Trends and Developments of Ion Chromatography in Pharmaceutical Analysis

As a highly flexible technique, ion chromatography (IC) has many practical applications in the pharmaceutical field. This article reviews some relevant trends and recent developments in IC application.

Testing in regulated environments

When it comes to the quality and safety of drugs, the pharmaceutical indus­try must meet rigorous standards. These standards are recorded as officially recognized pharmaceutical rules in pharmacopoeias and authorizing bodies such as governments and medical societies publish these as legal tools of customer protection. Drug identification relies on reliable and sensitive methods and instruments. This is also the case when determining a drug’s compliance with application regulations.

IC is the preferred method for determining active ingredients, excipients, active ingredients, trace impurities, as well as metabolites in the form of polar substances or inorganic and organic ions, in several pharma­ceutical solutions, pharmaceuticals, and even body fluids. The IC method can be used to detect a number of substances within a very short time in just one single analysis, and even differentiate between chemically similar analytes. Analyte concentration can vary from ng/L up to the percent range. The large range of elution systems and separation columns available means the IC method can be used for virtually any kind of analyte. Interfering effects that the sample matrix can cause are avoidable if the correct sample preparation is used and the correct detection method is selected. A feature of many current IC systems is inline sample preparation, since the focus of latest developments in IC has mostly been convenient use. Yet, ease-of-use is not the only benefit provided by automation of the IC process; if human interfer­ence is reduced, so is the risk of contamination and errors.

Depending on the requirements of matrix and analyte, a wide range of detection methods are available to choose from, including:

  • Electrochemical detection
  • Conductivity detection with and without suppression
  • Coupled detection techniques such as IC–inductively-coupled-plasma-MS and IC–mass-spectrometry (MS)
  • Spectrophotometric detection with and without post-col­umn derivatization (ultraviolet–visible spectrophotometry)

Pharmaceutical samples come in multiple different forms that require different IC approaches. Fol­lowing, is a summary of common sample types with relevant example analyses.

Pharmaceutical solutions

The term ‘pharmaceutical solutions’ refers to infusion, isotonic, or hemodialysis solutions. They include cations, anions, organic acids, and carbohydrates, at concentrations that often differ from one another by several orders of magnitude. In terms of production monitoring and final quality control, the analysis technique selected must be able to determine these ingredients with great precision. The analysis should also be rapid and involve minimal effort. This is fully achievable with IC, owing to its automatic inline sample preparation and intelligent analytical procedure.

Figures 1 and 2 show two example analyses of hemodialysis solutions. Hemodialysis is required by people with renal failure to compensate for the kidney’s loss of blood-cleansing function. Throughout the process, solutes are exchanged between the patient’s blood and a hemodialysis solution via a semi-permeable membrane. Among the various solutes exchanged are waste products such as phosphate and urea, which diffuse out of the blood and into the dialysis solution along the concentration gradient. The dialysis solutions have a complex composition, since its osmotic activity is changed when solutes are removed from the blood; it must therefore take place at a controlled rate, which requires the correct solute concentration. A strong change in osmotic activity can lead to dialysis disequilibrium syndrome, where solutes are washed out from other body compartments due to a low concentration of solute in the blood.

The simultaneous determination of acetate and citrate in diluted hemodialysis solution is shown in Figure 1. An anion standard was measured in part A and the sample determination is shown in part B. Since citrate has anticoagulant properties, it is added to hemodialysis solutions and acetate is added as a buffer substance. During hemodialysis, acetate is transferred to the patient’s bloodstream, which stabilizes the pH value of the blood. This is necessary because patients’ kidneys cannot excrete acid components, meaning patients are often acidotic. Aside from acetate and citrate, the chromatogram shows the presence of a close to physiological chloride concentration.

IC measurement on a Metrosep A Supp 7 - 250/4.0 using Na2CO3 gradient elution, followed by sequen­tial suppression and conductivity detection. Anion standard including acetate and citrate.

Figure 1A. IC measurement on a Metrosep A Supp 7 - 250/4.0 using Na2CO3 gradient elution, followed by sequen­tial suppression and conductivity detection. Anion standard including acetate and citrate.

Figure 1B. IC measurement on a Metrosep A Supp 7 - 250/4.0 using Na2CO3 gradient elution, followed by sequen­tial suppression and conductivity detection. Acetate and ci­trate in hemodialysis solution.

When physiological concentrations of solutes are used, the concentration gradient is reduced to a minimum and a dynamic equilibrium is achieved between the dialysis solution and the blood. This prevents the loss of certain solutes, including chloride. The determination of cations in hemodialysis concentrate following an automated inline dilution step is shown in Figure 2. As with chloride, the cations are present in close to physiological concentrations to prevent their drainage from the blood via osmosis.

Cations in diluted hemodialysis concentrate using the Metrosep C 4 - 150/4.0 column and non-suppressed conductivity detection.

Figure 2. Cations in diluted hemodialysis concentrate using the Metrosep C 4 - 150/4.0 column and non-suppressed conductivity detection.

