CN102617330B - Method for preparing ibuprofen arginine salt - Google Patents
Method for preparing ibuprofen arginine salt Download PDFInfo
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- CN102617330B CN102617330B CN201210067921.0A CN201210067921A CN102617330B CN 102617330 B CN102617330 B CN 102617330B CN 201210067921 A CN201210067921 A CN 201210067921A CN 102617330 B CN102617330 B CN 102617330B
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Abstract
The invention relates to a method for preparing ibuprofen arginine salt, which includes: reacting ibuprofen and arginine in C1-C4 fatty alcohol, cooling until crystals are precipitated after the reaction is completed, and collecting and drying the crystals to obtain the ibuprofen arginine salt. The solid raw material and the liquid raw material are directly reacted by a one-step method, complex steps and process of dissolving and charging respectively are avoided, a synthesis process step and reaction equipment are omitted, solvent usage is greatly reduced, and conditions are mild by using a cooling crystallization method. In a word, the method for preparing ibuprofen arginine salt has the advantages of short operating steps, simple process, easiness in implementation, low cost, reliability in quality, high yield and the like, and is more applicable to massive industrial production.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to adopt " single stage method " to prepare the method for ibuprofen arginine salt.
Background technology
Ibuprofen BP/EP (Ibuprofen, 1) is one of non-steroidal anti-inflammation and analgesic drugs (NSAID).This medicine, by suppressing cyclooxygenase, reduces the synthetic of prostaglandin(PG), and produces analgesia, anti-inflammatory action, by hypothalamus heat-regulating centers, plays refrigeration function.With its anti-inflammatory, antipyretic and analgesic effect is definite, the advantages such as untoward reaction is few, oral easy absorption are widely used, and especially paediatrics various diseases are being had to good treatment or auxiliary therapeutic action.The ibuprofen dosage form of listing is numerous both at home and abroad at present, comprises conventional tablet, slow releasing tablet, capsule, suspensoid, suppository, ointment, gelifying agent etc., is widely used clinically.
Because Ibuprofen BP/EP is almost insoluble in water, make it be only applicable to prepare solid preparation, the same with other oral non-steroidal anti-inflammatory analgesics, onset is relatively slow, and gi tract are had to hormesis, thereby has limited to the application aspect clinical treatment.
Ibuprofen arginine salt has another name called ibuprofen arginine, is a kind of salt that Ibuprofen BP/EP and L-arginine are combined into.Arginine, the nonessential amino acid of a kind of human body, contains two basic groups, carboxyl reaction salify in one of them basic group and Ibuprofen BP/EP in molecule.By with arginic salify, changed Ibuprofen BP/EP solvability, make its easily molten and water, uptake rate increases in vivo, because the increase of uptake rate, has shortened analgesic onset time, there is distinct quick-acting analgesic feature, in clinical, be mainly used in antipyretic-antalgic, other indications and Ibuprofen BP/EP are similar.After Ibuprofen BP/EP and arginine salify, due to water-soluble, greatly strengthen, can be used for preparing liquid preparation, especially oral liquid and injection liquid, be conducive to accelerate absorption rate, improves bioavailability, expands scope of medication.Therefore ibuprofen arginine salt has important pharmaceutical application, its preparation technology's quality directly has influence on clinical use and product development, cost control and environmental pollution, and optimizer preparation technology not only has social effect, has more huge economic worth.
Published ibuprofen arginine salifying process, is elaborated in patent and document: ES 2105948A1 and Tianjin pharmacy 1989; 1 (4): 18, typical preparation method is dissolved in Ibuprofen BP/EP in alcohol, arginine is soluble in water, two-phase is stirred lower dropping and is mixed, generate ibuprofen arginine salt, because resultant ibuprofen arginine salt is dissolved in reaction solvent, therefore need to adopt lyophilization, the method such as the precipitator method or distillating recovering solvent is removed solvent, ES 2105948A1 and Tianjin pharmacy 1989; 1 (4): what in 18, adopt is the method that reclaims solvent, and its technique is loaded down with trivial details, consuming time, raises the cost, reclaim solvent and need under heating for a long time, carry out, affect quality product, also there is the problem of multistep operation simultaneously, complex process.
