RU2162695C1 - Method of preparing ondansetron hydrochloride dihydrate, substance and pharmaceutical preparation - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry and technology. SUBSTANCE: ondansetron hydrochloride dihydrate is prepared by mixing 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carb- azole-4-one and 2-methylimidazole in medium of 55-65% aqueous dioxane in the presence of triethylamine at 33-42 C followed by mixture cooling and water addition. Obtained precipitate is filtered off, washed with water and suspended in 70-80% aqueous acetone followed by addition of hydrochloric acid and settling the reaction mixture for 0.5-1.5 h. Then acetone is added, precipitate is separated and dried at the room temperature. Obtained substance has crystals (size is less 90 mcm) being 95% of crystals have the size less 60 mcm. EFFECT: stable and pure product making. 8 cl, 2 tbl

Description

 The invention relates to medicine, specifically to pharmaceutical technology, and in particular to a method for producing a drug having an antiemetic effect - ondansetron (an international non-proprietary name approved by the World Health Organization).

 Pharmaceutical preparations containing ondansetron, during their presence on the market, have established themselves as effective drugs. These drugs are used to prevent nausea and vomiting caused by cytotoxic radiation and chemotherapy, as well as in the postoperative period. Ondansetron preparations are available in the form of tablets (active substance and excipients) and in the form of solutions for intravenous administration.

 With the obvious advantages of ondansetron and preparations based on it, the existing dosage forms of ondansetron have several disadvantages. The fact is that the preferred form for ondansetron pharmaceutical finished dosage forms (HFS) is hydrochloride dihydrate. Due to the pharmacology of ondansetron, the most preferred formulations are, in particular, tablets with a dosage of the active ingredient in the range of 4-5 mg or 8-10 mg per dose. During the preparation of tablets, the active substance is mixed with excipients. As you know, tablets should contain the same dose of the active component, since an overestimated content of the active substance can cause toxic side effects, and an underestimated one should not have a therapeutic effect at all.

 Since a low dosage (for example, 4 mg) is required per tablet, the question of the particle size of ondansetron is extremely important for the manufacturing process of HFS. The fact is that a uniform distribution of the drug substance in the tablet mass can be achieved only with finely divided ondansetron powder. However, ondansetron hydrochloride dihydrate is difficult to grind. For example, attempts to grind using sieves (which are usually used for these purposes in pharmacy) cause clogging of not only thin, but also coarse sieves. Grinding in another way (ball mills and other percussion devices) can cause a violation of the thermodynamic homogeneity of the substance, which will inevitably affect the stability of the drug.

 In addition, the question of creating a highly purified stable substance that over time would not undergo chemical degradation in dosage forms during storage, and in the context of a rigorous technological process of manufacturing a finished dosage form from a substance, would not change its chemical indicators.

 Physical factors affect the stability of drugs, from the time they are received to to patients. The stability of the dosage form largely depends on the process that was used to obtain the starting substance. An important role belongs to the starting products of the synthesis, selected solvents, and the purification of intermediate products.

 Stability largely depends on the chemical purity and physical properties of the drug substance. It is known that, depending on the crystallization conditions, the size of crystals, surface energy, and faceting can change. These physical properties affect the intensity of interaction with the environment, chemical activity, and therefore, the stability of the drug. The shape and size of the crystals depend on the nature, degree of purity of the solvent, temperature conditions and the duration of the crystallization process, the presence of related substances. These factors influence, for example, the formation of polymorphic forms of substances of medicinal substances.

A known method of producing ondansetron by the interaction of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 2-methylimidazole by heating (temperature from 80 ^o C to boiling ) in a solvent environment (USSR Patent N 1528319). The final product is isolated in the form of a base or a physiologically acceptable salt. The disadvantage of this method is the fact that the target product crystallizes into large conglomerates, and the yield of the final product is not high enough. In addition, without subsequent purification, the product cannot be used for the preparation of drugs.

 A known method of producing crystals of ondansetron hydrochloride dihydrate of reduced size (RF Patent N 2002745). The disadvantage of this method is the need for preliminary obtaining ondansetron in the form of a salt, which is then subjected to solvation-desolvation at high temperatures using a fairly sophisticated technology. In addition, the maximum crystal size of 250 μm is large enough to achieve a uniform distribution of the active substance in the drug.

 The objective of the invention is to develop an improved one-step method for producing crystalline ondansetron hydrochloride dihydrate with crystal sizes suitable for the process, while improving the stability and purity of the final product.

 The task is achieved by selecting a complex of reagents, solvents, as well as the conditions for the process of interaction of intermediates, which allow to obtain ondansetron, suitable for further use in the pharmaceutical industry.

To obtain the final product according to the proposed invention, the following sequence of actions must be observed:
1) 3 - [(Dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 2-methylimidazole are mixed in 55-65% aqueous dioxane in the presence of triethylamine at a temperature of 35-42 ^o C.

 2) The mixture is cooled and water is added.

 3) The precipitate obtained is filtered off, washed with water and suspended in 70-80% aqueous acetone.

 4) After that, hydrochloric acid is added and the reaction mixture is kept for 0.5-1.5 hours.

 5) At the final stage, acetone is added, the resulting precipitate is filtered off and dried at room temperature to obtain crystalline ondansetron hydrochloride dihydrate.

 The invention is illustrated by the following examples.

Example 1
26 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one, 24 g of 2-methylimidazole and 10 g of triethylamine in 100 ml of 60% are mixed aqueous dioxane at a temperature of 38 ^o C. Stir the mixture for 40 minutes, maintaining the reaction temperature at a constant level. After this, the mixture is cooled to room temperature at a rate of 0.9 ^o C / min, add 100 ml of water, the resulting precipitate is filtered off, washed with water on a filter (2 times 50 ml). The solid precipitate was suspended in 100 ml of 80% acetone at a temperature of 20 ^° C., 10 ml of concentrated hydrochloric acid was added and the reaction mixture was kept for 1.5 h. 100 ml of acetone was added to the mixture, the obtained precipitate was filtered off and dried in air at room temperature. temperature.

