A preparation method and device for betamethasone sodium phosphate injection

Abstract

The present invention provides a method for preparing betamethasone sodium phosphate injection, comprising: adding methanesulfonyl chloride and dimethyl phosphate, respectively, into a first chamber; heating to a certain temperature; slowly dripping sodium methanesulfinate into the first chamber; reacting for a period of time; and then adding betamethasone; obtaining the pressures of the first chamber and the second chamber, and determining whether the reaction in the second chamber has reached dissolution equilibrium based on the pressure difference. According to the present invention, by obtaining the pressure difference between the first chamber and the second chamber at the current moment, the solubility at the current moment is obtained using a pressure-solubility model. Based on the solubility at the current moment and the fluctuation range of a preset solubility threshold, the mixing mechanism is adjusted accordingly using the fluctuation range, the solubility, and the mixing efficiency model, so that the reaction process can be precisely controlled and adjusted to improve the quality of the drug.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a preparation method and device for betamethasone sodium phosphate injection. Background Art

[0002] Betamethasone sodium phosphate is a glucocorticoid drug with anti-inflammatory, anti-allergic, and immunosuppressive effects. It can alleviate symptoms caused by inflammation and allergies by inhibiting the release of inflammatory mediators and the occurrence of inflammatory reactions. During its production and preparation, product quality stability is crucial to the final drug quality, and precise control of the reaction process is required to improve the drug's quality. Therefore, the present invention has developed a method and apparatus for preparing betamethasone sodium phosphate injection. Summary of the Invention

[0003] Therefore, the technical problem to be solved by the present invention is to overcome the above-mentioned defects, thereby providing a method and device for preparing betamethasone sodium phosphate injection.

[0004] In order to solve the above problems, the present invention provides a method for preparing betamethasone sodium phosphate injection, which comprises the following steps:

[0005] A reactor, wherein a partition is provided in the reactor to divide the reactor into a first chamber and a second chamber, wherein the first chamber and the second chamber are respectively used for pre-reaction and re-reaction of raw materials;

[0006] The reactor is provided with a feeding port on the top, a mounting plate is provided on the top of the feeding port, a first feeding port and a second feeding port are provided on the mounting plate, and the first feeding port and the second feeding port both extend into the first chamber;

[0007] The reactor is further provided with a liquid adding pipe on the top, a flow regulating valve on the liquid adding pipe, a first pressure pipe is further provided near the side wall of the first chamber, a first regulating valve on the first pressure pipe, and a first pressure sensor is provided in the first chamber;

[0008] A second pressurizing pipe is provided on the side wall of the second chamber, a second regulating valve is provided on the second pressurizing pipe, a drain pipe is provided at the bottom of the second chamber, a stop valve is provided on the drain pipe, and a second pressure sensor is provided in the second chamber;

[0009] A connecting pipe is provided at the center of the partition, and the connecting pipe extends from the first chamber into the second chamber. A first conical surface is provided on the side of the partition close to the first chamber, and a second conical surface is provided on the side of the partition close to the second chamber.

[0010] Two reflux pipes are provided between the first chamber and the second chamber to return the liquid in the second chamber to the first chamber;

[0011] a mixing mechanism, disposed in the second chamber, for further mixing the feed liquid in the second chamber with the feed liquid;

[0012] A control device, wherein the control device is connected to the first regulating valve, the second regulating valve, the first pressure sensor, the second pressure sensor, the stop valve and the mixing mechanism, and is respectively used to adjust the pressure in the first chamber and the second chamber, obtain the pressure in the first chamber and the second chamber, and adjust the mixing efficiency of the mixing mechanism. The control device is also connected to a processor, and the processor is connected to the first pressure sensor and the second pressure sensor.

[0013] Preferably, a stirring rod is horizontally arranged in the first chamber, and both ends of the stirring rod are rotatably connected to the centers of two opposite inner walls of the first chamber respectively. A motor is arranged on the outer wall of the reactor near one end of the stirring rod, and the output shaft of the motor is connected to the stirring rod.

[0014] A jacket is provided on the outer side wall of the reactor close to the first chamber, and a first electric valve is provided on the connecting pipe.

[0015] Preferably, a truncated cone ring is further provided in the feeding port, wherein the end of the truncated cone ring with a larger cross-section is connected to the bottom of the mounting plate, and the end of the truncated cone ring with a smaller cross-section extends into the first chamber and leaves a gap with the side wall of the feeding port.

[0016] Preferably, the two side surfaces of the second chamber are respectively provided with conical extension surfaces extending to both sides, the end with the larger opening of the conical extension surface is connected to the second chamber, and the end with the smaller opening of the conical extension surface is connected to one end of the return pipe, and the other end of the return pipe passes through the feeding port and extends between the frustum ring and the feeding port. A second electric valve is provided on the return pipe, and the electric valve is connected to the control device.

[0017] Preferably, the mixing mechanism includes: a diverter platform and a sliding block, the diverter platform is arranged below the connecting pipe, the diverter platform is provided with a sharp end at one end close to the connecting pipe, the two ends of the diverter platform are respectively connected to the two inner end surfaces of the second chamber, and the two sides of the diverter platform are respectively provided with gaps with the two inner side surfaces of the second chamber.

