US3885026A

US3885026A - Preparation of porous tablets

Info

Publication number: US3885026A
Application number: US395796A
Authority: US
Inventors: Helmut Heinemann; Werner Rothe
Original assignee: Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1972-09-20
Filing date: 1973-09-10
Publication date: 1975-05-20
Anticipated expiration: 1992-05-20
Also published as: DE2246013A1; FR2199973A1; SE395366B; FR2199973B1; CH579394A5; JPS4969819A; GB1381588A; AT324568B; IT998618B

Abstract

In the production of tablets which are to undergo disintegration in use wherein the tablet components are mixed and pressed into predetermined shape, the improvement which comprises incorporating into the mix at least one inert readily volatilizable solid adjuvant, pressing the mix into shape, and thereafter volatilizing the adjuvant, whereby the resulting tablets are porous, strong, shape retaining and readily disintegratable. Volatilization can be effected by sublimation or application of vacuum. The adjuvant preferably comprises urethane, urea, ammonium carbonate, ammonium bicarbonate, hexamethylene-tetramine, benzoic acid, phthalic anhydride, naphthalene or camphor present in about 5 to 50 percent, especially about 10 to 30 percent, by weight of the total tablet mix.

Description

United States Patent [191 Heinemann et al.

[451 May 20, 1975 PREPARATION OF POROUS TABLETS [75] Inventors: I-Ielmut Heinemann, Heidelberg;

Werner Rothe, Hockenheim, both of Germany [73] Assignee: Boehringer Mannheim GmbH, Mannheim-Waldhof, Germany [22] Filed: Sept. 10, 1973 [21] Appl. No.: 395,796

[30] Foreign Application Priority Data [58] Field of Search 264/49, 54, 117, 140, 101, 264/109, 122; 23/293 R, 293 A; 241/1, 2, 18, 30; 424/14; 239/60; 252/135, 531

[56] References Cited UNITED STATES PATENTS 1,742,515 1/1930 Mandell 264/49 X 2,887,437 5/1959 Klioze et a1 424/14 3,175,521 3/1965 l-lershberg 424/14 X 3,371,984 3/1968 Kelly et a1 239/60 X 3,424,842 1/1969 Numberg 264/117 X 3,632,778 1/1972 Sheth et a1 264/117 X 3,639,286 2/1972 Ballestra et a1. 252/135 X 3,649,545 3/1972 Susuki et a1. 252/135 X 3,653,914 4/1972 Schmitt 264/122 X 3,674,700 7/1972 Gaiser 252/135 3,719,599 3/1973 Crivellaro et a1. 424/14 X 3,739,048 6/1973 Morita 264/54 X 3,781,428 12/1973 l-lennart et a1 239/60 X 3,789,119 1/1974 Fusari 264/117 X R18,506 6/1932 Mandel 264/49 X FOREIGN PATENTS OR APPLICATIONS 83,244 12/1971 Germany 264/49 OTHER PUBLICATIONS The Condensed Chemical Dictionary, Seventh Edition, Completely revised and enlarged by Arthur and Elizabeth Rose, New York, Reinhold, C1966, page 995.

Handbook of Chemistry and Physics, 52nd Edition, Editor: Robert C. Weast, Cleveland, Ohio, The Chemical Rubber Co., 01971, Page C-232.

Primary Examiner-Philip E. Anderson Attorney, Agent, or Firm-Burgess & Dinklage & Sprung [5 7] ABSTRACT In the production of tablets which are to undergo disintegration in use wherein the tablet components are mixed and pressed into predetermined shape, the improvement which comprises incorporating into the mix at least one inert readily volatilizable solid adjuvant, pressing the mix into shape, and thereafter volatilizing the adjuvant, whereby the resulting tablets are porous, strong, shape retaining and readily disintegratable. Volatilization can be effected by sublimation or application of 'vacuum. The adjuvant preferably comprises urethane, urea, ammonium carbonate, ammonium bicarbonate, hexamethylene-tetramine, benzoic acid, phthalic anhydride, naphthalene or camphor present in about 5 to 50 percent, especially about 10 to 30 percent, by weight of the total tablet mix.

13Claims, No Drawings PREPARATION OF POROUS TABLETS The present invention is concerned with a new process for the preparation of porous tablets.

Because of the ease of handling and the simplicity of dosing, not only pharmaceutical tablets but also reagent tablets are used to an ever increasing extent for diagnostic and analytical purposes. Most active materials and reagents cannot be tabletted by themselves since they form hard tablets which do not readily break down and, in addition, in many cases, tend to stick in the presses used.

