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Edoxaban trihydrate as well as preparation method and application thereof

A technology of shaban trihydrate and edoxaban, which is applied in the field of medicine, can solve the problems of high total amount of impurities, large number of edoxaban impurities, and difficulty in repeating the crystal form

Inactive Publication Date: 2018-02-06
TIANJIN HANRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] During the research process, repeating the method recorded in the literature in the prior art, the obtained edoxaban has a large number of impurities and a high total amount of impurities, and it is difficult to repeat the crystal form after amplification

Method used

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  • Edoxaban trihydrate as well as preparation method and application thereof
  • Edoxaban trihydrate as well as preparation method and application thereof
  • Edoxaban trihydrate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] In a 100L reaction kettle, add 6 kg of edoxaban (purity: 98.06%, HPLC) and 65 L of acetone-acetonitrile-ammonia water = 9:1:0.5 mixture, heat to 50°C-55°C, and keep warm for 20 minutes. Strain while hot. The filtrate was kept at 35°C-38°C for 1.5 hours; then naturally cooled to room temperature and held for 2.5 hours, the precipitated crystals were filtered and dried naturally at room temperature to obtain 5.71 kg of white crystals with a purity of 99.91%. The solvent residue test met the requirements. The moisture measured by Karl Fischer method is 8.97%.

[0032] Instrument model and measurement conditions: Rigaku D / max 2500 diffractometer; CuKa 40Kv 100mA; 2θ scanning range: 0-50 ° .

Embodiment 2

[0034] In a 100L reaction kettle, add 6 kg of edoxaban (purity 98.06%, HPLC) and 60 L of acetone-acetonitrile-ammonia water = 9:0.8:0.3 mixture, heat to 50°C-53°C, and keep warm for 20 minutes , filtered while hot. The filtrate was kept at 35°C-36°C for 1 hour; then naturally cooled to room temperature and held for 2 hours, the precipitated crystals were filtered and dried naturally at room temperature to obtain 5.56 kg of white crystals with a purity of 99.92%. The solvent residue test met the requirements. The moisture measured by Karl Fischer method is 8.98%.

[0035] The X-ray diffraction result that records is with embodiment 1.

Embodiment 3

[0037] In a 100L reaction kettle, add 6 kg of edoxaban (purity 98.06%, HPLC) and 70 L of acetone-acetonitrile-ammonia water = 9:0.5:0.7 mixture, heat to 52°C-54°C, and keep warm for 20 minutes , filtered while hot. The filtrate was kept at 37°C-38°C for 2 hours; then naturally cooled to room temperature and kept for 3 hours, the precipitated crystals were filtered and dried naturally at room temperature to obtain 5.66 kg of white crystals with a purity of 99.92%, and the solvent residue test met the requirements. The moisture measured by Karl Fischer method is 8.88%.

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Abstract

The invention belongs to the technical field of medicine, and in particular relates to a crystal form of Edoxaban trihydrate and a preparation method thereof. The invention also relates to a pharmaceutical composition containing the above-mentioned crystal form of Edoxaban trihydrate and its preparation method for treating antithrombotic drugs. in the application.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to crystals of edoxaban trihydrate and a preparation method thereof, and also relates to the application of the crystals in the manufacture of antithrombotic drugs. Background technique [0002] Edoxaban is a small-molecule oral anticoagulant that acts as a factor X (FXa) blocker. Activated coagulation factor X (FXa) in the coagulation process activates prothrombin FII into thrombin FIIa to promote fibrin formation, thereby forming thrombus. Therefore, FXa has become the main target for the development of a new generation of anticoagulant drugs. Edoxaban is an oral anticoagulant drug that inhibits thrombus formation through selective, reversible and direct inhibition of FXa, and its selectivity for FXa is 104 times higher than that of FIIa. Clinical trials at home and abroad have confirmed that this product can effectively inhibit VTE in patients undergoing lower limb ...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61K31/444A61P7/02
CPCC07D513/04C07B2200/13
Inventor 严洁
Owner TIANJIN HANRUI PHARMA
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