Journal of Ravishankar University–B,
33 (1), 47-57 (2020)
Clinical and Pharmaceutical Applications of IERs: A Mini Review
Anushree Saha, Manas
Kanti Deb*, Mithlesh Mahilang, Shubhra Sinha
School of Studies in Chemistry, Pt. Ravishankar Shukla
University Raipur-492010, Chhattisgarh, India
*Corresponding Author: firstname.lastname@example.org
[Received: 06 September 2020; Accepted: 21 September 2020]
Abstract. Ion exchange resins (IERs) are solid
poly-electrolytes which have both sorption and exchange capacity of several
organic compounds. They have the power to separate ionic and non-ionic
substances with the surrounding medium. The drug materials or substances are
adsorbed on resin, which is commonly known as resinate, these features of IERs
have useful applications in pharmaceutical formation (i.e., taste masking,
stability & solubility enhancement, etc.) and major applications in drug
delivery (i.e., oral, nasal, ophthalmic, transdarmal drug delivery). IE
principles have been exploited in the investigation of numerous drug industry
problems for many years. Synthetic IERs have been extensively employed in
pharmacy and medicine, especially for taste masking or controlled release of
drugs and have been expansively studied in the development of novel drug
delivery systems and other biomedical applications. In this review, the
fascinating IERs involving ion exchange processes in pharmaceutical and
clinical applications and also their recent advanced uses have been discussed.
resinate; taste masking; polymorphism elimination; drug delivery.
IERs or ion
exchange polymers are resins which act as a medium for the exchange of ions.
They are solid, insoluble, high molecular weight polyelectrolytes that have the
capability of exchanging their mobile ions of equivalent charge with the
surrounding medium. In general, IERs are in the form of small (0.5-1.0 mm
radius) microbeads; usually white or yellowish and are made-up from an organic
polymer substrate. The resins are prepared as spherical beads whose diameter is
around 1.0 to 2.0 mm. Notably, they appear solid even under the microscope;
however, the structure on a molecular scale is quite open. The IERs have a
gamut of properties which include the following: The first one in the list
includes exchange capacity, which is the number of ionic groups per unit weight
or volume (meq g-1 or meq mL-1). It is a quantitative
measure of its ability to take up the exchangeable counter-ions. Second is the
cross-linking property, which depends on the percentage of Divinyl benzene
(DVB) used in the copolymerization. The next following property is ionization.
It is a known fact that in all ion exchangers and the ionization of the
attached functional group is depends on the presence of water in the matrix.
The amount of water that will be imbibed by an ion-exchange resin sequentially
depends on the polymer cross-linking. The type and the strength of an IER are
determined by the functional group ionization. It is worth mentioning that the
strong acid cation and strong base anion-exchange resins are fully hydrated in
aqueous media. Also, the ions related to the functional group are always free
to exchange with the like charge ions present in the solution being processed.
Furthermore, particle size and form are also important, which follows that the
rate of IE reaction is dependent on the size of the resin particles. The next
is porosity and swelling. Porosity is the ratio between the volume of the
material and its mass. It is a strong factor that affects the limiting size of
the ions, which can penetrate the resin matrix. Stability is another important
property exhibited by the IERs. It is a notable fact that IERs are
indestructible and inert substances at ordinary temperature and they are also
resistant to chemical attack decomposition (excluding the more potent oxidizing
agents). However, the presence of gamma rays can degrade or degenerate IER.
Purity and toxicity are yet another important property of the IERs. Due to the
very high fraction of the resin in drug–resin complex (>60%), it becomes
essential to establish the safety/toxicity of the IERs. It is seen that most of
the commercial products cannot be used as such due to the presence of
impurities which ultimately cause severe toxicity. Besides, the selectivity of resin
for the counter ion is an essential property exhibited by them. IERs involve
electrostatic forces, hence the selectivity majorly depends on the relative
charge and ionic radius of hydrated ions competing for an exchange site. Some
extent the selectivity also depends on the hydrophobicity of competitor ion.
