CN1246306C - New method for preparing brufen arginine salt - Google Patents
New method for preparing brufen arginine salt Download PDFInfo
- Publication number
- CN1246306C CN1246306C CN 200410014369 CN200410014369A CN1246306C CN 1246306 C CN1246306 C CN 1246306C CN 200410014369 CN200410014369 CN 200410014369 CN 200410014369 A CN200410014369 A CN 200410014369A CN 1246306 C CN1246306 C CN 1246306C
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- China
- Prior art keywords
- ibuprofen
- preparation
- arginine salt
- arginine
- salt
- 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.)
- Expired - Lifetime
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- 238000000034 method Methods 0.000 title abstract description 8
- -1 brufen arginine salt Chemical class 0.000 title description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 31
- GCCOJNYCFNSJII-VWMHFEHESA-N [n'-[(4s)-4-amino-4-carboxybutyl]carbamimidoyl]azanium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N.CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 GCCOJNYCFNSJII-VWMHFEHESA-N 0.000 claims abstract description 29
- 239000004475 Arginine Substances 0.000 claims abstract description 19
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 150000002191 fatty alcohols Chemical class 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 4
- 239000013078 crystal Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- 235000009697 arginine Nutrition 0.000 description 17
- 239000000047 product Substances 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000026137 Soft tissue injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012716 precipitator Substances 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The present invention relates to the field of medicinal chemistry, which discloses a new method for preparing an ibuprofen arginine salt. The present invention is characterized in that by salt forming in alcohol solvent by using ibuprofen and arginine, the ibuprofen arginine salt is generated; based on different dissolvability of the ibuprofen arginine salt in solvent under the conditions of different temperatures and different water contents, and crystal seeds initiated in reaction, the product (ibuprofen arginine salt) is separated from reaction solvent in one step. The present invention has the advantages of simple and feasible production process, short flow, low cost, high yield and good product quality.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method of ibuprofen arginine salt.
Background technology
Ibuprofen BP/EP is the phenylpropionic acid non-steroidal anti-inflammatory analgesics, is used for rheumatic and rheumatoid arthritis, osteoarthritis, acute gout, headache, neurodynia, dysmenorrhoea, soft tissue injury etc. clinically.Ibuprofen BP/EP is water-soluble hardly, and China's clinical application is an oral preparations, and is the same with other oral non-steroidal anti-inflammatory analgesics, and onset is slower relatively, thereby limited to the application aspect clinical pain.
Ibuprofen arginine salt has another name called arginine Ibuprofen, is a kind of new salt of Ibuprofen BP/EP and L-arginine be combined into.Arginine, the nonessential amino acid of a kind of human body contains two basic groups, its PK in the molecule
B1=2.18, as a basic aminoacids, combine salify with carboxyl in the Ibuprofen BP/EP.Because arginic combination, changed the water-insoluble of Ibuprofen BP/EP, uptake rate increases in the body, thereby has changed the pharmacokinetic curve of Ibuprofen BP/EP, reaches the time (T of maximum plasma concentration
Max) reduce maximum blood concentration (C
Max) increase, especially T
MaxValue reduces to about 15 minutes by 1.5-2h.Since the increase of uptake rate, T
MaxValue reduces greatly, has shortened the analgesic onset time, has distinct quick-acting analgesic characteristics, is mainly used in analgesia in clinical.
Ibuprofen arginine salt is mainly used in the preparation oral solid formulation, as tablet, capsule, granule, powder etc., also can be used for preparing liquid preparation, as syrup, oral liquid etc., and is used to prepare injection, ointment, suppository or sprays etc.
Ibuprofen BP/EP is pure dissolubility, arginine is water-soluble, the resultant ibuprofen arginine salt is water-soluble, certain solubleness is arranged in the alcohol of different concns, disclosed in the past ibuprofen arginine salify technology has been done to elaborate: ES 2105948A1 and Tianjin pharmacy 1989 in following patent and document; 1 (4): 18, typical preparation method is dissolved in Ibuprofen BP/EP in the alcohol, arginine is soluble in water, two-phase is stirred to drip down and is mixed, generate ibuprofen arginine salt, because of the resultant ibuprofen arginine salt is dissolved in the reaction solvent, so need to adopt lyophilization, methods such as the precipitator method or distillating recovering solvent are removed solvent; ES 2105948A1 and Tianjin pharmacy 1989; 1 (4): what adopt in 18 is the method that reclaims solvent, and its technology is loaded down with trivial details, and is consuming time, raises the cost, and reclaiming solvent needs to carry out under heating for a long time, influences quality product.
Summary of the invention
It is simple to the purpose of this invention is to provide a kind of technology, with short production cycle, and cost is low, the ibuprofen arginine salt preparation method that yield is high.
