U.S. patent number 3,627,583 [Application Number 04/820,285] was granted by the patent office on 1971-12-14 for direct compression vehicles.
This patent grant is currently assigned to SuCrest Corporation. Invention is credited to Charles B. Broeg, Frank J. Lynch, Anthony Monti, John P. Troy.
United States Patent |
3,627,583 |
Troy , et al. |
December 14, 1971 |
DIRECT COMPRESSION VEHICLES
Abstract
Tablets are formed directly without granulation or slugging from
a mixture of an active material, such as a therapeutic material,
and as a direct compression vehicle, a dry, free-flowing, granular
sugar composition comprising generally spherical, porous, firm
agglomerates of 100 parts of solid sugar in from about 0.1 to about
30 parts of a cementum or matrix. The sugar agglomerates are
obtained by: 1. Spraying a particulate solid sugar with an aqueous
solution of binder; 2. Providing the resulting mixture with
sufficient high intensity agitation to uniformly intermingle the
sugar and binder and to build up agglomerates of a desired size; 3.
"Snowballing" the agglomerates to impart a general spherical shape
thereto and to firm or densify the agglomerate; 4. Drying; and if
necessary, 5. Separating over- and undersized agglomerates. The
mixture may also contain additives such as colors, flavorants and
the like.
Inventors: |
Troy; John P. (Hicksville,
NY), Monti; Anthony (Irvington, NY), Lynch; Frank J.
(Staten Island, NY), Broeg; Charles B. (Short Hills,
NJ) |
Assignee: |
SuCrest Corporation (New York,
NY)
|
Family
ID: |
25230384 |
Appl.
No.: |
04/820,285 |
Filed: |
April 29, 1969 |
Current U.S.
Class: |
127/29; 424/606;
424/687; 424/695; 424/722; 426/285; 426/548; 426/650; 127/63;
424/686; 424/690; 424/720; 424/723; 426/453; 426/539; 426/590;
514/772 |
Current CPC
Class: |
A23G
3/0289 (20130101); A23P 10/28 (20160801); A23G
2200/06 (20130101); A23G 2200/00 (20130101); A23G
3/346 (20130101); A23G 3/0294 (20130101); B01J
2/22 (20130101); A61K 9/2018 (20130101); A23G
3/346 (20130101); C13B 50/02 (20130101); A23G
3/346 (20130101); A23G 2200/06 (20130101); A23G
2200/00 (20130101) |
Current International
Class: |
A23G
3/34 (20060101); A23G 3/02 (20060101); A23L
1/00 (20060101); A61K 9/20 (20060101); C13F
3/02 (20060101); C13F 3/00 (20060101); B01J
2/22 (20060101); C13f 003/00 () |
Field of
Search: |
;127/29,30,63
;99/DIG.4 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
G Milosovich, Drug and Cosmetic Industry, 92(5), 557-558, 656,
662-669 (1963)..
|
Primary Examiner: Scovronek; Joseph
Assistant Examiner: Marantz; Sidney
Claims
What is claimed is:
1. A method for preparing tablets containing as a direct
compression vehicle a sugar composition comprising the steps of (a)
forming a uniform nongranulated mixture of an active material and a
dry, free-flowing, generally spherical, porous agglomerate of 100
parts of a solid pulverized sugar in 0.1 to about 30 parts of a
matrix of a polyhydroxy compound, and (b) compressing said mixture
into tablets, said agglomerate comprising at least 10 percent of
said mixture, and having a particle size of from about 12 to about
325 mesh, a moisture content of from about 0.1 to about 3 percent,
and having been prepared by a process including the steps of: (1)
Spraying a particulate solid sugar with an aqueous solution of
binder; (2) Providing the resulting mixture with sufficient high
intensity agitation to uniformly intermingle the sugar and binder
and to build up agglomerates of a desired size; and (3)
"Snowballing" the agglomerates to impart a general spherical shape
thereto and to firm or densify the agglomerate.
2. A tablet prepared in accordance with claim 1.
3. A method according to claim 1, wherein said matrix is a
carbohydrate.
