CN102617329B - Preparation method of ibuprofen arginine salt - Google Patents
Preparation method of ibuprofen arginine salt Download PDFInfo
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Abstract
The invention relates to a preparation method of ibuprofen arginine salt. The method comprises the following steps of: reacting ibuprofen with arginine in water; and after reacting, drying a reaction liquid. In the preparation method provided by the invention, an arginine solid and an ibuprofen solid are directly added into a reaction kettle, and purified water is added for reacting, so that the use of an organic solvent is avoided, the problem of environmental pollution is solved, and the production cost is reduced. After the reaction, drying is performed directly, and the organic solvent is not contacted, so that the production cost is reduced, the problem of environmental pollution is avoided, the yield is increased, and the production safety is enhanced. The method has the advantages of mild reaction conditions, implementation at the room temperature, reduction in energy consumption, energy saving, reduction in cost and environmental friendliness.
Description
Technical field
The present invention relates to the synthetic field of medicine, being specifically related to adopt water is the method that solvent, " single stage method " are prepared 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, plays refrigeration function by hypothalamus heat-regulating centers.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, 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, change 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, greatly strengthen due to water-soluble, can be used for preparing liquid preparation, especially oral liquid and injection liquid, is 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.
Disclosed ibuprofen arginine salifying process in the past, is elaborated in patent and document: ES 2105948A1, CN1246306C, CN101239901A, CN101817765A, CN101190889B, Tianjin pharmacy 1989; 1 (4): 18, Chinese Journal of Pharmaceuticals, 2002,33 (2): 58, Shandong medicine industry, 2000,19 (1): 15-16.Exist and use alcohol, aqueous alcohol, one or more organic solvents such as acetone above-mentioned preparation in ibuprofen arginine salt technique, exist technological operation step many, use the problems such as organic solvent, not only can cause complex process, production cost to increase, more can cause environmental pollution, bring production safety hidden danger.
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, toxicity is high, preparation cost is high, 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 water, after reaction finishes, reaction solution is drying to obtain.
Described arginine is L-arginine.
In preparation method of the present invention, the feed way of reactant is: in Ibuprofen BP/EP and arginic mixture, directly add water or Xiang Shuizhong to add respectively Ibuprofen BP/EP and arginine or Xiang Shuizhong to add Ibuprofen BP/EP and arginic mixture.
Particularly, feed way comprises: Ibuprofen BP/EP, arginine are added respectively reactor by (1), then directly adds water alcohol; (2) add reactor after Ibuprofen BP/EP and arginine are mixed in proportion in advance, then directly add water; (3) first in reactor, add water, then add wherein Ibuprofen BP/EP and arginine respectively; (4) first in reactor, add water, then Ibuprofen BP/EP and arginine are mixed in proportion in advance, finally mixed solid material is added in reactor.
Preparation method of the present invention has adopted water to replace traditional organic fatty alcohol, safer, nontoxic.The feed way adopting is " single stage method ", as its name suggests, abandoned prior art usual solid material is dissolved in respectively to the feed way that solvent mixes again.Be a step by multistep Process step combination, greatly simplified technique, and reduced the consumption of water medium, be more applicable for suitability for industrialized production.
The temperature of described reaction is 15～50 DEG C, preferably 25 DEG C; The time of described reaction is 1～6h, preferably 2h.
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 water are 1: 0.7～4; Preferably 1: 1.
Before described being dried, adopt the millipore filtration of 0.1～0.5 μ m to filter reaction solution; Preferably 0.22 μ m.
Drying means described in above-mentioned any one technical scheme for spraying is dry, drying under reduced pressure or lyophilize.
Described drying means all adopts the existing drying plant in this area, as spray-drier, freeze drier etc.
Wherein, described spray-dired drying conditions is:
Air output: 10～25m
3/ h;
Inlet temperature: 80～120 DEG C;
Temperature of charge: 40～60 DEG C;
Air outlet temperature: 25～45 DEG C;
Rotating speed: 2～10rpm;
Atomizing pressure: 0.1～0.5MPa.
The drying conditions of described drying under reduced pressure is:
Vacuum tightness :-0.01～-0.1MPa;
Heating temperature: 40～60 DEG C;
Time of drying: 5～16h.
Described cryodesiccated drying conditions is:
Freezing: the time: 4～6h, temperature-40 DEG C～-50 DEG C;
Distillation: time: 15～35h, temperature :-40 DEG C～-50 DEG C are warming up to 0 DEG C;
Dry: time: 6～20h, drying temperature: 0 DEG C～30 DEG C.
