A multiple membrane emulsification device and method for producing microspheres with a narrow particle size distribution

Abstract

The present application relates to a kind of multiple membrane emulsification device and the method for being used as the preparation of narrow particle size distribution microspheres, device includes first emulsification kettle and second emulsification kettle;The first emulsification kettle and the second emulsification kettle bottom are respectively connected first check valve and second check valve, two the first check valve is connected to porous membrane tube jacket and the membrane tube outer cavity formed by porous membrane tube, and the direction of conduction direction points to membrane tube outer cavity, two second check valve is connected to the membrane tube inner cavity of porous membrane tube, and the direction of conduction direction points to emulsification kettle, the porous membrane tube is arranged in the porous membrane tube jacket;The first emulsification kettle and the second emulsification kettle top are communicated pressure conversion mechanism, and the pressure conversion mechanism is used to control first emulsification kettle and second emulsification kettle to carry out pressure conversion, to drive emulsion to realize multiple membrane emulsification. Utilize multiple passage conversion valve control emulsification kettle between pressure difference conversion, drive emulsion multiple membrane emulsification, obtain uniform particle size emulsion, preparation solidification polymer microsphere.

Description

Technical Field

[0001] This invention relates to the field of polymer molding and processing equipment, and more particularly to a multi-pass emulsification device and a method for preparing microspheres with narrow particle size distribution. Background Technology

[0002] Polymer microspheres are widely used in biomedicine and medical devices, such as drug carriers, substance separation, vascular embolization, and collagen regeneration. Biodegradable medical polymer microspheres, in particular, can degrade in vivo into physiologically inert small molecule compounds, which can then be metabolized, absorbed, or excreted by the body. When used in clinical applications such as implantable medical devices and drug sustained-release devices, they degrade slowly after implantation, eliminating the need for secondary surgery, reducing patient suffering, and simplifying treatment procedures. The clinical requirements for medical polymer microspheres are high; the surface morphology, particle size, and distribution of the microspheres directly affect their use and clinical efficacy, placing high demands on the preparation technology. The emulsification-solvent evaporation method is the most commonly used preparation method for polymer microspheres. The process involves: first, dissolving the polymer in a suitable organic solvent to obtain an organic phase; dissolving surfactants such as polyethylene glycol, Tween, and methylcellulose in water to obtain an aqueous phase; then, adding the organic phase to the aqueous phase under mechanical stirring for emulsification to obtain an O / W emulsion; finally, evaporating the organic solvent in the emulsion droplets under certain conditions to obtain solidified microspheres. While the emulsification-solvent evaporation method for preparing microspheres is simple and requires no additional equipment, it also presents several challenges: Droplet size is highly dependent on the shear rate of the stirring impeller and the viscosity of the oil / water phase. The shear rate is influenced by various factors, including the shape, size, thickness, and submerged distance of the stirring impeller, making it difficult to maintain consistency during industrial production. Furthermore, the viscosity of the emulsion is related not only to temperature and concentration but also to many uncontrollable factors, such as the molecular weight and distribution of the microsphere polymer and the polymeric emulsifier. This results in microspheres with a wide particle size distribution and poor batch-to-batch reproducibility, requiring cumbersome subsequent sieving to obtain microspheres with a narrow particle size distribution. Additionally, the emulsification-solvent evaporation method uses large amounts of organic solvents, which is detrimental to operator health and can lead to environmental pollution.

[0003] Membrane emulsification offers significant advantages in controlling the particle size of microspheres. During emulsification across a porous membrane, the pore size of the membrane is the most crucial controlling factor for droplet size. There are two main types of membrane emulsification: direct membrane emulsification and rapid membrane emulsification. Direct membrane emulsification involves a pump that flows the aqueous phase (continuous phase) through one side of the porous membrane, while the organic phase (dispersed phase) is pressed through the membrane from the other side. The dispersed phase droplets grow at the membrane pore outlet and, after reaching a certain size, detach from the membrane pores under the drag force of the continuous phase flow. Direct membrane emulsification offers milder conditions and can produce relatively uniform microspheres, but its slow droplet formation rate makes it difficult to scale up for industrial production. Rapid membrane emulsification, on the other hand, involves preparing a pre-emulsion using conventional emulsification methods and then pressing the pre-emulsion through a porous membrane. During the membrane process, larger droplets in the pre-emulsion deform under pressure at the membrane pore openings, forming smaller, more uniform droplets. Rapid membrane emulsification offers higher emulsification efficiency and is more suitable for industrial production.

