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Novel febuxostat crystal form A and preparation method thereof

A technology of febuxostat and crystal form, which is applied in the field of pharmaceutical chemical crystallization, can solve problems such as difficulty in realizing industrial production, unstable preparation process, harsh conditions, etc., and achieve industrialized large-scale production, solvent recovery and application, and reaction conditions mild effect

Active Publication Date: 2014-02-19
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +1
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  • 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, a single crystal form, and 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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  • Novel febuxostat crystal form A and preparation method thereof
  • Novel febuxostat crystal form A and preparation method thereof
  • Novel febuxostat crystal form A and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0066] Add 100mL of isopropanol to the jacketed reaction flask containing 3g of febuxostat sample, stir at a stirring rate of 300r / min, heat up to 70°C, the system dissolves, keep at this temperature for 10min, and cool down to Add 0.06g of seed crystals with a median particle size of 5μm at 62°C, and then use the equal-time segmental cooling method to lower the temperature from 62°C to 15°C within 1 hour, and first drop the temperature from 62°C to 52°C within 20 minutes , 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 40°C for more than 6 hours and weighed to obtain a white powder solid with a yield of 95.0%. After checking the X-ray powder diffraction pattern of this white powder solid, see figure 1 , is a single febuxostat crystal form A, its particle size distribution diagram is shown in Figure 5 , its D 50 is 23.8μm, and it...

Embodiment 2

[0068] Add 200mL of isopropanol to the jacketed reaction flask containing 30g of febuxostat 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 Add 0.09g of seed crystals with a median particle size of 10μm at 62°C, and then use an equal-time segmental cooling method to reduce the temperature from 62°C to 15°C within 2 hours, and first drop the temperature from 62°C to 52°C within 40 minutes. Next, the temperature dropped from 52°C to 37°C within 40 minutes, and finally from 37°C to 15°C within 40 minutes, and suction filtered. 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 95.2%. 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 as Figure 5 similar, its D 50 It is 25.0 μm, and ...

Embodiment 3

[0070] Add 83.3L of isopropanol to the jacketed reaction flask containing 10kg of febuxostat sample, stir at a stirring rate of 600r / min, heat up to 75°C, the system dissolves and becomes light yellow-green, at this temperature Keep the temperature for 10 minutes, cool down to 62°C and add 0.1kg of seed crystals with a median particle size of 10μm, and then use the equal-time segmental cooling method to lower the temperature from 62°C to 15°C within 8 hours, firstly within 160 minutes. The temperature dropped to 52°C, then the temperature dropped from 52°C to 37°C in 160 minutes, and finally the temperature dropped from 37°C to 15°C in 160 minutes, and suction filtered. The wet sample was air-dried at 50°C for more than 6 hours and weighed to obtain a white powder solid with a yield of 96.7%. 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 t...

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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 95%; 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, the recovery and mechanical applying of the solvent are facilitated, 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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