JP2017205721A - Chromatographic separation method and device for separating multicomponent into three or more fraction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pseudo-moving bed type chromatographic separation method and device which can provide high separation performance with a small amount of eluate and adsorbent amount and can separate multicomponent into three or more fractions.SOLUTION: Stock solution and eluate are circulated through a packed bed made by endlessly connecting a plurality of unit packed columns in which selective adsorbent is packed. A first process of supplying at least one side of first eluate having weak desorption power and the stock solution into a circulation system and extracting a quantity equal to liquid quantity supplied from one portion of the packed column in which a component having a large moving speed is enriched, a second process of supplying second eluate having intermediate desorption power further from an upstream part and extracting the whole quantity flowing out from one portion of the packed column, a third process of supplying third eluate having strong desorption power further from upstream part and extracting a component having a small moving speed by the whole quantity flowing out from one portion of the packed column and a fourth process of circulating the liquid in a circulation system are combined. Supply positions of the stock solution and each eluate and an extraction position of each component are successively moved to the downstream side of the circulation system.SELECTED DRAWING: Figure 1

Description

  The present invention is a pseudo moving bed type chromatographic separation in which a large number of unit packed towers packed with an adsorbent having a selective adsorption capacity for a specific component of a stock solution containing three or more components are connected in series and endlessly. The present invention relates to a method and an apparatus for performing separation into three or more fractions.

  The simulated moving bed type chromatographic separation method and apparatus includes a large number of unit packed columns (hereinafter simply referred to as packed columns) packed with an adsorbent having a selective adsorption ability with respect to a specific component of two or more components contained in a stock solution. In addition, the undiluted solution and eluent are supplied to the endless packed bed by connecting the unit packed column at the most downstream and the unit packed column at the most upstream. In addition, a component (A component) having a high moving speed in the packed bed and a component (C component) having a low moving speed in the packed bed are extracted from different positions, and a stock solution supply position and an eluent supply position By moving the extraction position of the A component and the extraction position of the C component sequentially to the downstream side in the fluid circulation direction of the packed bed while maintaining a fixed positional relationship, the processing operation of the moving bed capable of continuously supplying the stock solution. It is well known that a separation method and apparatus for artificially realized.

  However, many simulated moving bed chromatographic separations are methods and devices that separate a stock solution containing two or more components into two fractions, but they are very specific to separate multiple components into three or more fractions. Simulated moving bed chromatographic separation has also been proposed in the past.

  For example, Patent Document 1 discloses a step of extracting a component having an intermediate affinity with an adsorbent (a component having an intermediate moving speed) while supplying an eluent and a stock solution to a series of improved simulated moving bed apparatuses, By repeating the process of extracting a component having a low affinity with the adsorbent (a component having a high moving speed) and a component having a high affinity (a component having a low moving speed) while supplying A method of continuous separation by operation is disclosed.

  Patent Document 2 discloses a unit packed column packed with a first adsorbent in which the moving speed of each component of the stock solution is A component> B component> C component, and a second that is A component> C component> B component. A separation method is disclosed in which unit packed columns packed with an adsorbent are alternately used as a plurality of packed columns connected endlessly.

  Furthermore, in Patent Document 3, after (two) components having a high moving speed in the adsorbent layer are developed with the first eluent having a weak desorption power, the moving speed is very low and the moving speed is very low. A method for separating three or more components is disclosed in which the components are desorbed with a second eluent having a strong desorption power.

JPB_1995024724 (Japanese Patent Publication No. 7-24724) JPB_0002740780 (Japanese Patent No. 2740780) Japanese Patent No. 4606092

  Since the conventional normal simulated moving bed system and the operation method described in Patent Document 1 basically use one type of eluent, the stock solution and the tailing containing a strongly adsorbing component (a phenomenon in which the concentration distribution becomes broad) In the case of supplying a stock solution containing components that are liable to cause water to the packed bed, it is necessary to use a large amount of eluent in order to desorb these components. By using a large amount of eluent, (1) the concentration cost of the extracted liquid is high, and (2) the differential pressure in the zone where the flow velocity is the highest (the zone between the eluent supply position and the slow component extraction position). In order to suppress the flow rate, it is necessary to reduce the overall flow rate, resulting in a decrease in production volume. (3) The number of unit packed columns between the eluent supply position and the slow component extraction position increases, and as a result, per adsorbent. There were drawbacks such as a drop in production.

  In addition, in the operation method described in Patent Document 2, the behavior of a component having a low transfer rate can be adjusted by using two types of adsorbents, but it is extremely difficult to select and combine the adsorbents, which is industrial. There is a problem that it is difficult to implement on a scale.

  Further, the separation method described in Patent Document 3 has a problem that when there are two or more components having strong adsorption power, each of the strong components cannot be separated and recovered.

  Furthermore, the simulated moving bed type chromatographic separation method that separates the multi-components described above into three or more fractions requires more columns and switching valves than the method that separates the fractions into two fractions. There is also a problem that the equipment cost becomes high.

  Therefore, the object of the present invention is to pay attention to various problems in the conventional separation method as described above, and to obtain high separation performance with a small amount of adsorbent, and to reduce the number of columns and valves as much as possible. It is an object of the present invention to provide a simulated moving bed type chromatographic separation method and apparatus for separating multiple components into three or more fractions, which can keep costs low.

