WO1981002521A1

WO1981002521A1 - Pharmaceutical vehicle composition and process of producing same

Info

Publication number: WO1981002521A1
Application number: PCT/US1980/000235
Authority: WO
Inventors: J Kanig; R Parvez; N Herman
Original assignee: Mendell Co Inc Edward; J Kanig; R Parvez; N Herman
Priority date: 1980-03-10
Filing date: 1980-03-10
Publication date: 1981-09-17
Also published as: EP0047734A1

Abstract

A pharmaceutical vehicle is provided which allows for direct compression, together with an active ingredient, in a tableting machine for formation of a product ready for pharmaceutical administration. The pharmaceutical vehicle is formed by compacting, in a roller compactor (10) such as a Chilsonator, a mixture, in particular ratios, of powdered cellulose, preferably alpha-cellulose, and dicalcium phosphate dihydrate. The compaction of these materials results in a self-supporting sheet which is a compacted mixture of the two materials. This sheet is broken apart, sieved to the proper size, and the resulting particles employed in the formation of tablets with active ingredients in a standard tableting press. The resulting tablets are more easily formed and show improvement, inter alia, in friability, disintegration, and dissolution. Small amounts of other materials may be included with the powdered cellulose and dicalcium phosphate dihydrate.

Description

PHARMACEUTICAL VEHICLE COMPOSITION AND PROCESS OF PRODUCING SAME

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical vehicles and a method for producing such vehicles for use in tableting presses. The art is an old one, and while various improvements have been introduced, they have come slowly, and the rapid and efficient production of tablets by the manufacturer of the final product is still subject to many drawbacks.

The field is generally referred to as direct compression and an essential element of this direct compression process and formulation is the vehicle which carries the active ingredient or ingredients and forms a major portion of the mass to be tabletec.

In dry, direct compression technology, the media available have generally been single-substance vehicles, such as lactose, cellulose, dicalcium phosphate, dextrose, starch, and sucrose. These vehicles conferred upon the overall formulation certain mechanical attributes of flowability and compactibility. Both properties are absolute essentials in a direct compression vehicle. The most recently developed material in this area has been microcrystalline cellulose. However, as with the other materials employed in this field, microcrystalline cellulose suffers from certain undesirable features. It has only fair flowability and relatively high hygroscopicity. Similarly, spray- dried lactose and dextrose change color on standing. Dicalcium phosphate, when used as a single component, often cannot incorporate large proportions of non- compressible active ingredients. In general, none of the available materials could meet all the demands of a formulator, i.e., flowability, compressibility, capacity, stability, bioavailability , and economy.

In addition to all of the other problems, the formation of the tablet by the classical wet granulation methods at the formulator's plant frequently required an inordinate amount of time. Obviously, this was an unacceptable situation.

Thus, the industry has long sought a direct compression vehicle which would supply the various desirable factors — flowability, compressibility, capacity, stability, and bioavailability — while still commanding a price which allowed its ready use, and which allowed speedy processing. In accordance with the present invention, such a material has been developed, along with a particular process, for forming it.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has unexpectedly been discovered that by compacting powdered cellulose, preferably alpha-cellulose, and dicalcium phosphate dihydrate in a roller compactor. such as a Chilsonator, a compacted, dry, direct compression material is obtained meeting the necessary criteria for tablet formation. The powdered cellulose and dicalcium phosphate dihydrate are blended in a ratio of 85:15 to 15:85. Best compressibility, as measured by tablet hardness, degree of friability, and other desired characteristics, is obtained when the ratio of powdered cellulose to dicalcium phosphate dihydrate is between 85:15 and 50:50 and this is the preferred range. Most preferably, the range is from 70:30 to 60:40.

The two materials are preblended and are then fed to a roller compactor, the two rolls haying a particular configuration to allow for compaction of the material. The configuration may be of a concentrically sine curved cavity, such as is shown in U. S. Patent

3,255,285 - Chilson. That portion of the patent is herein incorporated by reference. Prior to being fed to the roller compactor, the preblended materials can be, and preferably are, densified in a screw conveyor. This densification involves de-aeration of the powder to permit closer particle-to-particle contact.

