Bendamustine hydrochloride crystal and preparation method thereof

A technology of bendamustine hydrochloride and bendamustine hydrochloride is applied in the field of polymorphic form of bendamustine hydrochloride, and can solve the problems of complicated operation, unsuitable for industrialized production, and difficulty of solvent meeting pharmacopoeia standards, etc.

Inactive Publication Date: 2014-02-26
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

[0058] Example 1 Preparation of bendamustine hydrochloride polymorph I

[0059] Take 10 grams of bendamustine hydrochloride crude product and place it in a reaction flask, add 50ml of 1mol / L hydrochloric acid solution, heat to 70-80°C, dissolve, slowly cool to room temperature and stir for 1 hour, then cool down to 0-10°C to analyze Crystal for 5 hours. Filter, wash the filter cake with water, and wash with acetone.

[0060] The resulting solid was added to a 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, then cooled to 0-10°C for 5 hours of crystallization. Filter, wash the filter cake with acetone, collect the solid, and dry under reduced pressure (-0.09MPa) at 45°C with phosphorus pentoxide as an aid. Obtained 8.2 grams of white solid, yield 82%, purity 99.92%, X-diffraction data are the same as Table 1.

Embodiment 2

[0061] Example 2 Preparation of bendamustine hydrochloride polymorph I

[0062] Take 10 grams of bendamustine hydrochloride crude product and place it in a reaction flask, add 40ml of 1mol / L hydrochloric acid solution, heat to 70-80°C, dissolve, slowly cool to room temperature and stir for 1 hour, then cool down to 0-10°C to analyze Crystal for 5 hours. Filter, wash the filter cake with water, and wash with acetone.

[0063] The resulting solid was added to a 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, then cooled to 0-10°C for 5 hours of crystallization. Filter, wash the filter cake with acetone, collect the solid, and dry under reduced pressure (-0.09MPa) at 45°C with phosphorus pentoxide as an aid. Obtained 8.4 grams of white solid, yield 84%, purity 99.90%, X-diffraction data are the same as Table 1.

Embodiment 3

[0064] Example 3 Preparation of bendamustine hydrochloride polymorph I

[0065] Take 7.6 grams of bendamustine hydrochloride crude product and place it in a reaction flask, add 45ml of 1mol / L hydrochloric acid solution, heat to 70-80°C, dissolve, slowly cool to room temperature and stir for 2 hours, then cool down to 0-10°C to analyze Crystal 6 hours. Filter, wash the filter cake with water, and wash with acetone.

[0066] The resulting solid was added to a reaction flask, 270ml of acetone was added, heated to reflux and stirred for 1.5 hours, slowly cooled to room temperature and stirred for 2 hours, then cooled to 0-10°C for 8 hours of crystallization. Filter, wash the filter cake with acetone, collect the solid, and dry under reduced pressure (-0.09MPa) at 45°C with phosphorus pentoxide as an aid. 8.0 g of white solid was obtained, with a yield of 80% and a purity of 99.96%. The X-diffraction data are the same as in 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/16
Inventor 赵俊宗在伟杜有国
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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