The Analysis of Residual Solvents By Headspace Sampling and GC According to USP <467>

Význam tématu

Residual solvents can affect drug purity, safety and performance. USP <467> sets stringent guidelines for detecting organic volatiles in pharmaceuticals. Monitoring these solvents is essential for regulatory compliance and ensuring product quality in pharmaceutical manufacturing.

Cíle a přehled studie / článku

This application note presents a validated method for quantifying 26 residual solvents in drug products. The study aims to demonstrate compliance with USP <467> by using headspace sampling coupled with gas chromatography (GC) and flame ionization detection (FID). Calibration, linearity and repeatability are evaluated across safety classes.

Použitá metodika a instrumentace

Sample preparation involves spiking deionized water with a standard solution to obtain 100–500 ppm. Serial dilutions generate calibration standards. The analytical setup includes:

• Bruker SHS-40 automated headspace sampler with oven at 80°C and loop, valve, transfer line at 180°C
• Bruker 450-GC equipped with a 60 m × 0.32 mm BR-624ms capillary column (1.80 μm film) and FID at 270°C
• Carrier gas helium at 1 mL/min constant flow; injector at 200°C in split mode (1:10)
• Oven program: 40°C initial hold 20 min, ramp 10°C/min to 250°C

The system is controlled with Compass CDS software featuring audit trails and data integrity functions.

Hlavní výsledky a diskuse

Calibration curves for all 26 solvents yielded correlation coefficients above 0.97, with most exceeding 0.99, indicating excellent linearity across 100–500 ppm. Representative solvents from each safety class (pentane, benzene, dichloromethane, n-butanol) demonstrated R2 values of 0.9986, 0.9973, 0.9994 and 0.9997 respectively. Repeatability tests at 100 ppm showed relative standard deviations below 5% for all analytes. The method effectively covers a wide polarity range, from non-polar hydrocarbons to polar oxygenated compounds.

Přínosy a praktické využití metody

• Regulatory compliance: Aligns with USP <467> requirements for pharmaceutical QC
• Wide applicability: Detects diverse solvent classes in drug formulations
• Robust performance: High linearity and repeatability support routine analysis
• Data integrity: Secure software audit trails ensure reliable record-keeping
• Operational efficiency: Automated headspace sampling reduces manual handling

Budoucí trendy a možnosti využití

Potential enhancements include:

• Use of salt additives, such as sodium sulfate, to improve analyte transfer to the headspace
• Integration with mass spectrometric detectors for increased sensitivity and specificity
• Automated data processing and cloud-based trend monitoring for proactive quality control
• Application to a broader range of dosage forms and solvent classes beyond current pharmacopeial lists

Závěr

The combination of Bruker SHS-40 headspace sampling and 450-GC-FID provides a reliable, high-throughput solution for residual solvent analysis according to USP <467>. The method delivers excellent linearity, repeatability and compliance, making it suitable for routine QC in pharmaceutical laboratories.

Reference

• United States Pharmacopeia USP 32–NF 27. Organic Volatile Impurities / Residual Solvents <467>.