Note: Descriptions are shown in the official language in which they were submitted.
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Hydrolyzed Cellulose Granuiations for Phamiaceuticals
The present invention relates to a method for granulation of active
pharmaceutical compounds, to granular formulations thereof, and to
pharmaceutical tablets made from such granular formulations. More
specifically the invention relates to spray-drying an aqueous slurry of
hydrolyzed cellulose and one or more pharmaceutical actives to fom~
granular formulations for use in the manufacture of pharmaceutical tablets.
The methods and compositions of this invention are particularly useful for
pharmaceutical actives which are not readily compressible into tablets
following dry blending of excipients and pharmaceutical active, such as
ibuprofen and acetaminophen.
Neither ibuprofen nor acetaminophen is readily compressible into
satisfactory tablets from a dry mix of excipients heretofore used in the art.
To accomplish compression of such difficult-to-process pharmaceuticals into
acceptable tablets, several techniques have been used, with varying
degrees of success. As indicated above it is conventional to dry blend the
active with various tabieting additives, including microcrystalline cellulose,
and to then compress the resulting blend into tablets. The resulting tablets
tend to be friable and difficult to process commercially due primarily to
insufficient tablet hardness. In an effort to circumvent these problems, it
has been necessary to resort to more complex granulation techniques such
as spray drying. For example, U.S.. Patent 4,904,477 discloses spray drying
ibuprofen from a slurry containing pregelatinized starch, a disintegrant and a
wetting agent. Another example is U.S. Patent 4,710,519, which discloses a
process for spray drying a slurry of acetaminophen and a binder, in which
the binder may be, among other things, microcrystalline cellulose or a
mixture of microcrystalline cellulose and hydroxypropyimethylcellulose.
Thus, prior art efforts have focused on the use of microcrystallne cellulose
as a granulation 'aid. In addition, U.S. Patent 4,744,498 discloses spray
drying a slurry containing finely divided calcium carbonate and either
microcrystalline cellulose or the precursor wet cake from which
microcrystalline cellulose is formed. The resulting product is employed as
an excipient in vitamin or other pharmaceutical formulations using
conventional dry blending techniques.
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In accordance with the present invention, there is provided a method
for granulating pharmaceutical actives which comprises spray-drying an
aqueous slurry of hydrolyzed cellulose and a pharmaceutical active. The
method produces a relatively porous, substantially spherical, free flowing
granular formulation which may be readily compressed into pharmaceutical
tablets having improved hardness, decreased friability, and excellent
dissolution characteristics. In another aspect, the invention provides a
granular composition comprising dry particles of pharmaceutical active and
hydrolyzed cellulose in which the hydrolyzed cellulose is firmly bonded to
and substantially envelops the particles of pharmaceutically active material.
tn yet another aspect, the invention provides pharmaceutical tablets
manufactured by compression of the granular composition of this invention.
In the process aspect of this invention, an aqueous slurry of
hydrolyzed cellulose is employed, which is in large measure responsible for
the improved properties the granular formulations of this invention and for
the improved tablets made therefrom. In this aspect, the invention thus
provides a process for preparing a granular composition for preparation of
tableted pharmaceutical dosage forms comprising the steps of (a) intimately
mixing the pharmaceutical active particles with a smooth uniform aqueous
slurry of hydrolyzed cellulose to form a smooth uniform aqueous slurry
consisting essentially of hydrolyzed cellulose and pharmaceutical active; and
(b) spray-drying the resulting slurry at a temperature below the charring
temperature of the hydrolyzed cellulose and the melting point of the
pharmaceutical active, as measured by the temperature of the exhaust from
the spray dryer. The advantages and benefits of this invention are most
readily achieved when the conditions for spray-drying are selected to
produce spray-dried particles which are relatively porous and substantially
spherical, in which 90 percent of the granules are larger than about 50
microns and smaller than about 500 microns and median granule size is in
the range of about 150 to 300 microns. It is a further advantage of the
present invention to include in the slurry additional granulation and
tableting
additives, such as binders, fillers, disintegrants, flow aids, antiadherents,
and/or surfactants, so that the resulting granules can be directly compressed
into tablets with addition of nothing more than a lubricant.
