Study On Quality Standard Of API Conivaptan Hydrochloride

Conivaptan hydrochloride is mainly used in the treatment of hyponatremia patients with normal blood volume.Currently,conivaptan hydrochloride has not been approved for listing and used in China.API conivaptan hydrochloride was developed in this study.From the synthesis of raw materials to the establishment of the draft quality standard,a variety of analytical techniques and methods were used to conduct a large number of studies,and the detailed validation of developed methods were carried out.The structure confirmation and physical and chemical properties of the reference substance obtained from the refined raw materials were examined.Structural confirmation included IR,UV,MS,¹H-NMR,¹³C-NMR,HSQC,HMBC,DEPT,and COSY;Physical and chemical properties include:properties,solubility,moisture absorption and melting point.The results show that the structure and physicochemical properties of the product were consistent with the structure,and quality studies could be further carried out.The related substances and content of the product were determined by HPLC.The chromatographic conditions of related substances were optimized by referring to the literature.The chromatographic conditions were as follows:the chromatographic column was octadecyl bonded silica gel column?250 mm×4.6 mm,5?m?,column temperature was 40^?C;mobile phase A was 0.03 mol/L disodium hydrogen phosphate solution?adjusting pH to 5.7 with phosphoric acid?,mobile phase B was acetonitrile with the gradient elution mode;flow rate was 1.0 ml/min;and the detection wavelength was 220 nm.The validation results show that the main peaks of related substances and the chromatographic peaks of impurities met the baseline separation,and the system had good applicability.The established HPLC method is simple,specific and sensitive,and can be used for the determination of related substances of conivaptan hydrochloride.According to the chromatographic conditions of related substances and the characteristics of content determination,gradient elution was optimized into isometric elution[0.03 mol/L disodium hydrogen phosphate solution?adjusting pH to 5.7 with phosphoric acid?-acetonitrile?50:50?].Sample concentration was reduced to 50?g/ml.The detection wavelength was changed to 240 nm,and other chromatographic conditions were completely the same as those of the related substances.The results of content verification show that the method was rapid,simple,accurate and durable.The related substances and contents of three batches of samples all met the quality requirements of API conivaptan hydrochloride.Ethyl acetate,acetonitrile,tetrahydrofuran,toluene,pyridine,ethanol and N,N-dimethylformamide?DMF?were used in the synthetic process of this product.The above organic solvents were studied by gas chromatography?GC?.The chromatographic conditions of GC were as follows:the chromatographic column was100%PEG as stationary phase;initial temperature was 50^?C,holding time was 5 min,heating rate was 20^?C/min to 200^?C,holding time was 10 min;inlet temperature was200^?C;detector temperature was 250^?C;column flow rate was 1.0 ml/min;and the injection volume was 1?l.The results of validation show that the method was specific,sensitive and simple to operate,and could be used for the determination of residual solvents in this product.The results of residual solvents in the self-made reference substance and three batches of samples all met the requirements of residual solvents limit.The identification and general inspection of this product were studied.Identification items included chemical reaction method,HPLC and IR method;the general examinations of water content,drying weight loss,solution color and clarity,acidity,sulfate,burning residue,heavy metals were included.Three batches of samples were inspected,and all the results met the quality requirements.According to the determination results of above items,the internal control quality standard of the product was preliminarily formulated.The test results of three batches of samples all met the internal control quality standards and the requirements.