JP4652895B2 - Chromatography apparatus and solvent composition adjustment apparatus - Google Patents

Description

  The present invention relates to a chromatographic apparatus capable of using a mixed solvent containing two or more solvents as a mobile phase, and recovering and reusing the mobile phase, and a solvent composition adjusting apparatus usable for the same. The present invention relates to a simulated moving bed chromatography apparatus and a solvent composition adjustment apparatus.

  The simulated moving bed chromatography apparatus has an endless channel formed by connecting a plurality of columns in series. In the simulated moving bed chromatography apparatus, a sample solution containing a target substance and a mobile phase are supplied to any part of the endless channel, and the mobile phase is supplied from any two parts of the endless channel. Is discharged. When the supply of the sample solution and the discharge of the mobile phase are continuously performed, the target substance is contained in at least one of the discharged mobile phases and is taken out from the endless channel. Therefore, the simulated moving bed chromatography apparatus is known as a useful means for producing a target substance by separating and taking out the target substance from a mixture containing the target substance such as an optical isomer. It is used in the field of pharmaceutical production.

  In the simulated moving bed chromatography apparatus, from the viewpoint of effective use of the solvent, the mobile phase discharged from the endless flow path is recovered, the recovered mobile phase is appropriately purified, and the endless flow is recovered. An apparatus for reusing the mobile phase supplied to the road is known (for example, see Patent Document 1).

  On the other hand, in the simulated moving bed chromatography apparatus, a mixed solvent containing two or more solvents may be used for the mobile phase. In the case of reusing such a mobile phase in a simulated moving bed chromatography apparatus, it is possible to adjust the composition of the recovered mobile phase as necessary to achieve stable separation of the target substance stably. Is important.

  The apparatus used for regeneration of the mobile phase of the simulated moving bed chromatography apparatus using the mixed solvent as a mobile phase is an adjustment containing a mobile phase to be recovered from the simulated moving bed chromatography apparatus and the composition of which should be adjusted. A detector for detecting the composition of the mobile phase supplied to the adjustment tank, a supply tank for containing a solvent to be supplied to the mobile phase supplied to the adjustment tank, and a detection result of the detector. And a control device that controls the replenishment of the solvent from the replenishment tank, and the detector is a device that detects the dielectric constant, temperature, and liquid level of the mobile phase (for example, , See Patent Document 2).

  The apparatus is excellent from the viewpoint of adjusting the mixed solvent quickly and accurately. However, the apparatus may not accurately detect the composition of the mixed solvent when the dielectric constants of the respective solvents in the mixed solvent are relatively close. Therefore, when the apparatus is used, depending on the composition of the mobile phase, the composition of the mobile phase to be adjusted may not be accurately detected, and the mobile phase may not be reused.

In addition, when the mobile phase is repeatedly reused, a small amount of components in the mobile phase such as a solvent blended in a minute ratio, a low boiling point solvent, and impurities in the sample solution are regenerated and recycled. May gradually accumulate in mobile phase with use. When the composition of such a mobile phase is adjusted by replenishing the main component solvent, the amount of solvent to be replenished increases, and the amount of mobile phase to be adjusted may exceed the capacity allowed by the apparatus.
JP-A-6-239767 US Pat. No. 6,325,898

  The present invention makes it possible to reuse a mobile phase regardless of the composition of the mobile phase in a chromatographic apparatus such as a simulated moving bed chromatography apparatus using a mixed solvent containing two or more solvents as the mobile phase. Is an issue.

  The present invention uses a near-infrared spectrometer for the detector that detects the composition of the recovered mobile phase, adjusts the composition of the recovered mobile phase according to the detection result by the near-infrared spectrometer, Reuse for mobile phase of chromatography such as simulated moving bed chromatography.

  That is, the present invention supplies a sample solution containing a target substance and a mobile phase to a mobile phase flow path including a column to separate the target substance from the sample solution, and a separation unit separates the target substance from the sample solution. The collection unit for collecting the target substance by removing the mobile phase from the collected mobile phase containing the target substance, collecting the mobile phase removed by the collection unit, and changing the composition of the recovered mobile phase to the mobile phase An adjustment unit that adjusts the composition of the mobile phase that can be supplied to the flow path, using a mixed solvent containing two or more solvents as the mobile phase, and the mobile phase adjusted by the adjustment unit is the mobile phase. A chromatographic apparatus supplied to a flow path, wherein the adjustment unit includes an adjustment tank containing a mobile phase whose composition is to be adjusted, a detector for detecting the composition of the mobile phase supplied to the adjustment tank, and an adjustment Replenishment tank containing the solvent to be replenished in the mobile phase supplied to the tank, and detection In the chromatographic system and a control device for controlling the supply of the solvent from the replenishing tank in accordance with the detection result, the detector is a device which is near-infrared spectrometer.

  According to the said structure, the density | concentration of the solvent in the collect | recovered mobile phases is detected rapidly irrespective of the kind of solvent.

  In the present invention, the adjustment unit further includes a purification device for purifying the recovered mobile phase, and when the mobile phase purified by the purification device is supplied to the adjustment tank, the purity of the recovered mobile phase Is increased.

  In the present invention, when the detector detects the composition of the mobile phase in the adjustment tank, the composition of the mobile phase is detected with a simple configuration.

  In the present invention, the adjustment unit further includes a circulation channel for circulating the mobile phase in the adjustment tank, and the detector detects the composition of the mobile phase in the circulation channel, The composition of the mobile phase is detected in a state of being extracted from the adjustment tank.

  In this invention, the said adjustment part further has a liquid level gauge which detects the liquid level of the mobile phase in the said adjustment tank, and the said control apparatus moves in an adjustment tank based on the detection result of the said liquid level gauge. When the amount of the phase is obtained and the replenishment of the solvent from the replenishing tank is controlled based on the determined amount of the mobile phase and the composition of the mobile phase detected by the detector, the composition of the mobile phase is It will be adjusted promptly.

  In this invention, the said adjustment part further has the extraction flow path for extracting a mobile phase from the said adjustment tank, The said control apparatus extracts the mobile phase from an adjustment tank based on the detection result of the said detector. When the amount is further controlled, the amount of the mobile phase in the adjustment tank can be reduced, and the amount of any component in the mobile phase in the adjustment tank can be suppressed to a desired value.

In the present invention, the adjustment unit includes a removal device that removes any components in the mobile phase of the extraction flow path, and a return flow for returning the mobile phase from which any components have been removed by the removal device to the adjustment tank. If it has further a path, the arbitrary component in the mobile phase in the adjustment tank is diluted, and the concentration of the arbitrary component in the mobile phase in the adjustment tank is suppressed to a desired value.

  In the present invention, the adjustment unit includes a main channel for supplying a mobile phase to the adjustment tank, a bypass channel connected to the main channel, and an arbitrary component in the mobile phase in the bypass channel. A mobile phase flow rate adjustment device for adjusting the flow rate of the mobile phase in the main flow path and the bypass flow path, and a mobile phase in which the amount of any component is reduced is adjusted. The concentration of an arbitrary component in the mobile phase supplied to the tank and in the adjustment tank is suppressed to a desired value.

  In the present invention, the mobile phase contains a first solvent selected from methanol, ethanol, and isopropyl alcohol, and a second solvent selected from normal hexane and acetonitrile, and the first solvent and the second solvent. When the volume ratio (first solvent: second solvent) of the solvent is 10:90 to 50:50, it is preferable from the viewpoint of separating various target substances.

  In the present invention, the mobile phase further contains 0.01 to 0.5% by volume, more preferably 0.01 to 0.2% by volume of diethylamine, depending on the type of the target substance. It is preferable from the viewpoint of stabilization of the substance.

  In the present invention, the separation unit supplies a sample solution containing a target substance and a mobile phase to an endless flow path formed by connecting a plurality of columns in series to remove the target substance from the sample solution. When the separation unit is for separation, that is, when the chromatography apparatus of the present invention is a simulated moving bed chromatography apparatus, the sample solution can be continuously supplied to the flow path of the mobile phase. It becomes possible to continuously discharge the mobile phase containing the substance from the flow path of the mobile phase.

  In the present invention, the column is a column containing a separating agent containing an optically active polysaccharide or polysaccharide derivative. When the target substance is an optical isomer, the optical isomer as the target substance is separated. From the viewpoint, the polysaccharide is cellulose or amylose, and the polysaccharide derivative is more preferably selected from at least an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose.

  Further, the present invention provides a composition of a mixed solvent using a near-infrared spectroscopic analyzer when a device used in the adjustment unit of the chromatography device of the present invention, that is, when a mixed solvent such as the mobile phase is supplied. An apparatus capable of detecting and adjusting the noise is provided.

  That is, the present invention is an apparatus that can adjust the composition of a mixed solvent that contains two or more solvents and whose composition is to be adjusted, and an adjustment tank that contains the mixed solvent whose composition is to be adjusted; , A detector for detecting the composition of the mixed solvent stored in the adjustment tank, a supply tank for storing the solvent to be supplied to the mixed solvent stored in the adjustment tank, and supplying the solvent in the supply tank to the adjustment tank A replenishment flow path and a control device for controlling the supply of the solvent from the replenishment tank according to the detection result of the detector, wherein the detector is a near-infrared spectroscopic analyzer ( Solvent composition adjusting device).

According to the present invention, in a chromatographic apparatus for recovering, adjusting, and reusing a mobile phase containing two or more solvents, the composition of the mobile phase to be adjusted is detected by a near-infrared spectroscopic analyzer. Since the composition of the mobile phase is adjusted according to the detection result of the infrared spectroscopic analyzer, the mobile phase can be reused regardless of the composition of the mobile phase.

  Further, according to the present invention, it is possible to detect the concentration of a basic solvent such as diethylamine or an acidic solvent such as acetic acid which is added in a small amount to the mobile phase in order to stabilize the target substance during separation. A mobile phase containing such a small amount of added solvent can be reused.

  In the present invention, the adjustment unit further includes a purification device for purifying the recovered mobile phase, and when the mobile phase purified by the purification device is supplied to the adjustment tank, the purity of the mobile phase to be adjusted is further increased. This is more effective from the viewpoint of increasing the purity of the mobile phase to be reused.

