PS-Section 11 1/16/07.QXD - FMC BioPolymer

Figure 2: Cellulosic ProductsPulp CelluloseChemicalDerivatizationMechanicalDisintegrationChemicalDepolymerizationWet MechanicalDisintegrationSolubleCellulose Derivative+ WaterHydrocolloidSolutionFibrousCellulose FlocDryingMicrocrystalline CellulosePowderDispersingAgentColloidalMicrocrystalline Cellulose+ WaterAqueous ColloidImportance of the Commercial Introduction of Avicel PHMicrocrystalline Cellulose to Direct CompressionAvicel ® was introduced by FMC in 1964 inselected particle sizes and moisture contentsas an ingredient for direct compressiontableting. The concept of being able to avoidthe costly and time-consuming process ofwet granulation was one that many formulatorshad pursued for years. However, theonly product available at that time that hadbeen designed for direct compression tabletingwas spray dried lactose. Spray dried lactosehad many advantages to recommendits use and indeed it was used to produceproducts by the direct compression manufacturingprocess. It was flowable andrelatively compressible. Unfortunately, spraydried lactose had several problems whichlimited its use. One was a brown color thatdeveloped when used in tablets containingbasic amine drugs, caused by an impurityin the lactose which chemically reacted withamines. Another problem was lumping ofthe lactose in bulk drums on storage. Finally,even though it was compressible, there wereinstances where the compressibility of thelactose could not accommodate high levelsof 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.4

The commercial introduction of Avicel ® in1964 as a direct compression tablet excipientexpanded the usefulness of this methodof tablet manufacture. Combinations ofspray dried lactose and Avicel overcamecompressibility problems while the lactoseadded flowability to the Avicel productsavailable at that time. Direct compressiontableting became a reality, rather than aconcept, because of theavailability of Avicel.The Tableting Characteristics of Avicel PH Microcrystalline CelluloseAvicel can be directly compressed alonewithout the aid of a lubricant at humiditiesless than about 55%. However, above thisvalue, some punch face sticking can beobserved. In formulations, lubrication isalways necessary, although microcrystallinecellulose has been classified as an “antiadherent”and reduction in lubricant concentrationmay 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 compressibilityhas no practical significance in formulations.“Lubricant sensitivity” is sometimesused as a functional test to evaluate microcrystallinecellulose from several sources.As is the case with lubricants in general,especially the alkaline stearates, the effecton tablet hardness caused by the lubricantis a function of its concentration, mixingtime, and amount of shear induced bythe mixing process itself. Particle size of themicrocrystalline cellulose also influences“lubricant sensitivity”. Avicel PH-200 (180microns) is more sensitive to lubricant thanis Avicel PH-101 (50 microns) because thesame concentration of lubricant more efficientlycovers 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 theindividual crystals all aid in the plastic flowthat takes place. The acid hydrolysis portionof the production process introduces slipplanes 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 ofmicrocrystalline cellulose tablets resultsfrom hydrogen bonding between theplastically deformed, large surface areacellulose particles. Indeed, a microcrystallinecellulose tablet could be described as acellulose fibril in which the microcrystalsare compressed closely enough togetherso that hydrogen bonding between themoccurs. Microcrystalline cellulose is recognizedas the most compressible of any directcompression excipient, in that less compressionforce is required to produce a tablet ofa given hardness than is required for otherdirect 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/orfriability. 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 cellulose5

Figure 4: PH-102 — Used as above but larger particle size improves flow of fine powders.Figure 5: PH-103 — Same particle size as PH-101; reduced moisture content (3%); usedwhere moisture sensitive pharmaceutical active ingredients are present.8

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.9

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 weightvariation and to improve content uniformity in direct compression formulations and (as afinal mix additive) in wet granulation formulations.10

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.11

Avicel ® PH Microcrystalline Cellulose Functionalityin the Wet Granulation Manufacturing ProcessIt is well known that the wetting of neatmicrocrystalline cellulose with water, followedby drying and tablet compression,results in tablets of lower hardnesses thanare obtained by compression of neat microcrystallinecellulose without prior treatment.This procedure would be expected to notonly reduce the density of the particleagglomerates themselves thereby decreasingtheir internal surface area, but also wouldcause some adhesion between particleagglomerates, reducing external surfacearea 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 formulations,where a typical wet granulationbinder is present, and in which the microcrystallinecellulose is 5-20% of the portionof the formulation being granulated, hasbeen found to offer the following functionalities.Wet granulation, as a process, isdescribed in Section 2.Rapid, Even Wicking ActionThe 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 ConsistencyWhen microcrystalline cellulose is used ina product being granulated, there is far lesschance of the granulation turning into anunworkable, doughy mass than when it isnot used. This control of the granulatingfluid against overwetting of the granulationis no doubt in some way due to the largesurface area and adsorptive capacity ofthe microcrystalline cellulose.Less Screen BlockingDue 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 DryingEven 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 ContentUniformityWithout microcrystalline cellulose, dyes andlakes can be observed to migrate to thesurface of dried granules. This migration canalso be demonstrated in the case of watersolubleactive ingredients. Occasionally,some materials used as fillers in the granulationare the cause of mottling because theyare of a slightly different whiteness thanother formulation ingredients and migrateto granule surfaces. The exact mechanismby which microcrystalline cellulose preventsmigration and promotes a more uniformdistribution of color and/or drug in thegranule is not known, but it may beassociated with rapid and uniform drying12

