CN102018668A - Preparation method of aceglutamide - Google Patents
Preparation method of aceglutamide Download PDFInfo
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- CN102018668A CN102018668A CN 201010578234 CN201010578234A CN102018668A CN 102018668 A CN102018668 A CN 102018668A CN 201010578234 CN201010578234 CN 201010578234 CN 201010578234 A CN201010578234 A CN 201010578234A CN 102018668 A CN102018668 A CN 102018668A
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Abstract
The invention provides a preparation method of aceglutamide. By utilizing the new method provided by the invention, the defect of the relevant substances of the aceglutamide due to the existing method can be overcome. In the method, the temperature of 70-80 DEG C of the prepared water for injection is improved into the water temperature of 35-42 DEG C; and after the product is subjected to detection, an accelerated test, a long term stability test and the like, a data result shows that all indexes of the relevant substance, content and the like of the aceglutamide can reach the standard of the China Pharmacopeia 2010 edition after the new method provided by the invention is adopted. The method provided by the invention is simple and practicable and is suitable for industrial production on a large scale.
Description
Technical field:
The present invention relates to pharmaceutical preparation, be specifically related to process for preparing medicine, relate in particular to the preparation method of acetyl glutamine injection.
Background technology:
Aceglutamide is a cerebral function improving medicine, can improve the neurocyte metabolism. keep the effect of neural stress ability and reduction blood ammonia, improve brain function.Be mainly used in stupor, paralysis and the hypophrenia that hepatic coma, hemiplegia, high paraplegia, poliomyelitis sequela, neurosurgery etc. cause, memory disorder etc. clinically.At present, commonly used have an acetyl glutamine injection.
The composition of acetyl glutamine injection is as follows:
| Composition | Per 10,000 milliliters of recipe quantities | |
| 1 | Aceglutamide | 500g |
| 2 | Sodium hydroxide | 90-130g |
| 3 | Water for injection | Add to 10,000 milliliters |
The preparation method of existing acetyl glutamine injection is:
(1) water for injection (water temperature 70-80 ℃) of 60%-70% amount of preparation is put into Agitation Tank, adding, the weighing sodium hydroxide stirs.
(2) add weighing aceglutamide, stir.
(3) add water for injection to full dose, stir.
(4) solution titanium filter, microporous membrane cartridge filter circulating filtration.
(5) regulate pH value to the 5.0-6.5 scope.
(6) measure indexs such as middle product content, pH value.
(7) embedding is to ampoule.
(8) 116 ℃, the 30min sterilization.
(9) lamp inspection.
(10) printing package, warehouse-in.
Because the acetyl glutamine injection quality standard is included in " Chinese pharmacopoeia version in 2010 has increased the inspection of related substance especially, and therefore, the prepared product of said method can not reach new standard, needs to improve preparation method.Because of acetyl glutamine injection is an injection, must guarantee that product is aseptic, therefore under the situation that can not guarantee sterile production, the inventor tests and adopts 116 ℃, the terminal sterilization method of 30min, such processing is though reached aseptic index, but related substance obviously increases, and still can not reach new standard-required.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research design reduces the preparation method of its related substances in the acetyl glutamine injection, makes final product quality meet " Chinese pharmacopoeia version standard in 2010.The invention provides a kind of preparation method of acetyl glutamine injection,
The composition of acetyl glutamine injection is as follows:
| Composition | Per 10,000 milliliters of recipe quantities | |
| 1 | Aceglutamide | 500g |
| 2 | Sodium hydroxide | 90-130g |
| 3 | Water for injection | Add to 10,000 milliliters |
This preparation method comprises the following steps:
(1) will be 35-42 ℃ of water for injection for the water temperature of total amount 60%-70%, put into Agitation Tank, and add sodium hydroxide and stir;
(2) add aceglutamide, 35-42 ℃ of stirring;
(3) add water for injection to full dose, 35-42 ℃ of stirring;
(4) solution is used the titanium filter earlier, is filtered by 0.45 μ m and 0.2 μ m microporous membrane filters successively;
(5) regulate pH value to 5.0-6.5;
(6) measure the middle product content of acetyl glutamine injection 95.0-105.0%, pH value 5.0-6.5
(7) embedding is to ampoule;
(8) 116 ℃, the 30min sterilization;
(9) lamp inspection;
(10) printing package, the qualified warehouse-in of finished product detection.
The preferred water temperature of the described step of the inventive method (1) is a 38-39 ℃ of water for injection; More preferably water temperature is a 35-37 ℃ of water for injection.
