Quality Study Of Selexipag

Pulmonary artery hypertension（PAH）is a disease of the pulmonary arterioles characterized by vasoconstriction,vascular remodeling,smooth muscle cell proliferation,and in situ thrombosis.In recent years,with the progress in the pathogenesis of PAH,PAH has entered the era of new drug development.In particular,oral long-acting PGI₂ receptor agonists are widely used clinically due to their superior pharmacological activities.Selexipag is a novel long-acting prostacyclin（IP receptor）agonist for oral treatment of pulmonary hypertension.The drug is hydrolyzed by carboxylesterase into active metabolites in the human body to exert its efficacy,reduce the hospitalization rate and the risk of disease progression in PAH patients,and has a good market prospect.The U.S.Food and Drug Administration（FDA）granted its orphan drug status and are approved for listing in the United States in December 2015.Its quality standards have not been included in the national pharmacopoeia.This topic uses a variety of analytical techniques to study the quality of Selexipag APIs,and conducts methodological validation of each research method.The main content of this topic include the following:1.Structural confirmation:The structure of the sample was verified by NMR,MS and IR spectra.2.Quality study:Based on Selexipag’s production process and structural features,the appearance characters,identification,the test and assay method of Selexipag API were investigated:The physicochemical constants of Selexipag API,such as solubility,melting point,moisture content,ignition residue and heavy metal,were determined,and corresponding limits were established.In order to control the residues of impurities such as starting materials,intermediates,degradation products,and by-products in this product,the determination HPLC method of related substances were measured.The method was established as follows:the analysis was performed on a Shimadzu Wonda Cract ODS-2 column（4.6 mm×250 mm,5μm）with a mobile phase of acetonitrile-0.05%TFA（62:38,v/v）at a flow rate of 1.0 m L·min^-1.The detection was Ultraviolet Detector（UV）at 205nm and the column temperature was 35℃,the injection was 10μL.The agents such as methanol,ethanol,acetone,dichloromethane,tetrahydrofuran and toluene were used as solvents in the production process.According to the appendix of Chinese Pharmacopoeia 2015,headspace gas chromatography was used to research the above residual solvent.The samples were separated on Kromat PC-624（V）silica capillary column（30.0 m×0.32 mm,1.8μm）column using temperature programming:FID detector temperature was used with the temperature of 250℃.Content determination method was established and validatedThe qualitative and quantitative methods of Selexipag API have good specificity,high sensitivity,good accuracy,repeatability and durability,as well as effective control of product quality,to provide accurate and effective data for follow-up study.3.Study on stability.The results of influencing factors,accelerated tests and long-term tests indicated that there were no significant changes in the properties,hygroscopicity,melting point,content and related substances under high humidity,high temperature,and light conditions.Through the study of the above several aspects,the storage condition and shelflife of Selexipag were preliminary determined.