Sensitive derivatization methods for the determination of genotoxic impurities in drug substances using hyphenated techniques

• Developed genotoxic impurities determination methods through derivatization.
• Genotoxins which are vulnerable for derivatization were used as substrates.
• Various functional groups have been chosen to demonstrate different chemistries.
• Derivatization generated chromophores, enhanced sensitivity and stability.
• All the methods were validated as per regulatory guidelines.

Six sensitive derivatization methods for the determination of genotoxic impurities in selected drug substances were developed using hyphenated techniques. Some of the raw materials, reagents and reaction intermediates of the selected drug substances were identified as genotoxic impurities through DEREK software for windows. The genotoxic impurities which are amenable for derivatization were selected as substrates. Derivatizing agents were selected based on the functional groups of the genotoxic impurities. The chemistry involved in the derivatization was explained with suitable mechanisms. An appropriate hyphenated technique viz. LC–MS and GC–MS was opted based on the sensitivity and aromaticity of the derivatized genotoxic impurities. All the methods were validated as per International Conference on Harmonization guidelines. Correlation coefficient values were found about 0.99. The obtained % R.S.D values from replicate injections in the range of 2.3–4.8 and % recoveries of the added impurities in the range of 83.7–101.7 ensured the precision and accuracy, respectively.

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