Study On The Quality Of Azasetron Hydrochloride In A New Process

Azasetron hydrochloride?AZ?is applicable to digestive tract syndromes such as nausea,vomiting and irritability caused by taking anti-malignant tumor drugs?cisplatin,etc.?.After a comparative study of clinical administration in different types of serotonin antagonists,AZ is the best treatment for vomiting caused by platinum drugs.The existing quality standards of azasetron hydrochloride has not been embodied in pharmacopoeia at home and abroad,there are corresponding registration standard(WS_1-?X-319?-2004Z)only in China,however,this registration standards no longer meet the new situation of the strict drug supervision.Therefore,in order to ensure the safety and effectiveness of azasetron hydrochloride active pharmaceutical ingredient?API?,a quality standard draft for the new synthesis technology was established and its main impurities were structurally confirmed in this paper.In our research,a systematic and in-depth quality and stability study of azasetron hydrochloride API was carried out,and the properties and general examination method were studied according to properties and structural characteristics.We established methods for related substances,residual solvents and contene determination,and carried out a comprehensive methodological verification;On basis of the above research,a quality standard draft for azasetron hydrochloride API with a new synthesis technology was developed.Among them,RP-HPLC analysis was performed to determine the related substances of this product on an ODS column?4.6×250 mm,5?m?,used a mobile phase of0.05 mol/L KH₂PO₄?pH was adjusted to 3.0 by phosphoric acid?and acetonitrile in gradient mode with a flow rate at 1.0 mL/min,the column temperature was 30?and the detection wavelength was 220 nm.Impurity quantification method adopted the impurity reference substance method for known impurities,and the main component self-compare method with no calibration factor for unknown impurities.Then,a headspace capillary gas chromatography method for the determination of residual organic solvents?ethanol and dichloromethane?was developed.The non-aqueous titration method in the national registration standard was used for the content determination,and the end point determination was improved to potential method.At last,the results of the stability study showed that the product was stable for 10 days under the conditions of high temperature,high humidity and light,6 months after accelerated test,and 12 months after long-term test,which was consistent with the stability change trend of the marketed drug.In our research,the main impurities and possible potential impurities in azasetron hydrochloride were classified based on the finished and crude product,then the impurity A and B monomers were collected by HPLC preparative chromatography;In addition,the main impurity J monomer was obtained by destroying and completely degrading the raw material?AZ-SM1?with high concentration alkali.MS,MNR,and other methods were used to confirm these structures of impurities A,B,and J,which were 1-hydroxybenzotriazole?HOBt?,6-chloro-3-oxo-N-?quinine ring Alkenyl-3-amino?-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide,5-chloro-2-hydroxybenzoic acid,respectively.Finally,we conducts in-depth quality research on the starting materials and key intermediates?intermediate III and intermediate??,including the determination of physicochemical constants and weight loss on drying detection.Established methods for related substance detection and content determination,and formulated corresponding quality standard draft,which provided a guarantee for controllable quality of the final product.