Microsphere preparation reactor based on planar turn and three-dimensional eddy current and application thereof

Abstract

The application belongs to the technical field of microsphere preparation, and discloses a microsphere preparation reactor based on plane folding and three-dimensional vortex and application thereof. The microsphere preparation reactor comprises a reaction container and a stirring device. The reaction container is in a triangular prism or triangular column structure and is enclosed by a lower bottom surface and three side planes. The stirring device comprises a plurality of layers of stirring paddles, and the stirring device is vertically suspended in the reaction container and is driven and connected with a stirring motor through the upper bottom surface of the reaction container. The microsphere preparation reactor is designed to form a unique transverse folding turbulent flow and longitudinal circulating vortex under the stirring action of the stirring device, so that the size of the formed microsphere can be well controlled, the ascending circulating path of the formed droplet or soft ball in the continuous phase can be well controlled, the solvent diffusion rate and hardening rate during the solidification of the microsphere can be well controlled, the particle size and uniformity of the microsphere can be well controlled, the adhesion or explosion of the microsphere can be avoided, and better product yield and product encapsulation rate can be achieved.

Description

Technical Field

[0001] This invention belongs to the field of microsphere preparation technology, and particularly relates to the field of microsphere preparation technology of ester microsphere flavor masking technology, specifically to a microsphere preparation reactor based on planar folding and three-dimensional vortex and its application. Background Technology

[0002] Microspheres are spheres with a particle size in the micrometer range. In the field of drug delivery, drug-loaded microspheres refer to tiny spheres or spheroids formed by dissolving or dispersing drugs within polymer materials. The principle of drug loading in microspheres is to physically encapsulate or adsorb drugs onto or within the polymer surface. Microspheres can be classified according to their structure into porous microspheres, bilayer microspheres, and magnetic microspheres. Microsphere technology is mainly used in the pharmaceutical field for injectable and oral formulations.

[0003] Taste-masking technologies for oral medications include microparticle coating, macroporous resin adsorption, and microsphere technology. Among these, microparticle coating has several drawbacks: it is complex to operate; microparticles with a diameter of 300-1200 μm produce a poor taste (a strong gritty feel) when used to prepare dry suspensions; and because microparticle encapsulation is surface encapsulation (i.e., spraying and drying a coating solution onto the surface of API microparticles to achieve encapsulation), the API release rate in in vitro suspension preparations (pH 6.8) is between 0.5-2%, which is insufficient for masking the taste of extremely bitter APIs. As for resin adsorption technology, porous resins have adsorption properties in pharmaceutical production and are widely used in purification processes. However, due to their low adsorption rate (generally 5-20%) and resin content exceeding 80%, the high resin content in the medication can lead to side effects. Furthermore, the product is not perfectly spherical, resulting in poor flowability and potential uniformity issues when preparing compound formulations.

[0004] Currently, there is no complete set of standardized industrial equipment for microsphere preparation technology. The microsphere equipment used for different microsphere technologies varies greatly, resulting in many problems such as low sphericity of the microspheres, uneven microsphere size, low product yield and low product encapsulation rate. Industrial equipment for microsphere preparation is currently a blank area in the pharmaceutical machinery market.

[0005] The inventors of this application discovered two main problems during their research on microsphere preparation technology: When adding a dispersed phase to a continuous phase to form microspheres, there are two main issues:

[0006] 1) Because the microspheres formed in the early stage are relatively soft, they are easy to stick together, resulting in the final microspheres being of different sizes or even sticking together and failing to form microspheres.

[0007] 2) Because the microspheres are in different environments when in solution and when exposed to air, the rate of solvent diffusion / evaporation on the surface of the microspheres is different. In the early stage of microsphere formation, they are just spherical droplets. If they float at the interface between the reaction liquid and air, the solvent exposed to air evaporates faster, while the solvent inside the liquid evaporates slower. At this time, the pressure difference caused by the imbalance of solvent evaporation rate on the surface of the microspheres will cause the microspheres to burst and form a film on the surface where the reaction liquid and air come into contact, resulting in a low microsphere yield or even the failure of the entire experiment. Summary of the Invention

[0008] This invention aims to provide a microsphere preparation reactor based on planar folding and three-dimensional vortex. Through reactor structural design, a unique fluid dynamic design of transverse folding turbulence and longitudinal circulating vortex is formed under the stirring action of the stirring device. This design can effectively control the size of the microspheres, control the upward circulation path of droplets or soft spheres in the continuous phase after microsphere formation, control the solvent diffusion rate and hardening rate during microsphere solidification, ensure controllable microsphere particle size and uniformity, avoid microsphere adhesion or bursting, and achieve better product yield and product encapsulation rate.

[0009] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0010] A reactor for fabricating microspheres based on planar folding and three-dimensional vortex, such as Figure 1 The overall design drawing of the inverted triangular truncated cone reactor is shown, including a reaction vessel and a stirring device; the reaction vessel is a triangular truncated cone or triangular prism structure, which is enclosed by a bottom surface and three side planes; the stirring device includes several layers of stirring paddles, and the stirring device is vertically suspended in the reaction vessel, with its upper end passing through the top surface of the reaction vessel and connected to the stirring motor drive.

[0011] Furthermore, the cross-section of the reaction vessel is an isosceles triangle, such as... Figure 2 As shown, the base angle of the isosceles triangle is β, and the value of β ranges from 45° to 75°. When the stirring device in the reaction vessel stirs in one direction, the fluid inside the reaction vessel, especially the surrounding fluid, generates a certain intensity of folding fluid action in the lateral direction. This is beneficial for breaking up the microspheres, has a good anti-adhesion effect on the microspheres in the initial stage, and can ensure that the folding force will not damage the microspheres.

[0012] As a preferred embodiment, the cross-section of the reaction vessel is an equilateral triangle, i.e., β = 60°; for example... Figure 3 As shown, when the stirring device in the reaction vessel stirs in one direction, the fluid inside the reaction vessel, especially the fluid around the perimeter, generates a strong folding fluid effect in the transverse direction, and the folding effect on each side plane is more uniform, which can better disperse the microspheres, and has the best anti-adhesion effect on the microspheres in the initial stage without damaging the microspheres.

[0013] As a comparison with option 1, such as Figure 4 As shown, when the cross-section of reaction vessel 1 is square (or rectangular), the fluid tends to slightly veer in the lateral direction at the four corners of the reaction vessel. Initially, the microspheres tend to stick together to a certain extent and agglomerate, affecting the solidification of the microspheres into spheres.

[0014] As a comparison option 2, such as Figure 5 As shown, when the cross-section of the reaction vessel is hexagonal, the fluid at the six corners of the reaction vessel has almost no lateral backflow, and the microspheres are prone to agglomeration in the early stage.

[0015] As a comparison option 3, such as Figure 6 As shown, when the reaction vessel is a circular device with baffles, although strong backflow fluid can be generated at the baffles, the excessive backflow force can easily cause serious damage to the initial microspheres.

[0016] Comprehensive comparison shows that using a reaction vessel with an isosceles triangular cross-section can generate a better backflow fluid effect with moderate backflow strength. This can prevent the microspheres from sticking together and agglomerating, while also preventing excessive backflow force from damaging the microspheres. Among them, the equilateral triangle has the best effect.

