Rotary freeze-drying apparatus for unit dose filling of pharmaceuticals

Abstract

This invention relates to a rotary freeze-drying apparatus for unit-dose pharmaceutical filling, comprising a filling mechanism, a stopper mechanism, a rotary freezing module, and a freeze-drying chamber. The freeze-drying chamber is subsequently equipped with a combined induction heating system, which includes an induction heating coil and an induction heating inner component. The induction heating coil is spirally wound and installed on the outer wall of the induction heating inner component. A vial conveyor belt is installed inside the cavity of the induction heating inner component. The induction heating coil is fixed to an AC power supply of an induction heating control system. The AC power supply of the induction heating control system provides alternating current to the induction heating coil. The alternating current flowing through the induction heating coil generates an alternating magnetic field passing through the induction heating inner component, inducing eddy currents in the induction heating inner component, thereby achieving heating. This invention achieves the formation and heating of a uniformly dispersed layer while maintaining continuous operation of the freeze-drying process.

Description

Technical Field

[0001] This invention belongs to the field of freeze-drying, and in particular, it is a rotary freeze-drying apparatus for filling pharmaceutical compositions, biological compositions or medical nutrition products with a unit dose. Background Technology

[0002] Freeze-drying is a technique that dehydrates and dries ice particles under low pressure. It overcomes some of the shortcomings of traditional drying methods. Compared to traditional drying methods, freeze-drying offers advantages such as preserving the activity of biopharmaceutical components and producing finer particles.

[0003] The freeze-drying process typically involves placing a batch of material to be dried in a hollow, sealed chamber connected to a temperature-controlled base plate. During the first stage of drying, a sublimation interface forms on the surface of the frozen material during sublimation. As sublimation progresses, this interface moves downwards and inwards, removing most of the free water. Because the material remains frozen, it retains its porous structure. A second drying stage completes the freeze-drying process. In this second stage, the temperature is increased to remove any remaining bound water from the pores, thus eliminating residual moisture.

[0004] WO 2013036107 discloses a method for rotary freeze-drying of a unit-filled pharmaceutical product, comprising: A) storing a certain amount of the pharmaceutical product in an aqueous dispersion medium in at least one vial using a filling mechanism; B) rotating the vial using a rotator to form a dispersion layer adhering to the inner circumferential wall of the vial over a period of time; C) cooling and solidifying the vial according to step B) during the rotation of the vial, particularly forming ice crystals on the inner surface of the circumferential wall of the vial; D) drying the cooled composition by freeze-drying, wherein, during drying, a portion of the ice crystals formed in the dispersion or solution is sublimated by substantially uniformly heating the circumferential wall of the vial. Cooling and freezing of the product in the vial is achieved by applying a cold gas jet to the rotating vial, during which the cooling temperature of the product can be set between 0.5 and 100°C per minute. Non-contact temperature measurement is used to control the cooling stages of the liquid and ice, controlling the temperature of the cooling gas and the time for a set value. This operation method controls the temperature changes of the liquid phase and the water of crystallization, but further improvement is still needed. Goethals, W. et al. described the structure of frozen materials processed by rotary freeze-drying. The resulting product structure was visualized using micro-CT scanning technology.

[0005] However, the development of equipment capable of continuous freeze-drying remains a key challenge. Most current freeze-drying equipment can only perform the freeze-drying function and cannot alter the process parameters, representing a semi-automated state that significantly limits the development of freeze-drying technology. After years of development, no mature continuous freeze-drying equipment has yet been commercially available in China, hindering large-scale production.

[0006] Problems remain in developing an apparatus capable of providing a continuous freeze-drying process with high throughput, producing products that meet, for example, the requirements of the pharmaceutical industry. In particular, the formation and heating of a uniformly dispersed layer remain problematic while maintaining continuous freeze-drying operation. Furthermore, issues persist regarding particle formation, which can contaminate the product and lead to a decline in the quality of the final product.

[0007] Therefore, the object of the present invention is to solve one or more of the problems mentioned above related to freeze-drying liquid-containing compositions in a continuous process, and to further improve the methods of freezing, freeze-drying, and secondary drying. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the processing efficiency of the prior art and to provide a rotary freeze-drying device for filling pharmaceuticals in unit doses, which achieves the formation and heating of a uniformly dispersed layer while maintaining continuous operation of the freeze-drying process.