[0004] Membrane emulsification devices mainly consist of three parts: an organic phase vessel (for direct membrane emulsification) or a pre-emulsion vessel (for rapid membrane emulsification), a microporous membrane, and a flowing aqueous phase. Currently, several patents have improved membrane emulsification devices, primarily focusing on flow rate control and recycling of the aqueous phase. For example, patent 202010104468.0 describes the recycling of the aqueous phase and, to reduce the damage to emulsion droplets in the continuous phase caused by the water pump, incorporates a screen in the aqueous phase vessel to minimize droplet entry into the pump. Several studies have reported reducing particle size and distribution through multiple membrane emulsification processes. Needle-type emulsification connectors are also commercially available, encapsulating a porous membrane between two needle connectors, allowing direct connection of two needles. The emulsion undergoes multiple membrane emulsification processes through needle suction. Patent 202080025984.2 discloses an emulsion manufacturing method and manufacturing apparatus. The disclosed apparatus is equipped with two tanks (a supply tank and a recovery tank). The emulsion in the tank is pumped and circulated between the two tanks multiple times through a porous membrane for emulsification to prepare an emulsion with uniform particle size. However, the publicly available multi-pass emulsification device requires two sets of three-way valve switching devices at the bottom and top of the tank to switch between tank functions (supply / recovery), which requires frequent manual operation and is inconvenient to use. Moreover, when using a pump to transport the emulsion, the pump cannot fully pass the emulsion through the membrane during the membrane emulsification process, resulting in low efficiency and requiring more passes to compensate. Furthermore, the reuse of pipelines for different processes leads to mixing of emulsions between different processes due to the pump's inability to fully pass the emulsion through the membrane. In addition, there are many foreseeable problems with using a pump to transport the emulsion, such as the increased difficulty of sterilizing the instrument, especially online sterilization, the difficulty in precisely controlling the membrane pressure controlled by the pump pressure, and the fact that the pump is located in the emulsion passage, affecting the degree of emulsification of the emulsion itself. Membrane emulsification has been used in the preparation of emulsions and various polymer microspheres, but there are still many problems in the industrial production process: (1) The size of microspheres is mainly controlled by the pore size of porous membranes, and the uniformity of pore size directly affects the monodispersity of microspheres; (2) The technology for preparing porous membrane tubes with uniform pore size is mastered by foreign countries, and the purchase cost is high and the purchase cycle is long; (3) The flowability of the aqueous phase is achieved by pumps, but the existence of pumps increases the difficulty of sterilizing the instrument, especially online sterilization; (4) The automation level of the equipment is not high, the operation is cumbersome, and it is time-consuming and labor-intensive. Summary of the Invention

[0005] In order to solve the above-mentioned technical problems, or at least partially solve the above-mentioned technical problems, the present invention provides a multi-pass emulsification apparatus.

[0006] In a first aspect, the present invention provides a multi-stage membrane emulsification apparatus, comprising: a first emulsification vessel and a second emulsification vessel, wherein:

[0007] The bottoms of the first emulsifying vessel and the second emulsifying vessel are respectively connected to a first one-way valve and a second one-way valve. The two first one-way valves are connected to the outer cavity of the membrane tube formed by the porous membrane tube jacket and the porous membrane tube, and the conduction direction is towards the outer cavity of the membrane tube. The two second one-way valves are connected to the inner cavity of the porous membrane tube, and the conduction direction is towards the emulsifying vessel. The porous membrane tube is disposed inside the porous membrane tube jacket.

[0008] The tops of the first emulsifying vessel and the second emulsifying vessel are connected to a pressure switching mechanism, which is used to control the pressure switching between the first emulsifying vessel and the second emulsifying vessel to drive the emulsion to achieve multiple membrane emulsifications.

[0009] Furthermore, both the first and second emulsifying kettles are equipped with inlet pipes at their tops, inlet valves on the inlet pipes, and inlet funnels that can be detachably and fixedly connected to the inlet pipes. The bottoms of the first and second emulsifying kettles are equipped with outlets.

[0010] Furthermore, the bottom of the first emulsifying vessel and the second emulsifying vessel are respectively connected to a port of a three-way valve, and one port of the three-way valve is used as a liquid outlet; one port of each three-way valve is respectively connected to a first check valve and a second check valve.

[0011] Furthermore, the pressure conversion mechanism includes a multi-way conversion valve, which is connected to a pressure source via a pressure regulating valve. The pressure regulating valve is one or more of a self-regulating pressure regulating valve, a differential pressure regulating valve, and a flow regulating valve. The pressure source is one of a high-pressure gas cylinder, an air compressor, or a booster pump. The multi-way conversion valve is a three-position five-way multi-way conversion valve or two two-position three-way multi-way conversion valves, controlling the connection of the first emulsifying vessel or the second emulsifying vessel to a pressure source or an external source to achieve pressure conversion between the first emulsifying vessel and the second emulsifying vessel.

[0012] Furthermore, the multi-way switching valve is electrically connected to a multi-way switching valve drive circuit, which includes a time relay electrically connected to the multi-way switching valve, the time relay being controlled by a timing switch.

[0013] Furthermore, stirring mechanisms are respectively provided on the first emulsifying kettle and the second emulsifying kettle.

[0014] Furthermore, heating jackets are respectively provided on the outer sides of the first emulsifying kettle and the second emulsifying kettle.

[0015] Furthermore, at least two components formed by the porous membrane tube jackets and the porous membrane tubes are connected in series or in parallel between the first emulsifying vessel and the second emulsifying vessel.

[0016] Furthermore, the porous membrane tube includes glass microporous tubes and stainless steel laser microporous tubes with a wall thickness of 0.1-100mm; wherein, the glass microporous tubes include, but are not limited to, SPG porous membrane tubes, sand core porous membrane tubes, quartz porous membrane tubes, and ceramic porous membrane tubes.

[0017] Secondly, the present invention provides a method for preparing microspheres with a narrow particle size distribution, using the aforementioned multi-pass membrane emulsification apparatus, comprising:

[0018] The polymer to be used to make microspheres is dissolved in an organic solvent that is insoluble in water to prepare an organic phase solution of a set concentration.

