Note: Descriptions are shown in the official language in which they were submitted.
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DISINTEGI~NT COMPOSITION FOR DISPEI~TR~,F, SOl,TnS
Field Of The Invention
This invention relates to compositions and methods for preparing and using
the same, which compositions are useful as rapid disintegrants for water-dispersible
solid dosage forms of active agents. More particularly, this invention relates to
10 compositions comprising super disintegrants and co-disintegrants useful as
excipients for pharm~r.elltical, agricultural, food, industrial, household and like
commercially useful active compounds in solid dosage form which desirably shoulddisintegrate rapidly when placed in an aqueous environment. Compositions
cont~ining this novel disintegrant and an active agent, optionally with additives, is
15 also encompassed by this invention.
B~ ro-m-l Of The Inv~nti~n
It is the comrnon practice to m~nllf~cture solid dosage forms in which the
20 ingredients, i.e., active agents, excipients, adjuvants, etc. are processed into various
forms such as tablets, briquettes, pellets, granules, and the like. Among the more
preferred excipients are the disintegrants? and particularly super disintegrants, such
as croscarmellose or the like further described below. The solid dosage forms made
with these super disintegrants are durable and stable yet readily disintegrate when
25 added to an aqueous medium with concomitant release of the active components.
However, these super disintegrants are relatively expensive excipients.
Consequently, their application has been confined largely to high cost items such as
pharmaceutical tablets. They have not, for in~t~nre, proved economically feasible
30 in plepa~ g water-dispersible solid dosage forms of agricultural chemicals, e.g.,
insecticides, herbicides, fungicides, etc. which are of considerably lower per unit
price than pharrn~e~ltic~
Therefore, it is an object of this invention to provide compositions
35 combining a highly effective primary disintegrant (also referred to as super
disintegrant) with a co-disintegrant compositions which are at least as effective as
.. .. . . .. .. ~
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super disintegrants but which are much less costly, in which the co-disinte~rantsynergizes the disintegrant properties of the primary disintegrant.
Representative of earlier efforts in this field are, for example l}.S. Patent
4,744,987 (Mehra et al), directed to a blend of microcrystalline cellulose ~MCC)and calcium carbonate in pharm~ceut~ ls; PCT publication WO 92/12633 (Mehra
et al), which discloses a combination of MCC and a nitrogenous compound; and
Japanese Application 81/022,839 (Japan Metals and Chemical Co.) which employs a
disintegrant comprising bentonite and an alkali metal silicate for agricultural
1 0 formulations.
S-lmm~ry Of The lnv~nti--n
It has now been discovered, in accordance with the present invention, that
the quantity super disintegrants nl~ces~ry to rapidly disintegrate water-dispersible,
solid dosage forms cont~ining active agents may be substantially reduced, while at
the same time m~int~ining or increasing the rate of disintegration, by substituting
for a portion of the super disintegrant a co-disintegrant comprising a diatomaceous
earth, a hydrophilic zeolite or a combination thereof to obtain a disintegration rate
at least equal to, but preferably greater than that of the super disintegrant alone.
Alternatively, in accordance with this invention, a disintegration rate
increase can be achieved by simply adding minor amounts of co-disintegrant to a
constant amount of super disintegrant. Substitution of the co-disintegrant for super
disintegrant, is, however, preferred.
It will be understood, however, that in many applications, particularly those
used in relatively low unit cost formulations such as in the agricultural field, a less-
than-~ ulll disintegration rate may be justified if there is a sufficient cost saving.
Thus, for each application the weight percent of co-disintegrant which may be
substituted for the more costly super disintegrants in this invention is not a fixed
range, but rather may be adjusted to optimize either cost or disintegration rate, or
both.
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Generally, it has been found that the weight percent of the combined super
disintegrant and co-disintegrant which may be used in the total weight of any
formulation is about 0.0~ wt.% to about 10 wt%, preferably about 0.5-3.0 wt.%,
more preferably, about 1-3 wt%, depending on the nature of the active ingredients.
5 From these ranges it will thus be seen that the co-disintegrant alone, expressed as a
weight percent of the total composition, may comprise from about 0.01 to 9.0 wt%,
preferably about 0.1 to 2.7 wt%; and that the weight percent of the super
disintegrant may comprise from about 0.045 to 8.0 wt%, preferably about 0.045 to2.4 wt%.
The weight ratio of super disintegrant to co-disintegrant in the disintegrant
combination may range from about 4:1 to about 1:10~ preferably 3:1 to 1:5, and
most preferably about 2:1 to 1:1. That is to say, expressing it somewhat
differently, as much as about 25 to 90 wt. ~, preferably about 25 to 85 wt%, and15 more preferably about 33 to 50 wt%, of the amount of super disintegrant ~ se
which is necessary for sufficient disintegration may be replaced in the combination
of this invention by co-disintegrant by virtue of this discovery.
