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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
Delivering Pharmaceutical Performance 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 between the water-soluble polymer groups of these two companies. In 1989, Aqualon became a business unit of Hercules Incorporated.
Aqualon...A World Leader in Products That Manage the Physical Properties of Aqueous Systems
Functions Tablet Binding Power Thickening and Rheology Control Film Formation Water Retention Adhesive Strength Suspending and Emulsifying
Markets Pharmaceuticals Personal Care Water-Based Paints Construction Materials Food Paper Mills Printing Inks Aviation Fluids Oil and Gas Exploration
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.
Tablet Binder
KLUCEL hydroxypropylcellulose (HPC) provides premier performance as a tablet binder. KLUCEL exhibits a unique combination of thermoplasticity with organic solvent or aqueous solubility, allowing tough tablet preparation using many different formulation techniques. Unmatched tablet hardness and friability are found with low viscosity grades of KLUCEL, at typical use levels of 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 often used 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 recommended. Beyond unmatched tablet hardness and friability, benefits of tableting with KLUCEL include: Reduction or elimination of tablet capping; Smaller tablet size and production efficiency; and Lower compression and ejection forces. Thermoplastic Properties The benefits of KLUCEL as a tough tablet binder are well known. In pure tablet compacts, the high energy absorption and ductility of KLUCEL is shown in Figure 1 versus other binders and fillers. (References A and B.)
Stress, N 250 8 200 6 150 100 50 0 0 1 2 Strain, mm Figure 1: Pure Compacts Under Compression 3 4 KLUCEL EXF HPC PVP MC PGS 0 0 10 20 Compression Force, kN Figure 3: Low Shear Wet Granulation Tablets 4 2
High Tablet Hardness and Low Friability The thermoplasticity of KLUCEL allows production of tough tablets. Figures 2 through 5 demonstrate the binder performance of KLUCEL in comparison studies utilizing low shear and fluid bed granulation of tablets formulated with 83.3% poorly-compressible acetaminophen. These high dose studies show KLUCEL can be used at lower use levels to yield superior tablets, compared to tablets with higher binders levels of HPMC, MC, PVP and pregelatinized starch (PGS). High-dose acetaminophen formulations using lower levels of these poorer binders were simply poor, due to capping. Aqualon has found similar comparative results with other drug compounds. (References C, D, E, and F.)
Crushing Force, N 200 160
4% HPC 8% MC 8% HPMC
120
80 40 0 0 5
8% PVP
12% PGS
10 15 20 25 30
Friability, % 10
4% HPC 8% MC 8% HPMC
30
Tablet Binder
80% Dissolution Time, min 30 25 20 15 10 5 0 Selected references on tablet binding are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. A. Effects of Binder Toughness and Flowability on Pharmaceutical Tablet Performance (Aqualon Pharmaceutical Technology Report PTR-015) B. Correlating the Ejection Force of Tablets with the Toughness of Binders in the Solid Dosage Forms (Aqualon Pharmaceutical Technology Report PTR-009) C. Evaluation of Low-Viscosity Polymers in a Model High-Dose, Acetaminophen Formulation (Aqualon Pharmaceutical Technology Report PTR-011) D. Effect of KLUCEL EF and EXF Hydroxypropylcellulose as Granulating Agents in Low-Dose Hydrochlorothiazide Tablet Formulation (Aqualon Technical Information Bulletin VC-572A) E. Validation of Tablet Dissolution Method by High Performance Liquid Chromatography (Aqualon Pharmaceutical Technology Report PTR-006) F. An Evaluation of Fluidized Bed Granulation Methods for Preparing Tablets of a High-Dose, Poorly-Compactible Drug (Aqualon Pharmaceutical Technology Report PTR-010) G. Lot-to-Lot Uniformity of KLUCEL EXF Hydroxypropylcellulose as a Granulating Agent (Aqualon Technical Information Bulletin VC-588A) H. Assessment of Low-Viscosity Polymers as Direct 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 roller compaction binder in pharmaceutical applications
4% HPC
8% MC
8% HPMC
8% PVP
12% PGS
150
100
50
2% HPC
4% HPC
8% MC
8% PVP
8% PGS
Lower Compression and Ejection Forces Figure 6 demonstrates the lower ejection forces for HPC relative to PVP, measured at the tablet press. (Reference B.)
