Method for purging flow path of autosampler and device for purging flow path of autosampler

Abstract

The present application provides a flow path cleaning method for an automatic sampler, which can balance the decrease of analysis throughput and the increase of cleaning solution consumption. In a flow path cleaning process (S12), when a cleaning solution is supplied by a cleaning solution supply mechanism to a flow path switched by a flow path switching mechanism among a first flow path including a nozzle for sucking a sample and a sample ring for holding the sample sucked from the nozzle, and a second flow path including a cleaning tank for cleaning at least an outer wall of the nozzle, a control device changes a flow rate of the cleaning solution supplied between measurement of a first measurement item of the sample and measurement of a second measurement item of the sample, based on first cleaning information indicating a cleaning mode corresponding to the first measurement item of the sample, and second cleaning information indicating a cleaning mode corresponding to the second measurement item of the sample measured after the first measurement item.

Description

Technical Field

[0001] This disclosure relates to a method for cleaning the flow path of an automatic sampler, which is the sample introduction section of an automatic analytical apparatus for performing analyses of multiple measurement items, and to a flow path cleaning apparatus for the automatic sampler. Background Technology

[0002] One example of an automated analytical apparatus is the high-performance liquid chromatography-mass spectrometry (HPLC / MS) system. An HPLC / MS system combines a liquid chromatograph and a mass analyzer. By combining the separation of the chemical structure and physical properties of the target substance by HPLC with the separation and detection of the mass of the target substance by MS, qualitative and quantitative analysis of the components in the sample can be achieved. Based on this characteristic, qualitative and quantitative analysis of the target substance can be performed, for example, in cases where multiple similar substances exist mixed together due to metabolism in vivo, such as pharmaceuticals in biological samples, potentially leading to applications in clinical testing.

[0003] As a method for reducing residues in a liquid chromatography quality analysis apparatus, which is an example of an automated analysis device, when analyzing multiple samples, a technique for cleaning a sample injection needle and a cleaning mechanism for performing the cleaning are disclosed.

[0004] For example, Patent Document 1 discloses an automatic sampler for a liquid chromatograph that can clean the needle while providing cleaning solution to the cleaning tank, and can switch the type of cleaning solution and clean the needle according to the type of sample attached to the needle.

[0005] In addition, Patent Document 2 discloses an automatic sampler cleaning mechanism that uses a diaphragm pump to deliver cleaning fluid when cleaning the sample introduction needle and sample loop, thereby maintaining fluid delivery without losing time during fluid delivery as is the case with conventional pump and syringe mechanisms.

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: Japanese Patent Application Publication No. 2004-271241

[0009] Patent Document 2: Japanese Patent Application Publication No. 2008-145112 Summary of the Invention

[0010] The technical problem that the invention aims to solve

[0011] In recent years, the demand for automated analytical devices has included the ability to process multiple samples in a short time, i.e., increasing throughput, and suppressing the increase in testing costs associated with the increase in the number of samples processed. Therefore, it is preferable to increase throughput by shortening the processing time for each sample, and to reduce testing costs by minimizing reagent consumption per sample and reducing cleaning fluid consumption. On the other hand, due to the shortened processing time per sample and the reduced cleaning fluid consumption, the cleaning of the sample inlet before and after sample dispensing may sometimes be insufficient, resulting in carry-over residues that can cause measurement errors between multiple samples. Therefore, it is preferable to simultaneously increase throughput and reduce cleaning fluid consumption, thereby reducing carry-over residues.

[0012] However, when analyzing multiple samples consecutively, the time that the nozzle used to introduce (split) a specified amount of sample can spend processing one sample is limited, and sometimes there is not enough time to ensure that the nozzle is cleaned sufficiently after split.

[0013] In Patent Document 1, the influence of residues can be reduced by cleaning the needle simultaneously with providing the cleaning solution to the cleaning tank, or by switching the type of cleaning solution depending on the type of sample adhering to the needle. However, after measuring high-concentration samples, it is sometimes preferable to spend a longer time cleaning to reduce residues. That is, if cleaning is insufficient within the specified cleaning time, the analytical throughput can be reduced by sacrificing analytical throughput.

[0014] In Patent Document 2, a diaphragm pump is used to deliver the cleaning solution when cleaning the sample injection needle and sample loop, which reduces the time lost during cleaning solution delivery and thus makes efficient use of the limited cleaning time. Sufficient cleaning effect can be expected by setting the cleaning pump flow rate high in advance to minimize the impact of residues. However, even in measurements where the impact of residues is negligible or where cleaning is unnecessary, delivering the cleaning solution at a high flow rate can easily lead to excessive cleaning and increased consumption of the cleaning solution.

[0015] The problem to be solved by this disclosure is to provide a flow path cleaning method and apparatus for an automatic sampler that can simultaneously suppress the reduction in analytical throughput and the increase in cleaning fluid consumption.

[0016] Technical solutions to solve technical problems

[0017] The flow path cleaning method for the automatic sampler disclosed herein is characterized in that, when cleaning fluid is supplied by a cleaning fluid supply mechanism to a flow path switched by a flow path switching mechanism, the flow rate of the cleaning fluid supplied between the determination of the first determination item and the determination of the second determination item is changed based on cleaning information indicating a cleaning mode corresponding to a determination item of the sample, specifically, first cleaning information indicating a cleaning mode corresponding to a first determination item of the sample, and second cleaning information indicating a cleaning mode corresponding to a second determination item determined after the first determination item. Other solutions will be described in the embodiments for carrying out the invention.

