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Pharmaceutical Excipients A Business Unit of Hercules Incorporated
PharmaceuticalExcipients
A Business Unit of Hercules Incorporated
Table of Contents
Introduction............................................................................................. 1
Pharmaceutical Applications
Tablet Binder .......................................................................................... 2
Modified Release ................................................................................... 4
Liquid and Semi-Solid Formulations....................................................... 8
Tablet Coating ........................................................................................ 9
Aqualon Products
KLUCEL® hydroxypropylcellulose (HPC) .............................................. 10
AQUALON® and BLANOSE® sodium carboxymethylcellulose (CMC) .... 12
AQUALON® ethylcellulose (EC)............................................................ 14
NATROSOL® hydroxyethylcellulose (HEC) ........................................... 16
Aqualon has been delivering pharmaceutical performance since the 1950s.through the legacy of Hercules Incorporated and Henkel GmBH.
Aqualon was originally founded in 1987 as a joint venture betweenthe water-soluble polymer groups of these two companies. In 1989,
Aqualon became a business unit of Hercules Incorporated.
Delivering Pharmaceutical Performance
Functions• Tablet Binding Power • Water Retention• Thickening and Rheology Control • Adhesive Strength• Film Formation • Suspending and Emulsifying
Markets• Pharmaceuticals • Paper Mills• Personal Care • Printing Inks• Water-Based Paints • Aviation Fluids• Construction Materials • Oil and Gas Exploration• Food
Pharmaceutical Excipients• KLUCEL® hydroxypropylcellulose (HPC)
– Tablet binding, modified release, film coating
• NATROSOL® hydroxyethylcellulose (HEC)– Modified release, film coating, solution/suspension rheology
• AQUALON® and BLANOSE® sodium carboxymethylcellulose (CMC)– Solution/suspension rheology, tablet coating, modified release, film forming
• AQUALON® ethylcellulose (EC)– Modified release, microencapsulation, tablet coating and binding, flavor masking
Production Facilities• Alizay, France• Hopewell, Virginia, U.S.A.• Zwijndrecht, the Netherlands
Headquarters, Corporate Research Center, and Pharmaceutical Laboratory• Wilmington, Delaware, U.S.A.
For further information, including samples, technical literature, and sales information:• Visit our website at www.aqualon.com.• Contact any of the offices listed in this publication.
Aqualon...A World Leader in Products That Managethe Physical Properties of Aqueous Systems
1
Tablet Binder
KLUCEL® hydroxypropylcellulose (HPC) providespremier performance as a tablet binder. KLUCEL exhibitsa unique combination of thermoplasticity with organicsolvent or aqueous solubility, allowing tough tabletpreparation using many different formulation techniques.
Unmatched tablet hardness and friability are foundwith low viscosity grades of KLUCEL, at typical use levelsof 2 to 8%, in a wide variety of processing options–
• Wet Granulation (high or low shear or fluid bed):Grades EF and LF with regular particle size are oftenused in granulating solutions. Alternately, grade EXF,with fine particle size, can be added dry to otheringredients, followed by granulation with wateror solvent.
• Direct Compression or Dry Granulation(roller compaction or slugging):Grade EXF with fine particle size is recommended.
Beyond unmatched tablet hardness and friability, benefitsof tableting with KLUCEL include:• Reduction or elimination of tablet capping;• Smaller tablet size and production efficiency; and• Lower compression and ejection forces.
Thermoplastic PropertiesThe benefits of KLUCEL as a tough tablet binder arewell known. In pure tablet compacts, the high energyabsorption and ductility of KLUCEL is shown in Figure 1versus other binders and fillers. (References A and B.)
Figure 1: Pure Compacts Under Compression
Stress, N
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50
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KLUCEL® EXF HPC
PVP
MC
PGS
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High Tablet Hardness and Low FriabilityThe thermoplasticity of KLUCEL allows production oftough tablets. Figures 2 through 5 demonstrate the binderperformance of KLUCEL in comparison studies utilizinglow shear and fluid bed granulation of tablets formulatedwith 83.3% poorly-compressible acetaminophen. Thesehigh dose studies show KLUCEL can be used at loweruse levels to yield superior tablets, compared to tabletswith higher binders levels of HPMC, MC, PVP and pre-gelatinized starch (PGS). High-dose acetaminophenformulations using lower levels of these poorer binderswere simply poor, due to capping. Aqualon has foundsimilar comparative results with other drug compounds.(References C, D, E, and F.)
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Figure 2: Low Shear Wet Granulation Tablets
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Figure 5: Fluid Bed Granulation Tablets
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Lower Compression and Ejection ForcesFigure 6 demonstrates the lower ejection forces forHPC relative to PVP, measured at the tablet press.(Reference B.)
Selected references on tablet binding are available on the Aqualonwebsite at www.aqualon.com or by contacting one of our worldwideoffices shown in this brochure.
A. Effects of Binder Toughness and Flowability onPharmaceutical Tablet Performance(Aqualon Pharmaceutical Technology Report PTR-015)
B. Correlating the Ejection Force of Tablets with the Toughness ofBinders in the Solid Dosage Forms(Aqualon Pharmaceutical Technology Report PTR-009)
C. Evaluation of Low-Viscosity Polymers in aModel High-Dose, Acetaminophen Formulation(Aqualon Pharmaceutical Technology Report PTR-011)
D. Effect of KLUCEL ® EF and EXF Hydroxypropylcellulose as GranulatingAgents in Low-Dose Hydrochlorothiazide Tablet Formulation(Aqualon Technical Information Bulletin VC-572A)
E. Validation of Tablet Dissolution Method byHigh Performance Liquid Chromatography(Aqualon Pharmaceutical Technology Report PTR-006)
F. An Evaluation of Fluidized Bed Granulation Methods for PreparingTablets of a High-Dose, Poorly-Compactible Drug(Aqualon Pharmaceutical Technology Report PTR-010)
G. Lot-to-Lot Uniformity of KLUCEL ® EXF Hydroxypropylcelluloseas a Granulating Agent(Aqualon Technical Information Bulletin VC-588A)
H. Assessment of Low-Viscosity Polymers asDirect Compression Binders in a Model System(Aqualon Pharmaceutical Technology Report PTR-005-1)
I. G.W. Skinner et al, Drug Dev Ind Pharm 1999 Oct; 25(10):1121-8;The evaluation of fine-particle hydroxypropylcellulose as a rollercompaction binder in pharmaceutical applications
Tablet Binder
3
80% Dissolution Time, min
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00 5 10 15 20 25 30
Figure 6: Fluid Bed Granulation Tablets
Compression Force, kN
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8% PVP
4% HPC
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8% HPC
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Cellulose derivatives are often used to modify the releaseof drugs in tablet and capsule formulations. For tablets,cellulose derivatives provide utility as matrix componentsand coatings. These systems benefit from ease ofmanufacture, low cost and predictable in vivoperformance. This summary presents formulationguidance for some hydrophilic and hydrophobic systems.
