Chemistry Reference
In-Depth Information
had suffered complete inactivation, because it now lacked the previous
protection afforded by a high concentration of carbohydrate excipient.
This type of sugar devitrification is therefore highly damaging and
must be avoided. Usually this can be achieved by storage of the prep-
aration below T
g
, although isolated instances of crystallisation in glassy
mixtures, stored well below T
g
have also been reported.
74
By contrast to
the damaging crystallisation of a PHC described earlier, the crystallisa-
tion of a hydrate from a previously amorphous preparation can also
provide a beneficial desiccation effect, by removing water from the
amorphous phase, thereby increasing its T
g
and improving the storage
stability. The process has been termed ''self-stabilisation'',
100
and its use
is further discussed in Chapter 11 and illustrated in Figure 3 of Chapter
11. The degree of such desiccation depends on the mol ratio sugar:water
and on the crystallisation rate. The stabilising effect is therefore expected
to increase as the number of mols of water per mol of sugar increases,
i.e. in the order
(a,a-trehalose, melibiose, melezitose).2H
2
O
o
mannotriose.3H
2
O
o
(b,b-trehalose, stachyose).4H
2
O
o
raffinose.5H
2
O
7.7 Pharmaceutical Glasses: Formulation Aspects
During the development of a suitable formulation for a pharmaceutical,
and especially a biopharmaceutical preparation, several important as-
pects need to be taken into account. They will not all be discussed in
detail; hence, the following points should only serve as signposts,
pointing the reader in the right direction.
Perhaps of overriding importance are pharmacokinetic aspects. They
are particularly important for products with high protein contents.
Thus, the chosen excipient(s) must on no account reduce or interfere
with the functioning of therapeutic proteins. In other words, the chem-
ical stresses that might be introduced into a solution during freeze-
concentration must not lead to irreversible protein inactivation. The
popular ''water replacement'' hypothesis to account for lyoprotectant
effects of PHCs during drying ascribes the observed protection to the
replacement, presumably reversibly, of so-called the hydration water
molecules by sugar or alditol molecules.
101
On the other hand, the
literature also contains references to irreversible ''glycation'' condensa-
tions between proteins and sugars, in which sugars are randomly (?)
attached, presumably covalently, to sites on proteins, leading to their
inactivation.
102,103
The extensively documented Maillard browning
processes also bear witness to the deleterious reactions between sugars
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