The amount of water vapor in compressed air is determined by the temperature of the compressed air: while keeping the pressure of the compressed air basically constant, reducing the temperature of the compressed air can reduce the water vapor content in the compressed air, and excess water vapor will condense into liquid. A freeze dryer uses refrigeration technology to dry compressed air based on this principle. Therefore, the refrigerated dryer has a refrigeration system. The refrigeration system of Gree freeze dryer belongs to compression refrigeration, consisting of four basic components: refrigeration compressor, condenser, evaporator, expansion valve, etc. They are connected by pipelines to form a closed system, where the refrigerant continuously circulates and flows in the system, undergoes state changes, and exchanges heat with compressed air and cooling medium. The refrigeration compressor draws low-pressure (low-temperature) refrigerant from the evaporator into the compressor cylinder, compressing the refrigerant vapor and increasing both pressure and temperature; The high-pressure and high-temperature refrigerant vapor is compressed to the condenser, where the high-temperature refrigerant vapor exchanges heat with the cooler water or air. The heat of the refrigerant is carried away by the water or air and condensed, and the refrigerant vapor becomes liquid. This part of the liquid is then transported to the expansion valve, where it is throttled into a low-temperature and low-pressure liquid and enters the evaporator; The low-temperature and low-pressure refrigerant liquid in the evaporator absorbs the heat of compressed air and vaporizes (commonly known as "evaporation"), while the compressed air condenses a large amount of liquid water after being cooled; The refrigerant vapor in the evaporator is then sucked away by the compressor, and the refrigerant undergoes four processes in the system: compression, condensation, throttling, and evaporation, thus completing a cycle. In the refrigeration system of a freeze dryer, the evaporator is a device that delivers cold, and the refrigerant absorbs the heat of compressed air to achieve the purpose of dehydration and drying. The compressor is the heart, which plays a role in inhaling, compressing, and transporting refrigerant vapor. The condenser is a device that releases heat, transferring the heat absorbed in the evaporator along with the heat converted from the input power of the compressor to the cooling medium (such as water or air) for removal. The expansion valve/throttle valve has a throttling and pressure reducing effect on the refrigerant, while controlling and regulating the amount of refrigerant liquid flowing into the evaporator, and dividing the system into two parts: the high-pressure side and the low-pressure side.

Freezing of a product

When the solution is rapidly frozen (cooling by 10-50 ℃ per minute), the grain size remains visible under the microscope; On the contrary, the crystals formed during slow freezing (1 ℃/min) are visible to the naked eye. Coarse crystals leave large gaps during sublimation, which can improve the efficiency of freeze-drying. Fine crystals leave smaller gaps after sublimation, which hinders the sublimation of the lower layer. The finished product of rapid freezing has fine particles, uniform appearance, large specific surface area, good porous structure, fast dissolution rate, and relatively stronger moisture absorption of the finished product. There are two ways in which drugs are pre frozen in a freeze-drying machine: one is to cool the product and drying oven at the same time, and the other is to wait for the drying oven shelf to cool down to around -40 ℃ before placing the product. The former is equivalent to slow freezing, while the latter is between quick freezing and slow freezing, and is often used to balance freeze-drying efficiency and product quality. The disadvantage of this method is that when the product is put into the box, the water vapor in the air will quickly condense on the shelf. In the early stage of sublimation, if the plate heats up quickly, the large area of sublimation may exceed the normal load of the condenser. This phenomenon is particularly significant in summer. The freezing of the product is in a static state. Experience has shown that supercooling can easily occur to the point where the product temperature has reached the eutectic point. But the solute still does not crystallize. In order to overcome the supercooling phenomenon, the temperature at which the product freezes should be lower than a range below the eutectic point and should be maintained for a period of time until the product is completely frozen.