As used in this specification and claims, the term hydrolyzed cellulose
means a cellulosic material prepared by acid hydrolysis of cellulose.
CA 02252394 2005-02-18
3
Although there are different ways of effecting this hydrolysis, a typical
method for preparing hydrolyzed cellulose comprises the treatment of
original cellulosic material, for example a wood-derived pulp, with an
inorganic acid such as 2.5 N hydrochloric acid solution for 15 minutes at the
boiling temperature. This treatment has the effect of reducing the degree of
polymerization (DP) to a relatively constant level. A DP of 125 means that
the chain of cellulose is composed of 125 anhydroglucose units. Higher DP
values represent longer chain lengths of cellulose, and lower values
represent shorter chain lengths. The hydrolyzed cellulose in the slurries
utilized herein should have a minimum of 85% of the material with a DP of
not less than 50 nor more than 550. More preferably, 90% of this material
should have an actual DP within the range of 75 to 500. Even more
preferably, 95% of the material should have a DP of 75 to 450. The level-off
average DP, that is, the average DP of the total hydrolyzed cellulose
sample which is consistently approached for a particular type of pulp, should
be in the range of 125 to 374, preferably in the range of 200 to 300. The
source of the pulp being hydrolyzed results in variations of the level-off DP.
Hydrolyzed cellulose as used in this invention is a known composition more
fully described as level-off DP in U.S. patents 2,978,446 and 3,111,513.
The hydrolysis step described above effectively destroys non-
cellulosic components of the starting material as well as the fibrous,
amorphous structure of the cellulose, leaving the crystallite material that is
described above. Heretofore, the usual practice has been to dry this
material after it has been washed with water to remove the acid and all
soluble residues from the hydrolysis. A common method of drying is spray
drying, the method in general use for the preparation of microcrystalline
cellulose. It has been found that spray drying the crystallites prior to
granulation and incorporation into tablets results in making the cellulose
particles more dense, difficult to compress into tablets, and producing
tablets which are highly variable, tend to be friable, and lack sufficient
hardness for convenient processing.
Unexpectedly, the use of the crystallites that have not been
previously dried, namely hydrolyzed cellulose, results in improved
compressibility of the granular composition when it is spray dried. It is the
spray drying of slurries of hydrolyzed cellulose in combination with active
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y
pharmaceutical ingredients, and, optionally, a surfactant, a disintegrant, and
a flow aid, that is the essence of the invention and provides the benefits
described herein.
The process to prepare the granufations of this invention begins with
a slurry of hydrolyzed cellulose in water. The term slurry as used herein is
intended to mean an aqueous suspension of hydrolyzed cellulose particles
which have not previously been dried through application of heat or other
evaporative means. It is, however, intended to include a slurry of hydrolyzed
cellulose from which a significant portion of the water has been removed by
mechanical means such as filtration. The water content may be reduced
from about 90% to 55-65% to produce a suitable dewatered starting material
for use in the present invention. Reconstitution for use in this process is
accomplished by the simple addition of water to the material, followed by
thorough mixing. Preferably, the slurry used as a starting material in the
process will contain 15% to about 25% by weight solids.
The active pharmaceutical agent is then added to this hydrolyzed
cellulose slurry, and the resulting slurry is mixed thoroughly. The ratio of
pharmaceutical active to cellulosic solids in the slurry is directly
proportional
to the ratio and levels of these components desired in the finished granular
formulation and ultimately in the tableted pharmaceutical product. As
indicated below this may vary over a wide range in that the finished granule
may contain from about 1 to 97% of pharmaceutical active and from about 3
to 99% cellulosic solids, the balance, if any, being conventional granulation
and tableting additives, such as binders, fillers, disintegrants, flow aids,
antiadherents, and/or surfactants.