Described step (5) is regulated pH value with 10% acetic acid or 10% sodium hydroxide solution, and step (6) is for to detect by two the 6th page of methods of Chinese Pharmacopoeia.
The present invention is after improving one's methods, and it is 35-42 ℃ that dosing water for injection temperature drops to water temperature by 70-80 ℃, and through experimental study, the related substance index obviously descends, and has reduced product risks better.After accelerated test and long-term stable experiment etc. also showed employing new method of the present invention, every indexs such as acetyl glutamine injection related substance, content all reached " Chinese pharmacopoeia version standard in 2010.The inventive method is simple, does not increase new cost, is suitable for the scale suitability for industrialized production.
The specific embodiment:
Embodiment 1 preparation acetyl glutamine injection: (lot number 100201)
| Sequence number | Composition | Per 10,000 milliliters of recipe quantities (5000) |
| 1 | Aceglutamide | 500g |
| 2 | Sodium hydroxide | 90-130g |
| 3 | Water for injection | Add to 10,000 milliliters |
(1) water temperature with the 60%-70% amount of preparation is that 40-42 ℃ of water for injection is put into beaker, and adding, the weighing sodium hydroxide stirs.
(2) add weighing aceglutamide, 40-42 ℃ of stirring.
(3) add water for injection to full dose, 40-42 ℃ of stirring.
(4) solution is used titanium filter (model RT-TL) earlier, is filtered by 0.45 μ m and 0.2 μ m microporous membrane filters successively;
(5) 10% acetic acid or 10% sodium hydroxide solution are regulated pH value to the 5.0-6.5 scope.(6) measure product content (pressing two ones the 6th page of Chinese Pharmacopoeia, the 95%-105% of aceglutamide centre product labelled amount) in the middle of the acetyl glutamine injection, pH value indexs such as (5.0-6.5) qualified after.
(7) embedding is to ampoule.
(8) 116 ℃, the 30min sterilization.
(9) lamp inspection.
(10) detection of finished product related substance is qualified.(by " Chinese pharmacopoeia version standard in 2010)
Embodiment 2 preparation acetyl glutamine injections (lot number 100202)
Composition and preparation method are with embodiment 1, but the water temperature of the water for injection of step (1) and step (2) whipping temp are 35-37 ℃.
Embodiment 3 preparation acetyl glutamine injections (lot number 100301)
Form and prepare, but the water temperature of the water for injection of step (1) and step (2) whipping temp are 38-39 ℃ with embodiment 1.
Example 1-3 related substance check result:
From above 3 examples, see that related substance is lower than standard, meet " Chinese pharmacopoeia version standard in 2010 fully.
Below be that (wherein step (1) is put into Agitation Tank with the water for injection (water temperature 70-80 ℃) of 60%-70% amount of preparation, and adding, the weighing sodium hydroxide stirs by existing preparation technology.) production the product related substance by " Chinese pharmacopoeia version in 2010 detects and exceeds standard defectively, and 3 batch sample assays are as follows:
Embodiment 4 preparation acetyl glutamine injections (lot number 100506)
| Composition | 250,000 milliliters of recipe quantities (125000) | |
| 1 | Aceglutamide | 12500g |
| 2 | Sodium hydroxide | 2250-3250g |
| 3 | Water for injection | Add to 250,000 milliliters |
Preparation is with embodiment 1.
Embodiment 5 preparation acetyl glutamine injections (lot number 100507)
Form and prepare with embodiment 2.
Embodiment 6 preparation acetyl glutamine injections (lot number 100508)
Form and prepare with embodiment 3.
Embodiment 7 preparation acetyl glutamine injections (lot number 100501)
Form
| Sequence number | Composition | 500,000 milliliters of recipe quantities (100000) |
| 1 | Aceglutamide | 25000g |
| 2 | Sodium hydroxide | 4500-6500g |
| 3 | Water for injection | Add to 500,000 milliliters |
Preparation is with embodiment 1.
Embodiment 8 preparation acetyl glutamine injections (lot number 100502)
Form and prepare with embodiment 2.
Embodiment 9 preparation acetyl glutamine injections (lot number 100503)
Form and prepare with embodiment 3.
The acetyl glutamine injection of the foregoing description 1-9 preparation all meet " Chinese pharmacopoeia version quality standard in 2010. (row as follows)
The acetyl glutamine injection quality standard
" Chinese pharmacopoeia version in 2010
This product is the aseptic aqueous solution of aceglutamide.Contain aceglutamide (C
7H
12N
2O
4) should be 90.0%～110.0% of labelled amount.
