Qualitative Analysis Using HS-GC-FID/MS when Testing for Residual Solvents in Pharmaceuticals — JP18, USP467: Water-Soluble Samples —

Importance of the Topic

The monitoring of residual solvents in pharmaceutical products is crucial for ensuring patient safety, regulatory compliance, and product quality. Headspace gas chromatography coupled with flame ionization detection (HS-GC-FID) and mass spectrometry (HS-GC-MS) provides sensitive and specific analysis for volatile organic impurities in water-soluble pharmaceutical matrices.

Objectives and Study Overview

This application note evaluates the performance of Shimadzu’s HS-20 NX headspace sampler combined with GC-2030 (GC-FID) and GCMS-QP2020 NX (GC-MS) for qualitative and quantitative analysis of Class 1 and Class 2 residual solvents according to Japanese Pharmacopoeia (JP18) and USP <467> guidelines. The study aims to demonstrate separation performance, system suitability, and the added value of mass spectral confirmation in complex samples.

Methodology and Instrumentation

Procedure A was applied to prepare Class 1, Class 2A, and Class 2B standard solutions and pharmaceutical test samples. Analyses were performed under constant linear velocity using a 30 m SH-I-624 Sil MS column (0.32 mm I.D., 1.8 µm). Key parameters included:

• Oven temperature program: 40 °C (20 min) → 240 °C at 10 °C/min → 240 °C (20 min)
• Carrier gas: helium at 40 cm/s
• Headspace conditions: 80 °C equilibration, 45 min; 75 kPa vial pressure; 1 mL injection
• FID settings: 250 °C detector, H₂ 32 mL/min, air 200 mL/min
• MS settings: SCAN m/z 30–250; interface 250 °C; ion source 200 °C

Used Instrumentation

• Shimadzu HS-20 NX headspace sampler
• GC-2030 gas chromatograph with FID detector
• GCMS-QP2020 NX gas chromatograph–mass spectrometer
• LabSolutions integrated GCMS software with DB/CS data integrity modules

Key Results and Discussion

• System suitability tests for Class 1 standards achieved signal-to-noise (S/N) ratios and RSD values well within JP18/USP <467> criteria (e.g., S/N > 5 for 1,1,1-trichloroethane).
• High resolution enabled clear separation of recently classified Class 2 solvents tert-butyl alcohol and cyclopentyl methyl ether from coeluting peaks.
• FID chromatograms allowed quantitation, while MS spectra provided reliable identification of unknown or coeluting peaks.
• In a test sample, a peak initially assigned to cumene by FID was correctly identified as α-pinene by GC-MS, illustrating the importance of mass spectral confirmation.

Benefits and Practical Applications

• Combining HS-GC-FID with HS-GC-MS enables both accurate quantitation and definitive identification of residual solvents.
• Use of a single column across detectors simplifies method transfer and retention time matching.
• Mass spectral data help prevent misidentification, improving quality assurance in pharmaceutical laboratories.
• LabSolutions DB/CS ensures data integrity and compliance with regulatory requirements.

Future Trends and Potential Applications

The integration of high-throughput headspace sampling with advanced MS detectors is expected to expand into monitoring trace-level impurities in biopharmaceuticals, continuous manufacturing processes, and real-time quality control. Enhanced data analytics and AI-driven spectral library matching will further streamline solvent identification and regulatory reporting.

Conclusion

This study confirms that Shimadzu’s HS-GC systems equipped with FID and MS detectors meet the stringent requirements of JP18 and USP <467> for residual solvent analysis. The combined approach ensures robust quantitation, reliable peak identification, and comprehensive data integrity, supporting safe and compliant pharmaceutical production.