Technical scheme of the present invention is only to generate the ibuprofen arginine salt crystallization by a step salt-forming reaction.Based on the different solubility of ibuprofen arginine salt in the reaction solvent of differing temps, different concns, utilize the crystal seed that causes in the temperature difference, poor solubility and the reaction, the resultant ibuprofen arginine salt is directly separated out from reaction solvent.Remove the solvent precipitation that distillation is removed solvent or adopted usually in the prior art from, simplified reaction conditions, reduced production cost, and improved yield.
Concrete scheme of the present invention is as follows:
Ibuprofen BP/EP and arginine are dissolved in respectively in the straight or branched fatty alcohol of 1～5 carbon atom, and two-phase stirs to drip down mixes, and promptly generates the ibuprofen arginine salt crystal.Direct filtration, drying get final product according to a conventional method.When drip mixing, two-phase preferably the alcoholic solution of Ibuprofen BP/EP is added drop-wise in the arginic pure suspension.
The selected solvent of the present invention is the straight or branched aliphatics alcohols of 1～5 carbon atom, as methyl alcohol, ethanol, propyl alcohol, Virahol.Preferred alcohol.
The preferred aqueous ethanol of used ethanol; Preferred 70～90% (volume percent, down together) of its alcohol concn, preferred concentration is 80～99%.
According to the present invention, wherein Ibuprofen BP/EP and arginic mol ratio preferred 1: 1～2.
According to the present invention, wherein reactant (being Ibuprofen BP/EP and arginine) with the reaction total solvent weight ratio preferred 1: 3～7.
Preparation method of the present invention can carry out at room temperature, and preferred temperature of reaction is 30～80 ℃, and further the temperature of preferred reaction is 40～70 ℃.
Ibuprofen BP/EP and arginine are dissolved in respectively in the straight or branched fatty alcohol of 1～5 carbon atom of different moisture content, preferred alcohol, stir down the Ibuprofen BP/EP drop is added in the arginine mixed suspension, salt-forming reaction is carried out, Ibuprofen BP/EP and arginine are combined into ibuprofen arginine salt, up to reacting completely, this moment, solution was hypersaturated state, under mechanical stirring, put cold soln subsequently gradually, triggering the ibuprofen arginine salt crystallization produces, the ibuprofen arginine salt of separating out constantly separates out oversaturated ibuprofen arginine salt as crystal seed, until the ibuprofen arginine salt precipitation fully.
The chemical structure confirmatory test proves, ibuprofen arginine salt by this law preparation shows through ultimate analysis, the content of carbon, hydrogen, nitrogen-atoms is consistent with theoretical value in the sample, through ultra-violet absorption spectrum, infrared absorption spectrum, nuclear magnetic resonance spectrum (hydrogen nuclear magnetic resonance spectrum, nuclear magnetic resonance of carbon spectrum), mass spectrum integration analysis, prove conclusively the arginic acid salt that this sample is an Ibuprofen BP/EP, molecular formula is C
13H
18O
2C
6H
14N
4O
2, molecular weight is 380.47, structural formula is:
Ibuprofen arginine salt quantitative assay result by this law preparation shows: Ibuprofen BP/EP is by high performance liquid chromatography, and arginine is measured by nonaqueous titrations, and content is respectively 53.4%～54.8% and 45.2%～46.3%.
Whole technology simple possible provided by the invention, flow process is short, and requiring of equipment is low.The reaction conditions gentleness, almost no coupling product produces, and product is the off-white color solid, fusing point 165-167 ℃.In Ibuprofen BP/EP, recovery rate is about 90%, and the percentage labelled amount is more than 99%.
Embodiment
Embodiment 1
The preparation of ibuprofen arginine salt:
Ibuprofen BP/EP 51 grams are dissolved in 360ml 95% ethanol, arginine 46 grams are suspended in 250ml 80% ethanol, press 10ml/ and divide a speed, under 60 ℃ the Ibuprofen BP/EP drips of solution is added in the arginine mixed suspension, dropwises, the arginine solids disappeared, the reaction soln clarification, the following temperature of stirring is put cold, after about 5 minutes, the ibuprofen arginine salt precipitation occurs, and continues to be stirred to about 30 ℃ and stops, and-4 ℃ of refrigerators are placed and spent the night, suction filtration, collect product, washing with alcohol three times, 40 ℃ are dry down.Get product 83.4 grams.
The product yield is in Ibuprofen BP/EP: 89.2%, and percentage composition is: Ibuprofen BP/EP 53.62%, arginine 45.69%.
