POLYOX Water-Soluble Resins NF

in Pharmaceutical Applications

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POLYOXTM Water-Soluble Resins, NF Grade are nonionicpoly (ethylene oxide) polymers that meet all the specificationsof the United States Pharmacopoeia—National Formulary.They are white, free-flowing hydrophilic powders supplied ina wide variety of molecular weight grades, ranging from onehundred thousand to seven million daltons or amu.

They are essentially tasteless, colorless, nonionic, and non-caloric. This unusual combination of properties makes themuseful in a surprisingly broad array of pharmaceutical formu-lations. They have a long history of successful applications inuses such as controlled release solid dose matrix systems,transdermal drug delivery systems, and mucosal bioadhe-sives.

Extremely Fast Hydration and Gel FormationPOLYOX Resins are among the fastest-hydrating water-soluble polymers used in pharmaceutical systems. They veryquickly form hydrogels that initiate and regulate release ofactive ingredients. Systems using POLYOX Resins are oftensuperior to others in approaching zero order release models.

Unusually Wide Range of Molecular Weights

With molecular weights ranging from 100,000 to 7,000,000,POLYOX Water-Soluble Resins offer exceptional formulatinglatitude. You can select from many different options to helpcontrol dosage size, matrix release profiles, and productionmethods while maintaining consistent flow properties andtablet performance.

Compliance With FDA and Other Regulatory Requirements

POLYOX Water-Soluble Resins, NF Grade comply with theUSP polyethylene oxide NF monograph.

These products meet the requirements of the Food ChemicalsCodex, the International Codex Alimentarius, and the U.S.National Formulary (NF). These products have also beenapproved in drug products sold in all major European coun-tries. Approval for use in Japan is under way and anticipated.The NF product family is listed in Table 1.

An Introduction to POLYOX Water-Soluble Resins

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Brookfield Viscometer,POLYOX Water-Soluble Approximate Viscosity Range at 25°C, cP Model RVF,Resins, NF Grade Molecular Weight 5% Solution 2% Solution 1% Solution Spindle No./Speed, rpm

WSR N-10 NF 100,000 30 – 50 1/50(1)

WSR N-80 NF 200,000 55 – 90 1/50(1)

WSR N-750 NF 300,000 600 – 1,200 1/10WSR-205 NF 600,000 4,500 – 8,800 2/2WSR-1105 NF 900,000 8,800 – 17,600 2/2

WSR N-12K NF 1,000,000 400 – 800 1/10WSR N-60K NF 2,000,000 2,000 – 4,000 3/10

WSR-301 NF 4,000,000 1,650 – 5,500 2/2WSR Coagulant NF 5,000,000 5,500 – 7,500 2/2WSR-303 NF 7,000,000 7,500 – 10,000 2/2

The physical property data listed are considered to be typical properties, not specifications.(1)Model RVT.

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Table 1 — POLYOX Water-Soluble Resins For Pharmaceutical Applications

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A hydrophilic matrix tablet is a simple-to-formulate, yeteffective sustained-release drug-delivery system in which abio-active is uniformly distributed within a polymer matrix.The drug release mechanism is controlled by several variablesin a dynamic process. Upon wetting of the tablet, the polymeron the tablet surface hydrates to form a gel layer. The drugdiffuses from this surface gel layer, which expands with timeinto the interior of the tablet, allowing diffusion of the drugfrom the tablet core.

POLYOX Water-Soluble Resins are very hydrophilic polymers.They hydrate rapidly to form a gel layer on the tablet surfacefor the release of actives. Because POLYOX Resins are non-ionic, no interaction between drug and polymers is to beexpected. The data presented here show how molecularweight and concentration of POLYOX Resins affect therelease rate of a model water-soluble and water-insolubledrug in a matrix system.

