overview for an freeze dried technology or lyophilisation technology.

1. M. Pharm Sem-II Presentations
LYOPHILISATION
SUBMITTED TO
SAVITRIBAI PHULE, PUNE UNIVERSITY , PUNE
FOR
PARTIAL FULFILMENT OF REQUIREMENTS FOR THE AWARD OF
MASTER OF PHARMACY
IN THE SUBJECT
Pharmaceutical manufacturing technology
IN THE FACULTY OF SCIENCE AND TECHNOLOGY
Bhujbal Knowledge City,
MET’s Institute of Pharmacy,
Adgaon, Nashik, 422003.
Maharashtra, India
Academic Year- 2021--2021 1
Presented By-
Mr.Krishna Khamkar
Guided By-
Dr.S.P.Ahirrao

2. Content
• Definition
• Principle
• Process
• Avdantages
• Disavantages
• Application
• Conclusion
• Reference
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3. Definition
• A stabilizing process in which a substance is first frozen and
then the quantity of the solvent is reduced, first by sublimation
and then desorption to values that will no longer support
biological activity or chemical reactions.
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4. Principle
• Freeze drying or lyophilisation is the removal of ice or other frozen
solvents from a material through the process of sublimation and the
removal of bound water molecules through the process of desorption.
• Lyophilisation is performed at temperature and pressure condition below
the triple point,to enable sublimation of ice.
• The entire process is performed at low temperature and pressure by appling
the vaccum.
• The concentration gradient of water vapour between the drying front and
condenser is the driving force for removal of water during the
lyopholisation.
• Sublimation of water can take place at pressures and temperature below
triple point i.e. 4.579 mm of Hg and 0.0099 degree Celsius.
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5. Cont…
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At atmospheric pressure (approx. 1,000 mbar) water can have
three physical states
Solid;
Liquid;
Gaseous.
Below the triple-point (for pure water: 6.1 mbar at 0°C), only the
solid and the gaseous states exist
Phase diagram of water

6. Steps involved in lyophilisation
Freezing
drying
• Step 1
Primary
drying
• Step 2
Secondary
drying
• Step 3
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7. Process
• Pretreatment / Formulation
• Loading / Container (ex. Flask, Vials)
• Freezing at atmospheric pressure
• Primary Drying (Sublimation) under vacuum
• Secondary Drying (Desorption) under vacuum
• Removal of Dried Product from Freeze Dryer
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8. Freeze drying(solidification)
• Freezing the product solution to a temperature below its eutectic
temperature.
• Low temperature and low atmospheric pressure are maintained.
• The rate at which your sample freezes will affect the size of the ice crystals
that form. If not done properly, it can impact the speed of reconstitution,
length of the freeze-drying process and integrity and stability of your
sample.
• Unfrozen product may expand outside of the container when placed under
drying with high vaccume.
• Slower cooling results in large ice crystals and less restrictions channels in
the matrix during the drying process.
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9. 9

