Freeze-drying machine knowledge analysis of pre-freezing stage of freeze-drying technology

　　Freeze-drying machine knowledge analysis of pre-freezing stage of freeze-drying technology

　　The pre-freezing process of the lyophilizer is to solidify the free water in the solution, giving the dry product the same form as before drying, preventing irreversible changes such as foaming, concentration and solute movement during evacuation and drying, and minimizing the substance caused by temperature. Reduced solubility and changes in life characteristics.

　　There are two pre-freezing methods for the solution: pre-freezing in the freeze-drying tank and pre-freezing in the tank.

　　The pre-freezing method in the box is to directly place the product on the multi-layer shelf in the lyophilizer, and freeze it by the freezer of the lyophilizer. When a large number of vials and ampoules are lyophilized, it is convenient for entering and unpacking. Generally, the vials or ampoules are placed in several metal trays and then placed in the box to improve heat transfer. Some metal discs can be made into a movable bottom type. When entering the box, the bottom is pumped away, so that the vial is directly in contact with the metal plate of the freeze-drying box; for the non-priming plate, the bottom of the plate is required to be flat to obtain uniformity of the product. The large plasma bottle using the spin-drying method should be frozen beforehand and then added to the metal frame for heat conduction before being frozen into the box.

　　There are two methods for pre-freezing outside the box. Some small freeze dryers do not have a pre-frozen product and can only be pre-frozen using a low temperature refrigerator or alcohol plus dry ice. The other is a dedicated chiller that freezes the product of the large bottle into a shell-like structure and then into the lyophilization box.

　　Freeze dryer pre-freezing process:

　　When the temperature of the aqueous solution drops to a certain level, according to the eutectic concentration of the solution, the concentration begins to freeze in the light solution, and this temperature is called the freezing point. Generally, the freezing point is controlled by the concentration and decreases with the concentration. When the temperature of the solution is lower than the freezing point, a part of the solution will crystallize out, and the concentration of the remaining solution will rise, so that the freezing point will fall, and then continue to cool, and the ice crystal will increase with cooling, and the remaining solution concentration It increases with it. However, when the temperature drops to a certain point, the remaining solution is completely frozen. At this time, the frozen matter is mixed with ice crystals, and the temperature at this time is the eutectic point.

　　After the solution needs to be cooled to the freezing point, after the nucleus is generated, the free water will begin to crystallize in the form of ice, and the heat of crystallization will be released to raise the temperature to the freezing point. As the crystal grows, the concentration of the solution increases. When the eutectic concentration is reached and the temperature drops below the eutectic point, the solution will all freeze.

　　The number and size of crystal grains crystallized by the solution are related to the nucleation rate and crystal growth rate in addition to the nature of the solution itself. The two factors, nucleation rate and crystal growth rate, change with temperature and pressure. Therefore, we can control the temperature and pressure of the solution to control the number and size of crystal grains in the solution. In general, the faster the cooling rate, the lower the subcooling temperature, the more the number of crystal nuclei formed, the more the crystals are frozen before they grow, and the more crystal grains are formed, the finer the crystal grains; The smaller the number, the larger the grain size.

　　The shape of the crystal is also related to the freezing temperature. When freezing starts around 0 °C, the ice crystals are hexagonal symmetrical and grow forward in the direction of the six major axes. At the same time, several secondary axes appear, and all the ice crystals are connected to form a network structure in the solution. As the degree of subcooling increases, the ice crystals will gradually lose the hexagonal symmetry form of capacity recognition. In addition, the number of nucleation is large and the freezing speed is fast. It may form an irregular dendron with any number of axial cylinders. Not as many as six hexagonal crystals.

　　Crystallized units formed by freezing of biological fluids (such as blood plasma, muscle serum, vitreous humor, etc.) tend to be similar to the type of ice crystal formed by a single component aqueous solution. The type of crystallization mainly depends on the cooling rate and the concentration of body fluid. For example, plasma, muscle slurry, etc., when frozen at normal concentration, form hexagonal crystal units at higher subzero temperatures and slow cooling rates, and form irregular dendrites when rapidly cooled to low temperatures. Crystal.

　　Cell suspensions (such as red blood cells, white blood cells, sperm, bacteria, etc. suspended in distilled water, plasma or other suspension medium), when the temperature is slowly frozen at high temperatures, a large amount of ice grows in the suspension, and the cells are squeezed into two icicles. In the narrow pipeline, the suspended medium in the pipeline is concentrated by the precipitation of water and the solute is concentrated, and the water in the cell permeates out of the cell through the cell membrane, which causes concentration of the intracellular solute. At the same time, the growth of extracellular ice will also force the volume of the cell to shrink and deform. But at this time, there is no ice in the cells. When it freezes rapidly at low temperatures, intracellular ice will form inside the cells. The size, shape and distribution of ice are related to the cooling rate, the presence or absence of a protective agent, the nature of the protective agent, and the amount of water in the cells. Generally speaking, the faster the cooling rate and the lower the temperature, the more ice is formed in the cells. . The addition of a non-permeable protective agent to the suspension reduces the amount of ice formed in the cells during rapid freezing.

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