In order to solve the above-mentioned problem, the simulated moving bed chromatography separation method according to the present invention includes a plurality of units filled with an adsorbent having a selective adsorption ability for a specific component of a stock solution containing three or more components. A stock solution containing three or more components with respect to a packed bed formed endlessly by connecting packed columns in series and connecting the unit packed column in the most downstream portion and the unit packed column in the most upstream portion, and 2 By circulating more than one kind of eluent through the packed bed, a circulation system that forms adsorption zones that are sequentially separated in order of affinity for the adsorbent,
At least one of the first eluent and the stock solution having the weakest desorption power is supplied into the circulation system, and the circulation system is introduced from one place of the packed column enriched with the component having the fastest moving speed contained in the stock solution in the circulation system. A first step of extracting an amount equal to the amount of liquid supplied in the interior;
The second eluent having an intermediate desorption power is further supplied from the upstream portion, and the total amount flowing out from the unit packed column upstream from the supply position of the first eluent as an intermediate component of the moving speed contained in the stock solution. A second step of extracting
The third eluent having a strong desorption power is further supplied from the upstream portion, and the component having a low moving speed contained in the stock solution is extracted from the unit packed column in the upstream portion from the second eluent supply position. 3 steps,
Separation is performed by combining the fourth step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components,
The stock solution supply position, the first eluent supply position, the second eluent supply position, the third eluent supply position, and the extraction position of each component are circulated in accordance with the movement of the adsorption zone in the circulation system. It consists of a method characterized by performing an operation of sequentially moving to the downstream side of the system.

  In this method, it is preferable to perform the first step, the second step, and the third step simultaneously. In the first step, it is preferable to supply only one of the first eluent and the stock solution or to supply them individually at different timings.

In addition, the pseudo-transfer waste type chromatographic separation apparatus according to the present invention includes a plurality of unit packed columns filled with an adsorbent having a selective adsorption ability for a specific component of a stock solution containing three or more components in series. A stock solution containing three or more components and two or more kinds of eluents are connected to the packed bed formed endlessly by connecting the unit packed column in the most downstream portion and the unit packed column in the most upstream portion. For the circulation system in which adsorption zones are formed in order of the affinity for the adsorbent,
At least one of the first eluent and the stock solution having the weakest desorption power is supplied into the circulation system, and the circulation system is introduced from one place of the packed column enriched with the component having the fastest moving speed contained in the stock solution in the circulation system. A first step of extracting an amount equal to the amount of liquid supplied in the interior;
The second eluent having an intermediate desorption power is further supplied from the upstream portion, and the total amount flowing out from the unit packed column in the upstream portion from the supply position of the first eluent as an intermediate component of the moving speed contained in the stock solution. A second step of extracting,
A third eluent having a strong desorption power is further supplied from the upstream portion, and a component having a slow moving speed contained in the stock solution is extracted from the unit packed column in the upstream portion from the supply position of the second eluent. Process,
Separation means for performing separation by combining the fourth step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components;
The stock solution supply position, the first eluent supply position, the second eluent supply position, the third eluent supply position, and the extraction position of each component are circulated in accordance with the movement of the adsorption zone in the circulation system. Operating means for performing an operation of sequentially moving to the downstream side of the system;
It consists of what is characterized by having.

  In this apparatus, it is preferable that the separation means comprises means for simultaneously performing the first step, the second step, and the third step. In the first step, the first eluent and the stock solution may be supplied at the same time, but it is also preferable to supply them individually at different timings.

  The simulated moving bed type chromatographic separation method and apparatus according to the present invention is described as a method and apparatus for separating three components into three fractions as the simplest example, but there are four components having different affinity for the adsorbent. It is possible to separate each of the four or more multi-components into respective fractions by using a plurality of four or more eluents having different desorption powers.

In other words, the simulated moving bed type chromatographic separation method according to the present invention also shows a method for generalizing the simulated moving bed of multi-component separation.
A plurality of unit packed columns packed with an adsorbent having a selective adsorption capacity for a specific component of a stock solution containing four or more components are connected in series, and a unit packed column in the most downstream portion and a unit in the most upstream portion By connecting the stock solution containing four or more components and three or more kinds of eluents to the packed bed formed endless by connecting packed towers, the affinity for the adsorbent can be increased. For a circulation system that forms adsorption zones that are sequentially separated,
At least one of the first eluent and the stock solution having the weakest desorption power is supplied into the circulation system, and the circulation system is introduced from one place of the packed column enriched with the component having the fastest moving speed contained in the stock solution in the circulation system. A first step of extracting an amount equal to the amount of liquid supplied in the interior;
The second eluent having an intermediate desorption power is further supplied from the upstream portion, and the total amount flowing out from the unit packed column upstream from the supply position of the first eluent as an intermediate component of the moving speed contained in the stock solution. A second step of extracting
The third eluent having a strong desorption power is further supplied from the upstream portion, and the component having a low moving speed contained in the stock solution is extracted from the unit packed column in the upstream portion from the second eluent supply position. 3 steps,
The fourth eluent with the strongest desorption power is further supplied from the upstream part, and the component with the slowest moving speed contained in the stock solution is discharged from the unit packed column upstream from the third eluent supply position. A fourth step to be extracted;
Separation is performed by combining the fifth step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components,
The adsorbing zone in the circulation system shows the stock solution supply position, the first eluent supply position, the second eluent supply position, the third eluent supply position, the fourth eluent supply position, and the extraction position of each component. A method characterized by performing an operation of sequentially moving to the downstream side of the circulation system in accordance with the movement,
It becomes.

  According to the simulated moving bed type chromatographic separation method and apparatus of the present invention, when there are a large number of components having different affinities for the adsorbent, a large number of eluents having different desorption powers are used depending on the degree of the different affinities. Thus, by efficiently desorbing, the amount of eluent can be reduced and the time required for separation can be shortened, so that high separation performance can be obtained with a small amount of adsorbent.

