Excipients: Their Role in Rational Formulation Design - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 95

7.9 Operational Degrees of Freedom
Based on these discussions, it follows that the scientist charged with
developing a suitable formulation is often severely limited in the choice
of excipients. Other things being equal, physical and chemical principles
can, nevertheless, be applied and offer several lines of approach.
A choice exists between formulating a crystalline or an amorphous
product. Although conventional wisdom in the pharmaceutical industry
favours crystallinity, because of its believed association with stability,
earlier discussions have pointed out the fallacies in such assumptions,
especially where polymorphism or hydrate crystallisation cannot be
ruled out. It is also found that freezing often produces metastable
crystalline states that may eventually undergo transitions to more stable
modifications. Thus, a recent report described a hitherto unknown
monohydrate of mannitol formed during ''non-aggressive'' freeze-
drying. 57 It was characterised by X-ray diffraction (see Figure 5), which
produced a pattern with lines that could not be attributed to any of the
known polymorphs. Differential thermogravimetry indicated a weight
loss of 6% near 501C corresponding to one mol water. The diffracto-
gram, taken after removal of the water, contained only peaks that could
Figure 5 X-ray powder diffraction patterns of (1) a freeze-dried mannitol solution and
(2) the same preparation after heating at 701C for 30 min. Peaks marked with
asterisks do not appear in the diffractograms of any known mannitol poly-
morphs. All peaks in pattern (2) are attributable to b-ord-mannitol. Repro-
duced with permission from Yu et al. 57