Primary Drying: The Sublimation of Ice - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 108

temperature and chamber pressure in determining the sublimation rate
at a constant product temperature ( o T g ).
8.6 Adjustable Parameters: Formulation, Concentration
and Fill Depth
Setting the product composition of a pharmaceutical preparation, so as to
effect an efficient and economical drying cycle, will probably always be
beyond the remit of the process engineer. However, bearing in mind the
complexities of the freeze-drying process, its optimisation should be given
due consideration even by those responsible for product development.
The influence of the solid content makes itself felt during the later stages
of the drying process. At the beginning of the drying cycle, heat is
supplied to the shelves in order to balance the latent heat of sublimation
absorbed by the ice. As the ice front migrates downwards during subli-
mation, the network of the dried product offers an increasingly strong
resistance to further sublimation; the drying rate therefore decreases. The
effect of the dry product resistance is difficult to estimate accurately
because it depends very much on the actual texture (porosity), which, in
turn, is determined by the primary freezing process and any subsequent
annealing accompanied by maturation. It was shown earlier how ice
nucleation and crystal growth kinetics depend in part on the solid content
of the solution. It follows that a high solid content will decrease the
porosity of the dried portion of the plug and hence raise the resistance to
further sublimation.
On the other hand, an excessive reduction of the solid content results in
a plug that is brittle and mechanically too weak to withstand rough
handling of the containing vial during packaging and shipping. Although
neither the chemical stability nor the efficacy of the dried product will
necessarily suffer from a broken-up plug, its appearance is held to be
undesirable, even unacceptable, in some markets.
The important role played by the solution fill depth in determining the
sublimation rate has already been touched upon and can hardly be
overstated. It depends on the shape of the containing vessel in relation to
the fill volume. Ideally, a fill depth of 5 mm is to be recommended.
Freeze-drying of chemically labile products at fill depths in excess of 20
mm is to be avoided. Where for pharmacokinetic or other reasons (e.g.
solubility) a certain volume is prescribed for the administration of the
reconstituted solution, the limitation of fill depth has to be achieved by
other means. This often involves the use of a vial with a larger-than-ideal
diameter. For reasons of cost and suboptimal utilisation of freeze-drier