Discontinuous sample injection mass spectrometer control method and mass spectrometer

Abstract

The invention relates to the technical field of mass spectrometers, and particularly provides a control method of a discontinuous sampling mass spectrometer and a mass spectrograph, and the method comprises the steps: opening a discontinuous atmospheric pressure interface of the mass spectrometer, and sampling an ion flow of a target sample into an ion trap of the mass spectrometer; applying an alternating current signal of a preset waveform with a certain frequency range and amplitude, and screening out target ions in the ion current and constraining the target ions in an ion trap electric field; and under the condition that the number of the bound target ions in the ion trap does not meet the target requirement, continuing to open the discontinuous atmospheric pressure interface of the mass spectrometer, feeding the target ions of the target sample and binding the target ions into the ion trap of the mass spectrometer until the requirement of improving the target ions in the ion trap is met, and carrying out fragmentation and detection on the target ions. Therefore, the problems that the finally detected ion signal intensity is poor and the sensitivity of the mass spectrometer is relatively low when a portable discontinuous sample injection single ion trap mass spectrometer in the related technology is used for target ion analysis are solved.

Description

Technical Field

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

[0002] In the related technology, the mass spectrometer with discontinuous injection, that is, the mass spectrometer using the discontinuous atmospheric pressure interface to realize the atmospheric pressure ion source, is easy to carry and has a simple structure. The discontinuous atmospheric pressure interface technology was developed by the research group of Graham Cooks and Zheng Ouyang of 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 the opening and closing of the rubber tube is controlled by a mechanical valve.

[0003] 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, which will greatly shorten the time for the mass spectrometer using a discontinuous atmospheric pressure interface to open the mechanical valve to input sample ions into the mass spectrometer each time, resulting in too little ion source sampling input, affecting the mass spectrometer's response to the detection signal of the mass scanning analysis.

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

[0005] Currently, no effective solution has been proposed for the problem that when a portable non-continuous injection single ion trap mass spectrometer in the related art performs target ion analysis, the final detected ion signal intensity is poor and the sensitivity of the mass spectrometer is low. Summary of the invention

[0006] The present invention provides a control method and a mass spectrometer for a discontinuous injection mass spectrometer, which at least solve the problem in the related art that when a portable discontinuous injection mass spectrometer performs target ion analysis, the final detected ion signal intensity is poor and the sensitivity of the mass spectrometer is low.

[0007] According to one aspect of an embodiment of the present invention, a control method for a mass spectrometer with discontinuous injection is provided, comprising: opening a discontinuous atmospheric pressure interface of the mass spectrometer, injecting an ion flow of a target sample into an ion trap of the mass spectrometer, wherein the ion flow includes target ions; after screening the target ions in the ion flow, binding them in the ion trap; detecting whether the number of the target ions in the ion trap meets the target requirement; if the number of the target ions bound in the ion trap does not meet the target requirement, continuing to open the discontinuous atmospheric pressure interface of the mass spectrometer, injecting and binding the target ions of the target sample into the ion trap of the mass spectrometer until the requirement for increasing the number of target ions in the ion trap is met; if the number of the target ions meets the target requirement, fragmenting and detecting the target ions.

[0008] As an optional embodiment, after the target ions in the ion flow are screened, they are trapped in the ion trap, including: based on the radio frequency electric field of the ion trap, a preset AC voltage is superimposed on the ion trap to generate an AC signal with a preset waveform; and the impurity ions in the ion trap are resonantly ejected using the AC signal to screen out the target ions and retain them in the ion trap, wherein the impurity ions are ions other than the target ions in the injected ion flow.

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

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

[0011] As an optional embodiment, the target amplitude of the preset AC voltage is determined according to the potential well depths of the target ions and the impurity ions, including: determining the amplitude range of the preset AC voltage that meets the first requirement according to the potential well depth of the impurity ions, wherein the first requirement is based on the corresponding potential well depth of the impurity ions so that the amplitude range of the preset AC voltage resonates with the impurity ions and ejects the impurity ions from the ion trap; based on the potential well depth of the target ions, screening the target amplitude that meets the second requirement from the amplitude range, wherein the second requirement is based on the potential well depth of the target ions so that the target amplitude of the preset AC voltage will not eject the target ions from the ion trap when acting on the target ions; if there is no amplitude that meets the second requirement in the amplitude range, the minimum amplitude in the amplitude range is used as the target amplitude.

[0012] 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 further 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 and the injection amount, wherein the injection amount is determined based on the parameters of the ion source and the discontinuous atmospheric pressure interface of the mass spectrometer.

[0013] As an optional embodiment, the electric field strength of the ion trap for this injection is determined based on the mass-to-charge ratio of ions in the ion flow of the target sample, including: when this injection is the first injection, the radio frequency electric field strength is determined based on the mass-to-charge ratio and injection volume of the target ions, wherein the motion parameters of the target ions corresponding to the radio frequency electric field strength are within a preset parameter range; when this injection is not the first injection, the radio frequency electric field strength for this injection is determined based on the radio frequency electric field strength applied to the target ions after the last injection, wherein the electric field strength value for this injection is based on ensuring that the target ions after the last injection are bound in the ion trap, and the ion beam of this injection is bound in the ion trap by the electric field strength.

[0014] As an optional embodiment, 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 the target ions require multiple injections and the number of injections based on the ion number / signal intensity of the single injection of the target ions; determining whether the number of target ions in the ion trap meets the requirement based on whether the current number of injections reaches the number of injections; wherein, when the current number of injections reaches the number of injections, it is determined that the number of target ions in the ion trap meets the requirement.

[0015] As an optional embodiment, when the ion trap performs multiple injection and ion selection steps, before repeatedly opening the discontinuous atmospheric pressure interface of the mass spectrometer, the method also 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 injection; and after the pressure reaches the operating pressure range and is maintained for a preset time, continuing the target ion selection and then opening the discontinuous atmospheric pressure interface of the mass spectrometer.

[0016] As an optional embodiment, the ion trap is a quadrupole linear ion trap; it includes a front cover electrode, a quadrupole and a rear cover electrode; 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: by adjusting the potential of the front cover electrode to the target potential so that the electric field strength of the ion trap reaches the required electric field strength, the ion flow of the target sample is injected into the ion trap of the mass spectrometer.

