Section 11

Avicel® PH Microcrystalline Cellulose, NF, Ph Eur., JP, BPBy Dr. George E. Reier

Table of Contents

Avicel Microcrystalline Cellulose............................................................................................................1Table of Contents...............................................................................................................................1

Manufacturing Process ..........................................................................................................................2Importance of the Commercial Introduction of Avicel PH Microcrystalline Cellulose to

Direct Compression ...........................................................................................................................4The Tableting Characteristics of Avicel Microcrystalline Cellulose........................................................5A Comparison of Avicel Microcrystalline Cellulose

Types and their Uses .........................................................................................................................7Figure 3: PH-101...............................................................................................................................7Figure 4: PH-102...............................................................................................................................8Figure 5: PH-103...............................................................................................................................8Figure 6: PH-105...............................................................................................................................9Figure 7: PH-112...............................................................................................................................9Figure 8: PH-113.............................................................................................................................10Figure 9: PH-200.............................................................................................................................10Figure 10: PH-301...........................................................................................................................11Figure 11: PH-302...........................................................................................................................11

Avicel PH Microcrystalline Cellulose Functionality in the Wet Granulation Manufacturing Process...12 Rapid, Even Wicking Action ............................................................................................................12 Controls Wet Mass Consistency......................................................................................................12Less Screen Blocking ......................................................................................................................12Uniform, Rapid Drying .....................................................................................................................12Controls Color Mottling and Drug Content Uniformity ....................................................................12Acts as an Auxiliary Binder ..............................................................................................................13

Avicel PH Microcrystalline Cellulose as a Spheronizing Agent ...........................................................13Editor’s Note.........................................................................................................................................14Bibliography/Publications ....................................................................................................................15

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2

Manufacturing Process

In 1962, O. A. Battista and P. A. Smithreported the preparation by the AmericanViscose Company of microcrystalline cellu-lose from cellulose, hence the origin of theproduct name “Avicel”. The “PH” designa-tion indicates that the product is suitablefor pharmaceutical use. Cellulose is presentin much of the food of man but is inert tohuman digestive enzymes making it GRAS –or generally recognized as safe for humanconsumption by the United States Food and Drug Administration (FDA) and othergovernmental agencies throughout theworld. The process that produces Avicel® PHmicrocrystalline cellulose alters only thecellulose physical form and eliminatesimpurities. Avicel remains alpha-cellulose,the most abundant of all organic materials,in a highly purified powder form.Microcrystalline cellulose is the subject of harmonized monographs in the NF, theEuropean Pharmacopoeia and the JapanesePharmacopoeia.

Microcrystalline cellulose is purified, partiallydepolymerized cellulose prepared by usingmineral acid to hydrolyze cellulose pulp.Cellulose fibers contain many millions of cellulose microfibers. Two different regions can be distinguished in these microfibers, a paracrystalline region and a crystallineregion. The former is an amorphous andflexible mass of cellulose chains while thelatter is composed of tight bundles of cellulose chains in a rigid linear arrangementresembling bundles of wooden matchstick-like microcrystals. The hydrolysis processlargely removes the amorphous fraction,destroying the fiber-like morphology of thecellulose, and “unhinging” the cellulosemicrocrystals. By filtering and spray drying,microcrystalline cellulose particle agglomer-ates composed of microcrystals are

obtained, the particle size distribution andmoisture content of which can be variedthrough the spray drying process.

The actual manufacturing process beginswith specially selected rolls of wood pulpthat are diced, or cut, into small particles.These chopped particles are hydrolyzedunder heat and pressure by mineral acid,following which the mix is washed withwater and filtered. The hydrolysis processconverts insoluble hydroxides, oxides, andsulfates present in the wood pulp to solublecompounds, which are removed by thefiltering and washing processes, resultingin a product with exceptionally low inorganicimpurities. The filtered cake is resuspendedin water, and spray dried. The manufacturingprocess may be thought of as breaking the cellulose fibrous material down to a micro-crystalline form and then agglomeratingthese crystallites into aggregates or particles.

If a food grade sodium carboxymethylcellu-lose is added to the microcrystalline cellu-lose, with additional wet attrition before drying, a colloidal microcrystalline celluloseis produced (Avicel® RC/CL) which can function as a suspending agent, emulsionstabilizer, etc. A schematic diagram of thePH and RC/CL manufacturing processes is shown in Figure 1.

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Figure 1: The Avicel Manufacturing Process

Dicer

Reactor

Mix Tank

SprayDryer

Storageand

Packaging

Mixer

Drying andSubsequentProcessing

Storageand

Packaging

FilterPH

Pulp

RC/CL

Na CMC

Manufacturing plants in Newark, DE, andCork, Ireland, produce consistent Avicel®

products by this process that meet givenphysical and chemical specificationsdepending on the PH type. In addition, functional properties are periodically evaluated to assure that product from each manufacturing site is equivalent notonly chemically and physically, but in functionality as well.

Processing rolls of wood pulp in variousways can make different types of products in addition to the PH and RC/CL products(see Figure 2). Cellulose ethers are made bychemical derivatization of the alpha-cellu-lose, e.g., hydroxypropylcellulose, hydrox-ypropylmethylcellulose, etc. Cellulose “flocs” are powder products obtained bymechanical grinding of cellulose pulp, e.g.Elcema® and Solka-Floc®. They are notmicrocrystalline cellulose.

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Importance of the Commercial Introduction of Avicel PH Microcrystalline Cellulose to Direct Compression

Avicel® was introduced by FMC in 1964 inselected particle sizes and moisture contents as an ingredient for direct compressiontableting. The concept of being able to avoidthe costly and time-consuming process ofwet granulation was one that many formula-tors had pursued for years. However, theonly product available at that time that hadbeen designed for direct compression tablet-ing was spray dried lactose. Spray dried lac-tose had many advantages to recommendits use and indeed it was used to produceproducts by the direct compression manu-facturing process. It was flowable and relatively compressible. Unfortunately, spraydried lactose had several problems which

limited its use. One was a brown color thatdeveloped when used in tablets containing basic amine drugs, caused by an impurity in the lactose which chemically reacted withamines. Another problem was lumping of the lactose in bulk drums on storage. Finally,even though it was compressible, there wereinstances where the compressibility of the lactose could not accommodate high levels of poorly compressible drugs, and softtablets would result. The suppliers of spraydried lactose recognized these problems andthe products available on today’s market areimproved in these respects over the originalproduct offerings.