Experimental ProcedureTablet formulations (Table 2) were dry-blended in a doubleplanetary mixer. Tablets were pressed with a single punchCarver Laboratory Press in a one-half inch diameter die witha compression force of one metric ton. Drug release data wereobtained from uncoated tablets in a USP-specified dissolutionapparatus, which was equipped with baskets. The dissolutionmedium was simulated gastric fluid (without pepsin) at 37°C.Rotation speed of the baskets was kept at 50 rpm. All datapresented here represent an average of a minimum of threedeterminations. UV/visible spectroscopy was used to deter-mine the concentration of the actives in the dissolution media.

ResultsMolecular Weight

Figure 1 shows the effect of molecular weights of POLYOXWater-Soluble Resins on the release rate. Increasing themolecular weight while maintaining a constant polymerconcentration can drastically reduce the release rates. Theincreased molecular weight leads to an increase in gel strength,which tends to decrease the diffusion of the drug; however,there is a maximum molecular weight beyond which no furtherchange in release rate is affected. As can be seen, an increasein molecular weight from 5,000,000 to 7,000,000 does notappreciably alter the release rate for the water-soluble active,caffeine.

Figure 1 — Effect of Molecular Weight of POLYOXWater-Soluble Resins on In Vitro Release Rate ofCaffeine From a Matrix Tablet

An Ideal Choice for Controlled Release Systems

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Table 2 — Tablet Formulations

Weight Percent, Based on 500-mg Tablet

Ingredients A B C D E F G

Caffeine 10 20 30 20 20 – –

Riboflavin – – – – – 5 20

POLYOX Water-Soluble Resin NF 20 20 20 10 60 10 20

Lactose 69 59 49 69 19 84 59

Magnesium Stearate 1 1 1 1 1 1 1

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Polymer ConcentrationFigure 2 illustrates the effect of polymer concentration onrelease rate. Increasing polymer concentration increases thegel viscosity on the surface of the tablets, which will retardthe diffusion of the drug from the gel layer. Increasing theconcentration from 20 to 60 percent of a relatively lowmolecular weight POLYOX Water-Soluble Resin results in a drug release profile very similar to that obtained from 20 percent of a high molecular weight POLYOX Resin.However, this concentration effect is seen only for low molecular weight polymer. Figure 3 shows caffeine releasefrom matrix tablets produced from POLYOX WSR-303 NF(7,000,000 molecular weight). When polymer concentrationwas changed from 10 to 60 percent in the formulation, nodrastic changes in the release rate was observed. At a very lowpolymer concentration, the initial drug release is larger, butthe rate of release is very similar to that obtained for higherpolymer concentrations.

Figure 2 — Effect of Polymer Concentration andMolecular Weight on In Vitro Release Rate of CaffeineFrom a Matrix Tablet With POLYOX WSR-1105 NF

Figure 3 — Effect of Polymer Concentration on In VitroRelease Rate of Caffeine From a Matrix Tablet WithPOLYOX WSR-303 NF

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Drug LoadingFigure 4 summarizes matrix tablet release data obtained bychanging the drug concentration of caffeine in POLYOXWater-Soluble Resins. Since diffusion is the primary kineticfactor in the release of water-soluble actives from matrixtablets, data were plotted using a Higuchi plot format to illustrate this point better. As can be seen, the lines are almostparallel, showing that very little change in the release ratetakes place when the caffeine concentration is increased from50 to 150 mg in 500-mg tablets.

Figure 4 — Effect of Drug Loading on In Vitro ReleaseRate of Caffeine From a Matrix Tablet With POLYOXWSR Coagulant NF

Drug SolubilityRelease of insoluble actives from hydrophilic matrix systemsoccurs through a diffusion-erosion mechanism. POLYOXWater-Soluble Resins swell greatly when hydrated, and theresulting gel layer does not erode readily. The polymer, therefore, is an ideal vehicle for insoluble drugs in matrixtablets. Figure 5 illustrates how drug-delivery profiles ofwater-insoluble actives can be manipulated with polymer anddrug concentration in POLYOX Resin matrix tablets.

