Lyophilization

S. M. Mosghtofa Fariadi Rubal Sr. executive,R & Dh

Lyophilization Andez mountains

Definition
Lyophilization or freeze drying is a

process in which water is removed from a product after it is frozen and placed under a vacuum

Application
Freeze drying is a widely used method for

the stabilization of degraded substances:

- microorganisms - foods

- biological products and

- pharmaceutical products.

The advantages of lyophilization

1.Product is stored in dry state- stability problems are reduced

2.Product is dried without elevated temperatures-heat sensitive products

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 that ensures uniformity

7.Sterility of product can be achieved and maintained.

Disadvantages of lyophilization
1.Volatile compounds may be removed by high vacuum. 2. Single most expensive unit operation. 3. High energy costs (2-3times more than other methods). 4. Long process time.

Related Terminology
Eutectic Point: The lowest temperature at which a substance will

melt.
Triple Point: The temperature at which a substance can remain in

solid, liquid and gaseous form.

Sublimation: Vaporization or evaporation wholly from a solid

phase to gas without melting.

FREEZE DRYING PROCESS

FREEZE DRYING

FREEZING

PRIMARY DRYING OR ICE SUBLIMATION

SECONDARY DRYING OR WATER DESORPTION

The lyophilization process

The lyophilization process generally includes the following steps: Dissolving the drug and excipients in a suitable solvent, Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter. Filling into individual sterile containers and partially stoppering the containers under aseptic conditions.
Transporting the partially stoppered containers to

the lyophilizer and loading into the chamber under aseptic conditions

Typical lyophilization process

Component preparation Washing Sterilization Depyrogenation Compounding Solvent Filling Partial stoppering Tray loading Freezing Freeze drying Filling

Sublimation
Desorption Full stoppering

Excipients
Active Sterile filteration

The lyophilization process

Freezing the solution .

Freezing In this step, it is important to cool the material below its triple point

The lyophilization process

Applying a vacuum to the chamber and heating the

shelves in order to Evaporate the water from the frozen state. Primary drying During the primary drying phase, the pressure is lowered and enough heat is supplied to the material for the water to sublime. Secondary drying The secondary drying phase aims to remove unfrozen water molecules, since the ice was removed in the primary drying phase.

The lyophilization process

Complete stoppering of the vials usually by hydraulic

or screw rod stoppering mechanisms installed in the lyophilizers.

The lyophilization process

Lyophilizer Machine

Structure of freeze dryer

FREEZE DRYER

DRYING CHAMBER

CONDENSOR

VACCUM PUMP

REFRIGERATION CONTROL SYSTEM FACILITIES

Basic Principles of lyophilization process

QUALITY REQUIREMENTS
The most important objective in the developing a freeze dried product is to assure the quality requirements as: the original chemical or biological potency after reconstitution rapid and complete dissolution appropriate residual moisture level, and acceptable cake appearance. This requirements have to be met not only initially but throughout the shelf life of the product

Finished product inspection

Melt back - generally the lyophilized drug is in form

of cake but the cake may collapse due to change from solid to liquid state because of incomplete sublimation. Poor solubility - this may decrease the potency of the drug.

The development of a suitable formulation

The development of a suitable formulation and a freeze-dry cycle requires knowledge of some basic properties, such as: eutectic temperature temperature effect on solubility thermal properties of the frozen solution degree of super-cooling heat transfer properties of the freeze-dryer shelves, the metal trays, the containers and the frozen product equipment design and equipment capability.

OBJECTIVE OF FORMULATOR
Overall cycle to be carried out in the least amount of

time, while providing a stable and efficacious product which:

- contains a low moisture content, - undergoes rapid reconstitution, and - possesses the desired appearance.

Diagram of Water vapor

Factors Affecting Efficiency

sample size

surface area of the sample

thickness of the sample sample characteristics

eutectic temperature
solute concentration instrument factors

condenser temperature
vacuum

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.

CONCLUSIONS

Thank you for attention