KR100926150B1 - Chromatographic Method of Using Three-Zone Simulated Moving Bed Process Comprising Partial Recycle - Google Patents

Abstract

The present invention relates to a three-zone Mosidong bed process method using partial recirculation, and more particularly, after the eluent is injected into Zone 1 in one circulation of the mobile phase, the strong adsorptive power among the raw materials is determined by the eluent in Zone 1. Desorbed and discharged from the extract elution port (step 1); Desorbing of the raw material with weak adsorptive power by eluent in zone 2 (step 2); After injecting the raw material, the strong adsorptive material among the raw materials is adsorbed in the stationary phase in the zone 3 (step 3); Discharging the weak material of the raw material from the extraction residue elution port (step 4); And recirculating the remaining mobile phase discharged in step 4 to step 1 (step 5).

According to the present invention, the recycling process is added to the conventional three-zone Mosidong bed process, in terms of purity and concentration of the desired product when the front recycling process is applied, and the purity, yield and the yield of the desired product when the rear recycling process is applied. In terms of the degree of concentration, the results were improved compared to the conventional three-zone moxibustion process, and in both cases, the mobile phase consumption was reduced compared to the conventional three-zone superimposition bed process.

Three Zones Mosai Bed Process, Partial Recirculation, Exchange Time, Column, Stationary, Mobile Phase

Description

Chromatographic Method of Using Three-Zone Simulated Moving Bed Process Comprising Partial Recycle}

The present invention relates to a method of three-zone simulated moving bed process using partial recycle, wherein partial recycling is used to improve the efficiency of a conventional three-zone moxibustion process. Provides a three-zone mosidong bed process method.

The present invention relates to a three-zone capacitive bed process method using partial recycling, wherein the three-zone capacitive bed process is a kind of chromatography. Chromatography is a separation method that can separate similar components that make up a complex mixture.The mixed sample components are adsorbed, partitioned and ion exchanged between the stationary and mobile phases of the column. , Can be separated into a single component by the action, such as molecular size exclusion. Separation of the mixture using chromatography has the advantage of using a lower energy than other separation methods, and is particularly suitable for separation of heat-sensitive materials (medicine and herbal medicines, etc.), because the separation is mainly performed at room temperature.

Chromatography, which is mainly used in industrial sites, is batch chromatography. Batch chromatography involves filling the column with a stationary phase adsorbent, injecting the mobile phase into one inlet port, and passing it through the empty spaces of the stationary phase to one outlet port. The mixtures are separated using the time-dependent difference of the single components reaching the outlet port by interacting with the adsorbents and causing a difference in the rate of progression.

The batch chromatography has the advantage that the mixture can be easily separated using a simple device structure, but the composition of the liquid phase in the column is changed periodically with time, so inefficient use of the fixed phase in the column and a large amount of solvent are separated. If the dilution of the material to be separated and the affinity for the stationary phase is almost the same because it is used for performing, high purity separation is impossible and continuous operation is impossible.

Accordingly, it is necessary to develop continuous chromatography to overcome the disadvantages of batch chromatography and to apply commercially important separation processes. Such continuous chromatography is typical of a simulated moving bed process (SMB).

The mosai moving bed process is drawing attention as one of the continuous counter-current separation processes. The traditional four-zone Mosaidong bed process simulates the working principle of a true moving bed (TMB) process designed to overcome the shortcomings of batch processes or batch chromatography, enabling more efficient operation. to be. The batch process has the advantages of relatively low cost and easy installation. On the other hand, due to inefficient operation, the use of adsorbents and mobile phases is relatively low, and it is relatively difficult to simultaneously achieve the purity and yield of the desired product. The batch process is shown in FIG. 1 .

True moving bed process is a technology that increases the resolution by the continuous countercurrent of the adsorbent and the mobile phase flow. Compared to a batch process, a true mobile bed process is capable of achieving purity and yield simultaneously even in the partial separation of the desired product and impurities or another desired product, but the apparatus is relatively complex and the mechanical and physical friction, breakage and movement of the adsorbent are relatively complicated. Problems such as leaking of the phase are likely to occur. Schematic diagram of the true moving bed process are shown in Fig.

In general, the MOSI bed process subdivides the adsorbent of the TRM into 4 zones, and simulates the operation principle of the TRV process by moving the sample and mobile phase inlet ports and the extract and extract residues at regular exchange times. One process (see FIG. 3 ). The traditional four-zone mosidongbed process consists of a number of columns in each zone, each column filled with an adsorbent (or filler) that exhibits adequate resolution.

