A device, method and application of ursodeoxycholic acid preparation and purification

Abstract

The invention relates to the technical field of pharmaceutical separation, and discloses a device, method and application of ursodeoxycholic acid preparation and purification. The device comprises a separation tank, wherein a batching center cylinder is rotatably installed inside the separation tank, and a plurality of elution tubes are arranged around the batching center cylinder. The batching center cylinder rotates forward, and centrifugal force is used to load adsorption resin into each elution tube. Then, the batching center cylinder rotates reversely, and the volume of each elution tube is poured out by anti-centrifugal force, so as to achieve a more convenient effect of replacing the adsorption resin. The replaced adsorption resin is cleaned outside the device and reused. The purification method and application thereof realize column loading, sample loading and elution in the separation tank in sequence without stopping the machine for operation, and simplify the column loading and column replacement operations, so as to solve the problem that the separation and purification process in the prior art is complicated and not suitable for batch production, so as to meet the industrial production requirements of solvent recycling.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical separation, and in particular to a device and method for preparing and purifying ursodeoxycholic acid and applications thereof. Background Art

[0002] At present, the synthesis of ursodeoxycholic acid from chenodeoxycholic acid is a method with many industrial applications, but the reaction conversion rate is only 50-75%. In order to improve the utilization rate of raw materials and reduce production costs, the patent document with announcement number CN103755761B in the prior art discloses a method for purifying ursodeoxycholic acid using supercritical fluid technology, comprising: preparing a mixed organic solvent with a low molecular weight alcohol and a low molecular weight ester in a volume ratio of 1:99 to 9:1, and then mixing the mixed organic solvent with supercritical carbon dioxide in a volume ratio of 1:1 to 1:100. The volume flow ratio is pumped into a high-pressure extraction kettle to form a supercritical mixed solvent; the bile acid mixture is placed in a high-pressure extraction kettle, and then the supercritical mixed solvent is introduced, and the bile acid mixture is circulated and extracted for 0.5 to 10 hours at a pressure of 5 to 30 MPa and a temperature of 30 to 80°C to remove impurities such as bile acid and chenodeoxycholic acid in the bile acid mixture; after the extraction is completed, supercritical carbon dioxide is introduced at a temperature of 30 to 80°C and a pressure of 5 to 30 MPa, and circulated and dried for 0.5 to 20 hours to remove the residual organic alcohol / ester and obtain dry ursodeoxycholic acid. The purpose of this scheme is to provide a method for purifying ursodeoxycholic acid using supercritical fluid technology with simple process, solvent recycling, and relatively low production cost.

[0003] Among them, ursodeoxycholic acid and chenodeoxycholic acid (CDCA, 31,7α-dihydroxy-5β-cholestane-24-acid) are diastereomers of each other. The only difference between the two is the different structural configuration of the 7-hydroxyl group. The 7-hydroxyl group of ursodeoxycholic acid is β-configuration, while the 7-hydroxyl group of chenodeoxycholic acid is α-configuration. The 7-hydroxyl group of chenodeoxycholic acid can be oxidized to a keto group, namely 7-ketolithocholic acid (7-Ketolithocholic acid, 7-K, 3α-hydroxy-7-oxy-5β-cholanoic acid), and its 7-keto group is then converted to a β-hydroxyl group, namely ursodeoxycholic acid, through a reduction reaction. The product of ursodeoxycholic acid prepared by the electroreduction method will contain 7-ketolithocholic acid and some conversion byproducts. It can only be prepared with high purity ursodeoxycholic acid by further purification using column chromatography technology.

[0004] In the prior art, macroporous adsorption resin column chromatography is used to separate ursodeoxycholic acid, which meets the industrial production requirements of solvent recycling. However, the adsorption resin used in this separation method has a limited continuous use time and needs to be cleaned regularly. Frequent pouring out or loading the adsorption resin into the chromatography column is not convenient, which restricts the production efficiency of ursodeoxycholic acid batch purification. There is an urgent need to improve its process. Summary of the invention

[0005] The purpose of the present invention is to solve the shortcoming of low production efficiency of ursodeoxycholic acid batch purification in the prior art, and to propose an ursodeoxycholic acid preparation and purification device, method and application thereof.

