Reference compound for controlling quality of fondaparinux sodium

A reference compound, the technology of fondaparinux sodium, which is applied in the field of medicine, can solve the problems of low impurity content, large molecular weight of impurities, and difficulty in preparation and separation, and achieve the effect of improving quality standards

Active Publication Date: 2015-09-16
TIANJIN CHASE SUN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to the similar polarity between fondaparinux sodium and impurities, the separation of impurities is extremely difficult; and the content of impurities is very small, it is difficult to prepare and separate by ordinary methods
In addition, due to the large molecular weight and complex structure of impurities, a certain amount of impurities is required to meet the analysis and detection of HPLC, MS and NMR. Therefore, it is difficult to prepare and separate enough impurities for structural identification

Method used

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  • Reference compound for controlling quality of fondaparinux sodium
  • Reference compound for controlling quality of fondaparinux sodium
  • Reference compound for controlling quality of fondaparinux sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 Reference compound A (Rrt0.45):

[0049] Accurately weigh 1.5 g of pure fondaparinux sodium in a 500 ml round-bottomed flask, add 300 ml of 1 mol / L HCl aqueous solution to it, and stir in an oil bath at 40°C for 18 hours to generate acid degradation reference compound A (Rrt0. 45). Add 1 mol / L NaOH to adjust the pH to alkaline, desalt with Sephadex G-25 chromatographic column, and concentrate to dryness under reduced pressure to obtain the reference compound A crude product.

[0050] Weigh the crude product of reference compound A (Rrt0.45), dissolve it in purified water, use a high-performance preparative liquid chromatograph, select a strong base type anion exchange chromatographic column DIONEX CarboPac TMPA1 (250 × 9mm), and load a small amount of time. Separation, flow rate is 5.0ml / min, ultraviolet wavelength is 210nm, mobile phase A, B carry out gradient elution (mobile phase A: 117g / L aqueous sodium chloride solution, mobile phase B: water for injecti...

Embodiment 2

[0061] Example 2 Reference compound B (Rrt0.54):

[0062] Accurately weigh 1.5g of pure Fondaparinux sodium and 2.5g of NaCl into a 500ml soda-lime glass bottle, add 300ml of purified water to it, and seal it with an aluminum-plastic composite cover. High temperature destroyed reference compound B (Rrt 0.54). It was desalted by Sephadex G-25 chromatography, and concentrated to dryness under reduced pressure to obtain the reference compound B crude product.

[0063] The reference compound B (Rrt0.54) crude product was weighed, dissolved in purified water, and a high-efficiency preparative liquid chromatograph was used. The preparation conditions and separation steps were as shown in Example 1 to obtain a white solid reference compound B (Rrt0.54). 54).

[0064] Hydrogen and carbon spectrum data of reference compound B (Rrt0.54)

[0065]

[0066]

[0067] High-resolution mass spectrometry data of reference compound B (Rrt0.54)

[0068]

[0069] In the hydrogen spect...

Embodiment 3

[0071] Example 3 Reference compound C (Rrt0.77):

[0072] Accurately weigh 1.0g of pure fondaparinux sodium in a 500ml round-bottomed flask, add 200ml of 1 mol / L HCl aqueous solution to it, and stir at room temperature (20°C) for 65h to generate acid degradation reference compound C (Rrt0. 77). Add 1 mol / L NaOH to adjust the pH to alkaline, desalt with Sephadex G-25 chromatography column, and concentrate to dryness under reduced pressure to obtain the reference compound C crude product.

[0073] The reference compound C (Rrt0.77) crude product was weighed, dissolved in purified water, and a high-efficiency preparative liquid chromatograph was adopted. The preparation conditions and separation steps were as shown in Example 1 to obtain a white solid reference compound C (Rrt0.77). 77).

[0074] Hydrogen and carbon spectra of reference compound C (Rrt0.77)

[0075]

[0076]

[0077] High-resolution mass spectrometry data of reference compound C (Rrt0.77)

[0078]

...

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Abstract

The invention relates to the technical field of medicines and relates to a reference compound for controlling quality of fondaparinux sodium. Relevant reference compounds of fondaparinux sodium include a reference compound A (Rrt0.45), a reference compound B (Rrt0.54), a reference compound C (Rrt0.77), a reference compound D (Rrt0.93) and a reference compound E (Rrt1.20).

Description

technical field [0001] The technical field of medicine of the present invention relates to a quality detection method for fondaparinux sodium raw material medicine, and five related reference compounds. technical background [0002] Fondaparinux sodium is the first indirect inhibitor of antithrombin-dependent factor Xa developed and produced by Sanofi Winthrop Industrie in France. [0003] Fondaparinux sodium is a heparin pentasaccharide drug, its English name is Fondaparinux sodium, and its Chinese chemical name is: methyl O-(2-deoxy-6-O-sulfonic acid group-2-sulfonamido-α -D-glucopyranose)-(1→4)-O-(β-D-glucopyranosic acid)-(1→4)-O-(2-deoxy-3,6-O-disulfonic acid yl-2-sulfonamido-α-D-glucopyranose)-(1→4)-O-(2-O-sulfonamido-α-L-iduronic acid)-(1→ 4)-2-Deoxy-6-O-sulfonic acid group-2-sulfonamido-α-D-glucopyranoside ten sodium salt, the chemical structure is as follows (denoted by DEFGH from left to right 5 monosaccharides respectively) : [0004] [0005] Fondaparinux s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/00G01N30/88
Inventor 姚小青孙长海韩芙蓉干浩韩建闫建和孙福亮童燕周喜泽李振重
Owner TIANJIN CHASE SUN PHARM CO LTD
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