Micro-channel reactor system for continuous preparation of drug nano-preparation

Abstract

The invention discloses a micro-channel reactor system for continuous preparation of a drug nano-preparation, and relates to the technical field of micro-reactors, the micro-channel reactor system comprises micro-reactor equipment and a control assembly, the micro-reactor equipment is provided with a reaction medium inlet, a reaction medium outlet, a heat exchange medium inlet and a heat exchange medium outlet; the control assembly comprises an industrial personal computer, an air compressor, a booster pump, a pressure reducing valve, a gas mass flow meter, a high-pressure constant-current infusion pump, a back pressure valve and a high-low temperature all-in-one machine, the air compressor, the booster pump, the pressure reducing valve and the gas mass flow meter are sequentially connected, and the gas mass flow meter and the high-pressure constant-current infusion pump are respectively connected with the reaction medium inlet; the back pressure valve is connected with the reaction medium outlet, and the high and low temperature all-in-one machine is connected with the heat exchange medium inlet and the heat exchange medium outlet. Accurate automatic control is carried out on operation of the microreactor equipment through the control assembly, continuous preparation of nano-drugs is achieved, the production yield and efficiency are remarkably improved, and meanwhile the automatic control level is improved.

Description

Technical Field

[0001] This invention belongs to the field of microreactor technology, specifically relating to a microchannel reactor system for the continuous preparation of drug nanoparticles. Background Technology

[0002] Currently, the development direction of my country's chemical production not only focuses on achieving large-scale production, but also emphasizes improving production efficiency, product quality, and automation control levels while avoiding environmental pollution and energy waste. Continuous flow microreactor technology, with its unique microchannel structure, enhances mass and heat transfer processes, shortens reaction time, and improves reaction efficiency. Simultaneously, it significantly improves the uniformity and controllability of system temperature and concentration, greatly alleviating problems such as localized overheating or excessive reactant concentration, and therefore has been widely applied.

[0003] Currently, the preparation processes for drug nanoparticles, such as liposomes, lipid nanoparticles (LNPs), and polymer nanoparticles / nanocrysts, both domestically and internationally, suffer from several drawbacks. Traditional liposome preparation methods are complex, have poor reproducibility, and produce insufficiently uniform particle sizes. Furthermore, it is difficult to obtain products with different particle sizes as required without altering the lipid formulation. This is particularly problematic in continuous preparation processes, where issues such as liquid supply pulsation, widened residence time distribution, localized concentration gradients, and scaling / clogging can lead to unstable production quality. The introduction of microfluidic micromixing technology into nanoparticle preparation has resulted in more uniform particle sizes and higher reproducibility, demonstrating industrialization potential. However, in actual production, the use of microfluidic devices or microchannel reactors for drug nanoparticle preparation requires precise control. In existing technologies, chip deformation under continuous rinsing severely affects the stability of continuous preparation, failing to meet control requirements. Therefore, there is an urgent need to improve the control level of microfluidic technology. Summary of the Invention

[0004] To address one or more shortcomings of the existing technology, the present invention provides a microchannel reactor system for the continuous preparation of drug nanoparticles, which enables continuous and automated production, significantly improving production output and efficiency.

[0005] To achieve the above objectives, the present invention adopts one or more of the following technical solutions: In a first aspect, a microchannel reactor system for the continuous preparation of drug nanoparticles is provided, comprising a microreactor device and a control component. The microreactor device is provided with a reaction medium inlet, a reaction medium outlet, a heat exchange medium inlet, and a heat exchange medium outlet. The reaction medium inlet and the reaction medium outlet are respectively located at both ends of a microreaction channel, and the heat exchange medium inlet and the heat exchange medium outlet are respectively located at both ends of a heat exchange channel. The microreaction channel and the heat exchange channel are distributed in two parallel planes of the microreactor device. The heat exchange medium in the heat exchange channel can exchange heat with the reaction medium in the microreaction channel to control the temperature in the microreaction channel. The control components include an industrial computer, an air compressor, a gas mass flow meter, a high-pressure constant flow infusion pump, a back pressure valve, and a high-low temperature integrated unit. The air compressor and the gas mass flow meter are connected via pipelines. The gas mass flow meter and the high-pressure constant flow infusion pump are respectively connected to the inlet of the reaction medium. The back pressure valve is connected to the outlet of the reaction medium. The high-low temperature integrated unit is respectively connected to the inlet and outlet of the heat exchange medium. The air compressor, the gas mass flow meter, the high-pressure constant flow infusion pump, the back pressure valve, and the high-low temperature integrated unit are all electrically connected to the industrial computer.

[0006] By adopting the above scheme, the present invention can achieve precise automated control of microreactor equipment, realize continuous production, greatly improve production efficiency, and enhance the level of automation control.

[0007] Preferably, the control component further includes a first pressure gauge and a second pressure gauge. The first pressure gauge is disposed between the gas mass flow meter and the inlet of the reaction medium, and the second pressure gauge is connected to the outlet of the reaction medium, and is used to measure the pressure before the reaction and the pressure after the reaction, respectively.

[0008] Preferably, the control component further includes a booster pump and a pressure reducing valve. The booster pump is connected to the air compressor and the pressure reducing valve is connected to the gas mass flow meter, which can control the outlet pressure to be constant and improve the system pressure stability. The back pressure valve is equipped with a collection tank at its outlet. The bottom of the collection tank is equipped with an electronic balance, which can quickly collect and weigh the reaction product sample, facilitating the automatic collection of the required sample amount and automatic adjustment of the system operation status.

