Ranitidine bismuth(III) citrate
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.