Simulated moving bed separation method for chiral drug resolution

Abstract

The invention discloses a simulated moving bed separation method for chiral drug resolution, and belongs to the field of chemical separation. According to the method, a three-column intermittent simulated moving bed is adopted, and three sub-steps are executed in each switching period: (1) internal circulation flow of a closed loop formed by three chromatographic columns is provided; (2) opening an eluent pump, providing flow along the direction of the first chromatographic column, the second chromatographic column and the third chromatographic column, and collecting light components; (3) opening an eluent pump, providing flow through the first chromatographic column, and collecting heavy components; the feedstock pump is turned on, providing flow through the third chromatographic column, and collecting light components. Then, the port is switched along the flow direction, and the next switching period is started until the separation task is completed. The method provided by the invention can be used for splitting various chiral drugs, and effectively improves the equipment handling capacity of the stationary phase per unit mass on the premise of ensuring the product purity, and the solvent consumption is equivalent or lower; the system flow path is simpler, and the process is more stable; and the overall cost of equipment is greatly saved.

Description

Technical Field

[0001] This invention relates to the separation of optically active organic compounds, and more particularly to a simulated moving bed separation method for the resolution of chiral drugs. Background Technology

[0002] Chiral drugs are drugs that possess chiral characteristics. In terms of physicochemical properties, the enantiomers of chiral drugs are essentially the same, differing only in optical rotation, and are thus named dextrorotatory, levorotatory, and racemic, respectively. Due to significant differences in pharmacodynamics and pharmacokinetics among the enantiomers of chiral drugs, it is necessary to develop single-configuration isomers for drug safety and regulatory requirements. Currently, the separation and purification of single configurations of chiral drugs are generally achieved through chiral synthesis or chiral resolution. Resolution is the classic method for preparing chiral drugs; currently, over 65% of non-natural enantiomers are manufactured using chiral resolution methods. Chiral resolution methods mainly include crystallization, chromatography, membrane chromatography, and chiral extraction. Among these, chromatography is widely used due to its rapid and efficient resolution, and the high purity of the obtained enantiomers. In particular, simulated moving bed chromatography (SMB) technology is currently the mainstream method for the industrial-scale resolution of chiral drugs. Its core advantage is that it enables continuous operation, significantly improving yield and reducing production costs.

[0003] The basic principle of the SMB process is to simulate the countercurrent movement of the stationary and mobile phases through the connection of multiple chromatographic columns and the periodic switching of valves, achieving continuous feed and continuous discharge. The SMB process is implemented on an SMB system, which consists of several chromatographic columns connected in series. A typical two-component separation SMB system has two material outlets: an extraction port and a raffinate port, used to collect strongly adsorbed components (heavy components) and weakly adsorbed components (light components), respectively; and two material inlets: a feed port and an elution port, connected to the raw material to be separated and the eluent, respectively. These inlets and outlets divide the chromatographic column into four operating zones, conventionally referred to as zones I to IV. Each operating zone plays a different role and function in the separation process. Counting along the mobile phase flow direction from the elution port, Zone I, located between the elution port and the extraction port, primarily desorbs heavy components and regenerates the stationary phase. The extraction port, the main outlet for heavy components, is located at the end of this zone. Zone II, located between the extraction port and the feed port, desorbs light components and purifies heavy components. Zone III, located between the feed port and the raffinate port, primarily adsorbs heavy components, separating them from light components. The raffinate port, located at the end of this zone, is mainly used to output light components. Zone IV, located between the raffinate port and the elution port, adsorbs light components and regenerates the mobile phase. The mobile phase flow direction within the SMB is I-II-III-IV-I. Periodically switching the inlet and outlet positions along the mobile phase flow direction creates counter-current movement of the mobile and stationary phases relative to the inlet and outlet ports, enabling continuous operation of the adsorption process and achieving product separation and collection.

[0004] In standard continuously operating SMB processes, the gap between the decisive concentration fronts (i.e., the leading edge of component A and the trailing edge of component B) is narrow, and these edges are closer to the product outlet, leading to dispersion and a decrease in purity. To counteract the negative effects of dispersion, it is necessary to better simulate the countercurrent motion of the stationary phase, i.e., using more columns in each zone. Typical SMB systems employ a 4-zone, 8-column or 6-column configuration, with each column requiring stationary phase, resulting in a large total stationary phase consumption. Chiral stationary phases (CSPs) are typically composed of polysaccharide derivatives (such as cellulose or amylose), cyclodextrins, proteins, or Pirkle-type brush materials. These materials are complex to synthesize and require high purity, making them expensive and significantly more costly than conventional achiral stationary phases. The cost of a large amount of expensive stationary phase material often accounts for more than half of the total equipment cost, significantly increasing equipment costs, which is one of the main drawbacks of typical SMB systems.

[0005] To address this challenge, various improved SMB modes have been developed, such as those that reduce the required stationary phase while maintaining high product purity through more efficient operating modes. Among these, the Intermittent Simulated Moving Bed (ISMB) is an improved SMB based on intermittent feed and discharge operation. A typical ISMB system consists of four columns, divided into four functional zones by two inlets and two outlets. Each zone contains one column. The feed and eluent are introduced through the inlets (feed and elution ports), and the two products are produced from the outlets (raffinate and extract ports). The ISMB mode divides the switching time into two sub-steps, corresponding to two flow modes. In the first sub-step, zone IV is stopped (no mobile phase flows in zone IV), while the remaining functional zones and ports operate normally for feed and discharge. In the second sub-step, all inlets and outlets are closed, and the mobile phase circulates along the column sequence, redistributing the concentration. In this step, the flow rates of all four functional zones are the same. After the second sub-step is completed, the port is switched along the fluid flow direction, and the first and second sub-steps are repeated. Studies have shown that, while meeting the same high purity specifications, the productivity of ISMB in the 1-1-1-1 configuration is twice that of standard SMB in the 1-2-2-1 configuration.

[0006] Although ISMB has proven to be significantly superior to standard SMB, further research on this promising process has shown that approximately one-quarter of the stationary phase is not actually actively used for separation. In response, a three-column, two-step improved ISMB mode (referred to as 3C-ISMB) has been proposed. Compared to the aforementioned four-column, two-step standard ISMB process, the 3C-ISMB mode eliminates the fourth column in the first sub-step where no mobile phase flows. The 3C-ISMB system consists of three columns, each segment containing one column. Zone I is located between the elution port and the extraction port, Zone II between the extraction port and the feed port, and Zone III between the feed port and the raffinate port. Similarly, the switching time is divided into two sub-steps: in the first sub-step, Zones I and III are disconnected, and all functional zones and ports operate normally for feeding and effluent; the second sub-step is similar to ISMB, with all input and output ports closed, and fluid circulates only within the column sequence, i.e., no inlet or outlet stream is supplied to the system. After the second sub-step, the inlet and outlet ports are switched along the fluid flow direction, and the first and second sub-steps are repeated. It is evident that the fundamental difference between 3C-ISMB and typical ISMB lies in the absence of a fourth column for solvent regeneration. The stream containing the weakly retained component is directly recycled from the third zone back to the first zone. In typical ISMB, the first zone is almost completely regenerated by the end of the first sub-step, allowing it to be used in the second sub-step to adsorb the weakly retained component. However, during the second sub-step of 3C-ISMB, its first zone performs the function of the fourth zone in the first sub-step of typical ISMB. Studies have shown that the 3C-ISMB process can operate under conditions identical to the corresponding ISMB process (in terms of the ratio of mobile phase to stationary phase flow rate per column, or in terms of flow rate, switching time, and step ratio) within certain limits, achieving up to 60% higher productivity than typical ISMB without a significant increase in solvent consumption.