The three-zone Mosidong bed process removes Zone 4 from the traditional four-zone Mosidong bed process (see Figure 4 ). This is suitable for relatively high cases.

It also has the advantage that it can be easily applied in case of contamination of the extract by extraction residues, thus replacing the traditional four-zone mosidongbed process.

The three-zone mosaidong bed process as described above requires a relatively simple device equipment, and shows a relatively simple operation method compared to the four-zone mosaidong bed process. However, the mobile phase regeneration process, which was performed in Zone 4 of the traditional four-zone Mosaidong bed process, is omitted, resulting in high mobile phase consumption and low concentration of the extraction residue. This leads to an increase in the cost of operating the mosidong bed process and producing the desired product.

A method for solving inefficient mobile phase consumption, which is a disadvantage of the conventional three-zone mosi- cation bed process, has been introduced. Analysis of the concentration graph of the outlet port of zone 3 of a three-zone mosi- cation bed process to selectively recycle pure or slight extraction residues or mobile phases containing extracts. This method aims to overcome the disadvantages of the three-zone Mosidong bed process, which consumes relatively high mobile phase by dividing one exchange time of the Mosai bed process into three parts and recycling the middle part.

Accordingly, the present inventors have found a way to reduce the inefficient mobile phase consumption, which is a disadvantage of the conventional three-zone mosidong mobile bed process, increase the concentration of the extraction residue, as well as increase the concentration of the extraction residue, and complete the present invention. It was.

SUMMARY OF THE INVENTION An object of the present invention is to provide a three-zone mosi- cation bed process method using partial recirculation, which can improve the operation of the conventional three-zone mosi- cation bed process more efficiently by reducing the purity, concentration, and mobile phase consumption of the desired product. To provide.

In order to achieve the above object, the present invention provides a three-zone mosidong mobile bed process method using partial recycling.

According to the present invention, the three-zone mosi- cation bed process using partial recirculation adds a recirculation process to the conventional three-zone mosi- cation bed process, and in the case of applying the front part recycling process in terms of purity and concentration of the desired product, the rear part recycling process In this case, the result shows the improvement of the purity, yield and concentration of the target product compared to the conventional three-zone mosi- cation bed process, and the mobile phase consumption is reduced in comparison with the conventional three-zone mosi- cation bed process. Indicated.

In order to achieve the above object, the present invention is the step of injecting the eluent in the zone 1 in one circulation of the mobile phase, the strong adsorptive power of the raw material is desorbed by the eluent in the zone 1 and discharged from the extract elution port (step 1 ); Desorbing of the raw material with weak adsorptive power by eluent in zone 2 (step 2); After injecting the raw material, the strong adsorptive material among the raw materials is adsorbed in the stationary phase in the zone 3 (step 3); Discharging the weak material of the raw material from the extraction residue elution port (step 4); And recycling the remaining mobile phase discharged in step 4 to step 1 (step 5).

Steps 1 to 5 will be described in more detail step by step.

Step 1 according to the present invention is a step in which the eluent is injected into zone 1 in one circulation of the mobile phase, and the material having strong adsorptive power in the raw material is desorbed by the eluent in zone 1 and discharged from the extract elution port. In step 1, the strong adsorptive material injected from the raw material inlet port between the zone 2 and the zone 3 is separated from the weakly adsorbing material in the zone 2 and zone 3, and then desorbed in the zone 1 by the eluent, and then the extract elution port. Ejection from

Next, step 2 is a step in which the weaker adsorptive power of the raw material becomes the extraction residue, so that the extract elution port is desorbed by the eluent in the zone 2 so that contamination by the extraction residue does not occur. In the extract elution port, the material with strong adsorption power among the raw materials becomes the extract, so the zone flow rate in Zone 1 is selected in the range that can desorb the extract. Therefore, in step 1, the material having strong adsorption force is desorbed and extracted. In step 2, relatively weak adsorptive power of the raw material is desorbed.

Next, step 3 is a step of injecting the raw material, the material of the strong adsorptive power of the raw material is adsorbed in the stationary phase in zone 3. In Zone 3, the extract, which is a relatively strong adsorbing material among the raw materials, is adsorbed in the stationary phase, thereby preventing contamination of the extract from the extraction residue elution port and smoothing the separation of the extraction residue and the extract.

Next, step 4 is a step in which the weak adsorptive power of the raw material is discharged from the extraction residue elution port. In step 3, the most adsorptive material among the raw materials is adsorbed, so that the concentration of the extraction residue, which is a weak adsorptive force, is relatively high in the mobile phase, and the extraction residue may be separated from the extraction residue elution port.