[0018] Invention Effects

[0019] According to this disclosure, a flow path cleaning method and an apparatus for an automatic sampler can be provided, which can simultaneously suppress the reduction of analytical throughput and the increase of cleaning fluid consumption. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the automatic sampler in this embodiment.

[0021] Figure 2A This is a schematic diagram showing the 6-port 2-position valve of the sample inlet valve of this embodiment, and is a diagram showing the first position.

[0022] Figure 2B This is a schematic diagram showing the 6-port 2-position valve of the sample inlet valve of this embodiment, and a diagram showing the second position.

[0023] Figure 3 This describes the relationship between the applied voltage and flow rate to the cleaning pump in this embodiment.

[0024] Figure 4 This is a schematic diagram of the cleaning tank in this embodiment.

[0025] Figure 5 This is a schematic diagram of the sample table of this embodiment.

[0026] Figure 6 This is an example of a table used in this embodiment to determine the cleaning conditions before dispensing the sample.

[0027] Figure 7 This is a flowchart illustrating the flow path cleaning method of the automatic sampler according to this embodiment. Detailed Implementation

[0028] Hereinafter, embodiments (referred to as implementations) for carrying out this disclosure will be described with reference to the accompanying drawings. In the description of one embodiment below, another embodiment applicable to that embodiment will also be appropriately described. This disclosure is not limited to the following embodiment, but different embodiments can be combined with each other or arbitrarily modified within a range that does not significantly impair the effects of this disclosure. Furthermore, the same reference numerals are given to the same components, and repeated descriptions are omitted. In addition, components having the same function are given the same name. The illustrations are merely illustrative; for ease of illustration, changes may sometimes be made from the actual structure within a range that does not significantly impair the effects of this disclosure.

[0029] In the following description, the sample introduction section of the automated analytical apparatus that performs analysis on multiple measurement items will be referred to as an automatic sampler. Furthermore, while this embodiment focuses primarily on the sample introduction section of the automated analytical apparatus, this disclosure is not limited to automated analytical apparatuses but applies to all analytical apparatuses that include a sample introduction section.

[0030] Figure 1 This is a schematic diagram of the automatic sampler 1 according to this embodiment. The automatic sampler 1 includes a sample inlet valve 101, a sample loop 102, a measuring unit 103, a gear pump 104, system water 105, a cleaning pump 106, a cleaning tank 107, a sample cup 108, a nozzle 109, solenoid valves 110, 111, and 112, a liquid delivery pump 113, a separation column 114, a detector 115, and cleaning solutions 116 and 117 (containers for the cleaning solutions). These are all connected via flow paths such as piping (not shown). For example, the system water 105 and the cleaning solutions 116 and 117 are stored in tanks not shown.

[0031] The flow path cleaning device 10 of the automatic sampler 1 includes a first flow path 11, a second flow path 12, a cleaning fluid supply mechanism 13, a flow path switching mechanism 14, and a control device 118. The first flow path 11 includes a nozzle 109 for attracting sample and a sample ring 102 for holding the sample attracted from the nozzle 109. The inner wall of the nozzle 109 is cleaned by the flow of cleaning fluids 116 and 117 into the first flow path 11. If necessary, ultrapure water, system water 105, or other water can be used as the cleaning fluid to clean the inner wall of the nozzle 109.

[0032] The second flow path 12 includes a cleaning tank 107 for cleaning at least the outer wall of the nozzle 109. The cleaning fluid supply mechanism 13 supplies cleaning fluids 116 and 117 to the cleaning tank 107 via the first flow path 11 and the second flow path 12, respectively. Details will be described later. The nozzle 109 is placed in the cleaning tank 107 containing the cleaning fluids 116 and 117, and the nozzle 109 is brought into contact with the cleaning fluids 116 and 117, thereby cleaning at least the outer wall of the nozzle 109. If necessary, ultrapure water, system water 105, or other water can be used as the cleaning fluid to clean the outer wall of the nozzle 109. The cleaning fluid supply mechanism 13 includes a cleaning pump 106.

[0033] The flow path switching mechanism 14 switches the flow path from the cleaning fluid supply target provided by the cleaning fluid supply mechanism 13 to the first flow path 11 and the second flow path 12. The flow path switching mechanism 14 includes solenoid valves 110, 111, and 112.

[0034] Control device 118 controls the drive of autosampler 1 and is connected to autosampler 1 via an electrical signal line (not shown). Control device 118 will refer to... Figure 5 and Figure 6 As described later, the control device 118 adjusts the flow rates of the cleaning fluids 116 and 117 provided between the determination of the first and second measurements based on first cleaning information indicating a cleaning mode corresponding to the first measurement item and second cleaning information indicating a cleaning mode corresponding to the second measurement item measured after the first measurement item. The first and second cleaning information are examples of cleaning information indicating a cleaning mode corresponding to the measurement item of the sample.

