NO146043B - PROCEDURE FOR THE PREPARATION OF TABLETS WITH SHORT DECOMPOSITION TIME. - Google Patents

Description

The present invention relates to a method for producing tablets with a short breakdown time and containing a combination of trimethoprim [2,4-diamino-5-(3,4,5-trinetoxy-benzyl)pyrimidine] and sulfamethoxazole.

2,4-diaminopyrimidines are well known not only as folic acid and folinic acid antagonists in microorganisms that need these nutrients, but also as inhibitors of the enzyme dihydro-folate reductase in Streptococcus faecalis. When these compounds are used in combination with sulfonamides, a strong effect is obtained against a wide spectrum of microorganisms, which is due to a sequence blockade of the biochemical pathway that leads to a de novo synthesis of coenzyme F. Thus, 2,4-diamino- pyrimidines called sulfonamide enhancers. This enhancement can be shown both in vitro and in mice infected with Staphylococcus and Proteus species. In fact, this effect is so strong that significant results have been achieved in the treatment of animals and humans that have been infected with different types of microorganisms.

The most commonly used 2,4-diaminopyrimidine is trimethoprim-'

[2,4-diamino-5(3,4,5-trimethoxybenzyl)pyrimidine] which is usually combined with sulfamethoxazole [3-(4-aminobenzenesulfone-amido-5-methylisoxazole] in a ratio of 1:5 (trimethoprim : sulfamethoxazole) Thus, tablets containing 400 mg of sulfamethoxazole and 80 mg of trimethoprim have been available for a number of years (cf. BRD off.skr. 2.150.921).

Although the dose of a combination of the 2,4-diaminopyrimidine and sulfamethoxazole, hereinafter this combination is referred to as the "active ingredient", depends to some extent on the type of infection to be treated, it is usual to use doses of 100- 900 mg, e.g. about. 500 mg, and this dose is given in certain cases to adult patients from two to several times a week. day and night. Such amounts of active ingredients are usually added in the form of a tablet, and the amount of the active ingredients is usually 60-80% by weight. The remaining part of the tablet is usually known excipients such as a disintegrating agent, a granulating or binding agent, a lubricant and an inert filler.

At present, there are some difficulties with the supply of

these tablets due to their large size even when the amount of active ingredient is as low as 400 mg and constitutes up to 80% by weight of the tablet. These difficulties increase in particular when large amounts of active ingredient, e.g. more than 600

mg should be given to adult patients in a single dose, which is often the case. It is thus often found that the patient is relatively unenthusiastic about swallowing such tablets if their size is not reduced.

It has also been shown that if you increase the amount of the active ingredient to over 80% by weight, so that you reduce the overall size of the tablet, this only results in poor tablets. characteristics or properties, such as long decomposition or dissolution time, high brittleness value or low hardness value. These characteristics are very important because in such cases they cannot meet the medical standards employed by the health authorities in many countries. If the tablets have poor properties, then this can result in fragmentation and pulverization of the tablets during transport, and the patient will thus not receive the desired amount of the active ingredient.

It has now been found possible to produce a tablet with excellent properties and which has a higher amount of the active ingredient than has hitherto been possible. As the amount of the active ingredient increases, the amount of excipients will decrease accordingly, which means that one also achieves economic benefits by producing such tablets. It has also been found that an increase in the swelling capacity, as defined below, for a disintegrant is associated with a corresponding reduction in the disintegration time for a tablet produced according to the present invention. Although the low particle size of the active ingredient thus provides an improvement with respect to the tablet's characteristics, the addition of a disintegrant with a swelling capacity as defined below, of more than 5.0 ml/g, will a further improvement of said properties or characteristics. In particular, surprisingly low breakdown times have been found for tablets with a high content, e.g. 95% by weight of the active ingredient, while achieving a high hardness value of e.g. 12 kg.

According to the present invention, a method is provided for the production of tablets with a short breakdown time by compression in standard equipment of granules containing a mixture of trimethoprim and sulfamethoxazole in a ratio of from 1:20 to 20:1, preferably 1:5, and also containing a disintegrating agent and possibly other excipients, and this method is characterized by the fact that the granules are produced by a mixture containing 80-98% by weight (in relation to the weight of the finished tablet) • of trimethoprim and sulfamethoxazole with a particle size of below 40 ym are granulated using a granulating agent and by adding a disintegrating agent that has a swelling capacity of more than 5 ml/g either before or after granulation, the total amount of granulating agent and disintegrating agent being no more than 20% by weight of the dried granules which is compressed.

