Implementation of USP <467> “Residual Solvents” using a GERSTEL MPS 2 Syringe Based Headspace Autosampler

Importance of the Topic

The control of residual solvents in pharmaceutical products is essential to ensure patient safety and regulatory compliance. USP <467> defines standardized headspace GC protocols for detecting trace solvent residues in drug substances, excipients and finished dosage forms.

Objectives and Study Overview

This work demonstrates the implementation of USP <467> static headspace GC using a GERSTEL MPS 2 syringe‐based autosampler. A commercially available children’s acetaminophen suspension was spiked with acetonitrile at 2 000 µg/g (five times the USP limit) to challenge system performance and validate method robustness.

Methodology

Samples (10 mL vials) were incubated at 80 °C for 60 min. One milliliter of headspace was injected at 90 °C into a PTV inlet (split 2.5:1). Two capillary columns (30 m × 0.32 mm ZB-624, df 1.8 µm; and 30 m × 0.32 mm ZB-WAXplus, df 0.25 µm) were employed under helium flow (2.2 mL/min) with temperature programs optimized for each phase.

Instrumentation Used

• Agilent 6890 gas chromatograph with flame ionization detector
• Gerstel CIS 4 programmable temperature vaporizer inlet
• GERSTEL MPS 2 robotic headspace autosampler with 2.5 mL heated syringe
• Zebron™ ZB-624 and ZB-WAXplus capillary columns
• Helium carrier gas at constant flow

Main Results and Discussion

System suitability criteria from USP <467> were met across Procedures A, B and C:

Procedure A (ZB-624 column):

1. Class 1 peaks exhibited S/N ≥ 3 for system suitability and ≥ 5 for 1,1,1-trichloroethane (observed S/N = 14).
2. Resolution between acetonitrile and methylene chloride in Class 2 A was ≥ 1.0 (observed 1.7).
3. Precision (n=3) yielded %RSD 0.65–15.7% (average 4.7%).

Procedure B (ZB-WAXplus column):

• S/N for benzene ≥ 5 (observed 90), and resolution between acetonitrile and cis-1,2-dichloroethene ≥ 1.0 (observed 2.7).

Procedure C (quantitation on ZB-624):

• Calibration for acetonitrile (0–500 ppm) was linear (r² = 0.9998).
• Test solution at ~1770 ppm gave RSD = 2.0% (n=3).

Benefits and Practical Applications of the Method

The GERSTEL MPS 2 in PrepAhead mode maximizes throughput by overlapping incubation and analysis steps. The syringe‐based headspace approach aligns with current USP guidance and offers flexibility for evolving laboratory needs. High reproducibility and ease of configuration make it ideal for routine QA/QC and compliance testing in pharmaceutical development and manufacturing.

Future Trends and Possibilities

Emerging techniques such as dynamic headspace, large‐volume injection and solid‐phase microextraction may further extend sensitivity and selectivity. Enhanced software integration for real‐time data evaluation and automated sample preparation will streamline workflows. Continued updates in pharmacopeial standards will drive method innovation and instrument versatility.

Conclusion

The GERSTEL MPS 2 autosampler successfully implements USP <467> static headspace GC, delivering robust system suitability, precision and linearity for residual solvent analysis. This configuration represents a reliable, high‐throughput solution for pharmaceutical compliance testing.

References

1. United States Pharmacopeia Convention. USP <467> Residual Solvents. The United States Pharmacopeial Convention; 2007.
2. United States Pharmacopeial Convention. USP 32 NF27 General Chapter <467> Residual Solvents Table 5. The United States Pharmacopeial Convention; 2008.