Title of Invention

DIRECTLY COMPRESSIBLE, ULTRA FINE ACETAMINOPHEN COMPOSITIONS AND PROCESS FOR PRODUCING SAME

Abstract A directly compressible ultra fine acetaminophen granulation composition capable of being directly compressed into an acetaminophen tablet comprises from about 85 to about 95 wt % acetaminophen, from about 1 to about 4 wt % essentially water-insoluble tablet/capsule disintegrant, from about 0.5 to about 5.0 wt % polyvinylpyrrolidone, from about 0.5 to about 5.0 wt % totally pregelatinized starch, about 0.25 to about 3.0 wt % of a fluidizing agent, from about 0.25 to about 3.0 wt % of a lubricant, and optionally up to about 10 wt % of a co-active ingredient, the weight percents being based on the total weight of the dry components of the granulation composition, the granulation also comprising a moisture content of up to about 1.5 wt % based on the total weight of the dry components of granulation composition. This directly compressible acetaminophen granulation composition is produced by granulation in a top spray fluid bed granulator employing heated fluidization air, a first heated binder solution of a major portion of the polyvinylpyrrolidone dissolved in water, and a second binder solution of a minor portion of the polyvinylpyrrolidone and a portion of the totally pregelatinized starch and optionally a lubricant.
Full Text THE PATENTS ACT 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10]
"DIRECTLY COMPRESSIBLE, ULTRA FINE ACETAMINOPHEN COMPOSITIONS AND PROCESS FOR PRODUCING SAME"
RHODIA, INC., of 259 Prospect Plains Road, Cranbury, New Jersey 08512-7500, United States of America,
The following specification particularly describes and ascertain the nature of the invention and the manner in which it is to be performed:-


( DfRECTbY COMPRESSIBLE; ULTRA FINE ACETAMINOPHEN V COMrOSITIONG AND PROCESS TOR PRODUCING SAME )
Field of the Invention
This invention relates to directly compressible ultra-fine acetaminophen (N-acetyl-p-aminophenol or APAP) compositions and to a process for preparing such ultra-fine compressible granulated compositions. The invention also relates to the preparation of tablets from such compositions. The invention also includes such ultra-fine APAP granulations alone or combined with other pro-active ingredients present in low quantity.
Background of the Invention
Generally there are four methods in use in the United States for manufacture of tablets, namely direct compression, dry powder blend, pre-compressed dry powder blend and wet granulation, as explained in US Patent 4 ,439,453.
In the direct compression method, all the required tabletting ingredients (active and aids) are incorporated into a free flowing granulation which is supplied to the manufacturer of bulk tablets. The granulation requires no pre-processing or blending with additional aids in order to be tabletted. Rather, the free flowing granulation supplied to the tablet manufacturer can be charged directly to a tabletting press.
The direct compression method is a generally preferred method for a number of reasons including economical reasons. The analgesic aspirin is generally tabletted using such a direct compression method since crystalline aspirin is soft and exhibits good plasticity/elasticity when compacted into tablets.
However, because the analgesic acetaminophen has significantly different properties than aspirin, it is generally considered to be non-compressible and not readily amendable to production of directly compressible granulations thereof. Generally, the less desirable wet granulation method of tabletting has been used to tablet acetaminophen. Generally, these wet granulation processes require large amounts of
2

excipients, e.g., from about 25 to about 40% or more by weight of excipients. That is, in contrast to aspirin, the acetaminophen crystals are hard and brittle and are easily fractured. The acetaminophen crystals have essentially no plasticity/elasticity and, therefore, have required the use of unduly large amounts of aids, lubricants and/or excipients in order to be compressible into tablets by the direct compression method.
Therefore, there is a recognized need for a direct tabletting granulated acetaminophen composition that is free flowing and capable of being directly compressible into tablets, A further need is for such a
10 directly compressible acetaminophen granulation composition to provide a high load, for example, at least 80%, or preferably at least 90% or more, of acetaminophen active in the composition. Thus, the amount of excipients required in the compositions should be kept quite low, for example, 20% or less, preferably 10% by weight or less. In addition, the directly
15 compressible acetaminophen composition should readily be free flowing and readily permit dry blending with other active ingredients should that be desired or required. A further need is that the directly compressible acetaminophen composition be such as to provide good flow and compressibility characteristics so as to produce tablets of content
2p uniformity, acceptable hardness and friability, and also provide a fluid bed granulation with a characteristic rough surface morphology and a high surface area suitable for good blending potential with other co-actives.
Summary of the Invention
2(5 This invention provides a directly compressible
acetaminophen granulated composition. A directly compressible acetaminophen granulation composition of this invention and capable of being directly compressed into an acetaminophen tablet, comprises from about 80 to about 95 wt % acetaminophen, from about 1 to about 4 wt % 30 essentially water-insoluble tablet/capsule disintegrant, from about 0.5 to about 5.0 wt % polyvinylpyrrolidone (povidone), from about 0,5 to about 5.0 wt % totally pre-gelatinized starch, about 0.25 to about 3.0 wt % of a fluidizing agent, and from about 0.25 to about 3.0 wt % of a lubricant, the
3

