Chemistry Reference
In-Depth Information
CHAPTER 9
Secondary Drying: The Removal
of Unfrozen Water
9.1 Unfrozen (Residual) Water
After a multicomponent aqueous solution has been freeze-concentrated
to the limit and the ice has been sublimed, any residual unfrozen water
must be removed from the remaining solid solution by diffusion, des-
orption and evaporation (transfer to the condenser). This process is
termed ''secondary drying''. For an amorphous preparation, the amount
of unfrozen water remaining after the removal of ice may be typically
20-30% w/w, but much higher values, even 450% w/w, have been
found in some formulations. Attempts are on record to measure the
amount of water that remains in the freeze-concentrated solution phase
at T
0
g
, mainly by differential scanning calorimetry (DSC),
116,117
but such
measurements are subject to considerable experimental uncertainties,
which will be further discussed in Chapter 11.
Much lower amounts of water remain in crystalline systems, where
water only exists in the form of a thin adsorbed layer on the crystal
surfaces. Crystalline hydrates form an exception; here the water mole-
cules are hydrogen bonded to one another and/or to the solute mole-
cules, usually in stoichiometric ratios. They are thus an integral part of
the crystalline compound. Important examples from the point of view of
freeze-drying are NaCl.2H
2
O, mannitol.H
2
O, a,a-trehalose.2H
2
O
w
and
raffinose.5H
2
O. In the first case, the hydrate contains 38%w/w of water.
If, therefore, the dihydrate is able to crystallise during the freezing
w
It appears to be generally assumed that the word ''trehalose'' used in the literature refers to a,a-
trehalose; hence the mention of the dihydrate. However, its less well publicised isomer b,b-trehalose
crystallises as a tetrahydrate. This is a major difference that has important implications for the
behaviour of trehalose as excipient (C.J. Roberts and F. Franks, J. Chem. Soc. Faraday Trans. 1996,
92, 1337-1343).
121
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