It is an instrumental system continuation diagram of the chromatographic separation apparatus according to one embodiment of the present invention, and in particular, is an equipment system diagram of the chromatographic separation apparatus when performing three-component separation. It is the schematic diagram which assumed density distribution in the unit packed bed to the process 1-1 to 1-3 in the driving | operation of Table 1 of this invention. It is the schematic diagram which assumed concentration distribution in the unit packed bed to the process 1-1 to 2-2 in the driving | operation of Table 2 of this invention.

Hereinafter, the present invention will be described in detail together with preferred embodiments with reference to the drawings.
FIG. 1 shows a simulated moving bed type chromatographic separation apparatus according to an embodiment of the present invention. In the present embodiment, the chromatographic separation apparatus 1 includes four unit packed towers 4 (No. 1 to No. 4 packed towers), and a raw liquid supplied from the raw liquid tank 2 in each packed tower 4. An adsorbent 5 having a selective adsorption ability with respect to a specific component among three or more components contained in 3 is packed. Each packed column 4 is connected by piping 6 from the outlet of each packed column 4 to the inlet of the adjacent packed column 4 and connected in series as a whole, and the last unit packed column 4 (for example, FIG. 1 is connected to the inlet of the foremost unit packed column 4 (for example, No. 1 packed column 4 in FIG. 1) by a pipe 6, so that all the unit packed columns 4 are connected. Are connected endlessly. Therefore, the packed bed in which all the unit packed towers 4 are connected endlessly is formed as a circulation system 7 in which the fluid can circulate in the direction of the arrow.

  Between each adjacent packed tower 4 in the circulation system 7, shut-off valves R1, R2, R3, R4 capable of blocking the packed towers are provided. Between each shut-off valve R1 to R4 and the outlet of each packed tower 4 located on the upstream side thereof, a fraction having a high moving speed in the packed bed (A fraction: a component having a weak affinity for the adsorbent) A fraction extraction valves A1, A2, A3, and A4 are provided for the purpose of extracting a fraction containing a large amount of A). Each A fraction extraction line 8 is merged into a single A fraction merging pipe 9. Similarly, C fraction extraction valves C1, C2, and C2 extraction valves C1, C2 for the purpose of extracting a fraction having a low moving speed in the packed bed (C fraction: a fraction containing a large amount of components having a strong affinity for the adsorbent). C3 and C4 are provided. Each C fraction extraction line 10 is merged and grouped into one C fraction merge pipe 11. Furthermore, in this embodiment, the B fraction extraction valve B1 for extracting the B fraction, which is a fraction in which the moving speed in the packed bed is an intermediate speed between the A fraction and the C fraction. , B2, B3, and B4 are provided. Each B fraction extraction line 22 is merged and grouped into one B fraction merge pipe 23. In addition, as a two-way valve for the purpose of extracting the entire amount in the circulation step, A1, A2, A3, and A4, which are the extraction valves for the A fraction, are also used as the circulating fluid extraction valves. Each circulation extraction line is also used as the A fraction extraction pipe 8, and each circulation extraction line is joined and the A fraction combination pipe 9 is also used as the circulating liquid junction pipe. In the combined use of the A fraction merging pipe 9, switching valves A0 and Z0 that can be opened and closed are installed in order to switch between the feeding of the A fraction to the tank and the return of the circulating fluid to the pump. ing. For feeding the A fraction, the switching valve Z0 is closed and the switching valve A0 is opened, and for returning the circulating fluid, the switching valve A0 is closed and the switching valve Z0 is opened. A circulation return pipe 13 used for returning the circulating liquid is connected to the switching valve Z0 and joined to the first eluent supply line 20 upstream of the first eluent supply pump PE1.

  The circulation system 7 can be supplied with the stock solution 3 and the first eluent 16 accommodated in the first eluent tank 15. In addition, the second eluent 25 stored in the second eluent tank 24 can be supplied to the circulation system 7 by the second eluent supply pump PE2, and the second eluent 25 stored in the third eluent tank 28 is supplied. Three eluents 29 can be supplied by the third eluent supply pump PE3. In this embodiment, the stock solution 3 is supplied via the stock solution supply line 17 by a stock solution supply pump PF capable of controlling the supply flow rate. The stock solution supply line 17 is branched to each stock solution branch supply line 18, and the stock solution can be supplied to the inlet side of each unit packed tower 4 via each stock solution branch supply line 18. Each stock solution branch supply line 18 is provided with open and close stock solution supply valves F1, F2, F3, and F4, and the stock solution is supplied to the corresponding unit packed tower via the opened stock solution supply valve line. The In addition, when it is desired to operate the stock solution supply pump PF even in a process in which the stock solution is not supplied for stable operation of the stock solution supply pump PF, a valve FO and a stock solution circulation line 19 are provided in front of the stock solution supply valves PF1 to PF4. It may be returned to the stock solution tank 2.

In this embodiment, the circulating fluid is withdrawn in any of A1 to A4, and the first eluent supply pump PE1 between the first eluent kunk 15 and the first eluent supply pump PE1 is passed through the circulation return pipe 13. The first eluent supply pump PE1 that joins the upstream portion and can control the supply flow rate is supplied again to the circulation system 7 via the first eluent supply line 20. The first eluent supply line 20 is branched to each first eluent branch supply line 21, and the first eluent can be supplied to the population side of each unit packed column 4 via each first eluent branch supply line 21. It has become. Each first eluent branch supply line 21 is provided with a first eluent supply valve Ea1, Ea2, Ea3, Ea4 that can be opened and closed, and can be handled via the opened first eluent supply valve line. The eluent is supplied to the unit packed column 4.

