Control method for mass spectrometer with discontinuous sample introduction, mass spectrometer

Abstract

The present invention relates to the technical field of mass spectrometers, and specifically provides a control method and a mass spectrometer for a discontinuous sampling mass spectrometer. The method includes: opening the discontinuous atmospheric pressure interface of the mass spectrometer, injecting the ion current of the target sample into the ion trap of the mass spectrometer; applying an alternating current signal with a preset waveform containing a certain frequency range and amplitude to screen out the target ions in the ion current and confine them in the ion trap electric field; when the number of target ions confined in the ion trap does not meet the target requirement, continue to open the discontinuous atmospheric pressure interface of the mass spectrometer, inject and confine the target ions of the target sample into the ion trap of the mass spectrometer until the requirement for increasing the target ions in the ion trap is met, and fragment and detect the target ions. Thereby solving the problem that in the related art, when a portable discontinuous sampling single ion trap mass spectrometer analyzes target ions, the intensity of the finally detected ion signal is poor and the sensitivity of the mass spectrometer is low.

Description

Technical Field

[0001] The present invention relates to the technical field of mass spectrometers, and particularly to a control method and a mass spectrometer for a discontinuous sampling mass spectrometer. Background Art

[0002] In the related art, a discontinuous sampling mass spectrometer, that is, a mass spectrometer using a discontinuous atmospheric pressure interface to implement an atmospheric pressure ion source, is convenient to carry and has a simple structure. The discontinuous atmospheric pressure interface technology was developed by the research groups of Graham Cooks and Zheng Ouyang at Purdue University in the United States. The discontinuous atmospheric pressure interface usually connects the atmospheric pressure ion source and the vacuum chamber through a capillary and a rubber tube, and controls the opening and closing of the rubber tube through a mechanical valve.

[0003] Affected by the opening and closing of the rubber tube, the air pressure in the vacuum chamber will suddenly increase every time the mechanical valve is opened, which in turn causes the time for inputting sample ions into the mass spectrometer by opening the mechanical valve of the mass spectrometer using a discontinuous atmospheric pressure interface to be greatly shortened, resulting in too little ion source sampling input, affecting the response of the mass spectrometer to the detection signal of mass scanning analysis.

[0004] Especially when the concentration of the target compound is low, the low mass spectrometry response signal will affect the recognition and identification of the characteristic peaks of the target ions, which may lead to deviations in qualitative and quantitative results, thus affecting the use of the mass spectrometer in specific application fields.

[0005] Aiming at the problem that the final detected ion signal intensity difference is poor and the sensitivity of the mass spectrometer is low when the portable discontinuous sampling single ion trap mass spectrometer in the related art performs target ion analysis, no effective solution has been proposed yet. Summary of the Invention

[0006] A control method and a mass spectrometer for a discontinuous sampling mass spectrometer provided by an embodiment of the present invention at least solve the problem that the final detected ion signal intensity difference is poor and the sensitivity of the mass spectrometer is low when the portable discontinuous sampling mass spectrometer in the related art performs target ion analysis.

[0007] According to one aspect of an embodiment of the present invention, a control method for a mass spectrometer with discontinuous sample introduction is provided, including: opening the discontinuous atmospheric pressure interface of the mass spectrometer and introducing the ion current of the target sample into the ion trap of the mass spectrometer, wherein the ion current includes target ions; after screening the target ions in the ion current, confining them in the ion trap; detecting whether the number of the target ions in the ion trap reaches the target requirement; in the case where the number of the target ions confined in the ion trap does not reach the target requirement, continuously opening the discontinuous atmospheric pressure interface of the mass spectrometer, introducing and confining the target ions of the target sample into the ion trap of the mass spectrometer until the requirement for increasing the target ions in the ion trap is met; in the case where the number of the target ions reaches the target requirement, fragmenting and detecting the target ions.

[0008] As an optional embodiment, after screening the target ions in the ion current and confining them in the ion trap, it includes: based on the radio frequency electric field of the ion trap, superimposing a preset alternating voltage on the ion trap to generate an alternating signal with a preset waveform; using the alternating signal to resonantly eject the impurity ions in the ion trap, and screening out the target ions to remain in the ion trap, wherein the impurity ions are the ions other than the target ions in the introduced ion current.

[0009] As an optional embodiment, before superimposing a preset alternating voltage on the ion trap based on the radio frequency electric field of the ion trap to generate an alternating signal, the method further includes: determining the target amplitude of the preset alternating voltage according to the mass-to-charge ratio of the target ions and the impurity ions and the size of the ion trap; determining the target spectrum of the preset alternating voltage according to the characteristic frequencies of the target ions and the impurity ions; generating a preset alternating voltage with a corresponding waveform according to the target amplitude and the target spectrum.

[0010] As an optional embodiment, determining the target amplitude of the preset alternating voltage according to the mass-to-charge ratio of the target ions and the impurity ions and the size of the ion trap includes: determining the potential well depths of the target ions and the impurity ions according to the mass-to-charge ratio and the motion parameters of the target ions and the impurity ions, wherein the motion parameters are the solutions of the motion equation of the ion trap; determining the target amplitude of the preset alternating voltage according to the potential well depths of the target ions and the impurity ions, so that the preset alternating voltage ejects the impurity ions and retains the target ions in the ion trap.

[0011] As an alternative embodiment, determining the target amplitude of the preset alternating voltage according to the potential well depths of the target ions and the impurity ions includes: determining the amplitude range of the preset alternating voltage that meets the first requirement according to the potential well depth of the impurity ions, where the first requirement is that based on the corresponding potential well depth of the impurity ions, the amplitude range of the preset alternating voltage resonates with the impurity ions to eject the impurity ions from the ion trap; screening the target amplitude that meets the second requirement from the amplitude range according to the potential well depth of the target ions, where the second requirement is that based on the potential well depth of the target ions, the action of the target amplitude of the preset alternating voltage on the target ions will not eject the target ions from the ion trap; in the case where there is no amplitude in the amplitude range that meets the second requirement, taking the minimum amplitude in the amplitude range as the target amplitude.

[0012] As an alternative embodiment, before injecting the ion current of the target sample into the ion trap of the mass spectrometer by opening the discontinuous atmospheric pressure interface of the mass spectrometer, the method further includes: determining the electric field strength of the ion trap for this injection according to the mass-to-charge ratio and injection amount of the ions in the ion current of the target sample, where the injection amount is determined according to the parameters of the ion source and the discontinuous atmospheric pressure interface of the mass spectrometer.

[0013] As an alternative embodiment, determining the electric field strength of the ion trap for this injection according to the mass-to-charge ratio of the ions in the ion current of the target sample includes: in the case where this injection is the first injection, determining the radio frequency electric field strength according to the mass-to-charge ratio and injection amount of the target ions, where the radio frequency electric field strength corresponds to the motion parameters of the target ions within a preset parameter range; in the case where this injection is not the first injection, determining the radio frequency electric field strength for this injection according to the radio frequency electric field strength applied to the target ions after the previous injection, where the electric field strength value for this injection is such that on the basis of ensuring that the target ions after the previous injection are confined in the ion trap, the ion beam for this injection is confined in the ion trap by this electric field strength.

[0014] As an alternative embodiment, detecting whether the number of the target ions in the ion trap reaches the target requirement includes: determining the number / signal intensity of the target ions for a single injection according to the detection result of the target ions for a single injection under the same ion source parameter settings; determining whether the target ions need multiple injections and the number of injections according to the number / signal intensity of the target ions for a single injection; determining whether the number of the target ions in the ion trap reaches the requirement according to whether the number of the current injection reaches the number of injections; where in the case where the number of the current injection reaches the number of injections, it is determined that the number of the target ions in the ion trap reaches the requirement.

[0015] As an alternative embodiment, in the case where the ion trap performs multiple sample injection and ion selection steps, before repeatedly opening the discontinuous atmospheric pressure interface of the mass spectrometer, the method further includes: controlling the vacuum system of the mass spectrometer to evacuate the vacuum chamber of the mass spectrometer; detecting the pressure of the vacuum chamber, wherein the pressure of the vacuum chamber increases when the discontinuous atmospheric pressure interface is opened for sample injection; after the pressure reaches the operating pressure range and is maintained for a preset time, performing continued target ion selection, and then opening the discontinuous atmospheric pressure interface of the mass spectrometer.

[0016] As an alternative embodiment, the ion trap is a quadrupole linear ion trap; it includes a front cover electrode, a quadrupole, and a rear cover electrode; opening the discontinuous atmospheric pressure interface of the mass spectrometer and injecting the ion current of the target sample into the ion trap of the mass spectrometer includes: adjusting the potential of the front cover electrode to a target potential so that the electric field strength of the ion trap reaches the required electric field strength, and injecting the ion current of the target sample into the ion trap of the mass spectrometer.