[0017] 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, it includes: in the case of the first injection, controlling the potential of the front cover electrode of the ion trap 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, controlling the potential of the front cover electrode of the ion trap 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.

[0018] According to one aspect of an embodiment of the present invention, there is also provided a mass spectrometer with discontinuous injection, comprising: a processor, and a memory for storing a program, wherein the program comprises instructions, which, when executed by the processor, cause the processor to execute the above method.

[0019] The control method of the mass spectrometer with discontinuous injection provided by the present invention is to open the discontinuous atmospheric pressure interface of the mass spectrometer, inject the ion flow of the target sample into the ion trap of the mass spectrometer, screen out the target ions in the ion flow and bind them in the ion trap, and repeat the above process multiple times to achieve the purpose of increasing the number of target ions stored in the ion trap. The accumulated target ions are then fragmented and detected. Thereby, the number of injected target ions meets the requirements of test accuracy and sensitivity.

[0020] When the number of target ions bound in the ion trap does not 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, and multiple injections and ion selections are controlled to accumulate the number until the test accuracy and sensitivity requirements are met. This method achieves multiple discontinuous injections by controlling the mass spectrometer itself without relying on external hardware, and improves the test accuracy and sensitivity of the target ions. This method solves the problem of poor ion signal intensity and low sensitivity of the mass spectrometer in the portable single ion trap mass spectrometer with discontinuous injection when performing target ion analysis in the related art. BRIEF 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 briefly introduces the drawings required for use in the embodiments or the prior art descriptions. Obviously, the drawings described below are only some embodiments of the present invention, and for ordinary technicians in this field, other embodiments can be obtained based on these drawings without creative work.

[0022] Figure 1 The present invention is a flowchart of a method for controlling 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 the discontinuous injection mass spectrometer of the implementation mode created by 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 results 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 results of a single injection of a tacrolimus sample according to an embodiment of the present invention.

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

[0030] Fig. 9 It is a schematic diagram of the effect of ion kinetic energy on multiple injections in an embodiment of the present invention.

[0031] Fig.10 It is a schematic diagram of a control device for a mass spectrometer with discontinuous injection according to an embodiment of the present invention.

[0032] Fig.11 It is a structural schematic diagram of the electronic device created by the present invention. DETAILED DESCRIPTION

[0033] The embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although certain embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be construed as being limited to the embodiments described herein, which are instead provided to provide a more thorough and complete understanding of the present invention. It should be understood that the drawings and embodiments of the present invention are only for exemplary purposes and are not intended to limit the scope of protection of the present invention.

[0034] Among the related technologies, mass spectrometry is a highly specific analytical technology with high sensitivity and specificity. It analyzes the target ions screened by the mass analyzer; or uses tandem technology to dissociate the parent ions, and further analyzes the generated fragment ions to achieve qualitative and quantitative analysis of the compound structure. 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 the target ions, which may cause deviations in the qualitative and quantitative results, thereby affecting the use of the mass spectrometer in specific application fields.

[0035] Due to the high analytical sensitivity and specificity of mass spectrometry technology, mass spectrometers have become the most widely used chemical analysis instruments in the world, and miniaturization and portability are the future development direction of mass spectrometers. It analyzes the target ions screened by the mass analyzer; or uses tandem technology to dissociate the parent ions and further analyze the generated fragment ions to achieve qualitative and quantitative analysis of the compound structure. Among them, ion trap mass spectrometers are currently a hot research topic in the field of portable mass spectrometry because of their small size, 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 used in ion trap mass spectrometers equipped with continuous atmospheric pressure interfaces is large in size and has a complex hardware structure, which limits its portability to a certain extent.

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

[0038] Affected by the opening and closing of the rubber tube, the air pressure in the vacuum chamber will rise sharply every time the mechanical valve is opened. Usually, the pressure in the vacuum chamber before and after the valve is opened will increase by less than 0.1Pa-10Pa. When the rubber tube is opened, the ion sample under atmospheric pressure enters the ion trap in the vacuum chamber. Then, after the rubber tube is closed, the subsequent time sequence segment analysis of the ion trap is carried out when the air pressure in the vacuum chamber drops to a certain appropriate value, resulting in a relatively long analysis time of the ion trap mass spectrometer, which limits the stability and sensitivity of the instrument and limits the application range of the instrument.

[0039] Also limited by the problem of gas pressure changes, the time for opening the mechanical valve to input sample ions into the mass spectrometer each time a mass spectrometer using a discontinuous atmospheric pressure interface is greatly shortened, resulting in too little ion source sampling input, affecting the mass spectrometer's response to the detection signal of the mass scanning analysis.

[0040] Especially when the concentration of the target compound is low, the lower mass spectrometer response signal will affect the recognition and identification of the characteristic peaks of the target ions, which may cause deviations in the qualitative and quantitative results, thereby 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 usual two-stage tandem mass spectrometry working mode is as follows: the mass spectrometer will first inject the target ion, then select the ion, then excite and fragment it, and detect the fragment ions to complete the target ion analysis.

[0042] Currently, a variety of technologies have been developed to improve sensitivity by accumulating analyte ions. By developing ion accumulation technology, the number of captured effective ions is increased, thereby improving the sensitivity of low-content material detection. However, this technology is currently mainly implemented on dual 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 injection to realize the ion enrichment function of the single ion trap.

[0044] Figure 1 Flow chart of a method for controlling a mass spectrometer with discontinuous injection according to an embodiment of the present invention, Figure 1As shown, in order to solve the problem that the final detected ion signal intensity is poor and the mass spectrometer has low sensitivity when performing target ion analysis in a portable single ion trap mass spectrometer with non-continuous injection in the related art, the embodiment of the present invention provides a control method for a mass spectrometer with non-continuous injection, the method comprising:

[0045] Step S101, opening the discontinuous atmospheric pressure interface of the mass spectrometer, injecting the ion flow of the target sample into the ion trap of the mass spectrometer, wherein the ion flow includes the target ions;

[0046] Step S102, after screening the target ions in the ion flow, they are bound in an ion trap;

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

[0048] Step S104: when the number of target ions reaches the target requirement, the target ions are fragmented and detected.

