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New crystal of rivaroxaban and preparation method thereof

A technology for rivaroxaban and crystals, applied in the field of new rivaroxaban crystals and their preparation, can solve problems such as solvent residues, and achieve the effects of fast dissolution rate, good solubility and high purity

Active Publication Date: 2016-10-12
NANJING LIFENERGY R & D +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As for the other rivaroxaban solvates disclosed in the above-mentioned patent documents, because of the problem of solvent residues, it cannot be realized in the production of pharmaceuticals.

Method used

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  • New crystal of rivaroxaban and preparation method thereof
  • New crystal of rivaroxaban and preparation method thereof
  • New crystal of rivaroxaban and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Add 2 g (purity: 95.0%) of the crude product of rivaroxaban crystal form I to 8 g of formic acid to form a 20% rivaroxaban suspension, heat the suspension to dissolve rivaroxaban, add 40 g of acetonitrile and water 2g, then the solution was cooled to room temperature, solids were precipitated, filtered, the filter cake was placed in a vacuum drying oven, and dried under reduced pressure (vacuum degree of 0.085mPa, drying temperature of 20°C) to constant weight to obtain rivaroxaban crystal SMN -F.

[0043] The X-ray powder diffraction pattern of the crystal that present embodiment makes is 3.7±0.2, 7.3±0.2, 14.0±0.2, 14.5±0.2, 18.2±0.2, 18.4±0.2, 19.9±0.2, 20.6±0.2, Features at 21.8±0.2, 23.1±0.2, 25.0±0.2, 26.4±0.2, 28.4±0.2, 29.2±0.2, 31.9±0.2, 33.5±0.2, 34.1±0.2, 35.5±0.2, 36.8±0.2, 37.1±0.2 There are characteristic peaks at the absorption kurtosis, and its specific spectrum is as follows figure 1 shown.

[0044] The DSC collection of illustrative plates of the cr...

Embodiment 2

[0056] Add 2 g of rivaroxaban crystal form II crude product (purity: 97.3%) to 8 g of formic acid to configure a 20% rivaroxaban suspension, heat the suspension to dissolve rivaroxaban, add 60 g of acetonitrile and water 4g, then the solution was cooled to room temperature, solids were precipitated, filtered, the filter cake was placed in a vacuum drying oven, and dried under reduced pressure (vacuum degree of 0.80mPa, drying temperature of 30°C) to constant weight to obtain rivaroxaban crystal SMN -F.

[0057] The crystal product obtained in this embodiment has a purity of 99.91% and a water content of 7.63%. The characteristic data of this embodiment are the same as that of Embodiment 1.

Embodiment 3

[0059] Add 2 g (purity: 95.0%) of rivaroxaban crystal amorphous crude product into 18 g formic acid to form a 10% rivaroxaban suspension, heat the suspension to dissolve rivaroxaban, add 60 g of acetonitrile and 4g of water, then the solution was cooled to room temperature, solids were precipitated, filtered, the filter cake was placed in a decompression drying oven, and dried under reduced pressure (vacuum degree of 0.90mPa, drying temperature of 10°C) to constant weight to obtain rivaroxaban crystals SMN-F.

[0060] The crystal product obtained in this embodiment has a purity of 99.93% and a water content of 7.66%. The characteristic data of this embodiment are the same as that of Embodiment 1.

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Abstract

The invention discloses a new crystal of rivaroxaban and a preparation method thereof. The new crystal of rivaroxaban is crystal SMN-F, X-ray powder diffraction spectrum of which has diffraction peaks when a diffraction angle 2theta is 3.7+ / -0.2, 7.3+ / -0.2, 14.5+ / -0.2, 21.8+ / -0.2, 29.2+ / -0.2, 31.9+ / -0.2 and 33.5+ / -0.2. The preparation method of the rivaroxaban SMN-F crystal provided by the invention has the advantages of simple process, short time, and suitability for technological production, etc. At the same time, the rivaroxaban SMN-F crystal prepared by the method provided by the invention has the advantages of high purity, fast dissolution rate and good solubility, etc.

Description

technical field [0001] The invention belongs to the technical field of drug crystallization, and in particular relates to a new rivaroxaban crystal and a preparation method thereof. Background technique [0002] Rivaroxaban is the world's first oral direct factor Xa inhibitor developed by Bayer / Johnson & Johnson. Its molecular formula is C19H18ClN3O5S, CAS number: 366789-02-8, and its structural formula is as follows: [0003] [0004] Rivaroxaban highly selectively and competitively inhibits free and bound factor Xa and prothrombin activity, and prolongs activated partial thromboplastin time plate (PT) and prothrombin time (aPTT) in a dose-dependent manner. The essential difference between rivaroxaban and fondaparinux sodium / heparin is that it does not require the participation of antithrombin III, and can directly antagonize the free and bound Xa factor to reduce the activation of thrombin and prolong the coagulation time. It not only affects blood clots The formation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/5377A61P7/02
CPCC07B2200/13C07D413/14
Inventor 王卓异陈爱军李德富黄安民
Owner NANJING LIFENERGY R & D
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