[0035] The control device 118 is not shown, but may be configured to include, for example, a CPU (Central Processing Unit), RAM (Random Access Memory), ROM (Read Only Memory), etc.

[0036] The control device 118 is implemented by expanding the specified control program stored in ROM into RAM and executing it by the CPU.

[0037] In this embodiment, the sample is placed in the sample processing section (not shown) of the automated analyzer (not shown) and transferred to the pretreatment section (not shown). The sample is purified and concentrated in the pretreatment section, and the sample cup 108 containing the sample is transferred to the sample cup holding section (not shown) of the automated sampler 1. As the sample inlet valve 101, a 6-port 2-position valve is used in this embodiment, and a high-pressure valve with high pressure resistance (e.g., 100 MPa) is used.

[0038] Figure 2A This is a schematic diagram showing the 6-port 2-position valve of the sample inlet valve 101 according to this embodiment, and is a diagram showing the first position. The sample inlet valve 101 has six ports 201, 202, 203, 204, 205, and 206. Port 201 is connected to the separation column 114, ports 202 and 205 are connected to the sample ring 102, and port 203 is connected to the solenoid valve 111. Figure 1 Port 204 is connected to nozzle 109. Figure 1 Port 206 is connected to the liquid delivery pump 113.

[0039] The sample inlet valve 101 is not shown in the figure, but it has the following structure: by rotating the valve head to two positions, the flow path of the groove in the internal rotor seal is switched, thereby alternating the state in which adjacent ports are connected to each other. Figure 2A In the first position shown, the delivery pump 113, sample ring 102, and separation column 114 are connected via a flow path (not shown) in the sample inlet valve 101. In the first position, the flow path from the delivery pump 113 is connected to the sample ring 102, thus allowing delivery under high pressure conditions, for example, up to 100 MPa.

[0040] Figure 2B This is a schematic diagram showing the 6-port 2-position valve of the sample inlet valve 101 of this embodiment, and a diagram showing the second position. Figure 2B Position 2 shown, nozzle 109 ( Figure 1 ), sample ring 102 and solenoid valve 111 ( Figure 1 The sample is connected via a flow path (not shown) in the sample inlet valve 101. In position 2, the measuring unit 103 or the downstream gear pump 104 of the measuring unit 103 ( Figure 1 It is connected to the sample ring 102. Therefore, the maximum pressure is also below 1 MPa, typically under low pressure conditions such as 300 kPa.

[0041] From position 1 ( Figure 2A Switch to position 2. Figure 2B When switching from position 2 to position 1, the flow path in sample ring 102 changes from high pressure to low pressure. On the other hand, when switching from position 2 to position 1, the flow path in sample ring 102 changes from low pressure to high pressure.

[0042] Return to Figure 1In this embodiment, the sample ring 102 is made of stainless steel (SUS), for example, a tubing with an inner diameter of 0.3 mm, an outer diameter of 1 / 16 inch, a length of 283 mm, and a volume of 20 μL. The material can be other than SUS, such as polyetheretherketone (PEEK), PEEKsil (PEEK coated on the outer surface of molten silica), polytetrafluoroethylene (PTFE), or a copolymer of tetrafluoroethylene and perfluoroalkoxyethylene (PFA), etc. The dimensions can also be appropriately changed according to the measurement conditions.

[0043] The measuring unit 103 includes a syringe and a stepper motor (neither shown), and controls the driving amount of the syringe (not shown) via pulse control. In this embodiment, for example, a syringe with an inner diameter of 23.8 mm, a length of 85 mm, and a plunger capacity of 723 μL is used. The syringe can be driven by a servo motor instead of a stepper motor.

[0044] A gear pump 104 is positioned after the measuring unit 103, supplying system water 105 (i.e., pure water) to the measuring unit 103 and its injector (not shown) in the flow path. A two-way solenoid valve (not shown) is provided between the measuring unit 103 and the system water 105; by controlling the opening and closing of this two-way solenoid valve, system water 105 is supplied to the measuring unit 103. In this embodiment, the supply pressure is, for example, 300 kPa. This pressure can be appropriately varied, for example, by adjusting the pressure resistance of the two-way solenoid valve or solenoid valve 111 positioned before the gear pump 104. Furthermore, the flow rate of the system water 105 can be varied by the gear pump 104.

[0045] In this embodiment, the cleaning pump 106 is a tubular pump. The cleaning pump 106 may be a diaphragm pump. The flow path of the cleaning pump 106 is connected to the solenoid valve 110.

[0046] Figure 3 This diagram illustrates the relationship between the applied voltage to the cleaning pump 106 and the flow rate (liquid flow rate) in this embodiment. This relationship is stored, for example as a graphical representation, in the control device 118. Figure 1 The flow rate can be changed by altering the applied voltage to the cleaning pump 106. For example, increasing the applied voltage can linearly increase the flow rate. The applied voltage is controlled, for example, by a control device 118.

[0047] Return to Figure 1For example, a solenoid valve 112, such as a three-way solenoid valve, is provided upstream of the cleaning pump 106. The cleaning solutions 116 and 117 are used by switching the solenoid valve 112. In this embodiment, the cleaning solution 116 is, for example, acetonitrile, and the cleaning solution 117 is, for example, methanol. The type of cleaning solution 116 and 117 is determined according to the cleaning mode (cleaning conditions) set by the user for each measurement item. The cleaning solutions 116 and 117 are used to clean the first flow path 11, including the nozzle 109 and the sample ring 102. The cleaning solutions 116 and 117 can be supplied to the cleaning tank 107 by switching the solenoid valve 110.