  In the present invention, detecting the composition of the mobile phase in the adjustment tank is more effective from the viewpoint of simplifying the configuration of the apparatus.

  In the present invention, the adjustment unit further has a circulation channel for circulating the mobile phase in the adjustment tank, and when the composition of the mobile phase in the circulation channel is detected, the composition of the homogenized mobile phase Is more effective from the viewpoint of adjusting the composition of the mobile phase and increasing the accuracy of detection.

  In the present invention, the adjustment unit further includes a liquid level gauge for detecting the liquid level of the mobile phase in the adjustment tank, and the control device obtains the amount of the mobile phase in the adjustment tank based on the detection result of the liquid level gauge. When the replenishment of the solvent from the replenishing tank is controlled based on the determined amount of the mobile phase and the composition of the mobile phase detected by the detector, the type and amount of the solvent to be replenished in the adjustment tank are determined. Therefore, it is more effective from the viewpoint of quickly adjusting the mobile phase.

  In the present invention, the adjustment unit further has an extraction channel for extracting the mobile phase from the adjustment tank, and the control device further controls the extraction amount of the mobile phase from the adjustment tank based on the detection result of the detector. The mobile phase can be extracted from the adjustment tank, and the amount of any component in the mobile phase in the adjustment tank can be reduced. Therefore, components that are likely to accumulate in the mobile phase as the mobile phase is regenerated and reused, such as low-boiling components, are included in the mobile phase. When adjusting, it is more effective from the viewpoint of preventing the mobile phase from overflowing from the adjustment tank accompanying the adjustment of the mobile phase.

  In the present invention, the adjusting unit includes a removing device that removes an arbitrary component in the mobile phase of the extraction flow channel, and a return flow channel for returning the mobile phase from which the optional component has been removed by the removing device to the adjusting tank. If it has further, a mobile phase can be extracted from an adjustment tank, and arbitrary components can be remove | excluded from the extracted mobile phase, and a mobile phase can be returned to an adjustment tank. Therefore, components that are likely to accumulate in the mobile phase as the mobile phase is regenerated and reused, such as low-boiling components, are included in the mobile phase. When adjusting, it is more effective from the viewpoint of preventing the mobile phase from overflowing from the adjustment tank accompanying the adjustment of the mobile phase and reducing the supply amount of the main component solvent to be replenished.

  In the present invention, a main channel for supplying a mobile phase to the adjustment tank, a bypass channel connected to the main channel, and a pre-removal for removing any components in the mobile phase in the bypass channel When the adjustment unit further includes a device and a mobile phase flow rate adjustment device for adjusting the flow rate of the mobile phase in the main flow path and the bypass flow path, any component of the mobile phase before being accommodated in the adjustment tank The amount can be reduced. Therefore, components that are likely to accumulate in the mobile phase as the mobile phase is regenerated and reused, such as low-boiling components, are included in the mobile phase. When adjusting, it is more effective from the viewpoint of preventing the mobile phase from overflowing from the adjustment tank accompanying the adjustment of the mobile phase and reducing the supply amount of the main component solvent to be replenished.

  In the present invention, the mobile phase contains a first solvent selected from methanol, ethanol, and isopropyl alcohol, and a second solvent selected from normal hexane and acetonitrile, and the first solvent and the second solvent. When the volume ratio of the solvent to the solvent (first solvent: second solvent) is 10:90 to 50:50, it corresponds to separation of various target substances and the mobile phase regardless of the composition of the mobile phase. It is even more effective from the viewpoint of reusing.

  In the present invention, when the mobile phase further contains 0.01 to 0.5% by volume (more preferably 0.01 to 0.2% by volume) of diethylamine, it is separated depending on the type of the target substance. Sometimes it is more effective from the viewpoint of stabilizing the target substance and reusing the mobile phase regardless of the composition of the mobile phase.

  In the present invention, the separation unit supplies a sample solution containing a target substance and a mobile phase to an endless flow path formed by connecting a plurality of columns in series to remove the target substance from the sample solution. If the separation unit is for separation, that is, if the chromatography apparatus of the present invention is a simulated moving bed chromatography apparatus, it is more effective from the viewpoint of producing the target substance with high productivity.

  In the present invention, the column is a column containing a separating agent containing an optically active polysaccharide or polysaccharide derivative, and the target substance is an optical isomer from the viewpoint of efficiently separating the optical isomer. The polysaccharide is cellulose or amylose, and the polysaccharide derivative is more effective when selected at least from an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose. is there.

  Moreover, according to the solvent composition adjusting apparatus of the present invention, the composition of the mixed solvent can be continuously adjusted regardless of the composition of the mixed solvent, and a basic solvent such as diethylamine or an acidic solvent such as acetic acid can be used. A mixed solvent having a composition containing a small amount can be continuously adjusted.

  Further, the solvent composition adjusting device of the present invention is more effective from the viewpoint of increasing the purity of the mixed solvent to be adjusted, as well as the effect based on the adjusting unit described above, and more from the viewpoint of simplifying the configuration of the device. More effective, more effective from the viewpoint of improving the composition adjustment and detection accuracy of the mixed solvent, more effective from the viewpoint of quickly adjusting the mixed solvent, and mixing accompanying adjustment of the mixed solvent It is more effective from the viewpoint of preventing overflow of the solvent from the adjustment tank, prevents overflow of the mixed solvent from the adjustment tank accompanying the adjustment of the mixed solvent, and reduces the supply amount of the main component solvent to be replenished. More effective from the viewpoint.

  The chromatography apparatus of the present invention includes a separation unit for supplying a sample solution containing a target substance and a mobile phase to a flow path of a mobile phase including a column to separate the target substance from the sample solution, and a separation unit The collection unit for collecting the target substance by removing the mobile phase from the mobile phase containing the target substance separated in step (b), collecting the mobile phase removed by the collection unit, and determining the composition of the recovered mobile phase And an adjusting unit that adjusts the composition of the mobile phase that can be supplied to the mobile phase flow path. In the present invention, a mixed solvent containing two or more solvents is used for the mobile phase, and the mobile phase adjusted by the adjusting unit is supplied to the flow path of the mobile phase.

The separation unit can be appropriately configured according to the type of chromatography apparatus. For example, in the case where the chromatography apparatus is an apparatus that is usually provided with a single column, such as a high performance liquid chromatography apparatus, the separation unit includes a sample solution in the mobile phase flow path through which the mobile phase flows and the mobile phase flow path. A known configuration having an injector for injecting a sample, a column containing a separating agent for separating a target substance in a sample solution injected from the injector, and a detector for detecting the substance separated by the column Can be adopted.

  In the case where the chromatography apparatus is a simulated moving bed chromatography apparatus, the separation unit includes a sample solution containing a target substance and a mobile phase in an endless channel formed by connecting a plurality of columns in series. Can be employed to separate the target substance from the sample solution.

  The separation unit in the simulated moving bed chromatography apparatus may employ a known configuration as disclosed in, for example, Japanese Patent Application Laid-Open No. 6-239767. More specifically, the separation unit includes a plurality of columns, a connection channel that connects the plurality of columns in series to form an endless channel including the columns, and at least the sample solution and the mobile phase. Any one of them can be supplied to any of the connection flow paths, or can be constituted by a plurality of supply and discharge flow paths for discharging the mobile phase from any of the connection flow paths. The number of columns is not particularly limited, but is preferably 4-24.

  The collecting unit can adopt a known configuration as disclosed in, for example, Japanese Patent Laid-Open No. 6-239767, and can be configured by, for example, a concentrating device that concentrates the mobile phase discharged from the separating unit. . A single collection unit may be provided, or a plurality of collection units may be provided in accordance with the number of types of target substances contained in the sample solution. Moreover, well-known means, such as a vacuum concentration device, can be used for the concentration device. A single concentration device may be provided, or a plurality of concentration devices may be provided so as to concentrate the mobile phase stepwise.

  The adjustment unit includes an adjustment tank containing a mobile phase whose composition is to be adjusted, a detector for detecting the composition of the mobile phase supplied to the adjustment tank, and a solvent to be replenished to the mobile phase supplied to the adjustment tank. A replenishing tank to be accommodated and a control device for controlling replenishment of the solvent from the replenishing tank in accordance with the detection result of the detector. Except for the detector, the adjusting unit may adopt a known configuration as shown as a regulating device in US Pat. No. 6,325,898, for example.

  The detector is a near infrared spectroscopic analyzer. As the near-infrared spectroscopic analyzer, a known apparatus that can detect the concentration of the solvent contained in the mobile phase can be used. An example of such a near-infrared spectroscopic analyzer is MATRIX series manufactured by Bruker Optics.

  The said detector is provided so that the composition of the mobile phase supplied to the adjustment tank may be detected. By installing the detector in this way, the composition of the mobile phase to be adjusted and the composition of the mobile phase being adjusted are detected by the detector.

  The control device is not particularly limited as long as it is a device that can control the replenishment of the solvent from the replenishing tank according to the detection result of the detector. As the control device, for example, a known control device having an input device that gives information from outside, an output device that sends information to the outside, and a central processing unit (CPU) can be used. In order to control the replenishment of the solvent according to the detection result of the detector, the control device usually stores a calibration curve corresponding to the detector as shown in US Pat. No. 6,325,898. Is done. In the present invention, for example, a calibration curve showing a correlation between a detection value in a predetermined wavelength range by a near-infrared spectroscopic analyzer and the concentration of the solvent can be used as the calibration curve. Such a calibration curve is created in advance and stored, for example, in the control device.

The adjusting unit may include other components other than those described above. Examples of such other components include a purification device for purifying the recovered mobile phase. The said refiner | purifier will not be specifically limited if it is an apparatus which raises the purity of the collect | recovered mobile phases. Examples of the purification apparatus include a distillation apparatus as disclosed in JP-A-6-239767, an adsorption tower containing an adsorbent such as activated carbon, and the like.

