US3148123A

US3148123A - Granulating and coating tablets

Info

Publication number: US3148123A
Application number: US29576A
Authority: US
Inventors: Werner Jesse
Original assignee: General Aniline and Film Corp
Current assignee: GAF Chemicals Corp
Priority date: 1960-05-17
Filing date: 1960-05-17
Publication date: 1964-09-08
Anticipated expiration: 1981-09-08

Description

United States Patent 3,148,123 GULATING AND COATING TABLETS Jesse Werner, Holliswood, N.Y., assignor to General Aniline 8: Film Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed May '17, 1960, Ser. No. 29,576 7 Claims. (Cl. 167-82) This invention relates to a method of preparing new and improved granulations and coating for tablets.

In the pharmaceutical and food industries it is a Wellknown fact that very few crystalline or powdered materials can be compressed into suitable tablets on automatic tableting equipment in their crystalline or powdered form. The practice has developed of first preparing a granulation of the material because it is known that the grain-like structure thus formed is suitable for compression into tablets. The process of preparing a granulation according to the well-known methods consists of moistening the dry powder, with or without the addition of an adhesive substance, until the whole is converted into a crumbly mass. The mass is then forced through a screen in order to reduce the material to a grain-like structure of small granules. The most commonly used moistening agent is, of course, water although organic solvents are well known for this purpose. It is also common practice to add a substance such as gelatin, starch and acacia in order to assist in granulating the material.

Many highly useful materials are very difficult to granulate because they are unstable in the presence of water. The granulation which has been moistened with water also requires a considerable amount of time in order to dry it to a point suitable for further processing. Although many materials such as resins, zein, and similar substances can be used as granulating agents with volatile solvents, most of them have the disadvantage of being water-insoluble, off colored, or chemically active and are not considered wholly satisfactory to the art.

Heretofore tablets such as compressed have been coated with sugar by a lengthy and time-consuming process which consists in tumbling the tablets in a simple sugar syrup to wet the surfaces of the tablets; thereafter air is blown into the coating pans to partially dry the syrup. When the syrup becomes tacky a powdered filler is added. This filler is absorbed by the syrup and builds up the coating, at the same time keeping the tablets from sticking together.

During the first portion of the coating process considerable air is used to dry the tablets. When the initial coating has been built up and the final shaping and coating of the tablets is under way, considerably less air is used. The partially coated tablets are moistened with the syrup and are tumbled about so that they eventually assume an even, rounded shape.

After the tablets have been given the desired shape, they are given several coats of sugar syrup alone and colors may be added to these coats. After these coats have been dried, the tablets are polished with a suitable solvent wax mixture.

In carrying out coating procedures, a coating which amounts to approximately half the weight of the compressed tablet is usually employed. It is necessary to put such a coating on the tablets in order to give the protection which the coating gives from moisture.

In coating tablets, it is diflicult to get a satisfactory coating on sharp edges or corners and a tablet is not considered to be suitably coated unless the coating on the sharp edges and corners is of suitable thickness and strength. This means that in order to get an adequate coating on the corners or sharp edges it is necessary to apply an excessive amount of coating to other portions of the tablets. On an average, only about as much material will remain on these edges and corners as on the rest of the tablet so that about 40% more material is used than would be required if the coat were even.

The coating process is slow because the coatings must be built up in even layers. The operator can apply only very thin layers because the syrup cannot be applied in thick layers and cannot take up very large amounts of the powdered filler. After each application of syrup and filler, it is necessary to dry the tablet. The time for drying a subcoat may vary from one-half hour to more than two hours and the later drying steps may take even longer. A total of from sixty to eighty hours may be necessary.

It is, therefore, an object of this invention to provide a new and novel method of forming a granulation which will be free from the defects of the prior art methods.

Another object of the invention is to provide a new and novel granulating agent which is soluble in water and in organic solvents.

A further object of the invention is to provide a novel granulation which dries quickly to a hard material.

A still further object of this invention is to provide a new and improved coated tablet which has a relatively thin coating thereon and which can be applied in a shorter time, thus eliminating costly operations.

A still further object is to provide a tablet coating material which will permit the use of a thin elastic coating resistant to fracture. A still further object is to provide a coating composition for tablets which can be simply and readily applied and which will give a coating of the necessary thickness in a minimum time.

