Advanced LC-MS/MS method for selective quantification of nitrosamine impurities in Risperidone: Enhancing drug safety

Abstract

• Development and validation: a robust LC-MS/MS method was developed and validated for the precise quantification of nitrosamine impurities in risperidone drug substances. • Method optimization: critical parameters were optimized to ensure high selectivity and sensitivity for detecting trace-level nitrosamines. • Enhanced drug safety: the method enables reliable identification and quantification of potential carcinogenic impurities, reinforcing patient safety. • Application to marketed samples: analysis of commercial risperidone samples revealed variability in nitrosamine levels, highlighting the necessity for routine monitoring. • Quality control implications: this study emphasizes the importance of stringent regulatory standards and enhanced quality control measures in pharmaceutical manufacturing. In the current study, a simple, rapid, and sensitive analytical method was developed and validated for the determination and quantification of four nitrosamine drug substance-related impurities (NDSRIs) in Risperidone drug substance. Chromatographic separation was achieved on an ACE-5 PFP C18 column (150 mm × 4.6 mm × 3 µm) using gradient elution with 0.2 % formic acid and methanol. The method utilized a flow rate of 0.8 mL/min, an injection volume of 5 µL, and a column temperature of 40 °C. Positive electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode was used for quantification. The limit of detection (LOD) and limit of quantification (LOQ) ranged from 0.12 to 0.46 and 0.23–0.93 µg/mL, respectively. The calibration curves for NDIRs impurities (0.23–185.72 µg/mL) exhibited R² values between 0.998 and 0.999. Recoveries ranged varied from 94.9 to 124.4 %, with % RSD < 15.0 %. The results indicated that the method is reliable for monitoring all NINA, NBOP, NBP, and NB impurities in Risperidone.

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