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Thursday, December 15, 2011

Principle, Methods & Factors affecting Lyophilization / Freeze Drying

Lyophilization / Freeze Drying is the process of drying a frozen product by creating conditions for sublimation of ice directly to water vapor. This is achieved in 3 step process, these are

1. Freezing
2. Primary Drying and
3. Secondary Drying


In the first step, the product is frozen solid, which converts the water content of the material to ice. The final temperature must be below the product's eutectic, or collapse temperature, so that it maintains its structural soundness.
Once the product is frozen solid, the condenser and vacuum systems are energized for the next critical process step.

Primary Drying:

In the second stop, the objective is to remove the unbound, or easily removed ice from the product. This water is now in the form of free ice, which is removed by converting it directly from a solid to a vapor, in a process called sublimation. To accomplish sublimation, a uniform source of heat energy is applied to the ice crystals, turning them directly into water vapor.
The product and condenser chambers are placed under vacuum to encourage the orderly migration of water vapor to the system's ice-collecting condenser, and to ensure that the pressure of the water vapor remains below its "triple point", as required for sublimation to occur.
In manifold drying ambient room temperature provides heat to encourage removal of water vapor from frozen samples.

Secondary Drying:

Even after all the free ice is removed by the sublimation process, your product may still contain enough bound water to limit its structural integrity and shelf life.
During secondary drying, the sorbed water, or the water that was bound strongly to the solids in the product, is converted to vapor. This can be a slow process; the remaining bound water has a lower pressure than free liquid at the same temperature, which makes it difficult to remove. Secondary drying actually starts during the primary drying phase, but must be extended after the total removal of the free ice to achieve low enough residual moisture levels.
Freeze-drying is complete when all the free and bound water has been removed, resulting in a residual moisture level that guarantees the desired biological and structural characteristics of the final product.

Methods of Freeze Drying:

Three methods of freeze drying are commonly used:

1. Manifold Drying,
2. Batch Drying, and
3. Bulk drying.

Each method has a specific purpose, and the method used depends on the product and the final configuration desired.

Manifold Method:
In the manifold method, flasks,ampules or vials are individually attached to the ports of a manifold or drying chamber. The product is either frozen in a freezer, by direct submersion in a low temperature bath, or by shell freezing,(Either Liquid Nitrogen or Methanol can be used for freezing) depending on the nature of the product and the volume to be freeze dried.The prefrozen product is quickly attached to the drying chamber or manifold to prevent warming. The vacuum must be created in the product container quickly, and the operator relies on evaporative cooling to maintain the low temperature of the product.

Heat input can be affected by simply exposing the vessels to ambient temperature or via a circulating bath.For some products, where precise temperature control is required, manifold drying may not be suitable.Several vessels can be accommodated on a manifold system allowing drying of different products at the same time, in different sized vessels, with a variety of closure systems. Since the products and their volumes may differ, each vessel can be removed from the manifold separately as its drying is completed. The close proximity to the collector also creates an environment that maximizes drying efficiency.

Batch Method:
In batch drying, large numbers of similar sized vessels containing like products are placed together in a tray dryer. The product is usually prefrozen on the shelf of the tray dryer. Precise control of the product temperature and the amount of heat applied to the product during drying can be maintained. Generally all vials in the batch are treated alike during the drying process, although some variation in the system can occur. Slight differences in heat input from the shelf can be experienced in different areas. Vials located in the front portion of the shelf may be radiantly heated through the clear door. These slight variations can result in small differences in residual moisture.

Bulk Method:
Bulk drying is generally carried out in a tray dryer like batch drying. However, the product is poured into a bulk pan and dried as a single unit.Although the product is spread throughout the entire surface area of the shelf and may be the same thickness as product dried in vials, the lack of empty spaces within the product mass changes the rate of heat input. The heat input is limited primarily to that provided by contact with the shelf. Bulk drying does not lend itself to sealing of product under controlled conditions as does manifold or batch drying. Usually the product is removed from the freeze dry system prior to closure, and then packaged in air tight containers. Bulk drying is generally reserved for stable products that are not highly sensitive to oxygen or moisture.

Factors that affect the efficiency of lyophilization:

There are several factors which can affect the efficency of lyophilization, some of the major factors includes,
  • sample size
  • surface area of the sample
  • thickness of the sample
  • sample characteristics
  • eutectic temperature
  • solute concentration
  • instrument factors
  • condenser temperature
  • vacuum
The larger the surface area of the frozen material, the faster the rate of lyophilization, and, conversely, the thicker the frozen material, the slower the rate of lyophilization. Sample thickness affects the ability of a sample to absorb and transfer heat to the surface undergoing sublimation. Because water vapor must pass through dried material, the rate of lyophilization in thick samples is slower, especially if the dried material collapses onto the surface of the frozen material. Shell freezing minimizes collapsing by increasing the surface area.The volume of the freeze dry flask should be 2 to 3 times that of the material being frozen.

Sources and References:
A Guide to Freeze Drying for the Laboratory, LABCONCO, An Industry Service Publication.