Other objects and advantages will become more clearly apparent from the following description:

In attaining the foregoing objects, I have found that polyvinyl-Z-oxazolidone is a very effective granulating and coating agent. It is water-soluble and can be used in any of the more commonly known granulations. Because of its solubility in organic solvents, it is also Very effective for use in the preparation of granulations which must be made free from contact with water. Many important medical substances and foods are highly hygroscopic and these materials can now be very satisfactorily formed into a granulation by the use of a water-free solvent solution of polyvinyl-Z-oxazolidone as the granulating agent.

The polyvinyl-Z-oxazolidone which I have found useful in granulating and coating tablets of various types is characterized by the following general formula:

L J wherein n represents the extent of polymerization as indicated by the molecular weight which may range from 1,000 to 150,000 and R equals H or alkyl of l to 2 carbon atoms such as methyl or ethyl.

The foregoing polymer is prepared by the polymerization of N-vinyl-Z-oxazolidone by the conventional method while employing benzoyl peroxide or azo-bisisobutyronitrilo as a catalyst. The preparation of N-vinyl-Z-oxazolidone is accomplished by the dehydrochlorination of N- (fl-chloroethyl)-oxazolidone with metallic potassium in tertiary butyl alcohol or by the reaction of sodium methylate with the 2-chloroethyl ester of 2-chloroethyl carbamic acid in tetrahydrofuran as solvent, as is more fully described in the Journal of Organic Chemistry, volume 22, pages 849 to 851, July 1957, and in German patent application B 340321 Vb/ 12p, published March 29, 1956.

Polyvinyl-Z-oxazolidone is a whitish, powdery solid polymer which is water and alcohol soluble and which has a molecular weight of 1,000 to 150,000, depending on the extent of polymerization.

Polyvinyl-Z-oxazolidone has some of the properties of a surface active agent so that it aids in the disintegration of a granule or of a compressed tablet made from a granulation containing polyvinyl-2-oxazolidone. In fact, all or part of the commonly used disintegrator can be replaced with polyvinyl-Z-oxazolidone which is used in smaller amounts than ordinary disintegrators. The use of a non-aqueous polyvinyl-Z-oxazolidone granulating agent also makes it possible to combine various ingredients which are normally incompatible when moistened with water.

The use of polyvinyl-Z-oxazolidone as a granulating agent is readily adaptable to the tablet-making function and it provides hard granules which can be compressed into hard tablets with standard equipment. Since polyvinyl-2-oxazolidone forms uniform, free-flowing granules which dry hard, its use is especially adaptable to aqueous or solvent systems and to wet-granulation or direct-compression techniques. It forms granules of minimum bulk, promotes homogeneous dispersion of ingredients, and reduces clogging of screens. Formulations granulated with polyvinyl-Z-oxazolidone are self-binding but non-sticking to punches and dyes during compression. Compressed tablets do not cap or chip easily. In view thereof, the disintegration time is improved and tablet breakage or abrasion is reduced during subsequent coating operations and shipping. For example, certain of the vitamins tend to form soft granulations and soft tablets when made up in the ordinary way. These soft tablets are subject to high incidence of breakage and to abrasion during the coating process. The same materials granulated with polyvinyl-2- oxazolidone as the granulating agent form hard granules and hard tablets which are subject to much less breakage during coating. Again, the granulation made with polyvinyl-Z-oxazolidone is easier to dry because the amount of Water or solvent employed is smaller. Finally, the tablet made by compressing a granulation prepared with polyvinyl-Z-oxazolidone can be of smaller size because very dilute aqueous or solvent solutions of polyvinyl-2-oxazolidone are suitable. By comparison it has been necessary to use much more concentrated solutions of starch and acacia, and larger amounts of diluents and disintegrators have formerly been required. The smaller size of the tablet from a polyvinyl-2-oxazolidone granulation is a highly significant factor in the tablet industry. For example, in one representative product containing 100 mg. of activity and made up with starch as the granulating agent, tablets weighed grains. When polyvinyl- 2-oxazolidone was used, it was possible to reduce the size of the tablet until 10 tablets Weighed only 24 grainsa reduction of about 40% The amount of polyvinyl-Z-oxazolidone that is used in the preparation of a granulation in accordance with the practice of this invention may be varied widely to suit the individual situation. Amounts as little as 0.5% of polyvinyl-Z-oxazolidone of molecular weight from 1,000 to 150,000, based on the weight of the other dry ingredients of the granulation, will give a product having the desirable qualities previously indicated. For example, in one representative multiple vitamin preparation that was notorious for its soft and weak structure, the new preparation containing about 3% by weight of polyvinyl-Z-oxazolidone molecular weight 20,000, based on the dry weight of the other ingredients of the granulation resulted in hard granules which made up into a hard and strong tablet in the usual tableting operation.

