Ion Exchange Resins

Unique Solutions to Formulation Problems

Lyn Hughes

I
Some of the common problems faced by formulators and how using ion exchange resins may be able to solve them are discussed.
PHOTODISC, INC.

Lyn Hughes, PhD, is a global technical service manager for healthcare in the Process Solutions Groups at Rohm and Haas Company, Spring House Technical Center, 727 Norristown Road, Spring House, PA 19477-0904, tel. 215.641.7329, fax 215.619.1608, lhughes@ rohmhaas.com. 20 Pharmaceutical Technology

on exchange resins have been used to help formulate pharmaceuticals since the late 1950s. During that time, they have proven to be safe and effective excipients and are now used in many commercial formulations throughout the world. This article will look at some of the common problems faced by formulators and how using ion exchange resins may be able to solve them. Ion exchange resins are insoluble polymers that contain acidic or basic functional groups and have the ability to exchange counter-ions within aqueous solutions surrounding them. The equation in Figure 1 shows a representative reaction when drugs are loaded onto or released from the resins. A drug ion and an inorganic ion are exchanged. The reaction is an equilibrium, the position of which will depend on many factors such as salt concentration in the aqueous phase. This property enables drugs to be loaded onto resins (forming drug resinates) and then released in vivo by the salts present in gastro-intestinal
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Excipients & Solid Dosage Forms fluids. The resinates possess physical properties similar to those of the resin. These two propertiesdrug release and physical properties can be manipulated to create many variations of use to the formulator. Stability. The drug resinate is frequently more stable than the original drug. This tendency is exemplified by the stabilization of vitamin B12 in the oldest pharmaceutical resinate application. Vitamin B12 has a shelf life of only a few months, but the resinate is stable for more than two years. This technology is still used commercially today, more than 40 years after it was first introduced. Another example is nicotine. Nicotine discolors quickly when exposed to air and light but the resinate (used in nicotine chewing gums and lozenges) is much more stable. Poor dissolution. Many of todays drugs are poorly soluble because of slow dissolution and/or low solubility. The rate of release of poorly soluble, ionizable drugs from a resinate can be much quicker than the rate of dissolution of the pure drug. An excellent example is that of indomethacin, which is only soluble up to 6 ppm in simulated gastric fluid but is released very quickly from a resinate (see Figure 2). Stirring an excess of indomethacin in simulated gastric fluid for three days achieved a concentration of only 1 ppm, whereas exposing a resinate of indomethacin to the same fluid yielded a saturated solution within 30 minutes. Using micronization to increase the rate of dissolution can be problematic be22 Pharmaceutical Technology

N+(R)3 CI-

+ API-CO 2 Na

N+(R) 3 AP-CO2 -

NaCI

Figure 1: The equation shows a representative reaction when drugs are loaded onto or released from the resins.

cause the technique frequently requires specialized equipment and often involves a problem with agglomeration of the fine particles after grinding. The grinding process also can lead to melting and conversion to other crystal forms. These problems can be eliminated by the use of ion exchange resins. Deliquescence. Deliquescence is the property of a solid such that it absorbs so much water that it dissolves in the water it absorbs. Although this is not a common problem, it has been very difficult to solve and requires the use of specialized equipment or careful scheduling of production during dry seasons. However, the resinate of a deliquescent drug is not deliquescent, permitting its formulation into typical dosage forms in standard equipment. Figure 3 shows the results of tests conducted on resinates of sodium valproate, a well-known highly deliquescent drug. Even under such severe conditions, the resinates remain solid. In
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fact, the amount of water absorbed decreases as the Dissolution/release of indomethacin in amount of valproate in simulated gastric fluid 7 the resin increases. Under 6 typical ambient condi5 Indomethacin resinate tions, the resin remains Micronized Indomethacin 4 free-flowing even if water 3 is absorbed. 2 Polymorphism. Unlike 1 deliquescence, polymor0 20 40 50 60 70 0 10 30 80 phism is a very common Time (hours) problem in the pharmaceutical industry, and huge sums of money are Figure 2: The graph shows the level of concentration spent trying to identify versus the time it takes for indomethacin to dissolve in polymorphs and making simulated gastric fluid. stable, suitably soluble forms. Failure to resolve such probsome drugs are free-flowing solids. lems can result in significant stabilA very well established example of ity problems for the final dosage this is the nicotine resinate used in form. Ion exchange resins present a nicotine chewing gums and unique way to solve the problem. A lozenges. Nicotine is a liquid, but drug resinate is an amorphous solid the resinate is a stable, free-flowing that cannot crystallize or even form solid. hydrates. In addition, the release of Tablet disintegration. Some ion exthe drug from the resinate is indechange resins will swell significantly pendent of the crystal form that was when immersed in water. This used to make it. Consequently, the property has led to their use as very use of resinates can eliminate any effective tablet disintegrants. It is problems with polymorphism. Figusually necessary to use only a few ure 4 shows releasedissolution test percent of the tablet weight to get data on lansoprazole and its complete disintegration within sevresinates. These data clearly demon- eral minutes. strate that although the original Taste. Because resinates are insolcrystal forms of the drug had very uble in water, they have no taste. different dissolution rates, the reThis makes them excellent candilease rates from the resinates were dates for masking foul-tasting all the same. drugs. As long as the rate of release Physical state. Some drug subof the drug on contact with saliva is stances are liquids or difficult-tosufficiently slow (and it frequently handle solids. Because the physical is), this technology can work exproperties of the resinates are simitremely well. It is equally applicable lar to those of the resin and not the to liquid formulations (suspendrug, the resinates of these troublesions) and mouth-dissolving
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Concentration (mg/l) EXCIPIENTS & SOLID DOSAGE FORMS 2004