Finally, step 5 is to recycle the remaining mobile phase discharged from step 4 to step 1. In the conventional three-zone mosai moving bed process, the mobile phase eluted at the extraction residue elution port was not recycled, so that the mobile phase was consumed. In the present invention, the mobile phase was minimized by adding a recycling step (see FIG. 6 ). ).

The present invention also provides a three-zone mosai moving bed process method comprising dividing one exchange time of a port within one circulation of the mobile phase and performing recirculation of step 5 only for the front or rear portion thereof.

Referring to FIG. 7 , when recycling the front part by dividing one exchange time, since all raw materials of Zone 3 are adsorbed in the fixed phase in the recycling step, the mobile phase recycled to the injecting eluent does not contain the raw materials. It is possible to reuse the pure mobile phase, and as shown in Table 2 , in terms of purity and concentration of the desired product, it can be seen that the result is superior to that of the conventional three-zone Mosidong mobile bed process.

If Referring to Figure 8, two minutes to a replacement time of recycling the case, the front part of recycle the back and similarly, being recycled to the step of the discharge mobile phase in zone 3 inject the eluent, can be reused in the mobile phase, and Table As shown in the result of 2 , it can be seen that the results are superior to the conventional three-zone mosidong mobile bed process in terms of purity, yield and concentration of the desired product.

Furthermore, although there is no particular limitation on the dichotomy ratio of the above-mentioned exchange time according to the present invention, preferably, the portion of the extraction residue is eluted from the beginning of the exchange time based on the concentration graph of the extraction residue elution port and thereafter. It provides a three-zone mosai moving bed process, characterized in that it is divided into two parts at the end of the exchange time.

The bipartite ratio of said one exchange time is determined by the following formula.

Where x _split is the bipartite ratio, L is the length of the column, a _s is the moving speed of the extraction residue in the zone, and t is the exchange time.

In this case the dichotomy ratio is determined from 0 to 1. Depending on the ratio, it is possible to determine the recycling at the beginning or at the end of an exchange time.

Hereinafter, the present invention will be described in more detail with reference to Examples and the accompanying drawings. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

< Example  1> Front  Zone 3 with Recycling Law Mosai East Floor  Separation using the process method

Zone 3 Mosai East Floor  The composition of the process

The process equipment of the three-zone Mosidong bed process is a three-zone system in which the column containing the adsorbent is connected in series. Each zone consists of one column, and the flow rates of the two inlet ports (sample and mobile phase inlet ports) and the two outlet ports (extract and extract residues) are the zone flow rates for each zone. Determined. The flow rate of each zone and the exchange time of each inlet port and outlet port are designed for separation according to the adsorption formula of two materials to be separated.

A mixture of quinidine and cinchonidine was separated by a three-zone mosi- cation bed process in which front recirculation was applied using the above-described process apparatus.

Process conditions for performing the process are shown in Table 1 below.

Concentration of raw material (g / L) Quinidine 0.10 Ciconidine 0.10 Flow rate (ml / min) Raw material 1.000 Eluent 4.436 Extract 1.855 Extraction residue 3.581 Circulation rate Front recirculation 0.60 Back recirculation 0.40               Exchange time (min) 8.275

The process conditions are performed by fixing the concentration and the flow rate of the raw material, the dividing ratio represents the ratio of the front part to the rear part of the exchange time when one exchange time is 1.0. Results regarding the process conditions are as shown in FIG. 5 , and the process conditions are determined by applying a triangular theory well known in the art. [(a) Marco mazzotti Journal of Chromatography A. 2006 , 1126, 311-322 (b) Marco mazzotti; Giuseppe storti; Massimo morbidelli Journal of Chromatography A. 1997 , 769, 3-24.]

The adsorption equation of the two materials to be separated has a competitive Langeru adsorption model, and the results are shown in FIGS. 9 and 10 .

Figure 9 shows the process concentration distribution diagram, the right dotted line is the injection port of the raw material, the left dotted line is the extract elution port, the column length 0 cm is the port for injecting the eluent, and the column length is 30 cm The extraction residue elution port is shown. Also, a column length of 0 to 10 cm corresponds to Zone 1, a part of 10 to 20 cm corresponds to Zone 2, a part of 20 to 30 cm corresponds to Zone 3, and a red line is quinidine Concentration graph, the blue line is the concentration graph of the remaining residues of cicononidine, 11 and 13 are also the same as the description of FIG. 9 .