In the roller compactor, the blend of powdered cellulose and dicalcium phosphate dihydrate is formed into a compacted sheet. This sheet passes through a breaker bar to permit more manageable flow of the mass into the next stage of processing for particle sizing. The broken sheet of compressed powder is then fed to the comminutor, which may be a Fitzmill, so as to further reduce the broken sheet into particles of a desirable distribution range. The particles are then fed to a screener, or sizing mechanism, so as to separate the product from both fines and oversized materials. The commercial product has a particle size range of from 20 to 600 microns. Preferably, the particle size range is from 70 to 200 microns. The fines from the screening operation can be recycled to the original blending apparatus, while oversized particles are merely returned to the comminutor for further particle sizing and screening.

As is well known in the art, particle size distribution is a critical factor in both desirable properties of flowability and compressibility. The range of particle sizes in any given granulation is instrumental in the performance of the granulation in producing satisfactory compressed tablets. Any major shift in either direction (more fines or mere coarse particles) away from established optimum distribution may result in serious deficiencies in the effectiveness of any particular granulation. Such deficiencies can account for a complete failure of the mass to flow or compress, at one extreme, to other negative attributes such as tablet-to-tablet variations in weight, hardness, and content of active ingredient or ingredients. Any, or all, of these negative results nay account for an inferior product with deficient effectiveness in therapeutic efficacy.

The thus obtained product is useful as a direct compression vehicle in tableting with active ingredients. Small amounts of other materials can be added to the blend of powdered cellulose and dicalcium phosphate dihydrate for improved performance in the finally formed pharmaceutical tablet, or to aid in processing.

BRIEF DESCRIPTION OF THE DRAKING

The accompanying drawing represents the steps in the processing of the direct compression vehicle of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, powdered cellulose, preferably alpha-cellulose, and dicalcium phosphate dihydrate are blended in particular amounts. The ratio of the two materials is between 85:15 and 15:S5 in order to obtain, from the ultimate directly compressible material, a tablet with a wide range of desirable characteristics. Preferably, the ratio of powdered cellulose to dicalcium phosphate dihydrate is between 85:15 and 50:50, based, again, on the desired characteristics of a given tablet. Most preferably, the ratio is 70:30 to 60:40. The preferred powdered cellulose material is one whicft is composed of minute fibrous and amorphous cellulose particles which are, preferably, derived from wood pulp. The fibers of this powdered cellulose are, preferably, completely wettable, acting as natural wicks and, when employed in tablet formulation, accelerate tablet disintegration after oral administration. The cellulose useful in this process is. as defined in The united States Pharmacopeia, 20th Edition, 1980, at page 1219 for powdered cellulose. Preferably the cellulose employed has a fiber length of 20.-80 microns for best compactibility. Such a material is sold by Edward Mendell Co., Inc., the assignee of this application, under the trademark "REXCEL."

The specifications for the dicalcium phosphate dihydrate are as shown in the United States Pharmacopeia, 20th Edition, 1980, at page 112. Such a material is available from Edward Mendell Co., Inc. as "EMCOMPRESS."

The powdered cellulose and dicalcium phosphate dihydrate are blended, in the desired proportions, in a suitable vessel. Referring to the Figure, the materials are first admixed in a blending vessel 1, which may be vibrated by a vibrator 2, to insure better blending and mixing of the materials. The blended cellulose and dicalcium phosphate dihydrate are moved, via a conveyor 3, to a second olending vessel 4. They are conducted from this second blending vessel 4, via a horizontal feeder 5 and an attached vertical feeder 6, to a final hopper or blending vessel 7. The equipment just described for blending of the powdered cellulose and dicalcium phosphate dihydrate, up to the blending vessel or hopper 7, are not critical to the processing of the materials. It is only necessary that these materials be adequately mixed and blended up to this point, and any suitable equipment in the industry can be employed.

