Ion chromatography (or ion-exchange chromatography) is a
chromatography process that separates ions and polar molecules based
on their affinity to the ion exchanger. It works on almost any kind of
charged molecule—including large proteins, small nucleotides, and
amino acids. The two types of ion chromatography are anion-exchange
and cation-exchange. It is often used in protein purification, water
analysis, and quality control. The water-soluble and charged
molecules such as proteins, amino acids, and peptides bind to moieties
which are oppositely charged by forming ionic bonds to the insoluble
stationary phase. The equilibrated stationary phase consists of an
ionizable functional group where the targeted molecules of a mixture
to be separated and quantified can bind while passing through the
column—a cationic stationary phase is used to separate anions and an
anionic stationary phase is used to separate cations.
chromatography is used when the desired molecules to separate are
cations and anion exchange chromatography is used to separate
anions. The bound molecules then can be eluted and collected using
an eluant which contains anions and cations by running higher
concentration of ions through the column or changing pH of the column.
One of the primary advantages for the use of ion chromatography is
only one interaction involved during the separation as opposed to
other separation techniques; therefore, ion chromatography may have
higher matrix tolerance. However, there are also disadvantages
involved when performing ion-exchange chromatography, such as constant
evolution with the technique which leads to the inconsistency from
column to column.
4 Weak and strong ion exchangers
5 Typical technique
6 Membrane exchange chromatography
7 Separating proteins
7.1 Gibbs-Donnan effect
8.1 Clinical utility
8.2 Industrial applications
8.3 Drug development
9 See also
12 External links
Ion exchange chromatography
Ion chromatography has advanced through the accumulation of knowledge
over a course of many years. Starting from 1947, Spedding and Powell
used displacement ion-exchange chromatography for the separation of
the rare earths. Additionally, they showed the ion-exchange separation
of 14N and 15N isotopes in ammonia. At the start of the 1950s, Kraus
and Nelson demonstrated the use of many analytical methods for metal
ions dependent on their separation of their chloride, fluoride,
nitrate or sulfate complexes by anion chromatography. Automatic
in-line detection was progressively introduced from 1960 to 1980 as
well as novel chromatographic methods for metal ion separations. A
groundbreaking method by Small, Stevens and Bauman at Dow Chemical Co.
unfolded the creation of the modern ion chromatography. Anions and
cations could now be separated efficiently by a system of suppressed
conductivity detection. In 1979, a method for anion chromatography
with non-suppressed conductivity detection was introduced by Gjerde et
al. Following it in 1980, was a similar method for cation
As a result, a period of extreme competition began within the IC
market, with supporters for both suppressed and non-suppressed
conductivity detection. This competition led to fast growth of new
forms and the fast evolution of IC. A challenge that needs to be
overcome in the future development of IC is the preparation of highly
efficient monolithic ion-exchange columns and overcoming this
challenge would be of great importance to the development of IC.
The boom of
Ion exchange chromatography primarily began between
1935–1950 during World War II and it was through the "Manhattan
project" that applications and IC were significantly extended. Ion
chromatography was originally introduced by two English researchers,
agricultural Sir Thompson and chemist J T Way. The works of Thompson
and Way involved the action of water-soluble fertilizer salts,
ammonium sulfate and potassium chloride. These salts could not easily
be extracted from the ground due to the rain. They performed ion
methods to treat clays with the salts, resulting in the extraction of
ammonia in addition to the release of calcium.[unreliable source?]
It was in the fifties and sixties that theoretical models were
developed for IC for further understanding and it was not until the
seventies that continuous detectors were utilized, paving the path for
the development from low-pressure to high-performance chromatography.
Not until 1975 was "ion chromatography" established as a name in
reference to the techniques, and was thereafter used as a name for
marketing purposes. Today IC is important for investigating aqueous
systems, such as drinking water. It is a popular method for analyzing
anionic elements or complexes that help solve environmentally relevant
problems. Likewise, it also has great uses in the semiconductor
Because of the abundant separating columns, elution systems, and
detectors available, chromatography has developed into the main method
for ion analysis.
