Preparative liquid chromatograph

Abstract

This invention provides a preparative liquid chromatograph that can also handle situations where the actual second delay time changes after the start of sequence separation. During sequence separation, after a specific component is detected as a peak in either the first or second detector, the control device performs a maintenance operation on the time difference information stored in the information storage area. In this maintenance operation, the control device performs a peak determination to determine whether the difference between the first and second retention times is within a specified allowable range, thereby confirming whether the second delay time from the detection of the component in the second detector to the arrival of the component in the fraction collector has changed compared to the previous state. If the control device determines, through peak determination, that the second delay time has changed compared to the previous state, it updates the time difference information stored in the information storage area to the latest state using the calculated difference between the first and second retention times.

Description

Technical Field

[0001] This invention relates to a preparative liquid chromatograph. Background Technology

[0002] A preparative liquid chromatograph is known, which uses liquid chromatography to separate multiple components contained in a sample from each other and collects the desired components among the separated components in different collection containers (see Patent Document 1).

[0003] A preparative liquid chromatograph includes: a detector and a fraction collector, positioned downstream of a separation column used to separate components in a sample; and a control device that controls the operation of the fraction collector based on an output signal from the detector. Components separated by the separation column are represented as peaks in the output signal from the detector when introduced into the detector. The control device controls the operation of the fraction collector in such a way that it detects the component passing through the detector when a peak of the component to be collected is displayed in the output signal from the detector, and directs the portion corresponding to its peak into a collection container. The time from when the component to be collected passes through the detector to when the component reaches the fraction collector (hereinafter referred to as the delay time) depends on the internal capacity of the flow path between the detector and the fraction collector and the flow rate of the mobile phase. The control device calculates the delay time at a predetermined time point before the start of separation (e.g., the time point at which the flow rate of the mobile phase is set), and controls the operation of the fraction collector after the start of separation, taking the delay time into account.

[0004] Furthermore, in preparative liquid chromatography, there exists a situation where the flow path is branched between the separation column and the detector (referred to as the first detector), a portion of the eluent is taken out and directed to another detector, such as a mass spectrometer (referred to as the second detector), to detect components that are difficult to detect using the first detector, thereby improving the component separation performance. In this case, since the time required for the component eluent from the separation column to reach the first detector is not exactly the same as the time required to reach the second detector, when collecting components based on the signal output from the second detector, a different delay time (hereinafter referred to as the first delay time) needs to be applied compared to the case where components are collected based on the signal output from the first detector.

[0005] The second delay time is determined by the following method: calculating the difference between the retention time from the injection of the component into the mobile phase until the first detector detects the peak (referred to as the first retention time) and the retention time from the injection of the same component into the mobile phase until the component is detected by the second detector in the form of a peak (referred to as the second retention time), and adding the difference to the first delay time determined by the internal capacity of the flow path between the detector and the fraction collector and the flow rate of the mobile phase.

[0006] [Existing technical documents]

[0007] [Patent Literature]

[0008] [Patent Document 1] International Publication No. 2018 / 185872 Summary of the Invention

[0009] [The problem the invention aims to solve]

[0010] As described above, in a preparative liquid chromatograph including two detectors, in the initial setting before starting the injection of more than one sample and collecting the desired components in different collection containers, a second delay time is determined by injecting a standard sample containing a specific component, and this second delay time, together with the first delay time, is stored in the device as a parameter for separation.

[0011] During the execution of the separation sequence, the following situations may occur: blockage of the flow path connected to the second detector, etc., causing the actual second delay time to change from the value set before the start of the separation sequence. However, in current preparative liquid chromatographs, the separation parameters cannot be corrected during the execution of the separation sequence. Therefore, the following problem exists: even if such an event occurs, the separation sequence continues using the original second delay time, and the collection of components cannot be performed normally.

[0012] The present invention was made in view of the aforementioned problems, and its object is to provide a preparative liquid chromatograph that can also cope with situations where the actual second delay time changes after the start of sequence separation.