Figure 2: Cellulosic Products

Pulp

ChemicalDerivatization

Drying

Wet MechanicalDisintegration

DispersingAgent

MechanicalDisintegration

ChemicalDepolymerization

� Cellulose

SolubleCellulose Derivative

HydrocolloidSolution

Aqueous Colloid

FibrousCellulose Floc

Microcrystalline CellulosePowder

ColloidalMicrocrystalline Cellulose

+ Water

+ Water

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The Tableting Characteristics of Avicel PH Microcrystalline Cellulose

Avicel can be directly compressed alone without the aid of a lubricant at humidities less than about 55%. However, above this value, some punch face sticking can beobserved. In formulations, lubrication isalways necessary, although microcrystallinecellulose has been classified as an “antiad-herent” and reduction in lubricant concentra-tion may be achieved in some formulations.

Microcrystalline cellulose is often referred toas having “lubricant sensitivity”. While it istrue that the compressibility of a mixture ofmagnesium stearate and microcrystallinecellulose is less than that of microcrystallinecellulose alone, this reduction in compress-ibility has no practical significance in formu-lations. “Lubricant sensitivity” is sometimesused as a functional test to evaluate micro-crystalline cellulose from several sources. As is the case with lubricants in general,especially the alkaline stearates, the effecton tablet hardness caused by the lubricant is a function of its concentration, mixingtime, and amount of shear induced by the mixing process itself. Particle size of themicrocrystalline cellulose also influences “lubricant sensitivity”. Avicel PH-200 (180microns) is more sensitive to lubricant than is Avicel PH-101 (50 microns) because the same concentration of lubricant more effi-ciently covers the larger particle size PH-200than the smaller particle size (larger particlesurface area) PH-101.

When compressed, microcrystalline celluloseundergoes plastic deformation. Slip planes,

dislocations, and the small size of the individual crystals all aid in the plastic flow that takes place. The acid hydrolysis portion of the production process introduces slip planes and dislocations into the material.The spray dried particle itself, which has ahigher porosity compared to the absoluteporosity of cellulose, also deforms undercompaction pressure. The strength of microcrystalline cellulose tablets results from hydrogen bonding between the plastically deformed, large surface area cellulose particles. Indeed, a microcrystallinecellulose tablet could be described as a cellulose fibril in which the microcrystals are compressed closely enough together so that hydrogen bonding between themoccurs. Microcrystalline cellulose is recog-nized as the most compressible of any direct compression excipient, in that less compres-sion force is required to produce a tablet ofa given hardness than is required for other direct compression materials.

One of the functionality tests performed ondirect compression excipients in general,and specifically on Avicel, is “carryingcapacity”. Carrying capacity measures theamount of a drug substance, usually poorlycompressible, that can be added to theexcipient while still obtaining a satisfactorytablet with respect to hardness and/or friability. The more drug substance that canbe added to the excipient, or alternatively,the less excipient that is needed, the betterthe carrying capacity of the excipient.Typically, 20–25% microcrystalline cellulose

The commercial introduction of Avicel® in 1964 as a direct compression tablet excipi-ent expanded the usefulness of this methodof tablet manufacture. Combinations ofspray dried lactose and Avicel overcamecompressibility problems while the lactose

added flowability to the Avicel productsavailable at that time. Direct compressiontableting became a reality, rather than a concept, because of the availability of Avicel.

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will carry most direct compression formula-tions, although there have been individualapplications where less (≈10%) was suffi-cient or more (≈50%) was necessary.

When placed in water, a pure microcrys-talline cellulose tablet swells and disinte-grates. While microcrystalline cellulose is notas efficient a disintegrant on a gram for grambasis compared to disintegrants such ascorn starch, the swelling that it exhibits hasbeen utilized in some formulations for disin-tegrant purposes. This swelling and disinte-gration has been attributed to penetration of water into the cellulose matrix as a resultof pore capillary action with subsequent disruption of the hydrogen bonds holdingthe fibrils together. Swelling and disintegra-tion is not observed in non-polar liquids.

The hydrogen bonding which holds micro-crystalline cellulose compacts together con-tributes to the appearance and effectivenessof a film coating regardless of whether it isapplied from an aqueous or organic system.Free hydroxyl groups are present on the sur-face of the core tablet, which provide excel-lent binding sites for cellulosic films. Filmadhesion and tensile strength are increased

while blistering, wrinkling and flaking of thefilm coat are decreased.

Microcrystalline cellulose compactability is effected by moisture content. It has an equilibrium moisture content of about 5%, at which point most of the water is thought to be in the pore structure of the particle and hydrogen bonded to the small pieces ofmicrocrystalline cellulose therein. This water acts as an internal lubricant and increasesthe ease with which the individual microcrys-tals can slip and flow during compression. It has been reported that the strongest compacts are produced at a moisture content of 7.3%. On the other hand, as the moisture content is reduced below 5%, softer tablets result.

Compactability is affected by the porosity of the microcrystalline cellulose particle. Forexample, PH-101, PH-102, and PH-200 (seebelow for descriptive details) have about thesame neat compressibility even though theiraverage particle size varies from 50 to 180microns while PH-301 (50 microns) and PH-302 (90 microns) are more dense and less compressible or compactable.

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A Comparison of Avicel® PH Microcrystalline Cellulose Types and Their Uses

The reader is referred to page 7 of Section 4,Tablet Ingredients, and below, for a compari-son of physical properties of Avicel PH prod-ucts. Figures 3–11 are scanning electronmicrographs (SEMs) of all the products takenat the same magnification. These SEMsvisually show differences in particle size aswell as other morphological characteristics.

