Freeze-drying is a sublimation drying technology, which is a process of quickly freezing the dried substance at low temperature, and then directly subliming the frozen water molecules into steam, and escaping in a proper vacuum environment. The product obtained by freeze drying is called freeze dryer, and this process is called freeze drying. The substance is always in a low temperature (frozen state) before drying, and the ice crystals are evenly distributed in the substance, and the sublimation process will not be concentrated due to dehydration, thus avoiding the side effects such as foam and oxidation caused by water vapor. Dry matter is as porous as dry sponge, and its volume is basically unchanged, and it is easily soluble in water and restores its original state. Prevent physical, chemical and biological denaturation of dry matter to the greatest extent. Freeze-drying machine consists of refrigeration system, vacuum system, heating system and electrical instrument control system. The main components are drying box, condenser, refrigeration unit, vacuum pump, heating/cooling device, etc. Its working principle is to freeze the dried goods below the triple point temperature, and then directly sublimate the solid water (ice) in the goods into water vapor under vacuum conditions, and take it out from the goods to dry the goods. The pretreated materials are sent to the quick-freezing warehouse for freezing, then to the drying warehouse for sublimation and dehydration, and then packaged in the post-processing workshop. The vacuum system establishes low-pressure conditions for the sublimation drying chamber, the heating system provides latent heat of sublimation for the material, and the refrigeration system provides the required cooling capacity for the cold trap and the drying chamber. The equipment adopts efficient radiation heating, and the materials are heated evenly; Using efficient water catching cold trap can realize rapid defrosting; Adopt high-efficiency vacuum device to realize oil-water separation; Adopt parallel centralized refrigeration system, multi-channel on-demand refrigeration, stable working condition, which is conducive to energy saving; Adopt artificial intelligence control, with high control precision and convenient operation. The quality requirements of Xinyu Instrument Network for freeze-dried products are: unchanged biological activity, uniform appearance, full shape, firm structure, fast dissolution and low residual moisture. In order to obtain high-quality products, we should have a comprehensive understanding of the theory and technology of freeze drying. The freeze-drying process includes three stages: pre-freezing, sublimation and re-freeze-drying. Shortening the freeze-drying cycle reasonably and effectively has obvious economic value in industrial production.
Freezing of products
When the solution is rapidly frozen (the temperature drops per minute 10~50℃), the crystal grains keep the size visible under the microscope; On the contrary, under slow freezing (65438 0℃/min), the crystals formed were visible to the naked eye. After sublimation, the coarse crystal leaves a large gap, which can improve the freeze-drying efficiency, while the fine crystal leaves a small gap after sublimation, which hinders the sublimation of the lower layer. The quick-frozen finished product has fine particles, uniform appearance, large specific surface area, good porous structure and fast dissolution speed, so the finished product has strong hygroscopicity. There are two ways to pre-freeze drugs in freeze dryer: one is that the product and drying box are cooled at the same time; The other is to cool the shelf of the drying oven to about -40℃, and then put the product in. The former is equivalent to slow freezing, and the latter is between quick freezing and slow freezing, so it is often used to give consideration to freeze-drying efficiency and product quality. The disadvantage of this method is that the water vapor in the air will quickly condense on the shelf when the product enters the box, and in the early stage of sublimation, if the temperature of the plate rises rapidly, it is likely to exceed the normal load of the condenser due to sublimation in a large area. This phenomenon is especially obvious in summer. The freezing of products is static. Experience has proved that supercooling is easy to occur before the product temperature reaches * * * crystallizing point. However, the solute is still not crystallized. In order to overcome the supercooling phenomenon, the freezing temperature of the product should be below a range of * * * crystallizing point, and it should be kept for a period of time until the product is completely frozen.