[0013] [Technical means to solve the problem]

[0014] The preparative liquid chromatograph of the present invention includes: a delivery pump for delivering a mobile phase at a set flow rate; an injector for injecting a sample into the mobile phase delivered by the delivery pump; a separation column for separating components in the sample injected into the mobile phase by the injector; an outlet flow path fluidly connected to the outlet of the separation column for supplying eluent from the separation column; a branch flow path branching from the outlet flow path for extracting a portion of the eluent flow from the outlet flow path; a first detector fluidly connected to the outlet flow path for outputting a first signal corresponding to the concentration of the components in the eluent; a second detector fluidly connected to the branch flow path for outputting a second signal corresponding to the concentration of the components in the eluent supplied through the branch flow path; a fraction collector fluidly connected to the outlet of the first detector for collecting a desired portion of the eluent from the separation column into different collection containers; and a control device configured to control the operation of the delivery pump, the injector, and the fraction collector to execute a set separation sequence. The control device is configured as follows: it includes an information storage area that stores time difference information and a first delay time as initial setting information set before the start of the fractionation sequence. The time difference information is related to the time required to detect the component dissolved from the separation column in the form of a peak in the first signal and the time difference between the time when the component dissolved from the separation column is detected in the form of a peak in the second signal. The first delay time is the time when the component detected in the form of a peak in the first signal arrives at the fraction collector. During the execution of the fractionation sequence, in the first collection action of collecting the component detected in the form of a peak in the first signal into the collection container, the first delay time is applied to control the operation of the fraction collector. In the second collection action of collecting the component detected in the form of a peak in the second signal into the collection container, the second delay time is applied to control the operation of the fraction collector. The second delay time is calculated using the time difference information and the first delay time stored in the information storage area and is the time when the component detected in the form of a peak in the second signal arrives at the fraction collector. The control device is configured such that, during the execution of the extraction sequence, when a specific component that is detected as a peak in either the first signal or the second signal is injected into the mobile phase, a maintenance action is performed on the time difference information stored in the information storage area.The control device is configured as follows: during the maintenance operation, it calculates the difference between the first holding time from the injection of the specific component into the mobile phase to its detection as a peak in the first signal and the second holding time from the injection of the specific component into the mobile phase to its detection as a peak in the second signal; performs a peak determination on whether the calculated difference is within an allowable range set based on the time difference information; and in the peak determination, if the calculated difference deviates from the allowable range, it updates the time difference information stored in the information storage area using the calculated difference.

[0015] That is, in this invention, during the execution of the fractionation sequence, after injecting a specific component detected as a peak in either the first or second detector, a maintenance operation is performed on the time difference information stored in the information storage area. During this maintenance operation, a peak determination is performed to determine whether the difference between the first and second holding times is within a predetermined allowable range. This automatically confirms whether the second delay time from the detection of the component in the second detector to the arrival of the component in the fraction collector has changed compared to the previous state. Then, if the peak determination indicates that the second delay time has changed compared to the previous state, the time difference information stored in the information storage area is updated to the latest state using the calculated difference between the first and second holding times. Therefore, it is also possible to address situations where the second delay time changes after the start of the fractionation sequence.

[0016] [The effects of the invention]

[0017] According to the preparative liquid chromatograph of the present invention, during the execution of sequence separation, after injecting a specific component, a maintenance action is performed on the time difference information stored in the information storage area. If it is confirmed during the maintenance action that the second delay time has changed compared with the previous state, the time difference information stored in the information storage area is updated to the latest state. Therefore, it can also cope with the situation where the second delay time has changed after the sequence separation begins. Attached Figure Description

[0018] Figure 1 This is a schematic structural diagram illustrating an embodiment of the preparation of a liquid chromatograph.

[0019] Figure 2 This is a flowchart used to illustrate an example of the initial setup before executing the split sequence in the same embodiment.

[0020] Figure 3 This is a flowchart used to illustrate an example of an action in the sorting sequence of the same embodiment.

[0021] Figure 4 This is a flowchart used to illustrate one example of a maintenance action in the same embodiment.

[0022] Figure 5 It is a chromatogram of the first and second signals used to illustrate the first retention time, the second retention time, the difference between the first and second retention times, and the peak width.