[0007] It is evident that the 3C-ISMB has achieved a significant improvement in stationary phase utilization efficiency through its three-column configuration. Therefore, whether it is possible to further improve equipment productivity while maintaining a simplified three-column configuration remains a key focus.

[0008] In SMB chromatographic separation methods, key separation performance indicators include productivity, solvent consumption, and target component purity. For chiral drug separation using simulated moving bed chromatography, the stationary phases used are expensive and typically consist of chiral packing materials with particle sizes below 20 micrometers, making the entire system a high-pressure system. The operating flow rate is limited by the total pressure drop. Furthermore, chiral drugs themselves exhibit low selectivity and high adsorption strength. These factors collectively determine the specificities of the process design. Specifically, since stationary phase cost is dominant, productivity indicators need to be further weighted by the volume or mass of the stationary phase, i.e., the throughput per unit mass of stationary phase is the core metric. In contrast, the energy consumption required for solvent removal accounts for a relatively small percentage of the total cost. Therefore, maximizing the throughput per unit mass of stationary phase while ensuring product purity is the primary objective of the optimized design for SMB separation of chiral drugs.

[0009] SMB chromatography involves complex mechanisms, numerous operating parameters with strong coupling relationships, and conflicting influences on different performance parameters. This poses significant challenges to optimizing the separation process and evaluating its performance. While experimental methods can explore the operating parameters of SMB separation, this approach is time-consuming, incurs high material and labor costs, and struggles to identify the true optimal operating point, failing to fully utilize the equipment's separation efficiency. Therefore, researchers typically employ precise modeling and simulation to study SMB separation processes, enabling more efficient optimization and rapid performance evaluation. Numerous studies have demonstrated that chromatographic process models achieve very high accuracy with minimal scale-up effects.

[0010] In a typical SMB (Sequencing Block) system, there are five independent operating parameters: switching time and flow rates corresponding to the four zones. For ease of theoretical analysis and comparison, these parameters are usually converted into dimensionless liquid-to-solid flow ratios (m-values) for each column, along with an additional constraint. For chiral separation processes, this additional constraint is typically the maximum system pressure drop (a constant). Optimization of typical SMB separation processes is usually based on the "triangle theory" (also known as the "equilibrium theory"), seeking the optimal m-values ​​under complete separation conditions within an ideal chromatographic model framework. However, ideal chromatographic models assume an infinite number of plates, resulting in low accuracy. To improve simulation accuracy, some researchers conduct constrained optimization based on the triangle theory, i.e., fixing some operating parameters and adjusting others to find optimal operating conditions. Specifically, a four-column SMB system has four independent m-values, corresponding to the liquid-to-solid flow ratios m1, m2, m3, and m4 of the four columns. When equipment yield and purity are the primary design objectives, m1 and m4 are generally fixed at safe values, and a more precise chromatographic model is used to scan the (m2-m3) plane to find the optimal operating point. Typical ISMB and the previously mentioned 3C-ISMB modes both employ the aforementioned constrained optimization strategies to optimize process operating parameters and evaluate separation performance under optimized operating parameters. Furthermore, some researchers have adopted more complex and comprehensive non-constrained optimization strategies in typical SMB process development. For example, they use precise equilibrium diffusion chromatography models for simulation, while simultaneously employing genetic algorithms for global optimization. By adjusting all m values, they seek non-dominated solutions between two or more objectives within a complex multi-dimensional parameter space; this is known as multi-objective optimization (MOO). Summary of the Invention

[0011] This invention proposes a simulated moving bed separation method for chiral drug resolution. It employs a three-column intermittent simulated moving bed, executing three sub-steps within each switching cycle. This method significantly improves overall equipment yield while ensuring product purity. In particular, compared to the standard 3C-ISMB mode, this invention's separation method can also significantly increase the equipment throughput per unit mass of stationary phase, with comparable or lower solvent consumption. Simultaneously, the flow path of the mobile phase within the system is simpler, the process is more stable, and the overall equipment cost is lower.

[0012] To achieve the above objectives, the present invention adopts the following technical solution:

[0013] A simulated moving bed separation method for chiral drug resolution employs a three-column simulated moving bed system. The inlet and outlet positions are periodically switched along the flow direction of the mobile phase to simulate countercurrent flow between the stationary and mobile phases, achieving component separation. The method comprises the following three sub-steps executed in each switching cycle:

[0014] First sub-step: Close all external outlets and inlets, connect all three chromatographic columns (keeping any two columns connected to form a closed loop), turn on the internal circulation pump on the closed loop to provide internal circulation flow (so that the fluid circulates in the closed loop at an internal flow rate); the operation time of this step is set as the first operation time.

[0015] Second sub-step: Connect the first, second, and third chromatographic columns sequentially, while disconnecting the first and third columns; turn on the eluent pump to provide flow in the direction of first column → second column → third column, and collect the light component product at the light component product outlet; the operation time of this step is set as the second operation time.

[0016] Third sub-step: Turn on the eluent pump to provide flow from the external eluent inlet to the first column, and collect the heavy component product at the heavy component product outlet; turn on the feed pump to provide flow from the external feed inlet to the third column, and collect the light component product at the light component product outlet; disconnect the second column from both the first and third columns, and there is no flow in the second column; the operation time for this step is set as the third operation time.

[0017] In some specific embodiments of the present invention, the three-column simulated moving bed system includes three chromatographic columns, a feed pump, an eluent pump, an internal circulation pump, a feed inlet, an eluent inlet, a heavy component product outlet, a light component product outlet, and several valves. The first chromatographic column is located between the eluent inlet and the heavy component outlet, the second chromatographic column is located between the heavy component product outlet and the feed inlet, and the third chromatographic column is located between the feed inlet and the light component product outlet. The three chromatographic columns are connected in series and form a closed loop. In addition, an extra valve is provided at the outlet of any one of the chromatographic columns and connected to the inlet of the adjacent downstream chromatographic column via the internal circulation pump.

