the crystalline phase. If lyophilized between these temperatures,
then the phase with the higher critical temperature may retain its
physical structure while the other phase may “microcollapse” or
“micromelt” onto it [11].
Even amorphous materials when mixed in the same solution
without any crystalline components are not immune from phase
separation, and in some cases, distinct glass transition temperatures
may be observed for the multiple phases [23]. Therefore, it is
always advisable to carry out some basic characterization of candidate formulations prior to lyophilization, especially for complex
mixtures where the behavior may not be completely predictable
even if the individual components have been well characterized.
2.2.5 Freezing
in Practice
Products may be frozen in a variety of ways depending on operational requirements:
1. The liquid formulation may be frozen in a freezer or a cooling
tunnel prior to transfer to the freeze-dryer for desiccation.
Advantages include increased annual sample throughput
because the freeze-dryer is used only for drying. Disadvantages
include the greater risk of melt or contamination resulting from
the need to transfer material from the freezer into the dryer.
2. Pellet freezing. Strictly this is not a method of freezing but can
be useful when bulk products, including vaccines for
subsequent powder filling, are processed. The suspension is
sprayed into a cryogenic liquid or onto a cold surface to form
frozen droplets, which are then placed into trays or flasks for
freeze-drying. Under these conditions, sublimation rates are
typically very high because the thickness of the dry layer is
restricted only by the pellet radius, and drying proceeds in a
virtually unimpeded manner from each pellet.
3. The most widely used technique is to freeze the liquid formulation in the final container directly on the freeze-dryer shelf.
Although this method has the disadvantage that the dryer is
used for part of the cycle as a freezer, freezing and drying
samples within a single machine eliminates the need to transfer
samples from freezer to dryer and therefore improves sample temperature control, as well as reducing product vulnerability; this is generally the preferred method by regulatory
bodies.
4. Product may be frozen using controlled nucleation, where it is
loaded in the liquid state and the shelf temperature reduced to
below 0
C (typically between À2
C and À8
C) prior to the
mechanism of nucleation being triggered. A number of different mechanisms may be employed, as listed earlier in this
chapter. Controlled nucleation assists in obtaining a more
homogenous ice crystal size, which can positively impact the
Principles of Freeze-Drying
111
then the phase with the higher critical temperature may retain its
physical structure while the other phase may “microcollapse” or
“micromelt” onto it [11].
Even amorphous materials when mixed in the same solution
without any crystalline components are not immune from phase
separation, and in some cases, distinct glass transition temperatures
may be observed for the multiple phases [23]. Therefore, it is
always advisable to carry out some basic characterization of candidate formulations prior to lyophilization, especially for complex
mixtures where the behavior may not be completely predictable
even if the individual components have been well characterized.
2.2.5 Freezing
in Practice
Products may be frozen in a variety of ways depending on operational requirements:
1. The liquid formulation may be frozen in a freezer or a cooling
tunnel prior to transfer to the freeze-dryer for desiccation.
Advantages include increased annual sample throughput
because the freeze-dryer is used only for drying. Disadvantages
include the greater risk of melt or contamination resulting from
the need to transfer material from the freezer into the dryer.
2. Pellet freezing. Strictly this is not a method of freezing but can
be useful when bulk products, including vaccines for
subsequent powder filling, are processed. The suspension is
sprayed into a cryogenic liquid or onto a cold surface to form
frozen droplets, which are then placed into trays or flasks for
freeze-drying. Under these conditions, sublimation rates are
typically very high because the thickness of the dry layer is
restricted only by the pellet radius, and drying proceeds in a
virtually unimpeded manner from each pellet.
3. The most widely used technique is to freeze the liquid formulation in the final container directly on the freeze-dryer shelf.
Although this method has the disadvantage that the dryer is
used for part of the cycle as a freezer, freezing and drying
samples within a single machine eliminates the need to transfer
samples from freezer to dryer and therefore improves sample temperature control, as well as reducing product vulnerability; this is generally the preferred method by regulatory
bodies.
4. Product may be frozen using controlled nucleation, where it is
loaded in the liquid state and the shelf temperature reduced to
below 0
C (typically between À2
C and À8
C) prior to the
mechanism of nucleation being triggered. A number of different mechanisms may be employed, as listed earlier in this
chapter. Controlled nucleation assists in obtaining a more
homogenous ice crystal size, which can positively impact the
Principles of Freeze-Drying
111