Microsphere integrated post-processing method

Abstract

The present application relates to the technical field of microsphere processing, and discloses a microsphere integrated post-treatment method, which comprises the following steps: (1) filtering: continuously feeding microsphere slurry into a material tank, and enriching the microsphere wet suspension in the cylinder screen after filtering through the cylinder screen; (2) washing: feeding washing liquid into the material tank, feeding inert gas into the material tank after washing, and forming a filter cake on the bottom surface of the cylinder screen; (3) drying: adjusting the distance between the bottom of the plate-shaped paddle in the material tank and the bottom surface of the cylinder screen, continuously feeding inert gas and continuously pumping vacuum; adjusting the material tank to a partial swing inclined state, reducing the air intake flow, increasing the vacuum degree and the drying temperature, and adjusting the partial swing inclined direction of the material tank at regular time intervals during the period; and (4) discharging. The method can realize the post-treatment of microsphere filtering, washing and drying in the same device, and has the advantages of high filtering flux of large batches of materials, good material mixing effect, high drying efficiency and less powder residue compared with the existing process.

Description

Technical Field

[0001] This invention relates to the field of microsphere processing technology, and in particular to an integrated microsphere post-processing method. Background Technology

[0002] Filtration, washing, and drying of microspheres or microparticles are indispensable steps in the industrialization of microspheres, but they are also often the areas where problems frequently arise. For example, screen clogging is a common problem in flat screen filtration. Before drying, microspheres have high levels of residual solvent and moisture, resulting in surface viscosity. During solid-liquid separation, material gradually accumulates on the screen, forming a thick layer. This significantly reduces the material's ability to pass through the screen in the later stages of filtration. Even increasing the filtration pressure at this point cannot improve the filtration effect; it only makes the material pile up more densely, leading to filtration failure or even screen damage. The accumulation of microspheres on the screen surface is similar to that of a non-Newtonian fluid, with high viscosity, making it difficult to resuspend through vibration or other means. Therefore, preventing accumulation during filtration is the most effective way to achieve good filtration.

[0003] Drying the microspheres is the final process step before obtaining the finished product. This can be achieved through vacuum drying or freeze-drying, with vacuum drying being the most economical. Vacuum drying is further divided into vacuum airflow drying and vacuum depressurization drying, or a combination of both. Generally, vacuum airflow drying is more efficient than vacuum depressurization drying. Appropriate introduction of hot airflow can accelerate the removal of residual solvents and moisture from the microspheres. Therefore, it is essential to ensure uniform heating during the microsphere drying process to avoid localized material agglomeration and loss of drug activity.

[0004] Some microsphere products require the addition of a desiccant before drying to prevent adhesion between microspheres and drug inactivation caused by temperature increases during drying. To better utilize the desiccant, the microsphere formulation and the desiccant need to be uniformly mixed before drying. However, due to significant differences in their particle size, specific gravity, surface properties, and other powder properties, as well as the substantial differences in their percentage content, achieving uniform mixing is not easy.

[0005] Therefore, the process route for microspheres necessitates the development of a complete machine integrating filtration, washing, mixing, and drying. Such equipment must meet several requirements: 1) It must ensure a large filtration throughput to avoid clogging; existing ordinary flat screens are insufficient to meet this requirement. 2) It must ensure uniform mixing of powders with different specific gravities. Some microsphere varieties require the addition of a freeze-drying protectant after washing and before drying. However, residual water and solvents on the microsphere surface create a significant density difference between the microspheres and the desiccant, leading to uneven mixing and severe clumping in the finished product. 3) The microspheres must be heated evenly during drying; excessive localized drying can also cause severe clumping. 4) The equipment must be easy to disassemble and clean. Screens have many dead zones, making online cleaning difficult; therefore, easy disassembly, cleaning, and installation are essential. 5) It must facilitate finished product collection and reduce powder residue. The most common skeletal matrix for microspheres is polyester, which is not heat-resistant. Therefore, the microsphere production process is primarily aseptic. Transferring materials in different states between different devices must be free from external environmental contamination. Thus, the collection of finished microspheres must be conducted in a sterile environment without human intervention.

[0006] Existing filtration, washing, and drying (also known as three-in-one) equipment has many shortcomings, such as: 1) poor mixing effect, unable to effectively mix when the sample volume is large; 2) uneven heating during drying, with most samples only contacting the bottom flat screen and low utilization of the side wall jacket; 3) high powder residue; 4) inconvenient equipment disassembly, bulky equipment layout, and space-consuming. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides an integrated post-processing method for microspheres. This method allows for the simultaneous implementation of post-processing steps such as filtration, washing, and drying of microspheres within the same device. Compared to existing processes, it offers advantages such as high throughput for large-volume material filtration, excellent material mixing, high drying efficiency, and minimal powder residue.

[0008] The specific technical solution of this invention is: a microsphere integrated post-processing method, comprising:

[0009] (1) Filtration: Microsphere liquid is continuously fed into the material tank containing the cylindrical screen under stirring. Under the action of gravity and centrifugal force of stirring, the cylindrical screen achieves filtration of the microsphere liquid. The filtrate is continuously discharged from the material tank, and the trapped microsphere wet suspension is enriched in the cylindrical screen.

[0010] (2) Washing: After filtration, stop the flow of micro-flow liquid and introduce washing liquid into the material tank under stirring. After washing, discharge the washing liquid, stop stirring, and introduce inert gas into the material tank to squeeze out the liquid in the microsphere wet suspension. After the liquid is discharged, a filter cake is formed on the bottom surface of the cylindrical screen.

