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1. FREEZE DRYING
(LYOPHILIZATION)
Ravish Yadav

2. introduction
• Lyophilization /freeze drying a dehydration process used to
completely remove water from the materials while leaving the
basic structure and composition of the material intact.
•The commercial process was introduced at
the time of II world war & found its first
application in preservation of blood plasma,
manufacture of penicillin and other antibiotics.
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3. IMPORTANCE OF LYOPHILIZATION
• Sufficient porosity and surface area to permit rapid
reconstitution
• Enhanced product stability in a dry state
• Elegance
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4. • Phase :defined as any homogenous and physical part of system -
mechanically seperated from the other parts of the system.
• Triple point :point were 3 phases liquid,solid,vapour coexist at
particular temperature and pressure.
• Latent heat : heat is gained by a substance or system without
accompanying rise in temperature during a change of a stage
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5. • Eutetic point : A eutectic system is a mixture of chemical compounds
that has a single chemical composition that solidifies at a lower
temperature than any other composition made up of the same
ingredients. This composition is known as the eutectic composition
and the temperature is known as the eutectic temperature.
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6. PRINCIPLES INVOLVED IN FREEZE
DRYING
• Water is removed from frozen state by sublimation
• Drying is achieved by subjecting material to temperature and
pressures below triple point.
• The major factors that determine the phase which substance
takes place depends on
1. temperature
2. Pressure
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7. If temperature is b/w sea level
freeze point(320F/ 00 C) and
the sea level B.P
(2120F/1000C) the water takes
a liquid form.
If the temperature increases
above 320F while keeping the
pressure below 1 atm, the
water is warm enough, but
there is no enough pressure
for a liquid to form. It become
a gas
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8. Freeze drying process
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9. PROCESS OVERVIEW
• Vials are aseptically filled with solution/suspension
to be freeze dried and are usually partially
stoppered with special rubber closure that allow
escape of water vapor.
• Transferred under aseptic conditions into metal
trays of freeze drier .
• Trays are placed on shelves containing internal
channels allowing circulation of suitable heat
transfer fluids.
• The temperature is lowered for complete
solidification of the contents in the vial.
• Then the chamber is evacuated until the pressure is
less than V.P of ice at the temperature of product .
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10. • After the pressure is reached, heat
is applied to the shelves to provide
energy required for sublimation of
ice
• As the drying proceeds the frozen
layer decreases in thickness and the
thickness of the partially dried solid
increases- this phase is called
PRIMARY DRYING
• When the ice is gone additional
drying time is required to remove
water adsorbed to, or trapped by the
solid matrix-this is called
SECONDARY DRYING
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11. STAGES OF LYOPHILIZATION PROCESS
• Preparation and pretreatment
• freezing for solidifying water
• Primary drying (sublimation of ice under vacuum)
• Secondary drying (removal of residual moisture under high vacuum)
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12. 1. Freezing of the product
A. Phase diagram of water.
B. Freezing of aqueous solution.
C. Thermal treatment.
D. Characterization of freezing behavior.
2. Primary Drying
A. Sublimation
B. Heat transfer in Primary Drying.
C. Mass transfer in Primary Drying.
3. Secondary Drying
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13. FREEZING PROCESS
• This is the important, since microstructure formed
during the freezing determines the quality of final
product and rates of primary and secondary drying
• Physical events associated with the freezing process
-Super cooling
-Ice crystallization ( primary)
-Concentration of solutes during ice crystal growth
-Crystallization of the solute
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14. (A) Phase diagram of water
• At the tripe point (0.0098 0 C &
4.58mm Hg) solid, liquid and
gases co-exist in equilibrium .
• Freeze drying takes place below
triple point, where water passes
from the solid phase directly to
V.P without intermediate liquid
phase
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15. (B) Freezing of aqueous Solution:
• ab- product temp. decreases below
equilibrium freezing point.
• b- nucleation and crystal growth
of ice crystals occur - energy is
released , temp increases to Tf .
• Cooling then continues from Tf
to -degrees C ,with crystal
growing & interstitial fluid
becoming more concentrated
• At point C- Crystallization of
concentrated interstitial fluid is
initiated.
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16. • The intersection of the lines at point b is the eutectic point
which for sodium chloride is -21.5°C.
• The eutectic temperature is important in freeze drying because
it represents the maximum allowable product temperature
during primary drying
• If product temperature exceeds the eutectic temperature while
ice is still present, drying takes place from the liquid state
instead of the solid state and the desirable properties of a
freeze dried product are lost
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17. • Glass transition temperature:
- In most cases, solute doesn’t
crystallize during freezing - different
type of behavior is observed.
-Tg (glass transition temperature)
-It applies to amorphous systems,
which corresponds to change in the
viscosity of the solution from a
viscous liquid to glass.
- Tg is similar to that of eutectic
temp.
