General Principles of
Freeze Drying (The Lyophilization Process)
- The duration of secondary drying (isothermic
phase).
- The maximum temperature allowed in the
product during secondary drying.
Note: Products with excipients may exhibit tendencies
to retain water in the matrix, and are hygroscopic in ambient
air. The final residual moisture obtainable is dependent on
more conditions than the vacuum and moderate temperature generally
employed for this secondary phase.
Good vacuum is essential so that the mean free
path of water molecules from the product matrix is not impeded
by pressure. The lowest possible pressure is not necessarily
desirable (below 10-2 torr) because below this pressure, desorption
produces an assympotic rate (Fig. 7), and the phenomenon of
“backstreaming” the vacuum pump becomes more significant,
thus risking pollution the product matrix.
Factors affecting secondary
(terminal) drying phase:
By a series of reproducible runs on a scaleable
the optimum cycle can be established. If the process is automated
it is essential that:
- Cycle is performed with a guarantee of functional
security.
- Validation is simple.
- Allows maximum flexibility for a variety of
product drying protocols.
- In the pilot development phase, it is critical
that the favorable conditions for freezing and the optimum
parameters of primary and secondary drying be established.
Secondary Drying:
At the end of the sublimation phase (primary drying),
all the ice will have disappeared. The product will begin to
rise in temperature, and will tend to approach the control temperature
of the shelf. However, at this stage the product is not sufficiently
dry for long term storage. For most products, the residual moisture
is in the region of 5% to 7%.
The product now enters the desorption phase, during
which the last traces of water vapor are removed, along with
traces of the “bound” water within the product matrix.
This phase is identified as secondary drying. The aim of this
final phase is to reduce the product to the acceptable moisture
levels needed for long term storage (3% to 1%).
The reasons for drying the product to these levels
are desirable for several benefits:
- When the water content is higher than these
levels, the product will denature.
- When the residual moisture is forced
lower than these levels, many products may undergo chemical
or enzymatic changes.
Residual moisture in the product is generally
dependent on four factors:
- The product matrix (both in frozen and sublimation
mode)
- The vacuum in the drying chamber
