U.S. patent number 3,622,677 [Application Number 04/839,590] was granted by the patent office on 1971-11-23 for compressed tablets containing compacted starch as binder-disintegrant ingredient.
This patent grant is currently assigned to A. E. Staley Manufacturing Company. Invention is credited to Rolland W. P. Short, Frank Verbanac.
United States Patent |
3,622,677 |
Short , et al. |
November 23, 1971 |
**Please see images for:
( Certificate of Correction ) ** |
COMPRESSED TABLETS CONTAINING COMPACTED STARCH AS
BINDER-DISINTEGRANT INGREDIENT
Abstract
A directly compressed tablet containing as a binder-disintegrant
ingredient, a partially cold-water soluble, cold-water swelling
starch material derived from compacted granular starch, e.g.
compacted native corn starch. The compacted granular starch is a
superficially dry, free-flowing powder in which the starch is in
the form of a mixture of birefringent granules and nonbirefringent
fragments of granules, in which some aggregates of granules and
fragments are present. The use of the starch binder-disintegrant
ingredient allows active ingredients, e.g. pharmaceuticals, to be
tabletted by direct compression.
Inventors: |
Short; Rolland W. P. (Decatur,
IL), Verbanac; Frank (Decatur, IL) |
Assignee: |
A. E. Staley Manufacturing
Company (Decatur, IL)
|
Family
ID: |
25280152 |
Appl.
No.: |
04/839,590 |
Filed: |
July 7, 1969 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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646496 |
Jun 16, 1967 |
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Current U.S.
Class: |
514/778; 127/32;
264/118; 514/474; 514/960; 504/189; 8/526; 252/1; 514/166; 514/629;
106/206.1 |
Current CPC
Class: |
A61K
9/2059 (20130101); A61J 3/10 (20130101); Y10S
514/96 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61J 3/10 (20060101); A61j
003/10 () |
Field of
Search: |
;424/361 ;252/1 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rose; Shep K.
Parent Case Text
CROSS-REFERENCE
This application is a continuation-in-part of application Ser. No.
646,496, filed June 16, 1967 now abandoned.
Claims
We claim:
1. A directly compressed tablet requiring a disintegrant and a
binder, having resistance to breaking and crumbling, and being
capable of disintegrating in an aqueous medium, said tablet
comprising (a) an active ingredient by which said tablet derives
its utility and (b) a pulverulent cohesive binder for said active
ingredient, said binder comprising as the only dual-function binder
and tablet-disintegrant a directly compressible compacted starch
powder in a concentration that provides substantial binding action
and substantially accelerates disintegration of said tablet in an
aqueous medium, said compacted starch powder being a superficially
dry, free-flowing material in which the starch is in the form of a
mixture of birefringent granules and nonbirefringent fragments of
granules, in which some aggregates of granules and fragments are
present and having a cold-water solubility in the range of from
about 4 to about 40 percent by weight, dry substance basis, a
swelling power in the range of from about 2.5 to about 12, a loose
bulk density in the range of from about 0.50 to about 0.70 gram per
milliliter, a moisture content in the range of from about 9 to
about 16 percent, total weight basis, and a particle size
distribution such that said powder is essentially free of +40 mesh
size material and that on a total weight basis, at least 90 percent
of said powder is -80 mesh size, at least about 10 percent of said
powder is +270 mesh size, and from about 30 to about 90 percent of
said powder is -270 mesh size said powder being adapted to function
as the essential, bifunctional disintegrant and binder in the
direct compression method of tablet manufacture.
2. The compressed tablet according to claim 1 wherein said active
ingredient is a pharmaceutically active compound.
3. The compressed tablet according to claim 1 wherein said active
ingredient is a nonpharmaceutically active compound.
4. The compressed tablet according to claim 1 wherein said
compacted starch powder constitutes at least about 50 percent of
the total weight amount of binder in said tablet.
5. The compressed tablet according to claim 1 wherein the amount of
said active ingredient in said tablet is in the range of from about
5 percent to about 90 percent dry substance weight basis.
6. The compressed tablet according to claim 1 wherein said
compacted starch powder constitutes at least about 50 percent of
the total weight amount of binder in said tablet, has a cold-water
solubility in the range of from about 6 to about 20 percent, dry
substance weight basis, and a swelling power in the range of from
about 3.5 to about 10, and contains, on a total weight basis, from
about 45 to about 75 percent of material which is -270 mesh.
7. The compressed tablet according to claim 6 wherein said
compacted starch is a compacted granular cornstarch raw
material.
8. The compressed tablet according to claim 7 wherein said granular
cornstarch raw material is bleached native cornstarch and said
compacted starch powder has a cold-water solubility in the range of
from about 6 to about 15 percent, dry substance weight basis, and a
swelling power in the range of from about 5 to about 8.
Description
DISCLOSURE OF THE INVENTION
This invention relates to the manufacture of compressed tablets and
more particularly to compressed tablets which contain a starch
binder-disintegrant ingredient in the form of a directly
compressible compacted starch powder which permits the tablets to
be made by the direct compression technique.
Of the multitude of forms in which pharmaceutical products may be
dispensed, the compressed tablet form is, by far, that most
frequently employed today. Ease of packaging and handling, and,
most important accuracy of dosage in administration are among the
advantages stemming from the use of medicament-containing tablets.
For essentially the same reasons, the compressed tablet also plays
an important role in other fields as a dispensing unit. Examples of
nonpharmaceutical materials marketed in compressed tablet form
include such diverse materials as laundry detergents, confections,
artificial sweeteners, fish foods, plant growth regulators,
pesticides, herbicides, and dyes. While the actual characteristics
of various tablets differ depending on the particular nature and
planned use of the several tablets, the generally more important
characteristics fall into three areas of consideration.
Since most tablets are designed for use in accurately dispensing an
active material into a fluid medium, an evaluation of the tablet
includes a consideration of the tablet disintegration properties in
the fluid medium. While some tablets such as those designed for use
as a throat lozenge desirably are slowly disintegrative in the
fluid medium in which they are placed for use, in most cases rapid
disintegration of the tablet is desired. For example, a tablet
embodying an ingestible analgesic, such as aspirin, should rapidly
break down in the digestive fluid of the stomach to make the active
ingredient promptly available to the organism. The present
invention is particularly concerned with such tablets of relatively
rapid disintegration capability.
The second and third important tablet characteristics, friability
and hardness, are somewhat related in that as tablet hardness
increases the friability of the tablet generally decreases.