IE principles have been exploited in the
investigation of numerous drug industry problems. Before the development of
synthetic adsorbents, siliceous gel zeolites were extensively employed in
pharmaceutical research, chiefly in the development of simplified analytical
control procedures. The phenomenon of ion exchange was first identified and
described in 1850 as occurring naturally in alumino-silicate minerals
(Kitchener and Miller, 1958; Kunin, 1958; Simon, 1991). But, most of these
natural ion exchangers (e.g., zeolites and clays) decomposes irreversibly in
acid solutions and have a very low exchange capacity, which results in a
limited application in the hydrometallurgy field. In 1934, Adams and Holmes
synthesized phenol-formaldehyde resin and showed that this resin can be used as
a substitute for zeolites (Anand et al., 2001). Since as early as 1950,
synthetic ion exchange resins have been extensively employed in pharmacy and
medicine, especially for taste masking or controlled release of the drug. IERs
have been expansively studied in the development of a novel drug delivery
system and other biomedical applications. Numerous IER products have been
developed for instant release and sustained release purposes concerning oral
and peroral administration. The research in recent decades has revealed that
IERs are suitable for drug delivery technologies, including fast-dissolving,
controlled release, site-specific, transdermal, ion to phonetically assisted
transdermal, nasal, topical and taste masking systems. The diverse ion exchange
materials available can be categorized based on the nature of structural and
functional components and ion exchange process (Figure 1). IERs contain
positively or negatively charged sites and are accordingly classified as either
cation or anion exchanger. Based on the nature of the exchangeable ion of the
resins as a cation or anion, it is further classified as A) Cation exchange
resin (CER) and B) Anion exchange resin (AER), respectively (Dyer and Williams,
1999; Srikanth et al., 2010).
Figure 1. Classification of IER
The drug resin complexes are commonly known as resinates (Hughes,
2005). For several purposes such as drug delivery (DD), taste masking, stabilizing,
juice purification and clinical field, resinate are used. Resinates are
prepared by, a substance (like a drug) mixed with resin in a solution and
prevent sufficient time (few hours) for loading (Anand et al., 2001; Hughes,
2005). After that, the suspension of resin is filtered and washed. Resinates
can be dried at 600C in a vacuum oven which depends upon their application. In
some cases, the slurry of resinates is directly dried without filtration while
in others, in which liquid suspension of resinate was used, drying may not be
required. The dried form of resinate with their properties similar to real
resin can be used to form tablets, capsules, lozenges and chewing gums etc. It
can also be coated through a typical coating substance (Hughes, 2005).
In this present review,
different advancements in the applications of IERs mainly in the
pharmaceutical, drug delivery, therapeutic and clinical use of IERs have been
discussed. The main objective of this review is to discuss the further developments
in applications of IER, in the field of pharmaceutical science and as well as
the developments of IERs as drug liberation materials.
Pharmaceutical applications of
IER received considerable attention from pharmaceutical scientists
because of their following pharmaceutical applications:
2. Characteristic pharmaceutical
applications of IERs
bitter taste of drugs serves as a major problem (especially for pediatric and
geriatric patients) (Dyer and Williams, 1999; Srikanth et al., 2010). Taste
masking has therefore become a major challenge to the pharmaceutical industry.