From blending vessel III, 7, the blended materials are conducted via a horizontal screw feeder 8 and a vertical screv; feeder 9 to the rolls of a roller compactor 10. This is referred to as a T-feed to the roller compactor and is an essential component of the invention. In this T-feed, comprising the horizontal screw, conveyor 8 and the vertical screw conveyor 9, a densified powder mass is formed. The powder is densified sufficiently for controlled volume flow.

The densified powder mass is forced between the two rollers cf a roller compactor. As previously indicated, the roller compactor can be of the Chilsonator type, as described in U.S. Patent 3,255,285 - Chilson. The cavities in the two rolls of the roller compactor can be sine curved cavities, or other configurations, as desired.

A Chilsonator Model DM roller compactor is operated with a roll pressure of 1G00 to 2000 psi at a roll speed of 6 to 30 rpm. The feed rate to the roller compactor from the T-feed is such that a solid sheet exits froa. the roller compactor. If the material exiting from the roller compactor is powdery, then the rate of feed is increased; if the sheet is too brittle, as indicated by undue strain on the comminutor, then the rate of feed to the roller compactor is decreased. The hardness of this solid sheet is such that the direct compression vehicle ultimately produced has the requisite particle size distribution range and compressibility.

The sheet of material is then led through a breaker bar 11, or other apparatus, for reducing the solid sheet of compacted material to a form which is more manageable for screener sizing, such as fragments of a sheet at this stage.

After leaving the breaking apparatus 11, the portions of the compacted sheet are fed to a comminutor 12, where the portions are reduced to particles. The comminutor may be of the type known as a Fitzmill. A suitable Fitzmill, operable in the present invention, is the one sold by the Fitzpatrick Company of Elmhurst, Illinois, as model DKAS012. The particles formed in the comminutor 12 are fed to a screening apparatus 13. In the screening apparatus, the particles are separated into the desired size range, from 20 to 600 microns.

The specific size range to be obtained is based upon the use to which the precompacted, direct compression material is to be put. Preferably, the particle size range is from 70 to 200 microns. If desired, the oversized particles from the screening can be returned to the comminutor 12 for further processing, while the fines can be returned to blending vessel I for recompaction.

In place of the powdered cellulose, certain other materials can be employed in combination with the dicalcium phosphate dihydrate. These materials are non-freeiy flowing, comprised of short fibers, inert, and highly compressible. Such materials include microcrystalline cellulose, soya protein, and certain other fibrous vegetable materials which include bran and dried fruit cellular fiber. These could be employed in certain special circumstances, such as when a nutritional supplement is desired in a tablet base. Frequently, however, such materials are more expensive than the powdered cellulose without a substantial improvement in properties.

The flowability of the powdered cellulose, or substitute material, is not important. The function of the present process is to transform the materials into compressible agents; it is to take a powder which does not flow, and form it into a flowable material which can be used in a tableting press.

Again, there are materials which can be employed in place of the dicalcium phosphate dihydrate.

Such materials include lactose, calcium sulfate, calcium sulfate dihydrate, calcium carbonate, dextrose and dextrates, and magnesium oxide. Such materials would normally be used for shelf life and compatibility of certain active ingredients.

Both the powdered cellulose and dicalcium phosphate dihydrate should have an initial particle size of up to 1,000 microns, mean particle diameter. The conditions employed in the comminutor are varied to accommodate the original particle sizes of the material placed in the blending vessel. For example, screen size, rpm, and rate of feed of the material into the comminutor can be varied. In addition to the powdered cellulose and dicalcium phosphate dihydrate, other materials may be added for improvement of specific properties. For example, binders, such as starches, ethylcellulose, guar gum, tragacanth and acacia gum may be added. When added, they are added in levels of up to 25%.

