METHOD DEVELOPMENT AND VALIDATION BY GC-MS FOR QUANTIFICATION OF 1-CHLOROETHYL CYCLOHEXYL CARBONATE AS A GENOTOXIC IMPURITY IN CANDESARTAN CILEXETIL DRUG SUBSTANCE

Abstract

Objective: Candesartan Cilexetil is an Angiotension II receptor antagonist used mainly for the treatment of hypertension. The synthesis process of Candesartan uses 1-Chloroethyl Cyclohexyl Carbonate (CECC), which is potential genotoxic impurity as per the EMEA guideline. The method development and later validation activity was proposed and performed for the analysis of 1-Chloroethyl Cyclohexyl Carbonate (CECC) in Candesartan Cilexetil drug substance. Based on daily dose basis evaluation limit required was 0.49 µg/mL (i. e. 49 µg/g). Methods: The development activity was conducted by Gas chromatography technique with Mass spectrometer as detector. DB-5 make Agilent J&W column with length 50 meter, internal diameter 0.32 mm, film thickness 0.52 µm was used. Phase of DB-5 is 5% phenyl, 95% dimethyl polysiloxane and is an intermediate polarity phase with very good selectivity for polar compounds. Hexane was selected as diluent considering the selective solubility of CECC.  Results: Validation activity was planned and completed based on the International Conference on Harmonization (ICH) guidelines. The LOD and LOQ values were found to be 0.70 and 2.11 µg/g (i. e. 0.007 and 0.021 µg/mL) for CECC. Method very sensitive as method was related to genotoxic impurity. Also accuracy results were well in the range of 99 to 105 %. Linearity curve showed correlation coefficient of 0.99997. Conclusion: From validation data it was confirmed that the method is specific, precise, accurate, linear and sensitive for the required purpose. During the same activity three commercial batches were analyzed. Validation data as well as commercial batch data was enough to prove the method suitability