JP7592892B2 - Mass spectrometer and method for controlling the same - Google Patents

Description

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

A typical analytical device for analyzing liquid samples in mass spectrometry is a liquid chromatograph mass spectrometer. The liquid sample sent from the liquid chromatograph is ionized and introduced into the mass spectrometer to perform qualitative and quantitative measurements. Typical ionization methods include atmospheric pressure ionization (hereinafter APCI method) (Non-Patent Document 1) and electrospray ionization (hereinafter ESI method) (Non-Patent Document 2).

In the APCI method, the measurement sample is first atomized. Since the measurement sample is continuously delivered from a liquid chromatograph together with a solvent at a rate of several to 1,000 μL/min, an airflow-assisted spray using nitrogen gas or the like is often used for atomization. The atomized sample is then vaporized by heating, and the vaporized sample is introduced into a corona discharge generated by a needle-shaped electrode and ionized.

In the ESI method, like the APCI method, the liquid sample is atomized by an 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 and turn it into charged droplets. The charged droplets are heated and dried to reduce their size, and the excess charge caused by the reduced size of the charged droplets is ionized by Coulomb repulsion, causing ions to detach from the droplets.

In general, the APCI method has a high ionization efficiency for samples with low to medium polarity, while the ESI method has a high ionization efficiency for samples with medium to high polarity, and is said to enable measurement with good sensitivity. Therefore, operators using liquid chromatograph mass spectrometers need to select the ionization method taking into account the polarity of the substance to be measured.

“Atmospheric pressure ionization mass spectrometry. Corona discharge ion source for use in a liquid chromatograph-mass spectrometer-computer analytical system”, D. I. Carroll, I. Dzidic, R. N. Stillwell, K. D. Haegele, and E. C. Horning, Anal. Chem., 47, 2369 (1975). “Electrospray ionization for mass spectrometry of large biomolecules” JB Fenn, M Mann, CK Meng, SF Wong, CM Whitehouse, Science, 06 Oct 1989: Vol. 246, Issue 4926, pp. 64-71

Although the ionization method used in measurements with a liquid chromatograph mass spectrometer is basically selected based on the polarity, molecular weight, molecular structure, etc. of the target substance, in practice, an ionization method with high measurement sensitivity is often selected after actual measurements are performed using the APCI or ESI method.

The ion source has a high-temperature section for drying liquid samples, making it difficult to replace the ion source for each target substance separated by liquid chromatography. For this reason, when measuring actual samples, operators of liquid chromatography mass spectrometers would group together samples that had similar ionization characteristics to the target substance and measure them together.

To solve these problems, there are ion sources that are equipped with both APCI and ESI ionization methods. The target substances separated by liquid chromatography are branched and switched before entering the ion source, and the target substances that are best suited to either APCI or ESI are ionized.

This technique had issues such as the need to introduce the sample a long distance to the ion source, which reduces the separation of the liquid chromatograph, and the limited ionization conditions compared to a standalone ion source, resulting in reduced sensitivity.

Here, in liquid chromatography mass spectrometers, the measurement sample is often separated into components using a liquid chromatograph to measure the target substance. One method of using a liquid chromatograph is to mix water with an organic solvent such as acetonitrile or methanol, and separate the components while changing the mixing ratio. This mixture of water and organic solvent is called the eluent.

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

When a mixture of water and an organic solvent is ionized, in addition to the ions themselves, molecular ions called cluster ions, which are made up of multiple ions, may be generated. Cluster ions include molecular ions made up of multiple water molecules and molecular ions made up of water and organic solvent ions. When cluster ions are measured with a mass spectrometer, a signal is detected as a complex background in the low molecular weight range.

APCI, a typical conventional ionization method, introduces a vaporized measurement sample into a corona discharge to ionize it. ESI applies a high voltage to the atomizer or the liquid sample itself, and ionizes the liquid as it is atomized. Both ionization methods ionize the eluent as well as the target substance. As a result, signals from the target substance and the eluent are observed simultaneously in the mass spectrometer. Therefore, when the molecular weight of the target substance to be measured is small, the signals from the cluster ions and the signal from the target substance overlap, which can reduce sensitivity.