[0017] Furthermore, the angle between the side plane edge and the bottom surface of the reaction vessel is α, and the value of α ranges from 30° to 150°. The corresponding reaction vessel can be a regular triangular frustum, a triangular prism, or an inverted triangular frustum structure. The above structure can generate a longitudinal vortex of a certain intensity under the action of the stirring device, which longitudinally affects the upward trajectory of the microspheres in the reactor, thereby prolonging the rising time of the microspheres and allowing the microspheres to fully solidify in the reaction system, preventing the microspheres from easily bursting when they rise to the liquid surface due to insufficient solidification time.

[0018] Preferably, the reaction vessel can be an inverted triangular truncated pyramid, and the value of α ranges from 30° to 90°; when the reaction vessel is an inverted triangular truncated pyramid, under the stirring action of the stirring device, the longitudinal vortex hydrodynamic morphology of the liquid in the reaction vessel is as follows: Figure 7 As shown, strong eddies are generated in the middle and upper parts of the reaction vessel, especially in the upper part, which is extremely beneficial for extending the curing time of the microspheres and can effectively prevent the microspheres from bursting when they rise to the liquid surface. At the same time, the upper cross section of the inverted triangular truncated pyramid structure is larger than the lower cross section, and the stirring device is inserted into the reaction vessel from the top, which is conducive to the installation, disassembly and maintenance of the stirring device.

[0019] Optionally, the reaction vessel can be a regular triangular truncated pyramid, and the value of α ranges from 90° to 150°; when the reaction vessel is a regular triangular truncated pyramid, under the stirring action of the stirring device, the longitudinal vortex hydrodynamic morphology of the liquid in the reaction vessel is as follows: Figure 8As shown, the fluid generates eddies of a certain intensity in the middle and bottom of the reaction vessel, while the eddies at the top are smaller and almost invisible. The eddies in the middle and bottom are beneficial for extending the curing time of the microspheres and can also effectively prevent the microspheres from bursting when they rise to the liquid surface. Meanwhile, the upper cross section of the truncated triangular structure is smaller than the lower cross section. If the stirring device is installed from the top, the blades below the stirring device will be limited to a smaller size, which will not achieve the ideal stirring effect. If it is installed from the bottom, it will be not conducive to the installation, disassembly and maintenance of the stirring device.

[0020] Optionally, the reaction vessel can also be a triangular prism with α = 90°. When the reaction vessel is a triangular prism, under the stirring action of the stirring device, the longitudinal vortex hydrodynamic morphology of the liquid in the reaction vessel is as follows: Figure 9 As shown, the fluid tends to circulate at the bottom and top of the reaction vessel, with almost no eddies. The microspheres solidify in a short time. When the microspheres rise to the liquid surface, they are prone to bursting and forming a film due to the pressure difference, and the film aggregates.

[0021] Figures 10-12 The figures show the rise height-time curves of microspheres in reactors fabricating microspheres with three different structures: inverted triangular truncated pyramid, regular triangular truncated pyramid, and triangular prism. A comparison reveals that the inverted triangular truncated pyramid... Figure 10 ) and regular triangular prism ( Figure 11 The microspheres of the same type had similar rising speed and curing time, but the inverted triangular truncated cone had a slightly longer curing time and better curing effect. Figure 12 The triangular prism microspheres shown rise rapidly and have a short curing time. When the microspheres rise to the liquid surface, some of the microspheres with poor curing effect burst directly under the pressure difference to form a film.

[0022] Considering the preparation and installation process of the reaction vessel, as mentioned earlier, the inverted triangular truncated pyramid structure makes it easier to install the stirring device and facilitates disassembly and maintenance. Therefore, taking all factors into account, the preferred solution is a microsphere preparation reactor with an inverted triangular truncated pyramid structure, which is the best choice in terms of solidification effect and installation process. Figure 13 The diagram shows the upward trajectory of the microspheres during solidification in the inverted triangular truncated cone reaction vessel. Under the influence of lateral deflection and longitudinal vortex, the microspheres first rise in a zigzag pattern and then deflect downward. Figure 14 The diagram shows the longitudinal vortex effect of the inverted triangular truncated cone reaction vessel, where A represents the vortex, and the vortex effect is obvious.

[0023] Furthermore, the height of the reaction vessel is H, and the value of H ranges from 10cm to 200cm.

[0024] Preferably, the height H of the reaction vessel is in the range of 30cm to 120cm.

[0025] Furthermore, the stirring device is a turbine stirrer, a downpour impeller stirrer, or a turbine blade-downpour impeller combined stirring device; the stirring device includes 2-4 layers of stirring impellers, preferably 3 layers of stirring impellers; the length of each layer of stirring impellers is positively correlated with the size of the container at the corresponding position, that is, the stirring impellers selected for positions with larger container sizes are also larger, so as to achieve a better stirring effect and form a good lateral backflow and longitudinal vortex effect.

[0026] Furthermore, the reaction vessel is made of one of the following materials: plexiglass, organic plastic, stainless steel, titanium alloy, enamel glass, ceramic, or iron. The reaction vessel is formed by molding, casting, rolling, welding, or bonding. As a preferred embodiment, the reaction vessel is made of transparent plexiglass, which facilitates the visualization of the reaction vessel.

[0027] The oral microspheres of this invention need to have a diameter of 50-380 micrometers. After initial spheroidization, a certain amount of time is required for solvent diffusion and microsphere solidification in the continuous phase. Microsphere adhesion and aggregation in the continuous phase, and microsphere bursting to form a film before the shell solidifies, will both lead to spheroidization failure. These two phenomena are problems that need to be addressed first in the microsphere preparation process, and the injection method is an important means to solve these problems. By using internal liquid feeding and controlling the injection spheroidization dispersion effect through the feed position in the reactor, the particle size and particle size uniformity of the spheroids can be controlled. Therefore, the reaction vessel also includes an injection distributor for injecting the dispersed phase into the reaction vessel. The injection distributor is located at the bottom, middle and top of the reaction vessel, preferably at the bottom.

[0028] Optionally, the injection dispenser is a multi-needle injector with uniform distribution, comprising three sets of injection dispensers. Each set of injection dispensers includes several parallel syringes, and each side of the corresponding reaction vessel has several injection holes for mounting the syringes, such as... Figure 15 As shown; the number of injection holes on each side is referred to as injection points. For smaller reactors, the number of injection points can be set to 1 or 2, while for larger reaction vessels, the number of injection points can be set to 3-6 or even more.

[0029] The syringe is a cylindrical tubular structure, including a limiting and sealing boss at the bottom and an injection tube at the top; the circular surface of the injection tube has several sets of injection holes arranged in a circumferential direction; optionally, four sets of injection holes can be evenly spaced at the top, bottom, front, and back of the injection tube, such as... Figure 16 As shown; alternatively, two sets of injection holes can be evenly spaced at the top and bottom of the injection tube, such as... Figure 17 As shown; to ensure the injection effect, adjacent sets of injection holes can be arranged in an alternating pattern.

[0030] The injection tube is horizontally inserted into the bottom of the side plane of the reaction vessel, with the injection holes of the injection tube all located inside the reaction vessel cavity, and the limiting sealing boss located outside the reaction vessel. In specific installation, an installation hole can be opened at the bottom of the reaction vessel, and a rubber plug can be sealed in the installation hole. The injection tube is directly inserted into the rubber plug to reach the inside of the reaction vessel.

[0031] Optionally, the injection dispenser can be a ring-shaped circulating injector, such as... Figure 18 As shown, the annular circulating feeder has several injection holes evenly distributed on its annular top surface. The annular circulating feeder is inserted flat into the inner side of the bottom of the reaction vessel cavity, ensuring that the injection holes are evenly spaced within the reaction vessel cavity.