The patent of the smart atmosphere ibuprofen acid synthesis technique of open report and document also have: CN1246306C and Chinese Journal of Pharmaceuticals, 2002,33 (2): 58 and Shandong medicine industry, 2000,19 (1): 15-16.Wherein the feature of CN1246306C patent is: Ibuprofen BP/EP and smart atmosphere acid are dissolved in respectively to the lower dropping mixing of two-phase stirring in alcohol.Its shortcoming is: (1) needs two retort to dissolve respectively Ibuprofen BP/EP and the acid of smart atmosphere and to be insoluble to 95% second liquor-saturated due to smart atmosphere acid, be difficult for making uniform suspension, need strong stirring equipment otherwise there will be solid precipitation phenomenon at the bottom of tank, thereby greatly having increased conversion unit requirement and cost; (2), if dissolve arginine by aqueous alcohol, just there will be room temperature to be difficult for crystallization or the incomplete phenomenon of crystallization; (3) in CN1246306C the disclosed embodiments, due to what adopt, be that aqueous ethanol dissolves, so normal temperature is placed, be difficult to crystallization, must place and spend the night at-4 ℃ of refrigerators, time-consuming, effort, takes the energy; (4) there is the problem of multistep operation, complex process.
Chinese Journal of Pharmaceuticals 2002,33 (2): 58 and Shandong medicine industry magazine 2000,19 (1): the method that 15-16 reports is to adopt solvent (acetone) dilution method to obtain crystallization, namely in reaction solution, add approximately 3 times to the acetone of quantity of solvent, make crystallization.Its shortcoming has been to increase consumption and the kind of solvent, owing to being finally crystallization from mixed solvent, so, the difficult recovery of solvent, thus industrial production cost increased.In addition the method also need to be in refrigerator crystallization 12 hours, also exist time-consumingly, the problem of taking the energy, needs in quality control to measure the residual of two kinds of solvents, has increased the difficulty of Quality Control; Also there is the problem of multistep operation, complex process simultaneously; More, owing to increasing an organic solvent, making to pollute increases.
Patent and the document of the smart atmosphere ibuprofen acid synthesis technique of open report also have: CN101239901A, CN101817765A and CN101190889B.CN101239901A wherein, the feature of CN101817765A patent be first by a material with after dissolve with ethanol, and then add another one material stirring, its shortcoming is: (1) uses dissolve with ethanol material, need a large amount of ethanol, there is comparatively speaking higher production cost, also have inflammable and explosive problem simultaneously; (2) in technological operation, have two step processes, need to first dissolve a material, and then drop into next material, operation steps is longer.The feature of CN101190889B patent is with after 95% dissolve with ethanol Ibuprofen BP/EP, add again arginine, the method is compared with CN101239901A, the advantage of CN101817765A is to adopt 95% ethanol to reduce production cost, improved the security of producing, its main drawback is: (1) is first dissolved in Ibuprofen BP/EP 95% ethanol, under then stirring, adds arginine, in technological operation, there are two step processes, still comparatively loaded down with trivial details for industrial production; (2) weight ratio of reactant and ethanol is 1: 2-6, and its proportion is still bigger than normal, and production cost is higher, can cause environmental pollution.
Summary of the invention
For overcoming a series of shortcomings such as existing ibuprofen arginine salt preparation method step is many, solvent load is large, with high costs, the object of this invention is to provide a kind of preparation method of ibuprofen arginine salt.
Ibuprofen arginine salt preparation method provided by the invention reacts Ibuprofen BP/EP and arginine in the fatty alcohol of C1～C4, is cooled to crystal and separates out after reaction finishes, and then crystal is collected, is drying to obtain.
Described arginine is L-arginine.
In preparation method of the present invention, the feed way of reactant is: to directly adding fatty alcohol in Ibuprofen BP/EP and arginic mixture, adding respectively Ibuprofen BP/EP and arginine or add Ibuprofen BP/EP and arginic mixture in fatty alcohol in fatty alcohol.
