Lyophilization, or freeze drying, is a process that stabilizes substances by first freezing them and then removing the solvent through sublimation and desorption, mainly to preserve biological activity and extend shelf life. Developed during World War II, this technique is crucial for thermolabile compounds and involves steps like freezing, vacuum application, heating, and condensation. While it has advantages like maintaining sterility and precise fill weight control, disadvantages include potential damage to biological molecules and high costs.

1. Lyophilization Technology
(Freeze drying)
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2. PHARMA WISDOM HUB

3. Definition
Astabilizing processin which asubstanceisfirst frozen
and then the quantity of the solvent is reduced, first by
sublimation (primary dryingstage) and then desorption
(secondary drying stage)to valuesthat willno longer
support biological activity or chemicalreactions.
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4. History
Freeze drying wasfirst actively developed duringWORLD
WARII transport of serum.
The main aim wasto store the products without
refrigeration andto remove moisture fromthermolabile
compounds.
Atlas in 1961built 6production freeze drying cabinet for
Nestle group in Germany,Holland.
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5. Principle
 Lyophilization iscarried out usingasimple principle of physics sublimation.
Sublimation isthe transitionof asubstancefrom the solid to the vapour state,
without first passingthrough an intermediate liquidphase.
 Lyophilization isperformed at temperature andpressure conditionsbelow the
triple point, to enablesublimationof ice.
 Theentire processisperformed at low temperature and pressureby
applying vacuum,henceissuited for dryingof thermolabilecompounds.
 Theconcentration gradient ofwater vapour between the drying front and
condenseristhe driving force for removal of water duringlyophilization.
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6. Objectivesof lyophilization process
• Topreservethe biological activity of aproduct.
• Toreducethe productweightto lowerthe transportation cost.
• Toextend the shelf life orstability.
• Todry thermolabilematerials.
• Toeliminate the needfor refrigeratedstorage.
• Togetaccurate,steriledosinginto the final productcontainer.
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7. Basiccomponentsof aLyophilizer
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8. STEPS INVOLVED IN LYOPHILIZATION
FREEZING STAGE
PRIMARY DRYING STAGE
SECONDARY DRYING STAGE
PACKING
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9. Processing
Fundamental processstepsare:
1. Freezing:the product isfrozen.Thisprovides anecessary condition for low
temperature
2. Vacuum: after freezing, theproduct isplacedunder vacuum. Thisenablesthe
frozen solvent in the product to vaporize without passingthrough liquid phase,a
processknown as SUBLIMATION.
3. Heat:Heatisappliedto the frozenproductto accelerate sublimation.
4. Condensation: Low-temperature condenserplatesremove the vaporized
solvent from the vacuumchamber by converting it backtoasolid. This
completesthe process
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10. Lyophilizationprocess
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11. FreezeDrying
Freezing the productsolution to atemperature belowitseutectic
temperature.
Decrease the shelf temperature to-50oc.
Low temperature andlow atmosphericpressurearemaintained.
Freons areusedasrefrigerant.
Formation of icecrystalsoccurs.
The rate of icecrystallization define the freezing processandefficiency of primary
drying.
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12. PrimaryDrying(Sublimation)
Heat isintroduced from shelf to the product under graded
control by electrical resistancecoils or circulatingsilicone.
The temperature andpressureshould be below the triple
point of water i.e., 0.0098°Cand4.58mmHg.
The driving force isvapor pressuredifference between the
evaporating surfaceandthecondenser.
Easily removesmoisture up to 98%to 99%.
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13. SecondaryDrying (Desorption)
The temperature israised to 50°C–60°Candvacuum is
lowered about50mmHg.
Bound waterisremoved.
Rate of drying islow.
I t takesabout 10-20hrs.
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14. Lyophilization Process
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15. Packing
• After drying the vacuumisreplaced by
filtered dry air or nitrogen to
establish atmosphericpressure
• Ampoulesare sealedby eithertip
sealingor pull sealingmethod
• Vialsand bottles are sealedwith
rubber closuresand aluminumcaps
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16. FreezeDryProduct Characteristics
• Sufficientstrength
• Uniformcolor
• Sufficiently dry
• Sufficiently porous
• S
terile
• Freeof pyrogensandparticulates
• Chemicallystable both in dry state andreconstitution
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17. Productquality Freezedrying Conventionaldrying
Formof wetmaterial to be
dried
Whole, liquids Pieces,
powders
Pieces
Dryshapeandform Maintained Shriveled
Appearance Nearlysame Shriveled
color Maintained Faded
Rehydration Fast Slow
Heatexposure 0-150oC 200-300oC
Oxygenexposure Verylow High
Retainedvolatiles Excellent Poor
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18. Advantagesof Lyophilization
Removalof water at low
temperature
Thermolabile materials canbedried.
Compatible with aseptic operations
More precise fill weight control
Sterility canbemaintained.
Reconstitution iseasy
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19. Disadvantagesof Lyophilization
Many biological molecules are damagedby the stressassociated
with freezing, freeze-drying, orboth.
The product isprone to oxidation, due to high porosity and large surface
area.Therefore the product should bepackedin vacuumor usinginert gas
or in acontainer impervious to gases
Cost maybeanissue,dependingon the product
Long timeprocess PHARMA WISDOM HUB

20. CommonLyophilized Products
Pharmaceuticals –large and smallmolecules
Bacteria
Viruses
Vaccines
Plasma
Small zoologicalspecimens
 Fruit
Coffee
Flowers
Water-Damaged documents.
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21. Applications
Pharmaceutical andbiotechnology–to increasethe shelf lifeof products, suchasvaccines
andotherinjectables
Food industry
 to preservefood, very lightweight.
 to produce essencesor flavouringagents.
 freeze-driedfruits areproduced.
 Culinaryherbsarepreserved.
 Instant coffee powder isprepared.
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22. Technical Industries
 in chemicalsynthesis
 Formation of stableproducts.
Others
Flora& faunapreservation
 recovery of water-damagedbooksanddocuments.
Applications
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23. SomeLyophilized Formulations
Drug Category RouteOf
Administration
MarketedName
Amphotericin B& Cholestryl
sulphate
Anti-fungal IVInfusion at2-4 mg/kg/hr Amphotec® (Sequus
pharmaceuticals)
Chlorthiazide
sodium
Diuretic &anti-
hypertensive
IVInfusion ,IV bolus Diuril®
(Merck)
Cisplastin Anti-neoplastic IVInfusion,
Platinol® (Bristol
Myers Oncolgy)
Gemcitabine Anti-neoplastic IVInfusion over 30 min Genzer®
(Lilly)
Thiopentalsodium Shortacting
anesthetic IVInfusion
Pentothalsodium® (Baxter)
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24. References
The scienceandpracticeof pharmacybyRemington,21edition, vol-1. Pg828-831.
The TheoryAndPracticeof Industrial PharmacybyLeon Lachmann,Herbert.A.Lieberman
andJosephI. Kanig,1991.Pg62-64,672-674.
Pharmaceutial Engineering–PriniciplesandPracticesbyC.V.S.Subramanyam,J.ThimmaSetty,
SarasijaSureshandV.Kusum Devi.Pg401-405.
Aulton’s Pharmaceutics–TheDesignAndManufacture OfMedicines byMichealE.
Aulton, 2009.Pg195.
The Lyophilization of Pharmaceuticals:ALiterature Reviewby
N.A.Williams* andG.P.Polli. Journalof Pharmaceutical scienceandTechnology.
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