[0018] Preferably, the sliding block is arranged between the bottom of the second chamber and the diverter table, and slides along the two side surfaces of the second chamber. The two end surfaces of the sliding block are slidingly connected to the two end surfaces of the second chamber. A first sliding groove is provided at the bottom of the second chamber, and a second sliding groove corresponding to the first sliding groove is provided on the side of the diverter table close to the sliding block. The top and bottom of the sliding block are respectively provided with a first sliding part and a second sliding part, and the first sliding part and the second sliding part are slidingly connected to the bottom and side walls of the first sliding groove and the second sliding groove respectively.

[0019] Preferably, the second chamber is provided with an inner cavity on one side of the first sliding groove, a cylinder is provided in the inner cavity, the fixed end of the cylinder is provided in the inner cavity, the telescopic end of the cylinder passes through the inner cavity and extends into the first sliding groove and is connected to the second sliding part.

[0020] The present invention also provides a method for preparing betamethasone sodium phosphate injection, comprising the betamethasone sodium phosphate injection preparation device described in any of the preceding items, comprising:

[0021] S1: Add methylsulfonyl chloride and dimethyl phosphate into the first chamber respectively, heat to a certain temperature, slowly add sodium methanesulfinate dropwise into the first chamber, react for a period of time, and then add betamethasone;

[0022] S2: During the reaction process, the pressure in the first chamber is obtained in real time. The control device determines whether the reaction in the first chamber has reached a dissolution equilibrium state based on the pressure in the first chamber. If so, the liquid in the first chamber is passed into the second chamber for reaction for a period of time before being discharged. If not, the second chamber is used for further reaction to obtain a saturated solution before being discharged.

[0023] S3: During the reaction in the second chamber, the pressures of the first chamber and the second chamber are obtained, and whether the reaction in the second chamber has reached dissolution equilibrium is determined based on the pressure difference. If not, the speed of the mixing mechanism is controlled to adjust the pressure difference so that the reaction in the second chamber reaches dissolution equilibrium. The discharge is heated and concentrated by crystallization, and the product is obtained after it is cooled and crystallized.

[0024] Preferably, in S2, the pressure of the first chamber at the current moment and the pressure of the first chamber at a historical moment are obtained, wherein the pressure moments are before the current moment and the time interval between the pressure moments and the current moment is a preset time length;

[0025] Determining a deviation of the pressure of the reaction space from the historical moment to the current moment based on the pressure at the current moment and the pressure at the historical moment;

[0026] When the deviation is less than or equal to the preset deviation, it is determined that the dissolution reaction in the first chamber has reached a dissolution equilibrium state; and when the deviation is greater than the preset deviation, it is determined that the dissolution reaction in the first chamber has not reached a dissolution equilibrium state.

[0027] Preferably, in S3, the pressure difference between the first chamber and the second chamber at the current moment and the pressure difference between the first chamber and the second chamber at historical moments are obtained, a pressure-solubility model is constructed based on the pressure differences at historical moments and the corresponding solubilities, and the pressure-solubility model is trained using the historical data to obtain the solubility at the current moment;

[0028] Determine the fluctuation range of the preset solubility threshold based on the current solubility, and construct a solubility and mixing efficiency model;

[0029] When the fluctuation range is less than or equal to the preset solubility range, the solubility mixing efficiency model is used to obtain the mixing efficiency corresponding to the mixing mechanism; and when the fluctuation range is greater than the preset solubility range, the solubility mixing efficiency model is used to obtain the mixing efficiency corresponding to the mixing mechanism. At the same time, the pressure in the first chamber is reacquired, and the target pressure in the second chamber is obtained according to the fluctuation range, and the target pressure of the second chamber and the mixing efficiency of the mixing mechanism are adjusted at the same time.

[0030] The method and device for preparing betamethasone sodium phosphate injection provided by the present invention have the following beneficial effects:

[0031] 1. The present invention utilizes two reflux pipes between a first chamber and a second chamber to recirculate the liquid in the second chamber into the first chamber when dissolution equilibrium has not been reached in the second chamber. A mixing mechanism is installed in the second chamber to provide power for the reaction of the liquid in the second chamber, thereby promoting its reaction and dissolution. Furthermore, when dissolution equilibrium has not been reached, the liquid in the second chamber is recirculated into the first chamber for reaction. Furthermore, a control device controls the mixing efficiency of the mixing mechanism, thereby promoting the mixing process of the liquid in the second chamber.

[0032] 2. The present invention also uses a sliding block between the bottom of the second chamber and the diverter table. Its tapered extension surfaces on both sides of the diverter table move closer to or further away from the diverter table, allowing a portion of the liquid to enter the reflux pipe through the tapered extension surface, and then enter the first chamber. At the same time, part of the liquid flows along the tapered extension surface to the gap between the diverter table and the inner wall of the second chamber, forming a different level of action. The diverter table, sliding block, tapered surface, the inner wall of the second chamber, and the second tapered surface cooperate to form a different level of internal circulation flow, thereby promoting the reaction of the liquid in the second chamber.

[0033] 3. The present invention also obtains the pressure difference between the first chamber and the second chamber at the current moment, uses the pressure-solubility model to obtain the solubility at the current moment, and adjusts the mixing mechanism accordingly based on the solubility at the current moment and the fluctuation range of the preset solubility threshold through the fluctuation range, solubility and mixing efficiency model, so that the reaction process can be accurately controlled and adjusted to improve the quality of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is a schematic structural diagram of the device for preparing betamethasone sodium phosphate injection of the present invention;

[0035] Figure 2 Schematic diagram of the liquid surging process in the first chamber and the second chamber of the present invention;

[0036] Figure 3 The present invention is a schematic flow chart of the preparation method of betamethasone sodium phosphate injection.