[0009] Preferably, the microreactor includes an installation frame and a plurality of microchannel reactors. The microchannel reactors are embedded in and encapsulated within the installation frame. Each microchannel reactor is provided with a reaction medium inlet and a reaction medium outlet. A first sealing joint or a second sealing joint is provided at the reaction medium inlet, and a first sealing joint or a second sealing joint is provided at the reaction medium outlet. The second sealing joint is used to connect two adjacent microchannel reactors, and the first sealing joint is used to connect the microchannel reactor to an external pipeline, thereby connecting the microchannel reactor to the control component.

[0010] Preferably, the microchannel reactor includes a reaction plate, a supporting transition plate, and a heat exchange plate stacked together. The reaction plate includes a reaction plate body with a first groove forming the micro-reaction channel. The heat exchange plate includes a heat exchange plate body with a second groove forming the heat exchange channel. The supporting transition plate separates the reaction plate and the heat exchange plate. The reaction medium in the micro-reaction channel flows vertically, and the heat exchange medium in the heat exchange channel flows horizontally, with their flow directions perpendicular to each other.

[0011] Preferably, the microchannel reactor is equipped with a temperature sensor for measuring the reaction temperature. The temperature sensor is a patch thermocouple and a paperless recorder. The patch thermocouple is located on the side of the reaction plate opposite to the microreaction channel.

[0012] Preferably, the microreaction channel includes: At least two microchannel units are provided, each microchannel unit including a flow channel inlet, a flow channel outlet and a heart-shaped mixing cavity, wherein the cross-sectional area of ​​the heart-shaped mixing cavity at the flow channel inlet is larger than the cross-sectional area at the flow channel outlet; an arc-shaped baffle and at least one turbulence column are provided inside the heart-shaped mixing cavity, the concave side of the arc-shaped baffle faces the flow channel inlet, and the turbulence column has a cylindrical protruding structure and is disposed between the convex side of the arc-shaped baffle and the flow channel outlet; An intermediate flow channel connects adjacent microchannel units. One end of the intermediate flow channel is connected to the flow channel inlet of one microchannel unit, and the other end is connected to the flow channel outlet of another adjacent microchannel unit.

[0013] Preferably, several micro-reaction channels are arranged in parallel on the reaction plate and connected in series through connecting channels to form an S-shaped zigzag flow channel, with the fluid in adjacent micro-reaction channels flowing in opposite directions.

[0014] Preferably, the heat exchange channels are arranged in an S-shape on the heat exchange plate, and each heat exchange channel is provided with a plurality of spiral baffles at an incline. The spiral baffles are arranged in parallel at the same angle and are evenly distributed. The inclination angle of the spiral baffles is 30° to 45°, and the distance between adjacent spiral baffles is 1 / 3 to 1 / 2 of the depth of the heat exchange channel.

[0015] On the other hand, a control method for a microchannel reactor system for continuous preparation of drug nanoparticles is provided, based on any one of the above-mentioned microchannel reactor systems for continuous preparation of drug nanoparticles, comprising the following steps: S1. Check the power connection of each device in the microchannel reactor system and turn on each device; S2. Enter the control interface of the industrial computer and add the corresponding equipment in the equipment management interface. The added equipment should include at least an air compressor, a gas mass flow meter, a high-pressure constant flow infusion pump, a back pressure valve, and a high and low temperature integrated machine. S3. Enter the rule chain design interface of the industrial control computer, add a new rule, and enter the rule name and event type; S4. Construct a complete rule chain, and input the corresponding code into the executor within the rule chain to control the operation of a certain device; S5. Each rule chain corresponds to a certain action of the controlled device. Each action that the device can perform is designed as a corresponding rule chain. S6. Save the constructed rule chain, test each rule chain separately, and the rule chain is successfully written after the test is completed; S7. Enter the process design interface and arrange the corresponding rule chains of the added devices according to the reaction process; S8. Set up multiple different processes for continuous operation according to production needs.

[0016] By adopting the above technical solution, the beneficial effects of the present invention are as follows: 1. This invention achieves efficient mass and heat transfer and rapid micromixing through a microchannel reactor, effectively suppressing secondary nucleation and agglomeration caused by local supersaturation. It enables the preparation of smaller and more uniform nanoparticles. Furthermore, through control components connected to the microreactor equipment, the operation of the microreactor equipment is precisely automated, allowing the equipment to operate and produce continuously without interruption. This realizes the continuous preparation of nanomedicine formulations, significantly improving production yield and efficiency, and resulting in higher product quality. At the same time, it enhances the level of automation control in the field of microchannel technology.

[0017] 2. With the control components and control method of the present invention, users can log in to the operation interface on a PC or mobile terminal to monitor the reaction process and remotely control the reaction process. They can modify reaction parameters or start / stop corresponding equipment as needed, which greatly improves the safety of the reaction process.

[0018] 3. The back pressure valve of this invention can maintain the system reaction pressure, prevent liquid boiling and vaporization, improve the safety and stability of the system, and significantly increase the solubility of gas in liquid by increasing the overall system pressure, thereby improving reaction efficiency, while ensuring uniform and controllable reaction residence time.

[0019] 4. The microreactor device of the present invention is equipped with a first sealing joint and a second sealing joint. It utilizes a cylindrical tenon and mortise structure for sealing connection and combines it with a ring-shaped seamless welding to form a double sealing system. The thermal displacement compensation capability of the cylindrical tenon and mortise structure allows the plate to expand or contract freely when the temperature or humidity changes, perfectly absorbing the uneven thermal stress introduced by the gradient heat exchange layout. This effectively avoids cracking or deformation caused by thermal stress concentration and can achieve zero leakage at a high temperature of 250°C. It solves the risk of sealing failure in the prior art, thereby ensuring that the microchannel reactor and microchannel reaction system of the present invention can work stably for a long time, improving the service life of the microchannel reactor and reducing maintenance costs.

