WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Venkatesh et al. World Journal of Pharmacy and Pharmaceutical Sciences

Volume 2, Issue 6, 4764-4777. Review Article ISSN 2278 – 4357

OVER VIEW- ION EXCHANGE RESINS IN CONTROLLED DRUG

DELIVERY SYSTEM

Venkatesh DP*1, Roopa karki1, Divakar Goli1, Sajal Kumar Jha2

1
Acharya and BM Reddy College of Pharmacy, Soldevanahalli, Achit nagar post, Bangalore,
India. 560107.
2
Bengal College of pharmaceutical sciences and Research, Durgapur, West Bengal.

Article Received on ABSTRACT

21 September 2013,
Revised on 19 October 2013,
Accepted on 27 November
2013
*Correspondence for
Author:
* Venkatesh DP,
Acharya and BM Reddy
College of Pharmacy,
Soldevanahalli, Achit nagar
post, Bangalore, India.
venkateshdp@acharya.ac.in
Key words: Microencapsulation; Ion exchange resins; Drug-resinates; Controlled release.
Controlled release drug delivery systems are gaining popularity. One
of the attractive methods for modified drug delivery systems preferably
controlled type is ion-exchange resins as carriers for such systems. Ion-
exchange resinates of drugs can help in reducing the dose. Reduced
fluctuations in blood and tissue concentrations and maintenance of
drug concentration below toxic level can be achieved. Ample work
was done and patents were reported with the preparation and
evaluation of resinates for a large variety of drugs. Ion exchange resins
have specific properties like available capacity, acid base strength,
particle size, porosity and swelling properties. The ion exchange resins
are complexed with drug to form resinates by batch or column process.
Microencapsulated resinates provides better control over the drug
release because of the rate controlling membrane.

INTRODUCTION
Ion exchange resins are solid and suitably insolubilized high molecular weight
polyelectrolyte’s which can exchange mobile ions of similar charges with the surrounding
medium reversibly and stochiometrically. They are available in desired size ranges.[3] Ion
exchange resins have received considerable attention from pharmaceutical scientists because
of their versatile properties as drug delivery. Research over the last few years has revealed
that ion exchange resins are equally suitable for drug delivery technologies, including
controlled release, transdermal, nasal, topical and taste masking. The use of ion exchange

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resins has occupied an important place in the development of controlled or sustained- release
system because of their better drug retaining properties and prevention of dose dumping. Ion
exchange resins have been used as drug carriers in pharmaceutical dosage forms for
controlled release formulation.[2] The semi permeable coating around ion exchange resin
particles provides desired level of retardation of drug availability in the gastrointestinal tract
over a period of time.[4]

An ion exchange resins exhibited like small bead with a diameter between 1-2 mm, it is
fabricated from an organic polymer substrate backbone. Ion exchange systems are
advantageous for the drugs that are highly susceptible to degradation by enzymatic process.

Advantages [5] of ion exchange resins include

 Economic and readily available.
 Free from local and systemic toxicities.
 Drug-resinates can be formulated into various dosage forms like tablets, capsules,
suspensions etc.
 Can be used for several purposes such as taste masking, sustained and rapid release.
 Effectively useful in low concentration (5-20%w/w).
 Resins have high drug loading.

Types of Ion-exchange Resins [1],[6],[8]

There are two major classes of ion-exchange resins (a) Cation and (b) Anion exchange resins.

Strong acid
Cation exchange
acidacid
resins Weak acid
Ion exchange
resins Anion exchange
Strong base
resins

Weak base

Fig 1: Types of Ion exchange resins

Cation exchange resins contain covalently bond negatively charged functional groups and
exchanges positively charged ions. These are prepared by the copolymerization of styrene
and divinyl benzene and have sulfonic acid groups (-SO3H) introduced into most of the
benzene rings.

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CH 2
HC

CH 2
HC

CH
H 2C

Fig 3: Structure of styrene Fig 4: Structure of divinyl benzene

Anionic exchange resins have positively charged functional groups and it exchange
negatively charged ions.
Ion-exchange systems are advantageous for drugs that are highly susceptible to degradation
by enzymatic process.
The use of ion exchange resins into drug delivery systems have been encouraged because of
their physico-chemical stability, inert nature, uniform size, spherical shape assisting coating
and equilibrium driven reproducible drug release in ionic environment.

General method of preparation of drug resinates[1]

 The foremost step in the preparation of drug-resinates is to purify the resins carefully.
Purification generally done by cycling repeatedly between sodium and hydrogen forms with
cation-exchanger or between the chloride and hydrogen forms in case of anionic exchangers.
Final washing with water to remove all the impurities.
Drugs to be formulated into resinates, should have in their chemical structure acidic or basic
groups with its biological half life t1/2 between the ranges of 2 to 6 hours. It should be well
absorbed from all the areas of the gastrointestinal tract and also it should be stable in the
gastric juice.