10. Primary drying (sublimation)
• Sublimation is when a solid (ice) changes directly to a vapor without first
going through a liquid (water) phase.
• Sublimation is a phase change and heat energy must be added to the frozen
product for it to occur.
• Sublimation in the freeze drying process can be described simply as:
1)FREEZE - The product is completely frozen, usually in a vial, flask
or tray.
2)VACUUM - The product is then placed under a deep vacuum, well below
the triple point of water.
3)DRY – Heat energy is then added to the product causing the ice to
sublime.
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11. • Primary drying (sublimation) is a slow process conducted at cooler
temperatures, safely below the product’s critical collapse temperature.
Sublimation requires heat energy to drive the phase change process from
solid to gas. All three methods of heat transfer - conduction, convection and
radiation, must be considered when freeze drying a product.
• When the heat is transferred to the flask/product primarily through
convection and radiation from the surrounding environment. With little
control over heat flow into the product, it is more difficult to control the
process. When working with products with low collapse temperatures, it
may be necessary to wrap or insulate the flask to slow down the rate of heat
transfer and avoid collapse.
• In a shelf freeze dryer, most of the heat is transferred into the product
through conduction and it is important to maximize the surface contact of
the product/container/tray with the shelf. However, the effects of radiation
and convection also need to be considered for product uniformity and
process control purposes.
• convective heat transfer can help promote uniform product drying.
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12. • At the end of primary drying when all of the free ice crystals have been
sublimed, the product will appear to be dried. However, the moisture
content can still be in the 5-10% range due to the presence of “sorbed”
water molecules attached to the product.
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13. Secondary drying (Desorption)
• In addition to the free ice that is sublimed during primary drying, there
remains a substantial amount of water molecules that are bound to the
product.
• This is the water that is removed (desorbed) during secondary drying. Since
all of the free ice has been removed in primary drying, the product
temperature can now be increased considerably without fear of melting or
collapse.
• Secondary drying actually starts during the primary phase, but at elevated
temperatures (typically in the 30◦C to 50◦C range), desorption proceeds
much more quickly.
• Secondary drying rates are dependant on the product temperature. System
vacuum may be continued at the same level used during primary drying;
lower vacuum levels will not improve secondary drying times.
• Secondary drying is continued until the product has acceptable moisture
content for long term storage. Depending on the application, moisture
content in fully dried products is typically between 0.5% and 3%
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14. • In most cases, the more dry the product, the longer its shelf life will be.
However, certain complex biological products may actually become too dry
for optimum storage results and the secondary drying process should be
controlled accordingly.
• During secondary drying, a “sample thief” mechanism may be used to
periodically remove vials from the freeze dryer for residual moisture
content determination.
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15. Lyophilisation system
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16. Freeze drying equipments
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17. Advantages of Lyophilisation
• Thermolabile materials can be dried.
• Prolonged shelf life.
• Freeze drying takes place at very low temperature so the decomposition of
substance is minimized.
• Stability of the product maintained.
• Compatible with aseptic operations.
• 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.
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18. Disavdantages
• Volatile compounds may be removed by high vacuum.
• Single most expensive unit operation.
• Stability problems associated with individual drugs.
• Some issues associated with sterilization and sterility assurance of the dryer
chamber and aseptic loading of vials into the chamber.
• Long time process
• Many biological molecules are damaged by the stress associated with
freeze-drying .
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19. Lyophilised pharmaceutical products
Sr. No. LYOPHILIZED PRODUCTS PER VIAL THERAPEUTIC CATEGORY
1 ACETAZOLAMIDE INJECTION 500MG / VIAL Anti-glaucoma
2 ACYCLOVIR INJECTION
250MG/VIAL, 500MG/ VIAL,
1GM/VIAL
Antiviral
3 AMPHOTERICIN INJECTION 50MG/VIAL, 100MG/VIAL Antifungal
4
PHENYTOIN INJECTION
50MG/ML Anticonvulsant
5 AZITHROMYCIN INJECTION 500MG/VIAL Antibacterial Antibiotic
6 CASPOFUNGIN INJECTION 50MG/VIAL, 70MG/VIAL Antifungal
7 CLARITHROMYCIN INJECTION 500 MG/VIAL Antibiotic
8 COLISTIMETHATE INJECTION
100,000 IU / VIAL, 200,000
IU/VIAL
Antibiotic
9 DOBUTAMINE HCL INJECTION 50MG/ML, 250MG/VIAL Cardiac
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20. Applications
• In food industry
• In pharmaceuticals and biotechnology
• Other industries
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21. Conclusion
• The lyophilization technique proved to be an advantage for enhancing the
stability of the product because the moisture content of the formulation is
greatly reduced.
• In the freeze dried solid state, chemical or physical degradation reactions
are inhibited or sufficiently decelerated, resulting in an improved long term
stability
• Shelf life of the product is increased due to lyophilisation process
• The size of the product is also reduce and ease for the transportation.
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22. Reference
• The theory and practice of industrial pharmacy by Leon Lachmann, Herber
Liberman and joseph kanig.1991.pg no-62-64, 672-674
• Aultons pharmaceutics- The design and manufacture of medicines by
Micheal E.Aulton,2009 pg 195.
• https://www.spscientific.com/freeze-drying-lyophilization-basics/
• https://www.researchgate.net/publication/292047227_LYOPHILIZATION_
FREEZE_DRYING_-_A_REVIEW
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