Capillary GC Column Choices for Residual Solvent Analyses Using Direct Injection or Solid Phase Microextraction* (SPME)

Importance of Topic

Residual organic solvents in pharmaceutical products pose potential health risks if present above regulatory limits. Regulatory authorities such as ICH, USP, and EP classify solvents by toxicity and set daily exposure limits. Efficient, sensitive, and reliable analytical methods are essential for ensuring product safety and compliance.

Objectives and Overview

This bulletin evaluates capillary gas chromatography (GC) column options for residual solvent analysis by two approaches: traditional direct injection and solid phase microextraction (SPME). It compares three columns conforming to USP <467> and EP 2.4.24 specifications and explores a fast dual‐column SPME method for rapid screening.

Použitá Instrumentace

• GC columns: Equity-5 (5% phenyl-95% methyl polysiloxane), OVI-G43 (6% polycyanopropyl phenylsiloxane), SUPELCOWAX 10 (polyethylene glycol), Equity-1 (100% dimethylpolysiloxane), VOCOL (intermediate polarity)
• SPME fibers: 100µm polydimethylsiloxane (PDMS), 85µm polyacrylate
• GC system: Split/splitless injector, flame ionization detector (FID)
• Columns inlets and connections: combined dual-column injection port with matched flows

Methodology and Instrumentation

Direct injection: Standards of Class I, II, and III solvent mixtures were prepared and analyzed on each column under identical oven programs. Retention behaviors reflect interactions such as dispersive, dipole–dipole, π–π, and hydrogen bonding.

SPME approach: Aqueous samples (2 mL) with 25% NaCl and pH adjustments were extracted by headspace SPME (5 min at 50–60 °C). Dual columns (10 m × 0.20 mm ID) operated at 40 °C hold then 20 °C/min to 200 °C. Desorption (3 min at 250 °C) released analytes for FID detection.

Main Results and Discussion

Direct injection on Equity-5, OVI-G43, and SUPELCOWAX 10 showed distinct elution orders for 60 solvents. No single column resolved all analytes; however, dual‐column combinations (Equity-5 + SUPELCOWAX 10) achieved baseline separation under uniform conditions. Coelutions on a primary column were resolved on a secondary column.

SPME enabled rapid (< 10 min) extraction of 57 of 60 analytes at 5 µg/mL, with eight polar solvents classified as difficult. Detection limits were comparable to or better than headspace analysis for nonpolar analytes. SPME offers high reproducibility and negligible solvent use.

Benefits and Practical Applications

• Regulatory compliance: Meets ICH, USP, EP guidelines for residual solvent testing
• Speed and throughput: Fast dual‐column GC and SPME reduce cycle times
• Solvent minimization: SPME eliminates organic solvent injections
• Flexibility: Select primary and confirmation columns based on solvent polarity
• Quantitative reliability: Good precision and reproducibility for routine screening

Future Trends and Opportunities

Emerging trends include development of new stationary phases with tailored selectivity, advanced fiber coatings for broader analyte coverage, integration with mass spectrometry for enhanced sensitivity and identification, and automation of SPME workflows in high-throughput laboratories.

Conclusion

Strategic selection of capillary columns and introduction techniques is critical for robust residual solvent analysis. Traditional direct injection on dual columns ensures comprehensive separation, while SPME offers rapid, solvent-free extraction with comparable sensitivity. Laboratories should maintain multiple column chemistries and incorporate SPME to optimize efficiency and compliance.

Reference

1. ICH Q3C Impurities: Residual Solvents, FDA/CDER/CBER (1997).
2. USP 25–NF 20 <467> Residual Solvents (2001).
3. European Pharmacopoeia 4.0, 2.4.24 (2002).
4. Rosen Shaw S. et al., AAPS Poster, American Assoc. Pharm. Sci. (1994).
5. Yang X., Peppard T., J. Agric. Food Chem. 42:1925–1930 (1994).
6. Zhang Z., Pawliszyn J., Anal. Chem. 65:1843–1852 (1993).