When this technique was initially developed, it was primarily used for
water treatment. Since 1935, ion exchange chromatography rapidly
manifested into one of the most heavily leveraged techniques, with its
principles often being applied to majority of fields of chemistry,
including distillation, adsorption, and filtration.
Ion-exchange chromatography separates molecules based on their
respective charged groups. Ion-exchange chromatography retains analyte
molecules on the column based on coulombic (ionic) interactions.
Essentially, molecules undergo electrostatic interactions with
opposite charges on the stationary phase matrix. The stationary phase
consists of an immobile matrix that contains charged ionizable
functional groups or ligands. The stationary phase surface
displays ionic functional groups (R-X) that interact with analyte ions
of opposite charge. To achieve electroneutrality, these inert charges
couple with exchangeable counterions in the solution. Ionizable
molecules that are to be purified compete with these exchangeable
counterions for binding to the immobilized charges on the stationary
phase. These ionizable molecules are retained or eluted based on their
charge. Initially, molecules that do not bind or bind weakly to the
stationary phase are first to wash away. Altered conditions are needed
for the elution of the molecules that bind to the stationary phase.
The concentration of the exchangeable counterions, which competes with
the molecules for binding, can be increased or the pH can be changed.
A change in pH affects the charge on the particular molecules and,
therefore, alters binding. The molecules then start eluting out based
on the changes in their charges from the adjustments. Further such
adjustments can be used to release the protein of interest.
Additionally, concentration of counterions can be gradually varied to
separate ionized molecules. This type of elution is called gradient
elution. On the other hand, step elution can be used in which the
concentration of counterions are varied in one step. This type of
chromatography is further subdivided into cation exchange
chromatography and anion-exchange chromatography. Positively charged
molecules bind to anion exchange resins while negatively charged
molecules bind to cation exchange resins. The ionic compound
consisting of the cationic species M+ and the anionic species B- can
be retained by the stationary phase.
Cation exchange chromatography retains positively charged cations
because the stationary phase displays a negatively charged functional
displaystyle text R-X ^ - text C ^ + ,+, text M ^ + , text B
^ - rightleftarrows , text R-X ^ - text M ^ + ,+, text C ^ + ,+,
text B ^ -
Anion exchange chromatography retains anions using positively charged
displaystyle text R-X ^ + text A ^ - ,+, text M ^ + , text B
^ - rightleftarrows , text R-X ^ + text B ^ - ,+, text M ^ + ,+,
text A ^ -
Note that the ion strength of either C+ or A- in the mobile phase can
be adjusted to shift the equilibrium position, thus retention time.
The ion chromatogram shows a typical chromatogram obtained with an
anion exchange column.
It is possible to perform ion exchange chromatography in bulk, on thin
layers of medium such as glass or plastic plates coated with a layer
of the desired stationary phase, or in chromatography columns. Thin
layer chromatography or column chromatography share similarities in
that they both act within the same governing principles; there is
constant and frequent exchange of molecules as the mobile phase
travels along the stationary phase. It is not imperative to add the
sample in minute volumes as the predetermined conditions for the
exchange column have been chosen so that there will be strong
interaction between the mobile and stationary phases. Furthermore, the
mechanism of the elution process will cause a compartmentalization of
the differing molecules based on their respective chemical
characteristics. This phenomenon is due to an increase in salt
concentrations at or near the top of the column, thereby displacing
the molecules at that position, while molecules bound lower are
released at a later point when the higher salt concentration reaches
that area. These principles are the reasons that ion exchange
chromatography is an excellent candidate for initial chromatography
steps in a complex purification procedure as it can quickly yield
small volumes of target molecules regardless of a greater starting
Chamber (left) contains high salt concentration. Stirred chamber
(right) contains low salt concentration. Gradual stirring causes the
formation of a salt gradient as salt travel from high to low
Comparatively simple devices are often used to apply counterions of
increasing gradient to a chromatography column. Counterions such as
copper (II) are chosen most often for effectively separating peptides
and amino acids through complex formation.