[0019] Take a set amount of emulsifier, dissolve it in water, and prepare an aqueous solution of a set concentration;

[0020] The aqueous solution and the organic solution are respectively added to the first emulsification vessel and the second emulsification vessel of the multiple membrane emulsification device, and the stirring mechanism is controlled to stir at a set speed to perform pre-emulsification;

[0021] The multi-way switching valve is controlled to supply pressure to the first emulsification vessel and to the outside of the second emulsification vessel. When the pressure in the first emulsification vessel exceeds the opening pressure of the first one-way valve under the first emulsification vessel, the pre-emulsion is pressed from the first emulsification vessel into the outer cavity of the membrane tube. After passing through the porous membrane tube for emulsification, it enters the inner cavity of the membrane tube. Under the action of pressure, the second one-way valve at the lower end of the second emulsification vessel is opened, and the emulsion enters the second emulsification vessel, completing the first emulsification.

[0022] The multi-way switching valve is controlled to open the first emulsification vessel to the outside, and the second emulsification vessel is pressurized. When the pressure of the second emulsification vessel is greater than the opening pressure of the first one-way valve at the bottom of the second emulsification vessel, the pre-emulsion is forced from the second emulsification vessel into the outer cavity of the membrane tube. After passing through the porous membrane tube for emulsification, it enters the inner cavity of the membrane tube. Under the action of pressure, the second one-way valve at the lower end of the first emulsification vessel is opened, and the emulsion is forced into the first emulsification vessel to achieve the second emulsification.

[0023] The first and second membrane emulsification cycles are repeated. After a preset number of cycles or cycle time, the control relay connects the first and second emulsification vessels to the external atmosphere simultaneously, opens the emulsion discharge valve at the bottom of the vessel, collects the emulsion, evaporates the solvent in the organic phase of the emulsion to precipitate polymer microspheres, separates the solid and liquid to obtain solidified microspheres, and then washes and dries them to obtain microspheres.

[0024] The technical solutions provided in the embodiments of the present invention have the following advantages compared with the prior art:

[0025] In this application, the pressurization and atmospheric venting of the first and second emulsifying reactors are automatically controlled by a multi-way switching valve; the circulation of the emulsion between the two reactors is controlled by a one-way valve, simplifying the control process, supporting fully automated operation of multiple membrane emulsifications, reducing human error, and improving batch-to-batch repeatability of microsphere preparation. The multiple membrane emulsification device avoids the use of pumps, simplifies the equipment process, facilitates sterilization, avoids the impact of unstable pump pressure on the membrane emulsification process, and avoids the influence of the pump itself on the emulsion's emulsification effect. By using a pressure pump to deliver the emulsion through the membrane, the emulsion can be fully membrane-bound, ensuring emulsification efficiency.

[0026] After multiple membrane emulsifications, the droplet size is mainly controlled by the smaller micropores on the porous membrane tube. This can effectively reduce the impact of uneven micropore size on the droplet and microsphere particle size distribution. Even sand core membrane tubes with relatively poor micropore quality and low cost can achieve a narrower particle size distribution, which can reduce the cost of equipment and membrane tube consumables.

[0027] Adding heating jackets to the first and second emulsifying tanks serves two purposes: firstly, it provides a set temperature environment for the preparation process, preventing the impact of ambient temperature changes on the emulsification process; secondly, it allows heating to temperatures above sterilization temperature for real-time moist heat sterilization of the equipment. Since the first and second emulsifying tanks of the multi-membrane emulsification device support pressurization, they can support moist heat sterilization at 121°C.

[0028] The components formed by the porous membrane tube jacket and the porous membrane tube can be connected in series and in parallel to optimize the emulsification effect each time.

[0029] This application supports various types of porous membrane tubes, and the different characteristics of different porous membrane tubes support the preparation of microspheres with different large particle sizes. For example, by using the multi-pass emulsification device of this invention, in conjunction with porous sand core membrane tubes, large-particle-size polymer microspheres can be prepared. Attached Figure Description

[0030] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0031] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0032] Figure 1 This is a schematic diagram of a multi-pass emulsification apparatus provided in an embodiment of the present invention;

[0033] Figure 2This is a schematic diagram of a multi-pass emulsification device provided in an embodiment of the present invention;

[0034] Figure 3 A schematic diagram of the porous membrane tube jacket and porous membrane tube provided in an embodiment of the present invention;

[0035] Figure 4 A schematic diagram of a porous membrane tube provided in an embodiment of the present invention;

[0036] Figure 5 A schematic diagram of a series-connected porous membrane tube jacket and porous membrane tube provided in an embodiment of the present invention;

[0037] Figure 6 A schematic diagram of a parallel porous membrane tube jacket and a porous membrane tube provided in an embodiment of the present invention;

[0038] Figure 7 This is a histogram showing the effect of the number of membrane emulsification cycles on the microsphere particle size in Example 1 of the present invention.

[0039] Figure 8 This is a histogram showing the effect of the number of membrane passes on the microsphere size distribution span in Example 1 of the present invention.

[0040] Figure 9 This is a particle size distribution curve of the microspheres in Example 1 of the method of the present invention;

[0041] Figure 10 SEM image of microspheres prepared by Example 1 of the method of the present invention;

[0042] Figure 11 This is a histogram showing the effect of the number of membrane emulsification cycles on the microsphere particle size in Example 2 of the method of the present invention.

