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Preparation method of candesartan cilexetil crystal form I spherical crystal

A kind of candesartan medoxomil and crystallization technology, applied in the field of preparation of candesartan medoxomil crystal form I spherical crystal, can solve the problems such as no preparation method of candesartan medoxomil spherical crystal, achieve good fluidity, particle size The effect of uniform distribution, which is conducive to stable production

Active Publication Date: 2017-02-15
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 Chinese technicians have invented methods for preparing spherical crystals of various drugs, there is still no method for preparing spherical crystals suitable for candesartan cilexetil

Method used

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  • Preparation method of candesartan cilexetil crystal form I spherical crystal
  • Preparation method of candesartan cilexetil crystal form I spherical crystal
  • Preparation method of candesartan cilexetil crystal form I spherical crystal

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Add 10 g of candesartan cilexetil into a container containing 100 mL of 2-butanone, stir and dissolve at 20°C, and then filter and decolorize after stirring continuously for 60 minutes; transfer the filtrate to a crystallizer, control the system temperature to 10°C, Add methanol solvent for elution and crystallization, control the dropping time to 2h, and the volume of methanol used is 5 times that of 2-butanone; then filter and separate, wash the filter cake with methanol, and store the obtained product at a temperature of 40°C under 0.08MPa Drying was carried out under the condition of vacuum degree for 6h. The final product product appearance is spherical (such as figure 2 shown), the HPLC purity is 99.56%, the primary particle size is 180 microns, and the single-pass molar yield in the crystallization process is 89.7%.

Embodiment 2

[0021] Add 3 g of candesartan cilexetil into a container containing 100 mL of 2-butanone, stir and dissolve at 20°C, and then filter and decolorize after stirring continuously for 30 minutes; transfer the filtrate to a crystallizer, control the system temperature to 10°C, Add ethanol solvent for elution and crystallization, control the dropping time to 3 hours, and the volume of ethanol used is 6 times that of 2-butanone; then filter and separate, wash the filter cake with ethanol, and store the obtained product at a temperature of 60°C under 0.1MPa Drying was carried out for 5 h under the condition of vacuum degree. The appearance of the final product is spherical, the HPLC purity is 99.72%, the main particle size is 175 microns, and the single-pass molar yield in the crystallization process is 88.3%.

Embodiment 3

[0023] Add 5 g of candesartan cilexetil into a container containing 100 mL of 2-butanone, stir and dissolve at 30°C, and then filter and decolorize after stirring continuously for 40 minutes; transfer the filtrate to a crystallizer, control the system temperature to 20°C, Add isopropanol solvent to carry out elution crystallization, control drop time is 2h, isopropanol volume consumption is 4 times of 2-butanone; Carry out filtration separation then, wash filter cake with isopropanol, the product that obtains is in 50 ℃ temperature, under the condition of 0.06MPa vacuum for 5h. The appearance of the final product is spherical, the HPLC purity is 99.66%, the main particle size is 165 microns, and the single-pass molar yield in the crystallization process is 89.5%.

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Abstract

The invention relates to a preparation method of a candesartan cilexetil crystal form I spherical crystal, and belongs to the technical field of crystallization. The technical scheme adopted by the invention is that the preparation method comprises the following steps: firstly, adding candesartan cilexetil into ketone solvents, wherein the solid-liquid ratio of a solution is 0.01 to 0.1g / ml; stirring and dissolving at the temperature of 20 to 30DEG C, and continuously stirring for 30 to 60 minutes; secondly, filtering and decoloring; transferring filtrate into a crystallizer, controlling the temperature of a system to be 10 to 20DEG C, adding alcohol organic solvents, performing dilution crystallization, filtering, washing and drying to obtain a finished product disclosed by the invention. The candesartan cilexetil crystal form I spherical crystal by the preparation method provided by the invention is good in flowability and facilitates stable production of a preparation process.

Description

technical field [0001] The invention relates to a preparation method of candesartan cilexetil crystal form I spherical crystals, belonging to the field of crystallization technology. 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, slightly soluble in 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 was first jointly developed by Takeda Corporation of Japan and Astra Corporation of Sweden. It is a long-acting antagonist of angiotensin II subtype I receptor (AT1) , which can be completely converted into highly active candesartan during the absorption proc...

Claims

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Application Information

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