Particularly, feed way comprises: (1) adds respectively reactor by Ibuprofen BP/EP, arginine, then directly adds fatty alcohol; (2) add reactor after Ibuprofen BP/EP and arginine are mixed in proportion in advance, then directly add fatty alcohol; (3) first in reactor, add fatty alcohol, then add wherein Ibuprofen BP/EP and arginine respectively; (4) first in reactor, add fatty alcohol, then Ibuprofen BP/EP and arginine are mixed in proportion in advance, finally mixed solid material is added in reactor.
Preparation method's of the present invention feed way is " single stage method ", as its name suggests, abandoned prior art habitual solid material is dissolved in respectively to the feed way that solvent mixes again.By multistep Process step combination, be a step, greatly simplified technique.Simultaneously further reduced solvent load, reduced production cost, also reduced environmental pollution, be more applicable for suitability for industrialized production, be more conducive to environment protection.
Described fatty alcohol is the moisture fatty alcohol of volumetric concentration 92～98%; Preferred 95% moisture fatty alcohol.
Described fatty alcohol is methyl alcohol, ethanol, propyl alcohol or butanols, and based on production cost and security consideration, preparation method of the present invention preferably adopts ethanol as reaction solvent.
The temperature of described reaction is 40～80 ℃; Preferably 65 ℃.The time of described reaction is 10～60 minutes; Preferably 20 minutes.
The mol ratio of described Ibuprofen BP/EP and smart atmosphere acid is 1.0: 0.9～1.1; Preferably 1.0: 0.99.
The gross weight of described Ibuprofen BP/EP and smart atmosphere acid and the weight ratio of fatty alcohol are 1: 1～3; Preferably 1: 1.5.
The collection of described crystal, drying process are: crystal is filtered, and filter cake adopts anhydrous fatty alcohol washing, is then placed at 60～80 ℃ and is dried 5～10 hours.
Described drying mode is forced air drying.
Preparation method provided by the invention is based on crystallization technique, the product ibuprofen arginine salt generating is directly separated out at low temperatures from reaction solvent, removed the solvent precipitation that the distillation in traditional preparation method is removed solvent or conventionally adopted from, avoided use anhydrous solvent, reaction conditions and operation steps have further been simplified, reduce production cost, and improved the yield of target product.
Preparation method provided by the invention compared with prior art has the following advantages:
1, by single stage method, solid material and liquid solvent are directly reacted, loaded down with trivial details step and the technique of dissolving respectively, feeding in raw material have respectively been avoided, reduced synthesis technique step and conversion unit, shortened the technological process of production, thereby can obviously reduce production costs.
2, greatly reduced solvent load, compared with existing same class methods, solvent load shortens to original 20-50%, has reduced environmental pollution, has further reduced production cost.
3, adopted cooling crystallization method, mild condition, room temperature, has saved the energy, has saved cost.
Preparation method provided by the invention can make the yield of target product reach 92% or more than, good product quality, product purity can surpass 99.5%.
In a word, preparation method provided by the invention has that operation steps is short, technique is simple, easy to implement, with low cost, reliable in quality, yield advantages of higher, is more applicable for large-scale industrial production.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
The detection method of product of the present invention is: according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia nineteen ninety-five version), measure: instrument: Agilent 1100; Condition: chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, moving phase: phosphate buffered saline buffer (SODIUM PHOSPHATE, MONOBASIC 0.380g and Sodium phosphate dibasic 0.05g, be dissolved in water into 1000ml, with phosphoric acid, adjust PH to 3.0)-methyl alcohol (28: 78), detection wavelength is 220nm, and number of theoretical plate calculates and is not less than 1500 by arginine Ibuprofen.Sample thief is appropriate, add moving phase and make every 1ml containing the solution of 0.4mg, be need testing solution, get 20 μ L and inject liquid phase instrument, record chromatogram, separately get arginine Ibuprofen reference substance and be measured in the same method, by external standard method with calculated by peak area.