It is preferred to prepare tablets containing 1-5% by weight of the granulating agent and 1-5% by weight of the disintegrating agent, the latter agent having a swelling capacity, as defined below, of over 10 ml/g. A tablet containing 80 mg of trimethoprim and 400 mg of sulfamethoxazole is particularly preferred.

The particle size of the active ingredient is defined here as the "weight median diameter", hereafter denoted V.M.D. Each particle is thus considered a sphere with a volume identical to the real particle, and the V.M.D. is the "diameter", where 50% by weight of these hypothetical balls have a larger diameter than this number, and where 50% by weight have a smaller diameter than said number. Said V.M.D. can be determined by using a Coulter counter where the active ingredient dispersed in an electrolyte consisting of an aqueous solution of e.g. sodium chloride saturated with the active ingredient is passed through a small opening in a tube where an electrode is immersed on both sides. Changes in the resistance as the particles pass through the opening develop voltage pulses whose amplitudes are proportional to the volumes of the particles. The pulses are amplified and the number counted at different threshold values. Based on this data, the size distribution of the suspended particles and consequently the aforementioned weight median diameter can be determined.

The particular particle size of the active ingredient used in the present invention will be somewhat dependent on the desired content in the resulting tablet. If it e.g. is- necessary with 85% by weight of the active ingredient,

can e.g. the particle size should be between 20 and 30 µm. If, on the other hand, 95% by weight of active ingredient is required, it will be advantageous to use an even lower particle size, e.g., less than 15 um, preferably approx. 10 etc.

The particle size of the active ingredient can be easily reduced by precipitation technique or grinding of the particles by means of an apparatus or other known method for such purposes. Particularly advantageous are hammer mills which can be used either with a rigid or swinging hammer, and which can be suitably combined with a fan or a cyclone for collecting the material.

The swelling capacity of a disintegrating agent is defined here as the volume (ml) to which a 1 g tablet containing 95% by weight dry disintegrating agent and 5% by weight polyvinylpyrrollidone ("K30") will swell to when said tablet is in contact with an excess of water at a temperature of 21°C. The swelling capacity is determined by granulating the disintegrant (2 g) with 10% polyvinylpyrrollidone ("K30") (1 ml) and drying the resulting granules at 60°C. A compression of the granules to a hardness value of 12 kg gives tablets with a diameter of 15 mm and a weight of approx. 900 mg. Each tablet is then accurately weighed and placed on the bottom of a 25ml<1>s measuring cylinder.

A nylon disc with a thickness of 8 mm and with two grooves as a gear

a tight but sliding fit in the measuring cylinder is placed on top of the tablet. The slits or furrows stand on opposite

set sides of the disk in a vertical direction relative to the plane of the disk, and enables a thin hypodermic needle to be inserted or pushed down between the disk and the glass wall of the measuring cylinder. A weight of 5 g is placed on the nylon disk, and water is injected through one of the slits into the space surrounding the tablet r while the other slit allows air to escape. When the water level is at the top of the disc, the needle can be removed and water added so that a surplus is obtained, e.g. 25 ml. The volume under the disk is noted for certain periods of time until no further increase is obtained with regard to absorption. In certain cases, the disintegrants will absorb water and a viscous gel will form, and this reduces the rate of absorption so that one must have longer observation periods, e.g.

up to 48 hours, before the maximum voltage can be determined.

After the swelling is finished, the final volume can be read and corrected so that one gets the corresponding value for, 1 g of

the tablet, i.e. the swelling capacity value. The entire measurement should preferably be carried out at a constant room temperature, e.g. 21°C.

Disintegrants which have a swelling capacity of more than 5 ml/g are used in the present invention, and include e.g. calcium carboxymethylcelluloses ("E.C.G.505"), low viscosity sodium carboxymethylcelluloses ("Copagel"), ground endosperm of guar gum polysaccharide ("Supercol U" and "Supercol G.F."),

a sodium alginal ("Alginate YZ"), sodium starch glycolates ("Primojei"). The most preferred disintegrants are "Supercol U" and "Primojel".

The mechanisms of action and the postulated mechanisms of action of disintegrants are discussed in an account of the disintegration of tablets in J. Pharm. Pollock. 1972, 61, 1695-1711). Among the topics discussed here is swelling of the disintegration agent, but it appears that there is no direct correlation of the disintegration process with swelling. It is reported that some good disintegrants gave only poor swelling, while compounds that swelled significantly did not work well as disintegrants. There is no suggestion that, in the case of effective disintegrants, their relative swellability reflects their relative performance as disintegrants.