[0011] (3) Drying: Adjust the distance between the lower edge of the plate-shaped paddle inside the material tank and the bottom surface of the cylindrical screen to 1 / 5-1 / 3 of the filter cake thickness (i.e., part of the plate-shaped paddle is placed in the filter cake layer); continuously introduce inert gas into the material tank while stirring and continuously evacuate the vacuum. After the moisture on the surface of the microspheres is filtered out, adjust the material tank to a tilted state, reduce the air flow rate, increase the vacuum degree, and raise it to the target drying temperature; during the drying period, adjust the material tank to the opposite tilted direction.

[0012] (4) Discharge.

[0013] The method of this invention allows for the post-processing of microspheres, such as filtration, washing, and drying, to be performed within the same device. Compared to existing processes, it offers advantages such as high throughput for large-volume material filtration, good material mixing, high drying efficiency, and low powder residue. Specifically:

[0014] (1) In terms of filtration throughput: In view of the shortcomings of traditional flat screens being unsuitable for large batches of materials and prone to clogging, the method of the present invention adopts a three-dimensional cylindrical screen with high filtration throughput and is not prone to clogging. Furthermore, the plate-shaped paddles are designed to be liftable (that is, the distance between the lower edge of the plate-shaped paddles and the bottom surface of the cylindrical screen can be finely adjusted), making it suitable for filtering materials of different batches.

[0015] (2) Regarding material mixing during filtration: Microspheres are prone to sedimentation during filtration. This invention employs full-size plate-shaped impellers, maximizing the impeller edge length to increase the contact area between the impeller tip and the material. This allows the material to spread out within the fixed gap formed between the impeller and the inner wall of the cylindrical screen, maximizing the solvent evaporation area. Secondly, this invention designs the stirring shaft as telescopic, meaning the gap between the plate-shaped impellers and the cylindrical screen is adjustable. Thus, during filtration, due to the small distance between the full-size impellers and the inner wall of the cylindrical screen, the laminar flow formed after stirring is activated effectively washes the side and bottom screens of the cylindrical screen, effectively preventing microsphere sedimentation during filtration. Since the microsphere concentrate is a non-Newtonian fluid with a shear-thinning effect, the full-size plate-shaped impellers effectively keep the microspheres in the material tank continuously flowing, preventing the microsphere concentration from continuously increasing and clogging the screen.

[0016] (2) Regarding drying: Some microsphere varieties require the addition of a freeze-drying protectant after cleaning and before drying. However, a small amount of solvent residue on the surface of the microspheres results in a large density difference between the microspheres and the freeze-drying protectant, often forming floating powder on the wall. This prevents the microspheres from participating in the mixing process, leading to clumping of the finished product. During the drying process, the microspheres accumulate, and uneven heating can easily cause them to clump together. In the drying process of the present invention, after the stirring is started, the plate-shaped paddles carry the material to be relatively evenly distributed in the dynamic gap formed between the outer edge of the paddles and the inner surface of the cylindrical screen. The spread material adheres to the side and bottom surfaces of the cylindrical screen. The specific gravity of the material varies at different drying stages. As the degree of drying increases, the material will fall away from the inner surface of the cylindrical screen, while the wet material continues to replenish the inner surface of the cylindrical screen until all the material is dried. It is important to emphasize that the distance ratio between the lower edge of the plate-shaped paddles and the bottom surface of the cylindrical screen is very important during the drying stage. If the gap is too large, the material will not be able to participate in the stirring fully; if the gap is too small, the material will be easily squeezed into a cake, and it will be too close to the bottom screen, increasing the risk.

[0017] In addition, with the tilting of the material tank, the plate-shaped blades can make the wet microspheres cover all the inner surfaces of the screen, fully contact the desiccant, and mix thoroughly, so that the material is always in a dispersed or loose state and is heated evenly. Therefore, this design can ensure that all materials can be spread on the screen surface and heated evenly, thereby avoiding the accumulation of microspheres and the clumping of microspheres caused by uneven heating during the drying process. In addition, by changing the tilting angle of the tank during the drying process, the material is indirectly heated by heating the material tank. Since there is a gap between the cylindrical screen and the material tank, the material can be prevented from directly contacting the inner wall of the material tank, which would lead to uneven heating in some areas. (3) Regarding powder residue: The method of the present invention can make the powder material free of dead corners and residues during feeding and discharging by adjusting the tilting angle of the material tank.

[0018] Preferably, in step (1), the distance between the sidewall of the cylindrical screen and the side edge of the plate-shaped impeller is 1-5 mm, and the distance between the bottom surface of the cylindrical screen and the bottom of the plate-shaped impeller is 1-30 mm; the pore size of the cylindrical screen is 20-30 μm, the stirring speed is 40-60 rpm, the initial microsphere feed flow rate is 8-10 L / min, and when the feed outlet pressure is increased to 1.5-2 times, the microsphere feed flow rate is adjusted to 5-7 L / min. The ability to freely adjust the distance between the bottom surface of the cylindrical screen and the bottom of the plate-shaped impeller within 1-30 mm facilitates adaptive adjustments based on the microsphere feed flow rate during the filtration stage.

[0019] Preferably, a gap of 5-20 mm is provided between the cylindrical screen and the material tank. If the gap is too small, the space between the outer wall of the cylindrical screen and the material tank is too small, which is not conducive to the rapid dehydration process during filtration. Sufficient space needs to be reserved to discharge the liquid that has passed through the screen. If the gap is too large, it is not conducive to the material being heated during drying. The material tank jacket heats the material through thermal radiation, avoiding powder adsorption or aggregation caused by direct contact heating.

