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

Crystalline Polymorphism of Organic Compounds 189
sample preparation involves grinding in a mortar to an average particle size
£ 100 mm to minimise preferred orientation effects, the possibility of a pressure-induced
phase transformation during sample preparation must be considered.
The XRD pattern of an unground sample of the material may be
checked as a precautionary measure. Patterns are generally recorded on samples
with mass range 200–500 mg using automatic diffractometers with strip chart
output. The method is generally non-destructive, allowing recovery of the
sample. Film methods (e.g. the Debye-Scherrer technique) require a few mg of
material only and are still frequently used when only small amounts of polymorphic
forms can be isolated. According to the guidelines specified in the US
Pharmacopeia [125], agreement between a sample and a reference standard
should be within the calibrated precision of the diffractometer for diffraction
angle (typically a reproducibility of ± 0.10–0.20° in 2q) with permissible relative
intensity variations of up to 20%.
A recent analytical study stresses the growing need, prompted partly by
legislatory requirements, to differentiate polymorphs and to quantify polymorphic
mixtures in pharmaceutical production [126]. The compounds benzil and
benzoic acid were chosen as a model system for the development of an XRD
protocol which could be extended to the quantification of mixtures of drug
polymorphs. The study involved the evaluation of sample thickness, the determination
of preferred orientation effects, optimum milling conditions and the
construction of diffraction intensity-composition calibration curves for mixtures
of benzil and benzoic acid. Since the composition of such mixtures can be
accurately determined by an independent method, namely HPLC, validation of
the quantification of mixtures by the XRD protocol was possible. It was concluded
that the protocol is accurate for the model system to within a few percent.
It is desirable that the general validity of the approach suggested be tested on a
range of real polymorphic systems.
The information contained in an XRD pattern of a powdered material is a significantly
condensed version of that obtained by single crystal X-ray analysis
and it is a routine matter to reconstruct the XRD pattern of a polymorph by
computation, using as input the space group data, refined atomic coordinates,
atomic thermal parameters and unit cell data which have been obtained from a
single crystal X-ray study of that species. Some years ago, it was recommended
[127] that computation of the XRD pattern of a new polymorph should always
be carried out if single crystal data become available. The computed pattern,
being free of experimental aberrations, serves as the best reference pattern for
the polymorph in question. We have followed this practice and can strongly
endorse its usefulness, not only for the purpose of identifying the polymorphic
form present in a newly crystallized sample, but also for assessing the polymorphic
purity of such a sample. Figure 11 shows the experimental XRD pattern
of a polymorph of the non-steroidal anti-inflammatory drug tenoxicam and, for
comparison, the computed pattern based on the single crystal X-ray data [106].
The level of agreement in peak positions attests to the polymorphic purity of the
sample (no extraneous peaks being evident in the experimental pattern) while
the discrepancies in corresponding peak intensities indicate some degree of preferred
orientation in the sample. Finally, since the sample was a powder derived