[0009] The technical problem solved by this invention is achieved through the following technical solution:

[0010] A rotary freeze-drying apparatus for unit-dose drug filling includes a filling mechanism, a stopper mechanism, a rotary freezing module, and a freeze-drying chamber. The filling mechanism fills vials, and the stopper mechanism then presses the vials into place. After freezing in the rotary freezing module, the vials are freeze-dried in the freeze-drying chamber. The freeze-drying chamber is characterized by a combined induction heating system, which includes an induction heating coil and an induction heating inner component. The induction heating coil is spirally wound and installed on the outer wall of the induction heating inner component. A vial conveyor belt is installed inside the cavity of the induction heating inner component. The induction heating coil is fixed to an AC power supply of an induction heating control system. The AC power supply of the induction heating control system provides alternating current to the induction heating coil. The alternating current flowing through the induction heating coil generates an alternating magnetic field that passes through the induction heating inner component, causing eddy currents in the induction heating inner component and achieving heating.

[0011] Furthermore, the induction heating inner component is fixedly connected to trays at both ends, and the connecting trays at both ends are fixedly installed by connecting rods. An insulation layer is set outside the induction heating inner component. The insulation layer is made of non-magnetic induction and non-metallic materials such as quartz, polytetrafluoroethylene or polypropylene. The connecting trays and connecting rods are also made of non-metallic materials.

[0012] Furthermore, a magnetic yoke is provided around the induction heating coil to suppress the diffusion of magnetic field lines.

[0013] Furthermore, there are at least two combined induction heating systems, and the conveyor belt can circulate between the combined induction heating systems. A pressure sensor and a pusher system are installed on the conveyor belt at the outlet end of one combined induction heating system. When the bottle passes the pressure sensor, if the weight of a single vial does not reach the preset mass, it will be pushed into the conveyor belt of another combined induction heating system by the pusher system to continue heating. When the preset mass is reached, it will be conveyed out from the conveyor belt.

[0014] Furthermore, a first thermal imager and a second thermal imager are respectively installed at the inlet and outlet of the combined induction heating system.

[0015] A drying method for a unit-dose pharmaceutical rotary freeze-drying apparatus includes the following steps:

[0016] 1) Filling: The filling mechanism fills vials containing a unit dose of medicine. The vials enter the workstation via a conveyor belt, and the liquid begins to flow in. The filling mechanism then fills the vials, and the material to be filled enters the vials to be filled.

[0017] 2) Stopper: The stopper is positioned by the stopper mechanism and pushed downward into the bottle mouth, slightly deforming the stopper and pressing it into the vial. When it is pressed into the vial, the vial can be removed from below the stopper mechanism.

[0018] 3) Rotary freezing: The vial is positioned on the support and brought into the support platform from the side. A rotator is set in the rotary freezing module. The rotator rotates around the rotation axis, and at the same time, the rotary freezing module is isolated from the external environment to form a vacuum low-pressure environment.

[0019] 4) Freeze-drying: The vial enters the freeze-drying chamber and is freeze-dried in a vacuum and low-pressure environment until the freeze-drying is completed. Then, it is sent out of the freeze-drying chamber by a conveyor belt and enters the combined induction heating system for the second stage of induction heating drying.

[0020] 5) Activate the cooling function of the induction heating control system: Turn on the transmission belt and set the induction heating control system to the cooling function, that is, slowly increase the power to avoid the internal components of the induction heating heating from heating too quickly and causing damage to the material composition;

[0021] 6) Turn on the heating function of the induction heating control system: Turn on the induction heating function of the induction heating control system: Current flows into the induction coil through the induction heating control system, and the internal components of the induction heating system heat up under the action of the alternating electric field;

[0022] 7) Heat treatment: Cyclic heating treatment is carried out in the continuous transmission mode of the conveyor belt;

[0023] 8) End: Finally, the vial is discharged from the combined induction heating system.

[0024] The advantages and beneficial effects of this invention are as follows:

[0025] 1. The unit dose liquid high-speed filling device and rotary freeze-drying device of the present invention have a combined induction heating system after the freeze-drying chamber to improve heating efficiency, achieve rapid increase in the temperature of the flowing liquid, and at the same time improve the uniformity of temperature distribution inside the vial.