[0049] The control method of the mass spectrometer with the above-mentioned discontinuous injection provided in this embodiment opens the discontinuous atmospheric pressure interface of the mass spectrometer, injects the ion flow of the target sample into the ion trap of the mass spectrometer, binds the target ions in the ion flow in the ion trap, and repeats the above-mentioned injection and ion selection steps multiple times. After the target ions in the ion trap accumulate to a certain number, the target ions are fragmented and detected. Thereby, the number of injected target ions meets the requirements for improving the test accuracy and sensitivity.

[0050] When the number of target ions bound in the ion trap is low, the discontinuous atmospheric pressure interface of the mass spectrometer is opened multiple times to inject the target ions of the target sample and filter and bind them into the ion trap of the mass spectrometer until the number of target ions meets the detection requirements. This control method controls the number of injections when the number of target ions is insufficient to accumulate the number until the test accuracy and sensitivity requirements are met. This method achieves multiple discontinuous injections by controlling the mass spectrometer itself for discontinuous injection without relying on external hardware, and improves the test accuracy and sensitivity of the target ions.

[0051] The execution subject of the above steps can be a controller or a host computer of a mass spectrometer with discontinuous injection, or a controller of a mass spectrometer with discontinuous injection. The controller or the host computer can collect the working parameters of the mass spectrometer and control various parts.

[0052] The above-mentioned discontinuous injection mass spectrometer is also a mass spectrometer with a discontinuous atmospheric pressure interface. It should be noted that such mass spectrometers are generally portable, and the smaller the size, the better for easy carrying. Therefore, general discontinuous injection mass spectrometers are single ion trap mass spectrometers. The single ion trap it has is also the above-mentioned target ion trap.

[0053] When multiple injections are achieved through a single ion trap mass spectrometer with discontinuous injection, the relevant technology of multiple injections is similar to the conventional single injection and ion screening method, except that there are differences in the specific control strategy.

[0054] When injecting samples for the first time, the discontinuous atmospheric pressure interface of the mass spectrometer is opened first, and the ion flow of the target sample is injected into the ion trap of the mass spectrometer. The ion flow is generated by in-situ ionization of the target sample with high pressure, and the ion flow includes target ions and impurity ions.

[0055] 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. Then, the discontinuous atmospheric pressure interface is closed, and the gas pressure of the vacuum chamber is adjusted to a suitable level for ion selection through time control. The target ions in the ion flow are then screened out and confined in the electric field of the ion trap.

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

[0057] When the sample is injected later but not for the first time, the voltage applied to each electrode of the ion trap needs to be adjusted while the discontinuous atmospheric pressure interface is opened for injection, so that the electrode potential of the ion trap is maintained at a target value. This target value ensures that the target ions bound in the ion trap after the previous injection process are not lost, and also ensures that the ion beam can be bound in the ion trap during the injection process of opening the discontinuous atmospheric pressure interface this time.

[0058] The higher the speed of the ion flow, the greater the kinetic energy of the ions. When the target ions in the ion flow are trapped in the ion trap, the greater the electric field strength required, that is, the greater the voltage amplitude applied to the ion trap. When injecting the sample for the first time, in theory, it is only necessary to ensure that the ion flow can be effectively trapped in the ion trap.

[0059] It should be noted that when the sample is not injected for the first time, it is necessary not only to consider whether the ion flow can be effectively bound in the ion trap, but also to try to avoid the loss of ions already in the ion trap, and to avoid the target ions already bound and accumulated in the ion trap from being knocked out of the ion trap by the newly injected gas flow and ion beam. This requires controlling the electric field strength or applied voltage of the ion trap for non-first injection, and the specific method will be explained later.

[0060] After the number of target ions accumulates to a certain number, 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 for fragmenting and detecting the target ions in this embodiment can be an ion detector in the prior art. For example, an electron multiplier (EM), a Faraday cup (FC), a photomultiplier electrode, an array detector, etc.

[0061] The target ions can be detected by the ion detector, and the amplified ion signals can be output to form a mass spectrum. Or the required statistical graphs can be generated according to other parameters. Figure 2 and Figure 3 All are mass spectra. Figure 4 This 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 injected target ions and thus improving the test accuracy and sensitivity can be achieved. The problem of poor ion signal intensity and low sensitivity of the mass spectrometer in the portable non-continuous injection single ion trap mass spectrometer in the related art when performing target ion analysis is solved.

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

[0064] As an optional embodiment, after the target ions in the ion flow are screened, they are confined in an ion trap, including: based on the radio frequency electric field of the ion trap, a preset AC voltage is superimposed on the ion trap to generate an AC signal with a preset waveform; and the impurity ions in the ion trap are resonantly ejected using the AC signal to screen out the target ions and retain them in the ion trap, wherein the impurity ions are ions other than the target ions in the injected ion flow.

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

[0066] When the ion trap is subjected to radio frequency voltage, the difference in mass and charge between the impurity ions and the target ions results in different characteristic frequencies of the impurity ions and the target ions in the ion trap. By utilizing the different frequencies of the impurity ions and the target ions, resonance can be generated with the impurity ions by applying a spectrum AC voltage signal containing the characteristic frequencies of the impurity ions but not the characteristic frequencies of the target ions, thereby ejecting all the impurity ions from the ion trap through resonance and retaining the target ions.

[0067] Specifically, a preset AC voltage can be superimposed on the ion trap based on the radio frequency electric field of the ion trap to generate an AC signal, and then the AC signal is used to resonate and eject the impurity ions in the ion trap to screen out the target ions and retain them in the ion trap.

[0068] It should be noted that the AC voltage will also have an effect on the target ions, but it will not produce resonance, but it will still cause 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. In other words, the effect of the AC voltage on the target ions is not enough to eject the target ions from the ion trap. This requires that the amplitude of the AC voltage signal is also appropriately set.

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

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

[0071] The setting of amplitude needs to consider the kinetic energy of the target ions and impurity ions, the potential well depth, and the size of the ion trap. This ensures that under the action of the preset AC voltage, the impurity ions resonate, their amplitude increases exponentially, and the vibration amplitude can exceed the ion trap, thereby ejecting them. The amplitude of the target ions will not exceed the confinement range of the ion trap under the action of non-resonance, thereby screening the target ions and confining them in the ion trap.

