United States Patent [19] '
`Salpekar et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,600,579
`Jul. 15, 1986
`
`[54] N-ACETYL-P-AMINOPHENOL
`COMPOSITIONS CONTAINING PARTIALLY
`GELATINIZED STARCH AND METHOD
`FOR PREPARING SAME
`
`[75] Inventors: Anil M. Salpekar, Creve Coeur;
`Steven R. Freebersyser, Florissant;
`Douglas A. Robinson, Creve Coeur,
`all of Mo.
`
`[73] Assignee: Mallinckrodt, Inc., St. Louis, Mo.
`
`[21] Appl. No.: 502,067
`
`[22] Filed:
`
`Jun. 7, 1983
`
`[51] Int. Cl.4 .................... .. A61K 31/16; A61K 31/70
`[52] U.S. Cl. ..................................... .. 424/80; 514/ 629
`[58] Field of Search ............. .. .
`424/80; 514/629
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`2,798,838 7/1957 Robinson ............................ .. 167/82
`2,876,160 3/1959 Schoch et a1.
`167/82
`
`3,181,998 5/1965 Kanig . . . . . . . . . . . . . . . .
`
`3,499,962 3/1970 Wurzburg et a1.
`
`. . . .. 167/82
`
`424/35
`
`3,786,123 1/1974 Katzen . . . . . . . . . . . . . .
`
`. . . .. 264/53
`
`264/109
`3,851,032 11/1974 Andrews et a1. .
`424/80
`3,923,974 12/1975 Andrews et a1. .
`4,072,535 2/1978 Short et al. ....................... .. 106/210
`
`FOREIGN PATENT DOCUMENTS
`
`0011490 5/ 1980 European Pat. Off. .
`0040472 11/ 1981 European Pat. Off. .
`0070970 2/ 1983 European Pat. Off. .
`45-27111 9/1970 Japan .
`1287431 8/1972 United Kingdom .
`1390032 4/1975 United Kingdom .
`
`OTHER PUBLICATIONS
`“Polyplasdone XL TM Tablet Disintegrant”, GAF
`Corp. Bulletin No. 2302-099 (1980), 5 pages.
`“PLASDONE® Povidone USP,” GAF Corp. Bulle
`tin No. 2302-10 (1981), 14 pages (including covers).
`Dr. rer. nat. Paul Heinz List, “Arzneiformenlehr”,
`1976, p. 74, original and translation (2 pages).
`“LACTOSE—U.S.P. FAST-FLO,” Foremost Foods
`Company brochure, 1977, 8 pages.
`'
`Salpekar, Anil M.; “A Study of Some Important As
`pects of Tablet Lubrication”-Ph.D. Dissertation/Univ.
`Maryland; 1975; pages: title page, abstract (3 pages) and
`189-204.
`“Prototype Formulation: Acetaminophen Tablets”,
`Colorcon, Inc. Technical Data bulletin (2/ 81), 2 pages.
`“Evaluation of Starch 1500 as a Granulation Binder in
`the Formulation of Acetaminophen Tablets”, Color
`con, Inc. Technical Data bulletin (2/ 81) 6 pages.
`“Starch 1500 TM ”, Colorcon, Inc. brochure (1/81) 14
`pages.
`Primary Examiner—-Stanley J. Friedman
`Attorney, Agent, or Firm-—R. G. Jackson; L. N.
`Goodwin; R. J. Klostermann
`[57]
`ABSTRACT
`An N-acetyl-p-aminophenol composition capable ‘of
`being directly formed into a tablet having high hard
`ness, short disintegration time and short dissolution time
`'is disclosed. The composition includes N-acetyl-p
`aminophenol, a pharmaceutically acceptable partially
`gelatinized starch, a pharmaceutically acceptable lubri
`cant, water and optionally an auxiliary binder, an auxil~
`iary disintegrant or both of these optional components.
`Also disclosed is a method for preparing the essential
`components (and optional components if desired) and
`spray drying the slurry.
`
`16 Claims, N0 Drawings
`
`Par Pharm., Inc.