4. A tablet prepared in accordance with claim 3.
5. A method according to claim 3, wherein said sugar is sucrose and
said carbohydrate is invert sugar.
6. A tablet prepared in accordance with claim 5.
7. A method for preparing a direct compression vehicle comprising
compacting a dry, free-flowing, generally spherical, porous
agglomerate of 100 parts of a solid pulverized sugar in 0.1 to 30
parts of a matrix of a polyhydroxy compound, said agglomerate
having a particle size of from about 12 to about 325 mesh and a
moisture content of from about 0.1 to about 3 percent, said
agglomerate being prepared by a process including the steps of:
1. Spraying a particulate solid sugar with an aqueous solution of
binder;
2. Providing the resulting mixture with sufficient high intensity
agitation to uniformly intermingle the sugar and binder and to
build up agglomerates of a desired size; and
3. "Snowballing" the agglomerates to impart a general spherical
shape thereto and to firm or densify the agglomerate,
and thereafter comminuting said compacted agglomerate to a desired
particle size.
8. The product of claim 7.
9. A method for preparing a tablet comprising forming a uniform
admixture of the product of claim 8 and an active material, said
product comprising at least 10 percent of said mixture, and
compressing the mixture into tablets.
10. A tablet produced according to claim 9.
Description
This invention relates to tablets comprising an active material and
a direct compression vehicle. More particularly, this invention is
concerned with tablets comprising an active material and a direct
compression vehicle, which are formed from a mixture thereof
without prior granulation or slugging.
There are two general methods for forming tablets, i.e.,
compression of a dry particulate material and trituration, or
molding of a moist material, of which the first technique is by far
the most frequently employed. The compression technique may be
further subdivided into three major categories, viz direct
compression, wet granulation and dry granulation. The direct
compression technique is the most desirable, in that it employs the
fewest steps and, in the case of the production of tablets
containing sensitive or unstable actives, such as certain
pharmaceuticals, minimizes the exposure to water or other
conditions tending to adversely affect stability of the active.
Unfortunately, however, it has been found that the direct
compression technique is of limited applicability.
First, most active materials possess poor compression properties,
and thus are unsuitable for this technique. In addition, many
actives are required in such small amounts per unit dosage form
that direct compression of the active alone is impractical, if not
impossible. As a result, the active must be admixed with a direct
compression vehicle, i.e., an inert composition which is compatible
with the active and has good compressibility and binding action. In
addition, the direct compression vehicle should have good
flowability, good stability under normal ambient conditions, no
adverse effect on tablet disintegration time, the ability to
produce good tablet surfaces, and low cost.
To date, however, no material has been found which satisfies all of
these criteria. For example, of the most popular of such
compression vehicles, spray-dried lactose possesses poor stability
and discolors on storing, dicalcium phosphate provides tablets
having poor strength, and microcrystalline cellulose is
expensive.
One of the principal objects of this invention is to provide a
direct compression vehicle.
Another object of the invention is to provide an improved tablet as
the final product as a result of the more effective quality control
made possible by eliminating variables in the manufacturing
process.
Another object of the invention is to permit the use of a wide
variety of materials in the manufacture of tablets.
Another object of the invention is to provide a novel method of
manufacturing tablets in which the complicated steps inherent in a
granulation process are avoided.
Other objects and advantages in this invention will be apparent to
those skilled in the art of tablet manufacture when reviewing the
specification and claims of this invention.
It has been discovered in accordance with this invention that
certain sugar agglomerates are well suited for use as a direct
compression vehicle for the production of tablets. This material
comprises generally spherical, firm, porous agglomerates of sugar
particles in a cementum or matrix. The agglomerates are dry (from
about 0.1 to about 3 percent moisture), free-flowing particles
having particle size within the range of from about 325 to about 12
mesh. Tablets formed using such sugar agglomerates as the direct
compression vehicle are uniform, possess good physical properties,
do not discolor on aging, and readily dissolve in aqueous
media.
