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Levosimendan sodium crystal form B and preparation method thereof

A technology of sodium montane and crystal form, applied in the field of medicinal chemistry, can solve the problems of affecting the safety of clinical medication, excessive particulate matter in the medicinal solution, potential safety hazards, etc., and achieve the effects of avoiding irritation and hemolysis, and avoiding the use of ethanol.

Active Publication Date: 2020-09-29
CHENGDU XINJIE HIGH TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since absolute ethanol is the non-aqueous solvent used to solubilize levosimendan, although it is used after dilution with an isotonic solution such as 5% glucose injection in clinical use, in the dilution process, due to the concentration of absolute ethanol after being diluted It is easy to cause the precipitation of levosimendan, resulting in excessive particles in the drug solution, which affects the safety of clinical medication. At the same time, the intravenous infusion of the drug solution containing ethanol is irritating to muscles and blood vessels, which seriously leads to hemolysis.
[0004] Although the preparation of levosimendan injection can be achieved by using a solubilizer such as sulfobutylbeta cyclodextrin, usually the amount of this solubilizer used is Very high, it is known that the impact of cyclodextrin products on human safety is closely related to the dosage, and this high dosage also brings potential safety hazards

Method used

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  • Levosimendan sodium crystal form B and preparation method thereof
  • Levosimendan sodium crystal form B and preparation method thereof
  • Levosimendan sodium crystal form B and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Preparation of Levosimendan Sodium Crystal Form B

[0058] Add 0.7g of sodium hydroxide and 30ml of absolute ethanol to a 100ml flask and stir to obtain an ethanol solution of sodium hydroxide. Add 5.0g of levosimendan and 45ml of absolute ethanol to a 250ml flask, and stir to dissolve at room temperature. Add sodium hydroxide ethanol solution dropwise at room temperature, and keep the reaction for about 5 hours after dripping. After filtering, the filter cake was washed with 10 ml of absolute ethanol. After drying under reduced pressure at 40°C for 3 hours, 4.36 g of Levosimendan Sodium Crystal Form B was obtained, with a weight yield of 87.2%.

[0059] After testing, its X-ray powder diffraction pattern is figure 1 Basically the same, HPLC purity and figure 2 Basically the same.

[0060] figure 1 Among them, the B crystal form Levosimendan sodium has characteristic peaks at 12.194°, 14.556°, 18.299°, 27.404°, and 30.048°.

Embodiment 2

[0061] Example 2: Preparation of Levosimendan Sodium Crystal Form B

[0062] Add 0.7g of sodium hydroxide and 20ml of methanol to a 100ml flask, and stir to obtain a sodium hydroxide methanol solution. Add 5.0g of levosimendan and 30ml of methanol to a 250ml flask, and stir to dissolve at room temperature. Add sodium hydroxide methanol solution dropwise at room temperature, and keep the reaction for about 5 hours. After filtering, the filter cake was washed with 5 ml methanol. After drying under reduced pressure at 40°C for 3 hours, 4.9 g of Levosimendan Sodium Crystal Form B was obtained with a weight yield of 98%.

[0063] After testing, its X-ray powder diffraction pattern is figure 1 Basically the same, HPLC purity is figure 2 Basically the same.

Embodiment 3

[0064] Example 3: Preparation of Levosimendan Sodium Crystal Form B

[0065] Add 0.7g of sodium hydroxide and 30ml of ethanol to a 100ml flask and stir to obtain an ethanol solution of sodium hydroxide. Add 5.0g of levosimendan, 25ml of ethanol, and 25ml of isopropanol to a 250ml flask, and stir to dissolve at room temperature. Add sodium hydroxide ethanol solution dropwise at room temperature, and keep the reaction for about 5 hours after dripping. Filter and wash the filter cake with 10 ml isopropanol. After drying under reduced pressure at 40°C for 3 hours, 4.7 g of Levosimendan sodium crystal form B was obtained with a weight yield of 94%.

[0066] After testing, its X-ray powder diffraction pattern is figure 1 Basically the same, HPLC purity is figure 2 Basically the same.

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Abstract

The invention discloses a levosimendan sodium crystal form B, a preparation method of the levosimendan sodium crystal form B and a stable pharmaceutical composition of the levosimendan sodium crystalform B. Cu-Kalpha radiation is used, and an X-ray powder diffraction pattern expressed by a 2theta angle has one or more characteristic diffraction peaks at the positions of 2theta of 12.2 + / -0.2 degrees, 14.6 + / -0.2 degrees, 18.3 + / -0.2 degrees, 27.4 + / -0.2 degrees and 30.0 + / -0.2 degrees. The yield of the levosimendan sodium crystal form B is up to 98%.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a crystal form B of levosimendan sodium and a preparation method thereof. Background technique [0002] Levosimendan is the first marketed product in a new generation of cardiotonic drugs—calcium sensitizers. It is mainly used clinically to treat various acute heart failure symptoms. The drug was developed by the Finnish company Orion and was first launched in Sweden in October 2000. At present, Levosimendan has been used in dozens of countries including Europe and the United States. However, there is no public report about the use of levosimendan and its pharmaceutically acceptable salt compounds, especially the use of levosimendan sodium and its thermally stable crystal form in the open literature, and for the treatment of congestion Heart failure or symptoms of acute decompensated heart failure (ADHF). [0003] Levosimendan is almost insoluble in water. The preparation of levosi...

Claims

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Application Information

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IPC IPC(8): C07D237/04A61K31/50A61K9/19A61K9/08A61P9/04
CPCC07D237/04A61K31/50A61K9/19A61K9/0019A61K9/08A61P9/04C07B2200/13
Inventor 高建王刚强伍伟刘力超
Owner CHENGDU XINJIE HIGH TECH DEV CO LTD
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