Avicel® PH Microcrystalline Cellulose, NF, Ph

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
Editor’s Note.........................................................................................................................................14
Bibliography/Publications ....................................................................................................................15
1
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.
obtained, the particle size distribution and
moisture content of which can be varied
through the spray drying process.
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
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.
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.
2
Figure 1: The Avicel Manufacturing Process
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.
Dicer
Pulp
Reactor
PH
RC/CL
Filter
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.
Na CMC
Mix
Tank
Mixer
Spray
Dryer
Drying and
Subsequent
Processing
Storage
and
Packaging
Storage
and
Packaging
3
Figure 2: Cellulosic Products
Pulp
␣ Cellulose
Chemical
Derivatization
Mechanical
Disintegration
Chemical
Depolymerization
Wet Mechanical
Disintegration
Soluble
Cellulose Derivative
Fibrous
Cellulose Floc
Drying
Dispersing
Agent
+ Water
Hydrocolloid
Solution
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 today’s market are
improved in these respects over the original
product offerings.
4
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.
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.
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.
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, 20–25% microcrystalline cellulose
When compressed, microcrystalline cellulose
undergoes plastic deformation. Slip planes,
5
will carry most direct compression formulations, although there have been individual
applications where less (≈10%) was sufficient or more (≈50%) was necessary.
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.
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.
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.
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
6
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 3–11 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.
lowed 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.
The products first introduced were PH-101,
PH-102, PH-103, and PH-105. As discussed
above, these products and those that fol-
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.
7
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.
8
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.
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 weight
variation and to improve content uniformity in direct compression formulations and (as a
final mix additive) in wet granulation formulations.
10
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.
11
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.
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.
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.
Controls Color Mottling and Drug Content
Uniformity
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.
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
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
12
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.
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.
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.
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
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.
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
13
can slowly dissolve. Coating the pellets,
or by using other ingredients in the pellet
formulation, or both, can further control
drug release.
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
14
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.
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.
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.
10. Woods, L.C., “Microcrystalline cellulose,”
American Perfumer and Cosmetics, Vol. 80,
(4), p. 51, 1965.
2. Beal, H.M., Shah, S., Varsano, J.
“Tableting with Microcrystalline Cellulose,”
presented to the American Pharmaceutical
Association, Miami Beach, Florida, May 13,
1963.
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.
3. Beal, H.M., Shah, S., Varsano, J.,
“Pharmaceutical Applications of
Microcrystalline Cellulose I: Tableting,”
University of Connecticut, unpublished
research report, 1963.
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.
4. Battista, O.A., “Manufacture of
Pharmaceutical Preparations Containing
Cellulose Aggregates,” U.S. Patent
3,146,168, 1964.
13. “Novel Vitamin Containing
Compositions,” Hoffman-LaRoche and Co.,
British Patent 1,077,439, 1966.
5. Battista, O.A., “Manufacture of Cosmetic
Preparations Containing Cellulose Crystallite
Aggregates,” U.S. Patent 3,146,170, 1964.
14. Cohn, R., Nessel, R., Reier, G.E.,
“An Evaluation of Direct Compression
Excipients”, presented to American
6. Vora, K.M., “Availability of a Water
15
Pharmaceutical Association, Dallas, Texas,
April 1966.
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.
15. Augsburger, L.L., Shangraw, R.F., “Effect
of Glidants in Tableting”, Vol. 55, (4), p. 418,
1966.
25. Hynniman, C.E., Manudhane, K.S.,
Shangraw, R.F., “Direct compression of
ascorbic acid,” Pharmaceutical Acta
Helvetiae, Vol. 43 (257), 1968.
16. Reier, G.E., Shangraw, R.F.,
“Microcrystalline cellulose in tableting,”
Journal of Pharmaceutical Sciences,
Vol. 55 (5), p. 510, 1966.
26. Mauro, T., “Direct Compression as
Viewed from Avicel,” unpublished report,
Asahi Chemical Industry Co. Ltd., February
15, 1968.
17. Sisson, W.A., “Avicel Microcrystalline
Cellulose Tableting Applications,”
unpublished report, May 9, 1966.
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.
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.
28. Hu, V.K., “Evaluation of New Agents for
Direct Compression Formulation of Tablets,”
Masters Thesis, Philadelphia College of
Pharmacy and Science, 1969.
20. Sisson, W.A., “Avicel Microcrystalline
Cellulose, Its Production, Properties and
Applications,” 1966.
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.
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.
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.
22. Enezian, G.M., “Direct compression of
tablets using microcrystalline cellulose,”
Prod. Et Prob. Pharm., Vol. 23 (4), p. 185,
1968.
31. Livingstone, J.L., “Compressed tablets”,
Manufacturing Chemist and Aerosol News,
p. 23, March 1970.
23. Belfort, A.M., “Microcrystalline
Cellulose—Properties and Functions in
Pharmaceutical Preparations,” presented
at the University of Ghent, Belgium,
March 1968.
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
16
Pharmaceutical Association, Washington,
D.C., April 1970.
Compressible Vehicles in Pharmaceutical
Tableting,” Masters Thesis, Columbia
University, 1970.
33. Huttenrauch, R., Jacob, J., “Significance
of pressing powder for preparation of microcrystalline cellulose,” Pharmazie, Vol. 25,
p. 630, 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.
34. Shangraw, R.F., “Application of Powder
Technology in Capsules,” presented at the
Fifth Annual Educational Conference for
Industrial Pharmacists, January 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.
35. Kalschik, W., Schepky, G., “New Tablets,
Cores and Coated Tablets and the Method
of Their Production,” German Patent
1,811,809, 1970.
44. Maly, J., Chalabal, M. Heliova, M.
“Microcrystalline celluloses and their use
in tableting,” Arch. Pharm., Vol. 308, p. 114,
1970.
36. Cotty, J., Metral-Biollay, J.P., “The
importance of microcrystalline cellulose as
an adjuvant in the production of dragees,”
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18
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19
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21
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23
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24
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