[0048] Figure 4 This is a schematic diagram of the cleaning tank 107 according to this embodiment. The cleaning tank 107 cleans at least the outer side of the nozzle 109 by immersing the nozzle 109 in the provided cleaning solutions 116 and 117. The cleaning tank 107 includes a drain port 402, an organic solvent cleaning port 403, and a water cleaning port 404. Cleaning solutions 116 and 117 ( Figure 1 ) is supplied to organic solvent cleaning port 403, system water 105 ( Figure 1 The cleaning fluid 105 for cleaning the inside of the nozzle 109 is supplied to the water cleaning port 404. Additionally, as will be described later, the cleaning fluid and system water 105 for cleaning the inside of the nozzle 109 are discharged to the drain port 402.

[0049] return Figure 1 The sample cup 108 is a cup with precision management. In this embodiment, for example, the material is polypropylene, specifically a material with a lower inner diameter of 5 mm, an upper inner diameter of 6 mm, a height of 26 mm, and a volume of 250 μL. The sample cup 108 is held in the sample cup holding position (not shown). For example, a sample containing the target component after processing by the pretreatment unit (not shown) is transferred to the sample cup 108, and the sample cup 108 containing the sample is held in the sample cup holding position.

[0050] In this embodiment, the nozzle 109 is made of, for example, stainless steel (SUS), and is a pipe with an inner diameter of 0.8 mm, an outer diameter of 1.5 mm, a length of 50 mm, and a volume of 25 μL. The inner surface is ground to reduce residue. To suppress dead zone volume, a fitting corresponding to zero dead zone volume is used at the connection (not shown) between the pipe connecting the nozzle 109 and the sample inlet valve 101. This suppresses sample diffusion and reduces residue.

[0051] In this embodiment, solenoid valve 110 is a lock-type three-way solenoid valve. In the three-way solenoid valve, the flow path of cleaning pump 106 is connected to the COM (common port, not shown) side, the flow path of solenoid valve 111 is connected to the normally open (always open, not shown) side, and cleaning tank 107 is connected to the normally closed (always closed, not shown) side. When cleaning the sample ring 102, sample inlet valve 101, and the inside of nozzle 109, the flow path is connected to the normally open side. When cleaning solutions 116 and 117 are supplied to cleaning tank 107, the flow path is connected to the normally closed side. Thus, the cleaning solution is supplied to organic solvent cleaning port 403.

[0052] In this embodiment, the solenoid valve 111 is a lock-type three-way solenoid valve. In the three-way solenoid valve, the flow path of the sample inlet valve 101 is connected to the COM (common port, not shown) side, the solenoid valve 111 is connected to the normally open (always open, not shown) side, and the flow path of the measuring unit 103 is connected to the normally closed (always closed, not shown) side. When the measuring unit 103 is used for suction and discharge, and for liquid delivery from the gear pump 104, the flow path is connected to the normally closed side. When cleaning fluid 116, 117 is supplied from the cleaning pump 106, the flow path is connected to the normally open side, thereby performing cleaning of the first flow path 11, which includes the sample ring 102, the sample inlet valve 101, and the nozzle 109.

[0053] The delivery pump 113 has two plungers (neither shown), which are reciprocated by pulse control to continuously deliver two delivery solvents at high pressure, such as 100 MPa. In this embodiment, the delivery pump 113 has two built-in pumps (neither shown), and delivers liquid while changing the drive ratio of each pump according to the gradient conditions set by the user for each measurement item.

[0054] A mixer (not shown) is installed downstream of the delivery pump 113, where the delivery solvents from the two pumps are mixed. The mixer is, for example, a low-pressure solenoid valve (not shown). The solvent ratio of the delivery solvent can be changed by driving the low-pressure solenoid valve according to the mixing conditions set by the user for each analyte. In this embodiment, six liquids are used as delivery solvents: ultrapure water, acetonitrile, methanol, 1 mol / L formic acid, 1 mol / L ammonia, and 1 mol / L ammonium acetate. These six liquids are mixed by the low-pressure solenoid valve and then fed into the two pumps, allowing for gradient delivery while changing the drive ratio of the two pumps. The flow rate of the delivery solvent can be varied by the delivery pump 113.

[0055] In this embodiment, the separation column 114 is constructed, for example, by housing a packing material with an inner diameter of 1.0 mm, a length of 50 mm, and a particle size of 2.6 mm in a column body (not shown). As the separation mode, a reversed-phase mode is used, for example. However, the separation mode may also be any of the following: normal-phase mode, molecular weight fractionation mode, hydrophilic interaction chromatography mode (HILIC mode), and antigen-antibody reaction mode, instead of a reversed-phase mode.

[0056] In this embodiment, a detector, for example, used in a triple quadrupole mass spectrometer (Triple Q-MS), is used as detector 115. This is because of its excellent quantification capabilities. The mass analysis device may not be a triple quadrupole mass spectrometer, but may be an ion trap mass spectrometer (Iontrap-MS), a time-of-flight mass spectrometer (TOF-MS), or, in other words, a diode array detector, a UV detector, or a fluorescence detector.

