Ecuacion De Wilson

A Sensitive and Selective GC–MS Method for Analysis of Process-Related Genotoxic Impurities in Atenolol
2010, 71, 733–736

Yogeshwar Reddy Mamilla1,3,&, Kista Reddy Chetyala3, Ramesh Venna2, Raju Gajjela2, Kishore Katragadda1, Saravanan Govindasamy1, Suryanarayana Mulukutla1, Debashish Datta1
1 2 3

R&D Centre, Matrix Laboratories Ltd, Jinnaram, Medak 502325, India; E-Mail:yogeshwar.mamilla@matrixlabsindia.com National Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad, India Department of Chemistry, P.G. College of Science, Saifabad, Hyderabad, India

Received: 28 September 2009 / Revised: 4 January 2010 / Accepted: 20 January 2010 Online publication: 24 April 2010

Abstract
A sensitive GC–MS method for analysis of residues of allyl chloride (2),1,3-dichloro-2propanol (3), and 2,3-dichloro-1-propanol (4), genotoxic impurities in atenolol (1) drug substance, has been developed and validated. Under the optimum conditions used for sample preparation, recovery of 2, 3, and 4 from samples spiked at three concentrations, in triplicate, was from 97.1 to 99.3%, from 97.6 to 104.7%, and from 90.1 to 96.8%, respectively. Limits of quantificationand detection were 0.003 and 0.001 mg g-1, respectively, for standard solutions of the compounds. Response was a linear function of concentration in the range 0.003–0.018 mg g-1 with correlation coefficients 0.9910, 0.9964, and 0.9960 for 2, 3, and 4, respectively.

Keywords
Gas chromatography–mass spectrometry Atenolol Selected-ion monitoring

Introduction
Atenolol((RS)-2-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}acetamide) is used for treatment of cardiovascular diseases and conditions such as hypertension, coronary heart disease, arrhythmias, and angina (chest

Electronic supplementary material The online version of this article (doi:10.1365/ s10337-010-1503-3) contains supplementary material, which is available to authorized users.

pain), and to treat and reduce therisk of heart complications after myocardial infarction (heart attack) and angina [1]. In the synthesis of atenolol (1), ally chloride (2), 1,3-dichloro-2-propanol (3), and 2,3-dichloro-1-propanol (4) are important reagents. The chemical structures of compounds 1–4 are given in Fig. 1. Identification and quantification of compounds 2–4 as impurities in 1 are essential, because of their genotoxic nature[2]. Regulatory guidelines [3] stipulate a threshold of toxicological concern (TTC) value of 1.5 lg day-1 for intake of a toxic impurity. The permitted quantity in ppm is the ratio of the TTC in micrograms per day to the dose in grams per day. Because 200 mg atenolol is administered per day [4] in the form of tablets (25–200 mg; trade name Tenormin); the estimated permissible quantity of theseimpurities is 7.5 ppm per day. Several GC–MS studies have been conducted on atenolol and other b-blockers [5–8]. Forsdahl et al. [5] reported a method for sensitive detection of isopropylsubstituted b-blocking agents in human urine. Their sample-preparation step involved enzymatic hydrolysis, solid-phase extraction, and derivatization with N-methyl-N-trimethylsilyltrifluoroacetamide;

Limited ShortCommunication DOI: 10.1365/s10337-010-1503-3 0009-5893/10/04

Chromatographia 2010, 71, April (No. 7/8) Ó 2010 Vieweg+Teubner | GWV Fachverlage GmbH

733

300 270 240

OH

14.23
O H 2N

O

H N

CH3 CH3

Atenolol (1)
Cl

OH Cl

HO Cl Cl

210

H 2C

Cl

Abundance -->

180 150 120 90 60 30 0 2.0 4.0 6.0 8.0 10.0 12.0

15.02

Allyl chloride (2)1,3-Dichloro-2-propanol (3)

2,3-Dichloro-1-propanol (4)

14.0

16.0

18.0

20.0

22.0

24.0

26.0

28.0

Time (min)

Fig. 1. Total ion chromatogram obtained from allyl chloride (2, 5.18 min), 1,3-dichloro-2-propanol (3, 14.23 min), and 2,3-dichloro-1-propanol (4, 15.02 min)

GC–MS was then used for detection of atenolol as its bis, tris, and tetra-TMS derivatives. Angier and coworkers...