Analysis of Residual Solvents in Pharmaceuticals - Report No. 336

Significance of Residual Solvent Analysis in Pharmaceuticals

Accurate detection of residual solvents in pharmaceutical products is crucial for ensuring patient safety, compliance with regulatory standards (USP 467, JP17 Supplement II), and maintaining product efficacy. Headspace gas chromatography with flame ionization detection (HS-GC-FID) provides a robust and sensitive approach to quantify volatile impurities at trace levels.

Objectives and Study Overview

The primary aim of this application study was to demonstrate reliable quantification of 16 common residual solvents in pharmaceutical matrices using a Shimadzu Nexis GC-2030 system equipped with HS-20 headspace sampler and FID-2030 detector. Key goals included method sensitivity, chromatographic resolution, and compliance with official pharmacopeial requirements.

Methodology and Used Instrumentation

• Main Instrument: Shimadzu Nexis GC-2030 gas chromatograph
• Detector: FID-2030 flame ionization detector
• Headspace Sampler: HS-20
• Column: SH-I-624Sil MS, 30 m × 0.32 mm I.D., 1.8 µm film thickness

Gas chromatographic conditions:

• Column temperature program: 40 °C hold 20 min; ramp 10 °C/min to 240 °C; hold 20 min (total run time 60 min)
• Carrier gas: Helium at linear velocity of 35 cm/s
• Injection mode: Split 1:5, injection volume 1 mL
• FID conditions: 250 °C, H₂ flow 32 mL/min, air flow 200 mL/min, makeup He 24 mL/min

Headspace conditions:

• Oven temperature: 80 °C
• Sample line: 110 °C; transfer line: 120 °C
• Vial volume: 20 mL; heat retention time: 60 min
• Vial pressurization: 75 kPa for 1 min; loading time: 0.5 min
• Needle wash time: 5 min

Main Results and Discussion

The method achieved baseline separation of all 16 target solvents, including methanol, acetonitrile, dichloromethane, and xylene isomers, within a 60-minute run. Response linearity was confirmed across relevant concentration ranges with correlation coefficients >0.999. Limits of detection and quantification met or exceeded pharmacopeial requirements, demonstrating method suitability for routine quality control.

Chromatograms showed well‐defined peaks with minimal carryover, attributable to optimized split ratio and effective needle washing. The SH-I-624Sil MS column provided sharp, symmetrical peak shapes, enabling unambiguous identification of coeluting isomers (cis/trans 1,2-dichloroethylene and m,p-xylene vs. o-xylene).

Benefits and Practical Applications

• Regulatory Compliance: Conforms to USP 467 and JP17 guidelines for residual solvent limits.
• High Throughput: Automated headspace sampling reduces sample preparation time and enhances laboratory productivity.
• Robustness: Stable retention times and reproducible quantitation support long sequences without frequent recalibration.
• Versatility: Applicable to various pharmaceutical formulations (tablets, capsules, injectables).

Future Trends and Potential Applications

Advancements in column technology and detector sensitivity are expected to further lower detection limits and shorten analysis times. Integration of mass-spectrometric detection (HS-GC-MS) can enhance the identification of unknown volatiles. Automated data processing and cloud-based reporting tools will streamline compliance documentation and real-time monitoring in GMP environments.

Conclusion

The described HS-GC-FID method on the Nexis GC-2030 system offers a reliable, sensitive, and pharmacopeia-compliant solution for the quantification of residual solvents in pharmaceuticals. Its robustness and high throughput make it well suited for routine quality control laboratories.

Reference

Application News G324: Analysis of Residual Solvents in Pharmaceuticals, Shimadzu Corporation, First Edition Sep. 2022, ERAS-1000-0336