In addition, lubricants may be added. Such lubricants include materials such as magnesium stearate, calcium stearate, sodium stearate, stearic acid, and other animal and vegetable fatty acids. When employed with the combination of powdered cellulose and dicalcium phosphate dihydrate, lubricants are not generally needed, but may be used in amounts of up to 5%.

An additional type of material which may be added to the blend is a disintegrant. When the direct compression material is employed for certain active ingredients, the use of a disintegrant is indicated for enhanced dissolution of the ultimate tablet. Materials frequently employed as cisintεgrants include corn, wheat, potato, and rice starches, and their derivatives, along with carboxymethylcellulose. The disintegrant, when employed, is usually used in amounts of up. to 25%. It is not a requirement of the compression vehicle and, if added to the direct compression vehicle blend, is done so only to avoid the necessity, if any, for adding it to the end product.

It can equally well be added to the mixture of direct compression vehicle and active ingredient. When the powdered cellulose and dicalcium phosphate dihydrate are blended, compacted, and comminuted, according to the present invention, a particularly good carrier is formed, which does not require a disintegrant, as indicated above. This is due mainly to the fact that the cellulose, when wetted, swells and exerts pressure on the compacted mass (tablet) from within.

Because the direct compression material formed by the compaction of powdered cellulose and dicalcium phosphate dihydrate has good self- disintegration properties, as indicated, auxiliary disintegrants may not be required in an ultimate tablet formulation. The superior flow properties of the direct compression material formed according to the present invention permit the elimination of powder type glidants. Thus, it is not necessary to use materials which have been routinely used to aid in the flow of prior compression vehicles, such materials including fumed silica and other silicon dioxide prccucts. In addition to the particle sizes of the direct compression vehicle formed according to the present invention, the vehicle should have the following properties:

1. high compressibility when subjected to minimal pressures using a suitable tablet press, an excellent direct compression vehicle, per se, or men admixed with other components usually found in a medicinal tablet, will result in a compressed tablet which demonstrates the desirable qualities of adequate hardness, low friability, and similar attributes.

2. low friability — tablets which exhibit less than 0.8% loss in weight when subjected to 100 drops in a Roche Friabilator.

3. inherent lubricity tablets may be compressed on a rotary tablet press without the use of a lubricant

4. flowability — excellent flowability as evidenced by absence of any manifestation of a tendency to bridging or irregular flow pattern that may cause undesirable variation in tablet-to-tablet weight or content.

5. disintegration — excellent cisintegration in a period not exceeding 60 seconds in the U. S. P. XX Tablet Disintegration Test.

The shape of the particles formed in the direct compression vehicle of the present invention is an irregular sphere. Upon compaction in-e- tablets, this allows for inter-particulate compartments which provide for entrapment of small doses of active ingredients, thus providing for a uniformity in the final blend.

In order that those skilled in the art may be better enabled to practice the present invention, the following examples are given by way of illustration, and not by way of limitation.

Example 1

A quantity of 65 parts of powdered cellulose was blended with 35 parts dicalcium phosphate dihydrate.

The preferred alpha-cellulose, used in this Example, has the following specifications:

Moisture 7% maximum

Heavy Metals 0.002%

Ash 0.45 maximum pH (10% aqueous suspension) 5.0 - 7.5 Water soluble substances 1.5% maximum

Bulk density 1.5 - 2.5 ml/gm

The blend was fed through conveyors and blending hoppers, in accordance with the broad disclosure of the present invention to a roller compactor. The feed rate of the screw conveyor to the roller compactor was 10 rpm, the roll speed of the roller compactor was 6 rpm, and the pressure in the roller compactor was 1000 psi. The compacted sheet which emanated from the roller compactor was broken by a breaker bar and the material was then milled in a Fitzmill DKAS 012 at 4000 rpm, employing a 0.024 inch round hole perforated plate.

