Polymorphic substances of decitabine and medical compositions

A polymorph, decitabine technology, applied in the directions of drug combinations, antipyretics, sugar derivatives, etc., can solve problems such as increase of related substances, failure to significantly reduce related substances, degradation and destruction, etc.

Active Publication Date: 2012-09-12
NANJING CAVENDISH BIO ENG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Because decitabine is insoluble in water or organic solvents such as dichloromethane, chloroform, dimethyl sulfide, 1,1,1-trichloroethane, hexane, acetone, acetonitrile, methanol, ethyl acetate, etc., even if It is also necessary to use a large amount of solvent under heating, which is not conducive to industrial scale preparation; in addition, the method described in patent application No. 116 can not significantly reduce the related substances in the product, and it is very easy to be heated for a long time or in the process of contacting with a solvent. Lead to degradation and damage, so that the related substances increase significantly
[0007] On the other hand, the teaching method for the preparation of polymorphs in this patent application document does not take into account that the use of two or more types of substances that are harmful to the human body (such as halogenated hydrocarbons and dimethyl sulfide, etc.) should be avoided as far as possible when the final product is synthesized. Organic solvents with high toxicity to reduce the adverse effects of residual organic solvents in the product on the human body

Method used

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  • Polymorphic substances of decitabine and medical compositions
  • Polymorphic substances of decitabine and medical compositions
  • Polymorphic substances of decitabine and medical compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0162] The preparation of embodiment 1 polymorph I

[0163] plan 1,

[0164] Add 50.0 g of decitabine into the reaction flask, add 100 ml of DMSO, and raise the temperature to about 35° C. while stirring. After dissolving, add 400ml of acetone and 400ml of water, stir for about 10min, then cool down to 0-5°C to grow crystals for 30min. Suction filtration, filter cake rinse with a small amount of acetone. The filter cake was dried under reduced pressure at 50°C and -0.095MPa, and was assisted with phosphorus pentoxide. 31.0 g of white solid was obtained. Yield: 62%.

[0165]

[0166] Scenario 2,

[0167] Add 50.0 g of decitabine into the reaction flask, add 750 ml of DMF, and raise the temperature to about 35° C. while stirring. After dissolving, add 3000ml of water, stir for about 30min and then filter with suction. The filter cake was rinsed with a small amount of acetone. The filter cake was dried under reduced pressure at 50°C and -0.095MPa, and was assisted with...

Embodiment 2

[0172] The preparation of embodiment 2 polymorph II

[0173] plan 1,

[0174] Add 50.0 g of decitabine into the reaction flask, add 750 ml of DMF, and raise the temperature to about 35° C. while stirring. After dissolving, add 1500ml of acetone, stir for about 10 minutes, then cool down to 0-5°C to grow crystals for 30 minutes. Suction filtration, filter cake rinse with acetone. The filter cake was dried under reduced pressure at 50°C and -0.095MPa, and was assisted with phosphorus pentoxide. 40.0 g of white solid was obtained. Yield: 80%.

[0175]

[0176] Scenario 2,

[0177] Add 50.0 g of decitabine into the reaction flask, add 750 ml of DMF, and raise the temperature to about 35° C. while stirring. After dissolving, add 1500ml of ethyl acetate, stir for about 10 minutes, then cool down to 0-5°C to grow crystals for 30 minutes. Suction filtration, filter cake rinse with ethyl acetate. The filter cake was dried under reduced pressure at 50°C and -0.095MPa, and was...

Embodiment 3

[0186] The preparation technology of embodiment 3 decitabine aseptic powder preparation:

[0187] Dissolve 50 grams of decitabine raw material in 250ml of dimethylformamide or dimethyl sulfoxide solution, heat to 40°C under stirring to dissolve, add activated carbon and stir for ten minutes, filter through a 0.45um microporous membrane Filtration, the filtrate is then filtered with a 0.22um microporous membrane, and the filtered filtrate is transferred to a sterile clean area;

[0188] Add about 2000ml of water or acetone or a mixture of water and acetone, add activated carbon and stir for ten minutes, filter through a 0.45um microporous membrane, then filter through a 0.22um microporous membrane, and transfer the filtered filtrate to a sterile Clean area;

[0189] Water or an organic solvent or a sterile mixed solution of water and an organic solvent is added dropwise to the above-mentioned sterile solution of decitabine dimethylformamide or dimethyl sulfoxide in about 15 mi...

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Abstract

The invention discloses polymorphic substances I and II of decitabine, and a preparation method and medical compositions thereof.

Description

technical field [0001] The present invention relates to a polymorphic form of a pharmaceutical compound, more specifically, to a polymorphic form of decitabine. In addition, the present invention also relates to a preparation method of the polymorphic form and a pharmaceutical composition thereof. Background technique [0002] Suberjian Co., Ltd. has recorded three polymorphs of decitabine in Chinese patent application CN200580029911.6 (application number, hereinafter referred to as patent application No. 116) and provided a preparation method of its polymorphs. The preparation method They are: [0003] Form A: slurry in dichloromethane or hexane solvent (ambient), 12 days, vacuum oven dry (ambient); slow cooling in methanol solvent, vacuum oven dry (ambient); in 2-propanol Slurry in solvent (50°C), 12 days, vacuum oven drying (ambient); [0004] Form B: Slurry in dichloromethane:methanol (1:1) solvent (ambient), flash evaporation; flash evaporation in 1,1,1,3,3,3-hexafluo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/12A61K31/706A61P35/00A61P29/00A61P27/02A61P9/00A61P7/06A61P25/00A61P17/00A61P9/12A61P37/00A61P33/00A61P19/08
Inventor 许永翔杨浩
Owner NANJING CAVENDISH BIO ENG TECH
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