[0018] In some specific embodiments of the present invention, after the third sub-step is completed, the positions of all external inlets and outlets are switched forward by one column according to the flow direction of the mobile phase, and a new switching cycle is started on this basis. The above three sub-steps are executed again, and the switching of each inlet and outlet and the execution of the three sub-steps are repeated until the separation task is completed.

[0019] In some specific examples of the present invention, in each of the sub-steps, when there is flow between two adjacent chromatographic columns, the flow direction is first chromatographic column → second chromatographic column, second chromatographic column → third chromatographic column, and third chromatographic column → first chromatographic column.

[0020] In some specific embodiments of the present invention, the chromatographic column is packed with a coated or bonded chiral stationary phase, wherein the particle size of the chiral stationary phase is 5~20 μm.

[0021] In some specific examples of the present invention, the adsorption of both components in the chiral drug conforms to the Langmuir characteristics.

[0022] In some specific embodiments of the present invention, the adsorption of the light component in the chiral drug conforms to the Langmuir characteristic, and the adsorption of the heavy component conforms to the anti-Langmuir characteristic.

[0023] In some specific embodiments of the present invention, the adsorption of the light component in the chiral drug conforms to the anti-Langmuir characteristic, while the adsorption of the heavy component conforms to the Langmuir characteristic.

[0024] The present invention also provides a simulated moving bed system for the above-described separation method, comprising:

[0025] Three chromatographic columns connected in series, each filled with a chiral stationary phase; two external inlets, namely the raw material inlet and the eluent inlet; two external outlets, namely the heavy component product outlet and the light component product outlet; the first chromatographic column is located between the eluent inlet and the heavy component outlet, the second chromatographic column is located between the heavy component product outlet and the raw material inlet, and the third chromatographic column is located between the raw material inlet and the light component product outlet;

[0026] The system has three high-pressure flow pumps: a feed pump to provide external feed flow to the system; an eluent pump to provide external eluent flow to the system; and an internal circulation pump, located between any two columns, to provide internal flow to the system.

[0027] The sixteen valves are as follows: two external one-way valves at the inlet of each column, connected to the feed pump and the eluent pump respectively; two external one-way valves at the outlet of each column, connected to the heavy component product outlet and the light component product outlet respectively; one internal one-way valve at the outlet of each column, directly connected to the adjacent downstream column; and an additional valve at the outlet of one of the columns, connected to the adjacent downstream column via an internal circulation pump.

[0028] In some specific embodiments of the present invention, the chromatographic column is packed with a coated or bonded chiral stationary phase, wherein the particle size of the chiral stationary phase is 5~20 μm.

[0029] In some specific embodiments of the present invention, the high-pressure flow pump is a plunger pump.

[0030] In some specific embodiments of the present invention, the valve is a pneumatic valve or an electric valve, preferably a pneumatic valve.

[0031] In this invention, the inlet and outlet refer to the external inlet and external outlet. The external inlet refers to two external inlets, namely the raw material inlet and the eluent inlet; the external outlet refers to two external outlets, namely the heavy component product outlet and the light component product outlet.

[0032] In this invention, a simulated fluidized bed system containing three chromatographic columns is used to separate chiral drugs. Within each switching cycle, the following three sub-steps are executed: ① Connect all three columns to form a closed loop and turn on the internal circulation pump to provide internal circulation flow; ② Turn on the eluent pump to provide flow along the direction of the first column → second column → third column, collecting the light component product; ③ Turn on the eluent pump to provide flow through the first column, collecting the heavy component product; turn on the feed pump to provide flow through the third column, collecting the light component product. Then, the original first, second, and third columns are relabeled as the third column, first column, and second column, respectively, and the valves are relabeled accordingly (i.e., the positions of all external inlets and outlets are switched forward by one column). Based on this, the next switching cycle begins, and the above three sub-steps are executed again. The switching of each inlet and outlet and the execution of the three sub-steps are repeated until the separation task is completed. To verify the separation efficiency of the method of this invention, multi-objective optimization was performed using a computer to optimize both the separation methods of this invention and 3C-ISMB, obtaining the yield and solvent consumption under their respective independent optimized operating parameters. The results show that, compared with the 3C-ISMB mode, the separation method of this invention can be used for the separation of various types of chiral drugs and can significantly increase the equipment throughput per unit mass of stationary phase during the separation process, while maintaining comparable or even lower solvent consumption. Especially for chiral enantiomer systems where the light component has anti-Langmuir characteristics and the heavy component has Langmuir characteristics, conventional methods such as SMB and 3C-ISMB have low separation efficiency, while the separation method of this invention can increase the equipment yield by several times. Therefore, this invention has significant advantages in the field of chiral drug separation using expensive stationary phases.

[0033] Compared with the prior art, the present invention has the following beneficial technical effects:

[0034] The simulated moving bed separation method proposed in this invention, which executes three sub-steps in each switching cycle, can be used for the separation of various types of chiral drugs. It effectively increases the equipment throughput per unit mass of stationary phase while maintaining comparable or even lower solvent consumption. Especially for chiral enantiomer systems where the light component exhibits anti-Langmuir characteristics and the heavy component exhibits Langmuir characteristics, conventional methods such as SMB and 3C-ISMB suffer from low separation efficiency. Using the separation method of this invention can significantly increase equipment yield.

[0035] In the separation method of this invention, three sub-steps are executed within each switching cycle. In the second sub-step, the three chromatographic columns have the same flow rate, uniformly supplied by the eluent pump. In the third sub-step, the flow rates of the first and third chromatographic columns are supplied separately by the eluent pump and the feed pump, respectively, without mutual interference. In contrast, the 3C-ISMB method executes two sub-steps within each switching cycle. In the first sub-step, the flow rates of two inlets and one extraction port need to be controlled simultaneously. The flow rate within the second column is affected by the flow rates of both the eluent inlet and the extraction port. The flow rate within the third column is affected by the flow rates of both inlets and the extraction port. Therefore, although the separation method of this invention executes three sub-steps within each switching cycle, which at first glance seems more complex than the two sub-steps of 3C-ISMB, in reality, the external flow rates of the chromatographic columns in this invention are simpler, and it exhibits better stability and robustness in actual operation.

[0036] The simulated moving bed system employed in this invention uses a three-column system, which reduces the number of columns compared to typical SMB and ISMB modes, thereby significantly reducing the use of expensive chiral stationary phases; it also employs three high-pressure flow pumps, eliminating the need for one expensive high-pressure flow pump compared to the 3C-ISMB mode. Therefore, compared to existing technologies, the simulated moving bed system of this invention can effectively save on overall equipment costs. Attached Figure Description

[0037] Figure 1 This is a schematic diagram of a simulated moving bed system for chiral drug separation according to the present invention.

