CN102603709A - Thioctic acid compound and preparation method thereof - Google Patents
Thioctic acid compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of a thioctic acid compound. The method comprises the steps that: a raw material thioctic acid is dispersed in water; an alcohol solution of alcoholized sodium is added to the solution; the mixture is stirred while heated; the mixture is filtered, and the filtrate is collected; active carbon or macroporous adsorption resin is added to the filtrate, and absorption is carried out under room temperature; the material is filtered, and the filtrate is collected; an acid solution is added to the filtrate, and the mixture is stirred, until the pH value of the solution is 2.0-4.0; the solution is heated to a temperature of no higher than 60 DEG C; the temperature is maintained for a certain period of time, and condensation is carried out; the temperature is subject to gradient reduction, such that crystals are precipitated; the crystals are washed and dried, such that a high-purity thioctic acid compound is obtained. With the method provided by the invention, the purity of the obtained thioctic acid is no lower than 99.6%, and a melting point range is 60.2-60.8 DEG C. With the method provided by the invention, the quality of preparation products is improved, and toxic or side effects are reduced. The method is suitable for large-scale industrialized productions.
Description
Technical field
The present invention relates to a kind of Thioctic Acid compound and method for making thereof, belong to medical technical field.
Background technology
Thioctic Acid, its chemical name is: (±)-5-[3-(1, the 2-dithiolane)]-valeric acid, English name is: (R)-5-(1,2-dithiolan-3-yl) pentanoic acid, molecular formula is: C
8H
14O
2S
2, molecular weight: 206.33, CAS number is 1200-22-2, structural formula is:
Thioctic Acid is sulfur-bearing eight carbon resin acids, and the disulfide linkage (C that links to each other is arranged on 6,8
6And C
8On Wasserstoffatoms replaced by disulfide linkage), so claim 6 again, the 8-dithio-octanoic acid, have oxidation, the reduction two types.6,8 are gone up the sulfydryl dehydrogenation is oxidized form Thioctic Acid (two sulphur atoms link to each other through disulfide linkage), and hydrogenation becomes reduced form and is called Thioctic acid, dihydro-(disulfide bond reduction is a sulfydryl).Though Thioctic Acid does not belong to VITAMINs; But it can be used as coenzyme and participates in acyl group transfer in the substance metabolism process in the body; Play hydrogen and the effect (promptly as hydrogen carrier and acyl carrier) of shifting acyl group of passing; Have the function similar (biostearin), therefore also listed in the VITAMINs and tell about by the biological chemistry teaching material with VITAMINs.Thioctic Acid is not only tool water-soluble (slightly soluble) but also the fat-soluble light yellow crystal of tool, and racemize Thioctic Acid fusing point is at 60～61 ℃, and boiling point is 160～165 ℃.
The natural product that Thioctic Acid is separated from pork liver by ReedShi first, it is the cofactors of the oxidative decarboxylation reaction of α-Tong Wuersuan in pyruvic acid and the tricarboxylic acid cycle.Relevant multiple disease such as mellitus, ischemic reperfusion injury, heavy metal poisoning, radiolesion, degeneration DPN and HIV infection etc. have prevention and result of treatment to Thioctic Acid for the active oxidation radical.
Thioctic Acid is used to treat the DPN of mellitus in a large number at present.Isolated test shows that these article can reduce the lipid oxidation phenomenon of nervous tissue, and these article possibly stop proteinic glycosylation; And can suppress aldose reductase, thereby can stop glucose or semi-lactosi to transform into sorbyl alcohol, so the DPN that Thioctic Acid can prevent mellitus, controlling blood sugar and prevent to cause because of hyperglycemia.
Patent documentation US3223712 adopts 6, and 8-dichloro ethyl octylate and SULPHUR POWDER, sodium disulfide cyclization generate the Thioctic Acid ethyl ester, obtain the Thioctic Acid bullion through hydrolysis then, then with refining pure article of Thioctic Acid that make such as sherwood oil, normal hexane, isopropyl ether, hexanaphthenes; For freezing crystallization under general employing ETHYLE ACETATE made from extra care of Thioctic Acid and the hexanaphthene mixed solvent, through filtering, the filter cake drying under reduced pressure obtains the pure article of Thioctic Acid.