`Exhibit 1031
`Page 001
`
`

`

`1
`
`N-ACETYL-P-AMINOPHENOL COMPOSITIONS
`CONTAINING PARTIALLY GELATINIZED
`STARCH AND METHOD FOR PREPARING SAME
`
`4,600,579
`2
`(C) a pharmaceutically acceptable lubricant in an
`amount at least suf?cient to impart effective
`mold release properties to said tablet,
`(b) spray drying said slurry under spray drying condi-
`tions such that the spray dried particles include
`water an amount from about 0.5 to about 1.5%
`based on the total weight of the composition,
`said components being distributed throughout the parti
`cles of said composition such that at least a portion of
`said lubricant is dispersed within said particles and at
`least a portion of the lubricant is disposed on the outer
`surfaces of said particles.
`In yet another aspect, generally stated, this invention
`provides an orally administerable analgesic tablet
`formed from the pharmaceutical composition described
`above.
`
`10
`
`The present invention relates to an N-acetyl-p-amino
`phenol composition containing partially gelatinized
`starch, to a method for preparing the composition and
`to orally administerable analgesic tablets formed from
`the composition.
`N-acetyl-p-aminophenol (hereinafter referred to
`sometimes as acetaminophen or simply APAP) is gener
`ally non-compressible, especially in forming orally ad‘
`ministerable tablets.
`Accordingly, there is a substantial need in the art for
`a direct tabletting, free-flowing particulate APAP com
`position capable of being directly formed into a tablet
`having high hardness, short disintegration time and
`short dissolution time.
`It has now been found by practice of the present
`invention that such APAP composition can be formed.
`Advantageously, the composition of the present in
`vention can be directly formed into tablets by tablet
`operators without need for admixing tabletting adju
`vants or aids.
`In various embodiments of the present composition
`described hereinbelow, the mutually con?icting needs
`for tablets having high hardness and low disintegration
`and/or dissolution times can be met.
`
`20
`
`25
`
`30
`
`DESCRIPTION OF THE INVENTION
`Generally stated, the present invention provides a
`direct tabletting, free-?owing particulate pharmaceuti
`cal composition capable of being directly formed into a
`tablet having high hardness, short disintegration time,
`and short dissolution time, the composition comprising
`as components thereof:
`(A) N-acetyl-p-aminophenol,
`(B) a pharmaceutically acceptable partially gelati
`40
`nized starch having a Percent Gelatinization of
`from about 50 to about 75% and in an amount
`effective for imparting said hardness, disintegration
`time and dissolution time,
`(C) a pharmaceutically acceptable lubricant in an
`amount at least sufficient to impart effective mold
`release properties to said tablet, and
`(D) water in an amount from about 0.5 to about 1.5%
`based on the total weight of the composition,
`said components being distributed throughout the parti
`cles of said composition in at least approximately the
`same distribution achieved when the composition is
`prepared by spray drying an aqueous slurry including
`said components (A), (B), and (C).
`In another aspect, generally stated, this invention
`provides a method for preparing a direct tabletting,
`free-?owing particulate N-acetyl-p-aminophenol com
`position capable of being directly formed into a tablet
`having high hardness, short disintegration time and
`short dissolution time, said method comprising:
`(a) forming a slurry containing components dispersed
`substantially uniformly throughout an aqueous
`medium, said components comprising:
`(A) N-acetyl-p-aminophenol,
`(B) a pharmaceutically acceptable partially gelati
`nized starch having a Percent Gelatinization of
`from about 50 to about 75% and in an amount
`effective for imparting said hardness, disintegra
`tion time and dissolution time,
`
`55
`
`65
`
`DETAILED DESCRIPTION OF THE
`INVENTION AND OF THE MANNER AND
`PROCESS OF MAKING AND USING IT
`The N-acetyl-p-aminophenol component of the pres
`ent invention is preferably provided in ?nely de?ned
`form, i.e., the APAP is preferably of small particle size.
`For example, it has been found that if more than 50% by
`weight of the APAP particles are larger than 200 mesh
`(U.S. standard sieve) then the spherical conformation of
`the particles of the composition is adversely affected.
`For use in the present invention, preferably all of the
`APAP particles will pass through a 200 mesh screen,
`more preferably 75% will pass through a 325 mesh
`screen and most preferably all will pass through a 325
`mesh screen.