DF,TA~ ,n I)~ CRIPTIOI~
The composition of the invention may readily be prepared by combining the
super disintegrant with the co-disintegrant in any suitable manner for mixing
particulate materials, including dry blending, granulation, or the like. Such mixing
techniques are well known in the art.
Solid formulations are then prepared by mixing the blended components with
the desired active agent plus, if desired, any ancillary ingredients, and the resulting
mixture processed to include the desired forms such as tablets, pellets, beads,
granules, balls, bars, disks and briquettes. Wettable powders, which do not require
30 disintegrants, are excepted.
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Thus, formulations may be produced from the blend of disintegrants and
active agent by any of various known processes, including compression, roller
compaction, wet granulation, extrusion, spheronization, and/or pan granulation.
When tableting is the method selected for producing the solids, conventional
dry granulation, wet granulation, direct compression, spheronization or spray
drying may be used to prepare the blend for tableting. The selection of method
depends primarily on the active agent, the ability of the mixture of the disintegrants
and active agent to flow freely in the tableting m~rhinP or extruder, and the
cohesiveness of the ingredients. If the active agent can be admixed with the
disintegrants to produce a free flowing, dense powder, the mixture can be directly
compressed. In dry granulation, a dry powdery blend of the components is
compressed to form slugs if a tablet press is used. Alternatively, the dry blend is
roller compacted into sheets. The slugs or sheets are then sieved to form densified
granules for final tableting.
The hardness of the resulting tablet, granule, etc. can be determined
routinely by the formulator depending upon the amount and type of additives
employed and the degree of pressure in, e.g., the tableting machine. The degree of
hardness, may affect the disintegration rate, but as shown in Example 4 the increase
in disintegration time is not greatly affected by increasing hardness. For example,
tablets should be hard enough to resist ch~tking and/or breaking during normal
h~n~lling but readily disintegrate in an aqueous medium.
The super disintegrants which may be employed in this invention, and which
are well-known in the art, inc~ude such compounds as croscarmellose sodium (Ac-
Di-Sol, FMC Corp., Philadelphia, PA.), crospovidone, sodium starch glycolate,
and the like, or combinations thereof. See Handbook of Ph~ ceutical Excipients,
2nd Ed., American Pharm~ceutic~31 Association, pp. 141 et seq. (1994). Of these,croscarmellose sodium is ~lef~lled. Chemically, it will be seen that each of these
compounds represents examples of a wholly or partially cross-linked compound
such as a cross-linked cellulose or carboxymethyl cellulose, a cross-linked
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polymer, and a cross-linked starch, respectively. Also, other alkali metal salts may
be substituted for the sodium salts generally employed in these materials.
The co-disintegrant employed as the second component in the disintegrant
5 composition of this invention are water-insoluble, but highly hydrophilic materials
which include not only well-known natural diatomaceous silica (i e., kieselguhr or
infusorial earth), but also such materials as synthetic hydrous calcium silicateprepared by the hydrothermal reaction of natural diatomaceous silica and lime, in
which the lime content may range from 20 to 50 wt. %, usually about 26 wt% (e.g.,
10 Micro-Cel, sold by Manville Corp., Denver Colo.) In addition to lime there may
also be used m~gnf~sium compounds as well as other alk~linf earth elements in the
preparation of these synthetic materials. Of these silicas the synthetic calciumsilicate is preferred. Other silica-cont~ining materials, however, such as fumedsilica clays, and like inorganic substances are excluded from the purview of the15 invention. The co-disintegrant may also be a hydrophilic zeolite, preferably one
with large open pore structure for channeling of water into a compressed tablet.The co-disintegrant, it should be noted, as shown by the examples, should have
minim~l disintegrant properties when employed alone.
The active agents to be delivered with the disintegrants of the invention
include any liquids adsorbed on appropriate solids, semi-solids or solid compounds,
or mixtures of compounds which are to be eventually dispersed or dissolved in anaqueous medium including agricultural sprays, an industrial process or waste
stream, a body of water such as a river or lake, a swimming pool, an oil well, abody fluid, an aqueous food, food supplement or pharm~celltic~ or the like. Of
course, the active agent must not be reactive with the properties of the blend. The
solid forms of the invention, therefore, have application to a wide variety of fields
and products, including agricultural and veterinary products, pharmaceuticals,
~ animal and human foods, swimming pool additives, industrial biocides for oil wells
and other applications, co.cmPtics, household pesticides, industrial and laundrydetergents, and dye m~mlf~rtllring.
