Freeze-drying method and freeze-drying system

Abstract

The present application belongs to the technical field of freeze-drying, and relates to a freeze-drying method and a freeze-drying system. A freeze-drying method, comprising: injecting a liquid material into a freeze-drying container, continuously stirring the material by using a stirring device, and continuously introducing a heat exchange medium at -3°C to -8°C into a jacket to pre-cool the material to -3°C to -5°C; continuously vacuumizing the freeze-drying container, continuously stirring the material, and continuously introducing a heat exchange medium at -15°C to -50°C into the jacket to cool the material to -15°C to -45°C; continuously introducing the heat exchange medium, stirring and vacuumizing until the vacuum degree in the freeze-drying container is reduced to a low vacuum state; and continuing the continuous stirring and vacuumizing, and performing a heating and drying treatment on the obtained material. The freeze-drying method and freeze-drying system of the embodiments of the present application enable direct freeze-drying to form a powdery product with a small particle size, resulting in few process steps, high freeze-drying efficiency, low product loss and low contamination, and low costs.

Description

A freeze-drying method and freeze-drying system

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese Patent Application No. 202411589697.0, filed on November 8, 2024, entitled "A freeze-drying method and freeze-drying system", and Chinese Patent Application No. 202422732058.7, filed on November 8, 2024, entitled "A freeze-drying system", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of freeze-drying technology, and particularly to a freeze-drying method and freeze-drying system. Background Technology

[0004] Freeze-drying technology is used to prepare various pharmaceuticals, including antibiotics, vaccines, biological products, and plasma. Freeze-dried pharmaceuticals have a longer shelf life and are easier to transport and store. Many vaccines are also prepared using freeze-drying technology to reduce their degradation during transportation and storage.

[0005] Currently, most freeze-drying equipment used in large-scale production is tray-type freeze dryers, which involve placing materials on trays for freeze-drying. Existing tray-type freeze dryers have the following disadvantages: 1. The material needs to be frozen at a low temperature to form ice blocks in the early stages of freeze-drying, resulting in long freezing times and high energy consumption; 2. Heat exchange efficiency decreases as the freeze-drying process progresses; 3. The freeze-dried product requires further processing to obtain the desired powder form; 4. The overall process is complex, making the product susceptible to loss and contamination; 5. When freeze-drying materials with low bulk density, disposable freeze-drying trays are required, increasing freeze-drying costs. Another commonly used freeze-drying equipment is the dynamic freeze dryer, which also has disadvantages: dust is generated during the dynamic freeze-drying process, causing loss of the freeze-dried product, and using filters increases cleaning challenges and poses a significant risk of cross-contamination.

[0006] Application content

[0007] To address the shortcomings of existing technologies, the purpose of this application is to provide a freeze-drying method and system that can directly freeze-dry products with small particle sizes, achieving high freeze-drying efficiency, short processing time, high product yield, and low cost.

[0008] In a first aspect, embodiments of this application provide a freeze-drying method, wherein the freeze-drying system includes a freeze-drying container and a stirring device, the outer wall of the freeze-drying container is provided with a jacket, and the stirring device is provided inside the freeze-drying container. The freeze-drying method includes the following steps:

[0009] (1) Inject the liquid material into the freeze-drying container, use a stirring device to continuously stir the material at a speed of not less than 60 r / min, and continuously introduce the heat exchange medium at -3℃ to -8℃ into the jacket to pre-cool the material to -3℃ to -5℃.

[0010] (2) Continuously evacuate the freeze-drying container and continuously stir the material at a speed of not less than 60 r / min. Continuously introduce heat exchange medium at -15℃ to -50℃ into the jacket to cool the material to -15℃ to -45℃.

[0011] (3) Continuously introduce heat exchange medium, stir and evacuate until the vacuum degree in the freeze-drying container drops to a low vacuum state.

[0012] (4) Continue stirring and vacuuming to heat and dry the material obtained in step (3).

[0013] This application involves directly injecting liquid material (feed liquid) into a freeze-drying container, introducing a heat exchange medium at -3℃ to -8℃ into the jacket, and pre-cooling the material to -3℃ to -5℃ under suitable stirring speed. Then, a vacuum is drawn, and a heat exchange medium at -15℃ to -50℃ is introduced into the jacket. The material is then cooled to -15℃ to -45℃ under suitable stirring speed. By using a negative pressure evaporation and heat absorption pre-freezing method, most of the moisture in the material can be pre-evaporated while freezing, reducing freezing time and subsequent drying time. Combined with stirring, the material directly undergoes freeze-drying through an ice-water mixture, a slushy state, large-particle slushy, and small-particle slushy state, ensuring that the material forms small slushy particles throughout the freeze-drying process. This allows for direct freeze-drying to form a powder product with a small particle size. The process involves fewer steps, higher freeze-drying efficiency, less product loss and contamination, and lower cost.

[0014] In some embodiments of this application, in step (3), the stirring rate is reduced, and / or the vacuuming rate is reduced until the vacuum level inside the freeze-drying container drops to a low vacuum state.

[0015] When the material is frozen and stirred until it changes from a liquid state to a loose solid state like slush, most of the free water in the material has evaporated. At this point, the density of the material is low. Reducing the stirring rate can prevent the material from flying away and escaping. Reducing the vacuuming rate can reduce the flow rate of sublimation gas in the freeze-drying container, thereby reducing material loss. Combined with continued freezing and stirring, the free water in the material can be sublimated as much as possible until the vacuum degree in the freeze-drying container drops to a low vacuum state, at which point the free water in the material has almost completely sublimated.

[0016] In some embodiments of this application, the method for reducing the stirring rate is as follows: the original stirring rate is not less than 60 r / min, and the reduced stirring rate is 10 r / min to 20 r / min.

[0017] In some embodiments of this application, the method for reducing the vacuum pumping rate is to reduce the opening degree of the vacuum pumping regulating valve.

[0018] In some embodiments of this application, in step (3), a heat exchange medium at -15°C to -50°C is continuously introduced.

[0019] In some embodiments of this application, the low vacuum state is a vacuum degree of 8 Pa to 300 Pa.

[0020] In some embodiments of this application, the method of heating and drying is to heat in stages until the temperature reaches 25°C to 35°C.

[0021] After the free water in the material has been almost completely sublimated, this application continues to dry the material by raising the temperature in stages, so as to continue to efficiently sublimate and remove the bound water in the material, while avoiding damage to the quality of the product.

[0022] In some embodiments of this application, the method for each stage of heating includes: heating by 5°C to 12°C each time, and maintaining the temperature for 1 hour to 8 hours until the vacuum level inside the freeze-drying container drops to a low vacuum state.

[0023] In some embodiments of this application, the freeze-drying system further includes a temperature control device located in the circulation loop of the heat exchange medium. The heat exchange medium flowing out of the jacket is regulated by the temperature control device before being introduced into the jacket. The freeze-drying method further includes:

[0024] After the material is precooled to -3℃ to -5℃, a portion of the heat exchange medium at -3℃ to -8℃ is located in the jacket to precool the material. At this time, another portion of the heat exchange medium at -3℃ to -8℃ is continuously cooled to -15℃ to -50℃ under the control of the temperature control device. Heat exchange medium that has been cooled to -15℃ to -50℃ by the temperature control device is introduced into the jacket.