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

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

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

[0075] This embodiment takes a quadrupole linear ion trap mass analyzer as an example to illustrate the principle of AC voltage signal and ion screening. The quadrupole includes two sets of pairs of rods, the pairs of rods are applied with the same voltage, and the pairs of rods are applied with opposite voltage. The motion form of charged ions in the quadrupole electric field can be expressed in the form of Matthew's equation. Solving the Matthew's equation can obtain the motion parameter a u and q u .

[0076]

[0077]

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

[0079] The quadrupole is at (a u ,q u ) coordinate system is constant and has nothing to do with the values ​​of the quadrupole voltage U, V and the ion mass number m / z. Generally speaking, the quadrupole operating frequency Ω and the ion trap field radius r0 are constant, so when the voltage U, V and the ion mass number m / z are given, the corresponding a and q can be calculated through the formula and, thus, the stability of the ion under given conditions can be determined.

[0080] In this embodiment, when the linear ion trap uses a quadrupole as a mass analyzer, the quadrupole operates in RF-only mode, that is, only an AC RF voltage V is applied, and the DC voltage U = 0, so the motion parameter a = 0. 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 radio frequency RF voltage, the q value of an ion with a mass number of m can be calculated according to the qu formula to determine whether it is in the stable region.

[0082] Similarly, for an ion with a mass number m, its q value can be changed by changing the AC radio frequency RF voltage V, thereby allowing the ion to enter or leave the stable region, or adjusting its position in the stable region.

[0083] From this, it can be seen 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 captured by the trap, that is, it pops out of the ion trap.

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

[0085] In order to solve the frequency of the ion motion trajectory, the Matthew equation is solved and the frequency calculation formula is as follows:

[0086]

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

[0088] In the stable region of mass spectrometry, β u It is related to the motion parameters a and q. Specifically, as a increases, β u Gradually increases, with the increase of qβ u It will also gradually increase.

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

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

[0091] Ion selection is the process of "sweeping" irrelevant ions out of the ion trap and leaving only the ions of interest in the trap. It is an important ion operation for MSn. Ion selection also uses the principle of resonant excitation, but it applies AC signals to the unselected target ions to give them extra kinetic energy and allow them to leave the ion trap.

[0092] In order to select the ions that need to be retained, the RF voltage can be adjusted first to move the ion's q value to 0.75, which is called iso_q, that is, a deeper potential well depth. When q=0.75, the ion's potential well is deeper (subsequent Delmelt potential theory), and it is also farther away from the unstable region, and it is more stable in the well. Next, an AC signal with a variable frequency is applied, and the frequency must include the frequency ω=βΩ / 2 corresponding to all other q values ​​except the selected ion (i.e. q=0.75).

[0093] The inverse Fourier transform stored waveform (SWIFT) method is used to generate the AC signal required for ion selection. The frequency distribution (frequency domain function) must be given first, and then the signal in the time domain is generated by inverse Fourier transform. The spectrum of the AC signal will have a "blank" 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 characteristic frequency as 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, called the ion selection range, which is measured in ion mass.

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

[0095] The above-mentioned calculation methods related to the potential well depth are all existing in the relevant technology.

[0096] As described above, the potential well depths of the target ions and impurity ions are determined based on the values ​​of the motion parameters, the size of the ion trap, and the mass-to-charge ratio of the target ions and impurity ions in the ion trap. For the impurity ions, it is hoped that the amplitude will be increased through resonance to exceed the corresponding potential well depth, so that they will be ejected from the ion trap. For the target ions, it is hoped that after the amplitude of the preset AC voltage is superimposed, the corresponding potential well depth will still not be exceeded.

[0097] According to the amplitude and potential well depth 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 flow.

[0098] When determining the target amplitude of the preset AC voltage based on the potential well depth of the target ions and impurity ions, the kinetic energy of the target ions must also 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 produce ion collisions in the ion trap, or the charge effect caused by the excessive number of ions causes the target ions to have a larger kinetic energy in the ion trap, making them more easily ejected from the ion trap by resonance excitation. Therefore, the amplitude of the applied AC voltage signal must be lower than the intensity of a conventional single injection.

[0099] Specifically, when a pure solution of etomidate is tested using a mass spectrometer with a quadrupole linear ion trap, a preset AC voltage is applied to implement the ion selection step. The AC voltage intensity has an impact on the results of the multiple injection method. The AC voltage intensity is equivalent to the amplitude of the above preset AC voltage. Fig. 9 Schematic diagram of the effect of ion kinetic energy on multiple injections in an embodiment of the present invention. Fig. 9 As shown, the label at the bottom of the figure is the intensity of the etomidate fragment ion 141 under the conventional MS2 method. When the intensity of the AC voltage signal changes in the range of 4-11V, the target ion response signal does not change significantly.

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

[0101] In this process, the RF setting value did not change during the ion selection step for single injection and multiple injections, that is, the RF voltage was adjusted to move the q value of the etomidate ion to 0.75, at which time the ion potential well was deeper. When an AC voltage signal was applied for ion selection, it can be seen that the multiple injection method was more sensitive to the intensity of the AC voltage signal.

[0102] Because the depth of the ion potential well does not change under the two methods, the reason why multiple injections cannot apply higher energy is that the collisions of multiple injections or the charge effect caused by the excessive number of ions cause the target ions to have a larger kinetic energy in the ion trap and are more easily ejected from the ion trap by resonance excitation. Therefore, the amplitude of the applied AC voltage signal is lower than the intensity of a conventional single injection.

[0103] As an optional embodiment, the target amplitude of the preset AC voltage is determined according to the amplitude and potential well depth of the target ions and impurity ions, including: determining the amplitude range of the preset AC voltage that meets the first requirement according to the potential well depth of the impurity ions, wherein the first requirement is based on the corresponding potential well depth of the impurity ions so that the amplitude range of the preset AC voltage resonates with the impurity ions and ejects the impurity ions out of the ion trap; based on the potential well depth of the target ions, screening the target amplitude that meets the second requirement from the amplitude range, wherein the second requirement is based on the potential well depth of the target ions so that the target amplitude of the preset AC voltage will not eject the target ions out of the ion trap when it acts on the target ions; if there is no amplitude that meets the second requirement in the amplitude range, the minimum amplitude in the amplitude range is used as the target amplitude.