[0020] Preferably, in step (2), the thickness of the resulting filter cake is between 5 and 35 mm.

[0021] Preferably, in step (2), the washing liquid is introduced into the material tank in multiple batches. After all the washing liquid is introduced each time, the tank is stirred at a speed of 40-60 rpm without draining for 1-10 minutes, and then the washing liquid is drained and new washing liquid is introduced.

[0022] Preferably, in step (3), the stirring speed is 10-30 rpm.

[0023] As a preferred option, in step (3), the residual water and organic solvent on the surface of the microspheres need to be filtered off before drying, the flow rate of the inert gas is set to 5-20 L / min, the vacuum degree is -0.4 MPa to -0.6 MPa, and the duration is 0.5-1.5 h.

[0024] Preferably, in step (3), at the beginning of the drying stage, the air intake flow rate is reduced to 2-4 L / min, and the vacuum degree is increased to -0.7 MPa to -0.8 MPa. Preferably, in step (3), during the drying period, the material tank is tilted to form an angle of +40 to 50° with the vertical plane, and the material tank is adjusted to the opposite tilting direction every 0.5-1.5 hours.

[0025] Before drying, a large amount of inert gas needs to be introduced and a vacuum is applied to remove residual water and reagents from the surface. This ensures more thorough mixing of the wet microspheres and the freeze-drying protectant, preventing localized water dissolution and excessive use of the freeze-drying protectant. During the actual drying process, removing residual moisture inside the microspheres does not require a high inert gas flow rate; in fact, a high flow rate would reduce the drying efficiency and effect inside the microspheres. It is necessary to increase the vacuum level to allow moisture inside the microspheres to migrate to the surface and be carried away by a weak airflow. The tank should be periodically repositioned to ensure the material is in a state of uniform mixing and heating.

[0026] Preferably, the microsphere feed solution is a risperidone microsphere feed solution with a solid content of 0.1-0.5%, containing ethyl acetate, benzyl alcohol and surfactant; the temperature of the microsphere feed solution is controlled at <5℃ during filtration in step (1), and the washing solution in step (2) is an ethanol solution at <5℃; in step (3), after the inert gas is introduced, the temperature curve in the material tank is set as follows: 3-5℃, 8-12h; 5-10℃, 1.5-2.5h; 10-12℃, 8-12h; 10-15℃, 1.5-2.5h; 15℃, 4-6h; the inert gas temperature is consistent with that in the material tank.

[0027] Preferably, the microsphere feed solution is an octreotide microsphere feed solution with a solid content of <0.1%, containing n-heptane, dimethyl silicone oil, dichloromethane, and an emulsifier; during the filtration in step (1), the temperature of the microsphere feed solution is controlled at <15℃, and in step (2), the washing liquid is successively an aqueous solution containing n-heptane and an emulsifier at <15℃ and water. In step (3), before adjusting the material tank to a tilted state, a freeze-drying protectant is added to the material tank; after the inert gas is introduced, the temperature curve inside the material tank is set as follows: 13-15℃, 8-12h; 15-35℃, 1.5-2.5h; 35-40℃, 4-6h; 35-50℃, 1.5-2.5h; 50℃, 4-6h, and the inert gas temperature is consistent with that inside the material tank.

[0028] As a preferred embodiment, the discharge of material in step (4) specifically includes: after drying, adjusting the powder discharge port of the material tank to face downward and still in an inclined state, opening the valve to allow the material to fall freely and discharge, closing the valve, adjusting the material tank to the opposite inclined state, opening the valve, until all material is discharged.

[0029] Preferably, steps (1)-(4) are performed using an integrated microsphere filtration, washing, and drying device, which includes:

[0030] Fixture;

[0031] The material tank tilting mechanism is fixed to the top of the fixed frame;

[0032] The material tank is connected to one end of the material tank swing mechanism. Driven by the horizontally set swing shaft in the material tank swing mechanism, it swings synchronously with the swing shaft. A cylindrical screen with a top opening is detachably installed inside the material tank. A stirring shaft that penetrates vertically through the top of the material tank is set on the axis of the cylindrical screen. Several plate-shaped blades are set on the stirring shaft. There is a gap between the plate-shaped blades and the inner surface of the cylindrical screen. There is a gap between the cylindrical screen and the material tank.

[0033] The stirring and lifting drive mechanism is connected to the stirring shaft at its bottom and is used to drive the stirring shaft to rotate and lift relative to the material tank.

[0034] The working principle of the device of this invention is as follows: First, the stirring is turned on, and the stirring shaft drives the plate-shaped paddles to rotate relative to the cylindrical screen. Then, the liquid containing microspheres is continuously fed into the material tank. Under the action of gravity and stirring (centrifugal force), the material is screened, and the microspheres of the target particle size are trapped in the cylindrical screen. The filtrate is continuously discharged from the bottom of the material tank in real time. After filtration, the material feeding is stopped, and the feeding is switched to the feeding of washing liquid into the material tank. The material is cleaned under stirring conditions, and the washing liquid is discharged from the bottom of the material tank. After washing, the position of the retractable corrugated pipe is adjusted according to the thickness of the microspheres at the bottom of the cylindrical screen so that the gap between the bottom surface of the plate-shaped paddles and the cylindrical screen is controlled at 1 / 5-1 / 3 of the material thickness. The stirring state of the material is maintained, and the temperature of the material tank is controlled. The material tank is tilted under the drive of the tilting mechanism, so that it is tilted at a certain angle with the horizontal plane. Gas is continuously fed into the material tank from the bottom and a vacuum is continuously drawn from the top. After drying, the discharge port angle of the material tank is switched under the drive of the tilting mechanism, so that all the microsphere powder in the material tank is discharged.

