Drug Delivery and Therapeutic Applications of Ion Exchange Resins: An update
By - 08/20/2007
- 1979 reads
Jadhav Namdeo
Ion exchange resins are vinyl, divinyl benzene and polystyrene copolymers available as high molecular weight polyelectrolytes having extensive charged functional sites.1
They are insoluble in nature and exchange their exchangeable ions with same charge ions in the surrounding ionic medium.1-2 Mainly, resins are of two types; weak and strong cationic and anionic resins respectively.1
Apart from taste masking, resins have been used in modified drug release 3 drug stabilization 4 tablet disintegration 3-4 and even in therapeutics too.4 Long term physico-chemical stability 3-4 and safety 4 of ion exchange resins have provided an additional benefit to consider them as drug carriers for wide array of applications.
Types Of Ion Exchange Resins
Cation exchangers (Anionic resin)5
Cation-exchange resin is prepared by the copolymerization of styrene and divinyl benzene and have sulphonic acid groups (-SO3H) introduced into most of benzene rings. The functional group of these resins undergoes reaction (exchange) with the cations in the surrounding medium.
The mechanism of cation exchange can be depicted by the following reaction.
Resin- - ex+ + C+ →Resin- - C+ +ex+ (1)
Where, Resin- indicates polymer with SO3- sites available for bonding with exchangeable cation (ex+) and C+ indicates cation in the surrounding solution getting exchanged.
Anion exchangers (Cationic resin)5
These are the polyelectrolytes undergoing reaction with the anions of the surrounding solutions. They are prepared by first chlor-meythylating the benzene rings of styrene-divinylbenzene copolymer to attach CH2Cl groups and then causing these to react with tertiary amine such as triethylamine.
The mechanism of anion exchange can be depicted by the following reaction.
Resin+ - ex - + A- → Resin+ - A- + ex- (2)
Where, Resin+ indicates polymer with N+ sites available for bonding with exchangeable anion (ex-) and A- indicates cation in the surrounding solution getting exchanged.
Advantages of resins
1. Resins being polyelectrolytes have extensive binding sites leading to very high drug loading ability.2,9
2.They are chemically inert and free from local and systemic side effects.6,7
3.Because of ion exchange ability, they have been used in taste masking,2-4,9 modified release 2-4,7 and therapeutic applications.2-4,9
4.All conventional solid, semisolid and liquid dosage forms can be prepared by using resins.
5.They have been used in selective separation/recovery of pharmaceuticals from mixtures.8
6.Being stable to all sterilization means, can be formulated in to all sterile dosage forms.
Types Of Drug Resin Interactions
Figure 1.Electrostatic and hydrophobic interaction seen in drug resin complex.
Factors Affecting Resin Performance
Degree of cross linking 2, 9
Extent of cross linkage has tremendous effect on drug loading efficiency. If resin is having less degree of cross linking, then it is more porous and the extent of swelling due to hydration is more. Whereas, if it is less cross linked, then it has less swelling. Because of this, the drug loading ability of less cross linked resin is high than more cross linked. But, the drug release from former is rapid and sustained from latter ones.
Particle size5
The smaller resin beads offering more surface area have shown rapid exchange of ions but shorter diffusion path length. Whereas, the larger beads, have more diffusional path length leading to sustained release.
pH 5
pH is an important factor affecting drug complexation efficiency and drug release from drug resin complex. If the pH of surrounding medium is acidic then it promotes dissociation of basic drugs leading to formation of more ionic species available for drug loading. And , towards alkaline pH,the dissociation of acidic drugs will be promoted. With increase in dissociation the complexation efficiency gets improved. With increase in pH protonated fraction of cationic drug decreases and hence interaction with resin or loading with beads decreases. It has been observed that, release of phenylpropanolamine was rapid in eluants with low pH.
Size of exchanging ion5
It has been observed that, with increase in size of exchanging ion, slower was drug loading, and less diffusion rate followed by slow release.
Selectivity of counter ion2, 5
The ions with low selectivity for resin such as –H+ get replaced faster by cationic drugs resulting in higher loading.
Mixing time.2, 10
With increase in the mixing time, the swelling of resin goes on increasing and ultimately drug loading. In the initial phases, the drug loading seen was more and later on it was less. It has been reported that, complete drug loading can be achieved in 1 hour only by batch process.
Effect of temperature
For certain resins the effect of temperature on drug loading has been reported. High temperature may also cause swelling of resin.9 Cation exchange resin doesn’t get significantly affected by temperature changes unlike anion exchangers11.
pKa5
The pKa value of the resin is having significant influence on the rate at which the drug is released from the resinate in the gastric fluids. The anionic resins having sulfonic, phosphonic or carboxylic acid exchange groups have approximate pKa values of <1-6. And, cationic resins containing quaternary, tertiary, or secondary ammonium groups have pKa values of 5-13 and greater than 13.The pKa of drug also decides the extent of dissociation and complexation with the resin.