These methods can effectively prepare Thioctic Acid, but the purity of title product is not high, colour-difference, and content is low, has influenced the mass effect of its preparation.The product that is provided is handled or purification process is the ordinary method during organic chemistry synthesizes, and purity improves limited.
Summary of the invention
In order to overcome the defective of above-mentioned prior art, particularly overcome the low defective of Thioctic Acid purity of prior art for preparing, the invention provides a kind of method of refining Thioctic Acid compound.
The Thioctic Acid that process for purification provided by the invention was directed against is prepared Thioctic Acid bullion of present known compound method or commercially available Thioctic Acid bulk drug, below is referred to as the raw material Thioctic Acid that the present invention adopts.
The inventor through comprising the process for purification of following treatment step, can increase substantially the purity of raw material Thioctic Acid through discovering:
Step 1 is scattered in the raw material Thioctic Acid in the water, slowly adds the alcoholic solution of alcoholization sodium, and heating is stirred down, and Thioctic Acid is dissolved fully, filters, and collects filtrating, and its pH is 8.0-10.0;
Step 2 adds gac or macroporous adsorbent resin in above-mentioned filtrating, absorption is 10-60 minute under the room temperature, filters, and collects filtrating;
Step 3 slowly adds acid solution in above-mentioned filtrating, stir, to the pH value of solution be 2.0-4.0; Be warming up to and be not higher than 60 ℃, keep certain hour to concentrate, gradient reduces temperature then, separates out crystallization; Centrifuge washing, drying obtains highly purified Thioctic Acid compound.
The following specifically describes the present invention.
In step 1 of the present invention, the raw material Thioctic Acid is scattered in the water, slowly add the alcoholic solution of alcoholization sodium, heating is stirred down, and Thioctic Acid is dissolved fully, filters, and collects filtrating, and its pH is 8.0-10.0.
The inventor finds, make with extra care in the raw material Thioctic Acid of purifying generally to contain water or the alcohol insoluble matter impurity of introducing in the preparation process; In addition, the method final step that much obtains Thioctic Acid is the protection base that removes carboxyl, is the common protection base of carboxyl such as ester group, certainly will cause existing in the Thioctic Acid bullion a small amount of ester class impurity like this.These impurity are to cause one of not high reason of raw material Thioctic Acid purity.Owing to do not take the specific aim purification process, these impurity generally still are mingled in raw material Thioctic Acid bullion.And in the presence of alkaline matter, residual Ester can hydrolysis discharge the Thioctic Acid that contains acidic moiety, has so not only effectively reduced impurity, and has advantageously increased the productive rate of target product.
Therefore, in step 1 of the present invention, in the water-based system that contains Thioctic Acid, add the alcoholic solution of alcoholization sodium; The alcohol moiety of preferred said alcoholization sodium is identical with alcohols material in the solution; For example, when adopting ethanol, use sodium ethylate to handle as solvent; When adopting methyl alcohol, use sodium methylate to handle as solvent.
To carry out sooner and use solvent less as far as possible in order to dissolve, preferably under heating state, stir, preferred temperature is 30-55 ℃, more preferably 35-50 ℃, also is preferably 40-45 ℃.Through filtering or suction filtration, give up solid impurity then, obtain filtrating, its pH value is 8.0-10.0, is preferably 8.5-9.5, more preferably 8.8-9.2.Can contain the sodium thioctate that is formed by Thioctic Acid and alkaline matter on a small quantity in this filtrating, in purification step subsequently, this sodium salt is easy to be converted into the Thioctic Acid form in sour environment.
In step 2 of the present invention, in above-mentioned Thioctic Acid solution, add gac or macroporous adsorbent resin, absorption is 10-60 minute under the room temperature, filters, and collects filtrating.
Also contain the solvent of introducing in the preparation process, various raw material and intermediate product in the Thioctic Acid bullion, and various organism and pigment etc.What these materials had exists with trace, and what have has certain solubility in water or alcoholic solvent, is difficult to separate through modes such as filtrations remove.
The inventor finds that this type material is generally organic property material, can be removed by gac or absorption with macroporous adsorbent resin; In addition, generally also contain inorganic nature material such as the trace catalyst of introducing in the preparation process, various salt and heavy metal and deposit the bacterial endotoxin that produces in the process in the Thioctic Acid bullion.Also can effectively it separation be removed through suction type.
