Lyophilization, or freeze drying, is a process used to preserve thermolabile materials such as pharmaceuticals and foods. It involves freezing the material and then reducing pressure and adding heat to allow the frozen solvent, such as water, to sublime from the solid phase to gas. This avoids damage from melting. Key advantages are retaining structure, heat sensitivity, and allowing storage at room temperature. The process uses vacuum chambers, refrigeration systems, and condensers to freeze and dry the material in stages. Common applications are heat-sensitive drugs and vaccines.
2. CONTENTS
ď Definition
ď Principle
ď Components of freeze dryer
ď Steps involved in lyophilization
ď Advantages of freeze drying over conventional drying
ď Advantages
ď Disadvantages
ď Applications
ď Conclusion
ď References
3. DEFINITION
A stabilizing process in which a substance is first frozen
and then the quantity of the solvent is reduced, first by
sublimation (primary drying stage) and then desorption
(secondary drying stage) to values that will no longer
support biological activity or chemical reactions.
4. PRINCIPLE
ď§ Lyophilization is carried out using a simple principle of physics
sublimation. Sublimation is the transition of a substance from the
solid to the vapour state, without first passing through an
intermediate liquid phase.
ď§ Lyophilization is performed at temperature and pressure
conditions below the triple point, to enable sublimation of ice.
ď§ The entire process is performed at low temperature and pressure
by applying vacuum, hence is suited for drying of thermolabile
compounds.
ď§ The concentration gradient of water vapour between the drying
front and condenser is the driving force for removal of water
during lyophilization.
5. ď Lyophilization is carried out below the triple point to enable
sublimation of ice.
Fig 1. Phase diagram showing the triple point of water at 0.01°C,
0.00603 atm.
7. FREEZE DRYER DESIGN
ď ESSENTIAL COMPONENTS
ďź CHAMBER
â This is the vacuum tight box, sometimes called the lyophilization
chamber or cabinet.
â The chamber contains shelf or shelves for processing product.
â The chamber can also fit with a stoppering system.
â It is typically made of stainless steel and usually highly polished
on the inside and insulated and clad on the outside.
â The door locking arrangement by a hydraulic or electric motor.
ďź SHELVES
â The shelf act as a heat exchanger, supplying energy to the
product during the primary and secondary drying segments of
the freeze drying cycle
â The shelves will be connected to the silicone oil system through
either fixed or flexible hoses.
8. ďź REFRIGERATION SYSTEM
â The product to be freeze dried is frozen whilst on the
shelves.
â Compressors or sometimes-liquid nitrogen supplies the
cooling energy.
â Most often multiply compressors are needed and the
compressor may perform two duties, one to cool the
shelves and the second to cool the process condenser.
9. ďź SHELF FLUID SYSTEM
â The freeze-drying process requires that the product is first
frozen and then energy in the form of heat is applied
throughout the drying phases of the cycle.
â This energy exchange is traditionally done by circulating a
silicone oil through the shelves at a desired temperature.
â The temperature is set in an external heat exchange system
consisting of cooling heat exchangers and an electrical
heater.
10. ďź PROCESS CONDENSER
â The process condenser is sometimes referred as just the condenser or the
cold trap.
â It is designed to trap the solvent, which is usually water, during the
drying process.
â The process condenser will consist of coils or sometimes plates which
are refrigerated to allow temperature.
â These refrigerated coils or plates may be in a vessel separate to the
chamber, or they could be located within the same chamber as the
shelves.
â Hence there is designation âexternal condenserâ and âinternal
condenserâ. Physically, the external condenser is traditionally placed
behind the chamber.
â For an internal condenser the refrigerated coils or plates are placed
beneath the shelves. The position of the condenser does not affect
trapping performance.
12. 1. PRETREATMENT
⢠Pretreatment includes any method of treating the product prior to freezing.
⢠This may include
1. Concentrating the product,
2. Formulation revision (i.e., addition of components to increase stability
and/or improve processing),
3. Decreasing a high vapor pressure solvent or
4. Increasing the surface area.
13. 2. FREEZING
⢠The product must is frozen to a low enough temperature to be completely
solidify.
⢠The method of prefreezing and the final temperature of the frozen product
can affect the ability to successfully freeze dry the material.
⢠Rapid cooling results in small ice crystals, useful in preserving structures to
be examined microscopically, but resulting in a product that is, more
difficult to freeze dry.
⢠Slower cooling results in large ice crystals.
14. ⢠Most samples that are to be freeze dried are eutectics, which
are mixtures of substances that freeze at lower temperature
than the surrounding water.
⢠It is very important in freeze-drying to pre freeze the product
to below the eutectic temperature before beginning the freeze-
drying process.
⢠The second type of frozen product is a suspension that
undergoes glass formation during the freezing process.
15. 3. PRIMARY DRYING
⢠After prefreezing the product, conditions must be established in which ice
can be removed from the frozen product via sublimation, resulting in a dry,
structurally intact product.
⢠This requires very carefully control of the two parameters.
