CN103304400A - Method for efficiently preparing ibuprofen arginine - Google Patents
Method for efficiently preparing ibuprofen arginine Download PDFInfo
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- CN103304400A CN103304400A CN2012100641285A CN201210064128A CN103304400A CN 103304400 A CN103304400 A CN 103304400A CN 2012100641285 A CN2012100641285 A CN 2012100641285A CN 201210064128 A CN201210064128 A CN 201210064128A CN 103304400 A CN103304400 A CN 103304400A
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Abstract
The invention provides an efficient and simple and convenient preparation method for ibuprofen arginine. The method is characterized by comprising the following steps: first, salifying in water by one step to generate ibuprofen arginine aqueous liquor; and then, distilling, spraying and drying to directly obtain a product. The method provided by the invention is extremely simple, environment-friendly, high in yield, low in cost and short in production period. What is most important is that the product produced by the method is qualified and controllable in quality.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of ibuprofen arginine salt of extremely simple and effective.
Background technology
The chemistry of Ibuprofen BP/EP is called the 2-(4-isobutylphenyl) propionic acid, be one of non-steroidal anti inflammation and heat resolution anodyne (NSAIDS) of present turnout and usage quantity maximum, the annual production in the whole world surpasses ten thousand tons.
NSAIDS be a class can eliminate pain, swelling, four limbs are stiff and the on-steroidal hormone medicine of inflammation.NSAIDS is normally used for the painful diseases under the multiple situation: include but not limited to sacroiliitis, bursitis, tendinitis, gout, menstrual cramps, sprain, strain and other damage.NSAIDS also can be used for treating the mild pain that those postoperatives do not need narcotic analgesic, perhaps as the replacement therapy that can not accept the patients acuity pain of narcotic analgesic thing, perhaps as the successive treatment after the potent analgesic treatment, perhaps the potent analgesic of auxiliary easy habituation is to reduce the former consumption.NSAIDs is divided into the number of chemical type, but can be divided into non-selective usually and cyclooxygenase-2(COX-2) alternative medicine.Belong to non-selective NSAIDs and comprise Ibuprofen BP/EP, Naproxen Base etc., belong to the COX-2 alternative medicine and comprise celecoxib and rofecoxib etc.
From history, Ibuprofen BP/EP has a process of reinventing in the status in anti-inflammatory analgesic field, be the favorite the NSAIDS in nearly 20 years after the listing seventies in 20th century always, along with the attention to non-selective NSAIDS gastrointestinal side effect, and succeeding in developing of cox 2 inhibitor after this, in nearly 10 years, be in NSAIDS supporting role role again.After this, owing to being found of cox 2 inhibitor cardiovascular risk, Ibuprofen BP/EP etc. " always " medicine shines the new year again.Though acetylsalicylic acid is cardiovascular more safe than Ibuprofen BP/EP, but compare with acetylsalicylic acid, Ibuprofen BP/EP has stronger analgesic, anti-inflammatory and analgesic activity, and gastrointestinal side effect is much smaller, child patient also can use, strict ebm shows, Ibuprofen BP/EP and paracetamol are the safest ntipyretic analgesic medicines that children can use in the global range, yet, compare with paracetamol, Ibuprofen BP/EP has stronger analgesic, analgesic activity, the antiinflammation that has paracetamol simultaneously and do not had.
Ibuprofen BP/EP has two kinds of enantiomorphs, wherein has only the S-Ibuprofen BP/EP that activity is arranged, R-Ibuprofen BP/EP non-activity, yet, clinically still use racemic mixture, because the R-enantiomorph can change active S-form in vivo into.For simplicity, the following term of this paper " Ibuprofen BP/EP " is used in reference to the S-Ibuprofen BP/EP, any in R-Ibuprofen BP/EP or the racemoid.
Though Ibuprofen BP/EP has many advantages than other pain killer such as Asprin and paracetamol, its unusual indissoluble in water, water-soluble hardly, onset is slower relatively, thereby has limited it and used widely clinically.
