RU2247563C1 - Method for preparing solid medicinal formulation comprising glucosamine hydrochloride - Google Patents

Abstract

FIELD: pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a method for manufacturing a solid medicinal formulation - glucosamine hydrochloride tablets representing an anti-arthrosis preparation. Glucosamine hydrochloride, microcrystalline cellulose and average-molecular polyvinylpyrrolidone are placed in mixer followed by addition of talk and calcium stearate through a sieve in the process of stirring. Mixer is closed and stirring is continued and then mixture is tableted by the direct pressing method. Tablets are removed dust and dispensed. Invention provides making tablets by the improved technology wherein the labor-consuming granulation stage with using explosive reagent ethyl alcohol is excluded.

EFFECT: improved preparing method.

4 tbl, 3 dwg, 7 tbl

Description

The invention relates to the pharmaceutical industry and relates to a method for producing a solid dosage form of an anti-arthritic drug.

Known methods for producing dosage forms containing glucosamine (UK Patent GB 2101585 A, INT CL53 C 07 H 5/06, A 61 31/70), RF patent (RU) 2130310 C1, RF patent (RU) 2118156 C1.

In the pharmaceutical industry, tablets are produced according to the method described in RF patent No. 2130310, which is proposed as a prototype.

In the dosage form of tablets for internal use, the content of the components is indicated by weight and in mass (percent) fractions:

Glucosamine hydrochloride 0.3 g 75% Excipients 0.1 g 25% including: Aerosila 0.0260 g 6.50% Starch 0.0605 g 15.12% Stearic acid 0.0035 g 0.88% Polyvinylpyrrolidone high molecular weight (PVP) 0.01 g 2.5% to the total weight of the tablet 0.4 g 100.0%

It is possible to vary the quantitative content of the components of the auxiliary substances within 15%.

A predetermined amount of ground glucosamine hydrochloride is loaded into the mixer, then aerosil, starch and mixed until homogeneous. The mixture is moistened with a 10% solution of PVP in alcohol. The mass of the taken solution should contain the estimated amount of PVP. The moistened mixture is again mixed until smooth. The wet mass is granulated through a sieve with a hole diameter of 3 mm. The granulate is first dried at room temperature for 3 hours, then at 40 ° C to a residual moisture content of not more than 2%, dusted with the calculated amount of stearic acid and dry granulated through a sieve with a hole diameter of 1 mm.

The granulate is loaded into the hopper of a tablet machine and tableted. Get tablets of cylindrical shape with a notch, white with an average weight of 0.4 g, a diameter within 10 mm, a height within 4 mm. A slightly yellowish tint in the color of the tablets is allowed, which is associated with excipients. Tablets in appearance and their characteristics comply with the requirements of the State Pharmacopoeia of the XI edition of t. 2 151.

The disadvantage of this method of obtaining is the use in the composition of an explosive reagent - ethyl alcohol. As well as the use in the manufacturing process of the granulation stage, which leads to an increase in the cost of the production process.

The aim of the invention is to simplify the manufacturing process of glucosamine hydrochloride tablets. This goal is achieved by eliminating ethyl alcohol from the stages of production and using more advanced components as auxiliary substances: microcrystalline cellulose, talc, calcium stearate, which make it possible to exclude the granulation stage.

Technological parameters of glucosamine hydrochloride: large bulk density, good flowability, very low humidity, suggest the possibility of obtaining tablets by direct compression and to ensure dosing accuracy (Table 1).

It is known that only substances belonging to the cubic system are directly compressed into tablets, i.e. direct compression. The particle sizes of the substance glucosamine hydrochloride are in length and width from 0.08 to 0.2, which indicates their large scatter (Table 2). The average particle size is 0.174 × 0.230 mm. Studies have shown that the shape of the particles is mostly regular rhombic, as evidenced by the good flowability of the powder. However, rhombic powders rarely have good compressibility, i.e. For direct compression, the addition of auxiliary substances is required. An analysis of the literature data showed that most often microcrystalline cellulose (MCC), Avicel, polyvinylpyrrolidones (PVP) with different degrees of polymerization are used for this purpose. At the first stage, the dependence of the breaking strength of tablets on the amount of microcrystalline cellulose introduced (Avicel pH 101) was investigated.