The object of the present invention is to provide a mass spectrometer and a method for controlling a mass spectrometer that can improve the measurement sensitivity of a liquid chromatograph mass spectrometer compared to conventional methods.

The present invention includes multiple means for solving the above problems, and one example is characterized in that the mass spectrometer is provided with a control unit that controls the gas supply unit to supply mixed gas to the charge supply unit and the heated mixing chamber based on measurement item information.

According to the present invention, the measurement sensitivity of a liquid chromatograph mass spectrometer can be improved compared to the conventional method. Problems, configurations, and effects other than those described above will become clear from the description of the following examples.

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

An embodiment of the mass spectrometer and the control method for the mass spectrometer of the present invention will be described with reference to Figure 1.

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

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

The measurement sample in the mass spectrometer 1 is continuously pumped to the nebulizer 100 by the liquid chromatograph 300 at a speed of approximately several to 1000 μL/min.

The nebulizer 100 nebulizes the liquid sample sent from the liquid chromatograph 300. A typical nebulizer is a gas-assisted spray, which nebulizes the liquid sample by flowing a high-velocity gas around a capillary tube through which the liquid sample flows and bringing the liquid sample into contact with the high-velocity gas at the outlet of the capillary tube. Nitrogen gas or air is generally used as the high-velocity gas. Instead of a gas-assisted spray, an ultrasonic nebulizer such as that used in a humidifier can be used.

The heating and mixing chamber 110 is introduced with an atomizing fluid to vaporize and ionize the measurement sample fluid (atomized fluid) atomized in the atomizer 100. The heating and mixing chamber 110 is itself heated by a heater or the like, and the vaporization of the introduced atomized fluid is promoted by heat transfer from the heating and mixing chamber 110. Other heating methods include a method of generating a high-frequency heating electric field in the heating and mixing chamber 110 to heat the atomized fluid, and a method of heating with a light source that generates infrared rays.

The charge supply unit 120 generates seed ions from the seed ion gas to apply 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 the seed ions by a means of introducing the seed ion gas 122 into a corona discharge by a needle electrode of the APCI, or by a means of plasma discharge using the seed ion gas 122.

In addition, the charge supply unit 120 is at a positive pressure (higher pressure) than the heating and mixing chamber 110 to prevent the vaporized fluid from flowing in, generating a gas flow from the charge supply unit 120 to the heating and mixing chamber 110.

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

The measurement sample supplied from the atomizer 110 and vaporized in the heated mixing chamber 110 is mixed with the seed ions supplied from the charge supply unit 120 in the heated mixing chamber 110, thereby ionizing the measurement sample. Since the charge supply unit 120 is at a more positive pressure than the heated mixing chamber 110, fluid originating from the measurement sample does not flow into the charge supply unit 120, preventing contamination from the measurement sample. In addition, since the atomizer 100 only functions to atomize and the charge supply unit 120 only functions to supply charge, measurement stability is improved.

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

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

In order to adjust the amount of gas supplied to the analysis section 150 and the amount of gas introduced to the analysis section 150, an auxiliary gas 130 is supplied to the heating and mixing chamber. The auxiliary gas 130 is air, nitrogen, He, Ne, Ar, Xe, or a mixture of these gases. The flow rate of the auxiliary gas 130 can be determined from the difference between the sum of the flow rate of the liquid being introduced and the flow rate of the seed ion gas 122 and the gas flow rate passing through the first aperture 140, or can be determined based on the pressure of the vacuum chamber having the first aperture 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. By supplying the auxiliary gas 130, ionization that is less affected by the device environmental conditions is achieved.

In this way, the measurement sample ionized by the ion source equipped with the atomizer 100, the heated mixing chamber 110, and the charge supply unit 120 is introduced into the mass spectrometer and measured by the detection unit of the mass spectrometer.

The gas supply unit 500 supplies gas to the charge supply unit 120 and the heating and mixing chamber 110, and the gas type switching 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 mixed gas (seed ion gas 122, auxiliary gas 130) to the charge supply unit 120 and the heated mixing chamber 110 based on the measurement item information 410, and may be a single control device or may be composed of multiple control units each responsible for a different mechanism.

