CN102344360B - Preparation method of arginine dexibuprofen - Google Patents
Preparation method of arginine dexibuprofen Download PDFInfo
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Abstract
The invention discloses a preparation method of an arginine dexibuprofen raw medicine. The method comprises the steps of: dissolving dexibuprofen in ethanol, heating the mixture to a temperature of 50DEG C-60DEG C, adding L-arginine in a dropwise manner slowly and continuously under stirring within 10min-20min, continuing stirring for reaction for 2h-3.5h with the temperature maintained at 50DEG C-60DEG C, leaving the mixture to stand for 25min-35min and cool to a temperature of 18DEG C-30DEG C, conducting pumping filtration so as to obtain crystals, then washing and drying the crystals, thus obtaining white crystals, i.e. arginine dexibuprofen. The preparation method of the invention has simple process, high yield, no refining step, shortened production period, and no need for any special equipment, thus being suitable for industrial production.
Description
Technical field
The present invention relates to bulk drug preparing technical field, be specifically related to a kind of preparation method of arginine (s)-ibuprofen bulk drug.
Background technology
The chemical name of arginine (s)-ibuprofen: D-Alpha-Methyl-4-(2-methyl-propyl) toluylic acid L-Arginine salt, chemical structural formula is:
Molecular formula: C
13h
18o
2c
6h
14n
4o
2, molecular weight: 380.48.
Ibuprofen BP/EP is the representative medicine in NSAID (non-steroidal anti-inflammatory drug), there is anti-inflammatory, antipyretic, the effect that relieves the pain, take in multinational pharmacopeia, clinical application is extensive, particularly because Ibuprofen BP/EP has tight security, at present become the main products in antipyretic and analgesic, having replaced acetylsalicylic acid becomes the most general antipyretic and analgesic of application.
But Ibuprofen BP/EP solubleness is little, for solution Ibuprofen BP/EP solubleness in water is little and the low preparation of fusing point is prepared difficult problem, Ibuprofen BP/EP is become to organic salt with arginine abroad, can obtain crystalloid solid, product water dissolubility improves (can be made into aqueous injection, ratified by FDA), simultaneously product fusing point high (being greater than 150 ℃), drying process in preparation production process is not high to temperature control requirement, has solved preferably the above-mentioned deficiency of Ibuprofen BP/EP.This product is in the multinational listing including China, is domesticly called smart aminoprofen.
(S)-ibuprofen (being called for short: Seractil) pharmacologically active and Ibuprofen BP/EP in vivo has certain difference, but chemical property is just the same, also exist water-soluble little, product fusing point is low (80 ℃ of <), preparation is prepared difficult problem.According to smart aminoprofen thinking, acid Seractil and alkaline arginine are made to arginine Seractil, this product is soluble in water, absorb more in vivo, rapider, and fusing point exceedes 150 ℃, be crystallinity compound, be easy to prepare preparation.Aspect children, the heating children that (S)-ibuprofen causes upper respiratory tract infection have good solution thermal effect, cause danger if can avoid children to swallow solid pharmaceutical the agent of (S)-ibuprofen granulation, after granule is dissolved in water, take, the conformability of child patient is good, rapid-action.(S)-ibuprofen preparation process is simple, produces controlledly, and product is stable, and particle can reconstitute with hot water (Ibuprofen BP/EP and Seractil particle can only reconstitute with cold water, otherwise can make Ibuprofen BP/EP, Seractil melt, and separate out into wax in water).Therefore, Seractil is made to arginine Seractil and can as smart aminoprofen improves Ibuprofen BP/EP performance, be improved the deficiency of Seractil, be worth exploitation.