`The partially gelatinized starch component of the
`direct tabletting composition has a Percent Gelatiniza
`tion of from about 50 to about 75%. As used herein, the
`term “Percent Gelatinization” is a measure of the extent
`of gelatinization of the partially gelatinized starch rela
`tive to fully gelatinized starch and means the percent of
`Starch 1551 by National Starch Company (a fully gela
`tinized starch) required in a two-component mixture
`thereof with fully non-gelatinized corn starch such that
`the value of spectrophotometric absorbance for the
`mixture at a wavelength of 340 nanometers is the same
`as the spectrophotometric absorbance value exhibited at
`such wavelength for the partially gelatinized starch
`being characterized as having a given value (%) of
`Percent Gelatinization, subject to the provisos (1) that
`the absorbance values for both such mixture and such
`partially gelatinized starch (PGS) are measured on sam
`ples prepared therefrom by the modi?ed-Shetty proce
`dure described hereinbelow and (2) that the percentage
`amount of moisture in the sample prepared from such
`PGS is at least substantially the same as that in the
`sample prepared from such mixture.
`The modi?ed-Shetty procedure referenced above is a
`modi?cation of the procedure for determining the de
`gree of starch gelatinization set forth in Shetty et al.,
`“Determining the Degree of Starch Gelatinization,”
`Cereal Chemistry, Vol. 51, No. 3, pp. 364-375 (1974),
`incorporated herein by reference. Brie?y stated, the
`procedure set forth in the above-cited Shetty et al. arti
`cle includes selective digestion of the starch with
`DIAZYME® glucoamylase (Miles Laboratories) to
`release D-glucose, working-up the digested starch,
`treating the digested and worked-up starch with Wor
`thington Reagent to impart spectrophotometric absor
`bancy to the treated starch and subjecting the resulting
`
`Par Pharm., Inc.
`Exhibit 1031
`Page 002
`
`

`

`4,600,579
`3
`4
`sample to spectrophotometry. In the modi?ed-Shetty
`the Percent Gelatinization of the PGS component is
`procedure the following modi?cations are employed:
`within the above range.
`(1) Initially, three portions of the starch are washed
`The PGS is included in an amount effective for im
`parting to the composition the capability of being
`with 100 ml methanol and passed through a S-micron
`formed into tablets having high hardness (e.g., about 8
`Millipore ?lter. The washed starch portions are dried
`kp or more), short disintegration time (e.g., about 10
`for about 16 hours at 50° C. prior to weighing and assay
`minutes or less) and short dissolution time (e.g., about
`ing.
`20 minutes or less for 80% or more of the APAP to
`(2) The glucoamylase starch digestion is incubated at
`50° C. for 30 minutes.
`dissolve).
`'
`As used herein, the term “kp” means kiloponds, a
`(3) The spectrophotometric absorbancy is measured
`well known unit of force for expressing hardness or
`at a wavelength of 340 nanometers for each of the three
`crushing strength of pharmaceutical tablets when such
`treated portions of the starch and the arithmetic mean of
`hardness is determined on a Schleuniger Tablet Hard
`the three absorbance measurements is taken as the “ab
`ness Tester.
`sorbance value” recited above.
`In general, such effective amount of PGS is from
`Approximate Percent Gelatinization values can be
`about 5 or less to about 15 or more parts per 100 parts
`conveniently determined using a correlation graph gen
`of the composition.
`erated for the following starch standards: fully non
`Advantageously and unexpectedly, tablets formed
`gelatinized corn starch (containing zero % gelatinized
`from the compositions of this invention are generally
`starch), fully gelatinized starch (Starch l55l-National),
`found to exhibit little or no variation in tablet disintegra
`and a set of binary mixtures thereof containing different
`tion time with variation in tablet hardness, especially in
`known amounts of the fully gelatinized starch. For
`higher hardness ranges, e.g., from about 8 kp to about
`example, absorbance was determined by the modi?ed
`15 kp and in some instances to about 20 kp. This sub
`Shetty method for a set of standards including such
`stantial independence of disintegration time is highly
`starches individually and binary mixtures thereof con
`advantageous in aiding tablet formulators to produce
`taining 20%, 40%, 60% and 80% of Starch 1551. The
`large commercial quantities of tablets of requisite disin
`results were plotted on Cartesian coordinates and
`tegration time with minimal concern for tablet-to-tablet
`showed a substantially linear relationship between the
`variations in hardness as typically result from the inher
`amount, in percent, of fully gelatinized starch and the
`ent limitations of tablet-forming equipment or human
`corresponding absorbancy. Three data-generation runs
`error of operators thereof.