Technical scheme provided by the invention generates ibuprofen arginine salt by carrying out a step salt-forming reaction in water, and then drying directly obtains ibuprofen arginine salt.Remove the solvent precipitation that the distillation in traditional preparation method is removed solvent or conventionally adopted from, simplified reaction conditions and operation steps; Avoid using various organic solvents, alleviated the harm of organic reagent to environment, the security that has also improved product and preparation process, has greatly saved manufacturing cost simultaneously.
Preparation method provided by the invention compared with prior art has the following advantages:
1. arginine solid and Ibuprofen BP/EP solid are directly added in reactor, then add purified water stirring reaction, avoid using organic solvent, solved problem of environmental pollution, reduced production cost.
2. reaction finishes to be directly dried afterwards, does not contact organic solvent, has reduced production cost, has avoided problem of environmental pollution, has improved yield, has also improved production security.
3. the present invention adopts reaction conditions gentleness, and room temperature has reduced energy consumption, has saved the energy, has reduced cost, environmental protection.
4. preparation technology of the present invention has very high yield, can reach 95% or more than, and its quality product is high, product purity can reach 99.5% or more than.
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: measure according to high performance liquid chromatography (two annex VD of Chinese Pharmacopoeia nineteen ninety-five version): instrument: Agilent 1100; Condition: chromatographic condition and system suitability: with octadecylsilane chemically bonded silica be weighting agent, 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 tune 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.Getting ibuprofen arginine salt sample appropriate, add moving phase and make every 1ml containing the solution of 0.4mg, is need testing solution, gets 20 μ L injection liquid chromatographies, records 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 |
| Purified water | 7.36kg |
(2) operating process
Mechanical stirring, in 20L reaction flask, adds Ibuprofen BP/EP 4kg and arginine solid 3.36kg, then adds purified water 7.36kg, and room temperature (approximately 25 DEG C) stirs to clarify transparent, after about 2h, adopts 0.22 μ m filtering with microporous membrane, and filtrate is for subsequent use.
Embodiment 2
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| Purified water | 5.6kg |
(2) operating process
Mechanical stirring, in 20L reaction flask, adds purified water 5.6kg, then adds Ibuprofen BP/EP 4kg and arginine solid 3.36kg, and stirring at room temperature, to clear, after about 4h, adopts 0.22 μ m filtering with microporous membrane, and filtrate is for subsequent use.
Embodiment 3
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.36kg | 19.28mol |
| Purified water | 25.8kg |
(2) operating process
Mechanical stirring, in 50L reaction flask, adds arginine solid 3.36kg and Ibuprofen BP/EP 4kg, then adds purified water 25.8kg, stirs to clarify at 40 DEG C transparently, after about 3h, adopts 0.22 μ m filtering with microporous membrane, and filtrate is for subsequent use.
Embodiment 4
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.72kg | 21.35mol |
| Purified water | 7.72kg |
(2) operating process
Mechanical stirring, in 20L reaction flask, adds purified water 7.72kg, then adds Ibuprofen BP/EP 4kg and arginine solid 3.72kg, and stirring at room temperature, to clear, after about 5h, adopts 0.22 μ m filtering with microporous membrane, and filtrate is for subsequent use.
Embodiment 5
(1) charging capacity
| Reactant | Charging capacity | Mole number |
| Ibuprofen BP/EP | 4kg | 19.417mol |
| Arginine | 3.05kg | 17.50mol |
| Purified water | 7.05kg |
(2) operating process
Mechanical stirring, in 20L reaction flask, adds purified water 7.05kg, then adds Ibuprofen BP/EP 4kg and arginine solid 3.05kg, stirs to clarify at 35 DEG C transparently, after about 4h, adopts 0.22 μ m filtering with microporous membrane, and filtrate is for subsequent use.
Embodiment 6
Press the filtrate in embodiment 1, import in evaporating pan and carry out drying under reduced pressure.Drying conditions: 50 DEG C of oven temperatures, oil pump vacuumizes, and vacuum tightness is-0.1MPa that time of drying, 12h, obtained white foam shape solid 7.26kg, yield 98.6%, purity 99.6%.
Embodiment 7
Press the filtrate in embodiment 2, import in evaporating pan and carry out drying under reduced pressure.Drying conditions: 60 DEG C of oven temperatures, oil pump vacuumizes, and vacuum tightness is-0.05MPa that time of drying, 8h, obtained white foam shape solid 7.29kg, yield 99.0%, purity 99.6%.
