A mass spectrometry mass axis correction system based on online dual-ion mode correction and line cleaning by switching an eight-way valve

Abstract

The utility model discloses a kind of mass spectrum mass axis correction systems of online double ion mode correction and pipeline cleaning based on eight-way valve switching, including mass spectrum mass axis correction module, liquid chromatograph module and mass spectrum module;Mass spectrum mass axis correction module includes eight-way valve, liquid storage bottle, sample injection needle, micro-injection pump, first quantitative ring, waste liquid bottle and second quantitative ring;First eighth interface is equipped on eight-way valve, sample injection needle one end is inserted into the bottom of liquid storage bottle, other end is communicated with the import of micro-injection pump, and the outlet of micro-injection pump is communicated with first interface;First quantitative ring is communicated with third and second interface;Waste liquid bottle is communicated with fourth interface;The sample outlet of liquid chromatograph module is communicated with eighth interface;Second quantitative ring is communicated with sixth and seventh interface;The sample inlet of mass spectrum module is communicated with fifth interface.The above-mentioned system realizes online correction and cleaning, simple, ingenious, efficient.

Description

Technical Field

[0001] This utility model relates to a mass spectrometer mass axis calibration system based on online dual-ion mode calibration and pipeline cleaning using an eight-way valve, belonging to the field of online calibration technology for mass spectrometer mass axes. Background Technology

[0002] An accurate mass axis is the core foundation of mass spectrometry, directly determining the accuracy of qualitative analysis of compounds (such as correctly matching the theoretical mass-to-charge ratio of the target analyte) and the sensitivity of quantitative detection (such as ensuring efficient passage of ions through preset channels). Mass axis shift is mainly caused by environmental factors (such as drastic temperature changes leading to parameter drift in electronic components), aging of components due to long-term instrument operation, or dust accumulation. These factors may alter the voltage stability of key components, causing deviations between the actual detected mass-to-charge ratio and the theoretical value. While this shift is unavoidable, it can be corrected through calibration procedures. There are two main methods for mass calibration of existing mass spectrometers:

[0003] One method is offline calibration, which is the traditional mainstream method. This involves manually injecting a calibration solution in a single ion mode before analysis to calibrate the mass axis before starting sample testing.

[0004] Another type is the single-channel online calibration used in some high-end mass spectrometers. This involves continuously or periodically injecting calibration solution via a syringe pump to perform calibration in a single ion mode. When switching ion modes is required, the sample injection path of the calibration solution needs to be adjusted, resulting in lower analytical efficiency. Of course, some online calibration systems employ a multi-syringe pump + multi-channel design. Although they support both positive and negative ion mode calibration, their structure is complex, and cross-contamination between multiple channels is prone to occur.

[0005] This application aims to design an online mass spectrometry calibration device that automatically introduces calibration solution by switching via an eight-way valve. By switching the valve, positive ion calibration solution, negative ion calibration solution, and cleaning solution can be introduced in a cross-switching manner, which not only realizes online calibration of the mass axis of the mass spectrometer, but also enables (timed or on-demand) cleaning of the calibration solution channel, avoiding cross-contamination. Utility Model Content

[0006] This invention provides a mass spectrometry mass axis calibration system based on online dual-ion mode calibration and pipeline cleaning using an eight-way valve. This application embeds the online mass spectrometry mass axis calibration module into the liquid chromatography-mass spectrometry (LC-MS) equipment module to achieve alternating injection of calibration solution and cleaning solution, online calibration and cleaning. The structure is simple, ingenious, and efficient.

[0007] To solve the above-mentioned technical problems, the technical solution adopted by this utility model is as follows:

[0008] A mass spectrometry mass axis correction system based on online dual-ion mode correction and tubing cleaning using an eight-way valve, comprising a mass spectrometry mass axis correction module, a liquid chromatography module, and a mass spectrometry module;

[0009] The mass axis calibration module for mass spectrometry includes: an eight-way valve, a storage bottle, an injection needle, a micro-injection pump, a first quantitative loop, a waste bottle, and a second quantitative loop;

[0010] The eight-way valve has eight connection ports, which are arranged counterclockwise as follows: first port, second port, third port, fourth port, fifth port, sixth port, seventh port and eighth port;

[0011] The eight-way valve includes at least two switchable states, namely a first state and a second state. The first state is as follows: the first port and the third port are connected, the second port and the fourth port are connected, the fifth port and the seventh port are connected, and the sixth port and the eighth port are connected. The second state is as follows: the first port and the seventh port are connected, the second port and the eighth port are connected, the third port and the fifth port are connected, and the fourth port and the sixth port are connected.

[0012] One end of the injection needle is inserted into the bottom of the storage bottle, and the other end is connected to the inlet of the micro-injection pump through a tubing. The outlet of the micro-injection pump is connected to the first port on the eight-way valve through a tubing. The two ports on the first quantitative ring are connected to the third and second ports on the eight-way valve, respectively. The waste bottle is connected to the fourth port on the eight-way valve through a tubing.

[0013] The sample outlet of the liquid chromatography module is connected to the eighth port of the eight-way valve via a tubing; the two ports on the second quantitative loop are connected to the sixth and seventh ports of the eight-way valve, respectively; the injection port of the mass spectrometry module is connected to the fifth port of the eight-way valve via a tubing.