Arginine Seractil is the arginic acid salt of Seractil, with Seractil comparison, there is good water solubility, product is stable, product purity is high, and (Seractil and arginine salify are actually the process of once extracting, in Seractil, not carboxylic impurity is not if 4-isobutyl acetophenone is owing to being removed with arginic acid salt salify, and therefore, the related substance of arginine Seractil is significantly less than domestic Motrin).Be not subject to the restriction of gi tract pH value because arginine Seractil absorbs, thereby absorb soon, can bring into play early curative effect impact, curative effect is more secure.Therefore be badly in need of developing a kind of novel arginine (s)-ibuprofen raw material., more fully demonstrate the therapeutic action of Seractil.In addition, this product good water solubility also reduces gastrointestinal pH difference to medicine and absorption
A kind of preparation method of arginine (s)-ibuprofen is disclosed in Chinese patent application CN200810105086.9, see embodiment 2, that (S)-ibuprofen is dissolved in ethanol, under room temperature, drip the L-arginine aqueous solution-200ml ethanol of 50% (m/m), drip and finish rear room temperature reaction 1h, 0 ℃ of insulation 2h, filter, a small amount of washing with alcohol, vacuum-drying, obtains product.The method is to adopt the L-arginine aqueous solution-200ml ethanol to drip, speed and flow velocity that bad control drips, and react 1h under employing room temperature, 0 ℃ of insulation 2h, at this temperature, the arginine (s)-ibuprofen that first reaction is produced can be separated out, and causes end reaction incomplete, cause final product to have related substance high, the phenomenon of the low grade of yield.
Therefore, be necessary to develop a kind of preparation method of new arginine (s)-ibuprofen.
Summary of the invention
The invention provides a kind of operation simple, quality controllable and be suitable for the preparation method of the arginine (s)-ibuprofen of suitability for industrialized production.
A preparation method for arginine (s)-ibuprofen, comprises step:
(S)-ibuprofen is dissolved in ethanol or aqueous ethanolic solution, be heated to 50 ℃～60 ℃, under stirring, slowly drip continuously L-arginine, 10min～20min dropwises, keep 50 ℃～60 ℃ to continue stirring reaction 2 hours～3.5 hours, leave standstill 25min～35min, then be cooled to 18 ℃～30 ℃, suction filtration, obtain crystal, after washing, being dried, obtain white crystal, obtain arginine (s)-ibuprofen.
In order to reach better invention effect, preferably:
(S)-ibuprofen is dissolved in ethanol or aqueous ethanolic solution, is heated to 50 ℃, under stirring, slowly drip continuously L-arginine, 10min dropwises, and keeps 50 ℃ to continue stirring reaction 2 hours, leaves standstill 25min, be cooled to again room temperature, suction filtration, obtains crystal, washs 3 times, be dried and obtain white crystal, obtain arginine (s)-ibuprofen.
(S)-ibuprofen is dissolved in ethanol or aqueous ethanolic solution, is heated to 55 ℃, under stirring, slowly drip continuously L-arginine, 15min dropwises, and keeps 55 ℃ to continue stirring reaction 2.5 hours, leaves standstill 30min, be cooled to again room temperature, suction filtration, obtains crystal, washs 3 times, be dried and obtain white crystal, obtain arginine (s)-ibuprofen.
(S)-ibuprofen is dissolved in ethanol or aqueous ethanolic solution, is heated to 60 ℃, under stirring, slowly drip continuously L-arginine, 20min dropwises, and keeps 60 ℃ to continue stirring reaction 3.5 hours, leaves standstill 35min, be cooled to again room temperature, suction filtration, obtains crystal, washs 3 times, be dried and obtain white crystal, obtain arginine (s)-ibuprofen.
In described aqueous ethanolic solution, the concentration expressed in percentage by volume of ethanol is 80%～95%, more preferably 90%～95%, can better dissolve (S)-ibuprofen, so that (S)-ibuprofen better reacts for arginine (s)-ibuprofen with arginine, obtain the finished product that purity and yield are higher.
Washing washings used is that concentration expressed in percentage by volume is 95% ethanol or dehydrated alcohol.
Described dry temperature is 65 ℃～70 ℃.