[0038] Figure 2 This is a schematic diagram of the 3C-ISMB system in the comparative example. Detailed Implementation

[0039] To better illustrate the present invention and facilitate understanding of its technical solutions, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0040] Example

[0041] like Figure 1 As shown, in a specific embodiment of the present invention, a simulated moving bed system for chiral drug separation includes:

[0042] Three chromatographic columns C1, C2, and C3 are connected in series, and each column is packed with a chiral stationary phase;

[0043] There are two external inlets, namely the raw material inlet F and the eluent inlet D;

[0044] There are two external outlets: extraction outlet E (also known as heavy component product outlet) and raffinate outlet R (also known as light component product outlet).

[0045] Three high-pressure flow pumps are used: a feed pump PF, which provides external feed flow to the system; an eluent pump PD, which provides external eluent flow to the system; and an internal circulation pump PL, which is positioned between any two columns. Figure 1 The internal circulation pump PL is located between the first chromatographic column C1 and the third chromatographic column C3 to provide the internal flow rate of the system.

[0046] The sixteen valves are as follows:

[0047] Two external one-way valves 1 and 2 are installed at the outlet of the first chromatographic column C1 and connected to the raffinate port R and the extract port E respectively; two external one-way valves 3 and 4 are installed at the inlet of the first chromatographic column C1 and connected to the feed pump PF and the eluent pump PD respectively; and an internal one-way valve 5 is installed at the outlet of the first chromatographic column C1 and connected to the inlet of the second chromatographic column C2.

[0048] Two external one-way valves 6 and 7 are installed at the outlet of the second chromatographic column C2 and connected to the raffinate port R and the extract port E respectively; two external one-way valves 8 and 9 are installed at the inlet of the second chromatographic column C2 and connected to the feed pump PF and the eluent pump PD respectively; and an internal one-way valve 10 is installed at the outlet of the second chromatographic column C2 and connected to the inlet of the third chromatographic column C3.

[0049] Two external one-way valves 11 and 12 are installed at the outlet of the third chromatographic column C3 and connected to the raffinate port R and the extraction port E respectively; two external one-way valves 13 and 14 are installed at the inlet of the third chromatographic column C3 and connected to the feed pump PF and the eluent pump PD respectively; and an internal one-way valve 15 is installed at the outlet of the third chromatographic column C3 and connected to the inlet of the first chromatographic column C1.

[0050] And, in one of the chromatographic columns C j (j=1,2,3, Figure 1 (j=3) An additional internal one-way valve 16 is installed at the outlet, which is connected to the downstream adjacent chromatographic column (the downstream adjacent chromatographic column refers to the next adjacent column in the next sequence) via the internal circulation pump PL. Figure 1 The first chromatographic column is C1.

[0051] Chiral packing materials can be selected and packed using various existing known techniques. For example, chromatographic columns can be packed with coated or bonded chiral stationary phases with particle sizes ranging from 5 to 20 μm.

[0052] The separation method for chiral drugs using the aforementioned simulated moving bed system involves switching various valves and flow pumps, and periodically changing the positions of the external inlets and outlets along the flow direction of the mobile phase. This creates a counter-current flow between the mobile and stationary phases (simulating counter-current flow between the stationary and mobile phases) with the inlet and outlet as reference points, thereby achieving component separation. The following three sub-steps are executed in each switching cycle:

[0053] First sub-step: If j=1, open valves 10, 15, and 16, and close all other valves; if j=2, open valves 5, 15, and 16, and close all other valves; if j=3, open valves 5, 10, and 16, and close all other valves; thus forming a closed loop between the first column C1, the second column C2, and the third column C3, the internal circulation pump PL located on the closed loop is turned on to provide internal circulation flow, with the flow rate set to Q. L The operation time for this step is set to t1.

[0054] Second sub-step: Open valves 4, 5, 10, and 11, and close all other valves, so that the first chromatographic column C1, the second chromatographic column C2, and the third chromatographic column C3 are connected in sequence, while the first chromatographic column C1 and the third chromatographic column C3 are disconnected; turn on the eluent pump PD to provide flow in the direction of first chromatographic column C1 → second chromatographic column C2 → third chromatographic column C3, and set the flow rate to Q2. Collect the light component product at this flow rate in the raffinate port R; set the operation time of this step to t2.

[0055] Third sub-step: Open valves 2, 4, 11, and 13, and close all other valves; turn on the eluent pump PD to provide flow through the first column C1 at a flow rate of Q1, and collect the heavy component product at this flow rate at the extraction port E; turn on the feed pump PF to provide flow through the third column C3 at a flow rate of Q3, and continue to collect the light component product at this flow rate at the raffinate port R; the operation time for this step is set to t3; there is no flow in the second column C2 during the operation time of this step.

[0056] Time t of a single switching cycle s =t1+t2+t3.

[0057] In each of the above sub-steps, if there is flow between two adjacent chromatographic columns, the flow direction is C1→C2, C2→C3, C3→C1.

[0058] After the third sub-step is completed, following the flow direction of the mobile phase, switch the positions of all external inlets and outlets one column forward. That is, relabel the original C1, C2, and C3 columns as C3, C1, and C2, respectively. Relabel each valve accordingly, ensuring that the relabeled columns still meet the following requirements: the section between the eluent inlet and the heavy component outlet is the first column; the section between the heavy component product outlet and the feed inlet is the second column; and the section between the feed inlet and the light component product outlet is the third column. Based on this, start a new switching cycle and execute the above three sub-steps again. Repeat the port switching and execution of the three sub-steps until the separation task is completed.

[0059] Comparative Example

[0060] To compare with the 3C-ISMB mode, which has been proven to have high yield per unit mass of stationary phase equipment in the prior art, the 3C-ISMB mode is set as a comparative example. For ease of comparison, the simulated moving bed system used in the comparative example is substantially similar to the simulated moving bed system of the embodiments of the present invention. Specifically, as follows:

[0061] like Figure 2 As shown, a 3C-ISMB mode simulated moving bed system includes:

[0062] Three chromatographic columns C1, C2, and C3 are connected in series, and each column is packed with a chiral stationary phase;

[0063] There are two external inlets, namely the raw material inlet F and the eluent inlet D;

[0064] There are two external outlets: extraction outlet E (also known as heavy component product outlet) and raffinate outlet R (also known as light component product outlet).

[0065] Four high-pressure flow pumps are used: a feed pump PF, which provides external feed flow to the system; an eluent pump PD, which provides external eluent flow to the system; an extraction pump PE, which provides extract flow to the system; and an internal circulation pump PL, which is positioned between any two columns. Figure 2 The internal circulation pump PL is located between the first chromatographic column C1 and the third chromatographic column C3 to provide the internal flow rate of the system.

[0066] The sixteen valves are as follows:

[0067] Two external one-way valves 1 and 2 are installed at the outlet of the first chromatographic column C1 and connected to the raffinate port R and the extract port E respectively; two external one-way valves 3 and 4 are installed at the inlet of the first chromatographic column C1 and connected to the feed pump PF and the eluent pump PD respectively; and an internal one-way valve 5 is installed at the outlet of the first chromatographic column C1 and connected to the inlet of the second chromatographic column C2.

