Historical Background - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 7

parlance, has led to lengthy arguments between judges, advocates and
the so-called expert witnesses in courts of law. In the Oxford Dictionary,
''dry'' is defined as ''devoid of all natural moisture'', or in more technical
terms, ''anhydrous''. However, as mentioned earlier, in our ecosphere,
even under low relative humidity conditions, anhydrous organic mate-
rials have no existence. We must therefore look for another, more
practical definition of ''dry''.
In purely pharmaceutical terms, the meaning of ''stability'' is clear: it
relates to the maintenance of the exact molecular identity of a given drug
substance. Chemical instability can arise by different routes, which
include hydrolysis, oxidation, isomerisation, condensation, racemisation
and reactions with other components in solution. 10 This subject is
discussed in more detail in Chapter 5. A particularly troublesome group
of reactions is common in the processed food industry. These non-
enzymatic Maillard or ''browning'' reactions occur between peptides
and reducing sugars, especially in semi-dry environments. They are of
only minor significance in pharmaceutical processing, and the interested
reader is referred to one of the many monographs that deal with this
particular problem. 11
In the vast majority of chemical destabilisation/bioinactivation proc-
esses, water acts either as a catalyst or it participates as a reactant and/or
product. It therefore seems logical to conclude that the removal of water
should eliminate many causes of chemical instability. The situation is
not quite so clear however in the case of physical instability. Processes of
concern that can take place in the solid state include polymorphic solid/
solid transitions and the compaction of powders. Even low levels of
water vapour sorption may lead to other undesirable changes, e.g. solid/
liquid phase separations, recrystallisation in the solid state or polymor-
phic transitions. Since all these processes occur only in the solid state, it
follows that they cannot necessarily be eliminated by drying. The
important factors in physical and mechanical stabilisation are the actual
state of the solid produced by drying, the level of residual water and the
temperature and pressure employed during processing and storage.
Special consideration must be given to biopharmaceuticals, i.e. com-
plex preparations containing one or several biopolymers, often of pep-
tide origin, although similar considerations apply to polysaccharides,
phospho- and glycolipids, nucleotides and conjugates of the above, e.g.
immunoglobulins or lipoproteins. Even more sensitive to destabilisation
and inactivation are supramolecular assemblies such as viruses, multi-
subunit enzymes and lipid vesicles. Here, more subtle effects are at work,
which tend to destroy biological activity, even without affecting covalent
bonds. Thus, a protein relies for its specific biological activity on a