[0025] This application involves pre-cooling the material to -3℃ to -5℃, then continuously cooling a portion of the heat exchange medium from -3℃ to -8℃ to -15℃ to -50℃ under the control of a temperature control device. The heat exchange medium, cooled to -15℃ to -50℃ by the temperature control device, is then introduced into the jacket, rapidly cooling the pre-cooled material from -3℃ to -5℃ to -15℃ to -45℃. This allows the raw material solution and water in the material to reach the same eutectic point, facilitating subsequent efficient sublimation freeze-drying.

[0026] Secondly, embodiments of this application provide a freeze-drying system applicable to the freeze-drying method provided in the first aspect, comprising: a freeze-drying container, a temperature control device, and a stirring device; the freeze-drying container has a jacket on its outer wall, and a heat exchange medium is injected into the jacket; the temperature control device includes a heat exchange device and a housing; one end of the heat exchange device is connected to the inlet of the jacket via a first pipeline, and the other end of the heat exchange device is connected to the outlet of the jacket via a second pipeline; a pump body is provided on the first pipeline; the housing is located on the first pipeline and is connected to the inlet of the jacket and the heat exchange device; a third pipeline is connected to the first pipeline between the second pipeline and the inlet of the housing and the jacket; a first valve body is provided on the first pipeline and is located between the connection point of the third pipeline and the first pipeline and the inlet of the jacket; a second valve body is provided on the second pipeline and is located between the connection point of the third pipeline and the second pipeline and the outlet of the jacket; a circulation valve body is provided on the third pipeline; the stirring device is located inside the freeze-drying container and is used to stir the material injected into the freeze-drying container.

[0027] This application connects one end of a heat exchanger to the inlet of a jacket via a first pipeline, and the other end of the heat exchanger to the outlet of the jacket via a second pipeline. A pump is installed on the first pipeline to cool the heat exchange medium inside the jacket, thereby pre-cooling the material in the freeze-drying container to -3℃ to -5℃. A third pipeline is connected to the first pipeline via a housing that is connected to both the jacket inlet and the heat exchanger. A first valve body is installed on the first pipeline, located between the connection point of the third pipeline and the first pipeline and the inlet of the jacket. A second valve body is installed on the second pipeline. The valve body is located between the connection point of the third and second pipelines and the outlet of the jacket. A circulation valve body is installed on the third pipeline to facilitate the circulation and cooling of the heat exchange medium in the jacket to the required lower temperature, thereby achieving rapid cooling of materials pre-cooled to -3℃ to -5℃ in the freeze-drying container to -15℃ to -45℃. In conjunction with the stirring device, the material directly undergoes freeze-drying through ice-water mixture, ice slush, large-particle ice slush, and small-particle ice slush, ensuring that the material forms small ice slush particles throughout the freeze-drying process, which can be directly freeze-dried into powder products with small particle size. The process involves fewer steps, has higher freeze-drying efficiency, less product loss and contamination, and lower cost.

[0028] In some embodiments of this application, the stirring device includes a driving member and a stirring member. The driving member is used to drive the stirring member to rotate. The stirring member extends into the freeze-drying container from the top and extends towards the bottom of the freeze-drying container. The stirring member includes a stirring shaft and multiple stirring blades, which are distributed at intervals along the axial and circumferential directions of the stirring shaft.

[0029] This application sets up a stirring element that extends into the freeze-drying container from the top, making the freeze-drying container vertical, which is suitable for freeze-drying materials; by setting multiple stirring blades at intervals in the axial and circumferential directions of the stirring shaft, it is convenient to fully stir and freeze-dry the materials in the freeze-drying container.

[0030] In some embodiments of this application, the stirring blade is close to the edge of the inner wall of the freeze-drying container and the distance between the stirring blade and the inner wall of the freeze-drying container is less than 3 mm.

[0031] This application sets the distance between the edge of the stirring blade near the inner wall of the freeze-drying container and the inner wall of the freeze-drying container to be less than 3mm, so as to ensure that the material in the freeze-drying container can be fully stirred. When the material is frozen to form a slush and granular slush state, some slush and granular slush may adhere to the inner wall of the freeze-drying container. The above-mentioned setting of the stirring blade can also fully stir the slush and granular slush material adhering to the inner wall of the freeze-drying container, so as to ensure that the material forms small slush particles throughout the freeze-drying process and is freeze-dried fully and evenly.

[0032] In some embodiments of this application, the polishing cleanliness of the inner wall of the freeze-drying container and the outer wall of the stirring component is less than 4 μm.

[0033] This application utilizes a polishing cleanliness level of less than 4μm on both the inner wall of the freeze-drying container and the outer wall of the stirring component, which facilitates efficient stirring and freeze-drying of materials.

[0034] In some embodiments of this application, the freeze-drying container is connected to a vacuum pump.

[0035] This application connects a vacuum pump to a freeze-drying container to create a vacuum inside the container during the freeze-drying process, thereby efficiently pre-freezing and drying the material inside the freeze-drying container by absorbing heat through negative pressure volatilization.

[0036] In some embodiments of this application, it includes a controller configured to perform the following steps: (1) controlling the stirring device to continuously stir the liquid material in the freeze-drying container at a speed of not less than 60 r / min, and controlling the temperature control device to continuously introduce a heat exchange medium of -3℃ to -8℃ into the jacket to pre-cool the material to -3℃ to -5℃.

[0037] (2) Control the vacuum pump to continuously evacuate the freeze-drying container, and control the stirring device to continuously stir the material at a speed of not less than 60 r / min. Control the temperature control device to continuously introduce heat exchange medium of -15℃ to -50℃ into the jacket so that the material is cooled to -15℃ to -45℃.

[0038] (3) Control the temperature control device to continuously supply the heat exchange medium, control the stirring device to continuously stir, and control the vacuum pump to continuously evacuate until the vacuum degree in the freeze-drying container drops to a low vacuum state.

[0039] (4) Continue to control the stirring device to continuously stir and control the vacuum pump to continuously evacuate, and control the temperature control device to heat up and dry the material obtained above.

[0040] In some embodiments of this application, the controller is configured to reduce the stirring rate of the stirring device and / or reduce the vacuum pumping rate of the vacuum pump according to the material temperature in the freeze-drying container and the vacuum degree in the freeze-drying container when performing step (3), until the vacuum degree in the freeze-drying container drops to a low vacuum state.

[0041] This application uses a controller to automatically control the material processing method, so that when the material temperature is frozen to a certain level (i.e. the material changes from a liquid state to a preset state), the stirring rate is reduced, and / or the vacuuming rate is reduced, until the vacuum degree in the freeze-drying container drops to a low vacuum state, thereby reducing material loss and increasing product yield.

[0042] In some embodiments of this application, the freeze-drying container is connected to a nitrogen storage tank.