Loading of drugs: Loading of drugs is done by two ways [3]

a) Column process: A highly concentrated drug solution is eluted through a bed or column
of the resin, until equilibrium is established.
b) Batch process: The resin particles are stirred with a large volume of concentrated drug
solution. Subsequently the resin is to be washed to remove adhering free and un-associated
drug and thereafter it is air dried.

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Properties of ion exchange resins[1]

 Particle size: The rate of ion exchange reaction depends on the size of the resin particles.
Decreasing the size of the resin particle significantly decreases the time required for the
reaction to reach equilibrium with the surrounding medium.

 Porosity and swelling: The porosity of an ion-exchanger depends not only on the amount
of cross-linking substances used in polymerization but mainly on polymerization
procedures. The structural parameters considerably influence the swelling behaviour of
the resin and consequently have a marked effect on the release characteristics of drug
resinates.The amount of swelling is directly proportional to the number of hydrophilic
functional groups attached to the polymer matrix and is inversely proportional to the
degree of divinylbenzene cross-linking present in the resin.

 Cross-linkage: The percentage of cross-linking affects the physical structure of the resin
particles. Resins with low degree of cross-linking can take up a considerable amount of
water and swell into a structure that is soft and gelatinous. However, resins with a high
divinyl benzene content swell very little, the particles take up only a small amount of
water and consequently are somewhat and brittle.

 Available capacity: The capacity of an ion exchanger is a quantitative measure of its

ability to take-up exchangeable counter-ions and is therefore of major importance.
However in the preparation of drug resonates, the actual capacity obtained under specific
experimental conditions depends on the accessibility of the functional group for the drug
of interest.

 Acid base strength: The acid base strength of an exchange is dependent on various
ionogenic groups, incorporated into the resin. Resin containing sulfonic, phosphonic or
carboxylic acid exchange groups have approximate pKa values of 1, 2-3 and 4-6,
respectively. Anionic-exchangers are quaternary, tertiary or secondary ammonium groups
having apparent pKa values of greater than 13, 7-9 or 5-9, respectively. The pKa value of
the resin will have a significant influence on the rate at which the drug will be released
from resinates in the gastric fluid.

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 Selectivity of the resins for the counter ion

Factors other than size and charge also contribute to the selection by an ion-exchange
resin of one counter ion in preference to another. The extent of sorption increases with
i. The counter ion that, in addition to forming a normal ionic bond with the functional group
of an exchanger, also interacts through the influence of Vander- Waals forces with the
resin matrix.
ii. the counter ion least affected by complex formation with its co-ion or non exchanging
ion,
iii. the counter ion that induces the greater polarization.

 Stability: The resinous ion-exchangers are remarkably inert substances. At ordinary

temperature and excluding the more potent oxidising agents, vinyl benzene cross-linked
resins are resistant to decomposition through chemical attack, but degeneration in the
presence of storage gamma ray sources.

 Purity and Toxicity: The drug resinates combinations contain 60% or more of the resins.
Commercial products cannot be used as such because they contain impurities that cause
toxicity. Therefore careful purification of the resin prior to treatment with the drug is
required.

Applications in drug delivery system

The use of ion exchange resins has occupied an important place in the development of
controlled or sustained release systems because of their better drug retaining properties and
prevention of dose dumping2.

Sustained or controlled release formulations

The use of ion exchange resins for oral sustained release oral formulations occupies
important place. It has several advantages like:
 Rate constant for drug absorption is less variable.
 Readily controllable particle shape.
 Release rate of drug from resinates is found to be more predictable.
 Ion exchange resinates of drugs can help in reducing the dose.
 Maintenance of drug concentrations below toxic level can be achieved.

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[2]
Pharmaceutical applications : Some Pharmaceutical applications of ion exchange resins
includes
 Controlled/sustained drug delivery: Microencapsulated or coated resinates:
Microencapsulated of resinates provides better control over the drug release because of the
presence of a rate controlling membrane. The absorption of the drug from coated resinates is
a consequences of the counter ions into the coated resinates, release of drug ions from the
drug-resin complex by ion exchange process, and diffusion of drug ions through the
membrane into the surrounding absorption environment3, 4.

Drug release of the drug-resin complex and its microcapsules

It is controlled by three possible mechanisms
1. Mass or chemical reaction control: The exchange reaction between the counter ion and
drug.
2. Particle diffusion control: The release of drug through the porous within its particles.
3. Membrane diffusion control: The release of drug across the thin layer around the particle.
Pennkinetic systems further modification of the coating of resinates for improved
monitoring of the drug release pattern. In this system, resinates is pre-treated with
polyethylene glycol to maintain the geometry and improve the coating process and also helps
in controlling the rate of swelling of the resinate matrix in water [11].
 Cholesterol reducer: Cholestyramine resin USP, when used as an active ingredient,
binds bile acids; this leads to replenishment of bile acids; through increased metabolism of
serum cholesterol resulting in lowered serum cholesterol levels.
Cholestryamine and cholestipol are used in the treatment of type II hyperlipoproteinemia and
familial hyperlipoproteinamia in children and young adults.

