CN102344360A - Preparation method of arginine dexibuprofen - Google Patents
Preparation method of arginine dexibuprofen Download PDFInfo
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- CN102344360A CN102344360A CN2011102168268A CN201110216826A CN102344360A CN 102344360 A CN102344360 A CN 102344360A CN 2011102168268 A CN2011102168268 A CN 2011102168268A CN 201110216826 A CN201110216826 A CN 201110216826A CN 102344360 A CN102344360 A CN 102344360A
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- ibuprofen
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- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 title claims abstract description 96
- 239000004475 Arginine Substances 0.000 title claims abstract description 55
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 229960003428 dexibuprofen Drugs 0.000 title abstract 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000013078 crystal Substances 0.000 claims abstract description 29
- 238000003756 stirring Methods 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 14
- 238000005406 washing Methods 0.000 claims abstract description 12
- 235000019441 ethanol Nutrition 0.000 claims description 17
- 238000000967 suction filtration Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 7
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 abstract description 15
- 238000000034 method Methods 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- 235000009697 arginine Nutrition 0.000 abstract 2
- 229930064664 L-arginine Natural products 0.000 abstract 1
- 235000014852 L-arginine Nutrition 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000005086 pumping Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 37
- 239000000047 product Substances 0.000 description 24
- 238000012360 testing method Methods 0.000 description 13
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 12
- 229960001680 ibuprofen Drugs 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 239000002994 raw material Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 6
- 206010013786 Dry skin Diseases 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- -1 radicals valerate Chemical class 0.000 description 4
- 229940070710 valerate Drugs 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- JVGUNCHERKJFCM-UHFFFAOYSA-N mabuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(=O)NCCO)C=C1 JVGUNCHERKJFCM-UHFFFAOYSA-N 0.000 description 3
- 229950001846 mabuprofen Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- KEAGRYYGYWZVPC-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CC(C)CC1=CC=C(C(C)=O)C=C1 KEAGRYYGYWZVPC-UHFFFAOYSA-N 0.000 description 2
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940072709 motrin Drugs 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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 the 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-2-amino-5-guanidine radicals valerate, 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 the non-steroidal anti-inflammatory medicine; Have anti-inflammatory, analgesic, the effect that relieves the pain; Taken in multinational pharmacopeia, clinical application is extensive, particularly because Ibuprofen BP/EP has tight security; At present become the main products in the antipyretic and analgesic, having replaced Frosst) becomes the most general antipyretic and analgesic of application.
But Ibuprofen BP/EP solubleness is little, for solving the little and difficult problem of the low formulation preparation of fusing point of Ibuprofen BP/EP solubleness in water, Ibuprofen BP/EP is become organic salt with l-arginine abroad; Can obtain the crystalloid solid; The water-soluble raising of product (can be made into aqueous injection), product fusing point high (greater than 150 ℃) simultaneously by the FDA approval; Drying process in the preparation production process is not high to temperature control requirement, has solved the above-mentioned deficiency of Ibuprofen BP/EP preferably.This product is in the multinational listing that is comprising China, domesticly is called smart aminoprofen.
(S)-ibuprofen (be called for short: Seractil) in vivo pharmacologically active and Ibuprofen BP/EP has certain difference, but chemical property is just the same, also exist water-soluble little, the product fusing point is low (＜80 ℃), the problem that formulation preparation is difficult.According to smart aminoprofen thinking, the tart Seractil and the l-arginine of alkalescence are processed the l-arginine Seractil, this product is soluble in water, absorb more in vivo, rapider, and fusing point surpasses 150 ℃, is the crystallinity compound, is easy to prepare preparation.Aspect children; The heating children that (S)-ibuprofen causes upper respiratory tract infection have and well separate thermal effect, can avoid children to swallow solid pharmaceutical causing danger, take after granule is dissolved in water if (S)-ibuprofen is processed granule; The conformability of child patient is good, and is rapid-action.The (S)-ibuprofen preparation process is simple, produces controlledly, and product is stable, and particle can reconstitute (Ibuprofen BP/EP and Seractil particle can only reconstitute with cold water, otherwise Ibuprofen BP/EP, Seractil are melted, and in water, separate out into wax) with hot water.Therefore, Seractil is processed the l-arginine Seractil can improve the deficiency that the Ibuprofen BP/EP performance is improved Seractil, be worth exploitation as smart aminoprofen.