[0023] [Explanation of Symbols]

[0024] 2: Liquid delivery pump

[0025] 4: Syringe

[0026] 6: Separation tubing

[0027] 8: First detector

[0028] 10: Second detector

[0029] 12: Fraction Collector

[0030] 14: Control device

[0031] 16: Exit flow path

[0032] 18: Branch Office

[0033] 20: Branch Flow Path

[0034] 22: Monitor Detailed Implementation

[0035] Hereinafter, an embodiment of the preparative liquid chromatograph of the present invention will be described with reference to the drawings.

[0036] The preparative liquid chromatograph 1 mainly includes a liquid delivery pump 2, a syringe 4, a separation column 6, a first detector 8, a second detector 10, a fraction collector 12, and a control device 14.

[0037] Pump 2 is a device used to deliver the mobile phase. Injector 4 is a device used to inject the sample into the mobile phase delivered by pump 2. Separation column 6 is located downstream of injector 4. Multiple components of the sample injected into the mobile phase via injector 4 are separated from each other in separation column 6.

[0038] The first detector 8 is fluidly connected to the outlet flow path 16 at the outlet of the separation column 6, and the second detector 10 is fluidly connected to the branch flow path 20. The branch flow path 20 is a flow path formed by branching from the outlet flow path 16 at the branch 18 between the separation column 6 and the first detector 8. The flow of the dissolution liquid from the separation column 6 is split in the branch 18, with most of the dissolution liquid flow being introduced into the first detector 8 and a portion of the dissolution liquid flow being introduced into the second detector 10. The flow rate of the dissolution liquid passing through the branch flow path 20 and introduced into the second detector 10 is approximately 1 / 800 to 1 / 5000 of the flow rate of the dissolution liquid introduced into the first detector 8. The first detector is a detector such as an ultraviolet (UV) detector that outputs a signal (hereinafter referred to as the first signal) corresponding to the concentration of the components in the dissolution liquid flowing in the outlet flow path 16. The second detector is a mass spectrometer (MS) or similar detector that outputs a signal (hereinafter referred to as the second signal) corresponding to the concentration of the components in the dissolution taken from the outlet flow path 16 through the branch flow path 20. The second detector 10 is a detector used to supplement the detection characteristics of the first detector 8, and is used to detect components that do not appear in the form of a peak in the first signal output by the first detector 8.

[0039] The fraction collector 12 is fluidly connected to the outlet of the first detector 8. The fraction collector 12 is a device used to collect the desired portion of the dissolution from the separation column 6 in a fractional form in a collection container downstream of the first detector 8.

[0040] The control device 14 is used to control the operation of the liquid delivery pump 2, the syringe 4, and the fraction collector 12. The control device 14 can be implemented using a dedicated computer or a personal computer with dedicated software installed. A display for showing various information is electronically connected to the control device 14.

[0041] The control device 14 controls the operation of the fraction collector 12 in the following manner: after starting the fractionation sequence set by the user, one or more samples registered in the fractionation sequence are sequentially injected into the mobile phase through the syringe 4. Each component in the dissolution from the separation column 6 is detected in the form of peaks on the chromatogram of the first signal output from the first detector 8 or the chromatogram of the second signal output from the second detector 10. The components detected in the form of peaks are collected in different collection containers.

[0042] When the control device 14 performs the action of collecting the component detected in the form of a peak in the first signal output from the first detector 8 into the collection container (referred to as the first collection action), it considers the time T1 required from the time the component is detected in the form of a peak by the first detector 8 until the component reaches the fraction collector 12 (hereinafter referred to as the first delay time T1). That is, when the first delay time T1 has elapsed since the peak of the target component is detected in the first signal of the first detector 8, the control device 14 causes the fraction collector 12 to perform the action of collecting the dissolution into the collection container.

[0043] On the other hand, when the control device 14 performs the action of collecting the component detected in the second signal output from the second detector 10 in the form of a peak into the collection container (referred to as the second collection action), it takes into account the time T2 required from the time the component is detected by the second detector 10 in the form of a peak until the component reaches the fraction collector 12 (hereinafter referred to as the second delay time T2). That is, when the second delay time T2 has elapsed since the peak of the target component is detected in the second signal of the second detector 10, the control device 14 causes the fraction collector 12 to perform the action of collecting the dissolution into the collection container.

