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Section 11

Avicel PH Microcrystalline Cellulose, NF, Ph Eur., JP, BP


By Dr. George E. Reier

Table of Contents
Avicel Microcrystalline Cellulose............................................................................................................1 Table of Contents...............................................................................................................................1 Manufacturing Process ..........................................................................................................................2 Importance of the Commercial Introduction of Avicel PH Microcrystalline Cellulose to Direct Compression ...........................................................................................................................4 The Tableting Characteristics of Avicel Microcrystalline Cellulose........................................................5 A Comparison of Avicel Microcrystalline Cellulose Types and their Uses .........................................................................................................................7 Figure 3: PH-101...............................................................................................................................7 Figure 4: PH-102...............................................................................................................................8 Figure 5: PH-103...............................................................................................................................8 Figure 6: PH-105...............................................................................................................................9 Figure 7: PH-112...............................................................................................................................9 Figure 8: PH-113.............................................................................................................................10 Figure 9: PH-200.............................................................................................................................10 Figure 10: PH-301...........................................................................................................................11 Figure 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......................................................................................................12 Less Screen Blocking ......................................................................................................................12 Uniform, Rapid Drying .....................................................................................................................12 Controls Color Mottling and Drug Content Uniformity ....................................................................12 Acts as an Auxiliary Binder ..............................................................................................................13 Avicel PH Microcrystalline Cellulose as a Spheronizing Agent ...........................................................13 Editors Note.........................................................................................................................................14 Bibliography/Publications ....................................................................................................................15

Manufacturing Process
In 1962, O. A. Battista and P. A. Smith reported the preparation by the American Viscose Company of microcrystalline cellulose from cellulose, hence the origin of the product name Avicel. The PH designation indicates that the product is suitable for pharmaceutical use. Cellulose is present in much of the food of man but is inert to human digestive enzymes making it GRAS or generally recognized as safe for human consumption by the United States Food and Drug Administration (FDA) and other governmental agencies throughout the world. The process that produces Avicel PH microcrystalline cellulose alters only the cellulose physical form and eliminates impurities. 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, the European Pharmacopoeia and the Japanese Pharmacopoeia. Microcrystalline cellulose is purified, partially depolymerized cellulose prepared by using mineral 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 crystalline region. The former is an amorphous and flexible mass of cellulose chains while the latter is composed of tight bundles of cellulose chains in a rigid linear arrangement resembling bundles of wooden matchsticklike microcrystals. The hydrolysis process largely removes the amorphous fraction, destroying the fiber-like morphology of the cellulose, and unhinging the cellulose microcrystals. By filtering and spray drying, microcrystalline cellulose particle agglomerates composed of microcrystals are obtained, the particle size distribution and moisture content of which can be varied through the spray drying process. The actual manufacturing process begins with specially selected rolls of wood pulp that are diced, or cut, into small particles. These chopped particles are hydrolyzed under heat and pressure by mineral acid, following which the mix is washed with water and filtered. The hydrolysis process converts insoluble hydroxides, oxides, and sulfates present in the wood pulp to soluble compounds, which are removed by the filtering and washing processes, resulting in a product with exceptionally low inorganic impurities. The filtered cake is resuspended in water, and spray dried. The manufacturing process may be thought of as breaking the cellulose fibrous material down to a microcrystalline form and then agglomerating these crystallites into aggregates or particles. If a food grade sodium carboxymethylcellulose is added to the microcrystalline cellulose, with additional wet attrition before drying, a colloidal microcrystalline cellulose is produced (Avicel RC/CL) which can function as a suspending agent, emulsion stabilizer, etc. A schematic diagram of the PH and RC/CL manufacturing processes is shown in Figure 1.

Figure 1: The Avicel Manufacturing Process


Dicer

Pulp Reactor

Manufacturing plants in Newark, DE, and Cork, Ireland, produce consistent Avicel products by this process that meet given physical and chemical specifications depending on the PH type. In addition, functional properties are periodically evaluated to assure that product from each manufacturing site is equivalent not only chemically and physically, but in functionality as well. Processing rolls of wood pulp in various ways can make different types of products in addition to the PH and RC/CL products (see Figure 2). Cellulose ethers are made by chemical derivatization of the alpha-cellulose, e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. Cellulose flocs are powder products obtained by mechanical grinding of cellulose pulp, e.g. Elcema and Solka-Floc. They are not microcrystalline cellulose.