`were made, with correlation factors found for the three
`Partially gelatinized starch suitable for use in the
`runs of 0.9926, 0.9974 and 0.9952. The ?nal correlation
`composition can be prepared using any suitable starch
`graph was a plot of the three-run average absorbances
`gelatinization method and stopping the gelatinization
`found for each of the six gelatinized starch amounts (0,
`when the desired Percent Gelatinization has been ob
`20, 40, 60, 80 and 100%) versus such amounts. The
`tained. A suitable PGS is also commercially available
`spectrophotometric samples prepared from each such
`from Colorcon, Inc., West Point, Pa. as Starch 1500
`standard had moisture contents in the range from about
`(preferred).
`3 to about 5%. Tests on spectrophotometric samples
`The lubricant component may be any pharmaceuti
`prepared from Starch 1500 (Colorcon, Inc.) had mois
`cally acceptable lubricant, which may be, e.g. hydro
`ture contents in the 3 to 5% range and the Percent
`philic or hydrophobic. This component is present in a
`Gelatinization of that herein preferred partially gelati
`lubricating amount at least suf?cient to impart mold
`nized starch was approximated as 57.7%, the value of %
`release properties to tablets formed of the compositions
`fully gelatinized starch on the ?nal correlation graph
`and preferably insuf?cient to increase disintegration
`for the average absorbance found for the samples pre
`time and dissolution time of such tablets, and preferably
`pared from Starch 1500.
`insuf?cient to decrease the hardness obtainable for tab
`The partially gelatinized starch (hereinafter referred
`lets formed from compositions of this invention contain
`to as PGS) serves to impart good binder and disinte
`ing lower lubricating amounts of the same lubricant.
`grant properties as well as a good balance thereof to the
`Suitable lubricants for use as the lubricant component
`composition, which can be directly tabletted to form
`include, for example, stearic acid; metallic stearate
`tablets having high hardness, short disintegration time
`(such as sodium, calcium, magnesium and zinc stearate,
`and short dissolution time.
`etc.); sodium lauryl sulfate; polyethyleneglycol; hydro
`The term “direct tabletting” and terms of like import,
`genated vegetable oils; talc; and compatible mixtures of
`as used herein, mean that the composition can be
`two or more such materials. Stearic acid is preferred.
`formed into a tablet using well known tabletting appara
`In general, the stearic acid or other lubricant compo
`tus and processes without need for addition of any adju
`nent may be present in an amount from about 0.10 to
`vant material to the composition. Inclusion of PGS
`about 0.4%, preferably from about 0.15 to about 0.25%,
`having a Percent Gelatinization of less than about 50%
`based on the total amount of the composition. In order
`(e. g., 45% or less) usually results in unacceptably lower
`to avoid decreasing the hardness of the tablets formed
`compressibility (as evidenced, e.g., by unacceptably
`from compositions including stearic acid, it is critical
`lower tablet hardness). Inclusion of PGS having a Per
`that the amount of stearic acid does not exceed about
`cent Gelatinization of more than about 75% (e.g., 80%
`0.25%.
`or more) usually results in unacceptably longer tablet
`The composition also includes water in an amount
`disintegration time and/or unacceptably longer tablet
`effective for aid in direct tabletting. Such effective
`dissolution time. The lower hardness, longer disintegra
`amount is, in general, found to be from about 0.5 to
`tion time and longer dissolution time are relative to the
`about 1.5% based on the total weight of the composi
`corresponding tablet hardness, disintegration and disso
`tion, preferably about 1.0% on the same basis.
`lution times obtained under identical tabletting condi
`Optionally, the composition may further include a
`pharmaceutically acceptable compressibility-promoting
`tions for otherwise identical compositions except that
`
`40
`
`60
`
`65
`
`25
`
`45
`
`50
`
`Par Pharm., Inc.
`Exhibit 1031
`Page 003
`
`

`

`5
`binder as an additional binding agent in an amount ef
`fective for increasing the obtainable hardness of tablets
`formed from the composition.
`Materials suitable for use as the optionally included,
`but preferably included additional binder agent include,
`for example, starch paste (fully gelatinized starch); pre
`gelatinized starch (a fully gelatinized starch); polyvinyl
`pyrrolidone; hydroxypropylmethylcellulose; hydroxy
`propylcellulose; gelatin; natural gums (e.g., gum acacia,
`gum tragacanth, etc); sucrose; mannitol; ethylcellulose;
`synthetic polymer binders commonly used in the indus
`try; and compatible mixtures of two or more such mate
`rials. Polyvinylpyrrolidone (PVP) is preferred (prefera
`bly PLASDONE® PVP by GAF C0rp.).
