CN111018941A - Method for purifying glycyrrhetate - Google Patents
Method for purifying glycyrrhetate Download PDFInfo
- Publication number
- CN111018941A CN111018941A CN201911407482.1A CN201911407482A CN111018941A CN 111018941 A CN111018941 A CN 111018941A CN 201911407482 A CN201911407482 A CN 201911407482A CN 111018941 A CN111018941 A CN 111018941A
- Authority
- CN
- China
- Prior art keywords
- glycyrrhetate
- purifying
- sodium
- buffer
- metal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a purification method of glycyrrhetate, which comprises the following steps: forming a first solvent by using an organic solvent and water, then mixing the first solvent with glycyrrhetate to be purified to form a mixed system, uniformly stirring, adjusting the pH value of the system to 1.0-3.5, dissolving the glycyrrhetate, filtering, removing insoluble substances, adjusting the pH value of the system to 5.0-6.0, salting out the glycyrrhetate, filtering, respectively collecting filtrate and precipitate, washing the precipitate for a plurality of times by using a corresponding organic solvent, and drying to obtain the purified glycyrrhetate. The purification method of glycyrrhetate can be used for obtaining glycyrrhetate by purification with low energy consumption and high yield.
Description
Technical Field
The invention relates to the technical field of purification of active ingredients of medicinal materials, in particular to a method for purifying glycyrrhetate.
Background
Glycyrrhizic acid is one of the characteristic active ingredients of liquorice, and has the effects of resisting inflammation, resisting virus, protecting liver, detoxifying, enhancing immune function and the like. In the field of medicine, glycyrrhizic acid is clinically used for treating various acute and chronic hepatitis, bronchitis and AIDS, and has the functions of resisting and preventing cancers, inducing interferon, regulating cellular immunity and the like.
As a big country of liver diseases in China, the glycyrrhizic acid preparation is one of the first-line medicines for anti-inflammatory and liver-protecting treatment in the field of liver diseases at present. Glycyrrhizic acid is a ternary organic weak acid, and is often applied in various salt forms such as ammonium salt, sodium salt, potassium salt and the like in order to increase the water solubility. In 1992, monoammonium glycyrrhizinate is determined by the national ministry of health as the first choice medicine for treating chronic hepatitis, and currently, monoammonium glycyrrhizinate injection, diammonium glycyrrhizinate and the like are prepared in China.
At present, domestic monoammonium glycyrrhizinate manufacturers mainly adopt a physical recrystallization process of directly preparing monoammonium glycyrrhizinate in an ethanol glycyrrhizinate solution, and then carrying out multi-stage heating dissolution-cooling precipitation on a product through a 60-80% ethanol solution, so as to remove impurities and pigments of the product. However, because ammonium glycyrrhetate has a certain solubility in 60-80% ethanol solution, data statistics is provided, 10-20% of active ingredients remain in the filtrate after each physical recrystallization process treatment, that is, the yield of the active ingredients is gradually reduced along with the increase of the recrystallization times, and the energy consumption and time cost of the physical recrystallization process are added, so that the cost of the product is high finally.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide a method for purifying glycyrrhetate, which can purify and obtain the glycyrrhetate rapidly with low energy consumption and high yield.
In order to achieve the aim, the invention provides a method for purifying glycyrrhetate, which comprises the following steps: mixing: forming a first solvent (wherein the proportion of water is in the range of 0-20% by volume fraction) by using an organic solvent and water, mixing the first solvent with glycyrrhetate to be purified to form a mixed system, and uniformly stirring; dissolving: adding a first pH regulator into the mixed system, and controlling the pH value of the system to be 1.0-3.5 (in the experimental process, if the pH value of the system is controlled to be 1.0-3.5 under different solvent ratios, the glycyrrhetate can be completely dissolved), so that the glycyrrhetate is dissolved; filtering, respectively collecting filtrate and precipitate, discarding the precipitate, and reserving the filtrate; and (3) precipitation: adding a second pH regulator into the filtrate to regulate the pH value of the system to be between 5.0 and 6.0 (the residual concentration of the glycyrrhetate filtrate in the filtrate is low when the pH value of the system is controlled to be between 5.0 and 6.0 in the experimental process), so that the glycyrrhetate is separated out; filtering, and respectively collecting filtrate and precipitate; and post-treatment: washing the precipitate in the precipitation step with washing liquid, and drying to obtain purified glycyrrhetate.