[0068] Two external one-way valves 6 and 7 are installed at the outlet of the second chromatographic column C2 and connected to the raffinate port R and the extract port E respectively; two external one-way valves 8 and 9 are installed at the inlet of the second chromatographic column C2 and connected to the feed pump PF and the eluent pump PD respectively; and an internal one-way valve 10 is installed at the outlet of the second chromatographic column C2 and connected to the inlet of the third chromatographic column C3.

[0069] Two external one-way valves 11 and 12 are installed at the outlet of the third chromatographic column C3 and connected to the raffinate port R and the extraction port E respectively; two external one-way valves 13 and 14 are installed at the inlet of the third chromatographic column C3 and connected to the feed pump PF and the eluent pump PD respectively; and an internal one-way valve 15 is installed at the outlet of the third chromatographic column C3 and connected to the inlet of the first chromatographic column C1.

[0070] And, in one of the chromatographic columns C j (j=1,2,3, Figure 1 An additional internal one-way valve 16 is installed at the outlet of column j=3, which is connected to the downstream adjacent column via an internal circulation pump PL. Figure 2 The first chromatographic column is C1.

[0071] Chiral packing materials can be selected and packed using various existing known techniques. For example, chromatographic columns can be packed with coated or bonded chiral stationary phases with particle sizes ranging from 5 to 20 μm.

[0072] As can be seen, compared with the comparative system operating in 3C-ISMB mode, the system shown in this embodiment of the invention does not require an additional high-pressure flow pump as the extraction pump (PE). High-pressure flow pumps are relatively expensive, with laboratory-grade pumps costing hundreds of thousands of yuan each. Therefore, the system shown in this embodiment of the invention can effectively save equipment costs compared to the comparative system operating in 3C-ISMB mode. Furthermore, the three-column system used in this invention reduces the number of chromatographic columns compared to typical SMB and ISMB modes, thereby significantly reducing the use of expensive chiral stationary phases. Therefore, the simulated moving bed system of this invention can significantly save equipment costs.

[0073] The comparative example uses the 3C-ISMB process, employing a simulated moving bed system to separate chiral drugs. This is achieved by switching various valves and flow pumps, and periodically changing the positions of external inlets and outlets along the flow direction of the mobile phase. This creates a counter-current flow between the mobile and stationary phases (simulating counter-current flow between the stationary and mobile phases) based on the inlet and outlet, thus separating the components. The following two sub-steps are executed in each switching cycle:

[0074] First sub-step: Open valves 2, 4, 5, 10, 11, and 13, and close all other valves, so that the first chromatographic column C1, the second chromatographic column C2, and the third chromatographic column C3 are connected sequentially, while the first chromatographic column C1 and the third chromatographic column C3 are disconnected; turn on the eluent pump PD to provide flow from the external eluent port to the first chromatographic column C1, with a flow rate set to Q1; turn on the extraction pump PE to provide flow to the external extraction port, with a flow rate set to Q. E Then the flow rate in the second chromatographic column C2 is Q2 = Q1 - Q E Turn on the feed pump PF to provide flow from the external inlet to the third column C3, and set the flow rate to Q. F Then the flow rate in the third chromatographic column C3 is Q3 = Q2 + Q F The operation time for this step is set to t1.

[0075] Second sub-step: If j=1, open valves 10, 15, and 16, and close all other valves; if j=2, open valves 5, 15, and 16, and close all other valves; if j=3, open valves 5, 10, and 16, and close all other valves; thus connecting the first column C1, the second column C2, and the third column C3 to form a closed loop (i.e., the first column C1 is connected to the second column C2, the second column C2 is connected to the third column C3, and the third column C3 is connected to the first column C1). Turn on the internal circulation pump PL located in the closed loop, and set the flow rate to Q. L The operation time for this step is set to t2.

[0076] Single switching period t s =t1+t2.

[0077] In each of the above sub-steps, if there is flow between two adjacent chromatographic columns, the flow direction is C1→C2, C2→C3, C3→C1.

[0078] After the second sub-step is completed, following the flow direction of the mobile phase, switch the positions of all external inlets and outlets forward by one column. Specifically, relabel the original columns C1, C2, and C3 as columns C3, C1, and C2, and relabel the valves accordingly. Then, initiate a new switching cycle, repeating the first and second sub-steps. Repeat the port switching and execution of the two sub-steps until the separation task is completed.

[0079] It can be observed that in the first sub-step of 3C-ISMB, the flow rates of two inlets, D and F, and one outlet, E, need to be controlled simultaneously, and the flow rate within the second column C2, Q2 = Q, is also required. D -Q E Simultaneously affected by the corresponding inlet and outlet flow rates; the flow rate within the third column C3 is Q3 = QD +Q F -Q E Simultaneously affected by three corresponding inlet and outlet flow rates. In comparison, in the method of this invention, there is no external flow rate in the first sub-step; in the second sub-step, the three chromatographic columns are connected in series, with the same flow rate, uniformly provided by the eluent pump PD; in the third sub-step, the flow rates of the first chromatographic column C1 and the third chromatographic column C3 are provided independently by the eluent pump PD and the raw material pump PF, respectively, without affecting each other, while the internal flow rate of the second chromatographic column C2 is 0. It can be seen that although the separation method of this invention executes three sub-steps in each switching cycle, which at first glance seems more complicated than the two sub-steps of 3C-ISMB, in fact, the external flow rates of the chromatographic columns in each sub-step of this invention are simpler, and it also has better stability and robustness in actual operation.

[0080] To verify the effectiveness of the separation method of the present invention in improving productivity, the separation efficiency of the present invention is compared with that of 3C-ISMB. This comparison is conducted under the premise that both are optimized, that is, both are optimized separately to obtain the separation efficiency of the two separation modes under their respective optimized operating parameters, and then the separation efficiency of the two modes is compared.

[0081] Here, a non-limiting optimization strategy is adopted to perform multi-objective optimization on the separation method of this invention and the operating parameters of 3C-ISMB, and the separation performance of the two modes under their respective optimized operating parameters is obtained. The specific steps are as follows:

[0082] (1) Define the multi-objective optimization problem:

[0083] The optimization objective is to simultaneously maximize equipment yield and target product purity;

[0084] The constraints are set as follows: target product yield not less than 95%, maximum cumulative flow rate Q. P ;

[0085] Select the adjustable parameters as m1, m2, m3, and m4;

[0086] (2) The equilibrium diffusion chromatography model is used for simulation. At the same time, the non-dominated sorting genetic algorithm NSGA-II is used for global optimization to solve the multi-objective optimization problem. All adjustable operating parameters m1, m2, m3 and m4 are adjusted to obtain the non-dominated solution set (Pareto) between the maximum equipment yield and the target product purity.

