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Crystal form of Pralatrexate, pharmaceutical composition containing same, preparation method and application thereof

A composition and crystal form technology, which is applied in the fields of drug combination, antitumor drugs, organic chemistry, etc., can solve the problems of poor stability and low crystal form purity, and achieve the effects of good stability, simple preparation method and mild crystallization conditions.

Active Publication Date: 2016-06-22
SHANGHAI INST OF PHARMA IND CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome defects such as low purity and poor stability of the crystalline form of pralatrexate in the prior art, and provide a crystalline form of pralatrexate, a pharmaceutical composition containing it, and a preparation method thereof and application

Method used

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  • Crystal form of Pralatrexate, pharmaceutical composition containing same, preparation method and application thereof
  • Crystal form of Pralatrexate, pharmaceutical composition containing same, preparation method and application thereof
  • Crystal form of Pralatrexate, pharmaceutical composition containing same, preparation method and application thereof

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preparation example Construction

[0028] The preparation method of pralatrexate: according to the preparation method provided by DeGraw et al. in the experimental part of the document "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin" J. Med. Chem. 36: 2228-2231 (1993).

[0029] The preparation method of the crystal form of pralatrexate is as follows: heating and dissolving pralatrexate in a good solvent, then adding anti-solvent dropwise until turbidity appears, and cooling to crystallize.

Embodiment 1

[0033] Take 15.0g of pralatrexate (purity 98.01%), add 100ml of N,N-dimethylformamide, raise the temperature to 50°C, stir for 10 minutes, add 50ml of acetonitrile dropwise, cool and crystallize naturally, keep it at room temperature for 4 hours at 25°C and continue Crystallize, filter, rinse the filter cake with 30 ml of acetonitrile, and vacuum-dry the filter cake at 50°C to obtain 12.1 g of the crystalline form of pralatrexate (purity: 99.68%).

Embodiment 2

[0035] Take 15.0g of pralatrexate (purity 97.91%), add 50ml of N,N-dimethylformamide, raise the temperature to 80°C, stir for 10 minutes, add 25ml of acetonitrile dropwise, cool and crystallize naturally, and keep it at room temperature for 4 hours at 25°C to continue Crystallize, filter, rinse the filter cake with 30 ml of acetonitrile, and vacuum-dry the filter cake at 50°C to obtain 13.3 g of the crystalline form of pralatrexate (purity: 99.52%).

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Abstract

The invention discloses a crystal form of pralatrexate, a pharmaceutical composition containing the pralatrexate, and a preparation method and an application of the pralatrexate. According to the crystal form, in an X-ray powder diffraction pattern using a radiation source as Cu-Kalpha, characteristic absorption peaks are formed at the diffraction angles 2theta of 8.29 degrees, 15.73 degrees, 16.72 degrees, 17.21 degrees, 18.46 degrees, 19.01 degrees, 21.38 degrees, 25.25 degrees and 25.56 degrees; and the error range of 2theta is + / -0.2 degrees. The preparation method of the crystal form disclosed by the invention comprises the following steps: heating and dissolving pralatrexate into a good solvent; and dropwise adding an anti-solvent until turbidity is achieved, naturally cooling, and devitrifying, so as to obtain the crystal form. The crystal form of the pralatrexate disclosed by the invention has the advantages of high purity, good stability and the like.

Description

technical field [0001] The invention relates to a crystal form of pralatrexate, a pharmaceutical composition containing it, a preparation method and application thereof. Background technique [0002] Among small molecule drug compounds, many compounds exist in different crystal forms or polymorphic mixtures or solvates, each of which has different physical and chemical properties, and exhibits in terms of solubility, stability, and spectral characteristics. Therefore, the selection of raw materials with high purity and good stability plays a vital role in the production of pharmaceuticals. [0003] Pralatrexate is (2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]-3-butynyl]benzoyl The general name of ] amino] glutaric acid, its structural formula is: [0004] [0005] Pralatrexate is the first approved drug for the treatment of relapsed and refractory peripheral T-cell lymphoma, and its use in the treatment of esophageal cancer, gastric cancer, lung cancer, bladder...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/08A61K31/519A61P35/00
CPCC07D475/08
Inventor 胡志袁哲东刘航
Owner SHANGHAI INST OF PHARMA IND CO LTD
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