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Preparation method of lipoic acid impurity H

A lipoic acid and impurity technology, which is applied in the field of preparation of lipoic acid impurity H, can solve problems such as the large difference between the prescription process and product quality control level, unfavorable product quality control supervision, unstable high-temperature sterilization of lipoic acid injection, etc. To meet the needs of quality control, the effect of high purity

Inactive Publication Date: 2018-09-25
SICHUAN ZHIQIANG MEDICINE SCI & TECH DEV LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since lipoic acid is almost insoluble in water, lipoic acid injection has the characteristics of unstable high-temperature sterilization. As a result, different manufacturers of lipoic acid injection have different prescriptions for marketed products, and the prescription process and product quality control level are quite different, which is not conducive to product quality. Quality Control and Supervision by Drug Administrations

Method used

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  • Preparation method of lipoic acid impurity H
  • Preparation method of lipoic acid impurity H
  • Preparation method of lipoic acid impurity H

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Confirmation of the lipoic acid impurity H of embodiment 1 present invention

[0027] ①Refer to the known impurities recorded in the lipoic acid API in the European Pharmacopoeia (EP) as follows:

[0028]

[0029] ② Through the analysis and location research of the degraded impurities in the preparation process of lipoic acid raw materials, the impurities C~G that may be produced in the finished lipoic acid injection were sorted out, and the impurities C were degraded impurities in the preparation process of lipoic acid raw materials, and the impurities D~G It is an oxidized impurity in the finished product of lipoic acid raw material medicine. The strong degradation test analyzes the source of the impurity including photodegradation, oxidative degradation and high temperature degradation. For the specific location map, see figure 1 . At the same time, it was also found that another unknown impurity whose source and location cannot be known, as indicated by the red ...

Embodiment 2

[0030] The preparation of embodiment 2 lipoic acid impurity H of the present invention

[0031] Preparation of impurity H reaction equation:

[0032]

[0033] Add 10.0g of lipoic acid and 50ml of dried chloroform into a 500ml three-necked flask. Stir to dissolve, add 9.43g of carbonyldiimidazole, and stir at 20-30°C for 30min. After the temperature of the system was lowered to 0-4°C, 17.85 g of ethylenediamine was dissolved in 90 ml of dried chloroform, and then added dropwise to the reaction system. After the feeding is completed, the temperature is raised to 20-30° C. and the temperature is controlled for 8-10 hours until the reaction of the intermediate product is complete.

[0034] After the reaction was complete, the reaction solution was washed three times with 50 ml of 1 mol / L sodium hydroxide solution. After adding 50ml of purified water, add 0.05mol / L hydrochloric acid to adjust the pH to 2.5. Stir for 5 minutes, filter to remove incompatible substances, and the...

Embodiment 3

[0038] Embodiment 3 Preparation process parameter selection test of lipoic acid impurity H of the present invention

[0039] Comparative test one, the amount of raw material input is shown in the table below, and all the other operating steps are completely the same as embodiment 2:

[0040]

[0041] Contrast test 2, after the reaction is complete, whether to adjust the pH value and the pH value range during the washing process are as follows, and the rest of the operation steps and raw material dosage are the same as the above process:

[0042]

2mol / L hydrochloric acid to adjust pH

3mol / L sodium hydroxide to adjust pH

Finished product purity (%)

Example 1

2.5

12

95

Example 3

2

12

95

Example 4

3

11.5

92

Example 5

3

12

93

Comparative example 6

——

——

23

Comparative example 7

——

11

45

Comparative example 8

2.5

——

39

Comparative example 9

...

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Abstract

The invention provides a preparation method of a lipoic acid impurity H. The preparation method comprises the following steps: a, after stirring and dissolving lipoic acid and chloroform, adding carbonyl diimidazole and stirring at 20 to 30 DEG C; b, cooling to 0 to 4 DEG C and dissolving ethylenediamine in the chloroform; then dropwise adding a solution into a reaction system of step a; c, raising the temperature to 20 to 30 DEG C and controlling the temperature to react for 8 to 10 hours until an intermediate-state product reacts completely; d, after the product reacts completely, washing awashing solution with a 1mol / L sodium hydroxide solution; after adding purified water, adding 0.05mol / L acid to regulate the pH (Potential of Hydrogen) to 2 to 3; after stirring and filtering to remove insoluble substances, carrying out liquid separation; adding the chloroform into a water phase and then adding a 0.1mol / L sodium hydroxide solution to regulate the pH to 11 to 12 and stirring; aftercarrying out the liquid separation, washing an organic phase with a saturated saline solution; drying the organic phase with anhydrous sodium sulfate; filtering to remove the sodium sulfate; decompressing, distilling and concentrating the solution until the solution is dry, so as to obtain the lipoic acid impurity H. According to the preparation method provided by the invention, the new impurityH in the lipoic acid is confirmed; the invention provides the preparation method of the impurity; impurity mass spectrographic analysis of lipoic acid injection is completed. The impurity H prepared by the method is a powdery solid and has high purity; the requirements on quality control of the lipoic acid injection can be met.

Description

technical field [0001] The invention relates to a preparation method of lipoic acid impurity H. Background technique [0002] Lipoic acid, also known as α-lipoic acid, is a vitamin-like substance with strong antioxidant activity. Germany is the first country to clinically use lipoic acid to treat diabetic neuropathy, and it has a history of more than 40 years. At present in our country, many lipoic acid products have also been clinically used to treat diabetes and related complications, such as lipoic acid injection (specification: 12ml: 300mg) as a prescription drug for the clinical treatment of paresthesia caused by diabetic peripheral neuropathy symptom. [0003] Lipoic acid belongs to vitamin B compounds and is the most effective antioxidant among known antioxidants. It is widely used in the prevention and treatment of anti-oxidation, glucose metabolism, diabetes and its complications, and other diseases. It is mainly used clinically for diabetes Paresthesia caused by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D339/04
CPCC07D339/04
Inventor 毛兴荣范时根杜宗涛毛智远张中宝许晓明黄彦珺黄婷慧
Owner SICHUAN ZHIQIANG MEDICINE SCI & TECH DEV LTD
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