CN102993036A - Preparation method of aspirin-DL-lysine sterile raw material - Google Patents
Preparation method of aspirin-DL-lysine sterile raw material Download PDFInfo
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- CN102993036A CN102993036A CN2011102809093A CN201110280909A CN102993036A CN 102993036 A CN102993036 A CN 102993036A CN 2011102809093 A CN2011102809093 A CN 2011102809093A CN 201110280909 A CN201110280909 A CN 201110280909A CN 102993036 A CN102993036 A CN 102993036A
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Abstract
The invention provides a preparation method of an aspirin-DL-lysine sterile raw material used for treating diseases needing antipyresis, analgesia, anti-infection and the like. The preparation method comprises the following steps in sequence: adding a DL-lysine aqueous solution (subjected to heat source removal and bacteria removal) in an aspirin ethanol solution (subjected to heat source removal and bacteria removal) for a reaction at a temperature ranging from -5 to 0 DEG C, wherein the mass ratio of DL-lysine to aspirin is controlled within 1: (1.0-1.2); adding a certain weight of ethanol (subjected to heat source removal and bacteria removal); crystallizing at a low temperature; filtering; washing with ethanol; and drying at 55+/-1 DEG C under reduced pressure so as to obtain the aspirin-dl-lysine sterile raw material. According to the preparation method, reaction and crystallization are performed at a relatively low temperature, the preparation method is convenient and easy to operate, the quality is controllable, and the preparation method is applicable for commercialized mass production. Compared with the preparation method at a common temperature, the preparation method of the aspirin-DL-lysine sterile raw material, provided by the invention, has the advantages of greatly reducing the content of free salicylic acid in the aspirin-DL-lysine sterile raw material, decreasing clinical irritation as well as sensitization of medicines and increasing the quality of the aspirin-DL-lysine sterile raw material.
Description
Technical field
The present invention relates to the medical material preparation field, relate in particular to the preparation method of the aseptic raw material of a kind of di-lysine-aspirin.
Background technology
Di-lysine-aspirin is the composite salt of acetylsalicylic acid and Methionin, and its mechanism of action is the same with acetylsalicylic acid, main reduces prostaglandin(PG) and thromboxane synthetic by suppressing the activity of epoxidase, and reaches analgesic, analgesia, anti-infectious effect.Because its good water solubility, be applicable to muscle and intravenously administrable, can be distributed to rapidly after the administration in each tissue and reach maximum concentration, thereby demonstrate very strong analgesic activity, its effect generally is not less than conventional narcotic analgesic, and apnea suppresses or habituation, not yet find the impact on haematogenous mechanism and hepatic and renal function, this medicine contains the Methionin of needed by human simultaneously, so di-lysine-aspirin also has the promotion tissue repair, promote the neurocyte metabolism, improve the central nervous tissue vigor, improve the effects such as histanoxia.
Use clinically acetylsalicylic acid and have 90 years, because of its determined curative effect, toxicity is lower, still be antipyretic and analgesic commonly used to making, but because its solubleness is little, can only be for oral, and larger to GI irritation, even cause gastrorrhagia, and limit its clinical use range.Di-lysine-aspirin belongs to a kind of novel dipron of the derivative of acetylsalicylic acid, can supply the injection administration, and is rapid-action, effect is strong, has avoided the gastrointestinal reaction of acetylsalicylic acid, generally is used for the states such as West Europe and Japan.In this medicine venous channel can with common antibiotics, antiviral compatibility, to a certain degree avoided young infant after the intramuscular injection febrifuge because the agitation that causes of pain, opposing and successive treatment nursing uncooperative.Chinese Pharmaceutical Association and China Child Development Centre as national children recommended products, are it a kind of novel antipyretic-antalgic preparations of in recent years China's production.
The preparation method of existing di-lysine-aspirin is: acetylsalicylic acid is dissolved in the ethanol, stirs at normal temperatures to add the 1B aqueous solution, reacts complete, add gac, filter except thermal source, degerming, add again an amount of ethanol (except thermal source, degerming) low temperature stirring and crystallizing, vacuum-drying.Free salicylic acid content in the products obtained therefrom is higher, and this product is easily decomposed the generation Whitfield's ointment in storage process, cause medication pungency and sensitization all to increase.Country is more and more higher to the specification of quality of medicine in recent years, the particularly crystal formation of product, impurity etc., and therefore, we are optimized existing di-lysine-aspirin preparation technology, are intended to improve the safety and efficacy of product in clinical application.