[0104] When determining the target amplitude of the preset AC voltage according to the potential well depths of the target ions and the impurity ions, an amplitude range that meets the first requirement is first determined according to 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, the potential well depth of the target ion is used to select a target amplitude that meets the second requirement from the amplitude range to prevent the target ion from being ejected from the ion trap. It should be noted that if there are multiple amplitudes in the amplitude range that can prevent the target ion from being ejected, the maximum amplitude that meets the requirement can be selected to improve the ejection effect of the impurity ions.

[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 amount 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 first injection is to constrain the ion flow, and the purpose of the non-first injection is to constrain the ion flow while preventing the loss of the target ions previously bound in the ion trap. Therefore, before injecting the ion flow of the target sample into the ion trap of the mass spectrometer, it is necessary to determine a suitable electric field strength of the ion trap, or terminal voltage, to ensure the electric field strength of the ion trap.

[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] Still taking the quadrupole linear ion trap as an example, the binding energy of the ion trap, that is, the maximum ion energy that the ion trap can capture, is proportional to the Dehmelt potential D, which is a function of the motion parameter q and is proportional to the square V2 of the AC RF voltage V. The larger the absolute value of D, the greater the binding energy and the greater its ability to capture ions.

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

[0112]

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

[0114] In addition, the force exerted by the ion trap electric field on the ion flow can be calculated in combination with the injection volume of the target sample ion flow, and then the electric field strength of the ion trap for this injection can be calculated based on the force and the mass-to-charge ratio of the ions.

[0115] The injection volume of the ion flow is determined based on the ion source and discontinuous atmospheric pressure interface parameters of the mass spectrometer. For example, the injection volume of the ion flow 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 size of the spray high pressure applied to the target sample.

[0116] As an optional embodiment, the electric field strength of the ion trap for this injection is determined based on the mass-to-charge ratio of ions in the ion flow of the target sample, including: when this injection is the first injection, the radio frequency electric field strength is determined based on 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; when this injection is not the first injection, the radio frequency electric field strength for this injection is determined based on the radio frequency electric field strength applied to the target ions after the last injection, wherein the electric field strength value for this injection is based on ensuring that the target ions after the last injection are bound in the ion trap, and the ion beam of this injection is bound in the ion trap by the electric field strength.

[0117] When this is the first injection, there are no ions in the ion trap, and the radio frequency electric field strength can be determined directly based on the mass-to-charge ratio of the target ions.

[0118] In the case that this injection is not the first injection, the target ions left by the previous injection screening have been bound in the ion trap. When injecting, the RF electric field strength of this injection needs to be determined based on the RF electric field strength applied to the target ions after the previous injection. The electric field strength value of this injection is such that the ion beam of this injection is bound in the ion trap by the electric field strength on the basis of ensuring that the target ions after the previous injection are bound in the ion trap.

[0119] It should be noted that the radio frequency AC signal is the RF value applied to the quadrupole, which determines whether the ion is in the stable region and its position, and the motion parameter q value. When determining the radio frequency electric field strength for non-first injection, the influence of ion kinetic energy can also be considered. When the kinetic energy of the target ion that is first injected and retained is large, or when the kinetic energy of the ion flow of the injection is large, ion collisions will occur, causing losses to the target ions that have been screened and bound.

[0120] Therefore, the RF electric field strength of this injection needs to be determined based on the RF electric field strength applied to the target ions after the previous injection. Usually, the RF electric field strength of this injection is smaller than the RF electric field strength of the previous injection.

[0121] As an optional embodiment, before the number of target ions bound in the ion trap does not reach the target requirement, detecting whether the number of target ions in the ion trap reaches the target requirement, including: determining the number / signal intensity of 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 the target ions require multiple injections and the number of injections based on the number of ions / signal intensity of the single injection of the target ions; determining whether the number of target ions in the ion trap reaches the requirement based on whether the current number of injections reaches the injection number; wherein, when the current number of injections reaches the injection number, determining that the number of target ions in the ion trap reaches 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 the number of target ions only needs to be roughly estimated, it is not necessary to determine the detailed number. In this embodiment, the signal intensity of the target ions of 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 bound in the ion trap.

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

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

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

[0126] The above ion source parameters mainly include spray voltage and target material polarity.

[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. The number of injections of the target ions can then be determined based on the number / signal intensity required for target ion detection and the number / signal intensity of a single injection.

[0128] As an optional embodiment, when the ion trap performs multiple injections and ion selection steps, before repeatedly opening the discontinuous atmospheric pressure interface of the mass spectrometer, the method also 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 injection; and after the pressure reaches the operating pressure range and is maintained for a preset time, continuing the target ion selection and then opening the discontinuous atmospheric pressure interface of the mass spectrometer.

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

[0130] Specifically, before continuing to open 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, the step of continuing to open the discontinuous atmospheric pressure interface of the mass spectrometer is performed.

[0131] The reason why the pressure reaches the working pressure range and maintains the preset time is that only a small amount of air will enter each time the sample is injected, and the actual pressure fluctuation in the vacuum chamber will not be too large. This places too high a precision requirement on the detection device of the vacuum system. Therefore, by limiting the pressure maintenance time, the accuracy of pressure detection can be improved, and the use of more accurate pressure detection equipment can be avoided, reducing the cost of the mass spectrometer.

[0132] As an optional embodiment, the ion trap is a quadrupole linear ion trap; it includes a front cover electrode, a quadrupole and a rear cover electrode; 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: by adjusting the potential of the front cover electrode to the target potential so that the electric field strength of the ion trap reaches the required electric field strength, the ion flow of the target sample is injected into the ion trap of the mass spectrometer.

[0133] The above ion trap is a quadrupole linear ion trap, and the electric field strength in the quadrupole linear ion trap is achieved by adjusting the potential of the front cover electrode during sample injection to meet the requirements of the bound ion flow. In the subsequent repeated sample injection process, the electric field strength in the quadrupole linear ion trap can also be adjusted by the potential of the front cover 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 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] Since the quadrupole linear ion trap is relatively long, 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 the injection is the first injection, after the electric field potential of the ion trap is calculated according to the size of the ion trap and the relevant parameters of the atmospheric pressure interface, the potential of the front cover electrode of the ion trap is reduced by a first preset threshold value, so that the ion flow of the target sample coming from the discontinuous atmospheric pressure interface has enough kinetic energy to enter and stably move in the ion trap.