Ejection Force, kN 0.4
0.3
0.2
0.1
8% HPC 10 15 20 25 30
Modified Release
Cellulose derivatives are often used to modify the release of drugs in tablet and capsule formulations. For tablets, cellulose derivatives provide utility as matrix components and coatings. These systems benefit from ease of manufacture, low cost and predictable in vivo performance. This summary presents formulation guidance for some hydrophilic and hydrophobic systems. HYDROPHILIC MATRIX SYSTEMS Cellulose derivatives such as HPC or HEC are used in hydrophilic matrix systems. High molecular weight grades of KLUCEL HXF or HF HPC or NATROSOL HHX or HX HEC are typically used. As the polymers are exposed to water, they form a gel layer that will retard the release of the active ingredients. Drug release with these systems involve two simultaneous processes: Fickian diffusion and matrix relaxation and erosion. Along with drug load and solubility, polymer swelling, concentration and particle size, pH effects, other excipients and processing variables are important factors when formulating these systems. Drug Solubility The solubility of the drug in hydrophilic tablet matrices is an important factor influencing the choice of polymer to modify the release profile. Figures 1 and 2 show drug solubility effects for systems based on KLUCEL HPC and NATROSOL HEC. KLUCEL is most suitable for highly water-soluble drugs. NATROSOL is appropriate for near zero-order release attainable with sparingly and low solubility drugs. (References A and B.)
% Drug Released 100
80
Phenylpropanolamine (90.9% solubility) Acetaminophen (1.8% solubility) Theophylline (0.8% solubility) Diclofenac Sodium (0.18% solubility, pH 7)
60 40 20 0
8 12 16 Time, hours
20
24
Figure 2: Effect of Drug Solubility on Release From HEC Tablets 40% Drug, 30% NATROSOL 250 HHX HEC, 30% MCC
Robust Processing Options For highly soluble phenylpropanolamine (PPA), the robust processing nature of KLUCEL HXF is shown in Figure 3 with equivalent release profiles in wet granulation, roller compaction and direct compression. (References A and C.)
% Drug Released 100
80 60
40 20
80 60
Time, hours Figure 3: Equivalent Release From HPC Tablets Formulated With Various Processes 20% PPA, 30% KLUCEL HXF HPC, 50% MCC
40 0 20
Phenylpropanolamine (90.9% solubility) Acetaminophen (1.8% solubility) Theophylline (0.8% solubility) 8 12 Time, hours 16 20 24
Figure 1: Effect of Drug Solubility on Release From HPC Tablets 20% Drug, 30% KLUCEL HXF HPC, 50% MCC
Modified Release
KLUCEL Particle Size Again for PPA, Figure 4 shows particle size effects using fine grind HXF with slower drug release relative to regular grind HF. (References A, C, and D.)
% Drug Released 100 80 60 40 20 0
% Drug Released 100 80 60 40 20 0 0 30% KLUCEL HXF HPC 30% KLUCEL HF HPC 8 12 5 10 15 20 25 Time, hours Figure 6: HEC Is Non-ionic; Release From Tablets Is Independent of pH 50% Theophylline, 30% NATROSOL 250HHX HEC, 20% MCC 0.1 N pH 6.8 Buffer HCl
DI Water pH Change
4 Time, Hours
Stability of Release KLUCEL has been studied extensively for one-year stability under various storage conditions (25C, 40C at 80% relative humidity, and 50C). Figure 7 demonstrates the excellent release stability, as compared to the original release profile for PPA. Ongoing studies consider other storage conditions and drugs formulated with KLUCEL and NATROSOL. (Reference E.)