Embodiment 1
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| 95% ethanol | 13.5L(11.0kg) |
Reactant: ethanol (weight ratio)=1: 1.5
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add Ibuprofen BP/EP 4kg and arginine solid 3.36kg, then add 95% ethanol 11kg, heated and stirred to 65 ℃, after the about 20min of insulated and stirred, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake washes twice with dehydrated alcohol, is placed in 60～70 ℃ of forced air dryings 8 hours, obtains ibuprofen arginine, crystalline powder is white in color, output 6.80kg, yield 92.39%, purity 99.7%.
Embodiment 2
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| 95% ethanol | 10L(8.1kg) |
Reactant: ethanol (weight ratio)=1: 1.1
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add Ibuprofen BP/EP 4kg and arginine solid 3.36kg, then add 95% ethanol 8.1kg, heated and stirred to 65 ℃, after the about 60min of insulated and stirred, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake washes twice with dehydrated alcohol, is placed in 60～70 ℃ of forced air dryings 8 hours, obtains ibuprofen arginine, crystalline powder is white in color, output 6.94kg, yield 94.12%, purity 99.6%
Embodiment 3
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| 95% ethanol | 13.6L(11kg) |
Reactant: ethanol (weight ratio)=1: 1.49
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add Ibuprofen BP/EP 4kg and arginine solid 3.36kg, then add 95% ethanol 11kg, heated and stirred to 65 ℃, after the about 20min of insulated and stirred, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake is washed twice with dehydrated alcohol, be placed in 60～70 ℃ of forced air dryings 8 hours, obtain ibuprofen arginine, crystalline powder is white in color, output 6.78kg, yield 92.11%.Purity 99.7%
Embodiment 4
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| 95% ethanol | 16.3L(13.3kg) |
Reactant: ethanol (weight ratio)=1: 1.8
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add 95% ethanol 13.3kg, add successively Ibuprofen BP/EP 4kg and arginine solid 3.36kg, heated and stirred to 65 ℃, after the about 20min of insulated and stirred again, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake is washed twice with dehydrated alcohol, be placed in 60～70 ℃ of forced air dryings 8 hours, obtain ibuprofen arginine, crystalline powder is white in color, output 6.3kg, yield 85.6%.Purity 99.7%
Embodiment 5
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| 95% ethanol | 12L(9.8kg) |
Note: reactant: ethanol (weight ratio)=1: 1.33
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add successively arginine solid 3.36kg and Ibuprofen BP/EP 4kg, add 95% ethanol 9.8kg, heated and stirred to 65 ℃, after the about 30min of insulated and stirred again, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake is washed twice with dehydrated alcohol, be placed in 60～70 ℃ of forced air dryings 6 hours, obtain ibuprofen arginine, crystalline powder is white in color, output 6.85kg, yield 93.07%.Purity 99.6%
Embodiment 6
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| 95% ethanol | 27L(22kg) |
Note: reactant: ethanol (weight ratio)=1: 3
(2) operating process
Mechanical stirring, reflux condensing tube, in 50L reaction flask, add 95% ethanol 22kg, then add arginine solid 3.36kg and Ibuprofen BP/EP 4kg, heated and stirred to 65 ℃, after the about 30min of insulated and stirred, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake is washed twice with dehydrated alcohol, be placed in 60～70 ℃ of forced air dryings 10 hours, obtain ibuprofen arginine, crystalline powder is white in color, output 5.5kg, yield 74.7%.Purity 99.8%
Embodiment 7
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.72kg | 21.36mol |
| 95% ethanol | 12L(9.8kg) |
Note: reactant: ethanol (weight ratio)=1: 1.33
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add 95% ethanol 9.8kg, add successively arginine solid 3.72kg and Ibuprofen BP/EP 4kg, heated and stirred to 65 ℃, after the about 30min of insulated and stirred again, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake is washed twice with dehydrated alcohol, be placed in 60～70 ℃ of forced air dryings 8 hours, obtain ibuprofen arginine, crystalline powder is white in color, output 6.86kg, yield 93.2%.Purity 99.6%
