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Preparation method of azacitidine crystal form

A technology of azacitidine crystals and azacitidine, which is applied in the field of drug preparation, and can solve problems such as difficulty in drug quality control, inability to produce qualified drugs, and solvent residues

Active Publication Date: 2019-07-09
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventor has confirmed through experiments that the product obtained by the method provided by the patent WO2004082822 has the following defects. First, esters, ethers, alkanes, substituted alkanes, and ketone solvents are used as anti-solvents, and the crystal form of the obtained product is mixed. crystal, which brings difficulties to the quality control of medicines; second: use acetonitrile as anti-solvent to obtain crystal form I products, but the problem of solvent residue is serious, generally above 1000ppm, and the pharmacopoeia stipulates that the limit of acetonitrile is 410ppm; third: use alcohol As an anti-solvent, there are dual problems of crystal form purity and solvent residue
In summary, the patent WO2004082822 only provides a preparation method for the preparation of azacitidine crystal form I, but in the actual drug production process, these methods cannot produce qualified drugs

Method used

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  • Preparation method of azacitidine crystal form
  • Preparation method of azacitidine crystal form
  • Preparation method of azacitidine crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Mix 1g of azacitidine with 5ml of DMSO, heat to 75°C until the sample is completely dissolved, slowly add 30ml of a mixed solvent consisting of methanol / n-hexanol = 1:1, lower the temperature to room temperature and stir for 1h, filter, and the sample is at 80 After vacuum drying at ℃ for 24 hours, a 0.8g sample of Form I was obtained. The solvent residue in DMSO was measured to be 830ppm, and the purity was greater than 99.9%. The XRD pattern was as follows: figure 1 shown.

Embodiment 2

[0051] Mix 10g of azacitidine with 40ml of DMSO, heat to 90°C to dissolve the sample, slowly add 200mL of a mixed solvent consisting of methanol / n-heptanol = 1:1, continue stirring for 1h after the temperature drops to room temperature and filter, sample 70 After drying at ℃ for 24 hours, 9.1 g of a sample of crystal form I was obtained. The residual DMSO solvent was measured to be 1100 ppm, and the purity was greater than 99.9%. The XRD pattern and the attached figure 1 Basically the same.

Embodiment 3

[0053] Mix 1g of azacitidine with 8ml of DMSO, heat to 65°C to dissolve all the samples, slowly add 80ml of a mixed solution composed of ethanol / n-octanol=2:8, lower the temperature to room temperature and continue to stir for 1h to filter, then filter at 75°C Dry under vacuum for 20h to obtain 0.88g of the crystal form I sample, the DMSO solvent residue was measured to be 5722ppm, the XRD pattern and the attached figure 1 Basically the same.

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Abstract

The invention relates to a preparation method of an azacitidine crystal form I. The preparation method includes: using DMSO as a solvent and a mixed alcohol solvent as an anti-solvent. The crystal form prepared by the method is unitary, high in purity, free of crystal mixing, low in solvent residue and suitable for industrial application and production.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a method for preparing crystal form I of azacitidine. Background technique [0002] Azacitidine, also known as 5-azacytidine, chemical name: 1-(β-D-ribofuranosyl)-4-amino-1,3,5-triazin-2(1H)-one. In May 2004, azacitidine became the first drug approved by the U.S. FDA for the treatment of myelodysplastic syndrome (MDS). In December 2008, it was approved by the European Union and became the first drug in Europe that can significantly prolong the intermediate- 2 and the overall survival of high-risk MDS and AML patients, the drug was launched in Japan in March 2011. Azacitidine enjoys rare disease drug status in Europe, the United States and Japan. [0003] Azacitidine, a 5-aza analog of cytidine, belongs to a class of epigenetic antineoplastic agents known as hypomethylating drugs. Abnormal DNA methylation inactivates key genes regulating normal cell growth, differentiation a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/06A61P7/00A61P7/06A61P35/02
CPCC07H19/12C07H1/06C07B2200/13A61P7/00A61P7/06A61P35/02
Inventor 林青何雷余俊
Owner JIANGSU HANSOH PHARMA CO LTD
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