[character] this product is a white crystalline powder; Odorless, tasteless.
This product is dissolved in water, slightly soluble in ethanol.
This product an amount of (being equivalent to aceglutamide 0.25g approximately) is got in [discriminating] (1), adds hydrochloric acid solution (1 → 2) 2ml, about 30 minutes of heated and boiled, and constantly keep the skin wet, put coldly, regulate pH value with sodium hydroxide test solution and be about 6, get 2ml, add the about 2mg of 1,2,3-indantrione monohydrate, heating, solution shows bluish violet.
(2) in the chromatogram that under the assay item, writes down, the retention time unanimity of the retention time reference substance solution main peak of need testing solution main peak.
[inspection] pH value should be 4.5～7.0 (appendix VI H).
It is an amount of that related substance is got this product, makes the solution that contains aceglutamide 1mg among every 1ml approximately with the mobile phase dilution, as need testing solution; Measure according to the method under the aceglutamide item.If any impurity peaks, single impurity peak area must not be greater than 2 times (2.0%) of contrast solution main peak area in the need testing solution chromatogram, each impurity peak area and must not be greater than 3 times (3.0%) of contrast solution main peak area.
Bacterial endotoxin is got this product, checks (appendix XI E) in accordance with the law, and containing endotoxic amount in every 1mg aceglutamide should be less than 0.25EU.
The aseptic this product of getting is handled through membrane-filter procedure, with 0.1% aseptic peptone water solution gradation flushing (every film is no less than 100ml), with the positive contrast of staphylococcus aureus bacterium, checks (appendix XI H) in accordance with the law, should be up to specification.
Other should meet every regulation relevant under the injection item (appendix IB).
It is an amount of that [assay] precision is measured this product, makes the solution that contains aceglutamide 0.1mg among every 1ml approximately with the mobile phase dilution, measures according to the method under the aceglutamide assay item, promptly.
[classification] same aceglutamide.
[storage] shading, sealing is preserved.
[specification] (1) 2ml:0.1g (2) 5ml:0.25g (3) 5ml:0.3g (4) 5ml:0.6g
(5)10ml:0.5g(6)20ml:0.6
Embodiment 10
Embodiment 4-9 technology finished product of the present invention, accelerated test and long-term stable experiment data are examined the result entirely:
Three batches of acetyl glutamine injections of embodiment 4-6 (2ml:0.1g) product inspection result
Three batches of acetyl glutamine injections of embodiment 4-6 (2ml:0.1g) accelerated test data
Three batches of acetyl glutamine injections of embodiment 4-6 (2ml:0.1g) long-time stability data
Three batches of acetyl glutamine injections of embodiment 7-9 (5ml:0.25g) product inspection result
Three batches of acetyl glutamine injections of embodiment 7-9 (5ml:0.25g) accelerated test data
Three batches of acetyl glutamine injections of embodiment 7-9 (5ml:0.25g) long-time stability data
From above accelerated test and long-time stability data result, show adopt new technology of the present invention after, every indexs such as acetyl glutamine injection related substance, content all reach " Chinese pharmacopoeia version standard in 2010.
Claims (5)
1. acetyl glutamine injection preparation method, the composition of described acetyl glutamine injection is as follows:
The per 10,000 milliliters of injection liquid measures of composition
1 aceglutamide 500g
2 sodium hydroxide 90-130g
3 waters for injection add to 10,000 milliliters
It is characterized in that described preparation method comprises the following steps:
(1) will be that 35-42 ℃ of water for injection is put into Agitation Tank for the water temperature of total amount 60%-70%, and add sodium hydroxide and stir;
(2) add aceglutamide, 35-42 ℃ of stirring;
(3) add water for injection to full dose, 35-42 ℃ of stirring;
(4) solution is used the titanium filter earlier, is filtered by 0.45 μ m and 0.2 μ m microporous membrane filters successively;
(5) regulate pH value to 5.0-6.5;
(6) measure the middle product content of acetyl glutamine injection 95.0-105.0%, pH value 5.0-6.5;
(7) embedding is to ampoule;
(8) 116 ℃, the 30min sterilization;
(9) lamp inspection;
(10) printing package, the qualified warehouse-in of finished product detection.
2. according to the described method of claim 1, it is characterized in that the whipping temp of the water for injection water temperature of described step (1) and step (2) is 40-42 ℃.
