December 3, 2010

Polymeric Porous Framework Of A Bismuth Citrate-Based Complex: A Potential Vehicle For Drug Delivery

YANG Nan, MAO ZongWan and SUN HongZhe et al., at the Department of Chemistry, University of Hong Kong and Sun Yat-sen University have characterized a series of bismuth citrate complexes by X-ray crystallography and modeled the structure of ranitidine bismuth citrate, a medicine used widely for the treatment of peptic ulcer and gastric reflux disease. The polymeric framework of bismuth citrate may serve as a "drug carrier" for delivery of other drugs in the human body. This significant contribution is reported in SCIENCE CHINA Chemistry 2010, 53(10).

Elements that possess anti-bacterial activity have significant medical applications. Bismuth, the heaviest stable element in the periodic table, exhibits anti-bacterial activity against Helicobacter pylori (H. pylori) with minimal toxicity. It is used widely to treat peptic ulcers and gastrointestinal diseases. Ranitidine bismuth citrate (RBC) is a bismuth citrate-based (Bi(cit)-based) drug, developed in 1991. It exhibits efficacy in first-, second- and third-line H. pylori infection therapies when used in combination with other antibiotics, and is more effective than proton pump inhibitor-based (PPI-based) therapy. Because of the importance of Bi(cit)-based drugs, enormous efforts have been made to elucidate their structures. However, there are few structures that reflect the nature of Bi(cit)-based drugs in the stomach.

In this work, the frameworks of four Bi(cit)-based complexes, obtained under acidic conditions to mimic conditions in the stomach, were resolved. A structural model of RBC was proposed based on the crystal structure of one of these frameworks. The decomposition behavior of Bi(cit)-based complexes in aqueous solution was investigated using ESI-MS.

Bi(cit)-based complexes form polymeric porous frameworks with bismuth citrate dimeric units ([Bi(cit)2Bi]2-) forming the skeleton. Since citrate anions in the frameworks are present in the fully deprotonated, tetraanionic form ([C6H4O7]4"“), and coordinate with Bi3+ cations, the excess negative charges in these polyanionic frameworks must be balanced by further cations such as K+, [NH4]+, [H3NCH2CH2NH3]2+ or [C5H6N]+. This allows Bi(cit)-based complexes to encapsulate low-molecular mass molecules or ions, either by a diffusion process or via electrostatic interactions, similar to the "uptake process" of cations and small molecules by zeolites. Ranitidine cations were modeled into a simulated structure based on one experimental framework, revealing hydrogen-bond formation between ranitidine molecules and the citrate tetraanions. ESI-MS data indicated that the Bi(cit)-based frameworks degrade from high molecular weight polymers to low molecular weight species in acidic solution.

This paper reports a series of structures of Bi(cit)-based complexes in acidic solution (mimicking the acidic environment of the stomach), establishes an in silico model of a widely used anti-ulcer drug (ranitidine bismuth citrate), and uses experimental ESI-MS data to propose a possible metabolic fate for Bi(cit)-based drugs under the acidic conditions found in the stomach.


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