PH Filter

RC/CL Na CMC

Mix Tank

Mixer

Spray Dryer

Drying and Subsequent Processing

Storage and Packaging

Storage and Packaging

Figure 2: Cellulosic Products


Pulp

Cellulose

Chemical Derivatization

Mechanical Disintegration

Chemical Depolymerization Wet Mechanical Disintegration

Soluble Cellulose Derivative + Water Hydrocolloid Solution

Fibrous Cellulose Floc

Drying Dispersing Agent Microcrystalline Cellulose Powder Colloidal Microcrystalline Cellulose + Water Aqueous Colloid

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


Avicel was introduced by FMC in 1964 in selected particle sizes and moisture contents as an ingredient for direct compression tableting. The concept of being able to avoid the costly and time-consuming process of wet granulation was one that many formulators had pursued for years. However, the only product available at that time that had been designed for direct compression tableting was spray dried lactose. Spray dried lactose had many advantages to recommend its use and indeed it was used to produce products by the direct compression manufacturing process. It was flowable and relatively compressible. Unfortunately, spray dried lactose had several problems which limited its use. One was a brown color that developed when used in tablets containing basic amine drugs, caused by an impurity in the lactose which chemically reacted with amines. Another problem was lumping of the lactose in bulk drums on storage. Finally, even though it was compressible, there were instances where the compressibility of the lactose could not accommodate high levels of poorly compressible drugs, and soft tablets would result. The suppliers of spray dried lactose recognized these problems and the products available on todays market are improved in these respects over the original product offerings.

The commercial introduction of Avicel in 1964 as a direct compression tablet excipient expanded the usefulness of this method of tablet manufacture. Combinations of spray dried lactose and Avicel overcame compressibility problems while the lactose

added flowability to the Avicel products available at that time. Direct compression tableting became a reality, rather than a concept, because of the availability of Avicel.

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 be observed. In formulations, lubrication is always necessary, although microcrystalline cellulose has been classified as an antiadherent and reduction in lubricant concentration may be achieved in some formulations. Microcrystalline cellulose is often referred to as having lubricant sensitivity. While it is true that the compressibility of a mixture of magnesium stearate and microcrystalline cellulose is less than that of microcrystalline cellulose alone, this reduction in compressibility has no practical significance in formulations. Lubricant sensitivity is sometimes used as a functional test to evaluate microcrystalline cellulose from several sources. As is the case with lubricants in general, especially the alkaline stearates, the effect on tablet hardness caused by the lubricant is a function of its concentration, mixing time, and amount of shear induced by the mixing process itself. Particle size of the microcrystalline cellulose also influences lubricant sensitivity. Avicel PH-200 (180 microns) is more sensitive to lubricant than is Avicel PH-101 (50 microns) because the same concentration of lubricant more efficiently covers the larger particle size PH-200 than the smaller particle size (larger particle surface area) PH-101. When compressed, microcrystalline cellulose undergoes 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 a higher porosity compared to the absolute porosity of cellulose, also deforms under compaction pressure. The strength of microcrystalline cellulose tablets results from hydrogen bonding between the plastically deformed, large surface area cellulose particles. Indeed, a microcrystalline cellulose tablet could be described as a cellulose fibril in which the microcrystals are compressed closely enough together so that hydrogen bonding between them occurs. Microcrystalline cellulose is recognized as the most compressible of any direct compression excipient, in that less compression force is required to produce a tablet of a given hardness than is required for other direct compression materials. One of the functionality tests performed on direct compression excipients in general, and specifically on Avicel, is carrying capacity. Carrying capacity measures the amount of a drug substance, usually poorly compressible, that can be added to the excipient while still obtaining a satisfactory tablet with respect to hardness and/or friability. The more drug substance that can be added to the excipient, or alternatively, the less excipient that is needed, the better the carrying capacity of the excipient. Typically, 2025% microcrystalline cellulose

will carry most direct compression formulations, although there have been individual applications where less (10%) was sufficient or more (50%) was necessary. When placed in water, a pure microcrystalline cellulose tablet swells and disintegrates. While microcrystalline cellulose is not as efficient a disintegrant on a gram for gram basis compared to disintegrants such as corn starch, the swelling that it exhibits has been utilized in some formulations for disintegrant purposes. This swelling and disintegration has been attributed to penetration of water into the cellulose matrix as a result of pore capillary action with subsequent disruption of the hydrogen bonds holding the fibrils together. Swelling and disintegration is not observed in non-polar liquids. The hydrogen bonding which holds microcrystalline cellulose compacts together contributes to the appearance and effectiveness of a film coating regardless of whether it is applied from an aqueous or organic system. Free hydroxyl groups are present on the surface of the core tablet, which provide excellent binding sites for cellulosic films. Film adhesion and tensile strength are increased

while blistering, wrinkling and flaking of the film 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 of microcrystalline cellulose therein. This water acts as an internal lubricant and increases the ease with which the individual microcrystals 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. For example, PH-101, PH-102, and PH-200 (see below for descriptive details) have about the same neat compressibility even though their average particle size varies from 50 to 180 microns while PH-301 (50 microns) and PH-302 (90 microns) are more dense and less compressible or compactable.