[0014] When the eight-way valve is in the first state, the first port is used as the liquid storage inlet, the third port is used as the first quantitative loop inlet, the second port is used as the first quantitative loop outlet, the fourth port is used as the waste liquid outlet, the eighth port is used as the liquid chromatography injection port, the sixth port is used as the second quantitative loop inlet, the seventh port is used as the second quantitative loop outlet, and the fifth port is used as the mass spectrometry injection port.

[0015] When the eight-way valve is in the second state, the first port is used as the liquid storage inlet, the seventh port is used as the second quantitative loop inlet, the sixth port is used as the second quantitative loop outlet, the fourth port is used as the waste liquid outlet, the eighth port is used as the liquid chromatography injection port, the second port is used as the first quantitative loop inlet, the third port is used as the first quantitative loop outlet, and the fifth port is used as the mass spectrometry injection port.

[0016] In addition to the first and second states mentioned above, the eight-way valve of this application may also include other states, such as the third state: the first port and the seventh port are connected, the eighth port and the sixth port are connected, the second port and the fourth port are connected, and the third port and the fifth port are connected; or the fourth state: the first port and the third port are connected, the second port and the eighth port are connected, the fourth port and the sixth port are connected, and the fifth port and the seventh port are connected.

[0017] The aforementioned eight-way valve includes a valve body and a rotor. The rotor rotates or shifts within the valve body, achieving multi-path switching by changing the connectivity of the fluid channels. The valve body is a fixed outer shell with eight pre-set fluid interfaces (channels), typically arranged in a ring or matrix. The rotor is a movable component with grooves, through holes, or flow channels designed on its surface or internally. By rotating or moving, it aligns with the valve body interfaces, thereby guiding specific fluid paths. The eight-way valve in this application directly adopts existing related products, without fundamentally improving its internal structure, and will not be elaborated upon here.

[0018] In this application, the connection between pipelines and the connection between the inlet and outlet of each equipment and the pipeline refer to the connection and communication.

[0019] The cleaning solution is generally pure methanol, or a mixture of methanol and water (e.g., a 1:1 volume ratio of water and methanol, but other ratios can be used as needed), and will not cause pollution.

[0020] The aforementioned storage bottles include: a positive ion calibration solution storage bottle, a negative ion calibration solution storage bottle, and a cleaning solution storage bottle. One end of the injection needle is inserted into the bottom of any one of these bottles, while the other end is connected to the inlet of a micro-injection pump via tubing. That is, when positive ion mode calibration is required, one end of the injection needle is inserted into the bottom of the positive ion calibration solution storage bottle; when negative ion mode calibration is required, one end of the injection needle is inserted into the bottom of the negative ion calibration solution storage bottle; and when cleaning is required, one end of the injection needle is inserted into the bottom of the cleaning solution storage bottle.

[0021] As another specific implementation, a constant flow pump can be used instead of a micro-injection pump. The function of a micro-injection pump or a constant flow pump is to deliver and load positive ion correction solution, negative ion correction solution, or cleaning solution. Once the corresponding liquid delivery or loading is completed, the micro-injection pump or constant flow pump is turned off.

[0022] The aforementioned eight-way valve (both valve body and rotor) is made of stainless steel, offering advantages such as high strength and high pressure resistance. It performs well in neutral or weakly acidic / alkaline environments, is reasonably priced, and has good applicability. Of course, depending on the properties of the fluid, eight-way valves made of materials such as titanium alloy or polyetheretherketone (PEEK) can also be used.

[0023] The materials used for the above-mentioned pipelines can be stainless steel pipes with high pressure resistance and good thermal stability, or PEEK pipes with chemical corrosion resistance and biological inertness, depending on the properties of the fluid. Both are suitable for microfluidic systems (flow rate of 1 to 50 μL / min).

[0024] The materials used for the first and second metering rings can be stainless steel or PEEK, or other materials such as titanium alloy, depending on the special properties of the fluid.

[0025] The connecting tubing between the injection needle and the micro-injection pump, and the connecting tubing between the micro-injection pump and the eight-way valve, are all ≤50cm in length and ≤250μm in inner diameter to reduce the dead volume of the calibration system.

[0026] When using the aforementioned mass spectrometry mass axis calibration system based on online dual-ion mode calibration and tubing cleaning using an eight-way valve, the test flow path used in conjunction with the liquid chromatography module and the mass spectrometry module is as follows: liquid chromatography module, eighth interface, sixth interface, second quantitative loop, seventh interface, fifth interface, and mass spectrometry module. That is, liquid chromatography module (LC) → eighth interface → sixth interface → second quantitative loop → seventh interface → fifth interface → mass spectrometry module (MS). Of course, the aforementioned test flow path is only one preferred option, facilitating online calibration, cleaning, and testing. In the absence of calibration, both states can serve as the test flow path.

[0027] The cleaning flow path of the first metering loop is as follows: cleaning solution storage bottle, micro-injection pump or constant flow pump, first port, third port, first metering loop, second port, fourth port, and waste bottle. That is, cleaning solution storage bottle → micro-injection pump or constant flow pump → first port → third port → first metering loop → second port → fourth port → waste bottle.