[0043] This application connects a nitrogen storage tank to the freeze-drying container to verify the airtightness of the freeze-drying container and ensure good operation during vacuuming; at the same time, if there is residual material in the freeze-drying container after the material is discharged, the inside of the freeze-drying container can be purged with nitrogen. Attached Figure Description

[0044] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0045] Figure 1 is a schematic diagram of a freeze-drying system provided in an embodiment of this application;

[0046] Figure 2 is a schematic diagram of another freeze-drying system provided in an embodiment of this application;

[0047] Figure 3 is a schematic diagram of a freeze-drying container provided in an embodiment of this application;

[0048] Figure 4 is a schematic diagram of another freeze-drying container provided in an embodiment of this application;

[0049] Figure 5 is a schematic diagram of another freeze-drying container provided in an embodiment of this application.

[0050] icon:

[0051] In Figures 1 and 2: 1-Freeze-drying container; 11-Jacket; 12-Inlet; 13-Outlet; 14-First pressure gauge; 15-First thermometer; 2-Temperature control device; 21-Heat exchange device; 211-Plate heat exchanger; 212-Refrigeration unit; 213-Heating oil tank; 214-Supplementary oil tank; 22-Box body; 23-First pipeline; 231-First valve body; 24-Second pipeline; 241-Second valve body; 25-Pump body; 26-Third pipeline; 261-Circulation valve body; 27-Third thermometer; 3-Stirring device; 31-Driver; 32-Stirring shaft; 33-Stirring blade; 4-Vacuum pump; 41-Second pressure gauge; 42-Second thermometer; 43-Vacuum regulating valve; 5-Nitrogen storage tank; 51-Nitrogen regulating valve.

[0052] In Figures 3 to 5: 1-vacuum hole; 2-top cover; 3-reactor jacket; 4-support frame; 5-jacket discharge hemispherical valve; 6-jacket inlet; 7-stirrer; 8-sliding rod; 9-sliding guide rail; 10-jacket outlet; 11-spiral stirrer; 12-reactor body flaps. Detailed Implementation

[0053] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0054] In order to improve the current tray-type freeze-drying process, which has problems such as long freezing time, low freeze-drying efficiency, high cost, inability to directly obtain the required powdered product, and easy product loss and contamination.

[0055] This application provides a freeze-drying method, which uses a freeze-drying system including a freeze-drying container and a stirring device. The freeze-drying container has a jacket on its outer wall, and the stirring device is installed inside the freeze-drying container. The freeze-drying method includes the following steps:

[0056] (1) Inject the liquid material into the freeze-drying container, use a stirring device to continuously stir the material at a speed of not less than 60 r / min, and continuously introduce the heat exchange medium at -3℃ to -8℃ into the jacket to pre-cool the material to -3℃ to -5℃.

[0057] (2) Continuously evacuate the freeze-drying container and continuously stir the material at a speed of not less than 60 r / min. Continuously introduce a heat exchange medium of -15℃ to -50℃ into the jacket to cool the material to -15℃ to -45℃. Optionally, continuously introduce a heat exchange medium of -15℃ to -30℃ into the jacket to cool the material to -15℃ to -20℃.

[0058] (3) Continuously introduce heat exchange medium, stir and evacuate until the vacuum degree in the freeze-drying container drops to a low vacuum state.

[0059] (4) Continue stirring and vacuuming to heat and dry the material obtained in step (3).

[0060] Liquid material (feed liquid) is directly injected into the freeze-drying container. A heat exchange medium at -3℃ to -8℃ is introduced into the jacket. Under appropriate stirring speed, the material is pre-cooled to -3℃ to -5℃, allowing some of the moisture in the material to evaporate first, forming a certain ice-water mixture. This avoids the large amount of moisture evaporating at once and forming large lumps when directly vacuuming. Then, vacuum is applied, and a heat exchange medium at -15℃ to -50℃ is introduced into the jacket. The material is further cooled to -15℃ to -45℃ under appropriate stirring speed. Using negative pressure evaporation and heat absorption pre-freezing, most of the moisture in the material can be pre-evaporated while freezing, reducing freezing time and subsequent drying time. Combined with stirring, the material directly undergoes the freeze-drying process through the ice-water mixture, ice slush state, large ice slush particles, and small ice slush particles, ensuring that the material forms small ice slush particles throughout the freeze-drying process. This allows for direct freeze-drying to form a powder product with a small particle size. The process involves fewer steps, has high freeze-drying efficiency, less product loss and contamination, and low cost.

[0061] In some embodiments of this application, the particle size of the freeze-dried powder product is less than 10 μm.

[0062] In some embodiments of this application, the volume of liquid material injected into the freeze-drying container is less than 1 / 2 of the volume of the freeze-drying container.

[0063] Furthermore, the stirring speed is 60 r / min to 300 r / min. As an example, the stirring speed may be, but is not limited to, 60 r / min, 65 r / min, 70 r / min, 75 r / min, 80 r / min, 85 r / min, 90 r / min, 95 r / min, 100 r / min, 150 r / min, 200 r / min, 300 r / min, or any intermediate value between any two of the above values.

[0064] In some embodiments of this application, in step (1), the temperature of the heat exchange medium can be, but is not limited to, -3℃, -4℃, -5℃, -6℃, -7℃, -8℃, or any intermediate value between any two of the above values, and the material can be pre-cooled to, but is not limited to, -3℃, -4℃, -5℃, or any intermediate value between any two of the above values.

[0065] In some embodiments of this application, in step (2), the temperature of the heat exchange medium can be, but is not limited to, -15℃, -17℃, -20℃, -23℃, -25℃, -30℃, -35℃, -40℃, -45℃, -50℃, or any intermediate value between any two of the above values, and the material can be cooled to, but is not limited to, -15℃, -16℃, -17℃, -18℃, -19℃, -20℃, -25℃, -30℃, -35℃, -40℃, -45℃, or any intermediate value between any two of the above values.

[0066] In step (2), as the material temperature decreases, the pressure inside the freeze-drying container will decrease simultaneously as the vacuum is continuously drawn. The entire dynamic process changes from an ice-water mixture to a slush state. When the material is cooled to the preset -15℃ to -45℃, the state of the material is converted into a loose solid in the slush state.

[0067] In some embodiments of this application, in step (3), the stirring rate is reduced, and / or the vacuuming rate is reduced until the vacuum level inside the freeze-drying container drops to a low vacuum state.

[0068] In some embodiments of this application, the method for reducing the stirring rate is as follows: the original stirring rate is not less than 60 r / min, and the reduced stirring rate is 10 r / min to 20 r / min. As an example, the stirring rate can be controlled to be, but is not limited to, 10 r / min, 12 r / min, 15 r / min, 18 r / min, 20 r / min, or any intermediate value between any two of the above values.

[0069] In some embodiments of this application, the method for reducing the vacuuming rate is to reduce the opening degree of the vacuum regulating valve. For example, the original vacuum regulating valve is fully open, and the vacuum regulating valve is adjusted to 10% to 20% of the full opening degree to reduce the vacuuming rate, thereby reducing the flow rate of sublimation gas in the freeze-drying container.

[0070] In some embodiments of this application, in step (3), the heat exchange medium at -15°C to -50°C is continuously introduced, which can be consistent with the conditions for introducing the heat exchange medium in step (2).

