CN101709042B - Aseptic arginine glutamate and preparation method of powder injection thereof - Google Patents
Aseptic arginine glutamate and preparation method of powder injection thereof Download PDFInfo
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- CN101709042B CN101709042B CN 200910259679 CN200910259679A CN101709042B CN 101709042 B CN101709042 B CN 101709042B CN 200910259679 CN200910259679 CN 200910259679 CN 200910259679 A CN200910259679 A CN 200910259679A CN 101709042 B CN101709042 B CN 101709042B
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Abstract
The invention relates to aseptic arginine glutamate and a preparation method of powder injection thereof, comprising the following steps: 1) arginine is added in distilled water, after the arginine is completely dissolved, glutamic acid is added, and then the mixture is stirred to lead to react, the reaction is carried out until the solution is clarified, and then aseptic filtration is carried out; 2) the temperature of the filtrate is slowly reduced to be 10-15 DEG C, and then absolute alcohol with 1-3 times of volume of distilled water is added in the filtrate, the mixture is slowly stirred to be crystallized; 3) filtration and crystal vacuum drying are carried out to obtain the aseptic arginine glutamate; 4) the aseptic arginine glutamate is sub-packaged according to specification, so as to obtain the powder injection of the arginine glutamate. Compared with the prior art, in the preparation method of the arginine glutamate, the reaction of the arginine and the glutamic acid is single-step salifying reaction, the reaction process is short, the operation is simple, reaction time is not high, the alcohol can be recycled, and the preparation is easy to industrial production; in addition, the reaction yield is high, the prepared arginine glutamate has high water solubility, the product has good quality and the stability is good.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical chemistry, specifically, relate to the preparation method of a kind of aseptic arginine glutamate and powder injection thereof.
Background technology
Liver is a body of gland maximum in the human body, also is maximum digestive gland.Liver has the decomposition of carrying out sugar, store glycogen, detoxifcation, secretion of bile and engulf function such as defence.Also has hemopoietic function period the embryo.Human liver function heavy damage can cause ammonia metabolism disorder in the body, causes hyperammonemia state in the body, and the human body vitals are produced infringement (as causing hepatogenic encephalopathy).Glutargin is L-glutamic acid and arginic double salt; Smart L-glutamic acid can resolve into l-arginine and L-glutamic acid in vein input body; Wherein l-arginine is participated in bird acid circulation in human body, promotes the formation of urea, makes the ammonia that produces in the human body; Be transformed into nontoxic urea through urea cycle, by discharging in the urine; And too much ammonia is combined into nontoxic Stimulina in L-glutamic acid and the blood, and the latter dissociates ammonia through the effect of glutamine enzyme at kidney, is discharged by urine.L-arginine and L-glutamic acid effect combination can be removed the hyperammonemia state quickly and effectively, avoid producing serious organ injury.In addition, l-arginine and L-glutamic acid are the amino acid to the human body beneficial, have the effect of liver protecting, can recover impaired liver function, the enhances human body immunological competence.
Therefore, the Glutargin related drugs is mainly used in treatment because of the hyperammonemia due to acute and chronic hepatopathy such as liver cirrhosis, fatty liver, the hepatitis, the releasing of the cns symptom that is specially adapted to cause because of liver disease and the rescue of hepatic coma.Specifically; The disease and the situation that are suitable for mainly comprise: hepatic coma, hepatogenic encephalopathy, liver cirrhosis merge hepatitis B virus tire continue to increase, liver cirrhosis merge hepatitis C virus tire continue to increase, liver cirrhosis merges ascites, liver cirrhosis merges gestation, liver cirrhosis concurrent infection, liver cirrhosis surgical operation, acute, chronic hepatitis, fatty liver, shock, stupor, alcoholism, and neurosurgery, bone surgery, hepatobiliary surgery, bone gut surgery, burn and perform the operation etc.
At present, produce Glutargin and powder injection thereof both at home and abroad and mainly adopt following two kinds of methods:
L-arginine and L-glutamic acid is water-soluble 1., dissolving, filtration, filtrate decompression concentrates, and gets the arginine glutamic acid compsn; And then compsn is dissolved in 1～5 times the water for injection, stirring and dissolving under 60～90 ℃ of temperature is regulated pH value, and then through filtering, filtrates and left standstill room temperature cooling, crystallization, drying, pulverizing, packing 12～48 hours.Obviously, in the aforementioned production method, need carry out concentrating under reduced pressure in the preparation of compositions, increase the energy consumption of producing; In addition, steps such as the preparation of powder injection also needs loaded down with trivial details dissolving, filters, leaves standstill, cooling, crystallization, this has increased production cost undoubtedly, has reduced production efficiency.