Many amino acid comprise that arginine can obtain two kinds on its D type and L type, for simplicity, the following term of this paper " arginine " refers to D or L type arginine or D one arginine and L one arginic mixture, and arginine is the stronger amino acid of a kind of alkalescence, can with the carboxylic acid salify.Ibuprofen arginine salt has another name called arginine Ibuprofen, is a kind of organic salt of Ibuprofen BP/EP and arginine be combined into.Ibuprofen BP/EP is by being combined salify with arginine, changed the water-soluble of Ibuprofen BP/EP, the uptake rate of Ibuprofen BP/EP is increased, thereby improved the pharmacokinetic curve of Ibuprofen BP/EP, peak time (Tmax) reduces, maximum plasma concentration (Cmax) increases, particularly, the Tmax value reduced to about 15 minutes by 1.5-2 hour, this improvement is the increase that comes from uptake rate, the Tmax value reduces greatly, shortened the analgesic onset time, have significant quick-acting analgesic characteristics, clinical value (Mehlisch DR, Ardia A, the Pallotta T. Analgesia with ibuprofen arginate versus conventional ibuprofen for patients with dysmenorrhea:A crossover trial. Current therapeutic research of Ibuprofen BP/EP have greatly been promoted, 2003,64 (6): 327 – 37).
Ibuprofen arginine salt of many uses both can be for the preparation of oral solid formulation, as tablet, capsule, granule, powder etc., also can be used for preparing liquid preparation, as syrup, oral liquid, and some local application's preparations, as ointment, suppository or sprays etc.
Ibuprofen BP/EP is fat-soluble, and arginine is water-soluble, and the resultant ibuprofen arginine salt then is water-soluble; but certain solubleness is arranged in the alcohol of different concns; because ibuprofen arginine salt is of many uses, and is more to its Study on Preparation, wherein much applied for patent protection:
ES2105948AI and Tianjin pharmacy (1989,1 (4): 18) disclose a kind of typical preparation method: Ibuprofen BP/EP is dissolved in the alcohol, arginine is soluble in water, two-phase is stirred to drip down and is mixed, and generates ibuprofen arginine salt, but is dissolved in the reaction solvent because of the resultant ibuprofen arginine salt, adopt the method that reclaims solvent to reclaim ethanol then, technology is loaded down with trivial details, and is consuming time, and cost is higher.
China's granted patent application 200410014369 and Chinese granted patent application 200610129620 all disclose a kind of similar method for preparing ibuprofen arginine salt, it is characterized in that: by the salify in alcoholic solvent with Ibuprofen BP/EP and arginine, generate ibuprofen arginine salt, then based on ibuprofen arginine salt in differing temps, different solubility in the solvent of different moisture content, and the crystal seed that causes in the reaction, the resultant ibuprofen arginine salt is separated out from reaction solvent, yet, these class methods are because arginine dissolves difficulty in alcohol, and the arginic acid salt that generates has certain solubleness in alcoholic solution, thereby cause long reaction time, and productive rate also is subjected to certain influence, the more important thing is, because arginine solubleness in alcoholic solution is low, particularly solubleness will further reduce when temperature is low, thereby, to very easily sneak into free arginine in the final product, influenced degree of purity of production, finally cause the content fluctuation of Ibuprofen BP/EP in the bulk drug, difficult quality control brings hidden danger to clinical application.
Chinese Journal of Pharmaceuticals (2002,58) and Shandong medicine industry magazine (2,000 33 (2):, 19 (1): 15-16) disclose the method that the acetone diluted method obtains product, the acetone that namely in the pure liquid of salify, adds 3 times of amounts, because product solubleness reduction therein utilizes acetone that product is extruded, this method has increased solvent types and consumption, and difficult solvent recovery, not only increase cost, and not environmental protection, this method also need be placed in refrigerator more than 12 hours so that product is separated out fully simultaneously, thereby, also there is the problem of time-consuming power consumption.
Find by analyzing, present production technique is except having it separately the defective, some common deficiencies are still arranged, for example salify raw material Ibuprofen BP/EP and the arginic mol ratio of most of existing research use are not 1:1, not only increased cost, and exist and to be difficult to remove excessive Ibuprofen BP/EP or arginic problem, influenced end product quality; In addition, aforesaid method has all used organic solvent, though ethanol and acetone are the 3rd kind solvent, toxicity is lower, but the requirement of " the chemicals residual solvent investigative technique governing principle " of promulgating according to China pharmaceutical control and administration department, the 3rd kind solvent for refining link still needs to study its residual quantity, thereby, further increased the R﹠D costs of medicine.