The products first introduced were PH-101,PH-102, PH-103, and PH-105. As discussedabove, these products and those that fol-

lowed were designed as direct compressiontablet excipients. The reader is referred toSection 2 for a description of direct com-pression as a process. This remains themajor application for these products butother applications have been evaluatedsuch as uses in capsule filling, wet granula-tion formulation, and extrusion-spheroniza-tion technology. The latter two applicationsare of sufficient importance that separate discussions follow the product application information given below.

Figure 3: PH-101 — Most widely used for direct compression tableting, wet granulation andspheronization; also used in capsule filling processes, especially those employing tamping orother means of consolidation as part of the process.

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Figure 5: PH-103 — Same particle size as PH-101; reduced moisture content (3%); usedwhere moisture sensitive pharmaceutical active ingredients are present.

Figure 4: PH-102 — Used as above but larger particle size improves flow of fine powders.

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Figure 6: PH-105 — Smallest particle size; most compressible of the PH products; useful indirect compression of coarse, granular, or crystalline materials; can be mixed with PH-101 orPH-102 to achieve specific flow and compression characteristics; has applications in rollercompaction; poorly flowable by itself – cannot determine neat compressibility.

Figure 7: PH-112 — Same particle size as PH-102; much reduced moisture content (1.5%);used where very moisture sensitive pharmaceutical active ingredients are present.

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Figure 8: PH-113 — Same particle size as PH-101; much reduced moisture content (1.5%);used where very moisture sensitive pharmaceutical active ingredients are present.

Figure 9: PH-200 — Large particle size with increased flowability; used to reduce weight variation and to improve content uniformity in direct compression formulations and (as a final mix additive) in wet granulation formulations.

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Figure 10: PH-301 — Same particle size as PH-101 but more dense providing increasedflowability, greater tablet weight uniformity, the potential for making smaller tablets, andimproved mixability; useful as a capsule filling excipient.

Figure 11: PH-302 — Same particle size as PH-102 but more dense providing increasedflowability, greater tablet weight uniformity, the potential for making smaller tablets, andimproved mixability; useful as a capsule filling excipient.

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Avicel® PH Microcrystalline Cellulose Functionality in the Wet Granulation Manufacturing Process

It is well known that the wetting of neatmicrocrystalline cellulose with water, fol-lowed by drying and tablet compression,results in tablets of lower hardnesses thanare obtained by compression of neat micro-crystalline cellulose without prior treatment.This procedure would be expected to notonly reduce the density of the particleagglomerates themselves thereby decreas-ing their internal surface area, but also wouldcause some adhesion between particleagglomerates, reducing external surface area as well. Both actions will result in lessparticle interlocking and hydrogen bonding.

The use of microcrystalline cellulose (AvicelPH-101 or PH-102) in wet granulation formu-lations, where a typical wet granulationbinder is present, and in which the micro-crystalline cellulose is 5-20% of the portionof the formulation being granulated, hasbeen found to offer the following functionali-ties. Wet granulation, as a process, isdescribed in Section 2.

Rapid, Even Wicking Action

The property of microcrystalline cellulose torapidly adsorb water also allows it to rapidlydraw aqueous binder solutions (or water)into powder mixtures being granulated. Thispermits a faster addition both in time of fluidaddition as well as wet massing time.

Controls Wet Mass Consistency

When microcrystalline cellulose is used in a product being granulated, there is far lesschance of the granulation turning into anunworkable, doughy mass than when it isnot used. This control of the granulating fluid against overwetting of the granulation

is no doubt in some way due to the large surface area and adsorptive capacity of the microcrystalline cellulose.

Less Screen Blocking

Due to the improved workability of the wetmass and the decreased sensitivity to watercontent, wet screening, which can introduceshear and localized overwetting causingscreen blockage, is fast and trouble free.

Uniform, Rapid Drying

Even though microcrystalline cellulose allowsfor the rapid addition of granulating fluid, thewater does not become bound water but iseasily given up during the drying process,allowing for the more efficient use of dryingequipment. This property aids in preventingcase hardening and in the production of adried granulation having a uniform moisturecontent with fewer fines.

Controls Color Mottling and Drug ContentUniformity

Without microcrystalline cellulose, dyes andlakes can be observed to migrate to the surface of dried granules. This migration canalso be demonstrated in the case of water-soluble active ingredients. Occasionally,some materials used as fillers in the granula-tion are the cause of mottling because theyare of a slightly different whiteness thanother formulation ingredients and migrate to granule surfaces. The exact mechanismby which microcrystalline cellulose preventsmigration and promotes a more uniform distribution of color and/or drug in the granule is not known, but it may be associated with rapid and uniform drying

cellulose depending on the amount of micro-crystalline cellulose present and whether or not the material being granulated is large-ly soluble or insoluble. The effect is morepronounced in the case of insoluble materi-als. This is not to say that microcrystallinecellulose can be used as a replacement fora wet granulation binder, but it does confer

additional compressibility in many cases.

The use of microcrystalline cellulose (5-20%) as a post-granulation “add” to the running powder or final mix confers the same benefits as those found in directcompression (hard tablets at low compres-sion pressures, low friability, disintegrantenhancer, anti-adherent, lubricant enhancer,etc.). Microcrystalline cellulose often isthought of as a one-dimensional excipient,but as evidenced from the above discussionand the one that follows it has multiple functionalities.

as noted above. Having a uniform distribu-tion within the dried granule will result intablets, after dry milling of the granules, finalmixing and compression that are uniform insurface appearance and drug content. Thepossibility of losing large amounts of activeingredient to the dust collection system inthe fines which are generated during themilling process as the granules first break, is virtually eliminated, since the active ingredient is uniformly distributed throughoutthe granule and not concentrated on the surface. This source of possible analyticaldeviation from theoretical values is no longer a concern.