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 comparison of physical properties of Avicel PH products. Figures 311 are scanning electron micrographs (SEMs) of all the products taken at the same magnification. These SEMs visually show differences in particle size as well as other morphological characteristics. The products first introduced were PH-101, PH-102, PH-103, and PH-105. As discussed above, these products and those that followed were designed as direct compression tablet excipients. The reader is referred to Section 2 for a description of direct compression as a process. This remains the major application for these products but other applications have been evaluated such as uses in capsule filling, wet granulation formulation, and extrusion-spheronization technology. The latter two applications are 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 and spheronization; also used in capsule filling processes, especially those employing tamping or other means of consolidation as part of the process.

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%); used where moisture sensitive pharmaceutical active ingredients are present.

Figure 6: PH-105 Smallest particle size; most compressible of the PH products; useful in direct compression of coarse, granular, or crystalline materials; can be mixed with PH-101 or PH-102 to achieve specific flow and compression characteristics; has applications in roller compaction; 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.

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 increased flowability, greater tablet weight uniformity, the potential for making smaller tablets, and improved mixability; useful as a capsule filling excipient.

Figure 11: PH-302 Same particle size as PH-102 but more dense providing increased flowability, greater tablet weight uniformity, the potential for making smaller tablets, and improved 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 neat microcrystalline cellulose with water, followed by drying and tablet compression, results in tablets of lower hardnesses than are obtained by compression of neat microcrystalline cellulose without prior treatment. This procedure would be expected to not only reduce the density of the particle agglomerates themselves thereby decreasing their internal surface area, but also would cause some adhesion between particle agglomerates, reducing external surface area as well. Both actions will result in less particle interlocking and hydrogen bonding. The use of microcrystalline cellulose (Avicel PH-101 or PH-102) in wet granulation formulations, where a typical wet granulation binder is present, and in which the microcrystalline cellulose is 5-20% of the portion of the formulation being granulated, has been found to offer the following functionalities. Wet granulation, as a process, is described in Section 2. Rapid, Even Wicking Action The property of microcrystalline cellulose to rapidly adsorb water also allows it to rapidly draw aqueous binder solutions (or water) into powder mixtures being granulated. This permits a faster addition both in time of fluid addition as well as wet massing time. Controls Wet Mass Consistency When microcrystalline cellulose is used in a product being granulated, there is far less chance of the granulation turning into an unworkable, doughy mass than when it is not 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 wet mass and the decreased sensitivity to water content, wet screening, which can introduce shear and localized overwetting causing screen blockage, is fast and trouble free. Uniform, Rapid Drying Even though microcrystalline cellulose allows for the rapid addition of granulating fluid, the water does not become bound water but is easily given up during the drying process, allowing for the more efficient use of drying equipment. This property aids in preventing case hardening and in the production of a dried granulation having a uniform moisture content with fewer fines. Controls Color Mottling and Drug Content Uniformity Without microcrystalline cellulose, dyes and lakes can be observed to migrate to the surface of dried granules. This migration can also be demonstrated in the case of watersoluble active ingredients. Occasionally, some materials used as fillers in the granulation are the cause of mottling because they are of a slightly different whiteness than other formulation ingredients and migrate to granule surfaces. The exact mechanism by which microcrystalline cellulose prevents migration 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

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as noted above. Having a uniform distribution within the dried granule will result in tablets, after dry milling of the granules, final mixing and compression that are uniform in surface appearance and drug content. The possibility of losing large amounts of active ingredient to the dust collection system in the fines which are generated during the milling process as the granules first break, is virtually eliminated, since the active ingredient is uniformly distributed throughout the granule and not concentrated on the surface. This source of possible analytical deviation from theoretical values is no longer a concern. Acts as an Auxiliary Binder Tablets compressed from granulations containing microcrystalline cellulose are harder (at equal compression forces) and less friable than those compressed from granulations without microcrystalline

cellulose depending on the amount of microcrystalline cellulose present and whether or not the material being granulated is largely soluble or insoluble. The effect is more pronounced in the case of insoluble materials. This is not to say that microcrystalline cellulose can be used as a replacement for a 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 direct compression (hard tablets at low compression pressures, low friability, disintegrant enhancer, anti-adherent, lubricant enhancer, etc.). Microcrystalline cellulose often is thought of as a one-dimensional excipient, but as evidenced from the above discussion and the one that follows it has multiple functionalities.