[0006] In order to achieve the above-mentioned purpose, the present invention adopts the following technical scheme: an ursodeoxycholic acid preparation and purification device, comprising a separation tank, a dosing center cylinder is rotatably installed inside the separation tank, a servo motor is fixedly installed inside the separation tank, the dosing center cylinder is driven to rotate forward or reversely by the servo motor, a control valve is arranged inside the dosing center cylinder, the upper side of the control valve is a dosing chamber, a plurality of elution tubes are fixedly installed on the surface of the dosing center cylinder, each elution tube is connected to the dosing chamber, a centripetal controller is fixedly installed at the end of each elution tube, a control rod is slidably installed inside the centripetal controller, the control rod extends into the inner cavity of the elution tube, and a magnetic control valve connected to the inner cavity of the elution tube is fixedly installed on the lower side of the elution tube;

[0007] A permanent magnet block and an excitation coil in a ring array are fixedly installed inside the separation tank. The action of the centripetal controller is controlled by the permanent magnet block, and the opening and closing of the magnetic control valve is controlled by the excitation coil.

[0008] An input pipe and an output pipe are fixedly installed at the upper and lower ends of the separation tank respectively. The input pipe is connected to the batching chamber in the batching center tube, and the output pipe is connected to the lower port of the batching center tube. A collecting pipe is fixedly installed on the side of the separation tank, and the liquid outlet end of the magnetic control valve is connected to the collecting pipe. The adsorption resin in the elution tube can be replaced by utilizing the forward and reverse circular motion of the elution tube.

[0009] Preferably, the centripetal controller includes a mounting base block, a transmission shaft is slidably mounted inside the mounting base block, a control rod is fixedly connected to the transmission shaft coaxially, an electromagnetic coil is fixedly mounted inside the mounting base block, the electromagnetic coil is arranged around the transmission shaft, a wire group is embedded in the end of the mounting base block, the wire group is electrically connected to the electromagnetic coil, so as to realize the action of the centripetal controller controlled by the movement of the permanent magnet block and the centripetal controller.

[0010] Preferably, the magnetically controlled valve comprises a valve body, a valve plate is slidably mounted inside the valve body, a magnetic column is fixedly mounted on the side of the valve plate, a return spring is fixedly mounted inside the valve body, the return spring presses against the end of the magnetic column, so that the valve plate is in a flow-cutting state in the valve body, thereby realizing the opening and closing of the magnetically controlled valve being controlled by the excitation coil.

[0011] Preferably, the servo motor drives the batching center cylinder to rotate through the transmission of the synchronous wheel and the synchronous belt, and the angle between the axis line of the elution tube and the radial line of the batching center cylinder is not less than 30°.

[0012] Preferably, the control valve includes a guide ring and a conical plug. The guide ring is fixedly installed in the batching center tube, and the conical plug is slidably installed in the batching center tube. An electric telescopic rod is fixedly installed inside the output pipe, and the telescopic end of the electric telescopic rod is rotatably connected to the shaft rod at the bottom of the conical plug. The conical end of the conical plug can be inserted into the inner hole of the guide ring. The control valve is opened to empty the batching center tube, thereby realizing controllable discharge of the batching center tube.

[0013] Preferably, a discharge window is provided on the lower surface of the elution tube, and a replaceable filter membrane assembly is installed in the discharge window, a brush plate is fixedly installed on the surface of the control rod, the brush plate is in sliding contact with the upper surface of the filter membrane assembly, an annular tube is provided on the lower side of the elution tube, the discharge window of each elution tube is connected to the annular tube, the magnetic control valve is connected to the annular tube to achieve communication with each elution tube, and the elution flow rate of the elution tube is controlled by the magnetic control valve.

[0014] A collecting tank is fixedly installed inside the separation tank, the upper side of the collecting tank is an annular notch, the outlet end of the magnetic control valve extends into the annular notch, the inlet end of the collecting tube is connected to the collecting tank, and the eluent is discharged and collected from the collecting tube.