  In the present embodiment, the second eluent 25 is supplied via the second eluent supply line 26 by the second eluent supply pump PE2 capable of controlling the supply flow rate. The second eluent supply line 26 is branched to each second eluent branch supply line 27, and the second eluent can be supplied to the population side of each unit packed column 4 via each second eluent branch supply line 27. It has become. Each of the second eluent branch supply lines 27 is provided with a second eluent supply valve Eb1, Eb2, Eb3, Eb4 that can be opened and closed, and can be dealt with via the opened second eluent supply valve line. The eluent is supplied to the unit packed column 4.

  In the present embodiment, the third eluent 29 is supplied via the third eluent supply line 30 by the third eluent supply pump PE3 capable of controlling the supply flow rate. The third eluent supply line 30 is branched to each third eluent branch supply line 31, and the third eluent can be supplied to the inlet side of each unit packed column 4 via each third eluent branch supply line 31. It has become. Each of the third eluent branch supply lines 31 is provided with a third eluent supply valve Ec1, Ec2, Ec3, Ec4 that can be opened and closed. The eluent is supplied to the unit packed column 4.

  In the chromatographic separation apparatus 1 configured as described above, the separation process is performed as follows. First, each element of the simulated moving bed type chromatographic separation method and apparatus according to the present invention will be described.

(For each band)
The circulation system is divided into separate zones having different functions depending on the first eluent supply position, the second eluent supply position, the third eluent supply position, and the stock solution supply position.

(Band definition)
The first zone, the second eluent, includes the position where the component that moves slowly through the adsorbent layer from the third eluent supply position (hereinafter referred to as C component) and the position before the second eluent supply position. Supply of the first eluent to the second zone up to the position before the first eluent supply position, including the display position of the component (hereinafter referred to as B component) having an intermediate speed of moving the adsorbent layer from the supply position The third zone from the position to the front of the stock solution supply position, including the extraction position of the component that moves the adsorbent layer from the stock solution supply position (hereinafter referred to as component A) to the front of the third eluent supply position. The fourth band is assumed.

(Description of the fourth band and the third band)
In the fourth zone, the stock solution comes into contact with the adsorbent, the B component and the C component are adsorbed, and the A component is withdrawn from the unit packed tower in the downstream portion. There is a third zone upstream of the fourth zone, and the substitution of the A component carried to the third zone by the pseudo movement of the adsorbent from the adsorbent is performed. The first eluent is supplied to the unit packed column in the uppermost stream portion of the third zone, and the A component displaced by the first eluent is carried to the fourth zone in the downstream portion.

(Description of the second band)
There is a second zone upstream of the third zone. Here, the B component and the C component carried by the pseudo movement of the adsorbent, from the adsorbent by the second eluent of the B component. Is replaced. As the second eluent, one capable of eluting the B component from the adsorbent is selected. The substituted B component is shown from the unit packed tower in the most downstream part of the second zone.

(Description of the first band)
There is a first zone upstream of the second zone. Here, substitution of the C component carried to the first zone by the pseudo movement of the adsorbent from the adsorbent by the third eluent is performed. As the third eluent, the strongest eluent capable of forcibly eluting the C component from the adsorbent is selected. The substituted C component is shown from the unit packed tower in the most downstream part of the first zone.

(Simultaneous execution of the first step, the second step and the third step)
By performing the first step, the second step, and the third step at the same time, one cycle time can be shortened, and the stock solution processing amount per resin amount can be increased.

(Individual supply of stock solution and first eluent in the first step)
In the first step, by supplying either the first eluent or the stock solution, the concentration distribution of the stock solution supplied to the circulation system is difficult to spread in the circulation system, and thus high separation performance can be obtained. In the case where the A component and the B and C components can be easily separated, it is preferable to supply the first eluent and the stock solution at the same time because the time required for the separation can be shortened to increase the productivity.

(System circulation in the fourth step)
In the fourth step, since the liquid in the circulation system is circulated without supplying any stock solution and eluent, and showing off the separated components, the state of separation up to the desired purification conditions is accurate and easy. To improve separation efficiency.

In such a chromatographic separation according to the present invention, a component (C component) having a slow transfer rate in the circulation system.
By forcibly eluting the 3rd eluent, the amount of adsorbent in the first zone can be reduced compared to the conventional method, and the amount of eluent used for elution of the component (C component) having a slow moving speed can be reduced. It can be reduced, and the concentration cost of the C fraction can be reduced.

  This also applies to the separation of the B fraction, and the amount of adsorbent in the second zone is less than that of the conventional method by forcibly eluting the component (B component) with an intermediate transfer rate in the circulation system. In addition, it is possible to reduce the amount of the eluent used for elution of the component (B component) having an intermediate moving speed, and to reduce the concentration cost of the B fraction.

  In addition, in the conventional method, since regeneration is not performed, a problem such as a component having a strong adsorptive power contained in the undiluted solution is likely to be adsorbed and deteriorated by the adsorbent, and thus a step for removing such a component in advance is necessary. However, in the present invention, by using an eluent having a sufficiently strong desorption power as the third eluent, such a process can be eliminated, so that the process can be simplified.

  In addition, when a stock solution containing three or more components is separated into three or more fractions, the conventional method using one type of eluent is to form adsorption zones that are sequentially separated in order of affinity for the adsorbent. It was necessary to select only one eluent. In the present invention, the component having a low transfer rate uses the third eluent, and the component having the intermediate transfer rate is forcibly eluted using the second eluent. What is necessary is just to select an appropriate one to elute a component having a high speed, and a high separation performance can be obtained by selecting an appropriate eluent for the component to be separated according to the degree of affinity for the adsorbent. be able to.