weignt percents being cased on the total weight of the dry components of the granulation composition, the granulation also comprising a moisture content of up to about 1.5 wt % based on the total weight of the dry components of granulation composition.
5 The invention also comprises a process for producing such
directly compressible acetaminophen granulation compositions. The process for the production of the directly compressible acetaminophen granulation compositions comprises: placing, as dry ingredients in a top spray fluid bed granulator, and dry blending with inert fluidization gas
o) acetaminophen powder, the water-insoluble tablet/capsule disintegrant, a minor proportion of the totally pregelatinized starch, and at least a portion, or optionally all, of the fluidizing agent; heating the dry blend with heated pressurized fluidization gas, such as heated air, to fluidize and essentially uniformly heat the dry blend to a temperature in the range of about 25°C to
5 about 30°C; when the dry blend has reached the desired temperature, spraying a first binder solution of a major portion of the polyvinylpyrrolidone dissolved in water from an atomizing spray gun of the granulation onto the heated dry blend to commence granulation of the dry powder blend; drying the granulation until the granulated product rises to about 2°C above the
o end product temperature; spraying a second aqueous binder solution of the remaining minor portion of the polyvinylpyrrolidone, the remaining major portion of the totally pregelatinized starch, and optionally a lubricant, from an atomizing gun of the granulator onto the granulated product to further granulate and agglomerate the composition, and then drying this further
5 granulated product until a moisture content of 1.5 wt % or less, preferably about 1.0 to 1.5 wt %, is achieved. The dried, directly compressible acetaminophen granulation composition, including APAP alone or in combination with other actives, is unloaded from the fluid bed granulator, and then can, if desired, be blended with other suitable dry ingredients in a
suitable blender, to provide the directly compressible acetaminophen compositions of this invention.
The two spray process is necessary to effectively coat and agglomerate the ultra-fine particles to prepare fine particle sized granules

t 4

having a high surface area and characteristic rough surface myphology suitable for good blending potential, content uniformity, tablet hardness and dissolution.
Detailed Description of Invention and Preferred Embodiments
In the directly compressible composition of this invention, the ingredients thereof will generally be present in the following amounts expressed as percent by weight:
acetaminophen: 80 to 95%, preferably 87.5 to 92.5%
10 tablet/capsule disintegrant: 1 to 4%, preferably 1,5 to 3.5%

polyvinylpyrrolidone: 0.5 to 5%, preferably 2.75 to 3.25%
pregelatinized starch: 0,5 to 5%, preferably 2 to 4%
fluidizing agent: 0.25 to 3%, preferably 0.25 to 1.25%
lubricant: 0.25 to 3%, preferably 0.25 to 1.25%.
1$ The acetaminophen particles of the product are such that
preferably a maximum of 30 wt % is retained on a 60 US mesh screen, a
maximum of 75 wt % is retained on a 100 US mesh screen, a maximum of
95 wt % is retained on a 200 US mesh screen, and a minimum of 80 wt %
is retained on a 325 US mesh screen.
2(|) The polyvinylpyrrolidone employed for its binding
characteristics is preferably a lower molecular weight grade having an average molecular weight (Mw) of about 30,000 or less. As examples of grades of polyvinylpyrrolidone suitable for use in the invention, there can be mentioned povidone K30 or K29/32. Such polyvinylpyrrolidone impart a 25 low viscosity to the binder solutions. A major amount of the
polyvinylpyrrolidone is employed in the first binder solution as a particle coating agent, generally from about 80 to about 85 wt % of the total polyvinylpyrrolidone. The remaining minor amount of the polyvinylpyrrolidone, generally about 15 to 20 wt % of the total is employed 30 in the second binder or agglomerating solution with a major amount, generally preferably about 65 wt % of the pregelatinized starch.
A minor portion of the pregelatinized starch, generally preferably about 35 wt % is used in the dry bowl charge to the fluid bed
5

granulator as an intra-granular disintegrant, as well as a dry binder. The pregelatinized starch employed is totally pregelatinized starch, such as for example National Starch and Chemicals Corp. pregelatinized starch products 1551.
The total amount of the water-insoluble tablet/capsule disintegrant is used as a disintegrating agent in the dry bowl charge. The disintegrant is generally crosslinked sodium carboxymethylcellulose, sodium carboxylmethyl starch (also known as sodium starch glycolate), microcrystalline cellulose, soy protein, alginic acid, crosslinked
10 polyvinylpyrrolidone (also known as crosslinked povidone), and mixtures thereof, but is preferably crosslinked sodium carboxymethylcellulose (croscarmeilosee sodium).
Any suitable fluidizing agent may be employed in this invention, but preferably silicon dioxide is employed. This componentls—
10 multifunctional and serves as a glidant, porosity reducer, granulation densifier and moisture scavenger, but primarily is employed as a fluidization aid during fluid bed granulation. Addition of the fluidizing agent to the initial dry charge to the fluid bed granulator helps the powders in the fluidized state for particle coating during the granulation process.
20 Preferably at least about 50 wt % of the fluidizing agent is employed in the initial dry charge. Any remaining portion of the fluidizing agent not charged to the granulator in the dry charge can be blended with the product of the granulation process in a suitable blender to produce the final directly compressible composition.
25 Any suitable lubricant can be employed as the process of this
invention, such as for example, stearic acid or mixtures of fatty acids, hydrogenated vegetable oils, triglycerides of fatty acids, metal stearates or metal salts of fatty acid mixtures, sodium lauryl sulfate, polyethylene glycol, talc, and mixtures of lubricants, but preferably stearic acid is employed.
30 The lubricant can be added to the second binder solution or added in a dry form to the product of the granulation process by blending therewith in a suitable blender.
6

