METHOD DEVELOPMENT AND VALIDATION BY GC-MS FOR QUANTIFICATION OF 1-CHLOROETHYL CYCLOHEXYL CARBONATE AS A GENOTOXIC IMPURITY IN CANDESARTAN CILEXETIL DRUG SUBSTANCE
Keywords:
Candesartan Cilexetil, 1-Chloroethyl Cyclohexyl Carbonate, Gas chromatography, Mass spectrometer, Limit of Quantification (LOQ), Limit of Detection (LOD)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.Â
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.
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References
The European Agency for the Evaluation of Medicinal Products, ICH Topic S1B, Note for Guidance on Carcinogenicity: Testing for Carcinogenicity of Pharmaceuticals; 1998.
European Medicines Agency, Evaluation of Medicines for Human Use, Guideline on the Limits of Genotoxic Impurities; 2007.
Muller L. A rationale for determining, testing and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul Toxicol Pharmacol 2006;44:198-211.
David Jacobson-Kram. Advanced Drug Delivery Reviews; 2007;59(1);38-42.
Raman NV. Strategies for identification, control and determination of genotoxic impurities in drug substances: a pharmaceutical industry perspective. J Pharm Biomed Anal 2011;55(4):662-7.
The Merck index, 14th Edition; 2006. p. 281.
European Medicines Agency, ICH topic Q 2 (R1), Note for the Guidance on Validation of Analytical Procedures: Text and Methodology; 1995.
The European Agency for the Evaluation of medicinal Products, ICH topics Q 2 B, Note for the Guidance on Validation of Analytical procedures: Text and methodology, CPMP/ICH/281/95; 1997.