15 lyophilization

UNZA Pharmacy Training Lecture notes

2. 6/21/2020 2
LYOPHILIZATION

3. CONTENTS
Definition
Principle
Components of freeze dryer
Steps involved inlyophilization
Advantages of freeze drying over conventionaldrying
Advantages
Disadvantages
Applications
Conclusion
References

4. DEFINITION
A stabilizing process in which a substance is firstfrozen
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 chemicalreactions.

5. PRINCI PLE
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 liquidphase.
Lyophilization is performed at temperature and pressure
conditions below the triple point, to enable sublimation ofice.
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
duringlyophilization.

6. iscarriedoutbelowthetriplepointtoenableLyophilization
sublimation ofice.
Fig 1. Phase diagram showing the triple point of water at0.01°C,
0.00603atm.

7. COMPONENTS OF FREEZE DRYER

8. FREEZE DRYERDESIGN
ESSENTIALCOMPONENTS
CHAMBER
–This is the vacuum tight box, sometimes called the lyophilization
chamber orcabinet.
–The chamber contains shelf or shelves for processingproduct.
–The chamber can also fit with a stopperingsystem.
–Itistypicallymadeofstainlesssteelandusuallyhighlypolished
on the inside and insulated and clad on theoutside.
–The door locking arrangement by a hydraulic or electricmotor.
SHELVES
–Theshelfactasaheatexchanger,supplyingenergytothe
productduringtheprimaryandsecondarydryingsegmentsof
thefreezedryingcycle
–The shelves will be connected to the silicone oil system through
either fixed or flexiblehoses.

9. REFRIGERATIONSYSTEM
–The product to be freeze dried is frozen whilst onthe
shelves.
–Compressors or sometimes-liquid nitrogen supplies the
coolingenergy.
–Mostoftenmultiplycompressorsareneededandthe
compressormayperformtwoduties,onetocoolthe
shelvesandthesecondtocooltheprocesscondenser.

10. SHELF FLUIDSYSTEM
–The freeze- drying process requires that the product isfirst
frozen and then energy in the form of heat is applied
throughout the drying phases of thecycle.
–This energy exchange is traditionally done by circulatinga
silicone oil through the shelves at a desiredtemperature.
–The temperature is set in an external heat exchangesystem
consisting of cooling heat exchangers and anelectrical
heater.

11. PROCESSCONDENSER
–The process condenser is sometimes referred as just the condenser orthe
coldtrap.
–It is designed to trap the solvent, which is usually water, duringthe
dryingprocess.
–The process condenser will consist of coils or sometimes plateswhich
are refrigerated to allowtemperature.
–These refrigerated coils or plates may be in a vessel separate tothe
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 thechamber.
–For an internal condenser the refrigerated coils or plates areplaced
beneath the shelves. The position of the condenser does not affect
trappingperformance.

12. STEPS INVOLVED INLYOPHILIZATION
FREEZINGSTAGE
PRIMARYDRYINGSTAGE
SECONDARY DRYINGSTAGE
PACKING
PRETREATMENT

13. 1.PRETREATMENT
•Pretreatment includes any method of treating the product prior tofreezing.
•This mayinclude
1.Concentrating theproduct,
2.Formulation revision (i.e., addition of components to increasestability
and/or improveprocessing),
3.Decreasing a high vapor pressure solventor
4.Increasing the surfacearea.

14. 2.FREEZING
•The product must is frozen to a low enough temperature to becompletely
solidify.
•The method of prefreezing and the final temperature of the frozen product
can affect the ability to successfully freeze dry thematerial.
•Rapidcoolingresultsinsmallicecrystals,usefulinpreservingstructuresto
beexaminedmicroscopically,butresultinginaproductthatis,more
difficulttofreezedry.
•Slower cooling results in large icecrystals.

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

16. 3. PRIMARYDRYING
•Afterprefreezingtheproduct,conditionsmustbeestablishedinwhichice
canberemovedfromthefrozenproductviasublimation,resultinginadry,
structurallyintactproduct.
•This requires very carefully control of the twoparameters.
1.Temperature (-10 °C to 30°C)and
2.Pressure involved in freeze-dryingsystem(50mmHg).
•Therateofsublimationoficefromafrozenproductdependsuponthe
differenceinvaporpressureoftheproductcomparedtothevaporpressure
of the ice collector.

