TASTE MASKING BY ION EXCHANGE RESIN AND ITS NEW APPLICATIONS: A REVIEW

TASTE MASKING BY ION EXCHANGE RESIN AND ITS NEW APPLICATIONS: A REVIEW

1. K. Suhagiya*, A. N. Goyani and R. N. Gupta

Department of Pharmaceutical Sciences,Birla Institute of Technology, Mesra, Ranchi (Jharkhand), India

ABSTRACT More than 50% of pharmaceutical products are orally administered for several Reasons and undesirable taste is one of the important formulation problems that is Encountered with such oral products. Taste of a pharmaceutical product is an important parameter governing compliance. Hence taste masking of oral Pharmaceuticals has become important tool to improve patient compliance and the Quality of treatment especially in paediatrics. Different methods have been suggested for Masking of taste of bitter drugs, which includes, coating of drug particles with inert agents, taste masking by formation of inclusion complexes, molecular complexes of drug with other chemicals, solid dispersion system, microencapsulation, multiple emulsions, using liposome's, Prodrugs and mass extrusion method but ion exchange resin is one of most extensively Used method to overcome this problem. Ion-exchange resins (IER) have received considerable attention from pharmaceutical scientists because of their versatile properties as drug-delivery vehicles. In the past few years, IER have been extensively studied in the development of novel drug-delivery systems (DDSs) and other biomedical applications. Also Recently the New Applications of Ion Exchange Resin like Opthalmic Drug Delivery, Anti-Deliquescence, Improve Solubility, and Polymorphism has confirmed. This review highlights complete account of ion exchange resin and its application in drug delivery research are-discussed.

Keywords:

Taste Masking,

Ion Exchange resin,

Bitter Drugs,

Amberlite IRP,

Indion,

Tulsion,

Kyron

INTRODUCTION: One of the popular approaches in the taste masking of bitter drugs is based on Ion Exchange resin (IER). IER are solid and suitably insoluble high molecular weight poly- electrolytes that can exchange their mobile ions of equal charge with the surrounding medium. Synthetic ion exchange resins have been used in pharmacy and medicine for taste masking or controlled release of drug as early as 19501. Being high molecular weight water insoluble polymers, the resins are not absorbed by the body and are therefore inert². The long-term safety of ion exchange resins, even while ingesting large doses as in the use of cholestyramine to reduce cholesterol is an established unique advantage of IER due to the fixed positively or negatively charged functional groups attached to water insoluble polymer backbone. These groups have an affinity for oppositely charged counter ions, thus absorbing the ions into the polymer matrix.

Since most drugs possess ionic sites in their molecule, the resin's charge provides a means to loosely bind such drugs and this complex prevents the drug release in the saliva, thus resulting in taste masking. For taste masking purpose weak cation exchange or weak anion exchange resins are used, depending on the nature of drug. The nature of the drug resin complex formed is such that the average pH of 6.7 and cation concentration of about 40meq/L in the saliva are not able to break the drug resin complex but it is weak enough to break down by hydrochloric acid present in the stomach. Thus the drug resin complex is absolutely tasteless with no after taste, and at the same time, its bioavailability is not affected³. IER have received considerable attention from pharmaceutical scientists because of their versatile properties as drug delivery vehicles. In past few years, IER have been extensively studied in the development of Novel drug delivery system and other biomedical applications. Several IER products for oral and peroral administration have been developed for immediate release and sustained release purposes. Research over the last few years has revealed that IER are equally suitable for drug delivery technologies, including controlled release, transdermal, site-specific, fast dissolving, iontophoretically assisted transdermal, nasal, topical and taste masking systems.

POLYMER MATRIX: The most commonly used polymer backbone for anion exchange and strong cation exchange resin is based on polystyrene. Divinylbenzene (DVB) is included in the copolymerization for cross linking the polymer chains. The amount of DVB, usually expressed as percentage by weight has a strong effect on the physical properties. The weak cation exchange resins are generally polyacrylic or polymethacrylic acids with DVB as cross linking agents depending on the presence of ions4. Four major types of ion exchange resins are available which are summarized in Table 1.

CLASSIFICATION OF ION EXCHANGE RESINS (IER): The various ion exchange materials available can be classified as shown in Fig. 1 on the basis of nature of structural and functional components and ion exchange Process. Ion exchange resins contain positively or negatively charged sites and are accordingly classified as either cation or anion exchanger.

Table 1: Common ion exchange resin

Figure 1: Classification of ion exchange resins

Within each category, they are further classified as inorganic and organic resins. The functional group in cation exchanger and anion exchanger undergoes reaction with the cations and anions of the surrounding solution respectively. The strong cation exchanger contains sulphuric acid sites [Dowex-50] whereas weak cation exchangers [Amberlite IRC-50, Indion 204] are based on carboxylic acid moieties. The strong anion exchange resins [Dowex-1] have quaternary amine ionic sites attached to the matrix, whereas weak anion exchanger [Amberlite IR 4B] has predominantly tertiary amine substituents. Inorganic and organic exchange resin is further categorized into synthetic, semi-synthetic and natural depending on their source⁴.

SELECTION OF SUITABLE ION EXCHANGE RESIN: The selection of IER for drug delivery applications is primarily governed by the functional-group properties of the IER⁵. However, the following points need to be considered during selection:

• Capacity of the IER [i.e. the concentration of the exchangeable group in the resin, usually expressed in mill equivalents per gram (meq g–1) of dry resin];
• Degree of cross linking in the resin matrix;
• Particle size of resin;
• Nature of drug and site of drug delivery. It is also important to evaluate the resin in the pH- and ionic-strength environment, simulating the in vivo situation;
• Swelling ratio;
• Biocompatibility and biodegradability;
• Regulatory status of the IER.

