Liquid chromatograph

Abstract

The liquid chromatograph comprises: a liquid delivery pump; an analysis flow path; the pressure sensor is used for detecting the liquid feeding pressure of the liquid feeding pump; a sample injection unit that injects a sample into the analysis flow path; a switching unit that connects or disconnects the liquid delivery pump and the analysis flow path; a liquid delivery failure detection unit that detects a liquid delivery failure of the liquid delivery pump; an analysis operation execution unit that performs control so as to perform analysis on all samples predetermined in the analysis plan in the form of plan analysis; a cleaning operation execution unit that, when a poor liquid delivery is detected, stops the analysis, and executes a cleaning operation that delivers the mobile phase at a high flow rate while disconnecting the liquid delivery pump and the analysis flow path, thereby eliminating the poor liquid delivery; a confirmation operation execution unit that executes, after the cleaning operation, a confirmation operation for detecting whether or not a liquid delivery failure is detected; and a non-injection analysis execution unit that executes a non-injection analysis in which the sample is not injected and the mobile phase is conveyed under the same conditions as the interrupted sample analysis when the liquid delivery failure is not detected during the confirmation operation, and restarts the planned analysis after removing the remaining sample.

Description

[0001] This application is a divisional application of a patent application for an invention named "Liquid Chromatograph", with an application date of March 6, 2019, an application number of 201980093583.8 (the application number of the international application is PCT / JP2019 / 008798). Technical Field

[0002] The present invention relates to a liquid chromatograph. Background Art

[0003] A liquid chromatograph supplies a mobile phase to an analysis flow path provided with a separation column through a liquid delivery pump, injects a sample into the analysis flow path upstream of the separation column, separates the sample into components using the separation column, and detects the separated sample components using a detector (see Patent Document 1).

[0004] In liquid chromatography analysis, the stability of the liquid delivery flow rate of the mobile phase has a great influence on the analysis results. In the analysis of a sample, the generation of bubbles in the pump chamber of the liquid delivery pump causes fluctuations in the liquid delivery flow rate, and there are cases where liquid delivery failure occurs. If such liquid delivery failure occurs, the baseline of the detector signal is disrupted, and the reproducibility of the analysis results deteriorates. Therefore, when liquid delivery failure of the liquid delivery pump occurs during analysis, in most cases, re-analysis is required.

[0005] Especially when continuously performing analysis on multiple samples according to a preset analysis plan, if liquid delivery failure of the liquid delivery pump occurs during the planned analysis, the reliability of the sample analysis performed after the liquid delivery failure is low, wasting analysis time, samples, and solvents.

[0006] Therefore, it has been proposed that when liquid delivery failure of the liquid delivery pump occurs during analysis, the analysis is interrupted, the liquid delivery pump is connected to a drain pipe, and a cleaning operation of delivering the mobile phase at a high flow rate is performed to automatically eliminate the liquid delivery failure (Patent Document 2). After eliminating the liquid delivery failure, the interrupted analysis is restarted.

[0007] [Prior Art Documents]

[0008] [Patent Documents]

[0009] Patent Document 1: WO2017 / 006410A1

[0010] Patent Document 2: Japanese Patent Laid-Open No. 11-326300 Summary of the Invention

[0011] [Problems to be Solved by the Invention]

[0012] As described above, from the viewpoint of reproducibility of analysis results, it is preferred to interrupt the analysis and perform a cleaning operation when a liquid delivery failure occurs, then restart the interrupted analysis from the beginning, or skip the analysis of the sample and perform the analysis of the next sample. However, it is also considered that the sample of the interrupted analysis may remain in the analysis flow path, and the sample may affect the next analysis result.

[0013] Therefore, an object of the present invention is to automatically eliminate a liquid delivery failure of a liquid delivery pump when the liquid delivery failure occurs, and to perform a new analysis with good reproducibility after eliminating the liquid delivery failure.