Acts as an Auxiliary Binder

Tablets compressed from granulations containing microcrystalline cellulose areharder (at equal compression forces) andless friable than those compressed fromgranulations without microcrystalline

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Avicel® PH Microcrystalline Cellulose as a Spheronizing Agent

The extrusion-spheronization process isdescribed in Section 2. As noted, the massto be extruded must be cohesive, yetdeformable enough to flow through the diewithout sticking and able to retain its shapeafter extrusion. It must be plastic so that itcan be rolled into spheres in the spheronizerbut non-cohesive so that each sphereremains discrete. To accomplish this, anextrusion-spheronization aid is necessary.Such substances confer not only therequired plasticity of the mass but add thebinding properties that are necessary for pellet strength and integrity. During spher-onization, extrudates that are rigid but lack-ing in plasticity, form dumbbell shaped pellets and/or a high percentage of fines relative to spherical pellets. Extrudates thatare plastic, but without rigidity, tend toagglomerate into very large spherical balls.

Microcrystalline cellulose has been studiedextensively as an extrusion-spheronizationaid. Avicel PH-101 has come to be regardedas an essential formulation component forsuccessful extrusion-spheronization. It isthought that it acts as a molecular spongefor the water added to the formulation, alter-ing the rheological properties of the wetmass. It has also been proposed that micro-crystalline cellulose adds to the tensilestrength of the wet mass through autoadhe-sion (the interdiffusion of free cellulose poly-mer chains). It is autoadhesion that makespellets composed of neat microcrystallinecellulose that have been extruded andspheronized, hard, non-compressible andnon-disintegrating. When mixtures of drugand microcrystalline cellulose are extrudedand spheronized, the microcrystalline cellu-lose acts as a matrix from which the drug

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Editor’s Note

Dr. George E. Reier died Tuesday, August 3. 1999, after a prolonged illness. He was a retired Senior Pharmaceutical Associate of the pharmaceutical business, FMC BioPolymer.

George was a graduate student of Dr. Ralph F. Shangraw at the University of Maryland School of Pharmacy. His and other graduate students’ research in the early 1960s resulted in the first papers to appear in the scientific literature on the use of microcrystalline cellulose in tableting. Despite his illness, he worked diligently to complete this chapter on MCC — a tribute to his work ethic and his love of pharmaceutlcal research.

Dr. Reier was a gentleman in the true sense of the word and a stellar scientist by any measure. He was a gentleman with all the positive attributes of class, e.g., integrity, compassion, a sense of fairness, plus a quality of graciousness in manner, speech, style and image. George was modest and funny and self-deprecating and charitable to those he knew, as well as to strangers. He always had a smile. He was a source of knowledge and wisdom for all of us within FMC BioPolymer. We will miss his advice and counsel. I will miss George.

Thomas A. Wheatley, Technical Editor

can slowly dissolve. Coating the pellets, or by using other ingredients in the pelletformulation, or both, can further control drug release.

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Bibliography/Publications

The references presented herein are notintended to be all-inclusive for microcrys-talline cellulose. They are intended to provide a useful list of references for thereader who wishes to learn more or to studyin greater detail the properties and applica-tions of Avicel® PH MicrocrystallineCellulose. In some cases, references havebeen included that are not specific to theuse of microcrystalline cellulose in tablets so that the reader might supplement his/herunderstanding of the applications of thismaterial. For copies of these publications,please contact your local library or informa-tion services department.

1. Fox, C.D., Reier, G.E., Richman, M.D., Shangraw, R.F., “Microcrystalline Cellulose in Tableting,” Drug and Cosmetic Industry,Vol. 92, (2), p. 161, 1963.

2. Beal, H.M., Shah, S., Varsano, J.“Tableting with Microcrystalline Cellulose,”presented to the American PharmaceuticalAssociation, Miami Beach, Florida, May 13,1963.

3. Beal, H.M., Shah, S., Varsano, J.,“Pharmaceutical Applications ofMicrocrystalline Cellulose I: Tableting,”University of Connecticut, unpublishedresearch report, 1963.

4. Battista, O.A., “Manufacture ofPharmaceutical Preparations ContainingCellulose Aggregates,” U.S. Patent3,146,168, 1964.

5. Battista, O.A., “Manufacture of CosmeticPreparations Containing Cellulose CrystalliteAggregates,” U.S. Patent 3,146,170, 1964.

6. Vora, K.M., “Availability of a Water

Insoluble Steroid from Tablet Matrices,”Masters Thesis, University of Maryland,1964.

7. Reier, G.E., “Microcrystalline Cellulose in Tableting”, Ph.D. Thesis, University ofMaryland, 1964.

8. Beal, H.M, “Application of MicrocrystallineCellulose in Pharmaceuticals III: In VivoRelease of Active Ingredients from TabletGranulations,” University of Connecticut,unpublished research report, 1964.

9. Fox, C.D., Richman, M.D., Shangraw, R.F.,“Preparation and stability of glyceryl trinitratesublingual tablets prepared by direct compression”, Journal of PharmaceuticalSciences, Vol. 54, (3), p. 447, 1965.

10. Woods, L.C., “Microcrystalline cellulose,”American Perfumer and Cosmetics, Vol. 80,(4), p. 51, 1965.

11. Banker, G.S., DeKay, G.H., Lee, S.“Effect of water vapor pressure on moisturesorption and the stability of aspirin andascorbic acid in tablet matrices,” Journal of Pharmaceutical Sciences, Vol. 54 (8), p. 1153, 1965.

12. Morris, R.M., “Investigation of a NewAuxiliary Agent for Use in DirectCompression Formulas in Tableting,” Ph.D.Thesis, University of North Carolina, 1965.

13. “Novel Vitamin ContainingCompositions,” Hoffman-LaRoche and Co.,British Patent 1,077,439, 1966.

14. Cohn, R., Nessel, R., Reier, G.E., “An Evaluation of Direct CompressionExcipients”, presented to American

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Pharmaceutical Association, Dallas, Texas,April 1966.

15. Augsburger, L.L., Shangraw, R.F., “Effectof Glidants in Tableting”, Vol. 55, (4), p. 418,1966.

16. Reier, G.E., Shangraw, R.F.,“Microcrystalline cellulose in tableting,”Journal of Pharmaceutical Sciences, Vol. 55 (5), p. 510, 1966.