Excessive friability is undesirable since dusting and crumbling of
the tablet results in at least some diminution in active ingredient
dosage, detracts from the tablet appearance and consumer appeal,
and reduces the effectiveness of any tablet markings.
Insufficiently hard tablets, in addition to exhibiting the effects
of excessive friability, are prone to breakage and chipping,
particularly in transport where they may be subjected to repeated
mechanical shock.
Accordingly, for most purposes, and particularly for pharmaceutical
application, a hard, nonfriable tablet possessing acceptable
disintegration characteristics is the goal of the tablet
manufacturer. Other properties are, of course, important such as
color stability and nonhygroscopicity but the desideratum remains
the production of a tablet of the type described.
Certain materials such as sodium chloride, paradichlorobenzene,
hexamethylenetetramine, and certain medicaments are readily
directly compressed alone in dry form into a firm, coherent mass in
a tablet machine. However, the majority of active ingredients in
order to be tabletted require a binding agent to be added. The
tabletted formulations generally also contain additional
ingredients, such as lubricants, disintegrants, fillers, colorants,
and the like. The terms "binding agent," "binder," and "filler" are
self-explanatory. A disintegrant is an agent which is effective,
when the tablet is placed in the proper fluid environment, to
promote destruction of the tablet's physical integrity. A typical
disintegrant employed in tabletting is granular starch.
A given material may perform more than one of the single functions
of binding, filling, and promoting disintegration. The principal
component, other than the active ingredient, that is employed to
provide the improved compressed tablets of the present invention is
such a dual-functioning material and is referred to herein as a
"binder-disintegrant."
In general, three methods are known for the preparation of mixtures
suitable to be employed in a tablet-making machine. In two of the
methods commonly used for the preparation of tabletting machine
feed material, the goal in each is the preparation of the feed
material in the form of free-flowing granules. One technique
involves a dry, and the other a wet, method of granulation. Dry
granulation is also referred to as "slugging" or "double
compression." In accordance with the slugging technique, the
initially prepared pulverulent admixture of active ingredient,
filler, binder and the like is formed into large tablets or slugs
by dry compression molding. These slugs are then milled to granules
of predetermined size adapted to be used as the feed to the
tablet-making machine. This method is expensive, requiring
considerable equipment, labor, and power. The technique, moreover,
does not always provide suitable tablets.
The wet granulation technique involves adding a moistening agent
such as water or ethylene glycol to the tabletting ingredient
mixture to prepare a moistened mass, oven drying the wetted mass,
and milling the dried mass into granules adapted to be used in the
tabletting machine. The wet granulation method likewise is
undesirably time consuming and expensive. This method, moreover,
has the limitation of not being useful when the tablet ingredients
are incompatible to wetting or are heat sensitive.
The third and simplest procedure employed in preparing tabletting
formulations involves intimately and uniformly dry blending the
ingredients employed, e.g. active ingredient, binder, filler,
disintegrant, and lubricants, to provide a pulverulent mixture
displaying the requisite flowability for adequate feeding to the
tablet machine. Since in this method the granulation step is
eliminated, the formulations are said to be "directly compressible"
into tablets, and the tablet-forming operation is referred to as
"direct-compression" tabletting. This procedure, by virtue of its
simplicity, obviously is preferred for use. Using ingredients
heretofore available, however, the ingredient mixtures obtained by
mere dry mixing generally do not exhibit adequate flowability and
are not adapted to be fed directly to the tabletting machine to
prepare tablets of uniform and acceptable properties. The limited
acceptance of preparing compressed tablets by direct compression
has stemmed principally from the unavailability of suitable and
inexpensive direct compression binding agents. Of those materials
which do qualify by reason of their binding properties, moreover,
few are characterized by satisfactory overall properties. For
example, the most widely used material at present for binding
tablets by the direct compression method, spray-dried lactose, is
unacceptable in many uses because of its marked tendency to turn
brown on aging. The great percentage of tabletting operations,
therefore, have been forced to resort to other formulation
techniques such as the wet and dry granulation methods, and the art
has continued to search for an improved material capable of being
employed as a binder in the preparation of tablets by direct
compression which are rapidly disintegrative, resistant to breakage
and crumbling, and otherwise satisfactory.
Accordingly, it is an object of the present invention to provide an
improved binder for the manufacture of compressed tablets. It is
another object of the invention to provide such an improved binder
having characteristics that permit it to function also as a
disintegrant. It is an additional object of the invention to
provide active ingredient, binder ingredient formulations directly
compressible into tablets. It is yet a further object of the
invention to provide a compressed tablet containing a
binder-disintegrant ingredient, the tablet being hard, nonfriable,
and readily disintegrative in an aqueous medium. Yet another object
of the invention is to provide a method for preparing compressed
tablets. A particular object of the present invention is to provide
a means whereby tablets of excellent properties can be prepared by
direct compression. The means of attaining these and related
objects will be evident from the following description and
examples.
For a more complete understanding of the nature and scope of the
invention reference may now be had to the following detailed
description thereof with illustrative working examples, and to the
accompanying drawings, wherein:
FIG. 1 is a photomicrograph, taken under bright field illumination
of ordinary corn starch at a magnification of 425;
FIG. 2 is a photomicrograph corresponding to FIG. 1 but with the
light polarized;
FIG. 3 is a photomicrograph, taken under bright field illumination
of compacted corn starch, useful in accordance with the present
invention, at a magnification of 425; and
FIG. 4 is a photomicrograph corresponding to FIG. 3 but with the
light polarized.
Compacted starches constitute a known class of materials. They are
prepared by subjecting a granular starch raw material to pressure
in the presence of water to effect distortion and fracture of at
least some of the granules and produce adhesion between particles
of the resultant mass. The resultant compacted material may have
differing cold-water swelling properties and contain varying
amounts of cold-water soluble material depending primarily upon the
particular pressure, temperature, and moisture conditions utilized.
Specific techniques commonly employed include passing the starting
starch through the nip of rotating rolls operating at the same or
different speeds, as described in U.S. Pat. Nos. 2,098,293;
2,168,524; 2,464,081; and 3,196,044, and working the starch in the
course of an extrusion operation as shown in U.S. Pat. Nos.
3,137,592 and 3,159,505. Compacted starches heretofore have found
utility primarily as "dustless" carbohydrate nutrients in the
brewing industry and as binders in the preparation of rough-molded
products containing relatively coarse aggregate materials such as
foundry cores and charcoal briquettes.