% Drug Released 100 80 60 40
Figure 4: Fine Grind HPC Exhibits Slower Release Than Regular Grind HPC From Tablets 20% PPA, 30% KLUCEL HXF HPC, 50% MCC
Stable to pH Effects KLUCEL HPC or NATROSOL HEC are non-ionic polymers, so that hydration and viscosity development are not influenced by the pH of the dissolution media. Figures 5 and 6 show release profiles for KLUCEL HPC and NATROSOL HEC for changes in pH for theophylline formulations. (Reference B.)
% Drug Released 100 80 60 40 20 0
Original Held for 1 Year at 25C Held for 1 Year at 40C, 80% rh Held for 1 Year at 50C
20 0
pH 1.5 pH 6.8
6 8 Time, hours
10
12
14
Figure 7: HPC Tablets Exhibit Excellent One-Year Stability, Held Under Various Conditions 14% PPA, 25% KLUCEL HXF HPC, 58% Diluent 3 6 Time, hours 9 12
Figure 5: HPC Is Non-ionic; Release From Tablets Is Independent of pH 20% Theophylline, 30% KLUCEL HXF HPC, 50% MCC
Modified Release
HYDROPHOBIC MATRIX AND COMPRESSION COATINGS Hydrophobic matrices, composed of ethylcellulose for instance, do not swell or erode and thereby modify drug release via Fickian diffusion. Direct compression or solvent granulation may be used to incorporate ethylcellulose. Drug actives may alternately be coated in a similar method and incorporated in capsules or other dosage forms. The use of a compression coating will allow a time-delayed pulse release or a time-delayed sustained release, dependent upon the composition of the inner tablet core. Improved Compressible Grade: AQUALON T10 Pharm Ethylcellulose With innovative polymer engineering, Aqualon designed a new grade of ethylcellulose, AQUALON T10 Pharm EC, with optimized compactibility and powder flow. As shown in Figure 8, EC with high ethoxyl content and low viscosity provides improved compaction, without the need for reduction in particle size via micronization. (Low viscosity corresponds to low molecular weight polymer, when dissolved in test solvent.) Detailed studies have included physical, thermal and mechanical characterizations along with powder flow, compaction simulation and molecular modeling. (Reference I). Modified Release Direct Compression Tablets AQUALON T10 Pharm EC can be readily incorporated in stronger direct compression controlled release matrices, eliminating the need for solvents. Figures 8 and 9 show the improvement in crushing strength and retardation of drug release with this improved grade of EC in simple tablet models. (References I and J.)
Crushing Strength, kP 16
12 Time, hours
16
20
24
Drug Solubility An understanding of drug load and solubility are important to control drug release. Figure 10 shows the effect of drug solubility in a simple tablet model where Fickian diffusion controls release.
% Drug Released 100
Acetaminophen Solubility, % Drug Phenylpropanolamine 91 Propranolol HCl 5
80 60 40 20
1.8
Theophylline
0.8
Viscosity, cps 9 94 80 10
12 Time, hours
16
20
24
Figure 10: Effect of Drug Solubility on Release From AQUALON T10 EC:Drug (3:1) Tablets
12
Effect of Diluent/Filler In these systems, drug release can be modulated by the swellability and solubility of the filler, as shown in Figure 11. Insoluble, non-hydrating dicalcium phosphate provides a slow release profile. Soluble sugars (lactose and mannitol) showed intermediate release behavior. Microcrystalline cellulose (MCC), which is hydrophilic and swellable, but insoluble, displayed the fastest release profile. Soluble excipients are known to act as channeling agents, resulting in increased porosity with ongoing water penetration. Swellable excipients can dramatically increase in volume, causing stress relaxation of the matrix, allowing rapid water ingress.
