Freeze-drying is a technology that uses the principle of sublimation to dry, which is a process in which the dried substance is quickly frozen at a low temperature, and then the frozen water molecules are sublimed directly into water vapor escape under the appropriate vacuum environment. The product of freeze-drying is called a lyophilizer, and the process is called lyophilization.

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, avoiding the side effects such as foam and oxidation caused by water vapor. The dry material is a dry sponge porous, the volume is basically unchanged, and it is easily dissolved in water and restored to its original state. To a large extent, the physical and biological denaturation of dry substances is prevented.

The freeze dryer is composed of refrigeration system, vacuum system, heating system and electrical instrument control system. The main components are drying boxes, condensers, refrigerating units, vacuum pumps, heating/cooling devices, etc. Its working principle is to freeze the dried item below the triple point temperature, and then sublimate the solid water (ice) in the item directly into water vapor under vacuum conditions, which is excluded from the item and makes the item dry. After pre-treatment, the material is sent to the quick-freezing bin for freezing, then sent to the drying bin for sublimation and dehydration, and then packaged in the post-treatment workshop. The vacuum system establishes low pressure conditions for the sublimation drying chamber, the heating system provides latent sublimation heat to the material, and the refrigeration system provides the required cooling capacity to the cold trap and drying chamber. The equipment uses radiation heating, the material is heated evenly; The use of water trap, and can achieve rapid frost; Using vacuum unit, and can realize oil and water separation; Parallel centralized refrigeration system, multi-channel on-demand cooling, stable working conditions, beneficial to energy saving; Artificial intelligence control, high control precision, easy to operate.

The quality requirements of freeze-dried products are: unchanged biological activity, uniform appearance, full shape, solid structure, fast dissolution rate, low residual moisture. In order to obtain high quality products, there should be a comprehensive understanding of the theory and process of lyophilization. The freeze-drying process includes three stages: pre-freezing, sublimation and refreeze-drying. Reasonably and effectively shortening the cycle of freeze-drying has obvious economic value in industrial production.

First, the freezing of products

When the solution is quick-frozen (cooling 10~50℃ per minute), the grain size is kept in the microscope. On the contrary, when it is slowly frozen (1℃/ min), the crystals formed are visible to the naked eye. The coarse crystal leaves a large gap in the sublimation, which can improve the efficiency of lyophilization, and the fine crystal leaves a small gap after sublimation, so that the lower layer of sublimation is blocked, and the finished particles of quick freezing are fine, uniform appearance, large specific surface area, good porous structure, fast dissolution rate, and the humidity of the finished product is relatively stronger.

Drugs are pre-frozen in the freeze-drying machine in two ways: one is to cool the product and the drying box at the same time; The other is to wait for the drying oven shelf to cool to about -40 ° C, and then put the products into, the former is equivalent to slow freezing, the latter is between quick freezing and slow freezing, so it is often used to take into account the freeze-drying efficiency and product quality. The disadvantage of this method is that when the product is in 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 will be possible to exceed the normal load of the condenser due to the large area of sublimation. This is especially true in summer.

The product is frozen at rest. Experience has proved that the phenomenon of supercooling is easy to occur until the temperature of the product has reached the eutectic point. However, the solute is still not crystallized, and 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 maintained for a period of time until the product is completely frozen.

Second, sublimation conditions and speed

At a certain temperature, when the saturated vapor pressure of ice is greater than the partial pressure of water vapor in the environment, it can begin to sublimate. The suction and capture of water vapor by the condenser, which is lower than the product temperature, is a necessary condition for the maintenance of liters.

The distance a gas molecule travels between two successive collisions is called the mean free path, which is inversely proportional to the pressure. At atmospheric pressure, the value is very small, and the sublimed water molecules are easy to collide with the gas and return to the surface of the steam source, so the sublimation rate is very high. As the pressure decreases below 13.3Pa, the mean free path increases by 105 times, which significantly accelerates the sublimation rate, and the water molecules flying out rarely change their aspects, thus forming a directional vapor stream.

The vacuum pump plays a role in the freeze-drying machine to remove the primary gas in order to maintain the low pressure necessary for sublimation. 1g water vapor is 1.25L at normal pressure and expands to 10,000 liters at 13.3Pa, and it is impossible for ordinary vacuum pumps to remove such a large volume per unit time. The condenser actually forms a vacuum pump specially designed to trap water vapor.