[0032] The annular circulating injector includes an injection inlet and a circulation outlet. Both the injection inlet and the circulation outlet pass through the side plane of the reaction vessel and connect to the dispersed phase mixing tank. The annular circulating injector, together with the dispersed phase mixing tank, forms a circulation loop through the injection inlet and the circulation outlet, maintaining a fixed pressure value to ensure a stable injection speed. At the same time, it can also prevent the mixed liquid in the reaction vessel from flowing back into the injection pipe during the injection process, causing blockages, liquid backflow, and contamination of the mixing tank.

[0033] Furthermore, the reaction vessel also includes a cooling jacket, which is fitted around the outside of the reaction vessel and forms a cooling vessel cavity with the outer wall of the reaction vessel. The cooling jacket has a coolant inlet on one side of its bottom and a coolant outlet on one side of its top, which is used to cool the reaction vessel during the curing process, thereby accelerating the curing process and improving the curing effect.

[0034] In the preparation process of the flavor-masking microspheres of the present invention, after the dispersed phase and the continuous phase are mixed, they successively undergo the stages of spherical droplet (hereinafter referred to as droplet) formation, soft sphere formation, sphere wall solidification, sphere solidification, microsphere filtration and microsphere drying.

[0035] Droplet formation stage:

[0036] After the microsphere dispersed phase is fed into the bottom of the microsphere continuous phase, it gradually forms spherical droplets.

[0037] By regulating the sphericity and dispersibility of each material, we can prevent undispersed material units (i.e., large spheres) from bursting and forming a film on the liquid surface; and prevent materials from becoming too dispersible (i.e., having weak sphericity) and forming an emulsion that cannot form spherical droplets.

[0038] Soft ball formation stage:

[0039] As the solvent on the surface of the droplet rapidly diffuses into the continuous phase, the drug carrier on the surface of the droplet precipitates out, forming a relatively thin soft skin, thus forming a soft sphere.

[0040] Sphere wall curing stage:

[0041] 1) As the solvent diffuses from the soft sphere into the continuous phase of the microsphere and the solvent in the continuous phase of the microsphere diffuses back into the soft sphere, the wall of the soft sphere gradually solidifies, and the drug carrier skin on the surface of the soft sphere gradually thickens, forming a core sphere with a certain thickness (the core is still liquid).

[0042] 2) The solvent inside the core sphere diffuses further over time, and the thickness of the core sphere shell continues to increase.

[0043] Sphere solidification stage:

[0044] After the cored spheres are completely solidified, they become solid or hollow spheres with smaller particle sizes. The surface of the microspheres is highly compact, while the interior is also porous. The drug components exist in the form of molecular dispersions in the microspheres, which is more conducive to drug delivery and release.

[0045] This invention provides a microsphere preparation process, utilizing any of the above-mentioned microsphere preparation reactors based on planar folding and three-dimensional vortex, the process comprising the following steps:

[0046] Step S01: Prepare the dispersed phase by dissolving the raw material components of the flavor-masking microspheres in solvent A to form the dispersed phase;

[0047] Step S02: Prepare a continuous phase, selecting solvent B as the continuous phase;

[0048] Step S03: Inject the continuous phase into the reaction vessel and start the stirring device;

[0049] Step S04: Continuously inject the dispersed phase into the reaction vessel through the feed dispenser at the bottom of the reaction vessel to obtain the microsphere suspension;

[0050] Step S05: The microsphere suspension is filtered, washed, and dried to obtain microspheres.

[0051] Further, in step S01, solvent A is a mixed solvent of organic solvent C and water, wherein the mass percentage of water in solvent A is 0-35%, and organic solvent C includes at least one of methanol, ethanol, isopropanol, methyl ethylene glycol, acetone, tetrahydrofuran, methyltetrahydrofuran, toluene, xylene, acetonitrile, N,N-dimethylacetamide, ethyl acetate, n-butanol, dichloromethane, chloroform, tetrachloroethane, and methyl propylene glycol acetate.

[0052] In the dispersed phase, the choice of solvent C needs to consider three factors, including:

[0053] 1) Solvents that can form spheres in a continuous phase;

[0054] 2) Solvents with good solubility for drug carriers;

[0055] 3) Solvents with good API solubility and good diffusion in continuous phase.

[0056] Furthermore, the flavor-masking microsphere raw material, by weight, comprises the following components: 1.5-21.2 parts of drug ingredient, 35-110 parts of drug carrier, 0-30 parts of alkalizing agent, and 0-8 parts of plasticizer.

[0057] Furthermore, the drug ingredient is a compound with a bitter or unpleasant taste.

[0058] Furthermore, the drug carrier includes a pH-dependent carrier and a matrix-type carrier, wherein the amount of pH-dependent carrier is 5-40 parts and the amount of matrix-type carrier is 30-70 parts.

[0059] Furthermore, the pH-dependent carrier includes at least one of polyacrylic acid resin, methyl methacrylate-diethylaminoethyl methacrylate copolymer, and polyvinyl acetal diethylamino acetate; the skeleton carrier includes at least one of ethyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, cellulose acetate, polyvinyl acetate, ammonium methacrylate copolymer type A, ammonium methacrylate copolymer type B, crospovidone, and maltodextrin.

[0060] Furthermore, the alkalizing agent includes at least one of sodium carbonate, sodium bicarbonate, magnesium oxide, meglumine, and tromethamine; the plasticizer includes at least one of diethyl phthalate, tributyl citrate, polyethylene glycol 6000, and triethyl citrate.

[0061] Furthermore, the flavor-masking microspheres also include at least one of a light-blocking agent and an additive. The light-blocking agent includes at least one of zinc oxide and titanium dioxide, and the additive includes at least one of fumaric acid, magnesium stearate, silica, talc, and povidone.

[0062] Further, the solvent B mentioned in step S02 includes at least one of water, dichloromethane, ethanol and liquid paraffin.

[0063] Furthermore, the continuous phase in step S02 further includes a surfactant, the amount of which in the continuous phase is 0.01-2 wt%, and the surfactant includes at least one of sodium oleate, Tween, polyvinyl alcohol, sodium dodecyl sulfate and sodium carboxymethyl cellulose.

[0064] Furthermore, the temperature of the continuous phase in step S02 is 2-30°C, and the pH is 6-11.

[0065] Furthermore, the stirring speed of the stirring device is 50-900 rpm.

[0066] In addition, the present invention also provides a continuous microsphere preparation system, which uses any of the microsphere preparation reactors based on planar folding and three-dimensional vortex as described above. The continuous microsphere preparation system includes a continuous phase mixing tank, a dispersed phase mixing tank, a microsphere preparation reactor, a pressure reducing filter, a vaporization membrane separator, and an organic solvent recovery storage tank.

[0067] The continuous phase mixing tank and the dispersed phase mixing tank are respectively connected to the bottom inlet of the microsphere preparation reactor; the microsphere preparation reactor is provided with a microsphere outlet in the middle, which is connected to the top inlet of the pressure reducing filter through a solidification pipeline, and the bottom outlet of the pressure reducing filter is connected to the vaporization membrane separator; the vaporization membrane separator sends the separated organic solvent to the organic solvent recovery storage tank through a pipeline, and discharges the wastewater through a wastewater pipeline.

