Ion Exchange Resins in Formulation : An Update

Mrs. Ashwini R. Madgulkar

The ion exchange resins in drug delivery system are used to optimize presentation and bioavailability of established therapeutic agents. Formulations based on ion exchange resins are available in the market. Ion Exchange resins have found application not only as drug carriers, but also in a number of areas in formulations and drug delivery.

Various applications of resin in drug delivery formulations, recent developments and future scope are discussed in this review.

In the continuing search for novel drug delivery system to optimize presentation and bioavailability of established therapeutic agents, Ion exchange resins should be considered as polymers with unique advantageous properties.

Ion exchange resins (IER) may be defined as high molecular weight water insoluble polymers containing fixed positively or negatively charged functional groups in their matrix, which have an affinity for oppositely charged counterions ¹ .  

Since the majority of drugs possess an ionic site in their molecule, the charge of the resins provides a means to loosely attach such drugs to insoluble polymers.

Various studies has revealed that ion exchange resins are equally suitable for drug delivery technology ² , including controlled release, transdermal, site specific, fast dissolving, iontophoretically assisted transdermal, nasal, topical and taste masked system.

Ion exchange resins are classified as shown in table no.1 ¹

Properties of Pharmaceutical Grade Ion Exchange Resins ³ :

1) Fine, free flowing powders

2) Particle size of 25-150 microns

3) Contains functional groups capable of exchanging ions and/or ionic groups.

4) Insoluble in all solvents at all pH

5) Not absorbed by the body

6) Do not have a defined molecular weight

Mechanism

The ion exchange phenomenon is driven by electrostatic interactions between the resins and oppositely charges drugs ⁴ . The driving force behind this exchange is due to the electronic differences between the ions. The reversibility of this interaction is exploited in oral drug delivery in which the resins may carry the drug and release the payload in a certain region of the git due to a pH change or presence of competing ion.

Factors Affecting Loading of Drug onto Resins

1. Crosslinkage of Resin - Crosslinkage of Resins affects porosity and swelling properties of resins.  Low crosslinkage agents swell remarkably upon hydration. .  Higher grades have finer pore structure thus reducing loading efficiency with increase in crosslinking. Low crosslinkage increases the loading efficiency but also increases release rates ⁵ .

2. Particle Size - Particle size does not have effect on drug loading.  It affects only rate of exchange of ions species.  The rate of exchange decreases with bead diameter due to reduction in diffusive path lengths hence larger particle size affords a slow release pattern ⁵ .

3. pH- protonated fractions of moderately weak acid or basic drug and weak functionality resin undergoes change with pH changes thereby increasing/decreasing drug resin interaction and hence loading ⁶ .

4. Form of Resin – It was found that resins of H ⁺ form have high loading capacity, as it possesses lower pH value than Na ⁺ . It has been found that drugs loaded onto H ⁺ form of resin degrades while that a Na ⁺ form does not degrade ⁶ .

5. Size of exchanging ions- larger the size of exchanging ions, slower will be the    diffusion rates and release ⁷ .

6. Selectivity of Counter ions – The ions with low selectivity for resins such as H ⁺ gets replaced easily resulting in higher drug loading ⁸ .

7. Mixing Time – Drug loading increases rapidly in the initial 9 h and further increases between 20-30 h. probably because of surface absorptive phenomenon ⁹ .

Applications of Ion Exchange Resins: -

In theory, drug release from relies on the ionic environment and should therefore be less susceptible to other conditions such as enzyme contents, at site of absorption

(1) Controlled or Sustained Release System: -

A major drawback of controlled or sustained release systems is dose dumping, resulting in increased risk of toxicity.    Ion exchange resins offer better drug retaining properties and prevention of dose dumping.  The polymeric (physical) and ionic (chemical) properties of ion exchange resin will release the drugs more uniformly than that of simple matrices (because of physical properties only) ¹⁰ .

Resinates (drug loaded onto the strong ion exchanger)

Resinates used provides simplest form of controlled or sustained release delivery system.  Resinates can be filled directly in a capsule, suspended in liquids, suspended in matrices or compressed into tablets.  Drug will be slowly released by ion exchange phenomenon and absorbed ¹¹ , ¹² .

Microencapsulated or Coated resinates -Microencapsulation of resinates provides better control over the drug release because of presence of rate controlling membrane.  The absorption of the drug from coated resinates is a consequence of the entry of the counter ions into the coated resinates and release of drug ions from drug resin complex by the ion exchange process and diffusion of drug ions through the membrane into the dissolution medium ^13,14 .   