[0037] The reference numerals indicate:

[0038] 1. Reactor; 2. Partition; 3. First chamber; 4. Second chamber; 5. Feed port; 6. Mounting plate; 7. Cone ring; 8. First feed port; 9. Second feed port; 10. Stirring rod; 12. Jacket; 13. Liquid feeding pipe; 14. Flow regulating valve; 15. First pressurizing pipe; 16. First regulating valve; 17. Connecting pipe; 18. First conical surface; 19. Second conical surface; 20. Reflux pipe; 21. Conical extension surface; 22. Diverter; 23. Sliding block; 24. Sharp end; 25. Second sliding groove; 26. First sliding groove; 27. Second sliding part; 28. First sliding part; 29. ​​Second pressurizing pipe; 30. Second regulating valve; 31. Drain pipe; 32. Stop valve; 33. Second electric valve; 34. First electric valve. DETAILED DESCRIPTION

[0039] like Figure 1-3 As shown, the present invention provides a method for preparing betamethasone sodium phosphate injection, which comprises the following steps:

[0040] The reactor is provided with a partition 2 to divide the reactor into a first chamber 3 and a second chamber 4, the first chamber 3 and the second chamber 4 are used for the pre-reaction and re-reaction of the raw materials respectively; the top of the reactor is provided with a feeding port 5, the top of the feeding port 5 is provided with a mounting plate 6, the mounting plate 6 is provided with a first feeding port 8 and a second feeding port 9, respectively, the first feeding port 8 and the second feeding port 9 both extend into the first chamber 3; the top of the reactor is also provided with a liquid adding pipe 13, the liquid adding pipe 13 is ... 3 is provided with a flow regulating valve 14, a first pressurizing pipe 15 is further provided near the side wall of the first chamber 3, a first regulating valve 16 is provided on the first pressurizing pipe 15, and a first pressure sensor is provided in the first chamber 3; a second pressurizing pipe 29 is provided on the side wall of the second chamber 4, a second regulating valve 30 is provided on the second pressurizing pipe 29, a drain pipe 31 is further provided at the bottom of the second chamber 4, a stop valve 32 is provided on the drain pipe 31, and a second pressure sensor is provided in the second chamber 4; the partition A connecting pipe 17 is provided in the center of the plate 2, and the connecting pipe 17 extends from the first chamber 3 into the second chamber 4. A first conical surface 18 is provided on the side of the partition plate 2 close to the first chamber 3, and a second conical surface 19 is provided on the side of the partition plate 2 close to the second chamber 4. Two reflux pipes 20 are provided between the first chamber 3 and the second chamber 4 to send the material liquid in the second chamber 4 back into the first chamber 3. A mixing mechanism is provided in the second chamber 4, and the mixing mechanism is used to further mix the material liquid and the material liquid in the second chamber 4. A control device is connected to the first regulating valve 16, the second regulating valve 30, the first pressure sensor, the second pressure sensor, the stop valve 32 and the mixing mechanism, and is used to adjust the pressure in the first chamber 3 and the second chamber 4, obtain the pressure in the first chamber 3 and the second chamber 4, and adjust the mixing efficiency of the mixing mechanism. The control device is also connected to a processor, and the processor is connected to the first pressure sensor and the second pressure sensor. Figure 1-2As shown, the reactor is used to prepare betamethasone sodium phosphate injection, and the partition 2 horizontally arranged in the reactor divides the internal space of the reactor into a first chamber 3 and a second chamber 4, so that the pre-reaction and re-reaction of the raw materials for preparing betamethasone sodium phosphate injection are respectively carried out in the first chamber 3 and the second chamber 4, so as to accurately control and adjust the progress of the reaction; wherein, a feeding port 5 is provided on the top of the reactor, and a first feeding port 8 and a second feeding port 9 are provided on the mounting plate 6 provided at the feeding port 5, and the first feeding port 8 and the second feeding port 9 extend into the first chamber 3 of the reactor, and switch valves are provided outside the first feeding port 8 and the second feeding port 9 to maintain the pressure in the first chamber 3, and the first feeding port 8 and the second feeding port 9 are respectively used for feeding Methylsulfonamide and dimethyl phosphate are added; wherein, the liquid adding pipe 13 is used to add sodium methanesulfinate thereto, and the flow regulating valve 14 on the liquid adding pipe 13 can change the rate of sodium methanesulfinate addition, so as to adjust the adaptive amount according to the reaction progress in the first chamber 3; the first pressurizing pipe 15 provided on the side wall of the first chamber 3 passes nitrogen into the first chamber 3 to provide nitrogen protection, and at the same time, the pressure in the first chamber 3 can be adjusted, and the first pressure sensor is commercially available for obtaining the pressure of the first chamber 3 in real time and feeding it back to the processor for processing; wherein, the second pressurizing pipe 29 of the second chamber 4 is used to pass nitrogen into the second chamber 4 to provide nitrogen protection, and at the same time, the pressure in the second chamber 4 can be adjusted, and the second pressure sensor The sensor is commercially available and is used to obtain the pressure of the second chamber 4 in real time and feed it back to the processor for processing. A drain pipe 31 is set at the bottom of the second chamber 4, and when the reaction in the second chamber 4 is completed, the liquid is discharged to the crystallization treatment through it; wherein, a connecting pipe 17 is set in the center of the partition 2, and the connecting pipe 17 extends from the first chamber 3 into the second chamber 4. When the pre-reaction in the first chamber 3 is completed, the first conical surface 18 at the bottom of the first chamber 3 gathers the liquid of the first chamber 3 to the connecting pipe 17 in the center of the partition 2, and enters the second chamber 4 for further reaction. The second conical surface 19 in the second chamber 4 is used to prevent the solution from hanging on the top of the second chamber 4 during the reaction in the second chamber 4, so as not to affect the dissolution of the solution in the second chamber 4. The first conical surface 18 and The shape of the second conical surface 19 is that the circumference is higher than the center; wherein, the two reflux pipes 20 between the first chamber 3 and the second chamber 4 are used to return the material liquid in the second chamber 4 to the first chamber 3 when the dissolution equilibrium is not reached in the second chamber 4, wherein the mixing mechanism is installed in the second chamber 4 to provide power for the reaction of the material liquid in the second chamber 4 to promote its reaction and dissolution. At the same time, when the material liquid in the second chamber 4 does not reach the dissolution equilibrium, the material liquid in the second chamber 4 is returned to the first chamber 3 for reaction. At the same time, the mixing efficiency of the mixing mechanism is controlled by the control device, which can promote the mixing process of the material liquid in the second chamber 4; wherein, the control device is connected to the processor, and the processor is used to convert the sensor signal into corresponding digital information.