[0020] 5. In this invention, the microchannel unit on the microchannel reactor generates a micro-vortex effect through the combination of a heart-shaped mixing chamber, an arc-shaped baffle, and a turbulence column, which effectively improves the mixing effect of the fluid and the suspension rate of large particles, reduces the risk of channel blockage, and thus significantly improves the reaction efficiency.

[0021] 6. In this invention, the heat exchange channel and the micro-reaction channel are arranged perpendicularly, so that the heat transfer direction and the reaction medium transfer direction form a 90° angle. This reduces field coupling interference and avoids the problem of boundary layer thickening caused by unidirectional or counterdirectional flow in parallel flow. The heat exchange path is extended by the spiral baffle, making the heat exchange more complete. Furthermore, the corrugated microchannels with different densities at the inlet and outlet can quickly absorb the initial reaction heat at the inlet section and reduce the microchannel density at the outlet section to maintain thermal balance. This adapts to the heat load distribution of the strongly exothermic reaction, effectively controls the temperature difference, prevents local overheating, and improves the overall heat exchange capacity. Attached Figure Description

[0022] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0023] Figure 1 This is a schematic diagram of the system structure in one or more embodiments of the present invention; Figure 2 This is a schematic diagram of the microreactor device structure in one or more embodiments of the present invention. Figure 1 ; Figure 3 This is a schematic diagram of the microreactor device structure in one or more embodiments of the present invention. Figure 2 ; Figure 4 This is a cross-sectional view of the first sealing joint in one or more embodiments of the present invention; Figure 5 This is a cross-sectional view of the second sealing joint in one or more embodiments of the present invention; Figure 6 This is an exploded view of the microchannel reactor structure in one or more embodiments of the present invention; Figure 7 This is a schematic diagram of the reaction plate structure in one or more embodiments of the present invention; Figure 8 This is a planar schematic diagram of a microchannel unit in one or more embodiments of the present invention; Figure 9 This is a schematic diagram of the heat exchange plate structure in one or more embodiments of the present invention; Figure 10 This is a schematic diagram of the distribution of the inlet section channel and the outlet section channel in one or more embodiments of the present invention; Figure 11 This is a schematic diagram of the control interface flow in one or more embodiments of the present invention.

[0024] In the diagram: 1. Microreactor equipment; 2. Air compressor; 3. Booster pump; 4. Pressure reducing valve; 5. Gas mass flow meter; 6. Industrial computer; 7. High-pressure constant flow infusion pump; 8. First pressure gauge; 9. Second pressure gauge; 10. High and low temperature integrated unit; 11. Back pressure valve; 12. Electronic balance; 101. Microchannel reactor; 102. Mounting frame; 103. Reaction plate; 104. Supporting transition plate; 105. Heat exchange plate; 106. First sealing joint; 107. Second sealing joint; 1031, Micro-reaction channel; 1032, Reaction medium inlet; 1033, Reaction medium outlet; 1034, Connection channel; 1051, Heat exchange channel; 1052, Heat exchange medium inlet; 1053, Heat exchange medium outlet; 1054, Spiral baffle; 1061, Connector body; 1062, Double ferrule; 1063, Nut; 1071, Butt joint; 1072, Cloud head; 1073, Nut; 1031-1, Flow channel inlet; 1031-2, Heart-shaped mixing chamber; 1031-3, Flow channel outlet; 1031-4, Arc-shaped baffle; 1031-5, Turbulence column; 1031-6, Intermediate flow channel; 1032-1, Gas medium inlet; 1032-2, Liquid medium inlet; 1051-1, Inlet section channel; 1051-2, Outlet section channel. Detailed Implementation

[0025] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0026] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0027] Example 1 In one typical embodiment of this application, a microchannel reactor system for the continuous preparation of drug nanoparticles is provided, such as... Figures 1-10 As shown, the device includes a microreactor 1 and a control assembly. The microreactor 1 is provided with a reaction medium inlet 1032, a reaction medium outlet 1033, a heat exchange medium inlet 1052, and a heat exchange medium outlet 1053. The reaction medium inlet 1032 and the reaction medium outlet 1033 are respectively located at both ends of the microreaction channel 1031, and the heat exchange medium inlet 1052 and the heat exchange medium outlet 1053 are respectively located at both ends of the heat exchange channel 1051. The microreaction channel 1031 and the heat exchange channel 1051 are distributed in two parallel planes of the microreactor 1. The heat exchange medium in the heat exchange channel 1051 can exchange heat with the reaction medium in the microreaction channel 1031 to control the temperature in the microreaction channel 1031. The control components include an industrial computer 6, an air compressor 2, a booster pump 3, a pressure reducing valve 4, a gas mass flow meter 5, a high-pressure constant flow infusion pump 7, a back pressure valve 11, and a high-low temperature integrated unit 10. The air compressor 2, booster pump 3, pressure reducing valve 4, and gas mass flow meter 5 are connected sequentially through pipelines. The gas mass flow meter 5 and the high-pressure constant flow infusion pump 6 are respectively connected to the reaction medium inlet 1032, and the back pressure valve 11 is connected to the reaction medium outlet 1033. The high-low temperature integrated unit 10 is respectively connected to the heat exchange medium inlet 1052 and the heat exchange medium outlet 1053. The air compressor 2, gas mass flow meter 5, high-pressure constant flow infusion pump 7, back pressure valve 11, and high-low temperature integrated unit 10 are all electrically connected to the industrial computer 6.