Taste masking of distasteful drugs improves the compliance of patients and also
improves the product value (Dyer and Williams, 1999; Mahore et al., 2010; Sohi
et al., 2004; Srikanth et al., 2010). IERs are inexpensive so it can be used to
develop taste-masking (Roy, 1997). Since nearly all drugs have ionic sites,
these ionic charges of IERs provide a means to bind such drug molecules
loosely. The drug release in the saliva is prevented by this complex, thereby
resulting in taste masking. Normally, less cross-linked IERs are helpful in
taste masking (Illum, 1999). For taste masking, weak CER or AER are used,
depending on the nature of the drug. The average pH of the formed resin drug
complex is maintained to 6.7 (Berge et al., 1996). At salivary pH (6.8), drug
resin complexes (resinate) remain in intact form, making the drug
unapproachable for the taste sensation (Anand et al., 2001; Meidar, 1978). Saliva
can’t able to break the drug resin complex but it is weak enough to break down
by hydrochloric acid present in the stomach (Lu et al., 1991). The
taste-masking technique has been successfully done in drugs like paroxetine
(Hughes and Gehris, 2003), ranitidine (Hughes, 2004) and dextromethorphan
(Pisal et al., 2004), etc. Further polystyrene matrixes CER have been used to
mask the bitter taste of chlorpheniramine maleate, ephedrine hydrochloride and
diphenydramine hydrochloride (Manek and Kamat, 1981). And for masking quinolone
category antibacterial ciprofloxacin hydrochloride, Indion 234 is used (Kanios,
2002; Pisal et al., 2004).
The real drug materials are frequently less stable than drug
resinate. For the improvement in the stability of the original drug, resinates
are used (Srikanth et al., 2010). For example, the shelf life of vitamin B12
has few months whereas it’s resinate form has greater shelf life than their
purest form (Dyer and Williams, 1999; Srikanth et al., 2010). For these, weak
acid CER such as Indol-264 are commonly applying (Siegel, 1962). Further
nicotine exposure to light and air get discolor, but using resinate for forming
nicotine chewing gums and logenges is more stable (Dyer and Williams, 1999;
Hughes, 2005; Kankkunen et al., 2002; Srikanth et al., 2010).
of dissolution power
the case of poorly soluble drugs, IERs enhance the solubility of the drug,
because IERs are hydrophilic in nature and allow aqueous solutions to enter in
the cross-linked resin structure (Dyer and Williams, 1999; Hughes, 2005; Hughes
and Gehris, 2003; Mahore et al., 2010; Srikanth et al., 2010). For these
purposes, complex drug-resinate is used. Since each drug molecule is situated
at a functional group position of resin fragment, results in conversion to
other crystal forms (e.g. lattice energy, etc). These approaches enhancing the
drug dissolution rate (Malik et al., 2010).
is the ability of drug stuff to exist as two or more than two crystalline
phases, having dissimilar conformations or arrangement of molecule in the
crystal lattice (Brittanin and Grant, 1999; Irwin et al., 1990). In the
pharmaceutical industry polymorphism is a usual problem and to identify
polymorphs as well as making it stable, an appropriate soluble form huge sum of
money is spent. To overcome this problem, ion exchange resins (resinate form)
are used. The drug resin complex (resinate), is an amorphous solid that cannot
crystallize (Irwin, 1974). When the drug is released from resinate, it is
independent of the crystal form, that’s why it is used. Normally, resinates can
be used to eliminate any problem among polymorphism (Hughes, 2005; Srikanth et
pharmacy, tablet disintegrates have high swelling power. IERs have excellent
power to uptake water and swell (Mahore et al., 2010; Elder, 2005). The rate of
swelling of resin is because of the small particle size, making the resin
super-disintegrant. Such type of property has led to the resin as good tablet
disintegration. For example; weakly acidic CERs of pollacrilline a potassium
salt with methacrylic acid divinyl benzene matrix (Van abbe and Rees, 1998;
Vincent and Warfield, 1963). Although resins are insoluble, the affinity of
resin towards water is enormous and hence it acts as disintegrant (Van Rheenen
to the presence of atmospheric moisture, hygroscopic drugs are disposed of
agglomeration. The IER adsorption of such drugs may show a decrease in their
hygroscopicity. Moreover, the uniform, macro-reticular morphology of IER will
provide admirable flowability to the formulation (Chaubal, 2003).
physical properties of drug resinate mainly depend upon resin and not upon the
drug. Some drugs are present in liquid form or are difficult to stay or handle
as solids, resinates of such drugs are free-flowing solids (Hughes, 2005;
Sriwongjanya and Bodmeier, 1998). For example; in nicotine lozenges and chewing
gums, nicotine resinates are used. The nicotine resinate is a free-flowing,
stable solid whereas nicotine is in liquid form. The uniform, macroteticular
morphology of resin provides admirable flowability to the formulation (Hughes,
2005; Srikanth et al., 2010). Many of ion exchange resins are used in
pharmaceutical formation. Some of them are listed in Table 1.