[0035] Preferably, the diameter to height ratio of the material tank is 2:1 to 1:1, and the diameter to height ratio of the cylindrical screen is 3:1 to 1:1.

[0036] In this invention, the material tank is designed with a diameter greater than its height. During the research, the inventors discovered that dried microspheres tend to adhere to the inner surface of the cylindrical screen, especially the sides, due to their inherent properties. By controlling the ratio of the material tank diameter to its height to be 2:1-1:1 and the ratio of the cylindrical screen diameter to its height to be 3:1-1:1, the filtration throughput of the same cylindrical screen volume can be increased, while reducing powder residue when the material is discharged after drying.

[0037] Compared with the prior art, the beneficial effects of the present invention are: the method of the present invention can realize the post-processing of microspheres such as filtration, washing and drying in the same device, which has the advantages of high throughput of large batch material filtration, good material mixing effect, high drying efficiency and low powder residue compared with the existing process. Attached Figure Description

[0038] Figure 1 This is a process flow diagram of the method of the present invention;

[0039] Figure 2 This is a side view of the device of the present invention;

[0040] Figure 3 This is a schematic diagram showing the structural details between the plate-shaped paddle, the cylindrical screen, and the lower tank in the device of the present invention.

[0041] Figure 4 for Figure 3 Enlarged detail view of the area between the middle cylindrical screen and the lower tank;

[0042] Figure 5This is a top view of the plate-shaped blade in the device of the present invention.

[0043] Reference numerals: 1. Fixed frame; 2. Stirring and lifting drive mechanism; 3. Oscillating motor; 4. Oscillating shaft; 5. Oscillating shaft support frame; 6. Upper tank; 7. Lower tank; 8. Clamp; 9. Powder discharge interface; 10. Functional port; 11. Tank support arm; 12. Sight glass; 13. Temperature sensor; 14. Pressure sensor; 15. Heating jacket; 16. Drain / air inlet; 17. Liquid inlet; 18. Liquid outlet; 19. Cylindrical sieve; 20. Stirring shaft; 21. Telescopic corrugated pipe; 22. Support structure; 23. Sealing ring; 24. Groove; 25. Plate-shaped paddle; 26. Sealing cover; 27. Lifting slide rail; 28. Lifting frame; 29. ​​Lifting motor. Detailed Implementation

[0044] The present invention will be further described below with reference to embodiments. Unless otherwise specified, the apparatuses, connection structures, and methods involved in this invention are all well-known in the art.

[0045] General Implementation Examples

[0046] A microsphere integrated post-processing method, such as Figure 1 As shown, it includes:

[0047] (1) Filtration: The distance between the lower edge of the plate-shaped paddle inside the material tank and the bottom surface of the cylindrical screen is 1-30 mm. Under stirring (40-60 rpm), the microsphere liquid is continuously fed into the material tank containing the cylindrical screen (with a pore size of 20-30 μm). Under the action of gravity and centrifugal force of stirring, the cylindrical screen achieves filtration of the microsphere liquid. The filtrate is continuously discharged from the material tank, and the retained microsphere wet suspension is enriched in the cylindrical screen. The initial microsphere liquid flow rate is 8-10 L / min. When the liquid outlet pressure is increased to 1.5-2 times, the microsphere liquid flow rate is 5-7 L / min.

[0048] (2) Washing: After filtration, stop the flow of microfluidic liquid. While stirring, introduce washing liquid into the material tank in multiple batches. After each batch of washing liquid is introduced, maintain stirring at 40-60 rpm without discharging for 1-10 minutes, then drain the washing liquid and continue introducing new washing liquid. After washing, drain the washing liquid, stop stirring, and introduce inert gas into the material tank to squeeze out the liquid in the microsphere wet suspension. After draining the liquid, a filter cake (preferably 5-35 mm thick) is formed on the bottom surface of the cylindrical sieve.

[0049] (3) Drying: Adjust the distance between the lower edge of the plate-shaped paddle inside the material tank and the bottom surface of the cylindrical screen to within 1-10 mm, so that the distance is 1 / 5-1 / 3 of the thickness of the filter cake; continuously introduce inert gas into the material tank while stirring (10-30 rpm) and continuously evacuate the vacuum. The gas flow rate is 5-20 L / min, the vacuum degree is -0.4 MPa to -0.6 MPa, and continue for 0.5-1.5 h. After the moisture on the surface of the microspheres is filtered dry, reduce the gas flow rate to 2-4 L / min, increase the vacuum degree to -0.7 MPa to -0.8 MPa, and raise it to the target drying temperature; during the drying period, adjust the material tank to a tilted state (at an angle of 40-50° with the vertical plane), and adjust the material tank to the opposite tilted direction every 0.5-1.5 h.

[0050] (4) Discharge: After drying, adjust the powder discharge port of the material tank to face downward and still be in an inclined state, open the valve to allow the material to fall freely and discharge, close the valve, adjust the material tank to the opposite inclined state, open the valve, until all the material is discharged.

