JP7570497B2 - Analysis system and program for analysis system - Google Patents

Description

The present invention relates to an analytical system that combines liquid chromatography and Raman spectroscopy, etc.

When combining multiple analytical techniques, such as liquid chromatography and Raman spectroscopy, as a type of hyphenated technology that combines multiple analytical techniques, for example, as described in Patent Document 1, a sample holder such as a plate with wells formed therein as a sample holder may be used so that the fraction separated by the liquid chromatograph and collected by a fraction collector can be directly provided to another analytical device.

When using a plate such as that described above to separate the liquid flowing out of a liquid chromatograph, dropping the separated liquid from one liquid chromatography run may not use up all of the wells on the plate, and the wells that remain unused may be used for the next or subsequent liquid chromatography runs. Also, when performing analyses other than liquid chromatography, it may be possible to analyze only selected wells rather than analyzing all the wells on a plate at once.

In such cases, conventionally, users have had to take notes and manage the operation history of each well on the plate, such as which wells were used to separate and analyze the separated liquid, which places a heavy burden on the user. In particular, when multiple users share the same plate, the operation history of the plate is not communicated adequately, and there is a risk of human error, such as contamination of the separated liquid by dropping another separated liquid into a well that has already been used, or missing an analysis due to the wrong selection of the well to be analyzed.

JP 2019-132621 A

Therefore, the present invention aims to provide an analytical system that reduces the burden on the user of managing the operation history of each sample holder of a sample holder, even when a sample holder having multiple sample holders is used over multiple liquid chromatography runs, and that can prevent contamination of the separated liquid due to human error and missed analyses due to incorrect selection of the well to be analyzed.

That is, the analytical system according to the present invention is an analytical system including a liquid chromatograph that separates a liquid sample into its components, a fraction collector that fractionates a liquid containing the sample components separated by the liquid chromatograph into a plurality of sample holders formed in a sample holder, and an analytical device that analyzes the sample components contained in each fraction collected by the fraction collector, and is characterized by having a memory unit that stores an operation history for each of the sample holders.

According to the analytical system configured in this manner, since the memory unit stores the operation history for each of the sample holders, the user does not need to manage the operation history, such as whether each of the sample holders was used to collect the separated liquid, by memo or the like, and the burden on the user can be significantly reduced compared to the conventional system. In addition, since the user does not need to manage the operation history for each sample holder, it is possible to prevent contamination of the separated liquid due to human error and missed analysis due to incorrect selection of the well to be analyzed.

A specific embodiment of the present invention is an analysis system in which the analysis is Raman spectroscopy analysis.

It is preferable that the memory unit stores the operation history in association with a label attached to the sample holder.

If the memory unit stores, as the operation history, whether or not a particular sample holder has been used to collect the fractionated liquid, then when the same sample holder is used to collect the fractionated liquid obtained in subsequent liquid chromatography runs or when analyzing the liquid using a different analytical device, it is possible to easily identify sample holders that can be used or that should be selected.

In order to provide a more user-friendly analysis system, the memory unit may store the type of analysis and/or analysis conditions previously performed on each sample holder as the operation history, and may further include a history display unit that displays this operation history.

In order to further reduce human error, it is preferable to be able to restrict operations on each sample holder based on the operation history stored in the memory unit.

As described above, the analytical system of the present invention can provide an analytical system that significantly reduces the burden on the user in managing sample holders compared to conventional systems, and can prevent contamination of the separated liquid due to human error and missed analyses due to incorrect selection of the well to be analyzed.

FIG. 1 is a schematic diagram showing a configuration of an analysis system according to an embodiment of the present invention. FIG. 2 is a schematic diagram showing an example of a sample holder used in the embodiment. FIG. 2 is a functional block diagram showing configurations of an integrated management device, an LC control calculation unit, a fraction control calculation unit, and a Raman control calculation unit in the embodiment. 4 shows a portal screen, which is one of the operation screens displayed by the operation screen display unit in the embodiment. 13 shows a drip range setting screen, which is one of the operation screens displayed by the operation screen display unit in the embodiment. 4 shows an operation history display screen, which is one of the operation screens displayed by the operation screen display unit in the embodiment.