  Moreover, as said other component, the flow path for circulation for circulating the mobile phase in an adjustment tank is mentioned, for example. The circulation channel can be constituted by, for example, a pipe having one end connected to the bottom of the adjustment tank and the other end opened toward the adjustment tank, and a pump for feeding a mobile phase to the pipe. . Further, the detector can be arranged in the pipe by providing a suitable flange or the like on the pipe.

  Moreover, as said other component, the other detector which detects other properties other than the composition of a mobile phase is mentioned, for example. Although it does not specifically limit as said other detector, For example, the liquid level meter which detects the liquid level of the mobile phase in an adjustment tank, the thermometer which detects the temperature of a mobile phase, etc. are mentioned. Known devices can be used for the liquid level gauge and the thermometer.

  In the case where the adjustment unit further includes such other detectors, it is preferable that the control device performs control to reflect the detection results of these detectors in the supply of the solvent. For example, in the case where the adjustment unit further includes the liquid level gauge, the control device determines the amount of the mobile phase in the adjustment tank based on the detection result of the liquid level gauge, It is preferable to control replenishment of the solvent from the replenishing tank based on the composition of the mobile phase detected by the infrared spectroscopic analyzer. In this case, the control of the replenishment of the solvent from the replenishing tank is performed by, for example, obtaining the actual amount of each solvent in the mobile phase from the amount and composition of the mobile phase, and comparing this with the set value, The control which calculates | requires the difference with the quantity of this, and replenishes the adjustment tank with the calculated | required quantity of the solvent from the tank for supply is mentioned. The actual amount of the mobile phase obtained from the detection result of the liquid level gauge and the amount of the solvent to be replenished may be volume or weight.

  For example, when the adjustment unit further includes a thermometer, the control device performs control to correct the influence of the temperature of the mobile phase on the detection value by the infrared spectroscopic analyzer based on the detection result of the thermometer. It is preferable. In this case, the correction of the influence of the temperature of the mobile phase may be performed using numerical values or mathematical formulas obtained from empirical rules, or may be performed based on theoretical values.

  In the case where the adjustment unit further includes another detector, it is preferable that the control device stores additional data for performing the above-described control. Examples of such data include the density of various solvents contained in the mobile phase, and data and mathematical formulas indicating the correlation between the detected value by the infrared spectroscopic analyzer and the temperature of the detected mobile phase.

  Moreover, as said other component, the flow path for extraction for extracting a mobile phase from an adjustment tank is mentioned, for example. In the case where the adjustment unit further includes such an extraction channel, the control device preferably performs further control to reflect the detection result by the detector in the extraction of the mobile phase from the adjustment tank. For example, when the adjustment unit further includes an extraction channel, the control device preferably further controls the extraction amount of the mobile phase from the adjustment tank based on the detection result of the detector. In this case, the control of the extraction amount of the mobile phase is performed, for example, by setting an upper limit value for the amount or concentration of any component contained in the mobile phase in the adjustment tank, and from the detection result of the detector including the near-infrared spectrometer. Control of extracting the mobile phase from the adjustment tank so that the amount or concentration of the arbitrary component to be detected is compared with the upper limit value and the amount or concentration of the arbitrary component does not exceed the upper limit value can be mentioned.

The mobile phase extracted from the extraction channel may be discarded, stored in another container, or appropriately processed for reuse as the mobile phase. The components for appropriately processing the mobile phase extracted from the extraction flow path include, for example, a removal device that removes any component in the mobile phase of the extraction flow path from the mobile phase, And a return flow path for returning the mobile phase from which the components have been removed to the adjustment tank.

  As the removal device, a known appropriate device can be adopted based on the type and physical properties of the arbitrary component. For example, if the arbitrary component is a component having a high polarity, an adsorption tower containing an adsorbent such as activated carbon can be adopted for the removal device, and if the arbitrary component is a low boiling point component A distillation apparatus can be adopted as the removing apparatus. Further, the return channel can be constituted by a known member such as a pipe, a flange, a pump, and a valve in the same manner as the circulation channel.

  Moreover, as said other component, the component for removing arbitrary components from the mobile phase before being supplied to a control tank is mentioned. As such a component, for example, a main channel for supplying a mobile phase to the adjustment tank, a bypass channel connected to the main channel, and an arbitrary component in the mobile phase in the bypass channel And a pre-removing device for removing, and a mobile phase flow rate adjusting device for adjusting the flow rate of the mobile phase in the main flow path and the bypass flow path.

  The bypass channel is a channel that branches from the main channel and joins the main channel or the adjustment tank. The main flow path and the bypass flow path can be constituted by a known member such as a pipe or a flange. The pre-removal device can be configured in the same manner as the removal device. In addition, the mobile phase flow rate adjusting device can be configured by, for example, valves provided in the main flow path and the bypass flow path. The mobile phase flow rate adjustment device is controlled by the control device so that the flow rate of the mobile phase in the bypass flow path is based on the detection result of the detector, similarly to the extraction of the mobile phase to the extraction flow path described above. It is preferable.

  The arbitrary component is not particularly limited as long as it is a component contained in the mobile phase to be adjusted. Examples of the optional component include each component of the mixed solvent, a solvent contained in the sample solution, and by-products and impurities associated with the target substance.

  The optional component is preferably a trace component contained in a small amount in the mobile phase from the viewpoint of reducing the amount of mobile phase extracted and the amount removed by the removal device. The trace component is a component contained in the mobile phase in an amount of less than 1% by volume. Examples of the trace component include organic acids and organic bases added to a small amount of each component of the mixed solvent, a solvent contained in the sample solution, a by-product of the target substance, and impurities generated when the target substance is generated. And water mixed in the mobile phase and the sample solution.

  In the present invention, a mixed solvent containing two or more solvents is used as the mobile phase. The solvent used for the mobile phase is not particularly limited. As the solvent, a usual solvent used in column chromatography is used. Examples of the solvent include water, acid, alkali, and organic solvent.

  Examples of the organic solvent include methanol, ethanol, isopropyl alcohol, acetic acid, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, ethyl acetate, methyl acetate, diethylamine, and other highly polar solvents, chloroform, acetonitrile, and other nonpolar solvents, n -Various well-known organic solvents used for a mobile phase with a chromatography apparatus, such as solvents with low polarity, such as hexane, are mentioned.

  Further, examples of the organic solvent include heptane, tert-butyl methyl ether (MTBE), acetone, toluene, methylene chloride, 1,4-dioxane, and N, N-dimethylacetamide (DMAc). The composition of the mixed solvent can be appropriately set.

  The mobile phase preferably contains a first solvent selected from methanol, ethanol, and isopropyl alcohol and a second solvent selected from normal hexane and acetonitrile from the viewpoint of use for separation of the target substance. The volume ratio of the first solvent to the second solvent (first solvent: second solvent) is preferably 10:90 to 50:50. When the volume ratio of the first solvent is less than 10, separation of the target substance becomes extremely slow, and the target substance may not be substantially separated. Further, when the volume ratio of the first solvent is larger than 50, the elution of two or more substances to be separated is accelerated, which may adversely affect the separation of the target substance.

  Depending on the physical properties of the target substance, the mobile phase may contain a weakly acidic solvent or a weakly basic solvent from the viewpoint of increasing the stability of the target substance at the time of separation. Examples of the weakly acidic solvent include carboxylic acids such as acetic acid, and examples of the weakly basic solvent include amines such as diethylamine. The content of such a weakly acidic or weakly basic solvent varies depending on the physical properties of the target substance and the type of solvent used, but is preferably 0.01 to 0.5% by volume based on the entire mobile phase. More preferably, the content is 0.01 to 0.2% by volume. When the content is less than 0.01% by volume, the above-described effects due to the solvent may not be obtained. On the other hand, if the content is larger than 0.5% by volume, the above-mentioned solvent may adversely affect the target substance and the separating agent accommodated in the column.

  Specific examples of the mobile phase include two-component mixed solvents such as methanol-ethanol mixed solvent, isopropyl alcohol-n-hexane mixed solvent, ethanol-n-hexane mixed solvent, methanol-acetonitrile mixed solvent, methanol- Examples thereof include three-component mixed solvents such as acetonitrile-acetic acid mixed solvent, methanol-acetonitrile-diethylamine mixed solvent, isopropyl alcohol-n-hexane-diethylamine mixed solvent, and ethanol-n-hexane-diethylamine mixed solvent.

  The chromatographic apparatus of the present invention can be used for separation of various target substances by storing a separation agent in accordance with the type of the target substance to be separated in the column. For example, when the target substance is an optical isomer, the column is preferably a column containing a separating agent containing an optically active polysaccharide or polysaccharide derivative from the viewpoint of separating optical isomers with high separation efficiency. .

  The polysaccharide may be any of a synthetic polysaccharide, a natural polysaccharide, and a natural product-modified polysaccharide as long as it is an optically active polysaccharide. The polysaccharide is preferably a polysaccharide with a high regularity of the binding mode, and is preferably a chain polysaccharide. Examples of the polysaccharide include various polysaccharides, and cellulose and amylose are particularly preferable.

  The polysaccharide derivative is not particularly limited as long as it is a polysaccharide derivative that can be used for separation of optical isomers. As such a polysaccharide derivative, for example, a polysaccharide derivative containing the polysaccharide as a skeleton, wherein at least a part of the hydroxyl group and amino group of the polysaccharide is substituted with a functional group that acts on an optical isomer in a sample. Can be mentioned. Examples of the polysaccharide derivative include various polysaccharide derivatives, and at least one selected from an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose is particularly preferable. Specific examples of the polysaccharide derivative include various polysaccharide derivatives described in International Publication No. 95/23125 pamphlet.

The separating agent may be in the form of particles, or in the form of particles such as the form supported on a particulate carrier, or supported on an integral carrier accommodated in a column. It may be in the form of a molded product that is integrally accommodated in a column, such as a molded product or a molded product of a separating agent. In particular, the form of the molded product housed in the column is preferable from the viewpoint of suppressing pressure loss in simulated moving bed chromatography.