HYDROPHILIC MATRIX SYSTEMS
Cellulose derivatives such as HPC or HEC are used inhydrophilic matrix systems. High molecular weight gradesof KLUCEL® HXF or HF HPC or NATROSOL® HHX orHX HEC are typically used. As the polymers are exposedto water, they form a gel layer that will retard the releaseof the active ingredients. Drug release with these systemsinvolve two simultaneous processes: Fickian diffusionand matrix relaxation and erosion. Along with drug loadand solubility, polymer swelling, concentration and particlesize, pH effects, other excipients and processing variablesare important factors when formulating these systems.
Drug SolubilityThe solubility of the drug in hydrophilic tablet matrices isan important factor influencing the choice of polymer tomodify the release profile. Figures 1 and 2 show drugsolubility effects for systems based on KLUCEL® HPCand NATROSOL® HEC. KLUCEL is most suitable forhighly water-soluble drugs. NATROSOL is appropriatefor near zero-order release attainable with sparingly andlow solubility drugs. (References A and B.)
Modified Release
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Figure 2: Effect of Drug Solubility on Release From HEC Tablets–40% Drug, 30% NATROSOL® 250 HHX HEC, 30% MCC
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40
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Acetaminophen(1.8% solubility)
Theophylline(0.8% solubility)
Diclofenac Sodium(0.18% solubility, pH 7)
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Robust Processing OptionsFor highly soluble phenylpropanolamine (PPA), the robustprocessing nature of KLUCEL HXF is shown in Figure 3with equivalent release profiles in wet granulation, rollercompaction and direct compression. (References A and C.)
% Drug Released
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20
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Figure 3: Equivalent Release From HPC TabletsFormulated With Various Processes–20% PPA, 30% KLUCEL® HXF HPC, 50% MCC
Time, hours
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Figure 1: Effect of Drug Solubility on Release From HPC Tablets–20% Drug, 30% KLUCEL® HXF HPC, 50% MCC
Time, hours
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KLUCEL® Particle SizeAgain for PPA, Figure 4 shows particle size effects usingfine grind HXF with slower drug release relative to regulargrind HF. (References A, C, and D.)
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Figure 4: Fine Grind HPC Exhibits Slower Release Than RegularGrind HPC From Tablets–20% PPA, 30% KLUCEL® HXF HPC, 50% MCC
Time, Hours
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Stable to pH EffectsKLUCEL® HPC or NATROSOL® HEC are non-ionicpolymers, so that hydration and viscosity developmentare not influenced by the pH of the dissolution media.Figures 5 and 6 show release profiles for KLUCEL HPCand NATROSOL HEC for changes in pH for theophyllineformulations. (Reference B.)
Stability of ReleaseKLUCEL has been studied extensively for one-yearstability under various storage conditions (25°C, 40°C at80% relative humidity, and 50°C). Figure 7 demonstratesthe excellent release stability, as compared to the originalrelease profile for PPA. Ongoing studies consider otherstorage conditions and drugs formulated with KLUCELand NATROSOL. (Reference E.)
% Drug Released
DI Water
pH Change
pH 6.8 Buffer0.1 NHCl
Figure 6: HEC Is Non-ionic; Release From Tablets IsIndependent of pH–50% Theophylline, 30% NATROSOL® 250HHX HEC, 20% MCC
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Figure 7: HPC Tablets Exhibit Excellent One-Year Stability,Held Under Various Conditions–14% PPA, 25% KLUCEL® HXF HPC, 58% Diluent
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Figure 5: HPC Is Non-ionic; Release From Tablets Is Independent of pH–20% Theophylline, 30% KLUCEL® HXF HPC, 50% MCC
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HYDROPHOBIC MATRIXAND COMPRESSION COATINGS
Hydrophobic matrices, composed of ethylcellulose forinstance, do not swell or erode and thereby modify drugrelease via Fickian diffusion. Direct compression orsolvent granulation may be used to incorporateethylcellulose. Drug actives may alternately be coated ina similar method and incorporated in capsules or otherdosage forms. The use of a compression coating will allowa time-delayed pulse release or a time-delayed sustainedrelease, dependent upon the composition of the innertablet core.
Improved Compressible Grade:AQUALON® T10 Pharm EthylcelluloseWith innovative polymer engineering, Aqualon designeda new grade of ethylcellulose, AQUALON T10 Pharm EC,with optimized compactibility and powder flow. As shownin Figure 8, EC with high ethoxyl content and low viscosityprovides improved compaction, without the need forreduction in particle size via micronization. (Low viscositycorresponds to low molecular weight polymer, whendissolved in test solvent.) Detailed studies have includedphysical, thermal and mechanical characterizations alongwith powder flow, compaction simulation and molecularmodeling. (Reference I).
Modified Release Direct Compression TabletsAQUALON T10 Pharm EC can be readily incorporatedin stronger direct compression controlled releasematrices, eliminating the need for solvents. Figures 8 and 9show the improvement in crushing strength andretardation of drug release with this improved grade ofEC in simple tablet models. (References I and J.)
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Ethoxyl, Viscosity,% cps
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Drug SolubilityAn understanding of drug load and solubility are impor-tant to control drug release. Figure 10 shows the effectof drug solubility in a simple tablet model where Fickiandiffusion controls release.