[0028] The cleaning flow path of the second metering loop is as follows: cleaning solution storage bottle, micro-injection pump or constant flow pump, first port, seventh port, second metering loop, sixth port, fourth port, and waste bottle. That is, cleaning solution storage bottle → micro-injection pump or constant flow pump → first port → seventh port → second metering loop → sixth port → fourth port → waste bottle.

[0029] The positive ion correction solution loading flow path is as follows: positive ion correction solution storage bottle, micro-injection pump or constant flow pump, first interface, third interface, first metering loop, second interface, fourth interface and waste bottle; that is, positive ion correction solution storage bottle → micro-injection pump or constant flow pump → first interface → third interface → first metering loop → second interface → fourth interface → waste bottle.

[0030] The positive ion mode calibration flow path is as follows: liquid chromatography module, eighth interface, second interface, first quantitative loop, third interface, fifth interface, and mass spectrometry module; that is, LC → eighth interface → second interface → first quantitative loop → third interface → fifth interface → MS. The mobile phase carrying the positive ion calibration solution flows into the mass spectrometry module for calibration (positive ion mode calibration).

[0031] The loading flow path of the negative ion correction solution is as follows: negative ion correction solution storage bottle, micro-injection pump or constant flow pump, first interface, seventh interface, second metering ring, sixth interface, fourth interface and waste bottle; that is, negative ion correction solution storage bottle → micro-injection pump or constant flow pump → first interface → seventh interface → second metering ring → sixth interface → fourth interface → waste bottle.

[0032] The negative ion mode calibration flow path is as follows: liquid chromatography module, eighth interface, sixth interface, second quantitative loop, seventh interface, fifth interface and mass spectrometry module, that is, LC→eighth interface→sixth interface→second quantitative loop→seventh interface→fifth interface→MS. The mobile phase carrying the negative ion calibration solution flows into the mass spectrometry module for calibration (negative ion mode calibration).

[0033] Of course, the above is only one preferred implementation scheme for positive and negative ion mode correction, and the flow paths of the two can also be interchanged.

[0034] This application, through the rational selection of materials and flow path design, helps to improve the stability and accuracy of the analysis system.

[0035] The online mass spectrometry calibration system of this application can be embedded into the original equipment system without changing the original mass spectrometry or liquid chromatography-mass spectrometry equipment, which is highly flexible.

[0036] The calibration system of this application mainly consists of three modules: a liquid chromatography module (which includes common degassing systems, pump systems, injection systems, chromatographic separation systems, and UV / fluorescence detection systems), a mass spectrometry module (generally a high-resolution mass spectrometer), and a mass spectrometry mass axis calibration module (including a micro-injection pump or constant flow pump, an eight-way valve, a quantitative loop, a storage bottle, a waste bottle, and an injection needle, as shown in the figure). The modules are connected by stainless steel tubing or PEEK tubing (or other tubing materials selected according to the properties of the fluid). This application flexibly embeds the mass spectrometry calibration module into the liquid chromatography-mass spectrometry system, realizing online mass spectrometry calibration.

[0037] This application utilizes an eight-way valve with switchable first and second states for online dual-ion mode calibration and pipeline cleaning, such as... Figure 2 and Figure 3 As shown, the specific switching method is as follows:

[0038] When the sample is subjected to LC (Liquid Chromatography)-MS (Mass Spectrometry) testing, the eight-way valve switches to the first state (e.g., Figure 2 As shown), at this time, the mobile phase of the liquid chromatography-mass spectrometry (LC-MS) flows through the second metering loop. As part of the LC-MS system, the flow path is: LC → eighth port → sixth port → second metering loop → seventh port → fifth port → MS.

[0039] At this point, the calibration solution tubing and injection needle of the first quantitative loop can be cleaned: Insert the injection needle into the bottom of the cleaning solution reservoir (containing cleaning solution), and under the action of a micro-injection pump or a constant flow pump, the cleaning solution cleans the calibration solution tubing at a constant flow rate (1-500 μL / min). The flow path is: cleaning solution reservoir → micro-injection pump or constant flow pump → first port → third port → first quantitative loop → second port → fourth port → waste bottle; the cleaning process can be carried out simultaneously with the LC-MS test, and the flow paths of the two are independent and do not interfere with each other;

[0040] If mass spectrometry calibration needs to be inserted after the analysis of a certain sample in the sample test list, then 5-10 minutes before the end of the LC-MS test of that sample (this time can be optimized according to parameters such as the volume and flow rate of the calibration solution), the loading of the first quantitative loop of positive ion calibration solution should be performed. At this time, the eight-way valve is still in the first state and does not switch. Insert the injection needle into the bottom of the positive ion calibration solution storage bottle (containing positive ion calibration solution). Under the action of the micro-injection pump or constant flow pump, the positive ion calibration solution is loaded. The positive ion calibration solution loading flow path is: positive ion calibration solution storage bottle → micro-injection pump or constant flow pump → first interface → third interface → first quantitative loop → second interface → fourth interface → waste bottle;