[0068] Furthermore, the bottom outlet of the pressure-reducing filter is connected to the continuous phase mixing tank via a pipeline, and a second dispensing pump is installed on this connecting pipeline. The purpose of this pipeline is that during the curing reaction stage, a portion (e.g., 50%) of the continuous phase filtered by the pressure-reducing filter is returned to the continuous phase mixing tank for direct reuse, while the other portion (e.g., the remaining 50%) is separated and recovered by a vaporization membrane separator and stored in an organic solvent recovery storage tank for reuse in the dispersed phase mixing tank. This recycling method simplifies the process flow, saves resources, reduces the processing load of the vaporization membrane separator, and effectively reduces input costs.

[0069] Compared with the prior art, the beneficial effects of the present invention are:

[0070] (1) The microsphere preparation reactor based on planar folding and three-dimensional vortex provided by the present invention, by designing the reactor cross section to adopt an isosceles triangle or equilateral triangle structure, can generate transverse folding turbulence inside the reactor under the action of the stirring device. The transverse folding turbulence can effectively prevent the aggregation and adhesion of microspheres during the solidification process and improve the sphericity of microspheres during solidification.

[0071] (2) By designing the reactor as a triangular frustum or triangular prism structure, the present invention can generate a longitudinal circulating vortex inside the reactor. The longitudinal circulating vortex can effectively extend the rising trajectory of the microspheres, thereby extending the solidification time of the microspheres rising to the liquid surface. This prevents the microspheres from rising too fast in the early stage and rising to the liquid surface before they have fully solidified, and bursting to form a film on the liquid surface due to the pressure difference.

[0072] (3) This invention uses a reaction vessel with a triangular frustum or triangular prism structure to control the upward circulation path of droplets or soft spheres in the continuous phase after microspheres are formed by the combined action of transverse backflow turbulence and longitudinal circulating eddies. This controls the solvent diffusion rate and hardening rate during microsphere solidification, ensuring that the particle size and uniformity of the microspheres are controllable, achieving better product yield and product encapsulation rate. The microsphere encapsulation rate can reach up to 90%, and the microsphere particle size is scientifically controlled between 50-380 micrometers (the particle size of products prepared by conventional granulation technology or micro-pellet coating technology is between 300-1200 micrometers). The masked microspheres have high integrity and roundness, and the outer surface of the spheres is smooth and dense. The drug components are uniformly dispersed in the form of molecular dispersion within the microspheres, resulting in good encapsulation effect. The drug dissolves quickly in the stomach, and the masking effect is excellent. This solves the problem of the gritty feeling when taking dry suspensions orally, improves the comfort and compliance of patients, and provides a new dosage form that is easy and convenient for children, the elderly, and patients with swallowing difficulties to take.

[0073] (4) The continuous microsphere preparation system provided by the present invention uses the bottom diffusion method to prepare microspheres, and continuously feeds from the bottom of the reaction vessel and continuously discharges from the middle of the reaction vessel, which can realize automated and continuous production. It can achieve excellent encapsulation and taste masking effects for both water-soluble and fat-soluble drugs. The process is simple, does not require complex equipment, and the raw materials are readily available. It is suitable for continuous and automated scale-up production and has a wide range of applications.

[0074] (5) The continuous microsphere preparation system provided by the present invention allows for the return of a portion (e.g., 50%) of the continuous phase filtered out by the pressure reducing filter to the continuous phase mixing tank for direct reuse via pipeline, while the remaining portion (e.g., the remaining 50%) is separated and recovered by a vaporization membrane separator and stored in an organic solvent recovery storage tank for reuse in the dispersed phase mixing tank. This recycling method reduces the processing load of the vaporization membrane separator, simplifies the process flow, saves energy and is environmentally friendly, and effectively reduces input costs. Attached Figure Description

[0075] Figure 1 General design drawing of the inverted triangular truncated cone reactor

[0076] Figure 2 This is a schematic diagram of the transverse horizontal reversal hydrodynamic configuration when the cross-section of the reaction vessel is an isosceles triangle.

[0077] Figure 3 This is a schematic diagram of the transverse horizontal reversal hydrodynamic configuration when the cross-section of the reaction vessel is an equilateral triangle.

[0078] Figure 4 This is a schematic diagram of the lateral horizontal reversal hydrodynamic configuration when the cross-section of the reaction vessel is square (or rectangular).

[0079] Figure 5 This is a schematic diagram of the transverse horizontal reversal hydrodynamic morphology of a reaction vessel with a hexagonal cross-section.

[0080] Figure 6 A schematic diagram of the lateral horizontal backflow hydrodynamic configuration when the reaction vessel has a circular cross-section with baffles;

[0081] Figure 7 This is a schematic diagram of the longitudinal vortex hydrodynamics when the reaction vessel is an inverted triangular truncated pyramid.

[0082] Figure 8 This is a schematic diagram of the longitudinal vortex hydrodynamics when the reaction vessel is a regular triangular truncated pyramid.

[0083] Figure 9 This is a schematic diagram of the longitudinal vortex hydrodynamics when the reaction vessel is a triangular prism.

[0084] Figure 10 A graph showing the change in the rising height of the microspheres in the inverted triangular truncated cone reaction vessel over time;

[0085] Figure 11 The graph shows the change in the rising height of the microspheres in the truncated triangular reaction vessel over time.

[0086] Figure 12 This is a graph showing the change in the rising height of the microspheres in the triangular prism reactor over time.

[0087] Figure 13 A schematic diagram of the upward motion trajectory of microspheres during solidification in an inverted triangular truncated reactor.

[0088] Figure 14 This is a longitudinal vortex effect diagram of an inverted triangular truncated cone reaction vessel, where A represents the vortex.

[0089] Figure 15 This is a schematic diagram of a multi-needle dispenser for uniform distribution.

[0090] Figure 16 This is a schematic diagram of a peripherally perforated injector (installed inside a multi-needle dispenser);

[0091] Figure 17 This is a schematic diagram of a top-and-bottom perforated syringe (installed inside a multi-needle dispenser);

[0092] Figure 18 This is a schematic diagram of the structure of an annular circulating feeder;

[0093] Figure 19 Design drawing for reactor #1;

[0094] Figure 20 This is a picture of reactor #1.

[0095] Figure 21 Design drawing for reactor #2;

[0096] Figure 22 This is a picture of reactor #2.

[0097] Figure 23 Design drawing for reactor #3;

[0098] Figure 24 This is a picture of reactor #3.

[0099] Figure 25 Design drawing for reactor #4;

[0100] Figure 26 This is a picture of reactor #4.

[0101] Figure 27 The image shows a scanning electron microscope (SEM) image of the surface of the fumarate vorexam microspheres prepared in an embodiment of the present invention.

[0102] Figure 28 This is a scanning electron microscope cross-section of the fumarate vonoprazan microspheres prepared in an embodiment of the present invention;

[0103] Figure 29 Images of vonoprazan fumarate microspheres prepared in embodiments of the present invention;

[0104] Figure 30 Flowchart of continuous microsphere equipment and process;

[0105] Explanation of markings in the diagram:

[0106] 1-Reaction vessel; 2-Stirring device; 3-Cooling jacket; 4-Uniformly distributed multi-needle injector; 5-Limiting sealing boss; 6-Injection hole; 7-Injection tube; 8-Annular circulating injector; 9-First continuous phase mixing tank; 10-Second continuous phase mixing tank; 11-Dispersed phase mixing tank; 12-Microsphere preparation reactor; 13-Curing pipeline; 14-Ventilation hole; 15-Pressure reducing filter; 16-Exhaust port; 17-Vacuum pump; 18-Organic solvent recovery storage tank; 19-Vaporization membrane separator; 20-First infusion pump; 21-Wastewater pipeline; 22-Injection constant flow pump; 23-First dispensing pump; 24-First valve; 25-Second valve; 26-Third valve; 27-Fourth valve; 28-Second dispensing pump; 29-Second infusion pump;

[0107] 101 - Dispersed phase inlet; 102 - Microsphere outlet; 103 - Continuous phase inlet; 301 - Coolant inlet; 302 - Coolant outlet. Detailed Implementation

[0108] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0109] In the description of this invention, it should be understood that the terms "coaxial," "bottom," "one end," "top," "middle," "other end," "upper," "side," "top," "inner," "front," "center," "both ends," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limiting this invention.