It now surprisingly has been discovered that certain compacted
starch powers, described more fully hereinafter, advantageously are
characterized by properties which enable them to be dry mixed with
active ingredients and conventional tabletting aids, such as
fillers, lubricants, and the like, to prepare active
ingredient-containing formulations which are directly compressible
into tablets in conventional tabletting equipment. The present
invention therefore provides a highly valuable means whereby
tabletting operations may be greatly simplified, and the
troublesome and time-consuming preliminary granulation and slugging
steps which characterized most tabletting operations heretofore
available may be eliminated. The compacted starch powders employed
in the present invention, moreover, advantageously are
characterized by properties which satisfy both the requirements of
a binder for the active ingredient and a disintegrant for the
tablet in aqueous media. Consequently, suitable direct compression
tablets of satisfactory hardness, friability, and disintegration
properties advantageously may be prepared by means of the present
invention using the compacted starch powders as a sole,
dual-functioning binder-disintegrant, and the heretofore commonly
required practice of adding separate ingredients as the binder and
disintegrant with the attendant problems of properly mixing
multiple ingredients and balancing dosage levels no longer need be
followed. The starch binder-disintegrant ingredient employed in
preparing direct compression tabets in accordance with the present
invention, furthermore, easily and cheaply may be obtained from
readily available and inexpensive starting raw materials, namely
granular starches. Of such binder-disintegrant compacted starches
many embodiments are characterized by low color, color stability,
and acceptability for human consumption. The present invention,
therefore, includes what may be said to be a "universal" ingredient
for direct compression tabletting, whereby a wide range of active
ingredients, including many pharmaceuticals tabletted heretofore
only with great difficulty, if at all, now easily and inexpensively
may be satisfactorily tabletted by direct compression.
The compacted starch powders employed in the practice of the
present invention are derived from appropriately compacted granular
starch raw materials and are superficially dry, free flowing,
partially cold-water soluble materials which swell in cold water
and have a relatively high loose bulk density. The powders
themselves are directly compressible in conventional tabletting
equipment into relatively rapidly disintegrative placebo tablets of
high hardness and low friability. Microscopic examination of the
compacted starch powders reveals the starch content of the
materials to be in the form of a mixture of birefringent granules
and nonbirefringent fragments of granules, in which some aggregates
of granules and fragments are present. These characteristics of the
compacted starch powders on microscopic examination are apparent
from the photomicrographs reproduced in FIGS. 1-4. In FIG. 1
granules of ordinary corn starch are shown as viewed with
unpolarized light at 425 magnification. FIG. 2 shows the same
granules viewed with the light polarized at the same magnification.
It will be noted that in FIG. 2 the granules all exhibit
birefringence (i.e. the crosses) which is characteristic of starch
granules.
In FIG. 3 a sample of compacted starch powder, which is directly
compressible into tablets in accordance with this invention, is
shown as viewed with unpolarized light at 425 magnification. A
number of starch granules appear in FIG. 3 along with aggregates
and granular fragments. When the same sample of compacted starch
powder is viewed under polarized light at the same magnification,
it is clearly seen that the sample is a mixture of birefringent
granules and nonbirefringent fragments of granules, in which there
are aggregates of granules and fragments.
Compacted starch powders of the invention have the following
characteristics:
Property Broad Preferred
__________________________________________________________________________
Cold-water Solubility, % 4-40 6-20 Swelling Power 2.5-12 3.5-10
Loose Bulk Density, g./ml. 0.50 0.55-0.70 minimum Placebo Tablet
(Direct Compression) Properties Hardness, kg. 5 8 minimum minimum
Friability, % wt. loss 1.0 0.5 maximum maximum Disintegration Time,
min. 30 15 (in water) maximum maximum
__________________________________________________________________________
As used herein, the term "superficially dry" is intended to
indicate a powder is dry in the visual and tactile sense. A
"placebo" tablet is a tablet prepared by directly compressing one
material alone such as a compacted starch powder. The terms
"cold-water solubility," "swelling power," "hardness,"
"friability," "disintegration time," and "granular starch raw
material" are defined as follows:
Cold-water solubility-- The percent by weight of the starch dry
substance which dissolves in water at 25.degree. C. when determined
by the following procedure: One gram of the starch product being
tested is added to 100 ml. of water at 25.degree. C. in a
high-shear blender and mixing is carried out at 1,500 r.p.m. for 2
minutes. The resultant sample is then transferred to a 250 ml.
round-bottom centrifuge tube and centrifuged for 15 minutes at
2,000 r.p.m. A 25 ml. aliquot of the clear centrifugate is
transferred to a tared aluminum pan and evaporated to dryness on a
steam bath. The dish is then dried to a constant weight at
110.degree. C. The weight of the dried material in the pan
multiplied by 400 and divided by the dry substance weight of the
original sample is the cold-water solubility of the starch
material. By this test commonly available granular starches are
essentially cold-water insoluble, generally containing less than
about 2 percent by weight cold-water solubles and in the case of
unmodified starches less than about 1 percent.
Swelling power-- a measure of the ability of a starch to swell in
cold water as determined by method 56- 20 of "Cereal Laboratory
Methods" published by the American Association of Cereal Chemists.
For reference purposes, uncompacted granular starches generally
have a swelling power on the order of about 2.
Hardness--a measure of the strength of tablets (average of 10 or
more tablets) and their ability to retain their physical integrity,
expressed in terms of kilograms, as determined by the conventional
procedure using a model B tablet hardness tester of the
Strong-Cobb-Arner Company, Cleveland, Ohio, to obtain an indicated
pressure gauge reading at fracture of the tablet (tablet mounted on
edge in tester) and multiplying the indicated hardness value by a
factor of 0.78 to convert the gauge reading to actual pressure. For
example, a satisfactory active ingredient-containing tablet
generally should have a hardness in this test of at least about 4
kg.
Friability--a measure of the tendency of tablets (average of 10 or
more tablets) to crumble and dust, expressed in terms of percent
weight loss, as determined by the "Roche" test described in the
Journal of the American Pharmaceutical Association, Scientific
Edition, Vol. 45 pages 114- 116 (1956). For reference purposes, an
active ingredient-containing tablet displaying a weight loss of
less than about 1.0 percent generally is considered to have
acceptable friability.
Disintegration time--the time observed for tablets (range of six
tablets) to disintegrate in water as determined by a modification,
in which the use of discs is eliminated, of the procedure for
uncoated tablets described in Pharmacopeia of the United States of
America, 16th Edition, 934- 936 (1960).
