Analytical Separation Of Genotoxic Impurities And New Quality Standard For Olmesartan Medoxomil Production

Olmesartan medoxomil is a differential angiotensin ? receptor antagonist.In industrial synthesis processes,halogenated genotoxic impurities are always generated.In the thesis,the trace genotoxic impurities were detected and separated by high performance liquid chromatography in olmesartan medoxomil production process,and a new quality standard of olmesartan medoxomil was studied considering the genotoxic impurities control.The details were summarized as below:(1)An analytical separation method for brominated genotoxic impurities was developed,and the method was was performed on a C18 column(250×4.6 mm,5 ?m),with the volume ratio of 15:85 for 0.1% aqueous acetic acid(A): 0.1% aqueous acetic acid dissolved in acetonitrile(B)as the mobile phase at a flow rate of 1.5 ml·min-1.The detection wavelength was 254 nm,and the temperature of column was 25 oC.The bromoinated impurity 1 and impurity 2 was validated by specificity,linearity,limit of quantitation,limit of detection,precision,accuracy and obtained: The limit of quantity and the limit of detection in the present method were 0.0003% and 0.0001%,respectively,which were much lower than the standard limit(0.0037%).The calibration curves for impurity 1 and impurity 2 were well linear in the range of 0.03~0.25 ?g·mL-1.The average recoveries for impurity 1 and impurity 2 were 94.37% and 94.43%,and the relative standard deviation values were 2.38% and 2.72% respectively,indicating that the method was accurate and sensitive.(2)An analytical separation method for chlorinated genotoxic impurities was also developed,and performed on a Kromasil Eternity 5-PhenylHexyl column(250×4.6 mm),with the mobile phase of A(acetonitrile: 2.04 g·L-1 monopotassium phosphate solution was 20:80): B(2.04 g·L-1 monopotassium phosphate solution: acetonitrile was 80:20)by gradient elution(pH 3.4).The detection wavelength was 215 nm,and the temperature of column was 40 oC.The flow rate was maintained at 1.0 ml·min-1 with inject volume of 10 ?l.The method was validated;the limit of quantity and the limit of detection were 0.0003% and 0.0004% respectively,which were also lower than the standard limit(0.0037%).It can be used for the quality control of the chlorinated genotoxic impurities 1 and impurities 2 with its requirement sensitivity.(3)A new standard was suggested by establishing standard limits regarding the characters,identification,assay and test according the quality and testing results of three batches,including the related substances,residual solvents acetone,ethyl acetate and DMA used in the process,and the established limits of genotoxic impurities.In the end,with control of genotoxic impurities,the new standard including the limit of genotoxic impurities is expected to be employed to ensure the better quality control of olmesartan moedoxomil API routine production.