[0028] Using the above scheme, this embodiment utilizes micro-reaction channels of microscale channels to achieve efficient heat and mass transfer and rapid micro-mixing, enabling nucleation and self-assembly processes to be completed within a controlled residence time. This suppresses secondary nucleation and agglomeration caused by local supersaturation, resulting in nanoparticles with smaller particle size and higher uniformity. In addition, this embodiment establishes a large-scale, automated production system based on microchannel reactors, enabling precise automated control of the microreactor equipment and realizing continuous preparation of nanomedicines, greatly improving production efficiency and enhancing the level of automation control.

[0029] Specifically, such as Figure 1 As shown, the microchannel reactor system of this embodiment includes a microchannel reactor 101, an industrial control computer 6, an air compressor 2, a booster pump 3, a pressure reducing valve 4, a gas mass flow meter 5, a high-pressure constant flow pump 7, a back pressure valve 11, and a high-low temperature integrated unit 10. The air compressor 2 is used to produce the gas required for the reaction. The air compressor 2 is connected to the booster pump 3, which is driven by compressed air to boost the low-pressure gas to a high-pressure output to the pressure reducing valve 4. This provides a high-pressure gas source for the microchannel reactor 101, increasing the solubility of the gas in the liquid, improving the reaction rate, and ensuring stable fluid flow within the micron-level channels, preventing gas blockage. The pressure reducing valve 4 is connected after the booster pump 3 for precise pressure reduction. By maintaining the outlet pressure within the rated pressure range of the equipment and system, it ensures pressure stability, prevents damage to pipelines, equipment, and related components due to excessive pressure, and facilitates adjustment of the system's reaction pressure. In this embodiment, the booster pump 3 and the pressure reducing valve 4 are combined, which effectively improves the pressure stabilization effect of the pressure reducing valve 4, achieves extremely high pressure stability, and realizes constant outlet pressure, which is conducive to rapid response of flow regulation and improves system efficiency.

[0030] In this embodiment, the reaction medium inlet 1032 includes a gas medium inlet 1032-1 and a liquid medium inlet 1032-2. A gas mass flow meter 5 is connected between the pressure reducing valve 4 and the microreactor device 1. The gas mass flow meter 5 is connected to the gas medium inlet 1032-1, allowing for precise control of the gas flow rate entering the microreactor device 1. The gas mass flow meter 5 is used in conjunction with a gas flow display instrument to display the gas flow rate value in real time, facilitating monitoring.

[0031] In this embodiment, the high-pressure constant-flow infusion pump 7 is connected to the liquid medium inlet 1032-2 of the microreactor device 1 to transport the reaction raw material liquid. The back pressure valve 11 is connected to the reaction medium outlet 1033 of the microreactor device 1. On the one hand, it can apply a back pressure to the system, ensuring that the overall pressure inside the microchannel reactor 101 is always higher than the saturated vapor pressure of the solvent at the current temperature, thereby ensuring that the reactants are always in liquid form and that the reaction proceeds smoothly. On the other hand, it increases the overall system pressure, significantly increases the solubility of the gas in the liquid, improves the reaction efficiency, and helps to ensure uniform and controllable reaction residence time. In this embodiment, the back pressure valve 11 is a commercially available fully automatic back pressure valve.

[0032] In this embodiment, the high and low temperature integrated unit 10 is connected to the heat exchange medium inlet 1052 and heat exchange medium outlet 1053 via external pipes, thereby establishing a circulating heat exchange channel for the heat exchange medium with the microreactor device 1, which is used to regulate the temperature of the reaction liquid in the microchannel reactor 101. In this embodiment, silicone oil is used as the heat exchange medium. Therefore, the back pressure valve 11 can maintain the system reaction pressure while preventing liquid boiling and vaporization, ensuring the safety and stability of the system during operation.

[0033] The microchannel reactor 101 in this embodiment can achieve instantaneous mixing of reactants, ultra-efficient mass transfer and heat transfer in a microstructure device through its micro-reaction characteristics. The high and low temperature integrated machine 10 can achieve precise temperature control of the chemical reaction in the reactor, which is beneficial to improving the conversion rate of the chemical reaction.

[0034] Specifically, such as Figure 1 As shown, the control component also includes a first pressure gauge 8 and a second pressure gauge 9. The first pressure gauge 8 is installed between the gas mass flow meter 5 and the reaction medium inlet 1032 of the microreactor device 1 to measure the pressure before the reaction; the second pressure gauge 9 is installed between the microreactor device 1 and the back pressure valve 11 to measure the pressure after the reaction. Both the first pressure gauge 8 and the second pressure gauge 9 are communicatively connected to the industrial control computer 6 to transmit the collected pressure data to the server in real time.

[0035] Considering the need for product measurement in both experimental research and factory production, in this embodiment, a collection tank is provided at the outlet of the back pressure valve 11, and an electronic balance 12 is placed at the bottom of the collection tank. When the liquid product flows out of the back pressure valve 11 into the collection tank, the reaction product sample is collected quickly and weighed at the same time. The electronic balance 12 is connected to the server of the industrial control computer 6. When the amount of sample in the collection tank reaches the required weight, the system automatically stops running.

[0036] Specifically, the microreactor device 1 in this embodiment includes a mounting frame 102 and a plurality of microchannel reactors 101, such as... Figure 2 and Figure 3 As shown, a microchannel reactor 101 is embedded in a mounting frame 102 and welded and sealed. Several microchannel reactors 101 are connected in series and can sequentially carry out different reactions. Each microchannel reactor 101 is provided with a reaction medium inlet 1032 and a reaction medium outlet 1033. A first sealing joint 106 or a second sealing joint 107 is provided at the reaction medium inlet 1032, and a first sealing joint 106 or a second sealing joint 107 is provided at the reaction medium outlet 1033. Each microchannel reactor 101 is connected to an external pipeline through the first sealing joint 106 and then to the control component. Adjacent microchannel reactors 101 are connected through the second sealing joint 107. In this embodiment, the mounting frame 102 is made of metal.

