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Novel crystal form of argatroban and preparation method thereof

A technology of argatroban and crystal form, applied in the field of pharmaceutical crystallization, can solve the problems of harming methanol, consuming large amounts of water and energy, etc.

Active Publication Date: 2014-05-07
TIANJIN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In summary, the current preparation process of argatroban monohydrate either uses methanol that is harmful to human health, or consumes a lot of water and energy, and there are certain deficiencies

Method used

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  • Novel crystal form of argatroban and preparation method thereof
  • Novel crystal form of argatroban and preparation method thereof
  • Novel crystal form of argatroban and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Accurately weigh 12.0g of argatroban (HPLC purity 99.0%, R / S=62.2 / 36.8) into a 250ml crystallizer, add 170ml of ethanol and 9.5ml of water to form a mixed solution, heat to 45 degrees, dissolve Keep the temperature at 45°C for one hour; slowly cool down to 5°C at 0.5°C / min, keep warm for 2-4h, after the crystallization is complete, filter and wash, and vacuum-dry at 80°C for 8h to obtain 10.3g product with a yield of 86% (HPLC The detection purity was 99.9%, R / S=62.5 / 37.4). The powder X-ray diffraction pattern of the product and figure 1 Consistent, the water content is 3.8%, and the ratio of R / S meets the medical requirements.

Embodiment 2

[0026] Accurately weigh 14.0g argatroban (HPLC purity 99.0%, R / S=62.2 / 36.8) into a 250ml crystallizer, add a mixed solution composed of 130ml ethanol and 10ml water, heat and stir until dissolved, the temperature is about at 50°C, keep the constant temperature for 10min, slowly cool down to 10°C at 0.2°C / min, and keep warm for 2-4h. After the crystallization is complete, filter and wash, and vacuum-dry at 90°C for 7h to obtain 11.3g of product with a yield of 81% (HPLC The detection purity was 99.9%, R / S=62.6 / 37.3). The powder X-ray diffraction pattern of the product and figure 1 Consistent, the water content is 3.5%, and the ratio of R / S meets the medical requirements.

Embodiment 3

[0028] Accurately weigh 30.0g of argatroban (HPLC purity 99.0%, R / S=61.8 / 37.2) into a 400ml crystallizer, add 260ml of ethanol and 10ml of water to form a mixed solution, heat and reflux to 75 degrees, and wait until the solid After complete dissolution, cool slowly at 0.2°C / min to 15°C, keep warm for 2-4h, filter and wash after complete crystallization, and vacuum-dry at 100°C for 6h to obtain 26.1g of solid with a yield of 87% (purity detected by HPLC 99.9%, R / S=61.4 / 38.5), the powder X-ray diffraction pattern of the product and figure 1 Consistent, the water content is 3.4%, and the ratio of R / S meets the medical requirements.

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Abstract

The invention relates to a novel crystal form of argatroban and a preparation method thereof. The novel crystal form has characteristic peaks at 4.3+ / -0.1, 7.4+ / -0.1, 8.5+ / -0.1, 8.8+ / -0.1, 10.4+ / -0.1, 10.7+ / -0.1, 17.2+ / -0.1, 17.9+ / -0.1, 20.3+ / -0.1, 22.5+ / -0.1, 27.8+ / -0.1 and the like by diffraction angle 2theta. The preparation method comprises the following steps: dissolving an argatroban coarse product in a mixed solvent of ethanol and water to prepare argatroban liquor; heating to 40-75 DEG C, and stirring, dissolving and clarifying; then, cooling and recrystallizing, filtering, vacuum drying to obtain the novel crystal form of argatroban. The product is uniformly paved in an opened culture dish, wherein the thickness of a sample is less than 5mm and the sample is hermetically placed in a drier at 50-80 DEG C, X-Ray Diffraction detections are carried out on samples respectively in 30 days and 60 days, the results are compared with the result at the 0th day, and the result shows that the novel crystal form of argatroban does not changed and is good in stability.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical crystallization, and in particular relates to a crystal form of argatroban and a preparation method thereof. Background technique [0002] Argatroban (Argatroban), the chemical name is (2R,4R)-4-methyl-1-[N-((R,S)-3-methyl-1,2,3,4-tetrahydro- 8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid, molecular formula C 23 h 36 N 6 o 5 S, the molecular weight is 508.63, and the chemical structure formula is: [0003] [0004] Argatroban was developed and synthesized by Mitsubishi Chemical Research Institute in Japan in 1970. It was initially approved for the treatment of peripheral thrombosis and acute stroke. Argatroban is currently the only synthetic drug approved in the world for the treatment of acute stroke. It can directly and reversibly interact with thrombin, and has better anticoagulant and antithrombotic effects than heparin. The advantages of low reaction rate. [000...

Claims

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Application Information

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IPC IPC(8): C07K5/068
Inventor 龚俊波任日菊尹秋响侯宝红孙登琼张士欣姜磊王悦伟
Owner TIANJIN UNIV
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