 Taste masking: Bitter cationic drugs can get adsorbed onto the weak cation exchange
resins of carboxylic acid functionally to form the complex which is non bitter. Further
resinates can be formulated as dispersible tablets and mask the taste.
Avari et al. reported taste masking of highly bitter antibiotic, sparfloxacin with indion 204
weak cationic exchanger[3],[25].

 Improvement of tablet disintegration properties: Many tablets disintegrates owe their

action to capacity to absorb water and swell up. Fine particle size ion-exchange resins have

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shown superiority as disintegration agents due to their considerable swelling pressures upon
hydration [25].

 Improving the dissolution of poorly soluble drugs and Eliminating polymorphism:

Drug resin complexation converts drug to amorphous form. Hence, drug with poor solubility,
during the process of desorption, immediately releases the drug leading to improved drug
dissolution.

 Improving stability: Complexing active ingredients with ion-exchange resins prevents

harmful interaction with other components like vitamin B12 and carboxylic acid this
complexes as effective as free drug. Ion exchange resins can also be used as carrier for
immobilized enzymes to provide extended activity at localized sites.

 High purity of water: There will always be a need for purified water in the production of
pharmaceuticals. Water softening uses a cation exchange resin to exchange principally
calcium and magnesium ions for sodium ions and so prevent the formation of calcium
carbonate precipitates on reverse osmosis membranes.

Therapeutic Applications
Ion exchange resins have found use in the treatment of various pathological states such as
hyperacidity, treatment of ulcer; Na and K supplement depletion, nephrotic, pancreatic and
cardiac edema etc. Moreover, anion exchange resins have been used in the treatment of
hyperglycemias. Cholestyramine, a quaternary ammonium anion-exchange resin originally
was used to control pruritus in patients with elevated plasma bile acid concentrations. But
presently, it is recommended as an adjunctive therapy to patients with elevated serum
cholesterol. Another anion exchange resin Colestipole hydrochloride acts by increasing
fractional carbolic rate of low density lipoproteins (LDL) thereby decreasing LDL.

 Regulation of ion exchange resins for the food, water and beverage industries
The FDA has the responsibility to define conditions under which safe food additives may be
used in the production and preparation of foods and beverages. According to Section 25, use
of ion exchange resins under following conditions. i. The resins must be one of a preapproved
generic list of resin compositions (listed in 21 CFR 173.25); ii. The resins must be subjected
to pursue treatment by the manufacture and/or user in accordance with the manufacturer’s

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directions; iii. The resins must be found to result in not more than 1 part per million organic
extractives.

Methodology
The following methods are most frequently used for the preparation of microcapsules.
 Emulsion polymerization
 Suspension crosslinking
 Solvent evaporation
 Coacervation/phase separation
 Air suspension coating (Wurster process).

Chemical deterioration of the resins

Chemical deterioration of the resins is the result of several different processes. Breaking of
covalent bonds between the resin matrix and functional groups results in losses of the groups
and reduction of the ion exchange capacity. Exposing of strong anion exchange resins to the
combined influence of a strong alkali and elevated temperature results in chemical altering or
loss of the functional groups. Organic substances sorbed can cycle, i.e. regenerated and
washed.

Ion exchange resins possess different release properties. They have fixed ionic functional
groups which can provide binding of ionic drugs. Release of the bound drugs requires
exchange with counter ions such as hydrogen or sodium, which are available in
gastrointestinal tract. The overall drug release kinetics of the polymer coated ion exchange
resins are mainly dependent upon the drug and counter ion diffusion resistance in the coating
film and the boundary layer film surrounding the particles.

Manufacture of Ion Exchange resins [36]

Most of the ion exchange resins are made by the process of suspension polymerization. In
some cases the monomers are neutral (e.g styrene, methyl acrylate and acrylonitrile) and the
resulting polymer beads are then chemically modified to introduce the acid or base
functionally; for example, sodium polystyrene is prepared by suspension polymerization of a
mixture of styrene and divinyl benzene to make small polymeric beads. The beads are then
sulfonated using concentrated sulphuric acid and neutralized with sodium hydroxide to give a
functionalized product-a sodium form of a strongly acidic cation exchange resin.

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A few resins are made directly from acidic monomers; for example, polacrilex resin is made
by suspension polymerization of a mixture of methacrylic acid and divinyl benzene with no
further functionalization.
For use in pharmaceutical formulations, the resins are usually dried and then ground to a fine
powder, typically in the range of 40-150µm in size.