A simple device can be used to create a salt gradient.
is consistently being drawn from the chamber into the mixing chamber,
thereby altering its buffer concentration. Generally, the buffer
placed into the chamber is usually of high initial concentration,
whereas the buffer placed into the stirred chamber is usually of low
concentration. As the high concentration buffer from the left chamber
is mixed and drawn into the column, the buffer concentration of the
stirred column gradually increase. Altering the shapes of the stirred
chamber, as well as of the limit buffer, allows for the production of
concave, linear, or convex gradients of counterion.
A multitude of different mediums are used for the stationary phase.
Among the most common immobilized charged groups used are
trimethylaminoethyl (TAM), triethylaminoethyl (TEAE),
diethyl-2-hydroxypropylaminoethyl (QAE), aminoethyl (AE),
diethylaminoethyl (DEAE), sulpho (S), sulphomethyl (SM), sulphopropyl
(SP), carboxy (C), and carboxymethyl (CM).
Successful packing of the column is an important aspect of ion
chromatography. Stability and efficiency of a final column depends on
packing methods, solvent used, and factors that affect mechanical
properties of the column. In contrast to early inefficient dry-
packing methods, wet slurry packing, in which particles that are
suspended in an appropriate solvent are delivered into a column under
pressure, shows significant improvement. Three different approaches
can be employed in performing wet slurry packing: the balanced density
method (solvent’s density is about that of porous silica particles),
the high viscosity method (a solvent of high viscosity is used), and
the low viscosity slurry method (performed with low viscosity
Polystyrene is used as a medium for ion- exchange. It is made from the
polymerization of styrene with the use of divinylbenzene and benzoyl
peroxide. Such exchangers form hydrophobic interactions with proteins
which can be irreversible. Due to this property, polystyrene ion
exchangers are not suitable for protein separation. They are used on
the other hand for the separation of small molecules in amino acid
separation and removal of salt from water. Polystyrene ion exchangers
with large pores can be used for the separation of protein but must be
coated with a hydrophillic substance.
Cellulose based medium can be used for the separation of large
molecules as they contain large pores. Protein binding in this medium
is high and has low hydrophobic character. DEAE is an anion exchange
matrix that is produced from a positive side group of
diethylaminoethyl bound to cellulose or Sephadex.
Agarose gel based medium contain large pores as well but their
substitution ability is lower in comparison to dextrans. The ability
of the medium to swell in liquid is based on the cross-linking of
these substances, the pH and the ion concentrations of the buffers
Incorporation of high temperature and pressure allows a significant
increase in the efficiency of ion chromatography, along with a
decrease in time. Temperature has an influence of selectivity due to
its effects on retention properties. The retention factor (k = (tRg
− tMg)/(tMg − text)) increases with temperature for small ions,
and the opposite trend is observed for larger ions.
Despite ion selectivity in different mediums, further research is
being done to perform ion exchange chromatography through the range of
An appropriate solvent can be chosen based on observations of how
column particles behave in a solvent. Using an optical microscope, one
can easily distinguish a desirable dispersed state of slurry from
Weak and strong ion exchangers
A "strong" ion exchanger will not lose the charge on its matrix once
the column is equilibrated and so a wide range of pH buffers can be
used. "Weak" ion exchangers have a range of pH values in which they
will maintain their charge. If the pH of the buffer used for a weak
ion exchange column goes out of the capacity range of the matrix, the
column will lose its charge distribution and the molecule of interest
may be lost. Despite the smaller pH range of weak ion exchangers,
they are often used over strong ion exchangers due to their having
greater specificity. In some experiments, the retention times of weak
ion exchangers are just long enough to obtain desired data at a high
Resins (often termed 'beads') of ion exchange columns may include
functional groups such as weak/strong acids and weak/strong bases.
There are also special columns that have resins with amphoteric
functional groups that can exchange both cations and anions. Some
examples of functional groups of strong ion exchange resins are
quaternary ammonium (Q), which is an anion exchanger, and sulfonic
acid (S), which is a cation exchanger. These types of exchangers
can maintain their charge density over a pH range of 0–14. Examples
of functional groups of Weak ion exchange resins include
diethylaminoethyl (DEAE), which is an anion exchanger, and
carboxymethyl (CM), which is a cation exchanger. These two types
of exchangers can maintain the charge density of their columns over a
pH range of 5–9.