[0037] In this embodiment, as Figure 5 As shown, the second sealing joint 107 includes a flat joint 1071, a cloud-shaped head 1072, and a nut 1073. The first end of the cloud-shaped head 1072 is connected to the reaction medium outlet 1033 of the reaction plate 103 and welded and fixed to the supporting transition plate 104. The second end is provided with an inner conical surface for tenon-and-mortise connection with the first end of the flat joint 1071. The second end of the flat joint 1071 is connected to the reaction medium inlet 1032 of the reaction plate 103 and welded and fixed. The first end of the cloud-shaped head 1072 is machined with an external thread. The nut 1073 is sleeved on the outside of the cloud-shaped head 1072 and the flat joint 1071 and locked by the threaded connection. Adjacent microchannel reactors 101 are connected and sealed end to end through the second sealing joint 107. The cylindrical tenon and mortise structure formed by the flat joint 1071 and the cloud head 1072 can not only adapt to the local overheating caused by the strong exothermic reaction, but also absorb the uneven thermal stress introduced by the wave-shaped microchannel gradient heat exchange layout in this application. This effectively ensures that the microchannel reactor 101 of this application can work stably for a long time, avoid failure caused by thermal fatigue, as well as equipment cracking or deformation, and achieve zero leakage at a high temperature of 250℃.

[0038] In this embodiment, both the pressure reducing valve 4 and the high-pressure constant flow infusion pump 7 are connected to the reaction medium inlet 1032 via external pipes. Each reaction medium inlet 1032 is equipped with a first sealing joint 106 that is sealed to the external pipe, allowing gaseous or liquid raw materials to enter the micro-reaction channel 1031. Figure 4 As shown, the first sealing joint 106 includes a joint body 1061, a double ferrule 1062, and a nut 1063. The double ferrule 1062 includes a front ferrule and a rear ferrule. One end of the joint body 1061 has a step that is welded to the reaction plate 103. The other end of the joint body 1061 has an inner conical surface that contacts and clamps the front ferrule. The rear ferrule is coaxially disposed behind the front ferrule. The side of the joint body 1061 near the double ferrule 1062 has an external thread that mates with the nut 1063. When the nut 1063 is tightened, it presses the rear ferrule from the rear. The connector body 1061 and the double ferrule 1062 are fitted with a clearance. The connector body 1061 and the double ferrule 1062 form a cylindrical tenon and mortise structure. The interlayer displacement can be eliminated through thermal expansion adaptive compensation, ensuring the stable sealing of the microchannel reactor 101 under strong exothermic reaction and high temperature conditions. It can also realize the stable operation of high viscosity fluid with a solid content of 15% under a low pressure drop of 0.5MPa.

[0039] In this embodiment, the first sealing joint 106 is also provided at the reaction medium outlet 1033 for high-temperature sealing with the external pipeline, and is connected to the back pressure valve 11 through the external pipeline.

[0040] Specifically, such as Figure 6 As shown, the microchannel reactor 101 includes a three-layer structure consisting of a reaction plate 103, a supporting transition plate 104, and a heat exchange plate 105 stacked together. The heat exchange plate 105, the reaction plate 103, and the intermediate supporting transition plate 104 are welded together to form an integral sealed structure. The reaction plate 103 includes a reaction plate body with a first groove formed on it, creating a micro-reaction channel 1031. The heat exchange plate 105 includes a heat exchange plate body with a second groove formed on it, creating a heat exchange channel 1051. The supporting transition plate 104 separates the micro-reaction channel 1031 of the reaction plate 103 from the heat exchange channel 1051 of the heat exchange plate 105. A reaction medium inlet 1032 and a reaction medium outlet 1033 are respectively located at both ends of the micro-reaction channel 1031, and a heat exchange medium inlet 1052 and a heat exchange medium outlet 1053 are respectively located at both ends of the heat exchange channel 1051. The extension direction of the micro-reaction channel 1031 is perpendicular to the extension direction of the heat exchange channel 1051. The reaction medium in the micro-reaction channel 1031 flows vertically, and the heat exchange medium in the heat exchange channel 1051 flows horizontally, with their flow directions being perpendicular to each other.

[0041] The microchannel reactor 101 is equipped with a temperature sensor for measuring the reaction temperature. The temperature sensor uses a patch thermocouple and a paperless recorder. The patch thermocouple is located on the side of the reaction plate away from the micro-reaction channel and can detect temperature changes and convert them into readable signals. The paperless recorder can display the temperature data in the micro-reaction channel in real time.

[0042] Specifically, such as Figure 7 As shown, the reaction plate body has several third grooves, each forming a connecting channel 1034 for connecting two adjacent micro-reaction channels 1031, or between a micro-reaction channel 1031 and the reaction medium inlet 1032, or between a micro-reaction channel 1031 and the reaction medium outlet 1033. The fluid flow directions of any two adjacent micro-reaction channels 1031 are opposite, and adjacent micro-reaction channels 1031 are connected in series via the connecting channel 1034. This forms an S-shaped three-dimensional zigzag flow channel, which extends the reaction path and creates secondary vortices at the bends, improving fluid mixing and particle suspension. The reacted fluid is finally discharged through the reaction medium outlet 1033 at the lower end of the reaction plate 103.