2. l-arginine and L-glutamic acid are water-soluble, and 5 ℃ add anhydrous methanol down, carry out repeatedly recrystallization to get Glutargin, and 60 ℃ of vacuum-dryings prepare Glutargin finished product (US2851482) then.This patent mainly contains following two point defects:
2.1. this method uses anhydrous methanol to separate out Glutargin; As everyone knows; Methyl alcohol has intensive toxicity, and intake toxic reaction will occur when surpassing 4g, wrongly takes a cuvette and surpasses 10 grams and just can cause and lose the sight of both eyes; In large-scale production, brought a difficult problem, and the price of methyl alcohol is also quite expensive to environmental protection.In addition, arginine glutamic acid uses the arginine glutamic acid injection of methyl alcohol preparation for a long time as injection usefulness, can toxicity symptom might occur because of dissolvent residual.
2.2. this method need be carried out recrystallization repeatedly, needs a large amount of anhydrous methanols to come crystallization, this has increased production cost undoubtedly and has reduced production efficiency.Therefore present method is not suitable for the suitability for industrialized production Glutargin.
Therefore, be necessary to propose simple to operation, the Glutargin that production energy consumption is low and the preparation method of powder injection thereof.
Summary of the invention
The purpose of this invention is to provide simple to operation, the aseptic arginine glutamate that production energy consumption is low and the preparation method of powder injection thereof.
The preparation method of aseptic arginine glutamate of the present invention comprises: 1) under 25～40 ℃ condition, l-arginine is joined in the zero(ppm) water, treat that l-arginine dissolves fully after; Add L-glutamic acid; Stirring makes its reaction, after the clarification of question response to solution, and sterile filtration; 2) filtrating slowly is cooled to 10～15 ℃, in filtrating, adds the absolute ethyl alcohol of 1～3 times of zero(ppm) water volume then, slowly stirred crystallization; 3) filter, crystal vacuum-drying promptly gets aseptic arginine glutamate.
In addition, can with filtrating 40～50 ℃ the time concentrating under reduced pressure to reclaim ethanol, with the ethanol cycle utilization.
Wherein, in the step 1), said l-arginine and said L-glutamic acid are 1: 1～1.1 in molar ratio; The mass volume ratio of said l-arginine and zero(ppm) water is 1: 5.5～7.5 (being that every 1g l-arginine adds 5.5～7.5ml zero(ppm) water); The said normal pressure that is reflected at carries out;
In step 2) in comprise that also the temperature of crystallisation process control filtrating is 10～15 ℃;
Step 2) in, the said crystalline time is 1.5～3 hours;
In step 3), said vacuum-drying is 50～70 ℃ of vacuum-dryings 3～6 hours with crystal.
The present invention also provides the preparation method of aseptic arginine glutamate powder injection.This method need not Glutargin is further handled, and only need specify the packing of specification to get final product.
The preparation method of aseptic arginine glutamate powder injection of the present invention comprises: 1) under 25～40 ℃ condition, l-arginine is joined in the zero(ppm) water, treat that l-arginine dissolves fully after; Add L-glutamic acid; Stirring makes its reaction, after the clarification of question response to solution, and sterile filtration; 2) filtrating slowly is cooled to 10～15 ℃, in filtrating, adds the absolute ethyl alcohol of 1～3 times of zero(ppm) water volume then, slowly stirred crystallization; 3) filter, crystal vacuum-drying promptly gets aseptic arginine glutamate; 4) aseptic arginine glutamate is undertaken aseptic subpackaged by specification, promptly get the powder injection of Glutargin.
Wherein, in the step 1), the mol ratio of said l-arginine and said L-glutamic acid is 1: 1～1.1; The mass volume ratio of said l-arginine and zero(ppm) water is 1: 5.5～7.5 (being that every 1g l-arginine adds 5.5～7.5ml zero(ppm) water); The said normal pressure that is reflected at carries out;
In step 2) in comprise that also the temperature of crystallisation process control filtrating is 10～15 ℃;
Step 2) in, the said crystalline time is 1.5～3 hours;
In step 3), said vacuum-drying is 50～70 ℃ of vacuum-dryings 3～6 hours with crystal.