[0017] As an alternative embodiment, before opening the discontinuous atmospheric pressure interface of the mass spectrometer and injecting the ion current of the target sample into the ion trap of the mass spectrometer, it includes: in the case of the first sample injection, controlling the potential of the front cover electrode of the ion trap to decrease by a first preset threshold, so that the ion current entering from the discontinuous atmospheric pressure interface enters and stably moves in the ion trap; in the case of non-first sample injection, controlling the potential of the front cover electrode of the ion trap to decrease by a second preset threshold, wherein the second preset threshold is lower than the first preset threshold; so that the ion current of this non-first sample injection enters the ion trap and stably moves, and the target ions that have been trapped in the ion trap before this non-first sample injection will not pop out and escape.

[0018] According to one aspect of the embodiments of the present invention, there is also provided a mass spectrometer for discontinuous sample injection, including: a processor, and a memory storing a program, wherein the program includes instructions that, when executed by the processor, cause the processor to execute the above method.

[0019] The control method of the mass spectrometer for discontinuous sample injection provided by the embodiments of the present invention creates an ion current of the target sample by opening the discontinuous atmospheric pressure interface of the mass spectrometer and injecting it into the ion trap of the mass spectrometer, screening out the target ions in the ion current and trapping them in the ion trap, and repeating the above process multiple times to increase the number of target ions stored in the ion trap. Subsequently, the accumulated target ions are fragmented and detected. Thus, the number of target ions injected meets the requirements of test accuracy and sensitivity.

[0020] When the number of target ions trapped in the ion trap fails to meet the detection requirements, the discontinuous atmospheric pressure interface of the mass spectrometer is opened multiple times to inject the target ions of the target sample into the ion trap of the mass spectrometer. Multiple injections and ion selection are controlled to accumulate the quantity until the requirements of test accuracy and sensitivity are met. Without relying on external hardware, by controlling the mass spectrometer itself with discontinuous injection, multiple discontinuous injections are achieved, and the test accuracy and sensitivity of the target ions are improved. This solves the problem that in the related art, when a portable single-ion trap mass spectrometer with discontinuous injection performs target ion analysis, the final detected ion signal intensity is poor and the sensitivity of the mass spectrometer is low. Description of the Drawings

[0021] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the following described drawings are only some embodiments of the present invention, and those of ordinary skill in the art can obtain other embodiments based on these drawings without creative efforts.

[0022] Figure 1 It is a flowchart of a control method for a mass spectrometer with discontinuous injection according to an embodiment of the present invention.

[0023] Figure 2 It is a schematic diagram of the detection process of a mass spectrometer with discontinuous injection according to an embodiment of the present invention.

[0024] Figure 3 It is a schematic diagram of the detection result of a single injection of voriconazole in a blood sample according to an embodiment of the present invention.

[0025] Figure 4 It is a schematic diagram of the detection result of multiple injections of voriconazole in a blood sample according to an embodiment of the present invention.

[0026] Figure 5 It is a schematic diagram of the correlation between the number of injections and the signal intensity when detecting voriconazole according to an embodiment of the present invention.

[0027] Figure 6 It is a schematic diagram of the detection result of a single injection of tacrolimus sample according to an embodiment of the present invention.

[0028] Figure 7 It is a schematic diagram of the detection result of multiple injections of tacrolimus sample according to an embodiment of the present invention.

[0029] Figure 8 It is a schematic diagram of the correlation between the number of injections and the signal intensity when detecting tacrolimus sample according to an embodiment of the present invention.

[0030] Figure 9 It is a schematic diagram of the effect of ion kinetic energy on multiple samplings in the embodiments of the present invention.

[0031] Figure 10 It is a schematic diagram of a control device for a discontinuous sampling mass spectrometer in the embodiments of the present invention.

[0032] Figure 11 It is a schematic structural diagram of an electronic device of the present invention. Detailed implementation manners

[0033] Embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although some embodiments of the present invention are shown in the drawings, it should be understood that the present invention can be implemented in various forms and should not be construed as limited to the embodiments set forth herein. On the contrary, these embodiments are provided to more thoroughly and completely understand the present invention. It should be understood that the drawings and embodiments of the present invention are only for exemplary purposes and are not used to limit the protection scope of the present invention.

[0034] In related technologies, mass spectrometry is a highly specific analytical technique with high sensitivity and specificity. It analyzes target ions selected by a mass analyzer; or uses tandem techniques to dissociate parent ions and further analyzes the generated fragment ions to achieve qualitative and quantitative analysis of compound structures. When the concentration of the target compound is low, its low mass spectrometry response signal will affect the recognition and identification of the characteristic peaks of target ions, which may lead to deviations in qualitative and quantitative results, thus affecting the use of the mass spectrometer in specific application fields.

[0035] Due to the high analytical sensitivity and specificity of mass spectrometry, mass spectrometers have become one of the most widely used chemical analysis instruments in the world, and miniaturization and portability are the future development directions of mass spectrometers. It analyzes target ions selected by a mass analyzer; or uses tandem techniques to dissociate parent ions and further analyzes the generated fragment ions to achieve qualitative and quantitative analysis of compound structures. Among them, ion trap mass spectrometers are a research hotspot in the field of portable mass spectrometry due to their small volume, high working pressure, and time tandem mass spectrometry capabilities.

[0036] In order to achieve the portability of ion trap mass spectrometers, most common portable ion trap mass spectrometers currently use atmospheric pressure ion sources, and their atmospheric pressure interfaces are generally divided into continuous atmospheric pressure interfaces or discontinuous atmospheric pressure interfaces. The differential cavity volume of ion trap mass spectrometers equipped with continuous atmospheric pressure interfaces is relatively large, and the hardware structure is complex, resulting in certain limitations in their portability.

[0037] The discontinuous atmospheric pressure interface technology was developed by the research groups of Graham Cooks and Zheng Ouyang at Purdue University in the United States. The discontinuous interface usually consists of a section of rubber tube connecting two metal capillary tubes. The atmospheric pressure ion source and the vacuum chamber are connected through the capillary tubes and the rubber tube, and the opening and closing of the rubber tube are controlled by a mechanical valve, so that a low-pressure vacuum environment required for the normal operation of the ion trap in the vacuum chamber can be achieved even with a miniaturized vacuum pump.

[0038] Affected by the opening and closing of the rubber tube, the air pressure in the vacuum chamber will suddenly rise every time the mechanical valve is opened. Usually, the pressure in the vacuum chamber changes between less than 0.1 Pa and 10 Pa before and after the valve is opened. When the rubber tube is opened, the ion sample under atmospheric pressure enters the ion trap in the vacuum chamber. Subsequently, after the rubber tube is closed and the air pressure in the vacuum chamber drops to a certain appropriate value, the subsequent time sequence fragment analysis of the ion trap is carried out. This results in a relatively long analysis time for the ion trap mass spectrometer, and the stability and sensitivity of the instrument are limited, restricting the application range of the instrument.

[0039] Similarly limited by the problem of air pressure change, the time for the mass spectrometer with a discontinuous atmospheric pressure interface to input sample ions by opening the mechanical valve each time is greatly shortened, resulting in too little sampling input from the ion source and affecting the response of the mass spectrometer to the detection signal of mass scanning analysis.

[0040] Especially when the concentration of the target compound is low, the low mass spectrometry response signal will affect the identification and determination of the characteristic peaks of the target ions, which may lead to deviations in qualitative and quantitative results, thus affecting the use of the mass spectrometer in specific application fields.

[0041] The ion trap mass spectrometer is a common mass spectrometer that can perform multi-stage time series mass spectrometry analysis. The normal working mode of the second-stage tandem mass spectrometry is as follows: the mass spectrometer first injects the target ions, then performs ion selection, then excites and fragments them, and finally detects the fragment ions to complete the analysis of the target ions.

[0042] Currently, a variety of technologies have been developed to improve the sensitivity by accumulating analyte ions. By developing ion accumulation technologies, the number of effective ions captured is increased, thereby improving the detection sensitivity of low-content substances. However, currently, this technology is mainly implemented on double ion trap mass spectrometers, and this technology is still blank on portable single ion trap mass spectrometers.

[0043] In view of the above technical problems, this embodiment provides a control method for a single ion trap mass spectrometer with discontinuous sampling, realizing the ion enrichment function of the single ion trap.

[0044] Figure 1 It is a flowchart of a control method for a mass spectrometer with discontinuous sampling according to an embodiment of the present invention, as Figure 1As shown, in order to solve the problem that in the related art, when a portable discontinuous sampling single ion trap mass spectrometer performs target ion analysis, the difference in the ion signal intensity finally detected is large, and the sensitivity of the mass spectrometer is low. An embodiment of the present invention provides a control method for a discontinuous sampling mass spectrometer, and the method includes:

[0045] Step S101, open the discontinuous atmospheric pressure interface of the mass spectrometer, and inject the ion current of the target sample into the ion trap of the mass spectrometer, where the ion current includes target ions;

[0046] Step S102, after screening the target ions in the ion current, confine them in the ion trap;

[0047] Step S103, when the number of target ions confined in the ion trap does not reach the target requirement, continue to open the discontinuous atmospheric pressure interface of the mass spectrometer, inject and confine the target ions of the target sample into the ion trap of the mass spectrometer until the requirement for increasing the target ions in the ion trap is met;

[0048] Step S104, when the number of target ions reaches the target requirement, fragment and detect the target ions.