[0051] Optionally, the microsphere feed solution is a risperidone microsphere feed solution with a solid content of 0.1-0.5%, containing ethyl acetate, benzyl alcohol and surfactant; the temperature of the microsphere feed solution is controlled at <5℃ during filtration in step (1), and the washing solution in step (2) is an ethanol solution at <5℃; in step (3), after the inert gas is introduced, the temperature curve in the material tank is set as follows: 3-5℃, 8-12h; 5-10℃, 1.5-2.5h; 10-12℃, 8-12h; 10-15℃, 1.5-2.5h; 15℃, 4-6h; the inert gas temperature is consistent with that in the material tank.

[0052] Optionally, the microsphere feed solution is an octreotide microsphere feed solution with a solid content of <0.1%, containing n-heptane, dimethyl silicone oil, dichloromethane, and an emulsifier; during the filtration in step (1), the temperature of the microsphere feed solution is controlled at <15℃, and in step (2), the washing liquid is successively an aqueous solution containing n-heptane and an emulsifier at <15℃ and water. In step (3), before adjusting the material tank to a tilted state, a freeze-drying protectant is added to the material tank; after the inert gas is introduced, the temperature curve inside the material tank is set as follows: 13-15℃, 8-12h; 15-35℃, 1.5-2.5h; 35-40℃, 4-6h; 35-50℃, 1.5-2.5h; 50℃, 4-6h, and the inert gas temperature is consistent with that inside the material tank.

[0053] The above method is achieved through an integrated microsphere filtration, washing, and drying device, which includes:

[0054] Fixture;

[0055] The material tank tilting mechanism includes a tilting motor, a tilting shaft, and a tilting shaft support frame. The tilting shaft support frame is fixed on a fixed base. The tilting motor is driven by the tilting shaft. The tilting shaft passes through the tilting shaft support frame and can rotate relative to the tilting shaft support frame. The tilting shaft support frame is connected to the material tank. Under the drive of the material tank tilting mechanism, the material tank of this device can rotate 180° clockwise or counterclockwise along the tilting shaft.

[0056] The material tank is connected to one end of the material tank tilting mechanism and tilts synchronously with the tilting shaft driven by the horizontally set tilting shaft in the material tank tilting mechanism. The diameter-to-height ratio of the material tank is 2:1 to 1:1, and it includes an upper tank body and a lower tank body that are detachably sealed and connected. The upper tank is frustum-shaped, with powder discharge ports and at least one functional port on its outer side wall, and a tank support arm connected to the material tank tilting mechanism. The lower tank is cylindrical, with a heating jacket on its outer surface and a drain / air inlet penetrating the heating jacket on its bottom surface. The heating jacket has a liquid inlet on its bottom surface and a liquid outlet on its side. A cylindrical screen with a top opening (diameter-to-height ratio of 3:1-1:1) is fixed inside the material tank. A stirring shaft with a vertical axis penetrating the top of the upper tank is located on the inner axis of the cylindrical screen (the penetrating part is a retractable corrugated pipe (adjustable vertical distance 1-30mm), and the retractable corrugated pipe is sealed and rotated with the upper tank). A support structure is provided on the inner wall of the opening edge of the lower tank, and the opening edge of the cylindrical screen is detachably and sealed on the support structure. The connection between the support structure and the opening edge of the cylindrical screen, and the connection between the opening edge of the cylindrical screen and the opening edge of the upper tank, are sealed by the cooperation of sealing rings and grooves. The upper and lower tanks are sealed by clamps.

[0057] The stirring shaft is provided with several plate-shaped blades (preferably 2-12, more preferably 4-8) evenly distributed along the stirring shaft direction; there is a gap (preferably 1-30mm) between the bottom of the plate-shaped blades and the bottom surface of the cylindrical screen; there is a gap (preferably 1-5mm) between the side edge of the plate-shaped blades and the side wall of the cylindrical screen; there is a gap of 5-20mm between the cylindrical screen and the material tank; the thickness of the plate-shaped blades is 1-5mm, preferably 3-4mm; the side edge and bottom edge of the plate-shaped blades are chamfered at 40-50°; the plate-shaped blades are provided with through holes with a diameter larger than that of the microspheres, and the through holes are selected from square holes, rectangular holes, and round holes.

[0058] The stirring and lifting drive mechanism includes a stirring motor for driving the stirring shaft to rotate and a lifting motor for driving the stirring shaft to lift. Its bottom is connected to the stirring shaft. The stirring motor and the lifting motor are housed in the same housing, and a sealing cover is provided at the connection between the stirring and lifting drive mechanism and the upper tank.

[0059] The lifting mechanism includes a lifting slide rail, a lifting frame, and a lifting motor. The lifting slide rail and the lifting motor are fixed on a fixed frame. The lifting frame is located below the material tank and is movably connected to the lifting slide rail. The lifting motor drives the lifting frame to move up and down. Optionally, the lifting frame has a material tank limiter.

[0060] Example 1: Filtration, washing, and drying of 500L risperidone microsphere solution:

[0061] Material properties: Microspheres solid content 0.2% (w / v), aqueous solution, containing low concentrations of ethyl acetate, benzyl alcohol, and surfactant, <5℃. Washing solution: 25% ethanol, <5℃.

