CN109232707B - Method for removing solvent residues of diammonium glycyrrhizinate bulk drug - Google Patents
Method for removing solvent residues of diammonium glycyrrhizinate bulk drug Download PDFInfo
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- CN109232707B CN109232707B CN201811083233.7A CN201811083233A CN109232707B CN 109232707 B CN109232707 B CN 109232707B CN 201811083233 A CN201811083233 A CN 201811083233A CN 109232707 B CN109232707 B CN 109232707B
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- 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
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Abstract
The invention discloses a method for removing solvent residues of diammonium glycyrrhizinate bulk drug, which comprises the steps of carrying out primary decoloration recrystallization on a synthesized diammonium glycyrrhizinate crude product by using a mixed solvent, carrying out centrifugal filtration, drying under reduced pressure, placing, sucking filtration after water absorption and moisture absorption, and continuously drying under reduced pressure to obtain the diammonium glycyrrhizinate bulk drug, wherein the residual solvent ethanol of the diammonium glycyrrhizinate bulk drug is less than or equal to 2000ppm through detection, the residual solvent ethanol is far lower than the quality standard of the diammonium glycyrrhizinate bulk drug residual solvent in Chinese pharmacopoeia and is less than or equal to 5000ppm, the diammonium glycyrrhizinate bulk drug has the appearance of white.
Description
Technical Field
The invention belongs to the technical field of production of diammonium glycyrrhizinate raw material medicines, and particularly relates to a method for removing solvent residues of a diammonium glycyrrhizinate raw material medicine.
Background
The diammonium glycyrrhizinate bulk drug is a third-generation substitute of the effective components of the traditional Chinese medicine liquorice, and has stronger effects of resisting inflammation, protecting liver cell membranes and improving liver functions. At present, diammonium glycyrrhizinate raw material medicines are obtained by adopting a method of refining for multiple times after synthesis of diammonium glycyrrhizinate, a large amount of solvents are needed, the cost is high, and the obtained product has high solvent residue. Through retrieval, no report is found on a method for removing the solvent residue of the diammonium glycyrrhizinate bulk drug. The solvent residue is usually removed by drying and desolventizing. Experiments prove that the residual solvent of the diammonium glycyrrhizinate bulk drug is difficult to reach the residual solvent standard of Chinese pharmacopoeia of less than or equal to 5000ppm by adopting conventional reduced pressure drying, and the product can be darkened and partially deteriorated by long-time reduced pressure drying.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the method for removing the solvent residue of the diammonium glycyrrhizinate bulk drug, which is simple to operate, good in product quality and low in cost.
The purpose of the invention is realized as follows: a method for removing solvent residues of diammonium glycyrrhizinate bulk drug comprises the following steps:
step A, heating the diammonium glycyrrhizinate crude product and the mixed solvent, adding activated carbon for decolorization after the diammonium glycyrrhizinate crude product and the mixed solvent are dissolved, and performing hot filtration;
step B, heating the filtrate obtained in the step A, cooling after dissolving, adding the treated seed crystal, stirring for crystallization, and performing centrifugal filtration to obtain a diammonium glycyrrhizinate wet product;
step C, drying the diammonium glycyrrhizinate wet product obtained in the step B under reduced pressure to obtain a diammonium glycyrrhizinate primary dry product;
d, placing the primary dried diammonium glycyrrhizinate product obtained in the step C in a room with air humidity of 65-85%, standing and absorbing moisture;
and E, drying the material after moisture absorption obtained in the step D under reduced pressure again to obtain the diammonium glycyrrhizinate raw material medicine with low residual solvent.
Preferably, in the step A, the mixed solvent is 50-55% of ethanol solution.
Preferably, in the step a, the mass ratio of the diammonium glycyrrhizinate crude product to the mixed solvent is 1: 4 to 5.
Preferably, in the step B, the temperature of adding the treated seed crystal after heating and dissolving is 48-52 ℃.
Preferably, in the step D, the moisture absorption is performed for 10 hours or more by standing.
Preferably, in the step D, the mixture is placed at room temperature overnight to absorb moisture for 10-48 hours, and the weight of the material is increased by 6-12%.
Preferably, in the step C and the step E, the reduced pressure drying is carried out for 5-8 hours at the temperature of 50-60 ℃.
Due to the adoption of the technical scheme, the invention has the beneficial effects that: through a large number of intensive researches, the invention discovers that the diammonium glycyrrhizinate bulk drug is easy to absorb moisture and increase weight in the air, and a method for effectively removing residual solvent ethanol is found by utilizing a replacement principle; through detection, the residual solvent ethanol of the obtained diammonium glycyrrhizinate bulk drug is less than or equal to 2000ppm, the mass standard of the residual solvent ethanol of the diammonium glycyrrhizinate bulk drug is far lower than that of the diammonium glycyrrhizinate bulk drug in Chinese pharmacopoeia and is less than or equal to 5000ppm, white granular crystals with large crystal forms are formed in the appearance, the purity is high, the stability is good, and the product quality is improved to a great extent.
