Pharmaceutical Applications of Ion-Exchange Resins - Journal of

In the Classroom edited by

Products of Chemistry

George B. Kauffman

Pharmaceutical Applications of Ion-Exchange Resins

California State University Fresno, CA 93740

David P. Elder GlaxoSmithKline Pharmaceuticals, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom; [email protected]

Natural products demonstrating ion-exchange or adsorptive properties have been used for millennia for the treatment of ailments. The ancient Greeks were aware of the properties of charcoal for the treatment of poisoning and of clays, such as kaolin, for the treatment of diarrhea. The inability to characterize, modify, and vary the underlying physicochemical properties of charcoal and clays has meant that these agents have never gained wide acceptance in the modern era. In contrast, synthetic ion-exchange resins have clearly defined structures, and many variants with differing physicochemical properties have been synthesized, which have enjoyed wide applicability in medicine (1). Ion-exchange resins have a long commercial history. They were first invented over 60 years ago and were developed predominantly by Rohm and Haas and Dow Chemical Companies, both of whom continue to manufacture these products today. A generic structure of a cation-exchange resin based on the polymethacrylic polymer is shown in Figure 1. Ion-exchange resins are used to “soften” hard water. The presence of calcium or magnesium in water results in “hardness”. These mineral ions in the water react with metallic ⫺

O R⫹

O C

H

H

H

C

C

C

C

C H3

H

H

CH3

H

H

C

C

C

C

H

H

H

C O

⫺

O R⫹

n

Figure 1. Generic structure of a cation-exchange resin based on polymethacrylic acid; where R = hydrogen for Amberlite IRC-50 and IRP-64 and R = potassium (partial) for Amberlite IRP-88 (reproduced with permission of Rohm and Haas).

Table 1. Classification for Water Hardness (Hardness as Calcium Carbonate) Classification

Concentration/ (mg/L)

GPGa

Soft Moderate Hard Very hard

0–60

0–3.5

61–120

3.5–7

121–180

7–10.5

> 180

> 10.5

a

GPG is grains per gallon

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plumbing and chemical agents such as detergents to reduce the cleaning effectiveness of laundry, dish washing, and bathing. The calcium and magnesium ions are present typically in combination with sulfate, chloride, carbonate, and bicarbonate ions. These minerals are measured generally in either parts per million or as milligrams per liter. The American Society of Agricultural Engineers has classified water hardness as indicated in Table 1. There are four main reasons for removing these minerals before use; they • form soap curds that are difficult to clean • deposit scale that clogs plumbing and fixtures • build up scale in water-using appliances such as water heaters • require additional energy costs, and reduce equipment efficiency

For most applications with water in hard and very hard classifications, an ion-exchange water softener is the desired alternative. The hard water passes through a tank containing a high-capacity ion-exchange resin, usually microporous sulfonated polystyrene beads. The beads are supersaturated with sodium to cover both their exterior and interior surfaces. As the water passes through the bed of softening materials there occurs an ion-exchange reaction. Calcium and magnesium ions attach to the resin beads, while the sodium on the resin is released into the water. This “softening” process is illustrated in Figure 2. Ion-exchange beads are durable, but after softening a large quantity of hard water the beads become saturated with calcium and magnesium ions. When this occurs, the softener must be regenerated or recharged. This is done by flushing the ion-exchange resin with a salt solution to replenish the resin with sodium ions. Frequency of regeneration depends upon the hardness of the water, the quantity of water used, the size of the unit, and the capacity of resins to remove hardness. Sixty to seventy-five minutes are required for the salt solution to pass through the unit and flush the tank before soft water is again available. While the best known usage of ion-exchange resins is in water treatment, pharmaceutical applications were recognized in the early 1950s when Amberlite IRC-50 (2) was used in the successful purification of streptomycin (Rohm and Haas use the designation IRC to denote ion-exchange resin chemical grade and the designation IRP to denote ion-exchange resin pharmaceutical grade). Over the succeeding five decades, ion-exchange resins have found use as pharmacologically-active ingredients in drug formulations, inactive ingredients in tablets and capsule formulations (i.e., excipients), taste masking of bitter tasting drugs, controlled and extended release of drugs, and drug stabilization. This review will focus on these applications. However, it is worth noting that ion-

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Journal of Chemical Education

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In the Classroom

Table 2. Some Medicinal Applications of Ion-Exchange Resins Applications

Resin Description

Sodium reduction (hypertension and cardiac oedema)

Weakly acidic cation-exchange resins; e.g,. Amberlite IRP-64 and IRP-88

Potassium removal (renal problems)

Weakly acidic cation-exchange resins; e.g., Amberlite IRP-64

Gastric pH indicator (diagnostic tool)

Weakly acidic cation-exchange resins; e.g,. Amberlite IRP-64 azure blue indicator

Modified release of drug administration (allergy and cough control)

Strongly acidic cation-exchange resins; e.g., Amberlite IR-120

Functional excipient; palatability (tastemasking agent), disintegrant

Weakly acidic cation-exchange resins; e.g., Amberlite IRP-88 K salt

Vaginal pH control (vaginitis)

Weakly acidic cation-exchange resins; e.g., Amberlite IRP-64

Product stabilization (vitamin B12)

Weakly acidic cation-exchange resins; e.g., Amberlite IRP-64 salt of vitamin B12

Bile acid sequestreant (pruritis and cholesterol reduction)

Quaternary ammonium anion-exchange resin; e.g., Amberlite XE-268, colestyramine

NOTE: Information reproduced with permission of Rohm and Haas.