100: Analysis system S: Liquid sample SS: Separation liquid PL: Plate (sample holder)
W: Well (sample holder)
REFERENCE SIGNS LIST 10 chromatograph 20 fraction collector 30 Raman spectroscopic analyzer 40 integrated management device 42 operation screen display unit (operation history display unit)
44 ...Memory section

The analysis system 100 of this embodiment performs LC-Raman analysis using both liquid chromatography and Raman spectroscopy, and is a type of so-called hyphenated technology. Specifically, as shown in FIG. 1, the analysis system 100 includes a chromatograph 10, a fraction collector 20, a Raman spectroscopic analyzer 30, and an integrated management device 40 that integrates and manages the settings of these operations, data analysis, and display of analysis results. The chromatograph 10, the fraction collector 20, and the Raman spectroscopic analyzer 30 each include control and calculation units 1C, 2C, and 3C, which are dedicated software for operating the respective hardware and analyzing data. The integrated management device 40 is configured to operate as overlay software, and the integrated management device 40 and the control and calculation units 1C, 2C, and 3C of each device work together to operate as one analysis system 100.

Details of each device are provided.

The chromatograph 10 separates and detects the components of the liquid sample S using liquid chromatography.

As shown in Figure 1, the chromatograph 10 is configured to separate the liquid sample S into its components by pumping the mobile phase Z stored in the storage section 11 up into the flow path 13 using the pump 12 and then injecting the liquid sample S into the flow path 13 and sending the liquid sample S together with the mobile phase Z to a separation column 14. A component detector 15 that detects the separated components of the liquid sample S is provided downstream of the separation column 14.

The mobile phase Z is, for example, a mixture of multiple types of liquids, and in this example, is a mixture of water and an organic solvent such as ethanol. However, the mobile phase Z may be a single liquid or a gradient solvent having a concentration gradient.

The chromatograph 10 further includes an LC control and calculation unit 1C that controls each device such as the pump 12 and generates a chromatogram of the liquid sample S based on the output of the component detector 15. The LC control and calculation unit 1C is composed of a dedicated or general-purpose computer, and executes a program dedicated to the chromatograph stored in memory, and its functions are realized by the cooperation of each device.

More specifically, the LC control calculation unit 1C receives chromatograph setting information from the integrated management device 40, and controls the pump 12's delivery speed of the mobile phase Z based on that information, and generates data related to the chromatogram of the liquid sample S based on the output signal of the component detector 15. The LC control calculation unit 1C also outputs the generated data related to the chromatogram to the integrated management device 40.

As shown in FIG. 1, the fraction collector 20 is provided downstream of the component detector 15 of the chromatograph 10, and collects sample components derived from the liquid sample S that have passed through the component detector 15 together with the mobile phase Z. In this embodiment, the fraction collector 20 is configured to collect the sample components by dropping a predetermined amount of liquid containing the sample components derived from the liquid sample S and the mobile phase Z separated by liquid chromatography into different wells W of a plate PL having a matrix of wells W. In the following, the liquid collected by the fraction collector 20 on the plate PL is referred to as the collected liquid SS, and this collected liquid SS is a concept that includes not only a liquid containing sample components derived from the liquid sample S in the mobile phase Z, but also a liquid consisting only of the mobile phase Z.

Here, as shown in Figure 2, the plate PL is provided with an identification code indicating the plate name, etc., as an individual mark A. The identification code is, for example, a two-dimensional barcode such as DataMatrix (registered trademark), and is printed or engraved on the surface of the plate PL on which the wells W are formed. Note that the identification code is not limited to this, and may be a QR code (registered trademark) or a one-dimensional barcode, or the unique position of a notch formed in the plate PL may be used as the identification code.

The fraction collector 20 is configured in detail to include a movable probe 21 connected to the outlet flow path of the component detector 15, and is configured to drop a predetermined amount of the fractionated liquid SS one after another into the wells W of the plate PL placed on the stage 22. Here, when the fractionated liquid SS is a portion corresponding to a peak in the chromatogram, it contains sample components derived from the liquid sample S, but the fractionated liquid SS corresponding to the portion other than the peak may also contain sample components of a type that cannot be detected by the component detector 15.