In one embodiment of the present invention, in the mixing step, the organic solvent is at least one selected from the group consisting of alcohols, alcohol derivatives, and ketones; preferably, the organic solvent is at least one selected from methanol, ethanol, ethyl acetate and acetone.
In one embodiment of the present invention, in the mixing step, the first solvent is one selected from methanol-ethanol-water and ethyl acetate-ethanol-water.
In an embodiment of the present invention, in the mixing step, a mixing ratio of the first solvent to the glycyrrhetate to be purified is (10-80): 1(V/W), preferably (10-40): 1 (V/W).
In one embodiment of the present invention, in the dissolving step, the first pH adjusting agent is selected from the group consisting ofOne of the following components: h2SO4、HCl、H3PO4Polyphosphoric acid, CH3COOH, citric acid, oxalic acid, a buffer system with the buffer range of 1.0-3.5, cation exchange resin and a solution prepared from at least one of the substances.
In one embodiment of the present invention, the buffer system with a buffering range of 1.0 to 3.5 comprises disodium hydrogen phosphate-phosphate buffer (ph2.0), potassium dihydrogen phosphate-hydrochloric acid buffer (ph2.5), acetate buffer (ph3.5), and glycine-hydrochloric acid (ph 2.2).
In one embodiment of the present invention, in the dissolving step, the first pH adjusting agent is one selected from phosphoric acid and potassium dihydrogen phosphate-hydrochloric acid.
In one embodiment of the present invention, in the precipitating step, the second pH adjustor solution is at least one selected from the group consisting of: metal, metal oxide, metal hydroxide, salt formed by metal, anion exchange resin, ammonia gas, liquid ammonia, ammonia water, ammonium salt, triethylamine, a buffer system with the pH buffer range of 5.5-8.0 and a solution prepared by at least one of the substances; preferably, the metal is metal sodium, potassium, calcium, magnesium or zinc; the metal oxide is the oxide of sodium, potassium, calcium, magnesium and zinc; the salt formed by the metal is various acid salts formed by sodium, potassium, calcium, magnesium and zinc; the metal hydroxide is hydroxide of sodium, potassium, calcium, magnesium and zinc; the buffer system with the buffer range of pH 5.5-8.0 comprises sodium dihydrogen phosphate-sodium hydroxide (pH6.0), disodium hydrogen phosphate-sodium hydroxide (pH7.4), dipotassium hydrogen phosphate-potassium hydroxide (pH7.6), potassium dihydrogen phosphate-dipotassium hydrogen phosphate (pH5.8) and acetic acid-sodium acetate (pH 6.0). The total yield of glycyrrhetate obtained by the purification method is not less than 90%, and preferably, the second pH regulator is one selected from disodium hydrogen phosphate-sodium hydroxide and dipotassium hydrogen phosphate-potassium hydroxide.
In one embodiment of the present invention, in the post-treatment step, the washing solution is the same as the first solvent used in the mixing step.
In an embodiment of the present invention, the post-treatment step further comprises treating the filtrate obtained in the precipitation step, wherein the filtrate is used for solvent recovery or purification of a new batch of glycyrrhetate.
Compared with the prior art, the invention has the following beneficial effects:
(1) compared with the traditional process, the invention provides a low-energy-consumption and high-yield purification method of glycyrrhetate;
(2) the purification method does not use heating operation, so that the energy consumption is reduced in the glycyrrhetate dissolution process;
(3) the physical recrystallization cooling and placing process of the traditional process is not adopted in the purification method, so that the process time is shortened;
(4) in the purification process, when glycyrrhetate precipitates in the solvent, the residue in the filtrate is greatly reduced compared with the traditional process, and the yield of active ingredients in the purification process is improved.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The purification process of glycyrrhetate is described below by way of various examples.