[0057] Next, the cleaning method and steps for determining the cleaning conditions of the nozzle 109 in this embodiment will be explained.

[0058] Figure 5 This is a schematic diagram of the sample table in this embodiment. For the number of samples measured (not shown) and each measurement item for each sample, a cleaning mode is specified between the measurement of any measurement item and the measurement of the measurement item following that measurement item, performed before aliquoting the sample. Preferably, the cleaning mode for each measurement item is determined considering factors such as the detection sensitivity, dynamic range, and the influence of residues of the target component (measurement item in the sample) in the sample. The control device 118 of the automatic analysis apparatus (… Figure 1 ) Control flow path cleaning device 10 ( Figure 1 ), to perform cleaning according to the cleaning conditions specified in the set cleaning mode.

[0059] The assignment of cleaning modes in the sample table can be user-defined or automatically set. In the automatic setting case, for example, a database can be pre-defined containing a group of arbitrary first (e.g., No.1) assay items and their next (e.g., No.2) assay items, along with a database of appropriate pre-dispensing cleaning modes for each assay item within that group. Then, based on this database, the appropriate cleaning mode can be obtained according to the order of the assay items.

[0060] Figure 6This is an example of a table used in this embodiment to determine the cleaning conditions before dispensing the sample. For each test item, specific conditions (cleaning conditions) for the cleaning mode performed before sample dispensing are shown. For example, cleaning conditions representing the cleaning mode can be selected for each test item, such as cleaning modes A to D. The table includes cleaning information indicating the cleaning mode corresponding to the test item of the sample. The cleaning information includes cleaning information for cleaning the first flow path 11 (… Figure 1 The cleaning solutions 116 and 117 and the water used as cleaning solutions are disposed of through the second flow path 12. Figure 1 ) provided to cleaning tank 107 ( Figure 1 The cleaning fluids 116 and 117 are included in at least one of the following: the type of cleaning fluids 116 and 117, the flow rate of cleaning fluids 116 and 117, the cleaning time of the first flow path 11, and the cleaning time of the outer wall of the nozzle 109 in the cleaning tank 107. In the illustrated example, this includes the type of cleaning fluids 116 and 117 and water as cleaning fluid (each of the inner and outer walls of the nozzle 109), the flow rate of cleaning fluids 116 and 117 and water as cleaning fluid, and the cleaning time of each cleaning part (each of the inner and outer walls of the nozzle 109).

[0061] As mentioned above Figure 3 As illustrated, by changing the applied voltage, the flow rate of the cleaning solution can be varied, for example, within the range of 1 to 10 ml / min. Depending on the method of supplying the cleaning solution, it can also be done by changing the cleaning pump 106 ( Figure 1 The flow rate can be changed by replacing the applied voltage with the operation cycle of the nozzle 109. Furthermore, it is preferable to select a cleaning time within a range of 0 to 20 seconds, for example, the sum of the inner wall cleaning time and the outer wall cleaning time of the nozzle 109.

[0062] As an example, in cleaning mode A, methanol (MeOH) is used as nozzle 109 ( Figure 1 The cleaning process involves applying cleaning solutions to both the inner and outer walls of the device, with a flow rate of 2 ml / min. The cleaning time for the inner wall is 10 seconds, and the cleaning time for the outer wall is 10 seconds.

[0063] In cleaning mode B, methanol (MeOH) is used as the cleaning solution at a flow rate of 5 ml / min. The cleaning time for the inner wall is 15 seconds, and the cleaning time for the outer wall is 5 seconds. For example, cleaning mode B is preferred when the detection sensitivity of the analyte in the next analysis is low, and the influence of residues from the previous analysis is minimized.

[0064] In cleaning mode C, ultrapure water is used as the cleaning solution for the inner wall, and system water 105 is used as the cleaning solution for the outer wall. The flow rate of the cleaning solution is 2 ml / min, and the cleaning time for the inner wall is 10 seconds, and the cleaning time for the outer wall is 10 seconds. For example, if the analyte of the next analytical item is hydrophilic and water-based solvents are used for cleaning, cleaning mode C is preferred.

[0065] In cleaning mode D, ultrapure water is used as the cleaning solution for the inner wall, and system water 105 is used as the cleaning solution for the outer wall. The flow rate of the cleaning solution is 5 ml / min, the cleaning time for the inner wall is 15 seconds, and the cleaning time for the outer wall is 5 seconds. Cleaning mode D is preferred when the analyte is hydrophilic, the detection sensitivity is low, and the influence of residues from previous analyses is minimized.

[0066] Additionally, the cleaning conditions for each cleaning mode can be changed according to the user's wishes. When setting cleaning conditions for each measurement item, it is preferable to set each cleaning condition using the same steps.

[0067] Figure 7 This illustrates the automatic sampler 1 of this embodiment. Figure 1 The flowchart of the flow path cleaning method is shown. Figure 7 The flow path cleaning method shown can be achieved using the flow path cleaning device 10 ( Figure 1 This is done using [the following method / method]. For example, the test item is testosterone ([...]). Figure 5 Regarding the cleaning and sample dispensing procedures based on cleaning mode A before testing (see No. 1), please refer to further details. Figure 1 Please provide an explanation.