Tablets which break down quickly are only obtained by the addition of disintegration agents, such as carboxymethyl-cellulose, starch or the like; filling materials, such as lactose, phosphates or the like; and lubricants, such as talc, stearic acid, paraffin or the like. Whereas it is simple to find suitable, physiologically compatible adjuvants for pharmaceuticals, reagent tablets which, generally speaking, are to give optically clear solutions, cannot be produced or can only be produced with difficulty in this manner. In particular, the lubricants which are generally used and which are intended to prevent the adherence of the tablet masses in the presses used are mostly insoluble in water. It has, therefore, been suggested to press together adhesive reagents with very large amounts of readily tablettable fillers or to use very high pressures for the pressing. However, both processes are unsatisfactory since the tablets formed are either unnecessarily large or are too hard and difficult to break down.

Another known process gives so-called molded tablets." In this case, the tablet components are formed into a paste with water or an organic solvent, in which at least one of the components partially dissolves, to give a stiff slurry which is formed in special machines to give tablets, whereafter the tablets are carefully dried. Upon evaporation of the solvent, the substances dissolved therein adhere the undissolved particles, whereby the tablets receive their strength; at the same time, small hollow spaces are formed into which solvents can again penetrate when the tablets are dropped into liquid. Although these tablets are satisfactory with respect to speed of dissolution they are frequently too soft and brittle due to the presence of very fine canals so that difficulties arise in packing and transport. Furthermore, the use of the process is limited due to the fact that many reagents, especially enzymes and indicators, are damaged by solvents, and organic solvent vapors necessitate special safety precautions during the production of the tablets.

It is, therefore, an object of the present invention to provide a process which permits the production of readily dissolved, porous tablets in conventional tablet presses, without having to add lubricants, explosive agents or solvents.

In accordance with the present invention the conventional process of mixing tablet components and pressing the mix into predetermined shape is modified by incorporating into the mix at least one inert readily volatilizable solid adjuvant, pressing the mix into shape, and thereafter volatilizing the adjuvant, whereby the resulting tablets are porous, strong, shape retaining and readily disintegratable.

Due to the hard pressing in conventional tabletting machines, there are formed tablets of great mechanical stability and, at the same time, the addition of sparingly soluble lubricants is unnecessary. Since the pressed tablets, in contradistinction to molded tablets, are

form-stable, they no longer shrink upon removal of the adjuvant. Therefore, when the adjuvant is removed, it

5 leaves behind comparatively large hollow spaces and canals, through which solvent can penetrate.

As adjuvants, there can be used, in principle, all readily sublimable materials or materials which can readily be converted into gaseous decomposition products and which are readily tablettable and do not react with the other components of the tablets. By way of example, there may be mentioned urethane, urea, ammonium carbonate and bicarbonate, hexamethylenetetramine, benzoic acid, phthalic anhydride, naphthalene and camphor, urethane being especially preferred.

The tablet masses for water-soluble reagent tablets and pharmaceutical tablets can, in addition to one or more active materials, contain conventional soluble carrier materials, for example sodium chloride, potassium chloride, borax, phosphates, oligosaccharides, polyethylene glycols, tensides and other appropriate inorganic and organic materials. The volatile solid adjuvants can account for about 5 50 percent and preferably about -30 percent of the total tablet mass. it being understood that in the case of a high proportion of adjuvant there are formed comparatively large hollow spaces and thus tablets which break down more quickly but are also more brittle than in the case of using a small proportion of adjuvant. Although the adjuvants can be completely removed, the production time for the new tablets according to the present invention is shortened when the adjuvants are allowed to remain behind in the tablets in trace amounts, for example of less than about 1% by weight.

Where the tablet components are of sufficient ther' mal stability, the adjuvants can be removed by simple heating of the tablets above the sublimation or decomposition point. In the case of sensitive tablet components, for example of enzymes, it is advantageous to work in a vacuum, the conventional freeze drying plants with condensation separator having proved to be especially advantageous for this purpose.

The following Examples are given for the purpose of illustrating the present invention:

EXAMPLE I Tablet A: 1.850 kg of potassium chloride are sieved and pressed to form tablets of 8 mm diameter containing 185 mg of potassium chloride.

Tablet Bl: 1.850 kg of potassium chloride are mixed with 350 g of urethane (ethyl-urethane), sieved and pressed to form tablets of 8 mm diameter containing 185 mg of potassium chloride and 35 mg of urethane.