Finally, sufficient water is added, if necessary, to provide a slurry
having the maximum amount of solids that will permit this slurry to be
pumped to a spray dryer. Maximizing the solids content minimizes the
energy required for granulation and also has a beneficial effect on particle
size and size distribution of the resulting granules. It is also advantageous
to homogenize the slurry to provide a smooth homogeneous suspension
prior to delivering the slurry to the spray dryer.
In general the slurry may comprise about 10-75% by weight of total
solids, including pharmaceutical actives and any additives. It will be
understood by those skilled in spray-drying that the viscosity of the slurry
is
dependent on the percentage of solids in the slurry to be spray dried and
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that the viscosity may directly depend, at least in part, on the nature and
amount (drug loading) of the pharmaceutical active. For example,
ibuprofen, which is essentially insoluble in water, when combined with the
hydrolyzed cellulose slurry, forms a viscous slurry and requires that the
solids in the slurry, including the pharmaceutical active, not exceed about
35% by weight.
An advantageous range of solids for ibuprofen is about 15-35%,
preferably about 20-35%, most preferably about 28-33%. Acetaminophen
and pseudoephedrine hydrochloride, on the other hand, are respectively
70 sparingly and freely soluble in water, allowing the slurry to contain up to
about 55% by weight solids, counting both the acetaminophen and
pseudoephedrine hydrochloride as solids. An advantageous range of solids
for these actives is about 35-55%, preferably 40-50%, most preferably about
43-47%.
As will also be understood by those skilled in the art, the specific type
of dryer employed is not critical to the success of this invention. Drying may
be done, for .example, with a disk dryer or a tower dryer. If a disk dryer is
utilized, a large diameter dryer is preferred, since smaller spray dryers have
a tendency to produce smaller denser granules which are useful, but are not
preferred. A preferred type of dryer is a tower dryer, particularly one fitted
with a high pressure nozzle which is adapted to produce the desirable
particle size distribution and flow characteristics which characterize the
granulations produced in accordance with this invention. With either type of
dryer high productivity rates are readily obtained due the ability to operate
the spray dryers in a continuous, rather than batch, manner, It will also be
appreciated that the method of atomization in the dryer is important and may
affect the size and character of the resulting granules, regardless of which
type of dryer is utilized. In these regards, some experimentation may be
required in order to optimize the process for a particular blend of hydrolyzed
cellulose and pharmaceutical active.
In spray drying of the resulting slurry, an important aspect of the
process is the control of temperature within the spray dryer. The outlet
temperature of the dryer must be controlled carefuNy to avoid charring the
hydrolyzed cellulose and/or melting the pharmaceutical active. An outlet
temperature above about 120°C will char the cellulose, making it a
requirement that the outlet temperature not exceed this value. When drying
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low-melting actives, such as ibuprofen, the outlet temperature should be
kept below the melting point of the active ingredient. In the case of
ibuprofen, the maximum temperature should preferably be about 70°C,
whereas acetaminophen will tolerate outlet temperatures up to about
90°C.:
The dryer outlet temperature must therefore be selected for each specific
active pharmaceutical ingredient. Temperatures within the range of about
60°C to about 105°C are advantageous, and preferred temperatures
are in
the range of about 60°C to about 95°C.
The spray-dried granular product will normally contain less than 10%
by weight moisture after the spray-drying step. To obtain granular materials
having the preferred 5% moisture or the most preferred moisture content of
2.5% or lower, it may be advantageous to place a fluid bed dryer in series
with the spray dryer. Both vibratory and non-vibratory fluid bed dryers are
equally appropriate for this final drying step, which does not alter the
structure and size of the granular particles, but merely removes additional
water from them.
in accordance with the second aspect of this invention, the resulting
granular composition comprises (a) from about 1 percent to about 97
percent (preferably 5 to 95%) by weight of particles of a pharmaceutical
active and (b) from about 3 percent to 99 percent (preferably 5 to 90%) by
weight of hydrolyzed cellulose intimately bonded to and substantially
enveloping the pharmaceutical active particles. Advantageously, the
composition is one in which about 90 percent of the granules are larger than
about 50 microns and smaller than about 500 microns, and median granule
size is in the range of about 150 to 300 microns.