[0041] Once the first quantitative loop is filled with positive ion correction solution and the LC-MS test of the sample is complete, switch the eight-way valve to the second state (e.g., Figure 3As shown), the mobile phase of the liquid chromatography (LC) module is switched to a pure solvent (such as methanol). The flow path is: LC → eighth interface → second interface → first quantitative loop → third interface → fifth interface → MS. The mobile phase carrying the positive ion correction solution flows into the mass spectrometry module for correction (correction in positive ion mode). While the calibration (positive ion mode calibration) is being performed, the calibration solution tubing and injection needle of the second quantitative loop can be cleaned: the injection needle is inserted into the bottom of the cleaning solution reservoir (containing cleaning solution), and the cleaning solution is used to clean the calibration solution tubing at a constant flow rate (1-500 μL / min) under the action of a micro-injection pump or a constant flow pump. The flow path is: cleaning solution reservoir → micro-injection pump or constant flow pump → first port → seventh port → second quantitative loop → sixth port → fourth port → waste bottle; then, without switching the valve (second state), the loading of the negative ion calibration solution of the second quantitative loop continues. The injection needle is inserted into the bottom of the negative ion calibration solution reservoir (containing negative ion calibration solution), and negative ion calibration solution is loaded into the second quantitative loop under the action of a micro-injection pump or a constant flow pump. The flow path of the negative ion calibration solution loading is: negative ion calibration solution reservoir → micro-injection pump or constant flow pump → first port → seventh port → second quantitative loop → sixth port → fourth port → waste bottle.

[0042] After the second metering ring is filled with negative ion correction solution and the positive ion mode correction is completed, switch the eight-way valve to the first state (e.g., Figure 2 As shown in the diagram, the mobile phase of the liquid chromatography (LC) module is still a pure solvent (such as methanol), and the flow path is: LC → eighth port → sixth port → second quantitative loop → seventh port → fifth port → MS. The mobile phase carrying the negative ion correction solution flows into the mass spectrometry module for calibration (negative ion mode calibration). It is worth noting that during the mass axis calibration process, the quantitative loops loaded with the positive / negative ion correction solutions are different, and the calibration solution tubing and injection needle of different quantitative loops are cleaned.

[0043] After the mass spectrometry calibration procedure is completed, the eight-way valve can remain in its first state without switching, allowing for direct sample injection and LC-MS analysis. Meanwhile, the mass axis calibration module can execute a cleaning procedure, and this cycle repeats to achieve online dual-ion mode calibration and tubing cleaning.

[0044] It should be noted that the calibration process does not necessarily have to proceed from positive ion mode to negative ion mode first; it can also proceed from negative ion mode first to positive ion mode. The order does not matter.

[0045] This application employs a combination of an eight-way valve switch and a micro-injection pump (or constant flow pump, etc.) to achieve quantitative aspiration and injection of calibration solution into the mass spectrometry system via programmable control. Two calibration solutions (e.g., positive / negative ion calibration solutions) and a cleaning solution are introduced alternately according to a preset time sequence. Based on a "test-calibrate-test" mode, mass axis calibration can be completed simultaneously during sample analysis, improving the accuracy of mass spectrometry data. This is particularly suitable for high-precision quantitative analysis scenarios (such as clinical drug monitoring and environmental trace pollutant detection). This design not only saves the total testing time for high-throughput, long-duration tests but also performs online mass axis calibration periodically (or on demand), while ensuring data quality and analytical throughput.

[0046] This application combines existing automation technology to achieve automated operation, which helps control injection repeatability error, enables accurate delivery of μL-level calibration solution, eliminates dosage error from manual injection, and improves detection precision.

[0047] This application utilizes a closed-loop flow path design with an eight-way valve and a micro-injection pump (or constant flow pump, etc.) to avoid pipeline exposure and contamination caused by manual operation. It also introduces a self-cleaning mechanism for the pipeline, effectively preventing cross-contamination between different calibration solutions, reducing the risk of contamination, and is beneficial for trace substance analysis scenarios.

[0048] This application does not make any special improvements to the control methods, etc., and can directly adopt existing mature technologies, so it will not be elaborated here.

[0049] Any technologies not mentioned in this utility model are based on existing technologies.

[0050] This invention relates to a mass spectrometry mass axis calibration system based on online dual-ion mode calibration and tubing cleaning using an eight-way valve. Mass spectrometry calibration is interspersed throughout the sample analysis process. Therefore, for batch sample testing, calibration procedures can be flexibly inserted during the testing process, performing online mass axis calibration periodically (or as needed) to correct any deviations in the mass axis and ensure data quality. Testing and calibration or cleaning can be performed simultaneously without sacrificing sample throughput, thus improving testing efficiency. Calibration solutions can be automatically transferred via a micro-injection pump or a constant flow pump. On the one hand, this closed calibration system reduces tubing exposure and contamination caused by manual operation, and a cleaning step (cleaning the injection needle, tubing, quantitative loop, etc.) can be introduced to reduce cross-contamination between different calibration solutions. On the other hand, automatic transfer via a micro-injection pump or constant flow pump helps control injection repeatability errors, achieving precise delivery of μL-level calibration solutions, eliminating dosage errors from manual injection, and improving detection precision. Attached Figure Description

[0051] Figure 1 The four states of the eight-way valve are shown in the diagram (A is the first state, B is the second state, C is the third state, and D is the fourth state).