[0015] The present invention also proposes a method for preparing and purifying ursodeoxycholic acid, comprising the following specific steps:

[0016] S1, column loading, the pre-treated adsorption resin solution is introduced into the batching chamber of the batching center tube through the input pipe, the servo motor is started, and the batching center tube is driven to rotate at a speed of V1 to achieve dynamic balance, the adsorption resin solution is loaded into each elution tube under the action of centrifugal force, and the control valve is opened to discharge the excess solution in the batching chamber;

[0017] S2, loading, servo motor speed regulation, driving the batching center cylinder to rotate at V2 speed, the centripetal controller pushes the control rod to extend, pushes part of the solution in the elution tube into the batching center cylinder, and discharges it from the output tube, then closes the control valve, restores the V1 speed of the batching center cylinder, introduces the ursodeoxycholic acid crude solution from the input tube into the batching chamber of the batching center cylinder, and the ursodeoxycholic acid crude solution is loaded into each elution tube, and the control valve is opened to discharge the excess solution in the batching chamber;

[0018] S3, eluting, introducing the eluate into the batching chamber of the batching center tube through the input tube, controlling the opening and closing of the magnetic control valve by the excitation coil, controlling the liquid discharge speed of the eluate, storing the recovered liquid in different collection bottles according to the time gradient, determining the collection bottle containing ursodeoxycholic acid by liquid chromatography, and obtaining the ursodeoxycholic acid separation product by drying and crystallization;

[0019] S4, replacement of the adsorption resin solution, the servo motor rotates in the reverse direction, driving the batching center cylinder to rotate in the reverse direction, the solution in the elution tube flows back to the batching center cylinder, and then is discharged from the output tube, and step S1 is repeated to load the new adsorption resin solution into the column.

[0020] The application of the ursodeoxycholic acid preparation and purification method is suitable for the case where the adsorption force and resolution force of the substance to be separated on the adsorption resin are different, or the pore size of the adsorption resin has different selectivity for the substance to be separated.

[0021] The present invention has the following beneficial effects:

[0022] 1. The ursodeoxycholic acid preparation and purification device arranges a plurality of elution tubes around a batching center tube. The batching center tube rotates forward, and centrifugal force is used to load adsorption resin into each elution tube. The batching center tube rotates reversely, and the solution in each elution tube is poured out by anti-centrifugal force, so as to achieve a more convenient effect of replacing adsorption resin. The replaced adsorption resin is cleaned outside the device and reused, so as to meet the industrial production requirements of solvent recycling.

[0023] 2. The ursodeoxycholic acid preparation and purification device is provided with a centripetal controller at the end of the elution tube. The central tube of the batching rotates at different speeds. The centripetal controller provides different centripetal forces for the control rod, driving the control rod to extend and retract in the elution tube. The extension and retraction of the control rod not only has the function of controlling the capacity of the adsorption resin and the object to be separated in the elution tube, but also has the function of adjusting the height-to-diameter ratio of the inner volume of the elution tube. As the elution separation proceeds, the concentration of the object to be separated decreases. The chromatographic column with the original height-to-diameter ratio is always used for elution. Although the adsorption separation effect is good, the chromatographic column is too long, the pressure drop is large, the production time cost is high, and it is not conducive to improving the production efficiency.

[0024] The centripetal controller design of the present invention realizes the linkage control of the rotation of the central barrel of the ingredients and the telescopic action of the control rod. By adjusting the rotation speed of the servo motor, the elution can be adjusted differently according to the different adsorption forces and resolving powers of the substances to be separated on the adsorption resin, thus providing conditions for automated elution and separation.

[0025] 3. The ursodeoxycholic acid preparation and purification device can adjust the opening and closing size of the magnetic control valve by setting a magnetic control valve and an excitation coil, and by adjusting the current introduced into the excitation coil, so as to facilitate the control of the discharge speed of the eluent.

[0026] 4. The ursodeoxycholic acid preparation and purification method and its application carry out column loading, sample loading and elution in a separation tank in sequence without stopping the machine, and simplify the column loading and column replacement operations, solving the problem that the separation and purification process in the prior art is complicated and unsuitable for batch production, and greatly improving the production efficiency of ursodeoxycholic acid batch purification. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a schematic diagram of a partially cutaway three-dimensional structure of a separation tank proposed by the present invention (I);

[0028] Figure 2 This is a schematic diagram of a partially cutaway three-dimensional structure of a separation tank proposed by the present invention (II);

[0029] Figure 3 This is a schematic diagram of the front cross-section structure of the separation tank proposed by the present invention;

[0030] Figure 4 This is a schematic diagram of the front cross-section structure of the batching center tube proposed by the present invention;

[0031] Figure 5 for Figure 4 A schematic diagram of the structure enlargement at point A;

[0032] Figure 6 This is a schematic diagram of the three-dimensional structure of the batching center tube and the elution tube proposed by the present invention;

[0033] Figure 7 This is a schematic diagram of the purification method proposed by the present invention;

[0034] Figure 8 This is a schematic diagram of the forward and reverse rotation of the batching center tube proposed by the present invention (top view);

[0035] Fig. 9 This is a schematic diagram of elution in the purification method proposed by the present invention;

[0036] Fig.10 This is a schematic diagram of the curve showing the effect of chromatography columns with different aspect ratios on separation.