Modified Release
% Drug Released 100 80
60 40
than 25% more compactible than the other materials. As shown in Figure 14, this results in increased resistance to water infusion and coating strength, which is critical to achieving prolonged lag times. Tablets compressioncoated with AQUALON T10 EC at 5kN compression force achieved markedly longer lag times than tablets coated at 25 kN with other grades of EC.
% Drug Released 100 80 60
20 0 0
12 16 Time, hours
20
24 40 20 0
Ethoxyl, Viscosity, % cps 51.0 9.2 49.6 94 49.3 80 47.5 10 45.6 7.1 45.7 83
Figure 11: Diluent Effect on Drug Release From Directly Compressed Model Formulations 25% Acetaminophen, 40% AQUALON T10 EC, 34% Diluent
Pulse Release via Compression Coating A coating of ethylcellulose compressed around a tablet core can delay the delivery of actives for a controlled period of time. The factors that control this function are the coating compactibility and thickness, compression force applied and core swellability. Figure 12 provides a general mechanism for pulse release in these systems with compression force controlling release time, as shown in Figure 13. (Reference K.)
Compressed coat EC 99%, lubricant 1% Immersion in aqueous media
6 8 Time, hours
10
12
Figure 14: Comparison of AQUALON T10 Pharm EC Compression Coat Performance With Other EC Grades Theophylline Model Selected references on modified release are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Hydrophilic Systems A. Compression and Drug Release Characteristics of Directly Compressible KLUCEL Hydroxypropylcellulose Controlled Release Matrix Systems (Aqualon Pharmaceutical Technology Report PTR-019) B. Versatility of NATROSOL Hydroxyethylcellulose in Controlled Release Matrix Systems (Aqualon Pharmaceutical Technology Report PTR-017) C. KLUCEL Hydroxypropylcellulose Controlled Release Matrix Tablets 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 compositions comprising hydroxypropyl cellulose ethers ; granted 11/3/87, expires 11/18/05 (Contact Dow Chemical for further information.) E. One-Year Stability of Sustained-Release Matrix Tablets Formulated with KLUCEL HXF Pharm Hydroxypropylcellulose (Aqualon Technical Information Bulletin VC-565B) F. KLUCEL Pharm Hydroxypropylcellulose Application in a Sustained 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, Application in a Sustained-Release Matrix Capsule Dosage Form (Aqualon Technical Information Bulletin VC-554) Hydrophobic Matrix and Compression Coatings I. 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 For Time-Controlled Pulsed-Release Dosage Forms (Aqualon Pharmaceutical Technology Report PTR-022)
Water diffuses through pores of the EC barrier coating. Swelling force/axial relaxation of the inner tablet causes EC coating to open in clamshell manner.
Figure 12: Schematic of Model Compression Coated Pulse Release System % Drug Released 100 80 60 40 20
0 0 4
Compression Force, kN
5 10 25
20 24
8 12 16 Time, hours
Figure 13: Effect of Compression Force on Pulse Release Lag TimeTheophylline Model
Effect of Polymer Grade and Compactibility The compactibility of EC is highly dependent on ethoxyl content and viscosity, with the new grade being greater
CMC
HEC
HPC
EC
Increased Organo-Solubility
Liquid and semi-solid pharmaceutical dosage forms are important physicochemical systems for medical treatment. A variety of administration routes exist for these dosage forms, including oral, inhalation, dermal, parenteral and mucosal (buccal, vaginal, rectal and ophthalmic) modes. These liquid and semi-solid dosage forms require rheological control and stabilizing excipients as essential additives. With the proper choice of Aqualon water-soluble and organo-soluble excipients, these systems can exhibit (a) increased stability; (b) controlled viscosity to promote delivery; and (c) selected organoleptic properties such as improved mouth-feel. Syrups Syrups are often prepared without sucrose. Viscosity is adjusted by the use of AQUALON or BLANOSE CMC or NATROSOL HEC. Medium or high molecular weight products are generally preferred. Suspension Systems For systems like antacids or X-ray contrast fluids which require stabilization of the suspended solids, AQUALON or BLANOSE CMC is preferred because of the synergistic stabilizing effect of CMC with clays, either from natural or synthetic origin. Liquid Soaps NATROSOL HEC is preferred in the preparation of liquid soaps, because of its good compatibility with surfactant systems. In this case, higher molecular weight grades are recommended for greater efficiency.