17. Sisson, W.A., “Avicel MicrocrystallineCellulose Tableting Applications,” unpublished report, May 9, 1966.

18. Shangraw, R.F., “The Direct Compressionof Ascorbic Acid-Avicel Blends,” unpub-lished report, University of Maryland, 1966.

19. Hynniman, C.E., Manudhane, K.S.,Shangraw, R.F., “Direct Compression ofAscorbic Acid,” unpublished report,University of Maryland, 1966.

20. Sisson, W.A., “Avicel MicrocrystallineCellulose, Its Production, Properties andApplications,” 1966.

21. Shah, M.A., “Some effects of humidityand heat on the tableting properties ofmicrocrystalline cellulose formulations I,”Journal of Pharmaceutical Sciences, Vol. 57, (1), p. 181, 1968.

22. Enezian, G.M., “Direct compression oftablets using microcrystalline cellulose,”Prod. Et Prob. Pharm., Vol. 23 (4), p. 185,1968.

23. Belfort, A.M., “MicrocrystallineCellulose—Properties and Functions inPharmaceutical Preparations,” presented at the University of Ghent, Belgium, March 1968.

24. Graf, E., Graf, I., Walker R., Werner, H.,“Cellulose powder in tablet and dragee production,” Mitt. Adtsch. Pharmaz Ges u. Pharmaz, Ges., DDR 38, p. 165, 1968.

25. Hynniman, C.E., Manudhane, K.S.,Shangraw, R.F., “Direct compression ofascorbic acid,” Pharmaceutical ActaHelvetiae, Vol. 43 (257), 1968.

26. Mauro, T., “Direct Compression asViewed from Avicel,” unpublished report,Asahi Chemical Industry Co. Ltd., February15, 1968.

27. Maly, J., Chalabla, M., Heliova, M., “The effect of powdered celluloses on thestrength and disintegration of compressedtablets,” Acta Facultatis Pharm., Vol. 16, p. 113, 1968.

28. Hu, V.K., “Evaluation of New Agents forDirect Compression Formulation of Tablets,”Masters Thesis, Philadelphia College ofPharmacy and Science, 1969.

29. Fukuoka, E., Nagai, T., Nogami, H.,Sonobe, T., “Disintegration of aspirin tabletscontaining potato starch and microcrystallinecellulose,” Chem. Pharm. Bull., Vol. 17, (7),p. 1450, 1969.

30. Wakimoto, T., Takeda, A. Otsuka, A.,“Moisture sorption and volume expansion of microcrystalline cellulose tablets,” Arch.Pract, Pharm., Vol. 29, (4), p. 263, 1969.

31. Livingstone, J.L., “Compressed tablets”,Manufacturing Chemist and Aerosol News,p. 23, March 1970.

32. Kim, H., Shangraw, R.F., “Dissolution ofDrugs of Low Water Solubility from TabletsPrepared by Wet Granulation and DirectCompression”, presented to American

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Pharmaceutical Association, Washington,D.C., April 1970.

33. Huttenrauch, R., Jacob, J., “Significanceof pressing powder for preparation of micro-crystalline cellulose,” Pharmazie, Vol. 25, p. 630, 1970.

34. Shangraw, R.F., “Application of PowderTechnology in Capsules,” presented at theFifth Annual Educational Conference forIndustrial Pharmacists, January 1970.

35. Kalschik, W., Schepky, G., “New Tablets,Cores and Coated Tablets and the Methodof Their Production,” German Patent1,811,809, 1970.

36. Cotty, J., Metral-Biollay, J.P., “The importance of microcrystalline cellulose asan adjuvant in the production of dragees,”Labo-Pharma.-Problems et Technicques, Vol. 194 (12), p. 42, 1970.

37. Cohn, R., Hill, J.A., “MicrocrystallineCellulose as a Matrix,” Canadian Patent834,720, 1970.

38. Dunleavy, J.E., “Fat-Soluble Vitamin-Active Oil Containing MicrocrystallineCellulose Product,” Canadian Patent831,908, 1970.

39. Kedvessey, G., Sumegi, G.,“Investigations on the effects of some auxil-iaries in the physical properties of tablets,”Pharmazie, Vol. 25 (9), p. 544, 1970.

40. Rhodes, C.T., Banker, G.S., “Some pharmaceutical aspects of polymer science,”Canadian Journal of PharmaceuticalSciences, Vol. 5, (3), p. 61, 1970.

41. Chopra, R.K., “An Evaluation ofExperimental Materials as Directly

Compressible Vehicles in PharmaceuticalTableting,” Masters Thesis, ColumbiaUniversity, 1970.

42. Cole, E.T., Hersey, J.A., Rees, J., “Theeffect of rate of loading on the strength oftablets,” Journal of Pharm. Pharmacol., Vol. 22, Suppl. 645, 1970.

43. Ogura, K., Sobue, H., “Changes in morphology with milling of commercialmicrocrystalline cellulose,” J. Appl. PolymerScience, Vol. 14, (5), p. 1390, 1970.

44. Maly, J., Chalabal, M. Heliova, M.“Microcrystalline celluloses and their use in tableting,” Arch. Pharm., Vol. 308, p. 114,1970.

45. Hirschorn, J.O., Kornblum, S.S.,“Dissolution of poorly water-soluble drugs ii:excipient dilution and force of compressioneffects on tablets of a quinazolinone com-pound,” Journal of Pharmaceutical Sciences,Vol. 60, (3), p. 445, 1971.

46. Harder, S.W., Wood, J.A., Zuck, D.A.,“Some of the forces responsible for theadhesive process in the film coating oftablets,” Canadian Journal ofPharmaceutical Sciences, Vol. 6, (3), p. 63, 1971.

47. Iwaki, S., Naito, S.J., Shimizi, J.,“Techniques for manufacturing pharmacy ii:prediction of tableting troubles such as cap-ping and sticking,” Chem. Pharm. Bull., Vol. 19, (9), p. 1949, 1971.

48. Garamvolgyi-Horuath, Kedvessy, G.,Selmeczi, B., “Comparative investigations of the properties of tablets prepared by different methods as a function of pressure,”Pharm. Ind., Vol. 33, (9), p. 609, 1971.