  Further, in the conventional method, for example, the method of Japanese Patent No. 460692, the two-way valves Z1 to Z5 for the purpose of extracting the entire amount in the circulation process are provided. In this embodiment, the extraction valve for the A fraction is provided. By using A1 to A4, which are used for extracting the circulating fluid, the apparatus can be simplified.

  Therefore, a great effect of the present invention is that a high separation performance can be obtained with a small amount of adsorbent, and that it is simple and therefore can achieve an inexpensive simulated moving bed type chromatographic separation method and apparatus.

  Next, a more specific separation process of the method according to the present invention using the apparatus shown in FIG. 1 will be described. That is, in the chromatographic separation apparatus 1, a step of supplying the stock solution (hereinafter also referred to as “F” or “Feed”) and extracting the entire amount from the A fraction (hereinafter also simply referred to as “a”). The first eluent is supplied (hereinafter also referred to as Ea) and the entire amount is extracted from the A fraction extraction position, and the second eluent is supplied (hereinafter also referred to as Eb). ) And the B amount (hereinafter simply referred to as “b”) is extracted from the position, and the third eluent is supplied (hereinafter also referred to as “Ec”). It is possible to operate in five steps: a step of extracting from the position of extraction (hereinafter simply referred to as “c”), and a step of circulating the liquid in the system without any supply or extraction. And, the separation can be carried out by combining these steps.

(Fa process)
In the process of supplying the stock solution and extracting the entire amount from the A fraction extraction position, one of the stock solution supply valves is opened, and the stock solution is supplied into the circulation system 7 from the population side of the corresponding unit packed bed 4, Open the A fraction extraction valve A corresponding to the extraction position, close the shut-off valve immediately downstream of it, open the switching valve A0 through the A fraction extraction line 8 and the A fraction merging pipe 9, and the total amount of the A fraction Extract.

(Ea-a process)
In the step of supplying the first eluent and extracting the entire amount from the A fraction display position, one of the first eluent supply valves is opened, and the first eluent is circulated from the inlet side of the corresponding unit packed bed 4. Supply into the system 7, open the A fraction extraction valve A corresponding to the display position of the A fraction, close the shut-off valve immediately downstream thereof, and extract the A fraction extraction line 8 and the A fraction merging pipe 9 to open the switching valve A0 and extract the entire amount of the A fraction.

(Ea-Fa process)
In the step of simultaneously supplying the first eluent and the stock solution and withdrawing an amount equal to the amount of liquid supplied into the circulation system from the A fraction display position, any one of the first eluent supply valves is opened and The stock solution supply valve is opened, and the first eluent is supplied into the circulation system 7 from the population side of the corresponding unit packed bed 4 and simultaneously the stock solution is supplied into the circulation system 7 from the population side of the corresponding unit packed bed 4. Open the A fraction extraction valve A corresponding to the display position of the A fraction, close the shut-off valve immediately downstream thereof, and switch the switching valve A0 through the A fraction extraction line 8 and the A fraction junction pipe 9. Open and extract the amount equal to the amount of liquid supplied into the circulation system as the A fraction.

(Eb-b process)
In the step of supplying the second eluent and showing the entire amount from the B fraction extraction position, one of the second eluent supply valves is opened and the second eluent is circulated from the artificial side of the corresponding unit packed column 4. Supply into the system 7, open the B fraction extraction valve B corresponding to the extraction position of the B fraction, close the shutoff valve immediately downstream thereof, and extract the entire amount of the B fraction through the B fraction extraction line 22 .

(Ec-c process)
In the step of supplying the third eluent and extracting the entire amount from the C fraction extraction position, one of the third eluent supply valves is opened, and the third eluent is circulated from the artificial side of the corresponding unit packed column 4 to the circulation system 7. The C fraction extraction valve C corresponding to the extraction position of the C fraction is opened, the shut-off valve immediately downstream is closed, and the entire amount of the C fraction is extracted through the C fraction extraction line 10.

(Circulation process)
In the process of moving the liquid in the circulation system 7 without performing any supply or extraction (circulation process)
Open one of the A fraction extraction valves A, close the shut-off valve immediately downstream thereof, show the entire amount out of the circulation system 7 from the A fraction extraction line 8, and switch the switching valve Z0 through the A fraction junction pipe 9 The first eluent supply valve Ea corresponding to the supply position of the first eluent is supplied through the circulation return pipe 13 via the first eluent supply pump PE1.

  Each of the above steps can be performed simultaneously by supplying and extracting to separate unit packed beds.

Next, the opening / closing cycle of each valve shown in FIG. 1 will be described. An example of the operation is shown in Table 1, and a schematic diagram assuming the concentration distribution in the unit packed bed for each step is shown in FIG.
Table 1 shows the open / close control states of the valves, and the numbers in the table indicate the numbers of the respective valves (for example, 1 in the F section indicates 1 valve), and the valve in which the number is written. Indicates that the valve is opened. When the column is blank, the valve is closed. Further, in the terms of valves A, B, C, R and circulating fluid extraction valves (A1 to A4 and Z0), the numbers of valves for extracting the entire amount are shown. If the field is blank, the valve is not extracted. Furthermore, in the terms of the stock solution supply pump PF, the first eluent supply pump PE1, the second eluent supply pump PE2, and the third eluent supply pump PE3, the circle indicates the operating state. Indicates a stopped state. In Table 1, Steps 1-1 to 1-3 to Steps 4-1 to 4-3 show one cycle of the separation process in the chromatographic apparatus 1.