These sugar agglomerates are obtained by:
1. Spraying a particulate solid sugar with an aqueous solution of
binder;
2. Providing the resulting mixture with sufficient high intensity
agitation to uniformly intermingle the sugar and binder and to
build up agglomerates of a desired size;
3. "Snowballing" the agglomerates to impart a general spherical
shape thereto and to firm or densify the agglomerate;
4. Drying; and if necessary,
5. Separating over- and undersized agglomerates.
The particulate sugar can be a mono-, di- or tri-saccharide, such
as arabinose, xylose, ribose, fructose, mannose, galactose,
glucose, sucrose, maltose, lactose and the like, including mixtures
of two or more of such sugars, with sucrose being preferred. The
particulate sugar can be obtained synthetically, or it can be a
refined natural product, such as corn syrup solids, molasses
solids, honey solids, maple syrup solids and the like. The particle
size of the sugar is not narrowly critical so long as it is small
enough to permit formation of agglomerates of the desired size. For
most purposes, ordinary 6X powdered sugar, of which most (95 to 97
percent) passes through a 200-mesh screen, is suitable. If the
agglomerate is to be employed in the production of a chewable
tablet, however, it is desirable that more finely divided sugar be
used to avoid "grittiness." For this use, the sugar should have
substantially no particles, i.e., not more than 1 percent, having
sizes greater than about 40 microns, and at least 50 percent of the
particles should have sizes below about 25 microns. Preferred are
sugars having an average particle size of about 15 microns.
The second component which is employed to form the agglomerate is a
noncrystallizing aqueous solution of a polyhydroxy compound as a
binder. Illustrative polyhydroxy compounds include propylene
glycol, glycerol, erythritol, arabitol, xylitol, adonitol,
mannitol, dulcitol, sorbitol, sugars, such as arabinose, xylose,
ribose, glucose, mannose, fructose, sucrose, maltose and lactose,
dextrin and the like, with polyols of the formula HOCH.sub.2
(CHOH).sub.x CH.sub.2 OH, wherein x is 1 to 4, and sugars being
preferred. Propylene glycol, glycerol, mannitol, sorbitol, glucose,
fructose and invert sugar are of particular interest, with invert
sugar being most preferred. The aqueous binder composition can be a
solution of a pure compound, or can comprise two or most
polyhydroxy binders. The aqueous medium can be obtained
synthetically, or it can be a refined natural product, such as corn
syrup, molasses, honey, maple syrup and the like. Invert syrup is
preferred.
The concentration of binder in the aqueous medium is not narrowly
critical provided that it is not so high as to cause
crystallization or provide solutions so viscous as to prevent
spraying and intimate intermingling and uniform distribution of
binder and solids. Thus, the concentration will depend upon the
solubility of the binder. For example, glucose ordinarily cannot be
employed in amounts greater than about 48 percent, whereas
propylene glycol, glycerol, mannitol and sorbitol can be present in
amounts up to about 80 percent. When invert sugar is the binder,
concentrations of from about 50 to about 80 percent are employed,
with concentrations of from about 70 to about 75 percent being
preferred. Other than this, the amount of water in the aqueous
medium should be so correlated with the desired ratio of binder to
sugar that agglomeration occurs. Thus the amount of water should be
insufficient to form a paste and yet sufficient to minimize the
presence of powder, or unagglomerated sugar. In general, it has
been found that the mixture of particulate sugar and aqueous binder
medium should contain from about 2 to about 6 percent water, with
amounts of about 4 percent water being preferred.
The initial contact of the solids and liquids is effected by
spraying the aqueous medium onto the dry solids at a rate such that
there is employed from about 0.1 to about 30 parts of binding agent
per 100 parts of solid.
The mixing is ordinarily conducted at about room temperature
(65.degree. - 75.degree. F.). Higher and lower temperatures can be
employed, if desired, provided the properties of the aqueous medium
and the agglomerate product are not adversely affected. In
particular, the temperature of the aqueous medium may be varied to
achieve a desired viscosity for spraying. However, if the
temperature is too low, e.g., below about 50.degree. F., the
aqueous medium is ordinarily too viscous to be easily sprayed; and
if the temperature is too high, e.g., above about 200.degree. F.,
water may evaporate too rapidly to permit adequate control of the
characteristics of the binding solution. In addition, the use of
elevated temperatures during processing tends to result in a
discolored product, and also may cause dissolution of the dry
ingredient and thus adversely affect particle size and quality.
