Note: Descriptions are shown in the official language in which they were submitted.
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DIRECTLY COMPRESSIBLE ACETAMINOPHEN
GRANULATION
Background of the Invention
This invention relates to the preparation of
tablets comprising acetaminophen. In general, there are
four principle methods widely used in the United States
for tablet manufacture. The four methods are:
- Direct Compression - In this method, all re-
quired tableting aids are incorporated in a
free flowing granulation as supplied by the bulk
- analgesic manufacturer. The granulation re-
quires no pre-processing, or blending with
additional aids, and is charged directly to a
tableting press. This method is used extensively
in the manufacture of generic aspirin tablets.
- Dry Powder Blend - In this method all required
tableting aids are blended with crystal grade
acetaminophen or aspirin. The blend is then
charged directly to a tableting press. Gelatin
or polyvinylpyrrolidone coated acetaminophen
powder is sometimes used in place of crystal
grade acetaminophen.
- Pre-Compressed Dry Powder Blend - In this method
the dry powder blend containing all required
tableting aids -is pre-compressed either by roll
compaction or slugging. Roll compaction is the
most popular method of preparing granulated
~$
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aspirin. A homogenous blend of aspirin and
starch is roll compacted, milled, sifted and
drummed. The granulated product is charged
directly to a tableting press.
- Wet Granulation - This is the most popular
method of granulating acetaminophen. In this
method acetaminophen crystal or powder is
blended with intragranular excipients, then
wetted to a moist powder consistency with an
aqueous binder solution. In some cases the
powder is wetted to a dough consistency and
forced through a 10-14 mesh screen. The wetted
mass is then dried by conventional means,
milled, sifted, and blended with extragranular
excipients and lubricant. This mixture is
then fed to a tableting press.
Acetaminophen is not ordinarily amenable
to tableting by the same methods as aspirin. These
materials have significantly different properties.
Thus, crystalline aspirin is easily tableted, since
the crystals are quite soft and exhibit good plasticity/
elasticity when compacted to tablets. Further, cohesive/
adhesive bonding within the aspirin tablet is strong
and the aspirin, itself, provides good lubricity to the
formula. Accordingly, no lubricant is necessary in the
formula used for aspirin tableting. In contrast,
acetaminophen crystals are very hard and brittle and
fracture very easily. The crystals have essentially
no plasticity/elasticity and can be tableted by the
normal aspirin tableting methods only by using high
levels of excipients and large crystalline grade acet-
aminophen~ Furthermore, at least 25% or more excip-
ients are required in addition to high levels of lubri-
cant. The large acetaminophen crystals have the dis-
advantage of being slowly dissolved in the body and
require additional tableting aids to increase the rate
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of dissolution.
Accordingly, acetaminophen has been prefer-
ably tableted using the wet granulation method since
the direct compression method, the dry powder blending
method and the pre-compression method have not been
shown to be amenable in acetaminophen tableting for
the reasons noted above.
The direct compression method of preparing
tablets would be the method of choice for preparing
acetaminophen tablets if a formulation comprising
acetaminophen could be prepared which would allow the
use of such method. Accordingly, there is a need for
an acetaminophen formulation containing all required
tableting aids which may be used in direct compression
tableting.
Summary of the Invention
It is an object of this invention to provide
a formulation comprising acetaminophen which is directly
compressible to tablets.
It is a further object of this invention to
provide an acetaminophen tablet which is prepared by
a direct compression method.
The above objects of this invention are
achieved by the process and formulation of the present
invention, whereby an acetaminophen formulation having
a low excipient level is provided which thereby allows
economics in manufacture, because of the high cost of
excipients, and the ability to prepare a smaller
tablet having the same dosage of acetaminophen as
larger tablets prepared by other methods. Further,the
costly and tedious process of wet granulating is elim-
inated.
Although direct compression aspirin granula-
tion is extensively used to prepare aspirin tablets, a
similar formula and granulating process are not directly
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convertible to granulating acetaminophen because of the
difference in characteristics between aspirin and acet-
aminophen. The present invention describes a formula
and process which affords manufacture of direct com-
pression acetaminophen granulation having similar excip-
ient level and tableting characteristics as direct
compression aspirin granulation. Excellent quality
acetaminophen tablets having a high concentration of
acetaminophen are attained by the direct compression
method. Further, the granulation and tablets afforded
by this invention are stable and non-pinking. The
granulation is tabletable at a wide range of pressures
providing tablets having remarkably rapid disintegra-
tion and dissolution features.