[0071] In some embodiments of this application, the vacuum degree after step (2) is approximately 200 Pa to 300 Pa, and after step (3), the low vacuum state is a vacuum degree of 8 Pa to 300 Pa.

[0072] The vacuum degree corresponding to a low vacuum state can be calculated as follows: Determine the current material's Tc', Tc'-10℃=T1, and look up the saturated vapor pressure Pa1 corresponding to water through T1. Low vacuum is determined when the pressure is not higher than the Pa1 value, and the final operating pressure is Pa1-10pa.

[0073] In some embodiments of this application, the heating and drying method involves staged heating until the temperature reaches 25°C to 35°C. Each stage of heating includes increasing the temperature by 5°C to 12°C each time and maintaining it for 1 hour to 8 hours until the vacuum level inside the freeze-drying container drops to a low vacuum state. After almost all the free water in the material has sublimated, the material is dried by staged heating to continue to efficiently remove bound water from the material through sublimation, while avoiding damage to the product quality.

[0074] In some embodiments of this application, in steps (1) to (3), a heat exchange medium is continuously introduced into the jacket. This application achieves rapid and uniform cooling of the material by continuously introducing the heat exchange medium.

[0075] In some embodiments of this application, the freeze-drying system further includes a temperature control device located in the circulation loop of the heat exchange medium. The heat exchange medium flowing out of the jacket is regulated by the temperature control device before being introduced into the jacket. The freeze-drying method further includes: after the material is pre-cooled to -3℃ to -5℃, a portion of the heat exchange medium at -3℃ to -8℃ is located in the jacket to pre-cool the material. At this time, another portion of the heat exchange medium at -3℃ to -8℃ is continuously cooled to -15℃ to -50℃ under the control of the temperature control device, and the heat exchange medium cooled to -15℃ to -50℃ by the temperature control device is introduced into the jacket. After the material is pre-cooled to -3℃ to -5℃, a portion of the heat exchange medium at -3℃ to -8℃ is continuously cooled to -15℃ to -50℃ under the control of the temperature control device. The heat exchange medium, cooled to -15℃ to -50℃ by the temperature control device, is then introduced into the jacket. This causes the material pre-cooled to -3℃ to -5℃ to rapidly cool to -15℃ to -45℃, allowing the raw material solution and water in the material to reach the same eutectic point. This facilitates efficient sublimation freeze-drying in the subsequent process and prevents premature crystallization of water in the material, which would concentrate the raw material solution and alter the freeze-drying curve, resulting in failure to freeze-dry or poor freeze-drying effect.

[0076] In some embodiments of this application, in step (4), stirring and vacuuming can continue to be performed under the same conditions as in step (3).

[0077] In some embodiments of this application, the above-described freeze-drying method is applicable to various pharmaceuticals, including but not limited to antibiotics, vaccines, biological products, and plasma. It is particularly suitable for materials with low bulk density. Materials with low bulk density are loose and prone to scattering during traditional tray freeze-drying, making them difficult to pack and requiring disposable freeze-drying trays, resulting in higher costs. Using the above-described freeze-drying method for materials with low bulk density can reduce scattering losses, facilitate packing, and reduce costs.

[0078] This application provides a freeze-drying system, as shown in Figure 1, applicable to the freeze-drying method described above. The system includes: a freeze-drying container 1, a temperature control device 2, and a stirring device 3. The freeze-drying container 1 has a jacket 11 on its outer wall, and the jacket 11 is filled with a heat exchange medium. The temperature control device 2 includes a heat exchange device 21 and a housing 22. One end of the heat exchange device 21 is connected to the inlet of the jacket 11 via a first pipe 23, and the other end of the heat exchange device 21 is connected to the outlet of the jacket 11 via a second pipe 24. A pump body 25 is installed on the first pipe 23. The housing 22 is located on the first pipe 23 and connected to the inlet of the jacket 11 and the heat exchange device 21. The second pipeline 24 is connected to the first pipeline 23 between the inlet of the housing 22 and the jacket 11, and is connected to the third pipeline 26. The first pipeline 23 is provided with a first valve body 231, which is located between the connection between the third pipeline 26 and the first pipeline 23 and the inlet of the jacket 11. The second pipeline 24 is provided with a second valve body 241, which is located between the connection between the third pipeline 26 and the second pipeline 24 and the outlet of the jacket 11. The third pipeline 26 is provided with a circulation valve body 261. The stirring device 3 is provided inside the freeze-drying container 1 and is used to stir the material injected into the freeze-drying container 1.

[0079] As an example, a third thermometer 27 is provided on the first pipe 23 between the heat exchange device 21 and the housing 22 to facilitate the detection of the temperature of the heat exchange medium after heat exchange through the heat exchange device 21.

[0080] As an example, the freeze-drying container 1 is equipped with a first pressure gauge 14 and a first thermometer 15 to facilitate the detection of the pressure inside the freeze-drying container 1 and the temperature of the material inside the freeze-drying container 1.

[0081] The heat exchanger 21 is pre-activated and set to -3℃ to -8℃. The first valve body 231, the second valve body 241, the pump body 25, and the heat exchanger 21 are opened. The pump body 25 draws the heat exchange medium in the jacket 11 from the outlet of the jacket 11 and into the second pipeline 24, so that the heat exchange medium circulates to the heat exchanger 21 to cool down. The cooled heat exchange medium enters the jacket 11 through the first pipeline 23 and the inlet of the jacket 11. This process of circulating and cooling the heat exchange medium into the jacket 11 continues until the heat exchange medium cooled to -3℃ to -8℃ enters the jacket 11, thereby pre-cooling the material in the freeze-drying container 1 to -3℃ to -5℃. After the material in the freeze-drying container 1 cools down to -3℃ to -5℃, the heat exchanger 21 is pre-activated and set to -15℃ to -50℃. The first valve body 231 and the second valve body 241 are then closed. 241, and open the circulation valve 261. A portion of the heat exchange medium at -3℃ to -8℃ remains in the jacket 11 to continue pre-cooling the material in the freeze-drying container 1, while another portion of the heat exchange medium at -3℃ to -8℃ remains in the temperature control device 2, circulating and cooling between the second pipeline 24, the heat exchange device 21, the first pipeline 23, and the third pipeline 26 until the third thermometer 27 detects that the heat exchange medium has cooled to -15℃ to -50℃. Then, open the first valve 231 and the second valve 241, and close the circulation valve 261, so that the heat exchange medium cooled to -15℃ to -50℃ enters the jacket 11 through the first pipeline 23 from the inlet of the jacket 11, thereby cooling the material in the freeze-drying container 1 to -15℃ to -45℃. The flow rate of the heat exchange medium is controlled to be 8m3 / h to 12m3 / h.

[0082] In some embodiments of this application, the stirring device 3 includes a driving member 31 and a stirring member. The driving member 31 drives the stirring member to rotate. The stirring member extends into the freeze-drying container 1 from the top and extends towards the bottom of the freeze-drying container 1. The stirring member includes a stirring shaft 32 and multiple stirring blades 33, which are spaced apart along the axial and circumferential directions of the stirring shaft 32. The stirring member extending into the freeze-drying container 1 from the top means that the freeze-drying container 1 is vertical, which is suitable for freeze-drying materials. By arranging multiple stirring blades 33 spaced apart along the axial and circumferential directions of the stirring shaft 32, it is convenient to fully stir and freeze-dry the materials in the freeze-drying container 1.