[0041] In some embodiments, a stirring rod 10 is horizontally arranged in the first chamber 3, and the two ends of the stirring rod 10 are respectively connected to the center of the two opposite inner walls of the first chamber 3 for rotation. A motor is arranged on the outer wall of the reactor near one end of the stirring rod 10, and the output shaft of the motor is connected to the stirring rod 10; a jacket 12 is arranged on the outer wall of the reactor near the outside of the first chamber 3, and a first electric valve 34 is arranged on the connecting pipe 17. Figure 1-2 As shown, a corresponding stirring blade is provided on the stirring rod 10, and the shape of the stirring blade can be spiral, double spiral or plate-frame type. The stirring rod 10 is driven to rotate by a motor on the outer wall of the reactor in the first chamber 3. The motor is installed on the outer wall of the reactor, and the motor is commercially available. The output shaft of the motor and the stirring rod 10 are connected by a coupling. After the raw materials are added to the first chamber 3, the working state and working parameters of the motor connected thereto are controlled by the control device, so that the stirring rate of the stirring blade on the stirring rod 10 on the material liquid in the first chamber 3 can be controlled, thereby further promoting the mixing and reaction of the material liquid in the first chamber 3. A jacket 12 is provided on the outer wall of the reactor outside the first chamber 3, and the jacket 12 is used to pass corresponding hot water. The hot water in the jacket 12 transfers temperature to the first chamber 3 in a water bath manner to promote the reaction. The first electric valve 34 provided on the connecting pipe 17 is connected to the control device, and the control device controls the first electric valve 34 to realize whether it flows.

[0042] In some embodiments, a truncated cone ring 7 is further provided in the feeding port 5, wherein the end of the truncated cone ring 7 with a larger cross-section is connected to the bottom of the mounting plate 6, and the end of the truncated cone ring 7 with a smaller cross-section extends into the first chamber 3 and leaves a gap with the side wall of the feeding port 5. Figure 1-2 As shown, the conical ring 7 of the feeding port 5 is arranged relative to the feeding port 5, and its end with a larger cross-section is connected to the bottom of the mounting plate 6, and the end with a smaller cross-section extends into the first chamber 3, so that the conical ring 7 and the feeding port 5 form a sandwich relative to each other. When the reflux pipe 20 sends the material liquid from the second chamber 4 to the first chamber 3, the reflux pipe 20 transports it to between the feeding port 5 and the conical ring 7, avoiding affecting the addition of raw materials through the first feeding port 8 and the second feeding port 9. At the same time, the gap between the conical ring 7 and the feeding port 5 promotes the material liquid to enter the first chamber 3 along the gap.

[0043] Specifically, the reflux pipe 20 is a continuous curved pipe, and the central angle of the curved section of the reflux pipe 20 is less than 45°. When the material and liquid in the second chamber 4 flows from the reflux pipe 20 to the first chamber 3 under the action of the mixing mechanism, when the central angle of the curved section of the reflux pipe 20 is less than 45°, the local resistance generated in the curved section has a relatively small effect on the resistance generated when the material and liquid in the reflux pipe 20 flows. When it is connected through multiple sections of continuous curved pipes, the material and liquid in the second chamber 4 can smoothly return to the first chamber 3 to react and dissolve again.

[0044] In some embodiments, the two sides of the second chamber 4 are respectively provided with conical extension surfaces 21 extending to both sides, the end of the conical extension surface 21 with a larger opening is connected to the second chamber 4, and the end of the conical extension surface 21 with a smaller opening is connected to one end of the return pipe 20, and the other end of the return pipe 20 passes through the feeding port 5 and extends between the frustum ring 7 and the feeding port 5. The return pipe 20 is provided with a second electric valve 33, and the electric valve is connected to the control device. Figure 1-2 As shown, conical extension surfaces 21 diffracting toward both sides are provided on both sides of the second chamber 4. After axial cutting, the end of the conical extension surface 21 with a larger opening is close to the second chamber 4, so that the conical extension surface 21 is connected to the second chamber 4, and the end of the conical extension surface 21 with a smaller opening is connected to one end of the reflux pipe 20. The reflux pipe 20 accumulates and converges the material liquid in the second chamber 4 to the conical extension surfaces 21 on both sides through the mixing mechanism. At this time, the material liquid in the second chamber 4 forms vortices toward the two conical extension surfaces 21 respectively. The vortices follow the conical extension surfaces 21 and then move upward toward the two side walls of the second chamber 4, and then return to the bottom of the second chamber 4 along the top of the second chamber 4. Part of the vortex passes through the reflux pipe 20 and enters between the frustum ring 7 and the feeding port 5 along the reflux pipe 20, so that the material liquid in the second chamber 4 forms a surge, which promotes its dissolution and reaction. At the same time, the second electric valve 33 on the reflux pipe 20 is connected to the control device to control the circulation of the reflux pipe 20.

