This article focuses on analyzing the causes and solutions of the vial breakage during the freeze-drying process from the perspective of the breakage of the antibiotic vial vial. Under normal circumstances, glass bottles have a large tolerance range for temperature without breaking when heated evenly, such as baking in an oven or freezing in an environment of tens of degrees below zero. However, if the temperature of different parts of the same bottle (especially the bottom of the bottle) undergoes sudden cold or sudden heat changes, forming a relatively large temperature difference, then each part of the bottle will experience different expansion forces. When this force Exceeding the endurance of the glass will inevitably cause damage to the glass. This situation can easily occur during freeze-drying.
When we freeze-dry a certain antibiotic species, we start by placing the preparation bottle on the shelf in the drying box of the freeze dryer. The shelf is filled with heat-conducting medium and the temperature is controlled by an external device. During the pre-freezing period of the product, since the temperature is lowered under atmospheric pressure at this time, the heat transfer is carried out in three ways: conduction, convection and radiation. The temperature difference of each part of the glass bottle is not large, and the glass bottle is generally not broken. Since it is carried out in a low vacuum state, heat transfer is mainly carried out by radiation and conduction, and the effect of convection is very weak and can be ignored. Heating the shelf will directly affect the upper part of the glass bottle, and the heat radiation of the upper shelf to the product will only act on the upper part of the glass bottle. However, conduction and heat conduction at the part of the preparation grains are hindered and the received radiant heat conduction is relatively weak. When convective heat conduction basically does not exist, the original low temperature state is basically maintained. In this way, the temperature difference between the bottom of the glass bottle and the bottle body occurs. The bottle body at the drug column only receives a small amount of heat energy, and part of the energy is offset by the heat absorption of the sublimation of water, so the temperature of the bottle body is the lowest. At this time, the lower the pressure, the faster the temperature rise, the higher the thickness of the grain, the greater the temperature difference, the stronger the force on the bottle wall, and the lower quality or defective glass bottles will first fall off and break. Cracks, the number of fragments and the degree of fragmentation are related to the rate at which the temperature difference is formed.
The key to solving the problem of fragmentation and bottoming is to reduce the temperature difference of each part of the glass bottle. What is reflected in the freeze-drying process curve is to reduce the temperature line interval between the shelf temperature curve and the sample temperature curve. This can be achieved through vacuum control and temperature control in actual operation.
First, pre-cool the sample to 20°C below the eutectic point and keep the temperature for 1 hour. When the condenser temperature reaches below -60°C, the entire system is evacuated. After reaching the predetermined value, the temperature rise and drying will begin. At this time, the shelf temperature is set to be 15°C higher than that of the sample. At the same time, the main butterfly valve is adjusted to increase the steam pressure in the drying chamber to enhance the convective heat transfer, accelerate the heat transfer process, and promote the sample temperature to increase with the shelf temperature. When the pressure increases, pay close attention to changes in air pressure and temperature to ensure that the temperature difference between the sample and the shelf is within the range of 10 to 15°C. At this time, the temperature curve of the sample approaches the eutectic point as quickly as possible, and it sublimates rapidly at about 5°C below the eutectic point, and then completes the main drying.
After the main drying of the preparation is basically completed, the temperature can be quickly heated to make the shelf temperature directly reach the set value. Because the water in the glass bottle has basically been sublimated, the factors that affect the temperature homogenization no longer exist. Even if the temperature difference is greater than 20°C, the glass bottle will not be broken. After the shelf temperature curve coincides with the sample temperature curve, heat preservation and drying are performed, and finally the whole process of freeze drying is completed.
Through more than one year of freeze-drying practice, the above-mentioned method is used to adjust the temperature, and the temperature difference between the sample temperature and the shelf temperature is less than 15℃ during the sublimation process. This not only shortens the freeze-drying cycle, but also completely solves the problem. It solves the problem of glass bottle chipping and peeling off during freeze-drying process.