[0014] [Technical means to solve the problem]

[0015] The liquid chromatograph of the present invention comprises: a liquid delivery pump for delivering a mobile phase; an analytical flow path, including a separation column for separating a sample according to its components and a detector for detecting the sample components separated in the separation column; a pressure sensor for detecting the liquid delivery pressure generated by the liquid delivery pump; a sample injection unit for injecting the sample into the analytical flow path; a switching unit for switching so that the liquid delivery pump and the analytical flow path are in a connected state or a disconnected state; a liquid delivery failure detection unit configured to compare the variation amplitude of the liquid delivery pressure detected by the pressure sensor with a preset threshold value, and detect liquid delivery failure of the liquid delivery pump when the variation amplitude of the liquid delivery pressure exceeds the threshold value; an analytical action execution unit configured to control the actions of the liquid delivery pump, the sample injection unit and the switching unit, and execute the liquid delivery pump and the analytical flow path to be in a connected state and disconnected state in the form of a planned analysis for all samples predetermined in a preset analysis plan. an analysis performed by injecting the sample into the analysis flow path; a cleaning action execution unit, configured to, when the poor liquid delivery detection unit detects poor liquid delivery during the analysis of the sample, terminate the analysis of the sample being executed, and execute the cleaning action for a preset cleaning time, the cleaning action being to set the liquid delivery pump and the analysis flow path to a non-connected state, and to use the liquid delivery pump to deliver the mobile phase at a flow rate higher than that in the analysis; a confirmation action execution unit, configured to execute a confirmation action of whether the poor liquid delivery detection unit detects poor liquid delivery after the cleaning action is completed; and a non-injection analysis execution unit, configured to, when the poor liquid delivery detection unit does not detect poor liquid delivery in the confirmation action, execute non-injection analysis, the non-injection analysis is not to inject the sample, and to use the liquid delivery pump to deliver the mobile phase in the analysis flow path under the same conditions as the analysis of the sample, and the analysis action execution unit is configured to restart the planned analysis after executing the non-injection analysis.

[0016] [Effects of the Invention]

[0017] The liquid chromatography instrument according to the present invention is configured to, when a liquid delivery failure is detected during the analysis of a sample, abort the analysis of the sample being executed, perform a cleaning operation for a preset cleaning time. The cleaning operation is to set the state between the liquid delivery pump and the analysis flow path to a non-connected state, and use the liquid delivery pump to deliver the mobile phase at a flow rate higher than that during analysis. After the cleaning operation ends, a confirmation operation for detecting whether a liquid delivery failure is performed. When no liquid delivery failure is detected in the confirmation operation, a non-injection analysis is performed. The non-injection analysis is to not inject the sample and deliver the mobile phase in the analysis flow path under the same conditions as the analysis of the sample. Therefore, when there is a liquid delivery failure of the liquid delivery pump, the liquid delivery failure can be automatically eliminated through the cleaning operation, and the sample remaining in the analysis flow path can be flushed through the non-injection analysis after eliminating the liquid delivery failure, so that a new analysis can be performed with good reproducibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a structural diagram schematically showing an embodiment of a liquid chromatography instrument.

[0019] Figure 2 is a flow path structural diagram showing the state where the mobile phase supply flow path is connected to the analysis flow path in the same embodiment with thick solid lines.

[0020] Figure 3 is a flow path structural diagram showing the state where the mobile phase supply flow path is connected to the drain pipe in the same embodiment with thick solid lines.

[0021] Figure 4 is a flowchart for explaining the operation of the same embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0022] Hereinafter, an embodiment of a liquid chromatography instrument will be described with reference to the drawings.

[0023] As Figure 1 shown, the liquid chromatography instrument of the embodiment includes a liquid delivery pump 2, a mobile phase supply flow path 4, a pressure sensor 6, a separation column 8, a detector 10, an analysis flow path 12, an autosampler 14, and a management device 18.

[0024] The liquid delivery pump 2 is used to deliver the mobile phase and is provided on the mobile phase supply flow path 4. The pressure sensor 6 is provided on the mobile phase supply flow path 4 to detect the liquid delivery pressure of the liquid delivery pump 2.

[0025] The separation column 8 and the detector 10 are provided on the analysis flow path 12. An autosampler 14 is provided between the mobile phase supply flow path 4 and the analysis flow path 12. The autosampler 14 forms a sample injection part for injecting a sample into the analysis flow path 12.