[0049] The above control method for a discontinuous sampling mass spectrometer provided by this embodiment opens the discontinuous atmospheric pressure interface of the mass spectrometer, injects the ion current of the target sample into the ion trap of the mass spectrometer, confines the target ions in the ion current in the ion trap, and repeats the above injection and ion selection steps multiple times. After the number of target ions in the ion trap accumulates to a certain amount, fragment and detect the target ions. Thereby enabling the number of injected target ions to meet the requirements for improving the test accuracy and sensitivity.

[0050] When the number of target ions confined in the ion trap is low, open the discontinuous atmospheric pressure interface of the mass spectrometer multiple times, inject and screen and confine the target ions of the target sample into the ion trap of the mass spectrometer until the number of target ions reaches the detection requirement. This control method enables controlling the number of injections when the number of target ions is insufficient to accumulate the quantity until the requirements for test accuracy and sensitivity are met. It realizes not relying on external hardware, and by controlling the discontinuous sampling mass spectrometer itself, multiple discontinuous samplings are achieved, and the test accuracy and sensitivity of target ions are improved.

[0051] The execution subject of the above steps can be the controller of the discontinuous sampling mass spectrometer, the upper computer, or the controller of the discontinuous sampling mass spectrometer. Through this controller and upper computer, the working parameters of the mass spectrometer can be collected, and each part can be controlled.

[0052] The above-mentioned mass spectrometer with discontinuous sample introduction, that is, a mass spectrometer with a discontinuous atmospheric pressure interface. It should be noted that such mass spectrometers are generally portable, and for the convenience of carrying, the smaller the size, the better. Therefore, general mass spectrometers with discontinuous sample introduction are single ion trap mass spectrometers. The single ion trap they possess is the above-mentioned target ion trap.

[0053] When implementing multiple sample introductions with a single ion trap mass spectrometer with discontinuous sample introduction, the related technologies for multiple sample introductions are similar to those of conventional single sample introduction and ion screening methods, except that there are differences in specific control strategies.

[0054] During the first sample introduction, first open the discontinuous atmospheric pressure interface of the mass spectrometer, and inject the ion current of the target sample into the ion trap of the mass spectrometer. This ion current is generated by in-situ ionization of the target sample with high voltage, and this ion current includes target ions and impurity ions.

[0055] After opening the discontinuous atmospheric pressure interface of the mass spectrometer and injecting the ion current of the target sample into the ion trap of the mass spectrometer, close the discontinuous atmospheric pressure interface, and adjust the pressure in the vacuum chamber to be suitable for ion selection through time control. Subsequently, screen out the target ions in the ion current and confine them in the ion trap electric field.

[0056] Then repeat the above steps of opening and closing the discontinuous atmospheric pressure interface of the mass spectrometer, and performing screening and confinement multiple times, inject the target ions of the target sample into the ion trap of the mass spectrometer, and accumulate them.

[0057] During subsequent non-first sample introductions, while opening the discontinuous atmospheric pressure interface for sample introduction, it is necessary to adjust the voltages applied to each electrode of the ion trap so that the electrode potential of the ion trap remains at a target value. This target value ensures that the target ions confined in the ion trap during the previous sample introduction process are not lost, and at the same time ensures that the ion beam during the sample introduction process when opening the discontinuous atmospheric pressure interface this time can be confined in the ion trap.

[0058] The higher the velocity of the ion current, the greater the kinetic energy of the ions. When confining the target ions in the ion current in the ion trap, the greater the electric field strength required, that is, the greater the voltage amplitude applied to the ion trap. During the first sample introduction, theoretically, it is only necessary to ensure that the ion current can be effectively confined in the ion trap.

[0059] It should be noted that during non-first sample introductions, not only need to consider that the ion current can be effectively confined in the ion trap, but also try to avoid the loss of ions already present in the ion trap, and avoid the target ions that have been confined and accumulated in the ion trap being knocked out of the ion trap by the newly introduced gas flow and ion beam. This requires controlling the electric field strength or the applied voltage of the ion trap for non-first sample introductions, and the specific method will be described later.

[0060] After the number of target ions accumulates to a certain amount, it can be considered that the requirement is met, and then the target ions are fragmented and detected. It should be noted that the method of fragmenting and detecting the target ions in this embodiment can be one of the ion detectors in the prior art. For example, electron multiplier (EM), Faraday cup (FC), photomultiplier electrode, array detector, etc.

[0061] The ion detector can detect the target ions and output an amplified ion signal to form a mass spectrum. Or generate the required statistical chart according to other parameters. Such as Figure 2 and Figure 3 are both mass spectra, Figure 4 is a graph showing the relationship between the number of injections and the signal intensity.

[0062] Through the above steps, the technical effect of increasing the number of target ions injected and thus improving the test accuracy and sensitivity can be achieved. It solves the problem that in the related art, when a portable discontinuous injection single ion trap mass spectrometer performs target ion analysis, the finally detected ion signal intensity is poor and the sensitivity of the mass spectrometer is low.

[0063] After the above step S104, collision-induced dissociation can also be performed on the target ions enriched in the previous step to generate fragment ions; then the fragment ions are detected to complete the analysis of the target substance.

[0064] As an optional embodiment, after screening the target ions in the ion current, they are trapped in the ion trap, including: based on the radio frequency electric field of the ion trap, applying a preset AC voltage to the ion trap to generate an AC signal with a preset waveform; using the AC signal to resonantly eject the impurity ions in the ion trap and screen out the target ions to be retained in the ion trap, where the impurity ions are the ions other than the target ions in the injected ion current.

[0065] After the ion current enters the ion trap, all the ions in the ion current will be trapped in the ion trap, and the ions other than the target ions are impurity ions. The impurity ions need to be removed.

[0066] When a radio frequency voltage is applied to the ion trap, the mass and charge quantity differences between the impurity ions and the target ions result in different characteristic frequencies of the impurity ions and the target ions in the ion trap. Utilizing the characteristic that the frequencies of the impurity ions and the target ions are different, the impurity ions can be resonantly ejected from the ion trap in their entirety by applying a spectral AC voltage signal containing the characteristic frequency of the impurity ions but not the characteristic frequency of the target ions, and the target ions are retained.

[0067] Specifically, based on the radio frequency electric field of the ion trap, a preset AC voltage can be superimposed on the ion trap to generate an AC signal. Then, the AC signal can be used to resonantly eject the impurity ions in the ion trap, and the target ions are screened out and retained in the ion trap.

[0068] It should be noted that since the AC voltage also acts on the target ions, although there is no resonance, it still causes the loss of the target ions. The purpose of applying the AC voltage is mainly to eject the impurity ions and retain the target ions. That is, the action of the AC voltage on the target ions is not sufficient to eject the target ions from the ion trap. Therefore, the amplitude of the AC voltage signal also needs to be appropriately set.

[0069] As an optional embodiment, before superimposing a preset AC voltage on the ion trap based on the radio frequency electric field of the ion trap to generate an AC signal, the method further includes: determining the target amplitude of the preset AC voltage according to the mass-to-charge ratios of the target ions and impurity ions and the size of the ion trap; determining the target spectrum of the preset AC voltage according to the characteristic frequencies of the target ions and impurity ions; generating a preset AC voltage with a corresponding waveform according to the target amplitude and target spectrum.

[0070] When setting the AC voltage signal, it mainly includes spectrum setting and amplitude setting.

[0071] For the amplitude setting, the kinetic energies, potential well depths of the target ions and impurity ions, and the size of the ion trap need to be considered. To ensure that under the action of the preset AC voltage, the impurity ions resonate, their amplitudes increase exponentially, and the vibration amplitude can exceed the ion trap, so as to eject them. While the amplitude of the target ions will not exceed the confinement range of the ion trap under non-resonant action, so as to screen and confine the target ions in the ion trap.

[0072] Therefore, according to the mass-to-charge ratios of the target ions and impurity ions and the size of the ion trap, the potential well depth is determined, and according to the potential well depth, the target amplitude of the preset AC voltage is determined. The specific method will be described later.

[0073] The spectrum of the preset AC voltage signal can be a superposition of different frequency AC signals containing the characteristic frequencies of the impurity ions but not the characteristic frequencies of the target ions. That is, according to the characteristic frequencies of the target ions, the target spectrum of the preset AC voltage signal is determined.

[0074] After both the target spectrum and target amplitude are determined, a preset AC voltage signal with a corresponding waveform can be generated. That is, a corresponding preset AC voltage signal is generated according to the target amplitude and target spectrum.

[0075] In this embodiment, taking a quadrupole linear ion trap mass analyzer as an example, the principle of the AC voltage signal and ion screening is described. The quadrupole includes two pairs of rods. The same voltage is applied to the paired rods, and opposite voltages are applied to the adjacent rods. The motion form of charged ions in the quadrupole electric field can be expressed in the form of the Mathieu equation. Solving the Mathieu equation can obtain the motion parameters a u and q u .

[0076]

[0077]

[0078] where z is the ion charge number, e is the unit charge, V is the potential intensity of the RF electric field, m is the ion mass, Ω is the angular frequency of the ion trap electric field, and r0 is the radius of the ion trap field.

