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  • Ion Chromatography in Pharmaceutical Analysis: Emerging Trends and Future Directions

  • HRIT University, Ghaziabad, NCR-New Delhi.

Abstract

Ion Chromatography (IC) has become a cornerstone analytical technique in the pharmaceutical industry for profiling ionic impurities, ensuring regulatory compliance, and supporting drug substance and formulation development. This review comprehensively explores the advancements in IC, including novel column chemistries, detection techniques, automation, and hyphenation with mass spectrometry. It highlights applications in both organic and inorganic impurity analysis, discusses regulatory alignment with ICH and USP standards, and provides an outlook on the integration of green chemistry principles and digitalization in future IC applications.

Keywords

Ion chromatography, pharmaceutical analysis, ionic impurities, conductivity detection, green chemistry, hyphenated techniques, USP, ICH Q3D

Introduction

In pharmaceutical quality control and regulatory compliance, the precise quantification of ionic impurities is non-negotiable. Among the diverse analytical techniques available, Ion Chromatography (IC) stands out for its ability to detect and quantify anions and cations at trace levels. Since its introduction by Small et al. in 1975, IC has evolved significantly, becoming an indispensable tool for drug development, manufacturing, and release testing. This review article aims to elucidate the recent advancements, applications, and future perspectives of IC within pharmaceutical analysis.

2. Principle and Classification of Ion Chromatography

Ion chromatography operates on the principle of ion exchange between mobile and stationary phases, allowing ionic species to be separated based on charge and size. The major modes include:

• Anion Exchange Chromatography: Commonly used to detect Cl?, NO??, SO?²?, and phosphate impurities.

• Cation Exchange Chromatography: Targets Na?, K?, Ca²?, Mg²?, and other alkali/alkaline earth metals.

• Ion Exclusion and Ion Pair Chromatography: Suitable for weakly ionized or organic ionic species.

Detection is typically performed using suppressed conductivity, though UV, amperometric, and MS detection methods are gaining popularity.

3. Pharmaceutical Applications of IC

3.1 Analysis of Inorganic Impurities

IC is widely employed for detecting residual acids (e.g., HCl), bases (e.g., NH??), and counterions in active pharmaceutical ingredients (APIs). It supports compliance with:

• USP <621>, <1225>

• ICH Q3D elemental impurity guidelines

3.2 Counterion Confirmation in API Salts

Determining the presence and quantity of counterions in drug salts (e.g., Na?, Cl? in sodium chloride formulations) is essential for API identity and assay.

3.3 Excipient Purity and Compatibility Studies

IC is useful in evaluating excipients such as sodium starch glycolate or magnesium stearate, helping identify trace-level ionic contaminants that may affect formulation stability.

3.4 Water and Solvent Quality Monitoring

IC supports pharmacopeial testing of water used in manufacturing (WFI, purified water) for anions like nitrate, nitrite, and sulfate.

4. Advances in Ion Chromatography Instrumentation

4.1 Column Chemistry Enhancements
Newer columns exhibit:

• High selectivity and capacity

• Low bleed and high stability

• Compatibility with high-pressure IC (HPIC) systems

E.g., Thermo Scientific’s Dionex IonPac columns (AS11-HC, CS12A) offer extended durability and peak resolution.

4.2 Suppressor Technology

Modern self-regenerating suppressors (SRS) minimize noise and extend operational life, enabling detection limits in the ppb range.

4.3 Detection Integration

• Conductivity Detection (CD): Standard for high sensitivity to ions.

• UV/Vis Detection: For UV-active organic acids or drugs.

• Amperometric Detection: Sensitive to redox-active species like cyanide, sulfide.

• Mass Spectrometry (IC-MS): Enables structural elucidation and speciation of complex impurities.

4.4 Automation and Sample Handling

• Autosamplers, online dilution, filtration, and eluent generation reduce manual error and improve reproducibility.

• Integration with LIMS for GMP-compliant data handling.