Granular starch raw material-- the starting starch which has been
compacted in the preparation of the compacted starch powders of the
invention. The starting starch suitably may be any granular starch
derived from the root, stem, or fruit of a plant. Specific examples
of starch-yielding sources include corn, rice, wheat, potato,
tapioca, and arrowroot. The starting starch raw material suitably
may be unmodified, modified, derivatized, or cross-linked. Examples
of unmodified starches are the granular starches conventionally
prepared from natural starch sources by removal of fiber, gluten,
and other proteinaceous impurities, with or without subsequent
washing, drying, screening, bleaching, and/or sterilization.
Modified granular starches include thin-boiling starches made by
heating a water slurry of an unmodified starch below the
gelatinization temperature with a mineral acid (e.g. hydrochloric
acid) or an oxidizing agent (e.g. alkaline hypochlorite).
Derivatized granular starches include starch esters, e.g. starch
acetate and starch propionate, and starch ethers, e.g.
hydroxyethyl, carboxymethyl, and cyanoethyl starch, prepared from
unmodified or modified granular starches with retention of the
granular structure. Granular cross-linked starches include
ungelatinized starch products made by reacting an unmodified,
modified, or derivatized granular starch with a polyfunctional
reactant, e.g. phosphorous oxychloride or epichlorohydrin.
The free-flowing property of the compacted starch powders employed
in the invention is exemplified by the ability of the powders to
meet the following arbitrary test: a sample of powder being tested
is poured into a 24/40 standard taper glass powder funnel, the tip
of which is suspended normal to, and one inch above, a horizontal,
dry, smooth paper surface. Powder is poured through the funnel
until the cone of powder formed on the paper surface below reaches
the tip of the funnel, and the funnel plugs. The average radius of
the cone base is determined by taking four radius measurements from
the funnel tip along diameters intersecting at right angles and
averaging the values. From the cone height (1 inch) and the average
radius of its base, the angle formed by the inclined surface of the
powder cone and the horizontal, herein referred to as the "angle of
repose," can be determined using well-known trigonometric
principles, i.e. by calculating the tangent of the angle of repose.
A powder which is not free-flowing in the sense of the term as
employed herein displays an angle of repose in this test of more
than about 40.degree.The more preferred free-flowing
characteristics are displayed by compacted starch powders forming
an angle of repose in the range of from about 20.degree. to about
35.degree. .
Due to the availability and low cost of the starting raw material
required, compacted starch powders derived from corn starch, and
more preferably an unmodified corn starch, constitute the
binder-disintegrant ingredients preferred for utilization in the
present invention. Such starch raw materials, moreover, provide
resultant binder-disintegrant ingredients which display excellent
color stability during storage and in the ultimate tablet. By
reason of the excellent overall properties of tablets which can be
obtained by the use thereof, the particularly preferred
binder-disintegrant ingredients are superficially dry, free-flowing
powders of the above-described type characterized by a cold-water
solubility of from about 6 to about 15 percent and a swelling power
of from about 5 to about 8 and being derivatives of a bleached
native corn starch, e.g. hypochlorite-bleached native corn
starch.
The starch binder-disintegrant ingredients employed in the present
invention are prepared from the starting granular starch raw
materials by the same basic steps heretofore utilized in preparing
powders of compacted starches and in general involving compacting
the starting starch raw materials in the presence of water,
comminuting the resultant compacted material, and classifying the
comminuted intermediate into the desired particle size
fraction.
The compaction step suitably may be carried out in any convenient
device conventionally employed for this purpose. As described
above, the more commonly used devices include differential roll
mills, concurrent roll mills, extruders, and the like. The moisture
content of the granular feed starch and the temperature which the
starch attains during the compaction are important variables in
achieving a suitably modified compact. In preparing compacted
starches suitable for use in the present method, temperatures
should be limited to those below the gelatinization temperature of
the particular starch used. Higher temperatures provide compacts
which, when comminuted, yield powders which are overgelatinized and
have poor disintegrant properties. Optimum compaction conditions
generally include temperatures in the range of from about
20.degree. to about 50.degree. C.
The water content of the granular starch feed must be in the range
whereby the properties of the granular starch feed are altered to
the desired degree in the compaction treatment. For a given starch
and a given compaction device, limits for the moisture content will
exist at which the starch feed is either too dry or too wet for the
compaction to sufficiently change the properties of the starting
starch. For a given starch and compacting device, however, the
operable and optimum water content ranges easily may be determined
in the manner known and described hereafter, i.e., varying the feed
starch moisture content and noting the degree of starch
modification achieved in terms of the effect on the cold-water
solubility and swelling power of the starch. As a general rule, in
most conventional starch compaction equipment, water content in the
feed granular starch in the range of from about 20 to about 50
percent of the starch total weight is used to achieve the desired
amount of compaction. The lower moisture levels in this range, e.g.
from about 20 to about 30 percent, are generally more adapted for
use in roll-type compaction equipment such as differential roll
mills, and the higher water contents in this range, e.g. from about
30 to about 50 percent, are better adapted for use in devices
effecting the desired working in a confined space such as in a
screw-containing barrel-type extruder. Since commonly available
granular starches generally have a moisture content on the order of
10- 12 percent, water usually must be added to the granular feed
starch prior to compaction.
While, as stated above, the particular compaction technique
employed in preparing the starches employed as binder-disintegrants
in the present invention is not critical, a compaction method which
is particularly useful is exemplified by that disclosed in U.S.
Pat. No. 2,464,081 entailing the use of a differential mill. In a
typical application of this technique, a granular starch feed
having an adjusted moisture content in the range of from about 24
to about 32 percent by weight is fed through the mill operated with
a gap between the rolls in the range of 3 to 12 mils. Typical roll
speeds vary between 35 to about 70 feet (linear) per minute using a
speed differential of from about 10 to about 20 feet per minute.
Roll temperatures maintained by circulating water through the rolls
generally vary between about 10.degree. to about 40.degree. C. More
than one pass through the rolls generally is required to
sufficiently modify the starting starch properties with up to four
passes being common.
Another particularly useful compaction technique utilizes a
rotating pellet mill which is adapted to subject the starch feed to
the sufficient amount of working during the formation of pellets
therefrom. An example of a typical pelletting operation which
achieves suitable compaction generally employs a pellet mill having
dies 3/16 inch in diameter and 11/2 inches in length in which the
starting granular starch at a moisture content of from about 20 to
about 30 percent by weight is pelletized at a feed rate of 900 to
1,000 lbs. per hour with the mill rotating at 125- 150 r.p.m.
