Objective: Dimethyl sulfate has been highlighted as potential genotoxic and carcinogenic impurity. A sensitive Headspace gas chromatography (HS-GC) method with pre-column derivatization was developed and validated for the determination of dimethyl sulfate impurity in methoxsalen active pharmaceutical ingredient.Methods: HS-GC method on the column Agilent DB-5, 30m X 0.53 mm, film thickness 1.5 µm, with flame ionization detector (FID) was used. Derivatization reagent concentration, time of reaction and pH of the solution were optimized during method development. This analytical method was evaluated by performing method validation as per ICH guideline.Results: The proposed method was specific, linear, accurate, rugged and precise. The calibration curves showed good linearity over the concentration range of 0.5 μg/ml to 3.0 μg/ml and the correlation coefficient was 0.999. Method had very low limit of detection (LOD) and limit of quantification (LOQ) 2.0 μg/g and 5.0 μg/g respectively. Accuracy was observed within 98.1%–104.5%.Conclusion: The developed method was demonstrated to be accurate, robust and sensitive for the determination of dimethyl sulfate impurity in methoxsalen drug substance.

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Methyl iodide has been highlighted as a potential genotoxic impurity (PGI). A sensitive HS-GC method with ECD was developed and validated for the determination of methyl iodide impurity in Tedizolid phosphate, an active pharmaceutical ingredient. HS-GC method on DB-624,column 60m X 0.53mm, film thickness 3μm, with electron capture detector (ECD) was used. The proposed method was specific, linear, accurate, rugged and precise. The calibration curves showed good linearity over the concentration range of 0.78 μg/g to 11.7 μg/g and the correlation coefficient was 0.997. Method had very low limit of detection (LOD) and limits of quantification (LOQ) are 0.23 μg/g and 0.78 μg/g, respectively, with respect to test concentration. Accuracy was observed within the range 96.0% to 103.2%. This method is a further extended good quality control tool for low level quantitation of methyl iodide impurity in another API, alogliptin benzoate.