Crystal polymorphism of pharmaceuticals: probing crystal nucleation at the molecular level

Abstract

Paracetamol, sulfathiazole and l-glutamic acid are presented as examples of pharmaceutical crystal polymorphic systems. The effect of N-acylated sulfathiazole derivatives (3–6) on sulfathiazole crystallisation is discussed, and possible modes of action presented. Methods for the control of the crystal polymorphism of l-glutamic acid which utilise the principles of conformation mimicry and co-operative binding are presented. The preparation of a series of bis-amides of EDTA derived from sulfathiazole, 5-aminoisophthalic acid and 4-hydroxyaniline (i.e. compounds 9a–c) is presented, as is data on the effect of these compounds on the crystallisation of, respectively, sulfathiazole, l-glutamic acid and paracetamol.

Keywords::

• Crystal polymorphism
• paracetamol
• sulfathiazole
• l-glutamic acid
• EDTA

Acknowledgements

The authors are grateful to GlaxoSmithKline (Ireland) and Pfizer (Ireland) for support, and to the Irish Research Council for Science, Engineering and Technology for the award of an EMBARK Postgraduate Scholarship (to ALR). The authors also wish to thank Prof. M.A. Morris and Dr. J.D. Holmes for access to PXRD instrumentation.