[0137] In addition, when 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 to ensure that the ion flow of the target sample injected this time has sufficient kinetic energy to enter the ion trap, and 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 of the front end cover electrode potential drop during non-first injection is different from the first preset threshold value of the front end cover electrode potential drop during first injection, and the second preset threshold value is lower than the first preset threshold value. Moreover, as subsequent non-first injections are performed, the second preset threshold value of each non-first injection is lower than the second preset threshold value of the previous non-first injection, so that the target ions of each non-first injection can be stably operated in the quadrupole ion trap.

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

[0141] In the related technology, the analysis process using ion traps is a pulse analysis process. A complete analysis process consists of injection phase, target ion screening, collision fragmentation and scanning analysis and other time sequence segments. In the injection phase, 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 bind the target ions.

[0142] The multiple injection method of this embodiment realizes that when there are ions already in the ion trap, by controlling the kinetic energy of the ions, the ions already stored in the trap are not lost while continuing to open the atmospheric pressure interface for injection, so that the ions in the subsequent injection process can enter and be stored in the ion trap, thereby achieving the purpose of increasing the number of target ions in the ion trap. This embodiment can solve the above-mentioned problems of the discontinuous atmospheric pressure interface to a certain extent and improve the performance of the instrument, mainly including improving the sensitivity and increasing the duty cycle.

[0143] Figure 2 It is a schematic diagram of the detection process of the mass spectrometer with discontinuous injection according to the embodiment of the present invention, such as Figure 2 As 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 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, the signal intensity of the fragment ions can be significantly improved by increasing the number of target ions stored in the ion trap through multiple injections and ion selection processes, and then performing one excitation fragmentation and detection, thereby improving the monitoring sensitivity of the instrument to a certain extent.

[0144] The core of this implementation is to open the discontinuous atmospheric pressure interface to continue injection while keeping the target ions stored in the ion trap after the previous injection and ion selection stage as little as possible, so that the ions entering the ion trap for the next time can also be stored in the ion trap. Repeating this process can increase the number of target ions stored in the ion trap, and subsequent mass analysis processes such as tandem mass spectrometry can significantly improve 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 the conventional analysis process, during the injection stage, the potential of the front cover electrode close to the atmospheric pressure interface is reduced, and the ions enter the ion trap; after the injection stage, the voltage of the front cover electrode returns to normal voltage, thereby trapping the ions in the ion trap for subsequent analysis.

[0146] The key to the multiple injection method of this embodiment is that after completing the first injection and ion selection steps, the injection atmospheric pressure interface is opened repeatedly for injection. During this process, the potential of the front cover electrode must 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 a 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 injections is that the RF voltage value in the subsequent injection process must ensure that the newly incoming ions can be bound in the quadrupole field, and that the RF electric field is in an appropriate range so that the ions previously stored in the ion trap have a larger potential well depth and can be stably trapped in the ion trap. This will prevent the ions from being blown out of the ion trap due to the influence of the flow field due to their lower potential well depth during the opening of the atmospheric pressure interface. This method can store multiple ions in the ion trap and then perform subsequent tandem mass spectrometry analysis.

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

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

[0150] Frequent collisions during multiple injections or the charge effect caused by excessive ion numbers will affect their kinetic energy, resulting in a larger radial motion amplitude of low-mass ions in the ion trap. A lower AC voltage amplitude can ensure that the ion selection voltage applied during multiple injections will not screen out low-mass target ions with a larger motion amplitude, thereby achieving the purpose of increasing the number of ions in the ion trap through multiple injections.

[0151] The conventional single injection method can apply AC voltage in a wide range of amplitudes without affecting the signal intensity because the ion movement amplitude in this process is relatively consistent. In addition, the change of AC voltage amplitude during high mass ion selection does not significantly affect the signal intensity in the multiple injection method.

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

[0153] The main implementation method is to adjust the time interval after the atmospheric pressure interface is closed, so that the pressure after each injection is controlled within a relatively stable range, so that the ion selection step after each injection can be achieved. Then the atmospheric pressure interface is opened and the process is repeated.

[0154] In order to further illustrate the technical effect of this embodiment, two test examples are provided to illustrate the technical effect of this embodiment.

[0155] 1. Take the detection of voriconazole in blood samples as an example: first prepare a voriconazole blood sample with a final concentration of 200 ppb, then use acetonitrile to extract the voriconazole in the blood sample, use in situ ionization as the ion source, and insert the PCS (Paper Capillary Spray) kit into a single ion trap mass spectrometer with discontinuous injection for detection.

[0156] Figure 3 Schematic diagram of the detection result of a single injection of voriconazole in a blood sample according to an embodiment of the present invention, wherein the voriconazole signal measured by the traditional secondary tandem mass spectrometry method is as follows: Figure 3 As shown, the mass-to-charge ratio is 127 m / z, and both 224 m / z and 281 m / z are 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 FIG. 1 is a schematic diagram of the results of multiple injections of voriconazole in a blood sample according to an embodiment of the present invention. According to the method of this embodiment, the signal intensity of the secondary mass spectrometer obtained after 8 consecutive injections and ion selections is as follows: Figure 4 As 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] For this purpose, the corresponding relationship between different injection times and corresponding signal intensities was statistically analyzed. Figure 5 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, such as Figure 5 As shown, the signal intensity of the injection number 4 is about 4 times that of the injection number 1. The signal intensity of the injection number 8 is about 8 times that of the injection number 1.

[0161] 2. The 2 ppb tacrolimus blood extract solution was tested using nanoelectrospray ionization (nESI) and a single ion trap mass spectrometer with discontinuous injection.

[0162] Figure 6 Schematic diagram of the detection result of a single injection of a tacrolimus sample according to an embodiment of the present invention, Figure 6 As shown, it is the spectrum intensity under the traditional method of injecting once, selecting ions once, and then performing excitation fragmentation and fragment ion detection.

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

[0164] Figure 7 Schematic diagram of the results of multiple injections of tacrolimus samples according to the embodiment of the present invention. The ion signal intensity obtained after 10 consecutive injections and 10 ion selections and then excitation fragmentation and fragment ion detection is shown in FIG. Figure 7 shown.