The inventor notices; Macroporous adsorbent resin has good macroporous netlike structure and bigger ratio table amasss; Can be through the physical adsorption material that adsorb organic compound is nonpolar or polarity is more weak selectively from the aqueous solution; The resin absorption effect is the Van der Waals force that relies between it and the molecule (adsorbate) that is adsorbed; Carry out physical adsorption through its huge specific surface and work, the organifying compound is according to having adsorptive power and molecular weight size thereof separately to reach separation, purifying, removal of impurities, various objectives such as concentrated through certain solvent elution.Therefore can be with Thioctic Acid and impurity property separating substances; In addition, itself has decolorization resin, can remove the impurity of colour developing.
According to the preferred embodiment of the present invention, when adopting macroporous adsorbent resin, can select for example D101 type macroporous adsorbent resin, H-103 type macroporous adsorbent resin or HP-20 type macroporous adsorbent resin, preferred D101 type macroporous adsorbent resin as sorbent material.Selected macroporous adsorbent resin is commercial prod.
According to the preferred embodiment of the present invention; The add-on of gac or macroporous adsorbent resin is 0.5%-2.0% (g/ml), preferred 0.8%-1.8% (g/ml), more preferably 1.0%-1.5% (g/ml); In adsorption process, stir; Absorption is 10-60 minute under the general room temperature, preferably adsorbs 20-45 minute, more preferably adsorbs 30 minutes.
In step 3 of the present invention, in above-mentioned filtrating, slowly add acid solution, stir, to the pH value of solution be 2.0-4.0; Be warming up to and be not higher than 60 ℃, keep certain hour to concentrate, gradient reduces temperature then, separates out crystallization; Centrifuge washing, drying obtains highly purified Thioctic Acid compound.
We discover, for Thioctic Acid, adopt and reflux in the single solvent commonly used or the recrystallization or be suspended in the method for refluxing and stirring in the solvent of lowering the temperature, or be difficult to crystallization, or it is higher to separate out rear impurity content.Can not obtain ideal purity and directly the Thioctic Acid bullion is carried out optimum-poor solvent liberation method.
According to the present invention, the acid of in step 3, using has such characteristics, and this acid or its sodium salt have bigger solubleness in water and/or alcohol property solution, in crystallisation process subsequently, can not separate out like this, and have the effect of regulator solution electrolyte environment.
The acid of using in this step of the present invention is preferably hydrochloric acid or nitric acid, the hydrochloric acid of preferred concentration 0.02M-1M or nitric acid, Hydrogen chloride or the rare nitric acid of preferred 0.05M-0.5M.Adopt Hydrogen chloride or rare nitric acid to be more convenient for controlling the pH value, for example control the pH value and be 2.2-3.8, preferably control the pH value and be 2.5-3.5.And, comparatively speaking more water can be provided through adding dilute acid soln, and the solubleness of Thioctic Acid in water and little, the gradient cooling crystallization that helps carrying out is subsequently separated out.
The solution that is obtained is warming up to is not higher than 60 ℃, preferably be not higher than 58 ℃, more preferably no higher than 55 ℃ temperature, keep certain hour to concentrate, gradient reduces temperature then, carries out recrystallization.
According to the present invention, in the gradient cooling process, in 1 hour, cool the temperature to 42～45 ℃; In 1 to 3 hour, cool the temperature to 20～25 ℃ then; At last in 3 to 15 hours, in preferred 5 to 12 hours, most preferably cool the temperature to-5～12 ℃ in 8 to 10 hours; Preferred 0～10 ℃, most preferably 5～8 ℃.In this process, constantly there is crystal to separate out, complete until crystallization.
Surprisingly, after the above-mentioned processing of the present invention, obtain the Thioctic Acid of based on very high purity.Its reason possibly be that step 1 of the present invention and 2 has been removed and to producing deposition the impurity property material of disadvantageous effect arranged, and has influence on the environment of final recrystallization.
After the crystallization fully, carry out centrifuge washing, drying can adopt the pure water washing, and mode is dried in employing or the vacuum drying mode is carried out drying.
Through the Thioctic Acid highly finished product of the inventive method acquisition purifying, according to high effective liquid chromatography for measuring, its purity is greater than 99.6%, generally greater than 99.7%.
