Ranitidine bismuth citrate: A novel anti-ulcer agent with different physico-chemical characteristics and improved biological activity to a bismuth citrate-ranitidine admixture

Background: Ranitidine bismuth citrate (RBC) is a new chemical entity for the treatment of peptic ulcer disease. Results: RBC is freely soluble in water (more than 600 mg/mL at pH 4.6), whereas an equimolar admixture of its component molecules, bismuth citrate and ranitidine, formed an almost totally insoluble suspension. Even at very low pH values (around 2.0), the solubility of bismuth in ranitidine bismuth citrate was at least two-fold better than in the admixture. Comparison of several physico-chemical characteristics indicated that RBC possessed significantly different melting point properties, X-ray powder diffraction patterns, infra-red spectra and C-13-NMR solid-state spectra to the admixture. Ranitidine bismuth citrate inhibited human pepsin isoenzymes 1, 2, 3 and 5 but the admixture was inactive. RBC showed approximately two-fold greater anti-Helicobacter pylori activity in vitro than the admixture (geometric mean minimum inhibitory concentrations of 12.5 and 25.7 mg/L, respectively) and was more rapidly bactericidal. In a mouse model of gastric H. pylori colonization, 200 mg/kg of bismuth, given as RBC, eradicated the organism from all mice while only 10% of infections were eradicated by equivalent levels of bismuth in admixture form. Conclusion: It is believed that the significantly greater solubility of RBC, especially at lower pH values, is highly relevant to its better antipepsin and anti-H. pylori action compared to the insoluble admixture of bismuth citrate and ranitidine.