[0068] First, in the initial cleaning process S1, for example, the control device 118, which receives an instruction to execute cleaning mode A, searches... Figure 6 The table shown indicates the cleaning method for cleaning mode A, and the corresponding cleaning method is used to clean the inner and outer walls of nozzle 109.

[0069] When cleaning the inner wall, the control device 118 moves the nozzle 109 to the drain port 402 of the cleaning tank 107. Figure 4 Then, control device 118 puts solenoid valves 110, 111, and 112 to the normally open side, causing cleaning pump 106 to operate and flow through the first flow path 11 ( Figure 1 The cleaning solution 117 (methanol) is transferred to the nozzle 109. At this time, the control device 118 adjusts the voltage applied to the cleaning pump 106 and adjusts the flow rate of the cleaning solution 117 to 2 ml / min.

[0070] When cleaning the outer wall, the control device 118 moves the nozzle 109 to the organic solvent cleaning port 403 of the cleaning tank 107. Figure 4 Inside the second flow path 12, the solenoid valve 110 is switched to the normally closed side, and the solenoid valve 112 is set to the normally open side. The control device 118 activates the cleaning pump 106 and pumps the cleaning fluid 117 (methanol) through the second flow path 12. Figure 1 The cleaning solution 117 is transferred to the organic solvent cleaning port 403 of the cleaning tank 107. At this time, the control device 118 adjusts the voltage applied to the cleaning pump 106 and sets the flow rate of the cleaning solution 117 to 2 ml / min. During cleaning of the outer wall of the nozzle 109, the cleaning solution 117 overflowing from the organic solvent cleaning port 403 of the cleaning tank 107 is discharged to the discharge port (not shown) of the cleaning tank 107.

[0071] Next, in the cleaning process S2, the control device 118 moves the nozzle 109 to the drain port 402 of the cleaning tank 107. Figure 4 Then, cleaning is performed inside the nozzle 109. Cleaning is performed using system water 105, thereby cleaning the inner wall of the nozzle 109. Specifically, the control device 118 opens a two-way solenoid valve (not shown) located between the measuring unit 103 and the gear pump 104, and supplies system water 105 to the nozzle 109, thereby cleaning the nozzle 109.

[0072] Next, in the air aspiration step S3, the control device 118 moves the nozzle 109 onto the sample cup 108 to aspirate the sample. At this time, the control device 118 simultaneously performs gas aspiration as segmented air. During execution, the control device 118 switches the solenoid valve 111 to the normally closed side, then drives the measuring unit 103 and aspirates air. By inserting segmented air before aspirating the sample, the mixing of the cleaning fluid and the sample solution within the nozzle 109 is suppressed, reducing sample diffusion in the sample aspiration step S4 (described later). In this embodiment, the measuring unit 103, for example, drives 25 pulses to aspirate 5 μL of air.

[0073] Following the gas aspiration step S3, in the sample aspiration step S4, the control device 118 lowers the nozzle 109 along the height direction (Z direction) to the sample aspiration position and aspirates the sample by driving the measuring unit 103. In this embodiment, the measuring unit 103 drives 175 pulses, for example, to aspirate 35 μL of sample. If the sample is a biological sample, it can be serum, plasma, urine, biological tissue, etc. Besides biological samples, it can be calibration samples or QC (quality control) samples. The control device 118 processes the sample through a pretreatment unit (not shown) and transfers the sample cup 108 containing the sample to the sample cup holding unit (not shown) of the automatic sampler 1.

[0074] Next, in the sample transfer step S5, the sample is transferred. After the control device 118 returns the nozzle 109 to the starting position in the height direction (in the Z direction), it drives the measuring unit 103 to draw air, thereby transferring the drawn sample to the vicinity of the sample ring 102. In this embodiment, the measuring unit 103 drives, for example, 150 pulses to draw 30 μL of air.

[0075] Next, the backlash is performed in the backlash process S6. To eliminate the pressure difference generated in the flow path due to the syringe drive up to the sample transfer process S5, the syringe drive is operated on the discharge side. In this embodiment, the measuring unit 103 drives 5 pulses and discharges 1 μL of air.

[0076] Next, in valve switching process S7, the sample inlet valve 101 is switched. Control device 118 moves the sample inlet valve 101 from position 1 (…). Figure 2A Switch to position 2. Figure 2B Therefore, as Figure 2B As shown, nozzle 109, sample ring 102, and solenoid valve 111 are connected.

[0077] Next, in the first sample introduction step S8, the sample is introduced into the sample ring 102. After switching the sample introduction valve 101, the control device 118 drives the measuring unit 103 and discharges the sample into the sample ring 102. In this embodiment, for example, the measuring unit 103 drives 50 pulses, and 10 μL of sample is discharged into the sample ring 102. The amount of sample introduced into the sample ring 102 is variable depending on the driving amount of the measuring unit 103.

