Freeze drying is also called sublimation drying. It is a drying method that freezes water-containing materials below freezing point, converts water into ice, and then converts ice into steam under a relatively high vacuum to remove it. The material can be frozen in a freezing device first and then dried. However, it can also be frozen directly in the drying room by quickly evacuating it. The water vapor generated by sublimation is removed by a condenser. The vaporization heat required in the sublimation process is generally supplied by thermal radiation.

Freeze drying uses the principle of ice crystal sublimation. In a highly vacuum environment, the moisture in frozen food materials is sublimated directly from ice solid to steam without melting the ice. Generally, the moisture in vacuum drying materials is converted dry the food, so freeze drying is also called freeze sublimation drying.

Its main advantages are:

(1) The dried material maintains its original chemical composition and physical properties (such as porous structure, colloidal properties, etc.);

(2) The heat consumption is less than other drying methods. The disadvantage is that it is expensive and cannot be widely used. It is used for drying antibiotics, vegetables and fruits, etc.

The biological samples containing water are frozen and fixed, and the water in the samples is directly sublimated from ice under low temperature and high vacuum conditions to achieve the purpose of drying. During the drying process, the samples are not affected by surface tension and do not deform.

Vacuum freeze drying technology is a drying technology that freezes wet materials or solutions into a solid state at a relatively low temperature (-10℃～-50℃), and then sublimates the water in it into a gaseous state without passing through the liquid state under vacuum (1.3～13 Pa), and finally dehydrates the material. China is a major producer of raw materials, so the application prospects of this technology are very broad. However, it should be noted that vacuum freeze drying technology has been promoted very rapidly in my country. In comparison, its basic theoretical research is relatively lagging and weak, and there are not many professional and technical personnel. In addition, compared with other drying technologies such as airflow drying and spray drying, vacuum freeze drying equipment requires large investment, and energy consumption and drug production costs are high, which limits the further development of this technology. Therefore, it has become the most important problem currently facing the field of vacuum freeze drying technology to effectively strengthen basic theoretical research, achieve energy saving and consumption reduction, and reduce production costs while ensuring the quality of drugs.

principle

From physics, we know that water has three phases, O point is the common point of three phases, and OA is the melting point of ice. According to the principle of pressure reduction and boiling point reduction, as long as the pressure is below the triple point pressure (the pressure in the figure is below 646.5Pa and the temperature is below 0℃), the water in the material can be sublimated directly from water to water vapor without passing through the liquid phase. According to this principle, the wet raw materials of food can be frozen below the freezing point to turn the water in the raw materials into solid ice, and then in an appropriate vacuum environment, the ice can be directly converted into steam and removed, and then the water vapor can be condensed by a water vapor condenser in the vacuum system to dry the material. This method of using vacuum freezing to achieve drying is a process of physical state change and movement of water. This process occurs at low temperature and low pressure. Therefore, the basic principle of freeze drying is the mechanism of heat and mass transfer at low temperature and low pressure.

Freeze drying is different from ordinary heating drying. The moisture in the material is basically sublimated on the frozen solid surface below 0℃ and dried, and the material itself remains in the ice shelf when frozen. Therefore, the volume of the dried product remains unchanged and it is loose and porous. Ice needs heat when it sublimates. The material must be properly heated and a certain temperature gradient must be formed between the heating plate and the sublimation surface of the material to facilitate the smooth conduction of heat transfer.

The freeze-drying process of the product includes three stages: freezing, sublimation and re-drying.

freeze

First, cool the material to be freeze-dried to about 2°C with a suitable cooling device, and then place it in a freeze-drying box cooled to about -40°C (13.33Pa). Close the drying box, quickly introduce refrigerant (Freon, ammonia) to freeze the material, and keep it for 1 h or longer to overcome the supercooling phenomenon of the solution and completely freeze the product, so that sublimation can be carried out.

sublimation

The sublimation of the product is carried out under a high vacuum. During the process of reducing the pressure, the items in the box must be kept frozen to prevent overflow from the container. After the pressure in the box drops to a certain level, turn on the Roots vacuum pump (or vacuum diffusion pump). When the pressure drops to 1.33 Pa and below -60°C, the ice begins to sublime, and the sublimated water vapor forms ice crystals in the condenser. To ensure the sublimation of the ice, the heating system should be turned on to heat the shelf and continuously supply the heat required for the sublimation of the ice.

Re-drying

In the sublimation stage, ice sublimates in large quantities. At this time, the temperature of the product should not exceed the lowest eutectic point to prevent the formation of stiff blocks in the product or defects in the appearance of the product. In this stage, the shelf temperature is usually controlled between ±10°C. The water removed in the re-drying stage of the product is bound water. At this time, the water vapor pressure on the solid surface decreases to varying degrees, and the drying speed decreases significantly. Under the premise of ensuring product quality, the shelf temperature should be appropriately increased in this stage to facilitate the evaporation of water. Generally, the shelf is heated to 30-35°C. The actual operation should be carried out according to the freeze-drying curve of the product (the temperature, time, and vacuum curve drawn in advance through multiple experiments) until the product temperature coincides with the shelf temperature and reaches dryness.