Effect of Diluent/FillerIn these systems, drug release can be modulated by theswellability and solubility of the filler, as shown in Figure11. Insoluble, non-hydrating dicalcium phosphateprovides a slow release profile. Soluble sugars (lactoseand mannitol) showed intermediate release behavior.Microcrystalline cellulose (MCC), which is hydrophilic andswellable, but insoluble, displayed the fastest releaseprofile. Soluble excipients are known to act as channelingagents, resulting in increased porosity with ongoing waterpenetration. Swellable excipients can dramaticallyincrease in volume, causing stress relaxation of thematrix, allowing rapid water ingress.
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Figure 9: Effect of EC Variables on Drug Release ofEC:Acetaminophen (3:1) Tablets
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Figure 10: Effect of Drug Solubility on ReleaseFrom AQUALON® T10 EC:Drug (3:1) Tablets
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Figure 8: Effect of EC Variables on Compactibility ofEC:Acetaminophen (3:1) Tablets
Ethoxyl, Viscosity,% cps
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51.0 9.249.6 9449.3 8047.5 1045.6 7.145.7 83
Modified Release
Pulse Release via Compression CoatingA coating of ethylcellulose compressed around a tablet corecan delay the delivery of actives for a controlled period oftime. The factors that control this function are the coatingcompactibility and thickness, compression force applied andcore swellability. Figure 12 provides a general mechanism forpulse release in these systems with compression forcecontrolling release time, as shown in Figure 13. (Reference K.)
Effect of Polymer Grade and CompactibilityThe compactibility of EC is highly dependent on ethoxylcontent and viscosity, with the new grade being greater
Hydrophilic SystemsA. Compression and Drug Release Characteristics of Directly
Compressible KLUCEL® Hydroxypropylcellulose ControlledRelease Matrix Systems(Aqualon Pharmaceutical Technology Report PTR-019)
B. Versatility of NATROSOL® Hydroxyethylcellulose inControlled Release Matrix Systems(Aqualon Pharmaceutical Technology Report PTR-017)
C. KLUCEL® Hydroxypropylcellulose Controlled Release MatrixTablets Prepared by Roll Compaction: Effect of Polymer,Formulation and Processing Variables(Aqualon Pharmaceutical Technology Report PTR-018)
D. DA Alderman, U.S. Patent 4,704,285; Sustained release compositionscomprising hydroxypropyl cellulose ethers; granted 11/3/87, expires11/18/05 (Contact Dow Chemical for further information.)
E. One-Year Stability of Sustained-Release Matrix TabletsFormulated with KLUCEL ® HXF Pharm Hydroxypropylcellulose(Aqualon Technical Information Bulletin VC-565B)
F. KLUCEL® Pharm Hydroxypropylcellulose Application in aSustained Release Matrix Capsule Dosage Form(Aqualon Technical Information Bulletin VC-529)
G. Lot-to-Lot Variation in KLUCEL ® HXF Pharm Hydroxypropylcellulose,Effect on Drug Release in Sustained-Release Matrix Tablets(Aqualon Technical Information Bulletin VC-567C)
H. NATROSOL® 250HX Pharm Hydroxyethylcellulose, Applicationin a Sustained-Release Matrix Capsule Dosage Form(Aqualon Technical Information Bulletin VC-554)
Hydrophobic Matrix and Compression CoatingsI. Advanced Structure-Function Properties of Ethylcellulose:
Implications For Tablet Compactibility(Aqualon Pharmaceutical Technology Report PTR-021)
J. Ethylcellulose In Direct Compression Modified Release Tablets:Impact of Polymer Structure and Formulation Variables(Aqualon Pharmaceutical Technology Report PTR-023)
K. Ethylcellulose In Compression Coated Tablets: Implications ForTime-Controlled Pulsed-Release Dosage Forms(Aqualon Pharmaceutical Technology Report PTR-022)
Selected references on modified release are available on theAqualon website at www.aqualon.com or by contacting one of ourworldwide offices shown in this brochure.
7
% Drug Released
Figure 11: Diluent Effect on Drug Release From DirectlyCompressed Model Formulations–25% Acetaminophen, 40% AQUALON® T10 EC, 34% Diluent
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Compressed coatEC 99%, lubricant 1%
Immersion inaqueous media
Tablet core: with orwithout swelling agent(0-6% croscarmellose)
Water diffuses through pores of the ECbarrier coating. Swelling force/axialrelaxation of the inner tablet causes ECcoating to open in “clamshell” manner.
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Figure 13: Effect of Compression Force on Pulse ReleaseLag Time–Theophylline Model
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than 25% more compactible than the other materials. Asshown in Figure 14, this results in increased resistanceto water infusion and coating strength, which is critical toachieving prolonged lag times. Tablets compression-coated with AQUALON® T10 EC at 5kN compressionforce achieved markedly longer lag times than tabletscoated at 25 kN with other grades of EC.
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Figure 14: Comparison of AQUALON® T10 Pharm EC CompressionCoat Performance With Other EC Grades–Theophylline Model
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Liquid and Semi-Solid Formulations
Liquid and semi-solid pharmaceutical dosage forms areimportant physicochemical systems for medicaltreatment. A variety of administration routes exist for thesedosage forms, including oral, inhalation, dermal,parenteral and mucosal (buccal, vaginal, rectal andophthalmic) modes. These liquid and semi-solid dosageforms require rheological control and stabilizing excipientsas essential additives. With the proper choice of Aqualonwater-soluble and organo-soluble excipients, thesesystems can exhibit (a) increased stability; (b) controlledviscosity to promote delivery; and (c) selectedorganoleptic properties such as improved mouth-feel.
SyrupsSyrups are often prepared without sucrose. Viscosityis adjusted by the use of AQUALON® or BLANOSE®
CMC or NATROSOL® HEC. Medium or high molecularweight products are generally preferred.
Suspension SystemsFor systems like antacids or X-ray contrast fluids whichrequire stabilization of the suspended solids, AQUALONor BLANOSE CMC is preferred because of the synergisticstabilizing effect of CMC with clays, either from natural orsynthetic origin.
Liquid SoapsNATROSOL HEC is preferred in the preparation of liquidsoaps, because of its good compatibility with surfactantsystems. In this case, higher molecular weight gradesare recommended for greater efficiency.
