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Development and Validation of a Separation and Quantification Method for Residual Solvents in Active Substances by Headspace Gas Chromatography

Kaouthar Louati, Mouna Sayadi and Fathi Safta

The main objective was to develop and validate a method to assaying simultaneously nine residual solvents mentioned in the guidelines of the International Conference on Harmonization (ICH) Q3C: toluene, methanol, ethanol, acetone, propan-2-ol, ethyl acetate, tetrahydrofuran, dichloromethane and acetonitrile. Chromatographic separation was achieved on DB-624 column (30 m × 0.53 mm, 1.8 μm), nitrogen carrier gas and flame ionization detector. We have optimized the carrier gas flow, programming oven temperature and the split ratio. We have opted for the dimethyl sulfoxide as dissolution solvent. The developed method was validated for linearity, precision, accuracy and specificity and then applied for the research and quantification of residual solvents levels in two drug substances. Excellent results were obtained. The developed method proved to be simple, producing symmetric peak shape, good resolution and reasonable retention time for solvents elution before seventeen minutes, specific, precise and linear in the range from the reporting level limit of quantification to 120% of the limit value, with a correlation coefficient greater than 0.999. The use of n-butyl acetate as internal solvent has improved the linearity and precision, compensating for the occurring variability. The quantification of residual solvents levels in two drug substances nefopam and enoxaparin, did not exceed the amount specified by the ICH guidelines. Thus, our method can be applied for the routine quantification of residual solvents levels in different active substances, for pharmaceutical companies and research laboratories