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Preparation method for candesartan cilexetil crystals

A technology of candesartan cilexetil and crystallizer, applied in the field of crystallization, can solve the problems of poor fluidity, inability to effectively meet the different needs of customers, electrostatic adsorption, etc., and achieve the effect of uniform particle size distribution

Active Publication Date: 2017-02-22
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CN201310340686 uses a mixed solvent of lower alcohol and water to prepare candesartan cilexetil with a particle size of less than 20 microns through cooling and crystallization, but its product has electrostatic adsorption problems, resulting in poor fluidity and affecting the content uniformity of the preparation
In addition, the particle size distribution of the product obtained by this method is single, which cannot effectively meet the different needs of customers for particle size distribution.

Method used

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  • Preparation method for candesartan cilexetil crystals
  • Preparation method for candesartan cilexetil crystals
  • Preparation method for candesartan cilexetil crystals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add 1 g of candesartan cilexetil into a three-neck flask containing 100 g of methanol and water mixed solvent (mass ratio: 23:2), stir and dissolve at 30°C, and after continuous stirring for 60 minutes, filter and decolorize; transfer the filtrate into In the crystallizer, add 8 g of water to the crystallizer at 30 ° C, and the flow rate is 0.8 g / min; after adding water, add 0.01 g of seed crystals to the clear solution, and grow crystals at this temperature for 1 hour; Subsequently, 80 g of water was added to the crystallizer at a rate of 0.8 g / min, and then the crystal was grown for another 2 hours. Suction filter, wash the filter cake with water, and dry at 40° C. under normal pressure for 12 hours. The final product yield is 86.4%, and the HPLC purity is 99.91%, and the main particle size of the product is 14.70 microns (such as figure 1 Shown), there is no electrostatic adsorption between product particles.

Embodiment 2

[0027] Add 3 g of candesartan cilexetil into a three-neck flask filled with 100 g of methanol and water mixed solvent (mass ratio: 23:2), stir and dissolve at 45°C, and after continuous stirring for 40 minutes, filter and decolorize; transfer the filtrate into In the crystallizer, add 8 g of water to the crystallizer at 45 ° C, and the flow rate is 0.5 g / min; after adding water, add 0.02 g of seed crystals to the clear solution, and grow crystals at this temperature for 1 hour; Subsequently, 80 g of water was added to the crystallizer at a rate of 0.5 g / min, and then the crystal was grown for another 2 hours. Suction filter, wash the filter cake with methanol, and dry at 45° C. under normal pressure for 7 hours. The yield of the final product is 85.2%, the HPLC purity is 99.92%, the main particle size of the product is 13.82 microns, and there is no electrostatic adsorption phenomenon between the product particles.

Embodiment 3

[0029] Add 5 g of candesartan cilexetil into a three-neck flask filled with 100 g of ethanol and water mixed solvent (mass ratio: 9:1), stir and dissolve at 30°C, and after continuous stirring for 40 minutes, filter and decolorize; transfer the filtrate into In the crystallizer, add 15 g of water to the crystallizer at 30 ° C, and the flow rate is 1 g / min; after adding water, add 0.03 g of seed crystals to the clear solution, and grow crystals at this temperature for 1.5 hours; Subsequently, 200 g of water was added to the crystallizer at a rate of 2 g / min, and then the crystal was grown for another 3 hours. Suction filter, wash the filter cake with water, and dry at 40° C. under normal pressure for 12 hours. The final product yield is 87.1%, and the HPLC purity is 99.92%, and the main particle size of the product is 9.523 microns (such as figure 2 Shown), there is no electrostatic adsorption between product particles.

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Abstract

The invention belongs to the technical field of crystals, and particularly relates to a preparation method for candesartan cilexetil crystals. According to the technical scheme, the preparation method comprises the following steps: firstly, adding candesartan cilexetil into an alcohol aqueous solution, and continuing stirring for dissolving for 30 to 60 minutes at 25 to 45 DEG C, wherein the solid-to-liquid ratio of the solution is 0.01 g / g to 0.1 g / g; secondly, filtering, transferring a filtrate into a crystallizer, keeping the temperature at 25 to 45 DEG C, and adding water which is 1 to 3 times that in an initial solution in volume into the crystallizer in a fed-batch manner, wherein the fed-batch adding speed is 0.5 to 2 g / min; adding crystal seeds into the crystallizer, and growing the crystals for 1 to 2 hours; adding water which is 10 to 20 times that in the initial solution in volume into the crystallizer in a fed-batch manner, and growing the crystals for 2 to 4 hours, wherein the fed-batch adding speed is 0.5 to 5 g / min; thirdly, filtering. The invention provides the preparation method for a candesartan cilexetil crystal form I with a controllable particle size.

Description

technical field [0001] The invention relates to a preparation method of candesartan cilexetil crystallization, which belongs to the technical field of crystallization. Background technique [0002] Candesartan Cilexetil, chemical name (±)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2'-(1H -tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylate, the molecular formula is C 33 h 34 N 6 o 6 , molecular weight 610.66, CAS number 145040-37-5, white or off-white crystalline powder, easily soluble in chloroform, slightly soluble in absolute ethanol, almost insoluble in water. Its chemical structural formula is shown in the following formula. [0003] [0004] Candesartan cilexetil is the prodrug of candesartan, which is one of the ideal drugs for the treatment of hypertension. It was first jointly developed by Takeda Corporation of Japan and Astra Corporation of Sweden. It is a long-acting angiotensin Antagonists of II subtype I receptor (AT1) are ...

Claims

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Application Information

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IPC IPC(8): C07D403/10
CPCC07B2200/13C07D403/10
Inventor 王冠姜凯王振刘世超
Owner 迪嘉药业集团股份有限公司
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