1. Temperature (-10 °C to 30°C) and
2. Pressure involved in freeze-drying system(50mmHg).
⢠The rate of sublimation of ice from a frozen product depends upon the
difference in vapor pressure of the product compared to the vapor pressure
of the ice collector.
16. ⢠Heat enters the products by one of several mechanisms: -
1. By direct contact between the container base and the
shelf, so here the shape of the container is important.
2. By conduction across the container base and then through
the frozen mass to the drying front (also called the
sublimation interface)
3. By gaseous convection between the product and residual
gas molecules in the chamber.
4. By radiation
⢠Convection is certainly the most important of these
mechanisms
17. DETERMINATION OF THE END OF PRIMARY
DRYING
⢠Several analytical methods are available for
determining that primary drying is
complete. The most basic method is to
monitor the product temperature with a
thermocouple probe. The measured product
temperature will be colder than the shelf
temperature set point during active primary
drying because the heat from the shelf is
being used for the sublimation phase
change. When sublimation of ice crystals is
complete, the product temperature will
increase and approach the shelf
temperature. When the product temperature
equals the shelf temperature, it can be
inferred that primary drying is complete.
18. 4. SECONDARY DRYING
⢠After primary freeze-drying about 7-8% residual moisture content is
present so continues drying at warmer temperature is necessary to reduce
the residual moisture content to optimum values.
⢠This process is called âIsothermal Desorptionâ as the bound water is
desorbed from the product.
⢠Secondary drying is normally continued at a product temperature higher
than ambient but compatible with the sensitivity of the product.
⢠In contrast to processing conditions for primary drying which use low shelf
temperature and a moderate vacuum, desorption drying is facilitated by
raising shelf temperature(50 to 60°C) and reducing chamber pressure to a
minimum.
19. ⢠Care should be exercised in raising shelf temperature too
highly; since, protein polymerization or biodegradation may
result from using high processing temperature during
secondary drying.
⢠Secondary drying is usually carried out for about 10-20 hours,
whereas primary drying is carried out for 2hours.
20. PACKING
⢠After drying the vacuum is
replaced by filtered dry air or
nitrogen to establish atmospheric
pressure
⢠Ampoules are sealed by either tip
sealing or pull sealing method
⢠Vials and bottles are sealed with
rubber closures and aluminum
caps
21. ADVANTAGES OF FREEZE DRYING OVER
CONVENTIONAL DRYING
Product quality Freeze drying Conventional drying
Form of wet material
to be dried
Whole, liquids
Pieces, powders
Pieces
Dry shape and form Maintained Shriveled
Appearance Nearly same Shriveled
color Maintained Faded
Rehydration Fast Slow
Heat exposure 0-150oC 200-300oC
Oxygen exposure Very low High
Retained volatiles Excellent Poor
22. SOME LYOPHILIZED FORMULATIONS
Drug Category Route Of
Administration
Marketed Name
Amphotericin B &
Cholestryl sulphate
Anti-fungal IV Infusion at 2-4
mg/kg/hr
AmphotecÂŽ
(Sequus
pharmaceuticals)
Chlorthiazide
sodium
Diuretic & anti-
hypertensive
IV Infusion , IV
bolus
DiurilÂŽ
(Merck)
Cisplastin Anti-neoplastic IV Infusion,
PlatinolÂŽ
(Bristol Myers
Oncolgy)
Gemcitabine Anti-neoplastic IV Infusion over 30
min
GenzerÂŽ
(Lilly)
Thiopental sodium Short acting
anesthetic IV Infusion
Pentothal sodiumÂŽ
(Baxter)
23. ADVANTAGES
ďThermo labile materials can be dried
ďLoss of volatile materials is less.
ďMoisture level can be kept as low as possible
ďSterility can be maintained
ďFinal product can be stored in ambient temperature, if well
sealed with inert atmosphere
24. DISADVANTAGES
ďEquipment & running costs are high
ďIncreased handling and processing time.
ď Need for sterile diluents upon reconstitution.
ďIt is difficult to adopt the method for solutions containing non
aqueous solvents
ďProduct is prone to oxidation so it should be packed in vacuum
25. APPLICATIONS
⢠PHARMACEUTICAL
1. Pharmaceutical companies often use freeze-drying to
increase the shelf life of products, such as vaccines and
other injectables.
2. 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
1. Freeze-drying is used to preserve food and make it very
lightweight.
2. The process has been popularized in the forms of freeze-
dried ice cream.
26. CONCLUSION
ď A freeze dried product with the best attributes and quality.
ď In freeze drying, minimal structural changes or shrinkage.
ď In freeze drying process, nutrients are largely retained.
ď Freeze drying system includes vacuum and refrigeration equipments. The
initial costs are relatively high up to 4 times than conventional drying.
27. REFERENCES
1. Lachman L ,The theory & practice of Industrial Pharmacy,
Varghese publication,Bombay,Pg no: 762.
2. Subramanyam CVS , Pharmaceutical
Engineering,Published by Vallabh Prakashan,
Pg no: 307
3. Remington, The Science & Practice of Pharmacy,21st
edition,vol 2,pg no. 959.