For example, a low degree of cross linking of the resin will facilitate the exchange of large ions, but it will also cause volume changes in the resin upon conversion from one form to another. Similarly, the use of a strong IER will give a rapid rate of exchange, but it could also cause hydrolysis of the labile drugs because strong IER are effective acid-base catalysts. Therefore, a fine balance of all the parameters needs to be made to achieve optimal performance of drug-delivery systems (DDSs) containing IER.

CHARACTERIZATION OF IER: As the performance of DDSs depends on the quality of IER, it is important to evaluate IER at each stage of the preparation of resinates. The following parameters are generally evaluated:

• Particle size – measured directly with a set of micro sieves by screening⁶. The particle size of IER can also be determined by microscopy, Coulter counter ⁷ and other available techniques.
• Porosity – the porosity of dry IER can be determined through nitrogen adsorption at − 195°C, and by measuring the true density (mercury displacement)⁸. Scanning electron Microscopy reveals the internal pore structure. The use of an air-compression pycnometer for the determination of porosity has also been reported in the literature⁹.
• Moisture content – determined by Karl Fischer titrimetry. Excess water can be removed by drying in vacuum desiccators¹⁰.
• IE capacity – the IE capacity of strong CER is determined as meq g–1 by evaluating the number of moles of Na⁺, which are absorbed by 1 g of the dry resin in the hydrogen form^{11, 12} Similarly, the IE capacity of a strong basic AER is evaluated by measuring the amount of Cl⁻ taken up by 1 g of the dry resin in the hydroxide form.

MECHANISM OF BINDING OF ION EXCHANGE RESIN WITH DRUGS: The principle property of resins is their capacity to exchange bound or insoluble ions with those in solution. Soluble ions may be removed from solution through exchange with the counter ions adsorbed on the resin as illustrated in equation 1 and 2.

Re-So₃ ^– Na⁺ + Drug⁺               Re-SO₃ ^– Drug⁺ + Na⁺  .......................................................1

Re-N (CH₃) ⁺ Cl^– + Drug ^–             Re-N (CH₃) ⁺ Drug ^– + Cl ^– ............................................2

These exchanges 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 expression¹³ given in equation no. 3.

[D]_R [M]_S

KDM= --------------

[D]_S [M]_R

Where,

[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, p^Ka and the pH of the solutions.

Borodkin et al. used selectivity coefficient to express the interaction of eleven amino drugs with potassium salt of polacrin, a polycarboxylic acid resin. When loading of resin with an ion of less affinity, the exchange may be driven towards the direction of unfavorable equilibrium by flooding the influence with high concentration or by using chromatographic column procedures³.

RESINATE PREPARATION: Once the selection of a resin is made, the next step involves preparing its complex with drug, before designing a suitable delivery system. The main hurdle is to optimize the conditions of preparation, in order to obtain the desired drug loading in the resinates. Generally, the following steps are involved in the preparation of resinates:

• Purification of resin by washing with absolute ethanol, ethanol and water mixture¹⁴. Final washing with water removes all the impurities.
• Changing the ionic form of IER might occasionally be required to convert a resin from one form to another, if it does not have the desired counter ions¹⁵. Strongly acidic CER are usually marketed in Na⁺ form and strongly basic AER in Cl⁻ form. They are generally converted into hydrogen and hydroxide forms, respectively. The conversion can be achieved by soaking the resins with acid or alkali solutions, respectively. After changing the ionic form, the resin is subjected to washing with distilled water until elute becomes neutral in reaction, and finally is dried at 50°C.

Preparation of resinate is normally done by two techniques:

• Batch technique – after suitable pretreatment, a specific quantity of the granular IER is agitated with the drug solution until the equilibrium is established¹⁶ and;
• Column technique – resinate is formed by passing a concentrated solution of drug through the IER-packed column until the effluent concentration is the same as the eluent concentration.

DRUG RELEASE FROM IER:

• The rate and completeness of drug desorption in-vivo will be controlled by the diffusion rate of the drug through the polymer phase of the resin,(usually a function of molecular weight),the selectivity of the drug for the resin ,and the concentration of the electrolytes particularly in the hydrogen ion, in the desorption environment¹⁷.
• More hydrophobic drugs will usually elute from the resin at a lower rate, as will drugs with a relatively high selectivity for the carboxylic acid functional structure
• In the resin other resin-sorbate interactions are possible, and these can have a pronounced effect upon loading capacities and rates.
• An example of this might be the presence of the transition metal in the structure of the sorbate molecule which can result in considerable selectivity through the formation of a coordination compound with the resin.

PROPERTIES OF IER:

1. EXCHANGE CAPACITY: The capacity of an ion exchanger is a quantitative measure of its ability to take up exchangeable Counter-ions and refers to the number of ionic groups per unit weight or volume (meq per g or meq per mL). The weight-based value is generally much greater than the volume-based value since the resin is highly hydrated. However, in preparing drug– resinates, the actual capacity obtainable under specific experimental conditions would depend upon the accessibility of the functional groups for the drug of interest. The so-called ‘‘available capacity’’ will be related to the drug physicochemical properties and will be inferior to the total capacity. The exchange capacity may limit the amount of drug that may be sorbed onto a resin and the potency of a drug–resin complex. Weak cation exchangers derived from acrylic acid polymers have higher exchange capacity (~10 meq/g) than the sulfonic acid (~4 meq/g) or amine resins because of bulkier ionic substituents and the polystyrene matrix. Therefore, higher drug loads may often be achieved with the carboxylic acid resins¹⁸.
2. CROSS-LINKAGE: The degree of cross-linking depends on the percent DVB used in the copolymerization. The Ion-exchange products available today are limited to a range of 2–16 wt% DVB. Below 2 wt%, the finished ion-exchange materials lack the mechanical streng