Designed release rate at the desired level can be obtained by optimization of coating thickness.  Microencapsulation of resinates can be achieved by air suspension coating (wurster process) ¹³ , interfacial polymerization ¹⁵ , solvent evaporation ⁸ or pan coating.

Pennkinetic System   Modification of the coating of resinates for improved monitoring    of the drug release pattern has been the concept of pennkinetic system.  In this system, it is pretreated with polyethylene glycol 400 to maintain the geometry and improve coating process.  The pretreated resinates are then coated with ethyl cellulose or any other water insoluble polymer, polyethylene glycol helps in controlling the swelling rate of matrix in water, while an outer ethyl cellulose coating modifies the diffusion pattern of ions in and out of system ¹⁶ .

Hollow Fiber System has advantage of high surface area to volume ratio, loading flexibility, membrane permeability and potentially slower GI transit time.  These characteristics could provide a method to obtain controlled release for drugs in the small intestine/or in colon.  Hollow fibers made from suitable polymeric materials are filled with resinate to obtain a controlled or sustained release profile. Biodegradable hollow fibers can be used for drug delivery in the form of implants ¹⁷ .

 In matrix formation   Sriwongjanya Mongkol (1998), had studied the effect of ion exchange resins on drug release from matrix tablet, they found that drug release from HPMC tablet, containing drug resin complexes was significantly slower than from HPMC tablets containing drug without resins ¹⁸ .

(2) Site Specific Drug Delivery System:-

Gastroretentive Systems

Prolonged gastric retention of the drugs formulations could improve the bioavailability and reduce drug wastages.  Floating dosage forms are one of the alternatives designed to prolong gastric residence time drugs and bicarbonate was loaded onto the resins.  The system floats in the stomach because of exchange of chloride ions for bicarbonate counter parts, releasing the carbon dioxide.  The released gas is trapped inside the membrane, causing the system to float ^{19, 20} .

Ion exchange resins may have inherent bioadhesive properties similar to those of highly charged polyanions.  Hence ion exchange resins may be useful mucoadhesive systems for topical treatment of stomach such as in H.pylori infection for prolonging the gastric residence of amoxicillin and cimetidine ²⁰ .

Site-specific delivery of Drugs for Cancer Treatment

Entrapment of anticancer drugs in the form of microspheres or microcapsules is used to treat cancer.  Attempts have been made to deliver some of these drugs in a controlled release fashion to anticancer cells with help of ion exchange resin ^{21, 22} .

Sigmoidal Release System

A sigmoidal release system releases the drug from a multiple unit device after a predetermined lag time, and can achieve both time controlled and rhythmic and release. 

Eudragit RS an Anion Exchange Resin with limited quaternary ammonium groups is coated over beads with a sugar core surrounded by organic acid and drug mixture.  The ionic environment induced by addition of an organic acid to the system, was found be responsible for pulsatile release ²³ .

(3) Taste Masking: -

Many therapeutically useful drugs are quite bitter, limiting their utility in chewable tablets designed for pediatric or geriatric use.  Bitter testing drugs can be adsorbed onto ion exchange resins, thus effectively removing them from solution during the transit through the mouth, at salivary pH (6.8), remains in intact form, making the drugs unavailable for the taste sensation ^{24, 25, 26} .

(4) Nasal drug delivery: -

Attempts have been made to deliver therapeutic peptides or synthetic drugs   via nasal mucosa with ion exchange resin complexation approach.  A composition was developed to deliver nicotine in a pulsatile fashion to the systemic circulation via nasal route ²⁷ .

(5) Stability: -

Vitamin B12, which deteriorates on storage necessitating overages in formulation leading to increased cost, can be complexed with Indion264. The complex is as effective as free form of vitamin ²⁸ . Ion exchange resins can also be used as carrier for immobilized enzymes to provide extended activity at localized sites.

(6) Improvement of dissolution of poorly soluble drugs

In the case of poorly soluble ionizable drugs, the release of drug from resinate can be faster than the rate of dissolution of the solid form of the drug. The ion exchange matrices are relatively hydrophilic and so allow water and aqueous solution easy access into a 3-dimensional structure - eliminating problems with 'wetting out' the drug ^2. Studies have shown that molecular state of the entrapped drug changes from the crystalline to amorphous state; hence rate of dissolution is enhanced ²⁹ .