In preparing the first binder solution, the major portion of polyvinylpyrrolidone is dispersed and dissolved in water and heated to a temperature of about 50°C to about 70°C, preferably to about 70°C, Heating of this binder solution before use in the granulation process 5 provides improved spreading efficiency for coating onto the powder particles of acetaminophen to achieve good compressibility of the final product. Co-actives can also be incorporated into this first binder solution to ensure good content uniformity of the low dose co-actives.
In preparing the second binder solution, the remaining portions of polyvinylpyrrolidone and pregelatinized starch are dispersed in sufficient water and the solution heated to a temperature of from about 50°C to about 70°C, preferably to about 70°C, to insure total gelatinization of the starch granules, as well as producing efficient spreading of the second binder solution on the granulation. Optionally, low melting fatty acid mixtures, such as stearic acid or hudrogerated vegetable oils, can be dispersed within the second binder solution. During granulation with the second binder solution, the particles agglomerate while building up particle size. However, other process variables maintain the fine particle size of the granulation.
The two-spray process of this invention is critical to effectively coat and agglomerate the particles, to prepare fine particle size granules having high surface area of from about 0.8 to about 1.0 m2/g and characteristic "rough surface" morphology suitable for good blending potential, content uniformity, tablet hardness and dissolution.
Sufficient atomizing fluid (air) pressure is employed in the process to maintain a small droplet size for the binder solutions, and this in turn produces finer particle size in the resulting directly compressible granulated composition.
High fluidization air volume is required during fluidization of 0 the powder. For example, in large scale manufacture of about 400 kg of granulated product, an air volume of between about 1800 to 3500 cfm is generally employed. Such large air volume keeps the particles sufficiently separated while permitting binder solution to spread on the. particles in a

7

way that keeps granule growth to a minimum, producing a finer particle size of the granulation. Preferably, a three-stage level in the air volume is employed in such a large scale manufacturing process. Initially a fluidization air volume of about 1800 cfm is employed. The air volume is 5 then increased to about 2500 cfm about midway through granulation with the first binder solution, and then increased to about 3500 cfm at the beginning of the granulation with the second binder solution. This stepwise increase in fluidization air volume keeps the particles being granulated in a highly fluidized state to produce finer particle size of the granulated product
10 composition, and keeps the fluidized state of granulation substantially
constant even though the granule density keeps increasing from commencement to termination of the granulation process. The fluidization air employed is air heated to a temperature of at least 40°C, preferably at least about 50°C, and will generally be heated to within the range of from 15 about 40°C to 80°C, depending upon other process conditions including relative humidity.
Any suitable spray rate of binder solution may be employed in the process of this invention. In this previously mentioned large scale manufacturing process, a binder spray rate of from about 1700 to about
2 0 2400 g/min, preferably from about 1900 to about 2100 g/min, is employed.
By the process of this invention, a directly compressible acetaminophen composition can be provided that has a high loading of acetaminophen, preferably a load level of at least 90 wt % acetaminophen, and enables a tabletter to produce tablets with the same dose of
25 acetaminophen in each tablet.
The acetaminophen granulation produced by the process of this invention can be employed with low dose and other fine particle size active ingredients in tablets, such as for example, with psuedoephedrine hydrochloride, chloropheniramine maleate, dextromethorphan
30 hydrobromide, phenylpropanolamine hydrochloride, propoxyphen napsylate, hydrocodone, codeine phosphate and the like. The acetaminophen granulation of this invention can be blended with such other active ingredients in a simple mixing process and achieve good content


uniformity of the other active ingredients in any resulting tablets formed by direct compression of the resulting blend.
The process of this invention can also incorporate other low dose co-active ingredients in the granulation charge, such as for example, those used in cough and cold medications and narcotic analgesic medications, used in amounts of up to about 10% by weight, generally from about 5 to about 10%. Co-actives of cough and cold remedies for analgesic, decongestant, antihistamine, cough suppressant combinations can include, for example, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, phenylpropanolamine hydrochloride, chlorpheniramine maleate, and the like. Co-active narcotic analgesic medications can include, for example, propoxyphen napsylate, hydrocodone, codeine phosphate and the like. These co-actives can be incorporated in the granulation compositions produced by the process of this invention or can be blended with the resulting fine particle size granulation produced according to the process of this invention and achieve directly compressible granulation product having good content uniformity of the active ingredients.
The invention is illustrated, but not limited by, the following examples.
EXAMPLE 1
A laboratory-sized batch of directly compressible, ultra fine particle sized granulation of 90% acetaminophen was produced in a WSG-5 top spray fluidized bed granulator from Glatt GmbH of Germany.
The ingredients and their amounts employed in the dry charge and first and second binder solutions were as set forth in the following Table 1:


