This document provides an overview of lyophilization technology and freeze drying processes. It discusses: 1) The history of freeze drying including uses in medicine, food, and other industries. 2) How lyophilization works to remove water from pharmaceuticals through sublimation under reduced pressure and temperatures, leaving a dry and stable product. 3) The advantages of lyophilizing pharmaceuticals including improved stability, solubility, and ease of dosing compared to conventional drying methods. 4) Key aspects of the lyophilization process including heat and mass transfer dynamics and how process parameters like temperature, pressure and time impact the sublimation rate.

1. 1
Lyophilization Technology
The theory and practice of freeze-drying of
pharmaceuticals
M. Kamat and M. Yelvigi
The Center for Professional Advancement
January 30-31, 2013
New Jersey, USA
M. Kamat Jan, 2013

2. History
• Freeze-dried plasma/serum in WWII
– Even today: At-least 10 donors, 2 years RT, 200
mL water for constitution
• Bacteria/vaccines
• Food industry: coffee, fruits
• Military Rations/Astronaut Food/Hikers' food
• Museum articles
• Restoration of old artifacts (sunken ships, water-
damaged libraries)
2M. Kamat Jan, 2013

3. 3M. Kamat Jan, 2013

4. 4
Lyophilized Pharmaceuticals
• More than 140 lyophilized injectables
– Ampoules, syringes, vials, and large bottles
• > 30 biologicals, vaccines
• Freeze-dried skin grafts and tissues
• Quick-dissolve oral tablets (Claritin Reditabs)
M. Kamat Jan, 2013

5. Definition• Lyophilization is a coupled heat-mass-transfer process where
the frozen solvent, usually water, is removed initially by
sublimation under the conditions of reduced pressure and sub-
zero temperatures, and then by desorption under the conditions
of reduced pressure and above zero temperatures to yield a dry
product.
• Whereas, freeze-drying may be defined as vacuum drying below
0 ºC (coffee, cereals, space food, animals etc.)
• Keywords:
Required Undesirable
Frozen Instability
Sublimation Collapse/meltback
Desorption Vial breakage
Dry Product High moisture
Reconstitution Problems
5
We will use freeze drying and lyophilization as synonymous for this course
M. Kamat Jan, 2013

6. Why Lyophilization of
Pharmaceuticals
6
Advantages:
1. Stability: Aqueous Stability
• To make sure that no more than 10% degradation in 2-4
years
• Thermal Stability : High temperature conventional drying
may not be suitable
2. Improved Product Characteristics:
• Improved kinetic solubility (because of porosity and very
large surface area)
• Usually freeze-dried product is amorphous
• Variable recon. volume to get conc. (SubC conc.?)
3. Other Advantages:
• Shipping advantage (low weight)
• Less interaction with primary package of highly alkaline
solutions
• Less problems with glass delaminationM. Kamat Jan, 2013

7. Why Lyophilization of
Pharmaceuticals
7
Advantages: cont.
4. Accuracy of dosage
• Ease of filling complex formulation as a solution
• Doses as low as 0.1 mL (vaccines, GF etc.)
5. Well controlled headspace
• Nitrogen, Argon (oxygen and some time Freon too)
• Vacuum
6.Ease of Operation:
• Liquid filling operation: Automatic, accurate, well controlled
(well established)
• In-line sterilization filtration in the final container
M. Kamat Jan, 2013

8. Stability of Solution and Lyophilized
Forms
8
Product Solution
Form*
Lyophilized
Product
Caspofungin/Cancidas 1 hr at RT 2 years
Cyclophosphamide/Cytoxan 1 week (13%
loss)
3 years
Carboplatin/Paraplatin Particulates 2 years
Fosaprepitant/Emend 24 hr at RT > 2 years
Gemcitabine/Gemzar 24 hr at RT > 2 years
Ixabepilone/Ixempra 1 hr at RT > 2 years
Infliximab/Remicade 3 hr at RT > 2 years
Asoarginase/Erwinase 4 hr at RT > 2 years
* From Package Insert Information
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9. 9
1. API/Excipients substance need to be Sterile
• Handling: aseptic powder, bins, etc.
2. Fill Accuracy
• <100mg powder filling (auger, piston) is difficult
3. Particulate issues
4. Dusting problem
5. Environmental Factors:
• Humidity, Oxygen, Electrostatic Charge
6. Powder Characteristics (difficult):
• Flowability and segregation
• Particle Size, PSD, blend uniformity, Bulk density,
cohesiveness)
If thermal stability is not an issue why not powder
fill?
Most of the large dose antibiotics (penicillins, cephalosporins) are powder filled in billions of
quantities
M. Kamat Jan, 2013