Second, the 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 sublimate; The absorption and capture of water vapor by the condenser whose temperature is lower than the product temperature is a necessary condition to maintain the temperature. The distance traveled by gas molecules between two consecutive collisions is called the average free path, which is inversely proportional to the pressure. Under normal pressure, its value is very small, and the sublimated water molecules easily collide with the gas and return to the surface of the steam source, so the sublimation speed is very dispersed. With the pressure reduced below 13.3Pa, the average free path increased by 105 times, which significantly accelerated the sublimation speed, and the scattered water molecules rarely changed their appearance, thus forming a directional steam flow. The function of vacuum pump is to remove the permanent gas in the freeze-dryer to maintain the low pressure required for sublimation. The steam of 1g is 1.25L at atmospheric pressure, but it expands to 10000 liters at 13.3Pa, so it is impossible for a common vacuum pump to pump out such a large volume in a unit time. The condenser actually forms a vacuum pump for collecting water vapor. The temperature of product and condensation is usually -25℃ and -50℃. The saturated vapor pressure of ice at this temperature is 63.3Pa and 1. 1Pa, respectively, so there is a considerable pressure difference between sublimation surface and condensation surface. If the partial pressure of non-condensable gas in the system can be ignored at this time, it will promote the water vapor sublimated from the product to reach the condenser surface at a certain flow rate and form frost. The sublimation heat of ice is about 2822 J/g. If there is no heat supply during sublimation, the sublimation heat of the product can only be compensated by reducing the internal energy, and the sublimation will stop until its temperature and condenser temperature reach equilibrium. In order to maintain the temperature difference between sublimation and condensation, it is necessary to provide enough heat for the product.
Tertiary sublimation process
In the first stage of heating (a large number of sublimation stages), the product temperature should be a range lower than its * * * crystallizing point. Therefore, the shelf temperature should be controlled. If the product is partially dry, but the temperature exceeds its crystallizing point, the product will melt at this time. At this time, the molten liquid is saturated with ice, not with solute, so the dry solute will dissolve quickly, and finally it will be concentrated into a thin hard block, which is extremely bad in appearance and poor in dissolution speed. If the product melts in the later stage of a large amount of sublimation, it will dry due to a small amount of molten liquid. In the process of a large number of sublimation, although the temperature difference between the shelf and the product is great, the plate temperature, condenser temperature and vacuum are basically unchanged, so the sublimation heat absorption is relatively stable and the product temperature is relatively constant. As the product is dried layer by layer from top to bottom, the resistance of ice sublimation increases gradually. The product temperature will also rise slightly accordingly. Until the naked eye can no longer see 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 sublimation of the whole box of products, the plate temperature needs to be maintained for another stage before the second stage of heating. The remaining percentage of water is called residual water, which is different from free water in physical and chemical properties. Residual water includes chemically bound water and physically bound water, such as bound water crystallization, hydrogen bonded protein water, and water adsorbed on solid surface or capillary. Because the residual moisture is partially bound by gravity, its saturated vapor pressure is reduced to some extent, so the drying speed is obviously reduced. Although increasing the product temperature promotes the gasification of residual water, if it exceeds a certain limit temperature, the biological activity may also drop sharply. The highest drying temperature to ensure the safety of products should be determined by experiments. Usually in the second stage, we will raise the plate temperature to about +30℃ and keep it constant. At the beginning of this stage, due to the increase of plate temperature, there is less residual water, which is not easy to gasify, and the product temperature rises rapidly. However, as the product temperature gradually approaches the plate temperature, the heat conduction becomes slower, and it needs to wait patiently for a long time. Practical experience shows that the drying time of residual moisture is almost equal to the drying time of a large number of sublimation, and sometimes even exceeds it. Xinyu instrument network
Four freeze-drying curves
The freeze-drying curve can be obtained by recording the changes of shelf temperature and product temperature with time. The typical freeze-drying curve divides the shelf temperature into two stages. In the process of sublimation, the shelf temperature is kept low, which can generally be controlled between-10 and+10 according to the actual situation. In the second stage, according to the nature of the product, the shelf temperature is appropriately increased. This method is suitable for low melting point products. This method is also safer if the product performance is unclear, the machine performance is poor or the work is not stable enough. If the * * * crystallizing point of the product is high, the vacuum degree of the system can also be maintained well, and the refrigeration capacity of the condenser is sufficient, you can also use a certain heating speed to raise the shelf temperature to the highest allowable temperature until the freeze-drying is over, but it is also necessary to ensure that the temperature of the product does not exceed * * * crystallizing point during a large number of sublimation. If the product is unstable to heat, the second stage plate temperature should not be too high. In order to improve the sublimation speed in the first stage, the shelf temperature can be raised above the maximum allowable temperature of the product at one time; When a large number of sublimation stages are basically over, the plate temperature will drop to the highest allowable temperature. Although the latter two methods improve the sublimation speed, the anti-interference ability will be reduced accordingly, and the sudden reduction of vacuum and refrigeration capacity or power failure may melt the product. Mastering the first method reasonably and flexibly is still a common way at present.
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