Summary of the invention
The invention provides a kind of easy and simple to handle, quality controllable and be applicable to the preparation method of the aseptic raw material of di-lysine-aspirin of the large production of commercialization, the novelty of the method is low-temp reaction, crystallization, greatly reduce the foreign matter content in the product, improved product yield and quality.
The present invention is by being dissolved in 1B and acetylsalicylic acid respectively by a certain percentage in the hydrate alcohol, and the remix reaction adds an amount of ethanol crystallization, reduces the product foreign matter content by the control to temperature of reaction and recrystallization temperature, improves product yield.By the di-lysine-aspirin good stability that the method makes, foreign matter content is low, and content uniformity is easily controlled when the powder packing.
1, the preparation method of the di-lysine-aspirin powder pin of the present invention's proposition may further comprise the steps:
(1) take by weighing 1.0～1.5 parts of weight acetylsalicylic acid, add the ethanol stirring and dissolving of 10 times of weight, except thermal source, the millipore filtration degerming is cooled to-5 ℃～0 ℃ to it to crystallizer;
(2) taking by weighing 1.0～1.2 parts of weight DL-Lys, to be made into concentration be 30～35% solution, except thermal source, adds in the acetylsalicylic acid alcohol crystallizer insulation (5 ℃～0 ℃) reaction 30min after the degerming;
(3) take by weighing in ethanol (except thermal source, degerming) the adding crystallizer of 10 times of acetylsalicylic acid weight, solution temperature is controlled at-5 ℃～0 ℃ in the tank, 120～180 rev/mins of revolutions, stirring and crystallizing 4 hours, centrifuging;
(4) ethanol (except thermal source, degerming) with 4 times of acetylsalicylic acid weight divides the crystal that washs gained for 2 times, gets product in 4 hours at 55 ± 1 ℃ of drying under reduced pressure.
Reduce and improve the yield of product for the content that makes free salicylic acid in the di-lysine-aspirin product, preferably according to the following steps preparation:
(1) take by weighing 1.0～1.5 parts of weight acetylsalicylic acid, add the ethanol stirring and dissolving of 10 times of weight, except thermal source, the millipore filtration degerming is cooled to-5 ℃～0 ℃ to it to crystallizer;
(2) taking by weighing 1.0～1.2 parts of DL-Lys, to be made into concentration be 30% solution, except thermal source, adds in the acetylsalicylic acid alcohol crystallizer insulation (5 ℃～0 ℃) reaction 30min after the degerming;
(3) take by weighing in ethanol (except thermal source, degerming) the adding crystallizer of 10 times of acetylsalicylic acid weight, solution temperature is controlled at-5 ℃～0 ℃ in the tank, 120～180 rev/mins of revolutions, stirring and crystallizing 4 hours, centrifuging;
(4) ethanol (except thermal source, degerming) with 4 times of acetylsalicylic acid weight divides the crystal that washs gained for 2 times, gets product in 4 hours at 55 ± 1 ℃ of drying under reduced pressure.
Acetylsalicylic acid easily decomposes the generation Whitfield's ointment under solution state, we are controlled at temperature of reaction-5 ℃～0 ℃, reduces greatly it and decomposes, and has reduced the content of free salicylic acid in the finished product, has strengthened the security of clinical application.
Embodiment
Embodiment 1:
1. take by weighing the 4.0kg acetylsalicylic acid to stainless steel cask, add 40kg ethanol, stirring and dissolving, except thermal source, the millipore filtration degerming is cooled to-5 ℃～0 ℃ to it to crystallizer;
2. take by weighing DL-Lys 3.6kg to stainless steel cask, add 8.4kg pure water stirring and dissolving, except thermal source, add in the acetylsalicylic acid alcohol crystallizer insulation (5 ℃～0 ℃) reaction 30min after the degerming;
3. take by weighing 56kg ethanol and add 56g gac stirring 30min, filter carbon removal, degerming, get 40kg and add in the crystallizer, solution temperature is controlled at-5 ℃～0 ℃ in the tank, 140 rev/mins of revolutions, stirring and crystallizing 4 hours, centrifuging;
4. divide the crystal of 2 washing gained with 16kg ethanol, 55 ± 1 ℃ of drying under reduced pressure 4 hours, get the 6.25kg product, yield 86.2%.
