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Febuxostat crystal form A and preparation method thereof

A febuxostat and crystal form technology, applied in the field of medicinal chemical crystallization, can solve the problems of difficult industrial production, unstable preparation process, harsh conditions, etc., to improve bioavailability, create a green and safe production environment, and improve reaction conditions mild effect

Active Publication Date: 2014-02-19
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] At present, there are few literature reports on the preparation of febuxostat crystal form A, which is a single crystal form. Most of the disclosed preparation processes contain other crystal forms of febuxostat such as crystal form B, and the preparation process is unstable and the yield is low. Harsh conditions make it difficult to realize industrial production

Method used

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  • Febuxostat crystal form A and preparation method thereof
  • Febuxostat crystal form A and preparation method thereof
  • Febuxostat crystal form A and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Add 100ml of absolute ethanol and 6.67ml of purified water into a three-necked flask with 3g of sample, stir at a stirring rate of 600r / min, heat up to 70°C, the system dissolves and becomes light yellow-green, keep at this temperature After 10 minutes, the temperature was lowered to 62° C., and 0.009 g of seed crystals with a median particle size of 3 μm were added. Afterwards, the temperature is lowered from 62°C to 40°C within 0.5 hours by using the method of equal time and segmental cooling. First, the temperature is reduced from 62°C to 58°C within 10 minutes, and then the temperature is reduced from 58°C to 50°C within 10 minutes. Within 10 minutes, the temperature dropped from 50°C to 40°C, and suction filtered. The wet sample was vacuum-dried at 60°C for more than 6 hours and weighed to obtain a white powder solid with a yield of 86.2%. After checking the X-ray powder diffraction pattern of this white powder solid, see figure 1 , is a single febuxostat crysta...

Embodiment 2

[0069] Add 333.3mL of absolute ethanol and 27.8ml of purified water into the jacketed reaction flask containing 30g of sample, stir at a stirring rate of 400r / min, heat up to 70°C, the system dissolves, and keep at this temperature for 10min. Then lower the temperature to 62°C, add 0.15g of seed crystals with a median particle size of 5 μm, and then reduce the temperature from 62°C to 15°C within 1 hour by using an equal time segmental cooling method, and first drop the temperature from 62°C within 20 minutes. to 52°C, followed by a temperature drop from 52°C to 37°C within 20 minutes, and finally a temperature drop from 37°C to 15°C within 20 minutes, and suction filtration. The wet sample was air-dried at 60°C for more than 6 hours and weighed to obtain a white powder solid with a yield of 86.8%. After checking the X-ray powder diffraction pattern of this white powder solid and figure 1 Consistent, it is a single febuxostat crystal form A, and its particle size distributio...

Embodiment 3

[0071] Add 80L of absolute ethanol and 11.4L of purified water into a jacketed reaction flask containing 10kg of sample, stir at a stirring rate of 900r / min, heat up to 75°C, the system dissolves, keep at this temperature for 10min, and cool down to 62°C, add 0.1kg of seed crystals with a median particle size of 10.0μm, and then use an equal-time segmental cooling method to reduce the temperature from 62°C to 30°C within 1.5 hours, and firstly within 30 minutes. The temperature drops from 62°C to 54°C, followed by a temperature drop from 54°C to 44°C within 30 minutes, and finally a temperature drop from 44°C to 30°C within 30 minutes, and suction filtration. The wet sample was vacuum-dried at 60°C for more than 6 hours and weighed to obtain a white powder solid with a yield of 86.2%. After checking the X-ray powder diffraction pattern of this white powder solid and figure 1 Consistent, it is a single febuxostat crystal form A, and its particle size distribution is the same ...

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Abstract

The invention belongs to the field of chemical crystallization technologies for drugs and particularly relates to a novel single febuxostat crystal form A and a preparation method thereof. According to the crystal form A provided by the invention, the grain size D50 is 16-25 microns, the grain size distribution curve of the crystal form A is of normal unimodal distribution, a preparation of the crystal form A has good dissolubility and a zero-deflection dissolution curve, and the bioavailability is high. The invention further provides the preparation method which can be used for preparing the single febuxostat crystal form A, and the yield reaches up over 86%; meanwhile, the preparation process is stable, the crystallization conditions are mild, and the volume of a consumed solvent is small, so that during industrial large-scale production, the production cost is reduced greatly, and the recovery and mechanical applying of the solvent are facilitated; the solvent is an aqueous solution containing ethanol and is non-toxic and harmless, so that the construction of an environmental-friendly and safe production environment is facilitated, and the preparation method is very suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical crystallization, and in particular relates to a single febuxostat crystal form A and a preparation method thereof. technical background [0002] Febuxostat was approved for marketing in the European Union in April 2004, and was approved for marketing in the United States by the FDA in February 2009. [0003] Febuxostat is a non-purine selective xanthine oxidase / xanthine dehydrogenase inhibitor, which can inhibit the oxidation state and reduction state of xanthine oxidase, and is used for the treatment of hyperuricemia disease. Febuxostat is mainly metabolized by the liver, which can better avoid the adverse reactions of allopurinol caused by renal metabolism and excretion. [0004] The chemical name of febuxostat is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which has the chemical structural formula shown below: [0005] [0006] Chinese invention patent CN1...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 谢厅徐仲军周玉宝
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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