Advantages of utilizing a pellet mill are that one pass through the
mill usually is sufficient to provide the desired starch
modification and that a significantly reduced amount of fines is
produced as compared to most other compaction techniques.
The material produced by the required amount of compaction then is
ground and screened to a suitable particle size, the moisture
content being adjusted during the recovery of the desired powder
from the compact. For optimum results, the compact is dried prior
to being ground. Drying lessens the proportion of fines produced in
the grinding step and guards against possible further undesirable
starch alteration during grinding. In the drying, the moisture
content of the compacted material is commonly reduced to from about
4 to about 14 percent by weight.
The grinding suitably may be carried out in any grinder, mill or
combination of comminuting devices adapted to reduce the compact to
a free-flowing, directly compressible powder. It has been found
that the more suitable tablet binder-disintegrant powders are those
which are relatively fine. In the grinding step, therefore, the
compacted starch generally is reduced to a powder of which at least
about 30 percent of the total weight thereof is material of -270
mesh. The term "mesh," as used herein, refers to the U.S. Standard
Sieve Series, A.S.T.M. specifications. The presence of too great a
proportion of fines is not conducive to optimum tabletting so it
generally is preferred to control grinding to provide a powder
containing less than about 90 percent by weight material of -270
mesh. The more preferred powders obtained in the grinding step, by
virtue of the properties of the tablets obtained therefrom and
their adaptability to tabletting machine operation, are those
ground to from about 45 to about 75 percent by weight material of
-270 mesh. A specific grinding technique suitable for use involves
initially grinding the compact to -10 mesh and then completing
grinding in a mill adapted to recycle all +100 mesh material.
The water content of the compacted starch powder has an effect on
the binder-disintegrant properties of the material. Too low or too
high a water content detracts from the properties of the ultimate
tablets formed. Generally moisture contents in the range of from 9
to about 16 percent of the powder total weight are suitable with
the more preferred results usually being obtained at moisture
contents in the range of from about 11 to about 13 percent by
weight. Accordingly, following grinding, the moisture content of
resultant powder preferably is adjusted, if necessary, by drying or
the addition of water.
As stated, the binder-disintegrant starch powders preferred for use
contain a low proportion of coarse particles. Generally, it is
desired that the powder contains less than about 10 percent by
weight material of +80 mesh. The more preferred powders are
essentially free of +40 mesh material and contain less than about 5
percent of material of 40- 80 mesh. The preferred materials,
therefore, are screened to -40 mesh and preferably -80 mesh before
actual use. Screening is particularly desirable if the powder from
the grinding step subsequently is moistened to adjust its moisture
content since the moistening step increases the amount of +80 mesh
material in the powder. Oversize material can be ground to the
desired smaller particle size material.
Typical compacted starch powders suitable for use in the present
invention here are characterized by the following particle size
distribution:
Proportion of Powder, Particle Size % total weight
__________________________________________________________________________
40-80 mesh 0-5 80-200 mesh 5-30 200-270 mesh 10-40 through 270 mesh
45-75
__________________________________________________________________________
At least 10 percent should be between 80 and 270 mesh to help in
imparting free-flowing characteristics.
In the preferred preparation of tablets by the present invention,
an active material ingredient is thoroughly mixed by any suitable
dry blending technique with one or more of the above-described
compacted starch powders in relative amounts required to provide a
resultant superficially dry, free-flowing formulation directly
compressible into tablets, and the formulation then is tabletted by
direct compression.
Active ingredients contemplated to be employed in the preparation
of tablets by the present invention constitute all active
ingredients compatible with the above-described compacted starch
powders in formulations directly compressible into tablets. The
present invention is particularly adapted for use in preparing
tablets containing pulverulent pharmaceutically active materials.
Specific examples of pharmaceutically active ingredients which
advantageously may be tabletted by the present invention include
ascorbic acid, sodium p-aminosalicylate, phenacetin, and
N-acetyl-p-aminophenol, all materials which heretofore generally
have been tabletted only with great difficulty. The particular
nature of the active material is not critical, however, and
nonpharmaceutical active materials, e.g. pulverulent detergents,
dyes, pesticides, and foods, forming directly compressible mixtures
with the compacted starch powders can also be employed.
The amount of active material ingredient employed in preparing
tablets according to the present technique depends, inter alia,
upon the nature and relative compatibility of the active material,
and the end use for which the tablet is desired, the latter
dictating thereby the tolerable properties in terms of hardness,
friability, and/or disintegratability of the final tablet. Given
the minimum and preferred characteristics desired in the final
tablet, the tolerable limits on the weight ratio of active
ingredient to binder-disintegrant for a particular active
ingredient easily may be determined by the known technique of
sequentially increasing the active ingredient content of the
tablet. In general, acceptable active material-containing tablets
are those which display a hardness of at least about 4 kg.,
preferably above about 5 kg., and a friability corresponding to a
weight loss of less than about 1.0 percent, preferably less than
about 0.5 percent. For a tablet having suitable friability, a lower
hardness generally can be tolerated.
Depending upon the type and contemplated use of the final tablet,
the disintegration requirements may vary over a wide range. A
particular feature of the present invention is that a wide range of
active ingredients may be tabletted to provide tablets displaying
disintegration times in aqueous media of generally less than 30
minutes and more usually less than 15 minutes and in the range of
from about 0.5 to about 10 minutes. The rapid disintegration rates
of tablets prepared by the present method, as stated, stem from the
advantageous characteristics of the compacted starch powders to
function not only as excellent binding agents but as agents which
accelerate tablet disintegration as well. In general, specific
embodiments of tablets prepared in the invention contain from about
5 to about 90 percent by weight active ingredient, dry substance
basis. An additional feature of the present invention is that, by
the use of the binder-disintegrant compacted starch powders, even
many pulverulent active ingredients which themselves are
noncompressible or only poorly compressible, exemplified by the
pharmaceuticals named, may be formed into suitable tablets
containing from about 20 to about 50 percent and above of the
active ingredient based on the tablet dry substance weight.