[0079] The stable region of the quadrupole in the (a u , q u ) coordinate system is constant and independent of the quadrupole voltages U, V, and the value of the ion mass number m / z. Generally speaking, the working frequency Ω of the quadrupole and the radius r0 of the ion trap field are constant. Thus, when the voltages U, V, and the ion mass number m / z are given, the corresponding a and q can be calculated through the formula, thereby determining the stability of the ions under the given conditions.

[0080] In this embodiment, when the linear ion trap uses a quadrupole as the mass analyzer, the quadrupole operates in the RF-only mode, that is, only the AC RF voltage V is applied. At this time, the DC voltage U = 0, and the motion parameter a = 0 can be obtained. Therefore, the stable region of the linear ion trap is on the q-axis, and its range is 0 < q < 0.908.

[0081] Under the condition of a given AC RF voltage, the q value of an ion with a mass number of m can be calculated according to the qu formula, thereby determining whether it is in the stable region.

[0082] Similarly, for an ion with a mass number of m, its q value can be changed by changing the AC RF voltage V, so that the ion enters or leaves the stable region, or adjusts its position within the stable region.

[0083] It can be seen from this that when the AC RF voltage V is fixed, the smaller the ion mass m, the larger the q value. When q ≥ 0.908, the ion leaves the stable region and will not be trapped by the trap, that is, it pops out of the ion trap.

[0084] For the frequency of charged particles, in the radial direction of the linear ion trap (i.e., the xy direction), the motion trajectory of charged ions is a vibration form, mainly divided into two categories: stable motion trajectories and unstable motion trajectories.

[0085] To solve for the frequency of the ion motion trajectory, the Mathieu equation is solved, and the following formula for the frequency can be obtained:

[0086]

[0087] When n = 0, the frequency ω u,0 = 1 / 2β u Ω, which is the main motion trajectory frequency of the ion, abbreviated as ω. ω is called the fundamental frequency, which is less than the drive voltage frequency Ω applied to the quadrupole and is also the most commonly used frequency in mass spectrometry.

[0088] Within the stable region of mass spectrometry operation, β u is related to the motion parameters a and q. Specifically, as a increases, β u gradually increases, and as q increases, β u also gradually increases.

[0089] During ion selection, when an alternating electric field with the same frequency as the characteristic long-term frequency ω of the charged ions in the ion trap is applied to the ions, the ions will gain additional energy and their motion trajectories will continuously expand until they leave the ion trap. This process is called resonance excitation. In the mass spectrometer system, this alternating electric field is applied to a pair of rods and is called the AC voltage AC signal.

[0090] By controlling the RF and AC signals, an AC signal is applied to ions with a specific mass m at a specific q, and resonance excitation is used to operate on the ions, such as ion selection.

[0091] Ion selection is the process of "sweeping" out the irrelevant ions from the ion trap and only leaving the ions of interest in the trap. It is an important ion operation for performing MSn. Ion selection also utilizes the principle of resonance excitation, except that an AC signal is applied to the target ions that are not selected, causing them to gain additional kinetic energy and leave the ion trap.

[0092] To select the ions to be retained, the RF voltage can be adjusted first to move the q value of the ions to 0.75, which is called iso_q, that is, a deeper potential well depth. When q = 0.75, the potential well of the ions is deeper (subsequent Delmelt potential theory), and it is also farther from the unstable region, making it more stable in the trap. Then, an AC signal with a varying frequency is applied, and the frequency needs to include the frequencies ω = βΩ / 2 corresponding to all other q values except the selected ions (i.e., q = 0.75).

[0093] The method of storing waveform by inverse Fourier transform (SWIFT) is used to generate the AC signal required for ion selection. First, the frequency distribution (frequency domain function) needs to be given, and then the signal in the time domain is generated through inverse Fourier transform. There will be a "blank" in the spectrum of the AC signal at the characteristic frequency of the target ion, indicating that the spectrum of the AC signal does not contain a frequency signal with the same frequency as the characteristic frequency of the target ion. The position of this "blank" is determined by the mass of the selected target ion, and the width can be controlled by an adjustable parameter, which is called the ion selection range and is in units of ion mass.

[0094] As an alternative embodiment, according to the mass-to-charge ratios of the target ions and impurity ions and the size of the ion trap, the target amplitude of the preset AC voltage is determined, including: determining the potential well depths of the target ions and impurity ions according to the mass-to-charge ratios and motion parameters of the target ions and impurity ions; determining the target amplitude of the preset AC voltage according to the potential well depths of the target ions and impurity ions, so that the preset AC voltage ejects the impurity ions and retains the target ions in the ion trap.

[0095] The above calculation methods related to the potential well depth are all existing in the related art.

[0096] As described above, according to the values of the motion parameters, combined with the size of the ion trap, and the mass-to-charge ratios of the target ions and impurity ions in the ion trap, the potential well depths of the target ions and impurity ions are determined. For impurity ions, it is hoped that the amplitude increases through resonance and then exceeds the corresponding potential well depth, so that they are ejected from the ion trap. For target ions, it is hoped that after the amplitude of the preset AC voltage is superimposed, it still does not exceed the corresponding potential well depth.

[0097] According to the amplitudes and potential well depths of the target ions and impurity ions, the target amplitude of the preset AC voltage is determined, so that the preset AC voltage ejects the impurity ions and retains the target ions in the ion trap. Thus, the preset AC voltage is used to screen and confine the target ions from the particle stream.

[0098] When determining the target amplitude of the preset AC voltage according to the potential well depths of the target ions and impurity ions, the kinetic energy of the target ions also needs to be considered. In some cases, the effect of multiple injections will be affected by the kinetic energy of the ions. This is because multiple injections generate ion collisions in the ion trap, or the charge effect caused by too many ions leads to a large kinetic energy of the target ions in the ion trap, making them more likely to be resonantly excited and ejected from the ion trap. Therefore, the amplitude of the applied AC voltage signal should be lower than that of the conventional single injection.

[0099] Specifically, when testing an etomidate pure solution using a mass spectrometer with a quadrupole linear ion trap, during the ion selection step by applying a preset AC voltage, the intensity of the AC voltage affects the results of the multiple injection method. The intensity of the AC voltage is equivalent to the amplitude of the above-mentioned preset AC voltage. Figure 9 It is a schematic diagram of the ion kinetic energy of the embodiment of the present invention creation on the effect of multiple injections. As Figure 9 shown, the lower label in the figure is the intensity of the etomidate fragment ion 141 under the conventional MS2 method. When the intensity of the AC voltage signal varies within the range of 4 - 11V, the response signal of the target ion does not change significantly.

[0100] The upper label is the result measured by the multiple injection method of this embodiment. When the intensity of the AC voltage signal is greater than 8V, the effect of eight injections is not particularly obvious, and the signal improvement compared to the conventional single injection is only about 3 times; when the intensity of the AC voltage signal is reduced to below 8V, it can be seen that the signal increases significantly, and the signal intensity of 8 injections is increased to about 6 times that of the conventional method.

[0101] During this process, the set value of RF during the ion selection step for single injection and multiple injections does not change, that is, the RF voltage is adjusted to move the q value of the etomidate ion to 0.75. At this time, the ion potential well is deeper, and it can be seen that the multiple injection method is more sensitive to the intensity of the AC voltage signal when applying the AC voltage signal for ion selection.

[0102] Because the depth of the ion potential well under the two methods does not change, the reason why a higher energy cannot be applied for multiple injections is that the kinetic energy of the target ion in the ion trap is larger due to the charge effect caused by the collision or excessive number of ions during multiple injections, making it easier to be resonantly excited and ejected out of the ion trap. Therefore, the amplitude of the applied AC voltage signal should be lower than the intensity of the conventional single injection.

[0103] As an optional embodiment, according to the amplitudes and potential well depths of the target ion and impurity ions, determining the target amplitude of the preset AC voltage includes: determining the amplitude range of the preset AC voltage that meets the first requirement according to the potential well depth of the impurity ions, where the first requirement is that based on the corresponding potential well depth of the impurity ions, the amplitude range of the preset AC voltage resonates with the impurity ions to eject the impurity ions out of the ion trap; screening the target amplitude that meets the second requirement from the amplitude range according to the potential well depth of the target ion, where the second requirement is that based on the potential well depth of the target ion, the effect of the target amplitude of the preset AC voltage on the target ion will not eject the target ion out of the ion trap; in the case where there is no amplitude that meets the second requirement in the amplitude range, taking the minimum amplitude in the amplitude range as the target amplitude.

[0104] When determining the target amplitude of the preset AC voltage based on the potential well depths of the target ions and impurity ions, an amplitude range that meets the first requirement is first determined based on the potential well depth of the impurity ions, so that the amplitude within the amplitude range can eject the impurity ions from the ion trap through resonance.

[0105] Then, using the potential well depth of the target ion, a target amplitude that meets the second requirement is selected from the amplitude range to prevent the target ion from ejecting from the ion trap. It should be noted that if there are multiple amplitudes within the amplitude range that can prevent the target ion from ejecting, the maximum amplitude that meets the requirement can be selected to improve the ejection effect of the impurity ion.