`In general, such effective amount of optional binder is
`from about 0.5 or less to about 1.4 or more parts, prefer
`ably not more than 1.4, more preferably about 1.2 parts,
`per 100 parts of the composition.
`Optional or auxiliary binders preferably are not in
`cluded in an amount in excess of 25 parts per 100 parts
`of the PGS component, especially where fully gelati
`nized starch (pregelatinized or otherwise) is employed
`as the optional binder.
`As a further option, the composition may further
`include a pharmaceutically acceptable disintegration
`promoting material as an additional disintegration agent
`in an amount effective for decreasing the obtainable
`disintegration time of tablets formed from the composi
`tion.
`Materials suitable for use as the optionally included,
`but preferably included, additional disintegration agent
`include, for example, starch (e.g., corn starch and other
`non-gelatinized starches); sodium carboxymethyl starch
`(sodium starch glycolate); microcrystalline cellulose;
`cross-linked cellulose; cross-linked polyvinylpyrroli
`done; soy protein; alginic acid and compatible mixtures
`of two or more of such materials. Cross-linked polyvi
`nylpyrrolidone (hereinafter referred to as XL-PVP),
`sometimes referred to in the art as cross-linked povi
`done, is preferred (preferably POLYPLASDONE
`40
`XL TM cross-linked N-vinyl-Z-pyrrolidone from GAF
`Corporation).
`In general, such effective amount of the optional or
`auxiliary disintegration agent is from about 1 or less to
`about 5 or more parts, preferably about 2.2 parts, per
`100 parts of the composition.
`In a number of important applications, it is desired
`that the APAP composition have the capability of being
`directly tabletted into tablets having a hardness of at
`least 12 kp (preferably at least 14 kp and, when formed
`into tablets having a hardness of 12 kp, such tablets to
`have a disintegration time of 5 minutes or less).
`In general, such very high hardness/very low disinte
`gration time compositions capable of being directly
`tabletted into tablets having a hardness of at least 12 kp,
`are provided by compositions embodying this invention
`wherein both the auxiliary binding agent and the auxil
`iary disintegration agent are included in amounts from
`about 0.5 to about 1.4 parts per 100 parts of the compo
`sition and from about 1 to about 5 parts on the same
`basis, such amounts being for the two optional agents in
`the order given.
`In a preferred embodiment, a composition having
`such very high hardness and very low disintegration
`time includes the following components in the amounts
`indicated (together with water in an amount from about
`0.5 to about 1.5% based on the total weight of the com
`position):
`
`10
`
`25
`
`35
`
`45
`
`55
`
`65
`
`4,600,579
`
`6
`
`COMPONENTS
`APAP (acetaminophen)
`Partially gelatinized
`starch
`Stearic Acid
`Polyvinylpyrrolidone
`Cross-Linked Povidone
`
`APPROXIMATE AMOUNTS
`93-83
`5-10
`
`0.1-0.4
`0.5-1.4
`1-5
`
`The amounts shown are in parts per 100 parts (dry
`basis) of the composition.
`The best embodiment composition of this invention
`contemplated at the time of executing this patent appli
`cation is as follows, wherein the amounts given are in
`parts per 100 parts (dry basis) of the composition:
`
`COMPONENTS
`APAP (acetaminophen)
`Partially gelatinized
`starch
`Stearic Acid
`Polyvinylpyrrolidone
`Cross-Linked Povidone
`
`APPROXIMATE AMOUNTS
`90
`6.45
`
`0.15
`1.2
`2.2
`
`The last-given embodiment includes water in an
`amount desirably from about 0.5 to about 1.5%, prefera‘
`bly about 1% based on the total weight (dry basis) of
`the composition. Such composition of the last-given
`embodiment can be repeatedly, in general, formed into
`tablets having hardness of 12 kp or more (often 14 kp or
`more) and having disintegration time of 5 minutes or
`less (often 4 minutes or less) at 12 kp hardness.
`In use, the compositions of this invention advanta
`geously may be composited with other active or inac
`tive ingredients, either prior to compositing the compo
`nents to form the composition or after the composition
`is formed (e.g., by dry blending the composition with
`such ingredients), and thereafter directly compressed
`into tablets having eminently suitable values of hardness
`and disintegration time for a variety of end-use applica
`tions.
`‘
`The compositions of this invention are preferably
`made by the method set forth in the above section enti
`tled “Description of the Invention”, i.e., including a
`spray drying step.