exchange resins have also been used in pharmaceutical manufacturing for the isolation and purification of drugs and catalysis of reactions (3). Some established applications of ionexchange resins in the medicinal field are listed in Table 2. Theory The interactions between the drug and the ion-exchange resin are primarily chemical in nature, but do involve some physical adsorption, particularly with poly(styrene– divinylbenzene) resins (4). The intrinsic chemical process is a variant of the classical “double decomposition” process, with the resident ions on the ion-exchange resin (termed the

counter ion) exchanging with a suitable ion of the same charge; in this particular case, a drug ion (5). The affinities of these ionic species (drug and counter ion) for the ion-exchange resin are competitive in nature. Based on the nature of the ionic species being exchanged, the process is either anionic or cationic; with the resins utilized in the process being either anion-exchange resins, or cation-exchange resins, respectively. Ion-exchange resins are synthetic polymeric materials that contain basic or acidic groups that are able to interact with ionizable molecules to create insoluble complexes. Ionexchange resins are composed of two different components. softening process

recharge process

hard water containing calcium and magnesium

waste water containing calcium and magnesium

softened water containing sodium

brine solution containing sodium

ion-exchange resin with sodium attached

ion-exchange resin saturated with calcium and magnesium

Figure 2. Water-softening process based on ion-exchange reaction. Key to figure elements:

576

ion-exchange resin

calcium ions

magnesium ions

sodium ions


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Firstly, a functional component (basic or acidic) composed of different chemical moieties, for example, for acidic resins, carboxylic or sulfonic acid groups to which the counter ion(s), for example, potassium or hydrogen, are bound. Secondly, a structural component composed of the polymer matrix. Most current ion-exchange resins are based on polystyrene or polymethacrylic polymers. The resins themselves are completely insoluble in all biological media. The chemistry of the ion-exchange resins are such that the drug retains its biological characteristics, but it is immobilized onto a solid support (6). Upon reaching the delivery site, the exchange process is reversed, resulting in the liberation of the drug ions. Due to their high molecular weight and insoluble nature, ion-exchange resins are not absorbed by the body with the consequence that they are extremely safe to use in medicinal products and have limited side effects.

than that of the drug substance. They demonstrated that sodium valproate:resin complexes remained free flowing even after exposure to ambient temperature and humidities (24 ⬚C兾55% RH); whereas, the drug substance eventually deliquesced when stored under the same conditions. The data are summarized in Table 4. One interesting, and possibly counterintuitive observation was that increasing the drug loading in the drug–anionexchange resin complex actually decreased the quantity of moisture absorbed to levels below that of the uncomplexed anion-exchange resin (Table 5). Hughes and co-workers confirmed these intriguing results using a cationic drug that exhibits deliquescence, rivastigmine bitartrate, complexed with a cation-exchange resin. There was no explanation provided for these strange results.

Drug Stabilization The chemical stability of certain medicinal products are adversely affected by prevailing environmental factors, particularly temperature and humidity levels. Vitamin B12, cyanocobalamin, is used in the treatment of pernicious anemia, but tends to be relatively unstable in most pharmaceutical preparations. One elegant approach to the stabilization of this vitamin is salt formation, with the weak carboxylic acid resin, Amberlite IRP-64 (7). The data show a significant improvement in the stability of the cyanocobalamin (Table 3). Although the cyanocobalamin is stabilized as a relatively inert vitamin:resin complex, the biological activity remains unaffected as the vitamin is readily liberated in vivo. Ju et al. (8) demonstrated that the chemical stability of omeprazole: colestyramine complex (strong anionic-exchange resin), was better than for the drug alone. The decomposition of the drug–resin complex followed pseudo zero-order kinetics. The in vitro dissolution rates (the rate of the drug dissolving per unit time in the appropriate medium; usually, biological in nature, for example, simulated gastric or intestinal fluid) of the drug complex were also increased, compared with that of the drug substance. The toxicity of the new drug–resin complex was also found to be satisfactory (LD50 mouse 4.6 g兾kg), and the authors claimed improved bioavailability compared to omeprazole. Galat (9) was assigned a German patent for the stabilization of water-soluble derivatives of aspirin. The stabilization was achieved using anionic-exchange resins. Researchers (10) at Hoffman La Roche claimed improved stabilization of 7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2one using complexation with anion-exchange resins. The stability of the drug in aqueous anode or cathode departments of ionotophoretic devices (transdermal systems where the drug flux is controlled by a differential electrical current) during storage is a major practical issue. Formation of drug– ion-exchange resin complexes has been proposed as a general stabilization procedure (11). Recent work from the Rohm and Haas laboratories (12) have shown that drug–resin complexes can reduce excess water uptake of drug substances during manufacture and storage. Hughes and co-workers found that drug–resin complexes of drugs exhibiting deliquescence and high hygroscopicity retain the beneficial physical properties of the resin, rather www.JCE.DivCHED.org

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Table 3. Stabilization of Vitamin B12 in Tablet Formulations using Salt Formation with Amberlite IRP-64 Ion-Exchange Resin Vitamin B12–Resin Complex

Vitamin B12

Storage Conditions

Mass/ (µg/tablet)

Initial (%)

Mass/ (µg/tablet)

Initial (%)

Initial

1.18

60 days, 40 °C

0.65

100.0

1.16

100.0

55.1

1.10

94.8

6 months, 25 °C

1.00

84.7

1.10

94.8

12 months, 25 °C

0.89

75.4

1.09

94.0


Table 4. Water-Uptake Behavior of Sodium Valproate and Sodium Valproate–Anion-Exchange Resin Complexes Appearance after 30 min

Appearance after 60 min

Na valproate–colestyramine USP

Free flowing

Free flowing

Na valproate–Amberlite IRA-458

Free flowing

Free flowing

Na valproate–Amberlite IRA-67

Free flowing

Free flowing

Na valproate–colestipol USP

Free flowing

Free flowing

Sticky

Liquid

Drug–Resin

Na valproate


Table 5. Water-Uptake Behavior of Sodium Valproate and of Different Drug Loadings of Sodium Valproate–Colestipol USP Complexes Moisture Gain (% w/w)

