Lyophilization Technology (Freez Drying)

A stabilizing process in which a substance is first frozen and then the quantity of the solvent is reduced, first by sublimation (primary drying stage) and then desorption (secondary drying stage) to values that will no longer support biological activity or chemical reactions

1. Lyophilization Technology (Freeze drying) PHARMA WISDOM HUB

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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 (primary drying stage) and then desorption (secondary drying stage) to values that will no longer support biological activity or chemical reactions. PHARMA WISDOM HUB

4. History  Freeze drying was first actively developed during WORLD WAR II transport of serum .  The main aim was to store the products without refrigeration and to remove moisture from thermolabile compounds .  Atlas in 1961 built 6 production freeze drying cabinet for Nestle group in Germany, Holland. PHARMA WISDOM HUB

5. Principle  Lyophilization is carried out using a simple principle of physics sublimation. Sublimation is the transition of a substance from the solid to the vapour state, without first passing through an intermediate liquid phase.  Lyophilization is performed at temperature and pressure conditions below the triple point, to enable sublimation of ice. The entire process is performed at low temperature and pressure by applying vacuum, hence is suited for drying of thermolabile compounds. The concentration gradient of water vapour between the drying front and condenser is the driving force for removal of water during lyophilization. PHARMA WISDOM HUB

6. Objectives of lyophilization process To preserve the biological activity of a product. To reduce the product weight to lower the transportation cost. To extend the shelf life or stability. To dry thermolabile materials. To eliminate the need for refrigerated storage. To get accurate, sterile dosing into the final product container. PHARMA WISDOM HUB

7. Basic components of a Lyophilizer PHARMA WISDOM HUB

8. STEPS INVOLVED IN LYOPHILIZATION FREEZING STAGE PRIMARY DRYING STAGE SECONDARY DRYING STAGE PACKING PHARMA WISDOM HUB

9. Processing  Fundamental process steps are: Freezing : the product is frozen. This provides a necessary condition for low temperature Vacuum : after freezing, the product is placed under vacuum. This enables the frozen solvent in the product to vaporize without passing through liquid phase, a process known as SUBLIMATION . Heat : Heat is applied to the frozen product to accelerate sublimation. Condensation : Low-temperature condenser plates remove the vaporized solvent from the vacuum chamber by converting it back to a solid. This completes the process PHARMA WISDOM HUB

10. Lyophilization process PHARMA WISDOM HUB

11. Freeze Drying  Freezing the product solution to a temperature below its eutectic temperature.  Decrease the shelf temperature to -50 o c.  Low temperature and low atmospheric pressure are maintained.  Freons are used as refrigerant.  Formation of ice crystals occurs.  The rate of ice crystallization define the freezing process and efficiency of primary drying. PHARMA WISDOM HUB

12. Primary Drying (Sublimation)  Heat is introduced from shelf to the product under graded control by electrical resistance coils or circulating silicone .  The temperature and pressure should be below the triple point of water i.e., 0.0098°C and 4.58mmHg .  The driving force is vapor pressure difference between the evaporating surface and the condenser .  Easily removes moisture up to 98% to 99%. PHARMA WISDOM HUB

13. Secondary Drying (Desorption)  The temperature is raised to 50°C – 60°C and vacuum is lowered about 50mmHg .  Bound water is removed .  Rate of drying is low .  It takes about 10-20 hrs. PHARMA WISDOM HUB

14. L y o ph ili z a t i o n P r o c e s s PHARMA WISDOM HUB

15. P a c k i n g • After drying the vacuum is replaced by filtered dry air or nitrogen to establish atmospheric pressure • Ampoules are sealed by either tip sealing or pull sealing method • Vials and bottles are sealed with rubber closures and aluminum caps PHARMA WISDOM HUB

16. Freeze Dry Product Characteristics • Sufficient strength • Uniform color • Sufficiently dry • Sufficiently porous • S t e r ile • Free of pyrogens and particulates • Chemically stable both in dry state and reconstitution PHARMA WISDOM HUB

17. Product quality Freeze drying Conventional drying Form of wet material to be dried Whole, liquids Pieces, powders Pieces Dry shape and form Maintained Shriveled Appearance Nearly same Shriveled color Maintained Faded Rehydration Fast Slow Heat exposure 0-150 o C 200-300 o C Oxygen exposure Very low High Retained volatiles Excellent Poor PHARMA WISDOM HUB

18. Advantages of Lyophilization  Removal of water at low temperature  Thermolabile materials can be dried.  Compatible with aseptic operations  More precise fill weight control  Sterility can be maintained.  Reconstitution is easy PHARMA WISDOM HUB

19. Disadvantages of Lyophilization  Many biological molecules are damaged by the stress associated with freezing, freeze-drying, or both.  The product is prone to oxidation, due to high porosity and large surface area. Therefore the product should be packed in vacuum or using inert gas or in a container impervious to gases  Cost may be an issue, depending on the product  Long time process PHARMA WISDOM HUB

20. Common Lyophilized Products  Pharmaceuticals – large and small m o le c u les  Bacteria  Viruses  Vaccines  Plasma  Small zoological specimens  Fruit  Coffee  Flowers  Water-Damaged documents. PHARMA WISDOM HUB

21. Applications  Pharmaceutical and biotechnology – to increase the shelf life of products, such as vaccines and other injectables  Food industry to preserve food, very light weight. to produce essences or flavouring agents.  freeze-dried fruits are produced. Culinary herbs are preserved. Instant coffee powder is prepared. PHARMA WISDOM HUB

22.  Technical I n d u s t r i e s  in chemical synthesis  Formation of stable products .  Others  Flora & fauna preservation  recovery of water-damaged books and documents. Applications PHARMA WISDOM HUB

23. Some Lyophilized Formulations Drug Category Route Of A dm i n i st r a t i on Marketed Name Amphotericin B & Cholestryl sulphate Anti-fungal IV Infusion at 2-4 mg/kg/hr Amphotec® (Sequus ph a r m a c eu ticals ) C h l o r t h i a z i de sodium Diuretic & anti- hypertensive IV Infusion , IV bolus Diuril® (M e r c k ) Cisplastin Anti-neoplastic IV Infusion, Platinol® (Bristol Myers Oncolgy) Gemcitabine Anti-neoplastic IV Infusion over 30 min Gen z e r® (Lilly) Thiopental sodium Short acting anesthetic IV Infusion Pentothal sodium® (Baxter) PHARMA WISDOM HUB

24. References  The science and practice of pharmacy by Remington, 21 edition, vol-1. Pg 828-831.  The Theory And Practice of Industrial Pharmacy by Leon Lachmann, Herbert.A.Lieberman and Joseph I. Kanig, 1991. Pg 62-64, 672-674.  Pharmaceutial Engineering – Priniciples and Practices by C.V.S. Subramanyam, J. Thimma Setty, Sarasija Suresh and V. Kusum Devi. Pg 401-405.  Aulton’s Pharmaceutics – The Design And Manufacture Of Medicines by Micheal E. Aulton, 2009. Pg 195.  The Lyophilization of Pharmaceuticals: A Literature Review by N.A. Williams* and G.P. Polli. Journal of Pharmaceutical science and Technology. PHARMA WISDOM HUB

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