198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

200 M.R. Caira
(b) of the compound in question and on the orientation of the molecules in the
crystal. Specifically, a non-centrosymmetric packing arrangement is required
for a solid to exhibit NLO properties and, while it is possible to alter the value of
b by synthetic modification, encouraging molecules to adopt a non-centrosymmetric
packing arrangement is a formidable challenge.
The question of whether polymorphism is the “nemesis of crystal design”was
discussed at length nearly a decade ago [3]. Since then, however, systematic
studies in the areas of crystal nucleation, growth and morphology have led to
definite proposals for rational stereospecific control of polymorphism as well as
some success in its attainment in special cases [36]. Thus, while ab initio crystal
structure prediction is still a distant goal [72] and the preparation of specific,
desired phases is still elusive, there is at least the possibility of rational intervention
during the nucleation or growth stages of crystallization for influencing
the outcome, provided that the detailed polymorphic behaviour of the system
has been established from systematic study. This again provides strong justification
for the application of a wide range of techniques for comprehensive
studies of systems exhibiting polymorphism. As implied by case studies described
earlier in this report, there are numerous instances in industrial environments
where control of both crystal morphology and the polymorphic form of
a compound is vital, and here the outlook for success, based on the strategies to
be described briefly below, is promising.
4.2
Current Strategies and Prognosis for Crystal Engineering
Practical “control” of the polymorphic outcome of a crystallization process can be
interpreted at different levels, ranging from the purely empirical, such as the use
of identical crystallization conditions in the hope of obtaining a particular polymorph
in a reproducible manner, to a much more ambitious strategy based on,
e.g., rational design of additives which could suppress or inhibit nucleation of
undesired polymorphs through selective molecular recognition mechanisms,
thus allowing unhindered growth of a desired metastable polymorph. Between
these extremes, there are different variations, both physical and chemical, that are
effective in producing specific polymorphs, as exemplified below. Reports of this
kind appear in the recent patent literature, attesting to the technological and commercial
importance of the polymorphs concerned.A patent for the preparation of
Form 1 of the widely used antiulcerative drug ranitidine hydrochloride describes
its crystallization from a mixed solvent in the presence of seed crystals, the
preferred process involving in situ reaction of HCl with the free-base [159].
Industrial-scale preparation of the stable polymorphic form of N-(4-hydroxyphenyl)retinamide
is effected by successive chemical reactions with all-trans
retinoic acid as the starting material [160]. The desired polymorph is formed by
recrystallizing the wet product from 95% EtOH. The b-form of an organic phosphite,
reported to be an effective process stabiliser for polyolefins, has been prepared
by heating the compound at 125 °C in the absence of solvent [161].
Desolvation of pseudopolymorphs may be considered as a means of polymorphic
control. This was discussed earlier in this report in the context of