In view of the powder flowbility of Thioctic Acid, intrinsic dissolution rate, Pickering property and preparation operability huge to the influence of its active performance and the preparation prepared, and the Thioctic Acid that purity is largely increased dissolution rate, the property prepared and stable aspect also corresponding obvious improvement.
The invention solves the difficult problem that rough Thioctic Acid and Thioctic Acid bulk drug face, improved the quality product of preparation, reduced toxic side effect, ensured safety of clinical administration; And compared with prior art, present method technology is simple, and cost is low; Yield is high, and purity is high, is suitable for suitability for industrialized production.
Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
Embodiment
Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
The detection method of Thioctic Acid purity:
With the purity of high performance liquid chromatograph detection head Thioctic Acid sample, chromatographic condition is:
Use octadecylsilane chemically bonded silica to be weighting agent, granularity 5 μ m, specification: 150.0mm x 4.6mm, stainless steel column (Shimpack CLC-ODS);
Moving phase: acetonitrile-0.005mol/L potassium dihydrogen phosphate (v: v=50: 50).With phosphorus acid for adjusting pH value to 3.0; Flow velocity: 1.0ml/min;
Detect wavelength: 212nm;
Sample size: 20 μ l.
Embodiment 1
Accurately take by weighing the Thioctic Acid 10g according to the preparation of US3223712 reported method, it is 91% that HPLC measures purity.It is scattered in the 300ml water, slowly adds 0.2g and be dissolved in the sodium ethylate in the 50ml ethanol, 40 ℃ of insulated and stirred 30 minutes, Thioctic Acid is dissolved fully, filter, collect filtrating, pH value of solution is about 8.5.
In the filtrating that obtains, add the 3.5g gac, stir under the room temperature, adsorbed 40 minutes, filter, collect filtrating.
In filtrating, slowly add the hydrochloric acid soln of 0.5mol/L, stir, to the pH value of solution be 3.0, be warming up to 55-58 ℃ temperature, maintenance half a hour.In 1 hour, cool the temperature to 42～45 ℃, in 2 hours, cool the temperature to 22～25 ℃ then, in 5 hours, cool the temperature to 2～5 ℃ at last.In this process, constantly there is crystal to separate out, complete until crystallization.Centrifuge washing is 80 ℃ of oven dry at oven temperature then, obtains highly purified Thioctic Acid Thioctic Acid highly finished product 8.7g, and it is 99.6% that HPLC measures purity, and fusing point is 60.3～60.8 ℃.
Embodiment 2
Accurately take by weighing 10g Thioctic Acid raw material (Jiangsu Shenlong Pharmaceutical Co., Ltd., lot number 20100215), it is 96% that HPLC measures purity.It is scattered in the 250ml water, slowly adds 0.40g and be dissolved in the sodium ethylate in the 100ml ethanol, 35 ℃ of insulated and stirred 50 minutes, Thioctic Acid is dissolved fully, filter, collect filtrating, pH value of solution is about 9.2.
In the filtrating that obtains, add 3.0g D101 type macroporous adsorbent resin, stir under the room temperature, adsorbed 30 minutes, filter, collect filtrating.
In filtrating, slowly add the salpeter solution of 0.8mol/L, stir, to the pH value of solution be 2.5, be warming up to 54-58 ℃ temperature, kept 30 minutes.In 1 hour, cool the temperature to 42～44 ℃, in 3 hours, cool the temperature to 20～23 ℃ then, in 8 hours, cool the temperature to-2～5 ℃ at last.In this process, constantly there is crystal to separate out, complete until crystallization.Centrifuge washing is 80 ℃ of oven dry down at oven temperature then, gets Thioctic Acid highly finished product 9.3g, purity 99.7%, and fusing point is 60.2～60.7 ℃.
Embodiment 3
Accurately take by weighing 10g Thioctic Acid raw material (Shanghai Hyundai Pharmacy stock Co., Ltd, lot number 20100605), it is that purity is 97% that HPLC measures purity.It is scattered in the 200ml water, slowly adds 0.25g and be dissolved in the sodium methylate in the 50ml methyl alcohol, 45 ℃ of insulated and stirred 20 minutes, Thioctic Acid is dissolved fully, filter, collect filtrating, pH value of solution is about 9.0.
In the filtrating that obtains, add 4.0g HP-20 type macroporous adsorbent resin, stir under the room temperature, adsorbed 20 minutes, filter, collect filtrating.
