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

Importance of the Topic

In pharmaceutical manufacturing residual organic solvents can remain in final products with potential safety risks. Regulatory bodies classify these solvents based on toxicity and set exposure limits. Efficient, accurate analysis of residual solvents is vital for product quality, patient safety and compliance with ICH, USP and EP guidelines.

Objectives and Study Overview

This work compares capillary gas chromatography columns and sampling techniques for residual solvent analysis. It evaluates traditional direct injection and the faster solvent free solid phase microextraction approach. Three columns equivalent to USP and EP methods are assessed for class I, II and III solvents and a dual column SPME method is developed for rapid screening.

Methodology and Instrumentation

• Solvents classified by ICH in three toxicity classes, analyzed in mixtures by class
• Direct injection: three standard mixtures for class I, II and III at defined concentrations
• SPME sampling: fibers coated with PDMS or polyacrylate in heated headspace extractions
• Dual column GC: nonpolar Equity-1 and intermediate polarity VOCOL columns operated in parallel

Used Instrumentation

• Capillary gas chromatograph with flame ionization detector
• Columns: Equity-5, SUPELCOWAX 10, OVI-G43 for direct injection; Equity-1 and VOCOL for SPME dual analysis
• Injection: split mode, constant pressure carrier gas helium
• SPME fibers: 100µm PDMS for nonpolar and 85µm polyacrylate for polar solvents

Main Results and Discussion

Direct injection separations revealed that no single column resolves all 60 analytes. Complementary selectivity of Equity-5, OVI-G43 and SUPELCOWAX 10 ensures full coverage. Dual column runs under identical conditions allow simultaneous analysis in a single oven. SPME combined with short narrow bore columns reduced analysis time from 45 minutes to under 10 minutes. Extraction parameters were optimized by solvent class and pH. Most analytes at 5ppm or lower were quantifiable by SPME. Precision studies showed relative standard deviations below 7 and detection limits comparable to or better than headspace methods.

Benefits and Practical Applications

• Reduced analysis time and solvent consumption
• Simplified sample preparation with minimal hazard
• Enhanced throughput for routine QA/QC
• Flexibility to select primary and confirmation columns
• Ability to analyze a wide range of polar and nonpolar solvents

Future Trends and Potential Applications

Further adoption of SPME with automated sampling and coupling to mass spectrometry can improve sensitivity and specificity. Development of novel fiber coatings and high throughput GC platforms promises even faster analyses. Integration of dual or multidimensional columns into regulatory methods may streamline confirmation workflows and support richer impurity profiling.

Conclusion

The study demonstrates that a strategic combination of capillary columns and sampling techniques fulfills stringent residual solvent analysis requirements. Direct injection and SPME both have merits, with SPME offering rapid, solvent free screening. Employing multiple column chemistries ensures comprehensive separation and robust confirmation.

References

1. International Conference on Harmonization Q3C Impurities Residual Solvents
2. United States Pharmacopeia General Chapter 467
3. European Pharmacopoeia Section 2.4.24
4. Scypinski and Smith Poster Presentation AAPS Conference 1994
5. Yang and Peppard Journal of Agricultural and Food Chemistry 1994
6. Zhang and Pawliszyn Analytical Chemistry 1993