[0083] As an example, the agitator may be, but is not limited to, an anchor agitator or a ribbon agitator. The drive unit 31 may be, but is not limited to, a variable frequency motor.

[0084] In some embodiments of this application, the distance between the edge of the stirring blade 33 near the inner wall of the freeze-drying container 1 and the inner wall of the freeze-drying container 1 is less than 3 mm. Setting the distance between the edge of the stirring blade 33 near the inner wall of the freeze-drying container 1 and the inner wall of the freeze-drying container 1 to less than 3 mm ensures that the material inside the freeze-drying container 1 can be fully stirred. When the material freezes to form slush and granular slush, some slush and granular slush may adhere to the inner wall of the freeze-drying container 1. The aforementioned arrangement of the stirring blade 33 can also fully stir the slush and granular slush material adhering to the inner wall of the freeze-drying container 1, ensuring that the material forms smaller slush particles throughout the freeze-drying process and is freeze-dried sufficiently and uniformly.

[0085] Furthermore, the distance between the edge of the stirring blade 33 near the inner wall of the freeze-drying container 1 and the inner wall of the freeze-drying container 1 is 0.5 mm to 2.8 mm. As an example, the distance between the edge of the stirring blade 33 near the inner wall of the freeze-drying container 1 and the inner wall of the freeze-drying container 1 can be, but is not limited to, 2.8 mm, 2.5 mm, 2.2 mm, 2 mm, 1.8 mm, 1.5 mm, 1.2 mm, 1 mm, 0.8 mm, and 0.5 mm.

[0086] In some embodiments of this application, the polishing cleanliness of both the inner wall of the freeze-drying container 1 and the outer wall of the stirring component is less than 4 μm. This polishing cleanliness of both the inner wall of the freeze-drying container 1 and the outer wall of the stirring component is less than 4 μm, which facilitates efficient stirring and freeze-drying of materials.

[0087] Furthermore, the polishing cleanliness of the inner wall of the freeze-drying container 1 and the outer wall of the stirring component is both 0.1 μm to 3.5 μm. As an example, the polishing cleanliness of the inner wall of the freeze-drying container 1 and the outer wall of the stirring component can be, but is not limited to, 3.5 μm, 3 μm, 2.5 μm, 2 μm, 1.5 μm, 1 μm, 0.5 μm, 0.3 μm, 0.2 μm, and 0.1 μm.

[0088] In some embodiments of this application, the freeze-drying container 1 is provided with a feed inlet 12 at the top and a discharge outlet 13 at the bottom. With the feed inlet 12 at the top and the discharge outlet 13 at the bottom, the liquid enters the freeze-drying container 1 through the feed inlet 12, and the freeze-dried product formed after freeze-drying is discharged directly from the discharge outlet 13, which facilitates the processing of materials.

[0089] As an example, the discharge port 13 is provided with a discharge valve. This allows the discharge valve to be opened after freeze-drying to discharge the freeze-dried product. The discharge port 13 can be directly connected to subsequent processing equipment so that the freeze-dried product can be directly transported to the subsequent processing equipment for processing, thereby reducing the loss and contamination of the freeze-dried product.

[0090] In some embodiments of this application, a vacuum pump 4 is connected to the freeze-drying container 1. The vacuum pump 4 is connected to the freeze-drying container 1 to facilitate vacuuming within the freeze-drying container 1 during the freeze-drying process, thereby efficiently pre-freezing and drying the material inside the freeze-drying container 1 through negative pressure evaporation and heat absorption. As an example, the vacuum pump 4 can be, but is not limited to, a Roots screw vacuum pump 4.

[0091] In some embodiments of this application, it includes a controller configured to perform the aforementioned freeze-drying method, specifically performing the following steps: (1) controlling the stirring device to continuously stir the liquid material in the freeze-drying container at a speed of not less than 60 r / min, and controlling the temperature control device to continuously introduce a heat exchange medium of -3℃ to -8℃ into the jacket to pre-cool the material to -3℃ to -5℃.

[0092] (2) Control the vacuum pump to continuously evacuate the freeze-drying container, and control the stirring device to continuously stir the material at a speed of not less than 60 r / min. Control the temperature control device to continuously introduce heat exchange medium of -15℃ to -50℃ into the jacket so that the material is cooled to -15℃ to -45℃.

[0093] (3) Control the temperature control device to continuously supply the heat exchange medium, control the stirring device to continuously stir, and control the vacuum pump to continuously evacuate until the vacuum degree in the freeze-drying container drops to a low vacuum state.

[0094] (4) Continue to control the stirring device to continuously stir and control the vacuum pump to continuously evacuate, and control the temperature control device to heat up and dry the material obtained above.

[0095] In some embodiments of this application, the controller is configured to reduce the stirring rate of the stirring device and / or the vacuum pumping rate based on the material temperature and vacuum level inside the freeze-drying container during step (3) until the vacuum level inside the freeze-drying container drops to a low vacuum state. Specifically, the controller detects that the material temperature has dropped to -15℃ to -45℃, determines that step (2) is complete, and then controls the stirring device to reduce the stirring rate and / or controls the vacuum pump to reduce the vacuum pumping rate until the vacuum level inside the freeze-drying container drops to a low vacuum state.

[0096] As an example, a second thermometer 42, a vacuum regulating valve 43, and a second pressure gauge 41 are sequentially installed on the connecting pipe between the freeze-drying container 1 and the vacuum pump 4. This allows the freeze-drying container 1 and the vacuum pump 4 to be connected or disconnected via the vacuum regulating valve 43, the second thermometer 42 to detect the temperature in real time, and the second pressure gauge 41 to detect the pressure in real time.

[0097] After vacuum pump 4 is turned on, if the pressure detected by the second pressure gauge 41 is below 2 Pa, the test indicates that vacuum pump 4 is operating well and can continue to work. Simultaneously, after turning on vacuum pump 4, open vacuum regulating valve 43. When the first pressure gauge 14 detects that the pressure inside freeze-drying container 1 reaches 0 Pa ± 0.02 Pa, the test indicates that the freeze-drying container 1 has good sealing properties, vacuum pump 4 is operating well, and the freeze-drying container 1 and vacuum pump 4 are working well together, allowing for continued operation.

[0098] In some embodiments of this application, the freeze-drying container 1 is connected to a nitrogen storage tank 5. The connection of the freeze-drying container 1 to the nitrogen storage tank 5 is to facilitate the verification of the airtightness of the freeze-drying container 1 and to ensure good operation during vacuuming; at the same time, if there is residual material in the freeze-drying container 1 after the material is discharged, the inside of the freeze-drying container 1 can be purged with nitrogen.

