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

Importance of Residual Solvent Analysis

Pharmaceutical manufacturing often involves organic solvents that must be removed to trace levels to ensure patient safety. Regulatory agencies such as ICH, USP and EP mandate screening for a defined list of solvents grouped by toxicity. Reliable analysis of residual solvents supports quality control, compliance and risk management throughout drug development and production.

Objectives and Overview of the Article

This bulletin evaluates capillary gas chromatography (GC) column chemistries and sample-introduction techniques for residual solvent analysis. It compares traditional direct injection with solid-phase microextraction (SPME), assesses three stationary phases equivalent to USP/EP columns, and demonstrates a fast dual-column SPME approach.

Methodology and Instrumentation

Columns evaluated:

• Equity-5 (5% phenyl/95% dimethylpolysiloxane)
• OVI-G43 (6% cyanopropyl/phenyl siloxane)
• SUPELCOWAX 10 (polyethylene glycol)

Instrumentation included a capillary GC with flame ionization detection (GC-FID), constant pressure helium carrier gas, and split injection. Direct injection used a 30 m × 0.53 mm ID, 5 µm Equity-5 column with a 33:1 split. SPME employed coated fibers (100 µm PDMS or 85 µm polyacrylate) for heated headspace extractions. For rapid analysis, two narrow-bore columns (Equity-1 and VOCOL) were installed in a single inlet to achieve sub-10 minute runs.

Main Results and Discussion

Direct injection on the three stationary phases resolved 60 of 61 ICH-listed solvents. Differences in dispersive, dipole, π-π and hydrogen-bond interactions led to varied elution orders, enabling confirmation of coeluting peaks by dual-column analysis. Equity-5 plus SUPELCOWAX 10 separated all critical pairs under identical temperature programs, simplifying method setup.
SPME experiments showed 57 of 60 residual solvents could be quantified at or below 5 µg/mL. Nonpolar and moderately polar solvents exhibited good recoveries on PDMS fibers, while more polar compounds required polyacrylate fibers and salt addition. Heated headspace extraction at 50–60 °C for 5 minutes followed by 3 minute thermal desorption provided symmetric, quantifiable peaks with retention times within 10 % across dual columns.

Benefits and Practical Applications

Both direct injection and SPME fulfill regulatory requirements but offer distinct advantages. Direct injection is straightforward for high-volatility analytes, while SPME is solvent-free, reduces sample handling, and offers comparable sensitivity. The dual-column SPME approach delivers complete separation of complex mixtures in under 10 minutes, boosting sample throughput and reducing instrument occupation.

Future Trends and Possibilities for Application

Emerging developments may include specialized fiber coatings for ultra-polar solvents, automated SPME-GC interfaces, and coupling with mass spectrometry for enhanced specificity. Advances in column technology such as shorter, high-efficiency microbore columns and two-dimensional GC could further accelerate residual solvent screening while maintaining resolution.

Conclusion

Careful selection of GC stationary phases and sample introduction techniques is essential for robust, efficient residual solvent analysis. A two-column strategy with Equity-5 and SUPELCOWAX 10 or fast SPME with dual narrow bore columns can achieve full compliance with ICH, USP and EP guidelines. These approaches streamline workflows, improve laboratory productivity and uphold product safety.

Reference

• ICH Q3C: Impurities—Residual Solvents, FDA, 1997.
• USP <467> Residual Solvents, USP 25/NF 20.
• European Pharmacopoeia 4, Method 2.4.24.
• Rosen-Shaw S. et al., AAPS Poster, 1994.
• Yang X., Peppard T., J. Agric. Food Chem., 1994.
• Zhang Z., Pawliszyn J., Anal. Chem., 1993.