[0037] In the figure: 1 separation tank, 2 batching center tube, 3 servo motor, 4 control valve, 5 elution tube, 6 centripetal controller, 7 control rod, 8 magnetic control valve, 9 permanent magnet block, 10 excitation coil, 11 input tube, 12 output tube, 13 collection tube, 14 installation base block, 15 transmission shaft, 16 electromagnetic coil, 17 wire group, 18 valve body, 19 valve plate, 20 magnetic column, 21 return spring, 22 guide ring, 23 conical plug, 24 electric telescopic rod, 25 brush plate, 26 ring tube, 27 collection tank, 28 filter membrane assembly. DETAILED DESCRIPTION

[0038] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0039] In the description of the present invention, it is necessary to understand that the terms "upper", "lower", "front", "back", "left", "right", "top", "bottom", "inside", "outside", etc., indicating the orientation or position relationship are based on the orientation or position relationship shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the present invention.

[0040] Reference Figure 1-Figure 8 , a preparation and purification device of ursodeoxycholic acid, comprising a separation tank 1, a batching center cylinder 2 is rotatably installed inside the separation tank 1, a servo motor 3 is fixedly installed inside the separation tank 1, synchronous wheels are fixedly installed on the rotating end of the servo motor 3 and the surface of the batching center cylinder 2, and synchronous belts are sleeved on the surfaces of the two synchronous wheels. The servo motor 3 drives the batching center cylinder 2 to rotate forward or reversely through the transmission of the synchronous wheels and the synchronous belts, a control valve 4 is arranged inside the batching center cylinder 2, the upper side of the control valve 4 is a batching chamber, a plurality of elution tubes 5 are fixedly installed on the surface of the batching center cylinder 2, each elution tube 5 is connected with the batching chamber, a centripetal controller 6 is fixedly installed at the end of each elution tube 5, a control rod 7 is slidably installed inside the centripetal controller 6, the control rod 7 extends into the inner cavity of the elution tube 5, a magnetic control valve 8 connected with the inner cavity of the elution tube 5 is fixedly installed on the lower side of the elution tube 5, and a permanent magnet block 9 and an excitation coil 10 of a ring array are fixedly installed inside the separation tank 1.

[0041] Specifically, the centripetal controller 6 includes a mounting base block 14 fixedly connected to the elution tube 5, a ferromagnetic transmission shaft 15 is slidably mounted inside the mounting base block 14, the control rod 7 is fixedly connected to the transmission shaft 15 coaxially, an electromagnetic coil 16 is fixedly mounted inside the mounting base block 14, the electromagnetic coil 16 is arranged around the transmission shaft 15, and a wire group 17 is embedded at the end of the mounting base block 14, and the wire group 17 is electrically connected to the electromagnetic coil 16, refer to Figure 5 .

[0042] The centripetal controller 6 rotates with the batching center cylinder 2 to make a circular motion, and the wire group 17 cuts the magnetic field line of the permanent magnet block 9. The generated magnetic induction current is amplified by the amplifier circuit and introduced into the electromagnetic coil 16. The electromagnetic field of the electromagnetic coil 16 exerts a force F on the transmission shaft 15. 磁 The centrifugal force of the solution in the transmission shaft 15, the control rod 7 and the elution tube 5 is F 离 , F 磁 >F 离 , driving the control rod 7 to extend toward the centripetal controller 6, on the contrary, the control rod 7 moves away from the centripetal controller 6, F 磁 It is positively correlated with the movement speed V of the centripetal controller 6 , that is, by adjusting the rotation speed of the servo motor 3 , the telescopic action of the centripetal controller 6 can be controlled.