In another representative vitamin formula which was notorious for the softness of the tablet and for high incidence of breakage, polyvinyl-Z-oxazolidone M.W. 15,000 was substituted for other granulating agents and the preparation which contained about 1% by weight of polyvinyl- 2-oxazolidone M.W. 15,000 based on the dry weight of the other ingredients gave a hard granule which made up into a hard tablet and significantly lowered the breakage. And still another representative multiple vitamin preparation about 4% by weight of polyvinyl-Z-oxazolidone M.W. 10,000 was employed, based on the weight of the other dry ingredients in making up the granulations. In every instance, the substitution of polyvinyl-Z-oxazolidone as the granulating agent greatly improved the physical properties of the granulation and of the tablets made therefrom and reduced the distintegration time of the tablet and the size thereof.

As previously noted, the polyvinyl-Z-oxazolidone may be added in the form of either aqueous or organic solvent solution. Alternatively dry polyvinyl-Z-oxazolidone may be added to other ingredients which are moist from water or solvent in the making up of a granulation. Also, polyvinyl-Z-oxazolidone may be added in dry form to a partially dry by hygroscopic material of the type represented, for example by a dried liver extract. Still another method involves adding dry polyvinyl-Z-oxazolidone to other dry ingredients and wetting down the mixture with Water or solvent. While the theory is not fully understood, it is thought that polyvinyl-Z-oxazolidone derives enough water or solvent from the other ingredients to render it effective as a granulating agent.

Polyvinyl-Z-oxazolidone is very effective in the coating of tablets since it forms a smooth, durable film coat when modified by appropriate plasticizing agents. The resulting coating avoids appreciable increase in tablet size and simplifies production through elimination of the need for the usual subcoat powders and build-up coatings. It also promotes dispersion of dyes or pigments in coatings and makes uniformly colored tablets with a high gloss more easily obtainable. In the coating of tablets a small amount of polyvinyl-Z-oxazolidone is added to the syrup normally employed in coating. For this use, I have found that if from 1 to 5 parts by weight of polyvinyl-Z-oxazolidone are added to each 200 parts by weight of sugar in making the syrup, a final coating which is adequate for the tablet and which is thinner than coatings made by the conventional method can be built up on the tablet in a much shorter time than in following out heretofore standard procedures. The addition of the polyvinyl-Z-oxazolidone makes for a more elastic and stronger coating, so that adequate coverage can be obtained in fewer applications, thus reducing the amount of material and the time required for the coating process.

When such a coating is applied to a tablet, the resistance of the corners and the sharper edges of the tablets to chipping is increased from 25% to 50% and the resistance to fracture may be increased up to 50% Because of this, it is possible to reduce the overall coating on the tablet so that material saving is effected in materials, since the amount of coating on the smooth surfaces of the tablet may be reduced along with the rest of the coating.

When these new coating compositions are employed, it is possible to save up to or about 50% of the man hours involved and up to about 40% of the drying time.

The following examples will serve to illustrate the use of polyvinyl-Z-oxazolidone in granulations but it will be understood that the examples are not intended in any Way as a limitation of the invention.

Example I A granulation suitable for use in making a large quan tity of tablets is prepared according to the following directions:

Dissolve the polyvinyl-Z-oxazolidone in the alcohol and add with mixing to the dry blend of erythromycin stearate and sodium citrate anhydrous. After massing, force the massed material through a 4-mesh screen and dry for 24 hours at 120 F. The hard dry granules have a total weight of 220 lbs. and they contain approximately 1.43% by weight of polyvinyl-Z-oxazolidone.

Example II A granulation suitable for further working up into tablets is prepared according to the following directions:

Lbs. Chloramphemicol (chloromycetin) 13 Aluminum hydroxide U.S.P. gel (dry) 14 N-vinyl-S-methyloxazolidone M.W. 15,000 4 Ethyl alcohol 14 The chloroamphemicol and the aluminum hydroxide gel are charged into a mixer and thoroughly mixed with the addition of the polyvinyl-Z-oxazolidone in alcohol until the mixture is massed. The mass is then passed into a rotary granulator and the granulation is dried at about 120 F. Lubricants are blended with the granulation and hard tablets are compressed therefrom.

