Study Of Chiral Drug Solvents And Isomeric Impurities

Residual solvents and isomeric impurities during the development and production of chiral drugs have been a hot topic of concern,both of which are closely related to the stability and physicochemical properties of drugs,and the impurity standards are clearly defined in national pharmacopoeias.In this paper,we study the development of residual solvent detection method for chiral drug clopidogrel hydrogen sulfate and the removal of isomeric impurities of donepezil by splitting method as follows.Clopidogrel hydrogen sulfate,a chiral drug used for the prevention and treatment of arterial blood circulation disorders caused by platelet aggregation,was synthesized through chiral raw material unpaired.The impurity detection in the pilot test and in the trial test found that the content of the isomeric impurity R-configuration of clopidogrel sulfate was in accordance with the standard,clopidogrel sulfate was optically pure,and the residual solvent impurities used couldn’t be removed.In order to ensure the safety of drug use and environmental protection,the drug was controlled and tested for residual impurities of various organic solvents used in the preparation of APIs and intermediates,and two sets of residual solvent detection methodology were developed with reference to the pharmacopoeia.The static headspace gas chromatography method was adopted to detect four organic residual impurities in methanol,ethanol,dichloromethane and ethyl acetate in the finished product of clopidogrel sulfate,and the more rapid direct injection gas chromatographic method was used to detect triethylamine in ethyl thiophene intermediate p-toluenesulfonate.The experimental data showed that both test methods have good specificity,linearity,spiked recovery,precision,repeatability and stability,and can be used for the detection and analysis of organic residual impurities present in the development of industrial clopidogrel bisulfate products.Donepezil,a chiral drug for the effective treatment of Almozheimer’s disease(AD).Donepezil is currently marketed as a racemate,but studies have shown that the R and S conformations of donepezil differ in their inhibition of Acetylcholinase(ACh E)in AD patients in vitro and in vivo.An isomeric splitting method was adopted to obtain a single conformation of donepezil.Ultrasound was introduced into the conventional chemical splitting,and ultrasonic replacement splitting was constructed,which greatly shortened the reaction time and improved the efficiency.However,during the recrystallization process,it was found that the enantiomeric excess(ee)value of dissociated R-donepezil couldn’t be improved at about 90%.It was found that the high purity donepezil was prone to a small amount of self-elimination after dissociation,which was the reason why optical purity could not be obtained.We designed an ultrasonic kinetic cycle splitting based on racemization,which recycles the mother liquor to achieve "green splitting".However,the yield and ee value decreased after 6ultrasonic kinetic cycles,which may be due to the fact that only a small part of the mother liquor was deconvolved.