CA1045978A - Direct compression vehicle - Google Patents

Abstract

ABSTRACT
An intimate, co-dried mixture of a major amount of tricalcium phosphate and a minor amount of locust bean gum is useful for the preparation of tablets by the direct compression technique. The mixture is blended with an active material and fillers, disintegrating agents and lubricants, and the resulting blend is compressed without prior granulation or slugging to form a tablet containing at least about 10 weight per cent of the co-dried mixture.

Description

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This invention relates to direct compression vehicle~ ~ore particularly, this invention relates to a particulate composltion whlch can be admixed with an active materLal and, optionally, ~illers, disintegrating agents and lubricants, and the resulting mixture directly compressed into a tablet without the necessity of granu~
lation or slugging o~ the mixture~ ;~
There are two general methods for forming tab-lets, i.e. compression of a dry particulate material and trituration, or molding o~ a moi~t material, o~ which the ~irst technique is by far the most frequently employed.
The compression technique may be further subdivided into three ma~or categories, viz. direct compression~ wet granu~
lation and dry granulation. The di~e~t compression tech-nique is the most desirable, in that it employs the ~ewest steps and, in the case o~ the production o~ tablets con- ~
taining sensitive or unstable actives, such as certain phar- `-maceuticals, minimizes the exposure to water or other con- ;
ditions tending to adversely a~ect stability o~ the active~ ~;
20 Unfortunately, however, it haæ been found that the direct ~ ~
compression technique is of limited applicability.~ ;
First, most active materials possess poor com-pression properties, and thus are unsuited to this techni-que In addition, many actives are required in such small amounts per unit dosage ~orm that direct compression o~ the active alone is impractical, i~ not impossible. As a result, the active must be admixed with a direct compression vehicle, i.e., an inert composition which is co~p~tible with the active and has good compressibility. In addition, the direct compressLon vehicle should have good rlowability,

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~ood stability under normal ambient conditions, no adverse eEfect on tablet cli~integra-tlon time, the ability to pro-duce good tablet surfaces,and low cost.
To date~ however, no material has been ~ound ~ -which satisfies all of these crlteria. For example, of the most popular o~ such compression vehicles~ spray-dried lactose possesses poor stability and discolors on storing, dicalcium phosphate provides tablets having poor strength and high abrasiveness, and microcr~stalline cellulose is 10 expensive. ~ -According to this invention there is provided a particulate composition use~ul as a direct compression vehicle for forming tab}ets consisting essentially of a dry mixture o~:
(a) From about 100 parts by weight of an intimate co-dried blend o-f a minor but ef~ective portion of locust bean gum and a major portion o~ tri-calcium phosphate;
(b) Up to about 200 parts of granular tricalcium ~ ;~
phosphate, and (c) Locust bean gum in an amount of ~rom about 1 to about 7 weight per cent, based upon said co-dried blend and from about 3 to about 7 weight peri~aént, based upon the combined weight of said co-dried blend and granular tricalcium phosphate. ;
The direct compression vehicles of the present invention are an intimate, co-dried admixture o~ a minor portion of locust bean gum and a major portion o~ trical-cium phosphate. Neither locust bean gum nor tricalcium phosphate is use~ul as a direct compression vehicle because ... . , ,. ; - - . ,. . ,. ... . ~

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nelther can be compressed into a tablet o~ adequate strength. It i~ ~urprlsing then, that a co-dried mix-ture of the~e materials is 80 useful.
By the term "ma~or portion" is meant a por- -tion greater than about 50 weight per cent, and by the term "minor portion" is meant a portion less than about 50 weight per cent. The minimum e~ective amount of lo-cust bean gum is not narrowly critical, provided that the resulting tablet has the desired strength characterlstic~, whlch also depend upon the actlve component and other materials, e.g. fillers, disintegrating agents and lubri-cants, which may be incorporabed with the co-dried mixture which is compressed in-to the tablet. In general, however, ~
the direct compression vehicle of this invention should ~ ;
contain at least about 0.5 weight per cent, and preferably at least about 1 weight per cent locust bean gum. Tablet strength increases with increasing proportions of locust bean gum, but ordinarily, amounts in excess o~ about 20 -or 30 weight per cent are unnecessary. Higher proportions 20 can be employed, but there 1s no corresponding improvement ~-in tablet strength and, because locust bean gum is considera-bly more expensive than tricalcium phosphate, are not desirable from an economic standpoint. Amounts o~ locust bean gum in the range of ~rom about 1 to about 10 weight per cent are pre~erred, with an amount o~ about 5 weight per ~ent being particularly preferred.
The co-dried mixture is obtained by ~orming an aqueous suspension or dispersion o~ locust bean gum and tri~
calcium phosphate in the desired proportions, drying the aqueous mixture and reducing the dried product to a parti-. ~ .. . .

