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FREEZE-DRYING (LYOPHILIZATION) BY A.SREE PRIYA M-Pharmacy 1 st Sem (Pharmaceutics) Priyadarshini College Of Pharmaceutical Sciences


FREEZE-DRYING (LYOPHILIZATION) DEFINITION :- Freeze-drying is a process of drying in which water is sublimed from the product after it is frozen. It is a drying process applicable to manufacture of certain pharmaceuticals and biologicals that are thermolabile or otherwise unstable in aqueous solutions for prolonged storage periods, but that are stable in the dry state. The term “lyophilization” describes a process to produce a product that “loves the dry state”.


Theory The drugs which lose their viability in the liquid state and readily deteriorate if dried in air at normal atmospheric pressures, these may be heat sensitive or they may react readily with oxygen, so that in order to be stabilized, they must be dehydrated to a solid state and this is carried out by freeze-drying also known as lyophilization , gelsication or drying by sublimation . The dried product can be readily redissolved or resuspended by the addition of water prior to use, a procedure known as reconstitution.


principle The main principle involved in freeze drying is a phenomenon called sublimation, where water passes directly from solid state (ice) to the vapor state without passing through the liquid state. Sublimation of water can take place at pressures and temperature below triple point i.e. 4.579 mm of Hg and 0.0099 degree Celsius. The material to be dried is first frozen and then subjected under a high vacuum to heat (by conduction or radiation or by both) so that frozen liquid sublimes leaving only solid ,dried components of the original liquid.


FREEZE DRYERS Freeze dryers are composed of four basic components: 1. A chamber for Freezing and vacuum drying, 2. A vacuum source, 3. A heat source, and 4. A vapor-removal system.

Lyophilization Equipment ::

Lyophilization Equipment : A lyophilizer consists of a vacuum chamber that contains product shelves capable of cooling and heating containers and contents. A vacuum pump, A refrigeration unit and associated controls are connected to the vacuum chamber. Chemicals are generally placed in containers such as glass vials that are placed on the shelves within the vacuum chamber. Cooling elements within the shelves Freeze the product. once the product is frozen, the vacuum pump evacuates the chamber and the product is heated. Heat is transferred by thermal conduction from the shelf, through the vial, and ultimately to the product.


Processing: The fundamental process steps are: 1. Freezing : The product is frozen. This provides a necessary condition for low temperature drying. 2. Vacuum : After freezing, the product is placed under vacuum. This enables the frozen solvent in the product to vaporize with out passing through liquid phase, a process known as sublimation. 3. Heat : Heat is applied to the frozen product to accelerate sublimation. 4. Condensation : Low-temperature condenser plates remove the vaporized solvent from the vacuum chamber by converting it back to a solid. This completes the separation process.

The freeze drying process::

The freeze drying process: There are four stages in complete drying process: 1. Pretreatment 2. Freezing 3. Primary drying 4. Secondary drying.

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Pretreatment : It includes any method of treating prior to freezing. Methods of pretreatment include, freeze concentration, solute phase concentration, formulation to preserve product appearance, formulation to increase surface area etc…

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Freezing : Freezing is usually done using a Freeze drying machine. In this step it is important to cool the materials below its triple point, the lowest temperature at which solids and liquids phases of the material coexist. This ensures sublimation rather than melting.


, Primary drying : During the primary drying the pressure is lowered, and enough heat is supplied to the material for the water to sublimate. In this phase about 95% of water in the material gets sublimated. This phase may be slow (can be several days in the industry) because, if too much heat is added, the material’s structure could be altered. Pressure is controlled through the application of partial vacuum.

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Secondary drying : The secondary drying phase aims to remove unfrozen water molecules, since the ice was removed in primary drying phase. In this phase the temperature is raised than primary drying phase and can be above 0 °C. Usually the pressure is lowered in this phase to encourage desorption. After the freeze-drying process is complete, the vacuum is usually broken with an inert gas, such as nitrogen, before the material is sealed. At the end of the operation, the final residual water content in the product is extremely low, around 1% to 4%.

Lyophilization Container Requirements:

Lyophilization Container Requirements The container in which a substance is lyophilization must permit thermal conductivity, be capable of tightly sealed at the end of lyophilization cycle and minimize the amount of moisture to permeate its walls and seal. The enclosed reagent can only remain properly lyophilized if the container in which they processed meet the requirements.


FREEZE-DYERES Product viewable single shelf Freeze-dryer Development Freeze-dryer

Production Freeze-dryer:

Production Freeze-dryer


Advantages 1.Product is stored in dry state-few stability problems. 2.Product is dried without elevated temperatures. 3.Good for oxygen and/or air-sensitive drugs. 4.Rapid reconstitution time. 5.Constituents of the dried material remain homogenously dispersed. 6.Product is process in liquid form. 7.Sterility of product can be achieved and maintained.


Disadvantages 1. Volatile compounds may be removed by high vacuum. 2. Single most expensive unit operation. 3. Stability problems associated with individual drugs. 4. Some issues associated with sterilization and sterility assurance of the dryer chamber and aseptic loading of vials into the chamber. 5. High energy costs (2-3times more than other methods). 6. Long process time.

Applications ::

Applications : Pharmaceutical and biotechnology : Pharmaceutical companies often use freeze-drying to increase the shelf life of products, such as vaccines and other injectables.By removing the water from the material and sealing the material in a vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection. Food Industry :Freeze-drying is used to preserve food and make it very lightweight. The process has been popularized in the forms of freeze-dried ice cream , an example of astronaut food .

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Technological Industry : In chemical synthesis , products are often freeze-dried to make them more stable, or easier to dissolve in water for subsequent use. In bioseparations, freeze-drying can be used also as a late-stage purification procedure, because it can effectively remove solvents. Furthermore, it is capable of concentrating substances with low molecular weights that are too small to be removed by a filtration membrane. Other Uses : Organizations such as the Document Conservation Laboratory at the United States National Archives and Records Administration (NARA) have done studies on freeze-drying as a recovery method of water-damaged books and documents. In bacteriology freeze-drying is used to conserve special strains .


Acknowledgement I thank Mr. Ashok Mateti for giving his valuable suggestions.

References ::

References : The Theory and Practice of Industrial Pharmacy – By Leon Lachman, Herbert A. Lieberman, Joseph L. Kanic (THIRD EDITION) Remington. Lyophilization : compiled by Dr. Thanaset Senawong, Biochemistry, Science KKU

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Thank you.