Directly compressible, ultra fine acetaminophen compositions and process for producing same

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.

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 U.S.
 Pat. No. 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 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 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
 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
 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
 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 % essentially water-insoluble
 tabletcapsule disintegrant, from about 0.5 to about 5.0 wt %
 polyvinylpyrrolidone (povidone), from about 0.5 to about 5.0 wt % totally
 pre-gelantinized 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 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.
 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 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.degree. C. to about 30.degree. 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.degree. C. above the 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
 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 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%
 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%.
 The acetaminophen particles of the product are such that preferably a
 maximum of 30 wt % is retained on a 60 U.S. mesh screen, a maximum of 75
 wt % is retained on a 100 U.S. mesh screen, a maximum of 95 wt % is
 retained on a 200 U.S. mesh screen, and a minimum of 80 wt % is retained
 on a 325 U.S. mesh screen.
 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 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 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 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 polyvinylpyrrolidone
 (also known as crosslinked povidone), and mixtures thereof, but is
 preferably crosslinked sodium carboxymethylcellulose (croscarmellosee
 sodium).
 Any suitable fluidizing agent may be employed in this invention, but
 preferably silicon dioxide is employed. This component is 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. 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.
 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.
 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.
 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.degree. C. to about 70.degree. C., preferably to
 about 70.degree. C. Heating of this binder solution before use in the
 granulation process 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.degree. C.
 to about 70.degree. C., preferably to about 70.degree. 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 hydrogenated
 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 m.sup.2 /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 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 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 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
 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.degree. C.,
 preferably at least about 50.degree. C., and will generally be heated to
 within the range of from about 40.degree. C. to 80.degree. 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 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
 tablefter to produce tablets with the same dose of 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 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 Glaft 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
 1.sup.st Granulating Binder Solution
 Povidone (K-30) 175.0 2.50
 Water 1770.0 --
 2.sup.nd Granulating Binder Solution
 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.degree. C.
 product temp. 25-29.degree. 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 0.38 g/cc, and a flow rate of 6.7 g/sec. The particle size
 of the resulting granulation composition was:

atomizing air pressure 6 bars
 inlet temp. 64-71.degree. C.
 product temp. 25-31.degree. 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:

atomizing air pressure 6 bars
 inlet temp. 58-80.degree. C.
 product temp. 23-32.degree. C.
 binder spray rate 1999-2102 g./min.
 process air volume 3000 cfm
 The resulting granulation composition of the blended individual batches has
 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:

atomizing air pressure 5.6-5.7 bars
 inlet temp. 60-75.degree. C.
 product temp. 30-38.degree. 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 particle size
 of the resulting granulation composition was:

atomizing air pressure 3.5 bars
 inlet temp. 50-73.degree. C.
 product temp. 25-33.degree. 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:

atomizing air pressure 3 bars
 inlet temp. 55-70.degree. C.
 product temp. 30-34.degree. 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".times.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
 0.227
 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 with more
 than ten points, was within the range of from about 0.80 to about 1.0
 m.sup.2 /g.
 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 the
 scope of the invention be limited to the specific embodiments illustrated
 and described.