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Freeze-drying equipment performance selection This article talks about some experience in freeze-drying equipment performance selection, formula research, and freeze-drying technology. The freeze-drying method is to freeze a substance containing a large amount of moisture into a solid by cooling it in advance, and then directly sublimate the water vapor from the solid under vacuum conditions, and use the condensation method to capture the sublimated water vapor, causing the substance to be dehydrated and dried. Freeze-drying has the characteristics of avoiding the thermal decomposition of drugs, loose product texture, rapid dissolution after adding water, low moisture content (1% to 3%), good stability, convenient storage, less chance of contamination, and high product quality. Therefore, freeze-drying has been widely used in bioengineering, medical industry, food industry scientific research, etc. For example, Xiamen Tebao Bioengineering Co., Ltd.'s Teerli, Fujian Tianshen Microbial Engineering Co., Ltd.'s CellBijia, Xiamen Jianfa Pharmaceutical Co., Ltd.'s prostaglandin E1 for injection and acyclovir for injection are all freeze-dried drugs. 1 Performance selection of freeze-drying machine 1.1 The capacity and specifications of the freeze-drying machine, including shelf area, water capture capacity of the condenser, shelf size, shelf spacing, etc., should match the production volume. 1.2 The front and back sides of the shelf should be fairly flat, and the plate temperature should be uniform. Generally, the temperature difference at each point of the plate between plates should be controlled within ±1°C to ensure uniform quality of the entire batch of products. 1.3 The temperature of the condenser should be able to drop to the required temperature within 2.5 hours, which is generally below -45°C. If it fails to meet the requirements, it means that the condenser's ability to capture water vapor is insufficient. 1.4 The vacuum degree of the box, measured when the box is empty, should reach 2.66pa within 30 minutes and ensure that it is sealed without leakage. 1.5 The box body should be made of high-quality stainless steel, and the design should be reasonable and beautiful, which is not only easy to clean, but also highly corrosion-resistant. 1.6 Some devices attached to the freeze-drying machine 1.6.1 The hydraulic plugging device is used to plug the whole box in the box after freeze-drying, which can reduce production links and reduce the chance of contamination. The boards can move freely up and down, which is conducive to cleaning inside the box and makes it easy to access all parts of the box. 1.6.2 The limited leakage device is used to control the vacuum degree in the box and control the infiltration of nitrogen or clean air. It will be beneficial to the temperature rise of the product during the secondary drying stage and can shorten the freeze-drying cycle by 2 to 3 hours. 1.6.3 Control system. The most important thing is to control the shelf temperature. The product temperature, shelf temperature, condenser temperature, box vacuum, etc. can be recorded and saved through the recorder. Of course, interlocking alarms are also critical, as they can improve the reliability of operations and prevent products from suffering losses when operations or supporting facilities go wrong. 1.7 Domestic freeze dryer manufacturers include: Beijing Aviation Industry Research Institute, Shanghai Pudong Freeze Drying Equipment Factory, Shanghai Far East Pharmaceutical Machinery Factory, Shenzhen Wanbao Vacuum Technology Co., Ltd., Jiangyin Pharmaceutical Machinery Equipment Factory, etc., and many models are controlled by computers. They control the sublimation speed, moisture content index, and end point control through pressure, and the reliability of the operation is very high. 1.8 Each enterprise chooses an imported freeze-drying machine or a domestic freeze-drying machine according to its own needs. It should also consider many after-sales service issues such as price, installation and commissioning, repair and maintenance, and spare parts supply. 2. Research on the formulation of freeze-dried products. When a certain substance is given, its structure and characteristics should first be understood, and its eutectic point temperature should be measured. Then, based on the eutectic temperature, it can be judged whether additives (including excipients, stabilizers, etc.) need to be added. If additives are needed, consider what kind of substance and amount to add. After freeze-drying, observe and measure the appearance, moisture and other items, gradually modify the prescription and repeat the test until the indicators are similar or the same. 3 Freeze-drying process 3.1 Pre-freezing of products All products must be frozen solid before sublimation drying. Considering the quality of freeze-dried products and the economy of freeze-drying, the pre-freezing temperature should be about 10°C lower than the eutectic point, the pre-freezing time is generally between 2h and 4h, the thickness of the device is generally 10mm to 15mm, and the solid content is 4% to 25%. The appearance of the product after freeze-drying is related to the rate of pre-freezing. After slow freezing, the crystal lattice is larger and the ice crystals are hexagonally symmetrical, while after quick freezing, the ice crystals are irregularly shaped or spherical, with small gaps and high resistance during sublimation. 3.2 Sublimation drying, that is, the condenser temperature must reach below -40°C within 30 minutes before the first stage of drying and sublimation (generally -50°C is the most economical). Turn on the vacuum pump, then slowly open the large butterfly valve between the freeze-drying box and the condenser, and then turn on the Roots pump. When the vacuum in the freeze-drying box reaches about 10pa, switch to heating and sublimation drying. If the vacuum degree is too low, it will affect the sublimation rate, which can generally be controlled at 20~40pa. Turn on the oil heater, and then turn on the circulating oil pump to circulate and heat the oil in the shelf. Pay attention to controlling the oil temperature. Attention should be paid at this stage: the freezing temperature of the product should be lower than the eutectic point temperature of the product to ensure that the product is frozen firmly, and the temperature of the product sublimation and drying must be lower than its disintegration temperature. When all the ice crystals are eliminated, the first stage of drying is completed, and about 90% of the total moisture is removed at this time. Indications of completion of the first stage of drying: 1. The sublimation interface can be seen from the perspective window gradually advancing to the bottom of the container and disappearing; 2. The temperature of the condenser drops to the state before sublimation; 3. The pressure of the freeze-drying box drops to close to the pressure of the freezer. 3. 3 Analytical drying, that is, the second stage of drying. The drying temperature in this stage can be high enough, as long as the product is not burned and the product is not overheated and denatured. When the temperature of each laminate product reaches the maximum heating temperature, and its curves are basically the same, continue to keep warm and dry for a period of time, and the drying process will be completed. After the second stage of drying, the residual moisture content of the product depends on the requirements of the product type, and can generally be controlled between 1% and 5%. Empirical method for measuring the dryness of freeze-dried materials: After freeze-drying, close the vacuum valve between the freeze-drying box and the condenser. At this time, observe the recovery of the pressure in the freeze-drying box within 30 to 60 seconds (there is no leakage in the box). If the pressure in the freeze-drying box does not rise significantly, the freeze-drying can be completed. Generally, the pressure rises after 1 minute of shutdown.