Adjuvants, such as tabletting lubricants, fillers, antisticking
agents, coloring agents, and the like, conventionally employed in
preparing particular tablets by direct compression, suitably may be
incorporated in appropriately effective amounts into the
compressible formations formed in the present invention. A
lubricant such as talc, magnesium stearate, or stearic acid, when
employed, generally is added in an amount ranging up to about 10
percent by weight of the total tabletting formulation. Colloidal
silica constitutes a typical antisticking agent or so-called
"glidant." A glidant such as colloidal silica, when incorporated in
a formulation, usually is added in an amount ranging up to about 2
percent of the formulation total weight. Fillers, which may also
function as supplemental binders or disintegrants, where employed,
must not be added in amounts which impair undesirably the direct
compressibility of the tabletting formulations.
While the compacted starch powders employed in the present
invention are capable of satisfying the dual requirements of a
binder-disintegrant, the present invention, as stated, also
contemplates embodiments wherein effective amounts of another
direct compression binder such as lactose and the like and/or a
separate disintegrating agent such as native cornstarch also is
incorporated into the formulation. In most cases, however, the
addition of such additional binders is unimportant in view of the
excellent characteristics of the binder-disintegrant compacted
starch powder of this invention. In view of this, it will be
understood the present invention is directed primarily to
embodiments wherein the superficially dry, free-flowing
binder-disintegrant starch of this invention is the major binder
ingredient employed, i.e. present in an amount corresponding to at
least 50 percent of the total weight amount of tablet binding agent
employed, and more preferably is the sole binding agent added to
the formulation for this purpose. In some instances, a supplemental
disintegrant may provide some improvement. An example of this is in
the preparation of tablets of sodium p-amino-salicylate dihydrate
wherein the disintegration rate of the tablet advantageously may be
further accelerated by the addition of a conventional granular
starch disintegration aid.
The more desirable tablets are prepared from superficially dry
formulations containing from about 5 to about 15 percent moisture
based on the formulation total weight. Accordingly, appropriate
adjustment of the moisture content may be made, where necessary or
desirable, during the formulation operation to improve the
tabletting characteristics of the mixture. It may also be
desirable, after mixing the ingredients, to screen the formulation
to remove any oversize particles introduced in the active
ingredient or tabletting aids and thereby to improve tabletting
efficiency. In this respect, removal of +40 mesh particles by
screening generally is desirable.
In accordance with the present invention any conventional single or
rotary tablet making apparatus suitably may be employed in the
tabletting operation. As is standard in conventional tabletting
practice, optimum results are obtained for particular formulations
by the use of the highest pressure settings consistent with good
tablet press operation.
Tablets prepared from a given batch of tabletting formulation by
means of the present invention are essentially uniform in
thickness, weight, and active ingredient dosage level and have
excellent surface smoothness as indicated by the lack of pits and
cracks. A further characteristic of the tablets made according to
the invention is that a substantial duplication of tablet
properties is obtained by grinding the tablets to a free-flowing
powder and retabletting.
While the above discussion has been limited to the preparation of
tablets by direct compression, it further will be understood that
the described free-flowing, directly compressible active ingredient
and compacted starch powder-containing formulations, of course,
also can be employed in the preparation of compressed tablets
either by the double compression technique wherein slugs initially
are prepared from a formulation and the slugs subsequently dry
granulated to prepare tablet machine feed material or by the wet
granulation method wherein a wetting agent, such as water, is added
to a formulation, the moistened mass is dried without gelatinizing
the compacted starch powder ingredient, and the resultant dried
material is ground into granular feed for the tabletting machine.
Compressed tablets which can be prepared by either method have
essentially the same characteristics as those produced by direct
compression. In view of the adaptability of the formulations
prepared hereby to direct compression tabletting, however, the dry
and wet granulation methods are impractical and can be anticipated
to be rarely, if ever, employed.
The invention having been described in detail, the following
examples are presented to show specific embodiments thereof. It
will be understood the examples are given for illustration purposes
only and not by way of limitation.
EXAMPLE I
This example illustrates the preparation of suitable tablet
binder-disintegrant starches from an unmodified cornstarch and the
use of the binder-disintegrant starches in the preparation of
tablets by direct compression.
Three samples of ground hypochlorite-bleached native cornstarch
(starch A) having the properties set forth in table 1 were
converted to compacted starch powders by three different
techniques. The techniques employed were as follows:
Technique 1 (Pelletizing)
One sample of the hypochlorite-bleached native cornstarch was
moistened to a water content of 24-25 percent by weight and the
moistened starch was pelletized at a rate of about 960 pounds/hour
on a California Process Series CM-FB Master pellet mill having dies
3/16 inch in diameter and 11/2 inches in length and operated at
about 130 r.p.m. The resultant pellets (1/4 inches length) were
then dried in a rotary drier to 7.4 percent by weight moisture. The
dried pellets were then ground to -10 mesh in a Model DS-6 Series
1606 stainless steel Fitzmill grinder, and the -10 mesh material
was further ground to -100 mesh in a Model PC 20 Strong-Scott
Pulvocron grinder operated at 3,500 r.p.m. with the classifier at
1,000 r.p.m. and the tailings return at 100 percent. The resultant
powder was remoistened to 11.5-12.5 percent by weight water in a
horizontal ribbon blender, and the moistened material was screened
to -40 mesh. The properties of the resultant compacted starch
powder (starch A.sub.p) are set forth in table 1.
Technique 2 (Differential Roll-Milling)
The second sample of the ground hypochlorite-bleached native
cornstarch was compacted, after being moistened to a water content
of about 25.2 percent by weight, in an EEMCO Laboratory
differential roll mill having 12 -in. length rolls of 6 in.
diameter. The mill was operated with a mill gap of 12 mils, and
roll speeds of 50 and 70 linear feet/min. on the respective rolls.
Roll temperature was maintained at about 23.degree. C. by cooling
water circulating through the rolls. The compacted starch sheet
stripped from the rolls was then subjected to three additional
passes through the mill. The resultant compact was then dried to a
moisture content of 6-9 percent by weight. The dried compact was
ground first to less than about 1.0 mm. in a Wiley mill and then to
less than about 0.5 mm. in a Raymond hammer mill. The ground
material was then remoistened with water to a moisture content of
11.8 percent by weight, and screened to -80 mesh. The resultant
compacted starch powder (starch A.sub.DRM) had the properties set
forth in table 1.
Technique 3 (Compaction in Allis-Chalmers Compacter)
The third sample of the ground hypochlorite-bleached native
cornstarch was adjusted to a moisture content of 21.6 percent by
weight and then treated using force feeding in a compacter
manufactured by Allis-Chalmers Corp. having rolls 24 inches in
diameter and 8 inches in length. The compacter was operated with
the rolls at ambient temperatures, a roll gap of 0.05 inch, a roll
speed of 2.5 r.p.m., a force feeder speed of 15 r.p.m., and a
starting bearing pressure of 1,000 p.s.i.g. The ribbonlike compact
obtained was dried to 7 percent by weight water and then ground as
in technique 2 above. The ground material was then adjusted to a
moisture content of about 12.0 percent by weight, and then finally
screened to -80 mesh. The properties of the resultant compacted
starch powder (starch A.sub.AC) are set forth in table 1.
