General Principles of
Freeze Drying (The Lyophilization Process)
Introduction
Application and Uses
Freeze Drying, or lyophilization as it is referred to in the
Pharmaceutical and Diagnostic Industries, is a dehydration technique,
which enables liquid or slurry products, which have previously
been frozen to be dried under a vacuum. The applications of
freeze drying are numerous, but is generally employed when the
requirements demand:
- Preservation of temperature sensitive products,
particularly those of biological origin,
such as enzymes, blood plasma, vaccines, etc.
- To achieve a chemical balance, such as for
biological reagents.
- To provide a practical solution for certain
delivery problems, for example, the packaging of constituents
that cannot be mixed in the liquid state, but which are solidified
in successive stages and then freeze dried.
- To implement an important stage of a product
(such as concentration).
- To improve storage life and improved marketing
of the end product.
- To resolve certain filling problems. It may
be difficult, for instance, to divide several milligrams of
powder into precise vial dosages, due to the difficulty of
measuring tiny amounts, homogeneity, granulation, static electricity
etc.. The distribution of the product from the liquid state
eliminates such production problems.
- Product temperature sensitivity, and its relation
to taste.
Description of the Operation
Generally, the Freeze Drying, or Lyophilization cycle is divided
in three phases:
At the completion of the process, the treated
product will have retained its form, volume and original structure-as
well as all its physical, chemical and biological properties.
It can then be stored (provided packaging is effective to the
reduction of moisture migration) for an almost indefinite period
of time. As the product is porous, it can be re-dissolved by
the simple addition of a proper solvent.
From this description of the process of freeze
drying, three facts emerge:
- The sublimation characteristics of the product
are greatly dependent of the frozen structure.
- This structure cannot be altered during the
process.
- Product temperature plays an active role
in all three phases, and in execution it is
upon this that the choice of other parameters (vaccuum, heat
rate, etc.) is based.
Theoretical Basis of Freeze Drying
The theoretical principle of freeze drying
is clearly defined in the diagram "Pressure Temperature"
(Fig A).
In order to avoid the liquid phase, it
is absolutely essential to lower the partial pressure of water,
below the triple point pressure. A freeze drying cycle is shown
in this diagram, which has been designed to conform to a typical
example (described below):
- Freezing of a product from 20° C
to -20 C° at atmospheric pressure.
- Sublimation of the product at -20°
C.
- Transfer of evolved vapor to the condenser
at low temperature.
- Vacuum release.
- Defrost.
Freeze Drying is a complex operation, and
all facets cannot be addressed in this type of explanation.
Instead, certain aspects will be highlighted which play a part
in the development of a freeze drying operation:
- Freezing.
- Drying.
- Vacuum influence.
- The liquid shelf on which the product
is placed.
- Essential control aspects during freeze
drying.
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