Saturday, February 26, 2011


It is also referred to as “freeze-drying”, “sublimation-drying” or “cryodesiccation”.

It is the process of isolation of a substance (solid) from solution by freezing it and evaporating the ice under vacuum (by sublimation).

Process of lyophilization:
In the process of lyophilization, water or any other solvent is removed from a frozen solution by sublimation caused by reduction of the temperature and pressure to values at a lower level than the triple point.

Under the application of these conditions, heat applied is used as latent heat and the ice converts directly to the vapor state (by the process of sublimation).

Practically, the following features must be taken into account.

Temperature and pressure are necessary to be at a lower level than the triple point and it is usually -10 ºC to -30 ºC and 10 N/m2 to 30 N/m2 respectively. To achieve this pressure, the vapors must be removed or else the vapor pressure will affect this pressure.

Stages of the freeze-drying process:
Following stages are found in lyophilization:

1. Freezing
2. Vacuum
3. Primary drying
4. Secondary drying
5. Packaging

The material is usually frozen before the application of vacuum. A number of methods are used in freezing of the material.

In shell freezing, the bottle is partially filled with the material to be frozen. It is placed in a refrigerator almost horizontally and rotated slowly. In this way the material freezes along side the walls of the bottle and resulting in large area for heat transfer and sublimation.

In vertical spin freezing, small crystals of ice are produced. In this method, the bottles are first placed in a moderate coldness and rotated quickly in vertical position in a constant flow of very cold air. This result in the liquid becoming super cooled and freezing occurs rapidly.

Vacuum pumps are used to create the vacuum and reducing the pressure sufficiently.

On small scale, two-stage rotary pumps are used while on large scale ejector pumps are used.

Primary drying:
During the primary drying, two important processes are followed i.e. (1) vapors are removed by applying (2) the latent heat of sublimation. The apparatus similar to the vacuum oven can be used.

Heat transfer is crucial in this process as the extra heat may cause the material to melt and less heat may cause the process to be prolonged or no sublimation. So, heat transfer must be controlled.

Vapor removal is important to reduce a change in pressure. On the small scale, vapor is removed by using desiccant such as phosphorus pentoxide or by using a small condenser. And on the large scale condensation is helpful to remove vapors and by using pumps such ejector pumps.

The rate of drying in lyophilization is very low showing that the rate of drying of ice is about 1 mm depth per hour.

Secondary drying:
The primary drying may leave about 0-5 % of moisture in the solid, which can be removed by secondary drying process.

In this method, temperature may raise above 0 ºC to break any type of physico-chemical interactions between the frozen material and the water molecules resulting in the removal of the moisture.

High temperature can be used, as the risk of hydrolysis is negligible in the secondary drying because the secondary drying is an ordinary vacuum drying phase.

After the completion of freeze-drying process, vacuum is usually removed by the application of an inert gas such as nitrogen before the material is tightly closed. Great care is needed in the packaging of freeze dried products. Containers must be tightly closed to protect from moisture.

Freeze-drying equipment:
There are three types of freeze-dryers:

1. Rotary evaporators
2. Manifold freeze-dryers
3. Tray freeze-dryers

Aqueous solutions and/or dispersions of oxygen-sensitive or heat-sensitive drugs, biologicals such as blood products (such as peptides, proteins), antibiotics (other than penicillin), vaccines (such as BCG, yellow fever, smallpox) and enzyme preparations (such as hyaluronidase) and microbiological cultures are usually freeze-dried.

After freeze-drying and packing the material in a vial, the material can be stored, shipped and reconstituted later to the primary form for the use as injection.

It increases the shelf life of some of the pharmaceuticals for many years.

Advantages of lyophilization:
1. Decomposition and hydrolysis of the product is reduced as a result of prevention of the enzyme action due to very low temperature.
2. Oxidation is reduced as a result of high vacuum and less air.
3. The product is light and porous as the original solution was frozen and there is no incorporation of extra materials.
4. As the product is porous so this results in more solubility.

Disadvantages of lyophilization:
1. The high porous nature (results in more solubility) and highly dried state results in a highly hygroscopic product. So special conditions are required up to packaging.
2. The process is very slow and requires expensive instruments and plants.
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