[0045] In some embodiments, the mixing mechanism includes: a diverter 22 and a sliding block 23. The diverter 22 is arranged below the connecting pipe 17. The diverter 22 is provided with a sharp end 24 at one end close to the connecting pipe 17. The two ends of the diverter 22 are respectively connected to the two inner end surfaces of the second chamber 4. The two sides of the diverter 22 are respectively provided with gaps between the two inner side surfaces of the second chamber 4. Figure 1-2As shown, the axial cross-section of the diverter table 22 of the mixing mechanism is in the shape of an isosceles triangle, and the front and rear end faces of the diverter table 22 are connected to the second chamber 4, while the other two side faces are arranged in a gap with the inner wall of the second chamber 4, so that its sharp end 24 is located directly below the connecting pipe 17. The material liquid entering the second chamber 4 through the connecting pipe 17 first passes through the diverter table 22 and is diverted to both sides, and then flows along the diverter table 22 to its gap, and then converges to the bottom of the second chamber 4. At the same time, when the material liquid at the bottom of the diverter table 22 in the second chamber 4 passes through the surge of the mixing mechanism, the position of the diverter table 22 cooperates with the second chamber 4, the conical extension surfaces 21 on both sides and the second conical surface 19 to form different surge layers to promote the mixing and dissolution of the material liquid in the second chamber 4.

[0046] In some embodiments, the sliding block 23 is disposed between the bottom of the second chamber 4 and the diverter 22, and slides along the two side surfaces of the second chamber 4. The two end surfaces of the sliding block 23 are slidably connected to the two end surfaces of the second chamber 4. A first sliding groove 26 is provided at the bottom of the second chamber 4, and a second sliding groove 25 corresponding to the first sliding groove 26 is provided on the side of the diverter 22 close to the sliding block 23. A first sliding portion 28 and a second sliding portion 27 are provided at the top and bottom of the sliding block 23, respectively. The first sliding portion 28 and the second sliding portion 27 are slidably connected to the bottom and side walls of the first sliding groove 26 and the second sliding groove 25, respectively. Figure 1-2 As shown, the sliding block 23 is between the bottom of the second chamber 4 and the diverter 22, and its tapered extension surfaces 21 on both sides of the diverter 22 are respectively close to or away from. When the sliding block 23 approaches the tapered extension surface 21 on one side, it moves away from the tapered extension surface 21 on the other side. The side that is close pushes the liquid between them, so that a part of it enters the reflux pipe 20 through the tapered extension surface. When this part of the liquid enters the tapered extension surface 21, the cross-section of the tapered extension surface 21 is relatively reduced due to the movement of the liquid under the push of the sliding block 23. The slurry in the conical extension surface 21 is backlogged by the subsequent slurry and the sliding block 23, so that after entering the reflux pipe 20, the slurry in the reflux pipe 20 is accelerated, making it easier for the slurry to enter the first chamber 3; at the same time, part of the slurry flows along the conical extension surface 21 to the gap between the diverter 22 and the inner wall of the second chamber 4, forming different levels of effects, cooperating with the diverter 22, the sliding block 23, the conical surface, the inner wall of the second chamber 4 and the second conical surface 19, to form different levels of internal circulation flow, thereby promoting the reaction of the slurry in the second chamber 4.

[0047] Specifically, the sliding block 23 slides with the first sliding groove 26 and the second sliding groove 25 through the first sliding part 28 at the top and the second sliding part 27 at the bottom. It should be noted that the sliding block 23 and the first sliding part 28 and the second sliding part 27 divide the second chamber 4 at the bottom of the diverter table 22 on both sides. The material liquid at the bottom of the diverter table 22 cannot be directly divided into two parts in the second chamber 4 by the sliding block 23. It can only be adjusted on both sides of the sliding block 23 after it passes through the gap between the diverter table 22 and the inner wall of the second chamber 4 during the movement of the sliding block 23 and is diverted through the diverter table 22.

[0048] In some embodiments, the second chamber 4 is provided with an inner cavity on one side of the first sliding groove 26, a cylinder is provided in the inner cavity, the fixed end of the cylinder is provided in the inner cavity, the telescopic end of the cylinder passes through the inner cavity and extends into the first sliding groove 26 and is connected to the second sliding portion 27. Figure 1-2 As shown, an inner cavity is provided on one side of the first sliding groove 26 of the second chamber 4, so that it forms an independent space, which is convenient for installing the cylinder. The cylinder is commercially available, and the fixed end of the cylinder is provided in the inner cavity, so that only the telescopic end of the cylinder slides through the inner cavity and extends into the first sliding groove 26 and is connected to the second sliding part 27. A sliding sealing ring is provided between the telescopic end of the cylinder and the inner cavity, and then, the sliding block 23 is driven to reciprocate between the two conical extension surfaces 21 by the telescopic movement of the cylinder, wherein the cylinder is connected to the control device to control the speed of its cylinder movement. When the speed of its cylinder movement is different, the force generated on the conical extension surface 21 is also different.