[0052] Figure 2 This is a schematic diagram of the mass spectrometry mass axis correction system based on an eight-way valve for online dual-ion mode correction and pipeline cleaning (the eight-way valve is in the first state).

[0053] Figure 3 This is a schematic diagram of the mass spectrometry mass axis correction system based on an eight-way valve for online dual-ion mode correction and pipeline cleaning, as described in this invention (the eight-way valve is in the second state).

[0054] In the diagram, 1 is the first interface, 2 is the second interface, 3 is the third interface, 4 is the fourth interface, 5 is the fifth interface, 6 is the sixth interface, 7 is the seventh interface, 8 is the eighth interface, 9 is the positive ion calibration solution storage bottle, 10 is the negative ion calibration solution storage bottle, 11 is the cleaning solution storage bottle, 12 is the injection needle, 13 is the micro-injection pump or constant flow pump, 14 is the first quantitative loop, 15 is the second quantitative loop, 16 is the waste liquid bottle, 17 is the liquid chromatography module, and 18 is the mass spectrometry module.

[0055] like Figure 1 As shown, the eight ports can be switched to four different connection modes by rotating the rotor: the first state, the second state, the third state, and the fourth state. This application utilizes the first and second states, which are interchangeable. The eight-way valves in these two states are connected to the liquid chromatography module and the mass spectrometry module, respectively, forming a system as shown in the diagram. Figure 2 and Figure 3 The two connection methods shown are flexible and can be switched. Detailed Implementation

[0056] To better understand this utility model, the following embodiments further illustrate the content of this utility model, but the content of this utility model is not limited to the following embodiments.

[0057] The directional terms used in this application, such as up and down, left and right, horizontal, vertical, top and bottom, inside and outside, are all based on the relative orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing this application and are not intended to indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this application.

[0058] Example 1

[0059] like Figure 2-3 As shown, a mass spectrometry mass axis correction system based on online dual-ion mode correction and tubing cleaning using an eight-way valve switching includes a mass spectrometry mass axis correction module, a liquid chromatography module, and a mass spectrometry module.

[0060] The mass axis calibration module for mass spectrometry includes: an eight-way valve, a storage bottle, an injection needle, a micro-injection pump, a first quantitative loop, a waste bottle, and a second quantitative loop;

[0061] like Figure 1 As shown, the eight-way valve has eight connection ports, which are arranged counterclockwise as follows: first port, second port, third port, fourth port, fifth port, sixth port, seventh port and eighth port;

[0062] The eight-way valve includes at least two switchable states, namely a first state and a second state. The first state is as follows: the first port and the third port are connected, the second port and the fourth port are connected, the fifth port and the seventh port are connected, and the sixth port and the eighth port are connected. The second state is as follows: the first port and the seventh port are connected, the second port and the eighth port are connected, the third port and the fifth port are connected, and the fourth port and the sixth port are connected.

[0063] One end of the injection needle is inserted into the bottom of the storage bottle, and the other end is connected to the inlet of the micro-injection pump through a tubing. The outlet of the micro-injection pump is connected to the first port on the eight-way valve through a tubing. The two ports on the first quantitative ring are connected to the third and second ports on the eight-way valve, respectively. The waste bottle is connected to the fourth port on the eight-way valve through a tubing.

[0064] The sample outlet of the liquid chromatography module is connected to the eighth port of the eight-way valve via a tubing; the two ports on the second quantitative loop are connected to the sixth and seventh ports of the eight-way valve, respectively; the injection port of the mass spectrometry module is connected to the fifth port of the eight-way valve via a tubing.

[0065] When the eight-way valve is in the first state, the first port is used as the liquid storage inlet, the third port is used as the first quantitative loop inlet, the second port is used as the first quantitative loop outlet, the fourth port is used as the waste liquid outlet, the eighth port is used as the liquid chromatography injection port, the sixth port is used as the second quantitative loop inlet, the seventh port is used as the second quantitative loop outlet, and the fifth port is used as the mass spectrometry injection port.

[0066] When the eight-way valve is in the second state, the first port is used as the liquid storage inlet, the seventh port is used as the second quantitative loop inlet, the sixth port is used as the second quantitative loop outlet, the fourth port is used as the waste liquid outlet, the eighth port is used as the liquid chromatography injection port, the second port is used as the first quantitative loop inlet, the third port is used as the first quantitative loop outlet, and the fifth port is used as the mass spectrometry injection port.

[0067] like Figure 1 As shown, in addition to the first and second states mentioned above, the eight-way valve may also include other states, such as the third state: the first port and the seventh port are connected, the eighth port and the sixth port are connected, the second port and the fourth port are connected, and the third port and the fifth port are connected; or the fourth state: the first port and the third port are connected, the second port and the eighth port are connected, the fourth port and the sixth port are connected, and the fifth port and the seventh port are connected.