Stability
At ordinary conditions of temperature, oxygen, light and humidity resins are found stable and inert in nature.3-4
Toxicity
Chemically resins are polymerized styrene, vinyl and divinyl benzene molecules. Hence, although polymerized form of resin is inert in nature, purification of resin needs to be involved in their usage in drug formulations.12
Applications Of Ion Exchange Resins
Taste Masking
The taste perception of bitter drugs is experienced in the mouth at taste buds. Complexed drug resinates doesn’t release drug in mouth because of scarcity of exchangeable ions(pH 6.7;cation concentration, 40 meq/lit) in the saliva.2 Examples of drugs in which this technique has been successfully demonstrated include ranitidine,13 paroxetine 14and dextromethorphan.10 Same principle of taste masking has been implemented in the rapidly disintegrating dosage form prepared using Zydis technology 4.Studies have also showed the taste masking in case of quinolone category antibacterial ciprofloxacin hydrochloride using Indion 234 9,16and peripheral vasodilator buflomedil 16 using Amberlite IRP69. Patracia et. al. have prepared pseudoephedrine-Dowex 50WX8 complex as less bitter oral suspension.10 Also, mixture of coated and noncoated sulfonic acid resins loaded with dextromethorphan for taste masking and sustained release have been reported.10
Hence, majority of oral preparations contain cation exchange resins for masking the bitter taste of certain drugs containing amine or amide groups 17. Examples of such drugs include nicotinamide, diphenhydramine, and chlorpheniramine.18.
Disintegrant/Superdisintegrant
Majority of tablet disintegrants have rapid water uptake capacity due to swelling. Resins although insoluble, have great affinity for water and hence, act as disintegrant15. Moreover, because of their smaller particle size the rate of swelling is high making them superdisintegrant. Like conventional disintegrant, they don’t lump but,additionally impart strength to the tablets.
Potential superdisintegrant ability of Indion 414 has been reported by Purnima et al for mouth dissolve tablets of roxithromycin, montelukast sodium and dicyclomine hydrochloride 15.
Improved Dissolution 14
Drug resin complexation converts drug to amorphous form. Hence , drugs with poor solubility, during the process of desorption, immediately releases the drug leading to improved drug dissolution.
Powder Processing Aid 4
Handling qualities of hygroscopic drugs and drugs having caking tendency have been improved due to complexation with the resin. The fixed rigid structure of resins was seen to be responsible for that.
Drug Stabilization
The drug resin complexes are having electrostatic and hydrophobic type nonbonding interactions.4 Hence, drug at molecular level complexed with resin shows more stability as seen in vitamin B12 and carboxylic acid resin complex.4
Drug Delivery Applications
Oral modified release formulations
The use of ion exchange resins into drug delivery systems have been encouraged because of their physico-chemical stability, inert nature, uniform size, spherical shape assisting coating and equilibrium driven reproducible drug release in ionic environment. 4
Several preparations involving strong resinates of sulfuric acid (cation exchange resins) provided more moderate release than the weak resinates of carboxylic acid. 17, 18 Hence, resinates of strong cationic drugs are formulated as sustained release suspension, tablets, capsules and microparticles.17, 18 Mainly, Amphetamine, 19, 20 Propranlol HCl 21 Dextroamphetamine, 22 codeine 22and Chlorpheniramine (Penn kinetic system by Pennwalt Corporation USA)22are Complexed with strong cation exchanger for slow release.
Polymeric coating using ethyl cellulose and polyethylene glycol-4000 has been reported for exercising control over drug release.10 Microencapsulated tramadol-resin complex with 10, 25 and 45cps-viscosity grade ethyl cellulose have showed slow release23
The prolonged release of the active drug is accomplished by providing a semi-permeable coating around discrete, minute, ion exchange resin particles with which the drug component has been complexed to form an insoluble drug-resin complex. The semi-permeable coating creates a diffusion barrier and the thickness of which can be adjusted to provide the desired level of retardation of drug availability in the gastrointestinal tract over a period of time 21.
