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

194 M.R. Caira
approach when used on its own. However, used in combination with the Rietveld
method, its chances of success are very significantly improved, as recently
demonstrated for a polymorphic system [146]. Of two polymorphs, A and B, of
a guanidine derivative (1), only form B was available in the form of single
crystals and its structure was solved in the conventional manner using X-ray
diffraction methods. Polymorph A was available only as a powder and the structural
problem was further complicated by molecular features allowing not only
for different conformers of the molecule, but also different tautomers. Indexing
of 26 lines of an XRD pattern of polymorph A measured on a Guinier camera led
to the assignment of the triclinic system. Energy calculations using MOPAC93
were used to search for likely conformers and tautomers suitable for crystal
packing calculations. High-precision ab initio quantum mechanical methods
were used to confirm the trial models, the four most stable ones being chosen for
packing analysis using a corrected Dreiding force-field. Two routes were pursued,
one assuming the XRD indexing results, the other ignoring them. In the
first case, crystal structures were generated for the space group P1 – only, leading
to a most stable structure with unit cell parameters very close to those deduced
from the indexing. Subsequent optimisation and Rietveld refinement yielded a
final structure with an R-factor of around 10%. When the indexing results were
ignored, stable conformers were packed in common space groups (e.g. P1 – ,P2 1/c,
P2 12 12 1). Of the predicted force-field minimised structures, that which gave the
best agreement with the experimental XRD pattern turned out to be one in the
space group P1 – . Following interactive Rietveld refinement, this structure
(gratifyingly) converged to the same one as determined assuming the indexing
results. A very important feature of this study was the use of an ordinary inhouse
XRD pattern (as opposed to a high-resolution pattern) for the indexing
and Rietveld refinement steps. The authors pointed out that both the ab initio
quantum mechanical as well as the packing calculations for this problem consumed
enormous amounts of computational resources. They nevertheless predicted
that structure determination based on an ordinary powder pattern and
packing calculations could evolve into a reliable and inexpensive routine procedure
in view of the envisaged drop in computational costs which they state is
about an order of magnitude every three years.
The structure of a metastable and shortlived polymorph of the drug
piracetam (2) has been solved from XRD data using the AAP method [147].
This species (Form I) was prepared by heating a mixture of Forms II and III
and quenching at room temperature. Form I spontaneously transforms into II
at 298 K within a few hours of quenching, but it was possible to capture
high-resolution XRD data within two hours using a position-sensitive detector.
The same (known) molecular conformation as occurs in Forms II and III
1 guanidine derivative 2 piracetam