##SPC1##
The data in table 1 indicates that the three different compaction
methods can each produce compacted starch powders essentially
equivalent in these properties.
Superficially dry tabletting formulations were prepared by
thoroughly blending the resultant compacted starch powders, each in
turn, with separate powdered preparations of ascorbic acid,
phenacetin, sodium p-amino-salicylate dihydrate (NaPAS) a
N-acetyl-p-aminophenol (APAP) in the proportions set forth below in
table 2, incorporating talc and/or colloidal silica (Cab-o-Sil) as
tabletting aids into the formulations, and screening the resultant
mixtures to -40 mesh. The free-flowing powders obtained were then
directly tabletted on a Colton No. 204 four-punch press
manufactured by the Colton Division of Cherry-Burrell Corporation,
Detroit, Mich. A set of 3/8 inch diameter standard cap punches and
dies was employed, and the press was operated at 35 r.p.m. to
produce 140 tablets/min. The pressure setting of the press was
increased in each run to a value consistent with good press
operation as indicated by a "thump" in the tabletting. A sample of
each of the compacted starch powders also was tabletted using the
same tabletting procedure. The properties of the tablets obtained
also are set forth in table 2. ##SPC2## ##SPC3##
The above data indicates that the compacted starch powders are
directly compressible into tablets themselves and that suitably
hard, nonfriable, rapidly disintegrative tablets containing
relatively high levels of heretofore difficult-to-tablet drugs,
i.e. ascorbic acid, phenacetin, and APAP, advantageously can be
prepared using the compacted starch powders as sole
dual-functioning binder-disintegrant ingredients. Although the
NaPAS-containing tablets disintegrated relatively slowly, these
tablets had suitable hardness and friability properties; the
compacted starches are satisfactory binders even of this previously
difficult-to-tablet drug.
EXAMPLE II
In order to compare the binder-disintegrant properties of the
compacted starch powders employed in the present invention with
those of other compacted starches, the starting bleached native
cornstarch (starch A) of example I was converted to a compacted
starch powder using technique 3 of example I with the exception
that the moisture content of the starting starch was initially
adjusted to about 18 percent by weight so that the starch was
worked and modified to a lesser degree. The resultant compacted
starch powder was characterized by a 2.9 percent cold-water
solubles content, a swelling power of 3.0, a loose bulk density of
0.49 gm./ml., and flowability corresponding to an angle of repose
of more than 40.degree. .
The resultant compacted starch powder was tabletted alone using the
procedure of example I. The tablets obtained had an average
hardness of 3 kg., a friability corresponding to an average weight
loss of 1.93 percent, and a disintegration time in water of 0.5-1.5
minutes. As evidenced by the poor flowability of the powder and the
low hardness and high friability of the tablets prepared therefrom,
the low cold-water solubles content powder is not suitable for use
as a sole dual-functioning binder-disintegrant ingredient in
preparing acceptable tablets by direct compression.
EXAMPLE III
This example illustrates the preparation of suitable tablet
binder-disintegrant starches from oxidized cornstarch and the use
of the resultant binder-disintegrant starches in the preparation of
tablets by direct compression.
Two samples of ground alkaline hypochlorite-oxidized cornstarch
(starch B) were converted to compacted starch powder using
techniques 2 and 3 of example I. However, in using technique 2 the
feed starch had a moisture content of 31.0 percent by weight and
the roll temperature was maintained at 31.degree. C. and in using
technique 3 the feed starch had moisture content of 27.1 percent by
weight, the roll gap was 0.02 in., and the force feeder speed was 5
r.p.m. The properties of the resultant compacted starch powders
(starch B.sub.DRM and starch B.sub.AC, respectively) are set forth
in table 3 below. Using the procedure of example I, tablets were
formed from each of the compacted starch powders alone and
formulations prepared by thoroughly mixing each powder separately
with certain drugs and tabletting aids. The compositions of the
tablets and their properties are shown in table 4 below. ##SPC4##
##SPC5## ##SPC6##
EXAMPLE IV
This example illustrates the preparation of a suitable tablet
binder-disintegrant starch from native cornstarch and the use of
the resultant binder-disintegrant starch in making tablets.
Native cornstarch (starch C) was converted to a compacted starch
powder using technique 2 (differential roll-milling) of example I
except that a starch feed moisture content of 28.6 percent by
weight and a roll temperature of 10.degree. C. were employed. The
properties of the starting starch and resultant compacted powder
starch (starch C.sub.DRM) are set forth in table 3. As in the
procedure of the previous examples the compacted starch powder was
tabletted alone and thoroughly mixed with various drugs and
tabletting aids to provide formulations which were tabletted. The
compositions and properties of the tablets obtained are shown in
table 4.
EXAMPLE V
This example illustrates the preparation of a tablet
binder-disintegrant starch from a native high amylose starch and
the use of the resultant binder-disintegrant starch in preparing
tablets.
The procedure of technique 2 (differential roll-milling) of example
I was employed to convert a native high amylose starch (commonly
known as "Amylomaize" and designated starch D) to a compacted
starch powder except that a starch feed moisture content of 27.6
percent by weight and roll temperature of 10.degree. C. were used.
The properties of the starting starch and resultant compacted
starch powder (starch D.sub.DRM) are set forth in table 3. The
properties of placebo and drug-containing tablets prepared using
the compacted starch powder in the general tabletting procedure of
example I are shown in table 4.
EXAMPLE VI
This example illustrates the preparation and use of a tablet
binder-disintegrant starch derived from an acid-modified starch raw
material.
An acid-modified starch (starch E) having an alkali fluidity of
about 62 cc. (10 g. starch, as is basis, 77.degree. F. and 0.375 N
sodium hydroxide) was converted to a compacted starch powder
employing technique 2 (differential roll-milling) of example I
except that the starch feed moisture content utilized was 28.0-30.5
by weight, the roll gap was 6 mils, and the roll temperature was
maintained at 23.degree.-26.degree. C. A comparison of the
properties of the starting granular starch and the resultant
compacted starch powder (starch E.sub.DRM) obtained are set forth
in table 3. Following the tabletting procedure of example I,
placebo tablets (without drugs) were prepared using the compacted
starch powder alone. The properties of the tablets obtained are
reflected in table 4.
