HU200482B - Process for producing tablet disintegrator - Google Patents

Abstract

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of a 10-20 kN compression mold used for tabletting with 20-60 s disintegration volume of 10-35% sedimentation volume, a partially cross-linked carboxymethylated starch having a molecular weight of 174-185 glucose units, which is insoluble in a water-insoluble tablet compartment. by crosslinking the acetic acid with sodium salt in the presence of sodium hydroxide and crosslinking with epichlorohydrin or trimetaphosphate. It is an object of the invention to starch the starch first by carboxymethylation by reacting 500 parts by weight of starch in the presence of 80-130 parts by weight of the sodium salt of monochloric acid and 40-70 parts by weight of sodium hydroxide at 55-60 ° C for 1.5-2 hours. the temperature of the carboxymethyl starch sodium salt suspension is adjusted to 60-70 ° C, 5-14 parts by weight of epichlorohydrin or 8-17 parts by weight of trimetaphosphate are added, the mixture is reacted for 20-60 minutes and 30-70 parts by weight of acetic acid are added, 200-400 parts by weight of methanol are added and 50-200 parts by weight of water, the mixture is cooled to room temperature, centrifuged, washed with methanol in the centrifuge, and dried. CM 00 Tf o Λ description range: 8 pages, without figure -1-

Description

FIELD OF THE INVENTION The present invention relates to the preparation of partially cross-linked starch carboxymethylated starch, having a molecular weight of 10-35% per unit weight of 174-185 glucose units with a disintegration time of 20-60 s, and having a disintegration time of 20-60 s. monochloroacetic acid by carboxymethylation of the sodium salt in the presence of sodium hydroxide and crosslinking with epichlorohydrin or trimetaphosphate.

An important feature of tablets is the disintegration time. A tablet having a disintegration time of less than 15 minutes is generally considered suitable. Of course, the goal is often to reduce the disintegration time, since the active ingredients in the tablet can work faster if the disintegration time is reduced.

The tablets are disintegrated with additives. These additives are from dr. According to György Kedvessy Pharmaceutical Technology MEDICINA (1981) is generally macromolecular organic matter (for example, starch, cellulose or their derivatives).

It has long been thought that disintegration is caused by swelling of the excipient due to water (or digestive fluid).

Only recent studies have called this notion into question. The measured disintegration and swelling times differ greatly. A. PATEL, N. R. and HOPPONEN, R. E.: J. pharm. Sci 55 1065 (1955), INGRAM, J.T. and LOWENTHAL, W.: J. pharm. Sci 57, 393 (1968), HÜTTEN RAUCH, R. and JACOB, J.: PHARMAZIE 26. 293 (1971), according to the size and number of capillaries in the tablets (empty volume), the wettability of the excipient and the penetration of water. speed.

Since the wettability of the excipient is very important, it is preferable not to use starch or cellulose but derivatives thereof. Because starch is significantly cheaper than cellulose, starch derivatives are obviously used for tablet disintegration.

The use of * Carboxymethylamylum as a disintegrant as a disintegrant to improve tablet bindability * (Pharmacy 17. 125-128, April 1973) is known as the sodium salt of carboxymethyl starch (CMK). This paper examines CMK as a tablet disintegrator with 3 active ingredients, sodium salicylate, theobromine and lactose. The disintegration times are 673 and 1010 sec. between them. CMK is also known as a viscosity enhancing additive. This effect adversely affects the disintegration, since the water formed by the neck breaks the poles and thus prevents the penetration of water.

As a disintegrant, cyclodextrin is disclosed in * Cyclodextrin Polymer, New Tablet Bisintegrant Agent * (Pharmazie 39 (1984), H, 7,473, Eva Fenyvesi, B. Antal, B. Zadon and I. Cell). The decay time of cyclodextrin is 15-120 sec. between placebo tablets without active ingredient.

The two most famous tablet dispensers in the world are Primojel and Explotab. Primojelt Bolhuis et al., Acta Pharm. tech. 30, 1984 (1) 24-32 by Explotabot Rudnic et al., J. Pharm. Sci. 1985, 74. (6) 647-650. It is clear from the above articles, as well as further publications by both authors 2, that the tablet disintegrator is prepared by carboxymethylation of cross-linked starch.

