WO2023089685A1

WO2023089685A1 - Mass spectrometer and mass spectrometer control method

Info

Publication number: WO2023089685A1
Application number: PCT/JP2021/042194
Authority: WO
Inventors: 康照井; 幹太郎丸岡
Original assignee: 株式会社日立ハイテク
Priority date: 2021-11-17
Filing date: 2021-11-17
Publication date: 2023-05-25

Abstract

The present invention is equipped with a control unit 400 for controlling a gas supply unit 500 which has a plurality of different supply sources 570, a gas mixing unit 530 for producing a gas mixture by mixing the gases supplied from the plurality of different supply sources 570, and an electromagnetic valve 560 for controlling the composition of the gas mixture. Therein, the gas supply unit 500 is controlled so as to supply the gas mixture to an electric charge supply unit 120 and to a heating/mixing chamber 110 on the basis of measurement item information. As a result, the present invention provides a mass spectrometer and a mass spectrometer control method which make it possible to improve the measurement sensitivity of a liquid chromatography mass spectrometer in comparison to the prior art.

Description

Mass spectrometer and method of controlling mass spectrometer

The present invention relates to a mass spectrometer and a control method for the mass spectrometer.

A typical analytical device that analyzes liquid samples in mass spectrometry is a liquid chromatograph mass spectrometer. Qualitative and quantitative measurements are performed by ionizing the liquid sample sent out from the liquid chromatograph and introducing it into the mass spectrometer. Typical ionization methods include the atmospheric pressure ionization method (hereinafter referred to as APCI method) (Non-Patent Document 1) and the electrospray ionization method (hereinafter referred to as ESI method) (Non-Patent Document 2).

In the APCI method, the measurement sample is first atomized. Since the sample to be measured is continuously fed from the liquid chromatograph together with a solvent of several to 1000 [μL/min], atomization is often carried out by airflow-assisted spray using nitrogen gas or the like. After that, the atomized sample is heated to be vaporized, and the vaporized sample is introduced into a corona discharge generated by a needle-shaped electrode and ionized.

In the ESI method, as in the APCI method, the liquid sample is atomized by airflow-assisted spray, and a high voltage is applied to the atomizer to turn the mist into charged droplets. Alternatively, a high voltage is applied to the measurement sample itself to atomize it into charged droplets. The charged droplets are heated and dried to reduce the size of the charged droplets, and the excess charge due to the miniaturization of the charged droplets is detached from the droplets and ionized by Coulomb repulsion.

In general, the APCI method is said to have high ionization efficiency and high sensitivity for measurement samples with low to medium polarity, and the ESI method for measurement samples with medium to high polarity. Therefore, an operator using a liquid chromatograph-mass spectrometer must select an ionization method in consideration of the polarity of the substance to be measured.

The ionization method used for liquid chromatograph mass spectrometer measurement is basically selected according to the polarity, molecular weight, molecular structure, etc. of the target substance. High ionization methods are often selected.

　The ion source has a high-temperature part for drying the liquid sample, and it was difficult to replace the ion source for each target substance separated by the liquid chromatograph. Therefore, an operator of a liquid chromatograph-mass spectrometer used to collect and measure samples having ionization characteristics similar to those of a target substance when measuring actual samples.

In order to solve such problems, there are ion sources equipped with both APCI and ESI ionization methods. The target substances whose components are separated by the liquid chromatograph are branched and switched before entering the ion source, and the target substances, which are good at the APCI method and the ESI method, are ionized.

This method has problems such as a longer sample introduction distance to the ion source, which reduces the separation of the liquid chromatograph, and a decrease in sensitivity due to the limited ionization conditions compared to a single ion source. rice field.

Here, in the liquid chromatograph mass spectrometer, the target substance is often measured by separating the components of the measurement sample with the liquid chromatograph. A liquid chromatograph is used by mixing water with an organic solvent such as acetonitrile or methanol and separating the components while changing the mixing ratio. This mixture of water and organic solvent is called an eluent.

However, when the target substance changes, the organic solvent used for the eluent and the mixing ratio also change. Therefore, there is a problem that the composition of the liquid introduced into the mass spectrometer varies and cannot be uniquely determined.