The material, which had a bulk density of 0.55 g/ml, was sieved, with the following screen retentions:

Screen Size Percent Retained

(mesh, ϋ. S. Standard) on Screen

20 9.56

40 34.49

80 27.47

100 6.40

200 7.14

325 12.18 through 325 2.84

Example 2

In a manner similar to that described in

Example 1, the same ratios of materials were blended and processed in the same manner. The bulk density of the resulting material was 0.53 g/ml. and the percent retention was as follows: Screen Size Percent Retained

(mesh, U. S. Standard) on Screen

20 5.10

40 25.73

80 29.83

100 7.75

200 10.08

325 16.10 through 325 5.48

Example 3

In a manner similar to that described in Example 1, the same ratios of materials were blended and processed in the same manner. The bulk density of the resulting material was 0.53 g/ml. and the percent retention was as follows:

Screen Size Percent Retained

(mesh, U. S. Standard) on Screen

20 8.98

40 32.78

80 28.57

100 7.41

200 7.14

325 11.30 through 325 3.92

Example 4

In a manner similar to that described in Example 1, the same ratios of materials were blended and processed in the same manner. The bulk density of the resulting material was 0.53 g./ml. and the percent retention was as follows: Screen Size Percent Retained

(mesh, U. S. Standard) on Screen

20 6.89

40 29.70

80 30.01

100 7.09

200 8.36

325 13.78 through 325 3.73

Example 5

In a manner similar to that described in

Example 1, the same ratios of materials were blended and processed in the same manner. The bulk density of the resulting material was 0.54 g./ml. and the percent retention was as follows:

Screen Size Percent Retained

(mesh, U. S. Standard) on Screen

20 5.95

40 26.49

80 30.45

100 7.40

200 8.83

325 14.88 through 325 6.08

Example 6

A blend was formed in the same manner as in Example 1, and using the same materials. The resulting material had a bulk density of 0.59 g./ml. The retention on screening is as indicated below: Screen Size Percent Retained

(mesh U.S. Standard) on Screen

20 6.2

40 27.35

80 34.01

100 7.5S

200 6.29

325 10.70 through 325 5.06

example 7

Compressibility studies were carried out on the materials of the present invention, and compared with a microcrystalline cellulose sold under the name Avicel PH 101. In the f irst case , the material was blended with 50% corn starbh for testing purposes v/ith the following results : Mater ials Hardness in Strong Cobb Units

Avicel PH 101 3-7 :

Material of Example 1 with a particle size of 70-200 microns 13-17.5

Material of Example 1 retained on 20, 40 and 80 mesh screens 15-27

Corn starch was selected as representative of active ingredients which have poor compressibility. The test was repeated employing calcium carbonate in an amount of 50%, with the following results:

Materials Hardness in Strong Cobb Units

Avicel PH 101 3-7

Material of Example 1 with a particle size of 70-200 microns 9-13.5

Material of Example 1 retained on 20,

40, and 80 mesh screens 26-28 This indicates the improved hardness of the material of the present invention when compared with presently available, more expensive, direct compression vehicles.

The direct compression vehicles formed according to the present invention can be tableted with a v/ide variety of active ingredients. In general, the direct compression vehicle of the present invention can be incorporated with any active medicinal agent or food nutrient additive which is non-reactive with the components of the direct compression vehicle and will provide tablets having a wide range of desired properties. Among the materials which can be employed are multivitamins, potassium gluconate, potassium bromate, acetaminophen, and others. The specific properties are dependent on the active ingredient and the use to which it will be put. Many of these are materials which could not be tableted with most previous direct compression vehicles. Such materials include various lactoses and directly compressible sugars and starches.

The direct compression vehicle of the present invention can be combined with active ingredients over a broad range. From 10 to 99.9% of the vehicle can effectively be combined with from 90 to 0.1% of active ingredients.

Example 8

Aspirin was combined with the direct compression vehicle of Example 1 in a particle size range of 70 to 200 microns. Tablets were formed on a

Stokes Tablet Press, Model BB2, with a standard concave punch. The amount of aspirin used was 30%, and 4% sodium starch glycolate (sold by Edward Mendell Co., Inc. under the trademark "EXPLOTAB") and 0.5% magnesium stearate as a lubricant were also employed. The resulting tablets had a mass flow of 45 gm./sec. with a linearity quotient of 18.6.