The spray-dried granular compositions of the invention and the
process to make them is applicable to virtually all pharmaceutical active
agents, including combinations of these, regardless of whether the active
agents are water-soluble or water-insoluble. Typical of such pharmaceutical
active agents are: analgesics such as acetaminophen, ibuprofen,
ketoprofen, indomethacin, naproxen, acetaminophen with codeine and
acetaminophen with propoxyphene napsylate; antibiotics such as
erythromycin, cephalosporins, and minocycline hydrochloride; antiepileptics
such as phensuximide, phenytoin sodium, and valproate sodium;
antihistamines such as chlorpheniramine maleate, diphenhydramine
hydrochloride, and triprolidine hydrochloride; cough and cold drugs such as
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7
dextromethorphan hydrobromide, ephedrine sulfate, guiafenesin,
phenylpropanolamine hydrochloride, promethazine hydrochloride, and
pseudoephedrine hydrochloride; cardiovascular drugs such as captopril,
chlorthiazide, hydrochlorthiazide, diltiazem, nadolol, papaverine
hydrochloride, procainamide hydrochloride, propranolol hydrochloride,
quinidine gluconate, quinidine sulfate, and nifedipine; gastrointestinal drugs
such as cimetidine, loperamide hydrochloride, ranitidine, and famotadine;
and respiratory drugs such as albuterol sulfate, aminophylline, and
theophylline.
In order to produce granulations which are directly compressible into
tablets, the granular compositions of the invention, and the slurry from which
they are formed, may also advantageously be formulated to contain minor
amounts of conventional granulation and/or tableting additives, such as
surfactants, binders, fillers, disintegrants antiadherents and/or flow aids.
Suitable surfactants include sodium lauryl sulfate, dioctyl sodium
sulfosuccinate, polyoxyethyiene sorbitan fatty acid esters, such as TWEEN~
poiysorbates, and sorbitan fatty acid esters, such as SPAN~ sorbitan esters.
Sodium lauryl sulfate has advantageously been employed in the process of
the invention. The surfactant may be present in about 0.01-1 %, preferably
0.15-0.25%, most preferably about 0.15-0.22% by weight of the composition
on a dry basis.
Suitable disintegrants include croscarmellose sodium, crospovidone,
sodium starch glycolate, guar gum, magnesium aluminum silicate,
copolymers of methacrylic acid with divinylbenzene, potassium alginate,
starch, pregelatinized starch, or mixtures of two or more of the foregoing
disintegrants. The amounts suitable for use in the invention varies widely
within a range from about 0.1% to-5%, advantageously about 0.25% to
about 3%, by weight of the composition on a dry basis. Preferred
disintegrants are croscarmeliose sodium, crospovidone, and sodium starch
glycolate or combinations of these materials.
A flow aid or flow aid with antiadherent properties, such as colloidal
silica, may also be incorporated in the method and granular composition,
suitably at a level in the range of from about 0.1- 3%, advantageously from
0.5-1 %, preferably from 0.7-0.8%.
Such conventional additives may simply be added to the slurry from
which the granular formulations of this invention are derived. However,
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8
those skilled in the art will appreciate that the order of addition and the
level
at which each of these additives is most beneficially employed in a particular
formulation may require optimization within the variables set forth above.
For example, for granulations of water insoluble or slightly soluble additives
it is usually beneficial to add a surfactant prior to addition of the active
material.
