Development and Validation of a Headspace Gas Chromatography-Flame Ionization Detection Method for the Simultaneous Determination of 12 Residual Solvents in Avibactam Sodium Active Pharmaceutical Ingredient

In the industrial production process of avibactam sodium, the quantitative determination of residual solvents from the manufacturing process is critical for ensuring product quality and safety. This study aimed to develop and validate a headspace gas chromatography with flame ionization detector (HS-GC-FID) method for the simultaneous determination of 12 residual solvents in avibactam sodium active pharmaceutical ingredient (API). The targeted solvents include methanol (MET), ethanol (ET), acetone (ACE), isopropanol (IPA), acetonitrile (ACN), dichloromethane (DCM), tert-butanol (tBA), methyl tert-butyl ether (MTBE), ethyl acetate (EA), tetrahydrofuran (THF), toluene (Tol), and butyl acetate (BuOAc). Following method optimization, all 12 solvents were well-separated, with a resolution greater than 1.5 between closely eluting peaks. The method demonstrated excellent linearity, with mass concentrations of the solvents showing a strong correlation with chromatographic peak areas (coefficient of determination, R² ≥ 0.99). Accuracy was confirmed by the recovery study, yielding average recovery rates below 10.0%, while precision was found to be within acceptable limits. The validated method proved to be accurate, specific, and highly sensitive, making it suitable for the rapid determination of residual solvents in avibactam sodium API. This approach ensures compliance with regulatory requirements and supports quality control in pharmaceutical manufacturing.