Example 9

Potassium gluconate was combined with the same direct compression vehicle as in Example 8. The tablets were formed on a Manesty Beta Press. The amounts of direct compression vehicle were from 15 to 25%. These tablets had satisfactory hardness for the mechanical stresses experienced in packaging and shipping.

While the invention has been shown and described with certain specific examples, it should not be considered as so limited, but only as limited by the appended claims.

Claims

WE CLAIM:

1. A direct compression vehicle for tableting of active medicinal and food nutrient materials comprising a blend of powdered cellulose and dicalcium phosphate dihydrate. in a ratio of from 85:15 to 15:85, said blend having been compacted in a roller compactor.

2. The direct compression vehicle of Claim 1 wherein the ratio of powdered cellulose to dicalcium phosphate dihydrate is from 85:15 to 50:50.

3. The direct compression vehicle of Claim 2 wherein the ratio of powdered cellulose to dicalcium phosphate dihydrate is from 70:30 to 60:40.

4. The direct compression vehicle of Claim 1 wherein the powdered cellulose is alpha-cellulose.

5. The direct compression vehicle of Claim 1 wherein at least a portion of the dicalcium phosphate dihydrate is replaced with a material selected from the class consisting of lactose, calcium sulfate, calcium sulfate dihydrate, calcium carbonate, dextrose, dextrates, and magnesium oxide.

6. The direct compression vehicle of Claim 1 wherein at least a portion of the powdered cellulose is replaced with a material which is non-freely flowing, comprise i of short fibers, inert, and highly compressible.

7. The direct compression vehicle of Claim 6 wherein at least a portion of the powdered cellulose. is replaced with a material selected from the class consisting of microcrystalline cellulose; soya protein, and fibrous vegetable materials.

8. The direct compression vehicle of Claim 1 containing, in addition, up to 25%, by weight, based upon the total of the powdered cellulose and dicalcium phosphate dihydrate, of a binder selected from the class consisting of starches, ethyl cellulose, guar gum, tragacanth, and acacia gum.

9. The direct compression vehicle of Claim 1 containing in addition, up to 5%, by weight, based upon the combined weight of the powdered cellulose and dicalcium phosphate dihydrate, of a lubricant selected from the class consisting of magnesium stearate, calcium stearate, sodium stearate, stearic acid, and animal and vegetable fatty acids.

10. The direct compression vehicle of Claim 1 containing in addition, up to 25%, by weight, based upon the combined weight of powdered cellulose and dicalcium phosphate dihydrate, of a disintegrant selected from the class consisting of corn starch, wheat starch, potato starch, rice starch, and carboxymethylcellulose.

11. The direct compression vehicle of Claim 1 having a particle size of from 20 to 600 microns.

12. The direct compression vehicle of Claim 11 having a particle size of from 70 to 200 microns.

13. The direct compression vehicle of Claim 1 wherein compaction is carried out at a pressure of 1000 to 2000 psi.

14. The direct compression vehicle of Claim 1 wherein compaction is carried out at a roll speed of 6 to 30 rpm.

15. A method for producing a direct compression vehicle comprising: a. blending powdered cellulose and dicalcium phosphate dihydrate in a ratio of 85:15 to 15:85; b. feeding said blended material through a pair of screw conveyors, arranged in a T configuration, so as to densify the blend; c. feeding said densified blend through a roller compactor so as to compact the blend; and d. forming said compacted blend into particles.

16. The method of Claim 15 wherein the particles are separated into preselected size ranges.

17. The method of Claim 15 wherein the compacted material leaving said roller compactor is first broken into fragments and the fragments are then processed in a comminutor.

18. The method of Claim 15 wherein the roller compactor is a Chilsonator.

19. The method of Claim 16 wherein oversized materials from particle separation are returned to the comminutor.