Example III The following dry ingredients are thoroughly blended and wet with Water, massed, screened and dried:

Lbs. Cyclohexyl sulfamic acid Polyvinyl-Z-oxazolidone M.W. 10,000 0.1

1%. lbs. of calcium carbonate is blended in and the mixture is compressed.

Example IV An interesting use of polyvinyl-Z-oxazolidone is in densifying a light, fluffy powder mixture which is adapted for encapsulating. A suitable granulation is made up according to the following directions:

Lbs.

Aluminum aspirin 7.00

Talc .10 Ethyl alcohol 3.00 Polyvinyl-2-oxazolidone M.W. 8,000 .15

The ingredients are charged into a mass mixer. The dry mixture is wet with the solution of polyvinyl-Z-oxazolidone in alcohol and the material, after thorough mixing, is granulated through A1."-rnesh screen. It is dried at 120 C. and the material is ground to a suitably small size for filling into capsules.

Aluminum aspirin is notoriously diflicult to handle because of its extremely light, flufry nature. By granulating it with polyvinyl-Z-oxazolidone the material is densified and does not return to its flufiy state upon drying. It is, therefore, much more suitable for encapsulating.

Example V Charge the ox bile, dehydrocholic acid and magnesium oxide into a mass mixer and add the polyvinyl-Z-oxazolidone solution to the mix. Granulate through a A"-mesh screen and dry at 120 F. to less than 2% moisture. Grind to 12-mesh and blend in the talc and stearic acid. Compress into tablets.

In preparing the coating solutions in accordance with this invention, 100 parts by weight of water are employed with each 200 parts by weight of sugar. From 1 to 5 Distilled water Cane sugar 200 Color coating syrup (red):

Polyvinyl-Z-oxazolidone M.W. 12,000 6.0 PD and C red dye No. 1 Qs. Titanium dioxide 0.5 Distilled water 100.0 Cane sugar 200.0

In the preparation of uniformly colored tablets, polyvinyl-2-oxazolidone is unique since it promotes optimum distribution of color, minimizes color migration during drying operations, eliminates spotting and mottled effects, and speeds up production. The required concentration of the polymer varies from 1 to 10% on dry weight of total ingredients. When insoluble pigments or dyes are used, the coloring agent is mixed with starch and added to the premixed active ingredients, fillers, etc., and the mix ground to a suitable size and moistened with the solvent in which the polymer has been dissolved, such as, for example, the lower alcohols, acetone, butyrolactone, cyclohexanol, ethylene glycol, cellosolve, etc. When the coloring agent, pigment or dye, is solvent soluble, the polymer is dissolved in the solvent and the color added. The resulting solution is then used to wet the premixture of dry ingredients.

The following examples illustrate the use of polyvinyl- 2-oxazo1idone in the coating of tablets:

Example VI About 100,000 compressed tablets which have only a shellac sealing coat are placed in a coating pan. These represent about 137 pounds. These tablets are then given four applications of about two pounds each of a sub-coating syrup consisting of 3 parts by weight of polyvinyl-2- oxazolidone of 10,000 M.W., 100 parts by weight of distilled water and 200 parts by weight of sugar.

Between applications the coatings are dried in the conventional manner with an air blast.

The tablets are rounded by the application of about three pounds of the same solution. They are dried during this operation without any air blast.

Just before complete drying of the tablets, another application of syrup is made, and the tablets are allowed to dry without any air blast.

To the dried tablets a color coating is applied which consists of 5 parts by weight of polyvinyl-Z-oxazolidone of M.W. 12,000, 0.5 part by weight or" titanium dioxide, coloring material, 100 parts by weight of distilled water and 200 parts by weight of sugar. About nine separate applications are made of this syrup with about two pounds for each application, decreasing the quantity until the last two applications consist only of the quality necessary to wet the surface of all the tablets. An air blast is used continuously until the last three applications.

When the tablets are dried they are given an application of wax polishing solution. The subcoating and coloring require about four hours.

Example VII About 60 pounds of uncoated ammonium chloride tablets are placed in a coating pan and about 10 fluid ounces of a subcoating syrup consisting of 3 parts by weight of polyvinyl-Z-oxazolidone MfvV. 8,000, 100 parts by weight of distilled water and 200 parts by weight of sugar are applied. Sufficient coating powder to allow the tablets to roll freely is added. An air blast is applied until the tablets are dried.

This process is repeated. The tablets are then removed from the coating pan and dried at 100 F. overnight.