[0043] The magnetic control valve 8 includes a valve body 18, a valve plate 19 is slidably mounted inside the valve body 18, a magnetic column 20 is fixedly mounted on the side of the valve plate 19, and a return spring 21 is fixedly mounted inside the valve body 18. The return spring 21 presses against the end of the magnetic column 20 to make the valve plate 19 in the valve body 18 in a shutoff state. Figure 5 , an electric current is introduced into the excitation coil 10, and the magnetic field generated by the excitation coil 10 to attract the magnetic column 20 can be adjusted by adjusting the size of the introduced current, so as to adjust the size of the opening of the valve plate 19 and realize flow control. By setting the magnetic control valve 8 and the excitation coil 10, by adjusting the size of the current introduced into the excitation coil 10, the size of the opening and closing of the magnetic control valve 8 can be adjusted, which provides convenience for controlling the discharge speed of the eluent.

[0044] An input pipe 11 and an output pipe 12 are fixedly installed at the upper and lower ends of the separation tank 1, respectively. The input pipe 11 is connected to the batching chamber in the batching center tube 2, and the output pipe 12 is connected to the lower port of the batching center tube 2. A collecting pipe 13 is fixedly installed on the side of the separation tank 1, and the liquid outlet end of the magnetic control valve 8 is connected to the collecting pipe 13.

[0045] The control valve 4 includes a guide ring 22 and a conical plug 23. The guide ring 22 is fixedly installed in the batching center tube 2, and the conical plug 23 is slidably installed in the batching center tube 2. An electric telescopic rod 24 is fixedly installed inside the output pipe 12. The telescopic end of the electric telescopic rod 24 is rotatably connected to the shaft rod at the bottom of the conical plug 23. The conical end of the conical plug 23 can be inserted into the inner hole of the guide ring 22. The electric telescopic rod 24 drives the conical plug 23 to move up and down, thereby realizing the opening and closing of the control valve 4.

[0046] The lower surface of the elution tube 5 is provided with a discharge window, and a replaceable filter membrane assembly 28 is installed in the discharge window. A brush plate 25 is fixedly installed on the surface of the control rod 7. The brush plate 25 is in sliding contact with the upper surface of the filter membrane assembly 28. 磁 It is positively correlated with the movement speed V of the centripetal controller 6. The action of the centripetal controller 6 is controlled by adjusting the rotation speed of the central barrel 2. When the speed V changes, the centripetal controller 6 drives the control rod 7 to move back and forth, so that the brush plate 25 can clean the blockage on the surface of the filter membrane assembly 28, realizing real-time clearing of blockages during the elution and separation process.

[0047] An annular tube 26 is provided at the lower side of the elution tube 5, and the discharge window of each elution tube 5 is connected to the annular tube 26. The valve body 18 of the magnetic control valve 8 is fixedly connected to the annular tube 26, and is connected to the annular tube 26 to achieve communication with each elution tube 5. A collecting groove 27 is fixedly installed inside the separation tank 1, and the upper side of the collecting groove 27 is an annular notch. The outlet end of the magnetic control valve 8 extends into the annular notch, and the inlet end of the collecting tube 13 is connected to the collecting groove 27, that is, the material discharged from the liquid outlet end of the magnetic control valve 8 can be discharged from the collecting tube 13.

[0048] In this embodiment, the elution tube 5 is arranged at an angle. Figure 6 or Figure 8 As shown, the angle between the axis line of the elution tube 5 and the radial line of the batching center tube 2 is not less than 30°. The ursodeoxycholic acid preparation and purification device is provided with a plurality of elution tubes 5 around the batching center tube 2. The batching center tube 2 rotates forward, and the adsorption resin is loaded into each elution tube 5 by centrifugal force. Then, the batching center tube 2 rotates reversely, and the solution in each elution tube 5 is poured out by the reverse centrifugal force, so as to achieve the effect of more convenient replacement of the adsorption resin. The replaced adsorption resin is cleaned and processed outside the device and reused, so as to meet the industrial production requirements of solvent recycling.