Formulations of ibuprofen and combinations of acetaminophen and
pseudoephedrine hydrochloride serve as representative active agents which
present difficult formulation problems that are quite different from each
other. It is these extremes that indicate the breadth of applicability of the
techniques describe herein to a wide variety of active agents. 1n the
paragraphs which follow, all percentages are by weight of the solid
components of the composition.
For ibuprofen compressible granular formulations of this invention,
the ibuprofen content may range from about 40-90%, preferably from 60-
70%, and most preferably from 63-67%, depending on the weight of the
tablet being produced. The combinations of acetaminophen with
pseudoephedrine hydrochloride may contain 40-90%, preferably 60-90%,
and most preferably 75-85% of the former and 2-10%, more preferably 3-
8%, and most preferably 4-5% of the latter active agent. Because of these
differences in content of active pharmaceutical ingredient, the content of
hydrolyzed cellulose varies inversely with the content of the active
ingredient. For ibuprofen, the hydrolyzed cellulose may be present in 20-
45%, more preferably 30-36%, most preferably 30-33%. On the other hand,
for tablets comprising the combination of acetaminophen and
pseudoephedrine hydrochloride, the hydrolyzed cellulose content is about 5-
50%, more preferably 10-40%, and most preferably 11-13%. For other
active pharmaceutical ingredients the range of hydrolyzed cellulose will be
about 3-99% of the solids. The percentage of the other pharmaceutical
actives may range from about 1-97%, depending on the properties of the
specific material, and the dosage of the active agent that is to be delivered,
and whether or not other additives are employed in the formulation.
The tableted compositions of this invention comprise the foregoing
granular compositions and from about 0.5% to about 3% by weight of a
compatible pharmaceutically acceptable lubricant, advantageously about
0.75 - 2%, preferably about 1-1.5% by weight of the tablets. The lubricants
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9
minimize wear and tear on the tableting machines and minimize adherence
of the material to tooling surfaces. Suitable lubricants which may be used
are stearic acid, magnesium stearate, calcium stearate, hydrogenated
vegetable oils, talc, sodium stearyl fumarate and combinations thereof.
The following examples are presented for illustration purposes and
not to limit the scope of the invention. The examples illustrate the best
mode for practicing the invention including properties of the granular
compositions, the methods by which these compositions are made, the
incorporation into the granular compositions of granulation and tableting
additives such as surfactants, disintegrants and antiadherents/flow aids, and
the use of a tower spray dryer. Two very different active pharmaceutical
ingredients are exemplified to illustrate the diverse materials which can be
successfully formulated into spray-dried compressible granuiations of this
invention. It is believed that this method is advantageous for many other
active ingredients, even though they may be able to be compressed directly
from dry powder mixes or other known techniques. The advantages which
make this desirable for easily compressed pharmaceutical actives are the
high productivity of the spray-drying process and the resulting high
productivity of tablets possessing an unusually high degree of uniformity in
properties, as is demonstrated in Examples 1-3 below for ibuprofen and
combinations of acetaminophen and pseudoephedrine hydrochloride. This
method offers the additional potential of less severe tableting conditions
which, in tum, reduce the wear on tableting machines, tools, and dies.
For comparison purposes, Example 4 corresponds directly with
Example 2, except that Example 4 is prepared from an alternative source of
cellulose, namely, microcrystalline cellulose. This material is to be
distinguished from the hydrolyzed cellulose of this invention by the fact that
it has already been spray dried and is reconstituted into the slurry. The use
of this previously spray dried material results in a granular formulation
which
is not as compressible as the hydrolyzed cellulose granulation of the
invention. This can readily be seen from the uniformly reduced hardness of
tablets prepared at equivalent compression forces in Examples 2 and 4.