10. Disadvantage of lyophilization
• Additional unit process
• One more thing that can go wrong and that too
irreversibly !!)
• Costly and complex equipment needing greater
maintenance
• Transfer and scale-up issues compared to solution
products
• Long cycles (up to even 7 days): Cleaning, sterilization,
leak-testing may add another 24 hours
10M. Kamat Jan, 2013

11. Physical Chemistry of Lyophilization:
• Points to Consider
• Behavior of solutions during freezing
• Sublimation Process
• Heat Transfer Phenomenon
• Mass Transfer Phenomenon
• Coupling of Heat and Mass Transfer
• Requirements of Process
11M. Kamat Jan, 2013

12. Phase diagram of water
• Sublimation occurs between the solid and the vapor phase regions.
• Since only two phases are present (solid line), solid ice and the vapor ice are in
equilibrium.
• The diagram also says that once Temp of ice is fixed, the vapor pressure over
ice is automatically fixed, and vice-a-versa. 12
Triple point
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13. 13
~ 100 mTorr
~ 100 mTorr
Ref. point 1 mBar = 1000 µbar = 750 mTorr or 750 microns
0.33 mBar = 200 microns
1 atmosphere = 760 mm = 760,000 mTorrM. Kamat Jan, 2013

14. 14M. Kamat Jan, 2013

15. 15
Energetic of Phase Change
In Regular Evaporation Drying :
Vaporization
Liquid Water Water Vapor (∆Hvap)
In Sublimation Drying (Lyophilization)
Sublimation (no liquid)
Ice Water Vapor (∆Hsub)
M. Kamat Jan, 2013

16. 16
Energetic of Phase Change
Sublimation Drying (Lyophilization)
Sublimation (no liquid)
Ice Vapor state (∆Hsub)
Sublimation involves solid, liquid, and gas transitions and
need energy
H2Oice (-40 °C) H2Ovapor (25 °C), ∆Hsub
1. H2Oice (-40 °C) H2Oice (0 °C), ∆H1
2. H2Oice (0 °C) H2Oliq (0 °C), ∆H2
3. H2Oliq (0 °C) H2Oliq (25 °C), ∆H3
4. H2Oliq (25 °C) H2Ovapor (25 °C), ∆H4
Adding all these reactions, ∆Hsub = ∆H1 + ∆H2 + ∆H3 + ∆H4M. Kamat Jan, 2013

17. 17
Heat Energy Must Be Provided for Sublimation to Continue:
• Heat Energy must be provided for sublimation to
continue
• How much heat to be supplied ?
– 676 calories/gm of ice to be sublimed at ºC
• Latent heat of fusion (78 Calories) + Latent
heat of vaporization (598 Calories)
• If excess heat (more than required for phase change)
is supplied, the heat will be used to raise the
temperature of the product (not just for phase
change) and .....Eventually melt the ice.
M. Kamat Jan, 2013

18. Boiling Water
(Phase Change)
Temp=100 C
Temp= ~600 C
Temp= ~600 C
Probe in pot-full of water
on hot plate
Probe in emptied pot
on hot plate
Boiling Water in Kettle
M. Kamat Jan, 2013 18

19. 19
Heat Energy Must Be Provided for Sublimation to
Continue:
• What is the heat source
- From the heated shelves in the lyophilizer Chamber
(some cases: ambient heat, IR, MW etc.)
• How to increase the rate of sublimation
- Increase the driving force
1. Increase the heat supply (shelf temperature)
2. Increase the product temperature
Limit: (maximum allowable temperature)
3. For every 10 ºC rise in product temp, the rate of
drying doubles
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20. 20
ImportantImportant
• The low pressure above the ice keeps the product frozen
• The heat is transferred into the Vial
(Heat-Transfer)
• The water vapor is transferred out of vial
(Mass-Transfer)
• The two transfer processes must be equal to keep the product
frozen and sublimation process to continue
M. Kamat Jan, 2013