[0099] As an example, a nitrogen regulating valve 51 is installed on the connecting pipeline between the freeze-drying container 1 and the nitrogen storage tank 5 to control the supply and shut-off of nitrogen. When the nitrogen regulating valve 51 is opened, nitrogen is supplied into the freeze-drying container 1. When the first pressure gauge 14 detects that the pressure inside the freeze-drying container 1 reaches 0.08 MPa, the nitrogen regulating valve 51 is closed, and the container is left to stand for 15 minutes. If the pressure detected by the first pressure gauge 14 after 15 minutes does not fall below 0.078 MPa, the test indicates that the freeze-drying container 1 has good airtightness.

[0100] In some embodiments of this application, the first pressure gauge 14, the first thermometer 15, the heat exchange device 21, the first valve body 231, the second valve body 241, the pump body 25, the circulation valve body 261, the third thermometer 27, the drive unit 31, the vacuum pump 4, the second pressure gauge 41, the second thermometer 42, and the vacuum regulating valve 43 are electrically connected to the electrical control system. The electrical control system includes a host computer and a slave computer. As an example, the host computer is an industrial computer or an industrial human-machine interface; the slave computer is a PLC.

[0101] This application provides another freeze-drying system, as shown in Figure 2, which is also applicable to the freeze-drying method described above. This freeze-drying system is largely the same as the freeze-drying system shown in Figure 1, and will not be described in detail again. The heat exchange device 21 includes a plate heat exchanger 211, a refrigeration unit 212, a heating oil tank 213, and a replenishment oil tank 214. The plate heat exchanger 211 and the refrigeration unit 212 are circulated together. The plate heat exchanger 211 is connected to the jacket 11 through a second pipeline 24, and a replenishment oil tank 214 is provided on the second pipeline 24. The plate heat exchanger 211 is also connected to the heating oil tank 213, and the heating oil tank 213 is connected to the jacket 11 through a first pipeline 23.

[0102] When materials need to be heated or cooled, pump 25 starts, pumping the heat exchange medium from the first pipe 23 into the jacket 11 and out through the second pipe 24. The heat exchange medium then enters the plate heat exchanger 211 through the second pipe 24. After heat exchange in the plate heat exchanger 211, the heat exchange medium enters the heating oil tank 213, flows from the heating oil tank 213 into the housing 22, and then enters the inlet of pump 25, forming a cycle. When the heat exchange medium needs to be cooled, refrigeration unit 212 starts, and the refrigerant in refrigeration unit 212 enters the plate heat exchanger 211. The heat exchange medium exchanges heat with the refrigerant in refrigeration unit 212 through the plate heat exchanger 211, achieving cooling. When the heat exchange medium needs to be heated, the heater in heating oil tank 213 starts heating to thermally compensate for the heat exchange medium, achieving heating. The equipment controls the heating wire in heating oil tank 213 through a solid-state relay to control the temperature of the heat exchange medium.

[0103] This application provides a freeze-drying container, as shown in Figure 3. The freeze-drying container is a reaction vessel, including a vessel body and a top cover 2. The top cover 2 is provided with a vacuum hole 1. The vessel body has a reaction vessel jacket 3, which is provided with a jacket inlet 6 and a jacket outlet 10. A jacket discharge hemispherical valve 5 is provided at the bottom of the vessel body. The reaction vessel is provided with a stirrer 7, which is a vibrator in this embodiment. A spiral stirrer 11 is provided inside the reaction vessel. The reaction vessel is supported and installed by a support frame 4, and the reaction vessel is lifted and lowered by a matching sliding rod 8 and a sliding guide rail 9.

[0104] In this embodiment, the reactor is movably mounted on the support frame 4, and the reactor body can be disassembled downwards along the sliding guide rail 9 for easy maintenance and internal cleaning and inspection. During installation, the sliding rod 8 and the sliding guide rail 9 slide relative to each other, facilitating the assembly and disassembly of the reactor. During the stirring process, the spiral stirrer 11 has a certain spiral lifting effect, which can more evenly stir the mixture and improve the sublimation rate.

[0105] This application provides another freeze-drying container, as shown in Figure 4. The freeze-drying container is also a reaction vessel, and its structure is roughly the same as that in Figure 3. The difference is that the stirrer 7 in this embodiment is an anchor stirrer.

[0106] Similarly, the reactor is movable on the support frame 4, and the reactor body can be disassembled downwards along the sliding guide rail 9 for easy maintenance and internal cleaning and inspection. During installation, the sliding rod 8 and the sliding guide rail 9 slide relative to each other, which facilitates the assembly and disassembly of the reactor.

[0107] This application provides another type of freeze-drying container, as shown in Figure 5. The freeze-drying container is also a reaction vessel, and its structure is roughly the same as that in Figure 3. The difference is that the stirrer 7 in this embodiment is a segmented stirrer, and the vessel body is provided with vessel body flaps 12, which are used in conjunction with the spiral stirrer 11.

[0108] Similarly, the reactor is movable on the support frame 4, and the reactor body can be disassembled downwards along the sliding guide rail 9 for easy maintenance and internal cleaning and inspection. During installation, the sliding rod 8 and the sliding guide rail 9 slide relative to each other, facilitating the assembly and disassembly of the reactor. During the stirring process, the blades on the reactor body 12 and the spiral stirrer 11 interweave, allowing for better extension and separation of the material as it transforms from a liquid to a loose solid, thus increasing the sublimation area.

[0109] The features and performance of this application will be further described in detail below with reference to the embodiments.

[0110] Example 1

[0111] This embodiment provides a freeze-drying method. The freeze-drying system adopted is the freeze-drying system shown in Figure 1, including a freeze-drying container, a stirring device, and a temperature control device. The outer wall of the freeze-drying container is provided with a jacket, the stirring device is provided inside the freeze-drying container, and the temperature control device is located in the circulation loop of the heat exchange medium. The freeze-drying method includes:

[0112] (1) 5L of 10% raffinose aqueous solution was injected into the freeze-drying container through the feed inlet. The material was stirred at 60r / min using a stirring device. The heat exchange medium at -5℃ was continuously circulated into the jacket to pre-cool the material to about -3℃, which took 15min.

[0113] After the material is precooled to -3℃, a portion of the heat exchange medium at -3℃ is located in the jacket to precool the material. At this time, another portion of the heat exchange medium at -3℃ is continuously cooled to -20℃ under the control of the temperature control device.

[0114] (2) The freeze-drying container is continuously evacuated, and the material is continuously stirred at 60 r / min using a stirring device. The heat exchange medium at -20℃ is continuously circulated into the jacket using the above temperature control method to cool the material to about -15℃ in 5 minutes. At this time, the material is in the form of fine powder.

[0115] (3) Control the stirring rate to 20r / min and stir until the vacuum in the freeze-drying container drops to 10Pa; then raise the temperature to -10℃ and maintain it for 6h until the vacuum drops to 10Pa; then continue to raise the temperature in stages, raising the temperature by 10℃ in each stage and maintaining it for 6h, with the vacuum in the freeze-drying container dropping to 10Pa each time, until the temperature rises to 30℃ and is maintained for 6h, taking 32h.

[0116] The freeze-drying method in this embodiment takes approximately 34 hours to complete the entire freeze-drying process, with a final yield of approximately 80%.