[0087] (3) Select the target product purity, select the corresponding operation point from the Pareto solution set, read each m value and convert it into actual operation parameters (duration of each sub-step, flow rate of each stream), and at the same time read the corresponding maximum equipment yield UT and solvent consumption SC.

[0088] The relevant parameters are explained below:

[0089] Maximum cumulative traffic Q P The cumulative flow rate of all tandem columns corresponding to the maximum system pressure drop is applied to each sub-step with a different flow rate distribution. Q P It can be estimated using the following Darcy equation.

[0090]

[0091] Where ΔP max For maximum system voltage drop, is the constant of Darcy's equation, d is the inner diameter of the column, and L is the length of the column.

[0092] The m-value is the dimensionless ratio of mobile phase to stationary phase flow rate. Both the system of this invention and the 3C-ISMB comparative system have four independent m-values ​​(m1, m2, m3, m4). m1, m2, and m3 represent the mobile phase to stationary phase flow rates of the first column C1, the second column C2, and the third column C3 during the entire switching cycle, respectively, while m4 represents the mobile phase to stationary phase flow rate of the first column C1 during internal circulation.

[0093] Actual operating parameters (duration of each sub-step, flow rate of each column) can be obtained using the m value and Q. p Express.

[0094] The system of this invention uses three chromatographic columns and has three sub-steps with different flow distributions, corresponding to seven independent actual operating parameters: Q1, Q2, Q3, Q... L t1, t2, and t3 are expressed as follows:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] Where V is the volume of a single column and ε is the column porosity.

[0102] The 3C-ISMB comparative system uses three columns and has two sub-steps with different flow distributions, corresponding to six independent operating parameters: Q1, Q2, Q3, Q... Lt1 and t2 are expressed as follows:

[0103]

[0104]

[0105]

[0106]

[0107] Dimensionless equipment yield UT is defined as Q P The feed rate processed per column of stationary phase as a benchmark standard.

[0108]

[0109] Where, N C t represents the total number of chromatographic columns in the system. s To switch time, Q F The feed inlet flow rate has different values ​​in different steps of different operations. For the 3C-ISMB method, Q in the first sub-step... F =Q3-Q2, Q in the second sub-step F =0; For the method of the present invention, Q in the first sub-step F =0, Q in the second sub-step F =0, Q in the third sub-step F =Q3.

[0110] The purity of light components is defined as

[0111]

[0112] Among them, Q R c is the external outlet flow rate of the third column C3. 1,3 out c represents the concentration of the light component at the outlet of column C3 in the third chromatographic column. 2,3 out This represents the concentration of the heavy component at the C3 outlet of the third column. For the 3C-ISMB method, Q in the first sub-step... R =Q3, Q in the second sub-step R =0; For the method of the present invention, Q in the first sub-step R =0, Q in the second sub-step R =Q2, Q in the third sub-step R =Q3.

[0113] The purity of the recombinant component is defined as

[0114]

[0115] Among them, QE c is the external outlet flow rate of the first chromatographic column C1. 1,1 out c represents the concentration of the light component at the outlet of column C1 in the first chromatographic column. 2,1 out This refers to the concentration of the heavy component at the outlet of column C1. For the 3C-ISMB method, Q in the first sub-step... E =Q1-Q2, Q in the second sub-step E =0; For the method of the present invention, Q in the first sub-step E =0, Q in the second sub-step E =0, Q in the third sub-step E =Q1.

[0116] Furthermore, although solvent consumption is not a primary consideration in chiral separation processes, we still evaluate it as a secondary separation metric. Solvent consumption (SC) is measured by the eluent-to-feed volume ratio over a single switching cycle:

[0117]

[0118] Among them, t s To switch time, Q F Q is the feed flow rate. D The eluent flow rate has different values ​​in different steps of different operations. For the 3C-ISMB method, Q in the first sub-step... D =Q1, Q in the second sub-step D =0. For the method of this invention, Q in the first sub-step... D =0, Q in the second sub-step D =Q2, Q in the third sub-step D =Q1.

[0119] The separation efficiency of the 3C-ISMB mode and the separation method described in this invention is evaluated below, with the optimal equipment throughput under given target product purity and yield requirements as the primary indicator and the corresponding solvent consumption as the secondary indicator.

[0120] Specifically, the parameters of the SMB process will be described in detail using chiral drugs with different adsorption characteristics as examples, and the overall separation process will be evaluated based on this. Different separation systems have different column sizes, porosity (ε), and adsorption characteristics, which will be explained in the following specific examples. The following raw materials contain two chiral enantiomers simultaneously. The heavy component is the chiral enantiomer that is strongly adsorbed on the stationary phase, and the light component is the chiral enantiomer that is weakly adsorbed on the stationary phase.

[0121] Example 1

[0122] The adsorption characteristics of the system to be separated in this example conform to the bicomponent Bi-Langmuir model, and both chiral enantiomers (heavy component and light component) conform to Langmuir characteristics.

[0123] Here, we will use (±)Tröger's base as a representative example. According to the literature (S. Jermann, M. Mazzotti, Three column intermittent simulated moving bed chromatography: 1. Process description and comparative assessment, J. Chromatogr. A 1361 (2014) 125-138.), its adsorption characteristics conform to the following model:

[0124]

[0125] Where a1=1.56, a2=3.99, a3=0.0132, a4=0.0107, a5=0.304, a6=0.986, a7=0.136, and a8=0.61. q1 and q2 represent the concentrations of the light and heavy components in the stationary phase, respectively, and c1 and c2 represent the concentrations of the light and heavy components in the mobile phase, respectively, all in g / L.

[0126] System description: L=15 cm, d=0.46 cm, ε=0.63, ΔP max =40 bar, =0.1 bar min / cm 2 The total feed concentration was 15 g / L, and the two-component feed ratio was 1:1. The stationary phase was Chiralpak AD, and the mobile phase was ethanol.

[0127] Separation requirements: The target product is a light component, and the purity of the target product reaches 99% or higher, and the yield reaches 95% or higher.

[0128] Based on the aforementioned separation requirements, a multi-objective optimization of the simulated moving bed process was performed. The optimized operating parameters are as follows (the unit of each flow rate Q is ml / min, and the unit of each time t is min):

[0129] Using the method of this invention, the optimal operating parameters, expressed in terms of m values, are m1=4.90, m2=1.35, m3=3.52, and m4=0.98; the actual optimal operating parameters are Q1=4.43, Q2=1.48, Q3=2.70, and Q... L=1.48, t1=1.68, t2=0.20, t3=0.64. The maximum equipment throughput reached is UT=0.0517, and the corresponding solvent consumption is SC=1.81.