Embodiment 8
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.10kg | 17.80mol |
| 95% ethanol | 12L(9.8kg) |
Note: reactant: ethanol (weight ratio)=1: 1.38
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add 95% ethanol 9.8kg, add successively Ibuprofen BP/EP 4kg and arginine solid 3.10kg, heated and stirred to 65 ℃, after the about 30min of insulated and stirred again, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake is washed twice with dehydrated alcohol, be placed in 60～70 ℃ of forced air dryings 7 hours, obtain ibuprofen arginine, crystalline powder is white in color, output 6.0kg, yield 88.5%.Purity 99.7%
Embodiment 9
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| 95% ethanol | 12L(9.8kg) |
Note: reactant: ethanol (weight ratio)=1: 1.33
(2) operating process
Mechanical stirring, reflux condensing tube, in 20L reaction flask, add the Ibuprofen BP/EP 4kg and the arginine solid 3.36kg that mix, add 95% ethanol 9.8kg, heated and stirred to 65 ℃, after the about 30min of insulated and stirred, after solution clarification, stop heating, when stirring at room to solution is white in color muddiness, stop that teeter column is gentle and quiet puts crystallization 24 hours, suction filtration, filter cake washes twice with dehydrated alcohol, is placed in 60～70 ℃ of forced air dryings 8 hours, obtains ibuprofen arginine, crystalline powder is white in color, output 6.78kg, yield 92.11%, purity 99.6%
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (5)
1. a preparation method for ibuprofen arginine salt, is characterized in that, Ibuprofen BP/EP and arginine are stirred and reacted in the fatty alcohol of C1～C4, is cooled to crystal and separates out after reaction finishes, and then crystal is collected, is drying to obtain;
Described fatty alcohol is the ethanol of volumetric concentration 95%;
The temperature of described reaction is 65 ℃, and the time of described reaction is 10～60 minutes;
The weight ratio of described Ibuprofen BP/EP and arginic gross weight and fatty alcohol is 1: 1-1.5;
In described preparation method, Ibuprofen BP/EP and arginic feed way are: to directly adding fatty alcohol in Ibuprofen BP/EP and arginic mixture, adding successively Ibuprofen BP/EP and arginine or add Ibuprofen BP/EP and arginic mixture in fatty alcohol in fatty alcohol;
Described Ibuprofen BP/EP and arginic mol ratio are 1.0: 0.9～1.1;
The collection of described crystal, drying process are: crystal is filtered, and filter cake adopts anhydrous fatty alcohol washing, is then placed at 60-80 ℃ and is dried 5～10 hours.
2. preparation method according to claim 1, is characterized in that, the time of described reaction is 20 minutes.
3. preparation method according to claim 1, is characterized in that, described Ibuprofen BP/EP and arginic mol ratio are 1.0: 0.99.
4. preparation method according to claim 1, is characterized in that, the weight ratio of described Ibuprofen BP/EP and arginic gross weight and fatty alcohol is 1: 1.5.
5. according to the preparation method of claim 1, it is characterized in that, described drying mode is forced air drying.
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| CN103130637A (en) * | 2013-03-19 | 2013-06-05 | 中国药科大学 | Ibuprofen-arginine and preparation method thereof |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1513442A (en) * | 2003-06-26 | 2004-07-21 | 昆明市延安医院 | Prepn. and use of mixture of arginine-burfenum |
| CN1562966A (en) * | 2004-03-19 | 2005-01-12 | 中国药科大学 | New method for preparing brufen arginine salt |
| CN101940547A (en) * | 2010-09-10 | 2011-01-12 | 南京威尔曼药物研究所 | Method for preparing ibuprofen injection |
| CN102344360A (en) * | 2011-07-29 | 2012-02-08 | 海南新中正制药有限公司 | Preparation method of arginine dexibuprofen |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1513442A (en) * | 2003-06-26 | 2004-07-21 | 昆明市延安医院 | Prepn. and use of mixture of arginine-burfenum |
| CN1562966A (en) * | 2004-03-19 | 2005-01-12 | 中国药科大学 | New method for preparing brufen arginine salt |
| CN101940547A (en) * | 2010-09-10 | 2011-01-12 | 南京威尔曼药物研究所 | Method for preparing ibuprofen injection |
| CN102344360A (en) * | 2011-07-29 | 2012-02-08 | 海南新中正制药有限公司 | Preparation method of arginine dexibuprofen |
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