In addition, a first code reader 23 for reading an identification code given to the plate PL is attached to the mobile probe 21. When the mobile probe 21 moves to the initial position with the plate PL placed on the stage 22, the identification code of the plate PL is read by the first code reader 23, and the plate name of the plate PL, etc. are obtained.

In addition, the fraction collector 20 further includes a fraction control calculation unit 2C that generates fraction information, which is information regarding the control of the movable probe 21, etc., and the dripping state of the fractionated liquid SS into each well W of each plate PL, etc.

The fraction control calculation unit 2C is composed of a dedicated or general-purpose computer, and a program dedicated to the fraction collector stored in memory is executed, and its functions are realized through the cooperation of each device.

More specifically, the fraction control calculation unit 2C controls the position of the mobile probe 21 and the fractionation conditions (fractionation flow rate, fractionation time, etc.) of the fractionated liquid fractionated from the mobile probe 21 to the plate PL. The fraction control calculation unit 2C also generates fraction information such as a predicted fraction result, which is the usage range of the well W in the plate PL when the fractionated liquid SS is dropped based on the fraction setting information input from the integrated management device 40, and a fraction result when the fractionated liquid SS is actually dropped onto the plate PL. Data related to the fraction information generated by the fraction control calculation unit 2C is transmitted to the integrated management device 40.

Next, the Raman spectroscopic analyzer 30 will be described. The Raman spectroscopic analyzer 30 analyzes the sample components contained in the fractionated liquid SS, which has been dropped into a well W on a plate PL, by Raman spectroscopy after the fractionated liquid SS has been dried. The plate PL is transported to the Raman spectroscopic analyzer 30 by the user after it has been dried in the fraction collector 20, but the plate PL may also be transported between the fraction collector 20 and the Raman spectroscopic analyzer 30 by an automatic work changer.

As shown in Figure 1, the Raman spectroscopic analysis apparatus 30 comprises a light irradiator 31 that irradiates excitation light such as laser light onto wells W on a plate PL that hold sample components derived from the liquid sample S from which the fractionated liquid SS has been dried, a spectroscope 32 that disperses the Raman scattered light generated from the sample components when irradiated with the excitation light, a Raman scattering light detector 33 that detects the dispersed Raman scattered light, a camera 34 that takes a microscopic photograph of the wells W to which light is being irradiated, and a second code reader 35 for reading an identification code attached to the plate PL.

In addition, the Raman spectroscopic analysis device 30 further includes a Raman control calculation unit 3C that controls the position at which the laser light emitted by the light irradiator 31 is irradiated on the plate PL and generates a Raman spectrum based on the output of the Raman scattering light detector 33.

The Raman control calculation unit 3C is composed of a dedicated or general-purpose computer, and executes a program dedicated to the Raman spectroscopic analysis device stored in memory, and its functions are realized through the collaboration of each device.

More specifically, the Raman control and calculation unit 3C receives Raman spectroscopic analysis setting information from the integrated management device 40, controls each device based on that information, and performs Raman spectroscopic analysis of the sample components in each well W held on the plate PL. The Raman control and calculation unit 3C also generates data on the Raman spectrum based on the output from the Raman scattering light detector 33 obtained from the sample components in each well W.

The Raman control calculation unit 3C transmits to the integrated management device 40 a set of the Raman spectrum obtained from the sample components in each well W, including an identification code indicating the plate name, etc. of the plate PL read by the second code reader 35, the position information of the well W irradiated with the laser light, and the microscopic image data of the well W captured by the camera 34.

Next, the integrated management device 40 will be described. The integrated management device 40 is composed of a dedicated or general-purpose computer, and the program for the integrated management device stored in the memory is executed, and the functions are realized by the cooperation of each device. In addition, as shown in FIG. 3, the integrated management device 40 is connected to the LC control calculation unit 1C, the fraction control calculation unit 2C, and the Raman control calculation unit 3C by a wired or wireless network, and the integrated management device 40 transmits chromatographic setting information, fraction setting information, and Raman spectroscopic analysis setting information for setting analysis parameters, etc. to each of the control calculation units 1C, 2C, and 3C. In addition, the integrated management device 40 receives information on the analysis results obtained from each of the control calculation units 1C, 2C, and 3C and the operation results performed on the plate PL.