[0117] Example 2

[0118] This embodiment provides a freeze-drying method. The freeze-drying system used is the freeze-drying system shown in Figure 1. The freeze-drying method includes:

[0119] (1) 10L of 20% raffinose aqueous solution was injected into the freeze-drying container through the inlet. The solution was stirred at 60r / min using a stirring device. A heat exchange medium at -5℃ was introduced into the jacket to pre-cool the solution to about -3℃ for 25 minutes.

[0120] After the liquid feed is precooled to -3°C, a portion of the heat exchange medium at -3°C is located in the jacket to precool the liquid feed. At this time, another portion of the heat exchange medium at -3°C is continuously cooled to -40°C under the control of the temperature control device.

[0121] (2) Vacuum the freeze-drying container and continuously stir the liquid at 60 r / min. Introduce a heat exchange medium at -40°C into the jacket to cool the liquid to about -25°C in 12 minutes. At this time, the material is a loose solid.

[0122] (3) Continue to maintain a stirring speed of 60 r / min, adjust the vacuum regulating valve to 10% of full opening, reduce the vacuuming rate, and continue stirring until the vacuum degree in the freeze-drying container drops to 10 Pa; then raise the temperature to -20℃ and maintain it for 1 h; then continue to raise the temperature in stages, raising the temperature by 10℃ in each stage and maintaining it for 1 h, each time the vacuum degree in the freeze-drying container drops to 10 Pa, until the temperature rises to 30℃ and is maintained for 6 h, taking 95 h.

[0123] The freeze-drying method in this embodiment takes approximately 96 hours to complete the entire freeze-drying process, with a final yield of approximately 96%.

[0124] Example 3

[0125] This embodiment provides a freeze-drying method. The freeze-drying system used is the freeze-drying system shown in Figure 1. The freeze-drying method includes:

[0126] (1) Inject 10L of ATP aqueous solution with a mass concentration of 20% into the freeze-drying container through the feed port, stir the liquid at 80r / min using a stirring device, and introduce a heat exchange medium at -8℃ into the jacket to pre-cool the liquid to about -3℃, which takes 15min.

[0127] After the liquid feed is precooled to -3°C, a portion of the heat exchange medium at -3°C is located in the jacket to precool the liquid feed. At this time, another portion of the heat exchange medium at -3°C is continuously cooled to -20°C under the control of the temperature control device.

[0128] (2) Vacuum the freeze-drying container and continuously stir the liquid at 80 r / min. Introduce a heat exchange medium at -20°C into the jacket to cool the liquid to about -15°C in 15 minutes. At this time, the material is a loose solid.

[0129] (3) Reduce and maintain the stirring speed at 20 r / min, and adjust the vacuum regulating valve to 10% of full opening to reduce the flow rate of sublimation gas in the freeze-drying container. Continue stirring until the vacuum in the freeze-drying container drops to 30 Pa. Then raise the temperature to -15℃ and maintain it for 1 h. Then continue to raise the temperature in stages, raising it by 10℃ in each stage and maintaining it for 1 h. Each time the vacuum in the freeze-drying container drops to 30 Pa, until the temperature rises to 30℃ and is maintained for 6 h. The total time is 40 h.

[0130] The freeze-drying method in this embodiment takes approximately 40 hours to complete the entire freeze-drying process, with a final yield of approximately 92%.

[0131] Example 4

[0132] This embodiment provides a freeze-drying method. The difference between the freeze-drying method and Embodiment 3 is that the liquid material is pre-cooled to about -5°C in step (1).

[0133] The freeze-drying method in this embodiment takes 40 hours to complete the entire freeze-drying process, with a final yield of approximately 92%.

[0134] Example 5

[0135] This embodiment provides a freeze-drying method, which differs from that of Embodiment 3 in that:

[0136] (2) Vacuum the freeze-drying container and continuously stir the liquid at 80 r / min. Introduce a heat exchange medium at -40°C into the jacket to cool the liquid to about -35°C. This process takes 10 hours.

[0137] (3) Reduce and maintain the stirring speed at 20 r / min, and adjust the vacuum regulating valve to 10% of full opening to reduce the flow rate of sublimation gas in the freeze-drying container. Continue stirring until the vacuum in the freeze-drying container drops to 4 Pa. Then raise the temperature by 5°C and maintain it for 10 h. Then continue to raise the temperature in stages, raising it by 5°C in each stage and maintaining it for 10 h. Each time the vacuum in the freeze-drying container drops to 7 Pa, until the temperature rises to 30°C and is maintained for 6 h.

[0138] The freeze-drying method in this embodiment takes 90 hours to complete the entire freeze-drying process, with a final yield of approximately 92%.

[0139] Example 6

[0140] This embodiment provides a freeze-drying method, which differs from that of Embodiment 3 in that:

[0141] (2) Vacuum the freeze-drying container and continuously stir the liquid at 80 r / min. Introduce a heat exchange medium at -50°C into the jacket to cool the liquid to about -45°C. This process takes 12 hours.

[0142] (3) Reduce and maintain the stirring speed at 20 r / min, and adjust the vacuum regulating valve to 10% of full opening to reduce the flow rate of sublimation gas in the freeze-drying container. Continue stirring until the vacuum in the freeze-drying container drops to 4 Pa. Then raise the temperature by 5°C and maintain it for 10 h. Then continue to raise the temperature in stages, raising it by 5°C in each stage and maintaining it for 10 h. Each time the vacuum in the freeze-drying container drops to 7 Pa, until the temperature rises to 30°C and is maintained for 6 h.

[0143] The freeze-drying method in this embodiment takes approximately 116 hours to complete the entire freeze-drying process, with a final yield of approximately 85%.

[0144] Example 7

[0145] This embodiment provides a freeze-drying method. The difference between the freeze-drying method and Embodiment 3 is that in step (4), the freeze-drying container is stirred until the vacuum level drops to 10 Pa each time.

[0146] The freeze-drying method in this embodiment takes approximately 20 hours to complete the entire freeze-drying process, with a final yield of approximately 70%.

[0147] Comparative Example 1

[0148] This comparative example provides a freeze-drying method. A 10% (w / w) raffinose aqueous solution is added to a disposable freeze-drying tray to a height of 10 mm. The tray is then placed in a tray freeze-drying device, and the freeze-drying program is started. The shelf temperature is first lowered to -36°C and maintained for 5 hours to pre-freeze the product. Simultaneously, the cold trap is pre-cooled to -70°C. Then, the vacuum pump is turned on. Once the vacuum level reaches below 15 Pa, the shelf temperature is restored to -25°C at a rate of 5°C / h. This state is maintained for 72 hours until the curves of the Pirani vacuum gauge and the capacitive thin-film silicon vacuum gauge in the freeze-drying cavity coincide. The shelf is then heated a second time to 30°C at a rate of 5°C / h and maintained for 72 hours. The device is then purged with nitrogen to restore atmospheric pressure to the cavity. The disposable freeze-drying tray is removed from the isolator, the film is peeled off, and lumpy products are removed with a spatula. The product is then placed in a mixer and crushed by shaking. Finally, it is removed and enters the packaging process.

[0149] The freeze-drying method in this comparative example took 144 hours to complete the entire freeze-drying process, with a yield of approximately 92%.