[0130] Using the comparative 3C-ISMB model, the optimal operating parameters, expressed in m-values, are m1=5.06, m2=1.29, m3=3.47, and m4=0.89; the actual optimal operating parameters are Q1=2.58, Q2=0.25, Q3=1.60, and Q... L =1.48, t1=1.27, t2=1.63. The maximum equipment throughput reached was UT=0.0447, with a corresponding solvent consumption of SC=1.92.

[0131] As can be seen, in this example, compared with the 3C-ISMB mode of the comparative example, the method of the present invention can increase the equipment throughput by 16% and reduce the corresponding solvent consumption by 6% under optimized conditions.

[0132] Example 2

[0133] The system to be separated in this example is exactly the same as that in Example 1, with identical adsorption characteristics and system description. The difference lies in the separation requirements.

[0134] Separation requirements: The target product must be a heavy component, with a purity of 99% or higher and a yield of 95% or higher.

[0135] Based on the aforementioned separation requirements, a multi-objective optimization of the simulated moving bed process was performed. The optimized operating parameters are as follows (the unit of each flow rate Q is ml / min, and the unit of each time t is min):

[0136] Using the method of this invention, the optimal operating parameters, expressed in terms of m values, are m1=4.90, m2=1.35, m3=3.52, and m4=0.98; the actual optimal operating parameters are Q1=4.43, Q2=1.48, Q3=3.06, and Q... L =1.48, t1=1.51, t2=0.44, t3=0.56. The maximum equipment throughput reached is UT=0.0517, with a corresponding solvent consumption of SC=1.82.

[0137] Using the comparative 3C-ISMB model, the optimal operating parameters, expressed in m-values, are m1=4.55, m2=1.50, m3=3.61, and m4=0.62; the actual optimal operating parameters are Q1=2.23, Q2=0.50, Q3=1.70, and Q... L =1.48, t1=1.40, t2=1.48. The maximum equipment throughput reached is UT=0.0439, with a corresponding solvent consumption of SC=1.86.

[0138] As can be seen, in this example, compared with the 3C-ISMB mode of the comparative example, the method of the present invention can increase the equipment throughput by 18% and reduce the corresponding solvent consumption by 2% under optimized conditions.

[0139] Example 3

[0140] The system to be separated in this example is a chiral enantiomer whose adsorption characteristics conform to the mixed Langmuir I (M1) model. In the M1 model, the light component conforms to Langmuir characteristics, and the heavy component conforms to anti-Langmuir characteristics.

[0141] Here, (±)NMPA is used as a representative example for illustration. According to the literature (Breveglieri, T. Otgonbayar, M. Mazzotti, Optimizing the Yield of a Pure Enantiomer by Integrating ChiralSMB Chromatography and Racemization. Part 1: Experiments general Langmuir, Ind. Eng. Chem. Res. 60 (2021) 10710-10719), its adsorption characteristics conform to the following model:

[0142]

[0143] Where a1=0.95, a2=3.1, a3=0.03, a4=0.31. q1 and q2 represent the concentrations of the light and heavy components in the stationary phase, respectively, and c1 and c2 represent the concentrations of the light and heavy components in the mobile phase, respectively, all in g / L.

[0144] System description: L=15cm, d=0.46cm, ε=0.72, ΔP max =40 bar, =0.1 bar min / cm 2 The total feed concentration was 15 g / L, and the two-component feed ratio was 1:1. The stationary phase was Chiralpak AY, and the mobile phase was acetonitrile.

[0145] Separation requirements: The target product is a light component, and the purity of the target product reaches 99% or higher, and the yield reaches 95% or higher.

[0146] Based on the aforementioned separation requirements, a multi-objective optimization of the simulated moving bed process was performed. The optimized operating parameters are as follows (the unit of each flow rate Q is ml / min, and the unit of each time t is min):

[0147] Using the method of this invention, the optimal operating parameters, expressed in terms of m values, are m1=7.58, m2=1.91, m3=3.09, and m4=0.05; the actual optimal operating parameters are Q1=4.43, Q2=1.48, Q3=0.92, and Q... L =1.48, t1=1.24, t2=0.82, t3=0.89. The maximum equipment throughput reached is UT=0.0206, with a corresponding solvent consumption of SC=6.37.

[0148] Using the comparative 3C-ISMB model, the optimal operating parameters, expressed in m-values, are m1=7.24, m2=1.88, m3=3.00, and m4=0.27. The actual optimal operating parameters are Q1=2.73, Q2=0.63, Q3=1.07, and Q... L =1.48, t1=1.78, t2=1.34. The maximum equipment throughput reached was UT=0.0189, with a corresponding solvent consumption of SC=6.21.

[0149] As can be seen, in this example, compared with the 3C-ISMB mode of the comparative example, the method of the present invention can increase the equipment throughput by 9% and the corresponding solvent consumption by 2% under optimized conditions.

[0150] Example 4

[0151] The system to be separated in this example is a chiral enantiomer whose adsorption characteristics conform to the bicomponent Quadratic model. The Quadratic model can be used to describe both competitive and cooperative adsorption behaviors. In this system, the lighter component conforms to the anti-Langmuir characteristic, while the heavier component conforms to the Langmuir characteristic. It should be noted that this adsorption characteristic of the system leads to a decrease in enantioselectivity at high concentrations; therefore, this system represents the most difficult type of chiral enantiomer to separate.

[0152] Here, we will use (±)ibuprofen as a representative example. According to the literature (Li et al., Journal of Chromatography A, 1435 (2016) 92–99), its adsorption characteristics conform to the following model:

[0153] Its adsorption characteristics conform to the model:

[0154]

[0155] Where a1=52.2, a2=0.174, a3=0.23, a4=0.0598, a5=0.0282, a6=0. q1 and q2 represent the concentrations of the light and heavy components in the stationary phase, respectively, and c1 and c2 represent the concentrations of the light and heavy components in the mobile phase, respectively, all in g / L.

[0156] System description: L=15 cm, d=0.46 cm, ε=0.63, ΔP max =40 bar, =0.1 bar min / cm 2 The total feed concentration was 15 g / L, and the two-component feed ratio was 1:1. The stationary phase was Chiralpak OD, and the mobile phase was hexane / propanol.

[0157] Separation requirements: The target product is a light component, and the purity of the target product reaches 99% or higher, and the yield reaches 95% or higher.

[0158] Based on the aforementioned separation requirements, multi-objective optimization was performed on the simulated moving bed process. The optimized operating parameters are as follows (the unit of each flow rate Q is ml / min, and the unit of each time t is min):

[0159] Using the method of this invention, the optimal operating parameters, expressed in terms of m values, are m1=12.61, m2=10.20, m3=10.25, and m4=6.79; the actual optimal operating parameters are Q1=31.40, Q2=10.47, Q3=0.65, and Q... L =10.47, t1=2.03, t2=0.75, t3=0.18. The maximum equipment throughput reached is UT=0.000414, with a corresponding solvent consumption of SC=116.