Table 1

DRY BOWL CHARGE
Ingredient Amount (gm.) %w/w
Acetaminophen 6300.0 90.00
Croscarmellose Sodium 210.0 3.00
Silicon Dioxide (Syloid 244FP) 35.0 0.50
Starch, pregelatinized 84.5 1.21
1st Granulating Binder Solution
Ingredient Amount (gm.) % w/w
Povidone (K-30) 175.0 2.50
Water 1770.0 —
2nd Granulating Binder Solution
Ingredient Amount (gm.) % w/w
Povidone (K-30) 35.0 0.50
Starch, pregelatinized 150.0 2.14
Stearic Acid 10.5 0.15
Water 2225.0 —
Grand Total (dry) 7000.0 100%
The granulating process conditions employed were as
follows:
atomizing guns: single head, port size 1.8 mm, located 11"
above granulator bowl
atomizing air pressure 3 bars
inlet temp. 48-66°C
product temp. 25-29°C
binder spray rate 60 g./min.
process air volume 240-1400 cfm
10


The resulting granulation composition had a moisture content of 1.4%, a bulk density of 0.38 g/cc, and a flow rate of 6.7 g/sec. The particle size of the resulting granulation composition was:

US Mesh

% Cum. Retained



60 100 200 325

24.8 59.6 88.0 96.8




Directly compressible tablets from the resulting granulation composition were produced on a Manesty Betapress Series 16 (caplet tooling size 0.281" x 0.687") of Manestary Machines, Ltd. of the UK. The properties of the directly compressed tablets produced were as set forth in Table 2.



1)


Table 2
Force-main (ton)/pre-(lb) 0.5/- 1/- 1.5/- 21- 2.5/- 0.75/300 1/400
Ejection (lb) 70 90 90 90 90 80 90
Weight (mg) 549 551 550 546 551 551 552
Hardness (SCU) 9.6 16.6 14.2 13.6 13.3 12.8 17.0
Thickness (inch) 0.248 0.231 0.225 0.222 0.222 0.237 0.227
Friability (%) 0.49 0.35 0.69 0.86 0.78 0.47 0.33
EXAMPLE 2
A production-sized batch of directly compressible, ultra fine, particle sized granulation of 90% acetaminophen was produced in a GPCG-300 top spray fluidized bed granulator from Glatt GmbH of Germany.
The ingredients and their amounts employed in the dry charge and first and second binder solutions were as set forth in Table 3.
11

Table 3
DRY BOWL CHARGE
Ingredient Amount (km.) %w/w
Acetaminophen 360.0 90.00
Croscarmellose Sodium 12.00 3.00
Silicon Dioxide (Syloid 244FP) 2.00 0.50
Starch, pregelatinized 4.80 1.20
1st Granulating Binder Solution
Ingredient Amount (km.) %w/w
Povidone (K-30) 10.00 2.50
Water 101.0 —
Znd Granulating Binder Solution
ingredient Amount (km.) % w/w
Povidone (K-30) 2.00 0.50
Starch, pregelatinized 8.60 2.15
Stearic Acid 0.60 0.15
Water 127.0 —
Grand Total (dry) 400.00 100%
The granulating conditions employed were as follows:
atomizing guns: 6 head angle, port size 1.8 mm, located 34"
above granulator bowl
atomizing air pressure 6 bars
inlet temp. 64-71°C
product temp. 25-31°C
binder spray rate 2000-2400 g./min.
process air volume 1800-3400 cfm


The resulting granulation composition had a moisture content of 1.4%, a bulk density of 0.43 g/cc, and a flow rate of 6.8 g/sec. The particle size of the resulting granulation composition was:

19.6 64.8 92.9 98.4
US Mesh % Cum. Retained
60 100 200 325

Directly compressible tablets from the resulting granulation composition were produced on a Manesty Betapress Series 16 as in Example 1, The properties of the directly compressed tablets produced were as set forth in Table 4. 1)
Table 4

Force-main (ton)/pre-(lb) 0.5/- 1/- 1.5/- 21- 2.5/- 0.75/300 1/400
Ejection (lb) 90 120 120 120 120 120 120
Weight (mg) 553 554 556 555 556 555 556
Hardness (SCU) 10.6 15.9 17.0 14.2 13.3 13.8 16.1
Thickness
(inch) 0.244 0.228 0.224 0.222 0.221 0.234 0.228
Friability (%) 0.62 0.41 0.41 0.49 0.54 0.51 0.45
EXAMPLE 3
Four individual production-sized batches of directly 15 compressible, ultra fine particle sized granulations of 90% acetaminophen were produced on a GPCG-300 top spray fluidized bed granulator from Glatt GmbH. The four individual batches were then blended together in a " 125 cu. ft. Gemco blender to produce a final directly compressible blend.
13

The ingredients and their amounts employed in the dry charge and first and second binder solutions to produce each individual batch were as set forth in Table 5.
Table 5