[0043] Figure 12 This is a histogram showing the effect of the number of membrane passes on the microsphere size distribution span in Example 2 of the method of the present invention.

[0044] Figure 13 This is a particle size distribution curve of the microspheres in Example 2 of the method of the present invention;

[0045] Figure 14 SEM image of microspheres prepared by method Example 2 of the present invention;

[0046] Figure 15 This is a particle size distribution curve of the microspheres in Example 3 of the method of the present invention;

[0047] Figure 16 This is a particle size distribution curve of the control microspheres;

[0048] Figure 17 This is a SEM image of the control microspheres.

[0049] The labels and their meanings in the diagram are as follows:

[0050] 1. Feed funnel;

[0051] 2. First emulsifying kettle;

[0052] 3. Second emulsifying kettle;

[0053] 4. Heating jacket;

[0054] 5. Stirring mechanism; 51. Motor; 52. Stirring paddle;

[0055] 6. Three-way valve;

[0056] 7. First check valve;

[0057] 8. Second check valve;

[0058] 9. Porous membrane tube jacket; 91. Jacket body; 92. Membrane tube outer cavity connection port; 93. O-ring; 94. Fixing cap; 95. Membrane tube inner cavity connection port.

[0059] 10. Porous membrane tubes;

[0060] 11. Timer switch; 12. Time relay; 13. Multi-way switching valve; 14. Pressure regulating valve; 15. Pressure source; 16. Bracket. Detailed Implementation

[0061] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, 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, 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.

[0062] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0063] Example 1

[0064] See also Figure 1 and Figure 2 As shown, an embodiment of the present invention provides a multiple-pass emulsification apparatus, comprising:

[0065] In one example, the first emulsifying vessel 2 and the second emulsifying vessel 3 are both cylindrical structures of the same specifications. The bottom surfaces of the first emulsifying vessel 2 and the second emulsifying vessel 3 are fixed to the support 16, and the first emulsifying vessel 2 and the second emulsifying vessel 3 are set at the same height. The top of the first emulsifying vessel 2 and the second emulsifying vessel 3 are provided with a sealable liquid inlet structure. In one example of the liquid inlet structure, the top of the first emulsifying vessel 2 and the second emulsifying vessel 3 are both provided with a liquid inlet pipe, and the liquid inlet pipe is provided with a liquid inlet valve. The top of the liquid inlet pipe is provided with a thread, and the thread can be detachably screwed and fixedly connected to the liquid inlet funnel 1.

[0066] The first emulsifying vessel 2 and the second emulsifying vessel 3 are each equipped with a stirring mechanism 5. Each stirring mechanism 5 includes a motor 51 fixed to the top of the first emulsifying vessel 2 and the second emulsifying vessel 3. The output shafts of the two motors 51 extend into the first emulsifying vessel 2 and the second emulsifying vessel 3, respectively, and are connected to stirring paddles 52 of identical specifications. In specific implementation, the output shafts of the two motors 51 are coaxially arranged with the first emulsifying vessel 2 and the second emulsifying vessel 3.

[0067] Heating sleeves 4 are respectively provided on the outer sides of the first emulsifying vessel 2 and the second emulsifying vessel 3; in one example, the heating sleeve 4 includes a sleeve body that is sleeved on the outside of the first emulsifying vessel 2 and the second emulsifying vessel 3, and an adjustable temperature heater is provided on the inner side of the sleeve body, and the heater is electrically connected to a temperature regulating controller.

[0068] The first emulsifying vessel 2 and the second emulsifying vessel 3 are provided with liquid outlets at their bottoms. In specific implementation, the bottoms of the first emulsifying vessel 2 and the second emulsifying vessel 3 are also respectively connected to one port of a three-way valve 6, and one port of the three-way valve 6 is used as a liquid outlet; one port of each of the three-way valves 6 is respectively connected to a first one-way valve 7 and a second one-way valve 8, the two first one-way valves 7 are connected to the outer cavity of the membrane tube formed by the porous membrane tube jacket 9 and the porous membrane tube 10, and are oriented towards the outer cavity of the membrane tube; the two second one-way valves 8 are connected to the inner cavity of the membrane tube formed by the porous membrane tube jacket 9 and the porous membrane tube 10, and are oriented towards the three-way valve 6, and the porous membrane tube 10 is disposed inside the porous membrane tube jacket 9.

[0069] In one example, see Figure 3As shown, the porous membrane tube jacket 9 includes a tubular jacket body 91 with threads at both ends. Two membrane tube external cavity connection ports 92 are provided on the jacket body 91, located near both ends of the jacket body. The two membrane tube external cavity connection ports 92 are respectively connected to two first one-way valves 7. O-rings 93 for fixing the porous membrane tube 10 are inserted into both ends of the jacket body 91. The O-rings 93 have sealing flanges that seal with both ends of the jacket body 91. Fixing caps 94 are screwed to both ends of the jacket body 91. Membrane tube internal cavity connection ports 95 are provided on the fixing caps 94. The two membrane tube internal cavity connection ports 95 are respectively connected to two second one-way valves 8. The porous membrane tube 10 includes glass microporous tubes and stainless steel laser microporous tubes, with a wall thickness of 0.1-100 mm; wherein, the glass microporous tubes include, but are not limited to, SPG porous membrane tubes, sand core porous membrane tubes, quartz porous membrane tubes, and ceramic porous membrane tubes; see reference Figure 4 As shown, the porous membrane tube 10 is provided with cross-shaped micropores.