[0106] If there is no amplitude in the amplitude range that can avoid the ejection of the target ion, the minimum amplitude in the amplitude range can be selected to avoid the ejection of the target ion during the ion screening process as much as possible.

[0107] As an optional embodiment, the discontinuous atmospheric pressure interface of the mass spectrometer is opened, and before the ion flow of the target sample is injected into the ion trap of the mass spectrometer, the method also includes: determining the electric field strength of the ion trap for this injection based on the mass-to-charge ratio of the ions in the ion flow of the target sample, wherein the injection volume is determined based on the parameters of the ion source and the discontinuous atmospheric pressure interface of the mass spectrometer.

[0108] As mentioned above, the purpose of the initial injection is to confine the ion flow, while the purpose of the non-initial injection is to confine the ion flow while preventing the loss of the target ions previously confined in the ion trap. Therefore, before injecting the target sample ion flow into the ion trap of the mass spectrometer, it is necessary to determine an appropriate ion trap electric field strength, or terminal voltage, to ensure the ion trap electric field strength.

[0109] Before the sample is injected, the potential strength that can effectively confine multiple ions of the ion flow in the ion trap can be calculated based on the motion parameters.

[0110] Taking the quadrupole linear ion trap as an example, the trap's binding energy—the maximum energy of ions it can capture—is proportional to the Dehmelt potential D, which is a function of the motional parameter q and proportional to the square of the AC RF voltage V. The larger the absolute value of D, the greater the binding energy and the greater the trap's ability to capture ions.

[0111] The Delmelt potential, also known as the Pseudopotential Well, was proposed by Dehmelt and can be expressed by the following formula:

[0112]

[0113] Among them, z is the ionic charge number, e is the unit charge, V is the potential intensity of the radio frequency electric field, m is the ionic mass, Ω is the angular frequency of the ion trap electric field, r0 is the radius of the ion trap field, and q is one of the motion parameters.

[0114] In addition, the injection volume of the ion current of the target sample can be combined to calculate the force exerted by the ion trap electric field on the ion current, and then, based on the force and the mass-to-charge ratio of the ions, the electric field intensity of the ion trap for this injection can be calculated.

[0115] The injection volume of the ion current is determined according to the ion source of the mass spectrometer and the parameters of the discontinuous atmospheric pressure interface. For example, the injection volume of the ion current is determined by the ionization efficiency of the electrospray ionization source, and the ionization efficiency is related to parameters such as the polarity of the target sample and the magnitude of the spray high voltage applied to the target sample.

[0116] As an optional embodiment, determining the electric field intensity of the ion trap for this injection according to the mass-to-charge ratio of the ions in the ion current of the target sample includes: in the case where this injection is the first injection, determining the radio frequency electric field intensity according to the mass-to-charge ratio and the injection volume of the target ions, where the radio frequency electric field intensity corresponds to the motion parameter of the target ions within a preset parameter range; in the case where this injection is not the first injection, determining the radio frequency electric field intensity for this injection according to the radio frequency electric field intensity applied to the target ions after the previous injection, where the electric field intensity value for this injection is such that on the basis of ensuring that the target ions after the previous injection are confined in the ion trap, the ion beam for this injection is confined in the ion trap by the electric field intensity.

[0117] In the case where this injection is the first injection, there are no ions in the ion trap, and the radio frequency electric field intensity can be directly determined according to the mass-to-charge ratio of the target ions.

[0118] In the case where this injection is not the first injection, at this time, the target ions screened and retained from the previous injection have been confined in the ion trap. When injecting samples at this time, it is necessary to determine the radio frequency electric field intensity for this injection according to the radio frequency electric field intensity applied to the target ions after the previous injection. So that the electric field intensity value for this injection is such that on the basis of ensuring that the target ions after the previous injection are confined in the ion trap, the ion beam for this injection is confined in the ion trap by the electric field intensity.

[0119] It should be noted that the radio frequency alternating current signal is the RF value applied to the quadrupole rod, which determines whether the ions are in the stable region and their positions, and the motion parameter q value. When determining the radio frequency electric field intensity for non-first injections, the influence of ion kinetic energy can also be considered. When the kinetic energy of the target ions retained after the previous injection is large, or when the kinetic energy of the ions in the injected ion current is large, ion collisions will occur, resulting in losses of the screened and confined target ions.

[0120] Therefore, it is necessary to determine the radio frequency (RF) electric field intensity for the current injection based on the RF electric field intensity applied to the target ions after the previous injection. Generally, the RF electric field intensity for the current injection should be less than that of the previous injection.

[0121] As an alternative embodiment, before the number of target ions trapped in the ion trap fails to meet the target requirement, detecting whether the number of target ions in the ion trap meets the target requirement includes: determining the number / signal intensity of the target ions for a single injection based on the detection result of the target ions for a single injection under the same ion source parameter settings; determining whether multiple injections of the target ions are required and the number of injections based on the number / signal intensity of the target ions for a single injection; determining whether the number of target ions in the ion trap meets the requirement based on whether the number of the current injection reaches the number of injections; wherein, when the number of the current injection reaches the number of injections, it is determined that the number of target ions in the ion trap meets the requirement.

[0122] When determining the number of target ions, in order not to add new equipment to specifically detect the number of target ions, and since only a rough estimate of the number of target ions is required, without the need to determine the detailed number. In this embodiment, the signal intensity of the target ions for a single injection of the target sample can be determined through the detection result of a single injection, and the corresponding number or the number of injections can be evaluated to characterize the number of target ions trapped in the ion trap.

[0123] When detecting whether the number of target ions in the ion trap meets the target requirement, it is only necessary to determine whether the number of target ions in the ion trap meets the requirement based on whether the number of the current injection reaches the number of injections. Thus, it can be determined whether the number of target ions in the ion trap meets the target requirement.

[0124] Specifically, when the number of the current injection reaches the number of injections, it is determined that the number of target ions in the ion trap meets the requirement. Conversely, when the number of the current injection does not reach the number of injections, it is determined that the number of target ions in the ion trap does not meet the requirement.

[0125] When determining the number of injections, in order to improve the accuracy of determining the number of injections. The number / signal intensity of the target ions for a single injection is determined based on the detection result of the target ions for a single injection under the same ion source parameter settings.

[0126] The above-mentioned ion source parameters mainly include the spray voltage and the polarity of the target substance.

[0127] Using the same ion source parameters can improve the accuracy of the relationship between the number of injections and the number of target ions. Furthermore, based on the required number / signal intensity for target ion detection and the number / signal intensity for a single injection, the number of injections of the target ions is determined.

[0128] As an alternative embodiment, in the case where the ion trap performs multiple sample introduction and ion selection steps, before repeatedly opening the discontinuous atmospheric pressure interface of the mass spectrometer, the method further includes: controlling the vacuum system of the mass spectrometer to evacuate the vacuum chamber of the mass spectrometer; detecting the pressure of the vacuum chamber, wherein the pressure of the vacuum chamber will increase when the discontinuous atmospheric pressure interface is opened for sample introduction; after the pressure reaches the working pressure range and is maintained for a preset time, perform continuous target ion selection, and then open the discontinuous atmospheric pressure interface of the mass spectrometer.

[0129] Since the ion trap has high requirements for vacuum, each sample introduction ion current will carry a part of air, causing the pressure of the vacuum chamber to increase. Therefore, before repeated sample introduction, the vacuum system of the mass spectrometer can be controlled to perform evacuation operation, so that the vacuum environment for ion screening and confinement in the ion trap is always of high quality, thereby improving the accuracy and efficiency of target ion screening and confinement in the ion trap.

[0130] Specifically, before continuously opening the discontinuous atmospheric pressure interface of the mass spectrometer, the vacuum system of the mass spectrometer can be controlled to evacuate the vacuum chamber of the mass spectrometer. After the pressure reaches the working pressure range and is maintained for a preset time, perform the step of continuously opening the discontinuous atmospheric pressure interface of the mass spectrometer.

[0131] The reason for the pressure to reach the working pressure range and be maintained for a preset time is that only a small amount of air enters each time of sample introduction, and the actual pressure fluctuation of the vacuum chamber caused is not too large. In this way, the accuracy requirement for the detection device of the vacuum system is too high. Therefore, by limiting the pressure maintenance time, the accuracy of pressure detection can be improved, and the use of more precise pressure detection equipment can be avoided, reducing the cost of the mass spectrometer.

[0132] As an alternative embodiment, the ion trap is a quadrupole linear ion trap; it includes a front end cap electrode, a quadrupole, and a rear end cap electrode; opening the discontinuous atmospheric pressure interface of the mass spectrometer and introducing the ion current of the target sample into the ion trap of the mass spectrometer includes: adjusting the potential of the front end cap electrode to a target potential so that the electric field strength of the ion trap reaches the required electric field strength, and introducing the ion current of the target sample into the ion trap of the mass spectrometer.

[0133] The above ion trap is a quadrupole linear ion trap. During sample introduction, by adjusting the potential of the front end cap electrode, the electric field strength in the quadrupole linear ion trap can reach the requirement for confining the ion current. During subsequent repeated sample introduction, the electric field strength in the quadrupole linear ion trap can also be adjusted by the potential of the front end cap electrode.