Specifically, as shown in FIG. 3, the integrated management device 40 at least includes an input receiving unit 41 that receives input from a user, an operation screen display unit 42 that displays operation screens for each of the devices 10, 20, and 30 on the display DP, a setting information generation unit 43 that generates chromatographic setting information, fraction setting information, and Raman spectroscopy setting information related to the analysis based on the user's input on the operation screen and transmits the information to each of the devices 10, 20, and 30, a memory unit 44 which is a database that stores the chromatographic setting information, fraction setting information, and Raman spectroscopy setting information generated by the setting information generation unit 43, information regarding the analysis results and operation results received from each of the devices 10, 20, and 30, information regarding the plate PL being used, etc., and an analysis summary display unit 45 that displays an integrated analysis summary screen on the display DP based on the information recorded in the memory unit 44.

The input receiving unit 41 receives input from a user via an input device such as a keyboard or a mouse to an operation screen, an analysis summary screen, or the like.
The operation screen display unit 42 displays an operation screen for setting an analysis or displaying the analysis results on the display DP. An example of the operation screen to be displayed is a portal screen SC1 as shown in Fig. 4. This portal screen SC1 is an operation screen for selecting the settings related to the analysis of any of the chromatograph 10, the fraction collector 20, and the Raman spectrometer 30, or the display of the analysis results stored in the memory unit 44.

FIG. 5 is an example of an operation screen of the fraction collector 20 that is displayed as a window when, for example, a fraction region is selected by the user.
The plate PL to be used is set at a predetermined position, and the identification code of the selected plate PL is read by the first code reader 23 of the fraction collector 20 by selecting the read button, and the plate name, image, etc. of the plate PL to be used are displayed. The operation screen of FIG. 5 is a drop range setting screen SC2 for setting the drop range of the fractionated liquid SS for the plate PL based on the setting chromatogram, and the user can set the conditions for fractionating the fractionated liquid SS derived from the component detector 15 of the chromatograph 10 while referring to the setting chromatogram on this operation screen. When these settings are made, the setting information generating unit 43 transmits the fraction setting information to the fraction control calculation unit 2C. Then, the integrated management device 40 receives the prediction result of the range to which the fractionated liquid SS will be dropped from the position of the well W where the dropping is started, which is calculated by the fraction control calculation unit 2C, and the operation screen display unit 42 displays it on the image of the plate PL on the drop range setting screen SC2.

When the settings for dropping are finally approved by the user, the setting information generation unit 43 generates fraction setting information such as collection parameters to be sent to the fraction collector 20. The generated fraction setting information is then sent from the integrated management device 40 to the fraction control calculation unit 2C, which controls each device of the fraction collector 20 to collect the fractionated liquid SS onto the actual plate PL. The liquid sample S analyzed by the chromatograph 10 and an identification code indicating the plate name, etc. of the plate PL used for collection are then linked and stored in the memory unit 44.

Note that the operation screen displayed by the operation screen display unit 42 is not limited to the fraction collector 20. When the LC region is selected by the user on the portal screen SC1 in FIG. 3, the operation screen of the chromatograph 10 is displayed, and when the Raman region of the portal screen SC1 is selected by the user, the operation screen of the Raman spectrometer 30 is displayed. Based on the user's input to each operation screen, the setting information generation unit 43 generates chromatographic setting information or Raman spectroscopic analysis setting information for the chromatograph 10 or the Raman spectrometer 30, and transmits it to the corresponding device 10, 30. In this way, the settings required to start the analysis can be made by inputting only to the integrated management device 40, and a series of analyses can be performed without operating the dedicated software of each device 10, 20, 30.

Therefore, the memory unit 44 provided in the integrated management device 40 of the analysis system 100 in this embodiment also stores operation history regarding the types of operations previously performed on the plate PL, the conditions of the operations, the results of the operations, etc., as information regarding the plate PL described above.

The memory unit 44 stores this operation history for each of the multiple wells W provided on the plate PL, and stores, for example, as the operation history, information as to whether a certain well W provided on a certain plate PL has already had separation liquid SS dripped into it and been used for separation.

The memory unit 44 also stores, as an operation history, information about the wells W that have already been used to collect the collected liquid SS, such as the liquid chromatography conditions at the time of collection, the drying conditions for the collection, and the types of analyses that were performed under what conditions and in what order after drying.
The operation history for each well W is stored in the memory unit 44, for example, in association with an identification code indicating the plate name or the like attached to the plate PL as an individual label A.