[0044] The first delay time T1 can be determined using the flow rate L of the mobile phase delivered by the delivery pump 2 and the internal capacity V of the flow path between the first detector 8 and the fraction collector 12. That is, the first delay time T1 can be calculated using the following formula.

[0045] T1=V / L (1)

[0046] On the other hand, the second delay time T2 can be obtained by adding the time difference Δt between the time point when the component dissolved from the separation column 6 reaches the first detector 8 and the time point when the component dissolved from the separation column 6 reaches the second detector 10, and the first delay time T1. The time difference Δt can be obtained by taking the difference (t2-t1) between the time t1 (hereinafter referred to as the first holding time t1) from the time when the component is injected into the mobile phase by the syringe 4 until the component appears as a peak in the first signal of the first detector 8 and the time t2 (hereinafter referred to as the second holding time t2) from the time when the component is injected into the mobile phase by the syringe 4 until the component appears as a peak in the second signal of the second detector 10. That is, the second delay time T2 can be obtained by the following formula.

[0047] T2 = T1 - (t2 - t1) (2)

[0048] The first delay time T1, the time difference information Δt, and the second delay time T2 are set in the initial setting operation performed before the sorting sequence. The control device 14 is configured to perform the initial setting operation before executing the sorting sequence.

[0049] use Figure 1 and Figure 2 The flowchart illustrates an example of the initial setup operation. Furthermore, the following description assumes that the syringe 4 can move in and out of a container containing a standard sample. The standard sample is a sample containing a known component (hereinafter referred to as a specific component) that appears as a peak in both the first signal from the first detector 8 and the second signal from the second detector 10.

[0050] In the initial setup, the control device 14 allows the user to set the flow rate of the mobile phase (step 101). After the user sets the flow rate (L), the control device 14 uses the set flow rate (L) and information related to the internal capacity (V) of the flow path between the first detector 8 and the fraction collector 12 registered during the installation of the preparative liquid chromatograph (e.g., information related to the inner diameter and length of the piping) to calculate the first delay time T1 and store it in the information storage area provided in the control device 14 (step 102).

[0051] After the control device 14 delivers the mobile phase to the delivery pump 2 at a set flow rate, it injects the standard sample into the syringe 4 (step 103). After injecting the standard sample into the mobile phase, as... Figure 5 As shown, the control device 14 measures the first holding time (t1) from the injection of the standard sample to the detection of the peak P1 of the specific component in the chromatogram of the first signal of the first detector 8, and the second holding time (t2) from the injection of the standard sample to the detection of the peak P2 of the specific component in the chromatogram of the second signal of the second detector 10 (step 104), and calculates the difference (t2-t1) between the first holding time (t1) and the second holding time (t2), storing the calculated difference (t2-t1) as time difference information (Δt) in the information storage area (step 105). Furthermore, the control device 14 uses the calculated first delay time (T1) and the time difference information (Δt) to calculate the second delay time (T2), and stores the calculated second delay time (T2) in the information storage area (step 106).

[0052] After the initial setup is complete, the control device 14 begins the sorting sequence when the user instructs that the sorting sequence should be executed. Figure 1 and Figure 3 The flowchart illustrates the actions performed during the sequence extraction process.

[0053] After the separation sequence begins, the control device 14 controls the syringe 4 to inject one or more samples into the mobile phase in a predetermined order. After injecting a sample into the mobile phase using the syringe 4 (step 201), the control device 14, based on pre-registered sample information, confirms whether the injected sample contains a specific component that appears as a peak in either the first signal of the first detector 8 or the second signal of the second detector 10 (step 202).

