Lyophilization

Fts steril

1. LYOPHILIZATION

2. CONTENTS
Definition
Principle
Components of freeze dryer
Steps involved in lyophilization
Advantages of freeze drying over conventional drying
Advantages
Disadvantages
Applications
Conclusion
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
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.
Lyophilization is performed at temperature and pressure
conditions below the triple point, to enable sublimation of ice.
The entire process is performed at low temperature and pressure
by applying vacuum, hence is suited for drying of thermolabile
compounds.
The concentration gradient of water vapour between the drying
front and condenser is the driving force for removal of water
during lyophilization.

5. Lyophilizationiscarriedoutbelowthetriplepointtoenable
sublimationofice.
Fig 1. Phase diagram showing the triple point of water at 0.01°C,
0.00603 atm.

6. COMPONENTS OF FREEZE DRYER

7. FREEZE DRYER DESIGN
ESSENTIALCOMPONENTS
CHAMBER
–Thisisthevacuumtightbox,sometimescalledthelyophilization
chamberorcabinet.
–Thechambercontainsshelforshelvesforprocessingproduct.
–Thechambercanalsofitwithastopperingsystem.
–Itistypicallymadeofstainlesssteelandusuallyhighlypolished
ontheinsideandinsulatedandcladontheoutside.
–Thedoorlockingarrangementbyahydraulicorelectricmotor.
SHELVES
–Theshelfactasaheatexchanger,supplyingenergytothe
productduringtheprimaryandsecondarydryingsegmentsof
thefreezedryingcycle
–Theshelveswillbeconnectedtothesiliconeoilsystemthrough
eitherfixedorflexiblehoses.

8. REFRIGERATION SYSTEM
–The product to be freeze dried is frozen whilst on the
shelves.
–Compressors or sometimes-liquid nitrogen supplies the
cooling energy.
–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. SHELF FLUID SYSTEM
–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.
–This energy exchange is traditionally done by circulating a
silicone oil through the shelves at a desired temperature.
–The temperature is set in an external heat exchange system
consisting of cooling heat exchangers and an electrical
heater.

10. PROCESS CONDENSER
–The process condenser is sometimes referred as just the condenser or the
cold trap.
–It is designed to trap the solvent, which is usually water, during the
drying process.
–The process condenser will consist of coils or sometimes plates which
are refrigerated to allow temperature.
–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.
–Hence there is designation “external condenser” and “internal
condenser”. Physically, the external condenser is traditionally placed
behind the chamber.
–For an internal condenser the refrigerated coils or plates are placed
beneath the shelves. The position of the condenser does not affect
trapping performance.

11. STEPS INVOLVED IN LYOPHILIZATION
FREEZING STAGE
PRIMARY DRYING STAGE
SECONDARYDRYING STAGE
PACKING
PRETREATMENT

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
•Theproductmustisfrozentoalowenoughtemperaturetobecompletely
solidify.
•Themethodofprefreezingandthefinaltemperatureofthefrozenproduct
canaffecttheabilitytosuccessfullyfreezedrythematerial.
•Rapidcoolingresultsinsmallicecrystals,usefulinpreservingstructuresto
beexaminedmicroscopically,butresultinginaproductthatis,more
difficulttofreezedry.
•Slowercoolingresultsinlargeicecrystals.

14. •Mostsamplesthataretobefreezedriedareeutectics,which
aremixturesofsubstancesthatfreezeatlowertemperature
thanthesurroundingwater.
•Itisveryimportantinfreeze-dryingtoprefreezetheproduct
tobelowtheeutectictemperaturebeforebeginningthefreeze-
dryingprocess.
•Thesecondtypeoffrozenproductisasuspensionthat
undergoesglassformationduringthefreezingprocess.

15. 3. PRIMARY DRYING
•Afterprefreezingtheproduct,conditionsmustbeestablishedinwhichice
canberemovedfromthefrozenproductviasublimation,resultinginadry,
structurallyintactproduct.
•Thisrequiresverycarefullycontrolofthetwoparameters.
1.Temperature(-10°Cto30°C)and
2.Pressureinvolvedinfreeze-dryingsystem(50mmHg).
•Therateofsublimationoficefromafrozenproductdependsuponthe
differenceinvaporpressureoftheproductcomparedtothevaporpressure
oftheicecollector.

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
•Afterprimaryfreeze-dryingabout7-8%residualmoisturecontentis
presentsocontinuesdryingatwarmertemperatureisnecessarytoreduce
theresidualmoisturecontenttooptimumvalues.
•Thisprocessiscalled‘IsothermalDesorption’astheboundwateris
desorbedfromtheproduct.
•Secondarydryingisnormallycontinuedataproducttemperaturehigher
thanambientbutcompatiblewiththesensitivityoftheproduct.
•Incontrasttoprocessingconditionsforprimarydryingwhichuselowshelf
temperatureandamoderatevacuum,desorptiondryingisfacilitatedby
raisingshelftemperature(50to60°C)andreducingchamberpressuretoa
minimum.

19. •Careshouldbeexercisedinraisingshelftemperaturetoo
highly;since,proteinpolymerizationorbiodegradationmay
resultfromusinghighprocessingtemperatureduring
secondarydrying.
•Secondarydryingisusuallycarriedoutforabout10-20hours,
whereasprimarydryingiscarriedoutfor2hours.

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 0-150
o
C 200-300
o
C
Oxygen exposure Verylow High
Retained volatiles Excellent Poor

22. SOME LYOPHILIZED FORMULATIONS
Drug Category RouteOf
Administration
Marketed Name
Amphotericin B&
Cholestryl sulphate
Anti-fungal IV Infusion at 2-4
mg/kg/hr
Amphotec®
(Sequus
pharmaceuticals)
Chlorthiazide
sodium
Diuretic &anti-
hypertensive
IV Infusion , IV
bolus
Diuril®
(Merck)
Cisplastin Anti-neoplastic IV Infusion,
Platinol®
(Bristol Myers
Oncolgy)
Gemcitabine Anti-neoplastic IV Infusion over30
min
Genzer®
(Lilly)
Thiopental sodiumShort acting
anesthetic IV Infusion
Pentothalsodium®
(Baxter)

23. ADVANTAGES
Thermo labile materials can be dried
Loss of volatile materials is less.
Moisture level can be kept as low as possible
Sterility can be maintained
Final product can be stored in ambient temperature, if well
sealed with inert atmosphere

24. DISADVANTAGES
Equipment & running costs are high
Increased handling and processing time.
Need for sterile diluents upon reconstitution.
It is difficult to adopt the method for solutions containing non
aqueous solvents
Product 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
A freeze dried product with the best attributes and quality.
In freeze drying, minimal structural changes or shrinkage.
In freeze drying process, nutrients are largely retained.
Freeze drying system includes vacuum and refrigeration equipments. The
initial costs are relatively high up to 4 times than conventional drying.

27. REFERENCES
1.LachmanL ,The theory & practice of Industrial Pharmacy,
Varghese publication,Bombay,Pg no: 762.
2.SubramanyamCVS , Pharmaceutical
Engineering,Published by Vallabh Prakashan,
Pg no: 307
3.Remington, The Science & Practice of Pharmacy,21
st
edition,vol 2,pg no. 959.