Embodiment 2:
1. take by weighing the 5.0kg acetylsalicylic acid to stainless steel cask, add 50kg ethanol, stirring and dissolving, except thermal source, the millipore filtration degerming is cooled to-5 ℃～0 ℃ to it to crystallizer;
2. take by weighing DL-Lys 4.5kg to stainless steel cask, add 10.5kg pure water stirring and dissolving, except thermal source, add in the acetylsalicylic acid alcohol crystallizer insulation (5 ℃～0 ℃) reaction 30min after the degerming;
3. take by weighing 70kg ethanol and add 70g gac stirring 30min, filter carbon removal, degerming, get 50kg and add in the crystallizer, solution temperature is controlled at-5 ℃～0 ℃ in the tank, 140 rev/mins of revolutions, stirring and crystallizing 4 hours, centrifuging;
4. divide the crystal of 2 washing gained with 16kg ethanol, 55 ± 1 ℃ of drying under reduced pressure 4 hours, get the 7.72kg product, yield 85.2%.
Embodiment 3:
1 takes by weighing the 4.5kg acetylsalicylic acid to stainless steel cask, adds 45kg ethanol, stirring and dissolving, and stirring and dissolving, except thermal source, the millipore filtration degerming is cooled to-5 ℃～0 ℃ to it to crystallizer;
2. take by weighing DL-Lys 4.05kg to stainless steel cask, add 9.4kg pure water stirring and dissolving, except thermal source, add in the acetylsalicylic acid alcohol crystallizer insulation (5 ℃～0 ℃) reaction 30min after the degerming;
3. take by weighing 63kg ethanol and add 63g gac stirring 30min, filter carbon removal, degerming, get 45kg and add in the crystallizer, solution temperature is controlled at-5 ℃～0 ℃ in the tank, 140 rev/mins of revolutions, stirring and crystallizing 4 hours, centrifuging;
4. divide the crystal of 2 washing gained with 18kg ethanol, 55 ± 1 ℃ of drying under reduced pressure 4 hours, get the 6.97kg product, yield 85.4%.
Comparative Examples 1:
1. the 10.0g acetylsalicylic acid is dissolved in the 50.0g dehydrated alcohol, 20～25 ℃ are stirred down, the 7.14g DL-Lys are dissolved in dropping in the 9.4kg pure water in the acetylsalicylic acid ethanolic soln again, dropwise and continue reaction 30min;
2. add the 70.0g dehydrated alcohol, 0～5 ℃, 140 rev/mins lower stirring and crystallizing, filter, with absolute ethanol washing 2 times, 55 ± 1 ℃ of vacuum-drying 4 hours gets 11.9g, yield 75.3%.
The product that above-described embodiment 1～3 and Comparative Examples 1 is made according to the method for inspection of related substance carries out the mensuration of free salicylic acid content.
| Yield | Salicylic acid content | |
| Embodiment 1 | 86.2％ | 0.06％ |
| Embodiment 2 | 85.2％ | 0.03％ |
| Embodiment 3 | 85.4％ | 0.05％ |
| Comparative Examples 1 | 75.3％ | 0.16％ |
This shows, adopt the inventive method to carry out the production of the aseptic raw material of di-lysine-aspirin, the amount of free salicylic acid is controlled lowlyer in the finished product, and product yield is higher, and constant product quality, controllability are better than existing preparation method.
