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WO2015063886A1 - Liquid-chromatography apparatus - Google Patents

Liquid-chromatography apparatus Download PDF

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Publication number
WO2015063886A1
WO2015063886A1 PCT/JP2013/079398 JP2013079398W WO2015063886A1 WO 2015063886 A1 WO2015063886 A1 WO 2015063886A1 JP 2013079398 W JP2013079398 W JP 2013079398W WO 2015063886 A1 WO2015063886 A1 WO 2015063886A1
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WO
WIPO (PCT)
Prior art keywords
mobile phase
analysis
column
flow path
unit
Prior art date
Application number
PCT/JP2013/079398
Other languages
French (fr)
Japanese (ja)
Inventor
祐治 勝山
Original Assignee
株式会社島津製作所
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Publication date
Application filed by 株式会社島津製作所 filed Critical 株式会社島津製作所
Priority to PCT/JP2013/079398 priority Critical patent/WO2015063886A1/en
Publication of WO2015063886A1 publication Critical patent/WO2015063886A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/38—Flow patterns
    • G01N30/46—Flow patterns using more than one column
    • G01N30/466—Flow patterns using more than one column with separation columns in parallel
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/74—Optical detectors

Definitions

  • the present invention relates to a liquid chromatograph apparatus, and more particularly to a liquid chromatograph apparatus having a configuration capable of switching a plurality of mobile phases having different characteristics and a plurality of columns used for component separation.
  • FIG. 7 is a schematic diagram of a flow path configuration of a liquid chromatograph apparatus capable of switching between a column and a mobile phase (see, for example, Patent Document 1).
  • the liquid chromatograph apparatus includes a liquid feeding unit 1, an injector 2, a column unit 3, and a detector 4.
  • the liquid feeding unit 1 mixes the mobile phase solvent A sucked by the first liquid feeding pump 16 and the mobile phase solvent B sucked by the second liquid feeding pump 17 by the gradient mixer 18 and then sends them to the column.
  • Four solvent containers 10a to 10d are connected to the first liquid feed pump 16 via the first solvent switching valve 14 and the first deaeration unit 12, and the second liquid feeding pump 17 is connected to the second solvent switching valve 15 and Four solvent containers 11 a to 11 d are connected via the second degassing unit 13.
  • the solvent containers 10a to 10d contain, for example, an aqueous mobile phase solvent (a solvent containing water as a main component).
  • an aqueous mobile phase solvent a solvent containing water as a main component.
  • the four solvent containers 10a to 10d One of them is selected, and the solvent in the container is sucked by the first liquid feeding pump 16 as the mobile phase solvent A.
  • organic solvents solvents mainly composed of organic solvents
  • the second solvent switching valve 15 One of them is selected, and the solvent in the container is sucked by the second liquid feeding pump 17 as the mobile phase solvent B.
  • the flow rates of the two liquid feed pumps 16 and 17 can be controlled so as to change with the passage of time, whereby a gradient type feed in which the mixing ratio of the mobile phase solvents A and B changes with time. Liquid is possible.
  • the injector 2 includes an autosampler, selects one from a number of vials prepared in advance in the tray, sucks a predetermined amount of the sample solution in the vial, and injects it into the mobile phase at a predetermined timing.
  • the column unit 3 includes a pair of five columns 31a to 31e, a bypass flow channel 32, and a pair for selectively connecting any one of the columns 31a to 31e and the bypass flow channel 32 to the flow channel of the mobile phase.
  • Column flow path switching valves 30 and 33 These are housed in a column oven (not shown) and the temperature is adjusted appropriately.
  • the detector 4 provided on the flow path of the eluate from the column outlet is, for example, a photodiode array (PDA) detector.
  • PDA photodiode array
  • the light from the light source is irradiated onto the eluate, the light transmitted through the eluate is wavelength-dispersed, and the intensity of light of each wavelength is detected almost simultaneously by the photodiode array.
  • Detection signals repeatedly obtained at predetermined time intervals by the detector 4 are converted into digital signals, respectively, and output to the data processing unit 5 as three-dimensional data having three dimensions of time, wavelength, and absorbance.
  • the detector 4 is not limited to a PDA detector, and may be a mass spectrometer, for example. In some cases, a plurality of detectors are provided.
  • the mobile phase used for analysis can be switched by switching the flow path using the solvent switching valves 14 and 15.
  • the column used for analysis can be switched by switching the channel using the column channel switching valves 30 and 33. Therefore, it is possible to sequentially and continuously analyze a large number of samples while appropriately switching the mobile phase and the column. However, care must be taken when switching the mobile phase or column for the following reasons.
  • the pH of the mobile phase used for analysis is wide, but certain columns cannot be used with high pH mobile phases.
  • silica gel often used as a column packing carrier is dissolved in a high pH mobile phase. Therefore, a high-pH mobile phase remaining in the flow path upstream (injector 2 side) from the first column flow path switching valve 30 uses a filler that uses silica gel as a carrier when the flow path is switched. If it flows into the column, the mobile phase may damage the column. In order to prevent this, in the liquid chromatograph apparatus shown in FIG. 7, a preliminary liquid feeding operation called pre-run analysis is performed when the mobile phase and the column are switched.
  • the bypass flow path 32 is connected to the mobile phase flow path by the column flow switching valves 30 and 33, and the mobile phase used in the next analysis to be performed is supplied to the column unit 3 by the liquid feed pumps 16 and 17. Is done.
  • the mobile phase remaining in the flow channel upstream of the first column flow switching valve 30 immediately before the pre-run analysis is discharged to the outside through the bypass flow channel 32, that is, without passing through the columns 31a to 31e.
  • the mobile phase in the flow path upstream from the first column flow path switching valve 30 is replaced with the mobile phase used in the next analysis to be performed, and an undesirable mobile phase that may damage the column. Can be prevented from flowing into the column.
  • the high pH mobile phase as described above can be obtained. It is possible to reliably prevent introduction into a column that does not support a high pH mobile phase.
  • the pre-run analysis takes some time. For this reason, when carrying out continuous analysis with mobile phase or column switching, the number of executions of pre-run analysis is increased, and the total analysis time is increased accordingly, resulting in a decrease in analysis efficiency.
  • an extra mobile phase solvent is required as much as the pre-run analysis is performed, and the analysis cost increases.
  • the present invention has been made to solve these problems, and the purpose of the present invention is to perform the number of times of pre-run analysis for removing an undesired mobile phase in a flow path at the time of switching between the mobile phase and the column. It is an object of the present invention to provide a liquid chromatograph apparatus that can reduce the time required for continuous analysis and reduce the consumption of mobile phase solvent by reducing the amount of liquid as much as possible.
  • the first aspect of the liquid chromatograph apparatus made to solve the above problems is a mobile phase selection unit that switches a plurality of mobile phases, and a sample in the mobile phase that is switched by the mobile phase selection unit.
  • a liquid chromatograph apparatus comprising: a sample injection section for injecting a liquid; a plurality of columns; and a column flow path switching section for selectively introducing the mobile phase into which the sample has been injected into any of the plurality of columns.
  • the characteristics of the mobile phase used in one analysis of interest and the mobile phase used or used in the analysis performed immediately prior to the analysis when creating an analysis schedule for continuous analysis And a mobile phase determination unit that determines whether or not there is a specific characteristic change between the two analyses, c) When the mobile phase determination unit determines that there is a specific characteristic change in the mobile phase, a pre-run analysis for discharging the mobile phase through the bypass channel is performed before the execution of the one focused analysis.
  • a schedule adjustment unit for adjusting the analysis schedule It is characterized by having.
  • a second aspect of the liquid chromatograph apparatus which has been made to solve the above problems, includes a mobile phase selection unit that switches a plurality of mobile phases, and a sample in the mobile phase that is switched by the mobile phase selection unit.
  • a liquid chromatograph apparatus comprising: a sample injection section for injecting a liquid; a plurality of columns; and a column flow path switching section for selectively introducing the mobile phase into which the sample has been injected into any of the plurality of columns.
  • An analysis control unit for controlling the bypass flow path switching unit It is characterized by having.
  • the bypass channel switching unit may be integrated with the column channel switching unit, that is, the channel may be switched by the same valve.
  • the “mobile phase characteristics” are typically the pH value, pH range, or pH level of the mobile phase. Alternatively, it may be information relating to the pH of the mobile phase or information relating to factors that determine the pH of the mobile phase, such as the composition of the mobile phase solvent.
  • the mobile phase determination unit when creating the analysis schedule, the characteristics of the mobile phase used in the analysis of interest and the analysis performed immediately before the analysis.
  • Information about the characteristics of the mobile phase used in the analysis or used in the (scheduled) analysis that was used in or just prior to the analysis, and the mobile phase used between the two analyzes It is determined whether or not the characteristic change is a specific characteristic change.
  • the characteristic change is a specific characteristic change.
  • the information indicating the characteristics of the mobile phase used in one analysis is described in a method file that defines various analysis conditions for that analysis, and if the method file used for the analysis is specified.
  • the characteristics of the mobile phase may be determined from the information in the method file.
  • the method file and the column information (column connection information and attribute information) to be used are usually associated with each other, information indicating the characteristics of the mobile phase that can be handled for each column (for example, for high pH mobile phase) Column, low pH mobile phase column identification information, etc.) as attribute information etc. in advance, if a method file used for analysis is specified, the column associated with that method file is recognized, You may make it judge the characteristic of a mobile phase from the attribute information of this column.
  • the specific characteristic change is a change in the pH of the mobile phase, and more specifically, a change in which the mobile phase having a high pH is switched to the mobile phase having a low pH.
  • the mobile phase determination unit determines that there is a specific characteristic change
  • the mobile phase having a higher pH remains in the upstream channel than the column channel switching unit at the time of performing the analysis of interest. Probability is high.
  • the schedule adjustment unit automatically corrects the analysis schedule so that the pre-run analysis is performed before the analysis of interest is performed.
  • the analysis control unit automatically performs a pre-run analysis prior to executing the analysis to be performed.
  • the mobile phase used in the next analysis is supplied to the flow channel upstream of the column flow channel switching unit, and the high pH mobile phase remaining in the flow channel is pushed out just before that. And discharged through the bypass flow path.
  • the remaining high-pH mobile phase is not introduced into the column, and the high-pH mobile phase can be prevented from flowing into the low-pH mobile phase column.
  • switching from a low pH mobile phase to a high pH mobile phase there is a high possibility that a low pH mobile phase remains in the flow channel upstream of the column flow channel switching unit. Even if such a mobile phase is introduced into a column for a high pH mobile phase, there is no risk of damaging the column.
  • the pre-run analysis is omitted.
  • the high pH mobile phase is introduced into the low pH mobile phase column. Since it is not, the pre-run analysis is omitted.
  • the pre-run analysis is performed only before the execution of the analysis in which a mobile phase that may damage the column flows into the column.
  • the pre-run analysis is omitted unless there is a possibility of damaging the column.
  • unnecessary pre-run analysis can be omitted, and the total analysis time for continuous analysis can be shortened.
  • the mobile phase used for pre-run analysis can be saved, the amount of mobile phase used can be reduced and the analysis cost can be reduced.
  • the pre-run analysis is a column used for the next analysis by switching the flow path by the column flow path switching unit after discharging the mobile phase through the bypass flow path.
  • the column may be washed by flowing a mobile phase for a predetermined time.
  • liquid chromatograph apparatus information on the combination of the mobile phase and the column used in the analysis in the method file that defines the analysis conditions for performing the analysis or in connection with the method file It is preferable to have a configuration that holds
  • the execution of pre-run analysis for removing the mobile phase remaining in the flow path is reduced. Can do. Thereby, the time required for continuous analysis can be shortened and the analysis efficiency can be improved. In addition, the consumption of the mobile phase solvent can be suppressed, and the analysis cost can be reduced.
  • the block diagram of the principal part of the liquid chromatograph apparatus which is one Example of this invention.
  • the flowchart which shows the characteristic process in the case of the analysis schedule preparation in the liquid chromatograph apparatus of a present Example.
