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Bendamustine hydrochloride crystal and preparation method thereof

A technology of bendamustine hydrochloride and bendamustine hydrochloride, which is applied in the field of polymorphic forms of bendamustine hydrochloride, can solve the problem that the solvent is difficult to meet the Pharmacopoeia standard, the impurity is difficult to reach 0.1%, and it is not suitable for industrial production and other problems, to achieve the effect of easy industrial production, controllable quality and stable yield

Inactive Publication Date: 2012-02-15
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] (1) It is difficult for a single impurity to reach less than 0.1%;
[0011] (2) Solvent residues are difficult to meet the pharmacopoeia standards;
[0012] (3) The solubility is not ideal;
[0013] (4) The operation is cumbersome and not suitable for industrial production;

Method used

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  • Bendamustine hydrochloride crystal and preparation method thereof
  • Bendamustine hydrochloride crystal and preparation method thereof
  • Bendamustine hydrochloride crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Preparation of bendamustine hydrochloride polymorph I

[0060] Take 10 grams of crude bendamustine hydrochloride and place it in the reaction flask, add 50ml of 1mol / L hydrochloric acid solution, heat to 70~80℃, dissolve, slowly cool to room temperature and stir for 1 hour, then cool to 0~10℃ for precipitation Crystal for 5 hours. Filter, wash the filter cake with water and wash with acetone.

[0061] The obtained solid was added to the reaction flask, 300ml of acetone was added, heated to reflux and stirred for 2 hours, slowly cooled to room temperature and stirred for 1 hour, and then cooled to 0-10°C for 5 hours to crystallize. Filter, wash the filter cake with acetone, collect the solids, and dry at 45°C under reduced pressure (-0.09MPa) with phosphorus pentoxide for drying. 8.2 grams of white solid was obtained, the yield was 82%, and the purity was 99.92%. The X-diffraction data is the same as Table 1.

Embodiment 2

[0062] Example 2 Preparation of bendamustine hydrochloride polymorph I

[0063] Take 10 grams of crude bendamustine hydrochloride and place it in a reaction flask, add 40ml of 1mol / L hydrochloric acid solution, heat to 70~80℃, dissolve, slowly cool to room temperature and stir for 1 hour, then cool to 0~10℃ for precipitation Crystal for 5 hours. Filter, wash the filter cake with water and wash with acetone.

[0064] The obtained solid was added to the reaction flask, 400ml of acetone was added, heated to reflux and stirred for 2 hours, slowly cooled to room temperature and stirred for 1 hour, and then cooled to 0-10°C for 5 hours to crystallize. Filter, wash the filter cake with acetone, collect the solids, and dry at 45°C under reduced pressure (-0.09MPa) with phosphorus pentoxide for drying. 8.4 g of white solid was obtained, the yield was 84%, and the purity was 99.90%. The X-diffraction data is the same as Table 1.

Embodiment 3

[0065] Example 3 Preparation of bendamustine hydrochloride polymorph I

[0066] Take 7.6 grams of crude bendamustine hydrochloride and place it in a reaction flask, add 45ml of 1mol / L hydrochloric acid solution, heat to 70~80℃, dissolve, slowly cool to room temperature and stir for 2 hours, then cool to 0~10℃ Crystal for 6 hours. Filter, wash the filter cake with water and wash with acetone.

[0067] Add the obtained solid to the reaction flask, add 270ml of acetone, heat to reflux and stir for 1.5 hours, slowly cool to room temperature and stir for 2 hours, then cool to 0-10°C for 8 hours to crystallize. Filter, wash the filter cake with acetone, collect the solids, and dry at 45°C under reduced pressure (-0.09MPa) with phosphorus pentoxide for drying. 8.0 g of white solid was obtained, the yield was 80%, and the purity was 99.96%. The X-diffraction data is the same as Table 1.

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Abstract

The invention discloses a new bendamustine hydrochloride crystal and a preparation method thereof. On a characteristic X-ray powder diffraction pattern, the polymorph I of bendamustine hydrochloride disclosed by the invention has one or more characteristic peaks represented by 2theta at the positions as follows: 10.6+ / -0.2, 15.0+ / -0.2, 18.7+ / -0.2, 20.0+ / -0.2, 22.9+ / -0.2, and 26.5+ / -0.2. The new crystal of bendamustine hydrochloride has the characteristics of good solubility, good stability and the like. The operation method is simple and easy to operate, and is easy to industrially produce.

Description

technical field [0001] The present invention relates to polymorphs of pharmaceutical compounds, more particularly, to polymorphs of bendamustine hydrochloride. Background technique [0002] The chemical name of bendamustine hydrochloride is 4-[5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butyric acid hydrochloride, and the molecular formula is C 16 h 21 Cl 2 N 3 o 2 HCl, the chemical structure is as follows: [0003] . [0004] Bendamustine hydrochloride (bendamustine hydrochloride) was first developed in the early 1860s by Ozegowski et al. at the Microbial Experiment Association of the University of Jena, Germany. It is a bifunctional alkylating agent with a new mechanism of action and has antitumor properties. and cytocidal effect. Its anti-tumor and cytocidal effects are mainly attributed to the cross-linking of DNA single strands and double-links through alkylation, disrupting the function of DNA and DNA synthesis, resulting in cross-linking between...

Claims

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Application Information

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IPC IPC(8): C07D235/16
Inventor 赵俊宗在伟杜有国
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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