Lyophilization is a drying technique that utilizes sublimation principles. It involves rapidly freezing the material to be dried at low temperatures, then, in a suitable vacuum environment, the frozen water molecules sublime directly into water vapor and escape. The product obtained through lyophilization is called a lyophilizate. This process is known as lyophilization.
Substances remain at low temperatures (frozen) prior to drying, with ice crystals evenly distributed throughout the material. The sublimation process does not lead to concentration due to dehydration, thus avoiding side effects such as foaming and oxidation caused by water vapor. The dried substance has a dry, spongy, porous structure with minimal volume change, easily dissolving in water to revert to its original form. It significantly prevents the denaturation of dried substances in terms of physical, chemical, and biological properties.
The freeze-dryer is composed of a refrigeration system, vacuum system, heating system, and electrical instrument control system. The main components include the drying chamber, condenser, refrigeration unit, vacuum pump, and heating/cooling units. Its working principle involves freezing the item to be dried below the triple point temperature, then under vacuum conditions, the solid water (ice) in the item is directly sublimated into water vapor, eliminating it from the item to achieve drying. After pre-treatment, the material is sent to the quick-freezing storage for freezing, then to the drying chamber for sublimation and dehydration, and finally packaged in the post-processing workshop. The vacuum system establishes a low-pressure environment for the sublimation drying chamber, the heating system provides latent heat for sublimation, and the refrigeration system supplies the required cooling to the cold trap and drying chamber. This equipment uses radiant heating for uniform heating of the material; employs a water trap for rapid defrosting; utilizes a vacuum unit for oil-water separation; adopts a parallel centralized refrigeration system for multi-route on-demand cooling, ensuring stable operation and energy-saving benefits; and is controlled by artificial intelligence for high control accuracy and ease of operation.
The quality requirements for freeze-dried products are: unchanged biological activity, even appearance and color, full shape, robust structure, rapid dissolution speed, and low residual moisture content. To produce high-quality products, a comprehensive understanding of the theory and technology of freeze-drying is essential. The freeze-drying process consists of three stages: preliminary freezing, sublimation, and refreeze-drying. Effectively and rationally shortening the freeze-drying cycle holds significant economic value in industrial production.
Product Freeze
During rapid freezing (cooling by 10-50℃ per minute), the crystals remain visible under a microscope; conversely, during slow freezing (1℃/min), the crystals formed are visible to the naked eye. Coarse crystals leave larger voids during sublimation, enhancing the efficiency of freeze-drying. Fine crystals leave smaller voids, which can impede sublimation from the lower layers. Rapid-freezing products have a fine particle texture, uniform appearance, large specific surface area, good porous structure, fast dissolution rate, and a relatively higher moisture absorption capacity of the finished product.
Yao products are pre-frozen in a freeze dryer in two methods: one involves simultaneous cooling of the product with the drying chamber; the other entails cooling the drying chamber's shelves to around -40℃ before placing the product inside. The former is akin to slow freezing, while the latter falls between rapid and slow freezing. This method is often chosen to balance freeze-drying efficiency and product quality. The drawback is that when the product is loaded into the chamber, moisture vapor in the air quickly condenses on the shelves. During the initial sublimation phase, if the shelves warm up too quickly, a large-scale sublimation could potentially exceed the condenser's normal load, a phenomenon more pronounced during summer.
The product freezing is in a static state. Experience has shown that supercooling is prone to occur, even when the product temperature has reached the eutectic point, yet the solute remains uncrystallized. To overcome supercooling, the freezing temperature of the product should be lower than the eutectic point by a certain range, and it should be maintained for a period to ensure the product is fully frozen.
II. Conditions and Speed of Transcendence
When the saturated vapor pressure of ice at a certain temperature is greater than the partial pressure of water vapor in the environment, it can begin to sublime; the condenser, which has a lower temperature than the product, plays a crucial role in absorbing and capturing water vapor, which is an essential condition for maintaining sublimation.
The distance a gas molecule travels between two consecutive collisions is known as the mean free path, which is inversely proportional to pressure. At atmospheric pressure, this value is very small, causing water molecules to easily collide with the gas and return to the surface of the steam source, resulting in a slow sublimation rate. As the pressure drops below 13.3 Pa, the mean free path increases by a factor of 105, significantly accelerating the sublimation rate. The water molecules that are ejected rarely change direction, thus forming a directional steam flow.
Vacuum pumps play a crucial role in freeze-dryers by removing gases to maintain the necessary low pressure for sublimation. At atmospheric pressure, 1 gram of water vapor occupies 1.25 liters, but at 13.3 Pa, it expands to 10,000 liters. It is impossible for a standard vacuum pump to remove such a large volume of gas in a unit of time. The condenser essentially acts as a specialized vacuum pump designed to capture water vapor.