  • the flow-path block diagram of the liquid chromatograph apparatus which can switch a column and a mobile phase.
  • FIG. 1 is a configuration diagram of a main part of the liquid chromatograph apparatus of the present embodiment.
  • the liquid chromatograph apparatus further includes a data processing unit 5 that processes data obtained by the detector 4, a control unit 7 that performs various controls and performs a user interface, and data processing. Operation unit comprising a keyboard and a mouse connected to the control unit 7, an interface unit 6 responsible for signal interface between the unit 5 and the control unit 7 and the liquid feeding unit 1, the injector 2, the column unit 3, and the detector 4. 8.
  • a display unit 9 as a display monitor is provided.
  • the control unit 7 includes an analysis condition setting processing unit 70, a past analysis information storage unit 71, a schedule table creation unit 72, a pre-run analysis necessity determination unit 73, an analysis control unit 74, an analysis condition storage unit 75, and the like as functional blocks.
  • the analysis condition storage unit 75 includes storage areas such as a method file storage unit 75a, a column information storage unit 75b, and a mobile phase information storage unit 75c.
  • the substance of the data processing unit 5 and the control unit 7 is a personal computer, and each function is achieved by executing dedicated control / processing software installed in the personal computer.
  • the solvent switching valves 14 and 15 each select one solvent container, and the liquid feed pumps 16 and 17 have a predetermined flow rate from the selected solvent container.
  • Aspirate solvent The mobile phase solvent A sucked by the liquid feed pump 16 and the mobile phase solvent B sucked by the liquid feed pump 17 are uniformly mixed by the gradient mixer 18, and the mixed mobile phase passes through the injector 2 to the column unit 3. And flows in.
  • the sample in one vial selected under the control of the analysis control unit 74 is injected into the mobile phase at a predetermined timing.
  • the injected sample rides on the flow of the mobile phase and is introduced into any one of the columns 31a to 31e selected by the column flow switching units 30 and 33 (here, the selected column is denoted as 31x). .
  • the flow rate of the liquid feed pumps 16 and 17 is set so that the ratio of the mobile phase solvent B is low and the ratio of the mobile phase solvent A is high until a predetermined time elapses after the sample is injected.
  • Each is controlled.
  • As the mobile phase solvent A a solvent having a weak dissolution power is used, whereby each component in the sample is once adsorbed to the column 31x.
  • the ratio of the mobile phase solvent B is increased by changing the flow rates of the liquid feed pumps 16 and 17 as time elapses.
  • a solvent having a strong dissolution power is used, so that each component adsorbed on the column 31x is sequentially eluted from the column 31x according to its polarity and introduced into the detector 4.
  • Each component in the eluate is sequentially detected by the detector 4, and data obtained by digitizing a detection signal corresponding to the concentration is sent to the data processing unit 5 through the interface unit 6.
  • the data processing unit 5 stores the received data in a storage device such as a hard disk, creates a chromatogram by performing predetermined waveform processing, and displays the chromatogram on the screen of the display unit 9 through the control unit 7. Since the elution of the components from the column 31x is completed within a predetermined time from the time when the sample is injected in the injector 2, one analysis is completed when the predetermined analysis time elapses.
  • the mobile phase used in the analysis remains in the flow channel upstream of the column flow channel switching unit 30.
  • this mobile phase is a high pH mobile phase
  • this high pH mobile phase flows into the low pH mobile phase column in the next analysis after the column flow path switching unit 30 is switched, May be damaged. Therefore, in the liquid chromatograph apparatus according to the present embodiment, the following characteristic control and processing are performed when an analysis schedule is created in response to a user operation prior to execution of analysis.
  • FIG. 2 is a flowchart showing this characteristic control and processing.
  • a method file and related information in the liquid chromatograph apparatus of the present embodiment will be described.
  • the method file is a file that defines the operating conditions of each part such as the liquid feeding part 1 when performing the analysis. For example, the type of mobile phase used during the analysis, the type of column, and the flow rate of the liquid feeding pump during the analysis.
  • the user Prior to creating an analysis schedule for continuous analysis of multiple samples, the user creates a method file used for analysis.
  • the method file can be manually created by the user manually using the analysis condition setting processing unit 70.
  • an optimal method file corresponding to the sample for example, Patent Document 1 “Method Scouting” disclosed in Non-Patent Document 1 and the like may be used.
  • method files are created for various types of samples and stored in the method file storage unit 75a, and a user (operator) selects a method file corresponding to a target sample when creating an analysis schedule. Specify the analysis conditions.
  • the user registers the mobile phase solvent in the solvent container connected to each port of the solvent switching valves 14 and 15 by the analysis condition setting processing unit 70 and connects to each port of the column flow path switching valves 30 and 33. Register the column to be used.
  • the mobile phase information which is the former registration information includes connection position information for each port of the solvent switching valves 14 and 15 and attribute information indicating the type and composition of the mobile phase, and stores the mobile phase information in the analysis information storage unit 75. Stored in section 75c. .
  • column information which is the latter registration information includes connection position information for each port of the column flow path switching valves 30 and 33, and attribute information indicating a column type and the like.
  • the column attribute information includes pH correspondence information indicating whether the column is compatible with a high pH mobile phase or a low pH mobile phase.
  • the column information is stored in the column information storage unit 75b of the analysis information storage unit 75. In general, such mobile phase and column registration is not performed by a general operator but by a person having authority such as a system administrator. In some cases, creating a method file is the same.
  • FIG. 6 is a diagram schematically showing correspondence between a method file, column information, and mobile phase information.
  • the method file describes information indicating the type of mobile phase and the type of column used in the analysis, which are associated with the information in the mobile phase information and the information in the column information, respectively. It has been. Therefore, when a certain method file is specified, it is possible to extract the port to which the column is connected and the attribute information of the column from the information indicating the type of the column described in the method file. Similarly, from the information indicating the type of mobile phase described in the method file, it is possible to extract the port to which the solvent container containing the mobile phase solvent is connected and the attribute information of the mobile phase. It is.
  • step S1 The user (operator) performs a predetermined operation on the operation unit 8 to create a schedule table for continuous analysis of multiple samples (step S1). That is, when an analysis schedule creation is instructed by a predetermined operation of the operation unit 8 by the user, the schedule table creation unit 72 displays a schedule table as shown in FIG. Display on the screen.
  • One line on this schedule table shows the contents of analysis for one sample (sample), “vial number” is the number of the vial defined in the autosampler included in the injector 2, and “tray” is also auto The number of a plurality of trays prepared in the sampler, “sample name” is the name of each sample set as appropriate, and “method file name” is the file name of the method file used for the analysis.
  • the arrangement of each row in the schedule table indicates the analysis order in the continuous analysis.
  • the user performs a predetermined operation using the operation unit 8 and inputs appropriate information in each column of each row of the schedule table.
  • analysis for two samples having sample names “Sample2” and “Sample3” is set.
  • the pre-run analysis necessity determination unit 73 acquires the method file name specified in the first line of the set schedule table and stores the information stored in the analysis condition storage unit 75.
  • Column information defined in the method file is read (step S2).
  • the method file describes the combination of the mobile phase to be used and the column, and the column information includes the corresponding pH information.
  • the corresponding pH information of this column corresponds to the pH of the mobile phase used for analysis. Therefore, based on the corresponding pH information in the column information associated with the designated method file, it is determined whether or not the mobile phase used for the analysis is a low pH mobile phase (step S3).
  • step S3 If it is determined in step S3 that the mobile phase is not a low pH mobile phase, the mobile phase to be used is a high pH mobile phase. In this case, the process proceeds from step S3 to step S8 described later.
  • the pre-run analysis necessity determination unit 73 performs the analysis performed by the apparatus most recently in the past stored in the past analysis information storage unit 71. Read the schedule table. Then, the method file name used for the analysis performed immediately before is acquired, and is defined in the method file with reference to the information stored in the analysis condition storage unit 75, as in the process of step S2. Column information is read (step S4).
  • step S5 it is determined whether or not the mobile phase used for the analysis is a low pH mobile phase.
  • the past analysis information storage unit 71 updates the stored content so as to save the most recently performed schedule table.
  • step S5 If it is determined in step S5 that the mobile phase is a low pH mobile phase, the mobile phase remaining in the flow channel upstream of the first column flow valve 30 may be a low pH mobile phase. Is expensive. Even if this mobile phase is introduced into the high pH mobile phase column, there is no risk of damaging the column. Therefore, when it is determined Yes in step S5, it is determined that it is not necessary to perform the pre-run analysis (step S8), and the process proceeds to step S9. The same applies when it is determined No in step S3.
  • step S5 when it is determined in step S5 that the mobile phase is not a low pH mobile phase, there is a high possibility that a high pH mobile phase remains in the flow path upstream of the first column flow path valve 30. If this mobile phase is introduced into a low pH mobile phase column packed with a silica gel carrier, for example, the silica gel may be dissolved and damaged. Therefore, when it is determined No in step S5, it is determined that pre-run analysis is necessary (step S6). In response to this determination, the schedule table creation unit 72 adds a line for executing the pre-run analysis on the schedule table so that the pre-run analysis is performed immediately before the analysis focused in step S2 (step S7).
  • FIG. 3 shows an example in which the pre-run analysis is not added to the first line of the schedule table by the processes in steps S2 to S8, and
  • FIG. 4 shows an example in which the pre-run analysis is added to the first line of the schedule table by the same process.
  • 3A and 4A show the latest information (schedule table) stored in the past analysis information storage unit 71.
  • FIG. 1 in order to facilitate understanding, the method file names are “High PH method” and “Low ⁇ PH method” so that the file name itself can distinguish between high pH and low pH. It is clear from the above description that there is no need for such a file name.
  • step S5 it is found from the schedule table shown in (a) that the mobile phase used in the analysis performed most recently in the past is a low pH mobile phase.
  • the mobile phase used for the analysis described in the first row of the schedule table newly set this time shown in (b) is also a low pH mobile phase. Therefore, it is determined Yes in step S5, and the pre-run analysis is omitted. Therefore, the schedule table is not modified at all.
  • the mobile phase used for the analysis performed most recently in the past is a high pH mobile phase.
  • the mobile phase used for the analysis described in the first row of the schedule table newly set this time shown in (b) is a low pH mobile phase. Therefore, in switching the mobile phase from the immediately preceding analysis to the first analysis of this time, the mobile phase is switched from the high pH mobile phase to the low pH mobile phase. In this case, it is determined as No in step S5, and the processes in steps S6 and S7 described above are executed.
  • the first line of the schedule table includes a line for pre-run analysis. Is added.
  • the vial number “ ⁇ 1” means that no sample is injected.
  • a predetermined method file name is automatically set during pre-run analysis.
  • the method file used for the pre-run analysis can be appropriately determined by the operator or the system administrator. For example, the time for executing the pre-run analysis can be arbitrarily set.
  • the pre-run analysis necessity determination unit 72 determines whether or not all analysis checks have been completed for the schedule table set in step S1 (step S9). Specifically, for example, when the processing in steps S2 to S8 is completed for the analysis described in the first line of the schedule table, the analysis described in the next line of the schedule table before correction, that is, the second line is performed. It is determined whether or not there is. For example, in the example of FIG. 4B, since the second line exists in the schedule table before correction, it is determined No in step S9, the process returns to step S2, and the analysis described in the second line is performed in the above steps S3 to S3. The process of S8 is performed. In this case, however, the “previous analysis” in step S4 is not the latest analysis in the past, but the analysis described in the first line of the schedule table before correction.
  • Fig. 5 shows an example in which a pre-run analysis is added during the continuous analysis described in the schedule table. That is, the mobile phase used for the analysis described in the fourth row of the schedule table shown in FIG. 5A is a high pH mobile phase, and the mobile phase used for the analysis described in the fifth row is a low pH. Mobile phase. Therefore, when processing for the analysis described in the fifth line is performed, Yes is determined in step S3 and No is determined in step S5, and the pre-run analysis is added immediately before the analysis described in the fifth line. As a result, the schedule table is corrected as shown in FIG.