The integrated management device 40 may further include a history display unit that displays the operation history for each well W stored in the memory unit 44.

The operation history display unit is a function of the operation screen display unit 42 described above. For example, when a well W on the image of the plate PL on the drip range setting screen SC2 is selected, the operation screen display unit 42 displays an operation history display screen SC3 (FIG. 6) on the display DP, which indicates whether the selected well SW has been used or not. In FIG. 6, for the selected well W, the result R2 of liquid chromatography displayed as LC and the result R3 of Raman spectroscopy displayed as Raman are shown. Therefore, from this display, it can be seen that the separated liquid SS has already been separated from this well W and Raman spectroscopy has been performed. The operation history display screen SC3 of FIG. 6 does not display detailed conditions and number of times for each analysis, drying conditions for the separated liquid, etc., but it goes without saying that these information can be set to be displayed. It is also possible to simply display the operation history on the drip range setting screen SC2 itself, for example, by color-coding the wells according to the operation history. For example, in FIG. 5, the range of usable wells W is shown by area R1.

As an example of the operation of the analysis system 100 configured in this manner, a case where the range of dropping of the fractionated liquid by the fraction collector 20 is set will be described.
When the plate PL to be used is set at a predetermined position of the fraction collector 20, the first code reader 23 reads the identification code, and the operation history of each well W of the plate PL, which is linked to the identification code and stored in the memory unit 44, is read. The operation history read from the memory unit 44 is reflected in, for example, a plate image displayed on an operation screen for setting the conditions under which the liquid flowing out of the chromatograph 10 is dropped. In this embodiment, for example, based on the operation history for each well W stored in the memory unit 44, the setting information generating unit 43 can restrict the selection of a well W that has already been used to collect the collected liquid SS in response to an input from a user. Setting of analysis conditions and confirmation of history information using the operation history can be performed not only on the fraction collector 20 but also on the condition setting screen of the chromatograph 10 and the Raman spectroscopic analyzer 30.

According to the analysis system 100 configured in this manner, even when a plate PL having many wells W is used, the user does not need to manage the usage status of each well W by taking notes or the like. As a result, the burden on the user in managing the plate PL can be significantly reduced.

More specifically, the memory unit 44 stores whether each well W of the plate PL has been used to separate the separated liquid SS, so that it is easy to determine which wells W can be used to separate the separated liquid SS in the next analysis. In addition, in this embodiment, when selecting wells W to be used for separation, it is not possible to select wells W that have already been used, so that it is possible to more reliably prevent human error such as dripping different separated liquids SS into the same well.

The memory unit 44 can also store the liquid chromatography separation conditions when the fractionated liquid SS is collected, the dripping conditions of the fractionated liquid SS, the drying conditions after collection, and the like, so that the analysis conditions can be more strictly controlled for each sample component held in the multiple wells W. As a result, the user can be provided with information for determining which wells W to perform Raman spectroscopy analysis on and for judging the reliability of the results of Raman spectroscopy that has already been performed.

It is also possible to store information about what types of analyses were performed, under what conditions, and in what order after drying. For example, when performing Raman spectroscopic analysis multiple times on a group of wells W, it is possible to easily check whether the target wells W have been analyzed the specified number of times without any omissions, making the analysis system 100 extremely easy to use.

The present invention is not limited to the above.
For example, the memory unit that stores the operation history is not limited to being provided in the integrated management device as described above, but may be provided in, for example, each control and calculation unit, which is software dedicated to each piece of hardware that makes up the analysis system, and the integrated management device may read out and display the operation history stored in each of these control and calculation units.

For example, the operation history for each well does not necessarily have to be stored in association with an identification code attached to the plate, but may be stored in association with an identification code attached to each well.

As mentioned above, it is not limited to forcibly restricting the operation scheduled for each well based on the usage history of each well, but it is also possible to display an error message indicating that the same operation as the scheduled operation has been performed previously, and leave it to the user to decide whether or not to continue the operation. In addition, the user may be able to set the setting of whether or not to leave it to the user's discretion individually for each operation that can be input or set.

The memory unit does not necessarily have to store all of the above-mentioned operation histories, but may store at least any of the operation histories.