The urethane is subsequently sublimed from these tablets over 5 hours in a freeze drying plant at 20C and at a pressure of IO to 10. mm Hg.

Tablet B2: 1.850 kg of potassium chloride are mixed with 350 g of ammonium bicarbonate, sieved and pressed to form tablets of 8 mm diameter containing 185 mg of potassium chloride and 35 mg of ammonium bicarbonate.

The ammonium bicarbonate is driven off from these tablets over 8 hours in a drying cabinet at 90C.

Tablet B3: 1.850 kg of potassium chloride are mixed with 350 g of urea, sieved and pressed to form tablets of 8 mm diameter containing 185 mg of potassium chloride and 35 mg of urea.

The urea is sublimed from these tablets over 16 hours in a vacuum cabinet at 110C and 15 mm Hg.

Tablet B4: 1.850 kg of potassium chloride are mixed with 350 g of urotropin, sieved and pressed to form tablets of 8 mm diameter containing 185 mg of potassium chloride and 35 mg of urotropin.

The urotropin is removed from these tablets over 16 hours in a vacuum cabinet at 90C and 15 mm Hg.

The results of tests carried out on these tablets are set out in the following Table 1:

TABLE 1 Tablet Height, Hardness. Dissolving Breakability,

mm kg Time, sec. see.

EXAMPLE 2 Tablet C: 1.5 kg of dextrose are granulated with 300 ml of 40 percent aqueous alcohol, dried and sieved. The granulate is dry mixed with 50 g of polyethylene glycol (M.W. 5000 6000) and pressed to form tablets of 8 mm diameter containing 150 mg of dextrose.

Tablet D1: 1.550 kg of dextrose-polyethylene glycol granulate are dry mixed with 300 g of urethane. The tablet mass is pressed to form tablets of 8 mm diameter containing 150 mg of dextrose and 30 mg of urethane.

The urethane is sublimed from these tablets over 8 hours in a drying cabinet at 40C.

Tablet D2: 1.550 kg of dextrose-polyethylene glycol granulate are dry mixed with 300 g of ammonium carbonate. The tablet mass is pressed to form tablets of 8 mm diameter containing 150 mg of dextrose and 30 mg of ammonium carbonate.

The ammonium carbonate is removed from these tablets over 8 hours in a drying cabinet at 75C.

Tablet D3: 1.550 kg of dextrose-polyethylene glycol granulate are dry mixed with 300 g of benzoic acid. The tablet mass is pressed to form tablets of 8 mm diameter containing 150 mg of dextrose and 30 mg of benzoic acid.

The benzoic acid is sublimed from these tablets over 16 hours in a vacuum cabinet at 90C and 15 mm Hg.

Tablet D4: 1.550 kg of dextrose-polyethylene glycol granulate are dry mixed with 300 g of camphor. The tablet mass is pressed to form tablets of 8 mm diameter containing 150 mg of dextrose and 30 mg of camphor.

TABLE 2 Tablet Height, Hardness,

Dissolving Time, sec.

Breakability, sec.

EXAMPLE 3 Tablet E: g of polyethylene glycol (M.W. 5000 6000) are dissolved in 80 ml of 40 percent aqueous ethanol. With this solution, there are mixed 388 g of glucose, which is then dried and sieved. The granulate obtained is dry mixed with 12.5 g of nicotinamide-adenine-dinucleotide (NAD), 3.75 g of 2,5-diphenyl-3-(4,5-dimethyl-thiazolyl-2)- tetrazolium bromide (MTT) and 0.75 g of N- methylphenazine-methylsulfate (PMS). The mixture is pressed to form tablets of 12 mm diameter, each tablet containing 12.5 mg of NAD, 3.75 mg of MTT and 0.75 mg of PMS.

Tablet F: 15 g of polyethylene glycol (M.W. 5000 6000) are dissolved in 80 ml of 40 percent aqueous alcohol. With this solution, there are mixed 388 g of glucose, which is then dried and sieved. The granulate obtained is dry mixed with 12.5 g of NAD, 3.75 g of MTT, 0.75 g of PMS and 80 g of urethane. The mixture is pressed to form reagent tablets of 12 mm diameter which contain, per tablet, 12.5 mg of NAD, 3.75 mg of MTT and 0.75 mg of PMS. The urethane is sublimed from these tablets over 8 hours in a freeze drying plant at 0C and 10 to lO 3 mm Hg.