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The amount of active agent is not critical and thus can range broadly from
about 10 to 95 wt% of the total composition, with the balance comprising the
disintegrant of this invention plus, additives, adjuvants, etc., if any. Necessarily this
amount may encompass e.g. materials ranging from pharmaceutical to agricultural
5 materials, etc., plus necessary additives and adiuvants, and thus a large variation in
amounts must be determined by those skilled in each different art. It follows from
this, that the amount of disintegrant of this invention must also vary significantly
depending on the nature and amount of said active agent and other additives and
adjuvants, if any.
In the agricultural field, for example, the active agents include pesticides
such as herbicides, insecticides, fungicides, plant growth regulators, fertilizers and
biocides of all types. The pesticides include atrazine, benazone, bromoxynal,
trifluralin, propanil, metribuzin, alachlor, butachlor, bromoxynil, clomazone,
15 oxadiazon, lorsban, bifenox, aldicarb, monocrotophos, propoxur, diflubenzuron,
carbofuran, permethrin, carbonyl, cypermethrin, endosulfan, cyfluthrin, bifenthrin,
terbufos, fenamiphos, cadusafos, paclobutrazol, glyphosine, giberellic acid,
glycophosphate, phenylurea, and the like.
From these broad fields of use it follows that many other materials may be
included as additives, adjuvants, etc. in the final solid composition as long as they
do not interfere with the effectiveness of the active ingredient or disintegrantcomposition. Accordingly, those skilled in the formulations art will recognize that
various ingredients well-known to formulators of solid forms can be added to thecomposition of the invention to enhance the blending, shaping and like processes.
These include lubricants, gli-l~ntc, dispelsa~, suspending agents, surfactants, and
fillers or auxiliary binders, which are preferably employed in relatively small
amounts, if any, i.e., from zero up to about 20% by weight of the total solid dosage
form, more often less than about 10% by weight. However, this amount is not
critical and may comprise as much as a major proportion by weight i.e., in excess
of 50 wt% of the total formulation thus, in practice, the choice of additive and
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amount are matters of routine consideration and trial for the skilled formulator.
depending on the nature of the active agent
For example~ lubricants facilitate the ejection of compacted forms from a die
5 cavity. They may also reduce interparticle friction and prevent adhesion of
materials to die and punch surfaces. Typical lubricants are talc; long chain fatty
acid esters or salts thereof such as stearic and palmitic acids, and magnesium or
calcium stearate; and the like. Glidants are limited to improvement of the flow
properties of powders and granules, and include materials such as aerogenic silica,
10 fumed silicon dioxide and silica hydrogel
There may also be included as disintegrants such compounds as guar gum,
magnesium all-minllm silicate, copolymers of methacrylic acid with divinylbenzene,
potassium alginate, starch, and pregel~tini7~1 starch as additives to supplement the
15 above super disintegrants.
Other additives which may be utilized include known binders/fillers as
dicalcium phosphate, Starch I500 (sold by National Starch Co., Bridgewater N.J.),
lactose, and microcrystalline cellulose (MCC) compositions, for example, Lattice20 NTC 70, (sold by FMC Corp., Philadelphia, Pa.) which, is a coprocessed blend of
MCC and carboxymethyl cellulose or Lattice~, NT 200, which is microcrystalline
cellulose alone.
Dispersants may be employed to further break down disintegrated aggregates
25 to primary particle size, and include such materials as naphthalene condensates,
ligno-sulfonates, polyacrylates, and phosphate esters.
In the agricultural field particularly, the compounds are generally not applied
full strength but are typically applied as formulations which may be applied as such
30 or further diluted for application. Typical formulations include, for example, dust
and ~ranule compositions cont~ining the active ingredient in combination with one
or more agriculturally acceptable adjuvants, carriers or diluents, preferably with a
surface active agent, and optionally with other active ingredients. The choice of
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formulation depends, of course, on the type of pest and environmental factors
present at the particular locus of infestation.
With due consideration to these factors, the active ingredient of a typical
5 agricultural formulation may, for example, comprise 0.01 percent to 1 percent up to
about 90 or 95 percent by weight, preferably 1 percent up to 90 or 95 percent byweight, of the formulation. Agriculturally acceptable carriers, diluents, adjuvants,
surface active agents, and optionally other suitable active ingredients comprise the
balance of the formulation. Thus a typical formulation may contain from 0.01 to 95
(preferably 1 to 95) percent by weight active ingredient, from 0 to 30 percent by
weight surface active agent, and from 5 to 99.99 (preferably 5 to 99) percent byweight of an inert agriculturally acceptable carrier or diluent.
