Elemental Analysis in Active Pharmaceutical Ingredients (APIs) Development Using EDX: Residual Catalysts, Drug Salts, Contaminants

Importance of the Topic

The analysis of elemental impurities and residual catalysts in APIs is essential to ensure drug safety and compliance with regulatory guidelines such as ICH Q3D and pharmacopoeias. Energy Dispersive X-Ray Fluorescence (EDX) offers rapid, non-destructive elemental quantification with minimal sample preparation, making it highly relevant for pharmaceutical R&D and quality control.

Objectives and Study Overview

This application note demonstrates the use of the Shimadzu EDX-7000 spectrometer to address three key analytical challenges during API development:

1. Quantitative analysis of residual metal catalysts (Ir, Pt, Ru, Rh, Pd, Os) in small API samples
2. Determination of counter-ion composition in drug salts through quantification of Cl, Br, and S
3. Identification and quantification of particulate contaminants arising during manufacturing

Methodology and Instrumentation

The Shimadzu EDX-7000 system equipped with an SDD detector and Rh X-ray tube was employed under various measurement conditions:

• Sample introduction: Direct placement in polypropylene-lined containers (0.1–8 g sample masses)
• Measurement settings: Tube voltage 15 kV and 50 kV, filters selected per element group, integration times up to 1800 s
• Software: Calibration curve method for quantification, fundamental parameter method for FP-based analysis, and EDXIR-Analysis for integrated qualitative/quantitative profiling

Main Results and Discussion

• Residual Catalysts: Calibration curves exhibited excellent linearity (R ≥ 0.999). Quantitative recovery of six transition metals in as little as 0.1 g API showed errors below 10 % relative to spiked values.
• Drug Salts: Cl, Br, and S content determined by the FP method matched theoretical values within ±1 % across six commercial APIs, demonstrating high accuracy without wet chemical preparation.
• Contaminant Analysis: Particulates were characterized as stainless-steel debris (Fe, Cr, Ni dominant) using FP quantification and EDXIR-Analysis identification, underlining EDX’s capability for rapid contaminant screening.

Benefits and Practical Applications

• Simplicity: Eliminates complex digestion or derivatization steps, reducing analysis time and operator variability.
• Safety: Minimizes handling of toxic reagents (e.g., avoids OsO4 formation during Os analysis) through direct solid-sample measurement.
• Versatility: Single-instrument platform supports residual catalyst screening, counter-ion profiling, and contaminant identification in pharmaceutical workflows.

Future Trends and Potential Applications

• Integration with high-throughput screening for accelerated API candidate evaluation.
• Coupling EDX data with chemometric models for predictive impurity profiling.
• Development of miniaturized sample holders and automated sample changers for routine QC implementation.
• Expansion of spectral libraries in EDXIR-Analysis to cover broader industrial contaminant libraries.

Conclusion

EDX-7000 based elemental analysis provides a robust, efficient approach for pharmaceutical development and quality control. Its minimal sample preparation, accuracy, and broad application scope make it a valuable tool for ensuring regulatory compliance and accelerating R&D timelines.

References

1. ICH Q3D Guideline for Elemental Impurities in Pharmaceuticals (MHRA EMA, 2015)
2. Japanese Pharmacopoeia Supplement II (MHLW, 2019)
3. Shimadzu Application News X271: EDX Analysis of Elemental Impurities