Freeze drying - lyophilization

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1. FREEZE DRYING (LYOPHILIZATION) Ravish Yadav

2. introduction Lyophilization /freeze drying a dehydration process used to completely remove water from the materials while leaving the basic structure and composition of the material intact. The commercial process was introduced at the time of II world war & found its first application in preservation of blood plasma, manufacture of penicillin and other antibiotics. 2

3. IMPORTANCE OF LYOPHILIZATION Sufficient porosity and surface area to permit rapid reconstitution Enhanced product stability in a dry state Elegance 3

4. Phase : defined as any homogenous and physical part of system - mechanically seperated from the other parts of the system. Triple point :point were 3 phases liquid,solid,vapour coexist at particular temperature and pressure. Latent heat : heat is gained by a substance or system without accompanying rise in temperature during a change of a stage 4

5. Eutetic point : A eutectic system is a mixture of chemical compounds that has a single chemical composition that solidifies at a lower temperature than any other composition made up of the same ingredients. This composition is known as the eutectic composition and the temperature is known as the eutectic temperature. 5

6. PRINCIPLES INVOLVED IN FREEZE DRYING Water is removed from frozen state by sublimation Drying is achieved by subjecting material to temperature and pressures below triple point. The major factors that determine the phase which substance takes place depends on temperature Pressure 6

7. If temperature is b/w sea level freeze point(32 F/ 0 C) and the sea level B.P (212 F/100 C) the water takes a liquid form. If the temperature increases above 32 F while keeping the pressure below 1 atm , the water is warm enough, but there is no enough pressure for a liquid to form. It become a gas 7

8. Freeze drying process 8

9. PROCESS OVERVIEW Vials are aseptically filled with solution/suspension to be freeze dried and are usually partially stoppered with special rubber closure that allow escape of water vapor. Transferred under aseptic conditions into metal trays of freeze drier . Trays are placed on shelves containing internal channels allowing circulation of suitable heat transfer fluids. The temperature is lowered for complete solidification of the contents in the vial. Then the chamber is evacuated until the pressure is less than V.P of ice at the temperature of product . 9

10. After the pressure is reached, heat is applied to the shelves to provide energy required for sublimation of ice As the drying proceeds the frozen layer decreases in thickness and the thickness of the partially dried solid increases- this phase is called PRIMARY DRYING When the ice is gone additional drying time is required to remove water adsorbed to, or trapped by the solid matrix-this is called SECONDARY DRYING 10

11. STAGES OF LYOPHILIZATION PROCESS Preparation and pretreatment freezing for solidifying water Primary drying (sublimation of ice under vacuum) Secondary drying (removal of residual moisture under high vacuum) 11

12. 1. Freezing of the product Phase diagram of water. Freezing of aqueous solution. Thermal treatment. Characterization of freezing behavior. 2. Primary Drying Sublimation Heat transfer in Primary Drying. Mass transfer in Primary Drying. 3. Secondary Drying 12

13. FREEZING PROCESS This is the important, since microstructure formed during the freezing determines the quality of final product and rates of primary and secondary drying Physical events associated with the freezing process -Super cooling -Ice crystallization ( primary) -Concentration of solutes during ice crystal growth -Crystallization of the solute 13

14. (A) Phase diagram of water At the tripe point (0.0098 C & 4.58mm Hg) solid, liquid and gases co-exist in equilibrium . Freeze drying takes place below triple point, where water passes from the solid phase directly to V.P without intermediate liquid phase 14

15. ( B ) Freezing of aqueous Solution: ab - product temp. decreases below equilibrium freezing point. b- nucleation and crystal growth of ice crystals occur - energy is released , temp increases to T f . Cooling then continues from T f to -degrees C ,with crystal growing & interstitial fluid becoming more concentrated At point C- Crystallization of concentrated interstitial fluid is initiated. 15

16. The intersection of the lines at point b is the eutectic point which for sodium chloride is -21.5°C. The eutectic temperature is important in freeze drying because it represents the maximum allowable product temperature during primary drying If product temperature exceeds the eutectic temperature while ice is still present, drying takes place from the liquid state instead of the solid state and the desirable properties of a freeze dried product are lost 16

17. Glass transition temperature: - In most cases, solute doesn’t crystallize during freezing - different type of behavior is observed. - Tg (glass transition temperature) -It applies to amorphous systems, which corresponds to change in the viscosity of the solution from a viscous liquid to glass. - Tg is similar to that of eutectic temp. - If the product temp exceed Tg the product undergoes collapse 17