  Among the separating agents in the particulate form, the separating agent in the form of particles is, for example, as described in Japanese Patent No. 2783819, using the polysaccharide or polysaccharide derivative as the separating agent as a solvent. Dissolve the resulting solution dropwise into an insoluble solvent that does not dissolve the separating agent such as water, preferably an insoluble solvent containing a dispersing agent such as an anionic surfactant, with stirring. It is possible to manufacture by.

  Further, the separating agent in the form of the particles can form a porous body. Such a separating agent, for example, disperses bubbles or polygen in the solution of the separating agent, disperses the dispersed solution in the insoluble solvent, distills or replaces the solvent from the dispersed separating agent solution, A method of washing the resulting separating agent particles with a washing solvent that dissolves polygen, if necessary, may be mentioned. As the polygen, known particles such as a resin and a salt, which are more soluble in the washing solvent than the particles of the separating agent to be produced, are used.

  Among the particulate separation agents, a separation agent in a form supported on a particulate carrier can be produced by, for example, supporting the separation agent on a carrier by physical adsorption or chemical bonding. The separation agent is supported on the carrier by immersing the carrier in a solution containing the separation agent and, if necessary, another compound, reacting with the other compound as necessary, and distilling off the solvent in the solution, It can be carried out by a method of replacing the solvent in the solution with another solvent.

  Examples of the carrier include porous organic carriers such as polystyrene, polyacrylamide, polyacrylate, and derivatives thereof; porous materials such as silica, alumina, magnesia, glass, kaolin, titanium oxide, silicate, and hydroxyapatite. Inorganic carrier; and the like.

  Among the forms of molded products that are integrally accommodated in the column, the separation agent in the form of being supported on the integral carrier accommodated in the column is, for example, the method described above with the separation agent on the integral carrier. It is possible to manufacture by carrying it.

  In addition, the separating agent in the form of an integral molded article made of the separating agent is, for example, supplying the separating agent solution in the production of the particulate separating agent described above to a container of an appropriate shape, or supplying the separating agent solution. It can be produced by feeding directly to the column tube and then distilling or replacing the solvent.

  The solvent composition adjustment apparatus of the present invention is an apparatus capable of adjusting the composition of a mixed solvent containing two or more solvents, and an adjustment tank containing the mixed solvent whose composition is to be adjusted, and an adjustment tank A detector for detecting the composition of the mixed solvent contained in the tank, a replenishing tank for containing the solvent to be replenished to the mixed solvent contained in the adjusting tank, and a replenisher for supplying the solvent in the replenishing tank to the adjusting tank And a controller for controlling the supply of the solvent from the replenishing tank according to the detection result of the detector. The detector is a near infrared spectroscopic analyzer.

In the solvent composition adjustment apparatus of the present invention, the adjustment tank, detector, replenishment tank, control device, purification apparatus, extraction flow path, removal apparatus, return flow path, and circulation flow path are the same as those described above. It can comprise similarly to each component in the said adjustment part of a chromatography apparatus. Further, in the solvent composition adjusting apparatus of the present invention, the replenishing flow path is similar to the circulation flow path and the return flow path in the adjustment section of the chromatography apparatus of the present invention described above, and a pipe, a flange, a pump, It can be constituted by a known member such as a valve.
is there.

  Hereinafter, embodiments of the present invention will be described more specifically.

<First embodiment>
As shown in FIG. 1, the simulated moving bed chromatography apparatus of the present embodiment has 12 columns 1 to 12 and a connection in which the columns 1 to 12 are connected in series so as to form an endless flow path. The connection channel 13 is connected to the connection channel 13, the pump 14 for feeding the mobile phase in the connection channel 13, and the connection channel 13 between the columns. Supply or discharge channels 15 to 18 for supplying or discharging the mobile phase from the connection channel 13 are provided.

  Although only four supply and discharge channels are shown in FIG. 1, they are connected to all the connection channels that connect the columns. The supply / discharge flow path 18 from the column 1 constitutes the separation section.

  Further, the simulated moving bed chromatography apparatus includes three evaporators 19 to 21 and 22 to 24, storage tanks 25 and 26 that store the concentrated liquids concentrated by these evaporators, and these evaporators. It has an adjustment tank 29 in which the removed mobile phase is accommodated via the recovery flow paths 27 and 28.

  The evaporators 19 to 21 are connected in parallel to the adjustment tank 29 by a recovery channel 27 so that the mobile phase evaporated in each evaporator is supplied to the adjustment tank 29. The evaporators 19 to 21 are connected in series to the storage tank 25 so that the liquid phase of each evaporator is sequentially supplied to the subsequent evaporator and the storage tank. The evaporators 22 to 24 and the adjustment tank 29, and the evaporators 22 to 24 and the storage tank 26 are also connected in the same manner as the evaporators 19 to 21 and the adjustment tank 29, and the evaporators 19 to 21 and the storage tank 25. The evaporator 19 to the storage tank 26 constitute the collecting unit.

  Further, as shown in FIG. 2, the simulated moving bed chromatography apparatus includes a stirrer 30 that stirs the mobile phase accommodated in the adjustment tank 29, and a proximity detector that detects the composition of the mobile phase accommodated in the adjustment tank 29. Infrared spectroscopic sensor 31, temperature sensor 32 for detecting the temperature of the mobile phase accommodated in the adjustment tank 29, measuring instrument 33 to which signals from the near infrared spectroscopic sensor 31 and the temperature sensor 32 are input, and a measuring instrument 33, a control device 34 to which a signal is input, two supply tanks 35 and 36 for storing a solvent to be supplied to the mobile phase stored in the adjustment tank 29, and a respective supply tank and adjustment tank 29 , Supply pumps 37 and 38, pumps 39 and 40, and automatic valves 41 and 42 interposed in the respective supply channels.

  The pumps 39 and 40 and the automatic valves 41 and 42 and the control device 34 are electrically connected so that the pumps 39 and 40 and the automatic valves 41 and 42 are operated in accordance with a signal output from the control device 34. Yes. A recycling channel 43 for discharging the mobile phase from the adjustment tank 29 is connected to the adjustment tank 29. The recovery valve 27 and the automatic valve 42 constitute the adjustment unit.

  Further, in the simulated moving bed chromatography apparatus, each supply / discharge channel, an injector (not shown) for injecting a sample solution, a mobile phase supply source (not shown), a recycling flow A pipe, a branch pipe, an automatic valve, etc. (not shown) are used so that the passage 43, the evaporator 19, and the evaporator 22 are freely connected. Each flow path is constituted by a pipe. Further, the recycling flow path 43 from the adjustment tank 29 constitutes the solvent composition adjustment apparatus of the present invention.

Next, separation of the target substance by the simulated moving bed chromatography apparatus will be described. In this embodiment, the mobile phase is a mixed solvent in which a mixed solvent of 50% by volume of methanol and 50% by volume of acetonitrile is mixed with 0.01% by volume of diethylamine in total, and is separated in a column. The agent is, for example, particles made of a carbamate derivative of cellulose produced by the method described in Japanese Patent No. 2783819. The sample solution is a solution of a mixture of optical isomers such as a racemate, and the target substance is It is assumed to be an optical isomer.

  The supply / discharge flow path 15 connected between the column 12 and the column 1 supplies the mobile phase to the endless flow path. A supply / discharge channel 16 connected between the column 6 and the column 7 supplies the sample solution to the endless channel. The supply and discharge flow path 17 connected between the column 9 and the column 10 and the supply and discharge flow path 18 connected between the column 3 and the column 4 are formed from an endless flow path. Discharge the mobile phase.

  The optical isomer in the supplied sample solution is first adsorbed on the separation agent of the column 7. Of the optical isomers in the sample solution, a component that is easily adsorbed by the separating agent (hereinafter, this component is also referred to as “raffinate”) is strongly adsorbed by the separating agent and is difficult to be adsorbed by the separating agent (hereinafter, this component is (Also called “extract”) is easier to desorb than raffinate, and is distributed downstream in the flow direction of the mobile phase. Both raffinate and extract move through column 7 by the mobile phase flow.

  When the raffinate and the extract flow out of the column 7, the piping is switched, the mobile phase is supplied from the supply / discharge flow path connected between the column 1 and the column 2, and between the column 7 and the column 8. The sample solution is supplied from the supply / discharge channel connected to the column, and connected between the column 10 and the column 11, and connected between the column 10 and the column 11, and connected between the column 4 and the column 5. The mobile phase is discharged from the supply and discharge channels. When the time required for the raffinate and the extract to pass through the column 7 is one period, the flow path is changed to the downstream side by switching the pipe as described above for each period.

  When the above-described channel change is continued for several periods, the bias between the extract distribution and the raffinate distribution due to the adsorptivity to the separating agent becomes more apparent. The extract is mainly distributed and concentrated on the upstream side of the flow direction of the mobile phase in the endless channel with respect to the supply position of the sample solution, and the raffinate is mainly distributed and concentrated on the downstream side. The As shown in FIG. 1, in the case where the sample solution is supplied from the supply / discharge flow path 16, the supply / discharge flow that is the supply / discharge flow path of the three columns upstream from the supply position of the sample solution. The mobile phase containing the concentrated extract is discharged from the channel 17 and is concentrated from the supply position of the three columns downstream from the supply position of the sample solution, the supply as the discharge channel, and the discharge channel 18. The mobile phase containing raffinate is discharged.

  When the extract and the raffinate are discharged from the endless channel, the distribution of the extract and the raffinate in the endless channel becomes substantially constant. Thereafter, the channel is alternately switched every period, and the supply of the sample solution and the discharge of the mobile phase containing the separated target substance are continuously performed.

  Next, collection of a target substance by the simulated moving bed chromatography apparatus will be described.

  The mobile phase containing raffinate discharged from the supply / discharge flow path 18 is concentrated stepwise, for example, by the evaporators 19 to 21. For example, the mobile phase containing raffinate is concentrated by evaporator 19 to 30-50% by weight, then concentrated by evaporator 20 to 40-70% by weight, then evaporated by evaporator 21 to 60-99% by weight, It is accommodated in the storage tank 25. The mobile phase removed by each evaporator is supplied to the adjustment tank 29 by the recovery channel 27. The raffinate-containing composition stored in the storage tank 25 is purified by recrystallization, vacuum distillation, or the like as necessary.