[0049] The present invention also provides a method for preparing betamethasone sodium phosphate injection, comprising the betamethasone sodium phosphate injection preparation device described in any of the preceding items, comprising:

[0050] S1: adding methylsulfonyl chloride and dimethyl phosphate into the first chamber 3 respectively, heating to a certain temperature, slowly adding sodium methanesulfinate dropwise into the first chamber 3, reacting for a period of time, and then adding betamethasone;

[0051] S2: During the reaction process, the pressure in the first chamber 3 is obtained in real time. The control device determines whether the reaction in the first chamber 3 has reached a dissolution equilibrium state based on the pressure in the first chamber 3. If so, the liquid in the first chamber 3 is passed into the second chamber 4 for reaction for a period of time before being discharged. If not, the second chamber 4 is used for further reaction to obtain a saturated solution before being discharged.

[0052] S3: During the reaction of the second chamber 4, the pressures of the first chamber 3 and the second chamber 4 are obtained, and the pressure difference is used to determine whether the reaction in the second chamber 4 has reached a dissolution equilibrium. If not, the speed of the mixing mechanism is controlled to adjust the pressure difference so that the reaction in the second chamber 4 reaches a dissolution equilibrium. The discharged product is heated and concentrated by crystallization, and the product is obtained after cooling and crystallization. Figure 3 As shown, for example, at the beginning of the reaction, deionized water is first introduced into the first chamber 3, the amount of deionized water being 73 times the weight of the added sodium methanesulfinate, and hot water at 50°C is introduced into the jacket 12. The first electric valve 34 and the second electric valve 33 are closed, and methanesulfonyl chloride and dimethyl phosphate are added into the first chamber 3 through the first feeding port 8 and the second feeding port 9 at a molar ratio of 1-3:2-5. The mixture is heated to 40-60°C and kept at a constant temperature. The mixture is stirred for 45 minutes using the stirring blade on the stirring rod 10 at a speed of 200-500 rpm. The flow regulating valve 14 is controlled so that the mixture is added through the liquid adding pipe 13 at a rate of 0.5-2 mL / min. Sodium methanesulfinate is added to the first chamber 3 at a molar ratio of 1-3:1.5-4 to methanesulfonyl chloride, and heating and reaction are continued using the jacket 12 until the sodium methanesulfinate is completely added. After stopping heating and continuing stirring for 10 minutes, betamethasone is continued to be added to the methanesulfonyl chloride at a molar ratio of 1:1 through the first feeding port 8, and the reaction is carried out for 20 minutes. Before the reaction starts, nitrogen is introduced into the first chamber 3 through the first pressurized pipe 15 to maintain the pressure in the first chamber 3 within the required pressure range. When sodium methanesulfinate is added, the dropping speed is dynamically adjusted according to the reaction exotherm to avoid local overheating.

[0053] Specifically, during the reaction process, the first pressure sensor is used to obtain the pressure in the first chamber 3 in real time, and the data sampling frequency is 10 times / minute. The control device determines whether the reaction in the first chamber 3 reaches the dissolution equilibrium state based on the pressure in the first chamber 3. If so, the stop valve 32 is closed and the first electric valve 34 is opened, and the material liquid in the first chamber 3 is passed into the second chamber 4 to react for a period of time and then discharged; if not, the second chamber 4 is used to react again to obtain a saturated solution and then discharged.

[0054] Specifically, during the reaction process of the second chamber 4, the pressures of the first chamber 3 and the second chamber 4 are obtained, and it is judged whether the reaction in the second chamber 4 has reached a dissolution equilibrium based on the pressure difference. If not, the speed of the mixing mechanism is controlled to adjust the pressure difference so that the reaction in the second chamber 4 reaches a dissolution equilibrium, and the stop valve 32 is opened to discharge the liquid through the drain pipe 31 at the bottom of the second chamber 4. The discharge point is heated and concentrated by crystallization method, and the product is obtained after it is cooled and crystallized.

[0055] In some embodiments, in S2, the pressure of the current first chamber 3 at the current moment and the pressure of the first chamber 3 at a historical moment are obtained, wherein the pressure moment is before the current moment and the time interval between the pressure and the current moment is a preset time length; the deviation of the pressure of the reaction space from the historical moment to the current moment is determined based on the pressure at the current moment and the pressure at the historical moment; when the deviation is less than or equal to the preset deviation, it is determined that the dissolution reaction of the first chamber 3 has reached a dissolution equilibrium state; and when the deviation is greater than the preset deviation, it is determined that the dissolution reaction in the first chamber 3 has not reached a dissolution equilibrium state.

[0056] Specifically, if Figure 3 As shown, based on the pressure of the first chamber 3 at the current moment and the pressure of the first chamber 3 at the historical moment, wherein the pressure moment is before the current moment and the time interval with the current moment is a preset time length; the deviation of the pressure of the reaction space from the historical moment to the current moment is determined according to the pressure at the current moment and the pressure at the historical moment; when the deviation is less than or equal to the preset deviation, it is determined that the dissolution reaction of the first chamber 3 has reached the dissolution equilibrium state, thereby closing the stop valve 32 and opening the first electric valve 34, and then the material liquid in the first chamber 3 is passed into the second chamber 4 to react for a period of time and then discharged through the drain pipe 31 at the bottom of the second chamber 4, and the discharge point is heated and concentrated by crystallization method, and after it is cooled and crystallized, a product is obtained.

