The Quality Control Research Of Rabeprazole Sodium As Proton Pump Inhibitors

Rabeprazole sodium, as a new generation of proton pump inhibitors, the dissociation constant of which is bigger so that it can faster accumulation in parietal cells and relieve symptoms faster, at the same time its side effect is small as a part of the reversible H+/K+atpase inhibitor, and it also has the advantages of more targets, faster and stronger acid suppression effect. Rabeprazole Sodium has great market potential, due to its particularly prominent effect in removing pain and treatment of duodenal ulcer. This paper studied the synthesis and quality control of Rabeprazole Sodium.First of all, this paper synthetized Rabeprazole Sodium regarding2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride and2-thiolbenzimidazole as the starting material by three steps, especially in process of the thioether intermediate oxidized to Rabeprazole Sodium, we used the new catalysis system, increase the reaction yield, which is of great significance for the industrialized production.Secondly, we synthesized three common related substances (Impurity thioether intermediate, Impurity sulfone and Impurity sulfone-N-O), which could be used as a standard reference substance, due to their purity is above99%(HPLC). We used the LC-MS/MS technology to establish the MRM (multiple reaction monitoring) quantitative method of Rabeprazole Sodium and its three related substances content detection. The linear (r2=0.9992) of Rabeprazole Sodium was good with the concentration of180ng/mL to1800ng/mL and the linear (r2>0.9974) of three related substances was good with the concentration of0.6ng/mL15ng/mL, the recovery rate was in94.5%~106.2%. the accuracy (RSD<4.0%) and reproducibility was also good through the methodology validation, which proved that this method was accurate and reliable. By this method, we tested the five domestic pharmaceutical factories of Rabeprazole Sodium content and its related substances.Meanwhile, we has carried on the examination of organic residual solvents, using headspace sampling method. We established gas chromatographic quantitative methods to examin seven kinds of residual solvent, including methanol, ethanol, ethyl ether, acetone, ethyl acetate and dichloromcthane, acetonitrile. The linearity (r2>9927%) and precision (RSD<4.7%) of seven organic residual solvents was good through the methodology validation, which showed that this method was accurate and reliable. Finally, we checked the sample properties, solubility, ultraviolet absorption coefficient, heavy metal content, and analysed the infrared spectra, Raman spectra, X-ray diffraction contrast, element analysis,1H NMR and13C NMR identification of Rabeprazole Sodium, refering to2010edition of Chinese pharmacopoeia, Japanese pharmacopoeia (16) and API standard.