The way to get ondansetron hydrochloride dihydrate, substance and pharmaceutical drug
(57) Abstract:The invention relates to pharmaceutical industry. Ondansetron hydrochloride dihydrate obtained by mixing 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-it and 2-methylimidazole in an environment 55-65% aqueous dioxane in the presence of triethylamine, at a temperature 35-42oC, cooling the mixture, adding water, filtering the obtained precipitate, washing with water, and the suspension in 70-80% aqueous acetone followed by the addition of hydrochloric acid and keeping the reaction mixture for 0.5-1.5 h, the addition of acetone, separating the precipitate and drying at room temperature. The resulting substance has crystals with a particle size less than 90 μm, of which at least 95% have a size less than 60 microns. The method allows to obtain more stable and pure product. 3 s and 5 C.p. f-crystals, 2 tab. The invention relates to medicine, specifically to pharmaceutical technology, namely the method of production of drugs with antiemetic effect of ondansetron (international nonproprietary name adopted by the world Health Organization).Pharmaceuticalonline funds. These drugs are used to prevent nausea and vomiting caused by cytotoxic radiotherapy and chemotherapy, as well as in the postoperative period. Drugs ondansetron available in the form of tablets (active substance and excipients) and in the form of solutions for intravenous administration.In view of the obvious advantages of ondansetron and products based on existing dosage forms of ondansetron have several disadvantages. The fact that the preferred form for pharmaceutical finished dosage forms (drugs) of ondansetron hydrochloride is a dihydrate. Because of the nature pharmacology of ondansetron preferred preparative forms are, in particular, tablets with a dosage of the active ingredient within 4-5 mg or 8-10 mg per dose. In the preparation of tablets the active substance is mixed with fillers. As you know, the pill must contain the same dose of the active component, because inflated the content of the active substance can cause toxic side effects, and low - do not have a therapeutic effect.Because the pill require a low dosage (e.g., 4 mg) the question of the size of the particles it is Noah distribution of medicinal substance in tablet weight can only be achieved when fine powder of ondansetron. However, the ondansetron hydrochloride dihydrate is difficult to crush. For example, attempts grinding using sieves (which are usually used for these purposes in pharmacy) cause blockages not only thin, but also coarse sieves. Grinding other way (ball mills and other percussion devices) may cause a violation of thermodynamic homogeneity of the substance that will inevitably affect the stability of the drug.In addition, it is not fully resolved the issue remains on the creation of high purity stable substance, which over time would not be subject to chemical degradation in medicinal forms during storage, and the hard conditions of the technological process of manufacture of the finished dosage form of the substance does not change its chemical - technological parameters.Physical factors affect the stability of drug substances, starting from the moment of their receipt and to receive patients. The stability of the dosage form largely depends on the process that was used to obtain the original substance. An important role belongs to the original products of the synthesis, the selected solvents, purification of intermediate products.A method of obtaining ondansetron by reacting 3-[(dimethylamino)methyl] -1,2,3,9-tetrahydro-9 - methyl-4H-carbazole-4-it 2-methylimidazole when heated (temperature of 80oC to the boiling point) in the solvent (Patent USSR 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 in large conglomerates, and the output of the final product is not high enough. In addition, without further purification, the product cannot be used for making voice.A method of obtaining CR the soba is a need to prior ondansetron in the form of a salt, which is then subjected to solvation-desolvatation at high temperatures with the use of fairly sophisticated technology. In addition, the maximum size of the crystals of 250 μm is large enough to achieve a uniform distribution of the active substance in the voice.The task of the invention to provide an improved one-step method of obtaining crystalline ondansetron hydrochloride dihydrate with the size of the crystals that are suitable for the process, while improving the stability and purity of the final product.This object is achieved by selection of a set of reagents, solvents and conditions of the interaction process intermediates that allow you to get ondansetron, suitable for further use in the pharmaceutical industry.To obtain the final product according to the proposed invention it is necessary to observe the following sequence of actions:
1)Mix 3-[(dimethylamino)methyl] -1,2,3,9-tetrahydro-9 - methyl-4H-carbazole-4-it and 2-methylimidazole in an environment 55-65% aqueous dioxane in the presence of triethylamine, at a temperature 35-42oC.2)the Mixture is in the 70-80% aqueous acetone.4)then add hydrochloric acid and incubated the reaction mixture for 0.5 to 1.5 hours5)At the end add the acetone, the 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
Mixing 26 g of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl - 4H-carbazole-4-it, 24 g of 2-methylimidazole and 10 g of triethylamine in 100 ml of 60% aqueous dioxane at a temperature of 38oC. Stir the mixture for 40 min, maintaining the reaction temperature at a constant level. Then cool the mixture to room temperature with a rate of 0.9oC/min, add 100 ml of water, the precipitate is filtered off, washed with water on the filter (2 times 50 ml). The solid residue is suspended in 100 ml of 80% aqueous acetone at a temperature of 20oC add 10 ml of concentrated hydrochloric acid and incubated the reaction mixture for 1.5 hours To the mixture was added 100 ml of acetone, the precipitate is filtered off and dried in air at room temperature.The obtained white crystalline powder in the amount of 20 g (yield-55%), mol.weight 365.82, tvali by the method of IR-spectroscopy and HPLC. The substance was subjected to microscopy. After this was done the math particles of different size were statistically processed results of the calculation. The substance has a particle size shown in table. 1 (see the end of the description).Example 2
