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

190 M.R. Caira
a
b
Fig. 11 a, b. XRD patterns for a polymorph of tenoxicam: a experimental; b calculated from
single crystal data. (Reprinted with permission from [106], copyright 1995, American Chemical
Society and American Pharmaceutical Association)
from large single crystals previously identified by X-ray analysis, the overall
agreement of the patterns reveals the non-trivial result that grinding single
crystals of the polymorph does not effect a phase transformation to another
polymorph. In the case of the drug probucol (Fig. 3), the experimental XRD
patterns for the two polymorphs were identical as a result of transformation of
one polymorph into the other during sample preparation [59].
Neutron and electron diffraction techniques have also been used to some
extent to study the polymorphism of organic substances. Owing to its ability to
locate hydrogen atoms accurately in crystals, neutron diffraction is the method
of choice for distinguishing subtle differences in hydrogen bonding for polymorphic
crystal structures. However, the technique is costly and the low intensity
of neutron beams demands relatively large single crystals (around 1 mm 3 or
larger) which are seldom available. Crystallographic studies are therefore usually
carried out on polycrystalline samples, yielding powder neutron diffraction
patterns analogous to XRD patterns. A fairly recent development is the use of
pulsed neutron sources coupled with time-of-flight analysis [100]. As an example
of its application to the study of polymorphism, the case of cyclohexanol
may be cited [128]. Structural elucidation of three polymorphs (cubic (I), monoclinic
(II) and orthorhombic (III)) revealed that I is disordered, that II contains
a cyclic dimer of cyclohexanol, and that a polymeric arrangement exists in III.
Because incident electrons interact strongly with crystals, electron diffraction
is capable of yielding detailed structural information from very small crystals