[0110] Combination Figure 1 As shown, this invention provides a microsphere preparation reactor based on planar folding and three-dimensional vortex, including a reaction vessel 1 and a stirring device 2. The reaction vessel 1 is a triangular frustum or triangular prism structure, enclosed by a bottom surface and three side surfaces. The stirring device 2 is a turbine stirrer, a pressure paddle stirrer, or a turbine blade-pressure paddle combined stirring device. The stirring device includes 2-4 layers of stirring paddles. The stirring device 2 is vertically suspended in the reaction vessel 1, and its upper end passes through the top surface of the reaction vessel 1 and is driven by a stirring motor (not shown). A continuous phase injection port 103 is provided at the bottom of the reaction vessel 1 for injecting the continuous phase. A dispersed phase injection port 101 is provided near the bottom on each of the three side surfaces of the reaction vessel 1 for injecting the dispersed phase. When the reaction vessel is continuously injected from the bottom, a microsphere outlet 102 is provided on one side of the middle of the reaction vessel for discharging the solidified microspheres. In some other embodiments, when the reaction vessel is injected in a single-pass manner, the microsphere outlet 102 can also be located at the bottom of the reaction vessel.

[0111] The height of the reaction vessel 1 is H, and the value of H ranges from 10cm to 200cm. The material of the reaction vessel is one of plexiglass, organic plastic, stainless steel, titanium alloy, enamel glass, ceramic or iron. The reaction vessel is formed by molding, casting, rolling or welding. As a preferred option, the material of the reaction vessel is transparent plexiglass, which is beneficial to the visualization of the reaction vessel.

[0112] The bottom of the microsphere preparation reactor with planar folding and three-dimensional vortex is equipped with a material distributor; the material distributor can be a uniformly distributed multi-needle injector 4 or an annular circulating injector 8.

[0113] like Figure 15 As shown, the injection dispenser is a uniformly distributed multi-needle injector 4, which includes three sets of injection dispensers. Each set of injection dispensers includes several parallel syringes, which can uniformly inject material into the bottom of the reaction vessel 1. Each side of the corresponding reaction vessel has several injection holes for installing syringes. The number of injection holes on each side is referred to as the injection points. For smaller reactors, the number of injection points can be set to 1 or 2. For larger reaction vessels, the number of injection points can be set to 3-6 or even more.

[0114] like Figure 16 As shown, the syringe is a cylindrical tubular structure, including a limiting and sealing boss 5 at the bottom and an injection tube 7 at the top. The circular surface of the injection tube 7 has four sets of injection holes 6 arranged circumferentially (upper, lower, front, and rear, in the direction the injection tube is placed horizontally). To ensure injection effectiveness, in some other embodiments, two sets of injection holes can be evenly spaced at the top and bottom of the injection tube, such as... Figure 17 As shown; to ensure the injection effect, adjacent sets of injection holes can be staggered; the injection tube 7 is horizontally inserted into the bottom of the side plane of the reaction vessel 1, and the injection holes 6 of the injection tube 7 are evenly distributed in the cavity of the reaction vessel 1. The limiting sealing boss 5 is located on the outside of the reaction vessel 1, and the limiting sealing boss 5 is used to limit the insertion position of the injection tube 7; in specific installation, an installation hole can be opened at the bottom of the reaction vessel 1, and a rubber plug is sealed in the installation hole. The injection tube 7 is inserted into the rubber plug to reach the inside of the reaction vessel 1.

[0115] In some embodiments, the injection dispenser may also be configured as a ring-shaped circulating injector 8, such as... Figure 18 As shown, the annular circulating injector 8 has several injection holes 7 evenly distributed on its annular top surface. The annular circulating injector 8 is inserted horizontally into the bottom inner side of the reaction vessel cavity, ensuring that the injection holes 6 are evenly spaced within the reaction vessel cavity. The annular circulating injector 8 includes an injection inlet and an injection outlet. Both the injection inlet and the injection outlet pass through the side plane of the reaction vessel 1 and connect to the dispersed phase mixing tank. The annular circulating injector 8, through its injection inlet and circulation outlet, forms a circulation loop with the dispersed phase mixing tank, maintaining a fixed pressure value to ensure a stable injection speed. At the same time, it can also prevent the mixed liquid in the reaction vessel from flowing back into the injection pipe during the injection process, causing blockages, liquid backflow, and contamination of the mixing tank.

[0116] In addition, a cooling jacket 3 is also provided around the reaction container 1. The cooling jacket 3 and the outer wall of the reaction container 1 form a cooling container cavity. A coolant inlet 301 is provided on one side of the bottom of the cooling jacket 3, and a coolant outlet 302 is provided on one side of the top. It is used to cool the reaction container during the curing process, accelerate the curing process, and improve the curing effect.

[0117] Example 1

[0118] Combination Figure 1 As shown, this invention designed and manufactured reactor #1, the design drawings of which are as follows. Figure 19 As shown, a reactor for preparing inverted triangular frustum microspheres based on planar folding and three-dimensional vortex is obtained. The reactor is enclosed by a bottom surface and three side planes; the material is plexiglass, and the processing technology is an adhesive bonding process.

[0119] The reactor has an equilateral triangle cross-section with an interior angle ∠β = 60°;

[0120] The length of the bottom edge of the reactor is a1 = 11.5 cm, and the length of the top edge of the reactor is a2 = 18.5 cm;

[0121] The reactor has a height H = 40 cm and a capacity of 3 L.

[0122] The angle ∠α between the reactor's edge and its base is 84.2°.

[0123] The height h1 from the bottom edge of the dispersed phase injection port is 2cm. One dispersed phase injection port is opened on each side (the number of injection holes opened on each side is simply referred to as injection points, that is, there is one injection point here), with an opening diameter of 1.2cm.

[0124] The continuous phase feed inlet is located on the bottom surface of the reactor, with one opening and a diameter of 2cm.

[0125] The microsphere outlet is located on the bottom surface of the reactor, with one opening and an opening diameter of 2cm.

[0126] Configure a multi-needle injector with evenly distributed needles and use a peripherally perforated injector. Figure 16 );

[0127] Equipped with a three-layer downward-pressure mixing device, the mixing motor speed is 50-900 rpm, and the height of the mixing paddle from the bottom surface is as follows: lower layer h3 = 2cm, middle layer h4 = 20cm, and upper layer h5 = 36cm. See the actual equipment for details. Figure 20 .

[0128] Example 2

[0129] Experimental objective: To evaluate the feasibility of using reactor #1 for microsphere preparation (ethyl acetate / ethanol process).

[0130] Process conditions: Reactor type 1, continuous phase volume 3L.

[0131] The mass ratio of the dispersed phase solvent, ethyl acetate, anhydrous ethanol, and water is 7.8:3.9:1 (total 57.1g).