[0070] The tops of the first emulsifying vessel (2) and the second emulsifying vessel (3) are connected to a pressure switching mechanism. This mechanism controls the pressure switching between the first and second emulsifying vessels (2 and 3) to drive the emulsion through multiple membrane emulsification processes. In one example, the pressure switching mechanism includes a multi-way switching valve 13, which is connected to a pressure source 15 via a pressure regulating valve 14. The pressure regulating valve 14 is one or more of a self-regulating pressure regulating valve, a differential pressure regulating valve, and a flow regulating valve. The pressure source 15 is one of a high-pressure gas cylinder, an air compressor, or a booster pump. The multi-way switching valve is a three-position five-way multi-way switching valve or two two-position three-way multi-way switching valves, controlling the connection of the first emulsifying vessel 2 or the second emulsifying vessel 3 to the pressure source 15 or an external source to achieve pressure switching between the first emulsifying vessel 2 and the second emulsifying vessel (3). The multi-way switching valve 13 is either a solenoid valve or a mechanical valve.

[0071] In one example, the multi-way switching valve is a three-position five-way multi-way switching valve. The three-position five-way multi-way switching valve includes two coils controlling the valve core position: coil A and coil B. When neither coil A nor coil B is energized, the valve core is in one position. When coil A is energized and coil B is not energized, the valve core is in one position. A total of three positions are selectable. The three-position five-way multi-way switching valve includes one air inlet, two cylinder ports, and two exhaust ports. In this application, the air inlet of the three-position five-way multi-way switching valve is connected to a pressure source 15 via a pressure regulating valve 14. The two cylinder ports of the three-position five-way multi-way switching valve are respectively connected to the first emulsifying vessel and the second emulsifying vessel.

[0072] In one example, the multi-way switching valve 13 employs two two-position three-way multi-way switching valves. The valve core of each two-position three-way multi-way switching valve has two positions. Each valve includes an air inlet, a cylinder port, and an exhaust port, with the cylinder port selectively connected to either the air inlet or the exhaust port. In this application, the air inlet of one two-position three-way multi-way switching valve is connected to a pressure source 15 via a pressure regulating valve 14, and the cylinder port is connected to either the first emulsifying vessel 2 or the second emulsifying vessel 3.

[0073] In one example, the multi-way switching valve 13 is electrically connected to a multi-way switching valve drive circuit, which includes a time relay 12 electrically connected to the multi-way switching valve, the time relay 12 being controlled by a timer switch 11. The timer switch 11 controls the time relay 12 to configure the state switching time of the multi-way switching valve 13. In another example, the timer switch is replaced by a controller, which controls the state switching of the multi-way switching valve 13 manually or programmatically via the time relay 12.

[0074] In one example, two sets of the pressure regulating valve 14 and the pressure source 15 are provided, with one set serving as a backup.

[0075] Example 2

[0076] See Figure 5 As shown, the difference between this embodiment and Embodiment 1 is that at least two components formed by the porous membrane tube jackets 9 and porous membrane tubes 10 are connected in series between the first emulsifying vessel 2 and the second emulsifying vessel 3. When the components formed by the porous membrane tube jackets 9 and porous membrane tubes 10 are connected in series, the inner membrane tube connection ports 95 of adjacent porous membrane tube jackets 9 are sequentially connected to the outer membrane tube connection ports 92 of the other via one-way valves. The one-way valves point to the outer membrane tube connection ports 92. The two outermost inner membrane tube connection ports 95 on both ends of the porous membrane tube jackets 9 are respectively connected to two second one-way valves 8, and the two outermost outer membrane tube connection ports 92 on both ends of the porous membrane tube jackets 9 are respectively connected to two first one-way valves 7.

[0077] Example 3

[0078] See Figure 6As shown, the difference between this embodiment and Embodiment 1 is that at least two components formed by the porous membrane tube jackets 9 and porous membrane tubes 10 are connected in parallel between the first emulsifying vessel 2 and the second emulsifying vessel 3. When the components formed by the porous membrane tube jackets 9 and porous membrane tubes 10 are connected in parallel, the corresponding membrane tube inner cavity connection ports 95 of the porous membrane tube jackets 9 are interconnected, the corresponding membrane tube outer cavity connection ports 92 of the porous membrane tube jackets 9 are interconnected, the membrane tube outer cavity connection ports 92 at both ends of the porous membrane tube jackets 9 are respectively connected to two first one-way valves 7, and the membrane tube inner cavity connection ports 95 at both ends of the porous membrane tube jackets 9 are respectively connected to two second one-way valves 8.

[0079] Example 4

[0080] The difference between this embodiment and Embodiment 1 is that the main body 91 of the porous membrane tube jacket 9 is configured as a flat structure, and multiple corresponding threaded heads are provided at both ends of the main body 91. Each threaded head is connected to the porous membrane tube through an O-ring, so that at least two porous membrane tubes 10 are arranged side by side in the porous membrane tube jacket 9, and each threaded head is connected to a fixing cap 94.

[0081] Example 5

[0082] This invention provides a method for preparing microspheres with a narrow particle size distribution, comprising:

[0083] The polymer to be used to make microspheres is dissolved in an organic solvent that is insoluble in water to prepare an organic phase solution of a set concentration.

