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

Importance of the Topic

Residual organic solvents may remain in pharmaceutical products after synthesis and purification. Controlling these impurities is essential for patient safety and regulatory compliance. Gas chromatography (GC) is the gold standard for residual solvent analysis, and the choice of capillary column and sample introduction method directly affects sensitivity, selectivity and overall throughput.

Objectives and Overview of the Study

This work evaluates two approaches to residual solvent analysis: traditional direct injection methods following USP and EP guidelines on three capillary columns, and a rapid, solvent-free solid phase microextraction (SPME) method using dual narrow-bore columns. The goals are to compare column chemistries, demonstrate separation of 60 ICH-listed solvents in Classes I, II and III, and assess SPME performance in terms of analysis time, sensitivity and ease of operation.

Methodology and Instrumentation

Direct injection experiments were performed on three capillary columns equivalent to USP/EP specifications (Equity®-5, OVI-G43, SUPELCOWAX® 10). Solvent standards were prepared in DMSO, divided into three class-based mixtures, and analyzed with identical temperature programs. SPME experiments employed 10 m × 0.20 mm ID × 1.2 µm Equity®-1 (nonpolar) and VOCOL® (intermediate polarity) columns installed in a single port. Extraction conditions were optimized by class using 100 µm PDMS or 85 µm polyacrylate fibers, heated headspace sampling with salt and pH adjustment.

Instrumental Setup

• GC Oven: 35 °C (15 min) to 200 °C at 5 °C/min for direct injection; 40 °C (0.75 min) to 200 °C at 20 °C/min for SPME.
• Injection: Direct injection 1 µL, split 33:1, injector 225 °C; SPME split 5:1 at 40 °C.
• Detector: Flame ionization (FID) at 250 °C.
• Carrier Gas: Helium at 30 cm/s constant velocity (direct) or 35 cm/s at 40 °C (SPME).
• Columns (direct): Equity-5 (30 m × 0.53 mm, 5 µm), OVI-G43 (30 m × 0.53 mm, 3 µm), SUPELCOWAX 10 (30 m × 0.53 mm, 1 µm).
• Columns (SPME): Equity-1 and VOCOL both 10 m × 0.20 mm, 1.2 µm.

Main Results and Discussion

Direct injection required ~45 min per run. No single column separated all 60 solvents; combining Equity®-5 and SUPELCOWAX® 10 resolved all Class I–III analytes, and secondary columns (e.g., OVI-G43) provided confirmation of coelutions. SPME reduced analysis time to under 10 min, achieving baseline separation of key solvent classes on dual columns in a single injection port. Out of 60 target analytes, 57 were readily detected by SPME at or below 5 µg/mL; eight polar solvents were classified as difficult but remained quantifiable at higher concentrations.

Benefits and Practical Applications

• Direct injection follows pharmacopeial methods and ensures regulatory compliance for routine QC.
• Dual-column SPME offers high throughput, solvent-free sampling, and reduced fiber fouling.
• SPME analysis is fast (<10 min), cost-effective and minimizes sample preparation.
• Choice of fiber coating (PDMS vs. polyacrylate) allows targeting of nonpolar or polar analytes.

Future Trends and Potential Applications

Emerging developments in ultra-fast GC, advanced stationary phases and automated SPME materials will further shorten run times and improve sensitivity. Coupling SPME with two-dimensional GC or mass spectrometry promises enhanced resolution for complex mixtures. Ongoing fiber chemistry innovations may extend SPME applicability to challenging polar compounds, enabling broader adoption in pharmaceutical QA/QC and environmental monitoring.

Conclusion

Comparative evaluation demonstrates that combining two capillary columns tailored to complementary chemistries resolves all ICH residual solvents by direct injection, while SPME on dual narrow-bore columns delivers sub-10-minute analysis with comparable sensitivity for most analytes. Implementing both approaches in parallel offers laboratories the flexibility to balance regulatory requirements, throughput and operational efficiency.

References

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2. USP 25–NF20 <467> Residual Solvents, United States Pharmacopeia.
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