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culate composltion of the desired siz~.
To obtaln the deslred beneficial e~fects, ithas been found that a more intim~te mixture than that obtained by dry blen-ling is necessary. Accordingly, the locu~t bean gum and tricalcium phosphate are mixed in an aqueous medium. The amount o~ water ls not narrowly critical~ provided that the resulting aqueous ~ispersion ;~
is su~ficiently ~luld to permit mixing. In general, this requires that there be at least 25 parts water per part locust bean gum, with amounts of at least 50 parts water per part locust bean gum being pre~erred. The maximum amount o~ water is in no way critical, but amounts in excess of 200 parts per part o~ locust bean gum are un-necessary and only increase drying time and/or heat re-quirements and may preclude some drying techniques, sucha~ drum drying, which requires a relatively viscous liquid.
In general, amounts o~ from abou-t 50 to about 150 parts o~
water per part o~ locust bean gum are employed.
The water, locust bean gum and tricalcium phos-20 phate can be combined~ simultaneously, or in any order. In ;~
a pre~erred technique, however, locust bean gum is added to the water and the resulting mixture thoroughly stirred to form a clear sol o~ hydrated gum in water~ Then the tri-calcium phosphate is stirred in. Because trlcalcium phos-phate is only very slightly soluble in water, it is pre-~erably added in a -~inely divided ~orm to ensure that it is uni~ormly dispersed throughout the locust bean gum. In general, the particle size should be below about 100-mesh, and particle sizes in the range o~ ~rom about 200- to about 325-mesh are pre~erred.

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[)rying of the resultlng dispersion may be e~fected by a variety o~ techn:Lques, such a~ spray drying, tray Iry~ng, drum drying, and -the like.
The dried product ls then broken up into parti- ;
cles having the desired dimensions and$ i~ necessary, screened to achieve the proper size range and distribution. ~ -~
To ensure good flowability3 it ls desired that the particles be larger than 120-mesh, and pre~erably be in the range of from 40 to 80-mesh. The resulting particulate product com~
prises minute particles o~ the tricalcium phosphate dis~
persed throughout a locust bean gum matrix, and is substan-tially different in appearance and properties ~rom mixtures o~ the same dry materials obtained by blending or the wet granulation technique.
The particulate direct compression vehicle o~
this invention is admixed with the active which it is de-sired to incorporate into tablet ~orm and3 i~ desired, other common tablet components such as ~illers, dlsin- ;
tegrating agents and lubricants, and the mixture is tab-letted by known di~ect compression procedures. The pro-portions o~ vehlcle~ actives, ~illers, disintegrating agents and lubricants, are not critical, and obviously depend upon the active material and the unit dose desired in the tablet, as well a~ the properties de~ired in the tablet. In general, however, the direct compression vehicle can com~
prise at least lO pe~ cent of the tabletting mixture, and ma~ comprise a~ much as 99.9 per cent by weight, although amounts in the range o~ from about 30 to about 95 per cent ~
are more common. ~ -By the term "active materlal" is meant any ~.
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Teri~l intcr~tlc(l ror ln~c~t~on ~avLng~ a bcnericial or desirable eff~ct on the user. Suitable ~ctlve materials include therapelltic materi~ls, such as anesthetlcs, anti~
blotics, ~nl;l-tusslves~ vltamlns, Aspirin, antacids~ and 5 the llke; foo-l sturfs, such as cocoa, drled oats, fruit ~
flakes and the ].llce; edlble (~yes ~nd ot~er rood additi~es, and so on. The vchicle is a free-flowing granular material and imparts improved flow characteristics to the active materia.l and other components of the blencl, thereby assuring ease of tabletting.
The blend of direct compresslon vehicle~ active material and other additives is mixed and directly com pressed to form a tablet employing conventional techniques ~.
and apparatus.
Although the co-dried mixture is useful as a direct compression vehicle, it has been found desirable to :
modi~y it by blencling it with other materials prior to use as a direct compression vehicle.
For example, the co-dried composition can be 20 diluted with granular tricalcium phosph~.te without serious :
reduction.of tablet strength. By the term "granular", as employed herein, is mea.nt a product hav:lng particle slzes in excess of about 120-mes~l, and preferably in excess of 60 to 70-mesh. ~ su:l.î;able E,.ranular tricalcium phosphate is dis-closed in United States Patent No. 3~l3l~,719. The amount of tricalcium phosphate employed is not narrowly critical, but i t should not be so hiErh as to materia.lly redllce the tablet ;~ .
strength affordcd by the co-dried blend, and in general the ~.
weig,ht of granular tricalcium phosphate should not bc ~reater thar) twlce the weight of thc co-drled blend.