Simultaneously with the spraying, the mixture is agitated to
thoroughly intermingle the solid sugar and the aqueous binder
medium and to effect agglomeration. This requires high intensity
mixing, such as is obtained with a Patterson-Kelley blender or a
Lodige mixer.
Agitation is continued until agglomerates of the desired size are
formed, and ordinarily for a time sufficient to form agglomerates
about about 325 mesh, but insufficient to form significant amounts
of agglomerates larger than about 12 mesh. The size of the
agglomerate is also affected by the ratio of aqueous binder to
particulate sugar, with larger agglomerates being formed when a
greater proportion of liquid medium is present.
The agglomerates typically have a narrow size distribution. That
is, high yields, normally 80 percent or more, of the agglomerates
fall within a few screen sizes. For example, when operating to
produce a 20- to 80-mesh agglomerate, at least 80 percent, and in
some instances 90 percent or more, of the agglomerated product will
fall within this range.
Simultaneously with and/or subsequent to agglomeration, the
agglomerates are "snowballed," i.e., subjected to a tumbling or
rolling operation, to impart a general spherical shape thereto. In
addition, the agglomerates are firmed or densified whereby the bulk
density is increased by about 50 - 100 percent over that of the dry
particulate sugar, and normally is in the range of from about 30 to
about 50 pounds per cubic foot.
The apparatus employed can be any suitable equipment which will
achieve the desired results. A particularly preferred apparatus is
the Patterson-Kelley blender, which performs all three operations
of mixing, agglomerating and snowballing.
Finally, and when necessary, the agglomerates are dried to a
moisture content of less than about 3 percent, and preferably less
than about 1.5 percent. Although complete drying is theoretically
possible, the moisture content of the product need not be less than
about 0.1 to 0.2 percent. The temperature at which drying occurs is
not narrowly critical in all cases, but ordinarily the temperature
of the agglomerate should not exceed about 140.degree. F. To
achieve such drying, the product is preferably contacted with hot
air at a temperature not exceeding 190.degree. F. A preferred
drying technique is the use of a fluid bed dryer. In this manner,
very fine particles, i.e., dust, are separated from the
product.
If desired, the dried product may be screened to remove oversized
and undersized particles. Oversized particles are discarded or can
be reduced to smaller size. Undersized particles can be
recycled.
The resulting agglomerate is admixed with the active material and
the resulting mixture compressed without granulation or slugging to
form a tablet. The amount of the agglomerate obviously will depend
upon the properties of the active and any other additives which are
to be incorporated into the finished tablet, for it is well known
that the compactibility of tablet compounds and mixtures are
subject to wide variation. In general, however, the agglomerate
will comprise at least 10 percent of the tabletting mixture and,
therefore, at least 10 percent of the tablet. In most cases,
however, the agglomerate will comprise from about 70 to about 95
percent of the tabletting mixture and the tablet.
By the term "active material " is meant any material intended for
ingestion and having a beneficial or desirable effect on the user.
Suitable active materials include therapeutic materials, such as
anesthetics, antibiotics, antitussives, vitamins, aspirin,
antacids, and the like; food stuffs such as cocoa, dried oats,
fruit flakes, and the like; edible dyes and other food additives;
and so on.
In addition to the sugar direct compression vehicle and the active
material, there may be employed other commonly employed tablet and
wafer additives such as coloring agents, flavorants, lubricants,
gums and the like. Although ordinarily not required because of the
ready solubility of the product tablet in aqueous media,
disintegrants may also be employed.
The vehicle is a free-flowing granular material and imparts
improved flow characteristics to the active material and other
components of the blend, thereby assuring ease of tabletting. The
blend of direct compression vehicle, active material and other
additives is mixed and directly compressed to form a tablet
employing conventional techniques and apparatus.
The following examples are illustrative. As used throughout this
application, all parts and percentages are by weight unless
otherwise stated.
