Pharma’s Best Kept Secret
Ion exchange resins have received sizeable attention from pharmaceutical scientist due to their versatile properties as drug delivery vehicles, mention A Tagalpallewar, B Prabhakar, & RS Gaud of School of Pharmacy and Technology Management, NMIMHS, Mumbai.
In the recent years, considerable attention has been given to the development of controlled release drug delivery systems. The basic rationale being they optimize the biopharmaceutical, pharmacokinetic, Pharmaco-dynamic properties of a drug in such a way that its utility is maximized, side effects are reduced and cure or control of condition is achieved, in the shortest possible time by using smallest quantity of drug administered by most suitable route.
The advantages of sustained release drug delivery over conventional dosage form are:
i. Improved patient compliance due to less frequent drug administration; ii. Reduction of fluctuation in steady –state drug levels; iii. Maximum utilization of drug; iv. Increased safety margin of potent drug; v. Reduction in health care costs through improved therapy, shorter treatment period, less frequency of dosing
Ion exchange resins (IER) have received considerable attention from pharmaceutical scientist because of their versatile properties as drug delivery vehicles. Some drug delivery systems containing IER have been introduced into the market.
Definition: Ion exchange resins (IER)
IER are insoluble ionic materials possessing acidic or basic group covalently bound and placed in repeating positions on the resin chains. This charged group is associated with other ions of opposite charge. Depending on whether the mobile counter ion is a cation or an anion, it is possible to distinguish between cationic and anionic IER. The matrix carrier ionic groups such as –SO3, -COO, PO3a are present in cationic exchanger and –NH2 +, NH3+ N- groups are seen in anionic exchanger.
Chemically, IER are made of a structural component consisting of polymer matrix and a functional component to which the counter ion is bound. The structural component of IER comprises a stable acrylic polymer of styrene-divinylbenzene (DVB) co-polymer, whereas the functional components can be acidic (commonly sulfonic or carboxylic) or basic (amine).
IER can be classified based on the nature of the structural and functional components and ion exchange process.
Properties of IER
1. Particle size and form: The rate of ion exchange reactions depends on the size of the resin particles. Decreasing the size of resin particles significantly decreases the time required for the reaction to reach equilibrium with the surrounding medium.
2. Porosity and swelling: The limiting size of the ions, which can penetrate into a resin matrix, depends strongly on the porosity. Porosity depends on the amount of cross-linking substance used in polymerization method. The amount of swelling is directly proportional to the number of hydrophilic functional groups attached to the polymer matrix and is inversely proportional to the degree of DVB cross linking present in the resin.
3. Cross-Linking: The percentage of cross-linking affects the physical structure of the resin particles. Resins with low degree of cross-linking can take up large quantity of water and swell into a structure that is soft and gelatinous, However, resins with high DVB content are hard, brittle and swell very little.
4. Available Capacity: The capacity of an ion exchanger is a quantitative measure of its ability to take up exchangeable counter ions.
5. Acid-base strength: It depends on various inorganic groups, incorporated into the resin. Resin containing sulphonic, phosphoric or carboxylic acid exchange groups have approximate PKa values of 13,7-9 or 5-9 respectively. The PKa values of resins will have significant influence on the rate at which the drug will be released in the gastric fluid
6. Stability: IER are inert substances at ordinary temperature resistant to decomposition through chemical attack. These materials are indestructible. They degrade and degenerate in presence of strong gamma rays.
7. Purity and toxicity: Since the resin combination contains 60% or more of the resins, it’s necessary to establish its toxicity. Resins are not absorbed by body tissue and are totally safe for human consumption. Tests for toxicological tolerance showed that it does not have any pronounced physiological action at recommended dosage and is definitely non – toxic.
Mechanism and principle
Anion exchange resin contains a functional group capable of removing anions in acidic solution. Cation exchange resin contains acidic functional group capable of removing cations in basic solution. Although their exact composition may vary, they usually contain polystyrene polymers with sulphonic, carboxylic or phenolic group.
The use of IER to prolong the effect of drug is based on the principle that positively or negatively charged drug moiety combined with appropriate resins yield insoluble polysalt resinates.