[0084] Take a set amount of emulsifier, dissolve it in water, and prepare an aqueous solution of a set concentration;

[0085] The aqueous solution and the organic solution are respectively added to the first emulsification vessel and the second emulsification vessel of the multiple membrane emulsification device, and the stirring mechanism is controlled to stir at a set speed to perform pre-emulsification;

[0086] The multi-way switching valve is controlled to supply pressure to the first emulsification vessel and to the outside of the second emulsification vessel. When the pressure in the first emulsification vessel exceeds the opening pressure of the first one-way valve under the first emulsification vessel, the pre-emulsion is pressed from the first emulsification vessel into the outer cavity of the membrane tube. After passing through the porous membrane tube for emulsification, it enters the inner cavity of the membrane tube. Under the action of pressure, the second one-way valve at the lower end of the second emulsification vessel is opened, and the emulsion enters the second emulsification vessel, completing the first emulsification.

[0087] The multi-way switching valve is controlled to open the first emulsification vessel to the outside, and the second emulsification vessel is pressurized. When the pressure of the second emulsification vessel is greater than the opening pressure of the first one-way valve at the bottom of the second emulsification vessel, the pre-emulsion is forced from the second emulsification vessel into the outer cavity of the membrane tube. After passing through the porous membrane tube for emulsification, it enters the inner cavity of the membrane tube. Under the action of pressure, the second one-way valve at the lower end of the first emulsification vessel is opened, and the emulsion is forced into the first emulsification vessel to achieve the second emulsification.

[0088] The first and second membrane emulsification cycles are repeated. After a preset number of cycles or cycle time, the control relay connects the first and second emulsification vessels to the external atmosphere simultaneously, opens the emulsion discharge valve at the bottom of the vessel, collects the emulsion, evaporates the solvent in the organic phase of the emulsion to precipitate polymer microspheres, separates the solid and liquid to obtain solidified microspheres, and then washes and dries them to obtain microspheres.

[0089] Method Example 1: Preparation of polycaprolactone microspheres.

[0090] In this example, the porous membrane tube 10 used in the multiple membrane emulsification device is an SPG membrane tube with an outer diameter of 10 mm, a length of 125 mm, and a micropore diameter of 50 μm. The process is as follows:

[0091] Preparation of organic phase solution: Weigh 50g of polycaprolactone and dissolve it in 100mL of dichloromethane to obtain an organic phase solution with a concentration of 50%.

[0092] Preparation of the aqueous phase: Weigh 4g of polyvinyl alcohol, dissolve it in 400mL of water at 50℃ with stirring, and cool to room temperature to obtain the aqueous phase solution.

[0093] Preparation of polymer microspheres: The stirring mechanism 5 of the first emulsification vessel 2 and the second emulsification vessel 3 is set to 150 rpm. Stirring is started, and the aqueous phase solution is added to the first emulsification vessel 2 and the second emulsification vessel 3. Then, the organic phase solution is added, and pre-emulsification is carried out by the stirring mechanism 5 for 10 min. The pressure regulating valve 14 is adjusted to make the pressure supply pressure of the pressure source 15 0.12 MPa. The energizing and de-energizing duration of the time relay 12 is set to 3 min. The countdown duration of the timer switch 11 is set to 3 min, 6 min, 9 min, 12 min, and 15 min. The timer switch 11 controls the multi-way switching valve 13 to perform five reciprocating cycles of membrane emulsification through the time relay 12.

[0094] After emulsification is complete, collect the emulsion in a beaker through a three-way valve.

[0095] Curing, washing and drying of microspheres: The prepared emulsion was stirred at 100 rpm at room temperature to evaporate the organic solvent. The cured microspheres were then settled at the bottom of a beaker, and the supernatant was discarded. The collected microspheres were washed three times with 200 mL of purified water each time, and stirred at 100 rpm for 5 min. Finally, the settled microspheres were freeze-dried to obtain dried polycaprolactone microspheres.

[0096] The effect of the number of membrane emulsification cycles on the microsphere particle size is as follows: Figure 7As shown in the figure, the particle size of the microspheres decreased significantly after the second membrane pass through emulsification. With further increases in the number of membrane passes, the particle size continued to decrease, but the degree of decrease became less pronounced. For example, compared to the fifth membrane pass, the microsphere particle size decreased by less than 1 μm after the fourth pass. The effect of the number of membrane passes on the microsphere particle size distribution span is shown in the figure. Figure 8 As shown, the span decreases with increasing number of membrane passes; after five membrane passes, the span drops to 0.805. The particle size distribution curves of the microspheres prepared by five membrane passes are shown in the figure. Figure 9 As shown, the SEM image of the microspheres is as follows: Figure 10 As shown, the particle size distribution follows a normal distribution with a D50 of 30.88 μm; the microspheres have uniform particle size, smooth surface, and high sphericity.

[0097] Method Example 2: Preparation of polycaprolactone microspheres.

[0098] In this example, the porous membrane tube 10 used in the multiple membrane emulsification device is a sand-core membrane tube with an outer diameter of 10 mm, a length of 125 mm, and a micropore diameter of 50-60 μm. The configuration of the organic phase and aqueous phase is the same as in Method Example 1. During the microsphere preparation process, the energizing and de-energizing durations of the time relay are both 2.5 min, and the countdown durations of the timer switch are set to 2.5 min, 5 min, 7.5 min, 10 min, and 12.5 min. The remaining microsphere preparation process is the same as in Method Example 1.