[0062] Filtration: A cylindrical sieve with a 25μm pore size is installed. The stirring speed is set to 50rpm, and the temperature of the feed solution is controlled to be below 5℃ during filtration using a heating jacket. The microsphere feed solution enters the cylindrical sieve through the functional port, and the filtered solution is discharged through the drain port. The retained microsphere wet suspension continuously accumulates within the cylindrical sieve. The initial feed flow rate is controlled at 9L / min. When the feed outlet pressure increases to 1.5 times, the feed flow rate is adjusted to 6L / min. After all the feed solution has been collected, washing liquid is introduced in three stages, each with a volume of 15L and an inflow rate of 6L / min. After each washing liquid is completely introduced, the drain port is closed, and stirring is maintained without discharging for 3 minutes. The drain port is then reopened, and new washing liquid is introduced. After the final washing, stirring is stopped, and nitrogen gas is introduced through the functional port to expel the large amount of feed solution contained in the microsphere wet suspension. After filtration, a thick filter cake, approximately 2cm thick, is formed on the bottom surface of the cylindrical sieve.

[0063] Drying: Adjust the distance between the lower edge of the plate-shaped paddle and the cylindrical screen from 30mm to 5mm (approximately 1 / 4 of the filter cake thickness) by raising the motor. Start the stirring speed at 25rpm, introduce nitrogen gas at a flow rate of 10L / min, and evacuate to -0.5MPa for 1 hour to ensure thorough filtration of moisture from the microsphere surface. Reduce the inlet flow rate to 3L / min and increase the vacuum to -0.75MPa. Set the heating jacket temperature curve: 5℃, 10h; 5-10℃, 2h; 10℃, 10h; 10-15℃, 2h; 15℃, 5h. During drying, gradually increase the gas temperature to maintain consistency with the material tank temperature curve. During the drying process, tilt the material tank at a +45° angle to the vertical plane using a yaw motor. Adjust the angle between the tank and the vertical plane every hour, repeatedly switching between +45° and -45°.

[0064] Discharge: After drying, the powder discharge port of the material tank is connected to the αβ valve and then to the sterile material cylinder. A yaw motor rotates the material tank to a tilt angle exceeding +150°, allowing the material to fall freely into the sterile material cylinder. The αβ valve is then closed, and the yaw motor rotates the material tank to a tilt angle exceeding -150°. The αβ valve is then opened again until all the material has fallen into the sterile material cylinder, completing the discharge process.

[0065] The above operations are performed using an integrated microsphere filtration, washing, and drying device, such as... Figure 2 As shown, it includes a fixed frame 1, a material tank, a stirring and lifting drive mechanism 2, a material tank tilting mechanism, and a lifting mechanism. Specifically:

[0066] The material tank tilting mechanism includes a tilting motor 3, a tilting shaft 4, and a tilting shaft support frame 5. The tilting shaft support frame is fixed to the top of the fixed base. The tilting motor is driven by the tilting shaft. The tilting shaft passes through the tilting shaft support frame and can rotate relative to the tilting shaft support frame under the drive of the tilting motor. The tilting shaft support frame is connected to the material tank. Under the drive of the material tank tilting mechanism, the material tank can rotate 180° clockwise or counterclockwise along the tilting shaft.

[0067] The material tank has a diameter-to-height ratio of 1:1 and consists of an upper tank body 6 and a lower tank body 7 connected vertically (sealed by clamps 8). The upper tank body is frustum-shaped, with a powder discharge port 9, a functional port 10, and a tank support arm 11 (integrated with the upper tank body) on its outer wall for connection to the yaw shaft support frame. The lower tank body is cylindrical, with a sight glass 12, a temperature sensor 13, a pressure sensor 14, and a heating jacket 15 on its outer wall. The bottom surface has a drain / air inlet 16 penetrating the heating jacket, and the bottom of the heating jacket has a liquid inlet 17, while the upper side has a liquid outlet 18. Figure 3 As shown, the lower tank contains a cylindrical sieve 19 with a top opening (diameter-to-height ratio of 2:1). A stirring shaft 20, perpendicular to the top of the upper tank, is installed along the central axis of the cylindrical sieve (the penetrating part is a retractable corrugated pipe 21 (adjustable vertically from 1-30mm), the retractable corrugated pipe can rotate relative to the upper tank and has a sealing structure). Figure 4 As shown, a support structure 22 is provided on the inner wall of the opening edge of the lower tank. The opening edge of the cylindrical screen is detachably and sealed on the support structure. The connection between the support structure and the opening edge of the cylindrical screen, and the connection between the opening edge of the cylindrical screen and the opening edge of the upper tank, are sealed by the cooperation of a sealing ring 23 and a groove 24, respectively. The stirring shaft is provided with eight plate-shaped blades 25 evenly distributed along the stirring shaft direction. Figure 5 The plate-shaped blades have an adjustable gap (preferably 1-30mm) between the bottom of the blades and the bottom surface of the cylindrical screen. The side of the plate-shaped blades has a 5mm gap with the side wall of the cylindrical screen, and the cylindrical screen has a 10mm gap with the material tank. The plate-shaped blades are 3mm thick, and the side edges and bottom edges of the plate-shaped blades are chamfered at 45°.

[0068] The stirring and lifting drive mechanism includes a stirring motor for driving the stirring shaft to rotate and a lifting motor for driving the stirring shaft to lift (which can be achieved by existing technology). Its bottom is connected to the stirring shaft. The stirring motor and the lifting motor are housed in the same housing. A sealing cover 26 is provided at the connection between the stirring and lifting drive mechanism and the upper tank.

[0069] The lifting mechanism includes a lifting slide rail 27, a lifting frame 28, and a lifting motor 29. The lifting slide rail and the lifting motor are fixed on the fixed frame. The lifting frame is located below the material tank and is movably connected to the lifting slide rail. The lifting motor drives the lifting frame to move up and down. There is a material tank limiter on the lifting frame.