Granules, for agricultural use, for example, are solid or dry compositions of
15 active ingredient compressed, deposited, or agglomerated to forrn large particles.
Granules usually have an average particle size in the range of 150 to 5000 microns,
typically 425 to 850 microns. Granular formulations generally contain from 1 to 50
percent by weight of one or more of the surface active agents described above, and
from 50 to 98 percent by weight of one or more of the inert solid or dry carriers or
20 diluents described above. Granules may be produced by agglomeration of dusts or
powders, by compaction, by extrusion through a die, or by use of a granulation
disk.
The novel compositions of this invention provide not only a rapid rate of
25 disintegration of the solids at significant cost savings for super disintegrants, but
also, particularly in the pharmaceutical field, flexibility in dosage form design.
Furthermore, chemically incompatible actives, such as tablets cont~ining severaldifferent pesticides or combinations of herbicides and pesticides, can be separated in
the solid dosage forms by forming multilayers using known techniques.
The disintegrant composition of this invention may, as stated above, be
incorporated into conventional pharm~reutir~l preparations such as tablets (e.g.compressed tablets which may be coated, as with sugar paste). In such preparations
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the active agent may be present in admixture with a pharmacologically acceptablesolid carrier; for example it may be a solid such as corn starch. The dosage to ~e
employed may be determined by routine experimentation well known in the art.
The active agent may be ~lminictered in combination with other drugs together with
5 the novel disintegrant excipient.
The following examples will further illustrate the invention withoue limiting
the scope and spirit thereof, it being understood that the invention is entitled to the
full scope and range of equivalents intlic~ted in the appended claims.
In the following examples, Examples 1-7 show that synthetic, hydrous
calcium silicate works effectively with croscarmellose sodium, sodium starch
glycolate, and crospovidone three of the materials referred to above as 'super
disintegrants', in increasing the disintegration rate. Example 8 illustrates that
15 comparable results may be obtained with natural diatomaceous earth. It will be
noted that the combinations in the examples that included croscarmellose sodiurnwere most effective.
Since diatomaceous materials used have been approved for pharmaceutical
20 forrnulations, examples I through 4 are representative of a vitamin formulation,
such as niacinamide. Also, agricultural chemicals such as pesticides are frequently
tableted to produce unit doses that need only to be placed in a specified volume of
water prior to application. Example 5 is intended to exemplify the use of this
disintegrant combination in an agricultural pesticide forrnulation, since ferrous
25 sulfate is listed as a selective herbicide to control broadleaf weeds. Industrial uses
would include, for example, detergents such as are shown in examples 6 and 7, orgranular fertilizers, which could be formulated routinely by those skilled in the art.
Example 9 illustrates the use of a hydrophilic zeolite as a co-disintegrant.
In the examples, the additives include binders, such as microcrystalline
cellulose, starch and/or lactose, lubricants such as magnesium stearate and/or
stearic acid, and fillers such as dicalcium phosphate.
.. ~ . . ....
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J~xample 1
In a twin cone blender (made by Patterson-Kelley Co., East Strousburg, Pa.)
were combined 50 grams (25.0 wt %) of niacin~mi-le, 140 grams (70 wt %) of
5 dicalcium phosphate. 1.0 gram (0.5 wt %) of croscarmellose sodium (Ac-Di-Sol )(sold by FMC Corporation, Philadelphia, PA 19103), 4.0 grams (2.0 wt %) of
synthetic diatomaceous silica, and 4.0 grams (2.0 wt %) of stearic acid. All of
these dry materials had been passed through a 30 mesh U. S. Standard screen prior
to being placed in the blender. These components were blended for 10 minutes
10 after which 1.0 gram (0.5 wt %) of magnesium stearate was added to the blender.
Mixing was continued for an additional three minl-tPs. The blended material was
then colllplessed into tablets weighing 775 mg on a Stokes single station F press
(made by Stokes-Merrill, Inc., Bristol, Pa.) fitted with 12.7 mm (0.5 inch) flat-
faced, beveled-edge tooling. Twenty-four hours after compression, hardness was
15 measured for six tablets. The median hardness of these tablets was 10.2 Kp
(kiloponds). Also, disintegration tests were performed using USP 701 X XII
apparatus. These tests were done in 37~C distilled water. The average
disintegration time for six tablets was 1.3+0.4 minutes as judged usually. For
comparative purposes, a control formulation was pl el)al ed in which neither
20 croscarmellose sodium nor synthetic diatomaceous silica was included.