The described dry time is 4 hours～6 hours.
The reaction equation of synthetic method of the present invention is as follows:
In the present invention, the consumption of reaction raw materials does not have strict restriction, generally measures than reacting according to chemical reaction, can excessively react yet.
The raw materials used raw material that meets medicinal standard that is of the present invention.
The present invention utilizes final product arginine (s)-ibuprofen to be not dissolved in aqueous ethanolic solution or the characteristic of dehydrated alcohol, and (S)-ibuprofen is dissolved in aqueous ethanolic solution or dehydrated alcohol, therefore dissolve (S)-ibuprofen under comparatively high temps, drip arginic speed by control and improve the yield of reaction, last at lower temperature, stirring and crystallizing, has avoided the process that bulk drug will be refining, improve yield and the purity of product, shortened the production cycle.
Tool of the present invention has the following advantages:
1) the raw materials used raw material that meets medicinal standard that is of the present invention, product purity is high, its salification process is owing to being to dissolve under comparatively high temps, crystallization under lesser temps, identical with recrystallization process, be equivalent to carry out primary purification, the product appearance brilliant white making, crystal formation is neat, can reach medicinal standard, therefore need not refine through chemical examination product purity again.
2) nutritive substance that the arginine in product of the present invention is human body, can prevent and correct the hepatotoxicity causing due to long-term taking Ibuprofen BP/EP.Meanwhile, arginine is a kind of semi-dispensable amino acid, and its nitrogen protoxide (NO) generating through metabolism has important effect to immunity system; And the research of vivo and vitro also shows, the immune organ of arginine to human or animal and immunocyte grow and the secretion of associated hormone also has irreplaceable effect.
3) provide a kind of new preparation method of arginine (s)-ibuprofen raw material, can increase the supply of arginine (s)-ibuprofen raw material.
4) arginine Seractil preparation process is only single step reaction process, there is no complicated chemical reaction, and operational path choice is also little, and reaction requirement condition is lower, and constant product quality is controlled, and environmental pollution is also less.In a word, the method favorable reproducibility, less to surrounding environment influence, products obtained therefrom is stablized, is met the requirements, the economic benefit that tool is larger.
5) preparation technology of the present invention is simple, without passing through purification step, quality controllable again, and equipment that need not be special is cost-saving, and shortened process, is suitable for suitability for industrialized production, and the arginine (s)-ibuprofen raw materials quality that makes is good, good stability.
Embodiment
Embodiment 1
(S)-ibuprofen 20.83g (0.101mol) is dissolved in 72ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution, be heated to 55 ℃, under stirring, slowly drip continuously L-arginine 17.42g (0.1mol), 10min dropwises, keep 55 ℃ to continue stirring reaction 3 hours, leave standstill 30min, be cooled to room temperature, suction filtration, obtains crystal again, 5ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution washing 3 times, 65 ℃ dry obtains white crystal 37.66g for 6 hours, and yield is 98.98%, 175 ℃～178 ℃ of fusing points.
Above-mentioned white crystal is carried out to ultimate analysis, main component result is as follows: C:60.04%, H:8.51%, N:14.71% (being mass percent), theoretical value with arginine (s)-ibuprofen: C:59.97%, H:8.47%, N:14.71% (being mass percent) conforms to.The main component that shows above-mentioned product is D-Alpha-Methyl-4-(2-methyl-propyl) toluylic acid L-Arginine salt, i.e. arginine (s)-ibuprofen.
Embodiment 2
(S)-ibuprofen 22.12g (0.107mol) is dissolved in 72ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution, be heated to 50 ℃, under stirring, slowly drip continuously L-arginine 17.42g (0.1mol), 15min dropwises, keep 50 ℃ to continue stirring reaction 2 hours, leave standstill 25min, be cooled to room temperature, suction filtration, obtains crystal again, 5ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution washing 3 times, 70 ℃ dry obtains white crystal 37.46g for 4 hours, and yield is 98.45%, 175.2 ℃～177.6 ℃ of fusing points.