Active pharmaceutical ingredients

Medicines such as neomycin, gentamicin, bethanechol chloride and cefadroxil contain active pharmaceutical ingredients (APIs) that can be determined by the IC method in compliance with European Pharmacopoeia and US Pharmacopeia regulations. The pharmacopoeias contain detailed descriptions of the requirements regarding separation, precision, and recovery of the analytes. Shown in Figure 3 is the ion chromatogram of gentamicin analysis; gentamicin is an antibiotic belonging to a group of drugs called the aminoglycosides. These are bactericidal antibiotics that block the biosynthesis of bacterial proteins by binding to ribosomes and causing errors in the translation from messenger ribonucleic acid (mRNA) to DNA. Gentamicin includes a number of closely associated compounds, as follows:

  • Gentamicin C1
  • Gentamicin C1a
  • Gentamicin C2
  • Gentamicin C2a
  • Gentamicin C2b

Despite their structural similarity, good separation of the various gentamicin components is achievable by IC.

IC determination of the antibiotic gentamicin by pulsed amperometric detection; column: Polymer Laborato­ries RP-S; eluent: 60g/L Na2SO4, 1.75g/L sodium octanesulfonate, 1.34g/L NaH2PO4, 8mL/L THF (pH = 3, H3PO4); post-column addition: 300mmol/L NaOH.

Figure 3. IC determination of the antibiotic gentamicin by pulsed amperometric detection; column: Polymer Laborato­ries RP-S; eluent: 60g/L Na2SO4, 1.75g/L sodium octanesulfonate, 1.34g/L NaH2PO4, 8mL/L THF (pH = 3, H3PO4); post-column addition: 300mmol/L NaOH.

Impurities in pharmaceuticals

In addition to API analysis, the impurities in pharmaceutical products can also be determined by IC. Even when an impurity is present in just small concentrations, this can still lead to major side-effects. For instance, during the synthesis of the antihypertensive irbesartan, trace amounts of azide can be detected in the product as an impurity. Azide is very toxic to humans and its concentration in irbesartan is subject to stringent controls. The USP 621 of the US Pharmacopeia advises IC determination of azide following direct injection. Here, the API is removed from the analytical column using a transfer solution containing the IC eluent and an appropriate organic solvent, although the process is tedious, time consuming and not possible to automate.

The determination of azide is more sensitive, more selective and, most importantly, faster when inline matrix elimination is used. Here, the interfering pharmaceutical matrix is isolated from the analyte of interest during sample preparation. Shown in Figure 4 is the ion chromatogram demonstrating the analysis of an irbesartan sample spiked with various azide concentrations.

High sensitivity owing to matrix elimination

After sequential suppression, the signal is captured by a conductivity detector. Listed in Table 1 are the average recovery values of azide that were obtained over three measurements and also the mean conductivity determined by the detector, together with the relative standard deviation. Determining the azide in irbesartan with preceding matrix elimination meets all the requirements of the regulatory authorities in terms of the selectivity of the method, its detection and quantitation limits, linearity, precision, robustness, and accuracy. It can therefore be used as a faster and more sensitive alternative to the proposed determination according to USP 621.

Irbesartan sample spiked with 5-80μg/L azide; column: Metrosep A Supp 10 - 250/4.0; eluent: 5mmol/L Na2CO3, 5mmol/L NaHCO3; inline matrix elimination with 70:30(v/v) methanol/water.

Figure 4. Irbesartan sample spiked with 5-80μg/L azide; column: Metrosep A Supp 10 - 250/4.0; eluent: 5mmol/L Na2CO3, 5mmol/L NaHCO3; inline matrix elimination with 70:30(v/v) methanol/water.

Radio IC

Radiopharmaceuticals are radioactive substances that are used for medical purposes, particularly in diagnostics, but also for treating and preventing certain diseases. The goal of radio IC is to determine the radiochemical purity of these substances. Two prominent examples of radiotracers used in diagnostics by PET (positron emission tomography) are [18F]fluorocholine and [18F]fluorodeoxyglucose. These radiotracers are labeled with the radionuclide [18F]fluorine. During the radioactive decay of this unstable isotope, a proton in its nucleus changes into a neutron, a change that is accompanied by the emission of a neutrino and a positron. The positron couples with an electron in the surrounding tissue, which annihilates both particles and causes two photons (gamma rays) to be emitted in opposite directions, each with an energy of 0.511 MeV energy. Based on the data obtained via coincidence detection of the photon pair, the location of its emission in the body is calculated. This location closely corresponds with the location of the initial radiotracer molecule, thereby providing information on its activity.

The purity of radiotracers is vitally important. When a positron combines with an electron, highly energetic gamma rays are emitted that can harm the human body. When a pure radiotracer is used, the injection of radioactive contaminants such as free [18F]fluorine is avoided and the amount of radioactive substance administered is kept to a minimum. Radio IC establishes the quality control of radiotracers in the short time between their synthesis and the recording of the three-dimensional (3D) PET scan. The separation step in radio IC is the same as in regular IC, with the only exception being that it occurs behind lead doors. The detection step, which involves the addition of a radioactivity detector to the setup, is what does set radio IC apart from regular IC. The presence or, ideally, the absence of radioactive contaminants is shown by the radioactivity chromato­gram.