`The slurry preparation step is preferably carried out
`ina manner to achieve substantially complete hydration
`of the partially gelatinized starch component, prefera
`bly using a low shear mixing action so as not to increase
`the Percent Gelatinization of the PGS, at least not to
`increase it above the maximum desired percent gelatini
`zation of about 75%. Preferably, the stearic acid is thor
`oughly mixed in the slurry, i.e., substantially uniformily
`dispersed throughout the aqueous medium (e.g., water)
`employed.
`In the preferred embodiment of the method of this
`invention, the following procedure is followed.
`Slurry Makeup
`(A) To a suitable blender add the partially gelatinized
`starch and an equal amount of acetaminophen. There
`after, add a mixture of the stearic acid and cross
`linked povidone with stirring until a uniform blend is
`obtained.
`(B) Dissolve the polyvinylpyrrolidone in water, and,
`thereafter, to the resulting PVP solution add the
`blend from step A with agitation or mixing.
`
`Par Pharm., Inc.
`Exhibit 1031
`Page 004
`
`

`

`4,600,579
`8
`7
`(B) “dissolution time” means the time measured using
`(C) To the mixture resulting from step B add the bal
`ance of the acetaminophen while mixing is continued.
`the dissolution-time test method set forth in USP XX
`(D) Preferably, the agitation is continued until the re
`for APAP tablets;
`sulting slurry is smooth.
`(C) “hardness” means the hardness measured on a
`Spray drying conditions will be dependent on various 5 Schleuniger hardness tester;
`factors, such as feed slurry concentration, method of
`(D) “maximum hardness” means the maximum hard
`atomization, type of spray dryer, desired rate of drying,
`ness at which the tablets are substantially free of lamina
`relative humidity, and other factors which will be
`tion;
`readily apparent to those skilled in the art.
`(E) “friability” means the friability measured on a
`Preferred spray drying conditions are set forth in the 10 Roche Friabulator for 20 tablets and 100 revolutions.
`table below, along with an effective range of conditions
`In the Examples, unless otherwise indicated all tablet
`for each condition or parameter indicated, by way of
`hardness values are averages for 10 tablets and all tablet
`example for a counter-current spray dryer operated at a
`weights are averages obtained by weighing 20 tablets as
`slurry feed rate of about 10 kilograms per hour:
`a whole and dividing by 20. Unless otherwise indicated,
`.
`.
`.
`15 tablet disintegration times were measured for tablets
`spray Drying condltlons
`having about 12 kp hardness.
`
`Preferred
`
`Range
`
`.
`
`_
`
`.
`
`_
`
`.
`
`EXAMPLES 1-3
`
`Feed Slurry concentration
`Inlet mmpcmure
`Outlet temperature
`Awmization Pressure
`Feed Pressure
`
`35_6O%
`52%
`430° F 375° F7600» F,
`200" F.
`150° F.-250" F.
`28 Psi
`22-35 Psi
`52 PS‘
`45760 PS‘
`
`_ Compositions of this inyention were prepared follow
`20 mg the example preparation method referenced above.
`Shown in the table below are the components employed
`in the indicated amounts, together with measured tab
`letting results (i.e., tablet hardness, disintegration time
`and dissolution time).
`
`APpRoélMg‘TEB AMOUNTS
`a ( Ty as“)
`Ex. 2
`
`Ex. 3
`
`Ex. 1
`
`Practice of the present invention is illustrated by the 25
`following specific, but non-limiting examples. All
`amounts (including parts, %, etc.) given in the examples
`and throughout this disclosure, including the claims
`.
`.
`.
`.
`.
`which follow, are by weight unless indicated otherwise.
`gGp‘g‘p
`Unless indicated otherwise, the compositions in each 30
`(perm,t
`of the following Examples were prepared using the
`Gelatiriization)
`above described preferred method. This includes the
`Steam Acid
`steps of forming each slurry and spray drying the result=
`2132A“ Binder)
`ing slurry employing the preferred conditions set forth
`Xbpvp (Aux.
`above or at least substantially such preferred conditions. 35
`Disintegrant)
`Also, in each example unless indicated otherwise, spray
`drying was effected using counter current spray drying m
`in a counter-current spray dryer manufactured by Niro
`né?dness (lip)
`_
`9~3
`Atomizer Company (Model No. 6903) in accordance
`(Dh/lisi?figanon Tlme
`18'0
`with the manufacturer's instructions for use.