US Patent No. 3,689,794 describes the use of certain carboxymethylcelluloses as disintegrants. It is stated that their swelling ability is at least 10-20 times greater than that of known disintegration agents, but it is not stated how this was determined' nor which known agents are involved. In the patent's example IV, a tablet containing 77% sulfamethizol is indicated, but no physical properties are given. Repetition of the example gave a tablet which at a hardness of 10, 15 and over 20 kg (Monsanto) had a disintegration time of over 1 hour when sulfamethizole was replaced by a mixture of trimethoprim and sulfamethoxazole (1:5 ratio - 77% weight/ weight of tablet). Similar results were found for dis-integras ion times. When the amount of the mixture was increased to 95%, surprisingly good physical properties were achieved. It can be mentioned that in the above-mentioned account of tablet disintegration, it is stated that by increasing the concentration of active ingredient one would expect poorer disintegration of the tablet.

Granulating agents which can be used in the present invention include starch in the form of plant glue, starch derivatives such as "Snow Flake" starch, cellulose derivatives such as methyl cellulose, gelatin and preferably polyvinylpyrrolidine.

Trimethoprim and sulfamethoxazole can be prepared by a number of suitable methods which are described in the literature, e.g. trimethoprim can conveniently be prepared in the manner described in British patent no. 1261455, while sulfamethoxazole e.g. can be produced using the method described in British patent no. 814,276.

It may also be desirable to add small amounts of a suitable lubricant, e.g. magnesium stearate so that the tablet does not hang up in discs and molds in automatic tablet extrusion equipment. Preservatives and coloring agents can also be added as needed.

When carrying out the present method, compression is carried out in a common standard apparatus of a mixture which, as mentioned, contains 80-98% by weight of a combination of trimethoprim and sulfamethoxazole, the disintegrating agent and the granulating agent. The active ingredient and the disintegrant are mixed in a dry state at low speed, e.g. about. 15 rpm. in a plane, followed by wet-mixing for up to 30 minutes with a granulating solution, together with additional dissolving agent if necessary, to keep the consistency of the mass at an appropriate level. The material can then be ground or either trough-dried or dried in a fluidized bed. The dry material is sieved and a lubricant added to the granules that have been produced in this way. A compression of the granules in a standard apparatus to the desired hardness gives tablets of the desired size and shape.

As the term weight-% is used here, the weight of the indicated active ingredient or other agent is understood in relation to

the total weight of the tablet.

The advantageous properties of tablets produced according to the present invention are primarily due to the effects that occur between the disintegrating agent and trimethoprim, the sulfonamide and the granulating agent.

The decomposition time can be determined by the method which

is described in British Pharmacopia 1968, which involves rapid agitation of the tablet in water under standardized conditions until no fragments are retained on a

load-bearing wire mesh (see pages 1366 to 1367). British Pharmacopia 1968 also states that the disintegration time for each tablet must not exceed 15 minutes, and that this time should preferably be less than 10 minutes, more particularly under 5 minutes, due to safety reasons which is due to inevitable variations from tablet to tablet. In addition to this essential requirement, it is usually recommended that the moisture content in granules from which tablets are made should be below 2%.

The "hardness" of a tablet is the force required to crush the tablet, and this hardness should perhaps be more correctly stated as the crushing strength, and this can be accurately measured using several different standard methods. However, the Monsanto method is appropriate and suitable for testing tablets prepared as indicated in the present invention. Generally, this method involves using a Monsanto tablet hardness tester, which is a spring-loaded device capable of exerting radial pressure on the edge of the tablet, and the pressure force is read from a scale on the sleeve of the device.

The friability of tablets can be measured as the weight loss the tablets have Véd wear or impact, and can be tested using a "Roche Friabilator" on a weighed sample of tablets, e.g. 6 g, which in the device is exposed in e.g. 4 minutes, for wear caused by a rotating movement in the device. This movement and the resulting results can be compared to what tablets are exposed to when they are rubbed against each other or shaken against the walls of the tablet case they are in, as well as the impact that occurs from a free fall of 15 cm. something that can easily occur during various steps during packaging, processing or transport.