Topical Gels Aqueous or hydroalcoholic gels are often used for topical applications. KLUCEL HPC is preferred with hydroalcoholic carriers. Aqueous systems are typically formulated with KLUCEL HPC, NATROSOL HEC, or AQUALON or BLANOSE CMC, depending on the chemical compatibility with other ingredients. Topical Lotions and Creams Emulsified systems provide topical applications ranging from liquid (lotions) to more semi-solid systems (creams). Medium molecular weight NATROSOL HEC is used to modify the rheology and stabilize emulsions. Parenteral and Implant Applications Aqualon has not determined the safety of cellulose derivative products in parenteral or medical implant applications. Formulators need to pursue and ensure the safety of products that may contain cellulose derivatives.
Selected references on liquid and semi-solid formulations are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. A. BLANOSE Sodium CarboxymethylcelluloseAQUALON Sodium CarboxymethylcelluloseStabilizer for Antacids Suspensions (Aqualon Technical Information Bulletin VC-607) B. AQUALON Water-Soluble PolymersSurfactant Compatibility 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 in Pharmaceutical Gel Compositions (Aqualon Technical Information Bulletin VC-608)
Tablet Coating
Tensile Strength, MPa Low 15.5 High 89.7 Medium 28.3 High 58.7 Oxygen Transmission, cm3/m2/ atm O2 day Medium 776 Low 18 Low 33 High 3180 Water Vapor Transmission g/m2/day Low 126 Low 228 Medium 360 High 420
Film-Forming Polymer
Elasticity, 10-4/MPa
Elongation, %
KLUCEL EF HPC AQUALON or BLANOSE 7L CMC NATROSOL 250L HEC HPMC 5cps (for comparison)
Aqualon offers a variety of low-viscosity cellulosic polymers, which provide important mechanical, and barrier properties for tablet coating. The table above provides an overall property summary for three AQUALON water-soluble polymers. KLUCEL HPC The 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 aqueous film coating alone or to enhance the utility of strong, but brittle, 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 providing the barrier properties noted. Film formulation guidance is available for KLUCEL alone or in combination with HPMC, applicable to a wide variety of coating equipment and a wide variety of tablet cores. (References A and B.) AQUALON or BLANOSE CMC CMC provides films with high gloss and excellent barrier properties, with low transmission of oxygen and water vapor. Films formed with CMC are strong, but brittle, and need to be plasticized. CMC is compatible with a wide variety of plasticizers, including polyethylene glycol, polypropylene glycol and triacetin. Film formulation information is available. (Reference C.)
NATROSOL HEC As a film-forming highly-elastic polymer, HEC also provides low transmission of oxygen. Because the polymer is non-ionic, it is compatible with a variety of other ingredients, including actives and surfactants. AQUALON EC EC is soluble in a wide range of organic solvents. Its use as a coating for one or more active ingredients in a tablet can prevent them from reacting with other materials or with one another. It can prevent discoloration of easily oxidizable substances such as ascorbic acid. Further, EC can be used in combination with water-soluble polymers to prepare sustained-release coatings of fine particles and tablets, or to provide film coatings with reduced water solubility. For water-based film coatings, EC has been used in latex systems. EC masks the bitter taste of drugs, minimizing the need for added flavoring agents.