8
Topical GelsAqueous or hydroalcoholic gels are often used for topicalappl icat ions. KLUCEL® HPC is preferred withhydroalcoholic carriers. Aqueous systems are typicallyformulated with KLUCEL HPC, NATROSOL HEC, orAQUALON or BLANOSE CMC, depending on thechemical compatibility with other ingredients.
Topical Lotions and CreamsEmulsified systems provide topical applications rangingfrom liquid (lotions) to more semi-solid systems (creams).Medium molecular weight NATROSOL HEC is used tomodify the rheology and stabilize emulsions.
Parenteral and Implant ApplicationsAqualon has not determined the safety of cellulosederivative products in parenteral or medical implantapplications. Formulators need to pursue and ensure thesafety of products that may contain cellulose derivatives.
Selected references on liquid and semi-solid formulations areavailable on the Aqualon website at www.aqualon.com or bycontacting one of our worldwide offices shown in this brochure.
A. BLANOSE ® Sodium Carboxymethylcellulose–AQUALON® SodiumCarboxymethylcellulose–Stabilizer for Antacids Suspensions(Aqualon Technical Information Bulletin VC-607)
B. AQUALON ® Water-Soluble Polymers–SurfactantCompatibility and Recommendations(Aqualon Technical Information Bulletin VC-527A)
C. Rheology of AQUALON ® Water-Soluble Polymers in Solution(Aqualon Technical Information Bulletin VC-453C)
D. NATROSOL ® 250 Pharm Hydroxyethylcellulose inPharmaceutical Gel Compositions(Aqualon Technical Information Bulletin VC-608)
Solubility and Solution Properties of Aqualon Cellulose Derivatives
AqualonTradename
PolymerCharge
Anionic
SurfaceTension,
mN m
SolubilitySalt (NaCl)
CompatibilityWater,
AmbientTemp.
Soluble
HotWater
OtherOrganicSolvent
AnhydrousEthanol
AQUALON® and BLANOSE® CMC
NATROSOL® HEC
KLUCEL® HPC
AQUALON® EC
Non-Ionic
Non-Ionic
Non-Ionic
Soluble
Soluble
Insoluble
Insoluble
Insoluble
Soluble
Soluble
Medium/High
High
Medium
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Insoluble
Partial
Many Solvents
Many Solvents
71.0
66.8
43.6
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Relative TrendsAmong Aqualon
Cellulose Derivatives Increased Water Binding Capacityand Cold Water Solubility
IncreasedOrgano-Solubility
CMC HEC HPC EC
Soluble
Soluble
Insoluble >40°C
Insoluble
9
Tablet Coating
Aqualon offers a variety of low-viscosity cellulosicpolymers, which provide important mechanical, andbarrier properties for tablet coating. The table aboveprovides an overall property summary for threeAQUALON® water-soluble polymers.
KLUCEL® HPCThe flexibility and adhesion of KLUCEL are well known.Due to low surface and interfacial tensions of its solutions,film cracking and monogram bridging can be eliminated.This allows successful formulation of KLUCEL in aqueousfilm coating alone or to enhance the utility of strong, butbrittle, HPMC-based coatings.
KLUCEL imparts a variety of benefits:• Excellent film adherence to problem tablet
substrates such as vitamins;• Great reduction in film cracking on the edge
of tablets;• Improved barrier to water and oxygen
transmission; and• Elimination of bridging of tablet monograms.
In essence, KLUCEL can plasticize HPMC while providingthe barrier properties noted. Film formulation guidance isavailable for KLUCEL alone or in combination with HPMC,applicable to a wide variety of coating equipment and awide variety of tablet cores. (References A and B.)
AQUALON® or BLANOSE® CMCCMC provides films with high gloss and excellent barrierproperties, with low transmission of oxygen and watervapor. Films formed with CMC are strong, but brittle,and need to be plasticized. CMC is compatible with awide variety of plasticizers, including polyethylene glycol,polypropylene glycol and triacetin. Film formulationinformation is available. (Reference C.)
NATROSOL® HECAs a film-forming highly-elastic polymer, HEC alsoprovides low transmission of oxygen. Because thepolymer is non-ionic, it is compatible with a variety ofother ingredients, including actives and surfactants.
AQUALON® ECEC is soluble in a wide range of organic solvents. Its useas a coating for one or more active ingredients in a tabletcan prevent them from reacting with other materials orwith one another. It can prevent discoloration of easilyoxidizable substances such as ascorbic acid. Further, ECcan be used in combination with water-soluble polymersto prepare sustained-release coatings of fine particlesand tablets, or to provide film coatings with reduced watersolubility. For water-based film coatings, EC has beenused in latex systems. EC masks the bitter taste of drugs,minimizing the need for added flavoring agents.
A. KLUCEL® EF Pharm Hydroxypropylcellulose, Use inPlasticizer-Free Aqueous Film Coating(Aqualon Technical Information Bulletin VC-598A)
B. The Use of KLUCEL ® Pharm Hydroxypropylcellulose to Increase theUtility of Hydroxypropyl Methylcellulose in Aqueous Film Coating(Aqualon Technical Information Bulletin VC-556C)
C. J.L. Johnson, U.S. Patent 4,931,286; High gloss cellulose tabletcoating; granted 6/5/90, expires 4/19/09
D. G. Banker et al, Drug Dev Ind Pharm 1981, 7, 693-716; Evaluationof hydroxypropylcellulose and hydroxypropylmethylcellulose asaqueous-based film coatings
E. S.C. Porter and C.H. Bruno, “Coating of Pharmaceutical Solid-DosageForms” in Pharmaceutical Dosage Forms: Tablets, vol 3, 2nd ed,ed. H.A. Lieberman et. al., Marcel Dekker, 1990.
Selected references on tablet coating are available on the Aqualonwebsite at www.aqualon.com or by contacting one of our worldwideoffices shown in this brochure.