Referring to Figure 9 according to the flow of the mobile phase from the first half to the middle half, the end of the exchange time, the strong adsorption force, that is, the extract quinidine in zone 1 is desorbed in zone 1, the weak adsorption force in zone 2, that is, It can be seen that the extraction residue, ciconidine, is desorbed, and in zone 3, quinidine is adsorbed on the stationary phase, resulting in a relatively reduced concentration of quinidine in the mobile phase in the zone.

On the other hand, Figure 9 is the same as Figure 13 , which is the internal concentration distribution of the three-zone Mosidong bed process without recirculation, which is because the internal concentration distribution in the column is not recycled because the raw material is not included in the mobile phase to be recycled Same thing.

10 is a graph showing the concentration of the extraction residue, the dotted line is a graph showing the flow rate of the extraction residue in the extraction residue outlet port, the red line is the concentration graph of the quinidine extract, the blue line is the extract residue cicononidine Is a concentration graph, and FIG. 12 is also the same as the description of FIG. 10 .

Referring to FIG. 10 , at the beginning of one exchange time, only the mobile phase containing no raw material was recycled to Zone 1, and the residue was separated from the rear portion, so that the concentration of the residue was compared with that of no recycle (Comparative Example 1). It can be seen that is greatly improved (see Table 2 ).

< Example  2> Zone 3 with rear recycle method Mosai East Floor  Separation using the process method

In Example 2, a mixture of quinidine and cinchonidine was separated by applying a rearward recycle to the three-zone mosaidong bed process. Process conditions for the performance of the process is shown in Table 1 above, the adsorption equation of the two materials to be separated has a competitive Langeru adsorption model, the results are shown in Figures 11 and 12 .

FIG. 11 shows the concentration distribution map in the process. Referring to FIG. 11 , it can be seen that, unlike FIG. 9 , the concentrations of quinidine and ciconidine are high in the mobile phase injected from the eluent inlet port in the second half of the exchange time. This is because a large amount of raw materials quinidine and ciconidine are contained in the mobile phase that is recycled by recycling the latter part of the exchange time.

12 is a graph showing the concentration of the extraction residue. Referring to FIG. 12 , in contrast to the three-zone Mosai mobile bed process using the front recycle, the mobile phase is recycled at the rear in the three-zone Mosai mobile bed process to which the rear recycle is applied, and the concentration of the extract is shown. It can be seen that the concentration of the extraction residue was higher than without recycle (Comparative Example 1) because the separation of the extraction residue was separated at the beginning of the exchange time as low as (see Table 2 ).

< Comparative example  1> 3 zones Mosai East Floor  Separation using the process method

In the comparative example, a mixture of quinidine and cinchonidine was separated by a conventional three-zone mosaidong bed process. The process conditions are adsorption of the two materials to be separated the same as the above Table 1, may have a competitive Lang Muir adsorption model, the result is as shown in Fig. 14 and Fig.

FIG. 13 shows the concentration distribution diagram in the process. Referring to FIG. 13 , a substance having a high adsorption force, that is, an extract, quinidine is desorbed in zone 1 according to the flow of the mobile phase from the first half to the middle half and the end half of the exchange time. In Zone 2, the weak adsorption material, that is, the extraction residue, ciconidine, is desorbed, and in Zone 3, quinidine is adsorbed on the stationary phase and the concentration of quinidine is relatively decreased in the mobile phase in the zone.

These results are the same as the three-zone MosiC bed process with recirculation, but the consumption of mobile phase is higher and inferior in terms of purity and concentration of the target product compared to the three-zone MoCi bed process with recirculation.

Figure 14 is a graph of the concentration of the extract and extraction residue outlet port according to the number of exchange in the three-zone Mosidong bed process without recirculation can be seen that the concentration of the extract and the extraction residue increases as the number of exchange is increased.

This result is due to the continual steady state of the reciprocating layer process as the process of injection of raw materials and concentration distribution in the process increases as the number of port exchanges increases.

However, when the concentration distribution in the parent interphase process reaches a threshold, no further increase in concentration distribution occurs. Referring to Figure 14 it can be seen that the steady state is reached when the exchange occurs about 5 times in the case of ciconidine, about 10 times in the case of quinidine.

According to Example 1, Example 2, and Comparative Example 1, quinidine and cincony, respectively, through the three-zone mosi- cation bed process method, the front-recirculation three-zone mosi- cation bed process method, and the rear-recirculation three-zone mosi- cation bed process method. The mixture of dines was separated from the mobile phase in terms of purity and concentration of the desired product if the front recycle process was applied, and in terms of purity, yield and concentration of the target product, and both in the case of the latter recycle process. Consumption showed improved results compared to the conventional three-zone Mosidong bed process, the results are shown in Table 2 .

