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CN-117339500-B - Microsphere integrated post-treatment method

CN117339500BCN 117339500 BCN117339500 BCN 117339500BCN-117339500-B

Abstract

The invention relates to the technical field of microsphere processing and discloses a microsphere integrated post-treatment method which comprises the steps of (1) filtering, namely continuously introducing microsphere feed liquid into a material tank, enriching microsphere wet suspension in the cylindrical screen after filtering through the cylindrical screen, (2) washing, namely introducing washing liquid into the material tank, introducing inert gas into the material tank after washing, forming a layer of filter cake on the bottom surface of the cylindrical screen, (3) drying, namely adjusting the distance between the bottom of a platy blade in the material tank and the bottom surface of the cylindrical screen, continuously introducing the inert gas, continuously vacuumizing, adjusting the material tank to be in a deflection inclined state, reducing the air inlet flow, improving the vacuum degree, and drying temperature, and adjusting the deflection inclined direction of the material tank at regular time during discharging. Compared with the prior art, the method has the advantages of high mass material filtering flux, good material mixing effect, high drying efficiency and less powder residue.

Inventors

  • YU KONGDONG
  • LI HAIJIE
  • JIANG CHAOJUN
  • CHEN LINPING

Assignees

  • 浙江圣兆药物科技股份有限公司

Dates

Publication Date
20260512
Application Date
20230922

Claims (9)

  1. 1. The microsphere integrated post-treatment method is characterized by comprising the following steps of: 1) Filtering, namely continuously introducing microsphere feed liquid into a material tank containing a cylindrical screen under stirring, continuously discharging filtrate from the material tank after filtering by the cylindrical screen, and enriching trapped microsphere wet suspension in the cylindrical screen, wherein a stirring shaft which vertically penetrates through the top of the material tank is arranged on the axis of the cylindrical screen, a plurality of plate-shaped paddles are arranged on the stirring shaft, a gap is arranged 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 paddles is 1-5mm, the distance between the bottom surface of the cylindrical screen and the bottom of the plate-shaped paddles is adjusted to be 1-30mm, the trapping aperture of the cylindrical screen is 20-30 mu m, the stirring rotation speed is 40-60rpm, the initial microsphere feed liquid flux is 8-10L/min, and the microsphere feed liquid flux is adjusted to be 5-7L/min when the feed liquid outlet pressure is increased to 1.5-2 times; 2) Washing, namely stopping introducing microsphere feed liquid, introducing washing liquid into a material tank under stirring, discharging the washing liquid after washing, stopping stirring, introducing inert gas into the material tank to squeeze out liquid, and forming a layer of filter cake with the thickness of 5-35 mm on the bottom surface of a cylindrical screen after discharging the liquid; 3) The method comprises the steps of drying, namely adjusting the distance between the bottoms of platy paddles in a material tank and the bottom surface of a cylindrical screen to be 1/5-1/3 of the thickness of a filter cake, continuously introducing inert gas into the material tank under stirring, continuously vacuumizing, filtering water on the surfaces of microspheres, adjusting the material tank to be in a deflection inclined state, reducing the air inlet flow, improving the vacuum degree, and raising the vacuum degree to a target drying temperature; 4) And (5) discharging.
  2. 2. The method of claim 1, wherein in step 2), the washing liquid is introduced into the material tank for a plurality of times, and after each time the washing liquid is introduced, the washing liquid is discharged after the washing liquid is maintained in a stirring state at 40-60rpm for 1-10min, and new washing liquid is introduced continuously.
  3. 3. The method according to claim 1, wherein in the step 3), the stirring speed is 10 to 30rpm; Filtering residual water and organic solvent on the microsphere surface before drying, setting the gas flow of inert gas at 5-20L/min, vacuum degree at-0.4 MPa to-0.6 MPa, and lasting for 0.5-1.5h; Starting a drying stage, reducing the air inlet flow to 2-4L/min, and improving the vacuum degree to-0.7 MPa to-0.8 MPa; And (3) tilting the material tank in a tilting manner during drying, forming an included angle of 40-50 degrees with the vertical plane, and adjusting the material tank to be in an opposite tilting direction at intervals of 0.5-1.5 h.
  4. 4. The method according to any one of claims 1 to 3, wherein the microsphere feed liquid is risperidone microsphere feed liquid with a solid content of 0.1 to 0.5%, ethyl acetate, benzyl alcohol and surfactant are contained, the temperature of the microsphere feed liquid is controlled to be <5 ℃ during the filtration in the step 1), and the washing liquid is ethanol solution at <5 ℃ in the step 2).
  5. 5. The method according to claim 4, wherein in the step 3), the temperature curve in the material tank is set to be 3-5 ℃ and 8-12h, 5-10 ℃ and 1.5-2.5h, 10-12 ℃ and 8-12h, 10-15 ℃ and 1.5-2.5h, 15 ℃ and 4-6h after the inert gas is introduced, and the temperature of the inert gas is kept consistent with the temperature in the material tank.
  6. 6. The method according to any one of claims 1 to 3, wherein the microsphere feed liquid is octreotide microsphere feed liquid with a solid content of <0.1%, and comprises n-heptane, simethicone, methylene dichloride and an emulsifier, the temperature of the microsphere feed liquid is controlled to be <15 ℃ during the filtering in the step 1), and the washing liquid in the step 2) is an aqueous phase solution containing n-heptane and the emulsifier and water in sequence at <15 ℃.
  7. 7. The method of claim 6, wherein in step 3) the lyoprotectant is added to the canister prior to adjusting the canister to the deflected tilt position.
  8. 8. The method according to claim 7, wherein in the step 3), the temperature profile in the material tank is set to be 13-15 ℃,8-12h, 15-35 ℃,1.5-2.5h, 35-40 ℃,4-6h, 35-50 ℃,1.5-2.5h, 50 ℃ and 4-6h after the inert gas is introduced, and the inert gas temperature is kept consistent with the temperature in the material tank.
  9. 9. The method of claim 1, wherein steps 1) -4) are performed by a microsphere filtration washing drying integrated device comprising: a fixing frame; the material tank deflection mechanism is fixed at the top of the fixing frame; The material tank is connected to one end of the material tank deflection mechanism, and is synchronously deflected with the deflection shaft under the rotation drive of the deflection shaft horizontally arranged in the material tank deflection mechanism; and the bottom of the stirring lifting driving mechanism is connected with the stirring shaft and is used for driving the stirring shaft to rotate and lift relative to the material tank.