Two other formulations were also prepared, one in which 1.0 gram (0.5 wt
%) of croscarmellose sodium was included and the other in which 4.0 grams (2.0
wt %) of synthetic diatomaceous silica was included, but not both ingredients
25 simultaneously. In all co~ )alalive formulations the amount of dicalcium phosphate
was increased by the amount of diatomaceous silica and/or croscarmellose sodium
which had been omitted. The tablets were measured for hardness and disintegration
times in exactly the same llldnller as had been done for the tablets of this invention.
In Table 1 the tablets of the invention are labeled la, those of the control lb, those
30 in which diatomaceous silica was omitted lc, and those in which croscarmellose
sodium was omitted ld.
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Table 1
Formulation la lb lc ld
Ingredients (Weight Percent)
Niacinamide 25.0 25.025.0 25.0
Dicalcium phosphate 70.0 72.572.0 70.5
Croscarmellose sodium 0.5 0.5
Diatomaceous silica 2.0 . .0
Stearic acid 2.0 2.0 2.0 2.0
Magnesium stearate 0.5 0.5 0.5 0.5
Tablet Properties
Hardness (Kp) 10.2 10.510.1 10.1
Disintegration time (min)1.3+0.4 ,254.7+0.2 ,25
Fx~n~le 2
By the method of Example 1, S0 grams (25 wt %) of niacin~mide, 140
grams (70 wt %) of dicalcium phosphate, 1.0 gram (0.5 wt %) of sodium starch
glycolate, 4.0 grams (2.0 wt %) of synthetic ~i~tnm:lreous silica, 4.0 grams (2.0 wt
%) of stearic acid, and 1.0 gram (0.5 wt %) of magnesium stearate were combined
and compressed into tablets weighing 775 mg. The properties of these tablets were
1 0 measured as described in Example 1. Table 2 shows the formulations
corresponding to those in Table 1 with the sodium starch glycolate replacing
croscarmellose sodium. Example 2a is a formulation of the invention, and
Examples 2b-2d are comparative examples.
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Table 2
Formulation 2a 2b 2c 2d
Ingredients (Weight Percent)
Niacin~mide 25.0 25.025.0 25.0
Dicalcium phosphate 70.0 72.572.0 70.5
Sodium starch glycolate 0.5 0.5
Diatomaceous silica 2.0 2.0
Stearic acid 2.0 2.02.0 2.0
Magnesium stearate 0.5 0.50.5 0.5
Tablet Properties
Hardness (Kp) 10.8 10.511.2 10.1
Disinte~ration time (min)18.3+4.8 ,2523.0+3.4 ,25
Fxanlple 3
By the method of Example 1, 50 grams (25 wt %) of niacin~mide, 140
grams (70 wt %) of dicalcium phosphate, 1.0 gram (0.5 wt %) of crospovidone, 4.0grams (2.0 wt %) of synthetic diatomaceous silica, 4.0 grams (2.0 wt %) of stearic
acid, and 1.0 gram (0.5 wt %) of magnesium stearate were combined and
compressed into tablets weighing 775 mg. The properties of these tablets were
1 0 measured as described in Example 1. Table 3 shows the formulations
corresponding to those in Table 1 with the crospovidone replacing croscarmellosesodium. Example 3a is a formulation of the invention, and Examples 3b-3d are
comparative examples.
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Table 3
Formulation 3a 3b 3c 3d
Ingredients (Weight Percent)
Niacin~mirle 25.0 25.0 25.0 25.0
Dicalcium phosphate70.0 72.5 72.0 70.5
Crospovidone 0.5 0.5
Diatomaceous silica2.0 2.0
Stearic acid 2.0 2.0 2.0 2.0
Magnesium stearate 0.5 0.5 0.5 0.5
Tablet Properties
Hardness (Kp) 10.5 10.7 10.1
Disintegration time (min) 2.9+0.4 ,25 4.3+1.8 ,25
~x~n~le 4
In a twin cone blender were combined 125 grams (25.0 wt %) of
niacinamide, 350 grams (70 wt %) of dicalcium phosphate. 2.5 grams (0.5 wt %) ofcroscarmellose sodium, 10.0 grams (2.0 wt %) of synthetic diatomaceous silica. and
10.0 grams (2.0 wt %) of stearic acid. All of these dry materials had been passed
through a 30 mesh U. S. Standard screen prior to being placed in the blender.