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

[0167] Figure 8 is a schematic diagram of the correlation between the number of injections and the signal intensity when detecting a tacrolimus sample according to an embodiment of the present invention, such as Figure 8 As shown, the corresponding relationship between different injection times and corresponding signal intensities is statistically analyzed. The signal intensity of 4 injection times is about 4 times that of 1 injection times. The signal intensity of 8 injection times is about 8 times that of 1 injection times.

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

[0169] Fig.10 Schematic diagram of a control device for a mass spectrometer with discontinuous injection according to an embodiment of the present invention, Fig.10 As shown, in order to solve the problem that the final detected ion signal intensity is poor and the mass spectrometer has low sensitivity when performing target ion analysis in a portable single ion trap mass spectrometer with non-continuous injection in the related art, the embodiment created by the present invention provides a control device for a mass spectrometer with non-continuous injection, the device comprising: an injection module 1001, a selection module 1002, a continuous module 1003, and a detection module 1004. The device is described in detail below.

[0170] The injection module 1001 is used to open the discontinuous atmospheric pressure interface of the mass spectrometer and inject the ion flow of the target sample into the ion trap of the mass spectrometer, wherein the ion flow includes the target ions; the selection module 1002 is connected to the above-mentioned injection module 1001 and is used to select the target ions in the ion flow and bind them in the ion trap; the continuous module 1003 is connected to the above-mentioned selection module 1002 and is used to continue to open the discontinuous atmospheric pressure interface of the mass spectrometer when the number of target ions bound in the ion trap does not meet the target requirement, and inject the target ions of the target sample into the ion trap of the mass spectrometer until the number of target ions meets the target requirement; the detection module 1004 is connected to the above-mentioned continuous module 1003 and is used to fragment and detect the target ions when the number of target ions meets the target requirement.

[0171] The conventional tandem mass spectrometry analysis process is: open the discontinuous atmospheric pressure interface of the mass spectrometer, inject the ion flow of the target sample into the ion trap of the mass spectrometer; screen out the target ions in the ion flow and bind them 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 control method of the mass spectrometer with multiple discontinuous injections provided in this embodiment can enrich the target ions, thereby increasing the number of injected target ions, thereby improving the sensitivity of the instrument to a certain extent. It is achieved without relying on external hardware, by controlling the mass spectrometer with discontinuous injection itself, to achieve multiple discontinuous injections, and to improve the test accuracy and sensitivity of the target ions, and to a certain extent improve the detection performance of the discontinuous atmospheric pressure ion trap mass spectrometer.

[0172] According to one aspect of an embodiment of the present invention, there is also provided a mass spectrometer with discontinuous injection, comprising: a processor, and a memory for storing a program, wherein the program comprises instructions, and when the instructions are executed by the processor, the processor executes the above method.

[0173] Since the mass spectrometer works 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 repeated here.

[0174] The embodiments of the present invention also provide a non-transitory machine-readable medium storing 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 embodiments of the present invention.

[0175] The embodiments of the present invention further provide 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 embodiments of the present invention.

[0176] The embodiment of the invention also provides an electronic device, comprising: at least one processor; and a memory connected to the at least one processor in communication. The memory stores a computer program that can be executed by the at least one processor, and the computer program is used to enable the electronic device to perform the method of the embodiment of the invention when executed by the at least one processor.

[0177] refer to Fig.11 , a block diagram of an electronic device that can be used as a server or client of an embodiment of the invention will now be described, which is an example of hardware devices that can be applied to various aspects of the invention. The electronic device is intended to represent various forms of digital electronic computer devices, such as laptop computers, desktop computers, workbenches, personal digital assistants, servers, blade servers, mainframe computers, and other suitable computers. The electronic device can also represent various forms of mobile devices, such as personal digital processing, cellular phones, smart phones, wearable devices, and other similar computing devices. The components shown herein, their connections and relationships, and their functions are merely examples and are not intended to limit the implementation of the invention described and / or required herein.

[0178] like Fig.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 to 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 that can input information to the electronic device, and the input unit 1106 can receive input digital or character information, and generate key signal input related to user settings and / or function control of the electronic device. The output unit 1107 can be any type of device that can present 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 disk, an optical disk. The communication unit 1109 allows the electronic device to exchange information / data with other devices through 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 may be a variety of general and / or special 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, digital signal processors (DSPs), and any appropriate processors, controllers, microcontrollers, etc. The computing unit 1101 performs the various methods and processes described above. For example, in some embodiments, the method embodiments created by the present invention may be implemented as a computer program, which is tangibly contained in a machine-readable medium, such as a storage unit 1108. In some embodiments, part or all of the computer program may be loaded and / or installed on an electronic device via ROM 1102 and / or a communication unit 1109. In some embodiments, the computing unit 1101 may be configured to perform the above method in any other appropriate manner (e.g., by means of firmware).

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

[0182] In the context of the present invention, a machine-readable medium may be a tangible medium that may contain or store a program for use by or in conjunction with an instruction execution system, device, or apparatus. A machine-readable medium may be a machine-readable signal medium or a machine-readable storage medium. A machine-readable signal medium may include, but is not limited to, electronic, magnetic, optical, electromagnetic, or infrared systems, devices, or equipment, or any suitable combination of the foregoing. More specific examples of machine-readable storage media may include electrical connections based on one or more lines, portable computer disks, hard disks, random access memories (RAM), read-only memories (ROM), erasable programmable read-only memories (EPROM or flash memory), optical fibers, portable compact disk read-only memories (CD-ROMs), optical storage devices, magnetic storage devices, 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 inclusions, that is, "including but not limited to". The term "based on" means "based at least in part on". The term "one embodiment" means "at least one embodiment"; the term "another embodiment" means "at least one other embodiment"; the term "some embodiments" means "at least some embodiments". The modifications of "one" and "multiple" mentioned in the embodiments of the present invention are illustrative and not restrictive. Those skilled in the art should understand that unless otherwise clearly indicated 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 used for analysis, stored data, displayed data, etc.) involved in the embodiments of the present invention are all information and data authorized by the user or fully authorized by all parties, and the collection, use and processing of relevant data must comply with the relevant laws, regulations and standards of relevant countries and regions, and provide corresponding operation entrances for users to choose to authorize or refuse.