First, steps 1-1 to 1-3 in (Table 1) will be described.
(Regarding step 1-1 in Table 1)
In step 1-1, the stock solution supply valve F4 is opened to supply the stock solution into the circulation system 7, and the A fraction extraction valve A4 is opened, from which the entire amount of the A fraction is shown. At the same time, the second eluent supply valve Eb2 is opened to supply the second eluent into the circulation system 7, and the B fraction extraction valve B2 is opened, from which the entire amount of the B fraction is extracted. At the same time, the third eluent supply valve Ec1 is opened to supply the second eluent into the circulation system 7, and the C fraction extraction valve C1 is opened, from which the entire amount of the C fraction is extracted. Therefore, this step 1-1 supplies the stock solution as used in the present invention and supplies the first step and the second eluent while extracting the amount equal to the amount of the solution supplied into the circulation system from the A fraction extraction position and the total amount. This corresponds to the step of simultaneously supplying the second step of extracting the B from the B fraction extraction position and the third step of supplying the third eluent and extracting the entire amount from the C fraction extraction position.
This step 1-1 is shown in FIG. 2. N-cycle step 1-1 as a schematic diagram assuming the concentration distribution in the unit packed bed.

(Regarding step 1-2 in Table 1)
In step 1-2, the first eluent supply valve Ea3 is opened to supply the first eluent into the circulation system 7, and the A fraction extraction valve A4 is opened, from which the entire amount of the A fraction is extracted. At the same time, the second eluent supply valve Eb2 is opened to supply the second eluent into the circulation system 7, and the B fraction extraction valve B2 is opened, from which the entire amount of the B fraction is extracted. At the same time, the third eluent supply valve Ec1 is opened to supply the third eluent into the circulation system 7, and the C fraction extraction valve C1 is opened, from which the entire amount of the C fraction is extracted. Therefore, this step 1-2 supplies the first eluent as referred to in the present invention, and supplies the first eluent and the second eluent to extract from the A fraction extraction position an amount equal to the amount of liquid supplied into the circulation system. In addition, the second step and the third eluent for extracting the entire amount from the B fraction extraction position and the third step for extracting the entire amount from the C fraction extraction position are simultaneously performed. At this time, the stock solution is returned to the stock solution tank through the F0 valve.
This step 1-2 is shown in FIG. 2. N-cycle step 1-2 as a schematic diagram assuming the concentration distribution in the unit packed bed.

(Regarding step 1-3 in Table 1)
In step 1-3, the A fraction (circulating fluid) extraction valve A3 is opened, and the entire amount of circulating fluid is shown from the circulating system 7 there. The extracted circulating fluid is supplied again into the circulation system 7 from the first eluent supply valve Ea4 by the circulation pump. Therefore, this step 1-3 corresponds to the step (fourth step) in which the liquid in the circulation system is transferred without performing any supply, extraction, or shutoff in the present invention. At this time, the stock solution is returned to the stock solution tank through the F0 valve.
This step 1-3 is shown in FIG. 2. N-cycle step 1-3 as a schematic diagram assuming the concentration distribution in the unit packed bed.

(Valve switching)
In the series of steps 1-1 to 1-3 described above, the supply position of the stock solution, the first eluent, the second eluent, and the third eluent, the extraction positions of the A fraction, the B fraction, and the C fraction, and the blocking. The opening / closing position of the valve R and the position of the circulating fluid extraction valve in the circulation process are executed while maintaining a specific positional relationship, and when the series of steps 1-1 to 1-3 are completed, the specific positional relationship is maintained. However, the position of each control target valve is shifted to the downstream side, and the next series of steps 2-1 to 2-3 are executed. By performing this transition sequentially, a function equivalent to the operation operation of a known pseudo moving bed type chromatographic separation device can be achieved.

(About Step 2 and after in Table 1)
In Steps 2-1 to 2-3, Steps 3-1 to 3-3, and Steps 4-1 to 4-3, the above-described Step 1-1 is performed in a state where the positions of the valves are shifted one by one as described above. The same operation as in 1-3 is performed. When steps 1-1 to 4-3 are executed, one cycle of the separation process is completed.

Next, an example of another operation for the opening / closing cycle of each valve shown in FIG. 1 is shown in Table 2, and a schematic diagram assuming a concentration distribution in the unit packed bed for each step is shown in FIG.
Table 2 shows the open / close control states of the valves, and the numbers in the table indicate the numbers of the respective valves (for example, 1 in the F section indicates 1 valve), and the valve in which the number is written. Indicates that the valve is opened. When the column is blank, the valve is closed. Further, in the terms of valves A, B, C, R and circulating fluid extraction valves (A1 to A4 and Z0), the numbers of valves for extracting the entire amount are shown. If the field is blank, the valve is not extracted. Furthermore, in the terms of the stock solution supply pump PF, the first eluent supply pump PE1, the second eluent supply pump PE2, and the third eluent supply pump PE3, the circle indicates the operating state. Indicates a stopped state. In Table 2, Steps 1-1 to 1-2 to Steps 4-1 to 4-2 represent one cycle of the separation process in the chromatographic apparatus 1.