Products and condensation temperatures are typically -25℃ and -50℃ respectively. At these temperatures, the saturated vapor pressures of ice are 63.3Pa and 1.1Pa. Consequently, a significant pressure difference is created between the sublimation and condensation surfaces. If the partial pressure of non-condensable gases within the system is negligible, it will drive the water vapor released from the products to flow定向ly towards the condenser surface, where it will freeze into frost.
The latent heat of vaporization for ice is approximately 2822 J/g. If heat is not supplied during the sublimation process, the product must lower its internal energy to compensate for the sublimation heat, until its temperature equals that of the condenser, at which point sublimation ceases. To maintain the temperature difference between sublimation and condensation, sufficient heat must be provided to the product.
III. The Sublimation Process
During the heating stage (phase of rapid sublimation), the product temperature must be below its eutectic point by a certain range. Therefore, the shelf temperature needs to be controlled. If the product has partially dried but the temperature exceeds its eutectic point, product melting will occur. At this point, the melted liquid, being ice-saturated but not solute-saturated, will quickly dissolve the dried solute, concentrating into a thin, solid mass with poor appearance and poor dissolution rate. If the product melting happens during the late stage of rapid sublimation, the smaller amount of melted liquid will be absorbed by the dried porous solid, resulting in some defects in the freeze-dried mass. Upon addition of water for dissolution, the slow dissolution rate will still be noticeable.
During the extensive sublimation process, although there is a significant temperature difference between the shelves and the products, the sublimation heat absorption remains relatively stable due to the constant temperatures of the plates, condensers, and vacuum. As the products dry from top to bottom, the resistance to the sublimation of the ice layer gradually increases, causing a slight rise in product temperature. This continues until the ice crystals are no longer visible to the naked eye, indicating that over 90% of the moisture has been removed. The extensive sublimation process is essentially complete at this point. To ensure that the entire box of products has undergone sufficient sublimation, the plate temperature must be maintained for a period before proceeding to the second stage of heating. The remaining few percent of moisture is referred to as residual moisture, which differs from free moisture in its physical and chemical properties. Residual moisture includes chemically bonded water and physically bonded water, such as crystalline water in compounds, water bound by hydrogen bonds in proteins, and adsorbed water on solid surfaces or in capillaries. Due to the attraction that binds residual moisture, its saturated vapor pressure is reduced to varying degrees, resulting in a significant decrease in drying speed. Although increasing the product temperature promotes the vaporization of residual moisture, exceeding a certain temperature limit can also cause a sharp decline in biological activity. The higher drying temperature required to ensure product safety must be determined by experimentation. Typically, we raise the plate temperature by about +30℃ during the second stage and maintain it constant. In the early stages of this phase, the product temperature rises quickly due to the increased plate temperature and the limited amount of residual moisture that is difficult to vaporize. However, as the product temperature approaches the plate temperature, heat conduction becomes slower, necessitating patience for a considerable amount of time. Practical experience shows that the time required for residual moisture drying is almost equal to, and sometimes even exceeds, the time for extensive sublimation.
Section 4: Frozen Freeze-Dried Curve
By recording the changes in tray temperature and product temperature over time, you can obtain a freeze-drying curve. A typical freeze-drying curve involves dividing the tray temperature increase into two stages. During the extensive sublimation, the tray temperature is kept relatively low, generally controlled between -10°C and +10°C, depending on the specific conditions. In the second stage, the tray temperature is adjusted appropriately based on the product's properties, which is suitable for products with a lower melting point. If the product's performance is not well understood, or the machine's performance is poor or unstable, this method is also relatively reliable.
If the eutectic point of the product is high, and the system's vacuum level is maintained well, with sufficient refrigeration capacity of the condenser, a certain rate of temperature increase can be employed to raise the shelf temperature to an allowable higher level until freeze-drying is complete. However, it is also necessary to ensure that the temperature of the product does not exceed the eutectic point during extensive sublimation.
If the product is heat-sensitive, the plate temperature in the second stage should not be too high. To enhance the sublimation rate in stage *, the shelf temperature can be raised to a higher temperature than the product allows in a single step. After the bulk sublimation phase is largely over, the plate temperature should then be lowered back to the higher allowable temperature. While these two methods may slightly increase the sublimation rate, they also reduce the resistance to interference. Sudden drops in vacuum or cooling capacity, or a power outage, could cause the product to melt. Still, appropriately and flexibly managing these methods remains a commonly used approach.
