A generic approach for the determination of trace hydrazine in drug substances using in situ derivatization-headspace GC–MS

In situ derivatization-headspace GC–MS methodology has been developed for the determination of hydrazine in drug substance at low ppm levels. This general method uses acetone or acetone-d6 as the derivatization reagent. The resulting acetone azine or acetone azine-d12 can then be analyzed by headspace GC–MS. The method gives excellent sensitivity with a limit of quantitation (LOQ) as low as 0.1 ppm when the API (active pharmaceutical ingredient) samples are prepared at 10 mg per headspace injection vial. The spike recoveries of hydrazine at the 1 ppm level were between 79% and 117% in various APIs tested. The precisions (%RSD) of six preparations of the hydrazine standards at the concentration of 1 ppm level were typically between 2.7 and 5.6%. A linear range of concentrations from 0.1 to 10 ppm has been demonstrated with R2 ≥ 0.999. This general method has been tested in a number of API matrices and successfully applied to the determination of hydrazine in support of API batch releases and process chemistry at GlaxoSmithKline.