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Lyophilization Technology The theory and practice of freeze-drying of pharmaceuticals. M. Kamat and M. Yelvigi The Center for Professional Advancement January 30-31, 2013 New Jersey, USA. History. Freeze-dried plasma/serum in WWII
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Lyophilization TechnologyThe theory and practice of freeze-drying of pharmaceuticals M. Kamat and M. Yelvigi The Center for Professional Advancement January 30-31, 2013 New Jersey, USA M. Kamat Jan, 2013
History • Freeze-dried plasma/serum in WWII • Even today: At-least 10 donors, 2 years RT, 200 mL water for constitution • Bacteria/vaccines • Food industry: coffee, fruits • Military Rations/Astronaut Food/Hikers' food • Museum articles • Restoration of old artifacts (sunken ships, water-damaged libraries) M. Kamat Jan, 2013
Lyophilized Pharmaceuticals • More than 140 lyophilized injectables • Ampoules, syringes, vials, and large bottles • > 30 biologicals, vaccines • Freeze-dried skin grafts and tissues • Quick-dissolve oral tablets (Claritin Reditabs) M. Kamat Jan, 2013
Definition • Lyophilization is a coupled heat-mass-transfer process where the frozen solvent, usually water, is removed initially by sublimation under the conditions of reduced pressure and sub-zero temperatures, and then by desorption under the conditions of reduced pressure and above zero temperatures to yield a dry product. • Whereas, freeze-drying may be defined as vacuum drying below 0 ºC (coffee, cereals, space food, animals etc.) • Keywords: RequiredUndesirable Frozen Instability Sublimation Collapse/meltback Desorption Vial breakage Dry Product High moisture Reconstitution Problems We will use freeze drying and lyophilization as synonymous for this course M. Kamat Jan, 2013
Why Lyophilization of Pharmaceuticals Advantages: 1. Stability: Aqueous Stability • To make sure that no more than 10% degradation in 2-4 years • Thermal Stability : High temperature conventional drying may not be suitable 2. Improved Product Characteristics: • Improved kinetic solubility (because of porosity and very large surface area) • Usually freeze-dried product is amorphous • Variable recon. volume to get conc. (SubCconc.?) 3. Other Advantages: • Shipping advantage (low weight) • Less interaction with primary package of highly alkaline solutions • Less problems with glass delamination M. Kamat Jan, 2013
Why Lyophilization of Pharmaceuticals Advantages: cont. 4. Accuracy of dosage • Ease of filling complex formulation as a solution • Doses as low as 0.1 mL (vaccines, GF etc.) 5. Well controlled headspace • Nitrogen, Argon (oxygen and some time Freon too) • Vacuum • Ease of Operation: • Liquid filling operation: Automatic, accurate, well controlled (well established) • In-line sterilization filtration in the final container M. Kamat Jan, 2013
Stability of Solution and Lyophilized Forms * From Package Insert Information M. Kamat Jan, 2013
If thermal stability is not an issue why not powder fill? • API/Excipients substance need to be Sterile • Handling: aseptic powder, bins, etc. • Fill Accuracy • <100mg powder filling (auger, piston) is difficult • Particulate issues • Dusting problem • Environmental Factors: • Humidity, Oxygen, Electrostatic Charge • Powder Characteristics (difficult): • Flowability and segregation • Particle Size, PSD, blend uniformity, Bulk density, cohesiveness) Most of the large dose antibiotics (penicillins, cephalosporins) are powder filled in billions of quantities M. Kamat Jan, 2013
Disadvantage of lyophilization • Additional unit process • One more thing that can go wrong and that too irreversibly !!) • Costly and complex equipment needing greater maintenance • Transfer and scale-up issues compared to solution products • Long cycles (up to even 7 days): Cleaning, sterilization, leak-testing may add another 24 hours M. Kamat Jan, 2013
Physical Chemistry of Lyophilization: • Points to Consider : • Behavior of water during freezing • Heat Transfer Phenomenon • Mass Transfer Phenomenon • Coupling of Heat and Mass Transfer • Requirements of Process M. Kamat Jan, 2013
Physical Chemistry of Lyophilization: • Points to Consider • Behavior of solutions during freezing • Sublimation Process • Heat Transfer Phenomenon • Mass Transfer Phenomenon • Coupling of Heat and Mass Transfer • Requirements of Process M. Kamat Jan, 2013
Phase diagram of water • Sublimation occurs between the solid and the vapor phase regions. • Since only two phases are present (solid line), solid ice and the vapor ice are in equilibrium. • The diagram also says that once Temp of ice is fixed, the vapor pressure over ice is automatically fixed, and vice-a-versa. Triple point M. Kamat Jan, 2013
~ 100 mTorr ~ 100 mTorr Ref. point 1 mBar = 1000 µbar = 750 mTorr or 750 microns 0.33 mBar = 200 microns 1 atmosphere = 760 mm = 760,000 mTorr M. Kamat Jan, 2013
Energetic of Phase Change In Regular Evaporation Drying : Vaporization Liquid Water Water Vapor (Hvap) In Sublimation Drying (Lyophilization) Sublimation (no liquid) Ice Water Vapor (Hsub) M. Kamat Jan, 2013