These components were blended for 10 mim-tec after which 2.5 grams (0.5 wt %)
of magnesium stearate was added to the blender. Mixing was continued for an
additional three minutes. The blended material was then compressed into tablets
weighing 1750 mg on a Stokes single station F press fitted with 15.9 mm (0.625
inch) flat-faced, beveled-edge tooling. The compression forces were varied to
15 produce tablets having tablet hardness of 4, 8, and 12 Kp, respectively. Twenty-
four hours after cunlplession, hardness was measured for six tablets at each
~ compression force. Also, disintegration tests were performed using USP 701 XXII
apparatus. These tests were done in 37~C distilled water. The average
disintegration time for six tablets at each hardness was determined.
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WO 98/03064 14 PCT/US97/12183
For comparative purposes, a control formulation was prepared in which
croscarmellose sodium was the only disintegrant incorporated. ln the comparativeformulation the amount of dicalcium phosphate was increased by the amount of
synthetic diatomaceous silica that was omitted. Table 4 provides the composition of
5 the two formulations and a summary of hardness and disintegration times for the
tablets ~repalcd from them. Example 4a is a formulation of the invention, and
Example 4b is the comparative example.
Table 4
Formulation 4a 4b
Weight Weight
Ingredients Percent Percent
Niacinamide 25.0 25.0
Dicalcium phosphate 70.0 72.0
Croscarmellose sodium 0.5 0.5
Diatomaceous silica 2.0
Stearic acid 2.0 2.0
Magnesium stearate 0.5 0.5
Tablet Properties HardnessDisintegrationDisintegration
(Kp~time (min) time (min)
4.0 0.4 3.7
8.0 1.1 7.6
12.0 1 .9 1 1 .6
F.x~n~le S
In a twin cone mixer were placed 100 grams (50 wt %) of ferrous
sulfate, 62 grams (31 wt %) of anhydrous lactose, 30 grams (15 wt %) of Starch
1500, 4 grams (2 wt %) of microcrystalline cellulose (Lattice~X NTC-70, sold by
15 FMC Corporation, Philadelphia, PA), 2 grams (1 wt %) of sodium
croscarmellose, and 2 grams (1 wt %) of synthetic diatomaceous silica. All of
these dry materials had been passed through a 30 mesh U. S. standard screen
prior to being placed in the blender. These dry ingredients were blended for 10
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minutes after which they were placed in a 1.9 Iiter (2 quart) Hobart~ planetary
mixer. To the stirred dry mixture was added slowly 40 grams of distilled water.
Since a homogenous semi-paste was not formed with this amount of water,
additional water was added incrementally until the desired consistency was
5 ~tt:~in~l. A total of 78 grams (34 wt % of the dry formulation) of distilled water
was required to obtain this consistency. The paste that was formed was then
extruded through a 2.0 mm screen, and 35 grams of the extrudate was placed in
a 15.2 cm (6 inch) spheronizer operated at one-half speed for three minutes to
polish the product into uniform, dust-free granules. These granules were then
dried in an oven at 60~C for 120 minutes, resulting in a residual moisture below5%. The granule sizes ranged from 425-1180 microns. These granules were
described as being very durable. The disintegration time of the granules was
determined by the method of USP 701 XXII using a 100 mesh screen. A 5
gram sample of the granules was placed in the basket which was immersed in
15 37~C distilled water. The disintegration time of this sample was 1.1 minutes.This description is specific to Example 5a, but the same procedure was followed
for Examples 5b-5d. Table S shows the formulations corresponding to those in
Table 1, i.e. Example 5a is an example of the invention, and Examples Sb-Sd
are comparative examples.
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Table 5
Formulation 5a 5b 5c 5d
Ingredients (Weight Percent)
Ferrous sulfate 50 50 50 50
Lactose (anhydrous) 31 33 31 31
Starch 1500TM a) 15 15 15 15
Lattice NTC-70TMb) 2 2 2 2
Croscarmellose sodium 1 2
Diatomaceous silica 1 2
Water of granulation (%) 34 28 46 34
Granule Property
Disintegration time (min) 1.1 5.9 2.6 3.8
a) National Starch and Chemical Co., Bridgewater, N.J.
b) Microcrystalline cellulose in carboxymethyl cellulose ~FMC Corp.,
Phila, PA. )
Example 6
In a twin-cone blender were combined 133.2 grams (66.6 wt %) of Alconox
Detergent powder (Alconox, Inc., New York, NY 10003), an ~Ik~lin~ detergent
comprising a blend of sulfates, phosphates, and carbonates, and used, e.g., as alaboratory equipment cleaner, 60 grams (30.0 wt %) of Lattice NT200 (FMC
Corporation, Philadelphia, PA 19103), 3.0 grams (1.5 wt %) of croscarmellose
sodium (Ac-Di-Sol sold by FMC Corporation, Philadelphia, PA 19103), 3.0 grams
1 5 (1.5 wt %) of synthetic diatomaceous silica, and 0.8 gram (0.4 wt %) of magnesium
stearate. All of these dry materials had been passed through a 30 mesh U. S.