Compared with prior art, among the preparation method of Glutargin of the present invention, l-arginine and L-glutamic acid are a step salt-forming reaction; Reaction process is short, and simple to operate, temperature of reaction does not need too high; Ethanol is recyclable to be utilized again, be easy to suitability for industrialized production, and reaction yield is high; The Glutargin foreign matter content of preparation is few, and purity is high, constant product quality; And during preparation arginine glutamic acid powder injection, need not Glutargin is carried out aftertreatment, only need specify the aseptic subpackaged of specification to get final product.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1
The 40.0g l-arginine is dissolved in the 220ml zero(ppm) water, under agitation condition, adds 33.8g L-glutamic acid in the time of 40 ℃ and make its reaction, treat the solution clarification, through sterile filtration; To filtrate adds the 440ml absolute ethyl alcohol when slowly being cooled to 10 ℃, insulation was slowly stirred 3 hours; Crystallization is the back suction filtration fully, and crystal gets aseptic arginine glutamate 72.3g 60 ℃ of vacuum-dryings 6 hours, and total recovery is about 98.0%.
The complete National standard of quality product.Aseptic arginine glutamate is through the aseptic subpackaged injection arginine glutamic acid powder injection that promptly gets then.
Detected result is seen table 1.
Embodiment 2
The 80.0g l-arginine is dissolved in the 480ml zero(ppm) water, under agitation condition, adds 74.3g L-glutamic acid in the time of 35 ℃ and make its reaction, treat the solution clarification, through sterile filtration; Add the 500ml absolute ethyl alcohol when slowly being cooled to 12 ℃, insulation was slowly stirred 1.5 hours; Crystallization is the back suction filtration fully, and crystal gets aseptic arginine glutamate 146.6g 70 ℃ of vacuum-dryings 3.5 hours, and total recovery is about 95.0%.
The complete National standard of quality product.Aseptic arginine glutamate is through the aseptic subpackaged injection arginine glutamic acid powder injection that promptly gets then.
Detected result is seen table 1.
Embodiment 3
The 100.0g l-arginine is dissolved in the 750ml zero(ppm) water, under agitation condition, adds 90g L-glutamic acid in the time of 25 ℃ and make its reaction, treat the solution clarification, through sterile filtration; Add the 800ml absolute ethyl alcohol when slowly being cooled to 14 ℃, insulation was slowly stirred 2.5 hours; Crystallization is the back suction filtration fully, and crystal gets aseptic arginine glutamate 179.5g 55 ℃ of vacuum-dryings 5 hours, and total recovery is about 94.5%.
The complete National standard of quality product.Aseptic arginine glutamate is through the aseptic subpackaged injection arginine glutamic acid powder injection that promptly gets then.
Detected result attaches the table 1 of opinion:
The detected result of the product of table 1 embodiment preparation
| Glutargin | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| pH | 6.45 | 6.58 | 6.55 |
| Specific optical rotation | +28.50 | +29.35 | +28.40 |
| Transmittance | 98.5％ | 98.6％ | 99.0％ |
| Muriate | 0.11％ | 0.08％ | 0.10％ |
| Ammonium salt | 0.01％ | 0.01％ | 0.012％ |
| Vitriol | 0.01％ | 0.009％ | 0.075％ |
| Molysite | 2.50ppm | 2.55ppm | 3.01ppm |
| Heavy metal | 3.50ppm | 3.75ppm | 3.74ppm |
| Arsenic salt | 0.01ppm | 0.05ppm | 0.02ppm |
| Moisture content | 3.2％ | 2.7％ | 2.6％ |
| Scorching hot residue | 0.13％ | 0.05％ | 0.03％ |
| Content | 99.5％ | 99.4％ | 99.0％ |
| Fusing point | 193.2～194.3℃ | 193.2～194.5℃ | 193.4～194.5℃ |
Result by table 1 is visible, and the foreign matter content of prepared according to the methods of the invention aseptic arginine glutamate and powder injection thereof is few, and purity is high, constant product quality, and its performance is considerably beyond domestic and international existing aseptic arginine glutamate and powder injection product thereof.
