A SELECTIVE AND SENSITIVE METHOD DEVELOPMENT AND VALIDATION BY LC-MS/MS APPROACH FOR TRACE LEVEL QUANTIFICATION OF POTENTIAL GENOTOXIC IMPURITY OF BOC EPOXIDE IN ATAZANAVIR SULPHATE DRUG SUBSTANCE


Nelaturi Subbaiah, Gopireddy Venkata Subba Reddy

Abstract


Objective: To develop and validate a selective, sensitive, rapid and accurate method using LC-MS/MS technique to achieve efficient separation between active pharmaceutical ingredient (Atazanavir sulphate) and genotoxic impurity (BOC epoxide).

Methods: The quantification was carried out using the column puro sphere star RP 18 e (length 150 mm, internal diameter 4.6 mm, particle size 3.0 µm) with electrospray ionization in multiple reaction monitoring (MRM) detection mode. Eluent-A was 0.1% formic acid in water and eluent-B was 0.1% formic acid and 0.1% ammonium hydroxide solution (25%) in acetonitrile. The isocratic mode of elution was carried out for the elution of impurity with the shorter run time of 6 min. The flow rate was 1.0 ml/min and column oven temperature was maintained 25 °C.

Results: The method was validated as per ICH guidelines and arrived the limit of detection and limit of quantification for the potential genotoxic impurity and found to be 0.2 ppm and 0.5 ppm. The developed method was found linear in the concentration range of 0.5 ppm to 6 ppm and accuracy results were within the range.

Conclusion: The developed short span method found to be selective, sensitive, precise and accurate for the quantification of the BOC epoxide genotoxic impurity in atazanavir sulphate drug substance.


Keywords


Atazanavir sulphate, LC-MS/MS, Genotoxic impurity, Multiple reaction monitoring (MRM), DEREK nexus software

| PDF | HTML |

References


Chitturi SR, Somannavar YS, Peruri BG, Nallapati S, Sharma HK, Budidet SR, et al. Gradient RP-HPLC method for the determination of potential impurities in atazanavir sulphate. J Pharm Biomed Anal 2011;55:31–47.

Bhirud CH, Hiremath SN. Stability indicating RP-HPLC method for the determination of atazanavir sulphate in bulk and dosage form. Drug Invent Today 2013;5:81–6.

Bhavani KG, Krishna KBM, Srinivasu N, Ramachandran D. Determination of genotoxic impurity in atazanavir sulphate drug substance by LC-MS. J Pharm Biomed Anal 2017;132:156-8.

Balaji N, Sultana S. Ultra-high performance liquid chromatographic determination of genotoxic impurities in febuxostat drug substance and products. Asian J Pharm Clin Res 2017;10:324-30.

Natarajan S, Kempegowda BK, Bharathiar M. Determination of traceable genotoxic impurity cholroacetyl chloride a carcinogen by LC/MS/MS in drug substances. Asian J Pharm Clin Res 2016;9:97-100.

International conference on Harmonisation Q3A-Q3D Impurities-International Council for Harmonization guidelines; 2006. p. 1-11.

Bolt HM, Foth H, Hengstler JG, Degen GH. Carcinogenicity categorization of chemicals-new aspects to be considered in a European perspective. Toxicol Lett 2004;151:29–41.

Müller L, Mauthe RJ, Riley CM, Andino MM, De Antonis D, Beels C, et al. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul Toxicol Pharmacol 2006;44:198–211.

Jacobson-Kram D, McGovern T. Toxicological overview of impurities in pharmaceutical products. Adv Drug Delivery Rev 2007;59:38–42.

Guideline on the limits of genotoxic impurities, EMA guidance MEA/CHMP/QWP/251344; 2006.

Guideline for Assessment and Control of DNA Reactive (Mutagenic) Impurities in pharmaceuticals to Limit Potential Carcinogenic risk, M7 ICH; 2014.

Dipple A. DNA adducts of chemical carcinogens. Carcinogenesis 1995;16:437–41.

Koskinen M, Plna K. Specific DNA adducts induced by some mono-substitued epoxides in vitro and in vivo. Chem Biol Interact 2000;129:209–29.

Deductive Estimation of Risk from Existing Knowledge (DEREK) nexus, marketed by LHASA Ltd, Leeds, Yorkshire, U. K, DEREK nexus program Version Derek Nexus: 3.0.1, Nexus: 1.5.1; 2017.

Klick S. Evaluation of different injection techniques in the gas chromatographic determination of thermolabile trace impurities in a drug substance. J Chromatogr A 1995; 689:69–76.

Valvo L, Alimenti R, Alimonti S, Raimondi S, Foglietta F, Campana F. Development and validation of a liquid chromatographic method for the determination of related substances in verapamil hydrochloride. J Pharm Biomed Anal 1997;15:989–96.

Hsieh Y, A Korfmacher W. Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening. Curr Drug Metab 2006;7:479–89.

Lee MS, Kerns EH. LC/MS applications in drug development. Mass Spectrom Rev 1999;18:187–279.

Guidelines for Validation of Analytical Procedures, Q2 (R1), ICH; 1994.




About this article

Title

A SELECTIVE AND SENSITIVE METHOD DEVELOPMENT AND VALIDATION BY LC-MS/MS APPROACH FOR TRACE LEVEL QUANTIFICATION OF POTENTIAL GENOTOXIC IMPURITY OF BOC EPOXIDE IN ATAZANAVIR SULPHATE DRUG SUBSTANCE

Keywords

Atazanavir sulphate, LC-MS/MS, Genotoxic impurity, Multiple reaction monitoring (MRM), DEREK nexus software

DOI

10.22159/ijpps.2017v9i9.20248

Date

13-07-2017

Additional Links

Manuscript Submission

Journal

International Journal of Pharmacy and Pharmaceutical Sciences
Vol 9, Issue 9, 2017 Page: 143-148

Online ISSN

0975-1491

Statistics

106 Views | 68 Downloads

Authors & Affiliations

Nelaturi Subbaiah
Department of chemistry, S.R.N.B. Degree and P.G. College, Badvel, Kadapa, Andhra Pradesh, 516 227, India
India

Gopireddy Venkata Subba Reddy
Department of Chemistry, JNTUA college of Engineering, Pulivendula, Kadapa, Andhra Pradesh, 560 390, India
India


Article Tools



Refbacks

  • There are currently no refbacks.