  Similarly, the mobile phase containing the extract discharged from the supply / discharge flow path 17 is concentrated stepwise by the evaporators 22 to 24 and accommodated in the storage tank 26. Further, the mobile phase removed by each evaporator is supplied to the adjustment tank 29 through the recovery flow path 28. The extract-containing composition stored in the storage tank 26 is also purified by recrystallization, vacuum distillation, or the like as necessary.

  Next, the adjustment of the mobile phase using the simulated moving bed chromatography apparatus will be described. It is assumed that acetonitrile is stored in the supply tank 35 and methanol is stored in the supply tank 36.

  The mobile phase accommodated in the adjustment tank 29 is uniformly stirred by the stirring device 30. The near-infrared spectroscopic sensor 31 irradiates the mobile phase accommodated in the adjustment tank 29 with light, and the wavelength of the reflected light (or transmitted light) of the mobile phase in the near-infrared region (for example, 0.8 to 2.5 μm). Detect the intensity of each. The temperature sensor 32 detects the temperature of the mobile phase accommodated in the adjustment tank 29. The intensity for each wavelength in the near-infrared region detected by the near-infrared spectroscopic sensor 31 is sent to the control device 34 via the measuring device 33. The temperature detected by the temperature sensor 32 is sent to the control device 34 via the measuring device 33.

  For example, the control device 34 sets the intensity of the wavelength characteristic of acetonitrile in the detection result to a value of a predetermined temperature (for example, the temperature at which the mobile phase is used in the separation unit) according to the temperature of the mobile phase detected by the temperature sensor 32. Correct as necessary. This correction is performed, for example, when the temperature of the mobile phase has a significant difference with respect to a predetermined temperature. In addition, this correction is performed, for example, by adopting an actually measured value when the composition of the mobile phase at a predetermined temperature is detected in advance.

  On the other hand, the control device 34 includes the intensity of the wavelength peculiar to each solvent in the detection result of the near-infrared spectroscopic sensor 31 or a correction value thereof, and each solvent at a predetermined temperature stored in the control device 34. The intensity of the wavelength in the calibration curve is compared. Then, when the intensity of the wavelength or the like is smaller than the intensity of the wavelength in the calibration curve, the control device 34 determines that the wavelength intensity or the like peculiar to acetonitrile by the near infrared spectroscopic sensor 31 is a wavelength peculiar to acetonitrile in the calibration curve. The automatic valve 41 is opened and the pump 39 is operated to supply acetonitrile to the adjustment tank 29 until the desired concentration is obtained.

  Alternatively, the control device 34 is obtained from the intensity of the wavelength specific to acetonitrile in the detection result by the near-infrared spectroscopic sensor 31 or the intensity value of the wavelength corrected based on the detection result by the temperature sensor 32 and the calibration curve. Calculate the amount of acetonitrile corresponding to the difference in wavelength intensity specific to acetonitrile at the desired concentration, open the automatic valve 41 and operate the pump 39 to adjust the calculated amount of acetonitrile from the replenishment tank 35 Supply to tank 29.

  Similarly to acetonitrile, the controller 34 supplies methanol from the replenishing tank 36 to the pump 40 and the pump 40 if necessary based on the detection result of the near infrared spectroscopic sensor 31 and the calibration curve stored in the controller 34. It supplies to the adjustment tank 29 via the automatic valve 42.

  The control device 34 recycles the mobile phase accommodated in the adjustment tank 29 when the detected value of the intensity of the wavelength peculiar to each solvent and the intensity of the wavelength peculiar to each solvent in the calibration curve match within a predetermined tolerance. It discharges to the use channel 43. The mobile phase discharged to the recycling flow path 43 is supplied to the supply and discharge flow paths (supply and discharge flow path 15 in FIG. 1) for supplying the mobile phase to the endless flow path, and is simulated moving bed type. Reused for mobile phase in chromatography equipment.

In the simulated moving bed chromatography apparatus, the supply and discharge flow paths 15 to 18 are set at equal intervals so that three columns are sandwiched between each other. 1
The interval of 8 may not be equal. The interval between these flow paths can be appropriately set according to the type of the separating agent, the type of the target substance, and the like.

  In the simulated moving bed chromatography apparatus, two solvents (acetonitrile and methanol) having a large boiling point and high content are used as solvents to be replenished among the solvents in the mobile phase. Although the supply tanks 35 and 36 are provided, three supply tanks may be provided. If two of the three solvents azeotrope during recovery, it is possible to adjust the composition of the mobile phase with the remaining one type of replenishment. In such a case, only one replenishment tank is provided. It is also possible.

  Further, the simulated moving bed chromatography apparatus includes an adsorber and a guard column in the recycling flow path 43 in order to remove a small amount of impurities contained in the sample solution and entrained substances from the evaporator from the mobile phase. Further, an adsorption means such as the above may be provided. Further, in order to detect the amount of the mobile phase accommodated in the adjustment tank 29, a liquid level sensor may be further provided in the adjustment tank 29. Further, a recovery tank for temporarily storing the mobile phase evaporated and recovered by each evaporator before being stored in the adjustment tank 29 may be further provided. Further, a reprocessing tank for accommodating a mobile phase that is determined to be inappropriate for reuse as a result of the composition detection by the near infrared spectroscopic sensor 31 in the adjustment tank 29 may be further provided.

  In the present embodiment, in the case where one component is necessary and the other component is unnecessary among the extracted raffinate and extract, the other component is a known component such as heating or the use of an enzyme. It can be racemized by the method and reused in the sample solution. The method and conditions for racemization are appropriately determined according to the type of optical isomer.

  The simulated moving bed chromatography apparatus of the present embodiment is a separation that separates optical isomers by supplying a solution of a mixture of optical isomers to an endless channel formed by connecting a plurality of columns in series. The mobile phase containing the optical isomer separated by the separation unit, the collection unit collecting the optical isomer by evaporating the mobile phase from the mobile phase, the mobile phase removed by the collection unit being recovered, and the recovered mobile phase The adjustment unit adjusts the composition of the mobile phase to the composition of the mobile phase that can be supplied to the endless flow path, and the adjustment unit uses a mixed solvent in which a small amount of diethylamine is mixed with an equivalent mixture of acetonitrile and methanol. Since the mobile phase adjusted in step 1 is supplied to an endless flow path, sample solution supply and optical isomer separation can be performed continuously, and the mobile phase can be regenerated and reused for further optical resolution. can do.

  Further, in the simulated moving bed chromatography apparatus of the present embodiment, the adjustment unit includes the adjustment tank 29, the near-infrared spectroscopic sensor 31 that detects the composition of the mobile phase supplied to the adjustment tank, and the adjustment tank 29. A replenishing tank 35 containing acetonitrile as a solvent to be replenished in the mobile phase accommodated, a replenishing tank 36 containing methanol, and replenishing tanks 35 and 36 according to the detection result of the near infrared spectroscopic sensor 31. And the controller 34 for controlling the replenishment of the solvent from the solvent, the concentration of the solvent in the mobile phase is detected quickly, accurately and precisely. For this reason, it is possible to detect the composition of a mobile phase containing a solvent having a similar physical property such as dielectric constant, and a mobile phase containing a small amount of solvent compared to other solvents, regardless of the type of mobile phase. The mobile phase can be reused.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment uses the near-infrared spectroscopic sensor 31, and therefore, contamination, identification, and identification of a trace amount of impurities generated in the system, such as droplet entrainment in the evaporator, and Quantification is possible.

  Moreover, since the near-infrared spectroscopic sensor 31 detects the composition of the mobile phase in the adjustment tank 29, the simulated moving bed chromatography apparatus of this embodiment can detect the composition of the mobile phase with a simple configuration. it can.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment uses a mixed solvent containing methanol and acetonitrile in a volume ratio of 50:50 as a mobile phase, so that the development speed and distribution of raffinate and extract are clearly defined. It is possible to adjust the thickness appropriately. In addition, since a mixed solvent further containing 0.01% by volume of diethylamine is used for the mobile phase, the stability at the time of separation of optical isomers having basic functional groups or acidic functional groups is further enhanced. be able to.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment uses a particulate separation agent made of a carbamate derivative of cellulose, which is an optically active polysaccharide derivative, as the separation agent accommodated in the column. Can be separated with high separation efficiency.

  Moreover, since the simulated moving bed chromatography apparatus of this embodiment has the temperature sensor 32 that detects the temperature of the mobile phase accommodated in the adjustment tank 29, the mobile phase relative to the detection value by the near infrared spectroscopic sensor 31 is included. The influence of temperature can be corrected, and the composition of the mobile phase can be adjusted more accurately.

<Second Embodiment>
As shown in FIG. 3, the simulated moving bed chromatography apparatus of the present embodiment includes a recovery tank 51 in which the mobile phase removed by the evaporator is accommodated via recovery flow paths 27 and 28, and a recovery tank. The distillation apparatus 52 and the adjustment tank 29 are further provided with a distillation apparatus 52 which is a purification apparatus for purifying the mobile phase accommodated in 51, and the mobile phase distilled by the distillation apparatus 52 is supplied. Except for the point connected, it is comprised similarly to the simulated moving bed type chromatography apparatus of 1st embodiment.

  Separation and collection of the target substance in the simulated moving bed chromatography apparatus of the present embodiment are performed in the same manner as in the first embodiment. The adjustment of the mobile phase in the simulated moving bed chromatography apparatus of the present embodiment will be described.

  The mobile phase evaporated in the evaporators 19 to 24 is supplied to the recovery tank 51 via the recovery flow paths 27 and 28. The mobile phase accommodated in the recovery tank 51 is supplied to the distillation apparatus 52. The mobile phase supplied to the distillation apparatus 52 is distilled, and for example, other solvents and by-products contained in the sample solution are removed from the mobile phase as bottoms. Thus, for example, a mobile phase having a purity of 98% by mass or more is distilled from the distillation apparatus 52 and supplied to the adjustment tank 29. Adjustment of the mobile phase in the adjustment tank 29 is performed in the same manner as in the first embodiment.

