lyo process

8/13/2019 Lyo Process

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Expertise in Pharmaceutical Industry .1.

Shanghai TofflonScience and Technology Co., Ltd

Lyophilization Process

Add: 1509, Duhui Road,

Shanghai 201 108,

China

Tel: +86 21 6490 1123

Fax: +86 21 6490 5148

[email protected]

www.tofflon.com
mailto:[email protected]://www.tofflon.com/http://www.tofflon.com/http://www.tofflon.com/http://www.tofflon.com/mailto:[email protected]:[email protected]:[email protected]


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What is Lyophilzation?

Why we need Lyophilization?

What product can be Lyophilized?

How to Lyophilize?


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Lyophilization

A drying method used to increase the shelf life at roomtemperature 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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Freezing Drying

Secondary Drying

(Desorption Drying)

(for bonded water)

Primary Drying

(for free water)

A stabilizing process in which the product is first frozenand 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.


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Freeze Drying

Freeze drying is a stabilizing process. The first

phase of freezing is crystallizationof 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.


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While the terms can be used interchangeably, the

difference is basic

Lyophilization

product remains frozen during the

drying process preserving the crystalline structure. Freeze Dryingproduct does not need to remain

frozen during the entire drying process. Key point is the termfrozen

Lyophilization or Freeze Drying?


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Interstitial is an empty space or gapbetween 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.




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




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




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.
http://localhost/var/www/apps/conversion/tmp/scratch_5/Lyo%20product%20list.xls




Pressure Relationship between

Temperature and Saturated Vapor

Temp.

Press.

Pa

Temp.

Press.

Pa

60 19870 0 610

50 12663 -5 412

45 9560 -10 259

40 7350 -15 186

35 5610 -20 103

30 4230 -25 60.6

25 3170 -30 38.0

20 2330 -40 12.9

15 1700 -50 3.99

10 1220 -60 1.07

5 869 -70 0.26




Desorption

Sublimation

Water

Crystallization

Liquid

Water-Product

Crystallization

Solute

No water

Frozen?

No melting

No collapse




Why frozen?

Reduction of product temperature under Eutectic

Pointto induce crystallization to prevent:

Frothing under vacuum condition

Volume shrinkage

Solution concentration change during vapor

escape

Active ingredient lose




Eutectic Point

In solution, water is isolated from solute as water iscrystallized 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: 5-10lower

than eutectic temperature during freezing.




Eutectic Point Device

Eutectic point is measured

with distinctive change of

electrical resistance

towards phase transition

(liquid to solid).




Transducer

Resistance

Sensor

S S

Temperature

Sensor

Sample

Temperature

Resistance

Recorder


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-70 -55 -40 -25 -10 5 20 35 50 65

80

0 1 2 3 4 5 6 7 8 9

10

-70 -55 -40 -25 -10 5 20 35 50 65

80

0 1 2 3 4 5 6 7 8 9

10


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Samples of Eutectic Point

Substance Eutectic Point Substance Eutectic Point

Pure water 0 20% Glutin and 10% glucose -32

0.85%NaCl -22 20% Glutin and 10% sugar -19

10% Sugar -26 Blood serum -35

10% Glucose -27 Bioproducts -30

Degrease milk -26 Spinage -6

Gen-seng -15 Glycerite -46.5


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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 beconsidered

Pressure controlled under saturated vapor pressure

Lyophilization process recommendation: temperature

controlled around 5-10C lower than collapse

temperature (co-melting point) during primary drying

Sh h i T ffl S i d T h l C Ltd


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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)



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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.



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0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0.0 20.0 40.0 60.0 80.0 100.0

Vapor (Pa m3/h)

Moisture(%

)

Pressure Rising Test

Shanghai Tofflon Science and Technology Co Ltd


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Inflexion

Dew Point Test



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DTA

Formulation

Development

Eutectic Point

Dew Point

Sampling Device

Karl Fischer

Cycle

Development



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Curve of Lyophilization

1Torr = 1.333mbarT() P (Torr)Chamber Pressure

Condenser T

Product T

Shelf T

Chamber CoolingCondenser Cooling Primary Drying

Shelf Control T

Pressure Strict Control

Time (hr)

Condenser T

Shelf Control T

Product T

Shelf Control T

Product T

Condenser T

Chamber Pressure

Secondary Drying

Condenser Cooling-Evacuation


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Relationship between

Sublimation Speed and Time

50% water removing within 25% time



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Temp.

time

Chamber pressure

-10

-20

-30

-40

-50

10

20

30

Temperature

Pressure

Chamber pressure

Chamber pressureA B C D E F G

HA: CoolingB: -45soakC: Natural temp. upD: -20soak

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



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Temp.:-50

P2=4Pa

P3: Resistance

Temp.:-20

P1=103Pa

P=P1-P2-P3

P1: Saturated pressure on drying interface

P2: Saturated pressure on ice surface

P: Impetus depends on drying speed



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