  • step S10 Sequential analysis is executed.
  • the pre-run analysis is performed only when the high pH mobile phase remaining in the flow path upstream of the first column flow path switching valve 30 may be introduced into the low pH mobile phase column.
  • the mobile phase fed by the liquid feed pumps 16 and 17 flows to the bypass channel 32 via the first column channel switching valve 30 and is discharged to the outside via the first column channel switching valve 33. .
  • the pre-run analysis is performed only when there is a possibility that the column is damaged by the mobile phase. Therefore, the total analysis time in the continuous analysis is ensured while reliably protecting the column. Can be shortened. Moreover, the usage-amount of a mobile phase can also be suppressed.
  • the pre-run analysis is not performed when the mobile phase is switched from the low pH mobile phase to the high pH mobile phase, but the pre-run analysis is also performed when the mobile phase is switched from the low pH mobile phase to the high pH mobile phase according to the user selection. May be executed. In this case, even if the type of the mobile phase is switched, the execution of the pre-run analysis is omitted only when the pH of the mobile phase remains high or low.
  • the information indicating the correspondence with the high pH mobile phase and the correspondence with the low pH mobile phase is the pH correspondence information, but when the compatible pH range is the pH correspondence information, the pH What is necessary is just to judge the level of pH by judging the range.
  • the necessity of the pre-run analysis is determined at the stage of creating the analysis schedule, and the schedule table is corrected as necessary, but it is used in the analysis that is going to be performed during the actual execution of the analysis. It is also possible to determine whether or not to perform the pre-run analysis based on the relationship between the pH of the mobile phase and the pH of the mobile phase used in the analysis performed immediately before.

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Abstract

When a schedule table for serial analysis of multiple samples is set, it is determined, from information associated with a method file that is used for the first analysis, whether to use a low-pH-mobile-phase column or a high-pH-mobile-phase column. It is also determined, from information associated with a method file that was used for the most recent past analysis, whether a low-pH-mobile-phase column or a high-pH-mobile-phase column was used. If it is determined that there will be a switch from a high-pH mobile phase to a low-pH mobile phase between two analyses, the schedule table is corrected so as to add a preprocess in which mobile phase remaining in the channel is discharged to the outside without passing through the column. This prevents column damage by preventing a high-pH mobile phase from flowing into a low-pH-mobile-phase column in an analysis performed after the mobile phase and the column were switched. The aforementioned preprocess is not performed for mobile-phase/column switches for which there is no risk of column damage, increasing analysis speed and reducing the amount of mobile phase used.

Description

液体クロマトグラフ装置Liquid chromatograph
　本発明は液体クロマトグラフ装置に関し、さらに詳しくは、特性の相違する複数の移動相と成分分離に利用する複数のカラムとをそれぞれ切り替え可能な構成を有する液体クロマトグラフ装置に関する。 The present invention relates to a liquid chromatograph apparatus, and more particularly to a liquid chromatograph apparatus having a configuration capable of switching a plurality of mobile phases having different characteristics and a plurality of columns used for component separation.
　液体クロマトグラフ（ＬＣ）では、分析対象の化合物の種類等に応じて様々な種類のカラムが使い分けられ、また分析対象の化合物の種類や使用されるカラムの種類等に応じて様々な特性の移動相（溶離液）が利用される。図７は、カラム及び移動相の切り替えが可能である液体クロマトグラフ装置の流路構成の概略図である（特許文献１など参照）。 In a liquid chromatograph (LC), various types of columns are used depending on the type of compound to be analyzed, and various characteristics are transferred depending on the type of compound to be analyzed and the type of column used. A phase (eluent) is utilized. FIG. 7 is a schematic diagram of a flow path configuration of a liquid chromatograph apparatus capable of switching between a column and a mobile phase (see, for example, Patent Document 1).
　この液体クロマトグラフ装置は、送液部１、インジェクタ２、カラムユニット３、及び検出器４を備える。
　送液部１は、第１送液ポンプ１６により吸引された移動相溶媒Ａと、第２送液ポンプ１７により吸引された移動相溶媒Ｂとをグラジエントミキサ１８によって混合した上でカラムへと送出するものである。第１送液ポンプ１６には第１溶媒切替バルブ１４及び第１脱気ユニット１２を介して４つの溶媒容器１０ａ～１０ｄが接続され、第２送液ポンプ１７には第２溶媒切替バルブ１５及び第２脱気ユニット１３を介して４つの溶媒容器１１ａ～１１ｄが接続されている。 The liquid chromatograph apparatus includes a liquid feeding unit 1, an injector 2, a column unit 3, and a detector 4.
The liquid feeding unit 1 mixes the mobile phase solvent A sucked by the first liquid feeding pump 16 and the mobile phase solvent B sucked by the second liquid feeding pump 17 by the gradient mixer 18 and then sends them to the column. To do. Four solvent containers 10a to 10d are connected to the first liquid feed pump 16 via the first solvent switching valve 14 and the first deaeration unit 12, and the second liquid feeding pump 17 is connected to the second solvent switching valve 15 and Four solvent containers 11 a to 11 d are connected via the second degassing unit 13.
　溶媒容器１０ａ～１０ｄには例えば水系の移動相溶媒（水を主成分とする溶媒）が収容されており、第１溶媒切替バルブ１４による流路の切り替えによって、これら４つの溶媒容器１０ａ～１０ｄのうちの１つが選択され、該容器内の溶媒が移動相溶媒Ａとして第１送液ポンプ１６により吸引される。一方、溶媒容器１１ａ～１１ｄには例えば有機系の溶媒（有機溶媒を主成分とする溶媒）が収容されており、第２溶媒切替バルブ１５による流路の切り替えにより４つの溶媒容器１１ａ～１１ｄのうちの１つが選択され、該容器内の溶媒が移動相溶媒Ｂとして第２送液ポンプ１７により吸引される。２つの送液ポンプ１６、１７の流量は時間経過に伴ってそれぞれ変化するように制御することが可能であり、これによって移動相溶媒Ａ、Ｂの混合比率が時間的に変化するグラジエント方式の送液が可能となっている。 The solvent containers 10a to 10d contain, for example, an aqueous mobile phase solvent (a solvent containing water as a main component). By switching the flow path using the first solvent switching valve 14, the four solvent containers 10a to 10d One of them is selected, and the solvent in the container is sucked by the first liquid feeding pump 16 as the mobile phase solvent A. On the other hand, for example, organic solvents (solvents mainly composed of organic solvents) are accommodated in the solvent containers 11a to 11d, and the four solvent containers 11a to 11d are switched by switching the flow paths by the second solvent switching valve 15. One of them is selected, and the solvent in the container is sucked by the second liquid feeding pump 17 as the mobile phase solvent B. The flow rates of the two liquid feed pumps 16 and 17 can be controlled so as to change with the passage of time, whereby a gradient type feed in which the mixing ratio of the mobile phase solvents A and B changes with time. Liquid is possible.
　インジェクタ２はオートサンプラを含み、トレイに予め用意された多数のバイアルの中から１つを選択し、該バイアル中の試料液を所定量吸引し、所定のタイミングで移動相に注入する。 The injector 2 includes an autosampler, selects one from a number of vials prepared in advance in the tray, sucks a predetermined amount of the sample solution in the vial, and injects it into the mobile phase at a predetermined timing.
　カラムユニット３は、５本のカラム３１ａ～３１ｅと、バイパス流路３２と、カラム３１ａ～３１ｅ及びバイパス流路３２のいずれか１つを選択的に移動相の流路に接続するための一対のカラム流路切替バルブ３０、３３とを含む。これらは図示しないカラムオーブンに内装され、適宜に温度調整されるようになっている。 The column unit 3 includes a pair of five columns 31a to 31e, a bypass flow channel 32, and a pair for selectively connecting any one of the columns 31a to 31e and the bypass flow channel 32 to the flow channel of the mobile phase. Column flow path switching valves 30 and 33. These are housed in a column oven (not shown) and the temperature is adjusted appropriately.
　カラム出口からの溶出液の流路上に設けられた検出器４は、例えばフォトダイオードアレイ（ＰＤＡ）検出器である。この検出器４では、光源からの光を溶出液に照射し、溶出液を透過した光を波長分散させて各波長の光の強度をフォトダイオードアレイによってほぼ同時に検出する。検出器４により所定時間間隔で繰り返し得られた検出信号はそれぞれデジタル信号に変換され、時間、波長、吸光度という３つのディメンジョンを有する３次元データとしてデータ処理部５へ出力される。なお、検出器４はＰＤＡ検出器に限らず、例えば質量分析計でもよい。また、複数の検出器を併設した構成とする場合もある。 The detector 4 provided on the flow path of the eluate from the column outlet is, for example, a photodiode array (PDA) detector. In this detector 4, the light from the light source is irradiated onto the eluate, the light transmitted through the eluate is wavelength-dispersed, and the intensity of light of each wavelength is detected almost simultaneously by the photodiode array. Detection signals repeatedly obtained at predetermined time intervals by the detector 4 are converted into digital signals, respectively, and output to the data processing unit 5 as three-dimensional data having three dimensions of time, wavelength, and absorbance. The detector 4 is not limited to a PDA detector, and may be a mass spectrometer, for example. In some cases, a plurality of detectors are provided.
　この液体クロマトグラフ装置では、溶媒切替バルブ１４、１５による流路の切り替えによって、分析に使用される移動相の切り替えが可能である。また、カラム流路切替バルブ３０、３３による流路の切り替えによって、分析に使用されるカラムの切り替えが可能である。そのため、移動相及びカラムを適宜切り替えながら、多数の試料に対する分析を順次連続的に行うことができる。ただし、次のような理由により、移動相やカラムの切り替え時には注意を要する。 In this liquid chromatograph apparatus, the mobile phase used for analysis can be switched by switching the flow path using the solvent switching valves 14 and 15. In addition, the column used for analysis can be switched by switching the channel using the column channel switching valves 30 and 33. Therefore, it is possible to sequentially and continuously analyze a large number of samples while appropriately switching the mobile phase and the column. However, care must be taken when switching the mobile phase or column for the following reasons.
　即ち、分析に使用される移動相のｐＨは幅広いが、或る種のカラムは高ｐＨの移動相で使用することができない。例えばカラム充填剤の担体としてよく用いられるシリカゲルは高ｐＨの移動相に溶解してしまう。そのため、第１カラム流路切替バルブ３０よりも上流側（インジェクタ２側）の流路中に残っていた高ｐＨの移動相が流路の切り替えに伴ってシリカゲルを担体とする充填剤を用いたカラムに流れ込んでしまうと、該移動相がカラムを損傷するおそれがある。これを防止するために、図７に示した液体クロマトグラフ装置では、移動相及びカラムの切り替え時にプレラン分析と呼ばれる予備的な送液動作が実行される。 That is, the pH of the mobile phase used for analysis is wide, but certain columns cannot be used with high pH mobile phases. For example, silica gel often used as a column packing carrier is dissolved in a high pH mobile phase. Therefore, a high-pH mobile phase remaining in the flow path upstream (injector 2 side) from the first column flow path switching valve 30 uses a filler that uses silica gel as a carrier when the flow path is switched. If it flows into the column, the mobile phase may damage the column. In order to prevent this, in the liquid chromatograph apparatus shown in FIG. 7, a preliminary liquid feeding operation called pre-run analysis is performed when the mobile phase and the column are switched.