The sample holder for holding the fractionated liquid or the sample components contained in the fractionated liquid may be a sample holder having a plurality of sample holders for holding the fractionated liquid or the sample components as a single unit, and the sample holders do not necessarily have to be fixed together. One example of such a sample holder is a sample holder that uses independent containers such as test tubes as sample holders, and includes a plurality of containers and a test tube rack that can hold a plurality of these containers in an orderly arranged state. In addition, the sample holder having a plurality of sample holders integrated together is not limited to a plate having wells as described above, and may be a plate having a plurality of sample chips on the surface of which samples are placed, as the sample holders.

There is no particular limit to the number of sample holding portions provided on one sample holder, but the greater the number (e.g., 50 or more, 100 or more, 200 or more), the more pronounced the effects of the present invention will be.

In the above embodiment, the analysis system is described as having one each of a liquid chromatograph, a fraction collector, and a Raman analyzer, but it may also have multiple devices of the same type. In such a case, if an attempt is made to repeat an operation that has already been performed in one of the multiple devices capable of performing the same type of operation in another device, the operation may be restricted or a warning such as an error message may be displayed.

The analytical system of the present invention does not necessarily need to be equipped with a Raman spectroscopic analyzer, but may also be equipped with an analytical device that analyzes liquid samples separated by liquid chromatography using principles such as infrared spectroscopy, nuclear magnetic resonance or time-of-flight mass spectrometry, or may be a combination of multiple of these various analytical devices.

The functions of each part constituting the integrated management device are not limited to those realized by a normal computer. For example, the functions of each part described in the embodiment may be realized by installing software for the integrated management device on a mobile terminal such as a tablet terminal or a smartphone, and transmitting and receiving data between each device and the electronic terminal by wireless communication. In addition, the functions of each part may be realized in a server without performing substantial calculations on the mobile terminal, and the analysis summary screen generated by the analysis summary display unit and the operation screen generated by the operation screen display unit may be displayed on the mobile terminal.
Furthermore, the present invention is not limited to the above-described embodiment, and it goes without saying that various modifications are possible without departing from the spirit and scope of the present invention.

According to the present invention, even when a sample holder having a plurality of sample holders is used over a plurality of liquid chromatography runs, an analysis system can be provided which reduces the burden on the user in managing the operation history for each sample holder of the sample holder, as compared to conventional methods, and which can prevent contamination of the separated liquid due to human error, missed analyses due to incorrect selection of the well to be analyzed, etc.

Claims (8)

A liquid chromatograph that separates a liquid sample into components;
a fraction collector that divides a liquid containing the sample components separated by the liquid chromatograph into a plurality of sample holders formed on a sample holder;
and an analyzer for analyzing each sample component contained in each fraction collected by the fraction collector,
a storage unit that stores an operation history of each of the sample holders ;
An analytical system, wherein the storage unit stores an operation history for identifying a usable sample holder or a sample holder to be selected from among a plurality of sample holders . The analysis system according to claim 1, wherein the analysis device is a Raman spectroscopic analysis device. The analysis system according to claim 1 or 2, wherein the memory unit stores the operation history in association with a label attached to the sample holder. The analysis system according to any one of claims 1 to 3, wherein the memory unit stores, as the operation history, whether or not a certain sample holder has been used to separate the separated liquid. The analysis system according to any one of claims 1 to 4, wherein the memory unit stores, as the operation history, the type and/or analysis conditions of analysis previously performed on the sample holder used to collect the collected liquid. The analysis system according to any one of claims 1 to 5, further comprising a history display unit that displays the operation history. The analysis system according to any one of claims 1 to 6, which is capable of restricting operations on each of the sample holders based on the operation history stored in the memory unit. A program for use in an analysis system including a liquid chromatograph that separates a liquid sample into components, a fraction collector that fractionates a liquid containing the sample components separated by the liquid chromatograph into a plurality of sample holders formed in a sample holder, and an analysis device that analyzes each sample component contained in each fraction collected by the fraction collector, the program comprising:
A program for an analytical system, characterized by causing a computer to function as a memory unit that stores operation history for each sample holder, the operation history being for identifying a usable sample holder or a sample holder to be selected among a plurality of sample holders .

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