When a mixture of water and an organic solvent is ionized, molecular ions called cluster ions, in which multiple ions are combined, may be generated in addition to their own ions. Cluster ions include molecular ions in which multiple water molecules are bound together, and molecular ions in which water and organic solvent ions are bound together. detected.

APCI, which is a typical conventional ionization method, introduces a vaporized measurement sample into corona discharge and ionizes it. Also, in ESI, a high voltage is applied to the atomizer or the liquid sample itself, and the liquid is ionized when atomized. Both ionization methods ionize the target substance as well as the eluent. Therefore, the mass spectrometer simultaneously observes the signal derived from the target substance and the signal derived from the eluent. Therefore, when the target substance to be measured has a small molecular weight, the signal of the cluster ions overlaps with the signal from the target substance, which may reduce the sensitivity.

An object of the present invention is to provide a mass spectrometer capable of improving the measurement sensitivity of a liquid chromatograph-mass spectrometer compared to conventional methods, and a method of controlling the mass spectrometer.

The present invention includes a plurality of means for solving the above problems. One example is a mass spectrometer that supplies a mixed gas to a charge supply unit and a heating mixing chamber based on measurement item information. and a controller for controlling the gas supply unit.

According to the present invention, it is possible to improve the measurement sensitivity of a liquid chromatograph mass spectrometer compared to conventional methods. Problems, configurations and effects other than those described above will be clarified by the following description of the embodiments.

1 is a diagram showing the overall configuration of a mass spectrometer according to an embodiment of the present invention; FIG.

An embodiment of the mass spectrometer and the control method of the mass spectrometer of the present invention will be described with reference to FIG.

First, the overall configuration of the mass spectrometer will be explained using FIG. FIG. 1 is a diagram showing the overall configuration of the mass spectrometer of this embodiment.

A typical analysis device for analyzing liquid samples is a liquid chromatograph mass spectrometer (hereinafter referred to as mass spectrometer 1) as shown in FIG.

The sample measured by the mass spectrometer 1 is continuously sent to the atomizer 100 by the liquid chromatograph 300 at a speed of about several to 1000 [μL/min].

The atomizer 100 atomizes the liquid sample sent from the liquid chromatograph 300 . A typical atomizer is a gas-assisted spray, in which a high-speed gas is passed around a capillary tube in which a liquid sample flows, and the liquid sample and the high-speed gas are brought into contact with each other at the outlet of the capillary tube to atomize the liquid sample. Nitrogen gas and air are generally used as the high-speed gas. As an alternative to gas-assisted spraying, ultrasonic atomizers, such as those used in humidifiers, can be used.

An atomized fluid is introduced into the heating mixing chamber 110 in order to vaporize and ionize the measurement sample fluid (atomized fluid) atomized in the atomizer 100 . The heated mixing chamber 110 itself is heated by a heater or the like, and heat transfer from the heated mixing chamber 110 promotes vaporization of the introduced atomized fluid. As other heating methods, a method of generating a high-frequency heating electric field in the heating mixing chamber 110 to heat the atomized fluid, or a method of heating with a light source that generates infrared rays can also be used.

The charge supply unit 120 generates seed ions from the seed ion gas for applying an electric charge to the measurement sample fluid (vaporized fluid) vaporized in the heating and mixing chamber 110 and supplies the generated seed ions to the heating and mixing chamber 110. . The charge supply unit 120 generates seed ions by means of introducing a seed ion gas 122 during corona discharge by a needle electrode of APCI or by means of plasma discharge using the seed ion gas 122 .

In addition, the charge supply unit 120 has a positive pressure (higher pressure) than the heating mixing chamber 110 so that the vaporized fluid does not flow in, and a gas flow is generated from the charge supply unit 120 to the heating mixing chamber 110 .

The seed ion gas 122 supplied to the charge supply unit 120 is air, nitrogen, He, Ne, Ar, Xe, or a mixed gas thereof.

The measurement sample supplied from the atomizer 110 and vaporized in the heating and mixing chamber 110 and the seed ions supplied from the charge supply section 120 are mixed in the heating and mixing chamber 110 to ionize the measurement sample. Since the charge supply section 120 has a positive pressure from the heating and mixing chamber 110, the fluid derived from the measurement sample does not flow into the charge supply section 120, and contamination derived from the measurement sample can be prevented. Further, since the atomizer 100 has a function of only atomization and the charge supply section 120 has a function of only charge supply, measurement stability is improved.

