Investigation and structural elucidation of a new impurity in bulk drug of cilostazol by LC/MS/MS, FT-IR and NMR

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Graphical abstractHighlightsA new cilostazol impurity has been identified using MS, NMR, and IR.Quantification of the impurity by HPLC was studied.The mechanism for the impurity formation was proposed and confirmed by comparison experiments.Nitrogen inerting can effectively control the formation of the impurity in cilostazol bulk production.A new impurity was detected in bulk cilostazol (CIL) crude during routine analysis. The impurity (˜4%, the specification for unknown impurity in crude is not more than 0.20%) has a relative retention time of 1.46. Based on MS, NMR and IR spectral data, the impurity was identified as 6,6′-bis(4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy)-3,3′,4,4′-tetrahydro-[7,7′-biquinoline]-2,2′(1H,1′H)-dione(CIL-dimer). The precursor of CIL-dimer is an oxidative product of starting material 6-Hydroxy-3,4-dyhydro-1H-quinolin–2-one(6-HQ), CIL-dimer was formed in the following reaction with 5-(3-Chloro-propyl)-1-cyclohexyl-1H-tetrazol(CHCBT).

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