Example 1
Taking 1kg of the crude product of the monosodium glycyrrhetate, adding 20L of a mixed solution of methanol-ethanol-water (V/V/V, 15/80/5), and uniformly stirring;
adding a phosphoric acid solution into the system, and controlling the pH value of the system to be 1.0-3.0 to dissolve the glycyrrhizic acid salt; filtering to remove insoluble substances, and collecting filtrate;
adding 0.1M disodium hydrogen phosphate-sodium hydroxide (pH is adjusted to 10 by sodium hydroxide test solution) solution into the filtrate, and controlling the pH of the system to be 5.0-6.0 to separate out a precipitate;
filtering again, respectively collecting filtrate and precipitate, recovering solvent from the filtrate, washing the precipitate with methanol-ethanol-water (V/V/V, 15/80/5) for three times, respectively collecting washing liquid, and drying the precipitate to obtain 0.84kg of finished product of mono-sodium glycyrrhizinate with solid yield of 94.57%.
Example 2
Adding 30L ethyl acetate-ethanol-water (V/V/V, 15/80/5) to 1kg of monopotassium glycyrrhizinate, and stirring;
adding 0.9M potassium dihydrogen phosphate-hydrochloric acid (adding hydrochloric acid to adjust pH to 0.5), and controlling pH of the system to be 1.0-3.0 to dissolve glycyrrhizic acid salt; filtering to remove insoluble substances, and collecting filtrate;
adding 0.05M dipotassium hydrogen phosphate-potassium hydroxide (the pH value of potassium hydroxide is adjusted to 10) solution into the filtrate, and controlling the pH value of the system to be 5.0-6.0 to separate out a precipitate;
filtering again, respectively collecting filtrate and precipitate, recovering solvent from the filtrate, washing the precipitate with ethyl acetate-ethanol-water (V/V/V, 15/80/5) for three times, respectively collecting washing liquid, and drying the precipitate to obtain 0.85kg of finished product of glycyrrhizic acid monopotassium salt, with solid yield of glycyrrhizic acid monopotassium salt of 96.38%.
The following further describes the statistical process of the glycyrrhetate yield of the above examples 1-2.
The detection method comprises the following steps: liquid chromatography detection
(1) Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-0.01 mol/L phosphoric acid solution (38: 62) is used as a mobile phase; the detection wavelength is 252 nm; the flow rate is 1 ml/min; sample introduction amount: 10 mu L of the solution; the theoretical plate number is not lower than 2000 calculated according to the ammonium glycyrrhizinate peak, and the separation degree of the ammonium glycyrrhizinate peak and the internal standard substance peak is in accordance with the requirement.
(2) Preparation of internal standard solution: taking about 70mg of n-butyl p-hydroxybenzoate, accurately weighing, placing in a 100ml measuring flask, dissolving with diluted ethanol, diluting to scale, and shaking.
(3) Preparation of control solutions: taking about 20mg of monoammonium glycyrrhizinate as a reference substance, precisely weighing, placing into a 100ml measuring flask, adding diluted ethanol for dissolving, precisely adding 5ml of internal standard solution, diluting to scale with diluted ethanol, and shaking up.
(4) Sample solution preparation
Glycyrrhetate crude product/finished product: taking 20mg of the product, accurately weighing, placing in a 100ml measuring flask, dissolving with dilute ethanol, accurately adding 5ml of internal standard solution, then adding dilute ethanol to dilute to scale, and shaking up.
Table 1 example 1, example 2 glycyrrhetate refining yield statistics
| Item | Example 1 | Example 2 |
| Crude content (Dry) | 70.06％ | 69.71％ |
| Moisture content | 10.5％ | 11.6％ |
| The feeding amount is 1kg | 1.00 | 1.00 |
| Content of finished product (Dry) | 73.92％ | 73.97％ |
| Moisture content | 4.5％ | 3.8％ |
| Weight kg of finished product | 0.84 | 0.85 |
| Yield (%) | 94.57％ | 96.38％ |
As shown in the above data, the purification of monosodium glycyrrhizinate and monopotassium glycyrrhizinate in examples 1 and 2 resulted in 94.57% and 96.38% yields, respectively, with stable yields.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (8)
1. A method for purifying glycyrrhetate is characterized by comprising the following steps:
mixing: forming a first solvent by using an organic solvent and water, then mixing the first solvent with glycyrrhetate to be purified to form a mixed system, and uniformly stirring;
dissolving: adding a first pH regulator into the mixed system, and controlling the pH value of the system to be 1.0-3.5 to dissolve glycyrrhizic acid salt; filtering, respectively collecting filtrate and precipitate, discarding the precipitate, and reserving the filtrate;
and (3) precipitation: adding a second pH regulator into the filtrate, and regulating the pH value of the system to 5.0-6.0 to precipitate glycyrrhetate; filtering, and respectively collecting filtrate and precipitate; and
and (3) post-treatment: washing the precipitate in the precipitation step with washing liquid, and drying to obtain purified glycyrrhetate.
