Quality Studies Of The API Of Selexipag

Selexipag is an oral long-acting prostacyclin(PGI2)receptor agonist,and its active metabolites are highly selective for human prostacyclin receptors,thus the adverse reactions are greatly reduced compared to prostacyclin analogs.It is used to treat the pulmonary hypertension in clinical treatment,mainly to relieve clinical symptoms,increase activity tolerance,prevent disease progression,and prolong the survival of patients.Data from clinical studies show that Selexipag could reduce the morbidity /mortality risk by about 39% comparing with the placebo group patients received more than 4.3 years of treatment.The U.S.Food and Drug Administration(FDA)approved the listing of Selepag tablets from Acetylone on December 21,2015,and the China Food and Drug Administration approved the Selexipag import registration application in December2018.It is included in the priority review procedure as a clinically urgently needed variety.This subject conducts quality research on Selexipag APIs.According to the application requirements,it conducts comprehensive quality research on Selexipag APIs,formulates quality standards,and provides a research basis for the application.The main contents are as follows1.The quality control standards of starting material and intermediate were established using high-performance liquid chromatography(HPLC)and gas chromatography(GC).Analytical methods for related substances of the PDA and PDB were established,and methodological was validated.The main peaks of PDA and PDB and the chromatographic peaks of related substances can meet the baseline separation with good applicability.The established analytical method is simple,specific,and sensitive,and can be used for the determination of related substances in PDA and PDB.The headspace gas chromatography was established for the determination of residual solvents involved in the synthesis of two compounds.The method validation results show that this method can be used for the detection of residual solvents in samples with good specificity and high sensitivity.According to the characteristics of the content determination,HPLC analytical method for the content of the PDA and PDB were established and was used to the determination with satisfaction results.2.HPLC method was used to determine the related substances and content of selexipag.After screening and optimizing the chromatographic conditions,the chromatographic conditions of the relevant substances were obtained as follows: using an Agilent HC C18 column,acetonitrile-formic acid as the mobile phase and the gradient elution was used.The results show that both the main peak of selexipag and the peaks of all impurities can meet the baseline separation,and with good system suitability,and is suitable to control the related substances of selexipag,referring to the method of related substances,and the absorption of the selexipag,the wavelength was changed to 300 nm.3.Ethanol,dichloromethane,n-hexane and tetrahydrofuran was used as solvents in selexipag synthesis process used and the analytical method of residual solvent were investigated using headspace gas chromatography.The conditions for the determination of residual solvents were as follows: Kromat PC-624(V)capillary column.The FID detector temperature and injection port temperature are 250℃ and 200℃.The resolution of each solvent is greater than 1.5;the blank solvent does not interfere with the determination of residual solvents.Each solvent has a good linear relationship in its own linear range;and the method has specificity,precision,and accuracy,and the sample is stable within 12 hours.and this method can effectively control the residual solvent of this product4.The stability of the raw materials of selexipag was investigated.Thet est results of influencing factor,accelerated and 6-month long-term show that there was no significant changes in the indicators of the three batches of raw materials of selexipag under high humidity,high temperature and light conditions,The indicators included characteristics,dry weight loss,content,and related substances and soon.The quality standards of Selexipag APIs formulated are scientific,reliable and practical.Stability test investigations are still ongoing.