[0160] Using the comparative 3C-ISMB model, the optimal operating parameters, expressed in m-values, are m1=13.88, m2=10.81, m3=10.83, and m4=6.87; the actual optimal operating parameters are Q1=14.77, Q2=8.30, Q3=8.33, and Q... L =10.47, t1=1.10, t2=2.05. The maximum equipment throughput reached was UT=0.000129, with a corresponding solvent consumption of SC=423.

[0161] As can be seen, in this example, compared with the 3C-ISMB mode of the comparative example, the method of the present invention can increase the equipment throughput by 220% and reduce the corresponding solvent consumption by 73% under optimized conditions.

[0162] In summary, this invention employs a simulated fluidized bed system containing three chromatographic columns to separate chiral drugs. This is achieved by executing three sub-steps within each switching cycle: ① Connecting all three columns to form a closed loop and activating the internal circulation pump to provide internal circulation flow; ② Activating the eluent pump to provide flow along the first column → second column → third column, collecting the light component product; ③ Activating the eluent pump to provide flow through the first column, collecting the heavy component product; and activating the feed pump to provide flow through the third column, collecting the light component product. Then, the positions of all external inlets and outlets are shifted forward by one column, initiating the next switching cycle, and the above three sub-steps are executed again. This process of switching inlets and outlets and executing the three sub-steps is repeated until the separation task is completed. To verify the separation efficiency of this invention, it is compared with the 3C-ISMB mode, which has been proven to have high yield per unit mass of stationary phase in the prior art. To provide more accurate and comprehensive comparison results, a comprehensive non-limiting optimization strategy is used in each example and comparative example to determine their respective optimized separation efficiency. The results show that for the separation of various types of chiral drugs, compared with the comparative 3C-ISMB method, the separation method described in this invention can significantly increase the throughput of a single-column stationary phase device, while maintaining comparable or even lower solvent consumption. Especially for chiral enantiomer systems, represented by Example 4, where the light component exhibits anti-Langmuir characteristics and the heavy component exhibits Langmuir characteristics, conventional SMB and 3C-ISMB methods are inefficient. The method of this invention can significantly increase the device yield. Therefore, in the field of chiral drug separation using expensive stationary phases, the separation method of this invention has significant advantages.

[0163] It should be noted that the embodiments described above are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein. On the contrary, the present invention can be extended to all other methods and applications with the same function.

Claims

1. A simulated moving bed separation method for chiral drug resolution, employing a three-column simulated moving bed system, periodically switching the inlet and outlet positions along the flow direction of the mobile phase to simulate countercurrent flow of the stationary phase and mobile phase, thereby achieving component separation; characterized in that, The following three sub-steps are executed in each switching cycle: First sub-step: Close all external outlets and inlets, connect all three chromatographic columns to form a closed loop, and turn on the internal circulation pump on the closed loop to provide internal circulation flow; the operation time of this step is set as the first operation time. Second sub-step: Connect the first, second, and third chromatographic columns sequentially, while disconnecting the first and third columns; turn on the eluent pump to provide flow in the direction of first column → second column → third column, and collect the light component product at the light component product outlet; the operation time of this step is set as the second operation time. Third sub-step: Turn on the eluent pump to provide flow from the external eluent inlet to the first chromatographic column, and collect the heavy component product at the heavy component product outlet; Turn on the feed pump to provide flow from the external feed inlet to the third column, and collect the light component product at the light component product outlet; disconnect the second column from both the first and third columns, and there is no flow in the second column; the operation time for this step is set as the third operation time.

2. The simulated moving bed separation method for chiral drug separation as described in claim 1, characterized in that, The three-column simulated moving bed system includes three chromatographic columns, a feed pump, an eluent pump, an internal circulation pump, a feed inlet, an eluent inlet, a heavy component product outlet, a light component product outlet, and several valves. The first chromatographic column is located between the eluent inlet and the heavy component outlet, the second chromatographic column is located between the heavy component product outlet and the feed inlet, and the third chromatographic column is located between the feed inlet and the light component product outlet. The three chromatographic columns are connected in series to form a closed loop. In addition, an extra valve is installed at the outlet of any one of the chromatographic columns, which is connected to the inlet of the adjacent downstream chromatographic column via the internal circulation pump.

3. The simulated moving bed separation method for chiral drug separation as described in claim 1, characterized in that, After the third sub-step is completed, according to the flow direction of the mobile phase, switch the positions of all external inlets and outlets forward by one column and start a new switching cycle. Repeat the above three sub-steps, switching each inlet and outlet and executing the three sub-steps, until the separation task is completed.

4. The simulated moving bed separation method for chiral drug separation as described in claim 1, characterized in that, The chromatographic column is packed with a coated or bonded chiral stationary phase, wherein the particle size of the chiral stationary phase is 5~20 μm.

5. The simulated moving bed separation method for chiral drug separation as described in claim 1, characterized in that, The adsorption of both components in the chiral drug conforms to Langmuir characteristics.

6. The simulated moving bed separation method for chiral drug separation as described in claim 1, characterized in that, The adsorption of the light component in the chiral drug conforms to the Langmuir characteristic, while the adsorption of the heavy component conforms to the anti-Langmuir characteristic.

7. The simulated moving bed separation method for chiral drug separation as described in claim 1, characterized in that, The adsorption of the light component in the chiral drug conforms to the anti-Langmuir characteristic, while the adsorption of the heavy component conforms to the Langmuir characteristic.

8. A simulated moving bed system for chiral drug separation, comprising: Three chromatographic columns connected in series, each packed with a chiral stationary phase; There are two external inlets: a raw material inlet and an eluent inlet. There are two external outlets, namely the heavy component product outlet and the light component product outlet; the first chromatographic column is located between the eluent inlet and the heavy component product outlet, the second chromatographic column is located between the heavy component product outlet and the feed inlet, and the third chromatographic column is located between the feed inlet and the light component product outlet; The three high-pressure flow pumps are: one raw material pump, used to provide external raw material flow to the system; An eluent pump is used to provide external eluent flow to the system; an internal circulation pump is located between any two columns to provide internal system flow. The sixteen valves are as follows: two external one-way valves at the inlet of each column, connected to the feed pump and the eluent pump respectively; two external one-way valves at the outlet of each column, connected to the heavy component product outlet and the light component product outlet respectively; one internal one-way valve at the outlet of each column, directly connected to the adjacent downstream column; and an additional valve at the outlet of one of the columns, connected to the adjacent downstream column via an internal circulation pump.

9. The simulated moving bed system for chiral drug separation as described in claim 8, characterized in that, The chromatographic column is packed with a coated or bonded chiral stationary phase, wherein the particle size of the chiral stationary phase is 5~20 μm.

10. The simulated moving bed system for chiral drug separation as described in claim 8, characterized in that, The high-pressure flow pump is a plunger pump.

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