DRY BOWL CHARGE
Ingredient Amount (kg.) % w/w
Acetaminophen 360.0 89.69
Croscarmellose Sodium 10.00 2.49
Silicon Dioxide (Syloid 244FP) 2.00 0.50
Starch, pregelatinized 4.80 1.19
1st Granulating Binder Solution
Ingredient Amount (kg.) % w/w
Povidone (K-30) 10.00 2.49
Water 1010 —
2nd Granulating Binder Solution
Ingredient Amount (kg.) % w/w
Povidone (K-30) 2.00 0.50
Starch, pregelatinized 8.60 2.14
Water 120.0 —
Subtotal (dry) 397.4
Post Granulation Dry Additives
Ingredient Amount (kg.) %w/w
Silicon Dioxide (Syloid 244FP) 1.99 0.50
Stearic Acid 1.99 0.50
Grand Total 401.38 100%
The granulating process conditions employed were as follows:
atomizing guns: 6 head angle, port size 1.8 mm, located 34" above granulator bowl


atomizing air pressure inlet temp, product temp, binder spray rate process air volume

6 bars 58-80°C 23-32°C
1999-2102 g./min. 3000 cfm

The resulting granulation composition of the blended individual batches had a moisture content of 1.4%, a bulk density of 0.45 g/cc, and a flow rate of 5,3 g/sec. The particle size of the blended granulation composition was:

US Mesh Size % Cum. Retained.
60 7.5
100 33.0
200 74,5
325 94.0
Directly compressible tablets from the blended granulation composition were produced on a Manesty Betapress Series 16 as in Example 1. The properties of the directly compressed tablets produced were as set forth in Table 6,

Table 6
Force-main (ton)/pre-(lb) 0.5/- 1/- 1.5/- 2/- 2.5/- 0.75/300 1/400
Ejection (lb) 20 30 30 30 30 25 30
Weight (mg) 557 556 557 556 556 556 556
Hardness (SCU) 9.6 14.8 12.0 12.6 11.9 12.5 15.6
Thickness (inch) 0.250 0.233 0.228 0.225 0.223 0.238 0.231
Friability (%) 0.63
. r 0.34 0.83 0.97 101 0.45 0.4-1


EXAMPLE 4
A production-sized batch of directly compressible, ultra fine, particle sized granulation of 90.15% acetaminophen was produced in a GPCG-300 top spray fluidized bed granulator from Glatt GmbH of Germany and blended with dry additives in a 40 cu. ft. Gemco blender.
The ingredients and their amounts employed in the dry charge, first and second binder solutions, and dry additives were as set forth in Table 7,
10 Table 7

DRY BOWL CHARGE
Ingredient Amount (km.) %w/w
Acetaminophen 360.0 90.15
Croscarmellose Sodium 10.00 2.50
Silicon Dioxide (Syloid 244FP) 1.80 0.45
Starch, pregelatinized 4.80 1.20
1st Granulating Binder Solution
Ingredient Amount (km.) %w/w
Povidone (K-30) 10.00 2.50
Water 101.0 —
2na Granulating Binoer Solution
Ingredient Amount (km.) % w/w
Povidone (K-30) 2.00 0.50
Starch, pregelatinized 8.60 2.14
Water 120.0 —
Post Granulation Dry Additives
Ingredient Amount (kg.) %w/w
Silicon Dioxide (Syloid 244FP) 0.16 0.04
Stearic Acid 1.99 0.56
Grand Total 399.35 100%
The granulating conditions employed were as follows:


atomizing guns: 6 head angfe, port size 1.8 mm, located 34"
above granulator bowl
atomizing air pressure 5.6-5.7 bars
inlet temp, 60-75°C
product temp. 30-38°C
binder spray rate 1713-1849 g./min,
process air volume 1800-3500 cfm
The resulting granulation composition had a moisture content of 1.3%, a bulk density of 0,40 g/cc, and a flow rate of 5.1 g/sec. The 5 particle size of the resulting granulation composition was:

US Mesh

% Cum. Retained



60 100 200 325

11.0 51.5 89.5 98.0

Directly compressible tablets from the resulting granulation composition were produced on a Manesty Betapress Series 16 as in Example 1. The properties of the directly compressed tablets produced were as set forth in Table 8.
Table 8

Force-main (ton)/pre-(lb) 0.5/- 1/- 1.5/- 2/- 2.5/- 0.75/300 1/400
Ejection (lb) 25 25 25 25 25 30 30
Weight (mg) 559 559 557 559 557 555 557
Hardness (SCU) 13.7
■ ■ »"■■||1" ■ 11.9 12.4 11.9 11.9 17,0 19,6


Thickness | (inch) 0.238 0.230 0.22 5 0.223 0.222 0.229 0,226
Friability (%) 0.22 0.53 0.40 0.49 0.49 0.18 0.14
EXAMPLE 5
A laboratory-sized batch of directly compressible, ultra fine particle sized granulation of 90% acetaminophen with chlorpheniramine 5 maleate co-active was produced in a WSG-5 top spray fluidized bed granulator from Glatt GmbH of Germany and blended with dry additives.
The ingredients and their amounts employed in the dry charge, first and second binder solutions, and any additives were as set forth in the following Table 9.
Table 9

