Preparation method for lipoic acid polymer impurities and detection method for lipoic acid polymer impurities

A technology of d-lipoic acid and its composition, which is applied in the field of preparation and detection of lipoic acid polymer impurities, can solve the problems of undetectable polymer impurities, adverse reactions, curative effect and safety hazards, etc., and achieves simple operation, Easy to obtain raw materials and high detection sensitivity

Active Publication Date: 2016-03-30
河北迈科生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In view of the unstable characteristics of lipoic acid that is easily polymerized, its polymer impurities are likely to be mixed with these unknown impurities and not controlled separately, or not detected at all under the existing chromatographic conditions, which may cause polymer impurities to trigger Safety ris

Method used

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  • Preparation method for lipoic acid polymer impurities and detection method for lipoic acid polymer impurities
  • Preparation method for lipoic acid polymer impurities and detection method for lipoic acid polymer impurities
  • Preparation method for lipoic acid polymer impurities and detection method for lipoic acid polymer impurities

Examples

Experimental program
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Example Embodiment

[0051] Example 1 Preparation of dextro-lipoic acid oligomer

[0052] Dissolve 10g of dextro-lipoic acid monomer in 200mL of anhydrous dioxane, add 0.5g of azobisisobutyronitrile in catalytic amount, stir at 35-40℃ for 15min, then quickly cool to 10-15℃ In the meantime, keep stirring for 1h, add about 10mL of 5% dilute hydrochloric acid to terminate the reaction; put the reaction solution into a mixture of 400mL ethyl acetate and 400mL water, stir and separate into layers, take the ethyl acetate layer, and then use ethyl acetate for the water layer Extract twice with 200mL, combine the organic layers, concentrate at least the volume of about 50mL, add 300mL of isopropyl ether, precipitate a pale yellow semi-solid, filter, and vacuum dry at 30±2℃ for 10h to obtain the above-mentioned dextro-lipoic acid oligomer The composition is about 7.5g, the yield is 75%, and the HPLC purity is 98.5%.

Example Embodiment

[0053] Example 2 Purification of dextro-lipoic acid oligomer

[0054] Suspend 5 g of the crude dextro-lipoic acid oligomer obtained in Example 1 in 40 mL of methyl isoamyl ketone, stir and disperse, raise the temperature to between 45-50°C, and slowly add ethanol / water with a volume ratio of 1:1 The mixed solvent is about 15mL, keep warm and stir until it is completely dissolved, filter while hot, slowly reduce the temperature to 0-5℃, collect the precipitated light yellow semi-solid, and dry it under vacuum at 30±2℃ for 12h to obtain 3.5g refined product with purity of 99.5%.

Example Embodiment

[0055] Example 3 Preparation of refined product of dextro-lipoic acid oligomer

[0056] Dissolve 8g of dextro-lipoic acid monomer in 180mL of anhydrous tetrahydrofuran, add 0.4g of azobisisobutyronitrile in a catalytic amount, stir at 35-40℃ for 20min, then quickly cool down to 10-15℃ and keep warm Stir for 1 hour, add 20 mL of 5% dilute phosphoric acid to terminate the reaction; put the reaction solution into a mixture of 400 mL of ethyl acetate and 400 mL of water, stir to separate the layers, take the ethyl acetate layer, and extract the water layer twice with 200 mL of ethyl acetate. Combine the organic layers, concentrate at least the volume of about 40mL, add 250mL of isopropyl ether, precipitate a pale yellow semi-solid, filter, and vacuum dry at 30±2°C for 12h to obtain the composition of the dextro-lipoic acid oligomer, about 5.9 g, the yield is 78%, and the HPLC purity is 98.6%; the resulting product is further refined, that is, the above 5g sample is suspended in 45 mL...

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Abstract

The present invention relates to the field of pharmaceutical technology, particularly to a preparation method for oligomer impurities of dextro-lipoic acid and analysis detection methods for the oligomer impurities of dextro-lipoic acid. The preparation method for the oligomer impurities comprises: taking dextro lipoic acid as a monomer; dissolving the monomer in an organic solution with low concentration; under catalysis of a free-radical initiator, effectively controlling the polymerization degree for condensation; refining and obtaining a high purity dextro lipoic acid oligomer, the HPLC purity degree of which is higher than 98.5%, by a recrystallization system of water, ethanol and methyl isoamyl ketone so as to facilitate use applications of an impurity reference substance. The present invention also provides an analysis method for measuring the oligomer impurities in the lipoic acid bulk drug or preparation. The method adopts a means of high molecular exclusion chromatography, wherein the mobile phase is phosphate buffer and acetonitrile (97: 3), the detection wavelength is 254 nm, the flow velocity is 0.8 mL/min, the temperature of the column is 25 DEG C, and the injection quantity is 20 [mu]L. The establishment of the analysis method has important significance of qualitative, quantitative analysis and control of the polymer impurities in the lipoic acid bulk drug and preparation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation and detection method of a lipoic acid polymer impurity. Background technique [0002] R-lipoic acid, (English name R (+) Alpha Lipoic Acid) its molecular formula: C 8 h 14 o 2 S 2 , the molecular weight is 206.33, and the structural formula is as follows: [0003] [0004] Lipoic acid contains a disulfide five-membered ring structure with high electron density and high free radical reaction ability. It is known as "universal antioxidant" and can remove free radicals in the body, promote the body to use glucose to synthesize vitamin C, and effectively remove Melanin also has anti-inflammatory and anti-aging effects. It is currently widely used in the prevention and treatment of heart disease, diabetes, liver disease and Alzheimer's disease. [0005] Clinically, the current varieties of lipoic acid are mainly used to treat paresthesia caused by d...

Claims

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Application Information

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IPC IPC(8): C07C319/22C07C323/52G01N30/02
CPCC07C319/22C07C323/52G01N30/02G01N2030/027
Inventor 曹卫王继芳包玉胜闵涛柏丹丹
Owner 河北迈科生物科技有限公司
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