Description

Microsphere integrated post-treatment method Technical Field The invention relates to the technical field of microsphere processing, in particular to a microsphere integrated post-treatment method. Background The filtration, washing and drying of the microspheres or the particles are indispensable steps for the industrialization of the microspheres, and are often a link of frequent problems in the industrialization. For example, the blocking screen that frequently appears in the filtering process of the planar screen, before the microsphere is dried, the residual solvent and residual moisture in the microsphere are higher, so that the microsphere has certain surface tackiness, when solid-liquid separation is performed, the material on the screen can be gradually deposited, a thick material layer is formed, the material liquid penetrating ability in the later stage of screening is greatly reduced, at this time, even if the filtering pressure is increased, the penetrating screen effect cannot be improved, and only the material is accumulated more tightly, so that the filtering failure and even screen breakage are caused. The accumulation of the microsphere layer on the surface of the screen is similar to non-Newtonian fluid, the viscosity is high, and the microsphere layer is not easy to be resuspended by means of vibration and the like, so that the accumulation is avoided in the filtering process, and the method is the most effective screening method. The drying of the microspheres is the last process step before obtaining the finished product, and the implementation mode is vacuum drying and freeze drying, and the most economical mode is vacuum drying. Vacuum drying is divided into vacuum air flow drying and vacuum decompression drying or both, and the efficiency of the vacuum air flow drying is generally higher than that of the vacuum decompression drying, and the removal of residual solvent and moisture of the microspheres can be accelerated by properly introducing hot air flow. Therefore, uniform heating in the microsphere drying process needs to be ensured, and local material caking and loss of pharmaceutical activity are avoided. Part of microsphere products need to be added with a drying protective agent before drying so as to meet the requirements of adhesion among microspheres and drug inactivation caused by heating during drying. In order to better play the role of the drying protective agent, the microsphere preparation before drying and the drying protective agent are required to be uniformly mixed, but the microsphere preparation before drying and the drying protective agent are not easy to uniformly mix due to large powder chemical property differences of granularity, specific gravity, surface property and the like, and the content percentages are greatly different. Therefore, the technological path of the microsphere determines the need to develop a complete machine device integrating filtering, washing, mixing and drying. The equipment needs to meet various requirements, namely 1) large filtering flux needs to be ensured to avoid blocking the screen, the existing common plane screen is difficult to meet the requirements, 2) uniform mixing of different specific gravity powders needs to be met, part of microsphere varieties need to be added with freeze-drying protective agents after cleaning and before drying, the density difference between the microspheres and the drying agent is large due to the fact that a small amount of water, solvent and the like remain on the surfaces of the microspheres, the mixing is uneven, the agglomeration of finished products is serious, 3) the microspheres are uniformly heated during drying, the agglomeration of the finished products is also serious due to the fact that the local excessive drying is carried out, 4) the equipment needs to be convenient to detach and clean, the screen is difficult to clean on line due to the fact that a plurality of dead angles exist, therefore, the cleaning and the installation are convenient to detach and the installation are needed, 5) powder residues are reduced, the most common skeleton matrix of the microspheres is polyester, the microsphere production process is basically a sterile process, and the transfer of materials in different states between different equipment cannot have pollution of external environments, so that the collection of finished products of the microspheres cannot be interfered manually in a sterile environment. The existing filtering, washing and drying (also called three-in-one) equipment has many imperfect places, such as 1) poor mixing effect, incapability of effectively mixing when the sample amount is large, 2) nonuniform heating during drying, most samples only contact with a bottom plane screen, low side wall jacket utilization rate, 3) high powder residue, 4) inconvenient equipment disassembly, heavy equipment layout and space occupation. Disclosure of Invention In order to solve the technical pro