[0054] If the injected sample does not contain a specific component (step 202: No), the control device 14 performs the normal dispensing operation (step 203). On the other hand, if the injected sample contains a specific component (step 202: Yes), the control device 14 performs a maintenance operation simultaneously with the normal dispensing operation (step 204). The maintenance operation is as follows: it checks whether the time difference (t2-t1) between the current first holding time (t1) and the second holding time (t2) has changed compared to the time difference (Δt) stored in the information storage area. If the time difference (t2-t1) has changed compared to the time difference (Δt) stored in the information storage area, it updates the time difference information (Δt) and the second delay time (T2) stored in the information storage area using the newly calculated time difference (t2-t1). If the time difference information (Δt) and the second delay time (T2) stored in the information storage area are updated through the maintenance action (step 205: Yes), a warning is displayed on the display 22 to notify the user that the time difference information (Δt) and the second delay time (T2) have been updated (step 206). Through the warning, the user can identify abnormalities such as blockages in the branch flow path 20 connected to the second detector 10.

[0055] When the time difference information (Δt) and the second delay time (T2) stored in the information storage area are updated through the maintenance action, the control device 14 applies the updated second delay time (T2) to the subsequent second collection action. In this way, before the end of the set collection sequence (step 207), a maintenance action is performed every time a sample containing a specific component is injected into the mobile phase, thereby updating the second delay time (T2) to the latest state.

[0056] Furthermore, the control device 14 can be configured such that, when performing a second collection operation using a second delay time (T2) updated through a maintenance operation, it performs an operation to confirm the recovery rate of the component to be collected in the second collection operation. For example, if the syringe 4 is configured to be able to enter and exit a collection container containing the component collected by the fraction collector 12, the component to be collected is fully injected after the set sampling sequence is completed. Then, the peak area (A1) of the component in the chromatogram of the second signal is calculated, and the calculated peak area (A1) is compared with the peak area (A2) of the component in the chromatogram of the second signal used during the collection of the component, thereby confirming the result. If the peak area (A1) of the collected component is at least a predetermined ratio (e.g., 95%) of the peak area (A2) of the component before collection, it can be assessed that the second collection operation performed using the updated second delay time (T2) is without problems. On the other hand, if the peak area (A1) of the collected object component is lower than the predetermined ratio of the peak area (A2) of the object component before collection, it can be assessed that there is a problem with the second collection action performed by applying the updated second delay time (T2). In this case, the control device 14 may issue a warning to the user.

[0057] Next, use Figure 4 The flowchart illustrates an example of a maintenance action.

[0058] During maintenance, the control device 14 measures the first holding time (t1) and the second holding time (t2) associated with the specific component, using the peak of the specific component appearing in the chromatograms of the first and second signals, as a reference (step 301), and calculates the difference (t2-t1) between the measured first holding time (t1) and the second holding time (t2) (step 302). Then, the control device 14 performs a peak determination to determine whether the calculated difference (t2-t1) is within an allowable range set based on the time difference (Δt) stored in the information storage area (step 303). If the difference (t2-t1) is within the allowable range, the time difference information (Δt) stored in the information storage area is kept unchanged (step 304). On the other hand, when the calculated difference (t2-t1) deviates from the allowable range, the control device 14 rewrites the time difference information (Δt) in the information storage area into the newly calculated difference (t2-t1), thereby updating the time difference information (Δt) to the latest state (step 305).

[0059] Furthermore, in the peak determination (step 303), the control device 14 can also calculate the ratio (W1 / W2) of the peak width (W1) of a specific component on the chromatogram of the first signal to the peak width (W2) of a specific component on the chromatogram of the second signal, and determine whether the calculated ratio (W1 / W2) falls within a specified reference range. Figure 5 As shown, the peak widths (W1, W2) can be half the width of each peak. The control device 14 can be configured to issue a warning to the user if the ratio of the peak widths (W1 / W2) deviates from a specified reference range. If a blockage or other obstruction occurs in the flow path connected to any detector, the ratio of the peak widths (W1 / W2) will usually change, and this abnormality can be detected by monitoring the ratio of the peak widths (W1 / W2).

[0060] The embodiments described above are merely one example of the implementation of the preparative liquid chromatograph of the present invention. The implementation of the preparative liquid chromatograph of the present invention is as follows.

[0061] In one embodiment of the preparation of the liquid chromatograph of the present invention, it includes:

[0062] A liquid delivery pump delivers the mobile phase at a set flow rate;

[0063] A syringe is used to inject a sample into the mobile phase delivered by the pump.