Avicel PH Microcrystalline Cellulose as a Spheronizing Agent


The extrusion-spheronization process is described in Section 2. As noted, the mass to be extruded must be cohesive, yet deformable enough to flow through the die without sticking and able to retain its shape after extrusion. It must be plastic so that it can be rolled into spheres in the spheronizer but non-cohesive so that each sphere remains discrete. To accomplish this, an extrusion-spheronization aid is necessary. Such substances confer not only the required plasticity of the mass but add the binding properties that are necessary for pellet strength and integrity. During spheronization, extrudates that are rigid but lacking in plasticity, form dumbbell shaped pellets and/or a high percentage of fines relative to spherical pellets. Extrudates that are plastic, but without rigidity, tend to agglomerate into very large spherical balls.
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Microcrystalline cellulose has been studied extensively as an extrusion-spheronization aid. Avicel PH-101 has come to be regarded as an essential formulation component for successful extrusion-spheronization. It is thought that it acts as a molecular sponge for the water added to the formulation, altering the rheological properties of the wet mass. It has also been proposed that microcrystalline cellulose adds to the tensile strength of the wet mass through autoadhesion (the interdiffusion of free cellulose polymer chains). It is autoadhesion that makes pellets composed of neat microcrystalline cellulose that have been extruded and spheronized, hard, non-compressible and non-disintegrating. When mixtures of drug and microcrystalline cellulose are extruded and spheronized, the microcrystalline cellulose acts as a matrix from which the drug

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

Editors 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

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Bibliography/Publications
The references presented herein are not intended to be all-inclusive for microcrystalline cellulose. They are intended to provide a useful list of references for the reader who wishes to learn more or to study in greater detail the properties and applications of Avicel PH Microcrystalline Cellulose. In some cases, references have been included that are not specific to the use of microcrystalline cellulose in tablets so that the reader might supplement his/her understanding of the applications of this material. For copies of these publications, please contact your local library or information 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 Pharmaceutical Association, Miami Beach, Florida, May 13, 1963. 3. Beal, H.M., Shah, S., Varsano, J., Pharmaceutical Applications of Microcrystalline Cellulose I: Tableting, University of Connecticut, unpublished research report, 1963. 4. Battista, O.A., Manufacture of Pharmaceutical Preparations Containing Cellulose Aggregates, U.S. Patent 3,146,168, 1964. 5. Battista, O.A., Manufacture of Cosmetic Preparations Containing Cellulose Crystallite Aggregates, 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 of Maryland, 1964. 8. Beal, H.M, Application of Microcrystalline Cellulose in Pharmaceuticals III: In Vivo Release of Active Ingredients from Tablet Granulations, University of Connecticut, unpublished research report, 1964. 9. Fox, C.D., Richman, M.D., Shangraw, R.F., Preparation and stability of glyceryl trinitrate sublingual tablets prepared by direct compression, Journal of Pharmaceutical Sciences, 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 moisture sorption and the stability of aspirin and ascorbic acid in tablet matrices, Journal of Pharmaceutical Sciences, Vol. 54 (8), p. 1153, 1965. 12. Morris, R.M., Investigation of a New Auxiliary Agent for Use in Direct Compression Formulas in Tableting, Ph.D. Thesis, University of North Carolina, 1965. 13. Novel Vitamin Containing Compositions, Hoffman-LaRoche and Co., British Patent 1,077,439, 1966. 14. Cohn, R., Nessel, R., Reier, G.E., An Evaluation of Direct Compression Excipients, presented to American