In filtrating, slowly add the salpeter solution of 0.5mol/L, stir, to the pH value of solution be 2.2, be warming up to 52-55 ℃ temperature, kept 45 minutes.In 1 hour, cool the temperature to 42～44 ℃, in 2 hours, cool the temperature to 20～24 ℃ then, in 6 hours, cool the temperature to 0～5 ℃ at last.In this process, constantly there is crystal to separate out, complete until crystallization.Centrifuge washing is 80 ℃ of oven dry down at oven temperature then, gets Thioctic Acid highly finished product 9.4g, purity 99.8%, and fusing point is 60.3～60.7 ℃.
Embodiment 4
Accurately take by weighing the out of date Thioctic Acid raw material of 10g (Shanghai Hyundai Pharmacy stock Co., Ltd, 20070440), it is that purity is 84% that HPLC measures purity.It is scattered in the 300ml water, slowly adds 0.50g and be dissolved in the sodium ethylate in the 150ml ethanol, 45 ℃ of insulated and stirred 60 minutes, Thioctic Acid is dissolved fully, filter, collect filtrating, pH value of solution is about 8.8.
In the filtrating that obtains, add the 4.0g gac, stir under the room temperature, adsorbed 30 minutes, filter, collect filtrating.
In filtrating, slowly add the hydrochloric acid soln of 0.8mol/L, stir, to the pH value of solution be 2.2, be warming up to 55-58 ℃ temperature, kept 40 minutes.In 1 hour, cool the temperature to 40～44 ℃, in 3 hours, cool the temperature to 20～25 ℃ then, in 8 hours, cool the temperature to 2～6 ℃ at last.In this process, constantly there is crystal to separate out, complete until crystallization.Centrifuge washing is 60 ℃ of oven dry down at oven temperature then, gets Thioctic Acid highly finished product 8.1g, purity 99.6%, and fusing point is 60.3～60.8 ℃.
According to the above embodiments the present invention has been made detailed description.What need explanation is that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (10)
1. the Thioctic Acid compound shown in the formula I,
It is characterized in that its method for making comprises the steps:
Step 1 is scattered in the raw material Thioctic Acid in the water, slowly adds the alcoholic solution of alcoholization sodium, and heating is stirred down, and Thioctic Acid is dissolved fully, filters, and collects filtrating, and its pH is 8.0-10.0;
Step 2 adds gac or macroporous adsorbent resin in above-mentioned filtrating, absorption is 10-60 minute under the room temperature, filters, and collects filtrating;
Step 3 slowly adds acid solution in above-mentioned filtrating, stir, to the pH value of solution be 2.0-4.0; Be warming up to and be not higher than 60 ℃, keep certain hour to concentrate, gradient reduces temperature then, separates out crystallization; Centrifuge washing, drying obtains highly purified Thioctic Acid compound.
2. according to the method for making of the Thioctic Acid compound of claim 1, it is characterized in that, in the step 1; The alcoholic solution that in the water-based system that contains Thioctic Acid, adds alcoholization sodium; The alcohol moiety of said alcoholization sodium is identical with alcohols material in the solution, for example when adopting ethanol as solvent, uses sodium ethylate to handle; When adopting methyl alcohol, use sodium methylate to handle as solvent.
3. according to the method for making of the Thioctic Acid compound of claim 1 or 2, it is characterized in that, in the step 1, under heating state, stir that preferred temperature is 30-55 ℃, more preferably 35-50 ℃, also is preferably 40-45 ℃.
4. according to the method for making of the Thioctic Acid compound of one of claim 1-3, it is characterized in that in the step 1, the pH value of the sodium thioctate solution that is obtained is 8.0-10.0, is preferably 8.5-9.5, more preferably 8.8-9.2.
5. according to the method for making of the Thioctic Acid compound of one of claim 1-4; It is characterized in that; In the step 2, said macroporous adsorbent resin is selected from D101 type macroporous adsorbent resin, H-103 type macroporous adsorbent resin or HP-20 type macroporous adsorbent resin, preferred D101 type macroporous adsorbent resin.