`Dissolution
`__
`The PGS employed was Starch 1500 (Colorcon, Inc.)
`Time (T85)
`having an approximate Percent Gelatinization of
`(angst, than 10 minutes
`57.7%.
`As indicated in these examples, Example 1 contains
`All tablets were formed on a Manesty B3B 16-stati0n
`rotary tablet press (commercially available from 45 neither auxiliary binder nor auxiliary disintegrating
`Thomas Engineering Company) in aCCOrdanCe With the
`agent; Example 2 includes an auxiliary binder but no
`manufacturer’s instructions for use. The press was ?tted
`auxiliary disintegrating agent; and Example 3 includes
`with a tablet tooling designed to make cylindrical tab-
`both an auxiliary binder and an auxiliary disintegrating
`lets, each tablet having Opposite bevcl-edgé ?at fac?s
`agent. The disintegration time shown for Example 2 is
`and overall diameter of 13/32 inch. The press was oper- 50 for 13 kp hardness tablets,
`ated to form tablets having a nominal weight of about
`EXAMPLES 4-8
`360 mg
`Additional compositions of this invention were pre
`As used herein, the following terms have the mean-
`pared following the example preparation method refer
`ings indicated:
`(A) “disintegration time” means the time measured 55 enced above. Shown in the table below are the compo
`using the disintegration-time test method set forth in
`nents employed (for each of these examples) in the
`Us Pharmacoepia (hereinafter “Usp’d XX for 11H"
`indicated amounts, together with measured tabletting
`coated tablets except that the disks are not employed;
`results (i.e., tablet hardness and disintegration time).
`
`C
`omponent
`
`40
`
`(57:7)
`
`0-2
`l_
`_
`
`sggs
`(57:7)
`
`0~15
`1 a
`'_
`
`13
`6
`_
`
`23
`(57:7)
`
`01
`112
`2:;
`
`9‘4
`1'5
`(a)
`
`Components
`
`Ex. 4
`
`90
`Acetaminophen
`7.75
`PGS
`Mm
`Stearic Acid
`0.15
`Sodium Lauryl
`0.1
`Sulfaie NF
`Auxiliary Binder
`
`1.0
`
`Approximate Amounts % (Dry Basis)
`Ex. 5
`Ex. 6
`Ex. 7
`Ex. 8
`
`90
`5.45
`
`0.15
`—-
`
`1.4
`
`90
`5.4
`
`0.1
`0.1
`
`1.4
`
`90
`4.45
`
`0.15
`—
`
`1.4
`
`9O
`4.45
`
`0.15
`-
`
`1.4
`
`Par Pharm., Inc.
`Exhibit 1031
`Page 005
`
`

`

`4,600,579
`
`9
`-continued
`Approximate Amounts % (Dry Basis)
`Ex.
`Ex. 5
`Ex. 6
`Ex. 7
`
`8
`
`10
`
`3.0
`
`3.0
`
`3.0
`
`1.0
`
`14 kp‘
`3-5 min
`
`14 kp“
`3-5 min
`
`14 kp*
`3-4 min
`
`14 kp‘
`3-4 min
`
`Ex. 4
`
`Components
`Polyvinyl
`pyrrolidone
`Auxiliary Disintegrant
`Microcrystalline
`Cellulose
`Cross-Linked
`Cellulose
`Corn Starch
`N.F.
`Protein“
`Tablet Results
`Hardness
`Disintegration
`Time
`‘greater than 14 kp
`"‘“Emcosoy“ (Edward Mendell Co.)
`
`14 kp*
`3-5 min
`
`EXAMPLES 9-12
`Examples 9-12 illustrate the unexpected relationship
`of maximum hardness to increasing amounts of stearic
`acid in the tabletted compositions when correspond
`ingly decreasing amounts of PGS are employed.
`Compositions of this invention were prepared follow
`ing the example preparation method referenced above.
`Shown in the table below are the components employed
`in the indicated amounts, together with the maximum
`tablet hardness.
`
`20
`
`25
`
`EXAMPLE 13
`Example 13 illustrates advantageously and unexpect
`edly minor variation in tablet disintegration time with
`different tablet hardness values obtained for different
`extents of compression of each of the compositions of
`Examples 9-12 above.
`Tabletting results are shown in the following table for
`Example 13, wherein the “Group” letters for each com
`position indicate different extents of compression as
`reflected by the hardness value for each Group.
