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

192 M.R. Caira
Fig. 12. Powder dissolution rate curves for two nitrofurantoin polymorphs. (Reprinted with
permission from [61], copyright 1996, Gordon and Breach Publishers)
Measurements of the equilibrium solubilities of a polymorph as a function of
temperature permit evaluation of the enthalpy of dissolution from a van’t Hoff
plot (i.e. logarithm of solubility vs T –1 ). The point at which such plots intersect
for two different polymorphs of the same compound corresponds to the transition
temperature for their interconversion.
It should be stressed that the analytical methods surveyed above achieve their
optimum effectiveness and lead to deeper insights into polymorphism and
pseudopolymorphism when used in combination. A simple illustration is the
combined use of dissolution rate analysis and crystal structure analysis of two
polymorphs. Used individually, these techniques would produce merely data,
whereas the combined approach could lead to an explanation for the differences
in dissolution rates based on differences in crystal packing. Some reported
studies utilise a wide range of techniques, permitting a comprehensive analysis
of a polymorphic system, while others may use only two, but nevertheless effective,
complementary techniques (e.g. DSC and XRD). The following examples
selected from the recent literature illustrate this point.
Four polymorphic forms (I-IV) of the drug diflunisal (analgesic, anti-inflammatory)
were prepared and characterised by DSC, HSM, IR, XRD, and dissolution
studies [132]. The thermoanalytical methods revealed that on heating, all
polymorphs recrystallized to the stable one (Form I) prior to melting. Only one
transition peak in the DSC traces was observed, for the transformation of Form
III to Form I. Intermolecular hydrogen bonding features were deduced from IR
spectroscopy and this method was also shown to distinguish all the forms. Measurements
of the intrinsic dissolution rates indicated (unexpectedly) that Forms
II, III and IV had slightly lower values than that of the stable form. Results of this
kind are invaluable for ensuring correct formulation of the drug.Some examples
of other important drug polymorphic systems for which similar, fairly comprehensive
studies have recently been reported include acyclovir [133], meprobamate
[134], prasterone [111], ranitidine hydrochloride [135], and chloramphenicol
palmitate [136].
Other compounds whose polymorphism and/or pseudopolymorphism have
been investigated in recent years, together with the methods used, include
pentachloropyridine (DSC, Raman and IR spectroscopy) [137], cyclohexanol
(far-IR, adiabatic calorimetry) [138], nifedipine (HSM, IR, DSC) [139], sulfanil-