Above-mentioned white crystal is carried out to ultimate analysis, main component result is as follows: C:60.12%, H:8.48%, N:14.77% (being mass percent), theoretical value with arginine (s)-ibuprofen: C:59.97%, H:8.47%, N:14.71% (being mass percent) conforms to.The main component that shows above-mentioned product is D-Alpha-Methyl-4-(2-methyl-propyl) toluylic acid L-Arginine salt, i.e. arginine (s)-ibuprofen.
Embodiment 3
(S)-ibuprofen 21.94g (0.106mol) is dissolved in 72ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution, be heated to 60 ℃, under stirring, slowly drip continuously L-arginine 17.42g (0.1mol), 20min dropwises, keep 60 ℃ to continue stirring reaction 3.5 hours, leave standstill 35min, be cooled to room temperature, suction filtration, obtains crystal again, 5ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution washing 3 times, 68 ℃ dryly obtain white crystal 36.86g in dry 5 hours, and yield is 96.88%, 175.8 ℃～178.2 ℃ of fusing points.
Above-mentioned white crystal is carried out to ultimate analysis, main component result is as follows: C:60.08%, H:8.49%, N:14.77% (being mass percent), theoretical value with arginine (s)-ibuprofen: C:59.97%, H:8.47%, N:14.75% (being mass percent) conforms to.The main component that shows above-mentioned product is D-Alpha-Methyl-4-(2-methyl-propyl) toluylic acid L-Arginine salt, i.e. arginine (s)-ibuprofen.
Comparative example 1
25g (S)-ibuprofen is dissolved in 250ml ethanol, under room temperature, drips the L-arginine aqueous solution-200ml ethanol of 42.3g 50% (m/m), drip and finish rear room temperature reaction 1h, 0 ℃ of insulation 2h, filters a small amount of washing with alcohol, vacuum-drying, obtains 41.8g product, yield 90.5%.Ultimate analysis (C
19h
32n
404, %): calculated value: C 60.00, H8.42, N14.74; Measured value: C 60.22, H8.52, N14.56.
Differentiate:
(1) get respectively arginine (s)-ibuprofen 10mg prepared by embodiment 1, embodiment 2, embodiment 3 and comparative example 1, the 1ml that respectively adds water, jolting makes molten, then adds ninhydrin solution 1ml, jolting, embodiment 1, embodiment 2, embodiment 3 and comparative example 1 solution is aobvious purple all.Result shows: arginine (s)-ibuprofen prepared by embodiment 1, embodiment 2, embodiment 3 and comparative example 1 meets two arginine of Chinese Pharmacopoeia version in 2010 and differentiates a regulation checking.
(2) get respectively arginine (s)-ibuprofen prepared by embodiment 1, embodiment 2, embodiment 3 and comparative example 1, respectively add water and make the solution containing 0.6mg in every 1ml, measure according to ultraviolet visible spectrophotometry (two appendix IV A of Chinese Pharmacopoeia version in 2010), arginine (s)-ibuprofen prepared by embodiment 1, embodiment 2 embodiment 3 and comparative example 1 all has maximum absorption at the wavelength place of 265nm and 273nm.Result shows: arginine (s)-ibuprofen prepared by embodiment 1, embodiment 2, embodiment 3 and comparative example 1 conforms with the regulations.
Related substance
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; Be moving phase with chloroacetic acid solution (get 4g Mono Chloro Acetic Acid and be dissolved in 400ml water, by ammoniacal liquor adjusting pH value to 3.0)-acetonitrile (45: 55, volume ratio), detect wavelength 254nm, flow velocity 1.5ml/min.Number of theoretical plate should be not less than 2000 by Seractil peak.