as noted above. Having a uniform distributionwithin 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 activeingredient is uniformly distributed throughoutthe granule and not concentrated on thesurface. This source of possible analyticaldeviation from theoretical values is nolonger a concern.Acts as an Auxiliary BinderTablets compressed from granulationscontaining microcrystalline cellulose areharder (at equal compression forces) andless friable than those compressed fromgranulations without microcrystallinecellulose depending on the amount of microcrystallinecellulose present and whetheror not the material being granulated is largelysoluble or insoluble. The effect is morepronounced in the case of insoluble materials.This is not to say that microcrystallinecellulose can be used as a replacement fora wet granulation binder, but it does conferadditional compressibility in many cases.The use of microcrystalline cellulose(5-20%) as a post-granulation “add” tothe running powder or final mix confersthe same benefits as those found in directcompression (hard tablets at low compressionpressures, 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 multiplefunctionalities.Avicel ® PH Microcrystalline Cellulose as a Spheronizing AgentThe 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 forpellet strength and integrity. During spheronization,extrudates that are rigid but lackingin plasticity, form dumbbell shapedpellets and/or a high percentage of finesrelative 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, alteringthe rheological properties of the wetmass. It has also been proposed that microcrystallinecellulose adds to the tensilestrength of the wet mass through autoadhesion(the interdiffusion of free cellulose polymerchains). 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 celluloseacts as a matrix from which the drug13

can slowly dissolve. Coating the pellets,or by using other ingredients in the pelletformulation, or both, can further controldrug release.Editor’s NoteDr. George E. Reier died Tuesday, August 3. 1999, after a prolonged illness. He was aretired Senior Pharmaceutical Associate of the pharmaceutical business, FMC BioPolymer.George was a graduate student of Dr. Ralph F. Shangraw at the University of MarylandSchool of Pharmacy. His and other graduate students’ research in the early 1960s resultedin the first papers to appear in the scientific literature on the use of microcrystalline cellulosein 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 anymeasure. 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, styleand image. George was modest and funny and self-deprecating and charitable to thosehe knew, as well as to strangers. He always had a smile. He was a source of knowledgeand wisdom for all of us within FMC BioPolymer. We will miss his advice and counsel.I will miss George.Thomas A. Wheatley, Technical Editor14

Bibliography/PublicationsThe references presented herein are notintended to be all-inclusive for microcrystallinecellulose. They are intended toprovide a useful list of references for thereader who wishes to learn more or to studyin greater detail the properties and applicationsof Avicel ® PH MicrocrystallineCellulose. In some cases, references havebeen included that are not specific to theuse of microcrystalline cellulose in tabletsso that the reader might supplement his/herunderstanding of the applications of thismaterial. For copies of these publications,please contact your local library or informationservices department.1. Fox, C.D., Reier, G.E., Richman, M.D.,Shangraw, R.F., “Microcrystalline Cellulosein 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 WaterInsoluble Steroid from Tablet Matrices,”Masters Thesis, University of Maryland,1964.7. Reier, G.E., “Microcrystalline Cellulosein 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 directcompression”, 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,” Journalof 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 American15

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,” unpublishedreport, 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,” presentedat the University of Ghent, Belgium,March 1968.24. Graf, E., Graf, I., Walker R., Werner, H.,“Cellulose powder in tablet and drageeproduction,” Mitt. Adtsch. Pharmaz Gesu. 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 expansionof 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 American16

Pharmaceutical Association, Washington,D.C., April 1970.33. Huttenrauch, R., Jacob, J., “Significanceof pressing powder for preparation of microcrystallinecellulose,” 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., “Theimportance 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 auxiliariesin the physical properties of tablets,”Pharmazie, Vol. 25 (9), p. 544, 1970.40. Rhodes, C.T., Banker, G.S., “Somepharmaceutical aspects of polymer science,”Canadian Journal of PharmaceuticalSciences, Vol. 5, (3), p. 61, 1970.41. Chopra, R.K., “An Evaluation ofExperimental Materials as DirectlyCompressible 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 inmorphology 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 usein 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 compound,”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 cappingand sticking,” Chem. Pharm. Bull.,Vol. 19, (9), p. 1949, 1971.48. Garamvolgyi-Horuath, Kedvessy, G.,Selmeczi, B., “Comparative investigationsof the properties of tablets prepared bydifferent methods as a function of pressure,”Pharm. Ind., Vol. 33, (9), p. 609, 1971.17