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Although the presence of tricalcium phosphate ~ ;
ln amounts o~ up to about 2 times the amount o~ co-drled blend rloes not materlally af~ect tablet stren~th, it has been foun~ that as the proportion of co-dried blend de-creases,the incidence of "picking", i,e. the accumulation o-~ material on the die punch, increases. This can be mini-mized through the use of lubrican~s, such as magneslum stearate. However, as the amount o~ lubricant is increased above about 0.75 per cent, there is a serious loss of tablet strength and the dispersibility of the resulting tablet in water ls materially retarded. To minimize the need for lubrican-ts, the co-dried blend can be admixed with locust bean gum, which tends to act both as a lubricating and as a disintegrating agent. The effectlve amount o~ locust bean gum is not highly critical, and ordinarily will be about 5 to about 15 weight per cent, based upon the co-dried blend.
When granular tricalcium phosphate is present, the locust bean gum ordinarily will be employed in an amount of from about 3 to about 7 per cent, based upon the combined weight of co dried blend and granular tricalcium phosphate.
In some instances, the locust bean gum is unable to impart a desired disintegration rate. In such cases, it has been ~ound deslrable to employ a pharmaceutically accep-table aeidic material as~an auxilliar~ disintegration agent.
The combination of locust bean gum and acidic material pro-vides higher disintegration rates than are obtained with either material alone. The acidic material can be an organic acid, such as citric acid, 2-acetoxybenzoic acid, adipic acid~
fumaric acid, succinic acid, malic acid or tartaric acid, with citric acid and tartaric acid being preferred, or it . ~

~()4~978 can be a salt of a weak base and a strong ac~d~ such as f`errous sulfate~ aluminium sulfate or monocalcium phos-phate, with monocalcium phosphate being pre~erred. Citric acid is especially preferred. The amount of acidic materlal is not highl~ critical~ provided it is sufficient to impart the desired disintegration rate. In general, amounts of from about 1 to about 7 weight per cent, based upon co drled blendg and from about 1 to about 3 weight per cent~ based upon combined co-dried blend and granular trlcalcium phos-phate have been found useful.
The acidic material can be admixed with theco-driecl blend in any ~uitable ~ashion. To assure uniform distribution~ however, it has been found desirable to first admix the acidic material with a diluent~ preferably tri-calcium phosphate, and pulverize the mixture to form a pow-der, i.e~ a particulate material havlng particle si~es of less than 120-mesh, and preferably less than 150 to 250-mesh. ;
The powder i9 then admixed with co-dried blend and, if employed, the granular tricalcium phosphate. The ratio of .~ .
acidic material to diluent in the powder is not highly cri-tical, and approximately equal parts by weight (i.e~ 40 to 60 weight per cent acidic material and 60 to 40 weight per cent diluent) are satisfactory.
In accordance with this invention, a particularly .
preferred direct compression vehicle comprises a dry~
physical admixture of:
a. From about 30 to about 90 parts b~ weight of the co-dried mixture of locust bean gum and tricalcium phosphate of this in~ention, as described above;

. , ~LV9~ 7 b. Up to about 60 parts by wei~ht of' granular tricalcium phosphate, the combined weight -o~ co-drled mixt,ure and granular tr~calcium phosphate being from about 90 to about 95 ~; part~ by welght;
c. From about 3 to about 7 parts by weight of locust bean ~um~ and , ~:
d. From about 2 to about 5 parts by weight o~
a powderea blend o~ approximately equal parts by weight o~ tricalcium phosphate and ~n acidic material, especlally citric acid.
The following examples are illustrative. Unless otherwise specified, all parts and percentages are by weight.
EXAMP~E I i , A lO~eram portion of locust bean gum was added to 1000 cc. water and the resulting mixture thoroughly - stirred. ~hen 90 grams o~ tricalcium phosphate was added -;
and thorou~hly mixed to yield a creamy w~ite suspens~on.
The suspension was drum dried to yleld a ~ree-flowing pow-der, which was formed:into a 13/~2 ~nch, 0.5 gram tablet at 4500 psi. m e e~ectlon pressure needed to eject the tablets from the die was from 100 to 150 psi and the Stokes hardness of the tablets wa5 in excess o~ 45.
When disodium phosphate or calcium chlorlde were ., substituted ~or the tricalcium phosphate, ~ablets ha~ing a Stokes hardness o~ only 18 were obtained.
EXAMP~E II
A 30-gram portion of locust bean gum was added ;
to 1000 cc. wa~er and stirred to ~orm; a viscous mixkure.
3 Then 70 grams of tricalcium phosphate was added, ~ollowed by 10.