Drug:Resin Colestipol USP

59.6

11% Valproate:colestipol USP

54.3


48.6


41.8

Na valproate

Liquid



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In the Classroom

Disintegrants

Mechanism of Disintegration Absorption of a drug in the gastrointestinal tract from a solid oral dosage form (tablet or capsule) is dependent on the drug’s being liberated from the intact tablet in a soluble form prior to transit across the biological membrane. This process involves a combination of disintegration into particles of progressively smaller particle size, allied to dissolution of the resultant particles to produce the drug in solution (13). In many cases water uptake alone will cause disintegration, by rupturing the intra-particle cohesive forces that hold the tablet together and resulting in subsequent disintegration. If swelling occurs simultaneously with water uptake the channels for water penetration are increased by physical rupture and thus the penetration rate for the ingress of water into the tablet is accelerated. The most important features of the disintegration process are wetting, water uptake or wicking, swelling, deformation, and particle repulsion. There are several mechanisms that may contribute to the disintegration process. Bolhuis et al. (14) and Lerk et al. (15) studied the rate of wetting of disintegrants and concluded that if wetting was slowed then so to was disintegration. Khan and Rhodes (16) concluded that the ability of particles to draw up water into the porous network of a tablet (a process called wicking) was essential for efficient disintegration. Van Kamp et al. (17) indicated that the rate of water uptake is responsible for the action of a disintegrant. One of the most widely accepted mechanisms of disintegrant action is swelling. Gissinger and Stamm (18) found a positive correlation between rate of swelling and disintegrant activity. Bolhuis et al. (14) found that rapid swelling activity of the so-called super disintegrants, for example, sodium starch glycollate and croscarmelose sodium, were capable of overcoming the natural reluctance of hydrophobic excipients to draw up water into the porous network of a tablet. Podczek and Revesz measured the swelling ability of five common disintegrants (19). They found that the super-disintegrants, sodium starch glycollate (1680%) and croscarmelose sodium (600%) demonstrated the greatest swelling, but that the weak cation-exchange resin, Amberlite IRP-88 (190%) was better than polyplasdone XL (150%) or maize starch (110%). Shangraw et al. (20) investigated the sedimentation volumes of cross-linked starches and celluloses and found that they are significantly altered in acidic media, casting doubt as to whether swelling alone was the only mechanism responsible for tablet disintegration. The existence of plastic deformation under the stress of tablet compression has been known for many years and has been linked with the disintegration mechanism of some disintegrants (21). Ringard and GuyotHermann (22) have proposed a particle–particle repulsion theory to describe how nonswelling excipients can also act as functional disintegrants. The Use of Ion-Exchange Resins as Disintegrants Various excipients (inactive ingredients with functional applicability) have been added to tablet formulations to facilitate rapid disintegration. Physical or chemical incompatibility, as well as cost, source, grade, and the regulatory status (23) govern the selection of excipients. Traditionally, starches, alginic acid, carboxymethyl cellulose, and clays have been 578


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Table 6. Minimum-Effective Concentration of Disintegrants in Tablets Prepared Using a Calcium Phosphate/Carbonate Model System Disintegrant

Minimum-Effective Concentration (%)

Disintegration Time/min

Corn starch

20

15

Sodium carboxymethyl cellulose

20

15

Calcium sodium alginate

20

15

Sodium starch glycollate

20

08

Amberlite IRP-88

05

05


Table 7. Properties of Tablets Prepared Using a Calcium Phosphate/Carbonate Model System Disintegration Hardness Time/min /kg

Disintegrant

Friability (%)

Corn starch

120

10.5

0.8

Sodium carboxymethyl cellulose

090

12.1

0.7

Calcium sodium alginate

042

09.2

0.6

Sodium starch glycollate

026

09.0

0.9

002.5

06.3

2.8

Amberlite IRP-88


employed as disintegrants. The fine particle size ion-exchange resins have demonstrated their applicability owing to the tremendous swelling pressures they generate as they are hydrated. Rohm and Haas specifically developed Amberlite IRP-88 as a tablet disintegrant. It is the partial potassium salt of a carboxylic acid cation-exchange resin. The material is an efficient disintegrant at low levels in various tablet formulations. It appears to be efficient in many hydrophobic-tablet formulations, where standard disintegrants are less effective. van Abbe and Rees (24) demonstrated that in the presence of large quantities of water-insoluble excipients, the inclusion of Amberlite IRP-88 yielded tablets having disintegration times well within acceptable limits, but of adequate mechanical strength. The ion-exchange resin was compared to maize starch in a model phenobarbitone formulation and appeared to function as effectively, without being unduly sensitive to the presence of hydrophobic lubricants, such as magnesium stearate. Khan and Rhodes (25) examined the properties of five common tablet disintegrants in two insoluble direct-compression matrices. Amberlite IRP-88 appeared to be the most effective disintegrant in both direct-compression systems. A summary of the data in one of the model direct-compression formulations is shown in Table 6. However, tablets prepared using Amberlite IRP-88 were not as hard and demonstrated higher friability (ease of tablet breakup under induced attrition), when compared with other conventional tablet disintegrants. Summaries of the data in one of the model direct-compression formulations are shown in Table 7.


