General Principles of
Freeze Drying (The Lyophilization Process)
Freezing Temperature
In these examples, Point D on the curve, Fig 1
and Fig 2 represent the temperature of the complete freezing
of the product. The establishment of this eutectic zone is very
important. Between C and D, the concentration and consistency
of the liquid phase is increased, and in the case of biological
products, may produce a change in the bacteria as a result of
the hyper concentration of the active ingredient, and the mechanical
effect of the ice crystals.
During the sublimation phase, signs of melting
appear in the product, which induces a temperature higher than
that corresponding to the eutectic point. Temperature analysis
permits determination of the onset of the fusion temperature.
This acts as an indicator to help prevent “melt back”,
or other such accidents during the course of freeze drying.
Generally, a structure of large crystals presents
more difficulties with regard to freeze drying, in that a thick
crust forms at the surface. The appearance of the freeze dried
product is heterogeneous. This very often makes dissolution
difficult.
A product structure of fine crystals freezes more
easily. The freeze dried product has an amorphous appearance,
and re-dissolves more quickly. Obtaining the desired crystalline
structure is not always easy, as the formation of this type
of crystal depends on several factors:
- The nature of the product.
- The processing.
- Freezing speed.
- Type of freezing.
Given the diverse range of products, which may
be treated in the dryer, the desired freezing rate, and the
type of final packaging that may used, the manufacturer must
consider:
- The quantity of product per container.
- The form of the container.
- The type of freezing.
- And, plan for a freeze dryer that is flexible
to these different demands.
Freeze Drying
Once the product is properly frozen, it must be
sublimated (evaporated) at a low temperature under reduced pressure.
The ideal curve of lyophilization is depicted on Curve A of
Fig. 3, with temperature displayed on the ordinand line, and
time displayed on the abscissa.
With the product maintained at a constant temperature,
it will be necessary to supply the energy of sublimation, a
combination of the latent heat of fusion (which supplies the
transformation of the liquid to the ice state) and the sublimation
energy (about 700 calories per gram of ice evaporated). The
ability of vapor release from the matrix is a function of molecular
agitation inside the matrix.
Ideally, the temperature of the frozen product
should be brought to the highest temperature compatible with
the frozen condition, without exceeding it, which will lead
to the irreparable production of “foam” (commonly
known as melt back) and product deterioration. On the other
hand, if the heat energy is insufficient, the product will sublime
at too low a temperature (Curve E), and the length of the freeze
drying cycle will become abnormally long.
After the disappearance of the final ice crystals,
the temperature of the product rapidly increases, and must be
maintained at the most maximum permissible temperature to liberate
the lowest residual moisture embedded in the matrix (secondary
drying). The liquid shelves on which the product is loaded transfer
the required energy of sublimation. (Curves B, C, or D represent
the heating rate)
A chilled surface known as the ice condenser collects
the vapor from the evolving product. (Curve F) During lyophilization,
the pressure in the drying chamber follows the fluctuations
identified by Curves P or P1.
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