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Crystal V of dabigatran etexilate mesylate and preparation method thereof

A technology of dabigatran etexilate mesylate and crystals, which is applied in the field of new dabigatran etexilate mesylate crystals and its preparation, can solve problems such as the harmful effects of drug reproducibility, and is suitable for technological production , short time-consuming, high-purity effect

Active Publication Date: 2016-08-24
NANJING LIFENERGY R & D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Otherwise, this has a detrimental effect on the regenerative potency of the drug

Method used

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  • Crystal V of dabigatran etexilate mesylate and preparation method thereof
  • Crystal V of dabigatran etexilate mesylate and preparation method thereof
  • Crystal V of dabigatran etexilate mesylate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Add 0.2033 g of dry dabigatran etexilate mesylate into 0.5 mL of methanol to form a suspension, stir at 15°C until completely dissolved, and then slowly cool the solution to 5°C under stirring (the solution has no crystallization phenomenon), constant temperature, 4 mL of butyl acetate was added dropwise to the solution within 10 minutes to obtain a suspension, the crystal slurry was vacuum filtered, and the product was dried to constant weight at 35°C under normal pressure to obtain dabigatran mesylate in V crystal form ester.

[0058] The X-ray powder diffraction pattern of the crystal obtained in this example is 3.7±0.2, 4.5±0.2, 7.4±0.2, 8.1±0.2, 8.6±0.2, 9.3±0.2, 10.5±0.2, 11.0±0.2 at the diffraction angle 2θ , 12.8±0.2, 13.5±0.2, 14.3±0.2, 16.4±0.2, 17.2±0.2, 17.6±0.2, 19.8±0.2, 20.2±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 23.7±0.2, 24.2 There are characteristic peaks at ±0.2, 25.2±0.2, 26.5±0.2, 27.4±0.2, and 29.0±0.2 degrees. The specific spectrum is as follows fig...

Embodiment 2

[0068] Add 0.2013g of dry dabigatran etexilate mesylate into 0.4mL ethanol to form a suspension, stir at 10°C until the solids are completely dissolved, then slowly cool the solution to 0°C under stirring (the solution has no crystallization), Constant temperature, add 4 mL of butyl acetate dropwise to the solution within 5 minutes to obtain a suspension, vacuum filter the slurry, and dry the product at 45°C under normal pressure to constant weight to obtain Dabiga methanesulfonate in V crystal form Group esters.

[0069] The crystal product obtained in this example has a purity of 99.32%, and the characterization data are the same as those in Example 1.

Embodiment 3

[0071] Add 0.1998g of dry dabigatran etexilate mesylate into 0.35mL of n-pentanol to form a suspension, stir at 15°C until the solids are all dissolved, then slowly cool the solution to 5°C under stirring (the solution has no crystallization phenomenon ), constant temperature, 3mL of butyl acetate was added dropwise to the solution within 10 minutes to obtain a suspension, the slurry was vacuum filtered, and the product was dried to constant weight at 30°C under normal pressure to obtain the V crystal form methanesulfonic acid Bigatran etexilate.

[0072] The crystal product obtained in this example has a purity of 99.41%, and the characterization data are the same as those in Example 1.

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Abstract

The invention relates to a dabigatran etexilate mesylate crystal V and a preparation method thereof. The crystal V is defined by characteristic peaks of an X-ray powder diffraction spectrum at a diffraction angle 2 theta and DSC. The preparation method of the dabigatran etexilate mesylate crystal V comprises the following steps: adding an amorphous dabigatran etexilate mesylate crystal solid or a known dabigatran etexilate mesylate crystal solid with any crystal form to an alcohol solvent so as to prepare 400-600g / L of suspension liquid, completely dissolving the solid at the temperature of 5-15 DEG C, then cooling a solution to -5 DEG C to 5 DEG C, and then dropwise adding a solventing-out agent to the mixed solution, wherein the using amount of the solventing-out agent is 6-10 times of the volume of the solvent; and carrying out suction filtration on the formed suspension liquid, and drying a dabigatran etexilate mesylate crystal product to constant weight, thus obtaining the dabigatran etexilate mesylate crystal V. The preparation method of the dabigatran etexilate mesylate crystal V has the advantages that a technology is simple, the consumed time is short, and the prepared product has high purity, good thermodynamic stability and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine crystallization, in particular to a new dabigatran etexilate mesylate crystal and a preparation method thereof. Background technique [0002] Dabigatran etexilate is a double prodrug that is converted in vivo to dabigatran with anticoagulant activity. In order to improve the water solubility of the drug, it is usually made into the form of addition salt of dabigatran etexilate. The medicinal ingredient of currently commercially available capsules is dabigatran etexilate mesylate. The Chinese chemical name of dabigatran etexilate mesylate is 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl] -1-Methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester methanesulfonate, the English chemical name is ethyl3-[[[2-[[[ 4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionatemeth...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/4439A61P9/10
CPCC07D401/12
Inventor 汤传飞肖燕郝红勋鲍颖胡良明方文
Owner NANJING LIFENERGY R & D
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