　プレラン分析では、カラム流路切替バルブ３０、３３によりバイパス流路３２が移動相流路に接続され、次に実行される分析において用いられる移動相が送液ポンプ１６、１７によりカラムユニット３へ供給される。これによって、プレラン分析直前に第１カラム流路切替バルブ３０より上流側の流路中に残っていた移動相はバイパス流路３２を経て、つまりはカラム３１ａ～３１ｅを通ることなく外部に排出される。第１カラム流路切替バルブ３０より上流側の流路の移動相は次に実行される分析において用いられる移動相に置換されることになり、カラムを損傷する可能性がある不所望の移動相がカラムに流れることを回避することができる。 In the pre-run analysis, the bypass flow path 32 is connected to the mobile phase flow path by the column flow switching valves 30 and 33, and the mobile phase used in the next analysis to be performed is supplied to the column unit 3 by the liquid feed pumps 16 and 17. Is done. As a result, the mobile phase remaining in the flow channel upstream of the first column flow switching valve 30 immediately before the pre-run analysis is discharged to the outside through the bypass flow channel 32, that is, without passing through the columns 31a to 31e. The The mobile phase in the flow path upstream from the first column flow path switching valve 30 is replaced with the mobile phase used in the next analysis to be performed, and an undesirable mobile phase that may damage the column. Can be prevented from flowing into the column.
特開２０１３－２４６０１号公報JP 2013-24601 A
　上述したように従来の液体クロマトグラフ装置では、移動相やカラムが切り替えられたあとの試料に対する分析の実行前にプレラン分析を必ず行うようにすることで、上述したような高ｐＨの移動相が高ｐＨ移動相に対応していないカラムに導入されることを確実に防止することができる。しかしながら、プレラン分析には或る程度の時間が掛かる。このため、移動相やカラムの切り替えを伴う連続分析を実施する場合、プレラン分析の実行回数が多くなってその分だけ総分析時間が長くなり分析効率が低下する。また、プレラン分析を実行する分だけ余計に移動相溶媒が必要になり分析コストが上昇する。 As described above, in the conventional liquid chromatograph apparatus, by performing the pre-run analysis before performing the analysis on the sample after the mobile phase and the column are switched, the high pH mobile phase as described above can be obtained. It is possible to reliably prevent introduction into a column that does not support a high pH mobile phase. However, the pre-run analysis takes some time. For this reason, when carrying out continuous analysis with mobile phase or column switching, the number of executions of pre-run analysis is increased, and the total analysis time is increased accordingly, resulting in a decrease in analysis efficiency. In addition, an extra mobile phase solvent is required as much as the pre-run analysis is performed, and the analysis cost increases.
　本発明はこうした課題を解決するために成されたものであり、その目的とするところは、移動相及びカラムの切り替え時における流路中の不所望の移動相除去のためのプレラン分析の実行回数をできるだけ減らすことで、連続的な分析の際の分析所要時間を短縮するとともに移動相溶媒の消費量を抑えることができる液体クロマトグラフ装置を提供することにある。 The present invention has been made to solve these problems, and the purpose of the present invention is to perform the number of times of pre-run analysis for removing an undesired mobile phase in a flow path at the time of switching between the mobile phase and the column. It is an object of the present invention to provide a liquid chromatograph apparatus that can reduce the time required for continuous analysis and reduce the consumption of mobile phase solvent by reducing the amount of liquid as much as possible.
　上記課題を解決するためになされた本発明に係る液体クロマトグラフ装置の第１の態様は、複数の移動相を切り替える移動相選択部と、該移動相選択部により切り替えられた移動相中に試料を注入する試料注入部と、複数のカラムと、前記試料が注入された移動相を前記複数のカラムのいずれかに選択的に導入するカラム流路切替部と、を具備する液体クロマトグラフ装置において、
　a)前記移動相選択部により切り替えられた移動相をカラムに導入することなく排出するために、該カラムと前記カラム流路切替部との間に設けられたバイパス流路切替部及び該流路切替部に接続されたバイパス流路と、
　b)連続分析を行うための分析スケジュール作成時に、着目する１つの分析で使用される移動相の特性と該分析の直前に実行された又は実行される分析において使用された又は使用される移動相の特性とについての情報を取得し、それら２つの分析の間で特定の特性変更があるか否かを判定する移動相判定部と、
　c)前記移動相判定部により移動相に特定の特性変更があると判定された場合に、前記着目する１つの分析の実行前に前記バイパス流路を通して移動相を排出するプレラン分析を実行するように分析スケジュールを調整するスケジュール調整部と、
　を備えることを特徴としている。 The first aspect of the liquid chromatograph apparatus according to the present invention made to solve the above problems is a mobile phase selection unit that switches a plurality of mobile phases, and a sample in the mobile phase that is switched by the mobile phase selection unit. In a liquid chromatograph apparatus comprising: a sample injection section for injecting a liquid; a plurality of columns; and a column flow path switching section for selectively introducing the mobile phase into which the sample has been injected into any of the plurality of columns. ,
a) a bypass flow path switching unit provided between the column and the column flow path switching unit and the flow path for discharging the mobile phase switched by the mobile phase selection unit without introducing it into the column; A bypass flow path connected to the switching unit;
b) The characteristics of the mobile phase used in one analysis of interest and the mobile phase used or used in the analysis performed immediately prior to the analysis when creating an analysis schedule for continuous analysis And a mobile phase determination unit that determines whether or not there is a specific characteristic change between the two analyses,
c) When the mobile phase determination unit determines that there is a specific characteristic change in the mobile phase, a pre-run analysis for discharging the mobile phase through the bypass channel is performed before the execution of the one focused analysis. A schedule adjustment unit for adjusting the analysis schedule,
It is characterized by having.
　上記課題を解決するためになされた本発明に係る液体クロマトグラフ装置の第２の態様は、複数の移動相を切り替える移動相選択部と、該移動相選択部により切り替えられた移動相中に試料を注入する試料注入部と、複数のカラムと、前記試料が注入された移動相を前記複数のカラムのいずれかに選択的に導入するカラム流路切替部と、を具備する液体クロマトグラフ装置において、
　a)前記移動相選択部により切り替えられた移動相をカラムに導入することなく排出するために、該カラムと前記カラム流路切替部との間に設けられたバイパス流路切替部及び該流路切替部に接続されたバイパス流路と、
　b)分析実行時に、該分析で使用される移動相の特性と該分析の直前に実行された分析において使用された移動相の特性とについての情報を取得し、それら２つの分析の間で特定の特性変更があるか否かを判定する移動相判定部と、
　c)前記移動相判定部により移動相の特定の特性変更であると判定された場合に、実行しようとしている分析の前に、前記バイパス流路を通して移動相を排出するプレラン分析を実行するように前記バイパス流路切替部を制御する分析制御部と、
　を備えることを特徴としている。 A second aspect of the liquid chromatograph apparatus according to the present invention, which has been made to solve the above problems, includes a mobile phase selection unit that switches a plurality of mobile phases, and a sample in the mobile phase that is switched by the mobile phase selection unit. In a liquid chromatograph apparatus comprising: a sample injection section for injecting a liquid; a plurality of columns; and a column flow path switching section for selectively introducing the mobile phase into which the sample has been injected into any of the plurality of columns. ,
a) a bypass flow path switching unit provided between the column and the column flow path switching unit and the flow path for discharging the mobile phase switched by the mobile phase selection unit without introducing it into the column; A bypass flow path connected to the switching unit;
b) When performing an analysis, obtain information about the characteristics of the mobile phase used in the analysis and the characteristics of the mobile phase used in the analysis performed immediately before the analysis, and specify between the two analyzes A mobile phase determination unit that determines whether or not there is a characteristic change,
c) When the mobile phase determination unit determines that the mobile phase has a specific characteristic change, a pre-run analysis for discharging the mobile phase through the bypass channel is performed before the analysis to be performed. An analysis control unit for controlling the bypass flow path switching unit;
It is characterized by having.
　本発明に係る液体クロマトグラフ装置において、上記バイパス流路切替部は上記カラム流路切替部と一体化されている、つまりは同じバルブにより流路を切り替えるものであってもよい。 In the liquid chromatograph apparatus according to the present invention, the bypass channel switching unit may be integrated with the column channel switching unit, that is, the channel may be switched by the same valve.
　本発明に係る液体クロマトグラフ装置において、「移動相の特性」とは典型的には、移動相のｐＨ値やｐＨ範囲、又はｐＨの程度などである。或いは、移動相のｐＨに関連した情報又は移動相のｐＨを決める要素に関する情報、例えば移動相溶媒の組成などでもよい。 In the liquid chromatograph apparatus according to the present invention, the “mobile phase characteristics” are typically the pH value, pH range, or pH level of the mobile phase. Alternatively, it may be information relating to the pH of the mobile phase or information relating to factors that determine the pH of the mobile phase, such as the composition of the mobile phase solvent.
　本発明に係る液体クロマトグラフ装置の第１の態様において、移動相判定部は、分析スケジュール作成時に、着目している分析で使用される移動相の特性と、その分析の直前に実行された分析において使用された又はその分析の直前に実行される（予定されている）分析で使用される移動相の特性とについての情報を取得し、その２つの分析の間で、使用される移動相の特性の変更が特定の特性変更であるか否かを判定する。当然のことながら、その２つの分析において同じ移動相が使用される場合には特性の変更はない。また、その２つの分析において異なる移動相が使用される場合であっても、上記「特定の特性変更」以外の特性の変更である場合には、特定の特性変更なしと判断する。 In the first aspect of the liquid chromatograph apparatus according to the present invention, the mobile phase determination unit, when creating the analysis schedule, the characteristics of the mobile phase used in the analysis of interest and the analysis performed immediately before the analysis. Information about the characteristics of the mobile phase used in the analysis or used in the (scheduled) analysis that was used in or just prior to the analysis, and the mobile phase used between the two analyzes It is determined whether or not the characteristic change is a specific characteristic change. Of course, there is no change in properties when the same mobile phase is used in the two analyses. Further, even when different mobile phases are used in the two analyses, it is determined that there is no specific characteristic change if the characteristic change is other than the above "specific characteristic change".
　なお、或る１つの分析で使用される移動相の特性を示す情報は、その分析における様々な分析条件を規定するメソッドファイル中に記載しておき、分析に使用するメソッドファイルが指定されたならばそのメソッドファイル中の情報から移動相の特性を判断すればよい。又は、通常、メソッドファイルと使用するカラムの情報（カラムの接続情報や属性情報）とは対応付けられているので、カラム毎に対応可能な移動相の特性を示す情報（例えば高ｐＨ移動相用カラム、低ｐＨ移動相用カラムの識別情報など）を属性情報等として予め記憶しておき、分析に使用するメソッドファイルが指定されたならばそのメソッドファイルに対応付けられているカラムを認識し、該カラムの属性情報から移動相の特性を判断するようにしてもよい。 Note that the information indicating the characteristics of the mobile phase used in one analysis is described in a method file that defines various analysis conditions for that analysis, and if the method file used for the analysis is specified. For example, the characteristics of the mobile phase may be determined from the information in the method file. Or, since the method file and the column information (column connection information and attribute information) to be used are usually associated with each other, information indicating the characteristics of the mobile phase that can be handled for each column (for example, for high pH mobile phase) Column, low pH mobile phase column identification information, etc.) as attribute information etc. in advance, if a method file used for analysis is specified, the column associated with that method file is recognized, You may make it judge the characteristic of a mobile phase from the attribute information of this column.
　移動相の特性がｐＨである場合、特定の特性変更とは移動相のｐＨの変更であり、より具体的には、ｐＨが高い移動相からｐＨが低い移動相に切り替わる変更である。この場合、移動相判定部により特定の特性変更ありと判定されたときには、着目する分析を行う時点で、カラム流路切替部よりも上流側の流路中にｐＨが高い移動相が残っている可能性が高い。こうした移動相が低ｐＨ移動相用のカラムに導入されるとカラムが損傷を受ける可能性が高い。そこで本発明の第１の態様においてスケジュール調整部は、特定の特性変更があると判定された場合、着目している分析の実行前にプレラン分析を実行するように自動的に分析スケジュールを修正する。一方、本発明の第２の態様において分析制御部は、特定の特性変更があると判定された場合、実行しようとしている分析を実行するに先立って自動的にプレラン分析を実行する。 When the characteristic of the mobile phase is pH, the specific characteristic change is a change in the pH of the mobile phase, and more specifically, a change in which the mobile phase having a high pH is switched to the mobile phase having a low pH. In this case, when the mobile phase determination unit determines that there is a specific characteristic change, the mobile phase having a higher pH remains in the upstream channel than the column channel switching unit at the time of performing the analysis of interest. Probability is high. When such a mobile phase is introduced into a low pH mobile phase column, the column is likely to be damaged. Therefore, in the first aspect of the present invention, when it is determined that there is a specific characteristic change, the schedule adjustment unit automatically corrects the analysis schedule so that the pre-run analysis is performed before the analysis of interest is performed. . On the other hand, in the second aspect of the present invention, when it is determined that there is a specific characteristic change, the analysis control unit automatically performs a pre-run analysis prior to executing the analysis to be performed.