The dissolution time for a tablet can e.g. determined using the U.S.P. XVIII using an apparatus consisting of a cylindrical basket with a 1680 pm stainless steel mesh, a covered 100 ml glass shard, a constant temperature water bath and a variable speed motor. The dissolution medium which can e.g. be 0.6% hydrochloric acid, pH 1.2 is poured into the vessel which has previously been reduced in the bath with a constant temperature, and the medium is allowed to reach a temperature of 37°C. A tablet is placed in the basket, and the apparatus is assembled so that the basket is completely immersed in the medium. The curve can then be rotated, e.g. at a speed of 120 rpm, and samples are taken out at regular intervals using an injection measure and measured, e.g. by means of U.V. absorption.

Other advantages of the present invention will be apparent from the following examples which illustrate the invention.

Example 1

The swelling capacity of a number of disintegrants was determined using the method described earlier at a temperature of 21°C. Each disintegrant was then added to the following composition.

Sulfamethoxazole and trimethoprim whose mixture had a particle size of 11.6 µm were, together with the disintegrant, dry mixed in a Morton mixer before adding a solution (260 ml) containing P.V.P. "K30" (polyvinylpyrrolidone) and dioctyl sodium sulfosuccinate in equal parts alcohol and water.

A further addition of 200 ml of a solution containing only equal parts alcohol and water was added before the wet mass was passed through a 1000 µm sieve. The resulting granules were dried in a fluidized bed dryer for 20 minutes at 70°C before being sieved through a 1000 µm sieve. Magnesium stearate previously sieved through a 125 µm sieve was added to the granules and the resulting mixture was compressed in a Manesty D3 rotary compression machine into tablets with a hardness value of 12.0 kg (Monsanto). Properties and especially the breakdown time for each tablet were then determined.

These results clearly show that by using a disintegrant which has a swelling capacity of more than 5 ml, tablets with superior properties are obtained, particularly with regard to disintegration time.

Example 2

800 g of sulfamethoxazole and 160 g of trimethoprim were mixed and passed through an Apex comminution mill equipped with a B. 1762 screen.

The mill was run at a medium speed and where the blades were set so that a particle size of approx. 10 ym on the active ingredient. The resulting mixture of sulfamethoxazole and trimethoprim was dry mixed with 20 g of "Primogel"

in a Morton mixer.

20 g of gelatin was dissolved in 100 ml of water, and 200 ml of alcohol was added to the solution. The solution was added to the dry mixture so that a granulation was obtained. The resulting wet mass was sieved through a 1000 µm sieve and dried in a fluidized bed at 60°C for 20 minutes. The dried granules which had a moisture content of 0.4% were further '

sieved through a sieve of 1000 ym.

10 mg of magnesium stearate previously sieved through a 125 µm sieve was added to the granules and the resulting mixture was compressed in a Manesty D3 rotary press into tablets with a hardness value of 12.0 kg (Monsanto), a disintegration time of 45 seconds and a friability value of less than 0.2%-

The time for 50% of the tablet to dissolve in 0.6%

HC1 (pH 1.2) hereafter denoted as Tj-q, and the time which. was necessary for 80% of the tablet to be dissolved in 0.6% HC1 (pH 1.2) in the subsequently designated TgQ, were 7 and 20 minutes respectively.

Each of the tablets had a thickness of 5.5 mm, a diameter

of 11 mm, a weight of 505 mg and contained 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

Example 3

4000 g of sulfamethoxazole and 800 g of trimethoprim, a mixture whose particle size was 11.6 µm, was dry mixed with 95 g of "Primogel" in a Beken mixer for 10 minutes. 100 g of gelatin dissolved in 500 ml of water was diluted to 1000 ml with alcohol. This solution was added to the dry mixture along with a

250 ml<1>s of solution containing equal parts of alcohol and water, and the whole was mixed for 20 minutes. The resulting

wet pulp was then passed through an Apex quartering mill fitted with an A9 (6 ml's) sieve and the granules were trough dried overnight at 50°C. The granules, which had a moisture content of 0.47%, were further passed through a 1000 um sieve. 50 g of magnesium stearate previously sieved through a 125 µm sieve was added to the granules and the resulting mixture pressed in a Manesty D3 rotary press into tablets with a hardness value of 12.0 kg (Monsanto), a disintegration time of 46 seconds and a friability value of less than 0.2%. The Tj-q and Tqq values were 4 and 11 minutes respectively, and each of the tablets had a thickness of 5.56 mm, a diameter of 11 mm, a weight of 505 mg and contained .400 mg of sulfamethoxazole and 80 mg of trimethoprim.