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Taste Masking

Introduction Most medicinal products are initially developed as solid oral-dosage forms (26), typically tablets or capsules. However, more than 25% of the normal adult population have difficulty in swallowing tablets or capsules (27), and for the pediatric and geriatric populations this figure is undoubtedly higher. This unmet clinical need often prompts the development of oral-solution or oral-suspension-dosage forms as product-line extensions, facilitating ease of swallowing in these patient populations. Often the greatest formulation challenge in the development of these product-line extensions is the poor palatability of the drug substance in an aqueous vehicle. Taste masking has prompted many different approaches, including the utilization of flavors (28); lipophilic vehicles (29), for example, lipids, lecithins and surfactants; hydrophilic vehicles (30), for example, coatings and complexes with carbohydrates, cyclodextrins, ion-exchange resins, proteins, and zeolites; and miscellaneous taste-masking approaches (31), for example, salt preparation or modification of functional group(s). One of the more elegant approaches to improving palatability of ionizable drugs is the use of ion-exchange resins. As palatability relies on the substance being dissolved (or partially dissolved) to elicit the taste sensation, it follows that the formation of a high molecular weight complex will adversely affect the solubility of the compound. This minimizes undesirable organoleptic properties, such as taste or odor, by ensuring that the drug is present below the taste threshold. Selection of Ion-Exchange Resins Many of the more commonly occurring, bitter-tasting drugs tend to be amines and are, therefore, cationic in nature. Hence, they lend themselves to complexation with cation-exchange resins. However, the complexation process works equally well for anionic drugs with anion-exchange resins. Typically, the ionic drug substance forms a stable, palatable complex with the ion-exchange resins at buccal pHs (typically ca. pH 6). The drug–resin complex is readily dissociated at gastric pH forming the protonated resin and releasing the drug, which is subsequently available for absorption. This is demonstrated for a drug–cation-exchange resin (based on carboxylic acid moieties) in Scheme I. The rate and extent of drug release is a function of the ionization coefficient (pKa) of the ion-exchange resin and the drug, the selectivity of the resin for the drug, and the solubility of the drug. The key question is, which of the myriad commercially available ion-exchange resins are the most appropriate for use in taste-masking applications? Unfortunately, there are no easy

RCO2−(DRUG)+ + H+Cl− − + + − RCO2 H + (DRUG) Cl

Scheme I. Dissociation equilibria of a drug–resin complex under acidic conditions, where R is the resin backbone.

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answers to this difficult question. The answer will depend on many variables, including the solubility of the drug, its pKa, the pKa of the ion-exchange resin, and the pH of the targeted release site. For taste masking of cationic drugs that require rapid release in the stomach, the optimal choice is frequently a carboxylic acid resin, such as Amberlite IRP-64 or IRP-88, as they are efficiently protonated at gastric pH giving rise to excellent drug-release characteristics. However, in practice, experimentation is the only way to be certain, and working closely with resin suppliers will make the task easier and quicker. Each country, for example, the United States or group of countries, for example, European Union (EU), have their own national agencies that regulate the approval of drugs or inactive substances (excipients) that are incorporated into drug products. In the United States this body is the Food and Drug Administration (FDA) and in the EU it is the European Agency for the Evaluation of Medicinal Products (EMEA). In order to sell pharmaceutical products on a worldwide basis, the regulatory status (or approval status) of the proposed ion-exchange resin in different countries is critical (23). The regulatory status of excipients varies from one nation to another, even against a background of international harmonization. Initial review of the manufacturer’s literature and general excipient literature (32) should be followed by discussions with individual regulatory agencies in the countries concerned. Generally, however, only those resins that are approved for use in pharmaceutical products should be considered (Rohm and Haas use the suffix P prior to the resin grade; e.g., IRP to designate pharmaceutical grade). Amberlite IRP-64 and IRP-69 have been used to formulate a taste-masked and palatable formulation of bulflomedil (33). Similarly, the bitter tastes of methapyrilene, dextromethorphan, ephedrine, and pseudoephedrine were masked by first forming complexes with polymethacrylic acid ion-exchange resins. The drug–resin complexes were further coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose (HPMC) for effective taste masking (34). Ranitidine’s bitter taste was masked by the formation of drug–resin complexes with cation-exchange resins such as Amberlite IRP-64 and IRP-69 (35). Other cationexchange resins that have been utilized for taste masking (36) include Sephadex SE, a weak cation-exchange resin used to mask the bitter taste of benproperine phosphate, the active pharmacological agent in the antitussive Pirexyl. Antibacterials, such as ciprofloxacin have been loaded onto weak cation exchangers (37), such as Lewatit S-100 and Lewatit CNP and administered to animals in their feed. The improved taste is evident from acceptance of the feed by the animals.

Optimization of Drug–Resin Ratio Having selected the most appropriate resin to be used within the formulation, it is then necessary to find the most appropriate drug-to-resin ratio. This is because each different type of resin has a specific loading capacity, and using equimolar ratios of the drug and resin is rarely optimal. To maximize taste-masking efficiency a low ratio is required, but conversely to minimize cost a high ratio is required. The final outcome will be a balance between these two competing requirements. Experience has shown that molar ratios of


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In the Classroom

The authors found that both prototype formulations demonstrated similar release profiles (as defined above) to the existing commercial tablet formulation in 0.1 M HCl (Table 8) and on that basis were taken forward for further in vivo evaluation in a probe bioavailability study.

Table 8. In Vitro Release Profiles for Commercial Tablet Formulation and Two Prototype Drug–Amberlite IRP-88 Ion-Exchange Resin Formulations % Drug Released

Time/ min

Tablet

1:1 Drug–Resin

1:2 Drug–Resin

10

073

96

93

30

099

98

95

60

101

99

95

drug–resin of 0.1 (1:10) to 0.75 (3:4) are typical, but, as with resin selection, experimentation is the only way to evaluate the most appropriate ratio. The impact of adjusting the ratios of drug and Amberlite IRP-88 resin (1:1, 1:2, and 2:3) on the palatability and release performance of various suspension formulations was recently evaluated (38). The authors found that, whereas, the 1:1 and 2:3 drug–resin formulations demonstrated moderate taste masking (evaluated using taste panels to assess palatability), the 1:2 drug–resin formulation was the best tolerated candidate formulation. The 1:1 and 1:2 drug–resin formulations were then further evaluated using in vitro dissolution testing. Although dissolution is a kinetic rate measurement (mg cm᎑2 min᎑1), it is rarely expressed in this form. More typically it is expressed as percentage of label claim released per unit time, where the label claim is the quantity of drug (typically, in mg) contained within the pharmaceutical preparation, for example, tablet, capsule, or suspension, and the time is typically the period required for the pharmaceutical preparation to dissolve completely (usually between 5 and 60 min).