Figure 5 — In Vitro Release Rate of Water-Insoluble Actives From a POLYOX Water-SolubleResin Matrix Tablet

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20% Riboflavin20% POLYOX WSR-303 NF60% Lactose

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Figure 6 — Particle Size Effect on Riboflavin Release From Matrix Tablets Using POLYOX Water-Soluble Resins

Particle SizeParticle size can play a role in matrix tablet performance by influencing the initial rate of hydration and gel layer formation. The data in Figure 6 were generated by selectively separating a standard POLYOX WSR sample into 5 differentparticle size fractions. Tablets were produced from each fraction and drug release rates were measured. The data indicate some variation in release rate as a function of particlesize with the smaller particles producing slower initial releaserates. Interestingly, extreme drug dumping is not seen evenwhen using the very large particle size fraction due to therapid swelling characteristics of POLYOX WSR.

Figure 7 — Effect of pH on Release of Theophylline From Matrix Tablets Using POLYOX Water-Soluble Resins

pHWhen used in oral applications, POLYOX WSR systems donot show a strong pH response due to their nonionic nature.The data in Figure 7 show release profiles collected at differ-ent pH values for a theophylline matrix system. As expected,the release rate does not vary as a function of pH.

ConclusionsPOLYOX Water-Soluble Resins NF are highly versatilewater-soluble polymers. Upon exposure to water or gastricjuices, they hydrate and swell rapidly to form hydrogels with properties ideally suited for a controlled drug-deliveryvehicle. Their utility is not limited to the hydrophilic matrixsystem that is the subject of this discussion. POLYOX Water-Soluble Resins NF have been successfully used inother drug-delivery systems, such as osmotic pumps. Thepolymers are available in a wide range of molecular weights,which enables the formulator to readily custom design toindividual specifications.

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Water Granulation With POLYOXWater-Soluble Resins NF

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As environmental and manufacturing concerns limit the use oforganic solvents as granulating liquids, water is increasinglypreferred as a granulating solvent. The following study exploresthe performance of POLYOX Water-Soluble Resins in watergranulation. This work indicates that POLYOX Resins canoffer several important features in water granulation, including:

● Ability to be water granulated in a high shear unit.

● In addition to acting as a hydrophilic matrix or swellingagent, ability to also act as binders during granulation, eliminating the need for special binders.

● Readily release water during drying, leading to short drying times.

Experimental ParametersGranulatorHigh Shear Granulator equipped with chopper and impeller

Chopper Speed ....................3045 rpmImpeller Speed...................... 450 rpm

Fluid Bed DryerInlet Temperature..................60°COutlet Temperature ..............40°CAir Volume............................280 CFMDrying Time..........................15 – 45 minutes

Processing VariablesWater ConcentrationWater Addition RatePolymer Molecular Weight

ResponsesMean Particle Size Granule FriabilityGranule Morphology

ResultsThe initial set of experiments was carried out using 100%POLYOX Water-Soluble Resin. This enabled evaluation of thepolymer under various process conditions and is relevant toformulations containing high polymer and low drug loadings.Figure 8 shows the median particle size developed as a functionof water addition rate and concentration. The data indicatethat particle size is inversely related to the water addition rate.Because no wet mashing was used in this study, rapid wateraddition limits the time for particle growth, leading to asmaller median particle size. The median particle size wasfound to be directly related to the final water concentrationused in the granulation. Ten percent water was found to besufficient for many granulations.

In Figure 8 the purple data points represent 200,000 molecularweight polymer while the blue data points represent 4,000,000molecular weight polymer. The polymer molecular weightdid not have a significant impact on particle growth, as seenfor the runs consisting of 10% water and an addition rate of60 mL/min.

Figure 8 — Median Particle Size

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Note: Median particle sizesare listed valuesMW = 4,000,000 amuMW = 200,000 amu

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Figure 9 — SEM Micrograph of Granule, 800x

The granules could be dried in the fluid bed to less than onepercent moisture in about 15 minutes. Because no binder wasadded to the granulating liquid, additional work was performedto test the susceptibility of the dried granules to attrition.Because aggressive fluidization is known to cause attrition of friable granules, granules dried to less than one percentmoisture were mixed in the fluid bed for an additional 45minutes. No significant attrition was detected, indicating theproduct will withstand normal handling.