Example 4

4000 g of sulfamethoxazole and 800 g of trimethoprim whose mixture had a particle size of 11.6 µm were dry mixed with 9.5 g of "Primogel" in a Beken mixer for 10 minutes. A solution of 1300 ml of P.V.P. "K30" (104 g) and dioctyl sodium sulfosuccinate (4 g) in equal parts alcohol and water were added to the dry mixture along with 100 ml of additional solution containing equal parts alcohol and water. The wet mass was mixed for 10 minutes and then passed through an Apex fining mill equipped with an A9 screen. The resulting granules were dried on a tray overnight at 50°C. The dried granules had a moisture content of 0.70% and were then passed through a 1000 um sieve. 50 g of magnesium stearate previously sieved through a 125 µm sieve was added to the granules, and the mixture was dried in a Manesty D3 rotary press to give tablets with a hardness value of 12.4 kg, a disintegration time of 1 minute and 31 seconds and a friability value of less than 0.2%.

The <T>5q and TgQ values for the tablets were 7 and 29 minutes respectively, and each tablet had a thickness of 5.33 mm, a diameter of 11 mm, weight of 508.8 mg and contained 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

In addition to this, it can be stated that when the mixture was press-

one to machine room hardness (more than 20 kg), then the breakdown time was 9 minutes.

Example 5

The procedure of Example 4 was repeated except that "Primojel" was replaced by "Supercol U".

Pressing the mixture gave tablets with a hardness value of 12.5 kg, a disintegration time of 1 minute 45 seconds and a friability value of <0.2%.

The T5Q°9 Tgg values were 8 and 31 minutes, respectively

tablet had a thickness of 5.42 mm, a diameter of 11 mm,

a weight of 503.8 mg and contained 400 mg of sulfamethoxazole and 80

mg trimethoprim. ' . "

When the mixture was pressed to maximal hardness (>20 kg), so

the degradation time was 9 minutes.

Example 6 The procedure of Example 4 was repeated except that "Primogel" was replaced by "Alginate YZ"

Pressing the mixture gave tablets with a hardness value of

12 kg, a breakdown time of 1 minute and 5 3 seconds and a friability value of less than 0.2%.

The Tj_q and Tg0 values were 9 and 31 minutes, respectively

tablet had a thickness of 5.40 mm, a diameter of 11 mm,

a weight of 504.0 mg and containing 400 mg of sulfamethoxazole and 80

mg trimethoprim.

When the mixture was pressed to maximum hardness (>20 kg), so

the decomposition time was 5 minutes and 25 seconds.

Example 7

400 g of sulfamethoxazole and 80 g of trimethoprim where the mixture had a particle size of 11.8 yra, and 24 g of "Primogel" were mixed in a dry state for 10 minutes in a Z-blade mixer. A solution containing 16 g of gelatin, 1 g of dioctyl sodium sulfosuccinate, 57 g of alcohol and 80 g of purified water was prepared. The solution was wet mixed with the powder for 10 minutes

a slow speed was used. The wet mass was passed through a 1000 um sieve. The prepared granules were dried in a fluidized bed at 60°C for 30 minutes to a moisture content of 0.86%.

The dried granules were sieved through a 1000 µm sieve and 4.8 g of magnesium stearate sieved through the 125 µm sieve was mixed with the granules and the resulting mixture pressed in a Manesty D3 rotary machine to give tablets of

a hardness value of 14.5 kg (Monsanto), a breakdown time of 58 seconds and a friability value of 0.46%.

<T>50 °^ <T>80 values were 2 and 3 minutes respectively, and each

tablet had a thickness of 5.8 mm, a diameter of 11 mm, a weight of 526 mg and contained 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

Example 8

400 g of sulfamethoxazole and 80 g of trimethoprim whose mixture had a particle size of 11.8 µm, 80 g of "Primojel" and 30 g of lactose were granulated as indicated in Example 7. The granules were dried to a moisture content of 1.43%.

After sieving through a 1000 um sieve, magnesium stearate was obtained

(4.8 g) previously sieved through a 125 µm sieve, mixed with the granules, and the resulting mixture pressed on a Manesty D3 rotary machine into tablets with a hardness value of 14.8 kg (Monsanto), a disintegration time of 1 minute and 53 seconds and a brittleness value of 0.34%. T^ Q and Tg0 values were 2 minutes and 4 minutes respectively, each of the tablets had a thickness of 6.3 mm, a diameter of 11 mm, a weight of 572 mg and

contained 400 mg sulfamethoxazole and 80 mg trimethoprim.

