Analytical Method by Headspace-Gas Chromatography for Determination of Six Residual Solvents in Losartan Potassium Raw Material.

Residual solvents, or organic volatile impurities, are a potential toxic risk for pharmaceutical products and have been a manufacturers' concern for many years. Moreover, residual solvents can also affect the quality and stability of not only drug substances but also of drug products. The objective of this work is the development and validation of headspace gas chromatographic method for determination of six residual solvents (methanol, ethyl acetate, isopropyl alcohol, triethylamine, chloroform, and toluene) in losartan potassium raw material. Method development evaluated the critical parameters of sample diluent selection (dimethylsulfoxide and water), optimization of headspace conditions (incubation time and temperature), and chromatographic conditions (column temperature ramp speeds and sample split ratio). Validation was carried out in accordance to Brazilian guidelines. Dimethylsulfoxide was selected as the sample diluent, with an incubation time of 30 min at 100°C. The chromatographic determination was performed on a DB-624 capillary column using programmed temperature, running time of 28 min and a split ratio of 1:5. The method proved to be selective, with suitable sensitivity (limits of quantification below 10% of the specification limits determined by the ICH), precise (relative standard deviations ≤ 10.0%), linear (r ≥ 0.999 for all solvents' standard curves), accurate (average recoveries from 95.98% to 109.40%), and robust under the small modifications in the chromatographic conditions. A simple and reliable method was obtained. The analysis of a losartan potassium raw material batch has detected only isopropyl alcohol and triethylamine as residual solvents, indicating that purification processes applied to this active pharmaceutical ingredient production were capable to remove most solvents from synthesis step.