3. according to the described method of claim 1, it is characterized in that the water for injection water temperature of described step (1) and step (2) whipping temp 38-39 ℃.
4. according to the described method of claim 1, it is characterized in that the water for injection water temperature of described step (1) and step (2) whipping temp 35-37 ℃.
5. according to the described method of claim 1, it is characterized in that described step (5) is regulated pH value and used 10% acetic acid or 10% sodium hydroxide solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010578234 CN102018668B (en) | 2010-12-08 | 2010-12-08 | Preparation method of aceglutamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010578234 CN102018668B (en) | 2010-12-08 | 2010-12-08 | Preparation method of aceglutamide |
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| CN102018668A true CN102018668A (en) | 2011-04-20 |
| CN102018668B CN102018668B (en) | 2012-01-18 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102204885A (en) * | 2011-05-31 | 2011-10-05 | 上海华中药业有限公司 | Preparation method of aceglutamide glucose injection |
| CN104688674A (en) * | 2013-12-10 | 2015-06-10 | 上海朝晖药业有限公司 | Preparation method of bemegride injection |
| CN104688675A (en) * | 2013-12-10 | 2015-06-10 | 上海朝晖药业有限公司 | Preparation method of lidocaine hydrochloride injection |
| CN105037195A (en) * | 2015-06-26 | 2015-11-11 | 康普药业股份有限公司 | Aceglutamide, and injection and preparation method thereof |
Citations (4)
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|---|---|---|---|---|
| CN1444931A (en) * | 2003-04-18 | 2003-10-01 | 张嵩 | Aceglutamide injection |
| CN1471909A (en) * | 2003-04-18 | 2004-02-04 | 江西东亚药业有限责任公司 | High-capacitance |
| CN1830425A (en) * | 2005-03-08 | 2006-09-13 | 巴里莫尔制药（通化）有限公司 | Preparation method of acetyl glutamine injection |
| CN1868467A (en) * | 2005-05-27 | 2006-11-29 | 曾列丹 | Aceglutamine prepn. for injection, and its preparing method |
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2010
- 2010-12-08 CN CN 201010578234 patent/CN102018668B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1444931A (en) * | 2003-04-18 | 2003-10-01 | 张嵩 | Aceglutamide injection |
| CN1471909A (en) * | 2003-04-18 | 2004-02-04 | 江西东亚药业有限责任公司 | High-capacitance |
| CN1830425A (en) * | 2005-03-08 | 2006-09-13 | 巴里莫尔制药（通化）有限公司 | Preparation method of acetyl glutamine injection |
| CN1868467A (en) * | 2005-05-27 | 2006-11-29 | 曾列丹 | Aceglutamine prepn. for injection, and its preparing method |
Non-Patent Citations (3)
| Title |
|---|
| 《中国药业》 20081231 岳臣轩等 乙酰谷酰胺葡萄糖注射液工艺研究 第17卷, 第8期 2 * |
| 《齐鲁药事》 20061231 李军等 乙酰谷酰胺冻干粉针处方及工艺研究 第25卷, 第5期 2 * |
| 《齐鲁药事》 20061231 王红卫等 乙酰谷酰胺注射液的生产工艺研究 第25卷, 第6期 2 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102204885A (en) * | 2011-05-31 | 2011-10-05 | 上海华中药业有限公司 | Preparation method of aceglutamide glucose injection |
| CN104688674A (en) * | 2013-12-10 | 2015-06-10 | 上海朝晖药业有限公司 | Preparation method of bemegride injection |
| CN104688675A (en) * | 2013-12-10 | 2015-06-10 | 上海朝晖药业有限公司 | Preparation method of lidocaine hydrochloride injection |
| CN104688674B (en) * | 2013-12-10 | 2018-03-20 | 上海朝晖药业有限公司 | A kind of preparation method of bemegrid parenteral solution |
| CN104688675B (en) * | 2013-12-10 | 2018-04-24 | 上海朝晖药业有限公司 | A kind of preparation method of lidocaine hydrochloride injection |
| CN105037195A (en) * | 2015-06-26 | 2015-11-11 | 康普药业股份有限公司 | Aceglutamide, and injection and preparation method thereof |
| CN105037195B (en) * | 2015-06-26 | 2018-04-13 | 康普药业股份有限公司 | Aceglutamide and its parenteral solution and preparation method |
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| Publication number | Publication date |
|---|---|
| CN102018668B (en) | 2012-01-18 |
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