[0026] The autosampler 14 includes a switching valve 16, and the switching valve 16 has a switching to asFigure 2 The state in which the mobile phase supply flow path 4 is fluidically connected to the analysis flow path 12 is similar to the state in which the mobile phase supply flow path 4 is fluidically connected to the analysis flow path 12. Figure 3 The switching valve 16 has the function of connecting the mobile phase supply flow path 4 fluid to the drain pipe in any state. That is, the switching valve 16 realizes a switching unit for switching between the liquid delivery pump 2 and the analysis flow path 12 to a connected state or a disconnected state. In addition, the switching valve 16 can also be an injection valve that switches whether to insert a sample loop (not shown) holding a sample between the mobile phase supply flow path and the analysis flow path.

[0027] The management device 18 is used to manage the operation of the liquid delivery pump and the automatic sampler 14, for example, by a general-purpose personal computer or a dedicated computer. The management device 18 includes an analysis action execution unit 20, a liquid delivery failure detection unit 22, a cleaning action execution unit 24, a confirmation action execution unit 24, a non-injection analysis execution unit 26, a cleaning number setting unit 30, and a cleaning time setting unit 32. The analysis action execution unit 20, the liquid delivery failure detection unit 22, the cleaning action execution unit 24, the confirmation action execution unit 24, the non-injection analysis execution unit 26, the cleaning number setting unit 30, and the cleaning time setting unit 32 are functions obtained by a central processing unit (central processing unit (CPU)) provided in the management device 18 executing a prescribed program.

[0028] The analysis operation execution unit 20 is configured to perform chromatographic analysis on all samples specified in a pre-set analysis plan in the form of planned analysis. The analysis of one sample is performed by placing the mobile phase supply flow path 4 and the analysis flow path 12 in a fluid connection state ( Figure 2 The analysis of a sample is started by injecting the sample into the analysis flow path 12 using the automatic sample injector 14. Whether the analysis of a sample has been completed can be determined by whether a specified time has passed since the sample was injected into the analysis flow path (start of analysis). The so-called planned analysis means a series of actions from the injection of the sample into the analysis flow path until the specified time has passed until the analysis is completed for all samples scheduled in the analysis plan.

[0029] The poor liquid delivery detection unit 22 is configured to compare the variation range of the liquid delivery pressure detected by the pressure sensor 6 with a preset threshold value, and detect poor liquid delivery of the liquid delivery pump 2 when the variation range of the liquid delivery pressure exceeds the threshold value. The poor liquid delivery detection unit 22 detects poor liquid delivery during the analysis of the sample and the confirmation operation described below. Here, the variation range of the liquid delivery pressure refers to the difference between the maximum value and the minimum value of the liquid delivery pressure within a certain period of time.

[0030] The cleaning operation execution unit 24 is configured to execute a cleaning operation when a liquid feeding failure is detected by the liquid feeding failure detection unit 22 during the analysis of a sample. The cleaning operation means fluidly connecting the mobile phase supply flow path 4 to the drain pipe and feeding the mobile phase by the liquid feeding pump 2 at a flow rate higher than that during analysis for a specified time.

[0031] The confirmation operation execution unit 26 is configured to execute a confirmation operation after executing the cleaning operation, that is, fluidly connecting the mobile phase supply flow path 4 to the analysis flow path 12 and feeding the mobile phase by the liquid feeding pump 2 at a flow rate similar to that during analysis for a specified time, for example.

[0032] The cleaning operation execution unit 24 is configured to execute the cleaning operation again when a liquid feeding failure is detected by the liquid feeding failure detection unit 22 during the confirmation operation. However, when the liquid feeding failure is not eliminated even after the cleaning operation is executed a specified number of times, it is determined that there is an abnormality in the liquid feeding pump 2, and the analysis operation execution unit 20 is configured to end the planned analysis.

[0033] The non-injection analysis execution unit 28 is configured to execute a non-injection analysis when a liquid feeding failure is not detected during the confirmation operation. The non-injection analysis means that, in order to remove the sample remaining in the analysis flow path 12 from the analysis flow path 12, the sample is not injected and only the mobile phase is fed in the analysis flow path 12. The mobile phase fed in the analysis flow path 12 during the non-injection analysis may be under the same conditions (flow rate, composition, gradient distribution, etc.) as those of the analysis interrupted due to the detection of a liquid feeding failure, or may not be under exactly the same conditions as the interrupted analysis. The key is to be conditions that can remove the sample in the analysis flow path.