[0049] In this embodiment, a method for preparing and purifying ursodeoxycholic acid is also proposed. Combined with the reference "Ma Xiaolei. Separation and purification of ursodeoxycholic acid [D]. East China University of Science and Technology, 2014.", the separation of ursodeoxycholic acid by dynamic adsorption method using HZ-802 macroporous adsorption resin is understood. Taking the conversion of 7-ketolithocholic acid into crude ursodeoxycholic acid (ursodeoxycholic acid content 47%) by electroreduction as an example, the crude ursodeoxycholic acid is separated and purified, comprising the following specific steps:

[0050] S1, column loading, the pre-treated adsorption resin solution is introduced into the batching chamber of the batching center tube 2 through the input pipe 11, the servo motor 3 is started, and the batching center tube 2 is driven to rotate at a speed of V1 to achieve dynamic balance, and the adsorption resin solution is loaded into each elution tube 5 under the action of centrifugal force, and the control valve 4 is opened to discharge the excess solution in the batching chamber. Figure 7 As shown in (a);

[0051] S2, sample loading, servo motor 3 speed adjustment, drive batching center tube 2 to rotate at speed V2, V2>V1, centripetal controller 6 pushes control rod 7 to extend, push part of solution in elution tube 5 into batching center tube 2, and discharge from output tube 12, as shown in Figure 7 As shown in (b), then, the control valve 4 is closed, the speed V1 of the batching center cylinder 2 is restored, the ursodeoxycholic acid crude solution is introduced into the batching chamber of the batching center cylinder 2 through the input pipe 11, the ursodeoxycholic acid crude solution is loaded into each elution tube 5, and the control valve 4 is opened to discharge the excess solution in the batching chamber. Figure 7 As shown in (c);

[0052] S3, elution, the methanol eluent is introduced into the batching chamber of the batching center tube 2 through the input pipe 11, such as Figure 7 As shown in (d); Reference Fig. 9 , ursodeoxycholic acid is adsorbed by the adsorption resin, 7-ketolithocholic acid is preferentially eluted by the eluent, and is discharged from the magnetic control valve 8 through the filter membrane assembly 28 (0.45 μm microporous filter membrane) with the eluent, and then ursodeoxycholic acid is eluted, refer to Fig.10 The elution curve is obtained by controlling the opening and closing of the magnetic control valve 8 by the excitation coil 10, controlling the liquid discharge speed of the eluent, storing the recovered liquid in different collection bottles according to the time gradient, determining the collection bottle containing ursodeoxycholic acid by liquid chromatography, and obtaining the ursodeoxycholic acid separation product by drying and crystallization;

[0053] In step S3, the rotation speed of the servo motor 3 driving the batching center tube 2 is changed, and the control rod 7 is linked to the telescopic action to adjust the column distance (H1 / H2) of the elution tube 5, that is, the height-to-diameter ratio of the chromatography column is adjustable, and the height-to-diameter ratio H1 / S of the inner volume of the elution tube 5 is less than H2 / S, S is the cross-sectional difference between the inner cavity cross-section of the elution tube 5 and the cross-sectional difference of the control rod 7, and the reference Figure 4 , Fig.10 , obviously, Fig.10 In the middle figure h, the height-to-diameter ratio H2 / S is larger, which makes it easier to elute and separate ursodeoxycholic acid. The height-to-diameter ratio of the chromatography column is not the larger the better. The larger the height-to-diameter ratio of the chromatography column, the longer the adsorption time and the better the separation effect. However, if the chromatography column is too long, the pressure drop is large and the separation time cost is high. If the height-to-diameter ratio of the chromatography column is small, the adsorption time is short and the separation effect is not ideal. What needs to be strengthened is that the injection volume, elution flow rate, height-to-diameter ratio of the chromatography column and pH value directly affect the separation effect of ursodeoxycholic acid during the elution process and cannot be ignored. Among them, the injection volume, elution flow rate and pH value can be changed at any time, but the height-to-diameter ratio of the chromatography column is fixed and cannot be adjusted at any time. To change the height-to-diameter ratio of the chromatography column, the column must be replaced. This is also the reason why it is inconvenient to frequently pour out or load the adsorption resin into the chromatography column and is not suitable for industrial mass production.

[0054] S4, the adsorption resin solution is replaced, the servo motor 3 rotates in the reverse direction, driving the batching center tube 2 to rotate in the reverse direction, and the solution in the elution tube 5 flows back to the batching center tube 2 (refer to Figure 8 ), and then discharged from the output pipe 12, and step S1 is repeated to load the new adsorption resin solution into the column.

[0055] It should be noted that the purification method proposed in the present invention is applicable to the case where the adsorption force and resolution force of the substance to be separated on the adsorption resin are different, or the pore size of the adsorption resin has different selectivity for the substance to be separated.