Detailed Description
The technical scheme of the invention is further specifically described by the following embodiments.
Example 1
Putting 60g of diammonium glycyrrhizinate crude product and 240g of 50% ethanol solution into a 500ml four-mouth reaction bottle, heating to 65 ℃ for dissolving, adding 2.2g of activated carbon for decoloring for half an hour, and removing the activated carbon by hot filtration. Heating the filtrate to clear, cooling to 50 ℃, adding the treated seed crystal, stirring, cooling to crystallize, separating out a small amount of crystals at 47 ℃, continuing stirring, standing at 40 ℃ for crystallization, standing overnight, cooling to 0-5 ℃ with ice water the next day, and performing centrifugal filtration to obtain 84.6g of diammonium glycyrrhizinate wet product. Drying the obtained wet product at 55 deg.C under reduced pressure for 6 hr to obtain 49.2g of diammonium glycyrrhizinate dried product. The obtained primary dried product was left at an air humidity of 70% for 10 hours, and 53.2g of the moisture-absorbed material was weighed. And after the obtained moisture-absorbed material is subjected to suction filtration, drying for 6 hours at 55 ℃ under reduced pressure again to obtain 48.6g of diammonium glycyrrhizinate raw material medicine with a large white crystal form, wherein the content is 99.2% by detection, and the solvent residue is 1466 ppm.
Example 2
Putting 60g of diammonium glycyrrhizinate crude product and 240g of 50% ethanol solution into a 500ml four-mouth reaction bottle, heating to 65 ℃ for dissolving, adding 2.2g of activated carbon for decoloring for half an hour, and removing the activated carbon by hot filtration. Heating the filtrate to clear, cooling to 50 ℃, adding the treated seed crystal, stirring, cooling to crystallize, separating out a small amount of crystals at 47 ℃, continuing stirring, standing at 40 ℃ for crystallization, standing overnight, cooling to 0-5 ℃ with ice water the next day, and performing centrifugal filtration to obtain 86.8g of diammonium glycyrrhizinate wet product. Drying the obtained wet product at 55 deg.C under reduced pressure for 7 hr to obtain 48.8g of diammonium glycyrrhizinate dried product. The obtained primary dried product was left at an air humidity of 80% for 16 hours, and 53.7g of the moisture-absorbed material was weighed. And after the obtained moisture-absorbed materials are subjected to suction filtration, drying for 7 hours at 55 ℃ under reduced pressure again to obtain 48.7g of diammonium glycyrrhizinate bulk drug with a large white crystal form, wherein the content is 99.3 percent through detection, and the solvent residue is 882 ppm.
Example 3
Putting 60g of diammonium glycyrrhizinate crude product and 300g of 55% ethanol solution into a 500ml four-mouth reaction bottle, heating to 65 ℃ for dissolving, adding 2.2g of activated carbon for decoloring for half an hour, and removing the activated carbon by hot filtration. Heating the filtrate to dissolve, cooling to 52 ℃, adding the treated seed crystal, stirring, cooling for crystallization, separating out a small amount of crystals at 47 ℃, continuing stirring, standing at 40 ℃ for crystallization, standing overnight, cooling to 0-5 ℃ with ice water the next day, and performing centrifugal filtration to obtain 90.1g of diammonium glycyrrhizinate wet product. Drying the obtained wet product at 55 deg.C under reduced pressure for 8 hr to obtain 48.0g of diammonium glycyrrhizinate dried product. The obtained primary dried product was left to stand at an air humidity of 80% for 24 hours, and 53.5g of the moisture-absorbed material was weighed. And after the obtained moisture-absorbed material is subjected to suction filtration, drying for 8 hours at 55 ℃ under reduced pressure again to obtain 47.8g of diammonium glycyrrhizinate raw material medicine with a large white crystal form, wherein the content is 99.1% through detection, and the solvent residue is 762 ppm.
Example 4
Putting 60g of diammonium glycyrrhizinate crude product and 300g of 55% ethanol solution into a 500ml four-mouth reaction bottle, heating to 65 ℃ for dissolving, adding 2.2g of activated carbon for decoloring for half an hour, and removing the activated carbon by hot filtration. Heating the filtrate to dissolve, cooling to 52 ℃, adding the treated seed crystal, stirring, cooling for crystallization, separating out a small amount of crystals at 47 ℃, continuing stirring, standing at 40 ℃ for crystallization, standing overnight, cooling to 0-5 ℃ with ice water the next day, and performing centrifugal filtration to obtain 89.9g of diammonium glycyrrhizinate wet product. Drying the obtained wet product at 55 deg.C under reduced pressure for 8 hr to obtain 49.1g of diammonium glycyrrhizinate dried product. The obtained primary dried product was left at an air humidity of 70% for 48 hours, and 55.0g of the moisture-absorbed material was weighed. And after the obtained moisture-absorbed material is subjected to suction filtration, drying for 8 hours at 55 ℃ under reduced pressure again to obtain 48.2g of diammonium glycyrrhizinate raw material medicine with a large white crystal form, wherein the content is 99.2% by detection, and the solvent residue is 326 ppm.