The l-arginine Seractil is the arginic acid salt of Seractil; Compare with Seractil, have good water solubility, product is stable; Product purity is high, and (Seractil and l-arginine salify are actually the process of once extracting; Not carboxylic impurity such as 4-isobutyl acetophenone be not owing to being removed with the arginic acid salt salify in the Seractil, and therefore, the related substance of l-arginine Seractil is significantly less than domestic Motrin).Do not receive the restriction of gi tract pH value because the l-arginine Seractil absorbs, thereby absorb soon, can bring into play the curative effect influence early, curative effect is more secure.So urgent need will be developed a kind of novel arginine (s)-ibuprofen raw material., more demonstrate fully the therapeutic action of Seractil.In addition, these article good water solubility also reduces gastrointestinal pH difference to medicine and absorption
Disclosing a kind of preparation method of arginine (s)-ibuprofen among the one Chinese patent application CN200810105086.9, seen embodiment 2, is that (S)-ibuprofen is dissolved in the ethanol; The L-l-arginine aqueous solution-200ml ethanol of Dropwise 5 0% (m/m) under the room temperature drips and finishes back room temperature reaction 1h, 0 ℃ of insulation 2h; Filter; A spot of washing with alcohol, vacuum-drying gets product.This method is to adopt the L-l-arginine aqueous solution-200ml ethanol to drip, speed and flow velocity that bad control drips, and adopt under the room temperature and react 1h; 0 ℃ of insulation 2h; Under this temperature, the arginine (s)-ibuprofen of first reacted can be separated out, and causes end reaction incomplete; Cause final product to have the related substance height, the low phenomenon that waits of yield.
Therefore, be necessary to develop a kind of preparation method of new arginine (s)-ibuprofen.
Summary of the invention
It is simple, quality controllable and be suitable for the preparation method of the arginine (s)-ibuprofen of suitability for industrialized production to the invention provides a kind of operation.
A kind of preparation method of arginine (s)-ibuprofen comprises step:
(S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 50 ℃～60 ℃, stir down; Slowly drip the L-l-arginine continuously, 10min～20min dropwises, and keeps 50 ℃～60 ℃ to continue stirring reaction 2 hours～3.5 hours; Leave standstill 25min～35min, be cooled to 18 ℃～30 ℃ again, suction filtration; Get crystal, obtain white crystal after washing, the drying, promptly get arginine (s)-ibuprofen.
In order to reach better invention effect, preferably:
(S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 50 ℃, stir down, slowly drip the L-l-arginine continuously; 10min dropwises, and keeps 50 ℃ to continue stirring reaction 2 hours, leaves standstill 25min; Be cooled to room temperature again, suction filtration gets crystal; Wash 3 times, drying obtains white crystal, promptly gets arginine (s)-ibuprofen.
(S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 55 ℃, stir down, slowly drip the L-l-arginine continuously; 15min dropwises, and keeps 55 ℃ to continue stirring reaction 2.5 hours, leaves standstill 30min; Be cooled to room temperature again, suction filtration gets crystal; Wash 3 times, drying obtains white crystal, promptly gets arginine (s)-ibuprofen.
(S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 60 ℃, stir down, slowly drip the L-l-arginine continuously; 20min dropwises, and keeps 60 ℃ to continue stirring reaction 3.5 hours, leaves standstill 35min; Be cooled to room temperature again, suction filtration gets crystal; Wash 3 times, drying obtains white crystal, promptly gets arginine (s)-ibuprofen.
The alcoholic acid concentration expressed in percentage by volume is 80%～95% in the described aqueous ethanolic solution; Further be preferably 90%～95%; Can better dissolve (S)-ibuprofen, be arginine (s)-ibuprofen, obtain the higher the finished product of purity and yield so that (S)-ibuprofen and l-arginine better react.
Washing used washings is that concentration expressed in percentage by volume is 95% ethanol or absolute ethyl alcohol.
Described exsiccant temperature is 65 ℃～70 ℃.
The described exsiccant time is 4 hours～6 hours.
The reaction equation of compound method of the present invention is following:
The not strict qualification of the consumption of reaction raw materials is generally measured than reacting according to chemical reaction among the present invention, also can excessively react.
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 the aqueous ethanolic solution or the characteristic of absolute ethyl alcohol, and (S)-ibuprofen is dissolved in aqueous ethanolic solution or absolute ethyl alcohol, so under comparatively high temps, dissolve (S)-ibuprofen; Drip arginic speed through control and improve the yield of reaction; Last under lower temperature, stirring and crystallizing has avoided bulk drug to want the purified process; Improve the yield and the purity of product, shortened the production cycle.
