Quality Control Method And Stability Study Of Esomeprazole Sodium

Esomeprazole sodium is the sodium salt of Esomeprazole. Esomeprazole is the S-optical isomer of Omeprazole, and it is the first heterogeneous proton pump inhibitor. It can reduce the secretion of gastric acid by specifically inhibiting the proton pump of gastric parietal cytoplasm. Confirmed by a large number of clinical trials and drug research, Esomeprazole can maintain the intragastric pH>4 longer and have higher efficiency. Esomeprazole has better efficacy than the first two generations of proton pump inhibitors and has smaller individual difference. As the new generation of proton pump inhibitors, Esomeprazole has been widely used in the clinical treatment of many acid-related diseases. Esomeprazole sodium is synthesized by the Shanghai Institute of Pharmaceutical Industry and its quality control methods and stability research have been studied.The study on quality control and stability of drugs is an important content of drug pre-clinical studies. During the study on drug quality standards, a thorough analysis of drug quality should be done to guarantee the safety and reliability of drugs, and to guarantee the smooth progress of pre-clinical and clinical research, as well as the safety of post-marketing drugs. In this study, under the guidance of "Chinese Pharmacopoeia" and the technical requirements of the national drug quality research, the quality control methods and stability research of Esomeprazole sodium were systematically studied.In this study, the structure of samples was confirmed by elemental analysis, UV, IR and mass spectrometry. Chromatographic techniques such as HPLC and GC were performed to study the quality control methods and stability of samples, meanwhile the stress degradation of samples was further studied. The dissertation was divided into the following three parts: 1. The quality control study on Esomeprazole sodiumThe quality standard of Esomeprazole sodium was investigated according to "Chinese Pharmacopoeia" and technical specifications of the drug quality standards. The items of shape and properties, physical constant, identification, examination and assay were systematically studied to determine the appropriate detection methods.The method of residual organic solvents inspection was established to detect six residual organic solvents in Esomeprazole sodium. The result indicated that methylene chloride, ethyl acetate and toluene did not exist in samples, while the residual amount of methanol, acetone and isopropyl ether met the limit requirements from Chinese Pharmacopoeia.Silver nitrate method and HPLC method were established to perform the assay of the drug. HPLC was optimized to improve the peak shape. The assay was performed in Waters XTerra(?) MS C8 column (150mm ×4.6mm,3.5 μm) with isocratic elution using acetonitrile-20mM Ammonium acetate, pH 7.6 (28:72 (v/v)), the flowing rate was 1mL/min, the UV detection wavelength was 280nm, the column temperature was 25℃ and the sample volume was 20uL. The method was proved to be accurate and specified.The method was established to detect the enantiomeric purity of Esomeprazole sodium. The detection was performed in CHIRAL-AGP column with isocratic elution using acetonitrile-phosphate buffer, pH 6.0 (13:87 (v/v)), the flowing rate was 0.6mL/min, the UV detection wavelength was 302nm, the column temperature was 25℃ and the sample volume was 20μL. The method had a good resolution and reproducibility.The method of related substances inspection was established to detect seven related compounds in Esomeprazole sodium. Different mobile phase system was proved to influence the separation effect. The method was finally performed on Waters XTerra(?) MS C8 column with the gradient elution using acetonitrile-ammonium acetate buffer system. All the related compounds were successfully separated and the samples could be tested through this method.2. The stress degradation study on Esomeprazole sodiumIn this dissertation, the method of related substances inspection was used to study the stress degradation of Esomeprazole sodium according to ICH guidelines, providing information about degradation behaviors of the drug under different stress conditions, including acidic, alkaline, oxidative, photolytic and thermal condition. The drug was found to undergo extensive degradation under acidic and oxidative condition, degrade to a mild extent under alkaline and photolytic condition and be extremely stable under thermal condition. LC-MS method was carried out for the characterization of degradation products. The m/z values, retention time and fragmentation patterns helped to confirm the presence of known products under alkaline and oxidative conditions, and to propose the structures of unknown products under photolytic and acidic conditions. According to the characterization of degradation products, a more extensive degradation pathway of the drug was proposed.3. The stability study of Esomeprazole sodiumStability of Esomeprazole sodium was conducted according to the guiding principles of drug stability test. The impact fectors test had already been finished, while accelerated test and long-term test were still being carried out. In this research, the sample characteristics, the main component content and related substances of stability samples were analyzed. According to the results of impact factors test, it was found that Esomeprazole sodium was very stable under high temperature, but it was sensitive to light and had a significant moisture absorbance property. So Esomeprazole sodium was suggested to be stored without strong light and high humidity.