Ion Exchange ResinsUnique Solutions to Formulation ProblemsDr. L. Hughes, Global Technical Service Manager, HealthcareRohm and Haas Research Laboratories - Spring House

INTRODUCTION

Ion exchange resins have been used to helpformulate pharmaceuticals since the late 1950's.During that time they have proved to be safe andeffective excipients and are now used in manycommercial formulations throughout the world. Inthis article we will look at some of the commonproblems faced by formulators and how using ionexchange resins may be able to solve them.Ion exchange resins are insoluble polymers thatcontain acidic or basic functional groups and havethe ability to exchange counter-ions with aqueoussolutions surrounding them. The equation in Figure I shows a representativereaction when drugs are loaded onto or releasedfrom the resins. A drug ion and an inorganic ion areexchanged. The reaction is an equilibrium, theposition of which will depend on many factorsincluding salt concentration in the aqueous phase.This property allows drugs to be loaded onto resins(forming drug resinates) and then released in vivo bythe salts present in GI fluids. The resinates possessphysical properties similar to the resin. These twoproperties - drug release and physical properties - canbe manipulated to create many variations of use tothe formulator.

Figure I

STABILITY

The drug resinate is frequently more stable than theoriginal drug. This is exemplified by the stabilizationof vitamin B12 in the oldest pharmaceutical resinateapplication. Vitamin B12 has a shelf life of only a fewmonths, but the resinate is stable for > 2 years. Thistechnology is still used commercially today, morethan 40 years after it was first introduced. Anotherexample is nicotine. Nicotine discolors quickly onexposure to air and light but the resinate (used innicotine chewing gums and lozenges) is much morestable.

POOR DISSOLUTION

Many of today's drugs are poorly soluble due to slowdissolution and/or low solubility. The rate of releaseof a poorly soluble, ionizable drugs from a resinatecan be much quicker than the rate of dissolution ofthe pure drug. An excellent example is that ofindomethacin which is only soluble up to ca 6ppm insimulated gastric fluid, but is released very quicklyfrom a resinate. Figure II shows a graph ofconcentration vs time demonstrating this. Stirring anexcess of indomethacin in simulated gastric fluid for3 days achieved a concentration of only 1 ppm,whereas exposing a resinate of indomethacin to thesame fluid gave a saturated solution within 30minutes.

Figure II: Dissolution/Release of Indomethacin in Simulated Gastric Fluid

Using micronization to increase the rate ofdissolution can be problematic, frequently requiringspecialized equipment, and often having problemwith agglomeration of the fine particles aftergrinding. The grinding can also result in melting andconversion to other crystal forms (see below). Theseproblem are completely eliminated by using the ionexchange resin approach.

DELIQUESCENCE

Deliquescence is the property of a solid whereby itabsorbs so much water that it dissolves in the water itabsorbs. While this is not a common problem it hasbeen a very difficult one to solve, and requires the useof specialized equipment or careful scheduling ofproduction in dry seasons. However, the resinate of adeliquescent drug is not deliquescent, permitting itsformulation into typical dosage forms in standardequipment. Figure III show the results of testingresinates of sodium valproate, a well known highlydeliquescent drug. Even under such severeconditions the resinates remain solid. In fact, theamount of water absorbed decreases with increasedamount of valproate in the resin. Under typicalambient conditions the resin remains free-flowingeven if water is absorbed.

Figure III

POLYMORPHISM

Unlike deliquescence, polymorphism is a verycommon problem in the pharmaceutical industry andhuge sums of money are spent trying to identifypolymorphs and trying to make stable, suitably solubleforms. Failure to resolve such problems can result insignificant stability problems for the final dosageform. Ion exchange resins present a unique way todeal with the problem. A drug resinate is anamorphous solid that cannot crystallize or even formhydrates. In addition the release of the drug from theresinate is independent of the crystal form that wasused to make it. Consequently, using resinatescompletely eliminates any problems withpolymorphism.

Figure IV shows some release/dissolution test data onlansoprazole and its resinates. This data clearlydemonstrates that although the original crystal formsof the drug had very different dissolution rates, therelease rates from the resinates were all the same.

Figure IV: Dynamic in Vitro Dissolution Profiles

PHYSICAL STATE

While most drug substances are solids there are somethat are liquids or difficult-to-handle solids. Becausethe physical properties of the resinates are similar tothe resin not the drug, the resinates of thesetroublesome drugs will be free-flowing solids. A verywell established example of this is the nicotineresinate used in nicotine chewing gums and lozenges.Nicotine is a liquid, but the resinate is a stable, free-flowing solid.