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49. Cid, E., Jaminet, F., “Influence of adju-vants on the rate of dissolution and the stability of acetylsalicylic acid in tablets,” J. Pharm. Belg., Vol. 26, (1), p. 38, 1971.

50. Chalabala, M., Heliova, M., Maly, J.,“Preparation of compressed tablets contain-ing additives of some cellulose types withoutgranulation,” Acta Fac. Pharm. Univ.Comeniana, Vol. 20, p. 125, 1971.

51. Sangekar, S.A., Sarlie, M., Sheth, P.R.,“Effect of moisture on physical characteris-tics of tablets prepared from direct compres-sion excipients,” Journal of PharmaceuticalSciences, Vol. 61, (6), p. 939, 1972.

52. Jalal, I.M., Malinowski, H.J., Smith, W.E.,“Tablet granulations composed of spherical-shaped particles,” Journal of PharmaceuticalSciences, Vol. 61, (9), p. 1466, 1972.

53. Enezian, E.M., “Direct compression oftablets using microcrystalline cellulose,”Pharm. Acta Helvetiae, Vol. 47 (6/7), p. 321, 1972.

54. Huttenrauch, R., Jacob, J., Zobisch, B.,“Effect of particle size on the tableting properties of microcrystalline cellulose,”Pharmazie, Vol. 27, (6), p. 415, 1972.

55. Marshall, K., Sixsmith, D., Stanley-Wood,N.O., “Surface geometry of some microcrys-talline celluloses,” Journal of PharmPharmacol., Vol. 24, Suppl. 138P, 1972.

56. Kahn, K.A., Rhodes, C.T., “The production of tablets by direct compression,” Canadian Journal ofPharmaceutical Sciences, Vol. 8, (1), p. 1, 1973.

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58. Bolhuis, G.K., Lerk, C.F., “Comparativeevaluation of excipients for direct compres-sion,” Pharm. Weekblad, Vol. 108, (22), p. 469, 1973.

59. Voege, Von H., “Determination of microcrystallinity in celluloses by differentialthermal analysis,” Pharm. Ind., Vol. 35, (2), p. 78, 1973.

60. Miyake, Y., Shinoda, A., Furakawa, M.,Uesugi, K., Nasu, T., “Spheronizing mecha-nism and properties of spherical granules,”Yakuzaigaku, Vol. 33, (123), p. 161, 1973.

61. Malinowski, H.J., Smith, W.E., “Effects ofspheronization process variables on selectedtablet properties,” Journal of PharmaceuticalSciences, Vol. 63, (2), p. 285, 1974.

62. Marshall, K., Sixsmith, D., “Some physi-cal characteristics of microcrystalline cellu-lose,” Drug Development Communications,Vol. 1, (1), p. 51, 1974-1975.

63. Bavitz, J.F., Schwartz, J.B., “Direct compression vehicles, part 1,” Drug andCosmetic Industry Vol. 114, p. 44, 1974.

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65. DeLattre, L. Jaminet, F., “Study of somefactors influencing the bonding power ofexcipients for direct compression,” Pharm.Acta Helvetiae, Vol. 49, p. 108, 1974.

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67. Arita, T., Nakai, Y., Nakano, M.,Yamamoto, J., “Dissolution Rate andbioavailability of griseofulvin from a groundmixture with microcrystalline cellulose,”Journal of Pharmacokinetics andBiopharmaceutics, Vol. 2 (6), p. 487, 1974.

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71. Banker, G.S., Kildsig, D.O., Kramer, P.A.,Nadkarni, P.D., “Effect of surface roughnessand coating solvent on film adhesion totablets,” Journal of PharmaceuticalSciences, Vol. 64, (9), p. 1554, 1975.

72. Newton, J.M., Stanley, P., “The influenceof compaction pressure on the mechanicalcompaction pressure on the mechanicalstrength and strength variability of tablets”,Journal of Pharm. Pharmacol., Vol. 27,Suppl. 53P, 1975.

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77. Lamberson, R.L., Raynor, G.E. Jr.,“Tableting properties of microcrystalline cel-lulose,” Manufact. Chem., p. 55, June 1976.

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83. Khan, K.A., Rhodes, C.T., “Comparativeevaluation of some direct compression dilu-ents,” Pharm. Acta Helvetiae, Vol. 51, (1-2),p. 23, 1976.

84. Gillard, J., Toure, P., Roland, M.,“Determination of the binding energy of diluents during direct compression,” Pharm.Acta Helvetiae, Vol, 51, (7-8), p. 226, 1976.

85. Johansen, H., Moller, N., “Solvent deposition of drugs on excipients, part 1,influence of excipients and solvents on particle size and dissolution behavior ofphenylbutazone,” Acta. Pharm. Chemi. Sci. Ed., Vol. 4 (6), p. 114, 1976.

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90. Augsburger, L.L., David, S.T., “Plasticflow during compression of directly compressible fillers and its effect on tabletstrength,” Journal of PharmaceuticalSciences, Vol. 66, (2), p. 155, 1977.

91. Yamamoto, K., Matsuda, S., Nakano, M.,Arita, T., Nakai, Y., “Physicochemical proper-

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92. Crooks, M.J., Ho, R., Bagster, D.F.,“Tensile and shear testing of some pharma-ceutical powders,” Drug. Devel. Ind. Pharm.,Vol. 3, (4), p. 291, 1977.

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96. Rowe, R.C., “The adhesion of film coat-ings to tablet surfaces—the effect of somedirect compression excipients and lubri-cants,” Journal of Pharm. Pharmacol., Vol.29, (12), p. 723, 1977.

97. Hannula, A., Kristoffersson, E.,“Theophylline tablet formulation: effect ofinter- and intra-granular avicel and compres-sion force on the properties of plastic matrixtablets,” Acta Pharmaceutica Fennica, Vol.86, p. 13, 1977.

98. Mendes, R.W., Roy, S.B., “Tabletingexcipients, part I and II,” PharmaceuticalTechnology, Vol. 2, (3 & 9), pp. 32, 61, 1978.

