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.

 

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.

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.

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.

 

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)
  

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.

 

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.

 

"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.

For our products Amberlite™ IRP69 and Duolite™ AP143 the answer is quite simple – these are salts of strongly acidic and strongly basic resins respectively so that they are completely dissociated when hydrated. The pK of the parent acid or base will be similar to those of small molecule sulfonic acids and quaternary trialkyl aryl ammonium hydroxides.

 

For our product AMBERLITE™ IRP64, and its sister product AMBERLITE™ IRP88, there is no straightforward answer. This product comprises a polyethylene backbone with every other carbon substituted with a carboxylic acid group and a methyl group. Consequently it is a polyacid and each acidic group will have its own pK – there is no single pK value. This effect is more easily understood if one looks at various small molecule acids that contain more than one acid group, for example citric, tartaric, and glutaric acids. A quick look at published pK value shows that each of the acid groups has a different pK:

 

	1st ionization	2nd ionization	3rd ionization
Citric acid	3.08	4.74	5.40
Tartaric acid	2.98	4.34
Glutaric acid	4.34	5.41

 

 

The same situation occurs with polyacids except that there are now millions of carboxylic acid groups. The result is a continuum of pK values. The higher the fraction of groups converted to the salt form (higher loading), the higher will be the pK of the next acid group to be converted.
A value for pK has been determined for Amberlite® IRP64 using methods well established in the industry (ie determining the pH inside the resin at 50% conversion) and that value turns out to be ~4.0. However, this really represents the pK of the acidic groups that are becoming ionized at 50% conversion. Those that ionized before 50% have lower pK, and those that ionize later will have higher pK. Consequently the value of 4.0 can be used only as a rough guideline and experimental determination of drug loading must be carried out to get an accurate assessment of loading characteristics.

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.