Brief introduction of medical vacuum freeze drying technology principle
1. Definition and advantages of vacuum freeze-drying:
The product is completely frozen, and the ice crystals are sublimated under certain vacuum conditions, so as to achieve the purpose of low temperature dehydration. This process is called freeze drying (Freeze-drying), or freeze drying for short.
The lyophilized solid material exhibits a porous structure due to the sublimation of tiny ice crystals, and maintains the original volume when frozen. It is easily dissolved and restored after adding water. The temperature of the product is kept at a lower temperature during the sublimation process (generally lower than -250C), so it is especially suitable for the drying of heat-resistant substances such as enzymes, hormones, nucleic acids, blood and immune products. As a result of drying, more than 95 ~ 99% of water can be discharged, which is conducive to long-term storage of products. The product drying process is carried out under vacuum conditions, so it is not easy to oxidize. In view of the chemical, physical and biological instability of some biochemical drugs, freeze-drying has been proved to be a very effective method in practice. With the rapid development of biochemical drugs and biological agents, freeze-drying technology will increasingly show its importance and superiority.
2. Introduction to the structure and function of medical freeze dryer:
The medical freeze dryer is composed of refrigeration system, vacuum system, heating system, electrical instrument control system. The main components are drying oven, condenser, freezing unit, vacuum pump, heating / cooling device, etc.
The freeze-drying of the products is carried out in a drying oven. The shelves in the drying oven are made of stainless steel plates, and there are media ducts distributed in them, which can cool or heat the products. A vacuum sensor is installed at the back of the drying oven, which will vacuum It turns into an electric signal, and a sealing rubber ring is inlaid around the door of the box. Before use, it can be coated with vacuum silicone grease to ensure the sealing of the box.
The condenser is best to be wound cylindrical type. There are multiple sets of air-cooled coils wrapped around the stainless steel cylinder. Its working temperature is lower than the temperature of the product in the drying oven, and the lowest temperature can reach -550C. The water vapor sublimated from the product can be fully It is condensed on the inner surface of the stainless steel cylinder in contact with the cold coil to ensure the smooth progress of the freeze-drying process. The biggest advantage of the smooth cylinder structure is that it is easy to clean. After the freeze-drying is completed, the frost can be removed by electric heating. Layer removed.
The rotary vane vacuum pump is used to vacuum the system. An electromagnetic vacuum valve with automatic deflation is installed at the air inlet of the mechanical pump. It is controlled by the same power source as the rotary vane pump. When the pump is stopped, the electromagnetic valve is automatically closed. At the same time, deflation into the vacuum pump not only protects the vacuum system, but also prevents the vacuum pump from returning oil to the system.
In the refrigeration system, two 2.2Kw semi-closed refrigerators are used in parallel. The high-pressure refrigerant liquid (fluorine-free refrigerant V55C) from the wind condenser passes through the drying filter and the solenoid valve to reach the capillary and enters after throttling In the evaporator, due to the suction effect of the refrigerator, the pressure in the evaporator drops, and the liquid refrigerant absorbs the heat of the environment and rapidly boils and evaporates. The low-pressure refrigerant gas is frozen and pumped back, and then compressed into a high-pressure gas to complete a refrigeration cycle. The cold exhaust pipe in the heating / cooling device, the cold exhaust pipe in the condenser, and the cold air coil in the condenser are compliant with the refrigeration system Medium evaporation, they are supplied with refrigerant through two different solenoid valves.
The heating system consists of an electric heating tube, media (silicone oil), media pump, media box, etc., forming a circulation pipeline. After the silicone oil is heated by the electric heating tube, it is transported by the media pump to the media conduit in the shelf of the dry box to heat the product. Provides sublimation heat. When frozen, the silicone oil is cooled by the cooling pipe, which is transported by the media pump to the media duct in the center of the shelf of the drying oven to cool and freeze the product.
The electrical instrument control system is a mechanical and electrical integration design, controlled by a dedicated industrial computer. All shelf temperatures, media temperatures, and product temperatures can be displayed on a centralized display. For specific adjustment control, please refer to the system manual.
3. Basic principles and practice of freeze-drying
The quality requirements for freeze-dried products are: unchanged biological activity, uniform appearance and color, full shape, firm structure, fast dissolution rate, and low residual moisture. To obtain high-quality products, you should have a relatively comprehensive understanding of the theory and process of freeze-drying. The freeze-drying process includes three stages: pre-freeze, sublimation and re-freeze. Reasonably shortening the freeze-drying cycle has obvious economic value in industrial production.
(1) Freezing of products
When the solution is frozen quickly (10-50 ° C per minute), the grains remain the size visible under the microscope; on the contrary, when the solution is frozen slowly (1 ° C / min), the crystals formed are visible to the naked eye. Coarse crystals leave a larger gap in sublimation, which can improve the efficiency of freeze-drying. Fine crystals leave a smaller gap after sublimation, which hinders the sublimation of the lower layer, and the finished frozen particles are delicate, uniform in appearance, large in specific surface area, and porous The structure is good, the dissolution speed is fast, and the moisture absorption of the finished product is relatively stronger.
The drugs are pre-frozen in the freeze dryer in two ways: one is to cool the product and the drying box at the same time; the other is to wait for the shelf of the drying box to cool to about -40 ℃, and then put the product in, the former is equivalent to slow Freezing, the latter is between freezing and slow freezing, so it is often used to balance the efficiency of freeze-drying and product quality. The disadvantage of this method is that when the product enters the box, the water vapor in the air will quickly condense on the shelf, and in the early stage of sublimation, if the plate heats up faster, it may exceed the normal load of the condenser due to the large area of ​​sublimation. This phenomenon is particularly significant in summer.
