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In the freeze-drying process, the eutectic point and eutectic point of the material are the two most important parameters in the freeze-drying process. The pre-freezing temperature of the material should be 5-10°C lower than the eutectic point of the material. Ensure that the material is completely frozen. If the pre-freezing temperature is too low, it will prolong the freezing time, increase production costs, and waste time and energy; if the pre-freezing temperature is higher than the eutectic point, the moisture in the material cannot be completely frozen, so that the moisture cannot be completely Sublimation in the form of ice, prone to partial boiling and foaming during drying. Lead to quality problems such as shrinkage and loss of shape of the material. In addition, the dissolved solute contained in the unfrozen water cannot be resolved in situ during the drying process, but migrates to the surface of the material with the internal water, resulting in surface hardening of the freeze-dried product.
The eutectic point of a material refers to the temperature at which the completely frozen material gradually heats up and the ice crystals inside the material begin to melt. During sublimation drying, the temperature of the material should not be higher than its eutectic point, otherwise the material will melt, causing the material to boil, causing bubbles, inflation or shrinkage inside the material, which will affect the quality of the freeze-dried product. Therefore, it is of great significance to accurately determine the eutectic point and eutectic point of the material for the formulation of the freeze-drying process plan and the optimization control of the freeze-drying process.
When the product is freeze-dried, it needs to be packed into a suitable container and then pre-frozen before it can be sublimated and dried. The pre-freezing process is not only to protect the main properties of the material; but also to obtain a reasonable structure of the frozen product to facilitate the sublimation of water; and to have an appropriate filling capacity for future applications.
There are usually two ways of packaging products: bulk and bottled. Bulk can be used in metal trays, lunch boxes or glass containers; bottles can be used in glass bottles and ampoules. There are glass bottles and plasma bottles. Vaccine bottles, penicillin vials, etc. Ampoules also include flat-bottomed ampoules, long ampoules, and round ampoules; these need to be determined according to the future use of the product, and the bottle needs to be equipped with a suitable rubber stopper.
Products that need to be freeze-dried need to be formulated into a liquid with a certain concentration. In order to ensure a certain shape after drying, the best material content is between 10% and 15%.
The product is dispensed into containers with a certain ratio of surface area to thickness. The surface area is larger and the thickness is smaller. A large surface area is conducive to sublimation, and a large product thickness is not conducive to sublimation. Generally, the packaging thickness is not more than 10mm. Some products require large bottles. And when freeze-drying a large amount of products, the method of spin freezing can be used to freeze into a shell shape, or the tilting container can be frozen into an inclined plane to increase the surface area and reduce the thickness.
The pre-freezing method in the box is to directly place the product on the multi-layer shelf in the freeze-drying box of the freeze-drying machine, and freeze it by the freezer of the freeze-drying machine. When a large number of vials and ampoules are freeze-dried, for the convenience of entering and exiting the case, the vials or ampoules are generally divided into several metal trays, and then packed into the case. In order to improve heat transfer, some metal plates are made detachable, and the bottom is drawn away when entering the box, so that the vials are directly in contact with the metal plate of the freeze-drying box; for the plates that cannot be drawn down, the bottom of the plate is required to be flat to obtain uniformity of the product sex. The large plasma vials that adopt the spin freezing method should be frozen in advance and then be frozen with a metal frame or block for heat conduction.
There are two ways to prefreeze outside the box. Some small freeze dryers do not have a device for pre-freezing products. Prefreezing can only be done in a cryogenic freezer or alcohol plus dry ice. The other is a special rotary freezer, which can freeze the large bottle of product into a shell-like structure while rotating. Then enter the freeze-drying box.
There is also a special centrifugal pre-freezing method, which is used in centrifugal freeze dryers. Using the rapid evaporation of liquid under vacuum, it absorbs its own heat and freezes. The centrifugal force of the rotation prevents the gas in the product from escaping, allowing the product to freeze “peacefully” into a certain shape. The speed is generally around 800 rpm.
Freezing can have certain destructive effects on cells and living organisms, and its mechanism is very complicated. There is no unified theory, but it is generally believed that it is mainly caused by mechanical effects and solute effects.
The freezing process of biomass begins with the freezing of pure water, and the growth of ice crystals gradually causes the concentration of electrolytes. This is followed by solidification of the eutectic mixture. Eventually all became solid.
Mechanical effects are caused by the mechanical forces generated by the growth of ice crystals inside and outside the cell. Especially for the living body with cell membrane, the image is larger. Generally, the larger the ice crystal, the easier the cell membrane is to rupture, resulting in cell death; the smaller the ice crystal, the less mechanical damage to the cell membrane.
Slow freezing produces larger ice crystals, quick freezing produces smaller ice crystals; for that matter. Rapid freezing has less effect on the cells. Slow freezing can easily cause cell death.
The solute effect is that the interstitial liquid is gradually concentrated due to the freezing of water, thereby increasing the concentration of electrolytes, and proteins are more sensitive to electrolytes. The increase of electrolyte concentration causes the denaturation of protein and causes cell death; in addition, the increase of electrolyte concentration causes cell dehydration and death. The higher the interstitial liquid concentration. The damage caused by the above reasons is also more severe. The solute effect is most pronounced in a certain temperature range. This temperature range is between the freezing point of water and the full solidification temperature of the liquid. If this temperature range can be crossed at a higher speed, the effect produced by the solute effect can be greatly weakened.
In addition, the crystal size formed during freezing also affects the drying rate and the dissolution rate of the dried product to a large extent. Large ice crystals are easy to sublimate, but small ice crystals are not conducive to sublimation; but large ice crystals dissolve slowly, while small ice crystals dissolve quickly. The smaller the ice crystals, the more they can reflect the original structure of the product after drying.
To sum up, there needs to be an optimal cooling rate. In order to get the highest cell survival rate, the best product physical properties and dissolution speed. Of course, improving the survival rate has a lot to do with adding an anti-low temperature agent (one of the protective agents) to the product. For example, glycerin, dimethyl sulfoxide, sugars, etc. These anti-low temperature substances can help products expand the range of optimal cooling rates so that more cells can survive.
In order to obtain different cooling rates. It is necessary to adopt different pre-freezing methods; for example, sometimes it is necessary to start the cooling of the freeze-drying box after packing, and sometimes it is necessary to let the machine drop to a low temperature in advance, and then put the product into the freeze-drying box.
Therefore, three data should be determined before prefreezing. One is the rate of pre-freezing, and an optimal freezing rate should be tested according to different products. The second is the minimum temperature of pre-freezing, which should be determined according to the eutectic point of the modified product, and the minimum temperature of pre-freezing should be lower than the temperature of the eutectic point. The third is the pre-freezing time, which is determined according to the situation of the machine to ensure that all products are frozen before vacuuming. It will not come out of the bottle due to vacuuming. The smaller the temperature difference between each layer of the freeze-drying box and the parts of each layer, the shorter the pre-freezing time. The temperature of the general product reaches the pre-freezing temperature. Vacuum sublimation can start 1-2 hours after the lowest temperature.