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Excipients & Solid Dosage Forms tablets. It is particularly effective in liquid formu% Wt gain, 24 hours @40C/75%RH lations because the Liquified 120 resinate will represent 100 the thermodynamically 80 stable form so that leach60 ing of the drug into the 40 aqueous phase will not 20 occur. There are several 0 Resin 11% Sodium 18% 26% examples of the use of valproate valproate valproate valproate this technology in the marketplace, including a liquid form of paroxetine. Figure 3: The graph shows the results of testing resinates of sodium valproate, a well-known highly Extended release. One deliquescent drug. of the early applications of ion exchange resins in drug formulation is their use in it more difficult or less desirable to extended-release. The first commer- abuse such formulations. The techcial example of this is the Pennnology can be manipulated to reKinetic system in which dexduce the high associated with intromethorphan is loaded onto a tentional abuse, reduce the likelihood resin and the resin is then coated. of overdose by inadvertent abuse, This combination provides an and make illicit extraction more diffiextended-release liquid formulation cult and less efficient. that is still sold commercially (e.g., Delsym). The technique has also Multiple benefits been used for many years for exThe benefits described are not nectended-release diclofenac, but withessarily mutually exclusive to one out the coating. another. One example is the nicoUntil recently, this technology was tine chewing gum. In this case, the limited by the release profile. Almain reason for making the nicothough the overall release rate could tine resinate (nicotine polacrilex be changed, the shape of the release USP) is to extend the release of the profile was always the samea typinicotine from the chewing gum so cal first-order release. However rethat it lasts 1020 min. However, cent innovations have identified the resinate also increases the stabilways to change this shape signifiity of nicotine and makes it into an cantly, even to the point of achieveasily formulated, less-toxic solid. ing an almost constant release rate. Another example is Delsym, in Abuse liability. During the past which the main reason for the few years, there has been much pub- resinate coating is to create an licity about the abuse of prescripextended-release suspension. Howtion drugs (e.g., OxyContin). Ion ever, it also provides excellent taste exchange resins can be used to make masking. Finally, the use of a resin to
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stabilize vitamin B12 also improves bioavailability.

Dynamic in vitro dissolution profiles
Lansoprazole Conc, mg/L

Getting more information

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30 Unfortunate for the for25 mulator, ion exchange 20 resin technology related 15 to pharmaceutical for10 5 mulation is taught in 0 few, if any, schools and 20 30 40 50 10 60 0 Time, min cannot be found in many textbooks. Even conducting literature Figure 4: The graph shows releasedissolution test searches through various data about lansoprazole and its resinates. scientific journals gives only a fragmented description of ing, Proceedings of Ion Exchange the technology. The number of at the Millennium, (Cambridge, manufacturers of pharmaceutical UK, 1621 July 2000), pp. grade resins is also very limited and 306315 include Rohm and Haas, Dow S. Khanna, US patent 4,510,128 Chemical, Purolite, and Ion Ex W.J. Irwin, R. McHale, and P. J. change India. Listed below are Watts, Drug Delivery by Ion Exsome useful resources to help the change Part VII: Release of Acidic formulator find out more about Drugs From Anionic Exchange this technology. Resinate Complexes, Drug DevelTextbooks opment and Industrial Pharmacy, Freidrich Helfferich, Ion Exchange 16 (6), 883898 (1990). (Dover Publications, Mineola, NY, Web site 1995) www.rohmhaas.com/markets/ Robert Kunin, ed., Ion Exchange pharmaceutical.html Resins (Robert E. Krieger Publishing Co., Huntington, NY, 1990) Conclusion Remington The Science and PracIon exchange resin excipients tice of Pharmacy, (University of should be a part of every formulathe Sciences, Philadelphia, PA, tors basic toolkit. Although they are 2000, 20th ed.), pp. 903929. not as well-known in the industry Journal articles/patents as one might expect, ion exchange Y. Raghunathan, US patent resin excipients can bring unique 4,221,778 benefits and solve some very diffi D.P. Elder et al., Development of cult problems. P T a Palatable Liquid Formulation of a Bitter Tasting Drug Using Ion Exchange Resins for Taste Mask-

'as received' Form I Form II Resinate of 'as received' Resinate of Form I Resinate of Form II

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