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

Abstract

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.

Determination of 4, 4′-Bis (Bromomethyl) Biphenyl Genotoxic Impurity in Valsartan Drug Substances by HPLC

“…The percentage recovery of impurity in the drug substances was calculated. The recovery of the 4,4′-bis (bromomethyl) biphenyl in valsartan ranged from 97.62 to 104.59 % which is well within acceptance criteria 80% to 120% [20]. The low value of % RSD is confirming that the method is accurate.…”

“…Intermediate precision of the method was evaluated by injecting six individual preparation of the spiked sample at evaluation limit on a different day in the same laboratory. The % RSD for the content of 4,4′-bis (bromomethyl) biphenyl impurity was very low, confirming the high precision of the method [20]. The results are present in table 1.…”

“…The LOD and LOQ for 4,4'-bis (bromomethyl) biphenyl were estimated through signal-to-noise ratio of 3:1 and 10:1 respectively, by injecting a series of dilute solutions having known concentrations [20,24]. LOD of the impurity is defined as the lowest concentration that can be detected.…”

“…The deeply rooted literature survey reveals that synthetic impurities of valsartan content have been determined by LC-MS [16][17][18], UPLC [19], GC [20], HPTLC [21] and HPLC [22][23][24] analytical techniques but up to yet no any method is available for the determination of 4,4'-bis (bromomethyl) biphenyl genotoxic impurity in valsartan drug substances.…”