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Online control method of citicoline sodium crystallization process

A technology of citicoline sodium and control method, which is applied in the field of organic drug synthesis, can solve the problems of not getting ideal results, lack of research on the crystallization process, etc., and achieve good color, increase distribution range, increase uniformity and drug efficacy

Inactive Publication Date: 2020-08-04
NANTONG QIUZHIYOU BIOSCI & BIOTECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Then adding solvent ethanol etc. for crystallization, but due to the lack of research on the crystallization process, ideal results are often not obtained, and even viscous oil, amorphous powder or crystals with a wide particle size distribution can be obtained

Method used

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  • Online control method of citicoline sodium crystallization process
  • Online control method of citicoline sodium crystallization process
  • Online control method of citicoline sodium crystallization process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] One, the preparation of CDP-CNa reaction solution

[0050] Add 30g 5'-cytidylic acid, 69g phosphorylcholine, 100g glucose, 8.25g magnesium sulfate and 75g yeast in the reaction tank, and react at a temperature of 33°C for 10 to 12 hours, and the reaction molar conversion rate is 60% (ie The weight conversion reaches 94%). After the reaction, the reaction liquid was lowered to room temperature, and the yeast was filtered out. The filtrate was adsorbed and eluted by activated carbon and then separated by anion resin combined chromatography to obtain a CDP-CNa separation liquid with a concentration of 50 g / L.

[0051] 2. Concentration of CDP-CNa separation liquid

[0052] Adjust the above 50g / L CDP-CNa separation liquid with 5mol / L HCl to pH=6~7, then vacuum concentrate to 250g / L, and then use a 0.22μm filter membrane to obtain the CDP-CNa concentrate Microfiltration to obtain a CDP-CNa filtrate with a salt content of 3% and a concentration of 250 g / L.

[0053] 3. Low c...

Embodiment 2

[0057] One, the preparation of CDP-CNa reaction solution

[0058] Add 30g 5'-cytidylic acid, 69g phosphorylcholine, 100g glucose, 8.25g magnesium sulfate and 75g yeast in the reaction tank, and react at a temperature of 33°C for 10 to 12 hours, and the reaction molar conversion rate is 60% (ie The weight conversion reaches 94%). After the reaction, the reaction solution was lowered to room temperature, and the yeast was filtered out. The filtrate was eluted by active carbon adsorption and separated by combined chromatography of cationic resin and anionic resin to obtain a CDP-CNa separation solution with a concentration of 100g / L.

[0059] 2. Concentration of CDP-CNa separation liquid

[0060] Adjust the above 100g / L CDP-C Na separation liquid with 5mol / L HCl to pH = 6-7, then vacuum concentrate to 450g / L, and then use a 0.22μm filter membrane to obtain the CDP-C Na concentrate Microfiltration to obtain a CDP-CNa filtrate with a salt content of 3.5% and a concentration of 45...

Embodiment 3

[0065] One, the preparation of CDP-CNa reaction solution

[0066] Carry out operation with embodiment 1.

[0067] 2. Concentration of CDP-CNa separation liquid

[0068] Carry out operation with embodiment 1.

[0069] 3. Particle control of CDP-CNa

[0070] Take 100mL of the above-mentioned CDP-CNa filtrate with a concentration of 250g / L and add it to a 500mL crystallization bottle, raise the temperature to 45°C, keep the stirring speed at 120r / min, and add ethanol at a rate of SV1.5, when the ethanol concentration in the system is 65% (volume percent), add 0.75 gram (3%) CDP-CNa seed crystal, grow crystal 30min, then continue to feed ethanol with the speed of SV1.5 to the ethanol concentration in the system is 75% (volume percent), grow crystal 30min After cooling down to room temperature at 10°C / h, the solid was vacuum-filtered and dried by infrared for 2 hours or under reduced pressure for 4-6 hours, and the product obtained was CDP-CNa crystal.

[0071] The calculated y...

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Abstract

The invention discloses an online control method of a citicoline sodium crystallization process. The method is characterized by adding a solventing-out agent into a citicoline sodium concentrate whichis subjected to vacuum concentration to 200-450g / L; adding a CDP-C Na crystal seed; and growing the crystal for 30-60 minutes, then cooling, and repeatedly heating and cooling to recrystallize formedcrystal nucleus for multiple times so as to obtain a CDP-C Na crystal with controllable granularity and distribution. Compared with the prior art, by using the method of the invention, there are advantages of a good color and crystal form, and an ideal particle size and distribution range; and through slow cooling and repeated heating / cooling crystal growing, the distribution range is effectivelyenlarged, fine particles are reduced, the CDP-C Na crystals with controllable particle size and distribution are obtained, and mixing uniformity and a drug effect of the CDP-C Na crystals and other auxiliary materials are further improved.

Description

technical field [0001] The invention relates to the technical field of organic medicine synthesis, in particular to an online control method for the crystallization process of citicoline sodium. Background technique [0002] Citicoline sodium (CDP-CNa), like many nucleotide substances, is difficult to crystallize. Compared with other general organic compounds, this kind of substance was discovered later and has less experience accumulation. It is obviously far from meeting the requirements of the times to control production solely by experience or classic test data. Observing, analyzing or exploring conditions according to conventional methods, because you can't really grasp the laws, often get twice the result with half the effort, and it is difficult to obtain ideal results. But differences in crystalline quality, particle size and their size distribution range have a major impact on the quality of products, especially pharmaceuticals. For example: dissolution rate, bulk...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/74G01N15/02C07H19/10C07H1/06
CPCG01N30/02G01N30/06G01N30/74G01N15/0227C07H19/10C07H1/06
Inventor 张艳邱蔚然陈修足周洁张菁
Owner NANTONG QIUZHIYOU BIOSCI & BIOTECH