Summary of the invention
The inventor is by discovering, the Ibuprofen BP/EP salify has thermostability preferably later on, by more in depth discovering, ibuprofen arginine salt is behind pyroprocessing certain hour under water existence or the non-existent situation, still can obtain essentially no degraded reliably, i.e. the qualified product that produces of essentially no new related substance.
Simultaneously, the present inventor finds by further investigation, in the process of preparation ibuprofen arginine salt, can use mol ratio to be Ibuprofen BP/EP and the arginine raw material of 1:1, and need not wherein arginine or the excessive products therefrom of Ibuprofen BP/EP ratio still qualified.
Based on this, the invention provides that a kind of technology is extremely simple, cost is low, yield is high and with short production cycle, the more important thing is quality controllable ibuprofen arginine salt preparation method.
Technical scheme key of the present invention is to generate ibuprofen arginine salt solution by step salify operation, and then obtains qualified final product by different processing modes.
The key point of one step salify operation is only to have used water as becoming salt solvent, and adopted appropriate reaction conditions, for example different application of sample orders will produce different salify effects with the salify temperature, can directly obtain the aqueous solution of ibuprofen arginine salt by salt-forming condition of the present invention, adopt the different condition aftertreatment through research then, can obtain final qualified product.
In the salify engineering, Ibuprofen BP/EP can be once or gradation add.
In the process that adds Ibuprofen BP/EP, choose wantonly and heat up simultaneously or do not heat up, the preferred intensification.
Suitable salify temperature range is 30-150 ℃, preferred 50-120 ℃, and most preferably 70-100 ℃.
In salification process, the particularly optional employing of salify protection of inert gas under comparatively high temps, preferred nitrogen.
Different treatment mode condition behind the above-mentioned salify comprises that distillation or spraying drying directly obtain product.
When using the distillation aftertreatment:
The inventor finds by further investigation, in the distillation procedure in the salt solution ratio of water (being water and arginic weight ratio) scope an of the best is arranged, in this scope, can obtain up-to-standard end product, be higher than this scope, distillation procedure is extremely difficult, will produce unmanageable emulsion.
Water and arginic weight ratio scope are 0.1-50:1 in the above-mentioned salify operating process, preferred 1-20:1, most preferably 1.2-5:1.
For the ease of the emulsion in the control still-process, preferred vacuum stirs simultaneously in still-process.
When using the spraying drying aftertreatment:
The inventor finds by further investigation, in the spraying drying operation in the salt solution ratio (being water and arginic weight ratio) of water the scope an of the best is also arranged, in this scope, can obtain up-to-standard end product, be higher than this scope, spraying drying efficient is low excessively, be lower than this scope, solution is thickness too, can not produce desirable nebulization efficiency.
Under our selected water content condition, the purity that can not reduce product is handled in distillation or spraying.
Adopt the inventive method, it is the ibuprofen arginine of the method preparation among the embodiment 1-4, be reference substance with middle inspection institute Ibuprofen BP/EP, measure with ultraviolet spectrophotometry and HPLC method respectively, ultraviolet spectrophotometry result shows that the Ibuprofen BP/EP content of this product is respectively 54.2%, 54.2%, 54.3% and 54.2%, is equivalent to arginine and Ibuprofen BP/EP accurately according to the 1:1 salify; Content and purity that the HPLC method is measured: 99.66%, 99.72%, 99.79%, 99.74%, every batch total impurities all＜0.5%, single impurity all＜0.1%, in addition, every batch of product is all proved conclusively through ultimate analysis and proton nmr spectra.
Following examples provide the embodiment of foregoing invention, but they do not represent entire area of the present invention, can not be considered as limitation of the present invention.
The Ibuprofen BP/EP reference substance is available from middle inspection institute; Measure salify raw material arginine purity 99.7%, raw material Ibuprofen BP/EP purity 99.8% with the HPLC method.
Embodiment
Embodiment 1
250 ml waters are warming up to after 90 ℃ to the arginine that wherein adds 174g, stir the rapid solution that gets down, the Ibuprofen BP/EP that adds 206g then in the system, keep this temperature to be stirred to dissolving, under 90 ℃, vacuum concentration gets the 385g white solid under stirring, and product vacuum-drying is got the 380g the finished product again with gained solution, productive rate 100%, mp165-167 ℃.