First, the extent of cross-linking is determined by sedimentation or viscosity measurement, since no chemical method is available. From these data the degree of substitution required is determined.

Thus, the process for producing Primojel and Explotab is complicated and has many potential errors.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for producing a tablet disintegrator which provides disintegration of the tablets in less time than known disintegrators.

Numerous studies have been conducted to develop the present invention. During our investigations we have discovered the surprising effect that when the sodium salt of carboxymethyl starch is cross-linked to a different degree, the cross-linking effect of the cross-linking between the starch cannot make mucilage with water. it also ensures that the tablet disintegrates.

The process of the present invention is based on the discovery that if the starch is first carboxymethylated in a strongly alkaline medium and then crosslinked, a product having a tablet disintegrating properties better than hitherto known can be obtained.

The process of the present invention is further based on the discovery that this bursting effect can be achieved by crosslinking the sodium salt of the carboxymethyl starch, whether chemically covalently bonded or by a secondary van der Waals bond by physical process.

The process of the present invention comprises first starch carboxymethylation by reacting 500 parts by weight of starch in the presence of 80-130 parts by weight of sodium salt of monochloroacetic acid and 40-70 parts by weight of sodium hydroxide in a methanolic medium at 55-60 ° C for 1.5-2 hours, then adjusting the temperature of the resulting carboxymethyl starch sodium salt slurry to 60-70 ° C.

5-14 parts by weight of epichlorohydrin or 8-17 parts by weight of trimetaphosphate, the mixture is reacted for 20-60 minutes, then 30-70 parts of acetic acid, 200-400 parts of methanol and 50-200 parts of water are added, the mixture is cooled to room temperature, centrifuged and centrifuged. washed with methanol and dried.

Tests have shown that the tablet disintegrator produced by the process of the present invention has a significantly lower disintegration time (20-60 sec.) Than prior art tablet disintegrators.

Thus, tablets made with the tablet release device of the present invention can disintegrate very quickly and provide a faster effect than those made with prior art disintegrators.

The process of the present invention is practically the opposite of the process for the preparation of Primojel and Explotab. This determination can be performed with great precision, after which the desired degree of cross-linking occurs. Watermarks of 1% aqueous solution of a variety of substituted and cross-linked samples were recorded by NMR spectrometer. By analyzing the watermark waveform, the desired measure of water binding and swelling was determined

EN 200482 It was found from the studies that the amount of cross-linking agent can be determined for each of the various degrees of substitution while maintaining the disintegrating property of the various materials.

Thus, the process of the present invention has avoided the quality degradation due to minor differences in the composition, as noted in the Explotab and Primojel literature.

Several Primojel and Explotab samples were analyzed. The Primojel substitution is 0.27 and the Explotab substitution is 0.24. The measured half-width for both materials is 3.09 Hz, which means that both materials have a specific composition. This presents major technological difficulties due to inaccurate measurement methods and heterophase reaction. In the examples, materials of different compositions were prepared and had the same disintegration properties. As a result, technology requirements are reduced, resulting in, among other things, significant investment savings and less stringent raw material quality requirements, which solves a major procurement problem.

Of course, the tablet dispensers produced by the process of the present invention meet all specifications for tablet dispensers, except for Example 1, the latest specification for the sedimentation volume required by only a few pharmaceutical companies. (Some drug companies require 25-35% sedimentation volume).

Various embodiments of the process of the invention are illustrated in Figures 1-4. example.

A number of chemical and physical parameters have been determined for the tablet dispensers produced by the methods of the Examples.

An important parameter of the tablet dispenser is the Enslin number. The Enslin number was determined based on the application of Vessin and Kala * Viscosity Enhancers in the Tropics *. The Enslin number is used to compare the water uptake of different substances or tablets, measured in ml of water / g of substance or tablet.

Another important parameter of the tablet dispenser is the sedimentation volume, the limits of which are determined by the pharmaceutical companies (e.g. Hoffman-La-Roche, Ciba-Geigy, etc.) in their pharmacopoeia.