In the examples all percentages are by weight unless it is indicated to
be otherwise. In these examples, the materials utilized, unless otherwise
identified are as follows: colloidal silica (Cab-O-Sil~, Cabot Corp., Cab-O-
Sil
Div., Tuscola, Illinois); croscarmellose sodium (Ac-Di-Sol~, FMC
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/D
Corporation, Philadelphia, PA); ibuprofen (Albemarle Corp., Baton Rouge,
LA); acetaminophen (Hoechst-Celanese, Bishop, TX); pseudoephedrine
hydrochloride (Ganes Chemical, Carlstadt, NJ); tower dryer made by NIRO,
Inc., Colombia, MD;
Example 1
In a 208 liter vat stirred with a Lightnin'~ mixer was placed 58.400
kilograms of an aqueous slurry of hydrolyzed cellulose (21 % solids). A
solution of 0.064 kilograms of sodium lauryl sulfate in deionized water was
prepared and added to the slurry. In sequence, 0.31 kilograms of colloidal
silica, 1.100 kilograms of croscarmellose and 26.264 kilograms of ibuprofen
were added to the vat. Sufficient deionized water was added to the vat to
bring the total amount of water added to 47.20 kilograms. This reduced the
solids in the slurry to 27.09%. After mixing the slurry for a short period of
time, the mixer was changed to a high shear mixer which was used until the
slurry was smooth and uniform. The average viscosity of 4611 centipoise at
18°C was measured using a Brookfield LVT viscometer. This slurry was
spray dried using a 5.94 meter (19.5 foot) tall tower dryer having a 2.44
meter (8 foot) width. The dryer was fitted with a high pressure nozzle having
a 2.0 mm insert in the nozzle. The slurry was fed to the dryer by a nine-
stage Moyno pump at a pressure of 6550 kPa. The outlet temperature of
the dryer was 69.5°C. In line with the outlet of the tower dryer was a
vibratory fluid bed dryer which was installed to increase the dryness of the
product. This dryer was operated at an average temperature of 68°C,
resulting in a product having 2.28% moisture content. The spray drying of
this slurry required 16 minutes. The particle size distribution as determined
by a Microtrac~ instrument showed that 90% of the particles had a size
<482.19 microns; the median particle size being 274.21 microns; and 10%
of the particles were <162.71 microns. The composition of the granules on a
dry weight basis was 65.66% ibuprofen, 30.66% hydrolyzed cellulose,
0.16% sodium lauryl sulfate, 2.75% croscamellose sodium, and 0.77%
colloidal silica.
A mixture of 990 grams of the dr -~~ granular material and 10 grams
of lubricant, (Sterotex~ K, a hydrogenatea mixture of soybean and castor
oils, Karlshamns Co., Div. of Abitec, Columbus, Ohio) was placed in a
Patterson-Kelly "V" type blender and mixed for 10 minutes. Previously the
Sterotex K had been passed through a #60 U. S. standard sieve. This
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iI
9.5 mm special concave tooling. The properties of 10 tablets as determined
by an Erweka Multi-check Tester are shown in Table 1.
Table 1
s Mean Tablet Properties
Compression Tablet Relative Tablet Relative
Force Weight Std. Hardness Std.
Deviation. Deviation
(K9) (mg) (%) (kP) (%)
to
206 308 0.5 9.4 3.2
418 309 0.4 16.7 2.1
630 310 0.6 11.4 10.2
823 311 0.5 9.6 10.3
15 1046 311 0.5 8.3 17.1
1251 311 0.6 9..1 11.3
Example 2
In a 264.8 liter Ross Double Planetary mixer was placed 45.790
2 o kilograms of an aqueous slurry of hydrolyzed cellulose (21 % solids).
Then,
0.160 kilograms of sodium lauryl sulfate was added directly to the slurry
which was subsequently diluted with some deionized water. In sequence,
0.584 kilograms of colloidal silica, 0.560.kilograms of croscarmellose
sodium, 65.168 kilograms of acetaminophen, and 3.192 kilograms of
25 pseudoephedrine hydrochloride were added to the mixer. Additional
deionized water was added to the mixer to bring the total amount of water
added to 61.603 kilograms. The resulting slurry contained 43.72% solids.