2. The method for purifying glycyrrhetate according to claim 1, wherein in the mixing step, the organic solvent is at least one selected from the group consisting of alcohols, alcohol derivatives and ketones; preferably, the organic solvent is at least one selected from methanol, ethanol, ethyl acetate and acetone.
3. The method for purifying glycyrrhetate according to claim 1, wherein in the mixing step, the mixing ratio of the first solvent to the glycyrrhetate to be purified is (10-80): 1(V/W), preferably (10-40): 1 (V/W).
4. The method for purifying glycyrrhetate of claim 1, wherein the first pH regulator is selected from at least one of the following substances in the dissolving step: h2SO4、HCl、H3PO4Polyphosphoric acid, CH3COOH, citric acid, oxalic acid, a buffer system with the buffer range of 1.0-3.5, cation exchange resin and a solution prepared from at least one of the substances.
5. The method for purifying monovalent salt of glycyrrhizic acid as claimed in claim 4, wherein said buffer system with a buffer range of 1.0 to 3.5 comprises disodium hydrogen phosphate-phosphoric acid buffer solution, potassium dihydrogen phosphate-hydrochloric acid buffer solution, acetate buffer solution, and glycine-hydrochloric acid.
6. The method for purifying glycyrrhetate of claim 1, wherein in the precipitation step, the second pH regulator is at least one selected from the group consisting of: metal, metal oxide, metal hydroxide, salt formed by metal, anion exchange resin, ammonia gas, liquid ammonia, ammonia water, ammonium salt, triethylamine, a buffer system with the pH buffer range of 5.5-8.0, and a solution prepared by at least one of the substances; preferably, the metal is metal sodium, potassium, calcium, magnesium or zinc; the metal oxide is the oxide of sodium, potassium, calcium, magnesium and zinc; the salt formed by the metal is various acid salts formed by sodium, potassium, calcium, magnesium and zinc; the metal hydroxide is hydroxide of sodium, potassium, calcium, magnesium and zinc; the buffer system with the buffer range of pH 5.5-8.0 comprises sodium dihydrogen phosphate-sodium hydroxide (pH6.0), disodium hydrogen phosphate-sodium hydroxide (pH7.4), dipotassium hydrogen phosphate-potassium hydroxide (pH7.6), potassium dihydrogen phosphate-dipotassium hydrogen phosphate (pH5.8) and acetic acid-sodium acetate (pH 6.0).
7. The method for purifying glycyrrhetate of claim 1, wherein the washing solution is the same as the first solvent used in the mixing step in the post-treatment step.
8. The method of claim 1, wherein the post-treatment step further comprises treating the filtrate from the precipitation step for solvent recovery or for purification of a new batch of glycyrrhetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911407482.1A CN111018941A (en) | 2019-12-31 | 2019-12-31 | Method for purifying glycyrrhetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911407482.1A CN111018941A (en) | 2019-12-31 | 2019-12-31 | Method for purifying glycyrrhetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111018941A true CN111018941A (en) | 2020-04-17 |
Family
ID=70196788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911407482.1A Pending CN111018941A (en) | 2019-12-31 | 2019-12-31 | Method for purifying glycyrrhetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111018941A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021134408A1 (en) * | 2019-12-31 | 2021-07-08 | 中国医药健康产业股份有限公司 | Preparation, impurity removal and purification methods for glycyrrhizic acid monovalent salt |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210865A (en) * | 1997-09-11 | 1999-03-17 | 中国科学院新疆化学研究所 | Refining method of glycyrrhizin |
| CN101633683A (en) * | 2008-07-26 | 2010-01-27 | 刘力 | Antihepatitis medicament, preparation method thereof and use thereof |
| CN101654471A (en) * | 2009-09-14 | 2010-02-24 | 湖南康普制药有限公司 | Technology of large-scale refining production of glycyrrhetate |