[0078] Next, in the second sample introduction step S9, the sample is introduced into the separation column 114. After the sample is introduced into the sample ring 102, the control device 118 moves the sample introduction valve 101 from the second position ( Figure 2B Switch to position 1. Figure 2A Therefore, as Figure 2A As shown, a delivery pump 113, a sample loop 102, and a separation column 114 are connected. The sample solution in the sample loop 102 is introduced into the separation column 114 by the mobile phase delivered from the delivery pump 113.

[0079] Next, in the moving step S10, the control device 118 moves the measuring unit 103 to the starting position. Thus, a series of sample introductions are completed, the target component is separated from the sample in the separation column 114, and detected by the detector 115.

[0080] If the analysis ends without any other samples ("Yes" in judgment step S11), the control device 118 stops operating. On the other hand, if there are other samples and the analysis continues ("No" in judgment step S11), the control device 118 repeats the steps after the cleaning step S2 after performing the flow path cleaning step S12.

[0081] The flow path cleaning process S12 is performed by providing cleaning solutions 116 and 117 to either the first flow path 11 or the second flow path 12 between the measurement of the first measurement item and the measurement of the second measurement item. The control device 118 provides cleaning solutions 116 and 117 to the flow path switched by the flow path switching mechanism 14 in the first flow path 11 and the second flow path 12 via the cleaning solution supply mechanism 13. This cleans the first flow path 11, including the inner wall of the nozzle 109 and the sample ring 102, and the outer wall of the nozzle 109 in the cleaning tank 107. When providing cleaning solutions 116 and 117, the control device 118 changes the flow rate of the cleaning solutions 116 and 117 based on first cleaning information indicating a cleaning mode corresponding to the first measurement item of the sample and second cleaning information indicating a cleaning mode corresponding to the second measurement item measured after the first measurement item. For example, the flow rate of the cleaning solutions 116 and 117 can be adjusted accordingly. Figure 6 The standard cleaning conditions (standard conditions) shown are modified.

[0082] For example, in measuring testosterone ( Figure 5 Following the No. 1 test item, estradiol (the first test item in the list) is measured. Figure 5 When measuring item No. 2 in the test, according to... Figure 6 The flow rate change shown corresponds to the cleaning mode B for estradiol. Figure 6 The flow rates of the washing solutions 116 and 117 under ( ). Additionally, in cases of repeated testosterone measurements, such as Figure 5 As shown, after each measurement, a washout mode A corresponding to testosterone was performed.

[0083] In this way, when residues are likely to be generated due to the samples, reagents, etc. used in the first assay, thorough cleaning can be achieved, for example, by increasing the flow rate (total flow rate within the specified cleaning time), thus suppressing residue buildup and reducing accuracy. On the other hand, when the impact of residues can be ignored, cleaning can be omitted or simplified. Therefore, in such cases, reducing the flow rate (total flow rate within the specified cleaning time) and simplifying or omitting cleaning can both suppress the decrease in analytical throughput and suppress the increase in cleaning solution consumption.

[0084] In the case of measurements after the third measurement, the control device 118 further adjusts the flow rates of the cleaning solutions 116 and 117 based on the first cleaning information (e.g., the second measurement) and the third cleaning information, whereby the third cleaning information indicates the cleaning mode corresponding to the third measurement (e.g., the first measurement) performed before the first measurement. Thus, taking into account the influence of samples, reagents, etc., used in the measurements of the first and second measurements, cleaning can be performed before the measurement of the third measurement, thereby more effectively suppressing both the decrease in analytical throughput and the increase in cleaning solution consumption.

[0085] The control device 118 adjusts the supply time of the cleaning fluids 116 and 117 based on at least one of the first cleaning information and the second or third cleaning information. The supply time to the first flow path 11 is the cleaning time of the inner wall of the nozzle 109. Figure 6 The supply time provided to the cleaning tank 107 is the contact time between the nozzle 109 in the cleaning tank 107 and the outer wall, which is the cleaning time of the outer wall. Figure 7 By varying the delivery time in conjunction with the flow rate, it is possible to more effectively suppress both the decrease in analytical throughput and the increase in cleaning fluid consumption.

[0086] The control device 118 adjusts the flow rates of the cleaning solutions 116 and 117 based on the ease with which residues are generated in at least one of the samples or test items used immediately preceding the provision of the cleaning solutions 116 and 117. Preferably, the types of cleaning solutions 116 and 117 are kept constant. Since the ease with which residues are generated depends to some extent on the sample and the test item, the occurrence of residues can be suppressed in this way. For example, in the case of samples or test items that are prone to generating residues, by adjusting the flow rate... Figure 6 The standard conditions shown are faster and reduce the impact of residues. In this case, the rinsing time (the supply time of rinsing solutions 116 and 117) can be extended as needed. On the other hand, for samples or test items where residues are unlikely to occur, the flow rate can be kept less than... Figure 6 The standard conditions shown can suppress the amount of cleaning fluids 116 and 117 used. At this time, the supply time (cleaning time) of cleaning fluids 116 and 117 can be shortened as needed.

[0087] However, increasing the flow rate of cleaning solutions 116 and 117 does not necessarily require increasing the supply time; the supply time can remain unchanged or be shortened. Conversely, decreasing the flow rate of cleaning solutions 116 and 117 does not necessarily require shortening the supply time; the supply time can remain unchanged or be increased. Therefore, the supply time can be appropriately determined based on various conditions such as flow rate and the ease of residue formation.