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~145~78 300 cc. and 200 cc~ portions of water, with mixing to yiald a homogenous milky suspension. After drum drying and tablettin~ as described in Example I, the e~ection pressure was l~o psi and the Stokes hardne~s was 45.
Employlng procedures similar to those described in Example I, except that the suspension was oven dried at 60C., compositions containing from 0 to 7 weight per cent locust bean gum and 93 to 100 weight per cent tricalclum phosphate were produced and f'ormed into tabletsO The Stokes hardness and dispersibility were measured and are summarized as follows~
Tablet Composition wt.~ Product Properties Locust Bean Calcium Dispersi-Gum Phosphate Hardnessbilit~
- 100 1115 min.

1 99 271 min. ;

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7 93 394-1/2 min.
7 93 37.5 *Time to di~per~e in 10 cc. of water in closed test tube whlch was inverted at a rate of 30 times per minute.
EXAMPLE IV
A series o~ tabletting mixtures was prepared using locust bean gum, tricalcium phosphate and two co-dried mix-tures of locust bean gum and tricalcium phosphate containing 3~ or 5~ of locust bean gum. Each of the resulting mixtures - ~ -11, ..

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~LO~S978 wa~ used to prepare 13/32-inch tablets on a Carver Pre~s at ~500 pound.. pressure for 10 seconds and the tablets were evaluated :for Stokes hardness and capplng. The data for these experiments is summarized as follows:
Blend No.
Component Locust bean gum, ~ 5 5 4.5 5 Tricalcium phosphate~ %95 85 65.5 45 Co-dried blend (3% locust - - - 50 bean gum)~
Co-dried blend (5~ locust - 10 30 bea.n gum), %
Stokes Ha.~dness, kg. 28.5 31.5 32.6 3~
~apping Sev. Mod. None None :
From the abo~e da,ta it is evident that increased amounts o~ the co-dried blend a:~orded improved tablet strength and reduced the incidence oP capping.
EXAMPLE V
A mixture of 5 parts locust bean gum, 45 parts trical-clum phospha.te and 50 parts of a co-dried m~xture of tri-calcium phosphake and locust bean gum containing 3~ locusthean gum was prepared and admixed with magnesium steara.te and varying amounts oP citric acid. The resulting tab-letting mixtures were :~ormed into ta,blets and the disinte-gratlon time o~ the tablets wa.s determined by the standard U.S.P. disintegration test. The data ~or these experiments are summarized a,s Pollows:

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Experiment_No.

Mixture~ ~ gg 9~ g4 8g Magnesium stearate~
5 Citric Acid, ~ - 1 5 10 ~ ;
Disintegration time, min.30 2-1/2 1-1/4 1-1/4 EXAMPLE VI
A series o~ experiments was performed in which co-dried locu~t bean gum-tricalcium phosphate blends were 10 admixed with locust bean gum, magnesium stearate and mono- -~
calcium phosphate, the mixtures were employed to ~orm tab-lets, and the tablets were evaluated for disintegratlon time.
The data from these experiments are summarized as ~ollows:
Run No.
Mixture Composition 1 2 3 l~ 5 6 Blend A (1~ locust bean 100 - - - - -gum), pts.
Blend B (3% locust bean -100 gum~, pts.
Blend C (5~ locust bean - - 100 100 100 100 gum), pts.
Locust bean gum, pts. 5 5 5 5 5 5 Magnesium stearate, pts. 1.5 1.51.5 1.5 1.5 1.5 Monocalcium phosphate,pts. 5 5 5 10 15 20 Dislrltegration time, mln. 1 3 10-~ 10 8 10-~
Each o~ the direct compression vehicles oP the ~oregoing examples can be blended ln accordance with the Pollowing reclpes and compressed to ~orm tablets or waPers.