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99. Raynor, Jr., G.E., Steuernagel, C.R.,“Antiperspirant sticks by isostatic compres-sion,” Manuf. Chem & Aerosol News, Vol. 49,(4), p. 65, 1978.

100. Steuernagel, C.R., Stevens, E.P.,“Microcrystalline cellulose for cosmetics,”Drug and Cosmetic Industry, Vol. 122, (6), p. 54, 1978.

101. Shangraw, R.F., “Raw materials of natural origin in solid dosage forms, part Iand II,” Drug and Cosmetic Industry, Vols. 122 and 123, (6 & 1), pp. 68, 34, 1978.

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104. Hollenbeck, G.R., Kildsig, D.O., Peck,G.E., “Application of immersional calorimetryto investigation of solid-liquid interactions:microcrystalline cellulose-water system,”Journal of Pharmaceutical Sciences, Vol. 67,(11), p. 1599, 1978.

105. Lundgren, P., Nyqvist, H., Nystrom, C.,Wadsten, T., “Studies on the physical prop-erties of tablets and tablet excipients, part 1:adsorption of drugs to cellulose used intablets,” Acta Pharm. Suec., Vol. 15, (2), p. 150, 1978.

106. Rees, J.E., Rue, P.J., “Time dependentdeformation of some direct compressionexcipients,” J. Pharm. Pharmacol., Vol. 30,(10), p. 601, 1978.

107. Kahela, P., Anttila, M., Hurmerinta, T.,Liponkoski, L., “Effect of ball milling withmicrocrystalline cellulose on the bioavailabili-ty of spironolactone in dogs,” Acta Pharm.Fenn., Vol. 87, (4), p. 185, 1978.

108. Boer, A.H., Bolhuis, G.K., Lerk, C.F.,“Effect of microcrystalline cellulose on liquid penetration in and disintegration ofdirectly compressed tablets,” Journal ofPharmaceutical Sciences, Vol. 68, (2), p. 205, 1979.

109. Bhatia, R.M., Lordi, N.G., “Electricalconductor of directly compressible materialsunder pressure,” Journal of PharmaceuticalSciences, Vol. 68, (2), p. 222, 1979.

110. Mendes, R.W., Roy, S.B., “Tabletingexcipients part III.” PharmaceuticalTechnology, Vol. 3, p. 69, 1979.

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112. Bolhuis, G.K., deBoer, A.H., Lerk, C.F.,“Effect of microcrystalline cellulose on liquidpenetration in and disintegration of directlycompressed tablets”, Journal ofPharmaceutical Sciences, Vol. 68, (2), p. 205, 1979.

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114. Koerner, R.M., Koczak, M.J., “Isostaticcompaction behavior of avicel microcrys-talline cellulose for personal care products,”Drug and Cosmetic Industry, Vol. 124, (6), p. 64, 1979.

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116. Augsburger, L.L., Mitrevej, J.A.,“Adhesion of tablets in a rotary tablet press:1. instrumentation and preliminary study ofvariables affecting adhesion,” Drug Dev. Ind.Pharm., Vol. 6, (4), p. 331, 1980.

117. Al-Shora, H., Said, S., “SustainedRelease from Inert Matrices: 1. Effect ofMicrocrystalline Cellulose on Aminophyllineand Theophylline Release.” Int. J. Pharm.Vol. 6, (1), p. 11, 1980.

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120. Bowers, F.M., Shangraw, R.F., Wallace,J.W., “Morphology and functionality in tabletexcipients for direct compression, part I,”Pharmaceutical Technology, Vol. 5, (9), p. 69, 1981.

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123. Franz, R.M., Peck, G.E., “In vitroadsorption-desorption of fluphenazine dihy-drochloride and promethazine hydrochlorideby microcrystalline cellulose,” Journal ofPharmaceutical Sciences, Vol. 7, (11), p. 1193, 1982.

124. Sixsmith, D., “The compression characteristics of microcrystalline cellulosepowders,” Journal Pharm. Pharmacol., Vol. 34, (5), p. 345, 1982.

125. Humphrey, H.B., D”Stefan, D.A., Patel,M.R., Wadke, D.A., “Evaluation of a NewGrade of Microcrystalline Cellulose for DirectCompression Tabletting”, presented to theAcademy of Pharmaceutical Sciences, San Diego, CA, November 1982.

126. Liao, C.C., Jarowski, C.I., “OptimalSilica-Microcrystalline Cellulose Ratios forthe Preparation of Tablets Containing aSolution of Prednisolone,” presented to the Academy of Pharmaceutical Sciences,San Diego, CA, November 1982.

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129. Mitrevej, A., Hollenbeck, R.G.,“Influence of hydrophilic excipients on theinteraction of aspirin and water,” Int. J.Pharm., Vol. 14 (2-3), p. 243, 1983.

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131. Armstrong, N.A., Lowndes, D.H.L., “Theuse of mixtures of spray dried lactose andmicrocrystalline cellulose as direct compres-sion diluents,” Int. J. Pharm. Technol. Prod.Manuf., Vol. 5, (3), p. 11, 1984.

132. Krysteva, M.A., Sokolov, T.T., “ModifiedSpherical Microcrystalline Cellulose as aCarrier for Immobilization of Proteins,” presented to the Federation of EuropeanBiochemical Societies, Moscow, USSR, June 25-30, 1984.

133. Malamataris, S., Bin Baie, S., Pilpel, N.,“Plasto-elasticity and tableting of paraceta-mol, avicel and other powders,” JournalPharm. Pharmacol., Vol. 36, (9), p. 616,1984.

134. Pintye-Hodi, K., Sohajda-Szucs, E.,“Study on the compressibility of potassiumchloride. part 2. direct pressing with micro-crystalline celluloses,” Pharm. Ind., Vol. 46,(10), p. 1080, 1984.

135. Sottys, J., Lisowski, Z., Knapczyk, J.,“X-ray diffraction study of the crystallinityindex and the structure of the microcrys-talline cellulose,” Acta Pharm. Technol., Vol. 30, (2), p. 174, 1984.