| CN101830962A (en) * | 2010-05-20 | 2010-09-15 | 高颖 | Method for producing glycyrrhizin sodium aliphatate or glycyrrhizin potassium aliphatate |
| CN104151389A (en) * | 2014-07-16 | 2014-11-19 | 华东理工大学 | Method for rapidly extracting and purifying glycyrrhizic acid and salts thereof |
| CN106565815A (en) * | 2016-10-28 | 2017-04-19 | 新疆昆仑神农股份有限公司 | Monoammonium glycyrrhizinate purification method |
-
2019
- 2019-12-31 CN CN201911407482.1A patent/CN111018941A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210865A (en) * | 1997-09-11 | 1999-03-17 | 中国科学院新疆化学研究所 | Refining method of glycyrrhizin |
| CN101633683A (en) * | 2008-07-26 | 2010-01-27 | 刘力 | Antihepatitis medicament, preparation method thereof and use thereof |
| CN101654471A (en) * | 2009-09-14 | 2010-02-24 | 湖南康普制药有限公司 | Technology of large-scale refining production of glycyrrhetate |
| CN101830962A (en) * | 2010-05-20 | 2010-09-15 | 高颖 | Method for producing glycyrrhizin sodium aliphatate or glycyrrhizin potassium aliphatate |
| CN104151389A (en) * | 2014-07-16 | 2014-11-19 | 华东理工大学 | Method for rapidly extracting and purifying glycyrrhizic acid and salts thereof |
| CN106565815A (en) * | 2016-10-28 | 2017-04-19 | 新疆昆仑神农股份有限公司 | Monoammonium glycyrrhizinate purification method |
Non-Patent Citations (3)
| Title |
|---|
| 刘修树 等: "《天然药物化学》", 31 January 2017, 华中科技大学出版社 * |
| 杨和钧: "甘草甜素的用途和制法", 《黎明化工》 * |
| 苌云玉: "甘草酸盐制备方法研究", 《基层中药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021134408A1 (en) * | 2019-12-31 | 2021-07-08 | 中国医药健康产业股份有限公司 | Preparation, impurity removal and purification methods for glycyrrhizic acid monovalent salt |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111018941A (en) | Method for purifying glycyrrhetate | |
| CN110256494A (en) | Tenofovir Chinese mugwort draws phenol amine system column impurity and its synthetic method | |
| CN111018942B (en) | Preparation method of monovalent glycyrrhizinate | |
| CN103570663A (en) | Preparation method of high-purity quercetin | |
| CN103275206B (en) | Pregnant mare serum gonadotropin (PMSG) purifying method | |
| CN106883281A (en) | The method that chenodeoxycholic acid is extracted from duck bile | |
| CN106749101B (en) | A kind of preparation method of difenidol hydrochloride | |
| CN108218948B (en) | Preparation method of sodium aescinate | |
| CN101426795B (en) | Process for preparing dorzolamide | |
| CN111057124B (en) | Impurity removing method for glycyrrhetate | |
| CN104711301A (en) | Icaritin preparation method | |
| CN105440031A (en) | Method for purification of berberine hydrochloride from barberry root | |
| WO2021134408A1 (en) | Preparation, impurity removal and purification methods for glycyrrhizic acid monovalent salt | |
| CN102502570B (en) | Production method of medical sodium metavanadate | |
| CN101723988A (en) | Method for preparing oxaliplatin with very low content of impurities | |
| CN111072731B (en) | Method for purifying and obtaining glycyrrhetate from liquorice | |
| CN109111356B (en) | Caffeic acid synthesis refining process | |
| CN107312072A (en) | A kind of method of purifies and separates Atosiban | |
| CN106977569A (en) | The preparation method of the α hydroxyprogesterone acetates of 6 methylene 17 | |
| CN103304583B (en) | A kind of method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution | |
| CN102516301B (en) | Wogonin derivant for treatment | |
| CN101491647A (en) | Method for separating ergot total alkaloids in ergot stem extract | |
| CN105541815B (en) | A kind of preparation method of canagliflozin | |
| CN117069079B (en) | Preparation process and application of potassium dihydrogen phosphite | |
| CN108892677B (en) | Particle size control method of cefdinir |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200417 |
|
| RJ01 | Rejection of invention patent application after publication |