Technical advantages

Since vacuum freeze drying is carried out at low temperature and low pressure, and the water is directly sublimated, the product is endowed with many special properties. For example, vacuum freeze drying technology can also dehydrate heat-sensitive materials more thoroughly, and the dried medicines are very stable and easy to store for a long time. Since the drying of the material is completed in a frozen state, compared with other drying methods, the physical structure and molecular structure of the material change very little, and its organizational structure and appearance are well preserved. During the vacuum freeze drying process, the material does not have the problem of surface hardening, and a porous sponge is formed inside, so it has excellent rehydration and can be restored to the state before drying in a short time. Since the drying process is carried out at a very low temperature and is basically isolated from the air, it effectively inhibits the biological, chemical or physical changes of heat-sensitive substances, and better preserves the active substances in the raw materials, as well as maintains the color of the raw materials.

Basic theory

my country’s vacuum freeze drying equipment is becoming more and more perfect, but compared with developed countries, the research on the basic theory of this technology is lagging behind and weak, which hinders the improvement of the level of technology application. Therefore, the focus of research is shifting to this aspect. The focus of research is on the physical parameters of vacuum freeze drying and their influencing factors, process parameters, process mechanism and model, process optimization control, etc.

The basic parameters of vacuum freeze-drying technology include physical parameters and process parameters, which are the basis for realizing the vacuum freeze-drying process. The lack of these data will make it difficult to optimize the drying process for raw materials and fail to give full play to the system efficiency. Physical parameters refer to the thermal conductivity and transfer coefficient of materials. The research content in this area includes the determination and determination methods of physical parameter data, as well as the influence of environmental conditions such as pressure, temperature, relative humidity and material particle orientation on physical parameters. Process parameters include relevant parameters such as freezing, heating and material morphology. The study of the freezing process is intended to find the optimal freezing curve for the system. The research on the heating process focuses on two aspects: one is the improvement of the raw material carrier; the other is the selection of heating methods (heat transfer methods and heating sources). Determining the appropriate material morphology is also an important research content, which includes the particle morphology of the raw materials and the thickness of the material layer.

Studying the mechanism of vacuum freeze drying from the perspective of heat transfer and mass transfer, and establishing the corresponding mathematical model, will help to identify the factors affecting the process and predict the distribution of time, temperature and vapor pressure. The research is mainly limited to the homogeneous liquid phase, and some mathematical models have been proposed, such as the ice front uniform retreat model, sublimation model, adsorption-sublimation model, etc. Although these models describe the vacuum freeze drying process to varying degrees, there are still many restrictions in practical applications. Process optimization control is based on the above mathematical models. The control scheme is divided into quasi-steady-state model and non-steady-state model.

Production process

Since the freeze-drying process of biological products and medicines is relatively complicated, in order to ensure the quality of freeze-dried products and save energy, the pre-freezing temperature, sublimation endothermicity, etc. need to be strictly controlled during the production process so that each stage of the freeze-drying process works according to the pre-established process route.

Maintain pre-freezing temperature

In the vacuum freeze-drying process, the drug to be dried needs to be pre-frozen first, and then the water is directly changed from ice to gas under vacuum to dry the drug. During the entire sublimation stage, the drug must remain in a frozen state, otherwise a product with good properties cannot be obtained. During the drug pre-freezing stage, the pre-freezing temperature must be strictly controlled (usually a few degrees lower than the eutectic point of the drug). If the pre-freezing temperature is not low enough, the drug may not be completely frozen and will expand and bubble during vacuum sublimation; if the pre-freezing temperature is too low, it will not only increase unnecessary energy consumption, but also reduce the survival rate of some biological drugs after freeze-drying.

Focus on sublimation heat absorption

During the drying and sublimation stage, the material needs to absorb heat (about 2.8 kilojoules of heat is absorbed for each gram of ice that completely sublimates into water vapor). If the drug is not heated or the heat is insufficient, the water will absorb the heat of the drug itself during sublimation, which will lower the temperature of the drug, causing the vapor pressure of the drug to decrease, thus causing the sublimation rate to decrease, the entire drying time to be extended, and the productivity to decrease; if the drug is heated too much, the sublimation rate of the drug will certainly increase, but after offsetting the heat absorbed by the drug sublimation, the excess heat will increase the temperature of the frozen drug itself, causing the drug to partially or even completely melt, causing the drug to shrink and bubble, and the entire drying process will fail.

Automation

In order to obtain good freeze-dried drugs, a freeze-drying curve should be developed based on the performance of each freeze-drying machine and the characteristics of the drug after testing, and then the machine should be controlled so that the temperature changes in each stage of the freeze-drying process conform to the pre-established freeze-drying curve. The production process control of vacuum freeze drying can be controlled by computers to control the production system to work according to the pre-set freeze-drying curve. For example, the computer control of the freeze-drying process of streptomycin sulfate can be divided into two stages: in the first stage, at a temperature below the melting point, the water is sublimated from the frozen material, and about 98% to 99% of the water is removed at this time. In the second stage, the material temperature is gradually raised to or slightly above room temperature, and the water content can be reduced to less than 0.5% during this stage. The pre-freezing temperature of this process is about -40°C and the time is about two hours. In the drying and sublimation stage of freeze-dried drugs, the material temperature is about -30°C to -35°C, and the absolute pressure is about 4 to 7 Pa. The final drying temperature of streptomycin can be raised to 40°C, and the total drying time is about 18 hours. The use of computer automation control systems helps to ensure that drugs meet quality requirements.

Contact information: Milotech Corp

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