Spectroscopic studies on ranitidine (1) show that the nitroethene dialkylamine group in both the base and hydrochloride exists virtually exclusively in the enediamine tautomeric form and a low barrier to rotation about the carbon-carbon double bond can be demonstrated. The energy barrier to this rotation is partly influenced by intramolecular hydrogen bonding between the nitro and amino groups. In strongly acid solution, C-protonation with charge delocalisation occurs on the enediamine with consequent loss of conjugation. Two polymorphic forms of the hydrochloride have been identified by i.r. spectroscopy.Rani tidine, (N-(2-[( ( 5-[(dimethylamino)methyl]-2-furanyl}-methyl)thio]ethyl}-N'-methyl-2-nitroethene-l,l-diamine) (1) is a selective H,-receptor antagonist and a powerful inhibitor of gastric acid secretion recently introduced for the treatment of peptic ulcers and related disorders.'-* A key feature of the structure is the 1,1-bisalkylamino-2-nitroethene moiety. Recent publications 5 * 6 purport to show that this fragment of ranitidine exists in the nitronic acid form (2) and suggest that this may have a bearing on the interaction of ranitidine with the cytochrome P-450 mixed function oxygenase enzyme system in the liver (an interaction shown to be weak in the case of rat microsomal cytochrome P-450 in vitro ' and concluded to have negligible effect on the metabolism of other drugs in the clinical situation8). Our own work, which is described in this paper, shows that the nitronic acid form is not a correct portrayal and that the true structure of ranitidine is represented by (1). This also accords with the findings in these laboratories that all attempts to achieve 0-alkylation, which in (2) would be expected to occur, have been unsuccessful.Nitroenamines (l-amino-2-nitroethenes), including nitroketene aminals (l,l-diamino-2-nitroethenes), are a well known class of compounds whose synthesis, structure, and reactivity have been recently r e~i e w e d .~In theory, ranitidine could exist in one of the three main tautomeric forms (Figure 1). In addition, the enamine could exist as two geometrical isomers and the nitronic acid and imine forms could both exhibit further prototropic tautomerism within the amidine group as well as syn-anti isomerism about the C=N bonds. The imine form (3) can be immediately discounted on the basis of the n.m.r. spectrum which shows a one-proton singlet in the olefinic region but no signal due to a nitromethylene group. ExperimentalMaterials.-Ranitidine free base (m.p. 72 "C t) and hydrochloride (polymorph 1, m.p. 144.5 "C, and polymorph 2, m.p. 146.2 "C, as measured by differential scanning calorimetry) were synthesised by the Chemical Development, Glaxo Group Research Ltd., Ware,and I, 1 -bis(methylamino)-2-nitroethene(4) by the Chemical Research Department.Measurernenrs.-U.v. spectra were obtained on a PerkinElmer 402 or a Hewlett-Packard HP8450A spectrophotometer. 1.r. spectra were obtained on a Perkin-Elmer 357 or 377 spectrophotometer. 'H N.m.r. spectra were obtained on a Vari...

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Hydrolytic degradative studies o n ranitidine hydrochloride (1 ) have shown that t w o different pathways are operative under strongly acid and strongly alkaline conditions. A t intermediate p H values both pathways are operative whilst at very low p H values ranitidine hydrochloride is resistant t o hydrolytic cleavage. This resistance to hydrolysis may be ascribed to C-protonation of the enediamine.Chromatographic procedures, by virtue of their potential selectivity, are used extensively to assure the identity, strength, purity, quality and stability of medicinal preparations. Identification of the degradation products capable of formation during the storage of drug substances and their formulated pharmaceutical presentations is fundamental to the acquisition of proof that, were degradation to occur, the analytical methods applied to assure the efficacy and safety of the medicine, would reveal it. Since, under normal storage conditions, the only reactive influences to which a medicinal preparation is likely to be exposed include moisture, heat, light and the atmospheric gases, hydrolytic studies represent particularly pertinent artificial degradative investigations.This paper describes the results of the hydrolytic studies conducted on ranitidine hydrochloride, the British Approved Name for N,N-dimethyl-5-[2-( 1 -methylamino-2-nitrovinylamino)ethylthiomethyl]furfurylamine hydrochloride (l), a selective histamine H, antagonist used to treat peptic ulcers and related disorders. '-' this process is 2.3) in aqueous solution and which is complete in M-hydrochloric acid, can be interpreted as shown in Scheme 1. Here the solute species are shown as a mixture of Z and E isomers (la) and (lb) in accordance with the 'H n.m.r. evidence obtained from spectral determinations in D,O and CD,OD at various temperatures.' HCI Me, N&s-NH

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