　プレラン分析では、次の分析に使用される移動相がカラム流路切替部よりも上流側の流路に供給され、その直前に該流路中に残留していた高ｐＨの移動相は押し出され、バイパス流路を経て排出される。これにより、残留していた高ｐＨの移動相はカラムに導入されず、低ｐＨ移動相用のカラムに高ｐＨの移動相が流れ込むことを回避できる。一方、低ｐＨの移動相から高ｐＨの移動相に切り替わる場合には、カラム流路切替部よりも上流側の流路中には低ｐＨの移動相が残留している可能性が高い。こうした移動相が高ｐＨ移動相用のカラムに導入されても、カラムを損傷するおそれはない。そこで、この場合にはプレラン分析を省略する。また、移動相のｐＨが高い状態のままである場合、或いは、移動相のｐＨが低い状態のままである場合にも、低ｐＨ移動相用のカラムに高ｐＨの移動相が導入されるおそれはないので、プレラン分析を省略する。 In the pre-run analysis, the mobile phase used in the next analysis is supplied to the flow channel upstream of the column flow channel switching unit, and the high pH mobile phase remaining in the flow channel is pushed out just before that. And discharged through the bypass flow path. As a result, the remaining high-pH mobile phase is not introduced into the column, and the high-pH mobile phase can be prevented from flowing into the low-pH mobile phase column. On the other hand, when switching from a low pH mobile phase to a high pH mobile phase, there is a high possibility that a low pH mobile phase remains in the flow channel upstream of the column flow channel switching unit. Even if such a mobile phase is introduced into a column for a high pH mobile phase, there is no risk of damaging the column. Therefore, in this case, the pre-run analysis is omitted. In addition, when the pH of the mobile phase remains high, or when the pH of the mobile phase remains low, the high pH mobile phase is introduced into the low pH mobile phase column. Since it is not, the pre-run analysis is omitted.
　このようにして本発明に係る液体クロマトグラフ装置において、プレラン分析は、カラムを損傷するおそれのある移動相が該カラムに流れ込むような分析の実行前にのみ限定的に実施される。換言すれば、従来であればプレラン分析が実施されていたような場合でも、カラムを損傷するおそれがない限り、プレラン分析の実施は省略される。それによって、不所望の移動相がカラムに流れることによるカラムの損傷を回避しつつ、不要なプレラン分析の実行を省略して、連続分析の際の総分析時間を短縮することができる。また、プレラン分析に使用される移動相を節約できるので、移動相の使用量を抑え分析コストを低減することができる。 Thus, in the liquid chromatograph apparatus according to the present invention, the pre-run analysis is performed only before the execution of the analysis in which a mobile phase that may damage the column flows into the column. In other words, even if the pre-run analysis has been performed conventionally, the pre-run analysis is omitted unless there is a possibility of damaging the column. Thereby, while avoiding damage to the column due to an undesired mobile phase flowing into the column, unnecessary pre-run analysis can be omitted, and the total analysis time for continuous analysis can be shortened. In addition, since the mobile phase used for pre-run analysis can be saved, the amount of mobile phase used can be reduced and the analysis cost can be reduced.
　なお、本発明に係る液体クロマトグラフ装置において、上記プレラン分析は、上記バイパス流路を通して移動相を排出したのに引き続き、カラム流路切替部により流路を切り替えて次の分析に使用されるカラムに移動相を所定時間流して該カラムを洗浄するようにしてもよい。これにより、以前の分析の際の残滓等がカラムに残っている場合でも、分析に先立ってこれを洗浄し、コンタミネーションを防止することができる。 In the liquid chromatograph apparatus according to the present invention, the pre-run analysis is a column used for the next analysis by switching the flow path by the column flow path switching unit after discharging the mobile phase through the bypass flow path. The column may be washed by flowing a mobile phase for a predetermined time. As a result, even when a residue or the like from the previous analysis remains in the column, it can be washed prior to the analysis to prevent contamination.
　また、本発明に係る液体クロマトグラフ装置では、分析を遂行する際の分析条件を規定するメソッドファイル中に又は該メソッドファイルに関連して、該分析で使用する移動相とカラムとの組み合わせに関する情報を保持する構成とするとよい。 Further, in the liquid chromatograph apparatus according to the present invention, information on the combination of the mobile phase and the column used in the analysis in the method file that defines the analysis conditions for performing the analysis or in connection with the method file It is preferable to have a configuration that holds
　この構成によれば、上述したように或る分析に使用するメソッドファイルが指定されたときに、使用される移動相の特性を示す情報を簡便に取得することができる。また、使用する移動相とカラムとが一義的に決まるので、例えば或るカラムを使用する際に、このカラムを損傷するおそれのある移動相が分析条件の１つとして指定されてしまうことを回避することができる。 According to this configuration, as described above, when a method file to be used for a certain analysis is designated, information indicating the characteristics of the mobile phase to be used can be easily obtained. In addition, since the mobile phase and the column to be used are uniquely determined, for example, when a certain column is used, it is avoided that the mobile phase that may damage the column is specified as one of the analysis conditions. can do.
　本発明に係る液体クロマトグラフ装置によれば、使用する移動相やカラムを切り替えつつ連続的な分析を行う際に、流路中に残った移動相を除去するためのプレラン分析の実行を減らすことができる。それにより、連続分析に要する時間を短縮して分析効率を向上させることができる。また、移動相溶媒の消費量を抑え、分析コストを低減することができる。 According to the liquid chromatograph apparatus of the present invention, when continuous analysis is performed while switching the mobile phase and column to be used, the execution of pre-run analysis for removing the mobile phase remaining in the flow path is reduced. Can do. Thereby, the time required for continuous analysis can be shortened and the analysis efficiency can be improved. In addition, the consumption of the mobile phase solvent can be suppressed, and the analysis cost can be reduced.
本発明の一実施例である液体クロマトグラフ装置の要部の構成図。The block diagram of the principal part of the liquid chromatograph apparatus which is one Example of this invention. 本実施例の液体クロマトグラフ装置における分析スケジュール作成の際の特徴的な処理を示すフローチャート。The flowchart which shows the characteristic process in the case of the analysis schedule preparation in the liquid chromatograph apparatus of a present Example. 本実施例の液体クロマトグラフ装置におけるスケジュールテーブルの自動修正動作（修正なし）の一例を示す図。The figure which shows an example of the automatic correction | amendment operation | movement (without correction) of the schedule table in the liquid chromatograph apparatus of a present Example. 本実施例の液体クロマトグラフ装置におけるスケジュールテーブルの自動修正動作の一例を示す図。The figure which shows an example of the automatic correction operation | movement of the schedule table in the liquid chromatograph apparatus of a present Example. 本実施例の液体クロマトグラフ装置におけるスケジュールテーブルの自動修正動作の一例を示す図。The figure which shows an example of the automatic correction operation | movement of the schedule table in the liquid chromatograph apparatus of a present Example. 本実施例の液体クロマトグラフ装置におけるメソッドファイルとカラム及び移動相の対応付けを模式的に示す図。The figure which shows typically matching with the method file in the liquid chromatograph apparatus of a present Example, a column, and a mobile phase. カラム及び移動相の切り替えが可能である液体クロマトグラフ装置の流路構成図。The flow-path block diagram of the liquid chromatograph apparatus which can switch a column and a mobile phase.
　以下、本発明に係る液体クロマトグラフ装置の一実施例について、添付図面を参照して詳細に説明する。
　図１は本実施例の液体クロマトグラフ装置の要部の構成図である。図中、すでに説明した図７と同じ構成要素には同じ符号を付している。即ち、送液部１、インジェクタ２、カラムユニット３、及び検出器４は、従来の構成と同じである。 Hereinafter, an example of a liquid chromatograph apparatus according to the present invention will be described in detail with reference to the accompanying drawings.
FIG. 1 is a configuration diagram of a main part of the liquid chromatograph apparatus of the present embodiment. In the figure, the same components as those in FIG. That is, the liquid feeding unit 1, the injector 2, the column unit 3, and the detector 4 are the same as the conventional configuration.
　本実施例の液体クロマトグラフ装置はさらに、検出器４で得られたデータを処理するデータ処理部５、分析を遂行するための各種制御を行ったりユーザインターフェイスを担ったりする制御部７、データ処理部５及び制御部７と送液部１、インジェクタ２、カラムユニット３、及び検出器４との間の信号のインターフェイスを担うインターフェイス部６、制御部７に接続されたキーボードやマウスから成る操作部８、ディスプレイモニタである表示部９、などを備える。 The liquid chromatograph apparatus according to the present embodiment further includes a data processing unit 5 that processes data obtained by the detector 4, a control unit 7 that performs various controls and performs a user interface, and data processing. Operation unit comprising a keyboard and a mouse connected to the control unit 7, an interface unit 6 responsible for signal interface between the unit 5 and the control unit 7 and the liquid feeding unit 1, the injector 2, the column unit 3, and the detector 4. 8. A display unit 9 as a display monitor is provided.
　制御部７は、分析条件設定処理部７０、過去分析情報記憶部７１、スケジュールテーブル作成部７２、プレラン分析要否判定部７３、分析制御部７４、分析条件記憶部７５などを機能ブロックとして含む。また、分析条件記憶部７５は、メソッドファイル記憶部７５ａ、カラム情報記憶部７５ｂ、移動相情報記憶部７５ｃなどの記憶領域を含む。データ処理部５及び制御部７の実体はパーソナルコンピュータであり、パーソナルコンピュータにインストールされた専用の制御／処理ソフトウエアを実行することにより各機能が達成される。 The control unit 7 includes an analysis condition setting processing unit 70, a past analysis information storage unit 71, a schedule table creation unit 72, a pre-run analysis necessity determination unit 73, an analysis control unit 74, an analysis condition storage unit 75, and the like as functional blocks. The analysis condition storage unit 75 includes storage areas such as a method file storage unit 75a, a column information storage unit 75b, and a mobile phase information storage unit 75c. The substance of the data processing unit 5 and the control unit 7 is a personal computer, and each function is achieved by executing dedicated control / processing software installed in the personal computer.
　本実施例の液体クロマトグラフ装置における１回の分析動作を概略的に説明する。ここでは、グラジエント分析について説明するが、後述する本実施例の特徴的な制御はグラジエント分析を行う場合に限るものではない。 The analysis operation of one time in the liquid chromatograph apparatus of the present embodiment will be schematically described. Here, the gradient analysis will be described, but the characteristic control of the present embodiment described later is not limited to the case of performing the gradient analysis.
　制御部７における分析制御部７４の制御の下で、溶媒切替バルブ１４、１５はそれぞれ１つの溶媒容器を選択し、送液ポンプ１６、１７がその選択された溶媒容器から所定の流量で以て溶媒を吸引する。送液ポンプ１６により吸引された移動相溶媒Ａと送液ポンプ１７により吸引された移動相溶媒Ｂは、グラジエントミキサ１８によって均一に混合され、混合された移動相はインジェクタ２を経てカラムユニット３へと流入する。インジェクタ２では分析制御部７４の制御の下に選択された１つのバイアル中の試料が、所定のタイミングで以て移動相中に注入される。注入された試料は移動相の流れに乗って、カラム流路切替部３０、３３により選択されたカラム３１ａ～３１ｅのいずれか１つ（ここでは選択されたカラムを３１ｘと記す）に導入される。 Under the control of the analysis control unit 74 in the control unit 7, the solvent switching valves 14 and 15 each select one solvent container, and the liquid feed pumps 16 and 17 have a predetermined flow rate from the selected solvent container. Aspirate solvent. The mobile phase solvent A sucked by the liquid feed pump 16 and the mobile phase solvent B sucked by the liquid feed pump 17 are uniformly mixed by the gradient mixer 18, and the mixed mobile phase passes through the injector 2 to the column unit 3. And flows in. In the injector 2, the sample in one vial selected under the control of the analysis control unit 74 is injected into the mobile phase at a predetermined timing. The injected sample rides on the flow of the mobile phase and is introduced into any one of the columns 31a to 31e selected by the column flow switching units 30 and 33 (here, the selected column is denoted as 31x). .
