Preparation method of high-purity M2 crystal form mycophenolate sodium

A mycophenolate sodium, high-purity technology, applied in the field of preparation of high-purity M2 crystal form mycophenolate sodium, can solve the problem of not meeting the quality requirements well, not mentioning the influence of crystal form transformation, and not being suitable for preparation production Use and other issues to achieve the effect of easy industrial scale promotion and application, low cost and mild conditions

Active Publication Date: 2021-04-13
GUANGDONG BLUE TREASURE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] In the technology disclosed above, either the obtained M2 crystal form is not suitable for pharmaceutical requirements, or the bulk density of the obtained M2 crystal form of mycophenolate sodium is lower than 0.3g / ml, which is not suitable for the production and use of preparations
In addition, none of the disclosed technologies mentions the influence of drying process control on crystal transformation
More importantly, during the fermentation and extraction and purification of mycophenolate sodium, the by-product Z isomer (i.e. mycophenolate sodium EP impurity B) and mycophenolate sodium EP impurity A will be generated simultaneously. These two impurities are The key impurity in mycophenolate sodium, and the disclosed technology does not mention how to effectively remove it. The mycophenolate sodium Z isomer and mycophenolate sodium EP impurity A content obtained by the disclosed technology cannot well meet the pharmacopoeia Quality requirement not higher than 0.10% in

Method used

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  • Preparation method of high-purity M2 crystal form mycophenolate sodium

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Embodiment 1

[0050] Embodiment 1 A kind of preparation method of high-purity M2 crystal form mycophenolate sodium

[0051] The preparation method of described high-purity M2 crystal form mycophenolate sodium, comprises the steps:

[0052] S1. Use sodium carbonate to adjust the pH of 5L mycolic acid fermentation broth to 11, stir at room temperature for 2 hours, filter to obtain the filtrate, wash with water with pH 11, collect the top washing liquid, combine the top washing liquid and the filtrate, and obtain 5L of mycolic acid containing Mixture A of sodium phenate;

[0053] S2. Cool the mixed liquid A obtained in step S1 to 7°C, add sulfuric acid solution to adjust the pH to 4, let it stand for 1 hour, and filter to obtain 57g of precipitate;

[0054] S3. Dissolve 57g of the precipitate obtained in step S2 in 1000ml of methyl isobutyl ketone at 55°C to obtain a solution; add 4.6g of activated carbon to the solution, stir at 50°C for 20 minutes, and Filter the diatomaceous earth layer, ...

Embodiment 2

[0058] Embodiment 2 A kind of preparation method of high-purity M2 crystal form mycophenolate sodium

[0059] The preparation method of described high-purity M2 crystal form mycophenolate sodium, comprises the steps:

[0060] S1. Adjust the pH of 5L of mycolic acid fermentation broth to 10 with sodium carbonate, stir at room temperature for 2 hours, filter to obtain the filtrate, wash with pH 10 water, collect the top wash, and combine the top wash and filtrate to obtain 5.5 L of wheat-containing Mixture A of Sodium Corfenol;

[0061] S2. Cool the mixed solution A obtained in step S1 to 6° C., add sulfuric acid solution to adjust the pH to 3, let it stand for 1 hour, and filter to obtain 55 g of precipitate;

[0062] S3. Dissolve 55g of the precipitate obtained in step S2 in 1650ml of butyl acetate at 40°C to obtain a solution; add 4.5g of activated carbon to the solution, stir at 40°C for 30 minutes, and pass through a diatomite layer Filter, then wash the diatomite with 11...

Embodiment 3

[0066] Embodiment 3 A kind of preparation method of high-purity M2 crystal form mycophenolate sodium

[0067] The preparation method of described high-purity M2 crystal form mycophenolate sodium, comprises the steps:

[0068] S1. Adjust the pH of 5L of mycolic acid fermentation broth to 12 with sodium carbonate, stir at room temperature for 2 hours, filter to obtain the filtrate, wash with pH 12 water, collect the top wash, combine the top wash and filtrate to obtain 5.5 L of wheat-containing Mixture A of Sodium Corfenol;

[0069] S2. Cool the mixed solution A obtained in step S1 to 9°C, add sulfuric acid solution to adjust the pH to 5, let it stand for 1 hour, and filter to obtain 55g of precipitate;

[0070] S3. Dissolve 55g of the precipitate obtained in step S2 in 1100ml of ethyl acetate at 60°C to obtain a solution; add 5.5g of activated carbon to the solution, stir at 60°C for 15 minutes, and pass through a diatomite layer Filter, then wash the diatomite with 83ml of e...

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Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of high-purity M2 crystal form mycophenolate sodium. According to the high-purity M2 crystal form mycophenolate sodium provided by the invention, a preparation method for directly obtaining mycophenolate sodium by taking mycophenolic acid fermentation liquor as a raw material is adopted, the technological process is simple and short, the production efficiency is high, the yield is high, the cost is low, and an impurity Z isomer and a mycophenolate sodium EP impurity A generated in the mycophenolate sodium fermentation and purification process can be effectively removed; and the impurity content of the high-purity M2 crystal form mycophenolate sodium is lower than 0.10%, and the high-purity M2 crystal form mycophenolate sodium is high in safety.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of high-purity M2 crystal form mycophenolate sodium. Background technique [0002] Mycophenolate Sodium (trade name of the original drug "Miff") is another drug with mycophenolic acid (also known as mycophenolic acid) as the active drug after mycophenolate mofetil (trade name of the original drug "Xiexi") Component of immunosuppressant, which is metabolized in the body to produce mycophenolic acid (MPA). [0003] Xiaoxi was approved by the US FDA for kidney transplantation in May 1995, and has been approved for heart transplantation and liver transplantation successively. In 1997, it was approved by the Chinese SFDA for listing, and has entered the National Medical Insurance List (Class A) and the Essential Drug List. The listed dosage forms include injections, capsules, tablets, suspensions and dispersible tablets. [0004] Mifu wa...

Claims

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Application Information

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IPC IPC(8): C07D307/88
CPCC07D307/88C07B2200/13
Inventor 潘京陈继敏朱敏杰程晓东黄频乐方锐旋
Owner GUANGDONG BLUE TREASURE PHARMA
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