Standard screen prior to being placed in the blender. These co~ Jollenl~ were
blended for 5 minutes. The blended material was then compressed into tablets
weighing 3 grams on a Stokes single station F press fitted with 19.05 mm (0.75
20 inch) flat-faced, beveled-edge tooling. The compression forces applied were
sufficient to produce tablets having a hardness of approximately 5 Kp. Twenty-four
hours after col~ ssion, hardness was measured for six tablets. Also disintegration
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W O 98/03064 17 PCTAUS971~2183
tests were performed using USP 701 XXTI apparatus. These tests were done in
21 ~C distilled water. The average disintegration time for six tablets was
determined. For comparative pu poses, control formulations were prepared in
which no excipient was added; one in which only Lattice NT200 was included; one
5 in which only synthetic diatomaceous silica was in combination with Lattice NT200;
and one in which croscarmellose sodium was in combination with Lattice NT200.
In the comparative formulations the amount of Alconox detergent powder was
adjusted to make up for the added excipients. The comparative examples are
numbered 6a, 6b, 6c, and 6g, respectively. Table 6 provides the composition of all
1 0 formulations and a summary of hardness and disintegration times for the tablets
prepared from them. Examples 6d, 6e, and 6f are all examples of the invention;
however, Example 6e is the specific foLmulation of the invention that is described in
this example. All examples were prepared by the identical method, adjusting the
amounts of each component appl o~l iately .
Table 6
Example 6a 6b6c 6d 6e 6f 6g
Ingredient Weight Percent
Alconox 99.6 69.666.6 66.6 66.6 66.6 66.6
Microcrystalline
cellulosea 30.030.0 30.0 30.0 30.0 30.0
Croscarmellose
sodium - 0.75 1.5 2.25 3.0
Diatomaceous
silica 3.0 2.25 1.5 0.75
Magnesium
silicate 0.4 0.4 0.4 0.4 0.4 0.4 0.4
Tablet properties
Hardness (Kp) 5.4 4.9 4.7 5.0 4.9 4.9 4.8
Disintegration
time (seconds) > 1800 330 127 81 47 101 103
a Lattice N T200, F M C Corporation, Philadelphia, PA 19103
b Synthetic diatomaceous silica.
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W 098/03064 18 PCT~US97/12183
Example 7
By the method of Example 6, 136.2 grams (68.1 wt %) of Alconox
Delelgelll powder (Alconox, Inc., New York, N Y 10003), 60 grams (30.0 wt %) of
Lattice NT200, 1.5 grams (0.75 wt %) of croscarmellose sodium (Ac-Di-Sol ). 1.5
grams (0.75 wt %) of synthetic diatomaceous silica, and 0.8 gram (0.4 wt %) of
magnesium stearate were mixed in a twin cone blender. Tablets weighing
approximately 3.0 grams were compressed in the same manner as described in
Example 6. The same testing procedures were also used. This specific example is
identified as 7a, and the results for this example as well as two comparative
examples, 7b and 7c, are shown in Table 7.
Table 7
7a 7b 7c
Ingredient Weight Percent
Alconox 68.1 68.1 68.1
Microcrystalline cellulosea 30.0 30.0 30.0
Croscarmellose sodium 0.75 1.5
Diatomaceous silicab 0.75 - 1.5
Magnesium stearate 0.4 0.4 0.4
Tablet properties
Hardness (Kp) 5.0 5.2 5.2
Disintegration time
(seconds) 147 222 288
a Lattice NT200, FMC Corporation, Philadelphia7 PA 19103
b Synthetic diatomaceous silica.
Example 8
By the method of Example 6, 133.2 grams (66.6 wt %) of Alconox
Detelgelll powder 60 grams (30.0 wt 5~O) of Lattice NT200, 3 .0 grams (1.5 wt %)of croscarmellose sodium (Ac-Di-Sol ), 3.0 grams (1.5 wt %) of natural
diatomaceous silica, and 0.8 gram (0.4 wt ~) of magnesium stearate were mixed ina twin cone blender. Tablets weighing approximately 3.0 grams were compressed
in the same manner as described in Example 6. The same testing procedures were
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W O 9810306~ ~9 PCT~US97/12183
also used. This specific example of the invention is identifled as 8a. The results
for this example as well as comparative examples 6g, 8b, and 8c are shown in Table
8.
