LYOPHILIZATION

BASICS

What is lyophilization ?
❚Lyophilization is defined as a process of making a
product lyophilic i.e. water loving.
❚Material that has been lyophilized has been
described as bone dry.
❚Freeze drying or lyophilization is a process of drying
in which water is sublimated from the product after it
is frozen.
FREEZE DRYING PROCESS
Evolution of freeze drying.

Important terms
❚Phase : a phase is defined as a any homogenous and physical part of
system which is bounded by surface and is mechanicallly seperated from
the other parts of the system.
❚Triple point : it is a point were 3 phases namely liquid,solid and vapour
coexist at particular temperature and pressure.
❚Eutetic point : the components are completely missible with one another in
the liquid state.they do not from any compound and on solidification they
give rise merely to an intimate eutetic mixture and the temperature this
process occur known as eutetic point.
❚Eutetic temperature : temperature at which all the areas of concentrated
solutes are frozen.
❚Latent heat : heat is gained by a substance or system without
accompaining rise in temperature during a change of a stage.

Important terms
❚Latent heat of fusion : it is the amount of heat necessary to convert a unit
mass of substance form solid state to liquid state at temperature .the
pressure being to allow the coexistence of the two phases.
❚Latent of sublimation : it is the amount of heat necessary a unit mass of
substance from solid state to gaseous state at same temperature . The
pressure being to allow the coexistence of the two phases.

Why lyophilization ?
❚Ease of processing a liquid ,hence easy aseptic
handling.
❚Increase stability of a dry powder.
❚Rapid and easy dissolution of dry powder.
❚Enhanced product stability in a dry state.
Disadvantages of lyophilization
❚Increased handling and processing time.
❚Need for sterile diluent upon reconstitution.
❚Cost and complexity of equipment.
Structure of freeze dryer
Drying chamber
❚The drying chamber of freeze dryer consist of a
vaccum tight unit containing loading door and one or
more inspection window. Each chamber contains a
set of shelves that has hydrolic stoppering
mechanism and gas bleed system. Heat is applied
directly through electrical resistance coills or by
circulating hotwater, silicon or glycol.
Condenser
❚The condenser in the freeze dryer is a vacuum tight
unit seperated from chamber by a vacuum valve.
They contained a set of cooling plates refrigerated by
refrigeration system. Condenser is supplied with hot
water defrosting system. It was a cold trap used to
collect the moisture.
Vacuum pump
❚Each freeze dryer was equiped with a two stage
rotary gas ballast vacuum pump.vacuum pump was
an essential component of the freeze dryer and is
required for evacuated envouriment around the
product. Vacuum pump kept the chamber and
condensor sufficiently free from the residual gases,
water vapour stream to be able to flow from the
drying material.

Refrigeration system
❚The freeze dryer is provided with twin independent
direct expansion,single or multi-component
refrigeration plant. The commonly used refrigerant is
Freon R- 502 gas.
Control facilities
❚The freeze dryer is instrumented to control and
operate the various plant components like shelf
staking mechanism,hydraulic stoppering device &
chamber condensor valve.
❚Instrumentation is also available to measure and
record the various process variables like chamber
pressure,shelf temperature, product temperature and
condenser temperature.
Typical lyophilization process
Operation of freezedryer
Operation of freezedryer
❚Secondary drying stage involves the removal of adsorbed
water from the frozen product . This is the water which did
not as a ice during freezing and so did not sublime. To
accomplish the removal of this water the product
temperature is usually raised and the chamber pressure
reduced further. The product is usually processed until there
is less than 1% moisture left in the dried product.
Factors affecting process rate.
❚1) Depth of product in container : the greater the
depth of the product in the container the longer will
be the drying process.
❚2) vapour pressure differential: the actual driving
force for the process is the vapour pressure
differential between the vapour at the surface where
drying of the product is occuring and that at the
surface of the ice on the condenser.
Factors affecting process rate.
❚3) amount of solid in the product, their particle size
& their thermal conductance : the amount of solids in
the product ,their thermal conductance will affect the
rate of drying. The more solid present,the more
impedment will be provided to the escape of the
water vapour.
❚The smaller the ice crystal size ,faster the drying
rate.
Factors affecting process rate.
❚The poor the thermal conducting properties of the
solids in the product , the slower will be the rate of
heat transfer through the frozen material to the
drying boundary.
Factors affecting formulation
❚The active constituent of many pharmaceutical
products is present in such a small quantity that if
freeze dryed alone its prescence will be hard to
detect visually. Therefore excipents often are added
to increase the amount of solids.
❚The solids contents of original products must be
between approx 5 to 25%. Therefore mannitol or
gelatin are used as bulking agents.
Lyophilization cycles- facts
❚Eutectic determination is very essential for
optimizing the drying cycle.
❚For a cycle it is necessary to go atleast 10°c below
eutectic point. Any further reduction in the
temperature will ultimately increase the cycle
time.Also this reduces the drying cycle time by 50%.
❚By proper freezing the ultimate cycle time can be
reduced.
❚Optimizing of the drying cycle is done on lab scale.
Lyophilization cycles- facts
❚In drying the condenser temperature must be
atleast 15°c below the drying temperature.
❚During cycle breakage of vials at final stoppering
stage is seen which is upto 0.25%.this can be
reduced using siliconized rubber stoppers.
❚Cake drying if observed is a result of fast drying.

Lyophilization cycles- facts

❚Greater product thickness in vials will cause more
time to freeze dry the product.
❚Thumb rule for fill volume versus vial capacity is 2ml
for 10ml. But you can go max. upto 50%. But not
more than 50%.
❚The lyophilizer is sterilized after each product
change.
Lyophilization cycles- facts
❚For SIP cycle, it is not necessary to defrost the
condenser chamber. And similarly for CIP cycle.
❚Lyophilizers can be run on less load also, it is not
required to take dummy loads.
❚Cracks in cake come due to thermal changes ,slow
middle steps of drying can remove this.
lyophilizer
Validation of lyophilizer
❚Validation of filling and stoppering process using
media fill.
❚Validation of filling volume into containers.
❚Validation of sterilization of lyophilizer.
❚Validation of handling of partially stoppered vials.
❚Validation of lyophilization cycle using media fill.
❚Validation of the lyophilization cycle based upon
eutectic point of the product.
Validation of lyophilizers
❚Product validation in lyophilizer costs 150% of the
total cost of lyophilizer.
❚It is not necessary to use thermocouples in
production runs.
❚Direct correlation between the thermocouples and
the shelf temperature should be established and
then remove the thermocouples.
Validation of lyophilizers
❚Any minor change in the formula demands complete
validation of the cycle and stability study of the
product.
❚Probe placement in the vials should always be in the
center very close to bottom.
❚It is always recommended to use thermocouples
than R.T.D’s.(PT100).

Validation of lyophilizers
❚Power failures in validation studies should be
included and then stability study should be carried
out.
❚For cycle development always use the product
probes.
❚Hydraulic system validation include checking of
stoppered vials manually.
Finished product testing of lyophilized
products.
❚Dose uniformity - content uniformity and weight
variation.
❚Sterility testing
❚Stability testing - done since some amount of
moisture is still present in 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.