The steps 1-1 to 1-2 in Table 2 will be described.
(Regarding step 1-1 in Table 2)
In step 1-1, the first eluent supply valve Ea3 is opened and simultaneously the stock solution supply valve F4 is opened to supply the first eluent and the stock solution into the circulation system 7, and the A fraction extraction valve A4 is opened. To show the whole amount of A fraction. At the same time, the second eluent supply valve Eb2 is opened to supply the second eluent into the circulation system 7, and the B fraction extraction valve B2 is opened, from which the entire amount of the B fraction is extracted. At the same time, the third eluent supply valve Ec1 is opened to supply the second eluent into the circulation system 7, and the C fraction extraction valve C1 is opened, from which the entire amount of the C fraction is extracted. Accordingly, in this step 1-1, the first eluent and the stock solution referred to in the present invention are simultaneously supplied, and the same amount as the amount supplied to the circulation system is extracted from the A fraction extraction position, the second step elution. This corresponds to the step of simultaneously supplying the second step of supplying the liquid and extracting the entire amount from the B fraction extraction position and the third step of supplying the third eluent and extracting the entire amount from the C fraction extraction position.
This step 1-1 is shown in FIG. 3. N-cycle step 1-1 as a schematic diagram assuming the concentration distribution in the unit packed bed.

(Regarding step 1-2 in Table 2)
In step 1-2, the A fraction (circulating fluid) extraction valve A3 is opened, and the entire amount of circulating fluid is extracted from the circulation system 7 therefrom. The extracted circulating fluid is supplied again into the circulation system 7 from the first eluent supply valve Ea4 by the circulation pump. Therefore, this step 1-2 corresponds to the step (fourth step) in which the liquid in the circulation system is transferred without performing any supply, extraction, or shutoff in the present invention. At this time, the stock solution is returned to the stock solution tank through the F0 valve.
This step 1-2 is shown in FIG. 2. N-cycle step 1-2 as a schematic diagram assuming the concentration distribution in the unit packed bed.

(Valve switching)
In the series of steps 1-1 to 1-2 described above, the supply position of the stock solution, the first eluent, the second eluent, and the third eluent, the extraction positions of the A fraction, the B fraction, and the C fraction, and the blocking The opening / closing position of the valve R and the position of the circulating fluid unloading valve in the circulation step are executed while maintaining a certain specific positional relationship. When these series of steps 1-1 to 1-2 are completed, the specific positional relationship is established. While maintaining the above, the position of each control target valve is shifted to the downstream side, and the following series of steps 2-1 to 2-2 are executed. As a schematic diagram assuming the concentration distribution in the unit packed bed as the step 2-1, this is shown in FIG. 2. N-cycle. Step 2-1, and the step 2-2 is a model assuming the concentration distribution in the unit packed bed. This is shown in Figure 2. N-cycle. Step 2-2.
In this way, by sequentially shifting the position of each control target valve, a function equivalent to the operation operation of a known pseudo moving bed type chromatographic separation apparatus can be achieved.

(About Step 2 and after in Table 2)
In Steps 2-1 to 2-2, Steps 3-1 to 2-3, and Steps 4-1 to 4-2, the above-described Step 1-1 is performed in a state where the position of each valve is shifted one by one as described above. Execute the same operation as ~ 1-2. When steps 1-1 to 4-2 are executed, one cycle of separation processing is completed.

  Using the chromatographic separation apparatus 1 shown in FIG. 1, a stock solution consisting of 1 g / L of glucamic acid, 1 g / L of phenylalanine, and 1 g / L of arginine was converted to a sodium citrate buffer solution having a pH of 4.3 using a simulated moving bed type chromatographic separation apparatus. Was used as the first eluent, sodium citrate buffer at pH 6.5 was used as the second eluent, and 1/100 N NaOH aqueous solution was used as the third eluent. In the apparatus shown in FIG. 1, each unit packed bed 4 uses four cylindrical packed beds having an inner diameter of 0.9 cm and a height of 1 m, and each of the packed beds 4 has a sodium-type strongly acidic cation exchange resin “Amberlite”. "CR-1 3 1 0 (Dow Chemical Co.) was filled. The inside of each unit packed column 4 was kept at about 40 ° C. According to the operation method of Table 1 in this simulated moving bed, operation was performed at the time and pump flow rate for each step shown in Table 3, and the results shown in Table 4 were obtained.

  As is clear from Table 4, amino acids having different isoelectric points could be completely separated into three fractions using three small amounts of eluents having different pH. According to the simulated moving bed type chromatographic separation apparatus of the present invention, it is possible to obtain a high separation performance with a small amount of adsorbent, a small amount of eluent.

  The simulated moving bed type chromatographic separation method and apparatus according to the present invention can be applied to any stock solution that requires separation of three or more components. As an example, a natural product can be used as a raw material, and it can be purified into valuable products classified into vitamins, unsaturated fatty acids, and carotenoids using the simulated moving bed chromatography separation method according to the present invention.

1 Chromatographic separation device 2 Stock solution tank 3 Stock solution (F or Feed)
4 Unit packed bed 5 Adsorbent 6 Pipe 7 Circulation system 8 A fraction extraction line (also used as circulation extraction line)
9 A Fraction Merge Pipe 10 C Fraction Extraction Line 11 C Fraction Merge Pipe 13 Circulation Return Pipe 15 First Eluent Kunk 16 First Eluent (Ea)
17 Stock solution supply line 18 Stock solution branch supply line 19 Stock solution return line 20 First eluent supply line 21 First eluent branch supply line 22 B fraction extraction line 23 B fraction merge pipe 24 Second eluate tank 25 Second elution Liquid (Eb)
26 second eluent supply line 27 second eluent branch supply line 28 third eluent tank 29 third eluent (Ec)
30 3rd eluent supply line 31 3rd eluent branch supply line PE1 1st eluent supply pump PE2 2nd eluent supply pump PE3 3rd eluent supply pump PF Stock solution supply pumps A1, A2, A3, A4 A fraction Presentation valve (also used as circulating fluid extraction valve)
B1, B2, B3, B4 B fraction presentation valves C1, C2, C3, C4 C fraction presentation valves Ea1, Ea2, Ea3, Ea4 First eluent supply valves Eb1, Eb2, Eb3, Eb4 Second Eluent supply valve Ec1, Ec2, Ec3, Ec4 Third eluent supply valve F1, F2, F3, F4 Stock solution supply valve R1, R2, R3, R4 Shut-off valve F0 Stock solution return valve A0 A fraction switching valve Z0 Circulating fluid switching valve valve