Claims (6)
1. the preparation method of an aseptic arginine glutamate may further comprise the steps: 1) under 25～40 ℃ condition, l-arginine is joined in the zero(ppm) water; After treating that l-arginine dissolves fully, add L-glutamic acid, stir and make its reaction; After the clarification of question response to solution, sterile filtration; 2) filtrating slowly is cooled to 10～15 ℃, in filtrating, adds the absolute ethyl alcohol of 1～3 times of zero(ppm) water volume then, slowly stirred crystallization; 3) filter, crystal vacuum-drying promptly gets aseptic arginine glutamate;
Wherein, in the step 1), the mol ratio of said l-arginine and said L-glutamic acid is 1: 1～1.1;
The mass volume ratio of said l-arginine and zero(ppm) water is 1: 5.5～7.5;
The said normal pressure that is reflected at carries out.
2. the method for claim 1 is characterized in that, in step 2) in comprise that also the temperature of crystallisation process control filtrating is 10～15 ℃.
3. the method for claim 1 is characterized in that step 2) in, the said crystalline time is 1.5～3 hours.
4. the method for claim 1 is characterized in that, in step 3), said vacuum-drying is 50～70 ℃ of vacuum-dryings 3～6 hours with crystal.
5. the preparation method of an aseptic arginine glutamate powder injection may further comprise the steps: 1) under 25～40 ℃ condition, l-arginine is joined in the zero(ppm) water; After treating that l-arginine dissolves fully, add L-glutamic acid, stir and make its reaction; After the clarification of question response to solution, sterile filtration; 2) filtrating slowly is cooled to 10～15 ℃, in filtrating, adds the absolute ethyl alcohol of 1～3 times of zero(ppm) water volume then, slowly stirred crystallization; 3) filter, crystal vacuum-drying promptly gets aseptic arginine glutamate; 4) aseptic arginine glutamate is undertaken aseptic subpackaged by specification, promptly get the powder injection of Glutargin;
In the step 1), the mol ratio of said l-arginine and said L-glutamic acid is 1: 1～1.1; The mass volume ratio of said l-arginine and zero(ppm) water is 1: 5.5～7.5; The said normal pressure that is reflected at carries out.
6. method as claimed in claim 5 is characterized in that step 2) in, the said crystalline time is 1.5～3 hours; In step 3), said vacuum-drying is 50～70 ℃ of vacuum-dryings 3～6 hours with crystal.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102603576A (en) * | 2011-12-27 | 2012-07-25 | 开封制药(集团)有限公司 | Preparation method of medicinal arginine glutamate |
| CN102531969A (en) * | 2011-12-28 | 2012-07-04 | 蚌埠丰原医药科技发展有限公司 | Method for preparing sterile L-arginine |
| CN112679370B (en) * | 2020-12-30 | 2023-07-18 | 无锡晶海氨基酸股份有限公司 | Preparation method of medicinal arginine glutamic acid |
| CN112778164B (en) * | 2021-01-04 | 2022-05-06 | 无锡晶海氨基酸股份有限公司 | Method for efficiently producing medicinal arginine glutamic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2851482A (en) * | 1957-05-20 | 1958-09-09 | Gen Mills Inc | L-arginine-l-glutamate |
| CN101156842A (en) * | 2007-09-29 | 2008-04-09 | 北京和为康医药科技有限公司 | Pharmaceutical preparation containing arginine glutamic acid |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2851482A (en) * | 1957-05-20 | 1958-09-09 | Gen Mills Inc | L-arginine-l-glutamate |
| CN101156842A (en) * | 2007-09-29 | 2008-04-09 | 北京和为康医药科技有限公司 | Pharmaceutical preparation containing arginine glutamic acid |
Non-Patent Citations (4)
| Title |
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| 李爱平等.精氨酸复盐的合成研究及应用进展.《江苏化工》.2005,第33卷(第2期),第22-25页. * |
| 梅亚红等.L - 精氨酸 - L - 焦谷氨酸的应用及合成.《氨基酸和生物资源》.2005,第27卷(第2期),第45-47页. |
| 梅亚红等.L- 精氨酸- L- 焦谷氨酸的应用及合成.《氨基酸和生物资源》.2005,第27卷(第2期),第45-47页. * |
| 郑岚等.药用氨基酸复合盐的合成研究.《化学试剂》.2009,第31卷(第9期), * |
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