Solid-state investigation of the tautomerism of acetohexamide

Abstract

Polymorphism of the anti-diabetic drug acetohexamide has been investigated by numerous techniques. On the basis of Fourier-transform infrared (FT-IR) data, one of the most common forms, form A, has been proposed to exist in the enol-tautomeric state, whereas form B has been proposed to be in the keto-tautomeric state. The following article examines the solid-state tautomerism of acetohexamide using the techniques of X-ray crystallography and 13C solid-state nuclear magnetic resonance (NMR) spectroscopy. In the NMR spectra, resonances associated with the acetyl carbonyl and amide carbonyl groups are well resolved. By comparison of the spectra of acetohexamide with those of the related compounds chlorpropamide and tolbutamide, whose crystallographic structures have been determined, it is firmly established that both of the acetohexamide polymorphic forms are in the keto-form. The crystal structure of acetohexamide form A was solved and is reported herein. The structure not only shows the keto-tautomeric state of form A, but also confirms the NMR resonance assignments.