Optimization of Ion-Exchange Resin Particle Size The particle size of the ion-exchange resin is an important variable that can affect the performance of all pharmaceutical formulations, but especially suspension formulations, and therefore requires optimization. The rate of sedimentation of a suspended particle can be retarded by a reduction in particle size. In addition, large particles can also impart a gritty texture to the product (39), which can be detected by the tongue and hard palate (the so called “mouth feel”) of the consumer or patient. Elder et al. (38) evaluated the impact of particle size on performance of a drug–resin suspension formulation. Four batches of 1:2 drug–resin formulation were manufactured using Amberlite IRP-88 resin of differing particle size. These formulations were evaluated for suspendability, mouth feel, palatability, and in vitro release rate. The data are summarized in Table 9. Interestingly, there was no significant difference between the in vitro release rates of formulations manufactured using large (150 µm. They found that the release rate was practically independent of particle size, with slightly faster release profiles observed for the smallest size fraction. This appears to be in general accord with the work of Elder et al. (38), who showed similar results for drug–resin complexes, using the weak cation-exchange resin, Amberlite IRP-88. The data from the physical mixtures of drug and Amberlite IRP-69 resin showed similar in vitro release profiles, which were essentially independent of particle size, with slightly slower release


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profiles observed for the smallest size fraction. However, in both cases the differences did not appear significant. Earlier investigations by Raghunathan et al. (52) had shown differences in the in vitro release rate that were attributable to resin particle size. However, the authors only investigated two, very disparate size fractions; a very large size fraction (590–800 µm) and a more appropriate, smaller size fraction (80–95 µm). They prepared strong cation-exchange complexes with phenylpropanolamine and monitored the release in 0.1 N HCl. The release rates were different, but still relatively rapid in this medium from both size fractions, possibly indicating that the resin did not form a strong enough complex with the drug to make it a suitable choice for sustained-release development.

Sustained-Release Products Utilizing Ion-Exchange Resins There have been several oral sustained-release commercial products developed for the U.S. market based on the use of ion-exchange resins. Most notably, those products utilizing the Pennkinetic system developed by the Pennwalt Corporation. In this system, the drug–resin complex is pretreated with polyethylene glycol 400 to maintain the geometry and improve the coating process. The pretreated complex is then coated with ethylcellulose, or similar water insoluble polymers. Delsym (dextromethorphan polistirex) is a liquid-suspension product designed to provide 12-hour relief of coughs, containing 60 mg of dextromethorphan (as the HBr salt) bound to the strong cation-exchange resin Amberlite IRP69 in the ratio 1:2.5. Dextromethorphan is a nonaddictive narcotic developed as cough-suppressant. The drug–resin particles are coated with ethylcellulose to facilitate the slowing of the release rate of the drug. Tussionex (hydrocodone polistirex and chlorpheniramine polistirex) was developed for the 12-hour relief of cough and upper-respiratory symptoms associated with allergies or cold. Hydrocodone is a nonaddictive narcotic developed as a cough suppressant. Chlorpheniramine or chlorphenamine is an antihistamine used in the treatment of seasonal allergic rhinitis (hayfever). Both drugs are bound to strong cation-exchange resins of the sulfonated styrene–divinylbenzene copolymer type, but only the hydrocodone has an ethylcellulose coating. Penntuss (codeine polistirex and chlorpheniramine polistrirex) was developed for the 12-hour relief of cough and upper-respiratory symptoms associated with allergies or cold. Codeine is a nonaddictive narcotic developed as cough-suppressant. Both drugs are bound to strong cation-exchange resins of the sulfonated styrene–divinylbenzene copolymer type, but only the codeine has an ethylcellulose coating. Topical Applications of Ion-Exchange Resins Topical products are developed for local application to the skin for a wide range of therapeutic disorders, for example, psoriasis, dermatitis, eczema, et cetera. These preparations (typically, creams, lotions, and ointments) are dependent upon their buffering and adsorption characteristics. This has typically been achieved using inorganic compounds, such as

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talc, clay, boric acid, zinc oxide, et cetera. However, ion-exchange resins are particularly advantageous in topical preparations, owing to the following factors: their high intrinsic buffering and adsorption capacity (attributable to the high ion-exchange capabilities), lack of dermal irritancy, long duration of effect, inability of ion-exchange resins to permeate the skin (high molecular weight of polymer), and the drug– resin complex acting as a drug reservoir ensuring appropriate flux across the skin. Winters (53) incorporated 2% w兾w of the weak cationexchange resin, Amberlite IRP-64, into an antiperspirant hydrophilic ointment base. He demonstrated deodorization (via adsorption of unpleasant odors) coupled with complete absence of dermal irritation. Ward and Sperandio (54) described the development of a dermatitis ointment incorporating 10% w兾w of the weak cation-exchange resin, Amberlite IRP-64, into a hydrophilic ointment base. This was designed for the treatment of minor skin ailments. It showed no skin irritation, good lubrication, and the ability to buffer the applied skin surface to slightly acidic pHs. Percival (55) showed the utility of a cobalt:Amberlite IRP64 cream preparation for the treatment of athlete’s foot and related fungal infections. The addition of drug–ion-exchange resin complexes to topical formulations can complicate the process of passive diffusion (56); however, transdermal systems can be developed where a differential electrical current controls the drug flux. These so-called iontophoretic delivery systems have been applied to nicotine, tacrine, propranolol, nadolol, and sodium salicylate (57). The release rates of these drug–ion-exchange resin complexes were dependent on the hydrophilicity of the drug. Nadolol–ion-exchange resin complex (hydrophilic) showed faster release rates than tacrine or propranolol complexes (both hydrophobic). In general, the prevailing external conditions, pH, ionic strength, and temperature, affect the rate of drug release from ion-exchange resins. Ion-Exchange Resins as Pharmacologically Active Drug Ingredients Certain ion-exchange resins have found utility as drugs in their own right. Weak cation-exchange resins have been extensively utilized in reduction of circulating levels of sodium. Cation-exchange resins have also been utilized in the treatment of hyperkalemia. In this particular case, the sodium form of strong cation-exchange resins are utilized resulting in adsorption of potassium, which is readily exchanged with the sodium ion. Strong basic anion-exchange resins, for example, colestyramine and colestipol, have found great utility in the treatment of elevated levels of serum cholesterol. Colestyramine and colestipol are strong basic anionic-exchange resins in the chloride form. These resins adsorb bile salts from the gastrointestinal tract, leading to increased metabolism of cholesterol to replenish normal levels of these bile salts, which in turn results in significant reduction of serum cholesterol levels. There are USP monographs for colestyramine resin, colestyramine for oral suspension, colestipol hydrochloride, and colestipol hydrochloride for oral suspension (58).