[0099] This example uses a sand core membrane for emulsification. Figure 11 As shown, the particle size of the microspheres obtained through the first membrane-passing emulsification is significantly larger than that of the microspheres obtained through a single membrane-passing process using SPG membrane tubes. This is partly because the pore size and distribution of the sand core membrane tubes used are larger than those of the SPG membrane tubes. The particle size of the microspheres obtained through the second membrane-passing emulsification process decreases significantly. With further increases in the number of membrane-passing processes, the particle size continues to decrease. The D50 values ​​of the microspheres prepared through the fourth and fifth membrane-passing emulsification processes are less than 1 μm. The effect of the number of membrane-passing processes on the microsphere particle size distribution range is shown in the figure. Figure 12 As shown, the span decreases with increasing number of membrane passes. After five membrane passes, the span drops to 0.811, slightly higher than the span of microspheres prepared by five membrane passes using the SPG membrane tube. However, considering that the microspheres prepared in this embodiment have a larger particle size than those prepared by the SPG membrane tube, the microspheres prepared by five membrane passes using the sand core membrane tube should also have good size uniformity. The particle size distribution curve of the microspheres prepared by five sand core membrane passes is shown in the figure. Figure 13 As shown, the SEM image of the microspheres is as follows: Figure 14 As shown, the particle size distribution follows a normal distribution with a D50 of 37.49 μm. The microspheres have uniform particle size, smooth surface, and high sphericity. The prepared microspheres are not significantly different from the SPG membrane tube five-stage emulsification microspheres.

[0100] Method Example 3: Preparation of polycaprolactone microspheres.

[0101] The porous membrane tube of the multiple-pass emulsification device is a sand-core membrane tube with an outer diameter of 10 mm, a length of 125 mm, and a micropore diameter of 70-80 μm. The configuration of the organic phase and aqueous phase is the same as in Method Example 1. During the microsphere preparation process, the energizing and de-energizing time of the time relay is 2.0 min, and the countdown time of the timer switch is set to 10 min for five passes of emulsification. The remaining microsphere preparation process is the same as in Method Example 1; the curing, washing, and drying of the microspheres are the same as in Method Example 1.

[0102] The particle size distribution of polycaprolactone microspheres prepared using domestically produced sand core membranes with larger pore sizes is as follows: Figure 15 As shown, the D50 of the particle size is 45.46 μm, and the span is 0.816. This indicates that microspheres of different particle sizes can be prepared using porous sand-core membrane tubes with different pore sizes. The imported SPG membrane tube has a maximum pore size of 50 μm. Many polymer emulsions, especially high-molecular-weight polymers, often use lower concentrations to prepare microspheres. During curing, solvent evaporation makes it difficult to prepare microspheres with larger particle sizes. Therefore, this device, combined with porous sand-core membrane tubes, shows significant advantages in preparing large-diameter microspheres.

[0103] Comparison Example

[0104] The preparation methods for the aqueous and organic phases are the same as in Method Example 1. The organic and aqueous phases are poured separately into single-necked flasks, and a mechanical stirrer is turned on. The mixture is stirred at 1250 rpm for 30 minutes, then transferred to a 2000 mL beaker and cured at 100 rpm for microspheres. The curing, washing, and drying of the microspheres are the same as in Method Example 1.

[0105] The particle size distribution curve of microspheres prepared by mechanical emulsification is shown in the figure. Figure 16 Appearance Figure 17 As shown, the particle size distribution of the prepared microspheres deviates from a normal distribution, with a higher proportion of small particles. The D50 is 33.79 μm with a span of 1.331, indicating significantly poorer particle size uniformity compared to microspheres prepared by multiple membrane emulsification devices. The D90 is 60.77 μm, indicating the presence of a small number of larger microspheres. The microspheres are spherical, but some have surface cracks, indicating uneven particle size distribution.

[0106] In the embodiments provided by this invention, it should be understood that the disclosed structures and methods can be implemented in other ways. For example, the structural embodiments described above are merely illustrative. For instance, the division of units is only a logical functional division, and in actual implementation, there may be other division methods. For example, multiple units or components may be combined or integrated into another system, or some features may be ignored or not executed. Furthermore, the coupling or direct coupling or communication connection shown or discussed may be an indirect coupling or communication connection through some interfaces, structures, or units, and may be electrical, mechanical, or other forms.

[0107] The units described as separate components may or may not be physically separate. The components shown as units may or may not be physical units; that is, they may be located in one place or distributed across multiple network units. Some or all of the units can be selected to achieve the purpose of this embodiment according to actual needs.

[0108] Furthermore, the functional units in the various embodiments of the present invention can be integrated into one processing unit, or each unit can exist physically separately, or two or more units can be integrated into one unit. The integrated unit can be implemented in hardware or as a software functional unit.