The results of these tests indicate the resultant compacted starch
powder is a suitable binder-disintegrant ingredient for use in
preparing acceptable drug-containing tablets by direct compression
as in the previous examples.
EXAMPLE VII
This example illustrates the preparation an use of a tablet
binder-disintegrant starch obtained from a derivatized granular
starch raw material.
A granular derivatized cornstarch containing about 2.5 percent
acetyl groups (starch F) was converted to a compacted starch powder
using technique 2 (differential roll-milling) of example I except
that the feed starch moisture content was 28.3-31 percent by
weight, a roll gap of 12 mils was employed, and roll temperatures
were maintained at 23-24.degree. C. The properties of the starting
starch and the resultant compacted starch powder (starch F.sub.DRM)
are set forth in table 3. Using the tabletting procedure of example
I, placebo (drug-free) tablets were prepared from the compacted
starch powders. The properties of the tablets are shown in table
4.
When substituted as the binder-disintegrant ingredient in the
preparation of the drug-containing tablets described in the
preceding examples, the compacted starch powder provides tablets of
properties comparable to those mentioned.
EXAMPLE VIII
This example illustrates the preparation and use of a tablet
binder-disintegrant starch obtained from a cross-linked granular
starch raw material.
The procedure of example VI was repeated with the exception of
substituting a granular cross-linked cornstarch obtained by
reacting oxidized cornstarch with phosphorus oxychloride (starch G)
for the acid-modified starch. The properties of the starting starch
and resultant compacted starch powder (starch G.sub.DRM) are set
forth in table 3. The characteristics of the tablets obtained are
shown in table 4. Drug-containing tablets prepared by direct
compression, using the resultant compacted starch powder as a
binder-disintegrant ingredient as in the preceding examples, have
characteristics similar to such tablets described above.
EXAMPLE IX
This example illustrates the preparation and utilization of a
tablet binder-disintegrant starch derived from potato starch.
The procedure of example VII was repeated except that native potato
starch (starch H) was substituted for the derivatized cornstarch. A
comparison of the properties of the starting starch and the
resultant compacted starch powder (starch H.sub.DRM) is shown in
table 3, and the characteristics of the placebo tablets prepared
therefrom are listed in table 4. When employed as a
binder-disintegrant ingredient in preparing drug-containing
compressed tablets, such as those prepared above by direct
compression, the resultant compacted starch powder provides
acceptable tablets.
EXAMPLE X
This example illustrates an embodiment of the present invention
wherein a binder-disintegrant starch is employed in combination
with an uncompacted starch in the preparation of active ingredient
tablets by direct compression, the uncompacted starch being
employed as a filler and disintegrant ingredient in the
tablets.
A sample of starch D.sub.DRM (differential roll-milled native
cornstarch) described above in example IV was thoroughly mixed with
sodium p-aminosalicylate dihydrate (NaPAS) and ground bleached
native cornstarch containing about 10 percent by weight moisture in
a weight ratio of drug:compacted starch:uncompacted starch of
30:60:10, starch dry substance basis. Talc and colloidal silica
(Cab-o-Sil) also were added during the mixing in amounts of 6.0
percent and 0.0109 percent by weight of the total formulation,
respectively. The resultant powder which had a moisture content of
12.1 percent by weight was tabletted directly using the procedure
of example I. The resultant tablets were characterized by an
average hardness of 8.7 kg., a friability corresponding to an
average weight loss of 0.24 percent, and a disintegration time of
20-26 minutes.
EXAMPLE XI
This example illustrates embodiments of the present invention
wherein a binder-disintegrant starch is employed in the preparation
of tablets by direct compression wherein the tablets are intended
for nonpharmaceutical uses.
Using starch A.sub.p (pelletized bleached native cornstarch)
described in example I as the binder-disintegrant ingredient and
the tabletting procedure of example I, tablets that disintegrate
rapidly in water and have excellent hardness and friability
properties are prepared from the following formulations:
Plant Root-growth Stimulant Tablets Parts by weight
__________________________________________________________________________
Starch A.sub.p 90 1-Naphthalene acetic acid 9 Colloidal silica
(Cab-o-Sil) 1 Garlic Tablets Starch A.sub.p 23 Powdered garlic
(Dehydrated) 70 Colloidal silica (Cab-o-Sil) 2
__________________________________________________________________________
Table 5 below contains comparative data showing that compaction of
starch so as to impart the properties set forth above in table form
on page 7 renders the starch powder useful in forming tablets by
direct compression whereas the same starch, noncompacted, does not
have this property. In the table the heading "Allis-Chalmers
Compacter Conditions" refers to technique 3 set forth on page 22
above while the heading "Differential Roll Mill Conditons" refers
to technique 2 set forth above on pages 21 and 22. The starch used
in samples Nos. 1-10, 12 and 13 is ordinary powder native
cornstarch bleached with sodium hypochlorite to make it whiter
while the oxidized starch used in sample 11 is a corn starch
oxidized by sodium hypochlorite under alkaline conditions until it
has about 0.5 percent carboxyl groups.
The data in table 5 may be summarized as follows:
a. Sample 1, 2, 7, 8, 9 and 10, which were not compacted and which
did not fall within the parameters set forth on page 7 with respect
to at least two of cold-water solubility, swelling power, loose
bulk density, and moisture content, could not be tabletted.
b. Samples 3, 4, 5, 6, 11, 12 and 13, which were compacted, could
be tabletted. However, sample 3 had a cold-water solubility below
the required minimum and the tablets formed therefrom were not
satisfactory since they were not sufficiently hard and were
excessively friable. Samples 4, 5 and 6 had values for cold-water
solubility, loose bulk density and swelling power within the range
as set forth in the table on page 7.
c. Sample 13, which was compacted well beyond any of the others,
had excess cold-water solubility and excess swelling power. While
it could be tabletted, the tablets did not disintegrate in over 45
minutes, well beyond the requirements for a useful tablet
binder-disintegrant.
d. In the Allis-Chalmers Compacter, increasing compaction is
obtained by narrowing the gap, increasing the water content,
increasing the speed of the feeder, increasing the bearing pressure
or any combination of these. The data for samples 3, 4, 5 and 6
show that increasing the extent of compaction increased the tablet
hardness and disintegration time while decreasing friability.
##SPC7##
* * * * *