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In the Classroom

Figure 5. Gastrointestinal transit of a drug and radiolabelled ion exchange resin complex administered as an oral suspension (ref 5; figure reproduced with permission from author).

Other Pharmaceutical Applications A newer concept in ophthalmic suspensions is the use of microspheres or microparticulates. These are drug–polymer particles (erodible, nonerodible, or ion-exchange resins) that are suspended in a liquid carrier medium. Upon administration into the eye, particles reside at the delivery site and the drug is released from the carrier particle via diffusion, chemical reaction, polymer degradation, or ion-exchange mechanisms (59). Rajni et al. (60) developed an ophthalmic suspension of betaxolol:Amberlite IRP-69 resin complex for the treatment of glaucoma. They investigated the in vivo performance of the drug product in animals and humans. Attempts have been made to deliver therapeutic peptides or synthetic drugs via nasal mucosa utilizing the ion-exchange approach. Illum (61) was granted a U.S. patent for the nasal delivery of nicotine in a pulsatile fashion. A mixture of instant release (noncomplexed) and controlled release (complexed drug) was utilized to get the appropriate in vivo profile. The prerequisite for nasal delivery is a high ion-exchange capacity, typically in the order of 0.2 to 10 meq兾g (62).

Davis and co-workers (63–65) have utilized labeled ionexchange resins to measure gastrointestinal transit times. They included two radioisotopes within the formulation, which can be monitored simultaneously and independently, using gamma scintigraphy. They utilized 2% Amberlite IRP-69 radiolabeled with 111In and 2% Amberlite IRA-410 radiolabeled with 99Tc. A typical example of the procedure is shown in Figure 5 (66). Incompatibilities Ion-exchange resins are incompatible with strong oxidizing agents, amines, and particularly tertiary amines (67). In addition to the drug, ion-exchange resin (if utilized as a taste-masking agent) and suspending agent(s), a preservative system is essential for any aqueous suspension formulation. Preservation against microbial growth is an important consideration, not only in terms of safety and acceptability of the product, but also with respect to the physical integrity of the formulation. Inadequately preserved colloidal systems can agglomerate over time (68). The choice of cation resin (sul-

Table 12. Percentage of Free and Bound Paraben in Solution as a Function of Paraben Concentration in Drug–Amberlite IRP-88 Development Formulations Methyl Paraben (% w/v)

584

Propyl Paraben (% w/v)

Free Methyl Paraben (%)

Bound Methyl Paraben (%)

Free Propyl Paraben (%)

Bound Propyl Paraben (%) 43

0.025

0.0075

84

16

57

0.050

0.015

84

16

47

53

0.100

0.030

85

15

50

50

0.200

0.060

86

14

53

47

0.0075

0.025

82

18

52

48

0.015

0.050

83

17

51

49

0.030

0.100

80

20

41

59

0.060

0.200

86

14

37

63


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In the Classroom Table 13. Percentage of Free and Bound Propylparaben as a Function of Propylparaben Concentration in Drug–Amberlite IRP-88 (Drug) and Amberlite IRP-88 (Placebo) Development Formulations Free Propylparaben (%) (Drug)

Bound Propylparaben (%) (Drug)

Free Propylparaben (%) (Placebo)

Bound Propylparaben (%) (Placebo)

0.0075

50

50

83

17

0.015

52

48

91

09

0.025

55

45

91

09

0.03

52

48

90

10

0.05

54

46

61

39

0.06

53

47

57

43

0.1

52

48

60

40

0.2

44

56

---

---

0.3

24

76

61

39

0.4

18

82

51

49

Propylparaben (% w/v)

fonic acid versus carboxylic acid) can influence the intrinsic pH of the suspension, which in turn affects the choice of preservative system (69, 70). There have been several literature reports of interactions between common preservatives, for example, parabens and nonionic surfactants (polysorbate 80) causing micellization resulting in reduction of the microbial effectiveness of the preservative (parabens are ineffective in the bound state) (71). To establish whether parabens and ion-exchange resins were also incompatible, Elder et al. (38) manufactured eight development batches of the drug–ion-exchange resin complex containing various concentrations of methyl and propylparaben. These formulations were analyzed for total methyl and propylparaben content. In addition, the samples were centrifuged and the supernatant was assayed for free methyl and propylparaben content. The difference between the total and free paraben content provides an estimate of the quantities of parabens bound to the ion-exchange resin. The data are summarized in Table 12. The authors postulated that physical or chemical binding of the preservatives to the ion-exchange resin was occurring, which affected the levels of “free preservative”. Chemical binding of the preservatives to the cation-exchange resin is extremely unlikely, as both species are anionic; therefore, the likely cause is physical adsorption. However, the reduced levels of “free” preservative were still adequate to effectively preserve the suspension formulation. The degree of binding was related to alkyl chain length. This raised the question as to whether methyl and propylparaben compete for binding sites on the ion-exchange resin and whether the presence or absence of drug affects the binding potential. To investigate this further, Elder et al. (38) manufactured additional ion-exchange resin development batches (with and without drug substance, labeled as drug or placebo, respectively) containing varying levels of propylparaben. These formulations were analyzed for total propylparaben content. In addition, the samples were centrifuged