[0070] Comparative Example 1

[0071] Compared with Example 1, during the drying process, the distance from the lower edge of the plate-shaped paddle to the flat screen of the cylindrical screen was adjusted to 2 mm, which is 1 / 10 of the filter cake thickness.

[0072] Comparative Example 2

[0073] Compared with Example 1, during the drying process, the distance from the lower edge of the plate-shaped paddle to the flat screen of the cylindrical screen was adjusted to 10 mm, which is 1 / 2 of the filter cake thickness.

[0074] The implementation methods of Example 1, Comparative Example 1, and Comparative Example 2 were compared by detecting the moisture content and solvent residue of the finished product, and the yield of the finished product was used as the evaluation index. The results are shown in the table below.

[0075] Table 1

[0076]

[0077]

[0078] Compared with Example 1, Comparative Example 1, and Comparative Example 2, when the distance between the lower edge of the plate-shaped paddle inside the material tank and the bottom surface of the cylindrical screen is too large, the material cannot fully participate in the mixing. Only some of the material participates in the drying, and some of the material is dried in situ, resulting in incomplete drying and poor material flowability. When the distance between the two is too small, the material is easily squeezed to form a compacted filter cake, which increases the resistance of the mixing paddle. The formation of the filter cake can cause the microspheres to clump together, resulting in a decrease in the yield.

[0079] Example 2: Filtration, washing, and drying of 1000L octreotide microspheres:

[0080] Material properties: Microspheres solid content <0.1% (w / v), aqueous solution, containing medium concentration of n-heptane, low concentration of dimethyl silicone oil, dichloromethane, and emulsifier; solution temperature <15℃. Washing solution 1: Aqueous solution containing n-heptane and emulsifier, <15℃. Washing solution 2: Water.

[0081] Filtration: Install a cylindrical sieve with a 20μm pore size, turn on the material tank and set the stirring speed to 50rpm. Control the temperature of the liquid during filtration to <15℃ through the heat exchange jacket. The microsphere liquid enters the cylindrical sieve through the functional port, and the liquid that has passed through the sieve is discharged through the drain port. The retained microsphere wet suspension continuously accumulates in the cylindrical sieve. The initial liquid flow rate is controlled at 10L / min. When the liquid outlet pressure is increased to twice the original value, the liquid flow rate is adjusted to 5L / min. After all the liquid has been collected, the liquid at the inlet is replaced with washing liquid. Washing liquid 1 is introduced in three batches, each time with a volume of 30L and an inlet flow rate of 6L / min. After all the washing liquid has been introduced each time, the drain port is closed, and the stirring is maintained without discharging for 5 minutes. The drain port is then reopened, and new washing liquid is introduced. After washing with washing liquid 1 for 3 washes, it is replaced with washing liquid 2, and 20L is introduced. Stirring is stopped, and nitrogen is introduced through the functional port to squeeze out a large amount of liquid contained in the microsphere wet suspension. After filtration, a thick filter cake, about 1.5 cm thick, is formed on the bottom surface of the cylindrical sieve.

[0082] Drying: Adjust the distance between the lower edge of the plate-shaped paddle and the cylindrical screen from 30mm to 3mm (approximately 1 / 5 of the filter cake thickness) by raising the motor. Turn on the stirring speed to 10rpm, introduce nitrogen gas at a flow rate of 10L / min, and evacuate to -0.5MPa for 1 hour to ensure thorough filtration of moisture from the microsphere surface. Add mannitol powder quantitatively to the material tank through the functional port. Reduce the inlet gas flow rate to 2L / min, maintain a gas temperature of approximately 15℃, and increase the evacuation vacuum to -0.85MPa. Set the material tank jacket temperature rise curve: 15℃, 10h; 15-35℃, 2h; 35℃, 5h; 35-50℃, 2h; 50℃, 5h. During the drying process, gradually increase the gas temperature through the heat exchanger, maintaining a temperature rise curve consistent with the tank body. During the drying process, the tank is tilted at a +45° angle to the vertical plane by a yaw motor. The angle between the tank and the vertical plane is adjusted every 30 minutes, switching repeatedly between +45° and -45°.

[0083] Discharge: After drying, the powder discharge port connects to the αβ valve and then to the aseptic container. A yaw motor rotates the container to a tilt angle exceeding +150°, allowing the material to fall freely into the aseptic container. The αβ valve is then closed, and the yaw motor rotates the container to a tilt angle exceeding -150°. The αβ valve is then opened again until all material has fallen into the aseptic container, completing the discharge process.

[0084] The above operations are performed using the same integrated microsphere filtration, washing, and drying device as in Example 1.

[0085] Comparative Example 3

[0086] In contrast to Example 2, during the drying process, the plate-shaped paddles were replaced, increasing the distance between them and the inner surface of the cylindrical screen to 10 mm.

[0087] The implementation methods of Example 2 and Comparative Example 3 were compared using finished product yield, filtration and drying effects as evaluation indicators, as shown in the table below.

[0088] Table 2

[0089]

[0090] During filtration, when the distance between the plate-shaped paddles and the cylindrical screen increases, the screening effect of the side screens decreases, and the material mainly relies on the bottom screen. As the material accumulates, the screening effect decreases rapidly, and the screening efficiency drops significantly. When the distance between the plate-shaped paddles and the cylindrical screen is close, the laminar flow formed after the agitation is turned on will effectively wash the side and bottom screens of the cylindrical screen, which can effectively prevent the deposition of microspheres during filtration, increase the screening efficiency of the side screens, and thus improve the overall screening efficiency.