6. according to the method for making of the Thioctic Acid compound of one of claim 1-5, it is characterized in that, in the step 2; The add-on of gac or macroporous adsorbent resin is 0.5%-2.0% (g/ml), preferred 0.8%-1.8% (g/ml), more preferably 1.0%-1.5% (g/ml); In adsorption process, stir; Absorption is 10-60 minute under the general room temperature, preferably adsorbs 20-45 minute, more preferably adsorbs 30 minutes.
7. according to the method for making of the Thioctic Acid compound of one of claim 1-6, it is characterized in that in the step 3, said acid is hydrochloric acid or nitric acid, the hydrochloric acid of preferred concentration 0.02M-1M or nitric acid, Hydrogen chloride or the rare nitric acid of preferred 0.05M-0.5M.
8. according to the method for making of the Thioctic Acid compound of one of claim 1-7, it is characterized in that in the step 3, control pH value is 2.2-3.8, preferably 2.5-3.5.
9. according to the method for making of the Thioctic Acid compound of one of claim 1-8, it is characterized in that in the step 3, the solution of acquisition is warming up to and is not higher than 60 ℃, preferably is not higher than 58 ℃, more preferably no higher than 55 ℃ temperature; In the gradient cooling process, in 1 hour, cool the temperature to 42～45 ℃, in 1 to 3 hour, cool the temperature to 20～25 ℃ then; At last in 3 to 15 hours, in preferred 5 to 12 hours, most preferably cool the temperature to-5～12 ℃ in 8 to 10 hours; Preferred 0～10 ℃, most preferably 5～8 ℃.
10. the highly purified Thioctic Acid compound that makes according to the method for making of one of claim 1-9, its purity is greater than 99.6%, and melting range is 60.2～60.8 ℃.
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| CN110118835A (en) * | 2019-05-29 | 2019-08-13 | 北京悦康科创医药科技股份有限公司 | A kind of method of the high effective liquid chromatography for measuring lipoic acid injection in relation to substance |
| CN111100113A (en) * | 2018-10-26 | 2020-05-05 | 江苏同禾药业有限公司 | Preparation method of D-lipoic acid sodium salt |
| CN113292533A (en) * | 2021-05-25 | 2021-08-24 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in lipoic acid |
| CN116102532A (en) * | 2023-01-09 | 2023-05-12 | 国药集团威奇达药业有限公司 | Method for recovering lipoic acid from lipoic acid crystallization mother liquor |
| KR20230068105A (en) * | 2021-11-10 | 2023-05-17 | 한국바이오켐제약 주식회사 | A method for removing polymer impurities in thioctic acid and crystalizing thereof |
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| CN1354748A (en) * | 1999-08-14 | 2002-06-19 | Skw特罗斯特贝格股份公司 | Method for production of solvent-free alpha-liponic acid |
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| CN1354748A (en) * | 1999-08-14 | 2002-06-19 | Skw特罗斯特贝格股份公司 | Method for production of solvent-free alpha-liponic acid |
| CN101024641A (en) * | 2006-02-20 | 2007-08-29 | 南京莱尔生物化工有限公司 | R(1) lipoic acid and its salt preparation |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111100113A (en) * | 2018-10-26 | 2020-05-05 | 江苏同禾药业有限公司 | Preparation method of D-lipoic acid sodium salt |
| CN110118835A (en) * | 2019-05-29 | 2019-08-13 | 北京悦康科创医药科技股份有限公司 | A kind of method of the high effective liquid chromatography for measuring lipoic acid injection in relation to substance |
| CN110118835B (en) * | 2019-05-29 | 2022-02-18 | 北京悦康科创医药科技股份有限公司 | Method for determining related substances of lipoic acid injection by high performance liquid chromatography |
| CN113292533A (en) * | 2021-05-25 | 2021-08-24 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in lipoic acid |
| CN113292533B (en) * | 2021-05-25 | 2024-04-16 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in lipoic acid |
| KR20230068105A (en) * | 2021-11-10 | 2023-05-17 | 한국바이오켐제약 주식회사 | A method for removing polymer impurities in thioctic acid and crystalizing thereof |
| KR102686559B1 (en) | 2021-11-10 | 2024-07-19 | 한국바이오켐제약 주식회사 | A method for removing polymer impurities in thioctic acid and crystalizing thereof |
| CN116102532A (en) * | 2023-01-09 | 2023-05-12 | 国药集团威奇达药业有限公司 | Method for recovering lipoic acid from lipoic acid crystallization mother liquor |
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