Freeze Drying: DR - Sangeetha Subramanian

Freeze drying
Dr.Sangeetha Subramanian
Freeze drying
• Freeze drying is the removal of ice or other frozen solvents from a material
through the process of sublimation and the removal of bound water
molecules through the process of desorption.
Overview
• Lyophilization and freeze drying are terms that are used interchangeably
depending on the industry and location where the drying is taking place.
• Controlled freeze drying keeps the product temperature low enough during
the process to avoid changes in the dried product appearance and
characteristics.
• It is an excellent method for preserving a wide variety of heat-sensitive
materials such as proteins, microbes, pharmaceuticals, tissues & plasma.
Sublimation
• Sublimation is when a solid (ice) changes directly to a vapor without first
going through a liquid (water) phase.
• As shown below on the phase diagram for water, 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
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.
The steps required to lyophilize a product in a
batch process can be summarized as follows:
• Pretreatment / Formulation
• Loading / Container (Bulk, Flask, Vials)
• Freezing (Thermal Treatment) at atmospheric pressure
• Primary Drying (Sublimation) under vacuum
• Secondary Drying (Desorption) under vacuum
• Backfill & Stoppering (for product in vials) under partial vacuum
• Removal of Dried Product from Freeze Dryer
FREEZE DRYING EQUIPMENT
The main components of freeze drying equipment are:
• Refrigeration System
• Vacuum System
• Control System
• Product Chamber or Manifold
• Condenser
• The refrigeration system cools the (ice) condenser located inside the freeze
dryer. The refrigeration system can also be employed to cool shelves in the
product chamber for the freezing of the product.
• The vacuum system consists of a separate vacuum pump connected to an
airtight condenser and attached product chamber.
• Control systems vary in complexity and usually include temperature and
pressure sensing ability. Advanced controllers will allow the programming of
a complete “recipe” for freeze drying and will include options to monitor
how the freeze drying process is progressing. Choosing a control system for
the freeze dryer depends on the application and use (i.e. lab vs. production).
• Product chambers are typically either a manifold with attached flasks, or, a
larger chamber with a system of shelves on which to place the product.
• The purpose of the condenser is to attract the vapors being sublimed off of
the product. Because the condenser is maintained at a lower energy level
relative to the product ice, the vapors condense and turn back into solid
form (ice) in the condenser.
• The sublimated ice accumulates in the condenser and is manually removed at
the end of the freeze drying cycle (defrost step).
PHYSICAL PROPERTIES OF
MATERIALS AND FORMULATION
• Understanding the physical properties of materials that are freeze-dried is a
key part in developing a successful lyophilization process.
• Although a few products are simple crystalline materials, the vast majority of
products that are lyophilized are amorphous and form glassy states when
frozen.
Freezing
• It is extremely important that the sample be fully and completely frozen prior
to pulling a vacuum and starting the drying process. Unfrozen product may
expand outside of the container when placed under a vacuum.
Primary Drying
• The drying portion of freeze drying is actually a two part process consisting of
Primary Drying and Secondary Drying. The bulk of water removed from the
product during freeze drying is via sublimation of all of the free ice crystals during
the primary drying step. Organic solvents are also removed during primary drying.
• Primary drying (sublimation) is a slow process conducted at cooler temperatures,
safely below the product’s critical collapse temperature. Sublimation requires heat
energy to drive the phase change process from solid to gas. All three methods of
heat transfer - conduction, convection and radiation, must be considered when
freeze drying a product.
SECONDARY DRYING
• In addition to the free ice that is sublimed during primary drying, there
remains a substantial amount of water molecules that are bound to the
product. This is the water that is removed (desorbed) during secondary
drying. Since all of the free ice has been removed in primary drying, the
product temperature can now be increased considerably without fear of
melting or collapse.
• Secondary drying actually starts during the primary phase, but at elevated
temperatures (typically in the 30ºC to 50ºC range), desorption proceeds much more
quickly.
• Secondary drying rates are dependant on the product temperature.
• System vacuum may be continued at the same level used during primary drying;
lower vacuum levels will not improve secondary drying times.
• Amorphous products may require that the temperature increase from primary to
secondary drying be controlled at a slow ramp rate to avoid collapse.
• Secondary drying is continued until the product has acceptable moisture
content for long term storage.
• Depending on the application, moisture content in fully dried products is
typically between 0.5% and 3%.
• In most cases, the more dry the product, the longer its shelf life will be.
• However, certain complex biological products may actually become too dry
for optimum storage results and the secondary drying process should be
controlled accordingly.
STORAGE OF DRIED PRODUCT
• Lyophilized products are extremely hydroscopic and they must be sealed in
air tight containers following freeze drying to prevent rehydration from
atmospheric exposure.
• Freeze dryers can be configured with a “stoppering” capability to seal the
product while it is still under partial vacuum inside the unit.
• It is also common to backfill with an inert gas such as dry nitrogen before
sealing/stoppering the product.

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