Elemental Impurities in Aspirin: USP <232>/<233> and ICH Q3D Methods Using ICP-OES

Importance of the Topic

Controlling elemental impurities in pharmaceutical products is essential to ensure patient safety and regulatory compliance. Inorganic contaminants can originate from raw materials, manufacturing equipment, and packaging, and may pose serious health risks even at trace levels. Harmonized guidelines from USP<232>/<233> and ICH Q3D define strict limits and analytical procedures to quantify these impurities.

Objectives and Study Overview

This study aimed to validate the USP<232>/<233> methods for determining 24 elemental impurities in aspirin using Agilent ICP-OES. The main goals were to demonstrate linearity, accuracy, precision, specificity, and detectability in compliance with pharmacopeial and ICH guidelines.

Methodology and Sample Preparation

• Conversion of Permitted Daily Exposure (PDE) limits into sample concentration limits (J-values) based on a 3 g/day maximum aspirin dose.
• Calibration standards prepared at 0.5, 1.0, and 1.5 J using multi-element CRMs.
• Sample digestion by closed-vessel microwave system with HNO₃ and HCl, followed by dilution to 50 mL.
• Preparation of spiked samples at 0.5 J, 0.8 J, and 1.0 J for recovery, detectability, and precision tests.

Instrumentation Used

• Agilent 5110 Synchronous Vertical Dual View ICP-OES (compatible with 5800 VDV and 5900 SVDV).
• SeaSpray nebulizer with double-pass cyclonic spray chamber and 1.8 mm i.d. injector torch.
• UltraWAVE single-reaction-chamber microwave digestion system.
• SPS 4 autosampler and Agilent ICP Expert software for method control and data analysis.

Main Results and Discussion

• Calibration: Linear response achieved for all 24 elements over defined ranges around each J-value.
• Accuracy: Recoveries for spikes at 0.5 J, 1.0 J, and 1.5 J ranged between 70 % and 150 %, with overall means within 85–110 %.
• Precision: Repeatability (n=6) and ruggedness (over two days, n=12) showed RSDs < 20 % and < 25 %, respectively.
• Specificity: Consistent concentrations measured at two wavelengths per element confirmed absence of spectral interferences.
• Detectability: Instrumental and non-instrumental tests demonstrated reliable detection at 0.8 J and acceptable spike recovery (< 15 % difference from 1.0 J).

Benefits and Practical Applications

• Compliant with USP<232>/<233> and ICH Q3D requirements for elemental impurity analysis.
• High sample throughput (up to 2500 samples per day) and wide dynamic range support both low- and high-volume laboratories.
• Automated background correction and intuitive software reduce method development time and simplify routine testing.

Future Trends and Possibilities

• Integration with ICP-MS to extend detection limits for ultra-trace elements.
• Development of fully automated workflows for in-line process monitoring.
• Application to complex dosage forms and biopharmaceutical matrices.
• Expansion of certified reference materials to cover emerging contaminants.

Conclusion

The validated ICP-OES procedure on Agilent instrumentation successfully quantified 24 elemental impurities in aspirin according to USP<232>/<233> and ICH Q3D. The method demonstrated excellent performance in terms of linearity, accuracy, precision, specificity, and detectability, making it a robust solution for pharmaceutical quality control.

Reference

1. USP Chapter <232> Elemental Impurities–Limits, Pharmacopeial Forum, 42(2), 2016
2. USP Chapter <233> Elemental Impurities–Procedures, USP 38–NF 33, Second Supplement
3. ICH Guideline Q3D on Elemental Impurities, EMA/CHMP/ICH/353369/2013, March 2019
4. USP <232>/<233> and ICH Q3D Elemental Impurities Analysis: Agilent’s ICP-OES solution, Agilent publication 5991-8150EN
5. Simplify testing of elemental impurities in pharmaceuticals with Agilent’s Certified Reference Materials Kit, Agilent publication 5991-8177EN