In ion chromatography, the interaction of the solute ions and the
stationary phase based on their charges determines which ions will
bind and to what degree. When the stationary phase features positive
groups which attracts anions, it is called an anion exchanger; when
there are negative groups on the stationary phase, cations are
attracted and it is a cation exchanger. The attraction between
ions and stationary phase also depends on the resin, organic particles
used as ion exchangers.
Each resin features relative selectivity which varies based on the
solute ions present who will compete to bind to the resin group on the
stationary phase. The selectivity coefficient, the equivalent to the
equilibrium constant, is determined via a ratio of the concentrations
between the resin and each ion, however, the general trend is that ion
exchangers prefer binding to the ion with a higher charge, smaller
hydrated radius, and higher polarizability, or the ability for the
electron cloud of an ion to be disrupted by other charges. Despite
this selectivity, excess amounts of an ion with a lower selectivity
introduced to the column would cause the lesser ion to bind more to
the stationary phase as the selectivity coefficient allows
fluctuations in the binding reaction that takes place during ion
Ion chromatography system
A sample is introduced, either manually or with an autosampler, into a
sample loop of known volume. A buffered aqueous solution known as the
mobile phase carries the sample from the loop onto a column that
contains some form of stationary phase material. This is typically a
resin or gel matrix consisting of agarose or cellulose beads with
covalently bonded charged functional groups. Equilibration of the
stationary phase is needed in order to obtain the desired charge of
the column. If the column is not properly equilibrated the desired
molecule may not bind strongly to the column. The target analytes
(anions or cations) are retained on the stationary phase but can be
eluted by increasing the concentration of a similarly charged species
that displaces the analyte ions from the stationary phase. For
example, in cation exchange chromatography, the positively charged
analyte can be displaced by adding positively charged sodium ions. The
analytes of interest must then be detected by some means, typically by
conductivity or UV/visible light absorbance.
Control an IC system usually requires a chromatography data system
(CDS). In addition to IC systems, some of these CDSs can also control
gas chromatography (GC) and HPLC.
Membrane exchange chromatography
A type of ion exchange chromatography, membrane exchange is a
relatively new method of purification designed to overcome limitations
of using columns packed with beads. Membrane Chromatographic
devices are cheap to mass-produce and disposable unlike other
chromatography devices that require maintenance and time to
revalidate. There are three types of membrane absorbers that are
typically used when separating substances. The three types are flat
sheet, hollow fibre, and radial flow. The most common absorber and
best suited for membrane chromatography is multiple flat sheets
because it has more absorbent volume. It can be used to overcome mass
transfer limitations and pressure drop, making it especially
advantageous for isolating and purifying viruses, plasmid DNA, and
other large macromolecules. The column is packed with microporous
membranes with internal pores which contain adsorptive moieties that
can bind the target protein. Adsorptive membranes are available in a
variety of geometries and chemistry which allows them to be used for
purification and also fractionation, concentration, and clarification
in an efficiency that is 10 fold that of using beads. Membranes
can be prepared through isolation of the membrane itself, where
membranes are cut into squares and immobilized. A more recent method
involved the use of live cells that are attached to a support membrane
and are used for identification and clarification of signaling
Preparative-scale ion exchange column used for protein purification.
Ion exchange chromatography can be used to separate proteins because
they contain charged functional groups. The ions of interest (in this
case charged proteins) are exchanged for another ions (usually H+) on
a charged solid support. The solutes are most commonly in a liquid
phase, which tends to be water. Take for example proteins in water,
which would be a liquid phase that is passed through a column. The
column is commonly known as the solid phase since it is filled with
porous synthetic particles that are of a particular charge. These
porous particles are also referred to as beads, may be aminated
(containing amino groups) or have metal ions in order to have a
charge. The column can be prepared using porous polymers, for
macromolecules over 100,000 the optimum size of the porous particle is
about 1 μm2. This is because slow diffusion of the solutes within the
pores does not restrict the separation quality. The beads
containing positively charged groups, which attract the negatively
charged proteins, are commonly referred to as anion exchange resins.