EXAMPLE 1
To 90 parts of finely pulverized sucrose is rapidly added over a
period of 5 minutes by spraying at room temperature and while
agitating the pulverized sugar 14 parts of an aqueous invert sugar
solution (72 percent total solids) in a Patterson-Kelley
liquids-solids blender. After continuing agitation for an
additional 10 minutes, the agglomerated material is screened
through a vibrating 16-mesh screen and the screened material is
dried to a moisture content of 1.5 percent or less. To 97 parts of
dry agglomerated product is added, under agitation, 1 part of dry
citric acid, 0.25 part of dry flavoring material and 1.75 part of
magnesium stearate. The properly blended material is fed to a
tabletting press and wafers are formed from it.
EXAMPLE 2
Employing procedures similar to those described in example 1, 98
parts of finely pulverized sucrose is mixed with about 6.7 parts of
an aqueous invert sugar solution (30 percent total solids). The
agglomerated material is screened through a vibrating mesh screen
and the screened material is dried to a moisture content of 1.5
percent or less.
Equal parts of the agglomerate and vitamin C are blended. This
blend can be further mixed with other dry ingredients such as
minerals or other nutritionally active ingredients before being
compressed into tablets.
EXAMPLE 3
Employing procedures similar to those described in example 1, a
blend of 100 parts of finely pulverized dextrose monohydrate is
sprayed with 14 parts of dextrose syrup (48 percent total solids).
The agglomerated material is screened and dried to a moisture
content of 1.5 percent or less.
The agglomerated material can be directly compacted after adding
and blending the proper release agent (magnesium stearate). Rapidly
disintegrating ingredients can also be included in the formulation
prior to tabletting.
EXAMPLE 4
Employing procedures similar to those described in example 1, a
blend of 90 parts of finely pulverized sucrose and 10 parts of
finely comminuted dextrose are sprayed with about 14 parts of
invert syrup (72 percent total solids). The agglomerated materials
is screened, and dried to a moisture content of 1.5 percent or
less.
Equal parts of the agglomerate and aluminum hydroxide are blended
together. This blend can be further mixed with small amounts of
flavoring or other dry ingredients before being compressed into a
commercial antacid tablet.
EXAMPLE 5
Employing procedures similar to those described in example 1, 95
parts of finely pulverized dried molasses are sprayed with about
6.5 parts of affination syrup (76 percent total solids). The
agglomerated material is screened and dried to a moisture content
of 1.5 percent or less.
Equal parts of the agglomerate and dried ground oats are blended.
This product can be further mixed with other dry ingredients such
as minerals or other nutritives. After compacting, wafers for
animal feeding are obtained.
EXAMPLE 6
To 90 parts of pulverized sucrose having an average particle size
of 15 microns, less than 1 percent thereof exceeding 40 microns,
and more than 50 percent thereof less than 25 microns in size, the
said pulverized sugar being in a Patterson-Kelley liquids-solids
blender, there is rapidly added by spraying at room temperature
(65.degree. F.), and while agitating the pulverized sucrose, about
14 parts of an aqueous invert sugar solution (72 Brix). A small
amount of monocalcium phosphate is added to adjust the pH to 4.5 -
4.8 to prevent discoloration. After the addition of the invert
syrup has been completed, the blender is run for about 2 minutes to
complete the agglomeration. The total time of operation, i.e.,
spraying and agglomeration, is about 6 minutes.
The resultant agglomerated material, which contains about 3.8
percent water, is then screened through a vibrating 20-mesh screen.
The agglomerates coarser than 20 mesh are still relatively soft and
can be rubbed through an auxiliary screen and added to the first
product. The screened material is then placed in a rotary drier and
warm air at about 180.degree. F. is circulated through the drier to
dry the agglomerates to a water content of 1 percent. The drier is
operated so that the temperature of the agglomerates does not rise
above 140.degree. F. The dried product is then further screened on
an 80-mesh screen. The material remaining on the screen is the
finished product. That passing through the screen may be returned
to the blender for reprocessing, or may be employed as a fine
particle size granular product.
This agglomerate can be blended in accordance with the following
recipes and compressed.