Embodiment 8
Press the filtrate in embodiment 3, import in evaporating pan and carry out drying under reduced pressure.Drying conditions: 55 DEG C of oven temperatures, oil pump vacuumizes, and vacuum tightness is-0.02MPa that time of drying, 14h, obtained white foam shape solid 7.29kg, yield 99.0%, purity 99.6%.
Embodiment 9
Press the filtrate in embodiment 4, import in evaporating pan and carry out drying under reduced pressure.Drying conditions: 45 DEG C of oven temperatures, oil pump vacuumizes, and vacuum tightness is-0.08MPa that time of drying, 15h, obtained white foam shape solid 7.58kg, yield 98.1%, purity 99.5%.
Embodiment 10
Press the filtrate in embodiment 5, import in evaporating pan and carry out drying under reduced pressure.Drying conditions: 40 DEG C of oven temperatures, oil pump vacuumizes, and vacuum tightness is-0.1MPa that time of drying, 16h, obtained white foam shape solid 6.9kg, yield 97.8%, purity 99.5%.
Embodiment 11
Press the filtrate in embodiment 1, adopt spray-drying process, collect product.Adopt LPG-5 spray-drier, spraying drying conditions:
Air output: 15m
3/ h;
Inlet temperature: 100 DEG C;
Temperature of charge: 50 DEG C;
Air outlet temperature: 35 DEG C;
Rotating speed: 5rpm;
Atomizing pressure: 0.3MPa;
After spray-dried, obtain white powder 7.22kg, yield 98.0%, purity 99.7%.
Embodiment 12
Press the filtrate in embodiment 2, adopt spray-drying process, collect product.Adopt LPG-5 spray-drier, spraying drying conditions:
Air output: 20m
3/ h;
Inlet temperature: 90 DEG C;
Temperature of charge: 45 DEG C;
Air outlet temperature: 35 DEG C;
Rotating speed: 7rpm;
Atomizing pressure: 0.25MPa;
After spray-dried, obtain white powder 7.24kg, yield 98.4%, purity 99.7%.
Embodiment 13
Press the filtrate in embodiment 3, adopt spray-drying process, collect product.Adopt LPG-5 spray-drier, spraying drying conditions:
Air output: 12m
3/ h;
Inlet temperature: 110 DEG C;
Temperature of charge: 55 DEG C;
Air outlet temperature: 28 DEG C;
Rotating speed: 4rpm;
Atomizing pressure: 0.4MPa;
After spray-dried, obtain white powder 7.23kg, yield 98.2%, purity 99.7%.
Embodiment 14
Press the filtrate in embodiment 4, adopt spray-drying process, collect product.Adopt LPG-5 spray-drier, spraying drying conditions:
Air output: 22m
3/ h;
Inlet temperature: 105 DEG C;
Temperature of charge: 45 DEG C;
Air outlet temperature: 40 DEG C;
Rotating speed: 8rpm;
Atomizing pressure: 0.3MPa;
After spray-dried, obtain white powder 7.38kg, yield 95.6%, purity 99.5%.
Embodiment 15
Press the filtrate in embodiment 5, adopt spray-drying process, collect product.Adopt LPG-5 spray-drier, spraying drying conditions:
Air output: 15m
3/ h;
Inlet temperature: 100 DEG C;
Temperature of charge: 60 DEG C;
Air outlet temperature: 37 DEG C;
Rotating speed: 5rpm;
Atomizing pressure: 0.3MPa;
After spray-dried, obtain white powder 6.70kg, yield 95.0%, purity 99.5%.
Embodiment 16
Press the filtrate in embodiment 1, adopt freeze-drying, first filtrate is carried out to the freezing frozen solid that obtains, then, by freezing solid distillation, after distillation, most of moisture is removed, finally that product is further dry.
Adopt LYO-0.5m
2freeze drier, lyophilize condition is:
Freezing: the time: 5h, temperature-45 DEG C;
Distillation: time: 20h, temperature :-45 DEG C are warming up to 0 DEG C;
Dry: time: 15h, drying temperature: 25 DEG C.
After lyophilize, obtain white product 7.05kg, yield 95.7%, purity 99.7%.
Embodiment 17
Press the filtrate in embodiment 2, adopt freeze-drying.
