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New alprostadil crystal form, preparation method and application thereof in medicine composition

A technology of alprostadil and crystal form, applied to high-purity alprostadil new crystal form A, and its preparation field, can solve the problems of high toxicity of acetonitrile, complicated operation, etc., achieves improved product yield, simple preparation method, reduced The effect of the risk of product decomposition

Inactive Publication Date: 2015-05-06
YAOPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, the patent ended up using acetonitrile for recrystallization, which is more toxic
CN103319390 A discloses a kind of alprostadil crystal, its X-ray powder diffraction pattern is at 7.01°, 9.38°, 13.60°, 16.69°, 18.08°, 18.72°, 19.69°, 20.21°, 21.34°, 22.78°, 26.41° , 27.08°, 28.67°, 29.49°, 34.50°, 35.15°, 35.64° and 37.51° have characteristic peaks. However, this crystal form needs to use an ultrasonic field for a long time to grow crystals during the preparation process, and the operation is more cumbersome

Method used

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  • New alprostadil crystal form, preparation method and application thereof in medicine composition
  • New alprostadil crystal form, preparation method and application thereof in medicine composition
  • New alprostadil crystal form, preparation method and application thereof in medicine composition

Examples

Experimental program
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Effect test

Embodiment 1

[0035]At room temperature, dissolve 10.0 g of alprostadil crude product 1 (purity 65.0%) in 100 ml of a mixed solvent of ethyl acetate and ethanol (ethyl acetate: ethanol = 10: 1, V: V), and load the sample to 200 -300 mesh silica gel column. After the sample layer is uniformly adsorbed on the silica gel column, elute with a mixed solvent (ethyl acetate:ethanol=20:1, V:V) at a flow rate of 3ml / min, collect the alprostadil fraction, and decompose at 45°C. Concentrated under reduced pressure to obtain about 8.0 g of crude product 2 after passing through the column, the liquid phase purity (area normalization method) was 95.2%, and the yield was 80.0%.

[0036] Add 8.0 g of the obtained crude product 2 after passing through the column to 160 ml of ethyl acetate, stir well to obtain a suspension of alprostadil crude product 2, heat it to 50° C., but fail to dissolve, and add about 0.5 ml of ethanol to clarify the solution. Cool down at a rate of 5°C / 30min. At 38°C, a small amoun...

Embodiment 2

[0042] At room temperature, dissolve 10.0 g of alprostadil crude product 1 (purity 65.0%) in 50 ml of a mixed solvent of ethyl acetate and isopropanol (ethyl acetate:isopropanol=1:1, V:V), and Samples were loaded onto a 200-300 mesh silica gel column. After the sample layer is uniformly adsorbed on the silica gel column, it is eluted with a mixed solvent (ethyl acetate:isopropanol=10:1, V:V) at a flow rate of 3ml / min, and the alprostadil component is collected. ℃ and concentrated under reduced pressure to obtain about 8.1 g of the crude product 2 after passing through the column, the liquid phase purity (area normalization method) was 96.0%, and the yield was 81.0%.

[0043] Add 81ml of ethyl acetate to the obtained 8.1g crude product 2 after passing through the column, stir well to obtain a suspension of alprostadil crude product 2, heat to 60°C, fail to dissolve, add about 2.0ml of isopropanol to the solution clarify. Cool down at a rate of 5°C / 30min. At 40°C, a small amo...

Embodiment 3

[0045] At room temperature, dissolve 10.0 g of alprostadil crude product 1 (purity 65.0%) in 250 ml of a mixed solvent of ethyl acetate and methanol (ethyl acetate:methanol=20:1, V:V), and load the sample to 200 -300 mesh silica gel column. After the sample layer is uniformly adsorbed on the silica gel column, elute with a mixed solvent (ethyl acetate:methanol=30:1, V:V) at a flow rate of 3ml / min, collect the alprostadil fraction, and decompose at 45°C. Concentrated under reduced pressure to obtain about 8.2 g of crude product 2 after passing through the column, the liquid phase purity (area normalization method) was 94.6%, and the yield was 82.0%.

[0046] Add 8.2 g of the obtained crude product 2 after passing through the column to 246 ml of ethyl acetate, stir to obtain a suspension of the crude product 2 of alprostadil, and heat to 40°C. Cool down at a rate of 5°C / 30min. At 36°C, a small amount of crystals precipitated, and the crystallization was carried out for 2 hours...

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Abstract

The invention relates to a new alprostadil crystal form A, a preparation method thereof and an application thereof in a medicine composition. The preparation process disclosed by the invention is simple, and the prepared crystal form A is high in chemical purity, good in stability, and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a high-purity new crystal form A of alprostadil, a preparation method thereof and an application in a pharmaceutical composition. Background technique [0002] Alprostadil, (1R,2R,3R)-3-hydroxy-2(E)-(3S)-3-hydroxy-1-octenyl-5-oxocyclopentaneheptanoic acid, is an endogenous Physiologically active substances with multiple pharmacological activities: can significantly expand peripheral and coronary vessels, improve hemodynamics and hemorheology; inhibit platelet aggregation, reduce platelet hyperreactivity and thromboxane A (TXA) levels; inhibit vascular Free Ca2+ in smooth muscle cells inhibits the release of norepinephrine from vascular sympathetic nerve endings, relaxes vascular smooth muscle, improves microcirculation; activates lipoproteinase and promotes triglyceride hydrolysis, reduces blood lipids and blood viscosity, etc. At present, it is widely used clinica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C405/00A61K31/5575A61K9/19
Inventor 裴东游伟何刚吴东宝
Owner YAOPHARMA CO LTD
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