The ionized measurement sample passes through a hole called the first pore 140, is introduced into the analysis unit 150, and is detected. The heated mixing chamber 110 is in contact with the first pores 140 and reduces the temperature difference with the first pores 140 by heat transfer.

In the analysis unit 150, the first pore 140 serves as an interface separating the atmosphere and the vacuum. A room in the analysis unit 150 having the first pore 140 (a vacuum chamber having the first pore 140) is connected to a vacuum pump 170, and the area and length of the first pore 140 and the capacity of the vacuum pump 170 The amount of gas introduced into the analysis unit 150 is determined by the exhaust speed. Therefore, the total amount of gas supplied from the atomizer 100 and the amount of gas supplied from the charge supply unit 120 is the sum of the gas supply amount of the measurement gas to the analysis unit 150 and the gas introduction amount to the analysis unit 150 by the vacuum pump 170. may differ.

Auxiliary gas 130 is supplied to the heating and mixing chamber in order to adjust the gas supply amount to the analysis unit 150 and the gas introduction amount to the analysis unit 150 of the measurement gas. Auxiliary gas 130 is air, nitrogen, He, Ne, Ar, Xe, or a mixture thereof. The flow rate of the auxiliary gas 130 can be determined from the difference between the sum of the liquid flow rate being introduced plus the flow rate of the seed ion gas 122 and the gas flow rate passing through the first pore 140, or else the first It can be determined based on the pressure of the vacuum chamber with pores 140 .

The pressure of the vacuum chamber having the first pore 140 is detected, for example, by a pressure gauge 160 provided in the vacuum chamber. The provision of auxiliary gas 130 provides ionization that is less sensitive to system environmental conditions.

Thus, the measurement sample ionized by the ion source comprising the atomizer 100, the heating mixing chamber 110, and the charge supply section 120 is introduced into the mass spectrometer and measured by the detection section of the mass spectrometer.

The gas supply unit 500 supplies gas to the electric charge supply unit 120 and the heating mixing chamber 110, and switching of gas species and flow rate control are performed by the control unit 400.

The control unit 400 is a mechanism that controls the gas supply unit 500 to supply the mixed gas (seed ion gas 122 and auxiliary gas 130) to the charge supply unit 120 and the heating mixing chamber 110 based on the measurement item information 410. There may be a single control device, or a plurality of control units each having a different mechanism in charge.

The seed ion gas 122 and the auxiliary gas 130 consist of air, nitrogen, He, Ar, Xe, or a mixture thereof as described above.

The gas supply unit 500 includes a first flow control unit 510 that controls the gas flow rate of the seed ion gas 122 with a flow rate of 0, a second flow control unit 520 that controls the gas flow rate of the auxiliary gas 130 with a flow rate of 0, and the seed ion gas 122 . A gas mixing unit 530 that mixes ion gas and composite gas as auxiliary gas, and a single gas control unit 540 that controls the flow rate of single gas such as air, nitrogen, He, Ar, Xe, etc. that is the basis of seed ion gas and auxiliary gas. etc.

A single gas control unit 540 that controls the flow rate of a single gas includes a plurality of different types of single gas supply sources 570, an electromagnetic valve 560 that turns on/off the gas flow, and a single gas flow control unit 550 that controls the flow rate. Configured.

One or more types of this single gas control unit 540 are used. For example, when using Ar, nitrogen, or He gas, three systems are connected.

Next, the details of the flow rate control of the above seed ion gas and auxiliary gas will be described.

As described above, liquid chromatograph-mass spectrometers often separate the components of a measurement sample using a liquid chromatograph to measure the target substance. In component separation by liquid chromatography, measurement components are separated at the same time (timing) if they are the same substances under the same separation conditions. This time is called retention time. Therefore, a sample to be measured is introduced into the liquid chromatograph, and the target component is separated at a fixed retention time. Measurement is performed by changing the measurement conditions of the mass spectrometer (for example, mass to be observed and MSMS conditions) in accordance with the retention time for component separation.

For this reason, the substance to be measured (target substance) is known in advance by the measurer. At least the mass to be measured is known, and often the molecular structure is also known.

Here, the method of ionizing the target component using a seed ion gas (especially a rare gas) and electric discharge is called the Penning ionization method.