[0134] As an optional embodiment, the discontinuous atmospheric pressure interface of the mass spectrometer is opened, and the ion flow of the target sample is injected into the ion trap of the mass spectrometer, including: in the case of the first injection, the potential of the front cover electrode of the ion trap is controlled to be lowered by a first preset threshold value, so that the ion flow coming from the discontinuous atmospheric pressure interface enters and moves stably in the ion trap; in the case of not the first injection, the potential of the front cover electrode of the ion trap is controlled to be lowered by a second preset threshold value, wherein the second preset threshold value is lower than the first preset threshold value; so that the ion flow of this non-first injection enters the ion trap and moves stably, and the target ions that have been bound in the ion trap before this non-first injection will not pop out and escape.

[0135] Due to the long length of the quadrupole linear ion trap, the electric field strength of the bound ion flow is fixed. If the electric field strength is too large, it may make it difficult for ions to enter the ion trap or restrict their movement in the ion trap.

[0136] Therefore, when this injection is the first injection, after calculating the electric field potential of the ion trap based on the size of the ion trap and relevant parameters of the atmospheric pressure interface, the potential of the front cover electrode of the ion trap is reduced to a first preset threshold value, so that the ion flow of the target sample entering from the discontinuous atmospheric pressure interface has sufficient kinetic energy to enter and stably move in the ion trap.

[0137] In addition, if the initial kinetic energy of the ions is too large, the target ions already in the ion trap may be knocked out of the ion trap.

[0138] When this injection is not the first injection, the potential of the front cover electrode of the ion trap needs to drop by a second preset threshold value during this injection to ensure that the ion flow of the target sample of this injection has sufficient kinetic energy to enter the ion trap. At the same time, the target ions that have been bound in the ion trap before this injection will not escape from the front cover electrode due to excessive kinetic energy.

[0139] The second preset threshold value for the potential drop of the front cover electrode during a non-first injection is different from the first preset threshold value for the potential drop of the front cover electrode during the first injection, and the second preset threshold value is lower than the first preset threshold value. Furthermore, as subsequent non-first injections are performed, the second preset threshold value for each non-first injection is lower than the second preset threshold value for the previous non-first injection, thereby ensuring that the target ions for each non-first injection can stably operate in the quadrupole ion trap.

[0140] It should be noted that this embodiment also provides an optional implementation method, which is described in detail below.

[0141] In the related art, the analysis process using an ion trap is a pulsed analysis process. A complete analysis process consists of sequential segments such as a sample injection stage, target ion screening, collision fragmentation, and scanning analysis. During the sample injection stage, there are no ions in the ion trap before the ions enter the ion trap. At this time, the ion trap electric field only needs to confine the target ions.

[0142] The multiple sample injection method of this embodiment realizes that in the case where there are already ions in the ion trap, by controlling the ion kinetic energy, the ions that have been stored in the trap can continue to open the atmospheric pressure interface for sample injection without being lost, enabling the ions in the subsequent sample injection process to enter and be stored in the ion trap, thereby achieving the purpose of increasing the number of target ions in the ion trap. To a certain extent, this embodiment can solve the above problems of the discontinuous atmospheric pressure interface and improve the instrument performance, mainly including improving the sensitivity and the duty cycle.

[0143] Figure 2 It is a schematic diagram of the detection process of the discontinuous sample injection mass spectrometer according to the embodiment of the present invention. As Figure 2 shown, according to the characteristics of the ion trap, this embodiment increases the number of target ions stored in the ion trap by repeating the sample injection and ion selection steps, and then performs the excitation fragmentation and fragment ion monitoring steps to complete the target ion analysis. That is, when the concentration of the target compound in the sample is low, by performing multiple sample injections and ion selection processes, the number of target ions stored in the ion trap is increased, and then one excitation fragmentation and detection are performed, which can significantly increase the signal intensity of the fragment ions, thereby improving the monitoring sensitivity of the instrument to a certain extent.

[0144] The core of this embodiment is to open the discontinuous atmospheric pressure interface to continue sample injection on the premise of minimizing the loss of the target ions stored in the ion trap after the previous sample injection and ion selection stage, so that the ions entering the ion trap in the subsequent injection can also be stored in the ion trap. Repeating this process can increase the number of target ions stored in the ion trap, and then performing subsequent mass analysis processes such as tandem mass spectrometry can significantly increase the response value of the detection signal.

[0145] The discontinuous single-trap mass spectrometer involved in this embodiment is a linear ion trap in-situ ionization mass spectrometer. Under normal analysis conditions, during the sample injection stage, the potential of the front end cap electrode near the atmospheric pressure interface decreases, and ions enter the ion trap; after the sample injection stage ends, the voltage of the front end cap electrode returns to the normal voltage, thereby confining the ions in the ion trap for subsequent analysis processes.

[0146] The key to the multiple injection method of this embodiment lies in that after completing the first injection and ion selection steps, the injection atmospheric pressure interface is repeatedly opened for injection subsequently. During this process, the potential of the front cover electrode needs to be maintained at an appropriate value so that the electric field strength of the ion trap is maintained at an appropriate value. It is necessary to ensure that the ions in the atmospheric pressure interface have sufficient kinetic energy to enter the ion trap, and at the same time, there is sufficient potential barrier in the axial direction of the ion trap to ensure that the ions previously stored in the ion trap will not escape.

[0147] Another key point of multiple injection is that the RF voltage value during the subsequent injection process should not only ensure that the newly introduced ions can be trapped in the quadrupole field, but also ensure that the RF electric field is in an appropriate range so that the potential well depth of the ions previously stored in the ion trap is relatively large and they can be stably trapped in the ion trap. Thus, it is not likely that the ions with a lower potential well depth will be blown out of the ion trap by the influence of the flow field during the opening of the atmospheric pressure interface. This method can achieve the storage of multiple ions in the ion trap, and then subsequent tandem mass spectrometry analysis can be carried out.

[0148] In addition, the ion selection step is to apply an AC voltage with a certain amplitude in the RF electric field at this stage, so that the impurity ions other than the target ions resonate with the AC signal and are ejected from the ion trap. Only the target ions are stored in the ion trap after this stage.

[0149] Since the mass differences of the target ions of the analyte are relatively large, for the low-mass analyte, for the discontinuous injection single ion trap mass spectrometer used in this embodiment, when the mass number (i.e., mass-to-charge ratio) of the target ions of the target analyte is lower than 300 amu, compared with the conventional single injection method, the amplitude of the AC voltage applied during the ion selection process after each injection stage in the multiple injection method needs to be maintained at a lower value.

[0150] Because the frequent collisions or charge effects caused by excessive ion numbers during the multiple injection process will affect their kinetic energy, resulting in a relatively large radial movement amplitude of the low-mass ions in the ion trap. A lower amplitude of the AC voltage can ensure that the ion selection voltage applied during the multiple injection process will not screen out the low-mass target ions with a large movement amplitude, thus ensuring the purpose of increasing the number of ions in the ion trap by multiple injections.

[0151] For the conventional single injection method, the AC voltage can be applied within a very wide amplitude range without affecting the signal intensity because the ion movement amplitude is relatively consistent during this process. In addition, the change in the amplitude of the AC voltage during the ion selection process of high-mass ions has no obvious influence on the signal intensity in the multiple injection method.

[0152] During the process of the multiple injection method of this embodiment, since the atmospheric pressure interface is frequently switched on and off, the air pressure in the vacuum chamber will experience multiple pulsed elevation processes, and each sudden increase in air pressure will affect the target ion selection process after the next injection. Therefore, during this process, it is necessary to control the air pressure value before and after each injection to remain within the normal working range of the ion trap.

[0153] Its implementation method mainly controls the air pressure after each injection within a relatively stable range by adjusting the time interval after the atmospheric pressure interface is closed, so as to realize the ion selection step after each injection. Subsequently, the atmospheric pressure interface is opened to repeat this process.

[0154] To further illustrate the technical effects of this embodiment, two test examples are also provided to illustrate the technical effects of this embodiment.

[0155] I. Taking the detection of voriconazole in blood samples as an example: First, prepare a voriconazole blood sample with a final concentration of 20 ppb. Subsequently, extract voriconazole from the blood sample with acetonitrile. The ion source uses in-situ ionization, and insert the PCS (PaperCapillary Spray) kit into a discontinuous injection single ion trap mass spectrometer for detection.

[0156] Figure 3 is a schematic diagram of the detection result of a single injection of voriconazole in a blood sample in the embodiment of the present invention. The voriconazole signal measured by the traditional tandem mass spectrometry method is as Figure 3 shown. The mass-to-charge ratios of 127 m / z, 224 m / z, and 281 m / z are all fragment ions of voriconazole.

[0157] The signal intensity corresponding to the ion of 127 m / z is about 0.55*10^5, the signal intensity corresponding to the ion of 224 m / z is about 0.7*10^5, and the signal intensity corresponding to the ion of 281 m / z is about 0.95*10^5.