Adopt LYO-0.5m
2freeze drier, lyophilize condition is:
Freezing: the time: 5.5h, temperature-50 DEG C;
Distillation: time: 18h, temperature :-50 DEG C are warming up to 0 DEG C;
Dry: time: 20h, drying temperature: 20 DEG C.
After lyophilize, obtain white product 6.95kg, yield 94.4%, purity 99.7%.
Embodiment 18
Press the filtrate in embodiment 3, adopt freeze-drying.
Adopt LYO-0.5m
2freeze drier, lyophilize condition is:
Freezing: the time: 4.5h, temperature-50 DEG C;
Distillation: time: 25h, temperature :-50 DEG C are warming up to 0 DEG C;
Dry: time: 10h, drying temperature: 30 DEG C.
After lyophilize, obtain white product 7.08kg, yield 96.1%, purity 99.7%.
Embodiment 19
Press the filtrate in embodiment 4, adopt freeze-drying.
Adopt LYO-0.5m
2freeze drier, lyophilize condition is:
Freezing: the time: 5h, temperature-45 DEG C;
Distillation: time: 25h, temperature :-45 DEG C are warming up to 0 DEG C;
Dry: time: 20h, drying temperature: 15 DEG C.
After lyophilize, obtain white product 7.3kg, yield 94.5%, purity 99.7%.
Embodiment 20
Press the filtrate in embodiment 5, adopt freeze-drying.
Adopt LYO-0.5m
2freeze drier, lyophilize condition is:
Freezing: the time: 4.5h, temperature-50 DEG C;
Distillation: time: 30h, temperature :-50 DEG C are warming up to 0 DEG C;
Dry: time: 16h, drying temperature: 25 DEG C.
After lyophilize, obtain white product 6.68kg., yield 94.7%, purity 99.7%.
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 without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (5)
1. a preparation method for ibuprofen arginine salt, is characterized in that, Ibuprofen BP/EP and arginine are reacted in water, after reaction finishes, reaction solution is drying to obtain;
The temperature of described reaction is 15～50 DEG C; The time of described reaction is 1～6h;
The weight ratio of described Ibuprofen BP/EP and arginic gross weight and water is 1: 0.7～4;
In described preparation method, Ibuprofen BP/EP and arginic feed way are: in Ibuprofen BP/EP and arginic mixture, directly add water or Xiang Shuizhong to add respectively Ibuprofen BP/EP and arginine or Xiang Shuizhong to add Ibuprofen BP/EP and arginic mixture;
Described Ibuprofen BP/EP and arginic mol ratio are 1.0: 0.9～1.1;
Before dry, adopt the millipore filtration of 0.1～0.5 μ m to filter reaction solution;
Described drying means for spraying is dry, drying under reduced pressure or lyophilize;
Wherein, described spray-dired drying conditions is:
Air output: 10～25m
3/ h;
Inlet temperature: 80～120 DEG C;
Temperature of charge: 40～60 DEG C;
Air outlet temperature: 25～45 DEG C;
Rotating speed: 2～10rpm;
Atomizing pressure: 0.1～0.5MPa;
Wherein, the drying conditions of described drying under reduced pressure is:
Vacuum tightness :-0.01～-0.1MPa;
Heating temperature: 40～60 DEG C;
Time of drying: 5～16h;
Wherein, described cryodesiccated drying conditions is:
Freezing: the time: 4～6h, temperature-40 DEG C～-50 DEG C;
Distillation: time: 15～35h, temperature :-40 DEG C～-50 DEG C are warming up to 0 DEG C;
Dry: time: 6～20h, drying temperature: 0 DEG C～30 DEG C.
2. preparation method according to claim 1, is characterized in that, the temperature of described reaction is 25 DEG C; The time of described reaction is 2h.
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 water is 1: 1.
5. preparation method according to claim 1, is characterized in that, the dry preferably millipore filtration of 0.22 μ m that before reaction solution adopted filters.
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| CN103172544A (en) * | 2013-03-04 | 2013-06-26 | 杭州天诚药业有限公司 | Preparation method of arginine ibuprofen crystal |
| 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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| CN101214235A (en) * | 2008-01-11 | 2008-07-09 | 航天中心医院 | Ibuprofen amino acid salt injection and preparation thereof |
| CN101570480A (en) * | 2009-06-18 | 2009-11-04 | 航天中心医院 | Preparation method of dexibuprofen amino acid salt |
| CN102100686A (en) * | 2009-12-21 | 2011-06-22 | 北京润德康医药技术有限公司 | Medicinal composition containing ibuprofen and arginine and preparation method and application thereof |
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