　グラジエント分析では、試料の注入時点から所定の時間が経過するまでの間、移動相溶媒Ｂの比率が低く、移動相溶媒Ａの比率が高い状態となるように送液ポンプ１６、１７の流量がそれぞれ制御される。移動相溶媒Ａとしては、溶出力の弱い溶媒が用いられるため、これにより試料中の各成分が一旦カラム３１ｘに吸着する。続いて、送液ポンプ１６、１７の流量を時間経過に従って変化させて移動相溶媒Ｂの比率を上げていく。移動相溶媒Ｂとしては、溶出力の強い溶媒が用いられるため、これによりカラム３１ｘに吸着していた各成分がその極性に応じて順次カラム３１ｘから溶出されて検出器４に導入される。 In the gradient analysis, the flow rate of the liquid feed pumps 16 and 17 is set so that the ratio of the mobile phase solvent B is low and the ratio of the mobile phase solvent A is high until a predetermined time elapses after the sample is injected. Each is controlled. As the mobile phase solvent A, a solvent having a weak dissolution power is used, whereby each component in the sample is once adsorbed to the column 31x. Subsequently, the ratio of the mobile phase solvent B is increased by changing the flow rates of the liquid feed pumps 16 and 17 as time elapses. As the mobile phase solvent B, a solvent having a strong dissolution power is used, so that each component adsorbed on the column 31x is sequentially eluted from the column 31x according to its polarity and introduced into the detector 4.
　検出器４によって溶出液中の各成分は順次検出され、その濃度に応じた検出信号をデジタル化したデータがインターフェイス部６を介してデータ処理部５へ送られる。データ処理部５では受け取ったデータをハードディスク等の記憶装置に格納するとともに、所定の波形処理を行ってクロマトグラムを作成し、制御部７を通して表示部９の画面上に表示する。インジェクタ２において試料が注入された時点から所定時間内にカラム３１ｘからの成分の溶出は終了するから、所定の分析時間が経過して時点で１回の分析は終了する。 Each component in the eluate is sequentially detected by the detector 4, and data obtained by digitizing a detection signal corresponding to the concentration is sent to the data processing unit 5 through the interface unit 6. The data processing unit 5 stores the received data in a storage device such as a hard disk, creates a chromatogram by performing predetermined waveform processing, and displays the chromatogram on the screen of the display unit 9 through the control unit 7. Since the elution of the components from the column 31x is completed within a predetermined time from the time when the sample is injected in the injector 2, one analysis is completed when the predetermined analysis time elapses.
　上記のような１つの試料に対する１回の分析が終了した時点では、カラム流路切替部３０より上流側の流路中にはその分析で使用された移動相が残留している。この移動相が高ｐＨの移動相であった場合、カラム流路切替部３０が切り替えられたあとの次の分析においてこの高ｐＨの移動相が低ｐＨ移動相用のカラムに流れると、該カラムを損傷するおそれがある。そこで、本実施例の液体クロマトグラフ装置では、分析の実行に先立ちユーザの操作に対応して行われる分析スケジュール作成の際に、以下のような特徴的な制御及び処理を行う。図２はこの特徴的な制御及び処理を示すフローチャートである。 At the time when one analysis for one sample as described above is completed, the mobile phase used in the analysis remains in the flow channel upstream of the column flow channel switching unit 30. When this mobile phase is a high pH mobile phase, when this high pH mobile phase flows into the low pH mobile phase column in the next analysis after the column flow path switching unit 30 is switched, May be damaged. Therefore, in the liquid chromatograph apparatus according to the present embodiment, the following characteristic control and processing are performed when an analysis schedule is created in response to a user operation prior to execution of analysis. FIG. 2 is a flowchart showing this characteristic control and processing.
　図２を説明する前に、ここで、本実施例の液体クロマトグラフ装置におけるメソッドファイルとそれに関連した情報について説明する。
　本実施例の液体クロマトグラフ装置では、分析を実行する際にメソッドファイルが使用される。メソッドファイルは、分析を遂行する際の送液部１等の各部の動作条件を規定したファイルであり、例えば、分析時に使用する移動相の種類、カラムの種類、分析時の送液ポンプの流量、カラムオーブンの温度などの各種パラメータが記述されたファイルである。ユーザは多検体の連続分析を行うための分析スケジュールを作成するに先立って、分析の際に用いるメソッドファイルを作成しておく。 Before describing FIG. 2, here, a method file and related information in the liquid chromatograph apparatus of the present embodiment will be described.
In the liquid chromatograph apparatus of the present embodiment, a method file is used when executing analysis. The method file is a file that defines the operating conditions of each part such as the liquid feeding part 1 when performing the analysis. For example, the type of mobile phase used during the analysis, the type of column, and the flow rate of the liquid feeding pump during the analysis A file in which various parameters such as column oven temperature are described. Prior to creating an analysis schedule for continuous analysis of multiple samples, the user creates a method file used for analysis.
　メソッドファイルはユーザが分析条件設定処理部７０により、手作業で作成することも可能であるが、試料に応じた最適なメソッドファイルを自動的に作成する（探索する）ために、例えば特許文献１、非特許文献１等に開示されている「メソッドスカウティング」などを用いてもよい。一般的には、様々な種類の試料に対しそれぞれメソッドファイルが作成されてメソッドファイル記憶部７５ａに格納され、分析スケジュール作成時にユーザ（オペレータ）は、目的とする試料に応じたメソッドファイルを選択することで分析条件を指定する。 The method file can be manually created by the user manually using the analysis condition setting processing unit 70. However, in order to automatically create (search) an optimal method file corresponding to the sample, for example, Patent Document 1 “Method Scouting” disclosed in Non-Patent Document 1 and the like may be used. Generally, method files are created for various types of samples and stored in the method file storage unit 75a, and a user (operator) selects a method file corresponding to a target sample when creating an analysis schedule. Specify the analysis conditions.
　また、ユーザは分析条件設定処理部７０により、溶媒切替バルブ１４、１５の各ポートに接続される溶媒容器中の移動相溶媒を登録するとともに、カラム流路切替バルブ３０、３３の各ポートに接続されるカラムを登録しておく。前者の登録情報である移動相情報は、溶媒切替バルブ１４、１５の各ポートに対する接続位置情報と、移動相の種類、組成などを示す属性情報を含み、分析情報記憶部７５の移動相情報記憶部７５ｃに格納される。。一方、後者の登録情報であるカラム情報は、カラム流路切替バルブ３０、３３の各ポートに対する接続位置情報と、カラムの種類などを示す属性情報を含む。またこのカラム属性情報は、そのカラムが高ｐＨ移動相対応であるか、低ｐＨ移動相対応であるかを示すｐＨ対応情報を含む。これらカラム情報は、分析情報記憶部７５のカラム情報記憶部７５ｂに格納される。
　なお、一般的に、こうした移動相やカラムの登録は一般のオペレータではなく、システム管理者などの権限を持つ者により行われる。場合によっては、メソッドファイルの作成も同様である。 Further, the user registers the mobile phase solvent in the solvent container connected to each port of the solvent switching valves 14 and 15 by the analysis condition setting processing unit 70 and connects to each port of the column flow path switching valves 30 and 33. Register the column to be used. The mobile phase information which is the former registration information includes connection position information for each port of the solvent switching valves 14 and 15 and attribute information indicating the type and composition of the mobile phase, and stores the mobile phase information in the analysis information storage unit 75. Stored in section 75c. . On the other hand, column information which is the latter registration information includes connection position information for each port of the column flow path switching valves 30 and 33, and attribute information indicating a column type and the like. The column attribute information includes pH correspondence information indicating whether the column is compatible with a high pH mobile phase or a low pH mobile phase. The column information is stored in the column information storage unit 75b of the analysis information storage unit 75.
In general, such mobile phase and column registration is not performed by a general operator but by a person having authority such as a system administrator. In some cases, creating a method file is the same.
　図６は、メソッドファイルとカラム情報及び移動相情報の対応付けを模式的に示す図である。上述したように、メソッドファイルには、分析に使用される移動相の種類及びカラムの種類を示す情報が記述されており、それらはそれぞれ移動相情報中の情報、及びカラム情報中の情報に関連付けられている。したがって、或るメソッドファイルが指定されたとき、そのメソッドファイルに記述されているカラムの種類を示す情報から、そのカラムが接続されているポートやそのカラムの属性情報を引き出すことが可能である。また同様に、そのメソッドファイルに記述されている移動相の種類を示す情報から、その移動相溶媒が収容されている溶媒容器が接続されているポートやその移動相の属性情報を引き出すことが可能である。 FIG. 6 is a diagram schematically showing correspondence between a method file, column information, and mobile phase information. As described above, the method file describes information indicating the type of mobile phase and the type of column used in the analysis, which are associated with the information in the mobile phase information and the information in the column information, respectively. It has been. Therefore, when a certain method file is specified, it is possible to extract the port to which the column is connected and the attribute information of the column from the information indicating the type of the column described in the method file. Similarly, from the information indicating the type of mobile phase described in the method file, it is possible to extract the port to which the solvent container containing the mobile phase solvent is connected and the attribute information of the mobile phase. It is.
　図２に戻り、分析スケジュール作成の際の特徴的な制御及び処理について説明する。
　ユーザ（オペレータ）は操作部８で所定の操作を行うことにより、多検体の連続分析のためのスケジュールテーブルを作成する（ステップＳ１）。即ち、ユーザによる操作部８の所定操作によって分析スケジュール作成が指示されると、スケジュールテーブル作成部７２は例えば図３（ｂ）に示すようなスケジュールテーブル（ただし各欄は空欄）を表示部９の画面上に表示する。このスケジュールテーブル上の１行は１つの試料（サンプル）に対する分析の内容を示しており、「バイアル番号」はインジェクタ２に含まれるオートサンプラにおいて定められているバイアルの番号、「トレイ」は同じくオートサンプラに用意されている複数のトレイの番号、「サンプル名」は適宜に設定された各サンプルの名称、「メソッドファイル名」はその分析に使用されるメソッドファイルのファイル名である。また、スケジュールテーブルにおける各行の並びは、連続分析における分析順序を示す。 Returning to FIG. 2, characteristic control and processing in creating an analysis schedule will be described.
The user (operator) performs a predetermined operation on the operation unit 8 to create a schedule table for continuous analysis of multiple samples (step S1). That is, when an analysis schedule creation is instructed by a predetermined operation of the operation unit 8 by the user, the schedule table creation unit 72 displays a schedule table as shown in FIG. Display on the screen. One line on this schedule table shows the contents of analysis for one sample (sample), “vial number” is the number of the vial defined in the autosampler included in the injector 2, and “tray” is also auto The number of a plurality of trays prepared in the sampler, “sample name” is the name of each sample set as appropriate, and “method file name” is the file name of the method file used for the analysis. In addition, the arrangement of each row in the schedule table indicates the analysis order in the continuous analysis.