[0043] Specifically, such as Figure 7 As shown, two through holes are opened at the upper end of the reaction plate body to form two reaction medium inlets 1032, namely gas medium inlet 1032-1 and liquid medium inlet 1032-2. Gas medium inlet 1032-1 is connected to the gas supply pipeline where pressure reducing valve 4 is located through an external pipe. Liquid medium inlet 1032-2 is connected to high pressure constant flow pump 7 through an external pipe to provide liquid raw materials. The two reaction media converge in the connecting channel 1034 and then enter the micro-reaction channel 1031.

[0044] In this embodiment, as Figure 8As shown, the micro-reaction channel 1031 uses several microchannel units as the core mixing structure. Each microchannel unit has a heart-shaped structure, including a flow channel inlet 1031-1, a flow channel outlet 1031-3, and a heart-shaped mixing chamber 1031-2. The cross-sectional area of ​​the heart-shaped mixing chamber 1031-2 near the flow channel inlet 1031-1 is larger than the cross-sectional area near the flow channel outlet 1031-3. The inner wall of the heart-shaped mixing chamber 1031-2 is a smooth arc shape. The fluid entering from the flow channel inlet 1031-1 flows to the flow channel outlet 1031-3 in the heart-shaped mixing chamber 1031-2. After flowing out from the flow channel outlet 1031-3, it flows through the intermediate channel 1031-6 to the flow channel inlet 1031-1 of the next microchannel unit. An arc-shaped baffle 1031-4 is installed inside the heart-shaped mixing chamber 1031-2 near the flow channel inlet 1031-1. This baffle guides the fluid direction, and the fluid flows past both sides of the arc-shaped baffle 1031-4, converging behind it to induce eddies and enhance mass transfer capacity. Figure 7 and Figure 8 As shown, the arc-shaped baffle 1031-4 is arc-shaped, with its concave side facing the flow channel inlet 1031-1 and its convex side near the flow channel outlet 1031-3. A turbulence column 1031-5 is positioned behind the arc-shaped baffle 1031-4, near the convex side. The turbulence column 1031-5 is a cylindrical protrusion fixed within the heart-shaped mixing chamber 1031-2. After passing through the arc-shaped baffle 1031-4, the fluid impacts the turbulence column 1031-5. The cylindrical protrusion of the turbulence column 1031-5, with its unique flow characteristics, stably generates alternating Karman vortex streets, effectively shearing and entraining the fluid at a microscale, thus forming local turbulence, significantly improving particle suspension and preventing particle deposition. One or more baffle columns 1031-5 can be provided. In this embodiment, when one baffle column 1031-5 or three baffle columns 1031-5 are provided, the fluid flow direction is as follows: Figure 8 As shown.

[0045] The arc-shaped baffle 1031-4 has a diameter of 0.2 mm and a height of 0.1 mm, and the height of the turbulence column 1031-5 is set to 10%~15% of the depth of the heart-shaped mixing chamber 1031-2.

[0046] Specifically, such as Figure 9As shown, the heat exchange plate 105 includes a heat exchange plate body with two through holes forming a heat exchange medium inlet 1052 and a heat exchange medium outlet 1053, respectively. The heat exchange channels 1051 are distributed in an S-shaped structure on the heat exchange plate body. Several heat exchange channels 1051 are arranged in parallel and their extension direction is perpendicular to the extension direction of the micro-reaction channels 1031, so that the mainstream direction of the heat exchange medium and the mainstream direction of the reaction medium form a 90° angle, which effectively reduces field coupling interference, avoids the problem of boundary layer superposition and thickening caused by the same or opposite direction in parallel flow, and extends the heat exchange path, so as to fully exchange heat. In this embodiment, the heat exchange plate 105 adopts a three-layer composite laminate structure, consisting of an outer layer of stainless steel, a middle layer of ceramic and an inner layer of Hastelloy mesh, which takes into account both high strength and corrosion resistance. The surface of the heat exchange plate 105 is provided with an Al2O3-TiO2 composite coating. The dense stacking of nanoparticles forms a dense coating, which can effectively reduce interfacial thermal resistance. The thermal conductivity can reach 1800 W / (m²·K), which is about 50% higher than that of traditional microchannel reactors.

[0047] In this embodiment, as Figure 9 As shown, each heat exchange channel 1051 has several inclined spiral baffles 1054 arranged parallel to the flow direction of the heat exchange medium. The inclination angle of the spiral baffles 1054 is 30°~45°, and the spacing between adjacent spiral baffles 1054 is 1 / 3~1 / 2 of the depth of the heat exchange channel 1051. The spiral baffles 1054 can change the flow direction of the heat exchange medium, thereby making the heat exchange medium flow spirally in the heat exchange channel 1051, extending the heat exchange path by about 2.5 times, and further ensuring sufficient heat exchange.