At the same time, during pressing, the pressure of the ejection of the tablet from the matrix was estimated, which was measured using a manual hydropress.

As follows from Table 3, the strength of tablets containing MCC and the disintegration time were insufficient to ensure their quality, which was the basis for the search for additional binders with stronger cohesion.

To this end, the effect of collidone 25 (medium molecular weight PVP) on the above indicators was studied. As follows from Table 4, with an increase in the content of collidone 25, the disintegration time increases proportionally (up to 5 min), the tablet strength increases most intensively at a 10% PVP concentration, however, the pressure at which the tablets are ejected from the matrix also increases, their appearance worsens , sticking of the tablet to the punches occurs, roughness of the lateral surface, chips along the edges are observed. Given this, it was necessary to establish the necessary amount of release agents (for example, stearates). In addition, the addition of dry MCC and PVP reduced the flowability of the tablet mass to 5.6 g / s, which required the addition of glidants (talc).

Therefore, we investigated the dependence of the ejection force of the tablets from the matrices on the addition of calcium stearate, which is most often used as a release agent.

As follows from figure 1, the most intense decrease in the ejection force occurred until the content of stearate in the tablet mass of calcium equal to 0.625%, which was taken as the basis for the preparation of the tablet mixture.

To establish the optimal amount of talcum powder introduced into the tableted mass, we studied the effect of its content in the tableted mass on the flowability of the latter. As follows from figure 2, the decrease in the flowability of the mass is most intense when the content of talc in the range from 1.75% to 2.0%. Thus, the optimal amounts of ingredients were calculated for tabletting glucosamine hydrochloride by direct compression.

The technological characteristics indicated in Table 5 correspond to the quality parameters of tablet masses for direct compression.

The next stage of the work was to establish the optimal pressing pressure, since the compressibility was determined at a standard pressure of 120 MPa. The specified mixture was tableted at 0.4 g on a manual hydraulic press with a diameter of punches of 10 mm at various pressing pressures.

The determination of the efficiency coefficient (the ratio of the ejection pressure to the pressing pressure), the strength and disintegration of the tablets are presented in table.6.

As follows from table 6, the most intensively the strength of the tablets to split and their disintegration increased to a pressing pressure of 100 MN / m ² . The efficiency coefficient was 0.115, which is in an acceptable limit (the optimum is the ratio of the ejection pressure to the pressing pressure of not more than 1/10).

The results of determining the release of glucosamine hydrochloride from tablets prepared according to two technologies (Fig. 4) indicate that glucosamine hydrochloride completely passes into solution within 15 minutes, therefore, a change in the composition and technology of glucosamine hydrochloride tablets does not affect the biopharmaceutical characteristics of the drug.

The developed direct compression technology eliminates the granulation stage, i.e. reduces the production process, and also eliminates the use of a flammable reagent - alcohol.

In the developed dosage form - glucosamine hydrochloride tablets, the composition of the components is indicated in mass and percentage ratios per 1 tablet.

Glucosamine hydrochloride 0.3 g 75.0% Microcrystalline Cellulose 0.05 g 12.5% "AVICEL-pH 101" Medium molecular weight polyvinylpyrrolidone 0.04 g 10.0% ("Kollidona-25") Talcum powder 0.0075 g 1,875% Calcium stearate 0.0025 g 0.625% Average weight 0.4 g

It is possible to vary the quantitative content of the components of the auxiliary substances within 15%.

The essence of the method lies in the fact that 0.5 mm glucosamine hydrochloride, microcrystalline cellulose “AVICEL-pH 101” sifted through a sieve is placed in the mixer, and polyvinylpyrrolidone medium molecular weight “Kollidon-25”, talc and calcium stearate are introduced through the sieve during mixing. The mixer is closed and continued to mix. The mixture is then tabletted by direct compression. The resulting tablets are removed from dust and packaged.

Examples of specific performance. The loading of components (basic and auxiliary substances) is carried out based on 200 tablets in each series, and the content of the main active substance - glucosamine hydrochloride - is constant and amounts to 75%. The ratio of individual excipients varies within acceptable limits (up to 15%) in order to identify the best stability and release of glucosamine hydrochloride from the proposed dosage form, the total amount of excipients is unchanged at 25%.