[0158] Figure 4 is a schematic diagram of the detection result of multiple injections of voriconazole in a blood sample in the embodiment of the present invention. According to the method of this embodiment, the signal intensity of the tandem mass spectrometry spectrum obtained after 8 consecutive injections and ion selections is as Figure 4 shown. The signal intensity corresponding to the ion of 127 m / z is about 2.4*10^5, the signal intensity corresponding to the ion of 224 m / z is about 1.8*10^5, and the signal intensity corresponding to the ion of 281 m / z is about 6.6*10^5.

[0159] It can be clearly observed that the signal intensity of each ion increases by more than 3-5 times after 8 consecutive injections.

[0160] The corresponding relationship between the number of sample injections and the corresponding signal intensity was also statistically analyzed. Figure 5 is a schematic diagram of the correlation between the number of sample injections and the signal intensity when detecting voriconazole in the implementation mode of the present invention. As Figure 5 shown, the signal intensity at the injection number of 4 is approximately 4 times that at the injection number of 1. The signal intensity at the injection number of 8 is approximately 8 times that at the injection number of 1.

[0161] Second, the 2 ppb tacrolimus blood extraction solution was tested using a nanoelectrospray ionization nESI and a discontinuous injection single ion trap mass spectrometer.

[0162] Figure 6 is a schematic diagram of the single injection detection result of the tacrolimus sample in the implementation mode of the present invention. As Figure 6 shown, it is the spectral intensity under the process of injecting once by the traditional method, selecting ions once, and then performing excitation fragmentation and fragment ion detection.

[0163] Figure 6 In it, 620 m / z is the secondary mass spectrometry fragment ion of tacrolimus, and 621 m / z is the fragment ion of the internal standard tacrolimus. The signal intensity corresponding to the ion of 620 m / z is approximately 3.8×10^5, and the signal intensity corresponding to the ion of 621 m / z is approximately 7.6×10^5.

[0164] Figure 7 is a schematic diagram of the detection result of the tacrolimus sample in the implementation mode of the present invention. After continuously injecting 10 times using the method of this implementation mode and selecting ions 10 times, and then performing excitation fragmentation and fragment ion detection, the obtained ion signal intensity is as Figure 7 shown.

[0165] 620 m / z is the secondary mass spectrometry fragment ion of tacrolimus, and 621 m / z is the fragment ion of the internal standard tacrolimus. The signal intensity corresponding to the ion of 620 m / z is approximately 2.8×10^6, and the signal intensity corresponding to the ion of 621 m / z is approximately 5.2×10^6.

[0166] It can be clearly observed that the signal intensity of each ion increases by more than 6 - 9 times after continuously injecting 10 times.

[0167] Figure 8 is a schematic diagram of the correlation between the number of sample injections and the signal intensity when detecting the tacrolimus sample in the implementation mode of the present invention. As Figure 8 shown, the corresponding relationship between the number of different sample injections and the corresponding signal intensity was statistically analyzed. The signal intensity at the injection number of 4 is approximately 4 times that at the injection number of 1. The signal intensity at the injection number of 8 is approximately 8 times that at the injection number of 1.

[0168] In summary, this embodiment controls a mass spectrometer with a single ion trap for discontinuous sampling, enabling multiple samplings, which can greatly improve the detection sensitivity of the mass spectrometer with a single ion trap for discontinuous sampling.

[0169] Figure 10 It is a schematic diagram of a control device for a mass spectrometer with discontinuous sampling according to an embodiment of the present invention. As Figure 10 shown, to solve the problem that in the related art, when a portable mass spectrometer with a single ion trap for discontinuous sampling analyzes target ions, the final detected ion signal intensity difference is large and the sensitivity of the mass spectrometer is low. An embodiment of the present invention provides a control device for a mass spectrometer with discontinuous sampling, and the device includes: a sampling module 1001, a selection module 1002, a continuous module 1003, and a detection module 1004. The following is a detailed description of the device.

[0170] The sampling module 1001 is configured to open the discontinuous atmospheric pressure interface of the mass spectrometer and inject the ion current of the target sample into the ion trap of the mass spectrometer, where the ion current includes target ions; the selection module 1002 is connected to the above sampling module 1001 and is configured to select and confine the target ions in the ion current in the ion trap; the continuous module 1003 is connected to the above selection module 1002 and is configured to continue to open the discontinuous atmospheric pressure interface of the mass spectrometer and inject the target ions of the target sample into the ion trap of the mass spectrometer until the number of target ions reaches the target requirement when the number of target ions confined in the ion trap does not reach the target requirement; the detection module 1004 is connected to the above continuous module 1003 and is configured to fragment and detect the target ions when the number of target ions reaches the target requirement.

[0171] The conventional tandem mass spectrometry analysis process is as follows: open the discontinuous atmospheric pressure interface of the mass spectrometer and inject the ion current of the target sample into the ion trap of the mass spectrometer; screen out and confine the target ions in the ion current in the ion trap; then perform the fragmentation and analysis steps of the target ions. When the number of target ions is low, resulting in a low signal response value, the above control method for a mass spectrometer with multiple discontinuous samplings provided in this embodiment can enrich the target ions, thereby increasing the number of injected target ions, and thus improving the sensitivity of the instrument to a certain extent. It realizes the purpose of achieving multiple discontinuous samplings and improving the test accuracy and sensitivity of target ions by controlling the mass spectrometer with discontinuous sampling itself without relying on external hardware, and improves the detection performance of the discontinuous atmospheric pressure ion trap mass spectrometer to a certain extent.

[0172] According to one aspect of an embodiment of the present invention, there is also provided a mass spectrometer for discontinuous sample introduction, including: a processor and a memory storing a program, wherein the program includes instructions that, when executed by the processor, cause the processor to execute the above method.

[0173] Since the mass spectrometer operates according to the above control method, the mass spectrometer includes all the technical effects of the above method. Since the technical effects of the control method have been described in detail above, they will not be elaborated here.

[0174] An embodiment of the present invention also provides a non-transitory machine-readable medium storing a computer program, wherein the above computer program, when executed by a processor of a computer, is used to cause the computer to execute the method of the embodiment of the present invention.

[0175] An embodiment of the present invention also provides a computer program product, including a computer program, wherein the computer program, when executed by a processor of a computer, is used to cause the computer to execute the method of the embodiment of the present invention.

[0176] An embodiment of the present invention also provides an electronic device, including: at least one processor; and a memory communicatively connected to the at least one processor. The above memory stores a computer program that can be executed by the at least one processor, and the above computer program, when executed by the at least one processor, is used to cause the electronic device to execute the method of the embodiment of the present invention.

[0177] Reference Figure 11 , the block diagram of the structure of an electronic device that can be a server or a client as an embodiment of the present invention will now be described. It is an example of a hardware device that can be applied to various aspects of the present invention. The electronic device is intended to represent various forms of digital electronic computer devices, such as, a laptop computer, a desktop computer, a workbench, a personal digital assistant, a server, a blade server, a mainframe computer, and other suitable computers. The electronic device can also represent various forms of mobile devices, such as, a personal digital processor, a cellular phone, a smart phone, a wearable device, and other similar computing devices. The components shown herein, their connections and relationships, and their functions are only examples and are not intended to limit the implementation of the present invention described and / or claimed herein.

[0178] As Figure 11As shown, the electronic device includes a computing unit 1101, which can perform various appropriate actions and processes according to a computer program stored in a read-only memory (ROM) 1102 or a computer program loaded from a storage unit 1108 into a random access memory (RAM) 1103. In the RAM 1103, various programs and data required for the operation of the electronic device can also be stored. The computing unit 1101, the ROM 1102, and the RAM 1103 are connected to each other via a bus 1104. An input / output (I / O) interface 1105 is also connected to the bus 1104.

[0179] Multiple components in the electronic device are connected to the I / O interface 1105, including: an input unit 1106, an output unit 1107, a storage unit 1108, and a communication unit 1109. The input unit 1106 can be any type of device capable of inputting information into the electronic device. The input unit 1106 can receive input digital or character information and generate key signal inputs related to user settings and / or function controls of the electronic device. The output unit 1107 can be any type of device capable of presenting information and can include, but is not limited to, a display, a speaker, a video / audio output terminal, a vibrator, and / or a printer. The storage unit 1108 can include, but is not limited to, a magnetic disk, an optical disk. The communication unit 1109 allows the electronic device to exchange information / data with other devices via a computer network such as the Internet and / or various telecommunication networks and can include, but is not limited to, a modem, a network card, an infrared communication device, and / or a wireless communication transceiver, such as a Bluetooth device, a WiFi device, a WiMax device, a cellular communication device, and / or the like.

[0180] The computing unit 1101 can be various general-purpose and / or special-purpose processing components with processing and computing capabilities. Some examples of the computing unit 1101 include, but are not limited to, a CPU, a graphics processing unit (GPU), various dedicated artificial intelligence (AI) computing units, various computing units running machine learning model algorithms, a digital signal processor (DSP), and any appropriate processor, controller, microcontroller, etc. The computing unit 1101 executes the various methods and processes described above. For example, in some embodiments, the method embodiments of the present invention can be implemented as a computer program tangibly contained in a machine-readable medium, such as the storage unit 1108. In some embodiments, part or all of the computer program can be loaded and / or installed onto the electronic device via the ROM 1102 and / or the communication unit 1109. In some embodiments, the computing unit 1101 can be configured to execute the above methods in any other appropriate manner (e.g., by means of firmware).