Table 1. Precision and recovery of azide

Peak Area: Mean value (μS/cm) Relative standard deviation (%) Recovery (%)
5 µg/L spike ± 5.00 1.96 101.71
30 µg/L spike ± 0.30 0.14 103.38

n = 3 measurements

Table 2. Selection of IC applications in the pharma industry

Pharmaceutical or excipient


Acamprosate calcium


Acifluorfen, sodium





Dimethyl and diethyl sulfate

Anticoagulation solution

Phosphate, citrate

Arsenic trioxide

Arsenate, arsenite



Atorvastatin calcium salt

Cyanide, tetrabutylammonium



Bethanechol chloride

Bethanechol, sodium, calcium, decomposition product (HPTA)

Bromide salt



Methanesulfonic acid

Calcium gluconate


Calcium salt


Camphorsulfonic acid

Camphorsulfonic acid


Chloride, bromide


EDTA, hydrazine, sodium disulfite




Iron, EDTA

Cefepime hydrochloride


Ceftazidime sodium


Clopidogrel besylate

Anions, carbonate, cations


Quaternary alkylamines

Copovidone EP

Acetate, formate



Dextromethorphan HBr

Formic acid

(2,3-Dichlorophenyl) oxoacetonitrile

Cyanide, tetrabutylammonium

Diclofenac sodium

Sodium, potassium



Doxazosin, methanesulfonic acid



Propargyl alcohol

Enoxaparin sodium


Esomeprazole magnesium





Silicate, sodium


Sodium lauryl sulfate (SLS)

Ferumoxide (contrast enhancer)


Fluorouracil (also fluoruracil)




Gadopentetate dimeglumine


Gentamicin sulfate (see page 17)





Pharmaceutical or excipient


Glycine carbonate, sodium salt






Heparin sodium

Glucosamine and galactosamine

Ibandronic acid sodium

Ibandronate, phosphite, phosphate

Indinavir sulfate

Ethyl sulfate

Indomethacin sodium

2-ethylhexane acid


Cyanide, azide


Ibuprofen, valerophenone



Lanthanum carbonate








Losartan potassium



EDTA, dimethylamine

Metformin hydrochloride


(Mono)sulfiram (temosol)


Montelukast sodium

Methanesulfonic acid, acetate

Multivitamin tablets

Cations, Vitamin C

Mycophenolate mofetil


Nebivolol hydrochloride


Neomycin sulfate




Pioglitazone hydrochloride





Piperazine, N-methylpiperazine

RA-Thermoseal toothpaste

Potassium, zinc


Ribitol (adonitol)

S-Adenosyl methionine



Binding capacity of phosphate

Suxamethonium chloride

Choline chloride


Methanolic methylamine

Terbinafine hydrochloride

Monomethylamine, tetrabutylammonium


Carbohydrates, sulfate and sulfamate



Timolol maleate


Varenicline tartrate salt

Trifluormethanesulfonic acid


Camphorsulfonic acid


Potassium and zinc

Zoledronic acid

Phosphite, phosphate


Detection method: conductivity detection with suppression; direct conductivity detection; conductivity detection with and without suppression; amperometric detection; spectrophotometric detection

Summary and conclusion

IC can today be used in a wide range of applications in the pharmaceutical sector. Table 2 shows a selection of ca. 40 applications. The wide range of different columns, gradient and eluent options, sample preparation techniques and automation possibilities available to the user have meant the IC technique has become a highly versatile method.

About Metrohm

At Metrohm is one of the world’s most trusted manufacturers of high-precision instruments for chemical analysis. Metrohm was founded in 1943 by engineer Bertold Suhner in Herisau, Switzerland. Today, Metrohm is represented in 120 countries by subsidiaries and exclusive distributors. The global Metrohm Group also includes the Dutch companies Metrohm Applikon and Metrohm Autolab, manufacturers of online analyzers and instruments for electrochemical research, respectively. Recently, the Metrohm Group was joined by Metrohm Raman, a leading manufacturer of handheld Raman spectrometers.

Metrohm is the global market leader in analytical instruments for titration. Instruments for ion chromatography, voltammetry, conductivity, and stability measurement make the Metrohm portfolio for ion analysis complete. Instruments for Near-infrared and Raman spectroscopy are another, strongly growing segment of the Metrohm portfolio.

Metrohm is a problem solver, both in the laboratory and within the industrial process. To this end, the company offers their customers complete solutions, including dedicated analytical instrumentation as well as comprehensive application know-how. More than 30% of the company’s employees at the Metrohm international headquarters in Herisau work in R&D.

Metrohm has been owned 100% by the non-profit Metrohm Foundation since 1982. The Metrohm Foundation, which does not exert any influence on the company’s business operations, sponsors gifted students in the natural sciences, supports charitable and philanthropic purposes and, above all, ensures the independence of the company.

Sponsored Content Policy: publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.

Last updated: May 16, 2020 at 5:23 PM


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