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Pharmaceutical Association, Dallas, Texas, April 1966. 15. Augsburger, L.L., Shangraw, R.F., Effect of 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 Microcrystalline Cellulose Tableting Applications, unpublished report, May 9, 1966. 18. Shangraw, R.F., The Direct Compression of Ascorbic Acid-Avicel Blends, unpublished report, University of Maryland, 1966. 19. Hynniman, C.E., Manudhane, K.S., Shangraw, R.F., Direct Compression of Ascorbic Acid, unpublished report, University of Maryland, 1966. 20. Sisson, W.A., Avicel Microcrystalline Cellulose, Its Production, Properties and Applications, 1966. 21. Shah, M.A., Some effects of humidity and heat on the tableting properties of microcrystalline cellulose formulations I, Journal of Pharmaceutical Sciences, Vol. 57, (1), p. 181, 1968. 22. Enezian, G.M., Direct compression of tablets using microcrystalline cellulose, Prod. Et Prob. Pharm., Vol. 23 (4), p. 185, 1968. 23. Belfort, A.M., Microcrystalline CelluloseProperties and Functions in Pharmaceutical 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 of ascorbic acid, Pharmaceutical Acta Helvetiae, Vol. 43 (257), 1968. 26. Mauro, T., Direct Compression as Viewed from Avicel, unpublished report, Asahi Chemical Industry Co. Ltd., February 15, 1968. 27. Maly, J., Chalabla, M., Heliova, M., The effect of powdered celluloses on the strength and disintegration of compressed tablets, Acta Facultatis Pharm., Vol. 16, p. 113, 1968. 28. Hu, V.K., Evaluation of New Agents for Direct Compression Formulation of Tablets, Masters Thesis, Philadelphia College of Pharmacy and Science, 1969. 29. Fukuoka, E., Nagai, T., Nogami, H., Sonobe, T., Disintegration of aspirin tablets containing potato starch and microcrystalline cellulose, 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 of Drugs of Low Water Solubility from Tablets Prepared by Wet Granulation and Direct Compression, presented to American

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Pharmaceutical Association, Washington, D.C., April 1970. 33. Huttenrauch, R., Jacob, J., Significance of pressing powder for preparation of microcrystalline cellulose, Pharmazie, Vol. 25, p. 630, 1970. 34. Shangraw, R.F., Application of Powder Technology in Capsules, presented at the Fifth Annual Educational Conference for Industrial Pharmacists, January 1970. 35. Kalschik, W., Schepky, G., New Tablets, Cores and Coated Tablets and the Method of Their Production, German Patent 1,811,809, 1970. 36. Cotty, J., Metral-Biollay, J.P., The importance of microcrystalline cellulose as an adjuvant in the production of dragees, Labo-Pharma.-Problems et Technicques, Vol. 194 (12), p. 42, 1970. 37. Cohn, R., Hill, J.A., Microcrystalline Cellulose as a Matrix, Canadian Patent 834,720, 1970. 38. Dunleavy, J.E., Fat-Soluble VitaminActive Oil Containing Microcrystalline Cellulose Product, Canadian Patent 831,908, 1970. 39. Kedvessey, G., Sumegi, G., Investigations on the effects of some auxiliaries 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 Pharmaceutical Sciences, Vol. 5, (3), p. 61, 1970. 41. Chopra, R.K., An Evaluation of Experimental Materials as Directly

Compressible Vehicles in Pharmaceutical Tableting, Masters Thesis, Columbia University, 1970. 42. Cole, E.T., Hersey, J.A., Rees, J., The effect of rate of loading on the strength of tablets, Journal of Pharm. Pharmacol., Vol. 22, Suppl. 645, 1970. 43. Ogura, K., Sobue, H., Changes in morphology with milling of commercial microcrystalline cellulose, J. Appl. Polymer Science, 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 compression effects 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 the adhesive process in the film coating of tablets, Canadian Journal of Pharmaceutical 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 capping 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 adjuvants 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 containing additives of some cellulose types without granulation, Acta Fac. Pharm. Univ. Comeniana, Vol. 20, p. 125, 1971. 51. Sangekar, S.A., Sarlie, M., Sheth, P.R., Effect of moisture on physical characteristics of tablets prepared from direct compression excipients, Journal of Pharmaceutical Sciences, Vol. 61, (6), p. 939, 1972. 52. Jalal, I.M., Malinowski, H.J., Smith, W.E., Tablet granulations composed of sphericalshaped particles, Journal of Pharmaceutical Sciences, Vol. 61, (9), p. 1466, 1972. 53. Enezian, E.M., Direct compression of tablets 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 microcrystalline celluloses, Journal of Pharm Pharmacol., Vol. 24, Suppl. 138P, 1972. 56. Kahn, K.A., Rhodes, C.T., The production of tablets by direct compression, Canadian Journal of Pharmaceutical Sciences, Vol. 8, (1), p. 1, 1973. 57. Freida, M.A., Delonca, M.H., Joackim, M.J., Munerat, M.J., Binding activity of

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