  Since the simulated moving bed chromatography apparatus of the present embodiment has the distillation apparatus 52, in addition to the effects of the first embodiment, the purity of the mobile phase before being adjusted in the adjustment tank 29 is further increased. be able to. Therefore, it is more effective from the viewpoint of continuing to use the mobile phase for a long time and performing optical resolution stably.

<Third embodiment>
As shown in FIG. 4, the simulated moving bed chromatography apparatus of the present embodiment includes a circulation channel 55 for circulating the mobile phase in the adjustment tank 29 and the circulation channel 5 in the adjustment tank 29. And a pump 56 for circulating the mobile phase, and the near-infrared spectroscopic sensor 31 and the temperature sensor 32 are provided so as to detect the composition and temperature of the mobile phase in the circulation channel 55. Except for, it is configured in the same manner as the simulated moving bed chromatography apparatus of the first embodiment and the second embodiment.

Separation and collection of the target substance in the simulated moving bed chromatography apparatus of the present embodiment are performed in the same manner as in the first embodiment. The adjustment of the mobile phase in the simulated moving bed chromatography apparatus of the present embodiment will be described.

  The mobile phase accommodated in the adjustment tank 29 is uniformly stirred by the stirring device 30 and circulates in the circulation channel 55 by the pump 56. The near-infrared spectroscopic sensor 31 irradiates the mobile phase in the circulation channel 55 with light, and detects the intensity for each wavelength of reflected light (or transmitted light) of the mobile phase in the near-infrared region. The temperature sensor 32 detects the temperature of the mobile phase in the circulation channel 55. Operations after these detections are performed in the same manner as in the first embodiment.

  The simulated moving bed chromatography apparatus of the present embodiment has an effect that the composition of the mobile phase is detected with a simple configuration by detecting the composition of the mobile phase in the adjustment tank 29 by the near infrared spectroscopic sensor 31. Except for this, the same effects as those of the first embodiment and the second embodiment are obtained.

  Furthermore, in the simulated moving bed chromatography apparatus of the present embodiment, the mobile phase detected by the near-infrared spectroscopic sensor 31 and the temperature sensor 32 is a mobile phase that has been supplied with the solvent to be replenished and stirred. In the mobile phase to be tried, fluctuations in the concentration distribution due to the supply of the solvent and the mobile phase are suppressed, and fluctuations in the detection results by the near-infrared spectroscopic sensor 31 and the temperature sensor 32 are suppressed. Therefore, it is more effective from the viewpoint of improving the accuracy of detection of a small amount of components in the mobile phase, such as a droplet entrained component, a small amount of impurities, a small amount of solvent such as diethylamine, etc., and in adjusting the composition of the mobile phase. This is even more effective from the viewpoint of increasing accuracy.

<Fourth embodiment>
The simulated moving bed chromatography apparatus according to the present embodiment further includes a liquid level gauge that detects the liquid level of the mobile phase in the adjustment tank 29, and the liquid level gauge includes a near-infrared spectroscopic sensor 31 and a temperature sensor 32. Similarly to the above, except that it is connected to the control device 34 via the measuring device 33, it is configured in the same manner as the simulated moving bed chromatography device of the first embodiment.

  Separation and collection of the target substance in the simulated moving bed chromatography apparatus of the present embodiment are performed in the same manner as in the first embodiment. The adjustment of the mobile phase in the simulated moving bed chromatography apparatus of the present embodiment will be described.

  The mobile phase accommodated in the adjustment tank 29 is uniformly stirred by the stirring device 30. The near-infrared spectroscopic sensor 31 irradiates the mobile phase accommodated in the adjustment tank 29 with light, and detects the intensity for each wavelength of reflected light (or transmitted light) of the mobile phase in the near-infrared region. The temperature sensor 32 detects the temperature of the mobile phase accommodated in the adjustment tank 29. The liquid level gauge detects the position of the liquid level of the mobile phase stored in the adjustment tank 29. The intensity for each wavelength in the near-infrared region detected by the near-infrared spectroscopic sensor 31 is sent to the control device 34 via the measuring device 33. The temperature detected by the temperature sensor 32 is sent to the control device 34 via the measuring device 33. The position of the liquid level detected by the liquid level gauge is sent to the control device 34 via the measuring device 33.

  The control device 34 adjusts the intensity of the wavelength specific to each solvent in the detection result of the near infrared spectroscopic sensor 31 or the corrected intensity value of the wavelength based on the detection of the temperature of the mobile phase by the temperature sensor 32. The composition ratio of each solvent of the mobile phase accommodated in the tank 29 is determined. Moreover, the control apparatus 34 calculates | requires the volume of the mobile phase accommodated in the adjustment tank 29 from the position of the liquid level of the mobile phase in the adjustment tank 29 detected by the said liquid level gauge.

  And the control apparatus 34 is the composition ratio of each solvent of the mobile phase accommodated in the adjustment tank 29, the volume of the mobile phase accommodated in the adjustment tank 29, and in the mobile phase memorize | stored in the control apparatus 34. From the density of each solvent at a predetermined temperature, the weight of each solvent in the mobile phase accommodated in the adjustment tank 29 is obtained.

  Then, the control device 34 compares the weight of each solvent in the mobile phase stored in the adjustment tank 29 with the initial setting value of each solvent for each total weight of the mobile phase stored in the control device 34. For the solvent whose actual weight is smaller than the initial set value, a necessary amount of solvent that satisfies the initial set value is supplied from the replenishing tanks 35 and 36 to the adjusting tank 29.

  Alternatively, the control device 34 obtains the weight of each solvent to be included in the mobile phase from the volume of the mobile phase accommodated in the adjustment tank 29, and the theoretical value of the weight of each solvent in the obtained capacity of the mobile phase. And the actual weight of each solvent of the mobile phase accommodated in the adjustment tank 29, the type and amount of the solvent that needs replenishment are specified, and the necessary amount of solvent is adjusted from the replenishment tanks 35 and 36. Supply to tank 29.

  The supply of a predetermined amount of solvent from the replenishing tanks 35 and 36 includes the operation of the pumps 39 and 40, the use of a flow meter provided in the replenishing flow paths 37 and 38, and the other provided in the replenishing tanks 35 and 36 It can carry out by well-known methods, such as use of a liquid level gauge. Operations after the adjustment of the mobile phase are performed in the same manner as in the first embodiment.

  Since the simulated moving bed chromatography apparatus of the present embodiment has a liquid level meter that detects the liquid level of the mobile phase in the adjustment tank 29, the controller 34 controls the replenishment amount of the solvent to be replenished in the mobile phase. It can be determined by weight. Therefore, the composition of the mobile phase can be adjusted by supplying the solvent once or twice, and the composition of the mobile phase can be adjusted more rapidly. In addition, the simulated moving bed chromatography apparatus of the present embodiment has the same effects as those of the first embodiment described above.

  The simulated moving bed chromatography apparatus of the present embodiment is a form in which the liquid level meter is applied to the simulated moving bed chromatography apparatus of the first embodiment, but the second or third implementation. The present invention can be similarly applied to a simulated moving bed chromatography apparatus of the form. In the simulated moving bed chromatography apparatus of the second or third embodiment, when a liquid level gauge is installed as described in the present embodiment, in addition to the effects of the present embodiment described above, the second or The same effect as that of the third embodiment can be obtained.

<Fifth embodiment>
As shown in FIG. 5, the simulated moving bed chromatography apparatus of the present embodiment is connected to the bottom of the adjustment tank 29, and has an extraction channel 61 for extracting a mobile phase that is a mixed solvent from the adjustment tank 29. The removal device 62 that removes any component in the mobile phase of the extraction flow channel 61 is connected to the removal device 62 and the collection flow channels 27 and 28, and the mobile phase from which any component has been removed by the removal device 62. A return flow path 63 for returning the flow to the adjustment tank 29, an automatic valve 64 for opening and closing the extraction flow path 61, and a pump 65 for sending the mobile phase of the extraction flow path 61 toward the removal device 62. And has the same configuration as that of the first embodiment described above except that the automatic valve 64 and the pump 65 are further connected to the control device 34.

  The extraction channel 61 is connected to the bottom of the removing device 62. The removal device 62 is, for example, an adsorption tower filled with an adsorbent for adsorbing an arbitrary component in the mobile phase and removing it from the mobile phase. As the adsorbent, known adsorbents such as silica, alumina, and activated carbon that adsorb diethylamine from the mobile phase are used. The return channel 63 is connected to the top of the removal device 62.

  Further, the upper limit value of the amount (or concentration) of diethylamine in the mobile phase accommodated in the adjustment tank 29 is further set in the control device 34. This upper limit is, for example, the ratio (or concentration) of diethylamine in the mobile phase set as the desired mobile phase composition.

  The control device 34 determines the amount of diethylamine in the mobile phase in the adjustment tank 29 based on the detection value of the near infrared spectroscopic sensor 31. While the amount of diethylamine in the mobile phase in the adjustment tank 29 is below the upper limit, the control device 34 closes the automatic valve 64 and stops the pump 65.

  When the amount of diethylamine in the mobile phase in the adjustment tank 29 exceeds the upper limit, the control device 34 opens the automatic valve 64 and operates the pump 65. Thereby, the mobile phase in the adjustment tank 29 is extracted to the extraction channel 61.

  The mobile phase extracted from the adjustment tank 29 to the extraction channel 61 is sent from the extraction channel 61 to the removing device 62. From the mobile phase sent to the removal device 62, diethylamine in the mobile phase is adsorbed by the adsorbent. Thereby, diethylamine in the mobile phase is completely or partially removed from the mobile phase. By supplying the mobile phase to the removal device 62, the amount of diethylamine in the mobile phase is reduced.

  The mobile phase from which the amount of diethylamine has been reduced by the removing device 62 is returned to the adjustment tank 29 via the return channel 63 and the recovery channels 27 and 28.