Example 9

80 g of sulfamethoxazole and 400 g of trimethoprim whose mixture had a particle size of 28.4 µm, pregelatinized starch (96 g) and 16 g of "Primogel" were dry mixed for 10 minutes in a Z-blade blender. 200 g of distilled water was wet mixed with the powder for 10 minutes. The wet mass was then passed through a 1000 um sieve and the granules were dried to a moisture content of 1.25%.

4.8 g of magnesium stearate previously sieved through a sieve on

125 µm was added to the dry granules and the mixture was pressed on a Manesty D3 rotary machine into tablets with a hardness value of 9.8 kg (Monsanto), a disintegration time of

6 minutes and 10 seconds and a brittleness value of 0.30%.

<T>^q and Tgg value were respectively 5 minutes and 11 minutes-, each tablet had a thickness of 6.69 mm, a diameter of 11 mm, a weight of 597 mg and contained 80 mg of sulfamethoxazole and 400 mg of trimethoprim.

Example 10 400 g of sulfamethoxazole and 40 g of trimethoprim whose mixture had a particle size of 11 ym, and 32 g of "Primol gel" were mixed

et in a dry state for 10 minutes. A solution containing 28 g of polyethylene glycol 6000 and 122 g of distilled water was prepared. The solution was wet mixed with the powder for 10 minutes. The granules were prepared as indicated in example 7. Said granules were dried to a moisture content of 1.1%.

4.8 g of magnesium stearate previously sieved through a sieve on

125 ym, was added to the dry granules and the mixture pressed on a Manesty D3 rotary machine into tablets with a hardness value of 14.4 kg (Monsanto), a disintegration time of 7 minutes and 15 seconds and a friability of 0.33%. The T^q and Tg0 values were 14 minutes and 35 minutes, respectively

tablet had a thickness of 5.50 mm, a diameter of 11 mm, a weight of 545 and contained 440 mg of sulfamethoxazole and 40 mg of trimethoprim.

Example 11

400 g of sulfamethoxazole and 80 g of trimethoprim whose mixture had a particle size of 11.8 ym, and 96 g of "Alginate YZ"

was dry mixed for 10 minutes. A solution containing 16 g of polyvinylpyrrolidone "K30", 80 g of alcohol and 100 g of distilled water was prepared and the solution was mixed with the powder for 10 minutes at a slow speed. The granules were prepared as in example 1 and dried to a moisture content of 1.0%.

The dried granules were sieved through a 1000 µm sieve, and 4.8 g of magnesium stearate sieved to 125 µm was mixed with the granules, and the resulting mixture pressed on a Manesty BB3 rotary machine into tablets with a hardness value of 12.7 kg (Monsanto). a breakdown time of 6 minutes and 25 seconds and a friability value of 0.2%.

The Tori value was 5 minutes, and the tablets had a thickness

of 6.7 mm, a diameter of 11 mm, a weight of 597 mg and contained 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

While the above-mentioned examples relate to the incorporation of the disintegrant before granulation of the active ingredients, the example below shows the addition of the disintegrant after the granulation.

Example 12

Tablets were prepared using the method described in example 1 with the following variations: (a) "Primogel" was used as a disintegrant; (b) In a batch of tablets "Primogel" was incorporated into the granulate as described in Example 1; in another rate

was "Primogel" added after the granulation step;

(c) The decomposition time bee determined by means of the now usual

used method for European Pharmacopoeia; in the following, times are given for the breakdown of the first and last of the 6 tablets that were used in the test.

The tablets' properties were as follows:

Example 13

Trimethoprim was prepared by the methods described in British Patent No. 957,797. 1,142,654, - 1,261,455 and 1,133,766.

Claims (1)

Process for the production of tablets with a short disintegration time by compression in -standard apparatus of granules containing a mixture of trimethoprim and sulfamethoxazole in a ratio of from 1:20 to 20:1, preferably 1:5, and also containing a disintegrating agent and possibly other excipients, characterized in that the granules are produced by granulating a mixture containing 80-98% by weight (in relation to the weight of the finished tablet) of trimethoprim and sulfamethoxazole with a particle size of less than 40 µm using a granulating agent and by a disintegrating agent which has a swelling capacity of more than 5 ml/g is added either before or after granulation, the total amount of granulating agent and disintegrating agent being no more than 20% by weight of the dried granules which are compressed.