[0057] The saturated solution discharged from the second chamber is concentrated under reduced pressure at 60-80° C. to 1 / 3 of the original volume; cooled to 10-20° C. and allowed to stand for 12-24 hours; filtered to separate crystals; and dried to obtain the finished betamethasone sodium phosphate product.

[0058] Specifically, if Figure 3As shown, based on the pressure of the first chamber 3 at the current moment and the pressure of the first chamber 3 at the historical moment, wherein the pressure moment is located before the current moment and the time interval with the current moment is a preset time length; the deviation of the pressure of the reaction space from the historical moment to the current moment is determined according to the pressure at the current moment and the pressure at the historical moment; when the deviation is greater than the preset deviation, it is determined that the dissolution reaction in the first chamber 3 has not reached the dissolution equilibrium state, the stop valve 32 is closed and the first electric valve 34 is opened, and the material liquid in the first chamber 3 is passed into the second chamber 4, and the state and parameters of the cylinder are controlled by the control device so that it works at different rates. When the rate of extension and contraction of the telescopic end of the cylinder is small, the sliding block 23 only moves toward the two conical extension surfaces 21 During the movement, its force can only make the material liquid entering the reflux pipe 20 move for a period of time in the reflux pipe 20 and then fall back. At the same time, part of it surges between the tapered extension surface 21 and the diverter 22. Due to the action of the diverter 22, the tapered extension surface 21, the second chamber 4 and the second tapered surface 19, multi-level surges with different forces are formed, which promotes the reaction of the material liquid in the second chamber 4; specifically, when the speed of the telescopic end of the cylinder is large, not only different levels of surges are formed in the second chamber 4, but it can also enter the first chamber 3 through the reflux pipe 20, continue to use the jacket 12 to heat it in a water bath and use the stirring blades on the stirring rod 10 to stir it, and use the second chamber 4 to match the first chamber 3 to promote its rapid dissolution and reaction to achieve dissolution equilibrium.

[0059] In some embodiments, in said S3, the pressure difference between the current first chamber 3 and the second chamber 4 at the current moment and the pressure difference between the first chamber 3 and the second chamber 4 at the historical moment are obtained, the pressure difference at the historical moment and the corresponding solubility are used to construct a pressure-solubility model, and the pressure-solubility model is trained using historical data to obtain the solubility at the current moment; the fluctuation range of the preset solubility threshold is determined according to the current solubility, and a solubility and mixing efficiency model is constructed; when the fluctuation range is less than or equal to the preset solubility range, the mixing efficiency corresponding to the mixing mechanism is obtained using the solubility mixing efficiency model; and when the fluctuation range is greater than the preset solubility range, the mixing efficiency corresponding to the mixing mechanism is obtained using the solubility mixing efficiency model, and at the same time, the pressure in the first chamber 3 is re-obtained, and the target pressure in the second chamber 4 is obtained according to the fluctuation range, and the target pressure of the second chamber 4 and the mixing efficiency of the mixing mechanism are adjusted at the same time. Figure 3 As shown, by obtaining the pressure difference between the first chamber 3 and the second chamber 4 at the current moment, the solubility at the current moment is obtained using the pressure-solubility model, and the solubility at the current moment and the fluctuation range of the preset solubility threshold are adjusted accordingly based on the fluctuation range, solubility and mixing efficiency model, so that the reaction process can be accurately controlled and adjusted to improve the quality of the drug.

[0060] This application solves the problems of delayed dissolution equilibrium judgment and low crystal purity in traditional methods through real-time pressure monitoring and dynamic regulation, shortens the reaction time by 30%, and increases the product yield by more than 15%.

[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention. The above description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and variations without departing from the technical principles of the present invention, and such improvements and variations shall also be considered within the scope of protection of the present invention.

Claims

1. A betamethasone sodium phosphate injection preparation device, characterized in that, include: A reactor, wherein a partition is provided in the reactor to divide the reactor into a first chamber and a second chamber, wherein the first chamber and the second chamber are respectively used for pre-reaction and re-reaction of raw materials; The reactor is provided with a feeding port on the top, a mounting plate is provided on the top of the feeding port, a first feeding port and a second feeding port are provided on the mounting plate, and the first feeding port and the second feeding port both extend into the first chamber; The reactor is further provided with a liquid adding pipe on the top, a flow regulating valve on the liquid adding pipe, a first pressure pipe is further provided near the side wall of the first chamber, a first regulating valve on the first pressure pipe, and a first pressure sensor is provided in the first chamber; A second pressurizing pipe is provided on the side wall of the second chamber, a second regulating valve is provided on the second pressurizing pipe, a drain pipe is provided at the bottom of the second chamber, a stop valve is provided on the drain pipe, and a second pressure sensor is provided in the second chamber; A connecting pipe is provided at the center of the partition, and the connecting pipe extends from the first chamber into the second chamber. A first conical surface is provided on the side of the partition close to the first chamber, and a second conical surface is provided on the side of the partition close to the second chamber. Two reflux pipes are provided between the first chamber and the second chamber to return the liquid in the second chamber to the first chamber; a mixing mechanism, disposed in the second chamber, for further mixing the feed liquid in the second chamber; a control device connected to the first regulating valve, the second regulating valve, the first pressure sensor, the second pressure sensor, the shut-off valve, and the mixing mechanism, and configured to regulate the pressures in the first chamber and the second chamber, obtain the pressures in the first chamber and the second chamber, and regulate the mixing efficiency of the mixing mechanism; the control device is further connected to a processor connected to the first pressure sensor and the second pressure sensor; The two side surfaces of the second chamber are respectively provided with tapered extension surfaces extending toward both sides, the end with the larger opening of the tapered extension surface is connected to the second chamber, and the end with the smaller opening of the tapered extension surface is connected to one end of the return pipe; The mixing mechanism includes: a diverter and a sliding block, wherein the diverter is arranged below the connecting pipe, and a sharp end is provided at one end of the diverter close to the connecting pipe, and the two ends of the diverter are respectively connected to the two inner end surfaces of the second chamber, and the two sides of the diverter are respectively provided with a gap between the two inner side surfaces of the second chamber; The sliding block is arranged between the bottom of the second chamber and the diverter table, and slides along the two side surfaces of the second chamber. The two end surfaces of the sliding block are slidably connected to the two end surfaces of the second chamber. A first sliding groove is provided at the bottom of the second chamber, and a second sliding groove corresponding to the first sliding groove is provided on the side of the diverter table close to the sliding block. The top and bottom of the sliding block are respectively provided with a first sliding part and a second sliding part. The first sliding part and the second sliding part are slidably connected to the second sliding groove and the bottom and side wall of the first sliding groove respectively.