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and the supernatant was assayed for free propylparaben content. The data are summarized in Table 13. The binding profile of formulations containing a mixture of parabens (Table 12) are equivalent to suspensions manufactured with only propylparaben (Table 13), indicating that there is little or no competitive interaction between parabens for binding sites on the ion-exchange resin. The percentage of free propylparaben in placebo formulations is much greater than in formulations containing drug substance. However, as the concentration of preservative increases the percentage of free propylparaben decreases, appearing to plateau at concentrations in excess of 0.05% w兾v. In the placebo formulations the Amberlite IRP-88 resin is relatively polar (negatively charged) owing to the presence of free carboxylate groups on the resin backbone and the paraben ions (also negatively charged) will be electrostatically repulsed by Donnan exclusion. However, when the drug binds to the resin it reduces the number of free carboxylate groups, reducing the overall polarity and negative charge on the resin. This partial “neutralization” may facilitate binding of the parabens to the ion-exchange resin. Monographs There are several pharmaceutical monographs for ionexchange resins. In addition to the USP monographs for colestyramine resin, colestyramine for oral suspension, colestipol hydrochloride, and colestipol hydrochloride for oral suspension (see Ion Exchange Resins as Pharmacologically Active Drug Ingredients), there are also USP monographs for polacrilin potassium (72), anion-exchange resins (73), and cation-exchange resins (74). There is an extremely useful monograph in the Handbook of Pharmaceutical Excipients for polacrilin potassium (75). The monograph summarizes known information on these and related ion-exchange resins. It includes the product’s synonyms (Amberlite IRP-88; methacrylic acid polymer with


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585

In the Classroom

divinylbenzene, potassium salt; polacrilinum kalii), the chemical name and CAS registry number (2-methyl-2-propenoic acid polymer with divinylbenzene, potassium salt; 39394-765), and the common functional category (tablet and capsule disintegrant), along with their pharmaceutical applications in pharmaceutical formulation and technology. A typical description of the product is provided. In addition, a summary of the typical resin properties is provided (bulk density for Amberlite IRP-88: 0.48 g兾cm3; tapped density for Amberlite IRP-88: 0.62 g/cm3 (76); particle size distribution and solubility). The stability and storage conditions are outlined, as is the method of manufacture. Briefly, this can be summarized, as follows. The polacrilin resin (Amberlite IRP-64) is prepared by the copolymerization of methacrylic acid with divinylbenzene (DVB). Polacrilin potassium (Amberlite IRP88) is then produced by partial neutralizing this resin with potassium hydroxide. Other resins are similarly produced by copolymerization between styrene and divinylbenzene (Amberlite IRP-69, Amberlite IRP-67, Amberlite IR-120, and Amberlite IRA-400). Phenolic-based polyamine condensates (Amberlite IRP-58) may also be produced. Summary The historical uses of ion-exchange resins and a summary of the basic chemical principles involved in the ionexchange process have been discussed. Specific applications of ion-exchange resins are provided, including drug stabilization, pharmaceutical excipients (specifically disintegrants), taste-masking agents, oral sustained-release products, topical products for local application to the skin, ophthalmic delivery, nasal delivery, and as drugs in their own right (e.g., colestyramine), as well as measuring gastrointestinal transit times, are discussed. Finally, pharmaceutical monographs for ion-exchange resins are reviewed. Acknowledgments Acknowledgment is gratefully made to Lyn Hughes of Rohm and Haas, Philadelphia, PA for his assistance in preparing this article and reference to data generated in his laboratory. Literature Cited 1. Anonymous. In Ion Exchange and Polymeric Adsorption Technology in Medicine, Nutrition, and the Pharmaceutical Industry; Rohm and Haas: Philadephia, PA,1997. 2. Amberlite is a trade mark of the Rohm and Haas companies. http://www.rohmhaas.com/ (accessed Nov 2004). 3. Kunin, K. In Amber-hi-lites. Fifty years of Ion-Exchange Technology; Rohm and Haas: Philadephia, PA,1996. 4. Wallwork, S. C. In Physical Chemistry for Students of Pharmacy and Biology; Longmans, Green and Co.: New York, 1956; p 253. 5. Anand, V.; Kandarapu, R.; Garg, S. Drug-Discovery-Today 2001, 6, 905–914.