Mixing 26 g of 3-[(dimethylamino)methyl]-1,2,3,9 - tetrahydro-9-methyl-4H-carbazole-4-it, 24 g of 2-methylimidazole and 10 g of triethylamine in 100 ml of 55% aqueous dioxane at a temperature of 42oC. Stir the mixture for 65 min, maintaining the reaction temperature at a constant level. Then cool the mixture to room temperature with a speed of 0.4oC/min, add 100 ml of water, the precipitate is filtered off, washed with water on the filter (3 times 50 ml). The solid residue is suspended in 100 ml of 70% aqueous acetone at a temperature of 6oC add 10 ml of concentrated hydrochloric acid and incubated the reaction mixture for 40 minutes. To the mixture was added 100 ml of acetone, the precipitate is filtered off and dried in air at room temperature.The obtained white crystalline powder in the amount of 17 g (47%), mol.weight 365.87, so pl. 178,5oC.The obtained dispersed powder of ondansetron hydrochloride dihydrate identified by the method Azlicnogo size, the statistically processed results of the counting. The substance has a particle size shown in table. 2 (see the end of the description).Example 3
The impurity content of related compounds was determined by TLC.Methods: chromatographic plates of silica gel, 0.6 mm thick layer of silica gel 0.25 mm, 20 x 20 cm, Mobile phase: chloroform, ethyl acetate, methanol, ammonia in the ratio of 90:50:40:1.Received:
The substance of example 1 to 0.2 wt%.The substance according to example 2 and 0.2 wt%.From the obtained substance (example 1 and 2) formed tablets using commonly used for ondansetron hydrochloride dihydrate fillers. The quantitative content of the active ingredients in the tablets (in terms of ondansetron base is):
In example 1 (batch of 10 tablets):
For tablets 4 mg - from 3.6 to 4.4.For tablets 8 mg - from 7.2 to 8.8.According to example 2 (party of 10 tablets):
For tablets 4 mg from 3.6 to 4.4.For tablets 8 mg from 7.2 to 8.8.Chemical stability was determined as follows. The substance of example 1, the substance according to example 2 and control sample obtained by the method prototype (crystallites is whether with pharmaceutically acceptable carriers, used for preparation of tablets. The composition of the mixture: ondansetron hydrochloride dihydrate - 4 g, microcrystalline cellulose 80 g lactose - 80 g magnesium stearate - 1, then the tablets were stored in sealed vials at a temperature of 50oC for 4 weeks. Each of the chemical compounds, consisting of chemically unmodified ondansetron and decomposed components were placed in 500 ml water at 37oC in flask to dissolve. After that, took samples and filtered. The absorbance value was compared with the standard solution and determined the most stable samples that were ranked by the number of ondansetron, preserved in a chemically unchanged form. Of the three samples analyzed, the most stable was the pill, on the basis of the substance according to example 2, the least stable of tablets prepared from the control sample. 1. The way to get ondansetron by reacting 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-it and 2-methylimidazole in an environment of a solvent, wherein the reaction is carried out in an environment of 55 - 65% aqueous dioxane in the presence of triethylamine, at a temperature of 35 - 42oC, is cooled, water is added, the wasp is a promotional mix for 0.5 - 1.5 h, after which add the acetone, the precipitate is separated and dried at room temperature to obtain crystalline ondansetron hydrochloride dihydrate.2. The method according to p. 1, characterized in that the cooling is conducted at a rate of 0.2 to 0.9oC min.3. The method according to p. 1 or 2, characterized in that the suspension in 70 - 80% aqueous acetone and keeping the reaction mixture is carried out at a temperature of 4 - 20oC.4. The method according to any of paragraphs.1 to 3, characterized in that 100 wt.% the obtained crystals had a size of less than 230 μm and not less than 81 wt.% crystals have a size less than 60 microns.5. The method according to any of paragraphs.1 to 3, characterized in that 100% of the crystals have a size less than 90 μm and not less than 95 wt.% crystals have a size less than 60 microns.6. Substance containing crystalline ondansetron hydrochloride dihydrate, wherein 100 wt.% crystals have a size of less than 230 μm and not less than 81 wt.% crystals have a size less than 60 microns.7. Substance under item 6, characterized in that 100% of the crystals have a size less than 90 μm and not less than 95 wt.% crystals have a size less than 60 microns.8. Pharmaceutical composition containing ondansetron hydrocholoride dehydrate in the form of a substance on PP.6 and 7.
< / BR>where R is hydrogen, hydroxyl;
R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;
R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,
R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;
R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;
R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);
Z - group-CH - or N-atom;
m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts
FIELD: medicine, cardiology.
SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.
EFFECT: higher efficiency of therapy.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula :
or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula :
wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae  or  wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula  that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
29 cl, 1 tbl, 170 ex