5. Regulatory and Quality Control Integration

IC methods must adhere to validation criteria defined in:

• USP <1225>: Method validation

• USP <621>: Chromatographic systems

• ICH Q2(R2): Analytical procedure validation

Pharmaceutical manufacturers are required to validate IC methods for:

• Specificity, linearity, accuracy

• Precision (repeatability & intermediate precision)

• Robustness and LOD/LOQ

6. Emerging Trends in Ion Chromatography

6.1 Green Chemistry Integration

• Use of aqueous eluents in place of organic solvents

• Reagent-free ion chromatography (RFIC) systems
• Reduced energy consumption and waste production

6.2 Miniaturization and Microfluidics

• Lab-on-a-chip platforms for rapid IC with reduced sample volumes

• Portable IC devices for field or production floor testing

6.3 IC–MS and Hyphenated Techniques

• IC-MS/MS allows simultaneous separation and identification of unknown impurities

• Coupling with NMR or UV for multifaceted impurity profiling


6.4 Artificial Intelligence and Digitalization

• AI-based peak identification and baseline correction

• Predictive modeling for impurity behavior

• Use of cloud-based monitoring for compliance and data integrity

7. Case Studies and Research Applications

Case Study 1:

Quantification of Anions in Omeprazole Formulation
IC enabled the quantification of Cl? and SO?²? at trace levels (<10 ppm), supporting impurity profiling in delayed-release capsules.

Case Study 2:

Cation Analysis in API Manufacturing Process
In an atenolol API batch, Na? and Fe³? levels were successfully monitored and controlled using cation exchange IC, preventing unwanted catalysis during synthesis.

8. Limitations and Challenges

• Matrix effects: Interference from excipients can affect sensitivity.

• Cost and maintenance: IC-MS systems can be capital-intensive.

• Method development time: Optimization of mobile phase, suppressor current, and flow rate may require multiple iterations.

9. Future Directions

• Wider use of IC-MS for regulatory submissions

• Incorporation into continuous manufacturing setups

• Enhanced predictive quality assurance using IC data in QbD models

• Global harmonization in impurity limit guidelines and IC method acceptance

10. CONCLUSION

Ion Chromatography continues to be an indispensable technique for pharmaceutical analysis, particularly in controlling ionic impurities and complying with regulatory standards. Its adaptability to new detection systems, green principles, and digital advancements ensures it will remain at the forefront of analytical innovation. As regulatory expectations evolve and pharmaceutical formulations become more complex, IC will play a central role in ensuring product safety, efficacy, and global market compliance.

REFERENCES

  1. Small H, Stevens TS, Bauman WC. Analytical Chemistry, 1975.
  2. ICH Q3D(R1), Elemental Impurities, ICH Guidelines, 2019.
  3. USP <1225>, <621>, United States Pharmacopeia, 2021.
  4. Thermo Scientific, Dionex Application Notes.
  5. Samanidou VF, Analytical and Bioanalytical Chemistry, 2022.
  6. WHO Technical Report Series, Annex 2, 2020.
  7. Zhang K et al., J. Chromatogr. A, 2021.

Reference

  1. Small H, Stevens TS, Bauman WC. Analytical Chemistry, 1975.
  2. ICH Q3D(R1), Elemental Impurities, ICH Guidelines, 2019.
  3. USP <1225>, <621>, United States Pharmacopeia, 2021.
  4. Thermo Scientific, Dionex Application Notes.
  5. Samanidou VF, Analytical and Bioanalytical Chemistry, 2022.
  6. WHO Technical Report Series, Annex 2, 2020.
  7. Zhang K et al., J. Chromatogr. A, 2021.

Photo
D. Mahendra
Corresponding author

HRIT University, Ghaziabad, NCR-New Delhi.

Photo
Dr. R. K. Roy
Co-author

HRIT University, Ghaziabad, NCR-New Delhi.

D. Mahendra*, Dr. R. K. Roy, Ion Chromatography in Pharmaceutical Analysis: Emerging Trends and Future Directions, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 7, 1175-1178. https://doi.org/10.5281/zenodo.15844869

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