The uniqueness of the acetaminophen granula-
tions of the present invention is due to the following
considerations: (1) all excipients are incorporated
in the granulation. No further addition of excipients
is necessary for tableting. (2) the granulation
2~ contains a high, i.e. 80-90 wt. ~, concentrat~.on of
active analgesic agent, i.e. acetaminophen and (3) the
granulation requires no pre-processing prior to tableting.
In general, the method of preparing the acet-
aminophen granulation of the invention comprises
charging acetaminophen powder and other ingredients
to be used in the tablet to a fluidizer, fluidizing
the mixture with warm air while spraying the mixture
with an aqueous starch slurry, drying the mixture,
adding lubricant and mixing the ingredients to uniformity.
Preferred Embodiments
of the Invention
In accordance with the present invention, it
has been found that an acetaminophen formulation con-
taining ground cross-linked sodium carboxymethylcellulose
(NaCMC) fiber allows tableting of the acetaminophen
formulation by the direct compression method, a method
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which has heretofore been unavailable for the tablet-
ing of acetaminophen formulations. The formulation
comprising acetaminophen and ground NaCMC fiber pro-
vides superior quality tablets with respect to fri-
ability, dissolution, disintegration and tablet
aesthetics.
Typically, prior acetaminophen granulations
used for preparing tablets by the wet granulation
method contained approximately 25-40% excipients.
Commonly used excipients include binders such as
gelatin, polyvinylpyrrolidone, and gelatinized starch,
disintegrants such as corn starch and microcrystalline
cellulose, glidants such as silica, talc, and corn
- starch, and lubricants such as stearic acid and
stearate salts, e.g. magnesium stearate.
In contrast to the prior methods of tableting
acetaminophen granulations, the process and granula-
tion of the present invention allows the preparation
of acetaminophen tablets containing 80-90% acetaminophen.
The unique qualities of the granulation
of the present invention are attributable to the use of
ground NaCMC fiber during the fluidized bed granulation,
thereby allowing the higher percentages of acetaminophen
in the granulation and still achieving high quality
tablets.
In general, the granulations of the present
invention comprise from about 80 to about 90% by weight
acetaminophen, from about 0.1 to about 5.0% by weight
ground NaCMC fiber, from about 1.0 to about 15.0% by
weight pregelatinized starch, from about 0.1 to about
2.0% by weight lubricant, e.g. stearic acid or magnesium
stearate. Alternative or additional excipients may
include a binder, e.g. purified wood fiber; a disinte-
grant, e.g. sodium starch glycolate; an antioxidant,
e.g. sodium metabisulfite; a preservative, e.g. propyl-
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paraben; a surfactant, e.g. alkali metal salts of high
molecular weight alkyl sulfates or sulfonates and
similar materials of like nature.
A typical preferred formula useful for gran-
ulation in accordance with the present invention, itsmethod of preparation and the properties of the tablets
obtained thereby as compared to commercial tablets
are set forth in the following example and Table 1.
Example
The following formula is utilized in this
example:
Table 1
Ingredient Weight %
Milled Acetaminophen 90.0
Ground NaCMC Fi~er 3.50
Pregelatinized Starch 6.00
Stearic Acid 0-50
The above formulation is granulated in a
fluidized bed granulator. The granulating conditions
utilizing the formula are as follows:
6300 grams of milled acetaminophen and 245
grams ground NaCMC fiber are charged to the granulator
and fluidized for about 2 to 5 minutes in order to
homogenize the ingredients. A dispersion is then pre-
pared utilizing 420 grams pregelationized starch in5,580 grams water via vigorous agitation. While mixing,
the suspension is warmed to about 85C. to effect
gelling. The mixture is cooled and maintained at 60-70C.
Agitation is maintained to avoid film formation on the
surface. Just prior to use, 1.6 grams sodium meta-
bisulfite dissolved in 50 ml water is introduced and
mixed into the starch suspension. The dispersion is
atomized onto the fluidized acetaminophen/ground NaCMC
fiber over a period of 30-90 minutes under typical
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granulating conditions of air flow rate, temperature
and spray nozzle parameters. When binder addition is
completed, the batch is dried by continued fluidization
with warmair to a moisture level of 0.7 to 1.5%.
Magnesium stearate or stearic acid is added and blended
into the product by fluidization for 1 to 5 minutes
with ambient temperature air.
Although a 10% excipient level is shown in
the above example, excipient levels of up to 20~ and
even higher, e.g. 25-40~, can be selected so long as
ground NaCMC fiber is present in a range of about 0.1
to about 5.0% by weight. Other tableting aids and con-
centrations thereof besides those listed in thq example
can also be selected. Other acceptable binder solutions
lS which can be used are solutions of gelatin, polyvinyl-
pyrrolidone, polyethylene glycol or mixtures thereof
separately or admixed with gelatinous starch or other
binders.