For the determination of sedimentation volume, 2 g are dispersed in 200 ml of water at 20 ° C, a 100 ml graduated cylinder is filled with the resulting dispersion, the dispersion is allowed to stand for 24 hours, and the lower phase volume is read and reported as%.

EXAMPLE 1 640 parts of methanol, 60 parts of sodium hydroxide were added to a m ² autoclave, dissolved, 500 parts of potato starch were added and the mixture was heated, dissolved in 200 parts of water and 82 parts of monochloroacetic acid were added.

The carboxymethyl starch sodium salt mixture thus prepared was raised to 60 ° C and maintained for two hours as a cross-linking agent.

5.9 parts by weight of epichlorohydrin were used. The temperature of the mixture was then raised to 65 ° C and 5.9 parts of epichlorohydrin added. After standing for 40 minutes, 40 parts of acetic acid, 240 parts of methanol and 150 parts of water were added. The mixture was cooled to room temperature, centrifuged, washed in centrifuge with methanol and finally dried.

The main characteristics of the product prepared according to Example 1 were as follows:

substitution: 0.16 M / M Cross Binding: 0,021 M / M Sedimentation volume: 10.4 % Enslin number: 17.3 mL / g Half Value Width: 3.22 Hz

Example 2

The procedure was carried out as in Example 1, except that the substitution was carried out with 114 parts by weight of monochloroacetic acid and the crosslinking with 8.2 parts by weight of epichlorohydrin.

The main characteristics of the product obtained according to Example 2 were as follows:

Substitution: Cross-linking: Sedimentation volume: Enslin number: Half-width:

0.24 M / M 0.029 M / M 35%

22.9 ml / gr

3.16 Hz

Example 3

The procedure was carried out as in Example 1 except that the starch was substituted with 125 parts by weight of monochloroacetic acid and the crosslinking was carried out with 9.4 parts by weight of epichlorohydrin.

The main features of the product prepared according to Example 3 were as follows:

Substitution: Cross-linking: Sedimentation volume: Enslin number: Half-width:

0.28 M / M 0.032 M / M 32%

22.6 ml / gr

3.22 Hz

Example 4:

The procedure was carried out as in Example 1, except that the substitution with 125 parts by weight of monochloroacetic acid and the crosslinking with

12.5 parts by weight of trimetaphosphate.

The main characteristics of the product prepared according to Example 4 were as follows:

Substitution: 0.15 M / M

Cross-linking: 0.013 M / M

Sedimentation volume: 28%

Enslin number: 20.2 ml / gr

Half-width: 3.00 Hz

1-4. A number of experiments have been conducted with the tablet dispenser prepared according to the example of Example 1 and the known Primojel and Explotab tablet dispensers, which are described below:

Experiment 1:

Placebo tablets were prepared by dry (direct) compression at 15 kN.

HU 200482 A

Composition of tablets:

avicel ph 102 282.0 mg tablettaszétejtő 7.5 mg talc 4.5 mg Magnesium Stearate 6.0 mg

300.0 mg

The disintegration time of 20-20 tablets for each formulation was investigated and the results were dr. János Sváb: Biometric Methods in the Research (p. 41) based on Student's t-test

. The tests showed the following results: Disintegration time average according to the invention Disintegration time is an average primoy t Example 1 47.65 56.6 18,88 Example 2 49.1 56.6 7.83

The tests showed the following results:

Example 3 44.8 56.6 24.5

Example 4 52.2 56.6 8.6

The value of t for n = 19 and for a probability of error of 0.1% is 3.88. Thus, it appears that the tablets developed by the technology we have developed have significantly better disintegration properties.

Experiment 2:

Paracetamol tablets were prepared by wet granulation with 13 mm diameter single-ended, slightly concave stamps at 10 kN.