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

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

[0187] The above-described embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of protection. It should be pointed out that, for a person of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the attached claims.

Claims

1. A method for controlling a mass spectrometer with discontinuous injection, characterized in that: include: Opening a discontinuous atmospheric pressure interface of a mass spectrometer, injecting an ion flow of a target sample into an ion trap of the mass spectrometer, wherein the ion flow includes target ions; After screening the target ions in the ion flow, the target ions are trapped in the ion trap; When the number of target ions bound in the ion trap does not meet the target requirement, continue to open the discontinuous atmospheric pressure interface of the mass spectrometer, inject the target ions of the target sample and bind them into the ion trap of the mass spectrometer until the requirement for increasing the number of target ions in the ion trap is met; When the number of the target ions reaches the target requirement, the target ions are fragmented and detected.

2. The method according to claim 1, characterized in that: After screening the target ions in the ion flow, the target ions are trapped in the ion trap, including: Based on the radio frequency electric field of the ion trap, a preset AC voltage is superimposed on the ion trap to generate an AC signal with a preset waveform; The AC signal is used to resonate and eject the impurity ions in the ion trap, and the target ions are screened out and retained in the ion trap, wherein the impurity ions are ions other than the target ions in the injected ion flow.

3. The method according to claim 2, characterized in that Based on the radio frequency electric field of the ion trap, before superimposing a preset AC voltage on the ion trap to generate an AC signal, the method further includes: Determining a target amplitude of the preset AC voltage according to the mass-to-charge ratio of the target ions and the impurity ions and the size of the ion trap; Determining a target frequency spectrum of the preset AC voltage according to the characteristic frequencies of the target ions and impurity ions; A preset AC voltage of a corresponding waveform is generated according to the target amplitude and the target spectrum.

4. The method according to claim 3, characterized in that Determining a target amplitude of the preset AC 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 motion parameters of the target ions and the impurity ions, wherein the motion parameters are solutions to the motion equations of the ion trap; The target amplitude of the preset AC voltage is determined according to the potential well depths of the target ions and the impurity ions, so that the preset AC voltage ejects the impurity ions and retains the target ions in the ion trap.

5. The method according to claim 4, characterized in that Determining a target amplitude of the preset AC voltage according to the potential well depths of the target ions and the impurity ions includes: Determine, according to the potential well depth of the impurity ions, an amplitude range of the preset AC voltage that meets a first requirement, wherein the first requirement is to make the amplitude range of the preset AC voltage resonate with the impurity ions based on the corresponding potential well depth of the impurity ions, and eject the impurity ions from the ion trap; According to the potential well depth of the target ion, the target amplitude that meets the second requirement is selected from the amplitude range, wherein the second requirement is based on the potential well depth of the target ion, so that the target amplitude of the preset AC voltage will not eject the target ion from the ion trap when acting on the target ion; When there is no amplitude meeting the second requirement in the amplitude range, the minimum amplitude in the amplitude range is used as the target amplitude.

6. The method according to claim 1, characterized in that Opening the discontinuous atmospheric pressure interface of the mass spectrometer and injecting the ion flow of the target sample into the ion trap of the mass spectrometer, the method further comprises: The electric field strength of the ion trap for this injection is determined according to the mass-to-charge ratio of the ions in the ion flow of the target sample and the injection volume, wherein the injection volume is determined according to the parameters of the ion source and the discontinuous atmospheric pressure interface of the mass spectrometer.

7. The method according to claim 6, characterized in that 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 flow of the target sample includes: In the case where the injection is the first injection, the radio frequency electric field strength is determined according to the mass-to-charge ratio and injection amount of the target ion, wherein the radio frequency electric field strength corresponds to the motion parameter of the target ion being within a preset parameter range; In the case that the current injection is not the first injection, the RF electric field strength of the current injection is determined based on the RF electric field strength applied to the target ions after the previous injection, wherein the electric field strength value of the current injection is based on ensuring that the target ions after the previous injection are bound in the ion trap, and the ion beam of the current injection is bound in the ion trap by the electric field strength.

8. The method according to claim 1, characterized in that: Before the number of target ions trapped in the ion trap fails to reach a target requirement, the method further comprises: Determine the number / signal intensity of the target ions in a single injection according to the detection results of the target ions in a single injection under the same ion source parameter settings; Determine whether the target ion needs multiple injections and the number of injections according to the ion quantity / signal intensity of a single injection of the target ion; Determining whether the number of target ions in the ion trap reaches the requirement according to whether the current number of injections reaches the number of injections; Wherein, when the current number of injections reaches the number of injections, it is determined that the number of target ions in the ion trap meets the requirement.

9. The method according to claim 1, characterized in that: In the case where the ion trap performs multiple injection and ion selection steps, before repeatedly opening the discontinuous atmospheric pressure interface of the mass spectrometer, the method further comprises: 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 working pressure range and is maintained for a preset time, the steps of continuing target ion selection and then opening the discontinuous atmospheric pressure interface of the mass spectrometer are performed.

10. The method according to any one of claims 1 to 9, characterized in that The ion trap is a quadrupole linear ion trap; comprising a front cover electrode, a quadrupole and a rear cover electrode; Opening a discontinuous atmospheric pressure interface of a mass spectrometer and injecting an ion flow of a target sample into an ion trap of the mass spectrometer includes: The electric potential of the front end cover electrode is adjusted to a target potential so that the electric field strength of the ion trap reaches a required electric field strength, and the ion flow of the target sample is injected into the ion trap of the mass spectrometer.

11. The method according to claim 10, characterized in that Opening the discontinuous atmospheric pressure interface of the mass spectrometer and injecting the ion flow of the target sample into the ion trap of the mass spectrometer includes: In the case of the first injection, controlling the potential of the front cover electrode of the ion trap to be lowered to 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 non-first injection, the potential of the front cover electrode of the ion trap is controlled to be lowered to a second preset threshold, wherein the second preset threshold is lower than the first preset threshold; 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.

12. A discontinuous injection mass spectrometer, comprising: A processor, and a memory storing a program, wherein the program comprises instructions, which, when executed by the processor, cause the processor to perform the method according to any one of claims 1 to 11.

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