The amino acids that have negatively charged side chains at pH 7 (pH
of water) are glutamate and aspartate. The beads that are negatively
charged are called cation exchange resins, as positively charged
proteins will be attracted. The amino acids that have positively
charged side chains at pH 7 are lysine, histidine and asparagine.
The isoelectric point is the pH at which a compound - in this case a
protein - has no net charge. A protein’s isoelectric point or PI can
be determined using the pKa of the side chains, if the amino (positive
chain) is able to cancel out the carboxyl (negative) chain, the
protein would be at its PI. Using buffers instead of water for
proteins that do not have a charge at pH 7, is a good idea as it
enables the manipulation of pH to alter ionic interactions between the
proteins and the beads. Weakly acid or basic side chains (such as
in leucine, proline, alanine, valine, glycine…etc.) are able to have
a charge if the pH is high enough to deprotonate the amino group.
Separation can be achieved based on the natural isoelectric point of
the protein. Alternatively a peptide tag can be genetically added to
the protein to give the protein an isoelectric point away from most
natural proteins (e.g., 6 arginines for binding to a cation-exchange
resin or 6 glutamates for binding to an anion-exchange resin such as
Elution by increasing ionic strength of the mobile phase is more
subtle. It works because ions from the mobile phase interact with the
immobilized ions on the stationary phase, thus "shielding" the
stationary phase from the protein, and letting the protein elute.
Elution from ion-exchange columns can be sensitive to changes of a
single charge- chromatofocusing. Ion-exchange chromatography is also
useful in the isolation of specific multimeric protein assemblies,
allowing purification of specific complexes according to both the
number and the position of charged peptide tags.
In ion exchange chromatography, the
Gibbs–Donnan effect is observed
when the pH of the applied buffer and the ion exchanger differ, even
up to one pH unit. For example, in anion-exchange columns, the ion
exchangers repeal protons so the pH of the buffer near the column
differs is higher than the rest of the solvent. As a result, an
experimenter has to becareful that the protein(s) of interest is
stable and properly charged in the "actual" pH.
This effect comes as a result of two similarly charged particles, one
from the resin and one from the solution, failing to distribute
properly between the two sides; there is a selective uptake of one ion
over another. For example, in a sulphonated polystyrene resin,
a cation exchange resin, the chlorine ion of a hydrochloric acid
buffer should equilibrate into the resin. However, since the
concentration of the sulphonic acid in the resin is high, the hydrogen
of HCl has no tendency to enter the column. This, combined with the
need of electroneutrality, leads to a minimum amount of hydrogen and
chlorine entering the resin.
A use of ion chromatography can be seen in the argentation ion
chromatography. Usually, silver and compounds
containing acetylenic and ethylenic bonds have very weak interactions.
This phenomenon has been widely tested on olefin compounds. The ion
complexes the olefins make with silver ions are weak and made based on
the overlapping of pi, sigma, and d orbitals and available electrons
therefore cause no real changes in the double bond. This behavior was
manipulated to separate lipids, mainly fatty acids from mixtures in to
fractions with differing number of double bonds using silver ions. The
ion resins were impregnated with silver ions, which were then exposed
to various acids (silicic acid) to elute fatty acids of different
Detection limits as low as 1 μM can be obtained for alkali metal
ions. It may be used for measurement of HbA1c, porphyrin and with
Ion Exchange Resins(IER) have been widely used
especially in medicines due to its high capacity and the uncomplicated
system of the separation process. One of the synthetic uses is to use
Ion Exchange Resins for kidney dialysis. This method is used to
separate the blood elements by using the cellulose membraned
Another clinical application of ion chromatography is in the rapid
anion exchange chromatography technique used to separate creatine
kinase (CK) isoenzymes from human serum and tissue sourced in autopsy
material (mostly CK rich tissues were used such as cardiac muscle and
brain). These isoenzymes include MM, MB, and BB,
which all carry out the same function given different amino acid
sequences. The functions of these isoenzymes are to convert creatine,
using ATP, into phosphocreatine expelling ADP. Mini columns were
filled with DEAE-Sephadex A-50 and further eluted with tris- buffer
sodium chloride at various concentrations (each concentration was
chosen advantageously to manipulate elution). Human tissue extract was
inserted in columns for separation. All fractions were analyzed to see
total CK activity and it was found that each source of CK isoenzymes
had characteristic isoenzymes found within. Firstly, CK- MM was
eluted, then CK-MB, followed by CK-BB. Therefore, the isoenzymes found
in each sample could be used to identify the source, as they were
Using the information from results, correlation could be made about
the diagnosis of patients and the kind of CK isoenzymes found in most
abundant activity. From the finding, about 35 out of 71 patients
studied suffered from heart attack (myocardial infarction) also
contained an abundant amount of the CK-MM and CK-MB isoenzymes.