Assay method is got arginine (s)-ibuprofen appropriate (being equivalent to (S)-ibuprofen 75mg) prepared by embodiment 1, embodiment 2, embodiment 3 and comparative example 1, accurately weighed, put in 25ml measuring bottle, add moving phase appropriate, jolting makes to dissolve, add moving phase and be diluted to scale, shake up, as need testing solution; Precision measures this need testing solution 1ml, puts in 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution; Separately get 4-isobutyl acetophenone reference substance appropriate, accurately weighed, be mixed with the solution that concentration is 0.5mg/ml with acetonitrile, precision measures this solution 1ml, put in 50ml measuring bottle, add moving phase and be diluted to scale, shake up, precision measures 3ml, put in 10ml measuring bottle, add moving phase and be diluted to scale, shake up, in contrast product solution.Precision measures contrast solution 20 μ l, and injection liquid chromatography regulates instrumental sensitivity, makes principal constituent peak height be about 20%～25% of registering instrument full range; Precision measures need testing solution and the each 20 μ l of reference substance solution, and injection liquid chromatography, records 2 times to principal constituent peak retention time of color atlas respectively.In need testing solution color atlas if any impurity peaks, measure each impurity peaks peak area, known impurities peak area should be not more than reference substance solution main peak area (0.1%), single unknown impuritie peak area should be not more than 0.3 times (0.3%) of contrast solution main peak area, and unknown impuritie peak area summation should be not more than contrast solution main peak area (1.0%).
Result is as follows: in arginine (s)-ibuprofen prepared by embodiment 1, embodiment 2, embodiment 3 and comparative example 1, known impurities peak is respectively 0.0046%, 0.0042%, 0.0048%, 0.1202% (impurity peak area is with respect to the per-cent of the main peak area of reference substance solution); Single unknown impuritie peak is respectively 0.12%, 0.10%, 0.13%, 0.3230% (single unknown impuritie peak area is with respect to the per-cent of the main peak area of contrast solution); Unknown impuritie peak is respectively 0.06%, 0.08%, 0.07%, 1.210% (unknown impuritie peak area is with respect to the per-cent of the main peak area of contrast solution); Measurement result shows: in the color atlas of arginine (s)-ibuprofen solution of the present invention, known impurities peak area should be not more than reference substance solution main peak area (0.1%), single unknown impuritie peak area should be not more than 0.3 times (0.3%) of contrast solution main peak area, unknown impuritie peak area summation should be not more than contrast solution main peak area (1.0%), meets the requirements; And arginine (s)-ibuprofen prepared by comparative example 1 is undesirable.
Stability study experiment:
1, influence factor test
The arginine (s)-ibuprofen of embodiment 1,2,3 preparations is put into respectively to plate as sample, place by following three conditions.
1) strong illumination test: sample is removed to outer packaging, put under YG-A type medicine exposure experiments to light instrument, approximately to place 10 days under 4500 ± 500LX illuminance.
2) high temperature test: sample is removed to 60 ℃ of constant temperature of outer packing device and place 10 days.
3) high humidity test: place 10 days under 25 ℃ of relative humidity 92.5% conditions.
Sample under each test conditions above, respectively at the 5th, sampling on time in 10 days, measures according to every test method respectively, product is through tests such as high temperature, high humidity, illumination, and the indices of the arginine (s)-ibuprofen of embodiment 1,2,3 preparations has no considerable change.
2, accelerated test
Simulating respectively listing using the arginine (s)-ibuprofen of embodiment 1,2,3 preparations as sample packs, in 40 ℃ ± 2 ℃, under the condition of relative humidity 75% ± 5%, place 6 months, respectively at 1, sampling on time in 2,3,6 months, carry out every mensuration, result shows: under accelerated test condition, place 6 months, the indices of the arginine (s)-ibuprofen of embodiment 1,2,3 preparations and comparison in 0 day, without considerable change.