　ユーザは操作部８により所定の操作を行い、スケジュールテーブルの各行の各欄にそれぞれ適宜の情報を入力する。図３（ｂ）の例では、「Sample2」、「Sample3」というサンプル名を持つ２つのサンプルに対する分析が設定されている。ユーザによるスケジュールテーブルの設定が終了すると、プレラン分析要否判定部７３は設定されたスケジュールテーブルの１行目に指定されているメソッドファイル名を取得し、分析条件記憶部７５に格納されている情報を参照して、そのメソッドファイルに定義されているカラム情報を読み出す（ステップＳ２）。上述したようにメソッドファイルには、使用する移動相とカラムとの組み合わせが記述されており、カラム情報には対応ｐＨ情報が含まれる。このカラムの対応ｐＨ情報は分析に使用される移動相のｐＨに対応している。そこで、指定されたメソッドファイルに関連付けられているカラム情報中の対応ｐＨ情報に基づいて、その分析に使用する移動相が低ｐＨ移動相であるか否かを判定する（ステップＳ３）。 The user performs a predetermined operation using the operation unit 8 and inputs appropriate information in each column of each row of the schedule table. In the example of FIG. 3B, analysis for two samples having sample names “Sample2” and “Sample3” is set. When the user finishes setting the schedule table, the pre-run analysis necessity determination unit 73 acquires the method file name specified in the first line of the set schedule table and stores the information stored in the analysis condition storage unit 75. , Column information defined in the method file is read (step S2). As described above, the method file describes the combination of the mobile phase to be used and the column, and the column information includes the corresponding pH information. The corresponding pH information of this column corresponds to the pH of the mobile phase used for analysis. Therefore, based on the corresponding pH information in the column information associated with the designated method file, it is determined whether or not the mobile phase used for the analysis is a low pH mobile phase (step S3).
　ステップＳ３において移動相が低ｐＨ移動相でないと判定された場合には、使用される移動相は高ｐＨ移動相であり、その場合にはステップＳ３から後述するステップＳ８へと進む。これに対し、移動相が低ｐＨ移動相であると判定された場合には、プレラン分析要否判定部７３は過去分析情報記憶部７１に保存されている過去直近に当該装置で実施された分析のスケジュールテーブルを読み出す。そして、直前に実施された分析に使用されたメソッドファイル名を取得し、上記ステップＳ２の処理と同様に、分析条件記憶部７５に格納されている情報を参照して、そのメソッドファイルに定義されているカラム情報を読み出す（ステップＳ４）。このカラム情報から、その分析に使用された移動相が低ｐＨ移動相であるか否かを判定する（ステップＳ５）。
　なお、この処理を行うために、分析が実行される毎に過去分析情報記憶部７１は、最も新しく実施されたスケジュールテーブルを保存するように記憶内容を更新する。 If it is determined in step S3 that the mobile phase is not a low pH mobile phase, the mobile phase to be used is a high pH mobile phase. In this case, the process proceeds from step S3 to step S8 described later. On the other hand, when it is determined that the mobile phase is a low pH mobile phase, the pre-run analysis necessity determination unit 73 performs the analysis performed by the apparatus most recently in the past stored in the past analysis information storage unit 71. Read the schedule table. Then, the method file name used for the analysis performed immediately before is acquired, and is defined in the method file with reference to the information stored in the analysis condition storage unit 75, as in the process of step S2. Column information is read (step S4). From this column information, it is determined whether or not the mobile phase used for the analysis is a low pH mobile phase (step S5).
In order to perform this process, each time analysis is performed, the past analysis information storage unit 71 updates the stored content so as to save the most recently performed schedule table.
　ステップＳ５において移動相が低ｐＨ移動相であると判定された場合には、第１カラム流路バルブ３０よりも上流側の流路中に残っている移動相は低ｐＨ移動相である可能性が高い。この移動相は高ｐＨ移動相用カラムに導入されても、該カラムを損傷するおそれはない。そこで、ステップＳ５においてＹｅｓと判定されたときには、プレラン分析を行う必要はないと判断し（ステップＳ８）ステップＳ９へと進む。上記ステップＳ３においてＮｏと判定された場合も同様である。 If it is determined in step S5 that the mobile phase is a low pH mobile phase, the mobile phase remaining in the flow channel upstream of the first column flow valve 30 may be a low pH mobile phase. Is expensive. Even if this mobile phase is introduced into the high pH mobile phase column, there is no risk of damaging the column. Therefore, when it is determined Yes in step S5, it is determined that it is not necessary to perform the pre-run analysis (step S8), and the process proceeds to step S9. The same applies when it is determined No in step S3.
　これに対し、ステップＳ５において移動相が低ｐＨ移動相でないと判定されたときには、第１カラム流路バルブ３０よりも上流側の流路中に高ｐＨ移動相が残っている可能性が高い。この移動相が例えばシリカゲルを担体とする充填剤が充填された低ｐＨ移動相用カラムに導入されると、シリカゲルを溶かして損傷を与えるおそれがある。そこで、ステップＳ５においてＮｏと判定されたときには、プレラン分析の必要ありと判断する（ステップＳ６）。この判断を受けてスケジュールテーブル作成部７２は、ステップＳ２で着目した分析の直前にプレラン分析を行うように、スケジュールテーブル上でプレラン分析を実行するための行を追加する（ステップＳ７）。 On the other hand, when it is determined in step S5 that the mobile phase is not a low pH mobile phase, there is a high possibility that a high pH mobile phase remains in the flow path upstream of the first column flow path valve 30. If this mobile phase is introduced into a low pH mobile phase column packed with a silica gel carrier, for example, the silica gel may be dissolved and damaged. Therefore, when it is determined No in step S5, it is determined that pre-run analysis is necessary (step S6). In response to this determination, the schedule table creation unit 72 adds a line for executing the pre-run analysis on the schedule table so that the pre-run analysis is performed immediately before the analysis focused in step S2 (step S7).
　図３は上記ステップＳ２～Ｓ８の処理によりスケジュールテーブルの１行目にプレラン分析が追加されない場合の例、図４は同処理によりスケジュールテーブルの１行目にプレラン分析が追加される場合の例である。図３（ａ）、図４（ａ）は過去分析情報記憶部７１に保存されている過去直近の情報（スケジュールテーブル）である。なお、これら例では、理解を容易にするために、メソッドファイル名を「High PH メソッド」、「Low PH メソッド」とし、ファイル名自体で高ｐＨ、低ｐＨが区別可能であるようにしているが、こうしたファイル名とする必要がないことは上記説明から明らかである。 FIG. 3 shows an example in which the pre-run analysis is not added to the first line of the schedule table by the processes in steps S2 to S8, and FIG. 4 shows an example in which the pre-run analysis is added to the first line of the schedule table by the same process. is there. 3A and 4A show the latest information (schedule table) stored in the past analysis information storage unit 71. FIG. In these examples, in order to facilitate understanding, the method file names are “High PH method” and “Low 高 PH method” so that the file name itself can distinguish between high pH and low pH. It is clear from the above description that there is no need for such a file name.
　図３の例では、（ａ）に示されたスケジュールテーブルから過去直近に実施された分析に使用された移動相は低ｐＨ移動相であることが判明する。また、（ｂ）に示された今回新たに設定されたスケジュールテーブルの１行目に記述された分析に使用される移動相も低ｐＨ移動相である。したがって、ステップＳ５においてＹｅｓと判定され、プレラン分析は省略される。そのため、スケジュールテーブルは何ら修正されない。 In the example of FIG. 3, it is found from the schedule table shown in (a) that the mobile phase used in the analysis performed most recently in the past is a low pH mobile phase. In addition, the mobile phase used for the analysis described in the first row of the schedule table newly set this time shown in (b) is also a low pH mobile phase. Therefore, it is determined Yes in step S5, and the pre-run analysis is omitted. Therefore, the schedule table is not modified at all.
　一方、図４の例では、（ａ）に示されたスケジュールテーブルから過去直近に実施された分析に使用された移動相は高ｐＨ移動相であることが判明する。また（ｂ）に示された今回新たに設定されたスケジュールテーブルの１行目に記述された分析に使用される移動相は低ｐＨ移動相である。そのため、直前の分析から今回の最初の分析への移動相の切り替えにおいては、移動相が高ｐＨ移動相から低ｐＨ移動相に切り替わる。この場合、ステップＳ５においてＮｏと判定され、上述したステップＳ６、Ｓ７の処理が実行され、その結果、図３（ｃ）に示すように、スケジュールテーブルの１行目にはプレラン分析のための行が追加される。
　この行において、バイアル番号「－１」は試料が注入されないことを意味する。また、プレラン分析の際には予め定められたメソッドファイル名が自動的に設定される。このプレラン分析に使用されるメソッドファイルはオペレータ又はシステム管理者が適宜に定めることができ、例えばプレラン分析を実行する時間は任意にすることができる。 On the other hand, in the example of FIG. 4, it is found from the schedule table shown in (a) that the mobile phase used for the analysis performed most recently in the past is a high pH mobile phase. The mobile phase used for the analysis described in the first row of the schedule table newly set this time shown in (b) is a low pH mobile phase. Therefore, in switching the mobile phase from the immediately preceding analysis to the first analysis of this time, the mobile phase is switched from the high pH mobile phase to the low pH mobile phase. In this case, it is determined as No in step S5, and the processes in steps S6 and S7 described above are executed. As a result, as shown in FIG. 3C, the first line of the schedule table includes a line for pre-run analysis. Is added.
In this row, the vial number “−1” means that no sample is injected. In addition, a predetermined method file name is automatically set during pre-run analysis. The method file used for the pre-run analysis can be appropriately determined by the operator or the system administrator. For example, the time for executing the pre-run analysis can be arbitrarily set.
　スケジュールテーブル修正後、プレラン分析要否判定部７２はステップＳ１において設定されたスケジュールテーブルについて全ての分析のチェックが終了したか否かを判定する（ステップＳ９）。具体的には、例えばスケジュールテーブルの１行目に記述された分析についてステップＳ２～Ｓ８の処理が終了したならば、修正前のスケジュールテーブルの次の行、つまり２行目に記述された分析があるか否かを判定する。例えば図４（ｂ）の例では修正前のスケジュールテーブルに２行目が存在するので、ステップＳ９でＮｏと判定されてステップＳ２に戻り、その２行目に記述された分析について上記ステップＳ３～Ｓ８の処理を行う。ただし、この場合、ステップＳ４における「直前の分析」とは、過去直近の分析ではなく、修正前のスケジュールテーブルの１行目に記述された分析である。 After correcting the schedule table, the pre-run analysis necessity determination unit 72 determines whether or not all analysis checks have been completed for the schedule table set in step S1 (step S9). Specifically, for example, when the processing in steps S2 to S8 is completed for the analysis described in the first line of the schedule table, the analysis described in the next line of the schedule table before correction, that is, the second line is performed. It is determined whether or not there is. For example, in the example of FIG. 4B, since the second line exists in the schedule table before correction, it is determined No in step S9, the process returns to step S2, and the analysis described in the second line is performed in the above steps S3 to S3. The process of S8 is performed. In this case, however, the “previous analysis” in step S4 is not the latest analysis in the past, but the analysis described in the first line of the schedule table before correction.
　図５はスケジュールテーブルに記述された連続的な分析の途中でプレラン分析が追加される場合の一例である。即ち、図５（ａ）に示したスケジュールテーブルの４行目に記述された分析に使用される移動相は高ｐＨ移動相、５行目に記述された分析に使用される移動相は低ｐＨ移動相である。そのため、５行目に記述された分析に対する処理が行われる際に、ステップＳ３ではＹｅｓ、ステップＳ５ではＮｏと判定され、５行目に記述された分析の直前にプレラン分析が追加される。その結果、スケジュールテーブルは図５（ｂ）に示すように修正される。 Fig. 5 shows an example in which a pre-run analysis is added during the continuous analysis described in the schedule table. That is, the mobile phase used for the analysis described in the fourth row of the schedule table shown in FIG. 5A is a high pH mobile phase, and the mobile phase used for the analysis described in the fifth row is a low pH. Mobile phase. Therefore, when processing for the analysis described in the fifth line is performed, Yes is determined in step S3 and No is determined in step S5, and the pre-run analysis is added immediately before the analysis described in the fifth line. As a result, the schedule table is corrected as shown in FIG.