R-SO-3-H + + H2N- A –> R-SO-3 –H3 N-A
R-N+H3OH + HOOC-B –> R-N+H3-00C-B+H2O
Where H2N-A and HOOC-B represent a basic and acidic drug respectively and R-SO3-H+ and R-NH3-OH- represent cationic and anionic IER respectively The slow release of drug from IER was recognized by Saunder and Srivastava (1980), as a suitable approach to design sustained release preparation.
Resinates administered orally are likely to spend about 1-2 hours in the stomach in contact with an acidic fluid of pH 1.2 and then move into intestine for more than six hours where they will be in contact with a fluid of slightly alkaline PH.
IN THE STOMACH
R-SO-3 – H3 N+-A + HClÕ R-SO3-H+ + A-N+H3Cl R-N+H3-OOC-B + HClÕ R-N+H3Cl+ + B-COOH
IN THE INTESTINE
R-SO-3 – H3 N-A +NaCl Õ R-SO3-Na+ +A-N+H3 Cl-
R-N+H3- OOC-B +NaCl Õ R-N+H3Cl- + B-COO-Na+
1.Sustained Release Preparation: Improved drug safety may be achieved by controlling the rate of drug delivery from dosage form. Sustained release dosage forms are prepared by coating the tablets so that the rate of solubility is controlled or individually encapsulating micro particles of varying sizes so that rate of dissolution can be controlled.
With the development of modern synthetic IER pharmaceutical industry adapted the ion exchange technology to achieve sustained release of drug. Keating listed the following advantages of adsorbing basic nitrogen containing drug onto strong acid cation exchange resins and using them in dosage forms:
i. Prolonged release of drug from the complex for 8-12 hours in the gastrointestinal tract; ii. Reduced toxicity by slowing drug absorption; iii. Increased stability by protecting the drug from hydrolysis or other degradative changes in the gastro-intestinal tract; iv. Improved palatability; v. Availability of formulation in liquid and solid sustained release dosage forms.
Sustained release tablets: The rate of release of drug adsorbed onto various IER can be controlled by i. varying particle size, ii. matrix structure, and iii. chemistry of resins.
The release of drug from IER depends upon a series of ionic reactions between various body fluids and the drug resin complex. The first two factors control the diffusion of active ingredient through resin particles and third factor controls the equilibrium of drug resin complex and electrolyte in body fluids.
Schliching has done a complete and detailed study of an antihistaminic drug carbinoxamine using weak acid and strong acid cation exchange resins to develop a sustained release tablet of carbinoxamine.
Wolf compared the duration of antitussive effect of Noscapine Hydrochloride in a commercial resinate of Noscapine and sulfonated cross-linked polystyrene resins.
Another study showed that microencapsulated tramadol-resin complex gave slow release. Resinates of propanolol Hcl, chlorpheniramine maleate and phenyl propanolamine have been described to show sustained release. Manek and Kamat evaluated INDION® CRP-244 and CRP254 resins as sustained release and taste masking agents.
Drug stabilization: A component of the API is fixed onto the IER. This prevents harmful interaction with other components. E.g.. The stability of vitamin B12 (that deteriorates on storage) can be improved by complexing it onto a weak acid exchanging resin. This complex is as effective as free form of vitamin.
Taste masking: Taste masking in chewable tablets containing drugs with amino groups like dextromethorphine, ephedrine, pseudoephedrine has been successfully carried out using weak acid catIER. Taste masking of sparfloxacin is carried out by Bhalekar.
Saliva with average pH of 7.4 and cation conc. of about 40 meq/lit would only elute a limited percentage of drugs from polycarboxylic acid resins.
Tablet disintegration: The effectiveness of drug supplied as compressed tablet depends upon the ease or rate at which the tablet disintegrates in the gastrointestinal tract.
Tablets must withstand the rigors of packaging, shipment and storage and also disintegrate in the digestive juice and make the active constituent available for absorption during passage through gastrointestinal tract. Varieties of starches, cellulose derivative aliginic acid its salt and colloidal silicon dioxide are widely employed as tablet disintegrants in pharmaceutical formulations, due to their considerable swelling pressure as they get hydrated.
Cholesterol reducers: Cholesteramine resins when used as an active ingredient binds bile acid. This leads to the replenishment of bile acids through increased metabolism of serum cholesterol resulting in lowered serum cholesterol levels.