The conditions and speed of sublimation

Ice can begin to sublime when its saturated vapor pressure at a certain temperature is greater than the partial pressure of water vapor in the environment; The suction and capture of water vapor by a condenser with a lower temperature than the product is a necessary condition for maintaining the temperature rise. The distance traveled by gas molecules between two consecutive collisions is called the mean free path, which is inversely proportional to pressure. At normal pressure, its value is very small, and the sublimated water molecules are prone to collide with the gas and return to the surface of the steam source, resulting in a slow sublimation rate. As the pressure decreases below 13.3 Pa, the average free path increases by 105 times, significantly accelerating the sublimation rate. The water molecules that fly out rarely change their orientation, thus forming a directed steam flow. The vacuum pump plays a role in removing permanent gases in the freeze dryer to maintain the necessary low pressure for sublimation. At atmospheric pressure, 1g of water vapor is 1.25L, but at 13.3Pa, it expands to 10000 liters. It is impossible for a regular vacuum pump to extract such a large volume per unit time. The condenser actually forms a vacuum pump specifically designed to capture water vapor. The temperature for product and condensation is usually -25 ℃ and -50 ℃. The saturated vapor pressures of ice at this temperature are 63.3 Pa and 1.1 Pa, respectively, resulting in a significant pressure difference between the sublimation and condensation surfaces. If the partial pressure of non condensable gases in the system can be ignored at this time, it will cause 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 2822J/gram. If no heat is supplied during the sublimation process, the product can only compensate for the sublimation heat by reducing its internal energy until its temperature reaches equilibrium with the condenser temperature, and the sublimation stops. In order to maintain the temperature difference between sublimation and condensation, sufficient heat must be provided to the product.

Three sublimation processes

In the first stage of heating (extensive sublimation stage), the temperature of the product should be within a range below its eutectic point. Therefore, the shelf temperature needs to be controlled. If the product has been partially dried but the temperature exceeds its eutectic point, the product will melt, and the melted liquid will be saturated with ice but not saturated with solute. Therefore, the dried solute will quickly dissolve and eventually condense into a thin and stiff block, with an extremely poor appearance and slow dissolution rate. If the melting of the product occurs in the later stage of extensive sublimation, due to the small amount of melted liquid, it will be absorbed by the dried porous solid, causing damage to the block after freeze-drying. When dissolved with water, the dissolution rate can still be slow. In the process of extensive sublimation, although there is a significant temperature difference between the shelf and the product, the sublimation heat absorption is relatively stable and the product temperature is relatively constant due to the fact that the plate temperature, condenser temperature, and vacuum temperature remain basically unchanged. As the product dries layer by layer from top to bottom, the resistance to ice sublimation gradually increases. The temperature of the product will also slightly increase accordingly. Until the presence of ice crystals is no longer visible to the naked eye. At this point, over 90% of the moisture has been removed. The process of extensive sublimation has basically come to an end. In order to ensure that the entire box of products is fully sublimated, the plate temperature still needs to be maintained for one stage before the second stage of heating is carried out. The remaining percentage of water is called residual water, which differs in physical and chemical properties from free state water. Residual water includes chemically bound water and physically bound water, such as crystallized water, water bound by proteins through hydrogen bonds, and adsorbed water on solid surfaces or capillaries. Due to the binding of residual moisture by a certain gravity, its saturated vapor pressure decreases to varying degrees, resulting in a significant decrease in drying speed. Although increasing the temperature of the product promotes the gasification of residual moisture, if the temperature exceeds a certain limit, the biological activity may also sharply decrease. The maximum drying temperature required to ensure product safety should be determined through experimentation. Usually, in the second stage, we maintain a plate temperature of around 30 ℃ and keep it constant. At the beginning of this stage, due to the increase in plate temperature, there is less residual moisture and it is not easy to vaporize, so the temperature of the product rises rapidly. But as the temperature of the product gradually approaches the temperature of the board, heat conduction becomes slower and requires patience for a considerable period of time. Practical experience has shown that the drying time for residual moisture is almost equal to the time for a large amount of sublimation, and sometimes even exceeds it.