Therefore, in the concrete implementation, the operation is simple, and the implementation cost is low. Through detection, the residual solvent ethanol of the obtained diammonium glycyrrhizinate bulk drug is less than or equal to 2000ppm, which is far lower than the quality standard of the residual solvent of diammonium glycyrrhizinate bulk drug in Chinese pharmacopoeia, the residual solvent ethanol is less than or equal to 5000ppm, the product is a white granular crystal with a large crystal form, and the product has high purity, good stability and good quality.
Finally, it should be noted that the above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same, and although the present invention is described in detail with reference to the above-mentioned embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the specific embodiments of the present invention without departing from the spirit and scope of the present invention, and all the modifications or equivalent substitutions should be covered in the claims of the present invention.
Claims (3)
1. A method for removing solvent residues of diammonium glycyrrhizinate bulk drug is characterized by comprising the following steps:
step A, heating the diammonium glycyrrhizinate crude product and the mixed solvent, adding activated carbon for decolorization after the diammonium glycyrrhizinate crude product and the mixed solvent are dissolved, and performing hot filtration;
step B, heating the filtrate obtained in the step A, cooling after dissolving, adding the treated seed crystal, stirring for crystallization, and performing centrifugal filtration to obtain a diammonium glycyrrhizinate wet product;
step C, drying the diammonium glycyrrhizinate wet product obtained in the step B under reduced pressure to obtain a diammonium glycyrrhizinate primary dry product;
d, placing the primary dried diammonium glycyrrhizinate product obtained in the step C in a room with air humidity of 65-85%, standing and absorbing moisture;
step E, after the material obtained in the step D after moisture absorption is filtered, carrying out reduced pressure drying again to obtain the diammonium glycyrrhizinate raw material medicine with low residual solvent;
in the step A, the mixed solvent is 50-55% of ethanol solution;
in the step D, standing and absorbing moisture for more than 10 hours;
and in the step C and the step E, drying under reduced pressure for 5-8 hours at the temperature of 50-60 ℃.
2. The method for removing solvent residues of diammonium glycyrrhizinate bulk drug according to claim 1, characterized in that: in the step A, the mass ratio of the diammonium glycyrrhizinate crude product to the mixed solvent is 1: 4 to 5.
3. The method for removing solvent residues of diammonium glycyrrhizinate bulk drug according to claim 1, characterized in that: and in the step B, after heating and dissolving, cooling and adding the treated seed crystal at the temperature of 48-52 ℃.
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| CN111393499A (en) * | 2020-03-25 | 2020-07-10 | 河南豫辰药业股份有限公司 | Method for removing triterpenoid impurities in diammonium glycyrrhizinate bulk drug |
| CN114409720B (en) * | 2021-12-31 | 2023-12-29 | 江苏天晟药业股份有限公司 | Method for improving large-scale production content of diammonium glycyrrhizinate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743338A (en) * | 2004-09-01 | 2006-03-08 | 天津市资福医药科技开发有限公司 | Method for preparing diammonium glycyrhetate |
| CN104877012A (en) * | 2014-05-29 | 2015-09-02 | 上海天伟生物制药有限公司 | Crystal of cyclic peptide compound and preparation method and application of crystal |
| CN106478762A (en) * | 2016-08-29 | 2017-03-08 | 江苏天晟药业股份有限公司 | A kind of preparation method of diammonium glycyrhetate |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743338A (en) * | 2004-09-01 | 2006-03-08 | 天津市资福医药科技开发有限公司 | Method for preparing diammonium glycyrhetate |
| CN104877012A (en) * | 2014-05-29 | 2015-09-02 | 上海天伟生物制药有限公司 | Crystal of cyclic peptide compound and preparation method and application of crystal |
| CN108276479A (en) * | 2014-05-29 | 2018-07-13 | 上海天伟生物制药有限公司 | Crystal of cyclic peptide compound and its preparation method and application |
| CN108276478A (en) * | 2014-05-29 | 2018-07-13 | 上海天伟生物制药有限公司 | Crystal of cyclic peptide compound and its preparation method and application |
| CN106478762A (en) * | 2016-08-29 | 2017-03-08 | 江苏天晟药业股份有限公司 | A kind of preparation method of diammonium glycyrhetate |
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Effective date of registration: 20210104 Address after: 461100 Qianwang village, zhangpan Town, Jian'an District, Xuchang City, Henan Province Applicant after: HENAN YUCHEN PHARMACEUTICAL Co.,Ltd. Address before: 461100 Industrial Park, zhangpan Town, Xuchang County, Xuchang City, Henan Province Applicant before: HENAN HUI JIN PHARMACEUTICAL Co.,Ltd. |
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