Introduction
Ion chromatography (IC), a highly sensitive technique for separating and quantifying ionic species, was introduced in the 1970s and marketed by the Dionex Corporation. Initially developed for water and environmental analysis, IC has gradually been adopted by pharmaceutical laboratories.
However, the progression has been characterised by technological and regulatory challenges, from the initial suppressed systems to the emergence of alternative designs such as those provided by Metrohm. The different technologies adopted in instrumentation have also posed additional difficulties, particularly for harmonised pharmacopoeial methods.
My first experience of IC occurred in the early 1980s as an analyst at Kodak Research working on mixed halide titrations using silver nitrate. By using the Dionex system, I demonstrated that it could be applied to this type of analysis. In addition, as a part-time student studying for my GRSC qualifications, I was fortunate to have access to a non-suppressed system at Hatfield Polytechnic (now University of Hertfordshire), with equal success.
On joining Butterworth Laboratories in 1987, I discovered they were still using the same Dionex model I had used at Kodak 鈥� primarily to analyse anions following oxygen combustion of organic compounds as part of their Elemental Microanalysis services 鈥� a service Butterworth鈥檚 still continues to provide.
In this article, I will trace the evolution of IC in the pharmaceutical industry, highlighting the role of system architecture and regulatory accommodation.
The foundations of ion chromatography: Early development (late 1970s鈥揺arly 1980s)
Ion chromatography was invented by Hamish Small at Dow Chemical in 1975 and was soon commercialised by Dionex. The hallmark of this system was its ion suppression technology, which dramatically reduced background conductivity from the eluent, allowing for high-sensitivity detection of ions using conductivity detectors. This “suppressed conductivity” approach became the dominant technology in the environmental and industrial sectors 鈥� yet, pharmaceutical adoption was slow, confronted by obstacles that appeared to be:
- The need to regularly regenerate the suppression column limited the ability to run large numbers of samples in a single analytical run.
- Lack of system robustness and long-term reproducibility.
- Investment in training and equipment.
- Regulatory inertia and absence of compendial guidance.
- Continued reliance on well-established titration and classical wet-chemistry methods.
However, as IC developed, two distinct system architectures, suppressed and non-suppressed systems, emerged with diverging technologies:
Suppressed Ion Chromatography (Dionex/Thermo Fisher) utilises chemical or electrolytic suppression to reduce background conductivity and offers superior sensitivity for detecting low-level anion/cations . It is commonly used for pharmaceutical applications like water analysis, cleaning validation, residual ion quantification, carbohydrates and aminoglycoside antibiotics. However, suppressed ion chromatography requires careful control of suppressor performance and maintenance.
In contrast, Non-Suppressed Ion Chromatography (as implemented by Metrohm and others) utilises eluents such as bicarbonate-based solutions and columns that eliminate the need for suppression. Detection is typically carried out via direct conductivity or UV, making the technique more comparable to HPLC regarding instrumentation and workflow. It is applicable to a range of pharmacopoeial methods and the analysis of small-molecule ions.
From my perspective, the existence of these two system types raises concerns about method transferability and harmonisation, particularly when pharmacopoeias specify IC-based methods based on a specific technology. This could be particularly difficult for contract laboratories, which may need to invest in both technologies.
Continued technological development (1980s鈥�1990s)
Throughout the 1980s and 1990s, Dionex and Metrohm refined their respective platforms. Dionex improved suppressor durability and detection limits, while Metrohm focused on modular, user-friendly systems without suppression. Nevertheless, pharma’s reliance on wet chemistry and concerns about method validation remained dominant.
During this period, there were two notable developments:
- FDA began exploring IC for residual solvents and excipient profiling.
- IC gained use in specialised applications like nitrate detection in parenterals.
However, pharmacopoeial methods rarely mention IC explicitly. As a contract testing laboratory, Butterworth was often frustrated when proposing an IC method to enhance specificity, etc., for a client, only to be told that they wanted to stay with tried-and-tested HPLC with RI detection.
Regulatory awakening and pharmacopeial engagement (2000s)
By the 2000s, regulatory pressures to improve impurity profiling (e.g., ICH Q3A/B) and validate robust analytical methods brought IC to the forefront. Cleaning validation, counterion analysis, and inorganic impurity testing created space for IC鈥檚 capabilities.
The pharmacopoeial milestones during this period were:
- USP: Included IC in General Chapter <621> Chromatography, and later in <1225> Validation of Compendial Methods. IC was referenced in monographs for APIs (e.g., lithium carbonate), electrolytes (e.g., sodium chloride), and injectable formulations.
- EP: Introduced General Chapter 2.2.28 Ion Chromatography, outlining system suitability, detection modes, and method validation. The chapter was crafted to be technology-agnostic, accommodating suppressed and non-suppressed systems.
- JP: Followed similar developments, incorporating IC for elemental impurities and water testing.
Crucially, pharmacopoeias avoided prescribing system-specific setups, instead providing method conditions (e.g., column type, mobile phase, flow rate) and allowing the user to choose suppression if the system suitability criteria were met.
Widespread use and technological flexibility (2010s to the present)
Today, IC is broadly accepted in pharmaceutical quality control and R&D, and is used for:
- Water and excipient analysis
- Cleaning validation (e.g., detecting residual phosphates or chlorides)
- 网曝门 of counterions in salts (e.g., citrate, acetate, sodium, chloride)
- Profiling of inorganic impurities per ICH Q3D
Suppressed and non-suppressed systems are often interchangeable, provided they meet validation and compendial criteria. Vendors like Thermo Fisher (Dionex) and Metrohm continue to offer instrument-specific advantages, but laboratories must choose which systems best meet their specific application requirements, costs, etc.
Overall, pharmacopoeial strategies have focused on:
- Defining performance-based criteria (e.g., resolution, peak shape, detection limit) instead of instrument type.
- Providing flexible method conditions and optional adjustments within validated ranges.
- Encouraging user validation rather than enforcing a prescriptive method format.
This flexibility ensures that labs using either suppressed or non-suppressed IC systems can, in most cases, comply with monograph requirements. However, deducing which technology was used in developing the monograph method is often possible.
It also feels that data traceability has become one of the critical drivers behind the greater acceptance of the technique. It is also driving the replacement of traditional titrimetric methods with ion chromatography 鈥� the analysis of zinc determination as per the USP General chapter <591>, is a good example of this.
Conclusion: A journey of innovation and adaptation
The adoption of ion chromatography in the pharmaceutical industry has been gradual process, marked by initial resistance, technical divergence, and eventual regulatory harmonisation. The emergence of two distinct technologies 鈥� suppressed (Dionex) and non-suppressed (Metrohm) 鈥� introduced complexity, but the pharmacopoeias responded by designing inclusive, performance-based standards.
Today, ion chromatography is a validated, versatile technique within pharmaceutical QA/QC. Its acceptance reflects not only the maturation of the technology but also the industry’s growing willingness to adapt to tools that improve specificity, sensitivity, and compliance.
References
- Small, H. (1975). Ion Chromatography. Analytical Chemistry, 47(11), 1801鈥�1809.
- United States Pharmacopoeia General Chapters <621>, <1225>, and selected monographs.
- European Pharmacopoeia Chapter 2.2.28 Ion Chromatography and individual monographs.
- ICH Guidelines Q3A(R2), Q3B(R2), Q3D.
- Dionex and Metrohm technical notes and application literature.