The dried tablets are then returned to the coating pan. Four applications of 10 fiuid ounces each of the same syrup are applied. Dusting powder is added between applications in a conventional manner, and the tablets are dried by an air blast between applications. The rounding operation is carried out by applying 20 fluid ounces of the same syrup using a coating powder, but without applying an air blast.

The polyvinyl-2-oxazolidone utilized in the foregoing examples is essentially inert and non-toxic material. It is not assimilated from the gastro-intestinal tract in detractable quantities.

In lieu of the polyvinylQ-oxazolidones, I found that polyvinylimidazole, polyvinyl-3-morpholinone, polyvinyl- 2,6-dimethyl-3-morpholinone and polyvinyl-5-methyl-3- morpholinone of a molecular weight range of 1,000- to 200,000 may also be used for tablet binding and coating. These polymers have outstanding adhesive and filmforming properties which eifect better bonding within tablet granules.

I claim:

1. The process of preparing a material selected from the group consisting of crystalline and powdered materials in the form of compressed and coated tablets which comprises first blending said material with from 0.5 to by weight thereof of a polymer selected from the class consisting of polyvinyl imidazole and polyvinyl-3- morpholinones, wetting the said blend with a liquid selected from the clas conisting of water and a low boiling aliphatic alcohol to a massed mixture and then granulating the massed mixture followed by drying and compression into tablets and coating said tablets with an aqueous solution of said polymer and drying the same.

2. The process of preparing a material selected from the group consisting of crystalline and powered materials in the form of compressed and coated tablets which comprises first blending said material with from 0.5 to 10% by weight thereof of polyvinyl-imidazole and wetting the said blend with a liquid selected from the class consisting of water and a low boiling aliphatic alcohol to a massed mixture and then granulating the massed mixture followed by drying and compression into tablets and coating said tablets with an aqueous solution of said polyvinylimidazole.

3. The process of preparing a material selected from the group consisting of crystalline and powdered materials in the form of compressed and coated tablets which comprises first blending said material with from 0.5 to 10% by weight thereof of polyvinyl-3-morpholinone and wetting the said blend with a liquid selected from the class consisting of water and a low boiling aliphatic alcohol to a massed mixture and then granulat-ing the massed mixture followed by drying and compression into tablets and coating said tablets with an aqueous solution of said polyvinyl-3-morpholinone.

4. The process of preparing a material selected from the group consisting of crystalline and powdered materials in the form of compressed and coated tablets which cornprises first blending said material with from 0.5 to 10% by weight thereof of polyvinyl-2,6-dimethyl-3-morpholinone and wetting the said blend with a liquid selected from the class consisting of water and a low boiling aliphatic alcohol to a massed mixture and then granulating the massed mixture followed by drying and compression into tablets and coating said tablets with an aqueous solution of said polyvinyl-2,6-dimethyl-S-morpholinone.

5. The process of preparing a material selected from the group consisting of crystalline and powdered materials in the form of compressed and coated tablets which comprises first blending said material with from 0.5 to 10% by weight thereof of polyvinyl-5-methyl-3-morpholinone and wetting the said blend with a liquid selected from the class consisting of water and a low boiling aliphatic alcohol to a massed mixture and then granulating the massed mixture followed by drying and compression into tablets and coating said tablets with an aqueous solution of said polyvinyl-5-methyl-3-morpholinone.

6. The process according to claim 1 wherein the liquid is water.

7. The process according to claim 1 wherein the liquid is ethyl alcohol.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Drug & Cosmetic Industry, article by Rowell, September 1948, pp. 3083l0, 411-413.

Claims

1. THE PROCESS OF PREPARING A MATERIAL SELECTED FROM THE GROUP CONSISTING OF CRYSTALLINE AND POWDERED MATERIALS IN THE FORM OF COMPRESSED AND COATED TABLETS WHICH COMPRISES FIRST BLENDING SAID MATERIAL WITH FROM 0.5 TO 10% BY WEIGHT THEREOF OF A POLYMER SELECTED FROM THE CLASS CONSISTING OF POLYVINYL IMIDAZOLE AND POLYVINYL-3MORPHOLINONES, WETTING THE SAID BLEND WITH A LIQUID SELECTED FROM THE CLASS CONSISTING OF WATER AND A LOW BOILING ALIPHATIC ALCOHOL TO A MASSED MIXTURE AND THEN GRANULATING THE MASSED MIXTURE FOLLOWED BY DRYING AND COMPRESSION INTO TABLETS AND COATING SAID TABLETS WITH AN AQUEOUS SOLUTION OF SAID POLYMER AND DRYING THE SAME.