- If the product temp exceed Tg the
product undergoes collapse
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18. C. Thermal treatment:
• A solute of NaCl crystallize readily from solution during freezing
• Because of super cooling and rapid rate of freezing once ice crystals are nucleated, a
metastable amorphous solute may formed
• If system is then warmed to some temperature above the Tg and below the melting
point, the solute may crystallize
D. Characterization of freezing behavior
• This analysis help to determine whether the active component crystallizes upon on
freezing and the effect of excipients.
• The common methods for analysis of formulation to be F.D are
- Thermal analysis .
- Thermoelectric analysis.
- Freeze dried microscopy.
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19. PRIMARY DRYING
• Pressure is lowered and enough heat is supplied to the material for the
water to sublimate.
• 95% of the water in the material is sublimated
• The driving force for sublimation - difference b/n the V. P of ice at the
sublimation front and the partial pressure of water vapor in freeze dry
chamber
A. Sublimation of ice :
The rate of sublimation W for any substance is given by
W = 5.83 x 10-5 Pµ (M/T)
where,
Pµ= vapor pressure
M = molecular weight
T= temperature
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20. B. Transfer operation in Primary Drying:
• Transfer operations - driving force / resistance.
• The over all drying rate - driving force / sum of a series of
resistances to either heat or mass transfer
Heat transfer in Primary Drying:
• Transfer of heat from source i.e heating shelf to the product is
often the rate limiting step .
• 3 basic mechanism for heat transfer.
-Conduction
-Convection
- Radiation
• conduction is the primary mechanism of heat transfer.
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21. • Heat transfer by conduction is given by Fourier's law
dQ/dt =-k A dT/dX
dQ/dt= rate of heat transfer
A = area at right angle to direction of heat flow
dT/dx =temperature gradient
k =thermal conductivity constant
Mass transfer in Primary drying:
• Refers to the transfer of water vapor from the product through open
channels, created by the prior sublimation of ice to the condenser.
The sublimation rate is expressed as
Sublimation rate = pressure difference/resistance.
• The total resistance to mass transfer is the sum of several resistances in
the series of dried product, vial, chamber
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22. SECONDARY DRYING
•Remove unfrozen water molecules since the ice
was removed in the primary drying phase.
•Temperature is raised, to break physico-
chemical interaction formed b/n water
molecules and frozen material.
•Chamber pressure is decreased to the lowest
attainable level which favor desorption of water.
•The amount of residual water to be removed
depends on whether solute is crystallize before
primary drying .
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23. Factors affecting process rate
• Depth of product in container
• Vapour pressure differential
• Amount of solid in the product, their particle size & their
thermal conductance
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24. • PROCESS MONITORING:
Because of the importance of temperature and pressure in defining
the relative rate of heat and mass transfer in F.D,
Temperature measurement
• Different types used depend on temp. range,sensitivity accuracy,
reproducibility and cost
- Resistance thermometer (frequently used)
- Thermocouples
- Thermistors
Pressure measurement
• Manometers are used for pressure measurement
-Mercury manometer
-Capacitance manometer( frequently used)
-Mechanical manometer
-Thermal conductivity manometer.
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25. Process variables in F.D.Cycle
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26. USES
• Production of dosage forms
• For drying number of products
 Blood plasma and its fractionated products.
 Bacterial and viral cultures.
 Human tissue (arteries and corneal tissue).
 Antibiotics and plant extracts.
 Steroids, vitamins and enzymes.
• Freeze dried roses used in the wedding decoration.
• To restore water damaged materials, such as rare and valuable
manuscripts.
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27. Advantages
The entire operation is done below freezing point. This offers
several advantages.
• Thermolabile materials can be dried
• It is porous and uniform. The reconstitution - easy.
• Denaturation does not occur
• Migration of salts and other solutes does not take place.
• Loss of volatile material is less.
• Moisture level can be kept as low as possible.
• Sterility can be maintained
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28. disadvantages
• The process is very slow and uses complicated plant, which is very
expensive.
• It is not a general method of drying, but is limited to certain types
of valuable products that cannot be dried by any other means.
• The period of drying is high. Time cannot be shortened.
• It is difficult to adopt the method for solutions containing non-
aqueous solvents.
• The product is prone to oxidation, due to high porosity and large
surface area, therefore product should be packed in vacuum or
using inert gas or in container.
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29. REFERENCES
• C.V.S Subrahmanyam, Pharmaceutical engineering, Vallabh Prakashan publications, Delhi, 2006 ,
P.140-145
• Lachman,Herbert A. Lieberman, Pharmaceutical dosage forms, 4th edition, Varghese Publications,
New york, 2002, P.163-232
• Louis Rey, Joan C. May, Freeze Drying / Lyophilization of Pharmaceutical and Biological
Products, 2nd edition, Taylor and Francis Group publications, Delhi, 2003 P.1-32.
• http://www.rpi.edhttp://www.scribd.com/doc/377243/Lyophilization-
• Basicsu/dept/chem-eng/Biotech-Environ/LYO/definition.html
• http://www.rpi.edu/dept/chem-eng/Biotech-Environ/DOWNSTREAM/fig4.html
• http://www.scribd.com/doc/377243/Lyophilization-Basics
• http://www.freezedrying.com/freeze_drying_principles.html
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