Film-FormingPolymer
WaterVapor
Transmissiong/m2/day
OxygenTransmission,
cm3/m2/atm O2 day
Elasticity,10-4/MPa
TensileStrength,
MPa
Elongation, %
KLUCEL® EF HPC
AQUALON® or BLANOSE® 7L CMC
NATROSOL® 250L HEC
HPMC 5cps(for comparison)
Medium17.2
Low5.6
High33.0
Low7.6
Medium776
Low18
Low33
High3180
Low15.5
High89.7
Medium28.3
High58.7
Low126
Low228
Medium360
High420
High17.5
Low1.7
High15.8
Low3.2
Klucel®Hydroxypropylcellulose (HPC)KLUCEL® HPC is non-ionic water-soluble cellulose ether,formed by reaction of cellulose with propylene oxide.KLUCEL provides a remarkable set of physical propertiesfor tablet binding, modified release and film coating. Itcombines organic solvent or aqueous solubility,thermoplasticity and surface activity with aqueousthickening and stabilizing properties characteristic ofother water-soluble cellulose polymers available fromAqualon. KLUCEL has a long-standing history of safeand effective use in the pharmaceutical industry. ThePHARM grades of KLUCEL HPC comply with themonograph requirements of the National Formulary, theEuropean Pharmacopoeia, and the JapanesePharmacopoeia.
Common Applications and Product GradesTablet Binding for Immediate ReleaseLow viscosity grades of KLUCEL yield unmatched tablethardness and friability, at typical use levels of 2 to 8%, ina wide variety of processing options.
• Wet Granulation (high or low shear or fluid bed)Grades EF and LF with regular particle size are oftenused in granulating solutions. Alternately, grade EXF,with fine particle size, can be added dry to other ingredients,followed by granulation with water or solvent.
• Direct Compression or Dry Granulation(roller compaction or slugging)Grade EXF with fine particle size is highly recommended.
Modified ReleaseHigh viscosity grades of KLUCEL provide effectivediffusion-limiting matrix systems at use levels of15-40%, most suited for active ingredients with higherwater solubility.• Grades HXF with fine particle size or HF with regular
particle size are commonly used.
Tablet CoatingLow viscosity grades of KLUCEL impart good flexibilityand adhesion to films while providing a good barrier towater and oxygen transmission.• Grades EF and LF are commonly used.
Physical and Chemical Properties• Non-ionic, pH insensitive cellulose ether• Soluble in many polar organic solvents and in water
below 38°C, but insoluble in water above 45°C• Tough, yet ductile, thermoplastic polymer for
compression molding or extrusion• Film forming, yielding flexibility and adhesion
without plasticizers due to low surface andinterfacial tensions of solutions
• Thickening and stabilizing properties similar toother water-soluble cellulose polymers
• Compatible with a variety of surfactants: anionic,cationic and amphoteric
• Available in a wide range of viscosities andmolecular weights
KLUCEL® Aqueous Solution MolecularHPC Viscosity: Typical Brookfield WeightPHARM at Concentration (weightGrade Shown, mPas averaged)
HF 1,500-3000 at 1% 1,150,000MF 4,000-6,500 at 2% 850,000GF 150-400 at 2% 370,000JF 150-400 at 5% 140,000LF 75-150 at 5% 95,000EF 300-600 at 10% 80,000
10
11
Klucel®Hydroxypropylcellulose (HPC)
Selected references on the premier performance of KLUCEL HPC areavailable on the Aqualon website at www.aqualon.com or by contactingone of our worldwide offices shown in this brochure.
Tablet Binding for Immediate Release
A. Effect of KLUCEL ® EF and EXF Hydroxypropylcellulose as GranulatingAgents in a Medium-Dose Acetaminophen Tablet Formulation(Aqualon Technical Information Bulletin VC-559B)
B. Effect of KLUCEL ® EF and EXF Hydroxypropylcellulose as GranulatingAgents in Low-Dose Hydrochlorothiazide Tablet Formulation(Aqualon Technical Information Bulletin VC-572A)
C. Lot-to-Lot Uniformity of KLUCEL ® EXF Hydroxypropylcelluloseas a Granulating Agent(Aqualon Technical Information Bulletin VC-588A)
D. Assessment of Low-Viscosity Polymers as DirectCompression Binders in a Model System(Aqualon Pharmaceutical Technology Report PTR-005)
E. Correlating the Ejection Force of Tablets with theToughness of Binders in the Solid Dosage Forms(Aqualon Pharmaceutical Technology Report PTR-009)
F. Evaluation of Low-Viscosity Polymers in a ModelHigh-Dose, Acetaminophen Formulation(Aqualon Pharmaceutical Technology Report PTR-011)
G. G.W. Skinner et al, Drug Dev Ind Pharm 1999 Oct; 25(10):1121-8;The evaluation of fine-particle hydroxypropylcellulose as a rollercompaction binder in pharmaceutical applications
Modified Release
H. KLUCEL ® Hydroxypropylcellulose Application in aSustained Release Matrix Capsule Dosage Form(Aqualon Technical Information Bulletin VC-529)
I. One-Year Stability of Sustained-Release Matrix TabletsFormulated with KLUCEL ® HXF Pharm Hydroxypropylcellulose(Aqualon Technical Information Bulletin VC-565B)
J. Lot-to-Lot Variation in KLUCEL ® HXF Pharm Hydroxypropylcellulose,Effect on Drug Release in Sustained-Release Matrix Tablets(Aqualon Technical Information Bulletin VC-567C)
K. D.A. Alderman, U.S. Patent 4,704,285; Sustained releasecompositions comprising hydroxypropyl cellulose ethers; granted11/3/87, expires 11/18/05 (Contact Dow Chemical for further information.)