17. •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 thenthrough
the frozen mass to the drying front (also called the
sublimationinterface)
3.By gaseous convection between the product andresidual
gas molecules in thechamber.
4.Byradiation
•Convection is certainly the most important ofthese
mechanisms

18. DETERMINATION OF THE END OFPRIMARY
DRYING
•Several analytical methods are availablefor
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 iscomplete.

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

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

21. PACKING
•After drying the vacuum is
replaced by filtered dry air or
nitrogen to establish atmospheric
pressure
•Ampoules are sealed by eithertip
sealing or pull sealingmethod
•Vials and bottles are sealedwith
rubber closures and aluminum
caps

22. ADVANTAGES OF FREEZE DRYING OVER
CONVENTIONAL DRYING
Productquality Freezedrying Conventionaldrying
Form of wet material
to bedried
Whole, liquids
Pieces,powders
Pieces
Dry shape and form Maintained Shriveled
Appearance Nearly same Shriveled
color Maintained Faded
Rehydration Fast Slow
Heatexposure 0-150
oC 200-300
oC
Oxygenexposure Verylow High
Retainedvolatiles Excellent Poor

23. SOME LYOPHILIZED FORMULATIONS
Drug Category RouteOf
Administration
MarketedName
Amphotericin B &
Cholestrylsulphate
Anti-fungal IV Infusion at2-4
mg/kg/hr
Amphotec®
(Sequus
pharmaceuticals)
Chlorthiazide
sodium
Diuretic &anti-
hypertensive
IV Infusion ,IV
bolus
Diuril®
(Merck)
Cisplastin Anti-neoplastic IVInfusion,
Platinol®
(BristolMyers
Oncolgy)
Gemcitabine Anti-neoplastic IV Infusion over30
min
Genzer®
(Lilly)
Thiopental sodiumShortacting
anesthetic IVInfusion
Pentothalsodium®
(Baxter)

24. ADVANTAGES
Thermo labile materials can bedried
Loss of volatile materials isless.
Moisture level can be kept as low aspossible
Sterility can bemaintained
Final product can be stored in ambient temperature, ifwell
sealedwithinertatmosphere

25. DISADVANTAGES
Equipment & running costs arehigh
Increased handling and processingtime.
Need for sterile diluents upon reconstitution.
It is difficult to adopt the method for solutions containingnon
aqueous solvents
Product is prone to oxidation so it shouldbepackedinvacuum

26. APPLICATIONS
od and make itvery
n the forms of freeze-
•PHARMACEUTICAL
1.Pharmaceutical companies often use freeze- drying to
increase the shelf life of products, such as vaccinesand
otherinjectables.
2.By removing the water from the material and sealingthe
material in a vial, the material can be easily stored,
shipped, and later reconstituted to its original form for
injection.
•FOODINDUSTRY
1.Freeze- drying is used to preservefo
lightweight.
2.The process has been popularizedi
dried icecream.

27. CONCLUSION
A freeze dried product with the best attributes andquality.
In freeze drying, minimal structural changes orshrinkage.
In freeze drying process, nutrients are largelyretained.
Freeze drying system includes vacuum and refrigeration equipments.The
initial costs are relatively high up to 4 times than conventionaldrying.

28. REFERENCES
1.Lachman L ,The theory & practice of IndustrialPharmacy,
Varghese publication,Bombay,Pg no: 762.
2.SubramanyamCVS, Pharmaceutical
Engineering,Published by VallabhPrakashan,
Pg no:307
3.Remington, The Science & Practice ofPharmacy,21
st
edition,vol 2,pg no.959.

29. Any Questions or Additions

30. THANK YOU

31. Definethefollowingterms:
[Lyophilization,etc]
Respondtothefollowingquestions:
Giveadetailedaccountof………………
Explainindetailstheprocessof…………..
Describeindetailswithexamplesthe…………
Withexamples,illustratethepharmaceuticalapplicationsof……………

32. Groupworkdiscussionalquestions:
Explainindetailstheprocessof………
Describewithexamplesindetailsthe…………..
Withexamples,illustratethepharmaceuticalapplicationsof…….