In the Penning ionization method, molecules are ionized through multiple reactions from metastable excited species of noble gases generated by electrical discharge. In the ionization in the mass spectrometer 1, since the seed ion gas species, which is an important point in Penning ionization, have different internal energies, the energy imparted to the measurement component can be adjusted by appropriately selecting the seed ion gas. be.

For example, the metastable excited species generated from He gas has a high internal energy of 19.8 [eV], so it is thought that almost all molecules can be ionized. Ar gas can selectively ionize molecules with an ionization energy of 11.7 [eV] or less.

The above-mentioned internal energy has a unique value for each gas type, can be changed by changing the gas type, and the measurement target substance is known, so the seed ion gas is selected and controlled according to the measurement target substance By doing so, the background signal derived from the solvent is reduced, and the target substance itself can be ionized.

Therefore, information on the molecular weight of the measurement target substance is used as the measurement item information 410, and the control unit 400 controls the gas supply unit 500 based on the molecular weight information.

For example, an operator of a liquid chromatograph mass spectrometer inputs the molecular weight information of the target substance before measurement, mainly when performing quantitative analysis. The control unit 400 controls the gas supply unit 500 to select ions to be measured according to the values input during measurement. The relationship between molecular weight and ionization energy generally tends to be high on the low molecular weight side and low on the high molecular weight side. Become.

Also, for example, there is reversed-phase chromatography as a separation method using a liquid chromatograph. Reversed-phase chromatography is a method in which a highly polar solvent is passed through a low-polarity separation column to elute components with long carbon chains from target components with short carbon chains. It is generally assumed that components with short carbon chains are on the low molecular weight side and components with long carbon chains are on the high molecular weight side. As described above, the ionization energy generally tends to be high on the low molecular weight side and low on the high molecular weight side.

Furthermore, normal phase chromatography is also available as a separation method using liquid chromatography. Normal-phase chromatography is a method in which a low-polarity solvent is passed through a high-polarity separation column to elute high-polarity components from low-polarity target components. The magnitude of the polarity of the target component is also a factor that affects the measurement sensitivity in selecting the ionization method of the mass spectrometer. In general, target components with low polarity tend to be difficult to ionize, and thus tend to have high ionization energy, while components with high polarity tend to have low ionization energy.

In the liquid chromatographic separation described above, the components are separated in order of molecular weight and polarity depending on the separation conditions used. In the ionization of mass spectrometry, the ionization energy tends to change depending on the order of molecular weight and the degree of polarity.

Therefore, as the measurement item information 410, the separation method information of the liquid chromatograph that separates the measurement target substance is used, and the control unit 400 controls the gas supply unit 500 based on the separation method information.

For example, by determining the separation method by liquid chromatography, the measurer selects the gas species of the seed ion gas and its flow rate based on the information on the separation method. Helium gas has high internal energy and is considered to be the easiest to use from the viewpoint of ionization in the mass spectrometer 1 . On the other hand, there is a problem that the resource is limited and expensive.

Therefore, information on the type of gas supplied from the gas supply unit 500 is used as the measurement item information 410, and the control unit 400 controls the gas supply unit 500 based on the gas type information. At this time, the controller 400 switches the gas type during the measurement.

For example, using nitrogen that can be generated from air separation, the seed ion gas is switched during measurement based on the target component and information on the separation method by liquid chromatography.

Next, the effects of this embodiment will be described.

In the mass spectrometer 1 of the present embodiment described above, the gas supply unit 500 includes a plurality of different supply sources 570 and a gas mixing unit 530 that mixes gases supplied from the plurality of different supply sources 570 to produce a mixed gas. and a solenoid valve 560 that controls the composition of the mixed gas, and controls the gas supply unit 500 to supply the mixed gas to the charge supply unit 120 and the heating mixing chamber 110 based on the measurement item information 410. A control unit 400 is provided.

Therefore, in a liquid chromatograph-mass spectrometer, it is possible to reduce the effects of physical properties such as the polarity and molecular weight of the measurement target substance and achieve highly efficient ionization (high sensitivity). In addition, the cluster ion signal derived from the eluent used for liquid chromatography can be reduced, and the background signal can be reduced. Therefore, it is possible to perform highly sensitive measurements compared to conventional mass spectrometers.