The drug release from HPMC tablets containing drug-resin complexes was significantly slower than from HPMC tablets containing drug without resin.25 Nicorette chewing gum is an example in which the nicotine – cation exchange resin complex is encapsulated into a sorbitol-based matrix and releasing nicotine slowly during chewing providing the minimal supply of nicotine to facilitate smoking cessation 24,26.The drug- resinate complex of bromhexine in suspension form has been formulated to control drug release and reduce the frequency of dosage administration. Simultaneously, bioadhesive properties of ion-exchange resins may be useful mucoadhesive systems for local treatment of stomach infections like H. pylori for prolonging the gastric residence of amoxycillin and cimetidine 27, 28
Parenteral drug delivery 29
Microspheres of resin complexed with cytotoxic agents like Adriamycin and doxorubicin upon intra-arterial administration are entrapped in capillary beds. This works on the principle of chemo-embolisation of a drug loaded microspheres via the tumour arterial supply. As a result, microspheres containing cytotoxic drug can be delivered to well vascularise tumour tissues in sustained way specifically into tumour locale. This suppresses toxicity of chemotherapeutic agents due to their unavailability to entire systemic circulation. Recently, microspheres of resin complexed with radioisotopes have been used via same route for internal irradiation of tumour cells.
Ophthalmic drug delivery
Ophthalmic drug delivery of Betaxolol from resin involves release of drug from drug resin complex .The flocculated suspension prepared in Carbopol 934P as 0.25% Betaxolol in 0.25% BETOPTIC S Ophthalmic Suspension has been approved by FDA and is marketed in U.S since February 1990. Microparticulates of ion exchange resin and betaxolol (antiglaucoma drug) are reported for sustained ophthalmic drug delivery.30
Another example of ion exchange in ocular drug delivery was reported by Moreau et.al for delivery of ciprofloxacin complexed with polystyrene sulfonate for the treatment of eye infections.31
Nasal drug delivery 32
Amberlite IRP69, cation exchange resin having particle size 10 to 150 microns has been reported for nasal delivery of nicotine. Biphasic, extended drug delivery has been obtained by Hinchcliffe et. al for nicotine delivery.
Therapeutic Applications
Ion exchange resins have notably found use in the treatment of various pathological states such as hyperacidity, treatment of ulcer, Na and K supplement depletion, nephrotic, pancreatic and cardiac edema etc. 33 Moreover, anion exchange resins have been used in the treatment of hyperglycemias 34.Cholestyramine,a quaternary ammonium anion-exchange resin originally was used to control pruritus in patients with elevated plasma bile acid concentrations. But,presently, it is recommended as an adjunctive therapy to patients with elevated serum cholesterol. Another anion exchange resin Colestipole hydrochloride acts by increasing fractional carbolic rate of low density lipoproteins (LDL) thereby decreasing LDL.34, 35, 36
Tooth pastes, lacquers, prostheses coming in contact with tooth surface are rendered anti-carious by incorporating ion exchange resins containing fluorine, phosphate or calcium ions. 37.
Cation-exchange resin (Sodium polystyrene sulfonate) has been reported as an adjuvant in the treatment of hyperkalemia associated with oliguria or anuria secondary to acute renal failure38
Others
Adsorption and recovery of rifamycin B and rifamycin S 39
The antibiotic rifamycin S is a physiologically active derivative of the rifamycin B. Strongly or weakly basic anion exchange resins are reported for recovery of antibiotic rifamycin S from rifamycin B, by curtailing complex, multi-step processes involved in separation.
Preparation of stable coating composition 17
Colloidal and sedimentation stable coating composition containing ion exchange resins has been patented to prevent leaching of staining agents that often leach from the substrate into the coating causing discoloration of the coating 10
Removal of metal oxides and hydroxides
Cross linked porous resins and ion-exchange resins produced there from have a significantly high crushing strength and are used in the removal of colloidal silica, iron, aluminum and other metal hydroxides 37, 40.
Process for separating glucose and mannose with CA/NH4 - exchanged ion exchange resins41
The suffocated cross linked styrene-divinylbenzene resins have been patented to adsorb mannose from a mixture of glucose and mannose.
Conclusion:
Pharmaceuticals complexed using ion exchange resins have shown improved organoleptic performance of pharmaceuticals. They are used to mask the bitter taste, improve processing characters of drug molecules, modified release and physicochemical stabilization. Moreover, they are proved for their therapeutic application as hypolipemic agent. In conclusion, ion exchange resins can be of great value in developing new formulations for a variety of drugs and their potential is not fully explored. This is an area opening for high commercial outputs in near future.
References:
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About Authors
Mr. Mayuresh Shinde
Modern college of pharmacy, Pune
Mr. Hitesh R. Bhakre.
M.Pharm (IInd Year, deptt of Pharmaceutics)
Mrs. Neela M. Bhatia
M.Pharm., Asst. Professor in Pharmaceutical Chemistry.
Mr. Namdeo R. Jadhav
M.Pharm., Asst. Professor in Pharmaceutics
Author for correspondence: Email: nrjadhav18@rediffmail.com , Phone: 91-0231-2637286, Fax: 91-0231-2638833