Findings further show that many other diagnosis including renal
failure, cerebrovascular disease, and pulmonary disease were only
found to have the CK-MM isoenzyme and no other isoenzyme. The results
from this study indicate correlations between various diseases and the
CK isoenzymes found which confirms previous test results using various
techniques. Studies about CK-MB found in heart attack victims have
expanded since this study and application of ion chromatography.
Since 1975 ion chromatography has been widely used in many branches of
industry. The main beneficial advantages are reliability, very good
accuracy and precision, high selectivity, high speed, high separation
efficiency, and low cost of consumables. The most significant
development related to ion chromatography are new sample preparation
methods; improving the speed and selectivity of analytes separation;
lowering of limits of detection and limits of quantification;
extending the scope of applications; development of new standard
methods; miniaturization and extending the scope of the analysis of a
new group of substances. Allows for quantitative testing of
electrolyte and proprietary additives of electroplating baths. It
is an advancement of qualitative hull cell testing or less accurate UV
testing. Ions, catalysts, brighteners and accelerators can be
Ion exchange chromatography has gradually become a
widely known, universal technique for the detection of both anionic
and cationic species. Applications for such purposes have been
developed, or are under development, for a variety of fields of
interest, and in particular, the pharmaceutical industry. The usage of
ion exchange chromatography in pharmaceuticals has increased in recent
years, and in 2006, a chapter on ion exchange chromatography was
officially added to the United States Pharmacopia-National Formulary
(USP-NF). Furthermore, in 2009 release of the USP-NF, the United
States Pharmacopia made several analyses of ion chromatography
available using two techniques: conductivity detection, as well as
pulse amperometric detection. Majority of these applications are
primarily used for measuring and analyzing residual limits in
pharmaceuticals, including detecting the limits of oxalate, iodide,
sulfate, sulfamate, phosphate, as well as various electrolytes
including potassium, and sodium. In total, the 2009 edition of the
USP-NF officially released twenty eight methods of detection for the
analysis of active compounds, or components of active compounds, using
either conductivity detection or pulse amperometric detection.
An ion chromatography system used to detect and measure cations such
as sodium, ammonium and potassium in Expectorant Cough Formulations.
There has been a growing interest in the application of IC in the
analysis of pharmaceutical drugs. IC is used in different aspects of
product development and quality control testing. For example, IC is
used to improve stabilities and solubility properties of
pharmaceutical active drugs molecules as well as used to detect
systems that have higher tolerance for organic solvents. IC has been
used for the determination of analytes as a part of a dissolution
test. For instance, calcium dissolution tests have shown that other
ions present in the medium can be well resolved among themselves and
also from the calcium ion. Therefore, IC has been employed in drugs in
the form of tablets and capsules in order to determine the amount of
drug dissolve with time. IC is also widely used for detection and
quantification of excipients or inactive ingredients used in
pharmaceutical formulations. Detection of sugar and sugar alcohol in
such formulations through IC has been done due to these polar groups
getting resolved in ion column. IC methodology also established in
analysis of impurities in drug substances and products. Impurities or
any components that are not part of the drug chemical entity are
evaluated and they give insights about the maximum and minimum amounts
of drug that should be administered in a patient per day.
High performance liquid chromatography
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Library resources about
Ion exchange chromatography
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Van Deemter equation