Four freeze drying curves

Record the changes in shelf temperature and product temperature over time to obtain the freeze-drying curve. A typical freeze-drying curve system divides the temperature rise of the shelf into two stages. During a large amount of sublimation, the temperature of the shelf remains low and can generally be controlled between -10 and 10 depending on the actual situation. In the second stage, the shelf temperature is adjusted appropriately according to the properties of the product, which is suitable for products with lower melting points. If the performance of the product is not yet clear, the machine performance is poor, or its operation is not stable enough, this method is also more reliable. 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 raise the shelf temperature to the maximum allowable temperature until the freeze-drying is completed, but it is also necessary to ensure that the temperature of the product during mass sublimation does not exceed the eutectic point. If the product is thermally unstable, the second stage plate temperature should not be too high. In order to improve the sublimation speed of the first stage, the shelf temperature can be raised once to above the maximum temperature allowed by the product; When the stage of extensive sublimation is basically over, the plate temperature should be lowered to the maximum allowable temperature. Although these latter two methods increase the speed of extensive sublimation to some extent, their anti-interference ability is correspondingly reduced. Sudden decrease in vacuum degree and cooling capacity or power outage may cause the product to melt. Reasonably and flexibly mastering the first method is still a commonly used approach at present.

Characteristics of freeze-drying equipment:

1. LCD display, Chinese interface, with sample drying curve;

2. The imported compressor, equipped with a heat exchanger, increases the cooling capacity and improves the water capture capacity;

3. The cold trap has a large opening, no inner coil, and comes with sample pre freezing function;

4. Pre cooling rack, which can be used as a guide bucket to accelerate drying speed;

5. The cold trap and operating surface are made of all stainless steel, corrosion-resistant and easy to clean, with a transparent bell jar.

6. Transparent bell shaped drying chamber, safe and intuitive;

7. Stainless steel sample holder, with adjustable spacing between regular sample trays;

8. Novel design, small size, easy operation, reducing the occupation of laboratory countertops;

9. Optional nitrogen inflation valve can be added.

Precautions for using freeze-drying equipment:

power on

1. Turn on the main power switch on the left side of the chassis, and the air pressure display will show 110pk. 2. Press and hold the main switch key on the control panel for more than three seconds, and the temperature display will show the actual temperature of the cold trap; 3. Start the refrigeration machine and pre cool for more than 30 minutes; Place the sample into the sample rack, cover it with an organic glass cover, and start the vacuum pump; After the pressure digital display stabilizes, record the temperature and pressure values.

shutdown

1. Record the temperature and air pressure values before shutdown; Press and hold the inflation valve on the control panel, and immediately turn off the vacuum pump; When the pressure display shows atmospheric pressure, open the organic glass cover and take out the sample; 4. Turn off the refrigeration unit, press and hold the main power switch for more than three seconds, and finally turn off the main power switch; After the ice in the cold trap has completely turned into water, open the water outlet valve on the left side of the chassis to release water, clean the inner wall of the cold trap with a dry cloth, and cover it with a large filter paper to prevent dust.

Other issues to be noted

The preparation of samples should maximize their surface area and should not contain any acidic or alkaline substances or volatile organic solvents;

The two samples must be completely frozen into ice, and any residual liquid will cause gasification spray;

3. Note that the cold trap is about minus 65 degrees Celsius and can be used as a low-temperature refrigerator, but it must be operated with insulated gloves to prevent frostbite;

Before starting the vacuum pump, check whether the outlet valve is tightened, whether the inflation valve is closed, whether the contact surface between the organic glass cover and the rubber ring is clean and free of dirt, and whether it is well sealed;

In general, the machine should not be used continuously for more than 48 hours;

During the freezing process, the temperature of the 6 samples gradually decreases. The samples can be taken out and warmed up for a period of time (still in a frozen state) before continuing to dry to shorten the drying time.