[0034] The analysis operation execution unit 20 is configured to restart the planned analysis after the non-injection analysis ends. At this time, the sample scheduled after the sample of the interrupted analysis in the analysis plan may be injected into the analysis flow path 12 to restart the planned analysis, or when the sample of the interrupted analysis remains in the sample container, the sample of the interrupted analysis may also be injected into the analysis flow path 12 again to restart the planned analysis.

[0035] In addition, the analysis operation execution unit 20 may also be configured to execute the following preparation before injecting the sample into the analysis flow path 12 when restarting the planned analysis, that is, feeding the mobile phase at the initial concentration in the analysis of the sample in the analysis flow path 12 for a specified time. In this case, the user can freely set the preparation time for the management device 18.

[0036] In addition, the analysis operation execution unit 20 is configured to determine that there is an abnormality in the liquid feeding pump 2 and end the planned analysis when the number of times of liquid feeding failure detected by the liquid feeding failure detection unit 22 exceeds a preset allowable number of times.

[0037] The cleaning frequency setting unit 30 is configured to set the number of cleaning operations that serve as the criterion for determining an abnormality in the liquid feed pump 2 based on information input by the user. That is, the user can arbitrarily set the number of cleaning operations that serve as the criterion for determining an abnormality in the liquid feed pump 2. If it is determined that the liquid feed pump 2 is abnormal, the planned analysis is terminated. In addition, the function of the cleaning frequency setting unit 30 is not essential.

[0038] The cleaning time setting unit 32 is configured to set the time of the cleaning operation based on information input by the user. That is, the user can arbitrarily set the time of the cleaning operation. In addition, the function of the cleaning time setting unit 32 is not essential.

[0039] Use Figure 1 And Figure 4 A flowchart is used to illustrate an example of the actions in the planned analysis implemented by the above functions.

[0040] After starting the planned analysis, as long as there is a specimen to be analyzed, the analysis action execution unit 20 injects a predetermined specimen into the analysis flow path 12 (steps 101 and 102). During the analysis of the specimen, the liquid feed failure detection unit 22 calculates the variation range of the liquid feed pressure detected by the pressure sensor 6 at regular time intervals, and compares the calculated variation range with a threshold value to monitor whether a liquid feed failure occurs (step 103). When no liquid feed failure is detected until the analysis of the specimen is completed (step 104), the analysis proceeds to the next specimen, and the planned analysis ends when the analysis of all specimens is completed.

[0041] When the liquid feed failure detection unit 22 detects a liquid feed failure during the analysis of the specimen (step 103), the analysis action execution unit 20 interrupts the planned analysis. If the number of liquid feed failures that occur during the planned analysis does not exceed a preset allowable number (for example, 5 times), the cleaning action execution unit 24 performs a cleaning operation (steps 105 and 106). After the cleaning operation is completed, the confirmation action execution unit 26 performs a confirmation action to check whether the liquid feed failure has been eliminated (step 107). If the liquid feed failure has been eliminated, the non-injection analysis execution unit 28 performs a non-injection analysis (steps 108 and 109).

[0042] After the analysis operation execution unit 20 finishes the non-injection analysis, it restarts the planned analysis (step 101). On the other hand, when a liquid feeding failure is detected during the confirmation operation after the cleaning operation (step 108), the cleaning operation execution unit 24 repeats the cleaning operation within the range where the number of cleaning operations does not exceed a specified number (for example, 3 times) until the liquid feeding failure is eliminated (step 110). When the liquid feeding failure is not eliminated even after repeating the cleaning operation the specified number of times (step 110), the analysis operation execution unit 20 ends the planned analysis. In addition, when the analysis is ended due to a liquid feeding failure, it is preferable to create a data file in a form that can be distinguished from the normal data file when no liquid feeding failure is detected.

[0043] When the liquid feeding failure detection unit 22 detects a liquid feeding failure during the analysis of the sample (step 103), and the number of liquid feeding failures that occur during the planned analysis exceeds the allowable number, the planned analysis is ended (step 105).

[0044] In the embodiment described above, the switching unit for switching to make the connection state or non-connection state between the liquid feeding pump 6 and the analysis flow path 12 is implemented by the switching valve 16 in the autosampler 14, but the present invention is not limited thereto, and a switching unit for switching to make the connection state or non-connection state between the liquid feeding pump 6 and the analysis flow path 12 may be provided separately on the front stage side of the autosampler 14.