The temperature of products and condensation is usually -25℃ and -50℃. The saturated steam pressure of ice at this temperature is 63.3Pa and 1.1Pa respectively, so there is a considerable pressure difference between the sublimation surface and the condensing surface, if the partial pressure of non-condensing gas in the system can be ignored at this time, it will promote the water vapor sublimed out of the product to reach the surface of the condenser with a certain flow rate to form frost.

The heating heat of ice is about 2822J/ g, if the sublimation process does not supply heat, then the final product only reduces the internal energy to compensate for the heating heat, until its temperature and the condenser temperature balance, sublimation will stop. In order to maintain the temperature difference between sublimation and condensation, sufficient heat must be provided to the product.

Three, sublimation process

In the first stage of heating (a large number of sublimation stages), the product temperature is lower than its eutectic point within a range. Therefore, the shelf temperature should be controlled, if the product has been partially dry, but the temperature has exceeded its eutectic point, the product melting phenomenon will occur at this time, and the melting liquid is saturated with ice, and the solute is not saturated, so the dry solute will be quickly dissolved in, concentrated into a thin stiff block, the appearance is very bad, the dissolution rate is very poor, if the product melting occurs in a large number of sublimation later, Because the amount of melted liquid is small, it is absorbed by the dry porous solid, resulting in the defects of the block after lyophilization, and the dissolution rate can still be found to be slow when water is added to dissolve.

In a large number of sublimation processes, although the shelf and product temperatures are very different, but because the plate temperature, condenser temperature and vacuum temperature are basically unchanged, sublimation heat absorption is relatively stable, and the product temperature is relatively constant. As the product dries from top to bottom, the resistance to sublimation increases. The product temperature will also rise slightly. Until the ice crystals are no longer visible to the naked eye. At this time more than 90% of the water has been removed. The process of a large number of sublimation has basically ended, in order to ensure the completion of a large number of sublimation of the whole box products, the plate temperature still needs to maintain a stage and then carry out two stages of heating. The remaining few percent of the water is called residual water, which is different from the free state of water in physical and chemical properties, residual water includes chemically combined water and physically combined water, such as the crystallization of the combined crystal water, the water of the protein through hydrogen bonding and the adsorption of water on the solid surface or in the capillary. Because the residual water is bound by some gravity, its saturated vapor pressure is reduced to different degrees, so the drying speed is significantly reduced. Although the increase of product temperature promotes the gasification of residual water, the biological activity may also decline sharply if the limit temperature is exceeded. The higher drying temperature to ensure the safety of the product should be determined by the experiment. Usually, we set the plate temperature at +30℃ or so in the second stage and keep it constant. At the beginning of this stage, because the plate temperature rises high, the residual water is less and not easy to vaporize, so the product temperature rises faster. However, with the product temperature and plate temperature gradually closer, the heat conduction becomes more slow, the need to wait patiently for a considerable period of time, practical experience shows that the residual moisture drying time and a large number of sublimation time is almost equal and sometimes even more.

Fourth, freeze-freeze-drying curve

The freeze-drying curve can be obtained by recording the changes of shelf temperature and product temperature over time. The more typical freeze-drying curve system divides the shelf temperature into two stages, and the shelf temperature is kept low when a lot of sublimation is performed, which can generally be controlled between -10 and +10 according to the actual situation. The second stage according to the nature of the product will properly adjust the shelf temperature, this method is suitable for its low melting point of the product. If the performance of the product is not clear, the machine performance is poor or its work is not stable enough, it is more secure to use this method.

If the eutectic point of the product is high, the vacuum degree of the system can be maintained well, and the refrigeration capacity of the condenser is sufficient, a certain heating rate can also be used to increase the shelf temperature to the higher temperature allowed until the end of the freeze drying, but it is also necessary to ensure that the temperature of the product in a large number of sublimation shall not exceed the eutectic point.

If the product is unstable to heat, the two-stage plate temperature should not be too high. In order to improve the sublimation rate of the first stage, the shelf temperature can be raised to the higher temperature allowed by the product; When a large number of sublimation stage is basically over, then the plate temperature is reduced to the higher temperature allowed, although the latter two ways make a large number of sublimation speed has some improvement, but its anti-interference ability is reduced accordingly, the sudden reduction of vacuum degree and refrigeration capacity or power failure may make the product melt. Reasonable and flexible grasp of the * way, is still the most commonly used way.