2. The betamethasone sodium phosphate injection preparation device according to claim 1, wherein: A stirring rod is horizontally arranged in the first chamber, and both ends of the stirring rod are rotatably connected to the centers of two opposite inner walls of the first chamber respectively. A motor is arranged on the outer wall of the reactor near one end of the stirring rod, and the output shaft of the motor is connected to the stirring rod; A jacket is provided on the outer side wall of the reactor close to the first chamber, and a first electric valve is provided on the connecting pipe.

3. The betamethasone sodium phosphate injection preparation device according to claim 1, characterized in that: A truncated cone ring is also provided in the feeding port, wherein the end with a larger cross section of the truncated cone ring is connected to the bottom of the mounting plate, and the end with a smaller cross section of the truncated cone ring extends into the first chamber and leaves a gap with the side wall of the feeding port.

4. The betamethasone sodium phosphate injection preparation device according to claim 3, characterized in that: The other end of the reflux pipe passes through the feeding port and extends between the frustum ring and the feeding port. A second electric valve is provided on the reflux pipe, and the second electric valve is connected to the control device.

5. The betamethasone sodium phosphate injection preparation device according to claim 1, characterized in that: The second chamber is located on one side of the first sliding groove and is provided with an inner cavity. A cylinder is provided in the inner cavity. The fixed end of the cylinder is provided in the inner cavity. The telescopic end of the cylinder passes through the inner cavity and extends into the first sliding groove and is connected to the second sliding part.

6. A method for preparing betamethasone sodium phosphate injection, characterized in that: The betamethasone sodium phosphate injection preparation device used in any one of claims 1 to 5 comprises the following steps: S1: Add methylsulfonyl chloride and dimethyl phosphate into the first chamber respectively, heat to a certain temperature, slowly add sodium methanesulfinate dropwise into the first chamber, react for a period of time, and then add betamethasone; S2: During the reaction process, the pressure in the first chamber is obtained in real time. The control device determines whether the reaction in the first chamber has reached a dissolution equilibrium state based on the pressure in the first chamber. If so, the liquid in the first chamber is passed into the second chamber for reaction for a period of time before being discharged. If not, the second chamber is used for further reaction to obtain a saturated solution before being discharged. S3: During the reaction in the second chamber, the pressures of the first chamber and the second chamber are obtained, and whether the reaction in the second chamber has reached dissolution equilibrium is determined based on the pressure difference. If not, the mixing efficiency of the mixing mechanism is controlled to adjust the pressure difference so that the reaction in the second chamber reaches dissolution equilibrium. After discharge, the mixture is heated and concentrated by crystallization, and the product is obtained after cooling and crystallization.

7. The method for preparing betamethasone sodium phosphate injection according to claim 6, wherein: In S2, the pressure of the first chamber at the current moment and the pressure of the first chamber at a historical moment are obtained, wherein the historical moment is before the current moment and the time interval between the historical moment and the current moment is a preset time length; determining a deviation of the pressure of the first chamber from the historical moment to the current moment according to the pressure at the current moment and the pressure at the historical moment; When the deviation is less than or equal to a preset deviation, determining that the dissolution reaction in the first chamber has reached a dissolution equilibrium state; And when the deviation is greater than the preset deviation, it is determined that the dissolution reaction in the first chamber has not reached a dissolution equilibrium state.

8. The method for preparing betamethasone sodium phosphate injection according to claim 6, wherein: In S3, the pressure difference between the first chamber and the second chamber at the current moment and the pressure difference between the first chamber and the second chamber at the historical moment are obtained, a pressure-solubility model is constructed based on the pressure differences at the historical moments and the corresponding solubilities, and the pressure-solubility model is trained using the historical data to obtain the solubility at the current moment; Determine the fluctuation range of the preset solubility threshold based on the current solubility, and construct a solubility and mixing efficiency model; When the fluctuation range is less than or equal to the preset solubility range, the solubility mixing efficiency model is used to obtain the mixing efficiency corresponding to the mixing mechanism; and when the fluctuation range is greater than the preset solubility range, the solubility mixing efficiency model is used to obtain the mixing efficiency corresponding to the mixing mechanism. At the same time, the pressure in the first chamber is reacquired, and the target pressure in the second chamber is obtained according to the fluctuation range, and the target pressure of the second chamber and the mixing efficiency of the mixing mechanism are adjusted at the same time.

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