[0068] Example 2

[0069] Based on Example 1, the following improvements were made: The storage bottles include: a positive ion calibration solution storage bottle, a negative ion calibration solution storage bottle, and a cleaning solution storage bottle; one end of the injection needle is inserted into the bottom of any one of the positive ion calibration solution storage bottle, negative ion calibration solution storage bottle, and cleaning solution storage bottle, while the other end of the injection needle is connected to the inlet of a micro-injection pump via a tubing. That is, when positive ion mode calibration is required, one end of the injection needle is inserted into the bottom of the positive ion calibration solution storage bottle; when negative ion mode calibration is required, one end of the injection needle is inserted into the bottom of the negative ion calibration solution storage bottle; when cleaning is required, one end of the injection needle is inserted into the bottom of the cleaning solution storage bottle.

[0070] Example 3

[0071] Based on Example 2, the following improvements were made: the micro-injection pump was replaced with a constant flow pump. The function of the micro-injection pump or constant flow pump is to deliver and load the positive ion correction solution, negative ion correction solution, or cleaning solution. After the corresponding liquid delivery and loading are completed, the micro-injection pump or constant flow pump is turned off.

[0072] Example 4

[0073] Based on Example 3, the following improvements were made: The eight-way valve (valve body and rotor) is made of stainless steel, which has the advantages of high strength and high pressure resistance, performs well in neutral or weakly acidic / alkaline environments, and is moderately priced, making it highly applicable. Of course, depending on the properties of the fluid, eight-way valves made of materials such as titanium alloy or polyetheretherketone (PEEK) can also be used. All pipelines are made of stainless steel pipes with high pressure resistance and good thermal stability; of course, depending on the properties of the fluid, chemically resistant and biologically inert PEEK pipes can also be selected. The first and second metering rings are made of stainless steel; of course, depending on the properties of the fluid, PEEK or other materials such as titanium alloy can also be used.

[0074] Example 5

[0075] Based on Example 4, the following improvements were made: the connecting tubing between the injection needle and the micro-injection pump, and the connecting tubing between the micro-injection pump and the eight-way valve, are all ≤50cm in length (50cm in this example, but could also be 30cm, 40cm, etc.), and the inner diameter is ≤250μm (250μm in this example, but could also be 200μm, 150μm, etc.), in order to reduce the dead volume of the calibration system.

[0076] When using the above-mentioned mass spectrometry mass axis calibration system based on online dual-ion mode calibration and tubing cleaning using an eight-way valve, the test flow path used in conjunction with the liquid chromatography module and the mass spectrometry module is as follows: liquid chromatography module, eighth interface, sixth interface, second quantitative loop, seventh interface, fifth interface, and mass spectrometry module. That is, liquid chromatography module (LC) → eighth interface → sixth interface → second quantitative loop → seventh interface → fifth interface → mass spectrometry module (MS).

[0077] The first quantitative loop cleaning flow path is as follows: cleaning solution storage bottle, micro-injection pump or constant flow pump, first port, third port, first quantitative loop, second port, fourth port, and waste bottle. That is, cleaning solution storage bottle → micro-injection pump or constant flow pump → first port → third port → first quantitative loop → second port → fourth port → waste bottle.

[0078] The positive ion correction solution loading flow path is as follows: positive ion correction solution storage bottle, micro-injection pump or constant flow pump, first interface, third interface, first metering loop, second interface, fourth interface and waste bottle; that is, positive ion correction solution storage bottle → micro-injection pump or constant flow pump → first interface → third interface → first metering loop → second interface → fourth interface → waste bottle.

[0079] The positive ion mode calibration flow path is as follows: liquid chromatography module, eighth interface, second interface, first quantitative loop, third interface, fifth interface, and mass spectrometry module; that is, LC → eighth interface → second interface → first quantitative loop → third interface → fifth interface → MS. The mobile phase carrying the positive ion calibration solution flows into the mass spectrometry module for calibration (positive ion mode calibration).

[0080] The second quantitative loop cleaning flow path is as follows: cleaning solution storage bottle, micro-injection pump or constant flow pump, first port, seventh port, second quantitative loop, sixth port, fourth port, and waste bottle. That is, cleaning solution storage bottle → micro-injection pump or constant flow pump → first port → seventh port → second quantitative loop → sixth port → fourth port → waste bottle.

[0081] The loading flow path of the negative ion correction solution is as follows: negative ion correction solution storage bottle, micro-injection pump or constant flow pump, first interface, seventh interface, second metering loop, sixth interface, fourth interface and waste bottle; that is, negative ion correction solution storage bottle → micro-injection pump or constant flow pump → first interface → seventh interface → second metering loop → sixth interface → fourth interface → waste bottle.

[0082] The negative ion mode calibration flow path is as follows: liquid chromatography module, eighth interface, sixth interface, second quantitative loop, seventh interface, fifth interface and mass spectrometry module, that is, LC→eighth interface→sixth interface→second quantitative loop→seventh interface→fifth interface→MS. The mobile phase carrying the negative ion calibration solution flows into the mass spectrometry module for calibration (negative ion mode calibration).

