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

178 M.R. Caira
tion agitation, temperature, supersaturation and the rate of cooling of the solution
is necessary. Detailed methods for isolating metastable polymorphs from
the melt or from solution have been reviewed [81].
Desolvation of a pseudopolymorphic form by controlled heating leads to the
formation of a polymorph or a mixture of polymorphs of the parent compound,
hence providing an additional route to isolation of such species. For example, for
indomethacin quoted above, twelve pseudopolymorphs with the general formula
indomethacin ◊ (solvent) n (n =0.2–1.1) were isolated [83] and their products
of desolvation were characterised. Whereas mixtures of Forms I and II
resulted from heating the benzene, CCl 4,CHCl 3 and toluene pseudopolymorphs,
pure Form II was obtained from desolvation of the acetone pseudopolymorph.
The most soluble (and pharmaceutically desirable) polymorph, Form IV, was
obtained in a pure state by desolvation of the pseudopolymorph containing
methanol.
A technologically very important and potentially beneficial feature of some
polymorphs obtained in this way is the possibility that they may acquire altered
rheological or other properties (flowability, texture, particle size distribution,
compressibility) when compared with the same polymorphic crystalline forms
obtained by direct crystallization from solution. Two examples of considerable
pharmaceutical relevance may be cited, namely those of lactose and paracetamol.
The lactose used as an excipient in pharmaceutical tablets and capsules is
a-lactose monohydrate. It was found that thermal dehydration of this species or
desiccation of a-lactose containing methanol yielded a stable product with
superior binding properties and excellent flowability [84]. Tablets prepared by
compaction of the stable product had an overall porosity nearly equal to those
of tablets prepared with the original materials. The very poor compression
abilities of paracetamol prompted an investigation of solvation/desolvation as a
process for preparing pure paracetamol with improved properties [85]. A
crystalline hemisolvate of paracetamol was prepared by cooling a hot saturated
solution of the drug in dioxane. Desolvation of this species yielded pure paracetamol
with significantly improved technological properties including flowability,
die filling, and hardness/pressure profile.A crucial point is that this improvement
was not attributable to the production of a new polymorphic form of the
drug; the X-ray powder diffraction pattern of the desolvated material was the
same as that of the commercially available, monoclinic polymorph of paracetamol.
However, detailed examination with scanning electron microscopy revealed
that desolvation produces material with an unusually porous, sintered-like
texture which lends itself to compression more readily than other forms of the
drug. Interestingly, solvation/desolvation using other oxygen-donor solvents
(e.g. acetone, cyclohexanone) yielded paracetamol in the same (monoclinic)
form but failed to produce paracetamol crystals with the required texture. An
earlier review on polymorphism [37] lists several drug pseudopolymorphs
whose desolvation leads to significant particle-size reduction (or micronization)
of the ensuing polymorphic crystallites. This usually results in improved
dissolution and tabletting properties of the polymorph.
Mechanical grinding and compression of compounds represent another
possible route to polymorphs. In the former case, the local pressures induced by