Excipients: Their Role in Rational Formulation Design - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 84

Figure 1 Upper half: pK values of acids and bases 1 pH unit. Lower half: useful pH
ranges for some common buffering compositions. From Auffret 93
regulatory restrictions do not arise. Figure 1 shows pK values at 251Cof
some common buffer acids, bases and binary mixtures. 93 Volatile buffers
that would normally evaporate during the ice sublimation stage include
ammonium acetate, formate and carbonate. Their use enables buffer-
free dry products to be produced. Care must however be taken during
reconstitution, because gases, especially CO 2 , might become entrapped
in the dry product and then give rise to irruptive effervescence when
water is added to the product at the point of reconstitution.
Bulking agents are used simply to increase the total solids content in
order to achieve a mechanically more robust plug. They find application
especially when a low concentration of other solids has to be used, perhaps
for reasons of isotonicity or low aqueous solubility of the active substance.
Bulking agents, especially mannitol, also tend to improve the robustness
and appearance of the plug, an important consideration in some markets.
Any bulking agents used must, however, be able to crystallise during the
freeze-drying process; only in this state will they have a neutral effect on
product stability. By increasing the total solids content of the preparation,
their use also acts unfavourably on the rate of ice sublimation.
More complex is the choice of excipients designed to act as lyopro-
tectants of chemically labile bioactive components. Earlier discussions
have demonstrated that biopharmaceuticals, in particular, proteins, can
rarely be induced to crystallise during freezing. They thus remain in the
amorphous, supersaturated freeze-concentrate, where they become