Refining method of crystal type A azilsartan

A refining method and crystal form technology, which is applied in the field of medicine, can solve the problems of large amount of refining solvent, long drying time, and increase of related substances, and achieve the effects of lowering the refining dissolution temperature, reducing production costs, and reducing dosage

Active Publication Date: 2017-05-31
湖南千金湘江药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The main problems in the above process are: 1. The refining solvent system is chaotic or the purification process is complicated, resulting in complex crystal forms of azilsartan raw materials
Low drying temperature and long drying time
3. The control of drying temperature is not strong, it is easy to make azilsartan form a solvate, or because the particles of azilsartan are too thick or too fine, the moisture or solvent inside the particles cannot be completely dried, resulting in the increase of related substances and residual organic solvents
4. The amount of refined solvent is large, and the mass ratio of the organic solvent used to obtain the crystal form A is about 20 to 25 times, which is not conducive to the cost control of commercial production

Method used

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  • Refining method of crystal type A azilsartan
  • Refining method of crystal type A azilsartan
  • Refining method of crystal type A azilsartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Put 1kg of ethyl acetate and 3kg of absolute ethanol into a glass reactor and mix them. After heating the temperature to 50-55°C, add 1.3kg of azilsartan crude product, and control the temperature at 50-55°C and stir until the solution is clear.

[0028] Rapidly lower the temperature to 20-25°C, and maintain this temperature to stir and crystallize. Suction filtration, the filter residue is sieved and granulated by a swing granulator, the screen is 24 mesh, and then put into the boiling dryer, and the feeding port is closed. Set the air intake of the boiling dryer to 2800-3000m 3 / h, dry at room temperature for 50min, then gradually increase temperature at 38°C and dry for 70min, particle size control D(90): 300~400μm, dry at 50℃ for 2~3h, particle size control D(90): 100~200μm, material cool to 20±5 °C, 1.25 kg of finished product of azilsartan was obtained, the yield was 96%, the crystal form was A crystal form, the purity was 99.81%, and the residual solvent (ethano...

Embodiment 2

[0030] Put 10kg of ethyl acetate and 40kg of absolute ethanol into the refining tank to mix, and heat to 50-55°C. Add 14.29kg of azilsartan crude product, control the temperature at 50-55°C and stir until the solution is clear.

[0031] Pressure filtration to the crystallization tank, after the pressure filtration is completed, quickly cool down to 20-25°C, and maintain this temperature to stir and crystallize. Filtration, the filter residue is sieved and granulated by a swinging granulator, the screen is 24 mesh, put into the boiling dryer, and the feeding port is closed. Set the air intake to 2800~3000m 3 / h, dry at room temperature for 60min, then gradually increase the temperature at 42°C and dry for 50min, particle size control D(90): 300~400μm, dry at 50℃ for 2~3h, particle size control D(90): 100~200μm, cool the material to 20±5 °C, 13.29 kg of finished product of azilsartan was obtained, the yield was 93%, the crystal form was A crystal form, the purity was 99.82%, a...

Embodiment 3

[0033] Put 100kg of ethyl acetate and 200kg of absolute ethanol into the refining tank to mix, and heat to 50-55°C. Add 90.9kg of azilsartan crude product, control the temperature at 50-55°C and stir until the solution is clear.

[0034] Pressure filtration to the crystallization tank, after the pressure filtration is completed, quickly cool down to 20-25°C, and maintain this temperature to stir and crystallize. Filtration, the filter residue is sieved and granulated by a swinging granulator, the screen is 24 mesh, put into the boiling dryer, and the feeding port is closed. Set the air intake to 2800~3000m 3 / h, dry at room temperature for 60min, then gradually increase the temperature at 40℃ and dry for 60min, particle size control D(90): 300~400μm, dry at 50℃ for 2~3h, particle size control D(90): 100~200μm, cool the material to 20±5 °C, 85.45 kg of finished product of azilsartan was obtained, with a yield of 94%, crystal form A, a purity of 99.77% (ie the content of relate...

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Abstract

The invention relates to the field of medicine, and discloses a refining method of crystal type A azilsartan. The method comprises the following steps: S1, mixing ethyl acetate and absolute ethyl alcohol, heating, and then adding an azilsartan crude product, stirring to be completely dissolved, carrying out filter-pressing; S2, stirring the filtrate in the S1 at 20-25 DEG C to crystallize, filtering, granulating the filter residue through a 24-mesh sieve; drying the raw materials by use of a boiling drying and gradient warming way; drying for 50-70min at an ambient temperature condition, and then drying for 50-70min after warming 40+ / -2 DEG C, wherein the granularity control D (90) is 300-400 microns; drying for 2-3h after warming to 50+ / -2 DEG C, and the granularity control D (90) is 100-200 microns, cooling to obtain an azilsartan finished product. By use of the refining method disclosed by the invention, the dosage of a required organic solvent in refining is greatly reduced; and meanwhile, the stable crystal type A azilsartan is obtained since the raw materials are dried by use of the boiling drying and gradient warming way, the refining yield of 90% or above is acquired, the purity is 99.7% or above, the solvent residue (ethyl alcohol) is less than 0.3%, and the drying time is shortened to 3-6h.

Description

technical field [0001] The present invention relates to the field of medicine, and more specifically, relates to a method for refining crystal form A azilsartan. Background technique [0002] Azilsartan (English name Azilsartan) is an angiotensin II receptor antagonist drug under development for the treatment of hypertension, which selectively blocks the binding of angiotensin II to the AT1 receptor of vascular smooth muscle Blocking the vasoconstrictive effect of angiotensin II is mostly used to treat hypertension, and it is also the only angiotensin II receptor antagonist (sartan) drug currently in the late clinical stage. [0003] The patent reports of crystal form A azilsartan include CN1040755C, EP0520423, US5243054, CN102766139A, CN92105152C, CN103930419A and so on. Among them, Example 1 of Chinese patent CN92105152C (priority patent JP1991157194) discloses a preparation method of azilsartan. Azilsartan methyl ester was saponified in methanol / LiOH, and the crude prod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10
CPCC07B2200/13C07D413/10
Inventor 金秉德姚亮元袁红波袁秀菊尹军王琼瑶钟爱军
Owner 湖南千金湘江药业股份有限公司
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