Examination of the final granules by SEM indicates that theagglomeration leads to polymer bridging between particlesas seen in Figure 9. The high molecular weight of POLYOXResins would be expected to provide good granule strength.

In order to compare granulation prepared via water andethanol routes, a set of equivalent granulations was producedby these two approaches. The release profiles for the twotableted products are presented in Figure 10. Drug releasefrom the water granulation is very similar to that seen for theethanol granulation.

Figure 10 — Riboflavin Release Profile: Water VersusEthanol Granulation

Conclusions● POLYOX Water-Soluble Resins can be granulated using

100% water.

● The average particle size is dependent on the rate of wateraddition.

● POLYOX Resins are effective binders.

● Drug release from a water granulation is very similar to thatof an alcohol granulation.

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Beyond their role in controlled release matrix systems,POLYOX Water-Soluble Resins perform other valuable functions in pharmaceuticals. Often, a single POLYOX Resincan contribute several important properties in a single system.

Direct Compression Tablet Binding

POLYOX Resins perform well as binders in economicaldirect compression systems. They often provide better flowand compaction properties than other binders. And theirlubricity also assists tableting operations. This provides a sys-tem where a single excipient can provide both binding andrate-controlling properties.

Mucosal Bioadhesives

POLYOX Water-Soluble Resins offer a number of importantproperties for mucoadhesion—water solubility, hydrophilicity,high molecular weight, hydrogen bonding functionality, andgood biocompatibility. These resins have a long linear chainstructure which allows them to form a strong interpenetratingnetwork with mucus. Data indicate that molecular weights of4,000,000 and higher have the highest level of adhesion.

Using POLYOX Water-Soluble Resins NF inControlled-Release Dosages by Melt Extrusion

POLYOX Water-Soluble Resins are thermoplastic polymerswith a low melting point of ~ 68°C. They can be used in meltextrusion processes to prepare pharmaceutical dosage forms.During a melt extrusion process, a mixture of POLYOXResin, drugs, and optional fillers or plasticizers is fed into anextruder. The POLYOX Resin and other low melting pointcomponents are melted inside the extruder, and the moltenmixture is extruded through a die mounted at the front of thedevice. The extrudate can be further processed into familiarshapes of tablets, caplets, or pellets.

POLYOX Water-Soluble Resins NF Provide ExcellentBinding, Bioadhesion, and Melt Extrusion Properties

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A twin screw extruder allows low temperature extrusion of both low and high molecular weight POLYOX Resins. A small amount of vitamin E is often added to the mixture as an antioxidant to stabilize the solid dosage form. Various plasticizers such as water and glycerin can be added to reducethe melt viscosity. Solid and liquid ingredients can be added separately to the extruder and mixed in situ during the extrusion process.

As an example of a pharmaceutical solid dosage form producedby a melt extrusion process, three different grades of POLYOXResin with high, medium, and low molecular weights wereused to prepare tablets containing riboflavin. The POLYOXResin powder was pre-mixed with riboflavin and vitamin E ina blender. The mixture was then fed into a twin screw extrud-er fitted with a rod die. By using different grades of POLYOXResin and adding different amounts of microcrystalline cellulose, the tablets cut from extruded rods achieved sustained-release profiles ranging from 3 h to 24 h by in vitrodissolution tests using USP Method II at 37°C and 100 rpm in900 mL distilled water (Figure 11).

Figure 11 — Release Profiles of Riboflavin at 37°C in Distilled Water From Tablets (250 mg) Cut FromExtruded Rod Containing 15% by Weight RiboflavinDispersed in Three Different Grades of POLYOXResin or a Mixture of POLYOX Resin/MicrocrystallineCellulose (1:1)

Sample 1: POLYOX WSR-301 NF/microcrystalline cellulose = 1:1 Sample 2: POLYOX WSR-301 Sample 3: POLYOX WSR N-12K NF/microcrystalline cellulose = 1:1 Sample 4: POLYOX WSR N-12K NF Sample 5: POLYOX WSR N-750 NF/microcrystalline cellulose = 1:1Sample 6: POLYOX WSR N-750 NF

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Published August 2002

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