Analysis of Elemental Impurities in Pharmaceutical Products Following USP <232>/<233> on ICPMS-2030

Significance of the Topic

Elemental impurities in pharmaceutical products can pose serious risks to patient safety and drug efficacy. Since the traditional USP<231> colorimetric test lacks the sensitivity to detect toxicologically relevant concentrations, the implementation of USP<232>/<233> guidelines mandates precise trace-level analysis. ICP–MS has emerged as the method of choice due to its high sensitivity, low detection limits, and multi-element capability.

Objectives and Study Overview

The aim of this study was to establish and validate an ICP–MS method on the Shimadzu ICPMS-2030 for quantifying 24 elemental impurities in three dosage forms (tablet, capsule, liquid) in accordance with USP<232>/<233> and ICH Q3D guidelines. The study evaluates sample preparation, calibration strategies, method performance, and application to real drug samples.

Methodology and Used Instrumentation

Sample Preparation:

• Weighed 0.4 g of each drug sample
• Microwave digestion using a Milestone Ethos Easy system with a mixture of 65% HNO3, 37% HCl, and 30% H2O2 in closed vessels
• Diluted digests to 50 mL with deionized water; internal standards (Sc, Y, Ho, Bi) added at 10 µg/L
• Resulting dilution factor 125

ICP–MS Conditions:

• Shimadzu ICPMS-2030 with AS-10 autosampler and Octaplate collision cell
• Helium collision mode at 6.0 mL/min to reduce polyatomic interferences
• RF power 1.20 kW; plasma gas 8 L/min; auxiliary gas 1.10 L/min; carrier gas 0.70 L/min
• Mini-torch, specific nebulizer, and cyclone chamber at 5 °C

Main Results and Discussion

Calibration and Linearity:
Calibration standards at 0.5J, 1.0J, and 2.0J (derived from PDE values and maximum daily dose) exhibited correlation coefficients >0.9995 across all element classes, covering concentrations from low µg/L to high mg/L.

Method Performance:

• Spike recovery for Drug 2 at 1.0J between 88% and 110%, within USP acceptance (70–150%)
• Precision with RSD <2% for nearly all elements
• LODs and LOQs well below required J-based limits, enabling higher dilution factors

Analysis of Real Samples:
All 24 elements in three drug samples were either below the detection limit or present at levels far below USP <232> PDE thresholds, confirming the method’s robustness and compliance.

Benefits and Practical Applications

• High sensitivity and low detection limits ensure reliable trace analysis
• Wide dynamic range allows single set of calibration standards
• Helium collision mode supports HCl use in sample prep, improving element stability (e.g., Hg)
• Efficient closed-vessel digestion prevents volatile losses
• Low argon consumption and streamlined operation enhance cost-effectiveness

Future Trends and Opportunities

Advancements in automation and high-throughput sample preparation, coupling ICP–MS with separation techniques, real-time monitoring in manufacturing, and integration of data analytics and chemometrics are expected to further improve impurity profiling. Ongoing regulatory updates and harmonization will drive broader adoption of sensitive multi-element analysis in quality control.

Conclusion

The validated method on the Shimadzu ICPMS-2030 demonstrates excellent sensitivity, accuracy, and precision for quantifying 24 elemental impurities in pharmaceutical products, fully meeting USP <232>/<233> requirements. Its robust performance and operational efficiency support routine QC and regulatory compliance.

References

1. United States Pharmacopeia General Chapter <232> Elemental Impurities – Limits
2. United States Pharmacopeia General Chapter <233> Elemental Impurities – Procedures