[0088] As described above, according to embodiments of this disclosure, it is possible to obtain the sample table ( Figure 5 ) and cleaning modes ( Figure 6 By appropriately switching the cleaning conditions of nozzle 109 according to the conditions specified in the specification, the decrease in analytical throughput can be suppressed. Thus, a flow path cleaning method and flow path cleaning apparatus 10 for an automatic sampler 1 can be provided, which can suppress the waste of cleaning fluid consumption within a limited sample processing time, while suppressing residues between multiple samples, thereby improving the accuracy of the measurement results.

[0089] Furthermore, this disclosure is not limited to the above-described embodiments, but also includes various modifications. For example, the above-described embodiments are detailed descriptions provided for ease of understanding, and this disclosure is not necessarily limited to including all the structures described. Additionally, a portion of the structure of one embodiment may be replaced with a structure of another embodiment; conversely, a structure of another embodiment may be added to the structure of one embodiment. Furthermore, a portion of the structure in each embodiment may be added to, deleted from, or replaced with other structures.

[0090] Label Explanation

[0091] 1 Automatic Sampler

[0092] 10 Flow path cleaning device

[0093] 11 1st flow path

[0094] 12 2nd flow path

[0095] 13 Cleaning fluid suppliers

[0096] 14 Flow path switching mechanism

[0097] 101 Sample Inlet Valve

[0098] 102 sample rings

[0099] 103 Measurement Units

[0100] 104 gear pump

[0101] 105 system water

[0102] 106 cleaning pump

[0103] 107 cleaning tank

[0104] 108 sample cups

[0105] 109 nozzles

[0106] Solenoid valves 110, 111, and 112

[0107] 113 Liquid Delivery Pump

[0108] 114 Separation Column

[0109] 115 detector

[0110] 116 and 117 cleaning solutions

[0111] 118 control device

[0112] Ports 201, 202, 203, 204, 205, and 206

[0113] 402 Drain Port

[0114] 403 Organic Solvent Cleaning Port

[0115] 404 water cleaning port

[0116] S1 Initial Cleaning Process

[0117] S2 Cleaning Process

[0118] S3 Gas Suction Process

[0119] S4 Sample Attraction Process

[0120] S5 Sample Transfer Process

[0121] S6 back gap process

[0122] S7 valve switching process

[0123] S8 Sample Introduction Process 1

[0124] S9 Second Sample Introduction Process

[0125] S10 Moving Process

[0126] S11 Judgment Process

[0127] S12 flow path cleaning process.

Claims

1. A flow path cleaning method of an automatic sampler characterized by, when a flow path switched by a flow path switching mechanism among a first flow path including a nozzle for aspirating a sample and a sample ring for holding the sample aspirated from the nozzle and a second flow path including a cleaning tank for cleaning at least an outer wall of the nozzle is supplied with a cleaning liquid by a cleaning liquid supply mechanism, a control device changes a flow rate of the cleaning liquid supplied between measurement of a first measurement item of the sample and measurement of a second measurement item measured after the first measurement item, based on first cleaning information indicating a cleaning mode corresponding to the first measurement item, second cleaning information indicating a cleaning mode corresponding to the second measurement item, and third cleaning information indicating a cleaning mode corresponding to a third measurement item measured before the first measurement item, among cleaning information indicating a cleaning mode corresponding to a measurement item of the sample.

2. The flow path cleaning method of an automatic sampler according to claim 1, characterized in that, the control device changes a supply time of the cleaning liquid based on at least one of the first cleaning information, the second cleaning information, or the third cleaning information.

3. The flow path cleaning method of an automatic sampler according to claim 1 or 2, characterized in that, the cleaning information includes at least one of a kind of cleaning liquid for cleaning the first flow path, a kind of cleaning liquid supplied to the cleaning tank through the second flow path, a flow rate of the cleaning liquid, a cleaning time of the first flow path, and a cleaning time of an outer wall of the nozzle in the cleaning tank.

4. The flow path cleaning method of an automatic sampler according to claim 1 or 2, characterized in that, the control device changes the flow rate of the cleaning liquid based on easiness of generation of a residue of at least either one of the sample and the measurement item used immediately before the cleaning liquid is supplied.

5. A flow path cleaning device for an autosampler, characterized by, including: a first flow path including a nozzle for aspirating a sample and a sample ring for holding the sample aspirated from the nozzle; a second flow path including a cleaning tank for cleaning at least an outer wall of the nozzle; a cleaning liquid supply mechanism for supplying a cleaning liquid to the cleaning tank through the first flow path and the second flow path, respectively; a flow path switching mechanism that switches a supply target of the cleaning liquid supplied from the cleaning liquid supply mechanism to the first flow path and the second flow path; and a control device that changes a flow rate of the cleaning liquid supplied between measurement of a first measurement item and measurement of a second measurement item measured after the first measurement item, based on first cleaning information indicating a cleaning mode corresponding to the first measurement item, second cleaning information indicating a cleaning mode corresponding to the second measurement item, and third cleaning information indicating a cleaning mode corresponding to a third measurement item measured before the first measurement item, among cleaning information indicating a cleaning mode corresponding to a measurement item of the sample. ​

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