`
`Hardness
`Composition Group (KP)
`Example 9
`A 10.1
`”
`B
`12.4
`”
`C 13.8
`"
`D 19.4(a)
`Example 10
`A
`9.4
`"
`B
`11.7
`"
`C
`16.0
`"
`D 18.5(a)
`Example 11
`A
`8.1
`"
`B
`13.2
`
`Table for Example 13
`Approximate Tablet Results
`Disin
`Friability
`tegration
`Time (rt-tin.) (%)
`1.42
`0.54
`1.55
`0.41
`1.55
`0.41
`3.30
`0.27
`1.30
`0.55
`1.55
`0.27
`2.10
`0.42
`3.00
`2.2(b)
`1.55
`1.15
`2.50
`—-
`
`Thickness
`(inches)
`0.169
`0.164
`0.160
`0.154
`0.170
`0.164
`0.158
`0.154
`0.167
`0.160
`
`"
`Example 12
`"
`"
`
`C
`A
`B
`C
`
`14.3(a)
`7.8
`9.7
`13.4
`
`"
`
`D 14.5(a)
`
`4.15
`2.00
`1.30
`4.00
`
`1.35
`
`-—
`1.35
`
`—
`
`0.159
`0.174
`0.163
`0.160
`
`0.160
`
`(a)maximum hardness
`(b)2 of the 20 tablets were observed to be capped
`
`Weight
`(mg)
`364
`362
`362
`366
`362
`362
`360
`360
`361
`—
`
`—
`371
`360
`—
`
`—
`
`AppRogbMaiEBgigouNTs
`
`55
`
`Component
`APAP
`PGS
`
`Ex. 9
`9o
`6A5
`
`Ex. 10
`9O
`64
`
`Ex. 11
`9O
`63
`
`Ex. 12
`90
`62
`
`In another embodiment, the compositions of this in
`vention can be prepared by co-current spray drying of
`slurries prepared as set forth above.
`Preferred co-current spray drying conditions are set
`forth in the table below for a slurry feed rate of about
`.
`,
`.
`400 kilo grams per hour, along w1th an effective range of
`conditions for each conditlon or parameter indicated:
`
`.
`
`.
`
`.
`
`(Percent
`Gelatinization)
`Stearic Acid
`Water
`PVP (Aux. Binder)
`XL'PV? ‘
`(Aux. Dtsintegrant)
`MEL
`Maximum Hardness (kp) ,
`
`(57.7)
`
`(57.7)
`
`(57.7)
`
`(57.7)
`
`60
`
`-
`-
`-
`Approximate Cond1t1ons
`
`015
`0.95
`1.2
`2-2
`
`0.2
`0.98
`1.2
`2-2
`
`0.3
`1.03
`1.2
`2-2
`
`0.4
`1.01
`1.2
`2-2
`
`19.4
`
`18.5
`
`14.3
`
`14.5
`
`Feed slurry concentration
`65 Inlet temperature
`Outlet temperature
`Atomization pressure
`
`Preferred
`53%
`520" F.
`200" F.
`2400-2800 psi
`
`Range
`35-60%
`300' F.-600° F.
`150' F.-250° F.
`1000-4000 psi
`
`Par Pharm., Inc.
`Exhibit 1031
`Page 006
`
`

`

`4,600,579
`
`11
`EXAMPLE 14
`In this example, the following preferred composition
`of this invention was prepared using substantially the
`same method employed in Examples 1-3 except co-cur
`rent spray drying was employed at a slurry feed rate of
`approximately 400 kg/ hr.
`The composition is set forth below:
`
`12
`
`What is claimed is:
`1. A method for preparing a direct tabletting, free
`flowing particulate N-acetyl-p-aminophenol composi
`tion capable of being directly formed into a tablet hav
`ing high hardness, short disintegration time and short
`dissolution time, said method comprising:
`(a) forming a slurry containing components dispersed
`substantially uniformly throughout an aqueous me
`dium, said components comprising:
`(A) N-acetyl-p-aminophenol in an analgesic amount,
`(B) a pharmaceutically acceptable partially gelati
`nized starch having a Percent Gelatinization of
`from about 50 to about 75% and in an amount
`effective for imparting said hardness, disintegration
`time and dissolution time, and
`(C) a pharmaceutically acceptable lubricant in an
`amount at least sufficient to impart effective mold
`release properties to said tablet