Excipients: Their Role in Rational Formulation Design - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 89

solution against pH and/or salt denaturation, 99 while they also protect
the protein, although by a completely different mechanism, against the
damaging process of freeze-concentration.

7.5 Implications for Freeze-Drying

Depending on the physical behaviour and stability of the bioactive com-
ponent, both amorphous and eutectic systems can be successfully freeze-
dried but require different approaches. The most difficult cases are those
that exhibit partial crystallisation, which may lead to uncontrollable intra-
batch variability. Irrespective of the physical state of the system, maximum
temperatures for ice sublimation (T e or T g ) can be identified. Above these
temperatures, ice will melt at an appreciable rate, thus diluting the solution
phase. The product may then exhibit mechanical collapse, and most prob-
ably it will also become subject to chemical changes (usually deterioration).
In a frozen amorphous system at T g , the product will often retain a
significant amount of water, typically 20-50% w/w. At any stage
thereafter, if the temperature is allowed to rise unduly, the residual
glass softens into a viscous liquid with adverse consequences. Although
most of the residual water must be removed, the amorphous matrix must
be maintained in, or close to, the glassy state at all times. The maximum
safe storage temperature after the complete removal of water will be
given, at least for a limited period, by the glass temperature (T g ) of the
final dried composition. For extended shelf lives, say months or years,
glass transitions well in excess of the storage temperature must be aimed
at. This aspect will be further discussed in Chapter 11.
In a eutectic system, the whole composition or just the excipient may
be subject to crystallisation, but this process takes time to reach com-
pletion. It may be much longer than the time taken to freeze the product
to the desired temperature (T g ). After primary drying (ice sublimation),
only solid ''solutes'' remain. The mixture may then be carefully warmed
to its final storage temperature. The residual solid will not necessarily be
anhydrous and may, for example, contain water of crystallisation. In
addition, as the temperature is raised, the crystalline product may
undergo solid-solid transitions, i.e. over a period of time, a different
polymorph may become the preferred crystal habit. In a completely
crystalline preparation, the maximum safe storage temperature will be
governed by the component with the lowest melting point.
The physical state and the appearance of the dried cake are set during
the freezing process, i.e. the kinetics of ice nucleation and crystal growth.
Both can be controlled to some extent by variations in formulation and