21. 21
The Water Vapor Is Transferred Out of Vial
• The vapor then flows out of chamber into the condenser
section and gets deposited as ice on cold surfaces of
condenser plates.
• In old times :
• chemical traps (P2O5, silica desiccants)
• (and in food industry) directly to the pump/ballast (and
then oil change)
• The coldness of condenser does not affect the drying rate as
long as it is colder than the product temperature
• Above certain temperature, though, the ice condensation
power may decrease
• Very low condenser temperatures are not needed for
sublimation to happen: Just collect the sublimate
M. Kamat Jan, 2013

22. 22
Heat Transfer Phenomena
Flow of Heat :
Heating Medium Shelf Interior Shelf Surface
(thru the trays) Under the Vial Bottom Surface
of Vial Bottom of Ice Through the Ice
Sublimation Front
Rate of heat input = W)TT(
d
184.4Q i,CS −
λ
=
Where,
λ is the thermal conductivity of the container,
d is the thickness of the base of the container
Ts = Shelf temperature
Tc,i = Temperature at the ice interface
M. Kamat Jan, 2013

23. 23
Mass Transfer Phenomenon
We will discuss
This later
Vent
M. Kamat Jan, 2013

24. M. Kamat Jan, 2013 24

25. Heat and Mass transfer processes
Energy (in) = Energy (out)
(heat) (sublimation)
Heat transfer rate = Hs X mass transfer
rate
Q = sH x
( oP - cdP )
totalR
Rate of heat input = Heat of sublimation X Rate of mass
transfer
M. Kamat Jan, 2013 25

26. Effect of Resistance to Mass Transfer
26M. Kamat Jan, 2013

27. 27
Key Process Parameters
Tp (product temperature): Keep the product below Tcritical
Pc (chamber pressure): Keep sublimation process on
Ts (shelf surface temp): Provide energy for sublimation
M. Kamat Jan, 2013

28. Factors Which May Affect the Cycle
Action Effect on Cycle
Increase Product temperature Short
Decrease dried product resistance Short
(Freezing modifications)
Use of Trays Long
Better Contact of Glass Short
Increase Chamber Pressure Short
(Up to certain limits)
M. Kamat Jan, 2013 28

29. Process Parameters
Independent Parameters
(all programmable variables)
Not affected by the characteristics
and the load of the product
• Shelf Temperature (fluid)
• Time Duration (soaks)
• Ramping
Dependent Parameters
(non-programmable variables)
Affected by the characteristics and
the load of the product
• Condenser Temperature
• Chamber Pressure
• Product Temperature
• Product drying Time
M. Kamat Jan, 2013 29

30. 30
Stages of Lyophilization
• Fill the solution in the vials. Place stoppers
• Freezing the product on FD Shelves
• Start Cooling the condenser
• Produce Vacuum in the dryer
• Open the isolation Valve
• Check Pressure and Heat the product
• Start Primary drying
• Continue with Secondary Drying
• End-of-Drying
• Stopper and Remove the Product
• QC Testing
M. Kamat Jan, 2013

31. Schematics of a Lyophilizer
31From: Sundaram et al; BioPharm International, Volume 23, Issue 9, Sep 2010M. Kamat Jan, 2013

32. 32
Lyophilizer Chamber
M. Kamat Jan, 2013

33. Lyophilizer Units
33
Chamber
Condenser
Vacuum Pumps
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34. 34M. Kamat Jan, 2013

35. 35
FREEZE DRYING OF COFFEE INVOLVES FOUR STEPS:
•Pre-freezing coffee concentrate (40-45%) up to -5/-10 ° C followed
by foaming.
•Freezing of the pre-frozen coffee liquor at -50 ° C in a blast freezer.
•Sizing of the fr0zen coffee particles to a granular size of 3X3mm.
•Sublimation of the ice in a vacuum freeze dryer (VFD) under vacuum
(0.5 torr) and controlled temperature.
M. Kamat Jan, 2013