After all of the components were thoroughly mixed, the slurry was passed
through a Ross Homogenizer one time before being placed in a holding
3 o tank: At 23°C the viscosity was 1312 centipoise as measured by a
Brookfield LVT viscometer. This slurry was pumped from the holding tank to
a 5.94 meter (19.5 foot) tall tower dryer having a 2.44 meter (8 foot) width.
The dryer was fitted with a high pressure nozzle containing a 2.0 mm insert
and operated at 4482 kPa pressure. This drying operation required 28
35 minutes and yielded 36.97 kilograms of dry, granular product. The moisture
content of this granular material was 0.54%. Its particle size distribution as
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/2
measured by a Microtrac~ instrument showed that 90% of the granules were
<359.99 microns, the median particle size was 171.56 microns, and 10% of
the particles were <18.67 microns. The composition of the granules on a dry
basis was acetaminophen 81.46%, pseudoephedrine hydrochloride 4.89%;
hydrolyzed cellulose 12.02%, sodium lauryl sulfate 0.2%, croscarmellose
sodium 0.7%, and colloidal silica 0.73%.
In a Patterson-Kelly "V" type blender 990 grams of the granular
product and 10 grams of stearic acid (J. T. Baker) were blended for 5
minutes prior to preparing tablets on a Stokes B2 tablet press using 12.7
1 o mm standard round tooling. The properties of 10 tablets as determined by
an Erweka Multi-check Tester are shown in Table 2.
Table 2
MeanTablet Properties
Compression Tablet Relative Tablet Relative
Force Weight Std. Hardness Std.
Deviation Deviation
(Kg) (mg) (%) (kP) (%)
600 615 0.4 7.3 3.2
783 613 0.3 8.6 2.8
1003 616 0.5 11.4 5.8
1172 612 0.4 10.0 8.2
2 5 1384 616 0.3 12.7 12.8
1613 617 0.3 12.7 21.9
1800 612 0.3 10.6 22.2
2009 613 0.3 9.2 11.5
3 o Example 3
In a 264.8 liter Ross Double Planetary mixer was placed 87.600
kilograms of an aqueous slurry of hydrolyzed cellulose (21 % solids). Then,
0.096 kilograms of sodium fauryl sulfate was added directly to the slurry
which was subsequently diluted with some deionized water. In sequence,
3 5 0.462 kilograms of colloidal silica, 1.65 kilograms of croscarmellose
sodium,
and 39.396 kilograms of ibuprofen were added to the mixer. Additional
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~3
deionized water was added to the mixer to bring the total amount of water
added to 70.796 kilograms. The resulting slurry contained 29.8% solids.
After all of the components were thoroughly mixed, the slurry was passed
through a Ross homogenizer one time before being placed in a holding tank.
At 20°C the viscosity was 2038 centipoise as measured by a
Brookfield LVT
viscometer. This slurry was pumped from the holding tank to a 5.94 meter
(19.5 foot) tall tower dryer having a 2.44 meter (8 foot) width. The dryer was
fitted with a high pressure nozzle and 2.0 mm insert in the nozzle operated
at 3447 kPa pressure. This drying operation required approximately 4
i o hours. A vibrating fluid bed dryer was placed in series with the tower
dryer.
The moisture content of the granular material coming out of the fluid bed
dryer was 3.80%. Its particle size distribution as measured by a Microtrac~
instrument showed that 90% of the granules were <535.80 microns, the
median particle size was 298.91 microns, and 10% of the particles were
i 5 <149.38 microns. A more complete determination of the particle size
distribution was made using a Sonic Sifter for 2 minutes at an amplitude of
3. The sample had been passed through a 30 mesh screen prior to this
determination. The particle size distribution determined in this way was:
1.89% (30-50 mesh, 297-590 microns); 18.87% (50-60 mesh, 250-297
2 o microns); 32.08% (60-80 mesh, 177-250 microns); 16.98% (80-100 mesh;
149-177 microns); 7.55% (100-120 mesh, 125-149 microns); 16.98% (120-
170 mesh, 88-125 microns), and 5.66% (<170 mesh, 88 microns). The
composition of the granules on a dry basis was the same as in Example 1.