　そして、はじめに設定されたスケジュールテーブルに記述された全ての分析についての処理が終わると、スケジュールテーブルが確定するから、このスケジュールテーブルが分析制御部７４に渡され、分析制御部７４はこのスケジュールテーブルに従って順次分析を実行する（ステップＳ１０）。その結果、第１カラム流路切替バルブ３０より上流側の流路中に残った高ｐＨ移動相が低ｐＨ移動相用カラムに導入されるおそれがある場合にのみ、プレラン分析が実行される。プレラン分析では、送液ポンプ１６、１７により送給された移動相が第１カラム流路切替バルブ３０を経てバイパス流路３２に流れ、第１カラム流路切替バルブ３３を経て外部に排出される。 Then, when processing for all analyzes described in the initially set schedule table is completed, the schedule table is finalized, so this schedule table is passed to the analysis control unit 74, and the analysis control unit 74 follows the schedule table. Sequential analysis is executed (step S10). As a result, the pre-run analysis is performed only when the high pH mobile phase remaining in the flow path upstream of the first column flow path switching valve 30 may be introduced into the low pH mobile phase column. In the pre-run analysis, the mobile phase fed by the liquid feed pumps 16 and 17 flows to the bypass channel 32 via the first column channel switching valve 30 and is discharged to the outside via the first column channel switching valve 33. .
　以上のようにして、本実施例の液体クロマトグラフ装置では、移動相によりカラムが損傷するおそれがあるときのみプレラン分析が実行されるので、カラムを確実に保護しつつ、連続分析における総分析時間を短縮することができる。また、移動相の使用量も抑えることができる。 As described above, in the liquid chromatograph of the present embodiment, the pre-run analysis is performed only when there is a possibility that the column is damaged by the mobile phase. Therefore, the total analysis time in the continuous analysis is ensured while reliably protecting the column. Can be shortened. Moreover, the usage-amount of a mobile phase can also be suppressed.
　上記説明では、移動相が低ｐＨ移動相から高ｐＨ移動相に切り替わるときにはプレラン分析は実行されないが、ユーザの選択により、移動相が低ｐＨ移動相から高ｐＨ移動相に切り替わるときにもプレラン分析が実行されるようにしてもよい。この場合、移動相の種類が切り替えられても、移動相のｐＨが高ｐＨのまま又は低ｐＨのままである場合のみプレラン分析の実行が省略される。 In the above description, the pre-run analysis is not performed when the mobile phase is switched from the low pH mobile phase to the high pH mobile phase, but the pre-run analysis is also performed when the mobile phase is switched from the low pH mobile phase to the high pH mobile phase according to the user selection. May be executed. In this case, even if the type of the mobile phase is switched, the execution of the pre-run analysis is omitted only when the pH of the mobile phase remains high or low.
　また、上記実施例では、高ｐＨ移動相対応及び低ｐＨ移動相対応を示す情報がｐＨ対応情報とされていたが、対応可能なｐＨ範囲がｐＨ対応情報とされている場合には、そのｐＨ範囲を判断することでｐＨの高低を判定するようにすればよい。 Further, in the above embodiment, the information indicating the correspondence with the high pH mobile phase and the correspondence with the low pH mobile phase is the pH correspondence information, but when the compatible pH range is the pH correspondence information, the pH What is necessary is just to judge the level of pH by judging the range.
　また、上記実施例では、分析スケジュール作成の段階でプレラン分析の要否を判定し、必要に応じてスケジュールテーブルを修正していたが、実際に分析実行中にこれから実行しようとしている分析で使用される移動相のｐＨと直前に実行された分析で使用された移動相のｐＨとの高低の関係に基づいて、プレラン分析を実行するか否かを判断するようにすることもできる。 In the above embodiment, the necessity of the pre-run analysis is determined at the stage of creating the analysis schedule, and the schedule table is corrected as necessary, but it is used in the analysis that is going to be performed during the actual execution of the analysis. It is also possible to determine whether or not to perform the pre-run analysis based on the relationship between the pH of the mobile phase and the pH of the mobile phase used in the analysis performed immediately before.
　また、上記実施例は本発明の一例であり、本発明の趣旨の範囲で適宜変形、追加、修正を加えても本願特許請求の範囲に包含されることは明らかである。 Further, the above-described embodiment is an example of the present invention, and it is apparent that any modification, addition, or modification as appropriate within the scope of the present invention is included in the scope of the claims of the present application.
１…送液部
１０ａ～１０ｄ、１１ａ～１１ｄ…溶媒容器
１２、１３…脱気ユニット
１４、１５…溶媒切替バルブ
１６、１７…送液ポンプ
１８…グラジエントミキサ
２…インジェクタ
３…カラムユニット
３０、３３…カラム流路切替バルブ
３１ａ～３１ｅ…カラム
３２…バイパス流路
４…検出器
５…データ処理部
６…分析制御部
７…主制御部
７０…分析条件設定処理部
７１…過去分析情報記憶部
７２…スケジュールテーブル作成部
７３…プレラン分析要否判定部
７４…分析制御部
７５…分析条件記憶部
７５ａ…メソッドファイル記憶部
７５ｂ…カラム情報記憶部
７５ｃ…移動相情報記憶部
８…操作部
９…表示部 DESCRIPTION OF SYMBOLS 1 ... Liquid feeding part 10a-10d, 11a-11d ... Solvent container 12, 13 ... Deaeration unit 14, 15 ... Solvent switching valve 16, 17 ... Liquid feeding pump 18 ... Gradient mixer 2 ... Injector 3 ... Column unit 30, 33 ... column flow path switching valves 31a to 31e ... column 32 ... bypass flow path 4 ... detector 5 ... data processing section 6 ... analysis control section 7 ... main control section 70 ... analysis condition setting processing section 71 ... past analysis information storage section 72 ... schedule table creation unit 73 ... pre-run analysis necessity determination unit 74 ... analysis control unit 75 ... analysis condition storage unit 75a ... method file storage unit 75b ... column information storage unit 75c ... mobile phase information storage unit 8 ... operation unit 9 ... display Part

Claims (6)

  1. 　複数の移動相を切り替える移動相選択部と、該移動相選択部により切り替えられた移動相中に試料を注入する試料注入部と、複数のカラムと、前記試料が注入された移動相を前記複数のカラムのいずれかに選択的に導入するカラム流路切替部と、を具備する液体クロマトグラフ装置において、
    　a)前記移動相選択部により切り替えられた移動相をカラムに導入することなく排出するために、該カラムと前記カラム流路切替部との間に設けられたバイパス流路切替部及び該流路切替部に接続されたバイパス流路と、
    　b)連続分析を行うための分析スケジュール作成時に、着目する１つの分析で使用される移動相の特性と該分析の直前に実行された又は実行される分析において使用された又は使用される移動相の特性とについての情報を取得し、それら２つの分析の間で特定の特性変更があるか否かを判定する移動相判定部と、
    　c)前記移動相判定部により移動相に特定の特性変更があると判定された場合に、前記着目する１つの分析の実行前に前記バイパス流路を通して移動相を排出するプレラン分析を実行するように分析スケジュールを調整するスケジュール調整部と、
    　を備えることを特徴とする液体クロマトグラフ装置。     A mobile phase selection unit that switches a plurality of mobile phases, a sample injection unit that injects a sample into the mobile phase switched by the mobile phase selection unit, a plurality of columns, and a plurality of mobile phases into which the sample is injected In a liquid chromatograph apparatus comprising a column flow path switching unit selectively introduced into any of the columns,
    a) a bypass flow path switching unit provided between the column and the column flow path switching unit and the flow path for discharging the mobile phase switched by the mobile phase selection unit without introducing it into the column; A bypass flow path connected to the switching unit;
    b) The characteristics of the mobile phase used in one analysis of interest and the mobile phase used or used in the analysis performed immediately prior to the analysis when creating an analysis schedule for continuous analysis And a mobile phase determination unit that determines whether or not there is a specific characteristic change between the two analyses,
    c) When the mobile phase determination unit determines that there is a specific characteristic change in the mobile phase, a pre-run analysis for discharging the mobile phase through the bypass channel is performed before the execution of the one focused analysis. A schedule adjustment unit for adjusting the analysis schedule,
    A liquid chromatograph apparatus comprising:
  2. 　複数の移動相を切り替える移動相選択部と、該移動相選択部により切り替えられた移動相中に試料を注入する試料注入部と、複数のカラムと、前記試料が注入された移動相を前記複数のカラムのいずれかに選択的に導入するカラム流路切替部と、を具備する液体クロマトグラフ装置において、
    　a)前記移動相選択部により切り替えられた移動相をカラムに導入することなく排出するために、該カラムと前記カラム流路切替部との間に設けられたバイパス流路切替部及び該流路切替部に接続されたバイパス流路と、
    　b)分析実行時に、該分析で使用される移動相の特性と該分析の直前に実行された分析において使用された移動相の特性とについての情報を取得し、それら２つの分析の間で特定の特性変更があるか否かを判定する移動相判定部と、
    　c)前記移動相判定部により移動相の特定の特性変更であると判定された場合に、実行しようとしている分析の前に、前記バイパス流路を通して移動相を排出するプレラン分析を実行するように前記バイパス流路切替部を制御する分析制御部と、
    　を備えることを特徴とする液体クロマトグラフ装置。     A mobile phase selection unit that switches a plurality of mobile phases, a sample injection unit that injects a sample into the mobile phase switched by the mobile phase selection unit, a plurality of columns, and a plurality of mobile phases into which the sample is injected In a liquid chromatograph apparatus comprising a column flow path switching unit selectively introduced into any of the columns,
    a) a bypass flow path switching unit provided between the column and the column flow path switching unit and the flow path for discharging the mobile phase switched by the mobile phase selection unit without introducing it into the column; A bypass flow path connected to the switching unit;
    b) When performing an analysis, obtain information about the characteristics of the mobile phase used in the analysis and the characteristics of the mobile phase used in the analysis performed immediately before the analysis, and specify between the two analyzes A mobile phase determination unit that determines whether or not there is a characteristic change,
    c) When the mobile phase determination unit determines that the mobile phase has a specific characteristic change, a pre-run analysis for discharging the mobile phase through the bypass channel is performed before the analysis to be performed. An analysis control unit for controlling the bypass flow path switching unit;
    A liquid chromatograph apparatus comprising:
  3. 　請求項１又は２に記載の液体クロマトグラフ装置であって、
    　前記移動相の特性は移動相のｐＨであることを特徴とする液体クロマトグラフ装置。     The liquid chromatograph apparatus according to claim 1 or 2,
    The liquid chromatograph is characterized in that the characteristic of the mobile phase is the pH of the mobile phase.
  4. 　請求項３に記載の液体クロマトグラフ装置であって、
    　前記移動相の特定の特性変更は移動相のｐＨが高い状態から低い状態に変化するものあることを特徴とする液体クロマトグラフ装置。     A liquid chromatograph device according to claim 3,
    The liquid chromatograph is characterized in that the specific characteristic change of the mobile phase changes from a high state to a low state of the pH of the mobile phase.
  5. 　請求項１～４のいずれかに記載の液体クロマトグラフ装置であって、
    　前記プレラン分析は、前記バイパス流路を通して移動相を排出したのに引き続き、前記カラム流路切替部により流路を切り替えて次の分析に使用されるカラムに移動相を所定時間流して該カラムを洗浄するものであることを特徴とする液体クロマトグラフ装置。     A liquid chromatograph apparatus according to any one of claims 1 to 4,
    In the pre-run analysis, after the mobile phase has been discharged through the bypass flow path, the flow path is switched by the column flow path switching unit, and the mobile phase is allowed to flow through the column used for the next analysis for a predetermined time. A liquid chromatograph apparatus for cleaning.
  6. 　請求項１～５のいずれかに記載の液体クロマトグラフ装置であって、
    　分析を遂行する際の分析条件を規定するメソッドファイル中に又は該メソッドファイルに関連して、該分析で使用する移動相とカラムとの組み合わせに関する情報を保持するようにしたことを特徴とする液体クロマトグラフ装置。     A liquid chromatograph according to any one of claims 1 to 5,
    A liquid characterized by holding information on a combination of a mobile phase and a column used in the analysis in or in connection with the method file that defines the analysis conditions for performing the analysis Chromatographic device.
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