DRY BOWL CHARGE
Ingredient Amount (gm.) % w/w
Acetaminophen 6300.0 90.00
Croscarmellose Sodium 149.3 2.13
Silicon Dioxide (Syloid 244FP) 35.0 0.50
Starch, pregelatinized 84.5 1.21
1st Granulating B nder Solution
Ingredient Amount (gm.) % w/w
Povidone (K-29/32) 175.0 2.50
Chlorpheniramine Maleate 25.7 0.37
Water 2030.0 —
2nd Granulating Binder Solution
Ingredient Amount (gm.) %w/w
Povidone (K-29/32) 35.0 0.50
Starch, pregelatinized 150.0 2.14
Water 2225.0 —
Post Granulation Dry Additives
Ingredient Amount (gm.) %w/w


\9






ilicon Dioxide (Syloid 244FP)
tearic Acid
Grand Total

The granulating process conditions employed were as
follows:

/

atomizing guns: single head, port size 1.8 mm, located 11"
above granulator bowl
atomizing air pressure 3.5 bars
inlet temp. 50-73°C
producttemp. 25-33°C
binder spray rate 62 g./min.
process air volume 240-1400 cfm
The resulting granulation composition had a moisture content of 1.1%, a bulk density of 0.39 g/cc, and a flow rate of 5.4 g/sec. The particle size of the resulting granulation composition was:



US Mesh

% Cum. Retained



60 100 200 325

13.6 50.0 84.4 96.8

Directly compressible tablets from the resulting granulation composition were produced on a Manesty Betapress Series 16 (caplet tooling size 0.281" x 0.687") of Manestary Machines, Ltd. of the UK. The properties of the directly compressed tablets produced were as set forth in 15 Table 10.

Table 10
| Force-main (ton)/pre-(Ib) 1/- 1.5/- 0.75/300 1/400



Ejection (lb) 120 120 120 120
Weight (mg) 557 557 556 555
Hardness (SCU) 17.4 19.8 14,3 17.7
Thickness (inch) 0.231 0.225 0.238 0.230
Friability (%) 0.49 0.49 0.50 0.59
EXAMPLE 6
A laboratory-sized batch of directly compressible, ultra fine particle sized granulation of 89.69% acetaminophen was produced in a 5 WSG-5 top spray fluidized bed granulator from Glatt GmbH of Germany and blended with dry.
The ingredients and their amounts employed in the dry charge, first and second binder solutions, and dry additives were as set forth in the following Table 11.
Table 11

DRY BOWL CHARGE
Ingredient Amount (gm.) %w/w
Acetaminophen 6278,3 89,69
Crosslinked polyvinylpyrrolidone (Crospovidone) 174.3 2.49
Silicon Dioxide (Syloid 244FP) 35.0 0.50
Starch, pregelatinized 83.3 1.19
1st Granulating Binder Solution
Ingredient Amount (gm.) %w/w
Povidone (K-29/32) 174.3 2.49
Water 1760.0 —
2nd Granulating Binder Solution
Ingredient Amount (gm.) %w/w
Povidone (K-29/32) 35.0 0,50
Starch, pregelatinized 149.8 2.14
Water 2090.0 —



[ Post Granulation Dry Additives
Ingredient Amount (gm,) %w/w
Silicon Dioxide (Syloid 244FP) 35.0 0.50
Stearic Acid 35.0 0.50
Grand Total 7000.0 100%
The granulating process conditions employed were as
follows:

/

atomizing guns: single head, port size 1.8 mm, located 11"
above granulator bowl
atomizing air pressure 3 bars
inlet temp. 55-70°C
product temp. 30-34°C
binder spray rate 60 g./min.
process air volume 240-1400 cfm
The resulting granulation composition had a moisture content of 1.4%, a bulk density of 0,37 g/cc, and a flow rate of 5.6 g/sec. The particle size of the resulting granulation composition was;







US Mesh % Cum. Retained
60 25.2
100 62.8
200 88.4
325 97.6
Directly compressible tablets from the resulting granulation composition were produced on a Manesty Betapress Series 16 (caplet tooling size 0.281" x 0.687") of Manestary Machines, Ltd. of the UK. The properties of the directly compressed tablets produced were as set forth in Table 12.





Table 12

* Force-main (ton)/pre-(lb) 0.5/- 1/- 1.5/- 2/- 2.5/- 0.75/300 1/400
Ejection (lb) 30 35 35 35 30 35 35
Weight (mg) 555 557 556 554 555 558 558
Hardness (SCU) 13.5 13.7 12.2 12.4 12.7 16.2 18.6
Thickness
(inch) 0.237 0.228 0.225 0.224 0.223 0.230 0227
Friability (%) 0.27 0.85 0.36 0.36 0.45 0.22 0.22
The surface area of the particles of each of the above-produced granulations of Examples 1 to 6, measured by BET methodology 5 with more than ten points, was within the range of from about 0.80 to about 1.0m2/g.
22
With the foregoing description of the invention, those skilled in the art will appreciate that modifications may be made to the invention without departing from the spirit thereof. Therefore, it is not intended that 10 the scope of the invention be limited to the specific embodiments illustrated and described.


