Residual Solvent Analysis Implementing USP <467>

Importance of the Topic

Residual solvents are trace organic chemicals remaining after pharmaceutical manufacturing. Their control is essential to meet safety, regulatory and quality requirements. The revised USP <467> harmonizes with ICH guidelines, expands the scope of solvents tested, and standardizes procedures for reliable detection and quantification.

Objectives and Overview of the Study

This guide demonstrates how to implement the revised USP <467> method using static headspace–GC with FID detection. Key objectives include:

• Presenting Procedures A, B and C for identification, confirmation and quantification of residual solvents
• Comparing performance of two headspace autosampler designs (pressurized loop vs. heated syringe)
• Optimizing system suitability criteria and method parameters to improve pass rates

Methodology

The revised USP <467> employs static headspace extraction paired with capillary GC–FID. Samples are classified as water-soluble or water-insoluble, using appropriate diluents (water or DMSO/DMF/DMI). Three sequential procedures are defined:

• Procedure A (Identification): Assesses presence of Class 1 and Class 2 solvents on a 6% cyanopropylphenyl/94% dimethyl polysiloxane column under specified headspace and GC conditions. System suitability requires signal-to-noise ratios ≥3 and defined resolution thresholds.
• Procedure B (Confirmation): Verifies analyte identity with an alternate column chemistry (polar polyethylene glycol phase) under analogous conditions. Confirmation triggers when sample peaks exceed reference responses.
• Procedure C (Quantification): Uses compound-specific reference materials at 1/20 concentration limits to calculate solvent levels once identity is confirmed.

Instrumentation

The guide illustrates two headspace autosamplers:

• Pressurized-loop injection: Tekmar HT3 autosampler, loop split mode (5:1), headspace vial equilibration at 80 °C for 60 min, vial pressure 10 psi.
• Heated-syringe injection: Overbrook Scientific HT200H, syringe at 100 °C, equilibration 45 min, 1 mL injection volume.

GC platforms include Agilent/HP 6890 and equivalent systems equipped with FID (250 °C). Carrier gas helium at constant flow, columns tested: Rxi®-624Sil MS (G43) and Stabilwax® (G16) capillaries.

Main Results and Discussion

Both autosampler configurations met USP <467> system suitability requirements. Key findings:

• Signal-to-noise ratios ≥6 for critical Class 1 solvents (e.g., carbon tetrachloride) using optimized data rates (5–10 Hz).
• Resolution improvements by employing 1 mm split liners to reduce band broadening.
• Polar confirmation column delivered alternate selectivity and met system suitability (R > 1) for Class 2 Mixture A.
• DMSO use in water-insoluble samples required bake-out steps to prevent carryover; alternatives DMF/DMI recommended if interference persists.

Benefits and Practical Applications

The optimized workflows deliver higher system suitability pass rates, robust identification across 50+ solvents, and reproducible quantification. Laboratories gain:

• Standardized procedures aligned with USP and ICH requirements
• Technical tips to enhance sensitivity and resolution
• Flexibility in autosampler selection and diluent choice for diverse sample types

Future Trends and Applications

Emerging directions include:

• Integration of headspace–GC–MS for enhanced specificity and lower detection limits
• Automation and miniaturization of headspace samplers to increase throughput
• Use of inert liner materials and advanced coatings to minimize active site interactions
• Green solvent approaches and micro-extraction techniques to reduce sample and reagent volumes

Conclusion

The revised USP <467> method, when properly implemented, enables comprehensive screening and quantification of residual solvents in pharmaceutical matrices. Adherence to system suitability criteria, appropriate column selection, and optimized headspace parameters ensure compliance, accuracy and reliability.

References

1. United States Pharmacopeia General Chapter <467> Residual Solvents, USP 30/NF 25.
2. International Conference on Harmonization (ICH) Q3C Guideline on residual solvents.