Essential Chemistry and Biochemistry Associated with Low Temperature and Freezing - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 63

Table 3 Polymorphism and selected physical properties of mannitol

Modification I II III

Crystal habit Prismatic rods Prismatic rods Needles

Melting point (1C) 166.5 166 155 (incongruent)

Enthalpy of fusion (kJ mol 1 ) 53.5 52.1 53.7

Density (gcm 3 ) 1.490 1.468 1.499 0.004

Specific heat at 251C (Jg 1 k 1 ) 1.383 0.009 1.273 0.008 1.263 0.002

Source: Data from Burger et al. 66

Table 4 Crystallisation of glycine from frozen solutions

Substance Additives pH Crystallisation Eutectic (1C) Comments

Glycine None 7 Rapid -3.4 B-polymorph

Glycine-HCl 7 Very slow -28

Glycine-Na NaCl Slow -17.8 T g E -80

Glycine 3 Slow, g-polymorph -3.5 T g E -70

Source: Data from Akers et al. 68

Similar results were obtained by substituting KCl for NaCl, but LiCl
produced a lower eutectic point and also inhibited the crystallisation of
mannitol. The earlier paragraphs may suggest to the product developer
that, even if only for regulatory reasons, the use of mannitol in phar-
maceutical preparations should be avoided, a valid conclusion in the
author's own experience.
Amino acid crystallisation from a freezing aqueous solution provides
yet another interesting facet of the complexities that can be encountered
during freeze-drying operations, and that therefore deserves mention.
Here, chemically binary systems, mixtures of water þ amino acid display
complexities, arising from the zwitterionic nature of amino acids (and
peptides). Taking glycine as an example, its crystallisation behaviour is
strongly influenced by pH and salts; 68 examples are shown in Table 4.

5.7 Supersaturation and Vitrification: The Importance
of the State Diagram

Having already established that the phenomenon of supersaturation
(undercooling) of a solution during the removal of water may be
transient, despite being a common event, an important question then
arises: what might be the lifetimes of supersaturated solutions under
freeze-drying conditions, before solute crystallisation (precipitation)
occurs spontaneously and goes to completion? For most PHCs, these