Embodiment 2
After 1.5 premium on currency are warming up to 100 ℃, under nitrogen protection, to the Ibuprofen BP/EP of the arginine that wherein adds 0.87Kg and 1.03Kg; stir the rapid solution that gets down, vacuum concentration gets the 385g white solid under stirring, and product vacuum-drying is got the 380g the finished product again; productive rate 100%, mp165-167 ℃.
Embodiment 3
In the arginine of 0.87Kg, add about 7 premium on currency, after being warming up to 70 ℃ under stirring, the Ibuprofen BP/EP that adds 1.03Kg in the arginine solution, keep this temperature to be stirred to dissolving, with atomizer solution is sprayed into droplet then and is scattered in the hot gas flow, make feed liquid contained humidity rapid evaporation drying (～10 seconds), again product vacuum-drying is got the 1.90Kg the finished product, productive rate 100%, mp165-167 ℃.
Claims (11)
1. the preparation method of an ibuprofen arginine salt, its feature generate the ibuprofen arginine salt aqueous solution by carry out step salify operation in water earlier, and then directly obtain product by distillation or spraying drying.
2. the preparation method of claim 1, wherein Ibuprofen BP/EP and arginic mol ratio are 1:1.
3. claim 1 or 2 preparation method, wherein water and arginic weight ratio scope are 0.1-50:1 in the salify operating process.
4. the preparation method of claim 3, wherein water and arginic weight ratio scope are 1-20:1 in the salify operating process.
5. claim 3 or 4 preparation method, wherein water and arginic weight ratio scope are 2-10:1 in the salify operating process.
6. the preparation method of claim 1, wherein the salify operating process is the arginic aqueous solution of preparation earlier, adds Ibuprofen BP/EP then, perhaps water and arginine, Ibuprofen BP/EP is mixed together and makes salts solution.
7. the preparation method of claim 6, wherein suitable salify temperature range is 30-150 ℃.
8. the preparation method of claim 6, wherein suitable salify temperature range is 50-120 ℃.
9. the preparation method of claim 6, wherein suitable salify temperature range is 70-100 ℃.
10. the preparation method of claim 1-9 wherein directly obtains product by the distillation salts solution.
11. the preparation method of claim 1-9 wherein directly obtains product by the spraying drying salts solution.
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| CN2012100641285A CN103304400A (en) | 2012-03-13 | 2012-03-13 | Method for efficiently preparing ibuprofen arginine |
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| CN2012100641285A CN103304400A (en) | 2012-03-13 | 2012-03-13 | Method for efficiently preparing ibuprofen arginine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108997109A (en) * | 2018-08-30 | 2018-12-14 | 浙江三门恒康制药有限公司 | A kind of preparation method of lysine-ketoprofen |
| CN110922344A (en) * | 2019-12-31 | 2020-03-27 | 北京鑫开元医药科技有限公司海南分公司 | Salt forming preparation process of ibuprofen arginine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101214235A (en) * | 2008-01-11 | 2008-07-09 | 航天中心医院 | Ibuprofen amino acid salt injection and preparation thereof |
| CN101669929A (en) * | 2009-09-27 | 2010-03-17 | 北京博时安泰液体制剂科技有限公司 | Preparation method and application of ibuprofen liquid preparation |
| CN101810568A (en) * | 2010-03-29 | 2010-08-25 | 南京泛太化工医药研究所 | Injection containing ibuprofen and preparation method thereof |
-
2012
- 2012-03-13 CN CN2012100641285A patent/CN103304400A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101214235A (en) * | 2008-01-11 | 2008-07-09 | 航天中心医院 | Ibuprofen amino acid salt injection and preparation thereof |
| CN101669929A (en) * | 2009-09-27 | 2010-03-17 | 北京博时安泰液体制剂科技有限公司 | Preparation method and application of ibuprofen liquid preparation |
| CN101810568A (en) * | 2010-03-29 | 2010-08-25 | 南京泛太化工医药研究所 | Injection containing ibuprofen and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108997109A (en) * | 2018-08-30 | 2018-12-14 | 浙江三门恒康制药有限公司 | A kind of preparation method of lysine-ketoprofen |
| CN110922344A (en) * | 2019-12-31 | 2020-03-27 | 北京鑫开元医药科技有限公司海南分公司 | Salt forming preparation process of ibuprofen arginine |
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