ABSTRACT Nitrosamine impurities have emerged as critical quality concerns in pharmaceutical products due to their potential carcinogenicity and stringent regulatory limits. In the present study, a sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the determination of two process‐related nitrosamine impurities, RNZ Nitroso Impurity‐1 ( N ‐nitroso ranolazine epoxide impurity) (RNI‐1) and RNZ Nitroso Impurity‐2 (LAM‐derived nitrosamine impurity) (RNI‐2), in the ranolazine. Chromatographic separation was achieved on a Waters XBridge C18 column (150 mm × 4.6 mm, 3 µm) using a gradient elution of ammonium formate in water and methanol, with mass spectrometric detection performed in positive electrospray ionization mode using multiple reaction monitoring. The method was validated over a concentration range of 0.0102–0.32 ppm, with excellent linearity ( r = 0.999 for both impurities). The limits of detection and quantification were approximately 0.0034 and 0.0102 ppm, respectively, providing sensitivity well below the regulatory threshold of 0.2 ppm. Method precision and accuracy were satisfactory, with percentage relative standard deviation values ≤ 1.2% at the specification level and recoveries ranging from 91%–103% across the validated range. Forced degradation studies demonstrated that the method is stability‐indicating, with no formation of additional related substances and only minor increases in RNI‐2 under oxidative stress, remaining well below the specification limit. The developed LC–MS/MS method is robust, highly sensitive, and suitable for routine monitoring of trace‐level nitrosamine impurities in ranolazine, supporting regulatory compliance and quality assurance.
Diwakar et al. (Mon,) studied this question.
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