[0026] 2. The unit dose liquid high-speed filling device of the present invention is a rotary freeze-drying device for freeze-drying liquids containing a composition in a continuous process, which can process at least about 4,000 30R vials per day.

[0027] 3. The unit-dose liquid high-speed filling device of the present invention is a rotary freeze-drying device for freeze-drying liquids containing a composition in a continuous process, and provides a control mechanism in the freezing or drying step to allow adjustment of the freezing or sublimation rate, and both freezing and drying are controlled. Attached Figure Description

[0028] Figure 1 This is a schematic diagram of the high-speed liquid filling rotary freeze-drying apparatus for unit dose of the present invention;

[0029] Figure 2 This is a schematic diagram of the combined induction heating system of the unit dose liquid high-speed filling rotary freeze-drying device of the present invention;

[0030] Figure 3 for Figure 2 A side view diagram;

[0031] Figure 4 A schematic diagram of the structure of the induction heating sensor of the present invention.

[0032] Figure 5 This is a temperature map of the outer surface of the container wall measured by the first thermal imager of the present invention.

[0033] Explanation of reference numerals in the attached figures

[0034] 1-Vessel; 2-Induction heating control system; 3-First thermal imager; 4-Connecting rod; 5-Combined induction heating system; 6-Induction heating coil; 7-Insulation layer; 8-Conveyor belt; 9-Booster; 10-Push rod system; 11-Pressure sensor; 12-Connecting tray; 13-Connecting column; 14-Rotator; 15-Support platform; 16-Filling mechanism; 17-Bottling stopper mechanism; 18-Rotating freezing module; 19-Freeze-drying chamber; 20-Induction heating drying chamber; 21-Induction heating internal components; 22-Second thermal imager. Detailed Implementation

[0035] The present invention will be further described in detail below through specific embodiments. The following embodiments are merely descriptive and not limiting, and should not be used to limit the scope of protection of the present invention.

[0036] A rotary freeze-drying apparatus for unit-dose drug filling includes a filling mechanism 16, a stopper mechanism 17, a rotary freezing module 18, and a freeze-drying chamber 19. The filling mechanism 16 fills vials 1, and the stopper mechanism 17 then presses the stopper into the vials 1. After freezing in the rotary freezing module 18, the vials 1 are freeze-dried in the freeze-drying chamber 19. A combined induction heating system 5 is subsequently installed in the freeze-drying chamber 19. This combined induction heating system 55 includes an induction heating drying chamber 20, an induction heating coil 6, and an induction heating inner component 21. The induction heating coil 6 is spirally wound and installed on the outer wall of the induction heating inner component 21. A conveyor belt 8 for the vials 1 is installed inside the cavity of the induction heating inner component 21. The induction heating coil 6 is fixed to an AC power supply of an induction heating control system 2. The AC power supply of the induction heating control system 2 provides alternating current to the induction heating coil 6. The induction heating coil 6 is connected to the AC power supply of the induction heating control system via a wire, which can be supported by a connecting rod 4. The alternating current flowing through the induction heating coil 6 generates an alternating magnetic field that passes through the induction heating inner component 21, causing eddy currents to be generated in the induction heating inner component 21, thereby achieving heating.

[0037] The induction heating inner component 21 is fixedly connected to trays 12 at both ends, and the trays 12 at both ends are fixedly installed through connecting posts 13. An insulation layer 7 is provided on the outside of the induction heating inner component 21. The insulation layer 7 is made of non-magnetic field induction and non-metallic materials such as quartz, polytetrafluoroethylene, or polypropylene. The connecting trays 12 and connecting posts 13 are also made of non-metallic materials. A magnetic yoke is provided around the induction heating coil 6 to suppress the diffusion of magnetic lines of force.

[0038] In this embodiment, there are at least two combined induction heating systems, and the conveyor belts are arranged in a loop. The conveyor belt 8 can run in a loop between the combined induction heating systems 5. A pressure sensor 11 and a pusher system 10 are set at the outlet end of the conveyor belt 8 of one combined induction heating system 5. When the bottle 1 passes the pressure sensor 11, if the weight of a single bottle does not reach the preset mass, it will be pushed into the conveyor belt 8 of another combined induction heating system 5 by the pusher 9 of the pusher system 10 to continue heating. When the preset mass is reached, it will be conveyed out from the conveyor belt 8.