[0056] The method for preparing and purifying ursodeoxycholic acid sequentially performs column loading, sample loading and elution in a separation tank 1 without stopping the machine for operation, simplifies column loading and column replacement operations, solves the problem that the separation and purification process in the prior art is complicated and unsuitable for batch production, and greatly improves the production efficiency of batch purification of ursodeoxycholic acid.

[0057] The ursodeoxycholic acid preparation and purification device is provided with a centripetal controller 6 at the end of the elution tube 5. The central barrel 2 of the batching material rotates at different speeds. The centripetal controller 6 provides different centripetal forces for the control rod 7, driving the control rod 7 to extend and retract in the elution tube 5. The extension and retraction of the control rod 7 not only has the function of controlling the capacity of the adsorption resin and the object to be separated in the elution tube 5, but also has the function of adjusting the height-to-diameter ratio of the inner volume of the elution tube 5. As the elution separation proceeds, the concentration of the object to be separated decreases. The chromatographic column with the original height-to-diameter ratio is always used for elution separation. Although the adsorption separation effect is good, the chromatographic column is too long, the pressure drop is large, the production time cost is high, and it is not conducive to improving the production efficiency.

[0058] The centripetal controller 6 design of the present invention realizes the linkage control of the rotation of the central barrel 2 of the ingredients and the telescopic action of the control rod 7. By adjusting the rotation speed of the servo motor 3, the elution can be adjusted differently according to the different adsorption forces and analytical forces of the substances to be separated on the adsorption resin, thus providing conditions for automated elution and separation.

[0059] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. An ursodeoxycholic acid preparation and purification device, comprising a separation tank (1), characterized in that: A batching center cylinder (2) is rotatably mounted inside the separation tank (1), a servo motor (3) is fixedly mounted inside the separation tank (1), and the servo motor (3) drives the batching center cylinder (2) to rotate in a forward or reverse direction. A control valve (4) is arranged inside the batching center cylinder (2), and the upper side of the control valve (4) is a batching chamber. A plurality of elution tubes (5) are fixedly mounted on the surface of the batching center cylinder (2), and each elution tube (5) is connected to the batching chamber. A centripetal controller (6) is fixedly mounted at the end of each elution tube (5), and a control rod (7) is slidably mounted inside the centripetal controller (6), and the control rod (7) extends into the inner cavity of the elution tube (5); The centripetal controller (6) comprises a mounting base block (14) fixedly connected to the elution tube (5); a ferromagnetic transmission shaft (15) is slidably mounted inside the mounting base block (14); the control rod (7) is fixedly connected to the transmission shaft (15) coaxially; an electromagnetic coil (16) is fixedly mounted inside the mounting base block (14); the electromagnetic coil (16) is arranged around the transmission shaft (15); a wire group (17) is embedded at the end of the mounting base block (14); the wire group (17) is electrically connected to the electromagnetic coil (16); A magnetically controlled valve (8) is fixedly mounted on the lower side of the elution tube (5) and is in communication with the inner cavity of the elution tube (5); A permanent magnet block (9) and an excitation coil (10) in a ring array are fixedly installed inside the separation tank (1), the permanent magnet block (9) controls the action of the centripetal controller (6), and the excitation coil (10) controls the opening and closing of the magnetic control valve (8); An input pipe (11) and an output pipe (12) are fixedly mounted at the upper and lower ends of the separation tank (1), respectively; the input pipe (11) is in communication with a batching chamber in a batching center tube (2), and the output pipe (12) is in communication with a lower end of the batching center tube (2); a collecting pipe (13) is fixedly mounted on the side of the separation tank (1), and materials discharged from the liquid outlet end of the magnetic control valve (8) can be discharged from the collecting pipe (13).

2. The ursodeoxycholic acid preparation and purification device according to claim 1, characterized in that: The magnetically controlled valve (8) comprises a valve body (18), a valve plate (19) being slidably mounted inside the valve body (18), a magnetic column (20) being fixedly mounted on the side of the valve plate (19), and a return spring (21) being fixedly mounted inside the valve body (18), the return spring (21) being pressed against the end of the magnetic column (20), so that the valve plate (19) is in a flow-blocking state inside the valve body (18).

3. The ursodeoxycholic acid preparation and purification device according to claim 2, characterized in that: The servo motor (3) drives the batching center cylinder (2) to rotate through the transmission of the synchronous wheel and the synchronous belt, and the angle between the axis line of the elution tube (5) and the radial line of the batching center cylinder (2) is not less than 30 degrees.