  The mobile phase of the recovery channels 27 and 28 is a condensate of components evaporated in the evaporators 19 to 24. For this reason, diethylamine, which is a low-boiling component having the lowest boiling point in the mixed solvent as the mobile phase, evaporates several times in the evaporator along with the regeneration and reuse of the mobile phase, and thus in the condensate. The concentration tends to be higher than the initial concentration. For this reason, the mobile phase of the recovery channels 27 and 28 tends to be a mobile phase containing diethylamine at a higher concentration than the desired composition as the mobile phase.

  However, even if the mobile phase containing a high concentration of diethylamine increases in the adjustment tank 29, such a mobile phase is extracted from the adjustment tank 29 to the extraction channel 61. The amount of diethylamine in the adjustment tank 29 can be reduced along with the amount of phase.

  Further, diethylamine is removed from the extracted mobile phase by the removing device 62. In this way, the mobile phase in which the concentration of diethylamine is reduced and the concentrations of methanol and acetonitrile are increased relative to the initial mobile phase composition is supplied to the recovery flow paths 27 and 28. Therefore, by supplying the mobile phase from the return channel 63, the mobile phase in the adjustment tank 29 becomes a mobile phase having a lower concentration of diethylamine than the mobile phase supplied from the recovery channels 27 and 28.

  In this manner, the content of diethylamine is reduced in the mobile phase in the adjustment tank 29 as compared to before the mobile phase is extracted. Then, components other than diethylamine in the extracted mobile phase are returned to the adjustment tank 29. Therefore, the concentration of diethylamine in the mobile phase of the adjustment tank 20 is lower than before extraction of the mobile phase. Based on the reduced amount of diethylamine, the composition of the mobile phase in the adjustment tank 29 is adjusted.

Compared to the simulated moving bed chromatography device of the first embodiment, the simulated moving bed chromatography device of the present embodiment further includes an extraction channel 61, and the control device 34 includes a near infrared. Based on the detection result of the spectroscopic sensor 31, the extraction amount of the mobile phase from the adjustment tank 29 is further controlled so that the amount of diethylamine in the adjustment tank 29 does not exceed the upper limit value. Diethylamine concentrated in the mobile phase with repeated regeneration can be withdrawn from the adjustment tank 29. Therefore, the amount of diethylamine in the mobile phase in the adjustment tank 29 can be reduced, and the mobile phase can be prevented from overflowing from the adjustment tank 29 by replenishing the mobile phase with other components for dilution of diethylamine. it can.

  Further, the simulated moving bed chromatography apparatus of the present embodiment has a removal apparatus 62 that removes diethylamine in the mobile phase of the extraction channel 61 as compared with the simulated moving bed chromatography apparatus of the first embodiment. And a return flow path 63 for returning the mobile phase from which diethylamine has been removed by the removing device 62 to the adjustment tank 29, the mobile phase from which diethylamine has been removed can be further supplied to the adjustment tank 29. it can. Therefore, only diethylamine can be removed from the mobile phase in the adjustment tank 29. Moreover, since methanol and acetonitrile other than diethylamine are not removed, the supply amount of these solvents to the adjustment tank 29 can be reduced.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment has the same effects as those of the first embodiment described above. Further, the simulated moving bed chromatography apparatus of the present embodiment can be similarly applied to the simulated moving bed chromatography apparatus of the second or third embodiment. When the extraction moving channel 61 described in the present embodiment is provided in the simulated moving bed chromatography device of the second or third embodiment, in addition to the effects of the present embodiment described above, the second Or the effect similar to the effect of 3rd embodiment is acquired.

  In the present embodiment, a recycling channel 43 and an extraction channel 61 are provided as channels for discharging the mobile phase from the adjustment tank 29. According to such a configuration, since only the mobile phase whose composition is adjusted is supplied to the recycling flow path 43, it is more effective from the viewpoint of preventing impurities from being mixed into the reused mobile phase. is there. However, in the present invention, an outlet for discharging the mobile phase in the recycling flow path 43 to the outside may be provided so that the recycling flow path 43 can be used as an extraction flow path. Alternatively, a branch pipe branched from the recycling flow path 43 may be provided, and the branch pipe and the removal device 62 may be connected via the automatic valve 64 and the pump 65. According to such a configuration, the configuration of the flow path for discharging (extracting) the mobile phase from the adjustment tank 29 can be simplified.

  In the present embodiment, the return channel 63 is connected to the recovery channels 27 and 28. However, instead of connecting the return channel 63 to the recovery channels 27 and 28, the adjustment tank 29 is used. The same effect can be obtained even when connected to.

<Sixth embodiment>
As shown in FIG. 6, the simulated moving bed chromatography apparatus of the present embodiment has the same configuration as that of the above-described third embodiment, except that the extraction flow path 61 to the pump 65 are provided. About the structure from the extraction flow path 61 to the pump 65, it is the same structure as 5th Embodiment mentioned above except the removal apparatus 62 being a distillation apparatus.

  The distillation apparatus is an apparatus for distilling diethylamine from the mobile phase. The extraction flow path 61 is connected to the lower part of the distillation apparatus, and the return flow path 63 is connected to the bottom of the distillation apparatus, and supplies the bottoms of the distillation apparatus to the recovery flow paths 27 and 28. .

  The simulated moving bed chromatography apparatus of the present embodiment has the same effects as the third embodiment and the fifth embodiment described above.

<Seventh embodiment>
As shown in FIG. 7, the simulated moving bed chromatography apparatus of the present embodiment includes a bypass channel 66 connected to the recovery channels 27 and 28, and any mobile phase in the bypass channel 66 in the mobile phase. A pre-removing device 67 for removing diethylamine as a component, an automatic valve 68 for adjusting the flow rate of the mobile phase in the recovery flow paths 27 and 28, and a flow rate of the mobile phase in the bypass flow path 66 The configuration is the same as that of the first embodiment described above except that the automatic valve 69 is further included.

  The bypass channel 66 forms a channel that bypasses a part of the recovery channels 27 and 28. The pre-removal device 67 is an adsorption device having the adsorbent accommodated in the mobile phase flow path, similar to the removal device 62 in the fifth embodiment described above. The automatic valves 68 and 69 are each connected to the control device 34. The recovery channels 27 and 28 correspond to the main channel in the present invention, and the automatic valves 68 and 69 correspond to the mobile phase flow rate adjusting device in the present invention. Further, similarly to the fifth embodiment described above, an upper limit value of the amount (or concentration) of diethylamine in the mobile phase accommodated in the adjustment tank 29 is further set in the control device 34.

  The control device 34 determines the amount of diethylamine in the mobile phase in the adjustment tank 29 based on the detection value of the near infrared spectroscopic sensor 31. While the amount of diethylamine in the mobile phase in the adjustment tank 29 is below the upper limit value, the control device 34 closes the automatic valve 69.

  When the amount of diethylamine in the mobile phase in the adjustment tank 29 exceeds the upper limit, the control device 34 operates to open the automatic valve 69 and operates the automatic valve 68 to close. As a result, part or all of the mobile phase of the recovery channels 27 and 28 is supplied to the bypass channel 66.

  The mobile phase supplied to the bypass channel 66 passes through the pre-removal device 67. From the mobile phase supplied to the pre-removal device 67, diethylamine in the mobile phase is adsorbed by the adsorbent. Thereby, diethylamine in the mobile phase is completely or partially removed from the mobile phase.

  The mobile phase from which the amount of diethylamine has been reduced by the pre-removal device 67 is supplied again to the recovery amount channels 27 and 28. Thus, the mobile phase having a reduced concentration of diethylamine is supplied to the adjustment tank 29 according to the composition of the mobile phase in the adjustment tank 29.

  The simulated moving bed chromatography apparatus of the present embodiment can reduce the concentration of diethylamine in the mobile phase in the adjustment tank 29. Moreover, since methanol and acetonitrile other than diethylamine are not removed, the supply amount of these solvents to the adjustment tank 29 can be reduced.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment has the same effects as those of the first embodiment described above. Further, the simulated moving bed chromatography apparatus of the present embodiment can be similarly applied to the simulated moving bed chromatography apparatus of the second or third embodiment. When the simulated moving bed chromatography apparatus of the second or third embodiment is provided with the bypass channel 66 described in the present embodiment, in addition to the effects of the present embodiment described above, The same effect as that of the third embodiment can be obtained.

<Eighth embodiment>
The chromatography apparatus of the present embodiment is a high performance liquid chromatography apparatus, and has the same configuration as that of the first embodiment described above, except for the separation unit, as shown in FIG.

The separation unit includes a mobile phase channel 71 connected to the recycling channel 43 and two discharge channels 72 and 73 branched from the mobile phase channel 71. The mobile phase channel 71 includes a pump 74 for sending the mobile phase from the recycling channel 43, a heat exchanger 75 for adjusting the temperature of the mobile phase sent by the pump 74, and heat exchange. An injector 76 for injecting the sample solution into the mobile phase whose temperature is controlled by the vessel 75; a column 77 for separating the target substance in the mobile phase into which the sample solution has been injected; And a detector 78 for detecting the detected components. Also. The discharge channels 72 and 73 are provided with automatic valves 79 and 80 for opening and closing the discharge channels 72 and 73, respectively.

  In the present embodiment, the mobile phase containing the target substance separated by the column 77 is supplied to the discharge channel 72. The mobile phase containing components other than the target substance separated by the column 77 is supplied to the discharge channel 73. In this way, each discharge channel is selectively used depending on the components in the mobile phase after passing through the column 77.

  The chromatographic apparatus of the present embodiment has the same effects as those of the first embodiment described above, except that the sample solution supply and the optical isomer separation can be performed continuously. Play. In addition, the chromatography apparatus of the present embodiment can be applied to the second to seventh embodiments described above, and can supply sample solution and separate optical isomers continuously. Except for this effect, the same effects as those of the respective embodiments are obtained.