[0048] In this embodiment, the heat exchange channel 1051 includes an inlet channel 1051-1 and an outlet channel 1051-2. The longitudinal sections of the inlet channel 1051-1 and the outlet channel 1051-2 are respectively wavy. The distribution density of the inlet channel 1051-1 is greater than that of the outlet channel 1051-2. Specifically, as shown... Figure 10 As shown, the portion of heat exchange channel 1051 near the heat exchange medium inlet 1052 is designated as inlet channel 1051-1, and the portion near the heat exchange medium outlet 1053 is designated as outlet channel 1051-2. Inlet channel 1051-1 is connected to heat exchange medium inlet 1052, and outlet channel 1051-2 is connected to heat exchange medium outlet 1053. The longitudinal cross-sections of both inlet channel 1051-1 and outlet channel 1051-2 are wavy, extending vertically. Compared to traditional flat-bottomed channels (rectangular cross-section channels), this further increases the heat exchange area and improves the heat exchange medium flow rate, thus significantly enhancing heat exchange efficiency and adapting to the rapid heat exchange requirements under strong exothermic reactions and high mass transfer conditions. Figure 7As shown, the longitudinal cross-sectional inner diameter of the inlet channel 1051-1 and the outlet channel 1051-2 is 2.5 mm, and the outer diameter is 4 mm. The distribution density of the inlet channel 1051-1 is 20 channels / cm, and the distribution density of the outlet channel 1051-2 is 10 channels / cm, forming a microchannel gradient layout, which further optimizes the heat distribution. The larger heat exchange area of ​​the inlet channel 1051-1 allows for rapid absorption of reaction heat in the early stages of a violently exothermic reaction, while the reduced density of the outlet channel 1051-2 allows for stable heat release in the later stages of the reaction, maintaining thermal equilibrium. This effectively reduces the temperature difference within the microchannel reactor 101, successfully controlling the local temperature difference within 3℃, providing crucial optimal temperature conditions for the efficient reaction of the mass transfer unit, and simultaneously improving the overall heat exchange capacity.

[0049] Specifically, the intermediate support transition plate 104 is welded to the reaction plate 103 and heat exchange plate 105 to form an integrated structure, and is sealed by an annular sealing groove and a fluororubber gasket. Specifically, the reaction plate body has a first annular sealing groove (not shown in the figure) with a depth of 1 mm and a width of 2 mm on the outside of the micro-reaction channel, and the heat exchange plate body has a second annular sealing groove with a depth of 1 mm and a width of 2 mm on the outside of the heat exchange channel. The first fluororubber gasket is pressed into the first annular sealing groove, and the second fluororubber gasket is pressed into the second annular sealing groove, forming a high-temperature sealing barrier. In this embodiment, both the support transition plate 104 and the reaction plate 103 are made of stainless steel.

[0050] The working process of this embodiment is as follows: One end of the pressure reducing valve 4 is connected to the booster pump 3 to stabilize the pressure and protect the equipment and system. The other end is connected to the gas mass flow meter 5 to control the gas flow rate entering the pipeline. The industrial control computer 6 is located below the pressure reducing valve 4 and the gas mass flow meter 5. The high-pressure constant flow infusion pump 7 is located below the industrial control computer 6. The high-pressure constant flow infusion pump 7 and the gas mass flow meter 5 are respectively connected to the microreactor device 1. The reaction liquid flows out from the right outlet of the microreactor device 1, the pressure is read by the second pressure gauge 9, and then flows into the back pressure valve 11 to regulate the pressure before flowing into the collection tank at the top of the electronic balance 12. The high and low temperature integrated machine 10 is connected to the external pipeline of the microreactor device 1 to control the reaction temperature.

[0051] The operating procedures for each device in this embodiment are as follows: 1) Check the power connection of each device to ensure that each device is powered on normally; 2) Turn on the air compressor 2 and the high and low temperature integrated unit 10, and set the heating temperature of the high and low temperature integrated unit 10; 3) Turn on the gas mass flow meter 5, set the required gas flow rate, and purge the reaction pipeline; 4) After the high and low temperature integrated machine 10 heats up to the specified temperature, readjust the gas mass flow meter 5 to change the gas flow rate; 5) Turn on the high-pressure constant flow pump 7, set an appropriate flow rate, and input the reaction solution to rinse the reaction pipeline. After rinsing is completed, turn off the high-pressure constant flow pump 7. 6) Turn on the cleaning mode of the gas mass flow meter 5, purge for a period of time, then turn off the cleaning mode and reset it to the corresponding flow rate; 7) Open the high-pressure constant flow delivery pump 7 and the fully automatic back pressure valve, and set the corresponding flow rate and pressure respectively; 8) After the collection tank on the electronic balance 12 has collected the sample of the set weight, turn off the high-pressure constant flow infusion pump 7 and adjust the back pressure valve 11 to adjust the pressure to atmospheric pressure. 9) Gas mass flow meter 5 restarts the cleaning mode to remove the collected liquid from the reaction pipeline; 10) Turn off the high and low temperature integrated unit 10, the gas mass flow meter 5 and the back pressure valve 11 to complete the system operation.

[0052] Example 2 To achieve fully automated operation of the above-mentioned workflow and realize intelligent and efficient production, another typical embodiment of this application provides a control method for a microchannel reactor system for continuous preparation of drug nanoparticles. Based on the microchannel reactor system for continuous preparation of drug nanoparticles in Example 1, and referring to... Figure 11 Specifically, it includes the following steps: S1. Check the power connection of each device in the microchannel reactor system and turn on each device; S2. Enter the control interface of the industrial computer and add the corresponding equipment in the equipment management interface. The added equipment should include at least an air compressor, a gas mass flow meter, a high-pressure constant flow infusion pump, a back pressure valve, and a high and low temperature integrated machine. S3. Enter the rule chain design interface of the industrial control computer, add a new rule, and enter the rule name and event type; S4. Construct a complete rule chain, and input the corresponding code into the executor within the rule chain to control the operation of a certain device; S5. Each rule chain corresponds to a certain action of the controlled device. Each action that the device can perform is designed as a corresponding rule chain. S6. Save the constructed rule chain, test each rule chain separately, and the rule chain is successfully written after the test is completed; S7. Enter the process design interface and arrange the corresponding rule chains of the added devices according to the reaction process; S8. According to production needs, it can be set to run multiple different processes continuously, so that each piece of equipment can immediately start the next process after completing the previous process, thus achieving continuous production.