L. D.Y. Lee and C.M. Chen, U.S. Patent 6,103,263, granted 8/15/00,expires 11/17/14; Delayed pulse release hydrogel matrix tablet
Tablet Coating
M. G. Banker et al, Drug Dev Ind Pharm 1981, 7, 693-716; Evaluationof hydroxypropylcellulose and hydroxypropylmethylcellulose asaqueous-based film coatings
N. The Use of KLUCEL® Pharm Hydroxypropylcellulose to Increase theUtility of Hydroxypropyl Methylcellulose in Aqueous Film Coating(Aqualon Technical Information Bulletin VC-556C)
O. KLUCEL® EF Pharm Hydroxypropylcellulose, Use inPlasticizer-Free Aqueous Film Coating(Aqualon Technical Information Bulletin VC-598A)
Physical, Chemical, Toxicological and Microbiological PropertiesP. KLUCEL® Hydroxypropylcellulose,
Pharm Grade for Pharmaceutical Uses(Aqualon Product Data Bulletin 494-8)
Q. KLUCEL® Hydroxypropylcellulose Physical and Chemical Properties(Aqualon Product Booklet 250-2F)
R. KLUCEL® Hydroxypropylcellulose,Techniques for Dispersion and Dissolution(Aqualon Technical Information Bulletin VC-516A)
S. KLUCEL® HydroxypropylcelluloseSummary of Toxicological Investigations(Aqualon Toxicological Data Bulletin T-122E)
T. KLUCEL® Hydroxypropylcellulose–Microbiological Information(Aqualon Product Data Bulletin 4083)
U. C. Alvarez-Lorenzo et al, Drug Dev Ind Pharm 2000, 26(1),13-20; TheStability of Theophylline Tablets with a Hydroxypropylcellulose Matrix
12
CMC is an anionic, water-soluble polymer derived fromcellulose reacted with sodium monochloroacetate. CMCis a common thickener, binder, stabilizer, suspendingagent, and rheology control reagent. AQUALON® CMCand BLANOSE® CMC are products typically used in theUnited States and Europe, respectively.
AQUALON CMC grades designated P or PH arecompliant with the monograph requirements of the UnitedStates Pharmacopeia / National Formulary.
BLANOSE CMC grades designated P or PH arecompliant with the monograph requirements of theEuropean Pharmacopoeia and the United StatesPharmacopeia / National Formulary.
Aqualon can provide CMC types with customspecifications upon request with advance planning. Also,with advance request, and subject to lot selection andtesting fees, certain AQUALON CMC grades may alsobe tested to meet the monograph requirements of theEuropean Pharmacopoeia and the JapanesePharmacopoeia. With similar conditions, certainBLANOSE CMC grades may also be tested to meet them o n o g r a p h r e q u i r e m e n t s o f t h e J a p a n e s ePharmacopoeia.
Aqualon® and Blanose®
Sodium Carboxymethylcellulose (CMC)Common Applications
Ointments, Creams, and Lotions• Stabilizer, thickener, film-former
Jellies and Salves• Thickener, gelling agent, protective colloid,
film-former
Syrups and Suspensions• Thickener, suspending aid
Bulk Laxatives• Physiologically inert, high water-binding capacity
Mucoadhesives• Absorbency
Sustained Release• Thickener, diffusion barrier
Tablet Coating• Film-former
Physical and Chemical Properties andCommon Product Grades• Soluble in cold or hot water, insoluble in organic
solvents, compatible with water/alcohol systems• Film forming, imparting low water and oxygen
transmission to coatings• Wide range of substitution: The degree of substitution
is a measurement of the number of carboxymethylgroups present on the cellulose backbone.– Lower substitution (7 types) provide thixotropy– Higher substitution (9 and 12 types) provide little
or no thixotropy where smoother solutions withoutstructure are required
• Available in a wide range of viscosities and substitutions,shown on page 13. A variety of particle size subtypes arealso available.
13
Aqualon® and Blanose®
Sodium Carboxymethylcellulose (CMC)AQUALON® CMCTypical Viscosity, Degree of Substitutioncps 0.7 0.9 1.2High(1% concentration)1,500-3,000 7HF PH1,000-2,800 7H3SF PH
7HOF PHMedium(2% concentration)1,500-3,100 9M31F PH800-3,100 12M31P400-800 7MF PH 12M8P
7M8SF PH300-800 9M8F PHLow(2% concentration)25-50 7LF PHExtra Low(4% concentration)50-200 7L2P
Selected references on AQUALON or BLANOSE CMC are availableon the Aqualon website at www.aqualon.com or by contacting oneof our worldwide offices shown in this brochure.
Solution Thickening, Stabilizing and Suspending Agent
A. AQUALON ® Cellulose Derivatives–Excipients for Liquid or Semi-Solid Pharmaceutical Dosage Forms(Aqualon Booklet 250-48)
B. BLANOSE ® Sodium Carboxymethylcellulose–AQUALON® SodiumCarboxymethylcellulose–Stabilizer for Antacid Suspensions(Aqualon Technical Information Bulletin VC-607)
C. AQUALON® Water-Soluble Polymers–Surfactant Compatibility and Recommendations(Aqualon Technical Information Bulletin VC-527A)
Modified Release
D. AQUALON® Cellulose Gum–Utility in the Formulation ofSustained-Release Matrix Tablets(Aqualon Information Bulletin VC-542A)
Tablet Coating
E. J.L. Johnson, U.S. Patent 4,931,286; High gloss cellulose tabletcoating; granted 6/5/90, expires 4/19/09
Physical, Chemical, Toxicological and Microbiological Properties
F. AQUALON ® Sodium Carboxymethylcellulose Physical andChemical Properties (Aqualon Product Booklet 250-10H)
G. AQUALON ® Sodium Carboxymethylcellulose Product Specifications(Aqualon Product Data Bulletin 4116-4)
H. AQUALON® Cellulose Gum, Dispersion and Dissolution(Aqualon Technical Information Bulletin VC-524A)
I. Rheology of AQUALON® Water-Soluble Polymers in Solution(Aqualon Technical Information Bulletin VC-453C)
J. AQUALON® Cellulose Gum (Sodium Carboxymethylcellulose)–Summary of Toxicological Investigations(Aqualon Toxicological Data Bulletin T-123D)
K. AQUALON® Cellulose Gum–Microbiological Information(Aqualon Product Data Bulletin 4016)
L. Regulatory Status of AQUALON ® Cellulose Gum for Use in Foods(Aqualon Technical Information Bulletin VC-541A)
BLANOSE® CMCTypical Viscosity, Degree of Substitution mPa.s 0.7 0.9 1.2High(1% concentration)2,500-4,500 7H4F PH 9H4F PH1,500-2,500 7HF PH1,000-2,800 7H3SF PH
7HOF PHMedium(2% concentration)1,500-3,100 7M31F PH 9M31F PH 12M31P200-800 7M8SF PH 12M8P400-600 7MF PHLow(2% concentration)50-100 7M1F PH25-50 7LF PH
• Options for particle size: coarse (C), regular or finely (X) ground grades
• S-types provide smooth solutions, based on uniform substitution
• O-types provide solubility and viscosity stability on storage in low pH media
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Ethylcellulose (EC)AQUALON® EC is the non-ionic ethyl ether of cellulose,soluble in a wide range of organic solvents. Typically,ethylcellulose is used as a non-swellable, insolublecomponent in matrix or coating systems. When water-soluble binders cannot be used in dosage processingbecause of water sensitivity of the active ingredient,ethylcellulose is often chosen. The PHARM grades ofAQUALON EC are compliant with the monographrequirements of the United States Pharmacopeia/National Formulary and the European Pharmacopeia.
