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Fondaparinux sodium with low moisture and high purity and preparation method thereof

A fondaparinux sodium and water technology, applied in the field of chemical raw materials and its preparation, can solve the problems of infection of raw materials, inconvenient storage and transportation of raw materials, and breeding of bacteria in combination with water, so as to facilitate storage and transportation, increase stability, High safety effect

Active Publication Date: 2018-05-04
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Most of the freeze-drying processes reported in the pharmaceutical field are processes for preparing freeze-dried powder injections. There are few reports on the freeze-drying process of raw materials, and there is no report on the freeze-drying process of fondaparinux sodium at present; The bound water content is between 10% and 15%. If the solvent water used in the preparation process of fondaparinux sodium is not endotoxin-free water, it is easy to cause the bound water in the raw material to breed bacteria, thereby infecting the raw material, which is not convenient for raw material storage and transportation
[0008] Currently commercially available fondaparinux sodium has a content of 98%-99% and a moisture content of more than 10%. After detection by HPLC (high performance liquid chromatography, also known as high performance liquid chromatography), there is an impurity before the main peak, which is relatively The retention time is about 0.93, and according to long-term stability experiments, the impurity tends to increase during storage, and may not meet the requirements of drug quality standards after storage

Method used

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  • Fondaparinux sodium with low moisture and high purity and preparation method thereof
  • Fondaparinux sodium with low moisture and high purity and preparation method thereof
  • Fondaparinux sodium with low moisture and high purity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053](1) Pretreatment before freeze-drying: Dissolve 10.0 g of commercially available fondaparinux sodium (98.5% purity, 10% water) into 200 ml endotoxin-free purified water to prepare a solution with a concentration of 50 mg / ml. The solution is poured into a solvent filter and filtered. After the filtration is completed, the solution is poured into a tray and placed in a freeze dryer;

[0054] (2) Pre-freezing stage: lower the temperature of the freeze dryer partition to -45°C and keep it warm for 3 hours;

[0055] (3) Sublimation drying stage:

[0056] a) Raise the temperature of the separator from -45°C to -30°C within 1 hour, keep it warm for 1 hour, and set the vacuum degree to 0.1mbar;

[0057] b) Raise the temperature of the separator from -30°C to -25°C within 5 hours, keep it warm for 8 hours, and set the vacuum degree to 0.1mbar;

[0058] c) Raise the temperature of the separator from -25°C to 0°C within 10 hours, keep it warm for 3 hours, and set the vacuum degre...

Embodiment 2

[0065] Commercially available fondaparinux sodium is 10.0 g, with a purity of 98.2% and a water content of 15%.

[0066] The preparation method before the analysis and drying stage is the same as that in Example 1. Analytical drying stage The heating time during analytical drying was set at 3 minutes, and other conditions were the same as in Example 1.

[0067] Obtain fondaparinux sodium, the purity is 99.1%, the water content is 4.980%, its DSC sees figure 2 .

Embodiment 3

[0069] (1) Pretreatment before freeze-drying: Dissolve 100.0 g of commercially available fondaparinux sodium (99.0% purity, 13% moisture) into 2000 ml endotoxin-free purified water to prepare a solution with a concentration of 50 mg / ml. The solution is poured into a solvent filter and filtered. After the filtration is completed, the solution is poured into 4 trays and placed in a freeze dryer;

[0070] (2) The pre-freezing stage and (3) the sublimation drying stage are the same as in Example 1;

[0071] (4) Analytical drying stage: during analytical drying, the heating time is set to 1 minute, the set temperature is 35°C, the holding time is 10 hours, and the vacuum degree is set to 0mbar;

[0072] The moisture content that obtains fondaparinux sodium is 5.231%, and purity is 99.3%, and its DSC sees image 3 .

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Abstract

The invention discloses low-moisture high-purity fondaparinux sodium and a preparation method thereof. During a freezing process, by adjusting a heating rate, heat preservation time and vacuum degree in sublimation and secondary drying stages, the problems that the fondaparinux sodium is higher in moisture content, low in purity, and difficult to store, and the raw material of the fondaparinux sodium is easy to pollute by bacteria are solved. Meanwhile, an impurity in front of a main peak, which cannot be removed, is removed in a column chromatography stage, and the fondaparinux sodium obtained with the preparation method is low in impurity content and high in purity.

Description

technical field [0001] The invention belongs to the technical field of chemical raw materials and preparation thereof, and in particular relates to low-moisture and high-purity fondaparinux sodium and a preparation method thereof. Background technique [0002] Fondaparinux sodium (Fondaparinux sodium) is the first chemically synthesized antithrombotic drug that selectively inhibits factor Xa developed by Sanofi in France. It is a highly selective FXa inhibitor and was later transferred to GlaxoSmithKline. It was launched in Europe for the first time in 2001, and then in the United States in 2002. In 2008, Fondaparinux Sodium Injection was approved by the State Food and Drug Administration (CFDA) of GlaxoSmithKline to enter the Chinese market. The product name is: Android (ARIXTRA), for the prevention of venous thromboembolic events in patients undergoing major lower extremity orthopedic surgery such as hip fracture, major knee surgery or hip replacement. [0003] Fondaparin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/04C07H1/06
Inventor 郑敏徐仲军黄晔谢厅杨静陈雷
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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