49. Cid, E., Jaminet, F., “Influence of adjuvantson the rate of dissolution and thestability 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 containingadditives 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 characteristicsof tablets prepared from direct compressionexcipients,” Journal of PharmaceuticalSciences, Vol. 61, (6), p. 939, 1972.52. Jalal, I.M., Malinowski, H.J., Smith, W.E.,“Tablet granulations composed of sphericalshapedparticles,” 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 tabletingproperties of microcrystalline cellulose,”Pharmazie, Vol. 27, (6), p. 415, 1972.55. Marshall, K., Sixsmith, D., Stanley-Wood,N.O., “Surface geometry of some microcrystallinecelluloses,” Journal of PharmPharmacol., Vol. 24, Suppl. 138P, 1972.56. Kahn, K.A., Rhodes, C.T., “Theproduction of tablets by directcompression,” Canadian Journal ofPharmaceutical Sciences, Vol. 8, (1),p. 1, 1973.57. Freida, M.A., Delonca, M.H., Joackim,M.J., Munerat, M.J., “Binding activity ofsome substances and their effect on thephysical characteristics of granules andtablets,” Il Farmaco, Vol. 28 (1), p. 3, 1973.58. Bolhuis, G.K., Lerk, C.F., “Comparativeevaluation of excipients for direct compression,”Pharm. Weekblad, Vol. 108, (22),p. 469, 1973.59. Voege, Von H., “Determination ofmicrocrystallinity 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 mechanismand 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 physicalcharacteristics of microcrystalline cellulose,”Drug Development Communications,Vol. 1, (1), p. 51, 1974-1975.63. Bavitz, J.F., Schwartz, J.B., “Directcompression vehicles, part 1,” Drug andCosmetic Industry Vol. 114, p. 44, 1974.64. Bolhuis, G.K., DeBoer, A.H., Lerk. C.F.,“Comparative evaluation of excipients fordirect compression II,” Pharm. Weekblad,Vol. 109, (40), p. 945, 1974.65. DeLattre, L. Jaminet, F., “Study of somefactors influencing the bonding power ofexcipients for direct compression,” Pharm.Acta Helvetiae, Vol. 49, p. 108, 1974.66. Delacourte-Thiband, A., Devise, B.,Guyot, J.C., Traisnal. M., “Excipients and18

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83. Khan, K.A., Rhodes, C.T., “Comparativeevaluation of some direct compression diluents,”Pharm. Acta Helvetiae, Vol. 51, (1-2),p. 23, 1976.84. Gillard, J., Toure, P., Roland, M.,“Determination of the binding energy ofdiluents during direct compression,” Pharm.Acta Helvetiae, Vol, 51, (7-8), p. 226, 1976.85. Johansen, H., Moller, N., “Solventdeposition of drugs on excipients, part 1,influence of excipients and solvents onparticle size and dissolution behavior ofphenylbutazone,” Acta. Pharm. Chemi.Sci. Ed., Vol. 4 (6), p. 114, 1976.86. Sixsmith, D. “The effect of compressionon some physical properties of microcrystallinecellulose,” Journal of Pharm.Pharmacol., Vol. 29, (1), p. 33, 1977.87. Fukuoka, E., Hasegawa, J., Nakai, J.Nakajima, S., “Crystallinity and physicalcharacteristics of microcrystalline cellulose,”Chem. Pharm. Bull., Vol. 25, (1), p. 96, 1977.88. Bolhuis, G.K., Lerk, C.F., Smedema, S.S.,“Interaction of lubricants and colloidal silicaduring mixing with excipients,” Pharm ActaHelvetiae, Vol. 52, (3), 1977.89. Sixsmith, D., “The properties of tabletscontaining microcrystalline cellulose”,Journal Pharm. Pharmacol., Vol. 29, (82),1977.90. Augsburger, L.L., David, S.T., “Plasticflow during compression of directlycompressible 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 propertiesand intestinal absorption of a groundmixture of chloramphenicol palmitate withmicrocrystalline cellulose,” Yakugaku Zasshi,Vol. 97, (4), p. 367, 1977.92. Crooks, M.J., Ho, R., Bagster, D.F.,“Tensile and shear testing of some pharmaceuticalpowders,” Drug. Devel. Ind. Pharm.,Vol. 3, (4), p. 291, 1977.93. Ho. R., Bagster, M.J., Crooks, M.J.,“Flow studies on directly compressible tabletvehicles,” Drug Devel. Ind. Pharm., Vol. 3,(5), p. 475, 1977.94. Cemeli, J., Del Pozo, A., Parera, E.,Salazar, R., Fauli, E., “Direct compression:study of the most important physical parameters,part I, behavior of some excipientsduring direct compression,” Cienc Ind.Pharm., Vol 9, (9), p. 222, 1977.95. Fukuoka, E., Nakai, Y., Nakajima, S.,Yamamoto, K., “Crystallinity and physicalcharacteristics of microcrystalline cellulose ii.fine structure of ground microcrystalline cellulose,”Chem. Pharm. Bull., Vol. 25, (10),p. 2490, 1977.96. Rowe, R.C., “The adhesion of film coatingsto tablet surfaces—the effect of somedirect compression excipients and lubricants,”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 compressionforce 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, 1978.20

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