Ethylcellulose can be used to coat one or more activeingredients of a tablet to prevent them from reacting withother materials or with one another. It can preventdiscoloration of easily oxidizable substances such asascorbic acid, allowing granulations for easily compressedtablets and other dosage forms. Ethylcellulose can beused on its own or in combination with water-solublepolymers to prepare sustained release film coatings thatare frequently used for the coating of micro-particles,pellets and tablets.
Improved Compressible Grade: AQUALON® T10 ECWith innovative polymer engineering, Aqualon designeda new grade of ethylcellulose, AQUALON T10 EC, withoptimized compactibility and powder flow. As shown inFigure 1, EC with high ethoxyl content and low viscosityprovides improved compaction, without the need forreduction in particle size via micronization. (Low viscositycorresponds to low molecular weight polymer, whendissolved in test solvent.) Detailed studies have includedphysical, thermal and mechanical characterizations alongwith powder flow, compaction simulation and molecularmodeling. (Reference A.) Powder flow characterizationsare shown in the table on the next page.
Common Applications
Microencapsulation• Stabilize against active interactions, hydrolysis and
oxidation and/or retard release of active ingredients
Flavor Masking• Improved taste through suppression of strong flavors
or bitter taste of drugs, minimizing the need foradded flavoring agents.
Tablet Binder• Plastic flow, suitable for direct compression, injection
molding and melt extrusion
Modified Release Direct Compression Tablets• AQUALON T10 EC can be readily incorporated in
stronger direct compression controlled releasematrices, eliminating the need for solvents. Figures2 and 3 show the improvement in crushing strengthand retardation of drug release with this improvedgrade of EC. (References A and B.)
Tablet Coating• Impart sustained release to film coatings
Modified Release Compression Coating• AQUALON T10 EC may be used to coat tablet cores
forming a non-swelling, insoluble diffusion barrier toachieve either sustained release or time-controlled,delayed release profiles. (Reference C.)
Solution Thickening• Impart thickening for non-aqueous systems
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Crushing Strength, kP
Figure 2: Effect of EC Variables on Compactibility ofEC:Acetaminophen (3:1) Tablets
Ethoxyl, Viscosity,% cps
51.0 9
49.6 9449.3 8047.5 10
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kP18.8
Figure 1: High Ethoxyl Content and Low Viscosity Optimizationof Crushing Strength of Pure Polymer EC Compacts
Viscosity, cps% Ethoxyl
6.351
45 190
10
Physical and Chemical Properties• Non-ionic, pH insensitive cellulose ether• Soluble in many polar organic solvents;
insoluble in water.• Tough, yet ductile thermoplastic polymer for
compression molding or extrusion• Film forming, yielding flexible films over a wide range
of temperatures• Available in a wide range of viscosities and two
ethoxyl contents:
Typical Viscosity, cps(5% solution of 80/20 mixture
Type of toluene/ethanol)
High Ethoxyl Substitution (49.6-51.0%)T10 8-11
Standard Ethoxyl Substitution (48.0-49.5%)N7 6-8N10 8-11N14 12-16N22 18-24N50 40-52N100 80-105
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Aqualon®
Ethylcellulose (EC)
Selected references on AQUALON EC are available on the Aqualonwebsite at www.aqualon.com or by contacting one of our world-wide offices shown in this brochure.
Improved Compressible Grade: AQUALON® T10 Pharm ECA. Advanced Structure-Function Properties of Ethylcellulose:
Implications for Tablet Compactibility(Aqualon Pharmaceutical Technology Report PTR-021)
B. Ethylcellulose In Direct Compression Modified Release Tablets:Impact of Polymer Structure and Formulation Variables(Aqualon Pharmaceutical Technology Report PTR-023)
C. Ethylcellulose In Compression Coated Tablets: Implicationsfor Time-Controlled Pulsed-Release Dosage Forms(Aqualon Pharmaceutical Technology Report PTR-022)
Flavor MaskingD. AQUALON® Ethylcellulose for Use in Pharmaceuticals and
Flavorings to Improve Their Organoleptic Properties(Aqualon Product Marketing News Bulletin M-318B)
Physical, Chemical and Microbiological PropertiesE. AQUALON® Ethylcellulose (EC)
Physical and Chemical Properties(Aqualon Product Booklet 250-42A)
F. AQUALON® Pharm Ethylcellulose for Foodand Pharmaceutical Applications(Aqualon Product Data Bulletin 4176-1)
G. AQUALON® Ethylcellulose–A VersatileFilm-Forming Cellulose Ether(Aqualon Product Data Bulletin 452-7)
H. AQUALON® Ethylcellulose–Microbiological Information(Aqualon Product Data Bulletin 4150)
Ethoxyl, Viscosity,% cps
45.6 749.6 9449.3 8047.5 1051.0 9
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Figure 3: Effect of EC Variables on Drug Release ofEC:Acetaminophen (3:1) Tablets
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Comparison of Flow Properties
AQUALON® T10 ECHigh Ethoxyl,
Test Parameter Low Viscosity Micronized EC*Angle of Repose 25° 51°Angle of Slide 36° 51°Compressibility 12% 14%
IndexFlow rate 11 g/sec <1 g/min
(9 mm orifice)Mean Time to 4.5 sec 8.7 sec
Avalanche* Ethocel® Standard FP 10 Premium ethylcellulose is a registered trademark of The Dow Company,
Midland Michigan, U.S.A.