Table 8
6g 8a 8b 8c
lngredient Weight Percent
Alconox 66.6 66.6 66.6 68.1
Microcrystalline cellulosea 30.0 30.0 30.0 30.0
Croscarmellose sodium 3.0 1.5 - -
Diatomaceous silicab - 1.5 3.0 1.5
Magnesium stearate 0.4 0.4 0.4 0.4
Tablet properties
Hardness (Kp) 4.8 4.9 4.7 5.1
Disintegration time
(seconds) 103 138 178 329
a Lattice NT200, FMC Corporation, Philadelphia, PA 19103
b Natural diatomaceous silica.
F.~n~le 9
ln a twin cone blender were combined 173.2 grams (86.6 wt. %) of
automatic dishwashing deLel~ellt powder (an ~Ik~linP detergent comprising a blend
of sulfates, citrates and carbonates), 20.0 grams (10.0 wt. %) LatticeTM NT200,
3.0 grams (1.5 wt. %) modified cellulose gum (Accelerate DS812, sold by FMC
Corporation, Philadelphia. PA 19103) and 0.8 gram (0.4 wt. %) magnesium
stearate. Co-disintegrants were then added by blending 3.0 grams (1.5 wt.%) of
each test additive (synthetic diatomaceous silica, zeolite). All of these dry
materials had been passed through a 30 mesh U.S. standard screen prior to being
placed in the blender. These components were blended for 5 minutes. The blended
material was then compressed into tablets weighing 3 grams on a Stokes single
station F press fitted with 19.0 mm (0.75 inch) flat faced, beveled edge tooling.
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W O 98/03064 20 PCT~US97/12183
The coll,pression forces applied were sufficient to produce tablets having a
hardness of approximately 6 Kp. Twenty-four hours after compression, hardness
was measured for six tablets . Also disintegration tests were done in 21~C distilled
water. The average disintegration time for six tablets was determined. This is
5 Example 9a in Table 9. For colllpalaLive purposes, control formulations were
prepared in which no excipient was added; one in which only synthetic
diatomaceous silica was added; one in which only zeolite was added. In the
control formulation the amount of delel~enL powder was adjusted to make up for
the excipients, which were excluded. Table 9 provides the composition of all
10 formulations and a summary of hardness and disintegration times for the tablets
prepared from them. Examples 9a and 9b are examples of the invention. Example
9c is included in Table 9 for comparison.
Table 9
Formulation 9a 9b 9c
Automatic dishwashing
powderCD 86.6 86.6 86.6
LatticeTM NT 200 10.0 10.0 10.0
Modified cellulose gum 1.5 1.5 3.0
Di~tom~eous silica 1.5
Zeolite l.S
Magnesium stearate 0.4 0.4 0.4
Tablet pl~e~Lies
Hardness(Kp): 6.4+0.2 6.0+1.1 6.8 + 0.3
Disintegration time
(minutes): 4.1 + 1.2 5.8 + 1.0 9.8 + 0.9
From the above illustrations it will be seen most clearly that (i) in all the
examples, t'ne combination of a super disintegrant and a diatomaceous earth results
in a faster disintegration rate than a super disintegrant alone; (ii) Examples 1-3,
20 with their greater than 25-minute disintegration time, show that diatomaceous earth
alone does not act as an effective disintegrant, yet when added to a super
disintegrant it increases the rate of the latter; (iii) this is particularly true of the
combination of croscarmellose sodium and synthetic diatomaceous silica of Example
4, where, despite increasing hardness of the tablets tested, the disintegration time is
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W 098/03064 21 PCTrUS97/12183
not increased greatly, and indeed is improved with one combination (4a). as muchas four-fold; and (iv) as shown by Example 5, the reduction of the amount of more
costly super disintegrant and its replacement with less expensive diatomaceous earth
(5a) nevertheless resulted in a significant improvement in the disintegration rate
5 over the use of double the amount of super disintegrant alone (5c).
In Example 6, it will be seen that in Examples 6(d), 6(e), and 6(f). where
the disintegrants are combined in accordance with this invention, (where 6(e)
represents the specific formulation of the invention that is described in Example 6)
the disintegration rate is superior to that of any of the control examples; (a), (b), (f),
10 and (g). This is especially evident in Examples 6(e) and (c), where increasedamounts of diatomaceous silica are substituted for the super disintegrant. In
Example 7 this improvement is also demonstrated, especially in view of one of the
disintegration rates in Example 7(a), of the invention, which is about half that of the
control examples. In Example 8a, it will be seen that the combination of super
15 disintegrant with natural diatomaceous earth is effective over diatomaceous silica
alone.
