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Method for preparing hydroxypropyl-beta-cyclodextrin

A cyclodextrin and hydroxypropyl technology, applied in the field of medicine, can solve the problems of inappropriate use of pharmaceutical excipients, difficult control of drug quality, increase in impurity content, etc., and achieve a narrow range of product substitution, shorten drying time, batch effects with small differences in properties

Active Publication Date: 2011-05-04
石药集团中诺药业(石家庄)有限公司
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Problems solved by technology

[0008] The technology disclosed in Chinese patent 2009-09-02 with the publication number CN101519460 and the name "Synthesis method of hydroxypropyl-β-cyclodextrin" requires washing with ethanol, extraction with acetone, and a large amount of organic solvents. The use of hydroxypropyl-β-cyclodextrin will inevitably cause environmental pollution and residues in the product. In addition, the substitution degree of hydroxypropyl-β-cyclodextrin prepared by this method is between 4.6-7.8, which is not suitable for use as pharmaceutical excipients.
[0009] In August 2010, "Hebei Chemical Industry" published an article about the synthesis method of hydroxypropyl-β-cyclodextrin. The method stated that β-cyclodextrin and 1,2-propylene oxide were synthesized in the presence of sodium hydroxide In the step of carrying out the reaction, assuming that the water content of β-cyclodextrin is ≤10%, the molar ratio of sodium hydroxide, β-cyclodextrin and 1,2-propylene oxide is 9.4~10.5:1:8.9~9.9, If the water content of β-cyclodextrin is more than 10%, the molar number of sodium hydroxide and 1,2-propylene oxide is larger, and the substitution degree of hydroxypropyl-β-cyclodextrin generated under this ratio is between Between 4.0 and 5.0, the range is wide, the property is unstable, and the quality of the drug is not easy to control; in addition, the method uses ion exchange resin for purification, which will cause a small amount of decomposition of hydroxypropyl-β-cyclodextrin and increase the impurity content ;Using the freeze-drying method to dry, the time required is generally more than 20 hours, the time is long, and the feed liquid needs to be concentrated before freeze-drying, which is cumbersome to operate

Method used

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  • Method for preparing hydroxypropyl-beta-cyclodextrin

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Experimental program
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Embodiment 1

[0025] (1) Etherification reaction: In a 5000mL round bottom flask, add 2160mL of water for injection and 216g of sodium hydroxide, stir to dissolve, cool down to 5-10°C, add 681g of β-cyclodextrin (after drying), and stir until the solid is completely After dissolving, slowly add 315mL of 1,2-propylene oxide dropwise. During the dropping process, the temperature is controlled at 5-8°C, and the dropping time is 3.5 hours. After the dropwise addition is completed, continue to stir at 5-10°C for 3 hours. ;

[0026] (2) Neutralization: Add concentrated hydrochloric acid dropwise to the reaction solution obtained in step (1) to adjust the pH value to 7.1, and the obtained solution is set aside;

[0027] (3) Decolorization: Add 20 g of activated carbon to the solution obtained in step (2), control the temperature at 20°C to 25°C, stir for 30 minutes, filter to remove carbon, and use the filtrate for later use;

[0028] (4) Desalting and purification: perform nanofiltration on the ...

Embodiment 2

[0032] (1) Etherification reaction: In a 5000mL round bottom flask, add 1800mL of water for injection, 216g of sodium hydroxide, stir to dissolve, cool down to 5-10°C, add 681g of β-cyclodextrin (after drying), and stir until the solid is completely After dissolving, slowly add 336mL of 1,2-propylene oxide dropwise. During the dropping process, the temperature is controlled at 8-12°C, and the dropping time is 3.5 hours. After the dropwise addition is completed, continue to stir at 5-10°C for 3 hours. The obtained reaction solution is used for later use. ;

[0033] (2) Neutralization: Add concentrated hydrochloric acid dropwise to the reaction solution obtained in step (1) to adjust the pH value to 7.2, and the obtained solution is set aside;

[0034] (3) Decolorization: Add 20 g of activated carbon to the solution obtained in step (2), control the temperature at 20°C to 25°C, stir for 30 minutes, filter to remove carbon, and use the filtrate for later use;

[0035] (4) Desalt...

Embodiment 3

[0039](1) Etherification reaction: In a 5000mL round bottom flask, add 2160mL of water for injection and 216g of sodium hydroxide, stir to dissolve, cool down to 5-10°C, add 681g of β-cyclodextrin (after drying), and stir until the solid is completely After dissolving, slowly add 357mL of 1,2-propylene oxide dropwise. During the dropping process, the temperature is controlled at 8-12°C, and the dropping time is 3.5 hours. After the dropwise addition is completed, continue to stir at 5-10°C for 3 hours. The obtained reaction solution is used for later use. ;

[0040] (2) Neutralization: Add concentrated hydrochloric acid dropwise to the reaction solution obtained in step (1) to adjust the pH value to 7.2, and the obtained solution is set aside;

[0041] (3) Decolorization: Add 20 g of activated carbon to the solution obtained in step (2), control the temperature at 20°C to 25°C, stir for 30 minutes, filter to remove carbon, and use the filtrate for later use;

[0042] (4) Desa...

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Abstract

The invention discloses a method for preparing hydroxypropyl-beta-cyclodextrin, which comprises the steps of etherification, neutralization, decoloring, nanofiltration, resin purification, and spray drying. The method of the invention is small in pollution, and the yield in weight is more than 80 percent; meanwhile, the product prepared by using the method of the invention is narrow in substituted ratio range and low in impurity content, and can be used as a pharmaceutic adjuvant.

Description

technical field [0001] The invention relates to a method for preparing pharmaceutical auxiliary material hydroxypropyl-β-cyclodextrin, which belongs to the technical field of medicine. Background technique [0002] Hydroxypropyl-β-cyclodextrin is a product in which the hydrogen atom of the hydroxyl group on the glucose unit in the β-cyclodextrin molecule is replaced by a hydroxypropyl group. Compared with the parent cyclodextrin, hydroxypropyl-β-cyclodextrin is easily soluble in water, with a solubility of >50% at room temperature. When its concentration is <40%, it has good fluidity and is not viscous; it is stable to light and heat , can withstand 80 ℃, 4500lux light for 10 days; its aqueous solution can be autoclaved and stable in alkaline medium; its toxicity is small, it is basically not broken down and accumulated in the human body, and most of it is excreted with feces after oral administration , Parenteral administration is basically excreted with urine; h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/16A61K47/40
Inventor 胡利敏胡艳茹王国胜颜喜亚陈猛郎艳领张文生
Owner 石药集团中诺药业(石家庄)有限公司
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