3, place for a long time
The arginine (s)-ibuprofen of embodiment 1,2,3 preparations is packed as sample simulation listing, in 25 ± 2 ℃, under the condition of relative humidity 60 ± 10%, place, respectively at 0,3,6,9,12,18,24, sampling on time in 36 months, carries out every mensuration, and result shows: product is placed 9 months under test of long duration condition, the indices of the arginine (s)-ibuprofen of embodiment 1,2,3 preparations and comparison in 0 day, without considerable change.
Claims (3)
1. the preparation method of an arginine (s)-ibuprofen, it is characterized in that, comprise step: it is in 95% aqueous ethanolic solution that (S)-ibuprofen 20.83g is dissolved in to 72ml concentration of volume percent, be heated to 55 ℃, under stirring, slowly drip continuously L-arginine 17.42g, 10min dropwises, keep 55 ℃ to continue stirring reaction 3 hours, leave standstill 30min, be cooled to again room temperature, suction filtration, obtain crystal, 5ml concentration of volume percent is 95% aqueous ethanolic solution washing 3 times, 65 ℃ of dry white crystal 37.66g that obtain for 6 hours, yield is 98.98%, 175 ℃～178 ℃ of fusing points.
2. the preparation method of an arginine (s)-ibuprofen, it is characterized in that, comprise step: it is in 95% aqueous ethanolic solution that (S)-ibuprofen 22.12g is dissolved in to 72ml concentration of volume percent, be heated to 50 ℃, under stirring, slowly drip continuously L-arginine 17.42g, 15min dropwises, keep 50 ℃ to continue stirring reaction 2 hours, leave standstill 25min, be cooled to again room temperature, suction filtration, obtain crystal, 5ml concentration of volume percent is 95% aqueous ethanolic solution washing 3 times, 70 ℃ of dry white crystal 37.46g that obtain for 4 hours, yield is 98.45%, 175.2 ℃～177.6 ℃ of fusing points.
3. the preparation method of an arginine (s)-ibuprofen, it is characterized in that, comprise step: it is in 95% aqueous ethanolic solution that (S)-ibuprofen 21.94g is dissolved in to 72ml concentration of volume percent, be heated to 60 ℃, under stirring, slowly drip continuously L-arginine 17.42g, 20min dropwises, keep 60 ℃ to continue stirring reaction 3.5 hours, leave standstill 35min, be cooled to again room temperature, suction filtration, obtain crystal, 5ml concentration of volume percent is 95% aqueous ethanolic solution washing 3 times, 68 ℃ of dry white crystal 36.86g that obtain for 5 hours, yield is 96.88%, 175.8 ℃～178.2 ℃ of fusing points.
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| CN102854263B (en) * | 2012-08-31 | 2014-04-16 | 石家庄中硕药业集团有限公司 | Method for simultaneous determination of content of ibuprofen and arginine in ibuprofen injection |
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| CN101265178A (en) * | 2008-04-25 | 2008-09-17 | 北京阜康仁生物制药科技有限公司 | Amino acid salt of (S)-ibuprofen and medicinal composition thereof |
| KR20090083667A (en) * | 2008-01-30 | 2009-08-04 | 대화제약 주식회사 | Manufacturing method of dexibuprofen arginate |
| 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 |
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| KR20090083667A (en) * | 2008-01-30 | 2009-08-04 | 대화제약 주식회사 | Manufacturing method of dexibuprofen arginate |
| CN101265178A (en) * | 2008-04-25 | 2008-09-17 | 北京阜康仁生物制药科技有限公司 | Amino acid salt of (S)-ibuprofen and medicinal composition thereof |
| 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 |
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Address after: 570216, East B District, No. 6, Haikou Free Trade Zone, No. 168 Nanhai Road, Hainan, Haikou Patentee after: HAINAN HULUWA PHARMACEUTICAL GROUP CO., LTD. Address before: 570216, East B District, No. 6, Haikou Free Trade Zone, No. 168 Nanhai Road, Hainan, Haikou Patentee before: Hainan Gourd Doll Pharmaceutical Co., Ltd. |