Lyo Process

Shanghai Tofflon Science and Technology Co.
, Ltd
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
Expertise in Pharmaceutical Industry
.1.
Shanghai Tofflon Science and Technology Co., Ltd
What is Lyophilzation?
Why we need Lyophilization?

What product can be Lyophilized? How to Lyophilize?
.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.
.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)
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
that will no longer support biological growth or

chemical reactions.
.5.
Lyophilization or Freeze Drying?

While the terms can be used interchangeably, the
difference is basic
Lyophilization product remains frozen during the
drying process preserving the crystalline structure.
Freeze Drying product does not need to remain
frozen during the entire drying process.
Key point is the term frozen

.6.
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.
.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
.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.
.10.
.11.
Pressure Relationship between Temperature and Saturated Vapor

Temp. 60 50 45 40 Press. Pa 19870 12663 9560 7350 Temp. 0 -5 -10 -15 Press. Pa 610 412 259 186
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.
Liquid Water Crystallization Water-Product Crystallization Solute No water
Frozen? No melting No collapse

Desorption Sublimation
.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
.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.
.16.
Eutectic Point Device
Eutectic point is measured with distinctive change of electrical resistance towards phase transition (liquid to solid).
.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.
Samples of Eutectic Point

Substance Pure water 0.85%NaCl 10% Sugar 10% Glucose Degrease milk Gen-seng Eutectic Point 0 -22 -26 -27 -26 -15 Substance 20% Glutin and 10% glucose 20% Glutin and 10% sugar Blood serum Bioproducts Spinage Glycerite Eutectic Point -32 -19 -35 -30 -6 -46.5
.21.
Primary Dying
Primary drying to removing free water With minimum harm to the active ingredients
With good shape of the final products

During primary drying, two following points has to be considered
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
(Different Thermal Analysis)

.23.
.24.
Secondary Dying (Desorption Drying)

To remove remaining free water and bond water in absorptive state
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.
.25.
Pressure Rising Test

1.00
0.90 0.80 0.70 0.60 Moisture (%) 0.50 0.40 0.30 0.20 0.10 0.00 0.0 20.0 40.0 60.0 80.0 100.0 Vapor (Pa m3/h)
.26.
Dew Point Test
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
Shelf Control T Product T Shelf Control T Product 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.
-20 -40 -60
About 2-4 hrs
m/h About 10-16 hrs
About 4-6 hrs
About 2-4 hrs
Free water frozen
Heating the frozen product and sublimation, 90%-95% water removing
Removing bonding water, final moisture: 3%-0.5%.
Uniformity of water in product
1000 100 10 1 10 10
-1
-2
Freezing
Primary Drying
Secondary Drying
Soak
.30.
Relationship between Sublimation Speed and Time
50% water removing within 25% time
.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
P: Impetus depends on drying speed
Temp.:-20 P1=103Pa
Temp.:-50
P2=4Pa
P3: Resistance
P=P1-P2-P3 P1: Saturated pressure on drying interface
P2: Saturated pressure on ice surface

.33.
.34.

Lyo Process

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Lyo Process

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Shanghai Tofflon Science and Technology Co.

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Why we need Lyophilization?

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Shanghai Tofflon Science and Technology Co., Ltd

Shanghai Tofflon Science and Technology Co., Ltd

that will no longer support biological growth or

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Lyophilization or Freeze Drying?

Lyophilization product remains frozen during the

drying process preserving the crystalline structure.

Freeze Drying product does not need to remain

frozen during the entire drying process.

Key point is the term frozen

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Shanghai Tofflon Science and Technology Co., Ltd

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Pressure Relationship between Temperature and Saturated Vapor

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Liquid Water Crystallization Water-Product Crystallization Solute No water

Frozen? No melting No collapse

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Shanghai Tofflon Science and Technology Co., Ltd

Shanghai Tofflon Science and Technology Co., Ltd

Eutectic Point Device

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Samples of Eutectic Point

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

With good shape of the final products

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

(Different Thermal Analysis)

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Secondary Dying (Desorption Drying)

Shanghai Tofflon Science and Technology Co., Ltd

Pressure Rising Test

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Dew Point Test

Expertise in Pharmaceutical Industry

Shanghai Tofflon Science and Technology Co., Ltd

Expertise in Pharmaceutical Industry