WCPS: Analysis of Metal Impurities in Pharmaceutical Ingredients in Preparation for the New USP Methods

Significance of the Topic

Analysis of trace metal impurities in pharmaceutical raw materials is vital to ensure patient safety and regulatory compliance. Traditional USP<231> relies on sulfide precipitation and visual color comparison, which is outdated, subjective, and restricted in many regions. Modern ICP-MS offers enhanced sensitivity, specificity, and capacity to meet stringent USP<232>/<233> limits for toxic metals.

Study Objectives and Overview

The study aimed to evaluate the performance of Agilent 7700 and 7500 ICP-MS instruments under proposed USP<232>/<233> protocols. Key goals included demonstrating accurate quantification of 16 inorganic impurities in excipients (gelatin capsules) and APIs (amoxicillin) and validating method precision, accuracy, and robustness.

Methodology and Instrumentation

• Sample preparation: acid digestion in 1% HNO3 and 0.5% HCl, dilution via High Matrix Interface (HMI) to handle high total dissolved solids.
• Instrumentation: Agilent 7700x ICP-MS with third-generation octopole reaction system (ORS3) and kinetic energy discrimination (KED) using helium; complemented by the Agilent 7500 ICP-MS.
• Operating modes: no-gas mode for elements without significant polyatomic interferences; helium KED mode to remove interferences by energy discrimination.
• Calibration: multi-element standards prepared in dilute acid; calibration curves established for 16 target analytes.

Main Results and Discussion

• Detection limits and accuracy: All 16 elements (including Pb, As, Cd, Hg, Cr, Cu, Mn, Mo, Ni, Pd, Pt, V, Os, Ir, Rh, Ru) were quantified with recoveries between 81–111% across spike levels (0.5×, 1×, 1.5× PDE) and RSDs below 3%.
• Regulatory compliance: Measured concentrations in gelatin capsules and amoxicillin samples were below USP<232> permitted daily exposure limits, yielding consistent pass/fail outcomes.
• Interference removal: Helium KED effectively suppressed polyatomic interferences, enabling reliable quantification without additional chemical separations.
• High TDS capability: HMI maintained robust plasma conditions (oxide ratios ~0.5%), facilitating direct analysis of challenging matrices. Ultra-robust mode can lower oxide levels to 0.1–0.2% for very high TDS samples.

Benefits and Practical Applications

• Enhanced specificity and sensitivity compared to legacy colorimetric assays.
• Elimination of hazardous reagents (thioacetamide, H₂S) and high-temperature sample ignition, reducing analyte loss.
• Streamlined workflow for routine QC in pharmaceutical manufacturing and dietary supplement testing.
• Global regulatory acceptance with unified methodology for APIs and excipients.

Future Trends and Opportunities

• Integration of reactive gases (e.g., H₂) in ORS3 to achieve ultra-trace detection of elements such as Se and Fe at ppq levels.
• Hyphenation of ICP-MS with chromatographic techniques for speciation analysis of As and Hg when levels exceed PDE.
• Automation and high-throughput configurations to further increase laboratory productivity.
• Continued evolution of USP guidelines and harmonization across international pharmacopeias.

Conclusion

The Agilent 7700/7500 ICP-MS platforms, employing ORS3 with helium KED and HMI, deliver specific, accurate, and precise determination of inorganic impurities in pharmaceutical materials. Adoption of USP<232>/<233> methods addresses the limitations of the century-old USP<231> and ensures patient safety through rigorous metal impurity control.

Reference

• Liba A., Wall S., Hussain S. Analysis of Metal Impurities in Pharmaceutical Ingredients in Preparation for the New USP Methods. Agilent Technologies, January 2011.