We claim:
1. A directly compressible acetaminophen granulation composition capable of being directly compressed into an acetaminophen tablet, said granulation composition comprising from about 80 to about 95 wt % acetaminophen, from about 1 to about 4 wt % essentially water-insoluble tablet/capsule disintegrant, from about 0.5 to about 5.0 wt% polyvinylpyrrolidone, from about 0.5 to about 5.0 wt% totally pregelatinized starch, about 0.25 to about 3.0 wt % of a fluidizing agent, from about 0.25 to about 3.0 wt% of a lubricant, and optionally up to about 10 wt% of a co-active ingredient, the weight percents being based on the total weight of the dry components of the granulation composition, the granulation also, comprising a moisture content of up to about 1.5 wt % based on the total weight of the dry components of granulation composition, wherein the granules of the granulation composition have a surface, area of from about 0.8 to about 1.0 m2/g.
2. A directly compressible, acetaminophen granulation composition as claimed in claim 1 wherein the fluidizing agent is silicon dioxide, the
lubricant is stearic acid, and the tablet/capsule disintegrant is

selected from crosslinked sodium carboxymethyl-cellulose and
crosslinked polyvinylpyrrolidone.
3. A directly compressible acetaminophen granulation composition as
claimed in claim 1 wherein the acetaminophen comprises at least
about 90% by weight.
23

4. A directly compressible acetaminophen granulation composition as claimed in claim 2 wherein the acetaminophen comprises at least about 90% by weight.
5. A directly compressible acetaminophen granulation composition as claimed in claim 1 wherein the acetarmnophen is finely divided particles of acetaminophen such that £ maximum of 30 wt% is retained on a 60 US mesh screen, a maximum of 75 wt% is retained on a 100 US mesh screen, a maximum of 95 wt% is retained on a 200 US mesh screen, and a minimum of 80 wt % is retained on a 325 US mesh screen.
6. A directly compressible acetaminophen granulation composition as claimed in claim 2 wherein the acetaminophen is finely divided particles of acetaminophen such that a maximum of 30 wt% is retained on a 60 US mesh screen, a maximum of 75 wt % is retained on a 100 US mesh screen, a maximum of 95 wt % is retained on a 200 US mesh screen, and a minimum of 80 wt % is retained on a 325 US mesh screen.
7. A directly compressible acetaminophen granulation composition as claimed in claim 4 wherein the acetaminophen is finely divided particles of acetaminophen such that a maximum of 30 wt % is retained on a 60 US mesh screen, a maximum of 75 wt % is retained on a 100 US mesh screen, a maximum of 95 wt % is retained on a 200 US mesh screen, and a minimum of 80 wt % is retained on a 325 US mesh screen.
24

8. A directly compressible acetaminophen granulation composition as claimed in claim 2 wherein the acetaminophen comprises about 87.5 to about 92.5 wt %, the crosslinked sodium carboxymethylcellulose or crosslinked polyvinylpyrrolidone comprises from about 1.5 to about 3.5 wt %, the polyvinylpyrrolidone comprises from about 2.75 to about 3.25 wt %, the totally pregelatmized starch comprises from about 2.0 to about 4.0 wt %, the silicon dioxide comprises from about 0.25 to about 1.25 wt %, and the stearic acid comprises from about 0.25 to about 1.25 wt %.
9. A directly compressible acetaminophen granulation composition as claimed in claim 7 having a surface area of from about 0.8 to about
1.0m2/g,
10. A tablet comprising the granulation composition as claimed in claim
1 /
11. A tablet comprising the granulation composition as claimed in claim
2.
12. A tablet comprising the granulation composition as claimed in claim 4.
13. A tablet comprising the granulation composition as claimed in claim 7.
14. A tablet comprising the granulation composition as claimed in claim 8.
15. A tablet comprising the granulation composition as claimed in claim 9.
25

A process for producing a directly. compressible acetaminophen granulation composition comprising from about 80 to about 95 wt % acetaminophen, from about 1 to about 4 wt % essentially water-insoluble tablet/capsule disintegrant, from about 0.5 to about 5.0 wt% polyvinylpyrrolidone, from about 0.5 to about 5.0 wt Vo totally , pregelatinized starch, about 0,25 to about 3.0 wt % of a fluidizing agent, from about 0.25 to about 3.0 wt % of a lubricant, and optionally up to about 10 wt % of a co-active ingredient, the weight percents being based on the total weight of the dry components of the granulation composition, the granulation also comprising a moisture content of up to about 1.5 wt % based on the total weight of the dry components of granulation composition, said process comprising:
(1) placing in a top spray fluid bed granulator and mixing with inert ftuidization gas the acetaminophen, the water-insoluble tablet/capsule disintegrant, a minor portion of the totally pregelatinized starch, and at least a portion or optionally all of the fluidizing agent to produce a blend of dry ingredients;
(2) introducing inert heated pressurized fluidization gas to substantially uniformly heat the blend of dry ingredients of step (1) to
" a temperature of from about 25°C to about 30°C;
(3) providing to at least one atomizing gun of the top spray fluid
bed granulator a heated first granulating binder solution of a major
portion of the polyvinylpyrrolidone dissolved in water, and spraying
the heated blend of dry ingredients of step (2) with the heated First
26

binder solution;
(4) drying the granulation product resulting from step (3);
(5) providing to at least one atomizing air gun of the top spray fluid bed granulator a heated second granulating binder solution of the remaining minor portion of the polyvinylpyrrolidone and the remaining major portion of the totally pregelatinized starch, and optionally the lubricant, and spraying the dried granulation of step (4) with the heated second granulating binder solution; and
(6) drying the granulation resulting from step (5) until the 20 moisture content of the resulting granulation composition comprises from about 1.5 wt % or less, and blending therewith any of the fluidizing agent or lubricant not previously added.

