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New epalrestat crystal form as well as preparation method and application thereof

A technology of epalrestat and crystal form, which is applied in the field of new crystal form of epalrestat and its preparation, can solve the problems of affecting drug bioavailability, affecting dissolution, poor water solubility of epalrestat, etc.

Active Publication Date: 2021-11-16
SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Epalrestat has poor water solubility, and the different solubility of different crystal forms will affect its dissolution in the pharmaceutical composition, thereby affecting the bioavailability of the drug in the human body

Method used

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  • New epalrestat crystal form as well as preparation method and application thereof
  • New epalrestat crystal form as well as preparation method and application thereof
  • New epalrestat crystal form as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0048] The present invention also provides a method for preparing the new crystal form of epalrestat described in the above technical scheme, comprising the following steps:

[0049] Carboxymethylrhodanine and α-methylcinnamaldehyde are condensed in a reaction system including a reaction solvent, an organic basic catalyst and a phase transfer catalyst to obtain a condensation reaction feed liquid;

[0050] Mixing the condensation reaction feed liquid and the acid liquid to obtain the crude product of epalrestat;

[0051] The crude epalrestat, alcohol solvent and acid solution are mixed and refined to obtain the new crystal form of epalrestat.

[0052] In the present invention, unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0053] In the invention, 3-carboxymethyl rhodanine and alpha-methyl cinnamaldehyde are condensed in a reaction system including a reaction solvent, an organic basic catalyst and ...

Embodiment 1

[0080] Add 320mL of purified water and 40080mL of polyethylene glycol in turn to a 1000mL three-neck round bottom flask, and add 3-carboxymethylrhodanine (15.3g, 80mmol) and α-methylcinnamaldehyde (14.0g, 96mmol) in turn under stirring at room temperature After the addition, 3-dimethylaminopropylamine (8.0 mL, 64 mmol) was added dropwise at a rate of 5 mL / min. After the dropwise addition, the temperature was raised to 60° C. and the stirring was continued (300 rpm) for 2.0 h. Turn off the heating and lower the temperature naturally, and at the same time add 20.0 mL of concentrated hydrochloric acid dropwise to the reaction system. After the reaction system was cooled to 25°C, it was filtered, the filter cake was rinsed with 100 mL of purified water, and dried under vacuum at 40°C for 2.0 h to obtain crude epalrestat (24.5 g, 96%) as a yellow solid.

[0081]In a 250mL round-bottomed flask, the crude product of epalrestat (16.0g, 50mmol) was suspended in 100mL of anhydrous meth...

Embodiment 2

[0104] Add 320mL of purified water and 40080mL of polyethylene glycol in turn to a 1000mL three-neck round bottom flask, and add 3-carboxymethylrhodanine (15.3g, 80mmol) and α-methylcinnamaldehyde (14.0g, 96mmol) in turn under stirring at room temperature After the addition, 3-dimethylaminopropylamine (8.0 mL, 64 mmol) was added dropwise at a rate of 5 mL / min. After the dropwise addition, the temperature was raised to 60° C. and the stirring was continued (300 rpm) for 2.0 h. Turn off the heating and lower the temperature naturally, and at the same time add 20.0 mL of concentrated hydrochloric acid dropwise to the reaction system. After the reaction system was cooled to 25°C, it was filtered, the filter cake was rinsed with 100 mL of purified water, and dried under vacuum at 40°C for 2.0 h to obtain crude epalrestat (24.5 g, 96%) as a yellow solid.

[0105] In a 250mL round bottom flask, the crude product of epalrestat (16.0g, 50mmol) was suspended in 120mL of isopropanol, st...

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Abstract

The invention belongs to the technical field of medicines, and provides a novel epalrestat crystal form as well as a preparation method and application thereof. The X-ray powder diffraction pattern of the epalrestat new crystal form has characteristic diffraction peaks when the diffraction angles 2 theta are 6.39 + / -0.2 degrees, 7.57 + / -0.2 degrees, 12.69 + / -0.2 degrees, 14.67 + / -0.2 degrees, 15.04 + / -0.2 degrees, 21.79 + / -0.2 degrees, 24.36 + / -0.2 degrees, 25.59 + / -0.2 degrees, 27.30 + / -0.2 degrees and 31.48 + / -0.2 degrees. The epalrestat novel crystal form has excellent dissolution performance and water solubility, and the bioavailability of the epalrestat novel crystal form is improved; moreover, the epalrestat new crystal form has excellent flowability, the angle of repose can reach 26 degrees or below, the compression coefficient is smaller than 10%, the Hausner ratio is 1.00-1.11, and the epalrestat new crystal form is suitable for being used as a raw material medicine for production of prodrugs or pharmaceutical preparations of the epalrestat new crystal form.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a new crystal form of epalrestat and its preparation method and application. Background technique [0002] Epalrestat, a new type of aldose reductase inhibitor developed by Japan Ono Company, was first launched in Japan in 1992 for the treatment of diabetic complications, such as neuropathy, corneal epithelial disease, retinopathy and microvascular disease, etc. One of the causes of diabetic complications is abnormal osmotic pressure caused by hyperactivity of polyol metabolism, and aldose inhibitors can effectively treat diabetic complications by inhibiting the rate-limiting enzyme that converts glucose into sorbitol in polyol metabolism. Solve the abnormality of partial tissue osmotic pressure. [0003] Epalrestat, the chemical name is 5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-2-thio-2,4-thiazoldione-3-acetic acid, its chemical structure is as follows : [0004] [000...

Claims

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Application Information

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IPC IPC(8): C07D277/36A61K31/426A61P3/10A61P27/02
CPCC07D277/36A61P3/10A61P27/02C07B2200/13
Inventor 颜世强郭伟曹焕英杨杰何淑旺程中伟胡醒
Owner SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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