Analysis of Residual solvents USP 467 Class 2 MixA in pharmaceuticals

Importance of the Topic

The analysis of residual solvents in pharmaceuticals is critical for ensuring product safety and regulatory compliance. Class 2 solvents, with potential toxicity concerns, must be monitored at strict limits defined in USP 467. A reliable, sensitive, and reproducible method supports quality control laboratories in delivering safe drug products.

Objectives and Study Overview

This application note presents a headspace gas chromatography–flame ionization detection (HS-GC / FID) procedure for quantifying 15 Class 2 residual solvents (Mix A) in water-soluble drug formulations. The goal is to demonstrate chromatographic separation, detection limits, and method robustness under a specified temperature program and instrument setup.

Methodology and Instrumentation

An HS-GC / FID system (Shimadzu Nexis GC-2030 with FID-2030 and HS-20 autosampler) is employed. Sample vials (20 mL) are heated at 110 °C for 60 min and pressurized at 75 kPa for 1 min to transfer headspace gas. Separation is achieved on a 30 m × 0.32 mm I.D. SH-I-624Sil MS capillary column (1.80 μm film). The oven program holds 40 °C for 20 min, ramps at 10 °C/min to 240 °C, and holds for 20 min. Helium carrier gas flows at 35 cm/s; split ratio is 1:5; injection temperature is 140 °C. FID conditions: 250 °C detector temperature, He makeup (30 mL/min), air (400 mL/min).

Main Results and Discussion

The method achieved baseline separation of all 15 solvents, including low-boiling compounds (methanol, acetonitrile) and higher-boiling aromatics (toluene, chlorobenzene, xylenes, cumene). Retention time reproducibility was within 0.5 % RSD. Limits of detection and quantification met USP 467 criteria, demonstrating adequate sensitivity for regulatory thresholds. The temperature program balanced resolution and analysis time (~50 min total runtime).

Benefits and Practical Applications

• High resolution across a wide volatility range supports simultaneous analysis of polar and nonpolar solvents.
• Automated headspace sampling reduces manual handling and improves reproducibility.
• Method aligns with USP 467 regulatory requirements, facilitating straightforward implementation in QC labs.
• Robust temperature program and split conditions yield consistent quantitation for routine release testing.

Future Trends and Opportunities

Advancements may include coupling headspace GC with mass spectrometry for enhanced specificity, miniaturized or micro-GC systems for reduced analysis time, and green chemistry approaches to lower solvent consumption. Automated data processing and cloud-based reporting will streamline compliance. Expanding solvent panels to Class 1 and Class 3 lists can offer comprehensive residual solvent screening in a single run.

Conclusion

The described HS-GC / FID method on Shimadzu Nexis GC-2030 with SH-I-624Sil MS column provides a robust, validated approach for Class 2 Mix A residual solvent analysis in pharmaceuticals. It meets USP 467 requirements, offers reliable performance, and is readily adoptable in regulated laboratories.

Used Instrumentation

• Shimadzu Nexis GC-2030 gas chromatograph
• FID-2030 flame ionization detector
• HS-20 headspace autosampler
• SH-I-624Sil MS capillary column (30 m × 0.32 mm I.D., 1.80 μm film)