TABLET DISINTEGRATION

Certain of the ion exchange resins swell significantlyon exposure to water. This has led to their use as veryeffective tablet disintegrants. It is usually necessary touse only a few percent of the tablet weight to getcomplete disintegration within several minutes.

TASTE

Because resinates are insoluble in water they have notaste. This makes them excellent candidates for taste-masking foul tasting drugs. As long as the rate of releaseof the drug on contact with saliva is sufficiently slow(and it frequently is) this technology works extremelywell. It is equally applicable to liquid formulations(suspensions) and dissolve-in-the-mouth tablets. It isparticularly effective in liquid formulations becausethe resinate will represent the thermodynamicallystable form so that leaching of the drug into theaqueous phase will not occur. There are severalexamples of the use of this technology in the marketplace including a liquid form of paroxetine.

EXTENDED RELEASE

One of the early applications of ion exchange resinsin drug formulation is their use in extended release.The first commercial example of this was known as thePennKinetic system where dextromethorphan wasloaded onto a resin and the resin was then coated.This combination gave an extended release liquidformulation that is still sold commercially (Delsym®).The technique, but without the coating, has also beenused for many years for extended release diclofenac.Until recently this technology was limited by therelease profile. While the overall release rate could bechanged, the shape of the release profile was alwaysthe same - a typical first order release. However recentinnovations have identified ways to change this shapesignificantly, even to the point of achieving almostconstant release rate.

ABUSE LIABILITY

During the last few years there has been muchpublicity about the abuse of prescription drugs, egOxyContin®. Ion exchange resins can be used tomake it more difficult or less desirable to abuse suchformulations. The technology can be manipulated toreduce the high associated with intentional abuse,reduce the likelihood of overdose by inadvertentabuse, and make illicit extraction more difficult andless efficient.

MULTIPLE BENEFITS

The benefits described are not necessarily mutuallyexclusive to one another. One example is the nicotinechewing gum. Here the main reason for making thenicotine resinate (nicotine polacrilex USP) is toextend the release of the nicotine from the chewinggum so that it last 10-20 minutes. However theresinate also increases the stability of nicotine andmakes it into an easily formulated, less toxic solid.Another example is in Delsym® where the mainreason for the resinate/coating is to create anextended release suspension. However, it alsoprovides excellent taste-masking. Finally the use of aresin to stabilize vitamin B12 also improves bio-availability.

USING ION EXCHANGE RESINS

In most cases making the resinates is very simple. Thedrug is dissolved in a suitable solvent, eg water oraqueous ethanol, and the resin is added. The loadingtakes place at ambient temperature and usually takesa few hours to complete. The resinate is then isolatedeither by filtration or by spray-drying. In some casessuch as suspensions it may not even be necessary toisolate the resinate.

GETTING MORE INFORMATION

Unfortunately for the formulator, ion exchange resintechnology related to pharmaceutical formulation istaught in few, if any schools, and cannot be found inmany textbooks. Even doing literature searchesthrough the scientific journals gives only afragmented description of the technology. Below arelisted some useful resources to help the formulatorfind out more about this unique technology.

Textbooks

• Ion ExchangeFreidrich Helfferich, Dover publications, 1995.

• Ion Exchange ResinsRobert Kunin. Robert E. Krieger Publishing Co,1990.

• Remington - The Science and Practice of Pharmacy.20th Ed. Chapter 47. University of the Sciences,Philadelphia, 2000.

Journal Articles & Patents

• Y. Raghunathan. US 4,221,778.• D.P Elder, A Park, P. Patel and N. Marzolini

Proceedings of IEX 2000. Ion Exchange at theMillennium. J.A.Greig (ed), 2000. 306 - 315.

• S. Khanna. US 4,510,128.• W. J. Irwin, R. McHale, and P. J. Watts

Drug Development and Industrial Pharmacy, 16(6),883-898 (1990).

Websitewww.rohmhaas.com/markets/pharmaceutical.html.

CONCLUSION

Ion exchange resin excipients should be a part of theformulators' basic toolkit. Although not as wellknown in the industry as one might expect from theirwide utility they can bring unique benefits and solvesome very difficult problems.

For more information, please contact :Dr. L. Hughes, Rohm and Haas Research Laboratories,

Spring House, PA, USATel: 215 641 7329 - e-mail: lhughes@rohmhaas.com