Claims (6)

A plurality of unit packed towers packed with an adsorbent having a selective adsorption capacity for a specific component of a stock solution containing three or more components are connected in series, and the unit packed tower at the most downstream part and the unit at the most upstream part are connected. The affinity for the adsorbent can be increased by allowing a stock solution containing three or more components and two or more types of eluent to flow through the packed bed, which is formed endlessly by connecting packed columns. For a circulation system that forms adsorption zones that are sequentially separated,
At least one of the first eluent and the stock solution having the weakest desorption power is supplied into the circulation system, and the circulation system is introduced from one place of the packed column enriched with the component having the fastest moving speed contained in the stock solution in the circulation system. A first step of extracting an amount equal to the amount of liquid supplied in the interior;
The second eluent having an intermediate desorption power is further supplied from the upstream portion, and the total amount flowing out from the unit packed column upstream from the supply position of the first eluent as an intermediate component of the moving speed contained in the stock solution. A second step of extracting
The third eluent having a strong desorption power is further supplied from the upstream portion, and the component having a low moving speed contained in the stock solution is extracted from the unit packed column in the upstream portion from the second eluent supply position. 3 steps,
Separation is performed by combining the fourth step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components,
The stock solution supply position, the first eluent supply position, the second eluent supply position, the third eluent supply position, and the extraction position of each component are circulated in accordance with the movement of the adsorption zone in the circulation system. A pseudo moving bed type chromatographic separation method characterized by performing an operation of sequentially moving to the downstream side of the system.   The simulated moving bed chromatography separation method according to claim 1, wherein the first step, the second step, and the third step are performed simultaneously. A plurality of unit packed towers packed with an adsorbent having a selective adsorption capacity for a specific component of a stock solution containing three or more components are connected in series, and the unit packed tower at the most downstream part and the unit at the most upstream part are connected. The affinity for the adsorbent can be increased by allowing a stock solution containing three or more components and two or more types of eluent to flow through the packed bed, which is formed endlessly by connecting packed columns. For a circulation system that forms adsorption zones that are sequentially separated,
At least one of the first eluent and the stock solution having the weakest desorption power is supplied into the circulation system, and the circulation system is introduced from one place of the packed column enriched with the component having the fastest moving speed contained in the stock solution in the circulation system. A first step of extracting an amount equal to the amount of liquid supplied in the interior;
The second eluent having an intermediate desorption power is further supplied from the upstream portion, and the total amount flowing out from the unit packed column in the upstream portion from the supply position of the first eluent as an intermediate component of the moving speed contained in the stock solution. A second step of extracting,
A third eluent having a strong desorption power is further supplied from the upstream portion, and a component having a slow moving speed contained in the stock solution is extracted from the unit packed column in the upstream portion from the supply position of the second eluent. Process,
Separation means for performing separation by combining the fourth step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components;
The stock solution supply position, the first eluent supply position, the second eluent supply position, the third eluent supply position, and the extraction position of each component are circulated in accordance with the movement of the adsorption zone in the circulation system. Operating means for performing an operation of sequentially moving to the downstream side of the system;
A pseudo moving bed type chromatographic separation apparatus characterized by comprising:   The simulated moving bed type chromatographic separation apparatus according to claim 3, comprising means for simultaneously performing the first step, the second step and the third step. A plurality of unit packed columns packed with an adsorbent having a selective adsorption capacity for a specific component of a stock solution containing four or more components are connected in series, and a unit packed column in the most downstream portion and a unit in the most upstream portion By connecting the stock solution containing four or more components and three or more kinds of eluents to the packed bed formed endless by connecting packed towers, the affinity for the adsorbent can be increased. For a circulation system that forms adsorption zones that are sequentially separated,
At least one of the first eluent and the stock solution having the weakest desorption power is supplied into the circulation system, and the circulation system is introduced from one place of the packed column enriched with the component having the fastest moving speed contained in the stock solution in the circulation system. A first step of extracting an amount equal to the amount of liquid supplied in the interior;
The second eluent having an intermediate desorption power is further supplied from the upstream portion, and the total amount flowing out from the unit packed column upstream from the supply position of the first eluent as an intermediate component of the moving speed contained in the stock solution. A second step of extracting
The third eluent having a strong desorption power is further supplied from the upstream portion, and the component having a low moving speed contained in the stock solution is extracted from the unit packed column in the upstream portion from the second eluent supply position. 3 steps,
The fourth eluent with the strongest desorption power is further supplied from the upstream part, and the component with the slowest moving speed contained in the stock solution is discharged from the unit packed column upstream from the third eluent supply position. A fourth step to be extracted;
Separation is performed by combining the fifth step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components,
The adsorbing zone in the circulation system shows the stock solution supply position, the first eluent supply position, the second eluent supply position, the third eluent supply position, the fourth eluent supply position, and the extraction position of each component. A pseudo moving bed type chromatographic separation method comprising performing an operation of sequentially moving to the downstream side of the circulation system in accordance with the movement.   Production classified as valuable components, especially vitamins, unsaturated fatty acids, and carotenoids, characterized by being separated and purified using natural products as raw materials using the method of claim 1, claim 2 or claim 5 object.