136. Zografi, G., Kontny, M.J., Yang, A.Y.S.,Brenner, G.S., “Surface area and water vaporsorption of microcrystalline cellulose,” Int. J.Pharm., Vol. 18, (1-2), p. 99, 1984.

137. Bangudu, A.B., Pilpel, N., “Effects ofcomposition, moisture and stearic acid onthe plastoelasticity and tableting of parac-etamol-microcrystalline cellulose mixtures,”Journal Pharm. Pharmacol., Vol. 37, (5), p.289, 1985.

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140. McCurdy, V.E., “Effects ofMicrocrystalline Cellulose in Sugar CoatingSuspension on the Coating Process and on the Physical Properties of the CoatedTablets,” Ph.D. Thesis, Purdue University,1985.

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142. Parvez, R., Bolton, S., “Evaluation ofnew fine particulate cellulose as a directcompression tablet aid,” Drug Dev. Ind.Pharm., Vol. 11, p. 565, 1985.

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144. Khan, F. Pilpel. N., “Effect of particlesize and moisture on the tensile strength ofmicrocrystalline cellulose powder,” PowderTechnol., Vol. 48, (2), p. 155, 1986.

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146. Roberts, R.J., Rowe, R.C., “Effect of the relationship between punch velocity andparticle size on the compaction behavior ofmaterials with varying deformation mecha-nisms,” Journal Pharm. Pharmacol., Vol. 38,p. 567, 1986.

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149. Stanley-Wood, N.G., Johansson, M.E.,“Variation of adsorption forces with degreeof compaction,” Acta Pharm. Suec., Vol. 23,(5), p. 271, 1986.

150. Struszczyk, H., Boldowicz, D.,“Conception of microcrystalline celluloseapplication as polymeric carriers for the controlled release of acetylsalicylic acid,”Celluol. Chem. Technol., Vol. 20, (2), p. 201,1986.

151. Wan, L.S.C., Heng, P.W.S., “Action ofsurfactant on disintegration and dissolutionof tablets containing microcrystalline cellu-lose,” Pharm. Acta Helvetiae, Vol. 61, (5-6),p. 157, 1986.

152. Williams, R.O., “A Study of theCompaction Properties of Some BinaryMixtures of Powders Using Tablet Indices,”Ph.D. Thesis, University of Texas, 1986.

153. Hontz, J., “Assessment of SelectedFormulation and Processing Variables inFluid Bed Granulation,” Ph.D. Thesis,University of Maryland, 1987.

154. Mashadi, A.B., Newton, J.M.,“Characterization of the mechanical proper-ties of microcrystalline cellulose: a fracturemechanics approach,” Journal Pharm.Pharmacol., Vol. 39, (12), p. 961, 1987.

155. Nguyen Huu Phuoc, Ho Nam Tran,Buchmann, M., Kesselring, U.W.,“Experimentally optimized determination ofthe partial and total cohesion parameters ofan insoluble polymer (microcrystalline cellu-lose) by gas-solid chromatography,” Int. J.Pharm., Vol. 34, (3), p. 217, 1987.

156. Remon, J.P., Schwartz, J.B., “Effect ofraw materials and processing on the qualityof granules prepared from microcrystallinecellulose-lactose mixtures,” Drug Dev. Ind.Pharm., Vol. 13, (1), p. 1, 1987.

157. Rowe, R.C., Sadeghnejad, G.R., “Therheology of microcrystalline cellulose pow-der/water mixes-measurement using a mixertorque rheometer,” Int. J. Pharm., Vol. 38, (1-3), p. 227, 1987.

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159. Staniforth, J.N., Hart, J.P., “Use ofimage processing and bulk powder meas-urements for shape analysis of microcrys-talline cellulose particles,” Anal. Proc.,(London) Vol. 24, (3), p. 78, 1987.

160. Van der Watt, J.G., “Effect of the parti-cle size of microcrystalline cellulose on tabletproperties in mixtures with magnesiumstearate,” Int. J. Pharm., Vol. 36, (1), p. 51,1987.

161. Fielden, K.E., Newton, J.M., O”Brien, P.,Rowe, R.C., “Thermal studies on the interac-tion of water and microcrystalline cellulose,”J. Pharm. Pharmacol., Vol. 40, p. 674, 1988.

162. Staniforth, J.N., Baichwal, A.R., Hart,J.P., Heng, P.W.S., “Effect of addition ofwater on the rheological and mechanicalproperties of microcrystalline cellulose,” Int. J. Pharm., Vol. 41, p. 231, 1988.

163. Ghali, E.S., Klinger, G.H., Schwartz,J.B., “Modified drug release from beads prepared with combinations of two grades of microcrystalline cellulose,” Drug Dev. Ind.Pharm., Vol. 15, (9), p. 1455, 1989.

164. Millili, G.P., Schwartz, J.B., “Thestrength of microcrystalline cellulose pellets:effect of granulating with water/ethanol mix-tures,” Drug Dev. Ind. Pharm., Vol. 16, (8), p. 1411, 1990.

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168. Doelker, E., “Comparative compactionproperties of various microcrystalline cellu-lose types and generic products,” Drug Dev.Ind. Pharm., Vol. 19, (17-18), p. 2399, 1993.

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170. Ek, R., Alderborn, G., Nystrom, C.,“Particle analysis of microcrystalline cellu-lose: differentiation between individual parti-cles and their agglomerates," Int. J. Pharm.,Vol. 111, p. 43, 1994.

171. Beten, D.B., Yuksel, N., Baykara, T.,"The changes in the mechanic properties of a direct tableting agent microcrystallinecellulose by precompression,” Drug Dev. Ind. Pharm., Vol. 20, (14), p. 2323, 1994.

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174. Mollan, M.J., Chang, N., Celik, M.,“Effect of reworking on the postcompactionproperties of microcrystalline cellulose for-mulations,” Pharm. Tech., Vol. 19 (Oct.), p. 58, 1995.

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181. Patel, R., Podczeck, F., “Investigation of the effect of type and source of micro-crystalline cellulose on capsule filling,” Int. J. Pharm., Vol. 128, p. 123, 1996.

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