[0039] A first thermal imager 3 and a second thermal imager 22 are respectively installed at the inlet and outlet of the combined induction heating system 5 to measure the temperature of the vials at the outlet and inlet in real time, thereby adjusting and controlling the temperature of the combined induction heating system.

[0040] A drying method for a unit-dose pharmaceutical rotary freeze-drying apparatus includes the following steps:

[0041] 1) Filling: The filling mechanism 16 fills the vials 1 containing a unit dose of medicine. The vials 1 enter the work station via the conveyor belt 8 and begin to be filled. The filling mechanism 16 then fills the vials. The material to be filled enters the vials to be filled.

[0042] 2) Stoppering: The stopper is positioned by the stopper mechanism 17 and pushed downward into the bottle mouth, and the stopper is slightly deformed and pressed into the vial 1. When it is pressed into the vial, the vial can be taken out from below the stopper mechanism 17.

[0043] 3) Rotary freezing: The vial is positioned on the support and brought into the support platform 15 from the side. A rotator 14 is set in the rotary freezing module 18. The rotator 14 rotates around the rotation axis, while the rotary freezing module 18 is isolated from the external environment to form a vacuum low-pressure environment.

[0044] 4) Freeze-drying: The vial 1 enters the freeze-drying chamber 19 and is freeze-dried in a vacuum low-pressure environment until the freeze-drying is completed. It is then sent out of the freeze-drying chamber 19 by the conveyor belt 8 and enters the combined induction heating system 5 for the second stage of induction heating drying.

[0045] 5) Activate the cooling function of the induction heating control system 2: Turn on the transmission belt and set the induction heating control system 2 to the cooling function, that is, slowly increase the power to avoid the induction heating internal component 21 heating up too quickly and causing damage to the material composition.

[0046] 6) The induction heating control system 2 turns on the heating function: The induction heating function of the induction heating control system 2 is turned on: Current flows into the induction coil through the induction heating control system 2, and the induction heating internal component 21 heats up under the action of the alternating electric field;

[0047] 7) Heat treatment: Cyclic heating treatment is carried out in the continuous transmission mode of conveyor belt 8;

[0048] 8) End: Finally, the vial 1 is sent out from the combined induction heating system 5.

[0049] In continuous conveying mode, the first thermal imager 3, located at the inlet of the induction heating coil 6, determines the temperature and initiates heating. During the conveying process, a second thermocouple measures the temperature to determine if the liquid temperature has reached the set value. Once the set value is reached, the induction heating control system 2 reduces the power to maintain the temperature while the liquid is being conveyed forward on the conveyor belt 8. The processed material is obtained after exiting the induction heating coil 6.

[0050] In continuous operation mode, when vial 1 enters the induction heating range, the parameters of pusher system 10 are set. When it passes pressure sensor 1, if the weight of a single vial does not reach the preset mass, it will be pushed by booster 9 into another induction heating conveyor belt 8 for continued heating. Once the preset mass is reached, it will be conveyed out from conveyor belt 8.

[0051] Upon freezing, the liquid-containing composition undergoes at least partial sublimation. To uniformly heat the vials, heat should be supplied to the entire circumference of the vial. Placing the vials in a heating jacket or a chamber with a surrounding infrared radiator severely hinders continuous movement of the vials during the continuous freeze-drying process. This causes the vials to remain in the heating jacket or infrared heating chamber until the sublimation or desorption process is complete, and the vials in the jacket are typically unevaluable by optical measurement systems, thus hindering feedback-controlled heating of the vials. Therefore, the induction heating device of the rotary freeze-drying apparatus for unit-dose pharmaceuticals, through the design of a novel induction heating internal component 21, achieves a more uniform temperature distribution and improves heating efficiency during the heating process.

[0052] Although the embodiments and drawings of the present invention have been disclosed for illustrative purposes, those skilled in the art will understand that various substitutions, variations and modifications are possible without departing from the spirit and scope of the invention and the appended claims. Therefore, the scope of the invention is not limited to the contents disclosed in the embodiments and drawings.

