(it should be noted that this warming phase may also crystallize
solutes that are reluctant to crystallize upon initial cooling).
3. Cooling the product to terminal hold temperature prior to
chamber evacuation (although this may not be necessary if
annealing has caused the critical temperature of the formulation to increase above the holding temperature).
Annealing is particularly useful to:
1. Increase ice crystal size and networking, which reduces product
resistance to vapor flow (R p ) and consequently improves sublimation efficiency.
2. Crystallize solutes that are reluctant to crystallize during initial
cooling.
3. Provide greater uniformity of product structure throughout
the batch and between batches.
4. Integrated with rapid cooling, annealing may minimize the
development of a surface skin on the product while also
increasing ice crystal size, thereby facilitating sublimation.
5. Because annealing induces larger pores in the cake structure,
this can aid wetting and rehydration during the reconstitution
process. However, studies using controlled nucleation have
demonstrated that the reduction in specific surface area can
lead to secondary drying (desorption) efficiency being reduced,
and therefore, it may be necessary to increase the length of the
secondary drying step accordingly [12, 13].
Although annealing will increase the length of the freezing
stage of the cycle and possibly also the secondary drying stage as
highlighted above, overall freeze-drying cycle times may be significantly reduced because of improvements in drying efficiency resulting from annealing.
Care should be exercised when selecting temperatures and hold
times for annealing, particularly when defining the upper temperature for warming. Subjecting a labile product, such as a vaccine, to
temperatures above the eutectic temperature will expose the active
material to hypertonic solution as the sample partially melts, which
can damage sensitive biomolecules, cells, or organisms.
2.2.4 Solute Freezing
Behavior
Regardless of the precise freezing pattern, the formation of ice will
concentrate the remaining solution within the container. As the
proportion of ice increases within the mixture, solute concentration
will correspondingly increase. In the case of an aqueous 1% (w/v)
saline solution, this concentration effect will be considerable,
increasing to approximately 30% (w/v) just prior to freezing,
which may cause damage to biomolecules as a consequence of
solute concentration exposure rather than direct damage by ice
crystals. The behavior of the solute(s) within the solute concentrate
108
Kevin R. Ward and Paul Matejtschuk
solutes that are reluctant to crystallize upon initial cooling).
3. Cooling the product to terminal hold temperature prior to
chamber evacuation (although this may not be necessary if
annealing has caused the critical temperature of the formulation to increase above the holding temperature).
Annealing is particularly useful to:
1. Increase ice crystal size and networking, which reduces product
resistance to vapor flow (R p ) and consequently improves sublimation efficiency.
2. Crystallize solutes that are reluctant to crystallize during initial
cooling.
3. Provide greater uniformity of product structure throughout
the batch and between batches.
4. Integrated with rapid cooling, annealing may minimize the
development of a surface skin on the product while also
increasing ice crystal size, thereby facilitating sublimation.
5. Because annealing induces larger pores in the cake structure,
this can aid wetting and rehydration during the reconstitution
process. However, studies using controlled nucleation have
demonstrated that the reduction in specific surface area can
lead to secondary drying (desorption) efficiency being reduced,
and therefore, it may be necessary to increase the length of the
secondary drying step accordingly [12, 13].
Although annealing will increase the length of the freezing
stage of the cycle and possibly also the secondary drying stage as
highlighted above, overall freeze-drying cycle times may be significantly reduced because of improvements in drying efficiency resulting from annealing.
Care should be exercised when selecting temperatures and hold
times for annealing, particularly when defining the upper temperature for warming. Subjecting a labile product, such as a vaccine, to
temperatures above the eutectic temperature will expose the active
material to hypertonic solution as the sample partially melts, which
can damage sensitive biomolecules, cells, or organisms.
2.2.4 Solute Freezing
Behavior
Regardless of the precise freezing pattern, the formation of ice will
concentrate the remaining solution within the container. As the
proportion of ice increases within the mixture, solute concentration
will correspondingly increase. In the case of an aqueous 1% (w/v)
saline solution, this concentration effect will be considerable,
increasing to approximately 30% (w/v) just prior to freezing,
which may cause damage to biomolecules as a consequence of
solute concentration exposure rather than direct damage by ice
crystals. The behavior of the solute(s) within the solute concentrate
108
Kevin R. Ward and Paul Matejtschuk