[0109] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A multi-pass emulsification device, characterized in that, include: First emulsifying vessel (2) and second emulsifying vessel (3), wherein: The bottom of the first emulsifying vessel (2) and the second emulsifying vessel (3) are respectively connected to a first one-way valve (7) and a second one-way valve (8). The two first one-way valves (7) are connected to the outer cavity of the membrane tube formed by the porous membrane tube jacket (9) and the porous membrane tube (10), and the conduction direction is towards the outer cavity of the membrane tube. The two second one-way valves (8) are connected to the inner cavity of the porous membrane tube (10), and the conduction direction is towards the emulsifying vessel. The porous membrane tube (10) is provided inside the porous membrane tube jacket (9). A stirring mechanism (5) is provided on the first emulsifying kettle (2) and the second emulsifying kettle (3); The tops of the first emulsifying vessel (2) and the second emulsifying vessel (3) are connected to a pressure conversion mechanism. The pressure conversion mechanism is used to control the pressure conversion between the first emulsifying vessel (2) and the second emulsifying vessel (3) to drive the emulsion to achieve multiple membrane emulsification. The pressure conversion mechanism includes a multi-way switching valve (13), which is connected to a pressure source (15) via a pressure regulating valve (14). The pressure regulating valve (14) is one or more of a self-operated pressure regulating valve and a differential pressure regulating valve. The pressure source (15) is a high-pressure gas cylinder, an air cylinder, or a gas cylinder. One of a press or a booster pump; the multi-way switching valve is a three-position five-way multi-way switching valve or two two-position three-way multi-way switching valves, controlling the first emulsifying vessel (2) or the second emulsifying vessel (3) to connect to a pressure source (15) or an external source to realize the pressure switching of the first emulsifying vessel (2) and the second emulsifying vessel (3), wherein the multi-way switching valve (13) is electrically connected to a multi-way switching valve drive circuit, the multi-way switching valve drive circuit includes: a time relay (12) electrically connected to the multi-way switching valve, the time relay (12) being controlled by a timer switch (11).

2. The multiple-pass emulsification apparatus according to claim 1, characterized in that, The top of the first emulsifying vessel (2) and the second emulsifying vessel (3) are provided with inlet pipes, and inlet valves are provided on the inlet pipes. Inlet funnels (1) are detachably and fixedly connected to the inlet pipes. Outlet ports are provided at the bottom of the first emulsifying vessel (2) and the second emulsifying vessel (3).

3. The multiple-pass emulsification apparatus according to claim 2, characterized in that, The bottom of the first emulsifying vessel (2) and the second emulsifying vessel (3) are respectively connected to a port of a three-way valve, and the port of the three-way valve is used as a liquid outlet; the port of each three-way valve is respectively connected to a first check valve (7) and a second check valve (8).

4. The multiple-pass emulsification apparatus according to claim 1, characterized in that, Heating jackets (4) are respectively provided on the outside of the first emulsifying kettle (2) and the second emulsifying kettle (3).

5. The multiple-pass emulsification apparatus according to claim 1, characterized in that, At least two of the porous membrane tube jackets (9) and porous membrane tubes (10) are connected in series or in parallel between the first emulsifying vessel (2) and the second emulsifying vessel (3).

6. The multiple-pass emulsification apparatus according to claim 1, characterized in that, The porous membrane tube (10) includes a glass microporous tube and a stainless steel laser microporous tube, with a wall thickness of 0.1-100 mm; wherein, the glass microporous tube includes one of: SPG porous membrane tube, sand core porous membrane tube, quartz porous membrane tube, and ceramic porous membrane tube.

7. A method for preparing microspheres with a narrow particle size distribution, using the multi-pass emulsification apparatus as described in any one of claims 1-6, characterized in that, include: The polymer to be used to make microspheres is dissolved in an organic solvent that is immiscible with water to prepare an organic phase solution of a set concentration. Take a set amount of emulsifier, dissolve it in water, and prepare an aqueous solution of a set concentration; The aqueous solution and the organic solution are respectively added to the first emulsification vessel of the multiple membrane emulsification device, and the stirring mechanism is controlled to stir at a set speed to perform pre-emulsification. The multi-way switching valve is controlled to supply pressure to the first emulsification vessel and to the outside of the second emulsification vessel. When the pressure in the first emulsification vessel exceeds the opening pressure of the first one-way valve under the first emulsification vessel, the pre-emulsion is pressed from the first emulsification vessel into the outer cavity of the membrane tube. After passing through the porous membrane tube for emulsification, it enters the inner cavity of the membrane tube. Under the action of pressure, the second one-way valve at the lower end of the second emulsification vessel is opened, and the emulsion enters the second emulsification vessel, completing the first emulsification. The multi-way switching valve is controlled to open the first emulsification vessel to the outside, and the second emulsification vessel is pressurized. When the pressure of the second emulsification vessel is greater than the opening pressure of the first one-way valve at the bottom of the second emulsification vessel, the pre-emulsion is forced from the second emulsification vessel into the outer cavity of the membrane tube. After passing through the porous membrane tube for emulsification, it enters the inner cavity of the membrane tube. Under the action of pressure, the second one-way valve at the lower end of the first emulsification vessel is opened, and the emulsion is forced into the first emulsification vessel to achieve the second emulsification. The membrane emulsification process is repeated. After a preset number of cycles or cycle time, the first and second emulsification vessels are simultaneously connected to the external atmosphere to collect the emulsion. The solvent in the organic phase is removed by evaporation of the emulsion, and polymer microspheres are precipitated. Solid-liquid separation is performed to obtain solidified microspheres, which are then washed with water and dried to obtain microspheres.

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