[0181] The computer program for implementing the method of the embodiments of the present invention can be written in any combination of one or more programming languages. These computer programs can be provided to the processor or controller of a general-purpose computer, a special-purpose computer, or other programmable data processing devices, such that when executed by the processor or controller, the functions / operations specified in the flowchart and / or block diagram are implemented. The computer program can be executed entirely on the machine, partially on the machine, executed partially on the machine and partially on a remote machine as an independent software package, or executed entirely on a remote machine or server.

[0182] In the context of the embodiments of the present invention, a machine-readable medium can be a tangible medium that can contain or store a program for use by or in connection with an instruction execution system, apparatus, or device. A machine-readable medium can be a machine-readable signal medium or a machine-readable storage medium. A machine-readable signal medium can include, but is not limited to, an electronic, magnetic, optical, electromagnetic, or infrared system, apparatus, or device, or any suitable combination of the foregoing. More specific examples of a machine-readable storage medium would include an electrical connection based on one or more wires, a portable computer disk, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing.

[0183] It should be noted that the term "including" and its variations used in the embodiments of the present invention are open-ended, that is, "including but not limited to". The term "based on" is "at least partially based on". The term "one embodiment" means "at least one embodiment"; the term "another embodiment" means "at least one additional embodiment"; the term "some embodiments" means "at least some embodiments". The modifications of "one" and "a plurality" mentioned in the embodiments of the present invention are illustrative rather than restrictive. Those skilled in the art should understand that unless otherwise clearly specified in the context, it should be understood as "one or more".

[0184] The user information (including but not limited to user device information, user personal information, etc.) and data (including but not limited to data for analysis, stored data, displayed data, etc.) involved in the embodiments of the present invention are all information and data that have been authorized by the user or fully authorized by all parties. And the collection, use, and processing of relevant data need to comply with the relevant laws, regulations, and standards of relevant countries and regions, and corresponding operation entrances are provided for users to select to authorize or reject.

[0185] In the method embodiments provided by the embodiments of the present invention, the steps described may be executed in different orders and / or executed in parallel. In addition, the method embodiments may include additional steps and / or omit the steps shown. The protection scope of the present invention is not limited in this regard.

[0186] The term "embodiment" in this specification means that the specific features, structures or characteristics described in connection with the embodiments may be included in at least one embodiment of the present invention. The phrase appears in various positions in the specification and does not necessarily mean the same embodiment, nor does it mean being independent or alternative to other embodiments and mutually exclusive. The various embodiments in this specification are described in a related manner, and the same or similar parts between the embodiments are referred to each other. In particular, for device, equipment, and system embodiments, since they are basically similar to method embodiments, the description is relatively simple, and the relevant parts refer to the partial description of the method embodiments.

[0187] The above embodiments only represent several implementation manners of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as a limitation on the protection scope. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims

1. A control method for a mass spectrometer with discontinuous sample introduction, characterized in that, Comprising: Determine the electric field strength of the ion trap for the current injection according to the mass-to-charge ratio and injection volume of the ions in the ion current of the target sample, wherein the injection volume is determined according to the parameters of the ion source and the discontinuous atmospheric pressure interface of the mass spectrometer; In the case where the current injection is the first injection, determine the radio frequency electric field strength according to the mass-to-charge ratio and injection volume of the target ions, wherein the radio frequency electric field strength corresponds to the motion parameters of the target ions being within a preset parameter range; In the case where the current injection is not the first injection, determine the radio frequency electric field strength of the current injection according to the radio frequency electric field strength applied to the target ions after the previous injection, wherein the electric field strength value of the current injection is such that on the basis of ensuring that the target ions after the previous injection are confined in the ion trap, the ion beam of the current injection is confined in the ion trap by the electric field strength; Open the discontinuous atmospheric pressure interface of the mass spectrometer and inject the ion current of the target sample into the ion trap of the mass spectrometer, wherein the ion current includes target ions; Based on the radio frequency electric field of the ion trap, superimpose a preset alternating voltage on the ion trap to generate an alternating signal with a preset waveform; Use the alternating signal to resonantly eject the impurity ions in the ion trap and screen out the target ions to remain in the ion trap, wherein the impurity ions are the ions other than the target ions in the injected ion current; In the case where the number of target ions confined in the ion trap does not meet the target requirement, continue to open the discontinuous atmospheric pressure interface of the mass spectrometer, inject and confine the target ions of the target sample into the ion trap of the mass spectrometer until the requirement for increasing the target ions in the ion trap is met; In the case where the number of the target ions meets the target requirement, fragment and detect the target ions.

2. The method according to claim 1, wherein Before superimposing a preset alternating voltage on the ion trap based on the radio frequency electric field of the ion trap to generate an alternating signal, the method further includes: Determine the target amplitude of the preset alternating voltage according to the mass-to-charge ratio of the target ions and the impurity ions and the size of the ion trap; Determine the target spectrum of the preset alternating voltage according to the characteristic frequencies of the target ions and the impurity ions; Generate a preset alternating voltage with a corresponding waveform according to the target amplitude and the target spectrum.

3. The method according to claim 2, characterized in that, Determine the target amplitude of the preset alternating voltage according to the mass-to-charge ratio of the target ions and the impurity ions and the size of the ion trap, including: Determine the potential well depths of the target ions and the impurity ions according to the mass-to-charge ratios and motion parameters of the target ions and the impurity ions, wherein the motion parameters are the solutions of the motion equation of the ion trap; Determine the target amplitude of the preset alternating voltage according to the potential well depths of the target ions and the impurity ions so that the preset alternating voltage ejects the impurity ions and retains the target ions in the ion trap.

4. The method according to claim 3, wherein Determine the target amplitude of the preset alternating voltage according to the potential well depths of the target ions and the impurity ions, including: Determine the amplitude range of the preset AC voltage that meets the first requirement according to the potential well depth of the impurity ions, where the first requirement is to resonate the preset AC voltage with the impurity ions based on the corresponding potential well depth of the impurity ions and eject the impurity ions from the ion trap; Screen the target amplitude that meets the second requirement from the amplitude range according to the potential well depth of the target ions, where the second requirement is that the action of the target amplitude of the preset AC voltage on the target ions based on the potential well depth of the target ions will not eject the target ions from the ion trap; In the case where there is no amplitude that meets the second requirement in the amplitude range, use the minimum amplitude in the amplitude range as the target amplitude.

5. The method according to claim 1, characterized in that, Before the number of target ions trapped in the ion trap does not reach the target requirement, the method further includes: Determine the number / signal intensity of the target ions in a single injection according to the detection result of the target ions in a single injection under the same ion source parameters; Determine whether the target ions need multiple injections and the number of injections according to the number / signal intensity of the target ions in a single injection; Determine whether the number of target ions in the ion trap meets the requirement according to whether the number of current injections reaches the number of injections; Wherein, in the case where the number of current injections reaches the number of injections, it is determined that the number of target ions in the ion trap meets the requirement.

6. The method according to claim 1, wherein Before repeating to open the discontinuous atmospheric pressure interface of the mass spectrometer in the case where the ion trap performs multiple injections and ion selection steps, the method further includes: Control the vacuum system of the mass spectrometer to evacuate the vacuum chamber of the mass spectrometer; Detect the pressure of the vacuum chamber, where the pressure of the vacuum chamber will increase when the discontinuous atmospheric pressure interface is opened for injection; After the pressure reaches the working pressure range and maintains for a preset time, perform the step of continuing to select target ions, and then open the discontinuous atmospheric pressure interface of the mass spectrometer.

7. The method according to any one of claims 1 to 6, characterized in that, The ion trap is a quadrupole linear ion trap; it includes a front end cap electrode, a quadrupole rod, and a rear end cap electrode; Open the discontinuous atmospheric pressure interface of the mass spectrometer and inject the ion current of the target sample into the ion trap of the mass spectrometer, including: Adjust the potential of the front end cap electrode to the target potential to make the electric field strength of the ion trap reach the required electric field strength, and inject the ion current of the target sample into the ion trap of the mass spectrometer.

8. The method according to claim 7, characterized in that Before opening the discontinuous atmospheric pressure interface of the mass spectrometer and injecting the ion current of the target sample into the ion trap of the mass spectrometer, including: In the case of the first injection, control the potential of the front end cap electrode of the ion trap to decrease by a first preset threshold, so that the ion current entering from the discontinuous atmospheric pressure interface enters and stably moves in the ion trap; In the case of non-first injection, control the potential of the front end cap electrode of the ion trap to decrease by a second preset threshold value, where the second preset threshold value is lower than the first preset threshold value; so that the ion current of this non-first injection enters the ion trap and moves stably, and the target ions that have been trapped in the ion trap before this non-first injection will not pop out and escape.

9. A mass spectrometer with discontinuous sample introduction, comprising: A processor and a memory storing a program, characterized in that the program includes instructions that, when executed by the processor, cause the processor to execute the method according to any one of claims 1 to 8.

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