[0064] A separation column is used to separate components of a sample injected into the mobile phase via the syringe from one another.

[0065] The outlet flow path is fluidly connected to the outlet of the separation column, allowing the dissolution solution from the separation column to flow out.

[0066] A branch flow path, branching off from the outlet flow path, is used to extract a portion of the liquid flow of the dissolution solution from the outlet flow path;

[0067] A first detector is fluidly connected to the outlet flow path and outputs a first signal corresponding to the concentration of the component in the dissolution solution;

[0068] The second detector is fluidly connected to the branch flow path and outputs a second signal corresponding to the concentration of the components in the dissolution solution supplied through the branch flow path;

[0069] A fraction collector, fluidly connected to the outlet of the first detector, is used to collect the desired fraction of the dissolution from the separation column into different collection containers; and

[0070] The control device is configured to control the operation of the liquid delivery pump, the syringe, and the fraction collector to execute a predetermined dispensing sequence.

[0071] The control device is configured as follows: it includes an information storage area that stores time difference information and a first delay time as initial setting information set before the start of the fractionation sequence. The time difference information is related to the time required to detect the component dissolved from the separation column in the form of a peak in the first signal and the time difference between detecting the component dissolved from the separation column in the form of a peak in the second signal. The first delay time is the time when the component detected in the form of a peak in the first signal reaches the fraction collector. During the execution of the fractionation sequence, in the first collection action of collecting the component detected in the form of a peak in the first signal into the collection container, the first delay time is applied to control the operation of the fraction collector. In the second collection action of collecting the component detected in the form of a peak in the second signal into the collection container, the second delay time is applied to control the operation of the fraction collector. The second delay time is calculated using the time difference information and the first delay time stored in the information storage area and is the time when the component detected in the form of a peak in the second signal reaches the fraction collector.

[0072] Furthermore, the control device is configured such that, during the execution of the extraction sequence, when a specific component detected as a peak in either the first signal or the second signal is injected into the mobile phase, a maintenance operation of the time difference information stored in the information storage area is performed.

[0073] The control device is configured as follows: during the maintenance operation, it calculates the difference between the first holding time from the injection of the specific component into the mobile phase to its detection as a peak in the first signal and the second holding time from the injection of the specific component into the mobile phase to its detection as a peak in the second signal; performs a peak determination on whether the calculated difference is within an allowable range set based on the time difference information; and in the peak determination, if the calculated difference deviates from the allowable range, it updates the time difference information stored in the information storage area using the calculated difference.

[0074] In the first embodiment, the control device is configured to issue a warning to the user if the difference between the first holding time and the second holding time deviates from the allowable range in the peak determination. This configuration allows the user to easily identify abnormalities such as blockages in the branch flow path communicating with the second detector.

[0075] In the second state of the first embodiment, the control device is configured such that, in the peak determination, the difference between the times when the peaks of the specific components appearing in the first signal and the second signal, respectively, are calculated as the difference between the first hold time and the second hold time. The second state can be combined with the first state.

[0076] In the third state of the first embodiment, the control device is configured such that, in the peak determination, it calculates the ratio of the width of the peak of the specific component appearing in the first signal to the width of the peak of the specific component appearing in the second signal, determines whether the ratio is within a predetermined reference range, and issues a warning to the user if the ratio deviates from the predetermined reference range. The third state may be combined with the first state and / or the second state.

[0077] In the fourth state of the first embodiment, the syringe is configured to inject the component collected by the collection container as a sample into the mobile phase. The control device is configured such that, after performing the second collection action using a second delay time calculated with the updated time difference information, the component collected by the collection container is re-injected into the mobile phase using the second collection action performed with the second delay time, and the recovery rate of the component in the second collection action is evaluated based on the peak area in the second signal related to the re-injected component. This state allows for automatic evaluation of the existence of problems with the second collection action based on the updated time difference information during the sorting sequence, thus reducing the user's workload in verifying whether the performed second collection action has problems. The fourth state can be combined with the first state, the second state, and / or the third state.

