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Outline
I. What is freeze drying? II. Reasons for freeze drying III. Steps in freeze drying
A. Freezing B. Primary Drying C. Secondary Drying
Desired Freeze Dried Characteristics Intact cake Sufficient strength Uniform color Sufficiently dry Sufficiently porous Sterile Free of Pyrogens Free of particulate Chemically stable
B. Primary Drying
Removal of ice via sublimation Product temperature less than Collapse temperature
C. Secondary Drying
Remove adsorbed water Achieve moisture content needed for stability
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 8
Vacuum Pump
Product Shelf
Compressor
Heat Exchanger
Heater
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 9
40
Shelf Temperature
140
20
Chamber Pressure
120
Temperature (oC)
100
-20
80
-40
60
A
0 10
B
20 30 40
C
50 60
Time (Hours)
10
Pressure (millitorr)
Freeze Drying
Solution
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co.
Powder
11
A. Freezing Process
Cooling Supercooling Ice Nucleation
B.
C.
12
Crystalline Solutes
Eutectic Mixture
The temperature where solute and ice both exist in a rigid crystalline state is the eutectic temperature. For example, NaCl forms a eutectic mixture containing 23.3%NaCl and melts at -21.13oC.
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 13
Amorphous Solutes
Most solutes dont crystallize and form a random (amorphous) viscous glassy phase Amorphous solute After Freezing (Freeze Concentrate)
Glassy Mixture
In these systems the viscosity of solute phase increases until the solute is completely immobile and behaves like a glass. The temperature where the solute behavior changes from solution to a rigid glass is the glass transition temperature.
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 14
Physical State of the Solute and Temperature: Significant Impact on Freeze-Drying Behavior
15
16
B. Primary Drying The sublimation of ice from the frozen solution to create a dried layer of solute Solute must form a rigid structure to support its weight after the removal of ice. Maintaining product below the collapse temperature is critical to produce acceptable material Consequences of improper temperature control