Claims (6)
1. the preparation method of the aseptic raw material of di-lysine-aspirin is characterized in that, may further comprise the steps:
(1) take by weighing acetylsalicylic acid and 10 times of weight dissolve with ethanol of certainweight, degerming except thermal source, is cooled to-5 ℃～0 ℃ to it;
(2) certain density DL-Lys solution (degerming, except thermal source) is added in the acetylsalicylic acid alcoholic solution tank insulation (5 ℃～0 ℃) reaction;
(3) ethanol of 10 times of acetylsalicylic acid weight (degerming, except thermal source) is added in the retort, solution temperature is controlled at-5 ℃～0 ℃ in the tank, the control revolution, and crystallization filters;
(4) with the ethanol of 4 times of acetylsalicylic acid weight (degerming, except thermal source) washing crystal, drying under reduced pressure gets product.
2. the preparation method of the aseptic raw material of a kind of di-lysine-aspirin as claimed in claim 1 is characterized in that: acetylsalicylic acid and DL-Lys ratio are (1.0～1.2) in (1), (2) step: 1 (take weight as unit).
3. the preparation method of the aseptic raw material of a kind of di-lysine-aspirin as claimed in claim 1, it is characterized in that: temperature of reaction and recrystallization temperature all are controlled at-5 ℃～0 ℃ low temperature in (2), (3) step.
4. the preparation method of the aseptic raw material of a kind of di-lysine-aspirin as claimed in claim 1, it is characterized in that: the concentration of the DL-Lys aqueous solution is 30～35% in (2) step.
5. the preparation method of the aseptic raw material of a kind of di-lysine-aspirin as claimed in claim 1, it is characterized in that: the revolution that stirs in (3) step is 120～180 rev/mins.
6. the preparation method of the aseptic raw material of a kind of di-lysine-aspirin as claimed in claim 1, it is characterized in that: drying conditions is 55 ± 1 ℃ of drying under reduced pressure in (4) step.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552196A (en) * | 2020-11-23 | 2021-03-26 | 蚌埠丰原医药科技发展有限公司 | Method for preparing aspirin-lysine |
| CN114394910A (en) * | 2021-12-30 | 2022-04-26 | 蚌埠丰原医药科技发展有限公司 | Refining method of aspirin-lysine |
| CN114478287A (en) * | 2021-12-31 | 2022-05-13 | 蚌埠丰原医药科技发展有限公司 | Aspirin-lysine crystal form, preparation method and application |
Citations (2)
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|---|---|---|---|---|
| JPS5732212A (en) * | 1980-08-07 | 1982-02-20 | Mitsui Toatsu Chem Inc | Sterilizing method of acetylsalicylate salt |
| CN101633624A (en) * | 2009-08-04 | 2010-01-27 | 蚌埠丰原医药科技发展有限公司 | Preparation method of improved di-lysine-aspirin |
-
2011
- 2011-09-10 CN CN2011102809093A patent/CN102993036A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5732212A (en) * | 1980-08-07 | 1982-02-20 | Mitsui Toatsu Chem Inc | Sterilizing method of acetylsalicylate salt |
| CN101633624A (en) * | 2009-08-04 | 2010-01-27 | 蚌埠丰原医药科技发展有限公司 | Preparation method of improved di-lysine-aspirin |
Non-Patent Citations (4)
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| 《武汉化工学院学报》 19880330 汪树清等 L_赖氨酸乙酰水杨酸盐合成的初步研究 1-6 , 第01期 * |
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| 汪树清等: "L―赖氨酸乙酰水杨酸盐合成的初步研究", 《武汉化工学院学报》, no. 01, 30 March 1988 (1988-03-30) * |
| 黄行铁等: "赖氨匹林制造工艺的探讨", 《延边大学医学学报》, vol. 9, no. 04, 31 December 1986 (1986-12-31) * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552196A (en) * | 2020-11-23 | 2021-03-26 | 蚌埠丰原医药科技发展有限公司 | Method for preparing aspirin-lysine |
| CN112552196B (en) * | 2020-11-23 | 2024-02-02 | 蚌埠丰原医药科技发展有限公司 | Method for preparing lysine-piprolin |
| CN114394910A (en) * | 2021-12-30 | 2022-04-26 | 蚌埠丰原医药科技发展有限公司 | Refining method of aspirin-lysine |
| CN114478287A (en) * | 2021-12-31 | 2022-05-13 | 蚌埠丰原医药科技发展有限公司 | Aspirin-lysine crystal form, preparation method and application |
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Application publication date: 20130327 |