[0053] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Those skilled in the art should understand that the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A microchannel reactor system for continuous preparation of drug nanoparticles, characterized in that, The device includes a microreactor and a control component. The microreactor is provided with a reaction medium inlet, a reaction medium outlet, a heat exchange medium inlet, and a heat exchange medium outlet. The reaction medium inlet and the reaction medium outlet are respectively located at both ends of a microreaction channel, and the heat exchange medium inlet and the heat exchange medium outlet are respectively located at both ends of a heat exchange channel. The microreaction channel and the heat exchange channel are distributed in two parallel planes of the microreactor. The heat exchange medium in the heat exchange channel can exchange heat with the reaction medium in the microreaction channel to control the temperature in the microreaction channel. The control components include an industrial computer, an air compressor, a gas mass flow meter, a high-pressure constant flow infusion pump, a back pressure valve, and a high-low temperature integrated unit. The air compressor and the gas mass flow meter are connected via pipelines. The gas mass flow meter and the high-pressure constant flow infusion pump are respectively connected to the inlet of the reaction medium. The back pressure valve is connected to the outlet of the reaction medium. The high-low temperature integrated unit is respectively connected to the inlet and outlet of the heat exchange medium. The air compressor, the gas mass flow meter, the high-pressure constant flow infusion pump, the back pressure valve, and the high-low temperature integrated unit are all electrically connected to the industrial computer.

2. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 1, characterized in that, The control component further includes a first pressure gauge and a second pressure gauge. The first pressure gauge is disposed between the gas mass flow meter and the microreactor device, and the second pressure gauge is disposed between the microreactor device and the back pressure valve. The first pressure gauge is used to measure the pressure before the reaction, and the second pressure gauge is used to measure the pressure after the reaction.

3. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 1, characterized in that, The control assembly also includes a booster pump and a pressure reducing valve. The booster pump is connected between the air compressor and the pressure reducing valve, and the pressure reducing valve is connected to the gas mass flow meter.

4. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 1, characterized in that, The microreactor includes an installation frame and several microchannel reactors. The microchannel reactors are embedded in and encapsulated within the installation frame. Each microchannel reactor has a reaction medium inlet and a reaction medium outlet. A first sealing joint or a second sealing joint is provided at the reaction medium inlet, and a first sealing joint or a second sealing joint is provided at the reaction medium outlet. The second sealing joint is used to connect two adjacent microchannel reactors, and the first sealing joint is used to connect the microchannel reactor to an external pipeline, thereby connecting the microchannel reactor to the control component.

5. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 1, characterized in that, The microchannel reactor includes a reaction plate, a supporting transition plate, and a heat exchange plate stacked together. The reaction plate includes a reaction plate body with a first groove forming the micro-reaction channel. The heat exchange plate includes a heat exchange plate body with a second groove forming the heat exchange channel. The supporting transition plate separates the reaction plate and the heat exchange plate. The reaction medium in the micro-reaction channel flows vertically, and the heat exchange medium in the heat exchange channel flows horizontally, with their flow directions perpendicular to each other.

6. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 5, characterized in that, The microchannel reactor is equipped with a temperature sensor for measuring the reaction temperature. The temperature sensor is a patch thermocouple and a paperless recorder. The patch thermocouple is located on the side of the reaction plate away from the micro-reaction channel.

7. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 5, characterized in that, The microreaction channels include: At least two microchannel units are provided, each microchannel unit including a flow channel inlet, a flow channel outlet and a heart-shaped mixing cavity, wherein the cross-sectional area of ​​the heart-shaped mixing cavity at the flow channel inlet is larger than the cross-sectional area at the flow channel outlet; an arc-shaped baffle and at least one turbulence column are provided inside the heart-shaped mixing cavity, the concave side of the arc-shaped baffle faces the flow channel inlet, and the turbulence column has a cylindrical protruding structure and is disposed between the convex side of the arc-shaped baffle and the flow channel outlet; An intermediate flow channel connects adjacent microchannel units. One end of the intermediate flow channel is connected to the flow channel inlet of one microchannel unit, and the other end is connected to the flow channel outlet of another adjacent microchannel unit.

8. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 5, characterized in that, Several micro-reaction channels are arranged in parallel on the reaction plate and connected in series through connecting channels to form an S-shaped zigzag flow channel, with the fluid in adjacent micro-reaction channels flowing in opposite directions.

9. The microchannel reactor system for continuous preparation of drug nanoparticles as described in claim 5, characterized in that, Several heat exchange channels are arranged in an S-shape on the heat exchange plate, and several spiral baffles are inclinedly arranged in each heat exchange channel.

10. A control method for a microchannel reactor system for continuous preparation of drug nanoparticles, based on the microchannel reactor system for continuous preparation of drug nanoparticles as described in any one of claims 1-9, characterized in that, Includes the following steps: S1. Check the power connection of each device in the microchannel reactor system and turn on each device; S2. Enter the control interface of the industrial computer and add the corresponding equipment in the equipment management interface. The added equipment should include at least an air compressor, a gas mass flow meter, a high-pressure constant flow infusion pump, a back pressure valve, and a high and low temperature integrated machine. S3. Enter the rule chain design interface of the industrial control computer, add a new rule, and enter the rule name and event type; S4. Construct a complete rule chain, and input the corresponding code into the executor within the rule chain to control the operation of a certain device; S5. Each rule chain corresponds to a certain action of the controlled device. Each action that the device can perform is designed as a corresponding rule chain. S6. Save the constructed rule chain, test each rule chain separately, and the rule chain is successfully written after the test is completed; S7. Enter the process design interface and arrange the corresponding rule chains of the added devices according to the reaction process; S8. Set up multiple different processes for continuous operation according to production needs.

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