Ranitidine bismuth(III) citrate

Abstract

A variety of amines have been shown to solubilize bismuth(III) citrate, [Bi(Hcit)], and the nature of the adduct 1 between it and ranitidine [N,N-dimethyl-5-(3-nitromethylene-7-thia-2,4-diazaoctyl)furan-2-methanamine], which is currently on clinical trial as an antiulcer drug, has been investigated by 1H and 13C NMR spectroscopy and polarography. Complex 1 undergoes a structural transition in aqueous solution with an associated pKa of 6.2. Ranitidine appears to be involved in second-co-ordination-sphere interactions with polymeric bismuth(III) citrate species via the HNMe2 + group for which the pKa is raised from 8.64 to 8.90, whereas the pKa of the diaminonitroethene group of ranitidine (2.2) is unaffected. In solutions of 1 in (CD3)2SO this interaction increases the rate of NH exchange compared to free ranitidine. The chemical properties of 1 in aqueous solution differ from those previously reported for the potassium ammonium adduct, colloidal bismuth subcitrate, a drug in current clinical use. Complexation of both citrate and ranitidine to BiIII in acidic solutions (pH 2.5-3) was detected by polarography, which demonstrated the existence of rapid deprotonation equilibria for bismuth(III) citrate complexes in the range pH 1-5.8. Since antiulcer drugs are subjected to low-pH environments in the stomach, such equilibria may be relevant to the biological activity of ranitidine bismuth citrate.