[0045] An embodiment of the liquid chromatograph of the present invention includes: a liquid delivery pump (2) for delivering a mobile phase; an analysis flow path (12) including a separation column (8) for separating a sample into components and a detector (10) for detecting the sample components separated in the separation column (8); a pressure sensor (6) for detecting the liquid delivery pressure of the liquid delivery pump (2); a sample injection unit (14) for injecting a sample into the analysis flow path (12); a switching unit (16) for switching to make the connection state or non-connection state between the liquid delivery pump (2) and the analysis flow path (12); a liquid delivery failure detection unit (22) configured to compare the variation range of the liquid delivery pressure detected by the pressure sensor (6) with a preset threshold value, and when the variation range of the liquid delivery pressure exceeds the threshold value, detect the liquid delivery failure of the liquid delivery pump (2); an analysis operation execution unit (20) configured to control the operations of the liquid delivery pump (2), the sample injection unit (14), and the switching unit (16), and perform an analysis in which the connection state between the liquid delivery pump (2) and the analysis flow path (12) is set and a sample is injected into the analysis flow path (12) for all the samples predetermined in a preset analysis plan in the form of a planned analysis; a cleaning operation execution unit (24) configured to, when a liquid delivery failure is detected by the liquid delivery failure detection unit (22) during the analysis of a sample, abort the analysis of the sample being executed, and perform a cleaning operation for a preset cleaning time, where the cleaning operation is to set the non-connection state between the liquid delivery pump (2) and the analysis flow path (12), and use the liquid delivery pump (2) to deliver the mobile phase at a flow rate higher than that during the analysis; a confirmation operation execution unit (26) configured to, after the cleaning operation ends, perform a confirmation operation on whether a liquid delivery failure is detected by the liquid delivery failure detection unit (22); and a non-injection analysis execution unit (28) configured to, when a liquid delivery failure is not detected by the liquid delivery failure detection unit (22) during the confirmation operation, perform a non-injection analysis, where the non-injection analysis is to not inject a sample, and under the same conditions as the analysis of the sample, use the liquid delivery pump (2) to deliver the mobile phase in the analysis flow path (12), and the analysis operation execution unit (20) is configured to restart the planned analysis after performing the non-injection analysis.

[0046] In the first aspect of the embodiment, the non-injection analysis execution unit (28) is configured to, in the non-injection analysis, use the liquid delivery pump (2) to deliver the mobile phase in the analysis flow path (12) under the same conditions as the analysis performed immediately before the cleaning operation. With this aspect, the sample remaining in the analysis flow path (12) can be efficiently removed from the analysis flow path (12), and the reproducibility of the analysis of the next sample can be improved.

[0047] In addition, in the second form of the above-described embodiment, the cleaning operation execution unit (24) is configured to execute the cleaning operation again when a liquid feeding failure is detected by the liquid feeding failure detection unit (22) during the confirmation operation. In this form, since the cleaning operation is repeatedly executed multiple times, it is easy to eliminate the liquid feeding failure of the liquid feeding pump (2).

[0048] In the second form, the analysis operation execution unit (20) is configured to end the planned analysis when a liquid feeding failure is detected by the liquid feeding failure detection unit (22) during the confirmation operation after executing the cleaning operation a specified number of times. When the liquid feeding failure is not eliminated even after executing the cleaning operation multiple times, it is considered that there is a problem with the liquid feeding pump (2) itself. Therefore, the problem can be solved earlier by ending the planned analysis.

[0049] In such a case, it may include a cleaning times setting unit configured to set the specified number of times of the cleaning operation based on user input information. In this way, the user can arbitrarily set the number of times of the cleaning operation that serves as the determination criterion for whether there is a problem with the liquid feeding pump (2).

[0050] In the third form of the above-described embodiment, it includes a cleaning time setting unit configured to set the cleaning time based on information input by the user. In this form, the user can arbitrarily set the time of the cleaning operation.

[0051] In the fourth form of the above-described embodiment, the analysis operation execution unit (20) is configured to end the planned analysis when the number of liquid feeding failures detected by the liquid feeding failure detection unit (22) during the planned analysis exceeds a preset allowable number. When a liquid feeding failure is detected multiple times during one planned analysis, it is considered that there is a problem with the liquid feeding pump (2) itself. Therefore, in such a case, the problem can be solved earlier by ending the planned analysis.