Selection of ion exchange resins based on

 Capacity of ion exchange resins (The concentration of the exchangeable group in the
resin, usually expressed in milliequivalents per gram of dry resin).
 Degree of cross linking in the resin.
 Particle size of the resin.
 Nature of drug and site of drug delivery.
 Swelling ratio.
 Biocompatibility and biodegradability.
 Regulatory status of ion exchange resins.

Drug release from the resin depends on the two factors [5]
a) The ionic environment (i.e., pH and electrolyte concentration) within the gastrointestinal
tract.
b) The properties of resin.
Drug molecules attached to the resin are released by exchanging with appropriate charged
ions in the GIT, followed by diffusion of free drug molecule out of the resins. The process
can be depicted by the following equation (1) & (2) for anion exchange and cation exchange
respectively, where X & Y are ions in the GI tract.
Resin+ -Drug- + x- Resin+ -x- +drug- (1)
Resin- +Drug+ + Y+ Resin- -Y+ +Drug+ (2)
Resins involve ion exchange as reversible interchange of ions between solid and a liquid
phase in which there is a no permanent change in the structure of the solid.
These reactions are equilibrium reactions in which the extent of exchange is governed by the
relative affinity of the resins for particular ions. Relative affinity between ions may be
expressed as a selectivity co-efficient derived from mass action expression given in equation.
KDM = [D] R [M]s
[ D]s [M]R
Where

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[D]R = Drug concentration in resin

[ D]s = Drug concentration in the solution
[M]s = Counter ion concentration in the solution
[M]R = Counter ion concentration in the resin
Factors that influence selectivity include valency, hydrated size, pKa and pH of the solutions.

Drug suitable for resinate preparations

Drugs that are to be formulated into resinates should satisfy the following conditions:
 Drug should have acidic or basic groups in their chemical structure.
 The biological half life should be between 2-6 hours; drugs with t1/2<1 hr or >8 hrs are
difficult to formulate in this category.
 The drug is to be absorbed from all regions of the GI tract. In the case of limited
absorption zone, the bioavailability will be insufficient.
 Drug should be sufficiently stable sufficiently in the gastric juice, other wise; their
therapeutic effectiveness will drop drastically.

Evaluation of drug-resinates
The in-vitro tests demonstrate the release pattern of a drug from a resinate preparation dosage
form which depends on:
i. Size of resinate
ii. Degree of cross linkage
iii. Ionogenic groups of resins
iv. Nature of the drug
v. The test conditions e.g: Ionic strength of dissolution medium [37].

Boyd et al.,(1947) found that the release process of ionic drug ions from resinates eluted with
simulated gastric or intestinal fluids is controlled mostly by particle diffusion.
Chem et al.,(1992) carried out a comparative study of doxorubicin loading, release
characteristics and stability within sodium and hydrogen forms of ion-exchange resin
microspheres. They concluded that in comparison with H+ form, resins in the Na+ form can be
considered as better carriers for doxorubicin in terms of sustaining the release of drug and
maintaining the activity.

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Vimla Devi and Suneeta, (1993) prepared drug resonates of glypizide with four anionic
resins. They concluded that drug release and absorption are affected by hydrophobicity,
method of preparation, nature of polymer, particle size and nature of coat.

In-vivo tests
In-vivo procedures used for estimating drug activity of resinates include serum concentration
level determination, urinary excretion and toxicity studies. Blood concentration level
determinatuions have been used frequently [38].
Torres et al., (1955) studied the in vivo behaviour of enteric microcapsules containing
diclofenac-resin complexes with respect to uncoated complexes and a commercial product.
The bioavailability of the diclofenac released from the microcapsules and the uncoated resins
was studied in rabbits.

Table 1. Examples of Drug delivery systems using ion-exchange resins

Ion-exchange resin Drug Type of system Remarks

Indion 244 Bromohexine Microencapsulated Controlled release oral liquid
Hydrochloride resinate suspension was formulated.
Dowex 1-x2 Diclofenac Microencapsulated Flexible coating of of Eudragit RS
Sodium resinate 30 D having thickness of few
micrometers on resinate by wurster
process can give a good control over
drug release
Amberlite IL-120 Metoclopramide Resinate Method of determining diffusion
controlled release drug from resinate
was prepared.
Dowex1-X2,1- Theophylline Microencapsulated The pattern of release of the drug
X4,1-X8 resinate was dictated by the cross linking of
the resin and the coating process
used.
Amberlite CG-50 CPM Maleate Microencapsulated Polymethylmethacrylate-coated
W resinate resinates of higher diameter were
prepared and finely divided solids
added to reduce the microcapsule
size and to control release.
Indion 412 Fluvastatin Microencapsulated Drug resinates coated with ethyl
Sodium resinate cellulose and eudragit RS 100 shows
better controlled release.

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