Table 1. Some standard ion
exchange resins and their use in pharmaceutical
Roham and Haas
Taste masking agent
and Drug stabilizing agent
Roham and Haas
Taste masking and drug stabilizing agent
Roham and Haas
agent, Tablet disintegrant
Roham and Haas
Taste masking and drug stabilizing agent6
IERs in drug delivery
From most of the known applications of ion exchange resin, ‘Drug
delivery’ covers one of the wide areas. Especially, the drug bound to IER (i.e.
resinate) utilizes in drug delivery (Chaudhry and Saunders 1956; Raghunathan et
al., 1981) (Table 2). Since the significance of the drug delivery system is to
improve patient compliance. The drug delivery system should deliver a
particular drug to the target site of the body, over a period of time and at a
controlled rate (Chaudhry and Saunders, 1956). The use of IER in drug delivery
is because of physico-chemical properties of IER, like inert nature, uniform
size, good stability, porosity and spherical shape, etc (Akkaramongkolporn et
al., 2001; Dong et al., 2016). These physico-chemical properties of IER will
release the drug more perfectly than that of simple drug formulation (Chaubal,
2003) (Fig. 3 & 4).
Where, A+ and A- are ions in alimentary
Figure 3. The
release of drug from resinate by charged ions in alimentary tract
For the long-lasting release
of the drug, semi-permeable coatings are used. This provides drug accessibility
in the alimentary tract over a period of time (Ichikawa et al., 2001). Resinates
of cation exchange resin (strongly acidic) are used to formulate several
capsules, tablets and microparticles, etc. so that, strong (CE) resinates of
sulphuric acid are more suitable than that of weak (CE) resinates of carboxylic
acid for the sustained release of the drug (Jeong and Park, 2008).
Table 2. Names of IERs using in drug
determining diffusion-controlled release drug from resinate was presented
[Bhaskar et al.,
Amberlite and Dowex
affecting loading and release studied
[Irwin and Belaid,
Dowex 50 W
Fibers filled with
encapsulated resinate were prepared and evaluated for in vitro and on vivo
[Burke et al.,
oral liquid suspension was formulated
[Ulviya and Amrita,
Resicat ABM Na-042
Two binding sites
for Na+ and hence, two release rate processes were discovered by
oil/oil or oil/water solvent evaporation method
Figure 4. A typical
representation of drug release and preparation & mechanism of floating
Where, Resin is represented
by the inner blue circle, Positive (+) sign represents the integral ion of the
resin, A- is the counter ion, Na+ is sodium ion, hydrochloric acid
is represented by H+Cl-, C+ and X-
represents the drug ion and ion associated with drug ion, respectively, and
other ions represent the adsorption of ions at the resin surface, as well as at
the interior of the resin (Cuna et al., 2000).
Nasal drug delivery
of IERs to build up the novel nasal formulation of nicotine are established by
Cheng et al. (Cheng et al. 2002). The high capacity of IER material is a
condition for nasal drug delivery. Normally, excess amounts of nicotine were
overloaded in ion exchange resin (Mizushima et al. 1999). For the smoke
termination of pulsatile and continued plasma nicotine profile, the powder
forms of amber lite-nicotine resin complex are used (Cheng et al., 2002; Illum,
1999; Higaki et al., 1998).