However, DC in Table 2 is an abbreviation of Desorbent Consumption and indicates mobile phase consumption. * DC is a three-zone Mosai bed process without recirculation compared to the four-zone Mosai bed process, the front section three-section Mosai bed layer process, and the rear section recycle It shows the ratio of mobile phase consumption in the three-zone Mosai mobile bed process.

 fair result DC (ml / cycle) ＊ DC (%) Purity (%) Yield (%) Concentration (-) Extraction residue extract Extraction residue extract Extraction residue extract 4 district station 98.00 99.18 99.19 97.97 0.775 0.527 17.675 100 Example 1 98.36 99.59 99.59 98.33 0.696 0.528 18.928 107 Example 2 100.00 99.58 99.59 99.99 0.464 0.528 24.855 141 Comparative Example 1 98.36 99.59 99.60 98.33 0.278 0.528 36.708 208

Referring to Table 2 , the concentration of the extraction residue in the three-zone mosaidong bed process method (Example 1) to which the front recycle was applied was increased 0.418 compared with the conventional three-zone mosaidong bed process method (Comparative Example 1), In the three-zone Mosai copper bed process method (Example 2) to which the rear recycle was applied, the purity of the extract residue was 1.64%, the yield of the extract was 1.66%, and the concentration was increased by 0.186, respectively. In addition, the mobile phase consumption was reduced by 17.78 ml / cycle in Example 1, 11.853 ml / cycle in Example 2, respectively.

1 is a schematic diagram showing an apparatus and a separation process of a batch process,

2 is a schematic diagram showing the principle of operation of the true mobile bed process, concentration distribution of extracts and extract residues,

FIG. 3 is a schematic diagram of a four zone mosaidongbed process in a traditional manner with two columns per zone,

FIG. 4 is a schematic diagram of a three zone mosaidong bed process with zone 4 removed from the four zone mosai copper bed process,

FIG. 5 is a graph showing operating conditions determined using a triangular theory when two materials to be separated have a nonlinear isothermal adsorption equilibrium (Comparative Examples and Examples 1 and 2).

FIG. 6 is a schematic diagram of a three zone mosaidongbed process with partial recycle;

7 is a schematic diagram showing a front partial recycling method of a certain ratio of the exchange time in the three-zone Mosaidong bed process,

FIG. 8 is a schematic diagram showing a rear partial recycling method of a certain ratio of the exchange time in a three-zone mosai moving bed process,

FIG. 9 is a graph showing the internal concentration distribution of a three-zone Mosaidong bed process with frontal recycle as a result of Example 1,

FIG. 10 is a graph of the concentration of the extraction residue of the three-zone Mosidong bed process with frontal recycle as a result of Example 1,

FIG. 11 is a graph showing the internal concentration distribution of a three-zone Mosaidong bed process with back recycle as a result of Example 2,

FIG. 12 is a graph of the concentration of the extraction residue of a three-zone Mosidong bed process with back recycle as a result of Example 2,

FIG. 13 is a graph showing an internal concentration profile during one exchange time in a conventional three-zone mosiphonic bed process as a result of Comparative Example 1.

14 is a graph of the concentration of the extract and the extraction residue outlet port according to the number of exchange in the conventional three-zone mosidong bed process as a result of Comparative Example 1.

Claims (3)

In one cycle of the mobile phase, the step of injecting the eluent in the zone 1, the strong adsorptive power of the raw material is desorbed by the eluent in the zone 1 and discharged from the extract elution port (step 1); Desorbing of the raw material with weak adsorptive power by eluent in zone 2 (step 2); After injecting the raw material, the strong adsorptive material among the raw materials is adsorbed in the stationary phase in the zone 3 (step 3); Blocking the recirculation loop so that the material having weak adsorptive power is discharged from the extraction residue elution port (step 4); And Recirculating the loop after the extraction residue discharged in step 4, the mobile phase of the eluent is recycled to step 1 through the recycle loop (step 5) Chromatography method using a three-zone mosaidong bed process comprising a. The method of claim 1, wherein the recycling of step 5 is performed by dividing one exchange time of a port in one cycle of a mobile phase and selectively performing the front or rear portion thereof. Photography method. The ratio of the front part and the rear part of the one exchange time is determined by the beginning of the exchange time based on the concentration graph of the extraction residue elution port, and the portion of the extraction residue eluted thereafter and the end of the exchange time thereafter. Chromatography method using a three-zone mosaidong bed process, characterized in that divided into two parts.

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