The present invention has following advantage:
1) the raw materials used raw material that meets medicinal standard that is of the present invention, product purity is high, and its salification process is owing to be dissolving under comparatively high temps; Separate out crystallization under the lesser temps, identical with recrystallization process, be equivalent to carry out once refining; The product appearance brilliant white that makes; Crystal formation is neat, can reach medicinal standard through the chemical examination product purity, so need not make with extra care again.
2) l-arginine in the product of the present invention is the nutritive substance of human body, can prevent and correct owing to taking the hepatotoxicity that Ibuprofen BP/EP causes for a long time.Simultaneously, l-arginine is a kind of semi-dispensable amino acid, and it has important effect through the nitrogen protoxide (NO) that metabolism generates to immunity system; And the research of vivo and vitro also shows, l-arginine also has irreplaceable effect to the secretion of growing with associated hormone of human or animal's immune organ and immunocyte.
3) a kind of new preparation method of arginine (s)-ibuprofen raw material is provided, can have increased arginine (s)-ibuprofen supply of raw material amount.
4) the l-arginine Seractil prepares process and is merely the single step reaction process, does not have complicated chemical reaction, and the operational path choice is also little, and the reaction requirement condition is lower, and constant product quality is controlled, and environmental pollution is also less.In a word, this method favorable reproducibility, less to surrounding environment influence, products obtained therefrom is stablized, is met the requirements, the economic benefit that tool is bigger.
5) preparation technology of the present invention is simple, need not to pass through purification step again, and is quality controllable, need not special devices, practice thrift cost, and shortened process is suitable for suitability for industrialized production, good, the good stability of the arginine (s)-ibuprofen raw materials quality that makes.
Embodiment
Embodiment 1
(S)-ibuprofen 20.83g (0.101mol) is dissolved in 72ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution, is heated to 55 ℃, stir down, slowly drip L-l-arginine 17.42g (0.1mol) continuously; 10min dropwises, and keeps 55 ℃ to continue stirring reaction 3 hours, leaves standstill 30min, is cooled to room temperature again; Suction filtration gets crystal, 5ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution washing 3 times; 65 ℃ of dryings obtained white crystal 37.66g in 6 hours, and yield is 98.98%, 175 ℃～178 ℃ of fusing points.
Above-mentioned white crystal is carried out ultimate analysis, and staple result is following: 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 staple that shows above-mentioned product is D-Alpha-Methyl-4-(2-methyl-propyl) toluylic acid L-2-amino-5-guanidine radicals valerate, 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, is heated to 50 ℃, stir down; Slowly drip L-l-arginine 17.42g (0.1mol) continuously, 15min dropwises, and keeps 50 ℃ to continue stirring reaction 2 hours; Leave standstill 25min, be cooled to room temperature, suction filtration again; Get crystal, 5ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution washing 3 times, 70 ℃ of dryings obtained white crystal 37.46g in 4 hours; Yield is 98.45%, 175.2 ℃～177.6 ℃ of fusing points.
Above-mentioned white crystal is carried out ultimate analysis, and staple result is following: 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 staple that shows above-mentioned product is D-Alpha-Methyl-4-(2-methyl-propyl) toluylic acid L-2-amino-5-guanidine radicals valerate, 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, is heated to 60 ℃, stir down; Slowly drip L-l-arginine 17.42g (0.1mol) continuously, 20min dropwises, and keeps 60 ℃ to continue stirring reaction 3.5 hours; Leave standstill 35min, be cooled to room temperature, suction filtration again; Get crystal, 5ml95% (concentration expressed in percentage by volume) aqueous ethanolic solution washing 3 times, 5 hours dryings of 68 ℃ of dryings obtain white crystal 36.86g; Yield is 96.88%, 175.8 ℃～178.2 ℃ of fusing points.
Above-mentioned white crystal is carried out ultimate analysis, and staple result is following: 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 staple that shows above-mentioned product is D-Alpha-Methyl-4-(2-methyl-propyl) toluylic acid L-2-amino-5-guanidine radicals valerate, i.e. arginine (s)-ibuprofen.
