An advanced GC method for comprehensive residual solvent analysis: overcoming co-elution with orthogonal columns and quantification by mass spectrometry.

A robust and comprehensive gas chromatographic method was developed to identify and quantify the 57 residual solvents listed in the ICH guidelines, all in a single, 30-minute chromatogram. The proposed approach, featuring dual orthogonal column chemistry and a mass spectrometry (MS) detector, significantly improved the resolution and enabled the quantification of low-response and co-eluting solvents such as benzene, chloroform, formamide, pyridine, and 1,2-dichloroethene in a complex matrix of 57 solvents. The VF-624 and HP-5 dual-column was configured in series with an MS detector. Method parameters, such as carrier gas flow rate, oven temperature program, and selection of optimal mass spectrometry acquisition parameters, scan and selected ion monitoring (SIM), were tuned to achieve uncompromised sensitivity, resolution, and reproducibility. The method was validated according to ICH Q2(R1) guidelines and demonstrated acceptable specificity, linearity (R2 > 0.99), accuracy, precision, LOD, and LOQ. The real sample applicability was confirmed through analysis of a spiked fenoterol hydrobromide sample, establishing the method's robustness and suitability for testing the 57 residual solvents in pharmaceutical matrices. Additional evaluation with verapamil hydrochloride, amitriptyline hydrochloride, and their commercial formulations (tablets) further validated its broad applicability.