Alternative sample preparation and analysis approach for ICH/USP controlled metals by ICP-MS

Significance of the Topic

In pharmaceutical development, tracking both organic and inorganic impurities is crucial for ensuring drug safety, stability and compliance with regulatory standards. Elemental contaminants, originating from catalysts or production equipment, pose risks to patient health and product quality. As regulatory bodies such as ICH and USP require rigorous monitoring of elemental impurities, robust and efficient analytical methods are in demand.

Objectives and Study Overview

This study evaluates an alternative sample preparation strategy using organic solvent (DMSO) coupled with Agilent 7800 ICP-MS for quantifying ICH/USP controlled metals in active pharmaceutical ingredients (APIs). The goal was to replace time-consuming microwave acid digestion with a simpler, high-throughput approach while maintaining accuracy, precision and sensitivity.

Methodology and Instrumentation

Sample preparation involved weighing 100 mg of API into 50 mL falcon tubes, dissolving in DMSO, sonicating for 15 minutes and diluting to volume with DMSO. Calibration standards were prepared from NIST-traceable solutions in DMSO, and internal standards were introduced online via a peristaltic pump.

• Instrument: Agilent 7800 ICP-MS
• Sample introduction: Micromist nebulizer with Peltier-cooled quartz spray chamber
• Optics: Platinum cones, 1.5 mm injector torch, ORS4 collision/reaction cell
• Autosampler: Agilent SPS 4 with online internal standard addition
• Software: ICP-MS MassHunter 4.3 with USP chapter presets

Main Results and Discussion

Accuracy studies at 100% J value showed recoveries between 70–150% with relative standard deviations well within acceptance criteria. Intermediate precision experiments, conducted on different days and instruments, yielded RSD values below 25%. System suitability tests demonstrated drift under 20% for target elements. Calibration curves for As, Cd, Hg and Pb exhibited high linearity (R values near unity) and detection limits in the low µg/L range despite the organic matrix.

Benefits and Practical Applications of the Method

The DMSO-based preparation method eliminates the need for closed-vessel microwave acid digestion, reducing sample handling time and reagent consumption. Its compatibility with Agilent 7800 ICP-MS ensures high throughput and reliable quantification of elemental impurities in APIs and excipients, supporting QC laboratories in achieving USP chapters <232>/<233> compliance.

Future Trends and Opportunities

Advancements in ICP-MS cell technologies and solvent-resistant sampling systems may further enhance sensitivity and robustness for complex organic matrices. Integration of automated sample preparation platforms and expansion to additional elements could broaden applicability across pharmaceutical workflow stages, from raw material screening to final product release.

Conclusion

The optimized organic solvent approach combined with Agilent 7800 ICP-MS offers a streamlined, compliant and high-throughput solution for elemental impurity analysis in pharmaceutical ingredients. It delivers accurate, precise and sensitive results while simplifying laboratory workflows.

References

1. USP Chapter <232> Elemental Impurities – Limits, Pharmacopeial Forum, 2011, 42(2).
2. USP Chapter <233> Elemental Impurities – Procedures, USP 38–NF 33, Second Supplement.