2.2 Product Freezing
Regarded as the first step in the process, the formulated product
must be frozen before evacuating the chamber to induce sublimation. Freezing will:
1. Immobilize the components in the solution and prevent foaming as the vacuum is applied.
2. Reduce thermal inactivation of the dispensed product.
3. Induce a specific ice crystal structure within the frozen mass,
which will facilitate or inhibit vapor migration from the drying
cake. In short, the ice structure formed during freezing will
dictate subsequent freeze-drying behavior and the ultimate
morphology of the dried cake.
Ideally, freezing should minimize solute concentration effects
and result in all components being evenly distributed throughout
the frozen structure. However, it may not be possible to achieve
this ideal when solutions or suspensions are frozen, not least since
the latter can undergo some degree of sedimentation. When
addressing the freezing of aqueous solutions or suspensions, there
is the need to consider both the solvent (water in the case of
aqueous solutions) and solute(s) in the formulation. A comprehensive treatise on the fundamentals of freezing and annealing phenomena as they apply to freeze-drying is provided by Searles [10].
Frequently, the terms cooling and freezing are erroneously
interchanged and confusion in understanding the process may
occur and may be compounded by failing to distinguish between
shelf or product cooling and freezing. Cooling refers to the reduction of temperature of the freeze-dryer shelves, the fluid circulating
through the shelves, the vial, and tray mass, interior of the freezedryer, and the dispensed solution or suspension. Cooling does not
assume a change in state from liquid to solid and strictly should be
used to describe reducing temperature during the initial stage of
freeze-drying. Freezing refers to the abrupt phase change when
water freezes as ice. Except for very complex biomolecules or
cold-sensitive cells, cooling in the absence of freezing (chilling) is
generally not damaging to biomaterials.
When solutions or suspensions are frozen, they may cool appreciably below their thermodynamic freezing point prior to ice formation, a phenomenon defined as supercooling (sometimes
referred to as undercooling or subcooling). The extent of supercooling depends on cooling rate, sample composition and cleanliness, dispensed fill volume, container type, method of sample
cooling, and so on. Even when a simple solution is repeatedly
cooled or warmed, the onset and extent of supercooling will vary
from cycle to cycle. In the supercooled state, while the composition
of the solution remains unchanged, the cooled liquid is thermodynamically unstable and sensitive to ice formation. As the solution is
cooled to lower temperatures, the probability of ice crystallization
will correspondingly increase. For optimized freeze-drying, the
104
Kevin R. Ward and Paul Matejtschuk
Regarded as the first step in the process, the formulated product
must be frozen before evacuating the chamber to induce sublimation. Freezing will:
1. Immobilize the components in the solution and prevent foaming as the vacuum is applied.
2. Reduce thermal inactivation of the dispensed product.
3. Induce a specific ice crystal structure within the frozen mass,
which will facilitate or inhibit vapor migration from the drying
cake. In short, the ice structure formed during freezing will
dictate subsequent freeze-drying behavior and the ultimate
morphology of the dried cake.
Ideally, freezing should minimize solute concentration effects
and result in all components being evenly distributed throughout
the frozen structure. However, it may not be possible to achieve
this ideal when solutions or suspensions are frozen, not least since
the latter can undergo some degree of sedimentation. When
addressing the freezing of aqueous solutions or suspensions, there
is the need to consider both the solvent (water in the case of
aqueous solutions) and solute(s) in the formulation. A comprehensive treatise on the fundamentals of freezing and annealing phenomena as they apply to freeze-drying is provided by Searles [10].
Frequently, the terms cooling and freezing are erroneously
interchanged and confusion in understanding the process may
occur and may be compounded by failing to distinguish between
shelf or product cooling and freezing. Cooling refers to the reduction of temperature of the freeze-dryer shelves, the fluid circulating
through the shelves, the vial, and tray mass, interior of the freezedryer, and the dispensed solution or suspension. Cooling does not
assume a change in state from liquid to solid and strictly should be
used to describe reducing temperature during the initial stage of
freeze-drying. Freezing refers to the abrupt phase change when
water freezes as ice. Except for very complex biomolecules or
cold-sensitive cells, cooling in the absence of freezing (chilling) is
generally not damaging to biomaterials.
When solutions or suspensions are frozen, they may cool appreciably below their thermodynamic freezing point prior to ice formation, a phenomenon defined as supercooling (sometimes
referred to as undercooling or subcooling). The extent of supercooling depends on cooling rate, sample composition and cleanliness, dispensed fill volume, container type, method of sample
cooling, and so on. Even when a simple solution is repeatedly
cooled or warmed, the onset and extent of supercooling will vary
from cycle to cycle. In the supercooled state, while the composition
of the solution remains unchanged, the cooled liquid is thermodynamically unstable and sensitive to ice formation. As the solution is
cooled to lower temperatures, the probability of ice crystallization
will correspondingly increase. For optimized freeze-drying, the
104
Kevin R. Ward and Paul Matejtschuk