Received a white crystalline powder in an amount of 20 g (yield 55%), molar mass 365.82, mp 179 ^o C.

 The obtained dispersed powder of ondansetron hydrochloride dihydrate was identified by IR spectroscopy and HPLC. The substance was subjected to microscopy. After this, particles of various sizes were counted, and the results of the count were statistically processed. The substance has a particle size shown in table. 1 (see the end of the description).

Example 2
26 g of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one, 24 g of 2-methylimidazole and 10 g of triethylamine are mixed in 100 ml of 55% aqueous dioxane at a temperature of 42 ^o C. Stir the mixture for 65 minutes, maintaining the reaction temperature at a constant level. After this, the mixture is cooled to room temperature at a rate of 0.4 ^o C / min, add 100 ml of water, the resulting precipitate is filtered off, washed with water on a filter (3 times 50 ml). The solid precipitate is suspended in 100 ml of 70% acetone at a temperature of 6 ^o C, add 10 ml of concentrated hydrochloric acid and the reaction mixture is kept for 40 minutes. 100 ml of acetone was added to the mixture, the resulting precipitate was filtered off and dried in air at room temperature.

Received a white crystalline powder in an amount of 17 g (47%), mol.mass 365.87, so pl. 178.5 ^o C.

 The obtained dispersed powder of ondansetron hydrochloride dihydrate was identified by IR spectroscopy and HPLC. The substance was subjected to microscopy. After this, particles of various sizes were counted, and the results of the count were statistically processed. The substance has particle sizes shown in table. 2 (see the end of the description).

Example 3
The content of impurities of related compounds was determined by TLC.

 Method: 0.6 mm thick silica gel chromatography plates, 0.25 mm thick silica gel layer, 20 x 20 cm. Mobile phase - chloroform, ethyl acetate, methanol, ammonia in a ratio of 90: 50: 40: 1.

Received:
The substance according to example 1 - 0.2 wt.%.

 The substance of example 2 - 0.2 wt.%.

From the obtained substances (examples 1 and 2), tablets were formed using excipients commonly used for ondansetron hydrochloride dihydrate. The quantitative content of the active substance in tablets (in terms of ondansetron base is):
According to example 1 (batch of 10 tablets):
For 4 mg tablets, from 3.6 to 4.4.

 For tablets of 8 mg - from 7.2 to 8.8.

According to example 2 (batch of 10 tablets):
For 4 mg tablets, from 3.6 to 4.4.

 For 8 mg tablets, from 7.2 to 8.8.

Chemical stability was determined as follows. The substance of example 1, the substance of example 2 and a control sample obtained by the prototype method (crystalline composition of the control substance: 100% crystals less than 250 microns, 80% crystals less than 63 microns) were separately mixed with pharmaceutically acceptable carriers used for the preparation of tablets . The composition of the mixture: ondansetron hydrochloride dihydrate - 4 g, microcrystalline cellulose - 80 g, lactose - 80 g, magnesium stearate - 1 g. After this, the tablets were stored in sealed ampoules at a temperature of 50 ^o C for 4 weeks. Each of the chemical mixtures, consisting of chemically unchanged ondansetron and decomposed components, was placed in 500 ml of water at 37 ^o C in a flask for dissolution. After that, samples were taken out and filtered. The absorption value was compared with a standard solution and the most stable samples were determined, which were ranked by the amount of ondansetron, which remained chemically unchanged. Of the three samples subjected to analysis, the most stable were the tablets based on the substance of Example 2, the least stable were the tablets prepared from the control sample.

Claims (8)

1. The method of producing ondansetron by the interaction of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 2-methylimidazole in a solvent medium, characterized in that the reaction carried out in an environment of 55 - 65% aqueous dioxane in the presence of triethylamine, at a temperature of 35 - 42 ^o C, cooled, added water, the resulting precipitate was separated, washed with water, suspended in 70 - 80% aqueous acetone, hydrochloric acid was added and the reaction mixture was kept in during 0.5 - 1.5 hours, after which acetone is added, the resulting precipitate is separated and dried at room temperature temperature to obtain a crystalline ondansetron hydrochloride dihydrate. 2. The method according to claim 1, characterized in that the cooling is carried out at a rate of 0.2 - 0.9 ^o C min 3. The method according to claim 1 or 2, characterized in that the suspension in 70 - 80% aqueous acetone and maintaining the reaction mixture is carried out at a temperature of 4 - 20 ^o C.  4. The method according to any one of claims 1 to 3, characterized in that 100 wt.% Of the obtained crystals have a size of less than 230 microns and at least 81 wt.% Of the crystals have a size of less than 60 microns.  5. The method according to any one of claims 1 to 3, characterized in that 100% of the obtained crystals have a size of less than 90 microns and at least 95 wt.% Of the crystals have a size of less than 60 microns.  6. A substance containing crystalline ondansetron hydrochloride dihydrate, characterized in that 100 wt.% Crystals have a size of less than 230 microns and at least 81 wt.% Crystals have a size of less than 60 microns.  7. The substance according to claim 6, characterized in that 100% of the crystals have a size of less than 90 microns and at least 95 wt.% Crystals have a size of less than 60 microns.  8. A pharmaceutical composition comprising ondansetron hydrochloride dihydrate and pharmaceutically acceptable excipients, characterized in that it contains ondansetron hydrochloride dihydrate in the form of a substance according to claims 6 and 7.

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