[0052] [Description of Symbols]

[0053] 2: Liquid feeding pump; 4: Mobile phase supply flow path; 6: Pressure sensor; 8: Separation column; 10: Detector; 12: Analysis flow path; 14: Autosampler (sample injection unit); 16: Switching valve; 18: Management device; 20: Analysis operation execution unit; 22: Liquid feeding failure detection unit; 24: Cleaning operation execution unit; 26: Sample loop; 28: Confirmation operation execution unit; 30: Cleaning times setting unit; 32: Cleaning time setting unit.

Claims

1. A liquid chromatograph, include: Liquid delivery pump, delivering mobile phase; An analytical flow path, comprising a separation column for separating the sample into components and a detector for detecting the sample components separated in the separation column; A pressure sensor for detecting the liquid delivery pressure of the liquid delivery pump; A sample injection part, used to inject the sample into the analysis flow path; A switching unit, used for switching so that the liquid delivery pump and the analysis flow path are in a connected state or a disconnected state; a liquid delivery failure detection unit configured to compare the variation range of the liquid delivery pressure detected by the pressure sensor with a preset threshold value, and detect a liquid delivery failure of the liquid delivery pump when the variation range of the liquid delivery pressure exceeds the threshold value; an analysis operation execution unit configured to control the operations of the liquid delivery pump, the sample injection unit, and the switching unit, and to execute analysis by connecting the liquid delivery pump to the analysis flow path and injecting the sample into the analysis flow path for all samples predetermined in a pre-set analysis plan in the form of planned analysis; a cleaning action execution unit configured to, when the poor liquid delivery detection unit detects poor liquid delivery during the analysis of the sample, suspend the analysis of the sample being executed, and execute a cleaning action for a preset cleaning time to eliminate the poor liquid delivery, wherein the cleaning action is to set the liquid delivery pump and the analysis flow path to a disconnected state, and use the liquid delivery pump to deliver the mobile phase at a flow rate higher than that in the analysis; A confirmation operation execution unit configured to execute a confirmation operation to determine whether or not the liquid supply failure detection unit has detected liquid supply failure after the cleaning operation is completed; as well as The non-injection analysis execution unit is configured to execute the non-injection analysis when the liquid delivery failure detection unit does not detect the liquid delivery failure in the confirmation operation. The non-injection analysis is to not inject the sample and to use the liquid delivery pump to deliver the mobile phase in the analysis flow path at the same flow rate, composition and gradient distribution as the interrupted analysis performed before the cleaning operation is performed, thereby removing the sample of the interrupted analysis performed before the cleaning operation is performed and remaining in the analysis flow path from the analysis flow path, and The analysis operation execution unit is configured to restart the planned analysis after executing the non-injection analysis.

2. The liquid chromatograph according to claim 1, in, The cleaning operation execution unit is configured to execute the cleaning operation again when the liquid supply failure detection unit detects a liquid supply failure during the confirmation operation.

3. The liquid chromatograph according to claim 2, in, The analysis operation execution unit is configured to end the planned analysis when the liquid supply failure detection unit detects liquid supply failure in the confirmation operation after the cleaning operation is executed a predetermined number of times.

4. The liquid chromatograph according to claim 3, include: The cleaning frequency setting unit is configured to set the predetermined number of times of the cleaning operation based on user input information.

5. The liquid chromatograph according to claim 1, include: The cleaning time setting unit is configured to set the cleaning time based on information input by a user.

6. The liquid chromatograph according to claim 1, in, The analysis operation execution unit is configured to terminate the planned analysis when the number of liquid supply failures detected by the liquid supply failure detection unit exceeds a preset allowable number of times during the planned analysis.

7. The liquid chromatograph according to claim 1, in, The planned analysis is a series of operations that are continuously performed on all the samples specified in the analysis plan, from the injection of the sample into the analysis channel until a predetermined time has passed until the analysis is completed.

8. The liquid chromatograph according to claim 1, in, The analysis operation execution unit is configured to, after executing the non-injection analysis, inject a sample scheduled after the sample of the interrupted analysis in the analysis plan into the analysis channel to restart the planned analysis.

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