In a Patterson-Kelly "V" type blender 990 grams of the granular
2 5 product and 10 grams of Sterotex K (a hydrogenated mixture of soybean
and castor oils, sold by Karlshamns Co., Div. of Abitec, Columbus, Ohio)
were blended for 5 minutes prior to preparing tablets on a Stokes B2 tablet
press using 9.5 mm special concave round tooling. The properties of 10
tablets as determined by an Erweka Multi-check Tester are shown in Table
30 3.
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iy
Table 3
Mean Tablet Properties
Compression Tablet Relative Tablet Relative
Force Weight Std. Hardness Std.
Deviation Deviation
(K9) (mg) (%) (kP) (%)
io
209 313 1.2 7.6 5.8
399 313 0.9 14.0 2.4
598 314 0.8 9.4 7.8
827 311 1.0 8.4 8.9
1017 312 0.9 8.0 11.8
Example 4
In a 208.2 liter tank stirred with a Cowles' mixer were placed 28.848
kilograms of deionized water and 7.212 kilograms of microcrystalline
2 o cellulose (Avicel~ PH-101, FMC Corporation, Philadelphia, PA). The
microcrystalline cellulose was dispersed in the water, creating a smooth
slurry. Then, 0.120 kilograms of sodium lauryl sulfate was added directly to
the slurry which was subsequently diluted with some deionized water. In
sequence, 0.438 kilograms of colloidal silica, 0.420 kilograms of
croscarmeliose sodium, 48.876 kilograms of acetaminophen, and 2.934
kilograms of pseudoephedrine hydrochloride were added to the tank.
Additional deionized water was added to the tank to bring the total amount
of water added to 44.485 kilograms. The resulting slurry contained 44.48%
solids. After all of the components were thoroughly mixed, the slurry was
3 a placed in a holding tank. At 22°C the viscosity was 1319 centipoise
as
measured by a Brookfield LVT viscometer. This slurry was pumped from
the holding tank to a 5.94 meter (19.5 foot) tall tower dryer having a 2.44
meter (8 foot) width (made by Niro, Inc., Columbia, MD). The dryer was
fitted with a high pressure nozzle operated at 4826 kPa pressure. This
3 s drying operation required 15 minutes and yielded 28.12 kilograms of dry,
granular product. The moisture content of this granular material was 1.21 %.
CA 02252394 1998-10-16
WO 97/38678 PCT/US97/06313
IS
Its particle size distribution as measured by a Microtrac~ instrument showed
that 90% of the granules were <573.20 microns, the median particle size
was 282.52 microns, and 10% of the particles were <156.37 microns. The
composition of the granules on a dry basis was the same as in Example 2,
except that the cellulose content resulted from use of microcrystalline
cellulose rather than the hydrolyzed cellulose in of this invention.
In a Patterson-Kelly "V" type blender 990 grams of the granular
product and 10 grams of stearic acid (J. T. Baker) were blended for 5
minutes prior to preparing tablets on a Stokes B2 tablet press using 12.7
1 o mm standard round tooling. The properties of 10 tablets as determined by
an Erweka Multi-check Tester are shown in Table 4.
Table 4
Mean Tablet Properties
i s Compression Tablet Relative Tablet Relative
Force Weight Std. Hardness Std.
Deviation Deviation
(Kg) (mg) (%) (kP) (%)
20 373 620 0.3 3.2 5.0
631 623 0.4 6.8 3.8
888 623 0.2 9.4 3.2
1163 615 0.2 8.5 33.8
1496 620 0.2 fi.2 10.4
2 5 1806 610 0.7 7.1 14.4
2146 627 0.9 8.5 13.3
35