[0091] During drying, reducing the distance between the plate-shaped paddles and the cylindrical screen allows the material to spread evenly within the fixed gap formed by the paddles and the inner wall of the screen, maximizing the surface area for moisture and solvent evaporation and accelerating the drying process. There are differences in specific gravity between materials at different drying stages. As the material becomes drier, it will detach from the inner surface of the cylindrical screen, while wet material continues to be added to the inner surface until all material is dried.

[0092] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the present invention. Any simple modifications, alterations, or equivalent structural transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A microsphere integrated post-processing method, characterized in that... include: 1) Filtration: Microsphere liquid is continuously fed into a material tank containing a cylindrical screen under stirring. After filtration through the cylindrical screen, the filtrate is continuously discharged from the material tank, and the retained microsphere wet suspension is enriched in the cylindrical screen. A stirring shaft is installed on the central axis of the cylindrical screen, which is perpendicular to the top of the material tank. Several plate-shaped blades are installed on the stirring shaft. There is a gap between the cylindrical screen and the material tank. The distance between the side wall of the cylindrical screen and the side edge of the plate-shaped blades is 1-5mm. The distance between the bottom surface of the cylindrical screen and the bottom of the plate-shaped blades is adjusted to 1-30mm. The pore size of the cylindrical screen is 20-30μm. The stirring speed is 40-60rpm. The initial microsphere liquid flow rate is 8-10L / min. When the liquid outlet pressure is increased to 1.5-2 times, the microsphere liquid flow rate is adjusted to 5-7L / min. 2) Washing: Stop the flow of microsphere feed liquid, and pass washing liquid into the material tank while stirring. After washing, discharge the washing liquid, stop stirring, and pass inert gas into the material tank to squeeze out the liquid. After the liquid is discharged, a filter cake with a thickness of 5~35mm is formed on the bottom surface of the cylindrical screen. 3) Drying: Adjust the distance between the bottom of the plate-shaped paddles in the material tank and the bottom surface of the cylindrical screen to 1 / 5-1 / 3 of the filter cake thickness; continuously introduce inert gas into the material tank while stirring and continuously evacuate the vacuum. After the moisture on the surface of the microspheres is filtered out, adjust the material tank to a tilted state, reduce the air flow rate, increase the vacuum degree, and raise it to the target drying temperature; during the drying process, adjust the material tank to the opposite tilted direction at regular intervals. 4) Discharge.

2. The method as described in claim 1, characterized in that: In step 2), the washing liquid is introduced into the material tank in multiple batches. After all the washing liquid is introduced each time, the tank is stirred at 40-60 rpm for 1-10 minutes without draining the liquid. Then the washing liquid is drained and new washing liquid is introduced.

3. The method as described in claim 1, characterized in that: In step 3), the stirring speed is 10-30 rpm; Before drying, residual water and organic solvents on the surface of the microspheres need to be filtered off. The inert gas flow rate is set to 5-20 L / min, the vacuum degree is -0.4 MPa to -0.6 MPa, and the duration is 0.5-1.5 h. At the beginning of the drying stage, reduce the intake air flow rate to 2-4 L / min and increase the vacuum to -0.7 MPa to -0.8 MPa; During the drying process, the material container is tilted to an angle of 40-50° with the vertical plane, and the material container is adjusted to the opposite tilt direction every 0.5-1.5 hours.

4. The method according to any one of claims 1-3, characterized in that: The microsphere feed solution is a risperidone microsphere feed solution with a solid content of 0.1-0.5%, containing ethyl acetate, benzyl alcohol and surfactant; during the filtration in step 1), the temperature of the microsphere feed solution is controlled at <5℃, and the washing solution in step 2) is an ethanol solution at <5℃.

5. The method as described in claim 4, characterized in that: In step 3), after the inert gas is introduced, the temperature curve inside the material tank is set as follows: 3-5℃, 8-12h; 5-10℃, 1.5-2.5h; 10-12℃, 8-12h; 10-15℃, 1.5-2.5h; 15℃, 4-6h; the inert gas temperature is kept consistent with that inside the material tank.

6. The method according to any one of claims 1-3, characterized in that: The microsphere feed solution is an octreotide microsphere feed solution with a solid content of <0.1%, containing n-heptane, dimethyl silicone oil, dichloromethane and emulsifier; during the filtration process in step 1), the temperature of the microsphere feed solution is controlled at <15℃; in step 2), the washing liquid is successively an aqueous solution containing n-heptane and emulsifier at <15℃ and water.

7. The method as described in claim 6, characterized in that: In step 3), before adjusting the material tank to a tilted state, add a freeze-drying protectant into the material tank.

8. The method as described in claim 7, characterized in that: In step 3), after the inert gas is introduced, the temperature curve inside the material tank is set as follows: 13-15℃, 8-12h; 15-35℃, 1.5-2.5h; 35-40℃, 4-6h; 35-50℃, 1.5-2.5h; 50℃, 4-6h, and the inert gas temperature is kept consistent with that inside the material tank.

9. The method as described in claim 1, characterized in that: Steps 1)-4) are achieved using an integrated microsphere filtration, washing, and drying device, which includes: Fixture; The material tank tilting mechanism is fixed to the top of the fixed frame; The material tank is connected to one end of the material tank swing mechanism. Driven by the rotation of the horizontally set swing shaft in the material tank swing mechanism, it swings synchronously with the swing shaft. A cylindrical screen with a top opening is detachably installed inside the material tank. The stirring and lifting drive mechanism is connected to the stirring shaft at its bottom and is used to drive the stirring shaft to rotate and lift relative to the material tank.

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