Aqueous SolutionNATROSOL® Viscosity: TypicalHEC Brookfield at Molecular WeightPHARM Concentration (estimated fromGrade Shown, mPas intrinsic viscosity)
HHX 3,500-5,500 at 1% 1,300,000HX 1,500-2,500 at 1% 1,000,000H 1,500-2,500 at 1% 1,000,000M 4,500-6,500 at 2% 720,000G 250-400 at 2% 300,000L 75-150 at 5% 90,000
Selected references on the premier performance of NATROSOLHEC are available on the Aqualon website at www.aqualon.comor by contacting one of our worldwide offices shown in thisbrochure.Modified Release
A. NATROSOL ® 250HX Pharm Hydroxyethylcellulose, Applicationin a Sustained-Release Matrix Capsule Dosage Form(Aqualon Technical Information Bulletin VC-554B)
B. Versatility of NATROSOL® Hydroxyethylcellulose in ControlledRelease Matrix Systems(Aqualon Pharmaceutical Technology Report PTR-017)
Solution Thickening, Stabilizing, and Suspending Agent
C. AQUALON ® Cellulose Derivatives–Excipients for Liquidor Semi-Solid Pharmaceutical Dosage Forms(Aqualon Booklet 250-48)
D. NATROSOL® 250 Pharm Hydroxyethylcellulosein Pharmaceutical Gel Compositions(Aqualon Technical Information Bulletin VC-608)
E. AQUALON ® Water-Soluble Polymers–Surfactant Compatibility and Recommendations(Aqualon Technical Information Bulletin VC-527A)
Physical, Chemical, Toxicological and MicrobiologicalProperties
F. NATROSOL ® Hydroxyethylcellulose–A Nonionic Water SolublePolymer–Physical and Chemical Properties(Aqualon Product Booklet 250-11G)
G. NATROSOL® Hydroxyethylcellulose,Techniques for Dispersion and Dissolution(Aqualon Technical Information Bulletin VC-515B)
H. Rheology of AQUALON ® Water-Soluble Polymers in Solution(Aqualon Technical Information Bulletin VC-453C)
I. NATROSOL ® HydroxyethylcelluloseSummary of Toxicological Investigations(Aqualon Toxicological Data Bulletin T-101G)
J. NATROSOL® Hydroxyethylcellulose–Microbiological Information(Aqualon Product Data Bulletin 4082)
K. NATROSOL ® 250 Hydroxyethylcellulose–A NonionicWater-Soluble Cellulose Ether(Aqualon Product Data Bulletin 4146)
L. NATROSOL® Hydroxyethylcellulose for Usein Pharmaceuticals–A Position Statement(Aqualon Product Data Bulletin 4059-3)
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Natrosol®Hydroxyethylcellulose (HEC)NATROSOL® HEC is a non-ionic water-soluble celluloseether, formed by reaction of cellulose with ethylene oxide.It is used as (a) a modified release tablet matrix, (b) afilm former, and (c) a thickener, stabilizer and suspendingagent for oral and topical applications when a non-ionicmaterial is desired. NATROSOL is easily dispersed incold or hot water to give solutions of varying viscositiesand desired properties, yet it is insoluble in organicsolvents. The PHARM grades of NATROSOL HECcomply with the monograph requirements of the NationalFormulary and the European Pharmacopoeia.
Common Applications and Product GradesSolution Thickening, Stabilizing, andSuspending AgentMedium or high viscosity grades of NATROSOL are usedto control rheology, providing thickening andpseudoplasticity, and to stabilize emulsions with high salttolerance and surfactant compatibility. Clear solutions andgels may be formulated. Higher viscosity grades yieldgreater thickening efficiency.• Grades 250 M, H, HX, and HHX are typically
chosen for oral and topical liquid and gel formulations.
Modified ReleaseHigher viscosity grades of NATROSOL provide effectivediffusion-limiting matrix systems at use levels of 15-40%,most suited for active ingredients with low water solubility,where near zero-order release is desired.• Grades 250 HHX, HX, H, M, and G are preferred.
Tablet CoatingLow viscosity grades of NATROSOL impart flexibility tofilms while providing a good barrier to water and oxygentransmission.• Grade 250 L is the low viscosity grade of choice.
Physical and Chemical Properties• Non-ionic, pH insensitive cellulose ether• High solubility in cold or hot water with rapid
hydration; insoluble in organic solvents• High salt tolerance and surfactant compatibility
due to non-ionic nature• Film forming, imparting flexibility to coatings• Available in a wide range of viscosities and
molecular weights
www.aqualon.comprovides additional literatureand sample ordering online.
Hercules Incorporated and its Aqualon subsidiary (together referred to as “Hercules”) believes that all information provided with respect toits products is accurate at the time such information is provided. Unless otherwise agreed, Hercules makes no express, implied, or otherrepresentation, warranty, or guarantee concerning such information or the handling, use, or application of its products, whether alone orin combination with other products, except that its products are of Hercules’ standard quality. Users of Hercules’ products are advised toperform their own tests to determine the safety and suitability of each such product or product combination. Users are urged to read andunderstand the Material Safety Data Sheet (MSDS) and to abide by all use and safety recommendations detailed therein and on all productlabeling. Hercules does not recommend the use of its products in any manner which would violate any patent or intellectual property rights.Unless otherwise agreed, the purchasers of Hercules’ products assume all responsibility and liability for all loss or damage arising from theimproper handling or use of our products. This disclaimer supersedes any prior or different disclaimers for this product.
250-49B 8-06
Aqualon1313 North Market StreetWilmington, DE 19894-0001Tel: (800) 345-0447Fax: (302) 992-7287
Hercules GmbHPaul-Thomas-Strasse 56Postfach 13 01 25D-40599 DüsseldorfGermanyTel: +31 70-307 1061Fax: +31 70-319 1187
Hercules ChemicalsSingapore Pte. Ltd.200 Pandan Loop#07-01 Pantech 21Singapore 128388Tel.: +65 6775 5366Fax: +65 6776 9690
Hercules Mexico, S.A. de C.VSaltillo No 19, 7 pisoCol. Condesa C.P. 06100Mexico City, MexicoTel.: 525-211-0111Fax: 525-212-0883
www.aqualon.com
A Business Unit of Hercules Incorporated