4. The ursodeoxycholic acid preparation and purification device according to claim 3, characterized in that: The control valve (4) comprises a guide ring (22) and a conical plug (23); the guide ring (22) is fixedly mounted in the batching center tube (2); the conical plug (23) is slidably mounted in the batching center tube (2); an electric telescopic rod (24) is fixedly mounted inside the output pipe (12); the telescopic end of the electric telescopic rod (24) is rotatably connected to the shaft rod at the bottom of the conical plug (23); and the conical end of the conical plug (23) can be inserted into the inner hole of the guide ring (22).

5. The ursodeoxycholic acid preparation and purification device according to claim 4, characterized in that: The lower surface of the elution tube (5) is provided with a discharge window, and a replaceable filter membrane assembly (28) is installed in the discharge window. A brush plate (25) is fixedly installed on the surface of the control rod (7), and the brush plate (25) is in sliding contact with the upper surface of the filter membrane assembly (28). An annular tube (26) is provided on the lower side of the elution tube (5), and the discharge window of each elution tube (5) is connected to the annular tube (26). The valve body (18) of the magnetic control valve (8) is fixedly connected to the annular tube (26), and is connected to the annular tube (26) to achieve communication with each elution tube (5).

6. The ursodeoxycholic acid preparation and purification device according to claim 5, characterized in that: A collecting tank (27) is fixedly installed inside the separation tank (1), the upper side of the collecting tank (27) is an annular notch, the outlet end of the magnetic control valve (8) extends into the annular notch, and the inlet end of the collecting pipe (13) is in communication with the collecting tank (27).

7. A method for preparing and purifying ursodeoxycholic acid, characterized in that: Using the ursodeoxycholic acid preparation and purification device according to any one of claims 1 to 6, ursodeoxycholic acid crude product is purified and separated, comprising the following specific steps: S1, column loading, the pre-treated adsorption resin solution is introduced into the batching chamber of the batching center cylinder (2) through the input pipe (11), the servo motor (3) is started, and the batching center cylinder (2) is driven to rotate at a speed of V1 to achieve dynamic balance, and the adsorption resin solution is loaded into each elution tube (5) under the action of centrifugal force, and the control valve (4) is opened to discharge the excess solution in the batching chamber; S2, loading, the servo motor (3) is speed-regulated to drive the batching center cylinder (2) to rotate at a speed of V2, the centripetal controller (6) pushes the control rod (7) to extend, and pushes part of the solution in the elution tube (5) into the batching center cylinder (2), and discharges it from the output tube (12), then closes the control valve (4), restores the V1 speed of the batching center cylinder (2), and introduces the ursodeoxycholic acid crude solution into the batching chamber of the batching center cylinder (2) from the input tube (11), and the ursodeoxycholic acid crude solution is loaded into each elution tube (5), and the control valve (4) is opened to discharge the excess solution in the batching chamber; S3, eluting, introducing the eluate into the batching chamber of the batching center cylinder (2) through the input tube (11), controlling the opening and closing of the magnetic control valve (8) by the excitation coil (10), controlling the discharge speed of the eluate, storing the recovered liquid in different collection bottles according to the time gradient, determining the collection bottle containing ursodeoxycholic acid by liquid chromatography, and obtaining the ursodeoxycholic acid separated product by drying and crystallization; S4, replacement of the adsorption resin solution. The servo motor (3) rotates in the reverse direction, driving the batching center cylinder (2) to rotate in the reverse direction. The solution in the elution tube (5) flows back to the batching center cylinder (2) and then is discharged from the output tube (12). Step S1 is repeated to load the new adsorption resin solution into the column.

8. The method for preparing and purifying ursodeoxycholic acid according to claim 7, characterized in that: In the above-mentioned S3, the rotation speed of the servo motor (3) driving the batching center tube (2) is changed, and the control rod (7) is linked to the telescopic action to adjust the column distance of the elution tube (5).

9. An application of a method for preparing and purifying ursodeoxycholic acid, characterized in that: The method for preparing and purifying ursodeoxycholic acid according to claim 7 or 8 is suitable for the case where the adsorption force and resolution force of the substance to be separated on the adsorption resin are different, or the pore size of the adsorption resin has different selectivity for the substance to be separated.

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