Development and Validation of a Gas Chromatographic Method for Determination of Residual Solvents in Propofol API

Abstract

Objective: To develop and validate a simple, sensitive, and reliable Headspace Gas Chromatography method coupled with Flame Ionization Detection (HS-GC-FID) for the determination of residual solvents in Propofol Active Pharmaceutical Ingredient (API) in accordance with International Council for Harmonisation (ICH) guidelines.

Methods: Chromatographic separation was achieved using a DB-624 column with nitrogen as the carrier gas under optimized temperature programming conditions. N-Methyl-2-pyrrolidone (NMP) was used as the diluent for the preparation of standard and sample solutions. The residual solvents analyzed in the study were isopropyl alcohol (IPA) and cyclohexane. The developed method was validated as per ICH Q2(R2) guidelines for specificity, linearity, precision, accuracy, limit of detection (LOD), limit of quantification (LOQ), and robustness.

Results: The developed method demonstrated good specificity with well-resolved peaks and no interference at the retention times of IPA and cyclohexane. Excellent linearity was observed over the studied concentration range with correlation coefficients (R²) of 0.9904 and 0.9908 for IPA and cyclohexane, respectively. Precision studies showed low %RSD values, indicating good repeatability of the method. Accuracy studies demonstrated acceptable recovery results within the specified limits. The obtained LOD and LOQ values confirmed adequate sensitivity for trace-level analysis of residual solvents. Robustness studies indicated that minor deliberate variations in chromatographic conditions did not significantly affect the analytical performance of the method.

Conclusion: The validated HS-GC-FID method was found to be simple, precise, accurate, robust, and suitable for routine quality control analysis of residual solvents in Propofol API, ensuring compliance with pharmaceutical safety and regulatory requirements.