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 is composed of a first flow rate control unit 510 that includes a flow rate of 0 and controls the gas flow rate of the seed ion gas 122, a second flow rate control unit 520 that includes a flow rate of 0 and controls the gas flow rate of the auxiliary gas 130, a gas mixing unit 530 that mixes a compound gas that serves as the seed ion gas or auxiliary gas, and a single gas control unit 540 that controls the flow rate of single gases such as air, nitrogen, He, Ar, Xe, etc. that serve as the basis for the seed ion gas or auxiliary gas.

Each of the individual gas control units 540 that control the flow rate of the individual gases is composed of a supply source 570 of multiple different types of individual gases, an solenoid valve 560 that turns the gas flow on and off, and an individual gas flow control unit 550 that controls the flow rate.

This single gas control unit 540 uses one or more types of gas; for example, when using Ar, nitrogen, and He gas, three systems are connected.

Next, we will explain the details of flow rate control of the above-mentioned seed ion gas and auxiliary gas.

As mentioned above, in liquid chromatography mass spectrometers, the components of a measurement sample are separated using a liquid chromatograph, and the target substance is often measured. When components are separated using a liquid chromatograph, the measurement components are separated at the same time (timing) if they are the same substance and under the same separation conditions. This time is called the retention time. Therefore, when a measurement sample is introduced into a liquid chromatograph, the target component is separated at a fixed retention time. Measurements are performed by changing the measurement conditions of the mass spectrometer (for example, the mass to be observed and MSMS conditions) to match the retention time at which the components are separated.

For this reason, the substance to be measured (target substance) is known in advance by the person making the measurement. At the very 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 discharge is called the Penning ionization method.

In the Penning ionization method, metastable excited species of rare gases generated by discharge undergo multiple reactions, leading to the ionization of molecules. The important point about Penning ionization in the mass spectrometer 1 is that the seed ion gas species each have different internal energies, so by appropriately selecting the seed ion gas, it is possible to adjust the energy given to the measurement component.

For example, metastable excited species generated from He gas have a high internal energy of 19.8 eV, so it is believed that almost any molecule can be ionized. In addition, 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 and can be changed by changing the gas type, and since the target substance to be measured is also known, by selecting and controlling the seed ion gas and flow rate according to the target substance to be measured, the background signal from the solvent can be reduced and the target substance itself can be ionized.

Therefore, information on the molecular weight of the substance to be measured 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, when performing quantitative analysis, the operator of a liquid chromatograph mass spectrometer inputs molecular weight information of the target substance before measurement. The control unit 400 controls the gas supply unit 500 to select the ions to be measured according to the value input during measurement. The relationship between molecular weight and ionization energy generally tends to be higher on the low molecular weight side and lower on the high molecular weight side, so by switching the seed ion gas depending on the target substance when selecting ions for measurement, highly sensitive measurements are possible.

Another example of a separation method using liquid chromatography is reversed-phase chromatography. Reverse-phase chromatography is a method in which a highly polar solvent is passed through a low-polarity separation column to elute long carbon chain components from short carbon chain target components. Generally, it is assumed that short carbon chain components are on the low molecular weight side, and long carbon chain components are on the high molecular weight side. As mentioned above, ionization energy generally tends to be high on the low molecular weight side and low on the high molecular weight side.

Normal phase chromatography is another method of separation using liquid chromatography. Normal phase chromatography is a method in which a less polar solvent is passed through a more polar separation column to elute more polar components from the less polar target components. The polarity of the target components is also a factor that affects the measurement sensitivity when selecting the ionization method of a mass spectrometer. Generally, target components with low polarity are difficult to ionize, so the ionization energy is large, while components with high polarity tend to have low ionization energy.

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

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

For example, the operator determines the separation method using liquid chromatography, and then selects the gas type and flow rate of the seed ion gas 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 perspective of ionization in the mass spectrometer 1. However, it is a limited resource and has the problem of being expensive.

Therefore, information on the gas type 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 control unit 400 switches the gas type during measurement.

For example, nitrogen, which can be produced by separating air, is used, and the seed ion gas is switched during measurement based on the target components and information on the separation method using liquid chromatography.

Next, the effects of this embodiment will be explained.