[0078] In the fifth state sample of the first embodiment, the second detector is a mass spectrometer. The fifth state sample can be combined with the first state sample, the second state sample, the third state sample, and / or the fourth state sample.

Claims

1. A preparative liquid chromatograph, characterized in that, include: A liquid delivery pump delivers the mobile phase at a set flow rate; A syringe is used to inject a sample into the mobile phase delivered by the pump. A separation column is used to separate components of a sample injected into the mobile phase via the syringe from one another. The outlet flow path is fluidly connected to the outlet of the separation column, allowing the dissolution solution from the separation column to flow out. A branch flow path, branching off from the outlet flow path, is used to extract a portion of the liquid flow of the dissolution solution from the outlet flow path; A first detector is fluidly connected to the outlet flow path and outputs a first signal corresponding to the concentration of the component in the dissolution solution; The second detector is fluidly connected to the branch flow path and outputs a second signal corresponding to the concentration of the components in the dissolution solution supplied through the branch flow path; A fraction collector, fluidly connected to the outlet of the first detector, is used to collect the desired fraction of the dissolution from the separation column into different collection containers; and The control device is configured to control the operation of the liquid delivery pump, the syringe, and the fraction collector to execute a predetermined dispensing sequence. The control device is configured as follows: it includes an information storage area that stores time difference information and a first delay time as initial setting information set before the start of the fractionation sequence. The time difference information is calculated by subtracting the time required for the component to be detected as a peak in the first signal from the time when the component flowing out of the separation column is detected as a peak in the second signal. The first delay time is the time when the component detected as a peak in the first signal reaches the fraction collector. During the execution of the fractionation sequence, in the first collection action of collecting the component detected as a peak in the first signal into the collection container, the first delay time is applied to control the operation of the fraction collector. In the second collection action of collecting the component detected as a peak in the second signal into the collection container, a second delay time is applied to control the operation of the fraction collector. The second delay time is calculated by subtracting the time difference information stored in the information storage area from the first delay time and is the time when the component detected as a peak in the second signal reaches the fraction collector. Furthermore, the control device is configured such that, during the execution of the extraction sequence, when a specific component detected as a peak in either the first signal or the second signal is injected into the mobile phase, a maintenance operation of the time difference information stored in the information storage area is performed. The control device is configured as follows: during the maintenance operation, it calculates the difference between the first holding time from the injection of the specific component into the mobile phase to its detection as a peak in the first signal and the second holding time from the injection of the specific component into the mobile phase to its detection as a peak in the second signal; performs a peak determination on whether the calculated difference is within an allowable range set based on the time difference information; and in the peak determination, if the calculated difference deviates from the allowable range, it updates the time difference information stored in the information storage area using the calculated difference.

2. The preparative liquid chromatograph according to claim 1, wherein the control device is configured to issue a warning to the user if the difference between the first holding time and the second holding time is determined to deviate from the permissible range in the peak determination.

3. The preparative liquid chromatograph according to claim 1 or 2, wherein the control device is configured such that, in the peak determination, the difference between the times when the peaks of the specific component appear in the first signal and the second signal respectively during the injection of the specific component is calculated as the difference between the first holding time and the second holding time.

4. The preparative liquid chromatograph according to claim 1 or 2, wherein the control device is configured such that, in the peak determination, the ratio of the width of the peak of the specific component appearing in the first signal to the width of the peak of the specific component appearing in the second signal is calculated, and it is determined whether the ratio is within a predetermined reference range, and if the ratio deviates from the predetermined reference range, a warning is issued to the user.

5. The preparative liquid chromatograph according to claim 1 or 2, wherein the syringe is configured to inject the component collected by the collection container as a sample into the mobile phase. The control device is configured such that, after performing the second collection action using the second delay time calculated with the updated time difference information, the component collected by the collection container is re-injected into the mobile phase by the second collection action performed with the second delay time, and the recovery rate of the component in the second collection action is evaluated based on the peak area in the second signal related to the re-injected component.

6. The preparative liquid chromatograph according to claim 1 or 2, wherein the second detector is a mass spectrometer.

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