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6. Irwin, W. J.; Belaid, K. A. Drug Dev. Ind. Pharm. 1987, 13, 2017–2031. 7. Bouchard, E. F.; Friedman, I. J.; Taylor, R. J. Vitamin B12 Products andPpreparation Thereof. U.S. Patent 2,830,933, 1958. 8. Ju, R. G.; Myung, L. K.; Young, K. E.; Hyun, L. C.; Joo, H. W. Yakhak Hoeeji 1994, 38, 250–264. 9. Galat, A. Stabilisierte Aspirin-Derivative. German Patent P2200953, 1972. 10. Anonymous. Pharmaceutical Compositions and a Process for the Manufacture Thereof. Hoffman La Roche, British Pat. No. 1101366, 1968. 11. Irwin, W. J.; Machale, R.; Watts, P. J. Drug Dev. Ind. Pharm. 1990, 6, 883–898. 12. Hughes, L. In New Uses of Ion Exchange Resins in Pharmaceutical Formulation; Rohm and Haas: Philadephia, PA, 2002. 13. Kanig, J. L.; Rudnic, E. M. Pharm. Tech. 1984, 8, 50–63. 14. Bolhuis, G. K.; Smallenbroek, A. J.; Lerk, C. F. J. Pharm. Sci. 1981, 70, 1328-1330. 15. Lerk, C. F.; Bolhuis, G. K.; Smallenbroek, A. J.; Zuurman, K. Pharm. Acta. Helv. 1982, 57, 282–286. 16. Khan, K. A.; Rhodes, C. T. J. Pharm. Sci. 1975, 64, 447. 17. van Kamp, H. V.; Bolhuis, G. K.; Lerk, C. F. Proceedings of the 3rd International Conference on Pharmaceutical Technology Paris, May, 1983; pp 35–40. 18. Gissinger, D.; Stamm, A. Drug Dev. Ind. Pharm. 1980, 6, 511. 19. Podczek, F.; Revesz, P. Int. J. Pharm. 1993, 91, 183–193. 20. Shangraw, R. F.; Mitrevej, A.; Shah, M. Pharm. Technol. 1980, 4, 49. 21. Fuhrer, C. Wiss Verlagzges. In Leitfaden der Schädlingsbekämpfung; Heinze, K., Ed.; Wissenschaftliche Verlagsgesellschaft: Stuttgart, 1974; pp 58–66. 22. Ringard, J.; Guyot-Hermann, A. M. Drug Dev. Ind. Pharm. 1978, 2, 36. 23. Robertson, M. I. Int. J. Pharm. 1999, 187, 273–276. 24. van Abbe, N. J.; Rees, J. T. J. Am. Pharm. Assoc. 1958, 7, 487– 489. 25. Khan, K. A.; Rhodes, C. T. Can. J. Pharm. Sci. 1973, 8, 77–80. 26. Rubinstein, M. H. In Pharmaceutics: The Science Of Dosage Form Design; Aulton M. E., Ed.; Churchill Livingstone: London, 1988; Chapter 18, p 305. 27. Andersen, O.; Zweidorff, O. K.; Hjelde, T.; Rodland, E. A. Tiddskrift for Den Norske Laegeforening through Ovid 1995, 115, 947–949. 28. Schumacher, G. E. In Perspectives in Clinical Pharmacology; Francke, D. E., Whitney, H. A., Eds.; American Pharmacists Association: Washington DC, 1972; p 368. 29. Gowan, W. G.; Bruce, W. E. Aliphatic Esters as a Solventless Coating for Pharmaceuticals. Canadian Patent 2,082,137, 1993. 30. Fu, Lu M.-Y. Pharm. Res. 1991, 8, 706–712. 31. Anonymous. In The Merck Index: Encyclopaedia of Chemical Drugs and Biologicals, 10th ed.; Merck: Rahway, NJ, 1983; p 1165.


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In the Classroom 32. Anonymous. In Handbook of Pharmaceutical Excipients, 3rd ed.; Kibbe, A. H., Ed.; The Pharmaceutical Press: London, 2000. 33. Alan, H. R.; Christopher, F. L.; Herbert, H. T.; Eric, S. E. Taste-Masked Buflomedil Preparation. European Patent EP0501763, 1992. 34. Lu, M. F.; Borodkin, S.; Woodard, L.; Li, P.; Disener, C.; Hernandez, L.; Vadere, M. Pharm. Res. 1991, 8, 706–712. 35. Douglas, S. J.; Bird, F. R. Drug Adsorbates. U.S. Patent 5,219,563, 1992. 36. Spross, B.; Ryde, M.; Nystrom, B. Acta. Pharma. Suecica. 1965, 2, 1–12. 37. Lange, P. M. Ion Exchange Resins Loaded with Quinolonecarboxylic Acid Derivatives, for Taste Masking in Feed. U.S. Patent 5,152,986, 1992. 38. Elder, D. P.; Park, A.; Patel, P; Marzolini, M. In Ion Exchange at the Millennium; Greig, J. A., Ed.; Imperial College Press: London, 2000; pp 306–313. 39. Billany, M. R. In Suspensions in Pharmaceutics: The Science of Dosage Form Design; Aulton, M. E., Ed.; Churchill Livingstone Press: London, 2000; Chapter 15, p 271. 40. Keating, J. W. Pharmaceutical Preparations Comprising Cation Exchange Resin Adsorption Compounds and Treatment Therewith. U.S. Patent 2,990,332, 1964. 41. Lordi, N. G. In The Theory and Practice of Industrial Pharmacy, 3rd ed.; Lachman, L., Lierbeman, H. A., Kanig, J. L., Eds.; Lea and Febiger: Philadelphia, PA, 1986; p 450. 42. Kurowski, M. Int. J. Clin. Pharmacol. Ther. 1994, 32, 433– 440. 43. Amsel, L. P.; Hinsvark, O. N.; Rotenberg, K.; Scheumaker, J. L. Pharm. Technol. 1984, 8, 28–48. 44. Motycka, S.; Newth, C. J. L.; Nairn, J. G. J. Pharm. Sci. 1985, 74, 643–646. 45. Moldenhauer, M. G.; Nairn, J. G. J. Pharm. Sci. 1990, 79, 659–666. 46. Schlichting, D. A. J. Pharm. Sci. 1962, 51, 134. 47. Smith, H. A.; Evanson, R. V.; Sperandio, G. J. J. Amer. Pharm. Assoc. 1960, 49, 94–97. 48. Sriwongjanya, M.; Bodmeier, R. Eur. J. Pharm. Biopharm. 1998, 46, 321–327. 49. Kogan, P. W.; Rudnic, E. M.; Sesqueira, J. A.; Chaudry, I. A. Sustained Release Oral Suspensions. U.S. Patent 4,999,189, 1991. 50. Lui, Z.; Cheung, R.; Wu, X. Y.; Ballinger, J. R.; Bendayan, R.; Rauth, A. M. J. Controlled Release 2001, 77, 213–224. 51. Hussain, M. A. Pharm. Res. 1989, 6, 49–52. 52. Raghunathan, Y.; Amsel, I.; Hinsvark, O.; Bryant, W. J. Pharm. Sci. 1981, 70, 379–384. 53. Winters, J. C. J. Soc. Cosmet. Chem. 1956, 7, 3. 54. Ward, J. B.; Sperandio, G. J. paper presented to American Pharmaceutical Association, 113th Annual Meeting, Dallas, TX, 1966.

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55. 56. 57. 58.

59. 60. 61. 62. 63. 64. 65. 66.

67. 68.

69.

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71. 72. 73. 74. 75.

76.

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Pharmaceutical Applications of Ion-Exchange Resins - Journal of

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