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

Therefore, in a liquid chromatograph mass spectrometer, it is possible to reduce the effects of the physical properties of the substance to be measured, such as its polarity and molecular weight, and achieve highly efficient ionization (high sensitivity). It is also possible to reduce the cluster ion signal originating from the eluent used in the liquid chromatograph, and reduce the background signal. This makes it possible to carry out measurements with higher sensitivity than with conventional mass spectrometers.

In addition, the measurement item information 410 is information on the molecular weight of the substance to be measured, and the control unit 400 controls the gas supply unit 500 based on the molecular weight information, making it possible to perform highly sensitive measurements.

Furthermore, the measurement item information 410 is separation method information for a liquid chromatograph that separates the substance to be measured, and the control unit 400 controls the gas supply unit 500 based on the separation method information, thereby enabling highly efficient ionization (high sensitivity) that is suitable for ionizing the target component itself.

In addition, 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 making it possible to reduce operating costs during measurement and enable more efficient measurement.

Furthermore, the control unit 400 can switch gas types during measurement, enabling even more efficient measurements.

＜Other＞
The present invention is not limited to the above-mentioned embodiment, and various modifications and applications are possible. The above-mentioned embodiment has been described in detail to explain the present invention in an easily understandable manner, and the present invention is not necessarily limited to having all of 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 fine hole 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 rate control unit 520: Second flow rate control unit 530: Gas mixing unit 540: Individual gas control unit 550: Individual gas flow rate control unit 560: Solenoid valve 570: Supply source (gas source)

Claims (10)

a heating and mixing chamber for vaporizing and ionizing the nebulized liquid sample;
a charge supply unit that generates seed ions from a seed ion gas and supplies the seed ions to the heated mixing chamber;
A mass spectrometer comprising the charge supply unit and a gas supply unit that supplies a gas to the heating and mixing chamber,
The gas supply unit includes:
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;
and a solenoid valve for controlling the composition of the mixed gas.
a control unit that controls the gas supply unit to supply the mixed gas to the charge supply unit and the heating and mixing chamber based on measurement item information. 2. The mass spectrometer of claim 1,
The measurement item information is information on the molecular weight of a measurement target substance,
The mass spectrometer according to claim 1, wherein the control unit controls the gas supply unit based on the molecular weight information. 2. The mass spectrometer of claim 1,
The measurement item information is information on a liquid chromatograph separation method for separating a measurement target substance,
The mass spectrometer according to claim 1, wherein the control unit controls the gas supply unit based on the separation method information. 2. The mass spectrometer of claim 1,
the measurement item information is information on the type of gas supplied from the gas supply unit,
The mass spectrometer according to claim 1, wherein the control unit controls the gas supply unit based on the gas type information. 5. The mass spectrometer of claim 4,
The control unit switches the gas species during measurement. A method for controlling a mass spectrometer including a heating and mixing chamber that vaporizes and ionizes an atomized liquid sample, a charge supply unit that generates seed ions from a seed ion gas and supplies the seed ions to the heating and mixing chamber, and a gas supply unit that supplies gas to the charge supply unit and the heating and mixing chamber, comprising:
the gas supply unit includes a plurality of different gas sources, a mixing unit that mixes gases supplied from the plurality of different gas sources to prepare a mixed gas, and an electromagnetic valve that controls a composition of the mixed gas;
13. A method for controlling a mass spectrometer, comprising: controlling the gas supply unit to supply the mixed gas to the charge supply unit and the heating and mixing chamber based on measurement item information. 7. The method for controlling a mass spectrometer according to claim 6, further comprising:
The measurement item information is information on a molecular weight of a measurement target substance, and the gas supply unit is controlled based on the molecular weight information. 7. The method for controlling a mass spectrometer according to claim 6, further comprising:
The method for controlling 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. 7. The method for controlling a mass spectrometer according to claim 6, further comprising:
a control method for a mass spectrometer, the control method comprising: controlling the gas supply unit based on the gas type information; and controlling the gas supply unit based on the measurement item information. 10. The method for controlling a mass spectrometer according to claim 9,
A method for controlling a mass spectrometer, comprising: switching the gas species during measurement.

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