Energetic of Phase Change Sublimation Drying (Lyophilization) Sublimation (no liquid) Ice Vapor state (Hsub) Sublimation involves solid, liquid, and gas transitions and need energy H2Oice (-40 C) H2Ovapor (25 C), Hsub 1. H2Oice (-40 C) H2Oice (0 C), H1 2. H2Oice (0 C) H2Oliq (0 C), H2 3. H2Oliq (0 C) H2Oliq (25 C), H3 4. H2Oliq (25 C) H2Ovapor (25 C), H4 Adding all these reactions, Hsub = H1 + H2 + H3 + H4 M. Kamat Jan, 2013
Heat Energy Must Be Provided for Sublimation to Continue: • Heat Energy must be provided for sublimation to continue • How much heat to be supplied ? • 676 calories/gm of ice to be sublimed at ºC • Latent heat of fusion (78 Calories) + Latent heat of vaporization (598 Calories) • If excess heat (more than required for phase change) is supplied, the heat will be used to raise the temperature of the product (not just for phase change) and .....Eventually melt the ice. M. Kamat Jan, 2013
Boiling Water in Kettle Temp= ~600 C Temp=100 C Boiling Water (Phase Change) Temp= ~600 C Probe in pot-full of water on hot plate Probe in emptied pot on hot plate M. Kamat Jan, 2013
Heat Energy Must Be Provided for Sublimation to Continue: • What is the heat source - From the heated shelves in the lyophilizer Chamber (some cases: ambient heat, IR, MW etc.) • How to increase the rate of sublimation - Increase the driving force • Increase the heat supply (shelf temperature) • Increase the product temperature Limit: (maximum allowable temperature) • For every 10 ºC rise in product temp, the rate of drying doubles M. Kamat Jan, 2013
Important • The low pressure above the ice keeps the product frozen • The heat is transferred into the Vial • (Heat-Transfer) • The water vapor is transferred out of vial • (Mass-Transfer) • The two transfer processes must be equal to keep the product • frozen and sublimation process to continue M. Kamat Jan, 2013
The Water Vapor Is Transferred Out of Vial • The vapor then flows out of chamber into the condenser section and gets deposited as ice on cold surfaces of condenser plates. • In old times : • chemical traps (P2O5, silica desiccants) • (and in food industry) directly to the pump/ballast (and then oil change) • The coldness of condenser does not affect the drying rate as long as it is colder than the product temperature • Above certain temperature, though, the ice condensation power may decrease • Very low condenser temperatures are not needed for sublimation to happen: Just collect the sublimate M. Kamat Jan, 2013
Heat Transfer Phenomena Flow of Heat : Heating Medium Shelf Interior Shelf Surface (thru the trays) Under the Vial Bottom Surface of Vial Bottom of Ice Through the Ice Sublimation Front Rate of heat input = Where, is the thermal conductivity of the container, d is the thickness of the base of the container Ts = Shelf temperature Tc,i = Temperature at the ice interface M. Kamat Jan, 2013
Mass Transfer Phenomenon Vent We will discuss This later M. Kamat Jan, 2013
Heat and Mass transfer processes Energy (in) = Energy (out) (heat) (sublimation) Heat transfer rate = Hs X mass transfer rate Rate of heat input = Heat of sublimation X Rate of mass transfer M. Kamat Jan, 2013
Effect of Resistance to Mass Transfer M. Kamat Jan, 2013
Key Process Parameters Tp (product temperature): Keep the product below Tcritical Pc (chamber pressure): Keep sublimation process on Ts (shelf surface temp): Provide energy for sublimation M. Kamat Jan, 2013
Factors Which May Affect the Cycle ActionEffect on Cycle Increase Product temperature Short Decrease dried product resistance Short (Freezing modifications) Use of Trays Long Better Contact of Glass Short Increase Chamber Pressure Short (Up to certain limits) M. Kamat Jan, 2013
Independent Parameters (all programmable variables) Not affected by the characteristics and the load of the product Shelf Temperature (fluid) Time Duration (soaks) Ramping Dependent Parameters (non-programmable variables) Affected by the characteristics and the load of the product Condenser Temperature Chamber Pressure Product Temperature Product drying Time Process Parameters M. Kamat Jan, 2013
Stages of Lyophilization • Fill the solution in the vials. Place stoppers • Freezing the product on FD Shelves • Start Cooling the condenser • Produce Vacuum in the dryer • Open the isolation Valve • Check Pressure and Heat the product • Start Primary drying • Continue with Secondary Drying • End-of-Drying • Stopper and Remove the Product • QC Testing M. Kamat Jan, 2013
Schematics of a Lyophilizer M. Kamat Jan, 2013 From: Sundaram et al; BioPharm International, Volume 23, Issue 9, Sep 2010
Lyophilizer Chamber M. Kamat Jan, 2013
Lyophilizer Units Condenser Chamber Vacuum Pumps M. Kamat Jan, 2013
FREEZE DRYING OF COFFEE INVOLVES FOUR STEPS: • Pre-freezing coffee concentrate (40-45%) up to -5/-10 °C followed by foaming. • Freezing of the pre-frozen coffee liquor at -50 °C in a blast freezer. • Sizing of the fr0zen coffee particles to a granular size of 3X3mm. • Sublimation of the ice in a vacuum freeze dryer (VFD) under vacuum (0.5 torr) and controlled temperature. M. Kamat Jan, 2013