It is a figure which shows roughly the structure of one Embodiment of the simulated moving bed type chromatography apparatus of this invention. It is a figure which shows schematically the structure of the adjustment part in the simulated moving bed type chromatography apparatus shown in FIG. It is a figure which shows roughly the structure of other embodiment of the simulated moving bed type chromatography apparatus of this invention. It is a figure which shows roughly the other example of a structure of the adjustment part in the simulated moving bed type chromatography apparatus of this invention. It is a figure which shows schematically the structure of other embodiment in this invention. It is a figure which shows schematically the structure of other embodiment in this invention. It is a figure which shows schematically the structure of other embodiment in this invention. It is a figure which shows schematically the structure of one Embodiment of the chromatography apparatus of this invention.

Explanation of symbols

1-12, 77 Column 13 Connection flow path 14, 39, 40, 56, 65, 74 Pump 15-18 Supply / discharge flow path 19-24 Evaporator 25, 26 Storage tank 27, 28 Recovery flow path 29 Adjustment tank 30 Stirrer 31 Near-infrared spectroscopic sensor 32 Temperature sensor 33 Measuring instrument 34 Controller 35, 36 Supply tank 37, 38 Supply channel 41, 42, 64, 68, 69, 79, 80 Automatic valve 43 Recycling Flow path 51 Recovery tank 52 Distillation device 55 Circulation flow path 61 Extraction flow path 62 Removal apparatus 63 Return flow path 66 Bypass flow path 67 Pre-removal apparatus 71 Mobile phase flow path 72, 73 Discharge flow path 75 Heat exchanger 76 Injector 78 Detector

Claims (22)

A separation unit for supplying a sample solution containing a target substance and a mobile phase to a flow path of a mobile phase including a column to separate the target substance from the sample solution;
A collecting unit for collecting the target substance by removing the mobile phase from the mobile phase containing the target substance separated by the separation unit;
A mobile unit that recovers the mobile phase removed by the collecting unit, and an adjustment unit that adjusts the recovered mobile phase composition to a mobile phase composition that can be supplied to the flow path of the mobile phase;
The mobile phase is a chromatography device in which a mixed solvent containing two or more solvents is used, and the mobile phase adjusted by the adjustment unit is supplied to the flow path of the mobile phase,
The adjustment unit should replenish the adjustment phase containing the mobile phase whose composition is to be adjusted, the detector for detecting the composition of the mobile phase supplied to the adjustment rate, and the mobile phase supplied to the adjustment rate In a chromatography device having a replenishment tank for containing a solvent and a control device for controlling replenishment of the solvent from the replenishment tank according to the detection result of the detector,
The detector Ri NIR spectrophotometer der,
The adjustment unit further includes a liquid level gauge that detects a liquid level of the mobile phase in the adjustment tank, and the control device calculates an amount of the mobile phase in the adjustment tank based on a detection result of the liquid level gauge. determined, the amount of mobile phase obtained, said detector based on the composition of the detected mobile phase, and wherein that you control the replenishment of the solvent from the replenishment tank. The adjustment unit includes a main flow path for supplying a mobile phase to the adjustment tank, a bypass flow path connected to the main flow path, and before removing any components in the mobile phase in the bypass flow path. The apparatus according to claim 1 , further comprising a removal device and a mobile phase flow rate adjusting device for adjusting a flow rate of the mobile phase in the main flow path and the bypass flow path. A separation unit for supplying a sample solution containing a target substance and a mobile phase to a flow path of a mobile phase including a column to separate the target substance from the sample solution;
A collecting unit for collecting the target substance by removing the mobile phase from the mobile phase containing the target substance separated by the separation unit;
A mobile unit that recovers the mobile phase removed by the collecting unit, and an adjustment unit that adjusts the recovered mobile phase composition to a mobile phase composition that can be supplied to the flow path of the mobile phase;
The mobile phase is a chromatography device in which a mixed solvent containing two or more solvents is used, and the mobile phase adjusted by the adjustment unit is supplied to the flow path of the mobile phase,
The adjustment unit should replenish the adjustment phase containing the mobile phase whose composition is to be adjusted, the detector for detecting the composition of the mobile phase supplied to the adjustment rate, and the mobile phase supplied to the adjustment rate In a chromatography device having a replenishment tank for containing a solvent and a control device for controlling replenishment of the solvent from the replenishment tank according to the detection result of the detector,
The detector is a near-infrared spectrometer;
The adjustment unit includes a main flow path for supplying a mobile phase to the adjustment tank, a bypass flow path connected to the main flow path, and before removing any components in the mobile phase in the bypass flow path. The apparatus further comprising: a removing device; and a mobile phase flow rate adjusting device for adjusting a flow rate of the mobile phase in the main flow path and the bypass flow path. The adjustment unit further includes a liquid level gauge that detects a liquid level of the mobile phase in the adjustment tank, and the control device calculates an amount of the mobile phase in the adjustment tank based on a detection result of the liquid level gauge. determined, the amount of mobile phase obtained, said detector based on the composition of the detected mobile phase, according to claim 3, characterized in that for controlling the supply of said solvent from said replenishment tank Equipment. The said adjustment part further has the refiner | purifier for refine | purifying the collect | recovered mobile phase, The mobile phase refine | purified with the said refiner | purifier is supplied to the said adjustment tank, The any one of Claim 1 to 4 characterized by the above-mentioned. apparatus according to one paragraph or. The said detector detects the composition of the mobile phase in the said adjustment tank, The apparatus as described in any one of Claim 1 to 5 characterized by the above-mentioned. The adjustment unit further includes a circulation channel for circulating the mobile phase in the adjustment tank, and the detector detects a composition of the mobile phase in the circulation channel. Apparatus according to any one of claims 1 to 5 . The adjustment unit further includes an extraction flow path for extracting a mobile phase from the adjustment tank, and the control device further controls an extraction amount of the mobile phase from the adjustment tank based on a detection result of the detector. An apparatus according to any one of claims 1 to 7 , characterized in that: The adjustment unit further includes a removal device that removes any component in the mobile phase of the extraction flow channel, and a return flow channel for returning the mobile phase from which the optional component has been removed by the removal device to the adjustment tank. 9. The apparatus of claim 8, comprising: The mobile phase contains a first solvent selected from methanol, ethanol, and isopropyl alcohol, and a second solvent selected from normal hexane and acetonitrile, and the first solvent and the second solvent volume ratio (first solvent: second solvent) is 10: 90-50: apparatus according to the range of 50 claim, wherein in any one of 9. The apparatus of claim 10 , wherein the mobile phase further contains 0.01 to 0.5% by volume of diethylamine. The separation unit supplies a sample solution containing a target substance and a mobile phase to an endless flow path formed by connecting a plurality of columns in series to separate the target substance from the sample solution. Separation part,
The apparatus according to any one of claims 1 to 11 , wherein the apparatus is a simulated moving bed chromatography apparatus. The column according to any one of claims 1 to 12 , wherein the column is a column containing a separating agent containing an optically active polysaccharide or polysaccharide derivative, and the target substance is an optical isomer. Equipment. The apparatus according to claim 13 , wherein the polysaccharide is cellulose or amylose, and the polysaccharide derivative is at least selected from an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose. An apparatus that contains two or more solvents and can adjust the composition of a mixed solvent whose composition is to be adjusted,
An adjustment tank containing the mixed solvent whose composition is to be adjusted;
A detector for detecting the composition of the mixed solvent contained in the adjustment tank;
A replenishment tank that contains a solvent to be replenished to the mixed solvent contained in the adjustment tank;
A replenishment flow path for supplying the solvent of the replenishment tank to the adjustment tank;
A control device for controlling the supply of the solvent from the replenishing tank according to the detection result of the detector;
The detector Ri NIR spectrophotometer der,
The liquid level gauge further detects the liquid level of the mixed solvent in the adjustment tank, and the control device obtains the amount of the mixed solvent in the adjustment tank based on the detection result of the liquid level gauge. the amount of the mixed solvent, the detector based on the composition of the detected mixed solvent, and wherein that you control the supply of the solvent from the replenishment tank. A main channel for supplying a mobile phase to the adjustment tank, a bypass channel connected to the main channel, a pre-removing device for removing any component in the mobile phase in the bypass channel, and The apparatus according to claim 15 , further comprising a mobile phase flow rate adjusting device for adjusting a flow rate of the mobile phase in the main flow path and the bypass flow path. An apparatus that contains two or more solvents and can adjust the composition of a mixed solvent whose composition is to be adjusted,
An adjustment tank containing the mixed solvent whose composition is to be adjusted;
A detector for detecting the composition of the mixed solvent contained in the adjustment tank;
A replenishment tank that contains a solvent to be replenished to the mixed solvent contained in the adjustment tank;
A replenishment flow path for supplying the solvent of the replenishment tank to the adjustment tank;
A control device for controlling the supply of the solvent from the replenishing tank according to the detection result of the detector;
The detector is a near-infrared spectrometer;
A main channel for supplying a mobile phase to the adjustment tank, a bypass channel connected to the main channel, a pre-removing device for removing any component in the mobile phase in the bypass channel, and The apparatus further comprises a mobile phase flow rate adjusting device for adjusting the flow rate of the mobile phase in the main flow path and the bypass flow path. The liquid level gauge further detects the liquid level of the mixed solvent in the adjustment tank, and the control device obtains the amount of the mixed solvent in the adjustment tank based on the detection result of the liquid level gauge. 18. The apparatus according to claim 17 , wherein the supply of the solvent from the replenishing tank is controlled based on the amount of the mixed solvent and the composition of the mixed solvent detected by the detector. The apparatus according to any one of claims 15 to 18, further comprising a purifier for purifying the mixed solvent supplied to the adjustment tank. It further has an extraction channel for extracting the mixed solvent from the adjustment tank, and the control device further controls the extraction amount of the mixed solvent from the adjustment tank based on the detection result of the detector. An apparatus according to any one of claims 15 to 19 . The apparatus further comprises a removing device that removes any component in the mixed solvent of the extraction channel, and a return channel for returning the mixed solvent from which the optional component has been removed by the removing device to the adjustment tank. The apparatus of claim 20 . The has a regulating tank circulation passage for circulating the mixed solvent in addition, the detector from claim 15, characterized by detecting the composition of the mixed solvent of the circulation flow path 21 The apparatus as described in any one of.

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