[0150] Comparative Example 2

[0151] This comparative example provides a freeze-drying method, which differs from Example 1 in that: in step (3), the drying process is directly heated.

[0152] The phenomenon observed in this comparative freeze-drying method is that the material liquefies and collapses, indicating that the freeze-drying process has failed.

[0153] The embodiments described above are some, but not all, of the embodiments of this application. The detailed description of the embodiments of this application is not intended to limit the scope of the claimed application, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application. Industrial applicability

[0154] This application provides a freeze-drying method and system that can directly freeze-dry products with small particle sizes by step-by-step cooling and freezing. The process involves fewer steps, has higher freeze-drying efficiency, less product loss and contamination, and lower cost, making it industrially applicable.

Claims

1. A freeze-drying method, characterized in that, The freeze-drying system used includes a freeze-drying container and a stirring device. The outer wall of the freeze-drying container is provided with a jacket, and the stirring device is provided inside the freeze-drying container. The freeze-drying method includes the following steps: (1) Inject the liquid material into the freeze-drying container, use the stirring device to continuously stir the material at a speed of not less than 60 r / min, and continuously introduce the heat exchange medium of -3℃ to -8℃ into the jacket to pre-cool the material to -3℃ to -5℃. (2) Continuously evacuate the freeze-drying container and continuously stir the material at a speed of not less than 60 r / min, and continuously introduce a heat exchange medium of -15℃ to -50℃ into the jacket to cool the material to -15℃ to -45℃. (3) Continuously introduce heat exchange medium, stir and evacuate until the vacuum degree in the freeze-drying container drops to a low vacuum state; (4) Continue stirring and vacuuming to heat and dry the material obtained in step (3).

2. The freeze-drying method according to claim 1, characterized in that, In step (3), the stirring rate is reduced, and / or the vacuuming rate is reduced, until the vacuum level inside the freeze-drying container drops to the low vacuum state.

3. The freeze-drying method according to claim 2, characterized in that, The method to reduce the stirring rate is as follows: the original stirring rate is not less than 60 r / min, and the reduced stirring rate is 10 r / min to 20 r / min.

4. The freeze-drying method according to claim 2 or 3, characterized in that, The method to reduce the vacuum rate is to reduce the opening of the vacuum regulating valve.

5. The freeze-drying method according to any one of claims 1 to 4, characterized in that, In step (3), a heat exchange medium at -15℃ to -50℃ is continuously introduced.

6. The freeze-drying method according to any one of claims 1 to 5, characterized in that, The low vacuum state refers to a vacuum level of 8 Pa to 300 Pa.

7. The freeze-drying method according to claim 1, 3, 4 or 6, characterized in that, The heating and drying method involves heating in stages until the temperature reaches 25℃~35℃.

8. The freeze-drying method according to claim 7, characterized in that, The method for each stage of heating includes: increasing the temperature by 5°C to 12°C each time, and maintaining it for 1 hour to 8 hours until the vacuum level inside the freeze-drying container drops to the low vacuum state.

9. The freeze-drying method according to any one of claims 1 to 8, characterized in that, The freeze-drying system further includes a temperature control device located in the circulation loop of the heat exchange medium. The heat exchange medium flowing out of the jacket is conditioned by the temperature control device before being introduced into the jacket. The freeze-drying method further includes: After the material is precooled to -3℃ to -5℃, a portion of the heat exchange medium at -3℃ to -8℃ is located in the jacket to precool the material. At this time, another portion of the heat exchange medium at -3℃ to -8℃ is continuously cooled to -15℃ to -50℃ under the control of the temperature control device. Heat exchange medium that has been cooled to -15℃ to -50℃ by the temperature control device is introduced into the jacket.

10. A freeze-drying system, characterized in that, The freeze-drying method applicable to any one of claims 1 to 9 includes: A freeze-drying container, wherein a jacket is provided on the outer wall of the freeze-drying container, and a heat exchange medium is injected into the jacket; A temperature control device includes a heat exchanger and a housing. One end of the heat exchanger is connected to the inlet of the jacket via a first pipe, and the other end of the heat exchanger is connected to the outlet of the jacket via a second pipe. A pump is installed on the first pipe. The housing is located on the first pipe and is connected to the inlet of the jacket and the heat exchanger. A third pipe is connected to the first pipe between the second pipe and the housing and the inlet of the jacket. A first valve is installed on the first pipe and is located between the connection point of the third pipe and the first pipe and the inlet of the jacket. A second valve is installed on the second pipe and is located between the connection point of the third pipe and the second pipe and the outlet of the jacket. A circulation valve is installed on the third pipe. A stirring device is provided inside the freeze-drying container and is used to stir the material injected into the freeze-drying container.

11. The freeze-drying system according to claim 10, characterized in that, The stirring device includes a driving component and a stirring component. The driving component is used to drive the stirring component to rotate. The stirring component extends into the freeze-drying container from the top and extends towards the bottom of the freeze-drying container. The stirring component includes a stirring shaft and a plurality of stirring blades, which are distributed at intervals along the axial and circumferential directions of the stirring shaft.

12. The freeze-drying system according to claim 11, characterized in that, The stirring blade is located near the edge of the inner wall of the freeze-drying container and the distance between the stirring blade and the inner wall of the freeze-drying container is less than 3 mm.

13. The freeze-drying system according to claim 11 or 12, characterized in that, The polishing cleanliness of the inner wall of the freeze-drying container and the outer wall of the stirring element is less than 4 μm.

14. The freeze-drying system according to any one of claims 10 to 13, characterized in that, The freeze-drying container is connected to a vacuum pump.

15. The freeze-drying system according to claim 14, characterized in that, It includes a controller configured to perform the following steps: (1) controlling the stirring device to continuously stir the liquid material in the freeze-drying container at a speed of not less than 60 r / min, and controlling the temperature control device to continuously introduce a heat exchange medium of -3℃ to -8℃ into the jacket, so that the material is pre-cooled to -3℃ to -5℃; (2) Control the vacuum pump to continuously evacuate the freeze-drying container, and control the stirring device to continuously stir the material at a speed of not less than 60 r / min, and control the temperature control device to continuously introduce a heat exchange medium of -15℃ to -50℃ into the jacket, so that the material is cooled to -15℃ to -45℃. (3) Control the temperature control device to continuously supply heat exchange medium, control the stirring device to continuously stir, and control the vacuum pump to continuously evacuate until the vacuum degree in the freeze-drying container drops to a low vacuum state. (4) Continue to control the stirring device to continuously stir and control the vacuum pump to continuously evacuate, and control the temperature control device to heat up and dry the material obtained above.

16. The freeze-drying system according to claim 15, characterized in that, The controller is configured to reduce the stirring rate of the stirring device and / or the vacuum pumping rate of the vacuum pump according to the material temperature in the freeze-drying container and the vacuum degree in the freeze-drying container when performing step (3), until the vacuum degree in the freeze-drying container drops to the low vacuum state.

17. The freeze-drying system according to any one of claims 10 to 16, characterized in that, The freeze-drying container is connected to a nitrogen storage tank.

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