1. Pharmaceutical freeze drying Lyophilization basics An Introduction to Freeze-Drying

2. Pharmaceutical freeze drying Lyophilization and freeze drying are the process that were used inter changeably depending on the industry and location where the drying is taking place. Lyophilization is the process we use to remove water from a formulation at low temperatures (prevents thermal degradation) through a process of sublimation and the removal of bound water molecules through the process of desorption.

3. Pharmaceutical freeze drying Basic Lyophilizer System Components -Vacuum Pump: Vacuum is the drying force for change in pressure which is the driving force for freeze drying. A high vacuum and low pressure system to be created inside the chamber. -Temperature Controlled Shelves: Shelves with thermal fluid to control, monitor temperature. -Condenser (External or Internal): A coil or a plate that is very cold and lower than product temperature kept some where away from the product. The water generated during freeze drying process is migrated down the condenser and collected. -Compressible Shelves: To load the vials and also to full stopper the lyophilized vials -Temperature Monitoring Devices: sensors (RTD, thermocouples, thermistors) -Vacuum Monitoring Devices (Capacitance manometers, Pirani guage) -Bleed Valve: To control chamber pressure, for very precise pressure/vacuum level -Data Recording Device

4. Basic Lyophilizer System Components

6. Why do we lyophilize (freeze-dry)? We don’t want to freeze dry but we have to……… Products are not stable (<10% degradation) in the solution state at controlled room temperature for at least 2 years. Water Without water, living processes cease to function or go dormant – Water can however induce damage (Hydrolysis) – Spoilage and growth promotion of organisms The effects of water can be -Immobilized by freezing -Eliminated by drying The effects of water can be -slowed down by High salt content - slowed down by High sugar content

7. Merits of lyophilization Compatible with aseptic operations Drying takes place at low temperatures compared to conventional drying: Minimizes chemical decomposition Filling vials as liquid allows more precise fill weight control and avoids cross-contamination /containment problems

8. Limitations of Freeze-Drying – Drug may not be stable as a freeze-dried solid Example: Many cephalosporins – Many biological molecules are damaged by the stresses associated with freezing, freeze-drying, or both – Not all materials can be freeze-dried to form a pharmaceutically acceptable cake – Cost?- A bit expensive

9. What Can Be Freeze-Dried? Non Biologicals –Reactive Chemicals (Small Molecules) – Non Living Bio Products such as Vaccines – Enzymes – Hormones – Vitamins – Blood Products – Antibodies – Tissues for Surgery – Foods – Living Organisms –Seed Cultures – Miscellaneous –Museum Specimens/Taxidermy What Can’t Be Freeze-Dried? -Oil rich products -Sugar rich products -Products that form an impervious skin -High salt containing products (Tg’ suppressing substances)

10. Principle of lyophilization At normal temperature (around 25°C) and 1 atmospheric pressure, an aqueous solution contains dissolved solutes in water and the whole formulation exists as liquid. The liquid state of aqueous formulation can be altered by increasing the temperature to 100°C to form a vapor and decreasing the temperature to 0°C to form an Ice.

11. At normal temperature (around 25°C) and 1 atmospheric pressure, an aqueous solution contains dissolved solutes in water and the whole formulation exists as liquid. The liquid state of aqueous formulation can be altered by increasing the temperature to 100°C to form a vapor and decreasing the temperature to 0°C to form an Ice. There is an alternative way to alter the liquid state of water i.e., by decreasing the pressure from 1 atmosphere (increasing the vacuum) at the same temperature. water coexist as all the three phases (Solid, liquid, vapor) in equilibrium at 0°C temperature and 4.5 mm of Hg (4.58mTorr) pressure. This point is called Triple point of water. At triple point, at below atmospheric pressure, water is converted to solid without passing through the liquid phase, it is called as sublimation.

12. Sublimation -Sublimation is when a solid (ice) changes directly to a vapor without first going through a liquid (water) phase. -Low pressures are required for sublimation to take place. -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: FREEZE - The product is completely frozen, usually in a vial, flask or tray. VACUUM - The product is then placed under a deep vacuum, well below the triple point of water. DRY – Heat energy is then added to the product causing the ice to sublime. “Ice sublimes in an attempt to achieve vapor equilibrium. When chamber pressure = ice vapor pressure, sublimation stops.“

13. Steps of Lyophilization The steps required to lyophilize a product in a batch process can be summarized as follows: 1)Pretreatment / Formulation 2)Loading / Container (Bulk, Flask, Vials) 3)Freezing (Thermal Treatment) at atmospheric pressure 4)Primary Drying (Sublimation) under vacuum 5)Secondary Drying (Desorption) under vacuum 6)Backfill & Stoppering (for product in vials) under partial vacuum 7)Removal of Dried Product from Freeze Dryer

14. Pharmaceutically Elegant Product

15. Bye folks.. Will dig deep in next sessions..