Embodiment 2
The preparation of ibuprofen arginine salt:
Ibuprofen BP/EP 60 gram is dissolved in 410ml 95% ethanol, arginine 50.1 grams are suspended in 320ml 85% ethanol, press 10ml/ and divide and drip fastly, the Ibuprofen BP/EP drips of solution is added in the arginine mixed suspension under 50 ℃, press thereafter under 1 of the embodiment and operate with method.Get product 100.6 grams.
The product yield is in Ibuprofen BP/EP: 91.4%, and percentage composition is: Ibuprofen BP/EP 53.65%, arginine 46.14%.
Claims (9)
1, a kind of preparation method of ibuprofen arginine salt is characterized in that: Ibuprofen BP/EP and arginine are dissolved in respectively in the straight or branched fatty alcohol of 1-5 carbon atom, and two-phase stirs to drip down mixes, and cooling promptly generates the ibuprofen arginine salt crystallization.
2, the preparation method of claim 1, alcohol wherein is ethanol.
3, the preparation method of claim 2, wherein ethanol is aqueous alcohol, alcohol concn is 70-99%.
4, the preparation method of claim 3, wherein concentration of ethanol is 80-99%.
5, the preparation method of claim 1, wherein Ibuprofen BP/EP and arginic mol ratio are 1: 1-2.
6, the preparation method of claim 1, wherein the weight ratio of reactant and solvent is 1: 3-7.
7, the preparation method of claim 1, the temperature of reaction are 30-80 ℃.
8, the preparation method of claim 7, the temperature of reaction are 40-70 ℃.
9, the preparation method of claim 1 is characterized in that the alcoholic solution of Ibuprofen BP/EP is added drop-wise in the arginic pure suspension.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410014369 CN1246306C (en) | 2004-03-19 | 2004-03-19 | New method for preparing brufen arginine salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410014369 CN1246306C (en) | 2004-03-19 | 2004-03-19 | New method for preparing brufen arginine salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1562966A CN1562966A (en) | 2005-01-12 |
| CN1246306C true CN1246306C (en) | 2006-03-22 |
Family
ID=34478324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410014369 Expired - Lifetime CN1246306C (en) | 2004-03-19 | 2004-03-19 | New method for preparing brufen arginine salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1246306C (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101455654B (en) * | 2007-12-13 | 2013-03-06 | 天津医科大学 | Arginine ibuprofen gel and preparation method thereof |
| CN101570480A (en) * | 2009-06-18 | 2009-11-04 | 航天中心医院 | Preparation method of dexibuprofen amino acid salt |
| CN101817765A (en) * | 2010-04-16 | 2010-09-01 | 山东新华制药股份有限公司 | Preparation method of ibuprofen arginine salt |
| CN102180786A (en) * | 2011-03-30 | 2011-09-14 | 吴家安 | Dextral ibuprofen arginine and preparation method thereof |
| CN102617330B (en) * | 2012-03-15 | 2014-11-19 | 合肥科大生物技术有限公司 | Method for preparing ibuprofen arginine salt |
| CN103130637A (en) * | 2013-03-19 | 2013-06-05 | 中国药科大学 | Ibuprofen-arginine and preparation method thereof |
| CN106110328A (en) * | 2016-06-30 | 2016-11-16 | 山东理工大学 | A kind of utilize calcium phosphate precipitation auxiliary improve ibuprofen method of dissolubility in water |
| CN107935890A (en) * | 2017-12-28 | 2018-04-20 | 山东新华制药股份有限公司 | The preparation method of ibuprofen arginine parenteral solution amide impurities |
-
2004
- 2004-03-19 CN CN 200410014369 patent/CN1246306C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1562966A (en) | 2005-01-12 |
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Owner name: TAIYANGSHI (TANGSHAN) PHARMACEUTICAL CO. LTD.; CHI Free format text: FORMER NAME OR ADDRESS: CHINA PHARMACY UNIVERSITY |
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Address after: Hebei Tangshan City hi tech Development Zone zip code: 063020 Co-patentee after: CHINA PHARMACEUTICAL University Patentee after: SUNSTONE (TANGSHAN) PHARMACEUTICAL CO.,LTD. Address before: Tong Xiang Nanjing city of Jiangsu Province, No. 24 Patentee before: China Pharmaceutical University |
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Address after: 063020 Torch Road, Tangshan City hi tech Development Zone, Hebei 139, China Co-patentee after: CHINA PHARMACEUTICAL University Patentee after: China Resources Sanjiu (Tangshan) Pharmaceutical Co.,Ltd. Address before: 063020 Tangshan City hi tech Development Zone, Hebei Co-patentee before: CHINA PHARMACEUTICAL University Patentee before: SUNSTONE (TANGSHAN) PHARMACEUTICAL Co.,Ltd. |
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