General Principles of
Freeze Drying (The Lyophilization Process)
Importance of Vacuum
in the Freeze Drying Process
Freeze Drying can only take place if the partial
pressure of the vapor in the drying chamber is lower than the
water vapor pressure above the product. By strict definition,
the vacuum in the chamber is not essential, as sublimation can
take place at atmospheric pressure by passing dehydrated air
above the product. By artificially lowering the pressure in
the drying chamber the time can be reduced.
For example, a product sublimated at –20°
C (Fig 4) at the given vapor pressure shown as 0.8 torr. As
soon as the value in the chamber reaches below 0.8 torr, the
ice begins to sublime.
Flosdorff has shown that as soon as the pressure
in the chamber is reduced, evaporation increases, but the rate
of evaporation is not without limit, and reaches a maximum when
the pressure in the chamber has a value equal to about 50% of
the vapor pressure above the product.
The curve in Fig. 5 represents the changes in
evaporation rate for a product which is undergoing sublimation
at –20 C, as a function of the pressure in the chamber;
the rate reaching a maximum of 0.4 torr.
Contrary to widely held opinion, it is not necessary
to have a very low vacuum during the sublimation period, because
below the limit defined, the evaporation rate is not improved,
and that too low a pressure acts as a barrier to effective heat
transfer.
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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