[0132] The mass ratio of the dispersed phase solutes—API, EPO, N10, magnesium oxide, and triethyl citrate—was 1.12:3.2:7.2:3.0:1 (total 7.76 g).

[0133] Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (10℃), continuous phase pH: 7.

[0134] Injection parameters: Continuous injection is achieved using a multi-needle injector with evenly distributed needles at the bottom; the syringe is equipped with a peripherally perforated syringe. Figure 16 There are 3 injection points in total, with 1 injection point on each side. The feeding and stirring speed is 150 rpm and the feeding time is 16 min (peristaltic pump model: Sino 2S, feeding speed is 10 rpm). After feeding, the stirring speed is 100 rpm and the stirring time is 30 min.

[0135] Operating steps:

[0136] Step S01: Prepare the dispersed phase by dissolving the raw material components of the flavor-masking microspheres in solvent A to form the dispersed phase;

[0137] Step S02: Prepare a continuous phase, selecting solvent B as the continuous phase;

[0138] Step S03: Inject the continuous phase into the reaction vessel;

[0139] Step S04: Continuously inject the dispersed phase into the reaction vessel through the feed distributor at the bottom of the reaction vessel, and at the same time start the stirring device to stir;

[0140] Step S05: Open the dispersed phase outlet pipe in the middle of the reaction vessel, and discharge the solidified microspheres together with the continuous phase from the reaction vessel. After filtration, washing and drying, the microspheres are obtained.

[0141] The various indicators of the flavor-masked microspheres prepared by reactor #1 are shown in Table 1. The encapsulation rate of the microspheres prepared is over 90%.

[0142] Table 1

[0143] FC611-1 88.4 7.8 91.9 96.7 FC611-2 88.0 7.6 92.8 95.2 FC611-3 88.8 7.6 91.5 97.6

[0144] Example 3

[0145] Experimental objective: To evaluate the feasibility of using reactor #1 for microsphere preparation (ethyl acetate / acetone process).

[0146] Process conditions: Reactor type 1, continuous phase volume 3L.

[0147] The mass ratio of the dispersed phase solvent, ethyl acetate, acetone, and water is 7.8:3.9:1 (total 57.1g).

[0148] The mass ratio of the dispersed phase solutes—API, EPO, N7, magnesium oxide, triethyl citrate, povidone, magnesium stearate, titanium dioxide, and talc—is 5.6:15:37:15:5:2:2:1:1 (total 8.36 g).

[0149] Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (9℃), continuous phase pH: 7.

[0150] Injection parameters: Continuous injection is achieved using a multi-needle injector with evenly distributed needles at the bottom; the syringe is equipped with an upper and lower orifice syringe. Figure 17 There is one injection point on each side, for a total of three injection points. The feeding and stirring speed is 140 rpm, and the feeding time is 18 min (peristaltic pump model: Sino 2S, feeding speed is 12 rpm). After feeding, the stirring speed is 100 rpm, and the stirring time is 30 min.

[0151] Operating steps: Same as in Example 2.

[0152] The various indicators of the flavor-masked microspheres prepared by reactor #1 are shown in Table 2. The encapsulation rate of the microspheres prepared is over 90%.

[0153] Table 2

[0154] FC526-1 90.38 6.7 90.4 98.7 FC526-2 88.76 6.8 90.1 99.7

[0155] Example 4

[0156] Combination Figure 1 As shown, the present invention designed and manufactured reactor #2, as follows. Figure 21 As shown, a microsphere-based reactor based on planar folding and three-dimensional vortex was obtained. The reactor is shaped like an inverted triangular truncated pyramid, enclosed by a bottom surface and three side planes. The material is plexiglass, and the processing technology is an adhesive bonding process.

[0157] The reactor has an equilateral triangle cross-section with an interior angle ∠β = 60°.

[0158] The length of the bottom edge of the reactor is a1 = 16cm, and the length of the top edge of the reactor is a2 = 31cm.

[0159] The reactor has a height H = 45 cm and a capacity of 8 L.

[0160] The angle ∠α between the reactor ridge and the bottom surface is 79.1°.

[0161] The height h1 from the bottom edge of the dispersed phase injection port is 3cm, and there are 2 injection ports on each side (i.e., 2 injection points) with an opening diameter of 1.2cm.

[0162] The continuous phase feed inlet is located on the bottom surface of the reactor, with one opening and a diameter of 2 cm.

[0163] The microsphere outlet is located on one side of the middle of the reactor, at a height h2 = 22cm from the bottom edge. There is one outlet with an opening diameter of 2cm.

[0164] Configure a multi-needle injector with even distribution and use an upper and lower orifice injector ( Figure 17 ).

[0165] Equipped with a three-layer downward-pressure mixing device, the mixing motor speed is 50-900 rpm, and the height of the mixing paddle from the bottom surface is 3cm for the bottom layer, 23cm for the middle layer, and 38cm for the top layer. See the actual equipment for details. Figure 24 .

[0166] Example 5

[0167] Experimental objective: To evaluate the feasibility of using reactor #2 for microsphere preparation.

[0168] Process conditions: Reactor type 2#, continuous phase 6L.

[0169] The mass ratio of the dispersed phase solvents ethyl acetate, anhydrous ethanol, and water is 9.8:3.8:1 (total 99.6g).

[0170] The mass ratio of the dispersed phase solutes (API, E100, N7, magnesium oxide, triethyl citrate, povidone, magnesium stearate, titanium dioxide, and talc) is 5.6:15:46.2:5.8:3.3:2:2:1:1 (total 12.29 g).

[0171] Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (9℃), continuous phase pH: 7.

[0172] Injection parameters: Continuous injection is achieved using a multi-needle injector with evenly distributed needles at the bottom; the syringe is equipped with an upper and lower orifice syringe. Figure 17 There are 2 injection points on each side, for a total of 6 injection points, and 1 discharge port on the middle side. The continuous phase and the dispersed phase are fed synchronously. The continuous phase feed speed is 65 rpm (peristaltic pump model: Sino BS100-1A), and the dispersed phase feed speed is 15 rpm (peristaltic pump model: Sino 2S). The injection time is 17 minutes.

[0173] Operation steps: Same as in Example 2

[0174] The various indicators of the prepared taste-masking microspheres are shown in Table 3.

[0175] Table 3

[0176]

[0177] In this embodiment of the invention, the morphology of the vonoprazan fumarate microspheres prepared with test batch number FC606-1 is as follows: Figure 27-29 As shown, where, Figure 27 The surface image of the prepared vonoprazan fumarate microspheres is shown in the scanning electron microscope image. Figure 28 A scanning electron microscope cross-section of the prepared vonoprazan fumarate microspheres; Figure 29 Image of the prepared vonoprazan fumarate microspheres.

[0178] According to scanning electron microscopy, the fumarate vonoprazan microspheres prepared in the embodiments of the present invention are spherical and intact, with a smooth surface and a large number of nanoscale pores inside; the microscopic images show that the microspheres have a particle size of 100-300 μm, are uniform in size, and are spherical and intact.

[0179] Example 6

[0180] Combination Figure 1 As shown, this invention designed and manufactured reactor #3 ( Figure 23 A microsphere-based reactor based on planar folding and three-dimensional vortex was obtained. The reactor is triangular prism in shape, enclosed by a bottom surface and three side planes. The material is plexiglass, and the processing technology is adhesive bonding.

[0181] The reactor has an equilateral triangle cross-section with an interior angle ∠β = 60°.

[0182] The length of the upper and lower bottom edges of the reactor is a = 38 cm.

[0183] The reactor has a height H = 45cm and a capacity of 15L.