The freezing of the product is at rest. Experience has shown that the phenomenon of supercooling easily occurs until the temperature of the product has reached the eutectic point. However, the solute still does not crystallize. In order to overcome the phenomenon of supercooling, the freezing temperature of the product should be lower than a range below the eutectic point, and it needs to be kept for a period of time until the product is completely frozen.
(2) Conditions and speed of sublimation
When the saturated vapor pressure of ice at a certain temperature is greater than the partial pressure of water vapor in the environment, it can begin to sublime; the suction and capture of water vapor by a condenser with a temperature lower than that of the product is a necessary condition for maintaining the rise.
The distance a gas molecule travels between two consecutive collisions is called the mean free path, which is inversely proportional to the pressure. Under normal pressure, its value is very small, the sublimated water molecules easily collide with the gas and return to the surface of the steam source, so the sublimation speed is very diffuse. As the pressure decreases below 13.3Pa, the average free path increases by a factor of 105, which significantly accelerates the sublimation speed. The water molecules that fly out rarely change their own aspects, thus forming a directional steam flow.
The vacuum pump plays the role of removing permanent gas in the freeze dryer to maintain the low pressure necessary for sublimation. 1g of water vapor is 1.25L at normal pressure and expands to 10,000 liters at 13.3Pa. It is impossible for ordinary vacuum pumps to remove such a large volume per unit time. The condenser actually forms a vacuum pump that specifically captures water vapor.
The temperature of the product and coagulation is usually -25 ℃ and -50 ℃. The saturated vapor pressure of ice at this temperature is 63.3Pa and 1.1Pa respectively, so a considerable pressure difference is generated between the sublimation surface and the condensation surface, if the partial pressure of the non-condensable gas in the system can be ignored at this time Regardless, it will promote the sublimation of the water vapor from the product to reach the surface of the condenser at a certain flow rate to form frost.
The sublimation heat of ice is about 2822J / g. If no heat is supplied during the sublimation process, then the product can only reduce the internal energy to compensate for the sublimation heat until the temperature is equal to the temperature of the condenser, and the sublimation stops. In order to maintain the temperature difference between sublimation and condensation, sufficient heat must be provided to the product.
(2) Sublimation process
In the first stage of temperature increase (sublimation stage), the temperature of the product is a range lower than its eutectic point. Therefore, the shelf temperature should be controlled. If the product has been partially dried, but the temperature exceeds its eutectic point, the product will melt at this time, and the melted liquid is saturated with ice and not saturated with solute, so The dried solute will quickly dissolve into it, and finally condensed into a thin stiff block. The appearance is extremely poor and the dissolution rate is very poor. If the melting of the product occurs in the late stage of a large number of sublimation, the amount of melted liquid is small, so the porous solid is dried. Absorbed, resulting in defects after freeze-drying, the dissolution rate can still be found to be slow when dissolved with water.
In a large number of sublimation processes, although the shelf and the product temperature are very different, but because the plate temperature, the condenser temperature and the vacuum temperature are basically unchanged, the sublimation heat absorption is relatively stable, and the product temperature is relatively constant. As the product dries from top to bottom, the resistance to ice sublimation gradually increases. The product temperature will also increase slightly. Until the naked eye is no longer the existence of ice crystals. At this time, more than 90% of the water has been removed. The process of mass sublimation has basically ended. In order to ensure the complete sublimation of the whole box of products, the plate temperature still needs to be maintained for one stage before the second stage of temperature increase.
The remaining percentage of water is called residual water, which is different from the free state water in physical and chemical properties. The residual water includes chemically combined water and physically combined water, such as combined crystal water crystals, protein through hydrogen Bonded water and adsorbed water on solid surfaces or capillaries. Because the residual moisture is bound by gravity, its saturated vapor pressure is reduced to varying degrees, so the drying speed is significantly reduced. Although raising the temperature of the product promotes the vaporization of residual moisture, if it exceeds a certain limit temperature, the biological activity may also drop sharply. The maximum drying temperature to ensure the safety of products should be determined by experiment. Normally, in the second stage, we keep the plate temperature around + 30 ℃ and keep it constant. At the beginning of this stage, due to the increase in plate temperature, the residual moisture is low and it is not easy to vaporize, so the product temperature rises faster. However, as the product temperature and the plate temperature gradually get closer, the heat conduction becomes slower, and you need to wait patiently for a long period of time. Practical experience shows that the time for residual moisture drying is almost equal to the time for a large amount of sublimation, and sometimes even exceeds.
(4) Freeze-drying curve: record the changes of shelf temperature and product temperature with time to obtain the freeze-drying curve.
The typical freeze-drying curve divides the shelf heating into two stages. The shelf temperature is kept low during a large amount of sublimation. According to the actual situation, it can be generally controlled between -10 and +10. In the second stage, the shelf temperature is adjusted appropriately according to the nature of the product. This method is suitable for products with a lower melting point. If the performance of the product is unclear, the machine performance is poor or the work is not stable enough, this method is also more secure.
If the eutectic point of the product is high, the vacuum degree of the system can be maintained well, and the cooling capacity of the condenser is sufficient, you can also use a certain heating rate to increase the shelf temperature to the maximum allowable temperature until the end of freeze-drying. However, it is also necessary to ensure that the temperature of the product during mass sublimation must not exceed the eutectic point.
If the product is unstable to heat, the plate temperature in the second stage should not be too high. In order to increase the sublimation speed of the first stage, the shelf temperature can be raised to above the maximum allowable temperature of the product at one time; after the substantial sublimation stage is basically over, the plate temperature can be reduced to the maximum allowable temperature again. A large number of sublimation speeds have been improved, but its anti-interference ability has been reduced accordingly. Sudden reduction in vacuum and cooling capacity or power failure may cause the product to melt. Reasonably and flexibly mastering the first method is still the more commonly used method at present.
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