Ophthalmic drug delivery
ophthalmic drug delivery of Betaxolol involves taking away a drug from drug
resinate. The drug resin complex is formed when a CER (Amberlite IRP69) binds
with a positive ion drug. Normally 0.25% ophthalmic suspension of the drug
shows an increased bioavailability (Jani et al., 1994). For antiglaucoma drug
(Betaxolol), IERs microparticulates have been reported as a sustained release
ophthalmic drug carrier (Arnold, 1986). The delivery of ciprofloxacin complex
with polystyrene sulfonate for the eye infection treatment was reported by
Oral drug delivery
In the case of
oral drug delivery, the drug resin complex (resinate) is used. A resinate can
be used as a drug reservoir, which caused a change in drug release in
hydrophilic polymer tablets. The main negative aspect of the sustained release
is dose dumping, which has results in increased toxicity. The IER holds an
important place in controlled and sustained drug release system
(Akkaramongkolporn and Ngawhirunpat, 2003; Anand et al., 2001; Junyaprasert and
Manwiwattanakul, 2008; Hanninen et al., 2003; Hughes, 2004).
Transdermal drug delivery
IERs are also
involved in transdarmal drug delivery. From the Carbopol-based gel vehicles
containing IER, in which the ketoprofen had been bound and release was resolute
across 0.22 μm microporous membrane (Higaki et al., 1998; Yu et al., 2006).
Therapeutic applications of IERs
Reducing cholesterol level When USP resin
cholestyramine is used as an active ingredient, it binds with bile acids; leads
to replenish bile acid during increased metabolism of serum cholesterol, which
results in lowering the serum cholesterol level (Mehndal and Malshe, 1991).
Nicorette gum formation Nicotine chewing gum
(Nicorette gum) is extensively used as a product for the smoking cessation
program. As the chewing gum is chewed it provides continuing drug release
through glycol mucosa. Mainly it contains nicotine resinate (i.e. nicotine
adsorbed on an IER) (Bellamy and Hughes, 2003; Chakrabarti and Sharma, 1993;
Sriwongjanya and Bodmeier, 1998).
IERs in clinical field
CER with polystyrene
backbone is mostly used in clinical medicine. Two main types the sulphonated
and carboxylic acid resins are widely used (Anand et al., 2001; Payne, 1956).
The selectivity of adsorbing ions on ion exchange resin is most favourable than
the counter ion of the resin. In the condition of water and sodium retention,
diseases like toxemia of pregnancy, cardiac failure, nephrotic syndrome (renal
disease) and cirrhosis of the liver, resins are widely used (Anand et al.,
2001; Payne, 1956). Taking carboxylic acid resin containing cations can remove
Na+ ions from the alimentary canal and control edema. In the
stomach, other resins are furthermore consumed to lesser acidity and hence are
used to relieve ulcers in the stomach (Anand et al., 2001; Payne, 1956). In the
condition of remove Na+ by resins, it is claimed that for reducing
the blood pressure a low sodium diet is often efficient and the resin should be
used as underpinnings of a low sodium diet (Gill et al., 1952). In general, the
utility of resins in the clinical report is not very optimistic in hypertension
(Greenman et al., 1953).
Other applications of IERs
Nitro compound reduction
Different Nitro compounds are reduced as well as oxidised by IERs,
used in the form of nanocomposites which is made by the immobilization of metal
(i.e. silver and gold) nanoparticles in IER matrix (Jana et al., 2006; Praharaj
et al., 2004).
Feng et al. (2010) reported that the
heterogeneous catalyst: CER can be used for the biodiesel production (Feng et
al., 2010; Sharma et al., 2011).
As a surface adsorber
IERs are used as a good adsorber for the dyes, pigments, metal ion
(i.e. arsenic and mercury, etc.) and biomolecules such as; glucose, fructose,
galactose and mannose etc. (Dambies, 2005; Saari et al., 2010).
