Simultaneous and Trace Level Quantification of Five Potential Genotoxic Impurities in Ranolazine Active Pharmaceutical Ingredient Using LC-MS/MS
- 1 Center for Chemical Sciences and Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, Telangana, India
- 2 Aurobindo Pharma Laboratory Research Center II, Hyderabad, Telangana, India
- 3 Center for Chemical Sciences and Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, Telangana, India
Abstract
Highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of five potential genotoxic impurities in ranolazine active pharmaceutical ingredient. Chromatographic separation achieved using Poroshell C18 PFP 150 × 3.0 mm 2.7 μ column and 0.1% formic acid in water as Mobile phase A and 0.1% formic acid in methanol as mobile phase B using gradient elution and a flow rate of 0.4 ml/min with a run time of 18 minutes. Mass spectrometric conditions were optimized using electrospray ionization in positive mode. Method shows excellent linearity from 0.05 - 5.0 ppm of the ranolazine test concentration for all the five impurities. The correlation coefficient was observed greater than 0.99. Satisfactory recoveries were observed for all the five impurities within the range of 102.9% - 112.3%. Method has been validated as per ICH recommended guidelines with a LOQ of 0.15 ppm achieved. The developed method was able to quantify all the five impurities at a concentration level of 1 ng/ml (0.5 ppm with respect to 2 mg/ml ranolazine).
- USFDA, Guidelines for Industry (2008) Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches (Draft).
- United States Department of Health and Human Services, Food and Drug Administration (2008) Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches.
- Note for Guidance on Pharmaceutical Development, EMEA/ CHMP/167068/2004. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/quality/quality-pharmaceutical-development\
- ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. https://database.ich.org/sites/default/files/M7_R1_Guideline.pdf
- Rayner-Hartley, E. and Sedlak, T. (2016) Ranolazine: A Contemporary Review. Journal of the American Heart Association, 5, No. 3. https://doi.org/10.1161/JAHA.116.003196
- Stone, P.H., Gratsiansky, N.A., Blokhin, A., Huang, I.Z., Meng, L., ERICA Investigators (2006) Anti-anginal Efficacy of Ranolazine When Added to Treatment with Amlodipine: The ERICA (Efficacy of Ranolazine in Chronic Angina) Trial. Journal of the American College of Cardiology, 48, 566-575. https://doi.org/10.1016/j.jacc.2006.05.044
- Chaitman, B.R., Pepine, C.J., Parker, J.O., Skopal, J., Chumakova, G., Kuch, J., Wang, W., Skettino, S.L. and Wolff, A.A. (2004) Effects of Ranolazine with Atenelol, Amlodipine, or Diltiazem on Exercise Tolerance and Angina Tolerancy in Patients with Severe Chronic Angina. JAMA, 291, 309-316. https://doi.org/10.1001/jama.291.3.309
- Suresh Babu, V.V., Sudhakar, V. and Murthy, T.E.G.K. (2014) Validated HPLC Method for Determining Related Substances in Compatibility Studies and Novel Extended Release Formulation for Ranolazine. Journal of Chromatography and Separation Techniques, 5, 1000209.
- Madhavi, A., Subba Rao, D.V., Srinivasu, P. and Naidu, A. (2009) Development and Validation of a New Analytical Method for the Determination of Related Components and Assay of Ranolazine in Bulk Drug and Pharmaceutical Dosage Forms by LC. Chromatographia, 70, 333-338. https://doi.org/10.1365/s10337-009-1145-5
- Sharma, T., Moitra, S.K., Si, S.C. and Sankar, D.G. (2011) Stability Indicating LC Method for the Determination of Ranolazine Hydrochloride in the Bulk Drug and in Pharmaceutical Dosage Form. International Journal of Pharmacy and Pharmaceutical Sciences, 3, 327-332.
- Khedkar, A.N., Veer, S.U., Rakh, M. and Rao, J.R. (2015) Stability Indicating Method Development and Validation of Ranolazine Hydrochloride in Bulk and Tablet Dosage Form by HPTLC. International Journal of Pharmaceutical and Clinical Research, 7, 77-83.