17. A process as claimed in claim 16 wherein the moisture content resulting from step (6) is from about 1.0 to about 1.5 wt %.
18. A process as claimed in claim 17 in which the fluidizing agent is silicon dioxide and the lubricant is stearic acid, and the
19 tablet/ capsule disintegrant is selected from crosslinked sodium carboxymethylcellulose and crosslinked polyvinylpyrrolidone.
19. A process as claimed in claim 17, wherein the acetaminophen of the

composition comprises at least about 90 wt%.
20. A process as claimed in claim 17, wherein the acetaminophen is finely
divided particles of acetaminophen such that a maximum of 30 wt% is

retained on a 60 US mesh screen, a maximum of 75 wt% is retained
on a 100 US mesh screen, a maximum of 95 wt% is retained on a 200
27

US mesh screen, and a minimum of 80 wt% is retained on a 325 US
mesh screen.
A process as claimed in claim 18, wherein the acetaminophen
comprises about 87.5 to about 92.5 wt%, the crosslinked sodium
carboxymethylcellulose or crosslinked polyvinylpyrrolidone comprises
from about 1.5 to about 3,5 wt%, the polyvinylpyrrolidone comprises
from about 2.75 to about 3.25 wt%, the totally pregelatinized starch
comprises from about 2.0 to about 4.0 wt%, the fluidized agent
comprises from about 0.25 to about 1.25 wt% and the lubricant
comprises from about 0.25 to about 1.25 wt%.
A process as claimed in claim 16, wherein the granules of the
granulation of step(6) have a surface area of from about 0.8 to about
1.0m3/g.
A process as claimed in claim 20, wherein the granules of the
granulation of step(6) have a surface area of from about 0-8 to about
1.0m2/g.
A process as claimed in claim 16, wherein the first and second binder
solutions are heated to a temperature of from about 50°C to about
70°C.
A process as claimed in claim 24, wherein the pressurized
fluidization gas is introduced to the fluid bed granulator at a rate of
about 1800 cfm during step (2), increased to a rate of about 2400 cfm
during step (3), and further increased to a rate of about 3500 cfm
during step (5).
28

Documents:

in-pct-2002-00186-mum-abstract(25-07-2005).doc

in-pct-2002-00186-mum-abstract(25-07-2005).pdf

in-pct-2002-00186-mum-abstract.doc

in-pct-2002-00186-mum-abstract.pdf

in-pct-2002-00186-mum-cancelled page(14-02-2002).pdf

in-pct-2002-00186-mum-cancelled page.pdf

in-pct-2002-00186-mum-claims(granted)-(25-07-2005).doc

in-pct-2002-00186-mum-claims(granted)-25-07-2005.pdf

in-pct-2002-00186-mum-claims(grnted).doc

in-pct-2002-00186-mum-correspondence(ipo)-(19-02-2007).pdf

in-pct-2002-00186-mum-correspondence-19-02-2007-ipo.pdf

in-pct-2002-00186-mum-correspondence-25-10-2005.pdf

in-pct-2002-00186-mum-form 1-14-02-2002.pdf

in-pct-2002-00186-mum-form 13-25-07-2005.pdf

in-pct-2002-00186-mum-form 19-07-07-2004.pdf

in-pct-2002-00186-mum-form 1a-25-07-2005.pdf

in-pct-2002-00186-mum-form 2(granted)-(25-07-2005).doc

in-pct-2002-00186-mum-form 2(granted)-25-07-2005.pdf

in-pct-2002-00186-mum-form 2(grnted).doc

in-pct-2002-00186-mum-form 2-25-07-2005.pdf

in-pct-2002-00186-mum-form 3-14-02-2002.pdf

in-pct-2002-00186-mum-form 3-25-07-2005.pdf

in-pct-2002-00186-mum-form 5-14-02-2002.pdf

in-pct-2002-00186-mum-petiton under rule 137-25-07-2005.pdf

in-pct-2002-00186-mum-petiton under rule 138-24-10-2005.pdf

in-pct-2002-00186-mum-power of attoreny-25-03-2002.pdf

in-pct-2002-00186-mum-power of attoreny-25-07-2005.pdf


Patent Number 209325
Indian Patent Application Number IN/PCT/2002/00186/MUM
PG Journal Number 38/2007
Publication Date 21-Sep-2007
Grant Date 24-Aug-2007
Date of Filing 14-Feb-2002
Name of Patentee RHODIA, INC.
Applicant Address 259 PROSPECT PLAINS ROAD, CRANBURY, NEW JERSEY 08512-7500.
Inventors:
# Inventor's Name Inventor's Address
1 AJAY UPADHYAY 9 BATTISTA COURT, SAYREVILLE, NEW JERSEY 08872, USA
PCT International Classification Number A61K 31/165
PCT International Application Number PCT/US00/40864
PCT International Filing date 2000-09-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 09/397,356 1999-09-16 U.S.A.