18. C. Thermal treatment : A solute of NaCl crystallize readily from solution during freezing Because of super cooling and rapid rate of freezing once ice crystals are nucleated, a metastable amorphous solute may formed If system is then warmed to some temperature above the Tg and below the melting point, the solute may crystallize D. Characterization of freezing behavior This analysis help to determine whether the active component crystallizes upon on freezing and the effect of excipients. The common methods for analysis of formulation to be F.D are - Thermal analysis . - Thermoelectric analysis. - Freeze dried microscopy.   18

19. PRIMARY DRYING Pressure is lowered and enough heat is supplied to the material for the water to sublimate. 95% of the water in the material is sublimated The driving force for sublimation - difference b/n the V. P of ice at the sublimation front and the partial pressure of water vapor in freeze dry chamber Sublimation of ice : The rate of sublimation W for any substance is given by W = 5.83 x 10 -5 P µ (M/T) where, P µ = vapor pressure M = molecular weight T= temperature 19

20. B. Transfer operation in Primary Drying: Transfer operations - driving force / resistance. The over all drying rate - driving force / sum of a series of resistances to either heat or mass transfer Heat transfer in Primary Drying: Transfer of heat from source i.e heating shelf to the product is often the rate limiting step . 3 basic mechanism for heat transfer. -Conduction -Convection - Radiation conduction is the primary mechanism of heat transfer. 20

21. Heat transfer by conduction is given by Fourier's law dQ / dt =-k A dT / dX dQ / dt = rate of heat transfer A = area at right angle to direction of heat flow dT / dx =temperature gradient k =thermal conductivity constant Mass transfer in Primary drying: Refers to the transfer of water vapor from the product through open channels, created by the prior sublimation of ice to the condenser. The sublimation rate is expressed as Sublimation rate = pressure difference/resistance. The total resistance to mass transfer is the sum of several resistances in the series of dried product, vial, chamber 21

22. SECONDARY DRYING Remove unfrozen water molecules since the ice was removed in the primary drying phase. Temperature is raised, to break physico -chemical interaction formed b/n water molecules and frozen material. Chamber pressure is decreased to the lowest attainable level which favor desorption of water. The amount of residual water to be removed depends on whether solute is crystallize before primary drying . 22

23. Factors affecting process rate Depth of product in container Vapour pressure differential Amount of solid in the product, their particle size & their thermal conductance 23

24. PROCESS MONITORING: Because of the importance of temperature and pressure in defining the relative rate of heat and mass transfer in F.D , Temperature measurement Different types used depend on temp. range,sensitivity accuracy, reproducibility and cost - Resistance thermometer (frequently used) - Thermocouples - Thermistors Pressure measurement Manometers are used for pressure measurement -Mercury manometer -Capacitance manometer( frequently used) -Mechanical manometer -Thermal conductivity manometer. 24

25. Process variables in F.D.Cycle 25

26. USES Production of dosage forms For drying number of products Blood plasma and its fractionated products. Bacterial and viral cultures. Human tissue (arteries and corneal tissue). Antibiotics and plant extracts. Steroids, vitamins and enzymes. Freeze dried roses used in the wedding decoration. To restore water damaged materials, such as rare and valuable manuscripts.   26

27. Advantages The entire operation is done below freezing point. This offers several advantages. Thermolabile materials can be dried   It is porous and uniform. The reconstitution - easy.   Denaturation does not occur   Migration of salts and other solutes does not take place.   Loss of volatile material is less. Moisture level can be kept as low as possible. Sterility can be maintained 27

28. disadvantages The process is very slow and uses complicated plant, which is very expensive. It is not a general method of drying, but is limited to certain types of valuable products that cannot be dried by any other means. The period of drying is high. Time cannot be shortened.   It is difficult to adopt the method for solutions containing non-aqueous solvents. The product is prone to oxidation, due to high porosity and large surface area, therefore product should be packed in vacuum or using inert gas or in container.   28

29. REFERENCES C.V.S Subrahmanyam, Pharmaceutical engineering, Vallabh Prakashan publications, Delhi, 2006 , P.140-145 Lachman,Herbert A. Lieberman, Pharmaceutical dosage forms, 4 th edition, Varghese Publications, New york , 2002, P.163-232 Louis Rey, Joan C. May, Freeze Drying / Lyophilization of Pharmaceutical and Biological Product s, 2 nd edition, Taylor and Francis Group publications, Delhi, 2003 P.1-32. http://www.rpi.edhttp://www.scribd.com/doc/377243/Lyophilization- Basicsu /dept/ chem -eng/Biotech-Environ/LYO/definition.html http://www.rpi.edu/dept/chem-eng/Biotech-Environ/DOWNSTREAM/fig4.html http://www.scribd.com/doc/377243/Lyophilization-Basics http://www.freezedrying.com/freeze_drying_principles.html 29