Example 1

60.0 g sieved through a glucosamine sieve are taken, microcrystalline cellulose “AVICEL-pH 101” in the amount of 10.0 g, and polyvinylpirrolidone medium molecular weight “Kollidon-25” in the amount of 8.0 g is added through the sieve, talc - 1.5 g, calcium stearate 0.5 g. The mixer is closed and continued to mix, then tableted. The resulting tablets are removed from dust and packaged.

Example 2

60.0 g sieved through a glucosamine sieve are taken, microcrystalline cellulose “AVICEL-pH 101” in the amount of 9.0 g, and polyvinylpirrolidone medium molecular weight “Kollidon-25” in the amount of 9.0 g is added through the sieve, talc - 1.45 g, calcium stearate 0.55 g. The mixer is closed and continued to mix, then tableted. The resulting tablets are removed from dust and packaged.

Example 3

60.0 g sieved through a glucosamine sieve are taken, microcrystalline cellulose “AVICEL-pH 101” in the amount of 11.0 g and polyvinylpirrolidone medium molecular weight “Kollidon-25” in the amount of 7.0 g, talc - 1.55 g, calcium stearate 0.45 g. The mixer is closed and continued to mix, then tableted. The resulting tablets are removed from dust and packaged.

It was found that the best stability and release of glucosamine hydrochloride is provided in example 1.

The main regulatory and technical indicators of the obtained tablets in relation to average weight, disintegration, mechanical strength and quantitative content of the active substance were determined according to the State Pharmacopoeia XI (State Pharmacopoeia of the USSR, XI, M .: Medicine, T.2, 1989, p. 156).

The tablets obtained in the laboratory and production conditions were white with a yellowish tint, had a smooth shiny surface, smooth edges, which corresponds to the requirements of Global Fund XI, issue 2. A possible yellowish tint of the tablets is due to the fact that Collidon-25 and magnesium stearate can have this tint, the ratio of height and diameter corresponded to OST 64-072-89.

To establish the authenticity, the TLC method is used. Identification of the drug is carried out according to the correspondence Rf of the PCO stain with glucosamine hydrochloride stain in the chromatogram of extraction from tablets. To identify the drug in tablets, a chloride ion detection reaction and a qualitative reaction with the Elsong-Morgan reagent on the amino sugar are also proposed.

For quantitative determination of glucosamine hydrochloride in tablets, it is recommended to use the method of mercurimetry for hydrochloric acid. The metrological characteristics of the quantitative determination are given in table 7. As an alternative method, the Elson-Morgan method is proposed. The method is based on the interaction of the reaction product of glucosamine hydrochloride with acetylacetone and Erlich reagent (n-dimethylaminobenzaldehyde). The reaction produces a condensation product having a dark pink color with a maximum light absorption at 530 nm. The color develops gradually and stabilizes after 45 minutes. The calculation of the glucosamine hydrochloride content is proposed to be carried out according to the calibration schedule. Comparative results were obtained, however, the Elson-Morgan method is laborious, time-consuming, and the color obtained is not stable. As the results of determining the optical density, one should take the average value of at least three determinations.

An essential distinguishing feature of the proposed method for preparing a solid dosage form of a tablet containing glucosamine hydrochloride is that by selecting more advanced components (excipients) the tablets are produced by direct compression, the granulation stage and the use of an explosive reagent, ethyl alcohol, are excluded.

Thus, the preparation of a drug of a glucosamine hydrochloride tablet according to the proposed method is less time-consuming and more economical, the fire hazard of production is eliminated.

A comparative study of the biopharmaceutical characteristics of glucosamine hydrochloride tablets obtained by the known method (prototype) and again claimed showed that a change in technology and composition does not affect the characteristics of the analyzed objects.

The drug glucosamine hydrochloride in dosage form - tablets is approved for medical use as an anti-inflammatory and analgesic (order of the Ministry of Health of the Russian Federation No. 55 of 02.17.2000).