Selected references on tablet coating are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. A. KLUCEL EF Pharm Hydroxypropylcellulose, Use in Plasticizer-Free Aqueous Film Coating (Aqualon Technical Information Bulletin VC-598A) B. The Use of KLUCEL Pharm Hydroxypropylcellulose to Increase the Utility 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 tablet coating ; granted 6/5/90, expires 4/19/09 D. G. Banker et al, Drug Dev Ind Pharm 1981, 7, 693-716; Evaluation of hydroxypropylcellulose and hydroxypropylmethylcellulose as aqueous-based film coatings E. S.C. Porter and C.H. Bruno, Coating of Pharmaceutical Solid-Dosage Forms in Pharmaceutical Dosage Forms: Tablets, vol 3, 2nd ed, ed. H.A. Lieberman et. al., Marcel Dekker, 1990. 9
10
11
12
Medium (2% concentration) 1,500-3,100 7M31F PH 9M31F PH 12M31P 200-800 7M8SF PH 12M8P 400-600 7MF PH Low (2% concentration) 50-100 25-50 7M1F PH 7LF PH
Selected references on AQUALON or BLANOSE CMC are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Solution Thickening, Stabilizing and Suspending Agent A. AQUALON Cellulose DerivativesExcipients for Liquid or SemiSolid Pharmaceutical Dosage Forms (Aqualon Booklet 250-48) B. BLANOSE Sodium CarboxymethylcelluloseAQUALON Sodium CarboxymethylcelluloseStabilizer 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 GumUtility in the Formulation of Sustained-Release Matrix Tablets (Aqualon Information Bulletin VC-542A)
Tablet Coating E. J.L. Johnson, U.S. Patent 4,931,286; High gloss cellulose tablet coating ; granted 6/5/90, expires 4/19/09 Physical, Chemical, Toxicological and Microbiological Properties F. AQUALON Sodium Carboxymethylcellulose Physical and Chemical 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 GumMicrobiological Information (Aqualon Product Data Bulletin 4016) L. Regulatory Status of AQUALON Cellulose Gum for Use in Foods (Aqualon Technical Information Bulletin VC-541A)
13
Viscosity, cps 9 94 80 10
12
4 6.3 51 10 % Ethoxyl 45 190 Figure 1: High Ethoxyl Content and Low Viscosity Optimization of Crushing Strength of Pure Polymer EC Compacts Viscosity, cps 0 0
10
15
20
25
14
Comparison of Flow Properties AQUALON T10 EC High Ethoxyl, Low Viscosity Micronized EC* 25 36 12% 11 g/sec 4.5 sec 51 51 14% <1 g/min 8.7 sec
Test Parameter Angle of Repose Angle of Slide Compressibility Index Flow rate (9 mm orifice)
12 Time, hours
16
20
24
* Ethocel Standard FP 10 Premium ethylcellulose is a registered trademark of The Dow Company, Midland Michigan, U.S.A.
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 of toluene/ethanol)
Selected references on AQUALON EC are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Improved Compressible Grade: AQUALON T10 Pharm EC A. 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: Implications for Time-Controlled Pulsed-Release Dosage Forms (Aqualon Pharmaceutical Technology Report PTR-022) Flavor Masking D. AQUALON Ethylcellulose for Use in Pharmaceuticals and Flavorings to Improve Their Organoleptic Properties (Aqualon Product Marketing News Bulletin M-318B) Physical, Chemical and Microbiological Properties E. AQUALON Ethylcellulose (EC) Physical and Chemical Properties (Aqualon Product Booklet 250-42A) F . AQUALON Pharm Ethylcellulose for Food and Pharmaceutical Applications (Aqualon Product Data Bulletin 4176-1) G. AQUALON EthylcelluloseA Versatile Film-Forming Cellulose Ether (Aqualon Product Data Bulletin 452-7) H. AQUALON EthylcelluloseMicrobiological Information (Aqualon Product Data Bulletin 4150)
Type
Standard Ethoxyl Substitution (48.0-49.5%) N7 N10 N14 N22 N50 N100 6-8 8-11 12-16 18-24 40-52 80-105
15
Modified Release Higher viscosity grades of NATROSOL provide effective diffusion-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.
16
www.aqualon.com
provides additional literature and sample ordering online.
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250-49B 8-06