Also, the measurement item information 410 is information on the molecular weight of the measurement target substance, and the control unit 400 controls the gas supply unit 500 based on the molecular weight information, so highly sensitive measurement is possible.

Furthermore, the measurement item information 410 is separation method information for a liquid chromatograph that separates the measurement target substance, and the control unit 400 controls the gas supply unit 500 based on the separation method information to ionize the target component itself. Suitable for high-efficiency ionization (high sensitivity).

The measurement item information 410 is information on the type of gas supplied from the gas supply unit 500, and the control unit 400 controls the gas supply unit 500 based on the gas type information, thereby reducing operating costs during measurement. can be achieved, and more efficient measurement becomes possible.

Furthermore, the control unit 400 can perform more efficient measurement by switching the gas type during measurement.

<Others>
The present invention is not limited to the above embodiments, and various modifications and applications are possible. The above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the described configurations.

1: Mass spectrometer 100: Atomizer 110: Heated mixing chamber 120: Charge supply unit 122: Seed ion gas 130: Auxiliary gas 140: First pore 150: Analysis unit 160: Pressure gauge 170: Vacuum pump 300: Liquid Chromatograph 400: Control unit 410: Measurement item information 500: Gas supply unit 510: First flow control unit 520: Second flow control unit 530: Gas mixing unit 540: Single gas control unit 550: Single gas flow control unit 560: Solenoid valve 570: supply source (gas source)

Claims

a heated mixing chamber for vaporizing and ionizing the atomized liquid sample;
a charge supply for generating seed ions from a seed ion gas and supplying the seed ions to the heated mixing chamber;
A mass spectrometer comprising the charge supply and a gas supply supplying gas to the heated mixing chamber,
The gas supply unit
a plurality of different gas sources;
a mixing unit that mixes gases supplied from a plurality of different gas sources to prepare a mixed gas;
a solenoid valve that controls the composition of the mixed gas,
A mass spectrometer, comprising: a control section that controls the gas supply section so as to supply the mixed gas to the electric charge supply section and the heating mixing chamber based on measurement item information.
The mass spectrometer of claim 1, wherein
The measurement item information is information on the molecular weight of the measurement target substance,
The mass spectrometer, wherein the control unit controls the gas supply unit based on the molecular weight information.
The mass spectrometer of claim 1, wherein
The measurement item information is liquid chromatograph separation method information for separating the measurement target substance,
The mass spectrometer, wherein the control unit controls the gas supply unit based on the separation method information.
The mass spectrometer of claim 1, wherein
The measurement item information is information on the type of gas supplied from the gas supply unit,
The mass spectrometer, wherein the control unit controls the gas supply unit based on the gas type information.
A mass spectrometer according to claim 4, wherein
The mass spectrometer, wherein the controller switches the gas species during measurement.
a heating and mixing chamber for vaporizing and ionizing an atomized liquid sample; a charge supply unit for generating seed ions from a seed ion gas and supplying the seed ions to the heating and mixing chamber; the charge supply unit; A control method for a mass spectrometer comprising a gas supply unit for supplying gas to the chamber,
The gas supply unit includes a plurality of different gas sources, a mixing unit that mixes the gases supplied from the plurality of different gas sources to prepare a mixed gas, and an electromagnetic valve that controls the composition of the mixed gas. have
A method of controlling a mass spectrometer, comprising: controlling the gas supply unit to supply the mixed gas to the charge supply unit and the heating mixing chamber based on measurement item information.
In the control method of the mass spectrometer according to claim 6,
A control method for a mass spectrometer, wherein the measurement item information is information on a molecular weight of a substance to be measured, and the gas supply section is controlled based on the molecular weight information.
In the control method of the mass spectrometer according to claim 6,
A control method for a mass spectrometer, wherein the measurement item information is separation method information for a liquid chromatograph that separates a measurement target substance, and the gas supply unit is controlled based on the separation method information.
In the control method of the mass spectrometer according to claim 6,
A control method for a mass spectrometer, wherein the measurement item information is information on a gas type supplied from the gas supply unit, and the gas supply unit is controlled based on the gas type information.
In the control method of the mass spectrometer according to claim 9,
A control method for a mass spectrometer, comprising switching the gas species during measurement.