Table 1
Main technological characteristics of glucosamine hydrochloride Batch number Flowability, g / s Bulk weight, g / cm ³ Slope angle, degrees Humidity% 031297 7.4 ± 0.4 0.85 ± 0.01 thirty 0.34 ± 0.02 041297 8.1 ± 0.3 0.80 ± 0.04 26 0.23 ± 0.03 051297 7.9 ± 0.4 0.82 ± 0.05 29th 0.17 ± 0.02 011097 7.8 ± 0.5 0.79 ± 0.06 28 0.21 ± 0.02 021297 7.5 ± 0.1 0.84 ± 0.03 29th 0.33 ± 0.03 061297 8.0 ± 0.3 0.82 ± 0.02 27 0.27 ± 0.02

table 2
Glucosamine hydrochloride powder particle size determination results No. Length Width I II t ₁ mm I II t ₂ , MM 1. 4.90 8.85 0.395 4.15 6.65 0.250 2. 8.20 6.55 0.165 3.86 8.83 0.487 3. 1.95 3.86 0.191 2.89 8.25 0.536 4. 7.74 9.85 0.211 4.91 5.78 0,087 5. 1.95 4.28 0.233 6.90 7.83 0,093 6. 1.12 1.90 0,078 3,55 4.94 0,079 7. 7.00 9.83 0.283 7.60 2.83 0.477 8. 1.28 1.42 0.014 8.50 9.30 0,080 9. 7.25 8.31 0.106 1.89 4.02 0.213 10. 8.98 9.62 0,064 8.30 9.32 0.102

0.174

0.230

Table 3
Technological parameters of glucosamine hydrochloride tablets with the addition of microcrystalline cellulose The content of the MCC,% Split Strength, kg Ejection Pressure, MN / m ² Disintegration, s 2 0.2 1.7 twenty 4 0.3 1.4 35 6 0.7 1,0 45 8 0.9 0.8 65 10 1,1 0.7 85 12 1.3 0.7 100 14 1,5 0.6 90 16 1.4 0.6 80

Table 4
Change in technological parameters of tablets containing MCC (12.5%), with the addition of s / m PVP (collidone 25) PVP content,% Split Strength, kg Ejection Pressure, MN / m ² Disintegration, s 2 1.7 7.1 130 4 2.0 8.5 155 6 2,4 11.3 180 8 2,8 14.5 235 10 2.9 18.2 280 12 3.0 21,2 310

Table 5
The technological characteristics of the tablet mass of glucosamine hydrochloride optimized composition No. Name of indicator Dimension Value 1. Bulk density g / cm ³ 0.76 ± 0.04 2. Flowability g / s 9.1 ± 0.28 3. Slope angle hail 28 ± 1,0 4. The ejection pressure of the tablets from the matrix (P _pres 120 MN / m ² ) MN / m ² 14.8 ± 0.5 5. Split strength kg 2.8 ± 0.1 6. Disintegration from 270 ± 10

Table 6
Dependence of the main technological characteristics of the tablets on the pressing pressure R _pres , MN / m ² P _drawing, MN / m ² K _eff Split Strength, kg Disintegration, s twenty 1.4 0,070 0.4 thirty 40 2.6 0,065 12 80 60 5.9 0,098 1.8 130 80 8.3 0.104 2.2 210 100 11.5 0.115 2.6 250 120 14.8 0.123 2,8 270 140 22.4 0.160 2.9 310 160 28,2 0.176 3,1 330 180 32,4 0.180 3.0 300

Table 7.
Quantitative determination of glucosamine hydrochloride by photometry and mercury measurement. Method Hitch, g VoP, ml Found,% Metrological characteristics Mercury measurement 0.3060 10.8 0,309 0.3100 10.7 0,301

0.3063 10.7 0,304

0.3101 10.7 0,301 S = 0.00429 0.3053 10.6 0.296 dx = 0.005 0.3117 10.6 0.302 e = 1.49 Photometry 0,306 0.302

0.289

0.320 S = 0.0107 0.311 dx = 0,01071 0.298 e = 3.5%

Claims (1)

A method of producing tablets of glucosamine hydrochloride by tabletting, characterized in that the stage of tabletting is carried out by direct compression, while microcrystalline cellulose, polyvinylpyrrolidone medium molecular weight - collidone-25, talc, calcium stearate are introduced as auxiliary substances with the following substance content, g per average weight tablet 0.4 g: Glucosamine Hydrochloride 0.3 Microcrystalline Cellulose 0.05 Medium molecular weight polyvinylpyrrolidone - Collidone-25 0.04 Talcum powder 0.0075 Calcium Stearate 0.0025

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