Tizanidine and tizanidine hydrochloride: on the correct tautomeric form of tizanidine

Abstract

A crystallization series of tizanidine hydrochloride, used as a muscle relaxant for spasticity acting centrally as an α2-adrenergic agonist, yielded single crystals of the free base and the hydrochloride salt. The crystal structures of tizanidine [systematic name: 5-chloro-N-(imidazolidin-2-ylidene)-2,1,3-benzothiadiazol-4-amine], C9H8ClN5S, (I), and tizanidine hydrochloride {systematic name: 2-[(5-chloro-2,1,3-benzothiadiazol-4-yl)amino]imidazolidinium chloride}, C9H9ClN5S+·Cl−, (II), have been determined. Tizanidine crystallizes with two almost identical molecules in the asymmetric unit (r.m.s. deviation = 0.179 Å for all non-H atoms). The molecules are connected by N—H...N hydrogen bonds forming chains running along [2\overline{1}1]. The present structure determination corrects the structure determination of tizanidine by Johnet al.[Acta Cryst.(2011), E67, o838–o839], which shows an incorrect tautomeric form. Tizanidine does not crystallize as the usually drawn 2-amino–imidazoline tautomer, but as the 2-imino–imidazolidine tautomer. This tautomer is present in solution as well, as shown by1H NMR analysis. In tizanidine hydrochloride, cations and anions are connected by N—H...Cl hydrogen bonds to form layers parallel to (100).