ION EXCHANGE RESINS

FREQUENTLY ASKED QUESTIONS

How do I choose the right ion exchange resin?

Despite the fact that there are a limited number of ion exchange resins to choose from, there are some guidelines as to which type of product may be best suited to a particular application. This guide could also be used to identify drug substance which could be a candidate and benefit from resination.

Factors to consider :

• Are there any ionic functions present in the structure of the drug substance? Specifically, -COOH or amine functionalities which could be used to bind to an ion exchange resin.

• In the case of basic drugs (i.e. those containing an amine functionality), is release required quickly in the stomach or can release occur over a certain period of time?

• The amount of drug to be delivered. A single dosage of > 200 mg is likely to require a significant amount of resin which could result in either an unacceptably large tablet or an unpalatable liquid formulation.

• What is the drug's water solubility? This could affect the rate of uptake and release from the resinate.

A simple guide is given for information. If a particular drug substance has both acidic and basic groups then both types of resin should be studied in order to determine which will give the required release characteristics.

What is a functional polymer?

In pharmaceutical formulations a functional polymer is simply a polymeric material that performs an excipient function. These can include ion exchange resins, polymeric adsorbents, cellulosic polymers (disintegrants, matrix formers etc), and polymeric coatings (e.g. Eudragit® coatings). Ion exchange resins in particular are multifunctional, providing functions such as extended release, tablet disintegration, taste masking, and improved physical and chemical stability.

What is the molecular weight of an ion exchange resin?

An ion exchange resin is a three-dimensional polymeric matrix. The polymer matrix is made up of monomers cross-linked with divinylbenzene. It is made in a bead form which is then converted into the corresponding powder by grinding. Because of the high degree of cross-linking a single particle is essentially a single molecule and so has an extremely high molecular weight.  Because the resins are completely insoluble in all solvents it is not possible to measure the molecular weight independently. Furthermore, because each particle is one molecule, the concept of polydispersity is meaningless for ion exchange resins. Within a particle the polydispersity is 1 (a single molecule). Molecular weight will depend on particle size and has been estimated by calculation to be of the order of 10¹⁸.

To avoid possible confusion, however, it should be noted that the resins do contain some low molecular weight polymer impurity formed as a by-product of the grinding process. This polymer can be extracted with aqueous solutions and its MW can be measured by comparison to standards. This impurity is counted as part of the non-volatile extractables analysis. Based on Rohm and Haas studies the MW weight of the extractable polymer is in the range 10³ – 10⁶ daltons.

Are ion exchange resins soluble in any solvents?

No. Because of their three dimensional, highly cross-linked structure ion exchange resins are not soluble in any solvents. However, as the powders are produced by grinding, a small amount (<1% wt/wt) low cross-linked polymer is formed. This is referred to as ‘extractable polymer’, has molecular weight in the range 104 – 106, and does not affect the functioning of the ion exchange resin.

Are ion exchange resins being used in any commercial pharmaceutical formulations?

Yes, and have been used for over twenty years. The commercial use of ion exchange resins in pharmaceutical formulations fall into two categories – active ingredient and excipient. Below is a partial listing of examples.

Active Ingredients

• Sodium polystyrene sulfonate USP – active ingredient for the treatment of hyperkalemia. Works by removing potassium by ion exchange. (Boehringer Ingelheim and other companies).
  

• Cholestyramine USP – active ingredient for the treatment of hypercholesterolemia. Works by sequestering bile acids, preventing their re-absorption into the blood stream. (BMS Questran and generics.

Multifunctional Excipients

• Nicotine gums and lozenges for smoking cessation, eg Nicorette. Works by extending the release of the nicotine. (Pfizer, GSK, and other companies)

• Vitamin B12 stabilization. Vitamin B12 loaded onto a resin has greatly improved shelf-life compared to pure B12 (various companies)

• Paxil – taste-masked paroxetine oral suspension (GSK)

• Voltaren XR – extended release diclofenac (Novartis)

• Tussionex – extended release chlorpheniramine and hydrocodone (Celltech)

• Delsym – extended release dextromethorphan (Celltech)

• Betoptic – ophthalmic betaxolol (Alcon)

• Novonorm – repaglinide (Novonordisk)

• Pholtex – extended release phenyltoloxamine and pholcodine (3M)
  
  

How much drug can I load onto an ion exchange resin

The answer depends on the molecular weight of the drug and which ion exchange resin is used. The interaction between the two is one of ionic interaction and so depends on the ion exchange capacity of the resin. Theoretically the maximum loading is one mole of drug for every equivalent of ion exchange capacity. Ion exchange capacities are listed as part of the product specifications. In practical terms a drug:resin ratio of up to 1:1 w/w is usually attainable.

Where is the drug in the loaded resin?

The drug is located inside the particle, not just at it’s surface. The need for the drug to diffuse through the polymer matrix is what facilitates release rate control. Being located inside the particles is also what allows such high loading capacity – all of the ion exchange capacity is accessible. This accessibility decreases as the molecular weight of the drug increases, but molecular weights below ~1000 are usually no problem.

What is a resinate?

"Drug resinate" is the term used to describe the complex formed between a drug and an ion exchange resin. The term is appropriate because the complexation mechanism is salt formation, and the resinate can be considered as a salt form of the drug in which the counterion is a polymeric ion. The term ‘resination’ is used to described the process of making a resinate.

Can my drug be loaded onto an ion exchange resin?

If your drug is ionizable then the answer is almost certainly yes. Even very weakly basic or very weakly acidic drugs can be loaded. The table below list drugs that have been loaded onto ion exchange resins. The list is a combination of published data and Rohm and Haas in-house studies. The pKa's were obtained from the Chemical Abstract Service and were calculated using ACD software.