Claims

1. A rotary freeze-drying apparatus for unit-dose pharmaceutical filling, comprising a filling mechanism (16), a stopper mechanism (17), a rotary freezing module (18), and a freeze-drying chamber (19), wherein the filling mechanism (16) fills vials (1), and the stopper mechanism (17) presses the stopper into the vials (1), and the vials (1) are frozen in the rotary freezing module (18) and then freeze-dried in the freeze-drying chamber (19), characterized in that: The freeze-drying chamber (19) is subsequently equipped with a combined induction heating system (5), which includes an induction heating coil (6) and an induction heating inner component (21). The induction heating coil (6) is spirally wound and installed on the outer wall of the induction heating inner component (21). The cavity inside the induction heating inner component (21) is equipped with a conveyor belt (8) for a vial (1). The induction heating coil (6) is fixed to the AC power supply of the induction heating control system (2). The AC power supply of the induction heating control system (2) provides alternating current to the induction heating coil (6). The alternating current flowing through the induction heating coil (6) generates an alternating magnetic field through the induction heating inner component (21), causing eddy currents to be generated in the induction heating inner component (21) to achieve heating. The combined induction heating system (5) consists of at least two components. The conveyor belt (8) circulates between the combined induction heating systems (5). A pressure sensor (11) and a pusher system (10) are installed on the conveyor belt (8) at the outlet end of one combined induction heating system (5). When the bottle (1) passes the pressure sensor (11), if the weight of a single vial (1) does not reach the preset mass, it will be pushed into the conveyor belt (8) of another combined induction heating system (5) by the booster (9) of the pusher system (10) to continue heating. When the preset mass is reached, it will be conveyed out from the conveyor belt (8).

2. The rotary freeze-drying apparatus for unit dose filling of pharmaceuticals according to claim 1, characterized in that: The induction heating internal component (21) is fixedly connected to the two ends of the tray (12), and the two ends of the tray (12) are fixedly installed by the connecting column (13). An insulation layer (7) is set outside the induction heating internal component (21). The insulation layer (7) is made of quartz, polytetrafluoroethylene or polypropylene, which are non-magnetic field induction and non-metallic materials. The connecting tray (12) and the connecting column (13) are also made of non-metallic materials.

3. The rotary freeze-drying apparatus for unit-dose filling of pharmaceuticals according to claim 1, characterized in that: A magnetic yoke is provided around the induction heating coil (6) to suppress the diffusion of magnetic lines of force.

4. The rotary freeze-drying apparatus for unit dose filling of pharmaceuticals according to claim 1, characterized in that: A first thermal imager (3) and a second thermal imager (22) are respectively installed at the inlet and outlet of the combined induction heating system (5).

5. A drying method using a rotary freeze-drying apparatus for unit dose filling according to any one of claims 1-4, characterized in that: It includes the following steps: 1) Filling: The filling mechanism (16) fills the vials (1) containing a unit dose of medicine. The vials (1) enter the work station via the conveyor belt (8) and begin to be filled. The filling mechanism (16) then fills the vials, and the material to be filled enters the vials to be filled. 2) Stopper: The stopper is positioned by the stopper mechanism (17) and pushed down into the bottle mouth. The stopper is slightly deformed and pressed into the vial (1). When it is pressed into the vial, the vial can be taken out from below the stopper mechanism (17). 3) Rotary freezing: The vial is positioned on the support and brought into the support platform (15) from the side. A rotator (14) is set in the rotary freezing module (18). The rotator (14) rotates around the rotation axis, while isolating the rotary freezing module (18) from the external environment to form a vacuum low-pressure environment. 4) Freeze-drying: The vial (1) enters the freeze-drying chamber (19) and is freeze-dried in a vacuum low-pressure environment until the freeze-drying is completed. It is then sent out of the freeze-drying chamber (19) by the conveyor belt (8) and enters the combined induction heating system (5) for the second stage of induction heating drying. 5) Turn on the cooling function of the induction heating control system (2): Turn on the transmission belt and set the induction heating control system (2) to the cooling function, that is, slowly increase the power to avoid the induction heating internal components (21) heating up too fast and causing damage to the material composition; 6) Induction heating control system (2) turns on the heating function: turn on the induction heating function of the induction heating control system (2): the current flows into the induction coil through the induction heating control system (2), and the internal component (21) of the induction heating is heated under the action of the alternating electric field; 7) Heat treatment: Cyclic heating treatment is carried out in the continuous transmission mode of the conveyor belt (8); 8) End: Finally, the vial (1) is sent out from the combined induction heating system (5).

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