Simple and Sensitive Methods for the Determination of 2-(4′-Chloromethyl phenyl) Benzonitrile and 2-(4′-Bromomethyl phenyl) Benzonitrile Contents in Valsartan Drug Substance by Gas Chromatography

Simple and reliable gas chromatographic methods were developed, optimized, and validated for the determination of 2-(4′-chloromethyl phenyl) benzonitrile (2-CMPB) and 2-(4′-bromomethyl phenyl) benzonitrile (2-BMPB) contents in valsartan drug substance, using benzophenone as internal standard (IS). Efficient chromatographic separations were achieved on DB-1, 30？m length with 0.53？mm i.d., and 3？μm particle diameter column consists of 100% dimethyl polysiloxane as a stationary phase by passing helium as a carrier gas. The analytes were extracted in dichloromethane and monitored by flame ionization detector. The performance of these methods was assessed by evaluating specificity, precision, sensitivity, linearity, and accuracy. The limits of detection (LOD) and limits of quantification (LOQ) established for 2-CMPB are 0.10？μg？mL？1 and 0.32？μg？mL？1, respectively. For 2-BMPB, LOD is 0.31？μg？mL？1 and LOQ is 0.95？μg？mL？1. The average recoveries for 2-CMPB are in the range of 96.8% to 106.7% and for 2-BMPB (LOQ level) are 99.3%. The methods can be successfully applied for the routine analysis of valsartan drug substance. 1. Introduction Valsartan belongs to a class of medicines known as angiotensin II receptor antagonist, which helps to control high blood pressure and congestive heart failure or postmyocardial infarction [1–4]. Chemically, valsartan is N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine, having an empirical formula C24H29N5O3 with a molecular weight of 435.5. Valsartan is marketed under the trade name of Diovan [5] and is available as 40？mg, 80？mg, 160？mg, and 320？mg tablets for oral administration. In the synthesis process of valsartan drug substance, 2-(4′-chloromethyl phenyl) benzonitrile (2-CMPB) and 2-(4′-bromomethyl phenyl) benzonitrile (2-BMPB) were used as key raw materials. These residual organic raw materials may come through the manufacturing process. Based on structural alert, these raw materials come under genotoxic category. The maximum daily dosage of valsartan drug substance is 320？mg. As per threshold of toxicological concern (TTC) approach, these residual impurities should be less than 4.7？μg？g？1 [6–8]. Moreover, there is no specific information that is available in the literature on toxicity of these residual impurities confirming their carcinogenicity or mutagenicity. In the available literature many analytical procedures have been reported for the estimation of valsartan and its related substances [9–14]. A good number of analytical methods also reported for the determination of valsartan in