IERs are applicable in replacement of the magnesium and calcium
ions found in hard water (Fig. 3). In the softening of water, a CER in the
sodium form is used to remove hardness ions (Ca and Mg) from the water along
with difficult traces of iron (Fe) and manganese (Mn), which are also
frequently present (Alchin, 1998). The fresh resin contains Na+ ions
at its active sites but when it interacts with water, the above-mentioned ions
preferentially migrate out of the solution to the active sites present on the
resin surface, thus being replaced in solution by Na ions. The reason behind
this is so that there is no change in the total dissolved solids content of the
water, similar to that in the case of pH and anionic content (Greenleaf et al.,
Figure 5. Hard water to soft water formation in the presence of IERs
Removal of heavy metals ions
have been extensively employed in the removal processes of heavy metals from
wastewater because of the advantages like high exclusion efficiency, high
handling capacity and fast kinetics (Kang et al., 2004). IERs have the specific
ability to exchange their cations with the metal ions in the wastewater. Among
the materials used in IE processes, artificial IERs are usually favored, as
they are effective towards virtual removal of the heavy metal ions from the
solution (Alyuz and Veli, 2009). Das et al. (1999) reported the high
selectivity of the imidazolylazo resin matrix for efficient separation of
palladium (II) and silver (I) metals from synthetic mixtures, medicinal and
geological samples. This is due to the presence of soft basic pyrrolic N-H in
the imidazolylazo matrix, which plays a key role in the binding of metal ions
with the resin matrix. Similarly, they have also stated the heavy metal removal
application of IERs having benzimidazolylazo groups in the polystyrene
divinylbenzene matrix (Das et al., 1999). Chen et al. (2020) recently reported
an efficient lignin-based CERs one-pot preparation method for Pb removal.
purification process of water not only involves the removal of heavy metal ions
but also removing dyes, pigments, pesticides, micro-pollutants and all the
contaminations which decreases the quality of water sources. Many of the
researches have been done by using IERs or IER nanocomposites to overcome these
problems (Haddad et al., 2019; Jia et al. 2020). Jia et al. (2020) reported the
easy and quick removal process by employing magnetic IER for effective removal
of methyl orange and Congo red anionic dyes. Water purification involves the
removal of poisonous heavy metals ions of Cu, Pb and Cd from water by replacing
them with more innocuous ions, such as Na+ and K+. The
work reported by Xing et al. (2007) describes the removal of Cr and V ions by
absorption onto weak-base anionic resin (Xing et al., 2007). Almost all the
dissolved substance in natural water supplies is in the form of charged ions.
In brief, the procedure applied was deionization or demineralization (Alchin,
New development methods in polymers point towards the emphasis on the
wastewater treatment method with active sites which ultimately offers new
approaches (Calmon, 2018). To efficiently extract and recover the pentavalent
vanadium as vanadate ion and hexavalent chromium as chromate ion from
wastewater, the AERs were investigated as environment-friendly methods in batch
tests using macro-porous weak base resin Dex-V (Calmon, 2018). Recently, the
weak CER has been used as a taste masking iron suspension in the pharmaceutical
field (Kouchak et al., 2018). It is also involved in hydrometallurgical
processing (Sole et al., 2018).
of Resin immobilized metal nano-composites and employed as an adsorbent for
removal of various dyes from water and also for the removal of dyes from
different food samples. They can be utilized as efficient catalysts for
numerous oxidation and reduction processes. In addition, these nano-composite
particles may also be used for pharmaceutical formations i.e. for taste
masking, drug delivery, etc.
play an important role in most of the fields such as pharmaceutical
formulation, anhydrous loading, clinical, therapeutic, juice purification,
metal separation, water purification and water softening, etc. A broad array of
CER and AER is available to remove ionic contamination dissolved in water.
Resins are widely used for the demineralization and dealkalization process.
They are also used as chelating resin and as reducer resin for reducing one
compound to another. Moreover, several drug delivery concepts recently get
desirable performance. In the field of drug delivery research, the use of IERs
is gaining importance and commercial success. Including oral drug delivery, IER
scheme is being explored for nasal, ophthalmic, transdermal, as well as
site-specific routes. Ion exchange resins are now commercially available in
several products as adsorber, catalyst and in the form of resinate.
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