(7) Tablet disintegration

Some of the ion exchange resins swell significantly on exposure to water.  This had led to their use as very effective tablet disintegrant. Fine particle size ion exchange resins have shown superiority as disintegrating agent by only few percent of the tablet weight to get complete disintegration within several minutes ³⁰ . The disintegrant property of Indion 414 by incorporating Indion 414 in fast disintegrating dosage form like mouth dissolve tablets ³¹ is used now a days.

(8) Physical state

Many drug substances are liquids or difficult to handle solids. Because the physical properties of resinates are similar to the resin and not the drug, resinate can be easily handled. Nicotine is liquid, but the resinate is a stable, free flowing solids ² .

Deliquescence is the property of a solid where by it absorbs so much water that it dissolves in the water it absorbs.  It has been very difficult one to solve, and requires the use of specialized equipment or careful scheduling of production in dry seasons.

It is found that resinate of deliquescent and highly hygroscopic drugs retains the properties of the resin and are not deliquescent and remains free flowing powders.  Their water absorption characteristics are similar to those of unloaded resins, so that any formulations equipment that can handle the resins can handle   resinate of the deliquescent drug without need for special manufacturing conditions ² .

Recent developments

Loading of poorly water-soluble drugs

A novel anhydrous method for loading water insoluble drugs such as nicotine was reported ³² . In this nicotine was dissolved in fluorocarbon solvent and cation exchange resin was suspended in solution. Solvents like 1, 1, 1, 2- tetrafluoroethane (TFE) can be used.  Pressure (520 KPascal) that maintains the solvent in the liquid state for 1 sec. to 48 hrs.is employed. The solvent is evaporated to obtain a nicotine - loaded   resinate.

Polymorphism:

Polymorphism is a very common problem in the pharmaceutical industry and huge sums of money are spent trying to identify polymorphs and trying to make stable, suitably soluble forms. Ion exchange resins present a unique way to deal with the problem.  A drug resinate is an amorphous solid that cannot crystallize or even form hydrates.  In addition the release of drugs from   resinates is   independent of crystal form that was used to make it ² .

Iontophoretically assisted transdermal drug delivery system:

Ion exchange resin could be considered as concentrated electrolytes with one immobile ionic species. The addition of ion exchange resin to get or other composites vehicles complicates the process of passive drug release. The drug release was measured as a function of current density and NaCl concentration using a novel an iontophoretic cells ³³ . Ion-exchange resins have also been used in topical products for local application to the skin, including those where drug flux is controlled by a differential electrical current (ionotophoretic delivery).

In a study which employed resinates of cationic drugs ambroxal and chlorpheniramine, the amount of drug released from the resinate prepared by simultaneous loading of (dual resinate) ambroxal and chlorpheniramine was not significantly different from that from the classical ambroxal resinate or chlorpheniramine resinate, but was considerably higher than that from the concurrent administration of two classical resinates. These results indicated that the concurrent administration of   resinates affected drug release and the dual-drug resinate can be used as an alternative carrier for an ion-exchange delivery system ³³ .

Sustained release:

It is reported that addition of unloaded resins into drug complex further delays the   release of drug. When the loaded resins enter the GI tract, the drug starts to release by the mechanism of ion exchange, however, the unloaded resins starts to absorb some of the drug because it is on either side of the equilibrium, so that newly loaded resins now starts to release drug back into solution, in which drug is dissolved, so that release of drug occurs over a period of time ² .

Conclusion: 

The strengths of ion exchange resins as drug delivery system lies in their ability to complex the drug and release it when and where required. Ion exchange resin can be custom manufactured to suit the formulation needs such as functionality, particle size, form of resin etc.  Use of ion exchange resin is finding newer applications such as for handling deliquescent and hygroscopic substances, improving stability and as superdisintegrants. More work in areas such as nasal, ophthalmic drug delivery, implants and as multifunctional excipients is needed. There is need to optimize drug loading process, make it quick environment friendly and suitable for all type of drugs which will popularize use of ion exchange resins in formulation.

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         Pharmazie, 58(3),195-199 (2003)

Common Ion exchange resins ¹

About Authors:  

^* Mrs. Ashwini R. Madgulkar

*Author for correspondence

Dr. Mangesh R. Bhalekar,

Mr. Vinay J. Kolhe,

Ms. Krishna G. Patel,

Mr. Nitin D. Wable,