oscillator 363…Mixer 4…Control and Processing Unit 41...Storage section 42...Measurement Control Unit 43...Frequency change section 44…Plasma determination unit 45... Condition change section 46…Analysis Processing Unit C...Ion optical axis

Claims

1. A method for generating product ions by attaching radicals to precursor ions derived from sample molecules and then performing mass spectrometry, A raw material gas that will serve as the raw material for the radicals is supplied to the radical generation chamber. During the time period in which the raw material gas is supplied to the radical generation chamber, high-frequency power is supplied to the radical generation unit that generates radicals from the plasma of the raw material gas supplied to the radical generation chamber, while changing the frequency within a predetermined band. The plasma state of the raw material gas in the radical generation chamber is observed. When the plasma is lit, the frequency of the high-frequency power supplied to the radical generation unit is fixed. A method of mass spectrometry.

2. A high-frequency power at a predetermined starting frequency is supplied to the radical generation unit. If the plasma of the raw material gas does not light up even when high-frequency power at the predetermined starting frequency is supplied to the radical generation unit, high-frequency power is supplied to the radical generation unit while changing the frequency within the predetermined bandwidth. The mass spectrometry method according to claim 1.

3. The mass spectrometry method according to claim 1, wherein, after fixing the frequency of the high-frequency power supplied to the radical generation unit, when the plasma is turned off, the high-frequency power is supplied to the radical generation unit while changing the frequency within the predetermined band.

4. The mass spectrometry method according to claim 1, wherein, after the plasma of the raw material gas is lit, the amount of raw material gas supplied to the radical generation chamber and / or the amount of high-frequency power supplied to the radical generation unit is reduced.

5. A reaction chamber into which precursor ions derived from the sample molecule are introduced, Radical generation chamber, A radical generation unit that generates radicals from the plasma of the raw material gas supplied to the radical generation chamber, A high-frequency power supply unit configured to supply high-frequency power to the radical generation unit while changing the frequency within a predetermined bandwidth, A plasma detection unit for detecting the emission of light from the plasma of the raw material gas in the radical generation chamber, A control unit for controlling the operation of the radical generation unit and the high-frequency power supply unit, comprising: a control unit that supplies the raw material gas to the radical generation chamber, supplies high-frequency power to the radical generation unit while changing the frequency in a predetermined band, and fixes the frequency of the high-frequency power supplied to the radical generation unit when the plasma detection unit detects the emission of plasma from the raw material gas; A radical introduction unit that introduces radicals generated in the radical generation chamber into the reaction chamber into which the precursor ion has been introduced, A mass separation unit separates the product ions generated from the precursor ions in the reaction chamber according to their mass-to-charge ratio, An ion detection unit for detecting product ions separated in the mass separation unit and A mass spectrometer equipped with the following features.

6. The mass spectrometer according to claim 5, wherein the control unit supplies high-frequency power at a predetermined starting frequency to the radical generation unit, and if emission of plasma from the raw gas is not detected even when high-frequency power at the predetermined starting frequency is supplied to the radical generation unit, the control unit supplies high-frequency power to the radical generation unit while changing the frequency within the predetermined bandwidth.

7. The mass spectrometer according to claim 5, wherein the control unit fixes the frequency of the high-frequency power supplied to the radical generation unit, and when plasma emission is no longer detected, it supplies high-frequency power to the radical generation unit while changing the frequency within the predetermined bandwidth.

8. The mass spectrometer according to claim 5, wherein the control unit reduces the amount of raw material gas supplied to the radical generation chamber and / or the amount of high-frequency power supplied to the radical generation unit after the plasma detection unit detects the emission of plasma from the raw material gas.

9. The mass spectrometer according to claim 5, wherein the predetermined bandwidth is within the range of 2.4 GHz or more and 2.5 GHz or less.

10. The aforementioned high-frequency power supply unit An oscillator that changes the frequency of the high-frequency power output based on a control signal input from an external source, A frequency control unit transmits a control signal to the oscillator that changes the frequency within the predetermined bandwidth. The mass spectrometer according to claim 5, comprising:

11. The aforementioned high-frequency power supply unit A fixed oscillator that outputs a waveform signal of a predetermined fixed frequency, A modulation oscillator that outputs a waveform signal to modulate the frequency, A mixer that superimposes the waveform signal output from the modulation oscillator onto the waveform signal output from the fixed oscillator. The mass spectrometer according to claim 5, comprising:

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