[0184] The angle ∠α between the reactor ridge and the bottom surface is 90°.

[0185] The height h1 from the bottom edge of the dispersed phase injection port is 4cm, and there are 3 dispersed phase injection ports on each side with an opening diameter of 1.2cm.

[0186] The continuous phase feed inlet is located on the bottom surface of the reactor, with one opening and a direct opening length of 2 cm.

[0187] The microsphere outlet is located on the side of the middle part of the reactor, at a height h2 = 25cm from the bottom edge, with one opening and a direct opening length of 2cm.

[0188] Configure the injection distributor as a ring-shaped circulating injection device. Figure 18 ).

[0189] Equipped with a three-layer downward-pressure mixing device, the mixing motor speed is 50-900 rpm, and the height of the mixing paddle from the bottom surface is as follows: lower layer h3 = 5cm, middle layer h4 = 25cm, and upper layer h5 = 40cm. See the actual equipment for details. Figure 24 .

[0190] Example 7

[0191] Experimental objective: To evaluate the feasibility of using reactor #3 for microsphere preparation.

[0192] Process conditions: Reactor type 3#, continuous phase 9L.

[0193] The mass ratio of the dispersed phase solvent, ethyl acetate, acetone, and water is 7.8:3.9:1 (total 171.5g).

[0194] The mass ratio of the dispersed phase solutes, API, EPO, N7, magnesium oxide, triethyl citrate, and titanium dioxide is 5.6:15:37:15:5:1 (total 22.08 g).

[0195] Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: low temperature (10℃), continuous phase pH: 7.

[0196] Injection parameters: Bottom circulation injection, 3 injection points on each side of the reactor (select the specific number of injection points as needed, and seal unused injection points with rubber plugs), injection method equipped with a ring circulation injector (see...). Figure 18 The continuous phase and the dispersed phase are fed simultaneously. The feed speed of the continuous phase is 70 (peristaltic pump model: Snow BS100-1A), and the feed speed of the dispersed phase is 8 (peristaltic pump model: Snow 2S). The feeding time is 23 minutes.

[0197] Operation steps: Same as in Example 2

[0198] The various indicators of the taste-masking microspheres prepared by reactor #3 are shown in Table 4.

[0199] Table 4

[0200] FC602-3 93.3 4.8 61.1 97.8 FC607-1 86.3 5.6 63.9 99.3

[0201] Example 8

[0202] Combination Figure 1 As shown, this invention designed and manufactured reactor #4 ( Figure 25 A microsphere fabrication reactor based on planar folding and three-dimensional vortex was obtained. The reactor is shaped like a regular triangular truncated pyramid, enclosed by a bottom surface and three side planes. The material is plexiglass, and the processing technology is an adhesive bonding process.

[0203] The reactor has an equilateral triangle cross-section with an interior angle ∠β = 60°.

[0204] The length of the bottom edge of the reactor is a1 = 19cm, and the length of the top edge of the reactor is a2 = 12cm.

[0205] The reactor has a height H = 38 cm and a capacity of 3 L.

[0206] The angle ∠α between the reactor's edge and its bottom surface is 96.1°.

[0207] The height h1 from the bottom edge of the injection port is 2cm, and there is one hole on each side (i.e., one injection point), with an opening diameter of 1.5cm.

[0208] Configured with a multi-needle injector with even distribution, and using an upper and lower orifice injector ( Figure 17 );

[0209] The microsphere outlet is located on the bottom surface of the reactor, with one opening and a diameter of 2cm.

[0210] Equipped with a three-layer downward-pressurized mixing device, the mixing motor speed is 50-900 rpm, and the height of the mixing paddle from the bottom surface is as follows: lower layer h3 = 2 cm, middle layer h4 = 18 cm, and upper layer h5 = 35 cm. See the actual equipment for details. Figure 26 .

[0211] Example 9

[0212] Experimental objective: To evaluate the feasibility of using the innovative design of reactor #4 for microsphere preparation.

[0213] Process conditions: Reactor type 4#, continuous phase volume 3L.

[0214] The mass ratio of the dispersed phase solvent, ethyl acetate, anhydrous ethanol, and water is 7.8:3.9:1 (total 57.1g).

[0215] The mass ratio of the dispersed phase solutes (API, E100, N7, magnesium oxide, triethyl citrate, povidone, magnesium stearate, titanium dioxide, and talc) is 5.6:15:46.2:5.8:5:2:2:1:1 (total 8.36 g).

[0216] Continuous phase: 0.4% polyvinyl alcohol (05-88) aqueous solution, continuous phase temperature: room temperature, continuous phase pH: 7.

[0217] Injection parameters: Continuous injection is achieved using a multi-needle injector with evenly distributed needles at the bottom; the syringe is equipped with an upper and lower orifice syringe. Figure 17 There is one injection point on each side, for a total of three injection points. The feeding and stirring speed is 150 rpm, the dispersed phase feeding speed is 5 rpm (peristaltic pump model: Snow 2S), and the injection time is 15 minutes.

[0218] Operation steps: Same as in Example 2

[0219] The various indicators of the taste-masking microspheres prepared by reactor #4 are shown in Table 5.

[0220] Table 5

[0221] FC606-2 92.4 4.9 67.6 101.4 FC606-3 83.4 4.9 61.0 97.8

[0222] Example 10

[0223] A continuous microsphere preparation system, employing any one of the microsphere preparation reactors based on planar folding and three-dimensional vortexes from Examples 1-9 above, such as... Figure 30 As shown, the continuous microsphere preparation system specifically includes a continuous phase mixing tank (9 / 10), a dispersed phase mixing tank 11, a microsphere preparation reactor 12, a pressure reducing filter 15, a vaporization membrane separator 19, and an organic solvent recovery storage tank 18;

[0224] The continuous phase mixing tanks are arranged in parallel, including a first continuous phase mixing tank 9 and a second continuous phase mixing tank 10. The first continuous phase mixing tank 9 and the second continuous phase mixing tank 10 are connected in parallel to a first dispensing pump 23. A third valve 26 is installed on the outlet pipe of the first continuous phase mixing tank 9, and a first valve 24 is installed on the outlet pipe of the second continuous phase mixing tank 10. The first dispensing pump 23 is connected to the bottom dispersed phase inlet of the microsphere preparation reactor 12, and a fourth valve 27 is installed on the return pipe. The first dispensing pump 23 is a peristaltic dispensing pump, which injects the continuous phase into the microsphere preparation reactor 12 in the initial stage of the process. The two continuous phase mixing tanks work alternately in parallel, which can ensure the continuous operation of the system and improve the operating efficiency.

[0225] The dispersed phase mixing tank 11 is connected to the bottom dispersed phase inlet of the microsphere preparation reactor 12; an injection constant flow pump 22 is installed on the pipeline connecting the dispersed phase mixing tank 11 and the microsphere preparation reactor 12, which can ensure continuous and stable injection of the dispersed phase during the process; a microsphere outlet is provided in the middle of the microsphere preparation reactor 12, which is connected to the top inlet of the pressure reducing filter 15 through the solidification pipeline 13, and the bottom outlet of the pressure reducing filter 15 is connected to the vaporization membrane separator 19; the vaporization membrane separator 19 sends the separated organic solvent to the organic solvent recovery storage tank 18 through the pipeline, and discharges the wastewater through the wastewater pipeline 21.

