Warming Up To Laboratory Freeze Drying: Part I of IV

Although freeze drying is often used in food and pharmaceutical applications, the process is not always understood. In this, the first of a four-part series on freeze drying, representatives of Labconco Corp. (Kansas City, MO; 816-333-8811) explain the three major steps of the freeze-drying process: prefreezing, primary drying, and secondary drying.

Basic Process And Benefits
Prefreezing
Primary Drying
Secondary Drying

Basic Process And Benefits (Back to Top)
Freeze drying removes water and other solvents from frozen products through a process called sublimation. Sublimation occurs when a frozen liquid goes directly to the gaseous state without passing through the liquid phase. Because freeze-dried materials skip the liquid phase, they are stable, easy-to-use, and aesthetically pleasing. In contrast, products that either dry at ambient temperatures or pass through a liquid phase are often unstable and aesthetically poor.

Freeze drying has been used for many years in the food and pharmaceutical industries. Recently, the process has also been used to recover reaction products, stabilize microbial cultures, preserve whole animal specimens for museum displays, and restore water-damaged items.

Because specialized freeze-drying equipment is expensive, many believe that the process is impractical. However, freeze drying often saves money because it eliminates the need for refrigeration and creates a stable product at ambient temperatures. The freeze-drying process consists of three stages: prefreezing, primary drying, and secondary drying.

Prefreezing (Back to Top)
In the first stage, material is prefrozen. This is a crucial step because the method of prefreezing and the final temperature of the frozen product can affect the success of the entire freeze-dry process. Rapid cooling creates small ice crystals that are useful when preserving structures that will be examined with a microscope; however, the process also makes the product more difficult to freeze dry. Slower cooling results in a product with larger ice crystals and less restrictive channels in the matrix, making it easier to freeze dry.

Products freeze in two ways, depending on their makeups. The majority of products that are subjected to freeze drying consist primarily of water and solutes that are dissolved or suspended in the water. Most samples that are freeze dried contain eutectics—a mixture of substances that freeze at lower temperatures than the surrounding water. When the aqueous suspension is cooled, changes occur in the solute concentrations of the product matrix. As cooling proceeds, the water is separated from the solutes as it changes to ice. This creates concentrated areas of solute that have lower freezing temperatures than the water.

Although a product may appear to be frozen because ice is present, it won't be completely frozen until all of the solute in the eutectic mixture is frozen; this is called the eutectic temperature. The product must be prefrozen below the eutectic temperature before the freeze drying process is begun. If this is not done, small pockets of unfrozen material will expand and compromise the structural stability of the freeze-dried product.

The second type of frozen product is a suspension that undergoes glass formation during the freezing process. Instead of forming eutectics, these suspensions become increasingly viscous as the temperature is lowered. The product finally freezes at the glass transition point to form a vitreous solid. Products that undergo glass formations are extremely difficult to freeze dry.

Primary Drying (Back to Top)
After a product is prefrozen, conditions must be established in which ice can be removed from it via sublimation, resulting in a dry, structurally intact product. To perform this primary drying process, the temperature and pressure in the freeze-drying system must be carefully controlled.

The rate of sublimation of ice from a frozen product depends on the difference in vapor pressure of the product and the vapor pressure of the ice collector. Molecules migrate from the higher pressure sample to the lower pressure area. Since vapor pressure is related to temperature, the product temperature must be warmer than the cold trap (ice collector) temperature.

It is extremely important that the product's freeze-drying temperature remains between the temperature that maintains the product's frozen integrity and the temperature that maximizes the product's vapor pressure. This balance is key to optimum drying. The phase diagram shown in Figure 1 illustrates this point. Most products are frozen well below their eutectic or glass transition points (Point A), and then the temperature is raised to just below this critical temperature (Point B). Here, the products are subjected to a reduced pressure and the freeze-drying process begins.

Some products such as aqueous sucrose solutions can undergo structural changes during the drying process that create a phenomenon known as collapse. In this situation, the product is frozen below its eutectic temperature and warmed during the freeze-drying process. This affects the structure of the frozen matrix at the boundary of the drying front, resulting in a structural matrix collapse. To prevent products that contain sucrose from collapsing, the product temperature must remain below a critical collapse temperature during primary drying. The collapse temperature for sucrose is –32°C.

No matter what type of freeze-drying system is used, conditions must be created to encourage water molecules to flow freely from the product. Therefore, a vacuum pump is an essential component of a freeze-drying system; pumps should be used to lower the pressure of the environment around the product (to Point C). The other essential component is a collecting system—a cold trap that collects moisture that leaves the frozen product. The collector gathers all condensable gases such as water molecules. The vacuum pump removes all non-condensable gases.

The product's vapor pressure forces the sublimation of the water vapor molecules from the frozen product to the collector. The molecules have a natural affinity to move toward the collector because its vapor pressure is lower than that of the product. Because of this, the collector temperature (Point D) must be significantly lower than the product temperature. The vapor pressure differential is affected more by the product temperature than by the collector temperature.

Energy (heat) is the third essential component in freeze-drying systems. Almost 10 times as much energy is required to sublime a gram of water from the frozen to the gaseous state as is required to freeze a gram of water. Therefore, with all other conditions being adequate, heat must be applied to the product so that water can be removed as vapor from the frozen product.

The heat must be very carefully controlled. If the product is heated above the evaporative cooling temperature in the system, the product may be warmed above its eutectic or collapse temperature. Heat can be applied by several means. One method is to apply heat directly through a thermal conductor shelf like those used in tray drying. Another method is to use ambient heat as in manifold drying.

Secondary Drying (Back to Top)
After primary freeze drying is complete and all ice has sublimed, bound moisture is still present in the product. The product appears dry, but the residual moisture content may be as high as 7–8%. To optimize the residual moisture content, the product must be continuously dried at a warmer temperature. This process is called isothermal desorption, as the bound water is desorbed from the product.

Secondary drying is normally performed at a product temperature that is higher than ambient temperature, but still compatible with the sensitivity of the product. All other conditions such as pressure and collector temperature remain the same. Because the process is desorptive, the vacuum should be as low as possible (no elevated pressure) and the collector temperature as cold as can be attained. Secondary drying is usually carried out for approximately 1/3 to 1/2 the time required for primary drying.

For more information about freeze-drying processes or products, call Labconco at 816-333-8811.

Written by representatives of Labconco Corp.