A. confectionery tablets or wafers
1. lemon Flavored Confectionery Tablet:
100.0 pts. agglomerate
1.0 pt. citric acid, dry
0.25 pt. encapsulated lemon flavor
0.10 pt. yellow color No. 5
1.0 pt. magnesium stearate
2. Grape Flavored Tablet:
50.0 pts. agglomerate
50.0 pts. 6X powdered sugar
2.0 pts. tartaric acid
0.25 pt. grape flavor
0.05 pt. grape color
0.5 pt. calcium stearate
3. Cherry Flavored Confectionery Tablet:
100.0 pts. agglomerate
2.0 pts. fumaric acid
0.2 pts. cherry flavor
0.1 pt. red color
1.0 pt. magnesium stearate
B. pharmaceutical formulations
1.
50.0 pts. agglomerate
37.5 pts. aluminum hydroxide
1.0 pt. magnesium stearate
2.
100.0 pts. agglomerate
25.0 pts. calcium carbonate
5.0 pts. magnesium carbonate
1 drop peppermint
2.0 pts. magnesium stearate
3.
100.0 pts. agglomerate
25.0 pts. acetyl salicylic acid
15.0 pts. corn starch
2.0 pts. magnesium stearate
4.
90.0 pts. agglomerate
10.0 pts. vitamin C in dry form
2.0 pts. magnesium stearate
Other active ingredients of use in blends with the agglomerate are:
sodium bicarbonate, acetanilid, phenacetin, and magnesium
trisilicate.
C. specialty products
1. invertase Sugar Tablet
96.4 pts. agglomerate
3.6 pts. liquid triple strength invertase (K=0.9)
1.0 pt. magnesium stearate
2. Cocoa-Sugar Tablet
90.0 pts. agglomerate
10.0 pts. high fat cocoa
0.2 pts. dendritic salt
1.0 pt. magnesium stearate
After blending, the mixture is tabletted to form a cocoa-sugar
tablet.
3. Sugar-Synthetic Sweetener Tablet
450.0 pts. agglomerate
7.16 pts. calcium cyclamate
0.8 pts. sodium saccharin
5.0 pts. calcium stearate
4. Highly Concentrated Color Tablet
90.0 pts. agglomerate
10.0 pts. dried yellow FD&C No. 6
10.0 pts. sodium benzoate
5. Yeast Food Tablet
34.0 pts. calcium sulfate (2H.sub.2 O)
23.0 pts. flour
9.0 pts. ammonium chloride
0.25 pt. potassium bromate
17.75 pts. sodium dihydrogen phosphate
16.0 pts. salt
900.0 pts. agglomerate
10.0 pts. magnesium stearate
In the foregoing examples, the direct compression vehicle has been
a spherical agglomerate. In some instances, in which a high degree
of composition uniformity is desired, the use of the agglomerate
per se has been found disadvantageous. It is readily appreciated
that the ratio of invert to particulate sugar increases with
increasing agglomerate size. For example, in the case of a product
having agglomerates in the 80- 100 mesh range, the invert content
of the 200-mesh size particles is substantially less than the
invert content of the 80-mesh particles.
It has been further found that the agglomerates tend to segregate
according to size upon handling. For example, when a 80- 200 mesh
fraction of the agglomerates is stored in a bag, the 200-mesh
particles tend to settle out in the bottom of the bag during
handling. As a result of the different composition and size
segregation, the composition of tablets made from the agglomerates
will vary depending upon whether the agglomerate is taken from the
top or the bottom of the bag.
To avoid such product variations, it has been found desirable to
pulverize the agglomerate and then compact the pulverized
agglomerate, as for example by the use of a Fitzpatrick
Chilsonator, and reduce the resulting compacted sheet to particles
of a desired size. If desired, the granules of compacted
agglomerate may be screened to provide a product of more restricted
size variation.
The resulting compacted agglomerate may be employed in a manner
identical to the agglomerate itself. Thus, it may be substituted
for the agglomerate in any of the foregoing examples to achieve a
tablet of substantially identical characteristics.
* * * * *