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~4S97 A. CONFECTIONERY TP ~ILrs OR wAr~D.
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1. I,E~ON FLAVO~FD confectlonery ta,blet:
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25.0 pts. direct compression vehicle 75.0 pts. a~glomerated sugar -1~0 pts. citric acid~ dry .25 pt. encap~ulated lemon ~lavor ,10 pt. yellow color #5 1.0 pt. magnesium stearate 2. GRAPE FLAVORED confectionery tablet:
50.0 pts. direct compression vehicle 50.0 pts. agglomerated sugar 2.0 pts. tartaric acid .25 pt. grape ~lavor .05 pt. grape color .5 pt. calcium stearate 3. CHERRY FLA~ORED con~ectionery tablet:
75.0 pts. direct compression vehicle 25.0 pts. agglomerated sugar 2.0 pts. ~umarlc acid .2 pt. cherry flavor .~ pt. red color 1.0 pt. magnesium stearate B, PHARMACEUTICAL FORMULATIONS
1. 50.0 pts. direct compression vehicle 37.5 pts. aluminum hydroxide 1.0 pt~ magnesium stearate . ~

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2. 100~0 pts. direct compression vehicl 25.0 pts. calclum carbonate 5~0 pts~ magnesium carbonate 1 drop peppermint oil ~ -2.0 pts. magnesium stearate 3~ lOOrO pts. direct compression vehicle 25.0 pts. acetyl salicyllc acid 15.0 pts. corn starch 2.0 pts. magnesium stearate

4~ 90.0 pts. direct compression vehicle 10.0 pts. vitamin C in dry ~orm 2.0 pts, magnesium stearate Other active ingredients o~ use in blends with the direc-t compres~ion vehicle are: sodium bicarbonate, acetanilid~
phenecetin and magnesium trisilicate.
C. SPECIALTY PRODUCTS
1. INVERTASE TABLET
96.4 pts. direct compression vehicle `
3.6 pts. liquid triple strength ~ `
20inverta~e (K=O.9) "
1.0 pt. maenesium stearate `~
2. COCOA-SUGAR TABLET
35.0 pts. direct compression vehicle ~
55.0 pts. agglomerated sugar ,~ -25 10.0 pts. high -~at cocoa 0.2 pt. dendritic salt 1.0 pt. magnesium stearate ~ `~
After ble~ding the mixture is tab-letted to ~orm a cocoa-sugar tablet.
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90.0 pt~, dlrect compression vehicle lO.0 pts. dried yellow FD&C ~6 ~ y~ o~ rA~
34 . o pts, calcium sulfate ( 2H20) 23.0 pts. ~lour 9.0 pt~. ammonium chloride :
0 . 25 pt . pota~sium bromate 17.75 pts. sodium dihydrogen phosphate 16.0 pts, salt ~.:
gO0.0 pts. direct compression vehicle lO.l pts. magnesium stearate ~.

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Claims (4)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN
EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED
AS FOLLOWS:-

1. A particulate composition useful as a direct compression vehicle for forming tablets consisting essentially of a dry mixture of:
a. about 100 parts by weight of an intimate co-dried blend of a minor but effective portion of locust bean gum and a major portion of tricalcium phosphate;
b. up to about 200 parts of granular tricalcium phosphate;
c. locust bean gum as a lubricating agent and disinte-grating agent in an amount of from about 1 to about 7 weight per cent based upon said co-dried blend, and from about 3 to about 7 weight per cent, based upon the combined weight of said co-dried blend and granular tricalcium phosphate; and d. a pharmaceutically-acceptable acidic material as an auxiliary disintegrating agent in an amount of from about 1 to about 7 weight per cent, based upon said co-dried blend, and from about 1 to about 3 weight per cent, based upon the combined weight of said co-dried blend and granular tricalcium phosphate.

2. A composition according to claim 1 wherein said acidic material is selected from the group consisting of citric acid, 2-acetoxybenzoic acid, adipic acid, fumaric acid, succinic acid, malic acid, tartaric acid, ferrous sulfate, aluminum sulfate and monocalcium phosphate.

3. A composition according to claim 2 wherein said acidic material is citric acid.

4. A particulate composition useful as a direct compression vehicle for forming tablets consisting essentially of:
a. from about 30 to about 90 parts by weight of a particulate, intimate co-dried mixture of a minor but effective portion of locust bean gum and a major portion of tricalcium phosphate;
b. up to 60 parts by weight of granular tricalcium phosphate, the combined weight of co-dried mixture and tricalcium phosphate being from about 90 to about 95 parts by weight;
c. from about 3 to about 7 parts by weight of locust bean gum; and d. from about 2 to about 5 parts by weight of a powdered blend of approximately equal parts by weight of citric acid and tricalcium phosphate.