[0226] The solidification pipeline 13 has a vent hole 14 on the side. The purpose of this is to avoid the siphon phenomenon in the reaction vessel when the dispersed phase is discharged, which would affect the liquid flow in the reaction vessel and the solidification process of the dispersed phase.

[0227] The pressure reducing filter 15 is connected to an external vacuum pump 17, and the vacuum pump is connected to the exhaust port 16.

[0228] The bottom outlet of the pressure-reducing filter 15 is connected to two continuous phase mixing tanks (9 / 10) via a pipeline. A second dispensing pump 28 is installed on this connecting pipeline. A fourth valve 27 is installed on the pipeline connecting the second dispensing pump 28 to the first continuous phase mixing tank 9, and a second valve 25 is installed on the pipeline connecting the second dispensing pump 28 to the second continuous phase mixing tank 10. The purpose of this reflux pipeline is to allow a portion (e.g., 50%) of the continuous phase filtered by the pressure-reducing filter 15 to be refluxed back to the continuous phase mixing tank for direct reuse during the curing reaction stage. The remaining portion (e.g., the remaining 50%) is separated and recovered by the vaporization membrane separator 19 to recover the organic solvent, which is then stored in an organic solvent recovery storage tank for reuse in the dispersed phase mixing tank. This recycling method simplifies the process, saves resources, reduces the processing load on the vaporization membrane separator 19, and effectively reduces investment costs.

[0229] A first infusion pump 20 is installed on the pipeline between the pressure reducing filter 15 and the vaporization membrane separator 19 to facilitate the delivery of the liquid filtered by the pressure reducing filter 15 to the vaporization membrane separator 19 for separation.

[0230] The bottom of the microsphere preparation reactor 12 is connected to the top inlet of the pressure reducing filter 15 via a pipe, and a second liquid pump 29 is installed on the connecting pipe. The purpose of this pipe is to facilitate the transfer of all the mixed liquid and microspheres below the microsphere outlet in the middle of the reaction vessel to the pressure reducing filter 15 for filtration during the final stage of the curing reaction.

[0231] The continuous microsphere preparation system of this invention can achieve continuous and automated production through the setting and control of pipeline connections, dispensing pumps, and valves. It can also partially recycle the continuous phase filtered by the pressure reducing filter, reducing the processing load of the vaporization membrane separator, simplifying the process flow, saving energy and protecting the environment, and effectively reducing investment costs.

[0232] The above description is merely an embodiment of this application and is not intended to limit the invention. Any modifications, equivalent substitutions, and improvements made within the scope of this application should be included within the protection scope of this invention.

Claims

1. A microsphere fabrication reactor based on planar folding and three-dimensional vortex, characterized in that, It includes a reaction vessel and a stirring device; the reaction vessel is an inverted triangular truncated pyramid structure, enclosed by a bottom surface and three side planes; the stirring device includes several layers of stirring paddles, the stirring device is vertically suspended in the reaction vessel, and its upper end passes through the top surface of the reaction vessel and is connected to the stirring motor for drive. The microsphere preparation reactor also includes a feed distributor and a cooling jacket. The feed distributor is located at the bottom of the reaction vessel and is used to inject the dispersed phase into the reaction vessel. The cooling jacket is fitted outside the reaction vessel and forms a cooling vessel cavity with the outer wall of the reaction vessel. A coolant inlet is provided on one side of the bottom of the cooling jacket and a coolant outlet is provided on one side of the top. The injection dispenser is a multi-needle dispenser with even distribution, comprising three sets of injection dispensers, each set of injection dispensers including several parallel syringes; the syringe is a cylindrical tubular structure, including a limiting sealing boss at the bottom and an injection tube at the top; several sets of injection holes are arrayed along the circumference on the circular surface of the injection tube; the injection tube is horizontally inserted into the bottom of the side plane of the reaction vessel, with the injection holes of the injection tube all located inside the reaction vessel cavity, and the limiting sealing boss located outside the reaction vessel; Alternatively, the injection dispenser may be an annular circulating injector, with a plurality of injection holes evenly distributed on the annular top surface of the annular circulating injector. The annular circulating injector is inserted horizontally into the inner side of the bottom of the reaction vessel cavity, ensuring that the injection holes are evenly spaced within the reaction vessel cavity. The annular circulating injector includes an injection inlet and a circulation outlet, both of which pass through the side plane of the reaction vessel and connect to the dispersed phase mixing tank. The annular circulating injector, through its injection inlet and circulation outlet, together with the dispersed phase mixing tank, forms a circulation loop.

2. The microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 1, characterized in that, The cross-section of the reaction vessel is an isosceles triangle, and the base angle of the isosceles triangle is β, with the value of β ranging from 45° to 75°.

3. The microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 2, characterized in that, The cross-section of the reaction vessel is an equilateral triangle with β = 60°.

4. The microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 1, characterized in that, The angle between the side plane edge and the bottom surface of the reaction vessel is α, and the value of α is greater than 30° and less than 90°.

5. The microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 1, characterized in that, The height of the reaction vessel is H, and the value of H ranges from 10cm to 200cm.

6. The microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 5, characterized in that, The height H of the reaction vessel ranges from 30cm to 120cm.

7. The microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 1, characterized in that, The mixing device is a turbine mixer, a downpour impeller mixer, or a turbine blade-downpour impeller combined mixing device; the mixing device includes 2-4 layers of mixing impellers.

8. The microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 1, characterized in that, The reaction vessel is made of one of the following materials: organic plastic, stainless steel, titanium alloy, enamel glass, ceramic, or iron. The reaction vessel is formed by molding, casting, rolling, welding, or bonding.

9. A microsphere preparation reactor based on planar folding and three-dimensional vortex as described in claim 8, characterized in that, The reaction vessel is made of plexiglass.

10. A microsphere preparation process, using the microsphere preparation reactor based on planar folding and three-dimensional vortex as described in any one of claims 1-9, characterized in that, The process includes the following steps: Step S01: Prepare the dispersed phase by dissolving the raw material components of the flavor-masking microspheres in solvent A to form the dispersed phase; Step S02: Prepare a continuous phase, selecting solvent B as the continuous phase; Step S03: Inject the continuous phase into the reaction vessel and start the stirring device; Step S04: Continuously inject the dispersed phase into the reaction vessel through the feed dispenser at the bottom of the reaction vessel to obtain the microsphere suspension; Step S05: The microsphere suspension is filtered, washed, and dried to obtain microspheres.

11. A continuous microsphere preparation system, characterized in that, The continuous microsphere preparation system includes a batching system, a microsphere preparation system, and a processing and recovery system. The batching system includes a continuous phase batching tank and a dispersed phase batching tank. The microsphere preparation system includes a microsphere preparation reactor based on planar folding and three-dimensional vortex as described in any one of claims 1-9. The processing and recovery system includes a pressure reducing filter, a vaporization membrane separator, and an organic solvent recovery storage tank. The continuous phase mixing tank and the dispersed phase mixing tank are respectively connected to the bottom inlet of the microsphere preparation reactor; a microsphere outlet is provided in the middle of the microsphere preparation reactor, and the microsphere outlet is connected to the top inlet of the pressure reducing filter through a solidification pipeline, and the bottom outlet of the pressure reducing filter is connected to the vaporization membrane separator; the vaporization membrane separator sends the separated organic solvent to the organic solvent recovery storage tank through a pipeline, and discharges the wastewater through a wastewater pipeline.

12. The continuous microsphere preparation system according to claim 11, characterized in that, The bottom outlet of the pressure reducing filter is connected to the continuous phase mixing tank via a circulation pipeline.

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