![ Define the following terms:
[Lyophilization, etc]
Respond to the following questions:
Give a detailed account of ………………
Explain in details the process of …………..
Describe in details with examples the…………
With examples, illustrate the pharmaceutical applications of ……………](https://image.slidesharecdn.com/15-lyophilization-200630111026/85/15-lyophilization-31-320.jpg)
15 lyophilization
- 3. CONTENTS Definition Principle Components of freeze dryer Steps involved in lyophilization Advantages of freeze drying over conventional drying Advantages Disadvantages Applications Conclusion References
- 4. 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.
- 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.
- 6. is carried out below the triple point to enableLyophilization sublimation of ice. Fig 1. Phase diagram showing the triple point of water at 0.01°C, 0.00603 atm.
- 7. COMPONENTS OF FREEZE DRYER
- 8. FREEZE DRYER DESIGN ESSENTIAL COMPONENTS CHAMBER – This is the vacuum tight box, sometimes called the lyophilization chamber or cabinet. – The chamber contains shelf or shelves for processing product. – The chamber can also fit with a stoppering system. – It is typically made of stainless steel and usually highly polished on the inside and insulated and clad on the outside. – The door locking arrangement by a hydraulic or electric motor. SHELVES – The shelf act as a heat exchanger, supplying energy to the product during the primary and secondary drying segments of the freeze drying cycle – The shelves will be connected to the silicone oil system through either fixed or flexible hoses.
- 9. REFRIGERATION SYSTEM – The product to be freeze dried is frozen whilst on the shelves. – Compressors or sometimes-liquid nitrogen supplies the cooling energy. – Most often multiply compressors are needed and the compressor may perform two duties, one to cool the shelves and the second to cool the process condenser.
- 10. SHELF FLUID SYSTEM – The freeze-drying process requires that the product is first frozen and then energy in the form of heat is applied throughout the drying phases of the cycle. – This energy exchange is traditionally done by circulating a silicone oil through the shelves at a desired temperature. – The temperature is set in an external heat exchange system consisting of cooling heat exchangers and an electrical heater.
- 11. PROCESS CONDENSER – The process condenser is sometimes referred as just the condenser or the cold trap. – It is designed to trap the solvent, which is usually water, duringthe drying process. – The process condenser will consist of coils or sometimes plates which are refrigerated to allow temperature. – These refrigerated coils or plates may be in a vessel separate to the chamber, or they could be located within the same chamber as the shelves. – Hence there is designation “external condenser” and “internal condenser”. Physically, the external condenser is traditionally placed behind the chamber. – For an internal condenser the refrigerated coils or plates areplaced beneath the shelves. The position of the condenser does not affect trapping performance.
- 12. STEPS INVOLVED IN LYOPHILIZATION FREEZING STAGE PRIMARY DRYING STAGE SECONDARY DRYING STAGE PACKING PRETREATMENT
- 13. 1. PRETREATMENT • Pretreatment includes any method of treating the product prior to freezing. • This may include 1. Concentrating the product, 2. Formulation revision (i.e., addition of components to increasestability and/or improve processing), 3. Decreasing a high vapor pressure solvent or 4. Increasing the surface area.
- 14. 2. FREEZING • The product must is frozen to a low enough temperature to be completely solidify. • The method of prefreezing and the final temperature of the frozen product can affect the ability to successfully freeze dry the material. • Rapid cooling results in small ice crystals, useful in preserving structures to be examined microscopically, but resulting in a product that is, more difficult to freeze dry. • Slower cooling results in large ice crystals.
- 15. • Most samples that are to be freeze dried are eutectics, which are mixtures of substances that freeze at lower temperature than the surrounding water. • It is very important in freeze-drying to pre freeze the product to below the eutectic temperature before beginning the freeze- drying process. • The second type of frozen product is a suspension that undergoes glass formation during the freezing process.
- 16. 3. PRIMARY DRYING • After prefreezing the product, conditions must be established in which ice can be removed from the frozen product via sublimation, resulting in a dry, structurally intact product. • This requires very carefully control of the two parameters. 1. Temperature (-10 °C to 30°C) and 2. Pressure involved in freeze-drying system(50mmHg). • The rate of sublimation of ice from a frozen product depends upon the difference in vapor pressure of the product compared to the vapor pressure of the ice collector.
