Intriguing 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: debmanas@yahoo.com

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.

Keywords: IERs; resinate; taste masking; polymorphism elimination; drug delivery.

Introduction

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

Resinate preparation

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 IERs:

IER received considerable attention from pharmaceutical scientists because of their following pharmaceutical applications:

Figure 2. Characteristic pharmaceutical applications of IERs

Taste masking

The 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).

Stability enhancement

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).

Improvement of dissolution power

In 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).

Polymorphism Elimination

Polymorphism 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 al., 2010).

Disintegration

In 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 2004).

Powder processing aid

Due 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).

Improving physical property

The 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

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 tract.

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).

Figure 4. A typical representation of drug release and preparation & mechanism of floating beads

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).

Roots of drug delivery

Nasal drug delivery

The applications 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

From IERs, 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 Illum (1999).

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).

Biodiesel production

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).

Water softening

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., 2006).

Figure 5. Hard water to soft water formation in the presence of IERs

Removal of heavy metals ions

IE processes 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.

Water purification

The 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, 1998).

Recent advancements

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).

Future Prospective

Synthesis 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.

Conclusion

IERs 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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