Composition of tablets:

paracetamol active ingredient excipient 28 mg

500 mg

200 mg of which

700 mg

Compressive strength (N) fresh stored *

Wear loss (%) fresh stored

Disintegration time fresh stored

Volume (mm ³ ) initially stored *

1 st 60 72 0.55 0.43 22 22 681.1 678.8 Example 2 74 83 0.69 0.53 20 22 678.6 679.1 Ex. 3 90 114 0.70 0.44 20 24 674.7 674.1 Example 4 87 102 0.61 0.45 20 24 670.5 670.5 pri- mojel 76 81 0.71 0.32 27 24 681.5 678.1 Explo- tab 74 65 0.5 0.38 42 36 679.9 670.8

* Note: Unopened tablets stored at room temperature for 6 weeks

Composition of tablets:

From the measurement data, it can be seen that the physical characteristics of the tablet release tablets produced by the process of the invention are less varied during storage than the known tablet release tablets of Primojel and Explotab. This is especially the case for wear loss and volume. The table shows that eg. Explotab shrinks significantly during storage, whereas tablet tablets made by the process of the present invention do not.

Experiment 3:

Tablets containing paracetamol caffeine were prepared by wet granulation at 10 and 20 kN. The tests showed the following results:

paracetamol caffeine extender of which 27.8 mg tablet dispenser 500 30 165 mg mg mg 695 mg

a = fresh b = 6 weeks under climatic conditions, packet55 stored unoccupied (50 degrees C, 78% RH)

Sample 3 minutes 6 minutes (% dissolved) 15 minutes 30 minutes Example 1 a 84.89 96.75 97.33 98.44 b 83.31 96.13 94.00 97.88 Example 2 a 91,00 95.54 101.49 100.85 b 91.38 100.5 101.39 101.54

HU 200482 A

Sample 3 families 6 minutes (% dissolved) 15 minutes 30 minutes Example 3 a 84,53 99.68 97.55 101.51 b 92.64 103.59 102.70 99.86 Example 4 a 79.8 98.00 101.52 97.6 b 90.62 96.50 101.52 99.86 Primojel a 91 100.78 100.45 99.15 b 78.95 88.01 88.26 101.33 Explotab a 67.27 81.69 94.59 95.10 b 66.87 79.99 91.08 100.35

Note: Measurements are made by photometry, values greater than 100% are within the error limits of the measurement method.

The higher the dissolution, the better the quality of the tablet dispensers. There is a particularly large difference in the dissolved amount of the tablet dispenser that is already known and produced by the methods of the present invention in three to six minutes, whereas the rapid effectiveness of the tablet is primarily determined by the amount of dissolved three and six minutes.

Tablets containing paracetamol + caffeine disintegration time

10 kN press 20 kN press Example 1 38 60 Example 2 30 50 Example 3 30 50 Example 4 28 40-50 Primojel 99 96 Explotab 89 386

It can be seen from the table that the disintegration time of the paracetamol + caffeine tablets containing the tablet disintegrant produced by the process of the present invention is significantly lower than that of the tablets containing the disintegrating tablet produced by the known methods.

1-4. The tablet dispenser prepared according to the example of Example 1 has the following additional physical and chemical parameters:

Molecular weight: 174-185 (depending on degree of substitution)

Weight per unit volume: 700-860 g / dm ³ pH: 5.5-7.5

Water content: maximum 10%

Heavy metal content: maximum 20 ppm

The tablet disintegrator swells in cold water but is practically insoluble, with a maximum of 10% residual soluble in ethyl alcohol.

Claims (1)

A process for the preparation of partially cross-linked starch monocarboxylated carboxymethylated starch with a compression force of 10-20 kN for tabletting, having a 10-35% sedimentation volume, a molecular weight of 174-185 glucose units, with a disintegrating capacity of 10% to 174-185 glucose units. by carboxymethylation of the sodium salt in the presence of sodium hydroxide and crosslinking with epichlorohydrin or trimetaphosphate, characterized in that the starch is first carboxymethylated so that 500 parts by weight of starch in 80-130 parts by weight of sodium hydroxide and 40 parts by weight of monochloroacetic acid After reacting at 55-60 ° C for 1.5-2 hours, the temperature of the resulting carboxymethyl starch sodium salt suspension is adjusted to 60-70 ° C, 5-14 parts of epichlorohydrin or 8-17 parts are added. trimetaphosphate, 20-60 minutes, 30-70 parts of acetic acid, 200-400 parts of methanol and 50-200 parts of water are added, the mixture is cooled to room temperature, centrifuged, the centrifuge is washed with methanol and dried.