- 17. • Heat enters the products by one of several mechanisms: - 1. By direct contact between the container base and the shelf, so here the shape of the container is important. 2. By conduction across the container base and then through the frozen mass to the drying front (also called the sublimation interface) 3. By gaseous convection between the product and residual gas molecules in the chamber. 4. By radiation • Convection is certainly the most important of these mechanisms
- 18. DETERMINATION OF THE END OF PRIMARY DRYING • Several analytical methods are available for determining that primary drying is complete. The most basic method is to monitor the product temperature with a thermocouple probe. The measured product temperature will be colder than the shelf temperature set point during active primary drying because the heat from the shelf is being used for the sublimation phase change. When sublimation of ice crystals is complete, the product temperature will increase and approach the shelf temperature. When the product temperature equals the shelf temperature, it can be inferred that primary drying is complete.
- 19. 4. SECONDARY DRYING • After primary freeze-drying about 7-8% residual moisture content is present so continues drying at warmer temperature is necessary to reduce the residual moisture content to optimum values. • This process is called ‘Isothermal Desorption’ as the bound water is desorbed from the product. • Secondary drying is normally continued at a product temperature higher than ambient but compatible with the sensitivity of the product. • In contrast to processing conditions for primary drying which use low shelf temperature and a moderate vacuum, desorption drying is facilitated by raising shelf temperature(50 to 60°C) and reducing chamber pressure to a minimum.
- 20. • Care should be exercised in raising shelf temperature too highly; since, protein polymerization or biodegradation may result from using high processing temperature during secondary drying. • Secondary drying is usually carried out for about 10-20 hours, whereas primary drying is carried out for 2hours.
- 21. PACKING • 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
- 22. ADVANTAGES OF FREEZE DRYING OVER CONVENTIONAL DRYING 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 0-150oC 200-300oC Oxygen exposure Very low High Retained volatiles Excellent Poor
- 23. SOME LYOPHILIZED FORMULATIONS Drug Category Route Of Administration Marketed Name Amphotericin B & Cholestryl sulphate Anti-fungal IV Infusion at 2-4 mg/kg/hr Amphotec® (Sequus pharmaceuticals) Chlorthiazide sodium Diuretic & anti- hypertensive IV Infusion , IV bolus Diuril® (Merck) Cisplastin Anti-neoplastic IV Infusion, Platinol® (Bristol Myers Oncolgy) Gemcitabine Anti-neoplastic IV Infusion over 30 min Genzer® (Lilly) Thiopental sodium Short acting anesthetic IV Infusion Pentothal sodium® (Baxter)
- 24. ADVANTAGES Thermo labile materials can be dried Loss of volatile materials is less. Moisture level can be kept as low as possible Sterility can be maintained Final product can be stored in ambient temperature, if well sealed with inert atmosphere
- 25. DISADVANTAGES Equipment & running costs are high Increased handling and processing time. Need for sterile diluents upon reconstitution. It is difficult to adopt the method for solutions containing non aqueous solvents Product is prone to oxidation so it should be packed in vacuum
- 26. APPLICATIONS od and make it very n the forms of freeze- • PHARMACEUTICAL 1. Pharmaceutical companies often use freeze-drying to increase the shelf life of products, such as vaccines and other injectables. 2. By removing the water from the material and sealing the material in a vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection. • FOOD INDUSTRY 1. Freeze-drying is used to preserve fo lightweight. 2. The process has been popularized i dried ice cream.
- 27. CONCLUSION A freeze dried product with the best attributes andquality. In freeze drying, minimal structural changes or shrinkage. In freeze drying process, nutrients are largelyretained. Freeze drying system includes vacuum and refrigeration equipments. The initial costs are relatively high up to 4 times than conventional drying.
- 28. REFERENCES 1. Lachman L ,The theory & practice of IndustrialPharmacy, Varghese publication,Bombay,Pg no: 762. 2. Subramanyam CVS , Pharmaceutical Engineering,Published by Vallabh Prakashan, Pg no: 307 3. Remington, The Science & Practice of Pharmacy,21st edition,vol 2,pg no. 959.
- 29. Any Questions or Additions
- 30. THANK YOU
- 31. Define the following terms: [Lyophilization, etc] Respond to the following questions: Give a detailed account of ……………… Explain in details the process of ………….. Describe in details with examples the………… With examples, illustrate the pharmaceutical applications of ……………
- 32. Group work discussional questions: Explain in details the process of……… Describe with examples in details the………….. With examples, illustrate the pharmaceutical applications of…….