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Lyophilization Process
Add: 1509, Duhui Road, Shanghai 201 108, China Tel: +86 21 6490 1123 Fax: +86 21 6490 5148 info@tofflon.com www.tofflon.com
.1.
What is Lyophilzation?
.2.
Lyophilization
A drying method used to increase the shelf life at room
temperature of otherwise unstable substances. When reconstituted, the product regains original characteristics even after long periods of time.
A wet substance is frozen, then exposed to an atmosphere of low relative humidity (achieved by
creating a vacuum). The contained ice sublimes - that is, it changes directly from the solid to the vapor state without melting. The resulting humidity in the product is so low it will not support microbial growth or chemical reaction.
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.3.
A stabilizing process in which the product is first frozen and then the amount of solvent (water or other) is removed first by sublimation and then by desorption to values that will no longer support biological growth or chemical reactions.
Freezing
Primary Drying (for free water)
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Drying
Secondary Drying (Desorption Drying) (for bonded water)
.4.
Freeze Drying
Freeze drying is a stabilizing process. The first phase of freezing is crystallization of the solvent (or water) which forms a structure in the product. The solvent is removed first by sublimation and then by desorption to values
.5.
difference is basic
Interstitial is an empty space or gap between spaces full of structure or matter. Is the interstitial area completely frozen (combination product with water)? Complete crystallization means Lyophilization. Not complete crystallization means Freeze Drying.
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.7.
Advantages
High solubility owing to shape substantially maintained after drying
Oxidize-able substances are well protected under vacuum conditions Long preservation period owing to 95%-99.5% water removal Loading quantity accurate and content uniform Little contamination owing to aseptic process Minimal loss of active ingredient Minimal loss in volatile chemicals and heat-sensitive nutrient and fragrant components. Minimal changes in the properties because microbe growth and enzyme effect can not be exerted under low temperature Transportation and storage under normal temperature
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.8.
Suitable Product
Generally depends on the properties of the product. With unstable thermal property With high added value With aseptic process With accurate loading quantity With low solubility
With long period preservation at normal temperature With good shape after process
.9.
Category of Product
1. Bio-product (oncology, anti-cancer, gene, vaccine): Interferon, hepatitis, hormones,
growth factors, transfer factors, bird flu, cholera, hydrophobia, smallpox, measles, etc. 2. Blood product: Blood plasma, EPO, etc.
3. Chem-product (antibiotics): Ceafotetan, cefoparazone, ertapenem, penicillin, azithromicin, omeprazole, lansoprazole, pantaprazole, esomeprazole, etc.
4. Others: Herb, vitamin, microbe and etc.
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.10.
.11.
35
30 25 20 15 10 5
5610
4230 3170 2330 1700 1220 869
-20
-25 -30 -40 -50 -60 -70
103
60.6 38.0 12.9 3.99 1.07 0.26
.12.
.13.
.14.
Why frozen?
Reduction of product temperature under Eutectic Point to induce crystallization to prevent: Frothing under vacuum condition
Volume shrinkage
Solution concentration change during vapor
escape
Active ingredient lose
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.15.
Eutectic Point
In solution, water is isolated from solute as water is crystallized to ice, which brings higher concentration of solutions. At certain temperature or temperature zone, same compositions both in liquid and in solid state coexist, the solution is eutectic solution, the temperature or temperature zone is eutectic temperature or eutectic zone, or fully solidified temperature, which is the highest temperature from liquid to solid during freezing. Lyophilization process recommendation: 5-10 lower than eutectic temperature during freezing.
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.16.
Eutectic point is measured with distinctive change of electrical resistance towards phase transition (liquid to solid).
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.17.
Temperature
Transducer
Resistance Recorder
Resistance Sensor SS
Temperature Sensor
Sample
.18.
.19.
-70 -55 80
-40
-25
-10
20
35
50
65
-70 -55 80
-40
-25
-10
20
35
50
65
0 10
10
.20.
.21.
Primary Dying
Primary drying to removing free water With minimum harm to the active ingredients
Pressure controlled under saturated vapor pressure Lyophilization process recommendation: temperature controlled around 5-10C lower than collapse temperature (co-melting point) during primary drying
.22.
Co-melting Point
During primary drying, frozen solution begins melting at certain temperature. At the moment, the temperature is co-melting point or start-melting temperature. Co-melting point is the lowest temperature from solid to liquid.
DTA
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.24.
Desorption rate is determined by heating temperature, not heating time. When certain balance achieved, it is useless to prolong drying time without increasing shelf temperature. Without damage to product, product temperature shall be increased as high as possible. Meanwhile condenser pressure (temperature) shall be dropped as low as possible.
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.25.
.26.
Inflexion
.27.
Formulation Development
DTA
Eutectic Point
Cycle Development
Sampling Device
Dew Point
Karl Fischer
.28.
Curve of Lyophilization
T()
1Torr = 1.333mbar
Chamber Pressure
P (Torr)
Time (hr)
Condenser T
Product T
Shelf T Condenser T Condenser T Chamber Pressure Chamber Cooling Condenser Cooling Primary Drying Condenser Cooling-Evacuation Shelf Control T Pressure Strict Control Secondary Drying
.29.
Freezing
+40 +20 0
Condenser
Shanghai Technology Co., Ltd Primary Drying Tofflon Science and Secondary Drying
Soak
Temp.
1000 100 10 1 10 10
-1
-2
Freezing
Primary Drying
Secondary Drying
Soak
.30.
.31.
Shanghai Tofflon Science and Technology Co., Ltd Temp. Chamber pressure
30 20 10 time -10 -20 -30 -40 -50 A B C D E F G A: Cooling B: -45 soak C: Natural temp. up D: -20 soak Chamber pressure H Temperature Pressure
.32.
Chamber pressure
E: Preparing drying F: Starting primary drying G: End of primary drying H: Secondary drying
A-D: Cooling stage E: Soak stage F-G: Primary drying H: Secondary drying
Temp.:-20 P1=103Pa
Temp.:-50
P2=4Pa
P3: Resistance
.34.