Analysis for Residual Solvents in Pharmaceuticals -JP18, USP467 : Class 2B Standard Solution

Importance of the Topic

Residual solvent analysis ensures pharmaceutical safety by detecting and quantifying trace organic solvents that may pose toxicity risks. Compliance with ICH Q3C guidelines, such as JP18 and USP467 Class 2B limits, is critical for quality assurance in drug production and regulatory approval.

Study Objectives and Overview

This study evaluates a combined headspace GC‐FID and GC‐MS approach for the reliable detection of eight Class 2B residual solvents in pharmaceutical formulations. The aim is to demonstrate method robustness, sensitivity, and suitability for routine quality control according to pharmacopeial standards.

Methodology and Instrumentation

The analysis employs a Shimadzu GCMS‐QP2010 NX coupled with an HS‐20 NX headspace sampler and an FID‐2030 detector. Separation uses an SH‐I‐624Sil MS column (30 m × 0.32 mm I.D., 1.8 µm). GC oven programming starts at 40 °C (20 min), ramps to 240 °C at 10 °C/min, with a total run time of 60 min. Split injection (1:5) and helium carrier gas at 40 cm/s linear velocity ensure efficient analyte transfer. Headspace conditions include 80 °C oven temperature, 45 min equilibration, 110 °C sample line, and 75 kPa vial pressure. FID operates at 250 °C with H2, He, and air flows of 32, 24, and 200 mL/min, respectively. MS detection uses electron ionization, a source at 200 °C, interface at 250 °C, and scan range m/z 30–250 with 0.3 s event time.

Main Results and Discussion

The method achieved baseline separation of eight solvents: hexane, nitromethane, chloroform, 1,2-dimethoxyethane, 1,1,2-trichloroethylene, pyridine, methylbutylketone, and tetraline. Retention times ranged from approximately 5 to 32 minutes. FID provided quantitative data with high sensitivity, while MS offered confirmatory identification through mass spectral profiles. Method linearity, repeatability, and detection limits met pharmacopeial requirements.

Benefits and Practical Applications

• Combination of FID and MS ensures both accurate quantitation and definitive compound confirmation.
• Headspace sampling minimizes matrix interferences and simplifies sample preparation.
• Robust method suitable for routine QC laboratories in pharmaceutical manufacturing.
• Full compliance with ICH Q3C, JP18, and USP467 guidelines.

Future Trends and Applications

Advancements in fast GC, low‐thermal‐mass columns, and high‐speed MS detectors will further reduce analysis time and improve throughput. Integration of automation and software for real-time data processing is likely to enhance laboratory efficiency. Emerging green solvents and miniaturized headspace systems may reduce energy consumption and solvent waste.

Conclusion

The combined headspace GC‐FID/GC‐MS method on the SH‐I‐624Sil MS column delivers reliable, sensitive, and compliant residual solvent analysis for pharmaceutical quality control. Its versatility and robustness make it an effective tool for ensuring product safety and regulatory adherence.

References

• Shimadzu Application News 01-00221 (JP, ENG), First Edition: Sep. 2022.