The results of tests carried out on these tablets, in the manner described in Example 1, are set out in the following Table 3: 45

TABLE 3 Tablct Height,

Hardness, kg

Dissolving Time, sec.

Breakability,

sec.

EXAMPLE 4 Tablet G: 500 g of sodium chloride are ground,

mixed with 116 g of sodium p-nitrophenyl phosphate, precompressed and sieved. There are then pressed tablets of 5 mm diameter each containing 1 1.6 mg of sodium p-nitrophenyl phosphate.

Tablet H: 500 g of sodium chloride are ground,

mixed with 116 g of sodium p-nitrophenyl phosphate and 134 g of urethane, precompressed and sieved. There are then pressed tablets of 5 mm diameter containing 11.6 mg of sodium pnitrophenyl phosphate. These tablets are heated for 10 hours in a drying cabinet at 30C to sublime the urethane.

The results of tests carried out on these tablets, in the manner described in Example 1, are set out in the following Table 4:

The various components of the tablet mix including active materials, adjuvant, carrier, etc., may range in size from about 0,0l to 1,0 and preferably about 0.05 to 0,5 mm. Desirably the average size of the adjuvant particles ranges from about 5 to 50 percent and preferably about to 30 percent of that of the balance of the particles making up the tablet mix.

It will be appreciated that the instant specification and examples are set -forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.

What is claimed is:

1. In the production of pharmaceutical or reagent tablets which are to undergo disintegration in use wherein the tablet components are mixed and pressed into predetermined shape. the improvement which comprises incorporating into the mix at least one inert solid adjuvant, sublimable at a temperature up to about 1 10C pressing the mix into tablets, and thereafter subjecting the tablets to at least one of vacuum and heating to a temperature up to about 1 10C so as to sublime the adjuvant, whereby the resulting tablets are porous, strong, shape retaining and readily disintegratable.

2. Process according to claim 1, wherein the adjuvant is sublimed by application of a vacuum.

3. Process according to claim 1, wherein the adjuvant comprises about 5 to 50 percent by weight of the total tablet mix.

4. Process according to claim 3, wherein the adjuvant comprises about 10 to 30 percent by weight of the total tablet mix.

5. Process according to claim 1, wherein the tablet mix additionally comprises a soluble carrier.

6. Process according to claim 1, wherein the adjuvant is urethane.

7. Process according to claim 1, wherein the adjuvant is urea.

8. Process according to claim 1, wherein the adjuvant is hexamethylenetetramine.

9. Process according to claim 1, wherein the adjuvant is benzoic acid.

10. Process according to claim 1, wherein the adjuvant is phthalic anhydride.

11. Process according to claim 1, wherein the adjuvant is naphthalene.

12. Process according to claim 1, wherein the adjuvant is camphor.

13. The product produced by the process of claim 1.

1; 33 UNl'lEl) sm'uss l-A'LENI mutt CERTIFICATE OF CORRECTION Patent No. 3 ,885.,O26 4 Dated May 20 1975 Inventor (s) HELMUT HEINEMANN ET AL I It is certified that error appearsln the above-identified patent and that said Letters Patent are hereby corrected as shown below:

i 3 "1 Col. 2, line-58, cancel "l0 to l0 and substitute Col. 4, line 2, cancel "l0 to l0 and substitute Col. 4, line'hl, cancel 'l0 to l0 and substitute Signed and Sealed this thirtieth Day of September 1975 [SEAL] Arrest:

RUTH ct MASON c. MARSHALL DANN Allesling Officer Commissioner of Palnls and Trudtmarkx

Claims

1. IN THE PRODUCTION OF PHARMACEUTICAL OR REAGENT TABLETS WHICH ARE TO UNDERGO DISINTEGRATION IN USE WHEREIN THE TABLET COMPONENTS ARE MIXED AND PRESSED INTO PREDETERMINED SHAPE, THE IMPROVEMENT WHICH COMPRISES INCORPORATING INTO THE MIX AT LEAST ONE INERT SOLID ADJUVANT, SUBLIMABLE AT A TEMPERATURE UP TO ABOUT 110*C PRESSING THE MIX INTO TABLETS, AND THEREAFTER SUBJECTING THE TABLETS TO AT LEAST ONE OF VACUUM AND HEATING TO A TEMPERATURE UP TO ABOUT 110*C SO AS TO SUBLIME THE ADJUVANT, WHEREBY THE RESULTING TABLETS ARE POROUS, STRONG, SHAPE RETAINING AND READILY DISINTEGRATABLE