[0083] The aforementioned mass spectrometer mass axis correction system based on online dual-ion mode correction and tubing cleaning using an eight-way valve utilizes the interchangeable first and second states of the eight-way valve, such as... Figure 2 and Figure 3 As shown, the specific switching method is as follows:

[0084] When the sample is subjected to LC (Liquid Chromatography)-MS (Mass Spectrometry) testing, the eight-way valve switches to the first state (e.g., Figure 2 As shown), at this time, the mobile phase of the liquid chromatography-mass spectrometry (LC-MS) flows through the second metering loop. As part of the LC-MS system, the flow path is: LC → eighth port → sixth port → second metering loop → seventh port → fifth port → MS.

[0085] The first quantitative loop can perform cleaning of the calibration solution tubing and injection needle: the injection needle is inserted into the bottom of the cleaning solution reservoir (containing cleaning solution), and the cleaning solution is used to clean the calibration solution tubing at a constant flow rate (1-500 μL / min) under the action of a micro-injection pump or constant flow pump. The flow path is: cleaning solution reservoir → micro-injection pump or constant flow pump → first interface → third interface → first quantitative loop → second interface → fourth interface → waste bottle; the cleaning process can be performed simultaneously with LC-MS testing, and the flow paths of the two are independent and do not interfere with each other;

[0086] If mass spectrometry calibration needs to be inserted after the analysis of a certain sample in the sample test list, then 5-10 minutes before the end of the LC-MS test of that sample (this time can be optimized according to parameters such as the volume and flow rate of the calibration solution), the first quantitative loop calibration solution should be loaded. At this time, the eight-way valve is still in the first state and does not switch. Insert the injection needle into the bottom of the positive ion calibration solution storage bottle (containing positive ion calibration solution). Under the action of the micro-injection pump or constant flow pump, the positive ion calibration solution is loaded. The positive ion calibration solution loading flow path is: positive ion calibration solution storage bottle → micro-injection pump or constant flow pump → first interface → third interface → first quantitative loop → second interface → fourth interface → waste bottle.

[0087] Once the first quantitative loop is filled with positive ion correction solution and the LC-MS test of the sample is complete, switch the eight-way valve to the second state (e.g., Figure 3As shown), the mobile phase of the liquid chromatography (LC) module is switched to a pure solvent (such as methanol). The flow path is: LC → eighth interface → second interface → first quantitative loop → third interface → fifth interface → MS. The mobile phase carrying the positive ion correction solution flows into the mass spectrometry module for correction (correction in positive ion mode). While the calibration (positive ion mode calibration) is being performed, the calibration solution tubing and injection needle of the second quantitative loop can be cleaned: the injection needle is inserted into the bottom of the cleaning solution reservoir (containing cleaning solution), and the cleaning solution is used to clean the calibration solution tubing at a constant flow rate (1-500 μL / min) under the action of a micro-injection pump or a constant flow pump. The flow path is: cleaning solution reservoir → micro-injection pump or constant flow pump → first port → seventh port → second quantitative loop → sixth port → fourth port → waste bottle; then, without switching the valve (second state), the loading of the negative ion calibration solution of the second quantitative loop continues. The injection needle is inserted into the bottom of the negative ion calibration solution reservoir (containing negative ion calibration solution), and negative ion calibration solution is loaded into the second quantitative loop under the action of a micro-injection pump or a constant flow pump. The flow path of the negative ion calibration solution loading is: negative ion calibration solution reservoir → micro-injection pump or constant flow pump → first port → seventh port → second quantitative loop → sixth port → fourth port → waste bottle.

[0088] After the second metering ring is filled with negative ion correction solution and the positive ion mode correction is completed, switch the eight-way valve to the first state (e.g., Figure 2 As shown in the diagram, the mobile phase of the liquid chromatography (LC) module is still a pure solvent (such as methanol), and the flow path is: LC → eighth port → sixth port → second quantitative loop → seventh port → fifth port → MS. The mobile phase carrying the negative ion correction solution flows into the mass spectrometry module for calibration (negative ion mode calibration). It is worth noting that during the mass axis calibration process, the quantitative loops loaded with the positive / negative ion correction solutions are different, and the calibration solution tubing and injection needle of different quantitative loops are cleaned.

[0089] After the mass spectrometry calibration procedure is completed, the eight-way valve can remain in its first state without switching, allowing for direct sample injection and LC-MS analysis. Meanwhile, the mass axis calibration module can execute a cleaning procedure, and this cycle repeats to achieve online dual-ion mode calibration and tubing cleaning.

[0090] Table 1: Explanation of different operations:

[0091]

[0092]

[0093] The examples above employ a combination of an eight-way valve switch and a micro-injection pump (or constant flow pump, etc.) to achieve quantitative aspiration and injection of calibration solutions into the mass spectrometry system via programmable control. Two calibration solutions (e.g., positive / negative ion calibration solutions) and a cleaning solution are introduced alternately according to a preset time sequence. Based on a "test-calibrate-test" mode, mass axis calibration can be completed simultaneously during sample analysis, improving the accuracy of mass spectrometry data, especially suitable for high-precision quantitative analysis scenarios (such as clinical drug monitoring and environmental trace pollutant detection). This design not only saves the total testing time for high-throughput, long-duration tests but also performs online mass axis calibration periodically (or on demand), while ensuring data quality and analytical throughput. Combined with existing automation technologies, automated operation can be achieved, which is beneficial for controlling injection repeatability errors, achieving precise delivery of μL-level calibration solutions, eliminating dosage errors from manual injection, and improving detection precision.

[0094] The mass spectrometry mass axis calibration systems described above, based on online dual-ion mode calibration and tubing cleaning using an eight-way valve, integrate mass spectrometry calibration into the sample analysis process. Therefore, for batch sample testing, calibration procedures can be flexibly inserted during the testing process, performing online mass axis calibration periodically (or as needed) to correct any deviations in the mass axis and ensure data quality. The closed-loop design of the eight-way valve and micro-injection pump (or constant flow pump, etc.) avoids tubing exposure and contamination caused by manual operation. Furthermore, a self-cleaning mechanism can be introduced to effectively prevent cross-contamination between different calibration solutions, reducing the risk of contamination and benefiting trace substance analysis scenarios. This system improves testing efficiency without sacrificing sample throughput.

Claims

1. A mass spectrometer mass axis correction system based on online dual-ion mode correction and tubing cleaning using an eight-way valve switching method, characterized in that: Includes a mass spectrometry mass axis correction module, a liquid chromatography module, and a mass spectrometry module; The mass axis calibration module for mass spectrometry includes: an eight-way valve, a storage bottle, an injection needle, a micro-injection pump, a first quantitative loop, a waste bottle, and a second quantitative loop; The eight-way valve has eight connection ports, which are arranged counterclockwise as follows: first port, second port, third port, fourth port, fifth port, sixth port, seventh port and eighth port; The eight-way valve includes at least two switchable states, namely a first state and a second state. The first state is as follows: the first port and the third port are connected, the second port and the fourth port are connected, the fifth port and the seventh port are connected, and the sixth port and the eighth port are connected. The second state is as follows: the first port and the seventh port are connected, the second port and the eighth port are connected, the third port and the fifth port are connected, and the fourth port and the sixth port are connected. One end of the injection needle is inserted into the bottom of the storage bottle, and the other end is connected to the inlet of the micro-injection pump through a tubing. The outlet of the micro-injection pump is connected to the first port on the eight-way valve through a tubing. The two ports on the first quantitative ring are connected to the third and second ports on the eight-way valve, respectively. The waste bottle is connected to the fourth port on the eight-way valve through a tubing. The sample outlet of the liquid chromatography module is connected to the eighth port of the eight-way valve via a tubing; the two ports on the second quantitative loop are connected to the sixth and seventh ports of the eight-way valve, respectively; the injection port of the mass spectrometry module is connected to the fifth port of the eight-way valve via a tubing.

2. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 1, characterized in that: The storage bottle includes: Positive ion correction solution storage bottle, negative ion correction solution storage bottle and cleaning solution storage bottle; one end of the injection needle is inserted into the bottom of any one of the positive ion correction solution storage bottle, negative ion correction solution storage bottle and cleaning solution storage bottle, and the other end of the injection needle is connected to the inlet of the micro-injection pump through a tubing.

3. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 1 or 2, characterized in that: The micro-injection pump is replaced by a constant flow pump.

4. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 1 or 2, characterized in that: The eight-way valve is made of stainless steel, titanium alloy or polyetheretherketone.

5. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 1 or 2, characterized in that: All pipelines are made of stainless steel or polyetheretherketone.

6. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 1 or 2, characterized in that: The first and second quantitative rings are made of stainless steel, titanium alloy or polyetheretherketone.

7. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 1 or 2, characterized in that: The connecting tubing between the injection needle and the micro-injection pump, and the connecting tubing between the micro-injection pump and the eight-way valve, shall all be ≤50cm in length and ≤250μm in inner diameter.

8. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 1 or 2, characterized in that: The test flow path for the combined liquid chromatography module and mass spectrometry module is as follows: liquid chromatography module, eighth interface, sixth interface, second quantitative loop, seventh interface, fifth interface, and mass spectrometry module.

9. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 3, characterized in that: The cleaning flow path of the first metering ring is as follows: cleaning solution storage bottle, micro-injection pump or constant flow pump, first interface, third interface, first metering ring, second interface, fourth interface and waste bottle; the cleaning flow path of the second metering ring is as follows: cleaning solution storage bottle, micro-injection pump or constant flow pump, first interface, seventh interface, second metering ring, sixth interface, fourth interface and waste bottle.

10. The mass spectrometer mass axis correction system based on eight-way valve switching for online dual-ion mode correction and tubing cleaning according to claim 3, characterized in that: The positive ion correction solution loading flow path is as follows: positive ion correction solution storage bottle, micro-injection pump or constant flow pump, first interface, third interface, first metering loop, second interface, fourth interface and waste bottle; The positive ion mode calibration flow path is as follows: liquid chromatography module, eighth interface, second interface, first quantitative loop, third interface, fifth interface, and mass spectrometry module; The loading flow path of the negative ion correction solution is as follows: negative ion correction solution storage bottle, micro-injection pump or constant flow pump, first interface, seventh interface, second quantitative ring, sixth interface, fourth interface and waste liquid bottle; The negative ion mode calibration flow path is as follows: liquid chromatography module, eighth interface, sixth interface, second quantitative loop, seventh interface, fifth interface and mass spectrometry module.

Images