Comparative Examples 1
The 25g (S)-ibuprofen is dissolved in the 250ml ethanol, drips the L-l-arginine aqueous solution-200ml ethanol of 42.3g 50% (m/m) under the room temperature, drip and finish back room temperature reaction 1h; 0 ℃ of insulation 2h filters a spot of washing with alcohol; Vacuum-drying gets the 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) gets the arginine (s)-ibuprofen 10mg that embodiment 1, embodiment 2, embodiment 3 and Comparative Examples 1 prepare respectively; Respectively add water 1ml, jolting makes molten, adds ninhydrin solution 1ml again; Jolting, embodiment 1, embodiment 2, embodiment 3 and Comparative Examples 1 solution all show purple.The result shows: the arginine (s)-ibuprofen of embodiment 1, embodiment 2, embodiment 3 and Comparative Examples 1 preparation meets two l-arginine of Chinese Pharmacopoeia version in 2010 and differentiates a regulation of inspection.
(2) get the arginine (s)-ibuprofen that embodiment 1, embodiment 2, embodiment 3 and Comparative Examples 1 prepare respectively; Respectively add water and process the solution that contains 0.6mg among every 1ml; Measure according to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2010 A), the arginine (s)-ibuprofen of embodiment 1, embodiment 2 embodiment 3 and Comparative Examples 1 preparation all has maximum absorption in the wavelength of 265nm and 273nm.The result shows: the arginine (s)-ibuprofen of embodiment 1, embodiment 2, embodiment 3 and Comparative Examples 1 preparation is up to specification.
Related substance
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be weighting agent; (get the 4g Mono Chloro Acetic Acid and be dissolved in the 400ml water, regulate pH value to 3.0 with ammoniacal liquor)-acetonitrile (45: 55, volume ratio) is a moving phase, detects wavelength 254nm, flow velocity 1.5ml/min with chloroacetic acid solution.Number of theoretical plate should be not less than 2000 by the Seractil peak.
Assay method is got the arginine (s)-ibuprofen an amount of (being equivalent to (S)-ibuprofen 75mg) of embodiment 1, embodiment 2, embodiment 3 and Comparative Examples 1 preparation, and accurate the title decides, and puts in the 25ml measuring bottle; It is an amount of to add moving phase, and jolting makes dissolving, adds moving phase and is diluted to scale; Shake up, as need testing solution; Precision is measured this need testing solution 1ml, puts in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, as contrast solution; It is an amount of that other gets 4-isobutyl acetophenone reference substance, and accurate the title decides, and uses acetonitrile to be mixed with the solution of concentration as 0.5mg/ml; Precision is measured this solution 1ml, puts in the 50ml measuring bottle, adds moving phase and is diluted to scale; Shake up, precision is measured 3ml, puts in the 10ml measuring bottle; Add moving phase and be diluted to scale, shake up, as reference substance solution.Precision is measured contrast solution 20 μ l, injects liquid chromatograph, regulates instrumental sensitivity, makes the principal constituent peak height be about 20%～25% of registering instrument full range; Precision is measured each 20 μ l of need testing solution and reference substance solution, injects liquid chromatograph respectively, 2 times of record color atlas to principal constituent peak RT.In the need testing solution color atlas if any impurity peaks; Measure each impurity peaks peak area; The 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%).
The result is following: the 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) in the arginine (s)-ibuprofen of embodiment 1, embodiment 2, embodiment 3 and Comparative Examples 1 preparation; 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); The unknown impuritie peak is respectively 0.06%, 0.08%, 0.07%, 1.210% (the unknown impuritie peak area is with respect to the per-cent of the main peak area of contrast solution); Mensuration result shows: the known impurities peak area should be not more than reference substance solution main peak area (0.1%) in the color atlas of arginine (s)-ibuprofen solution of the present invention; 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 the arginine (s)-ibuprofen of Comparative Examples 1 preparation is undesirable.
The stability study experiment:
1, influence factor test
The arginine (s)-ibuprofen of embodiment 1,2,3 preparations is put into plate respectively as sample, place by following three conditions.
1) strong illumination test: sample is removed outer packaging, put under the YG-A type medicine exposure experiments to light appearance, with about 4500 ± 500LX illuminance held 10 days.
2) high temperature test: sample is removed 60 ℃ of constant temperature of outsourcing device placed 10 days.
3) high humidity test: 25 ℃ of relative humidity, 92.5% condition held 10 days.
More than sample under each test conditions; Respectively at sampling on time in the 5th, 10 day, measure according to each item TP respectively; Product is through tests such as high temperature, high humidity, illumination, and each item index of the arginine (s)-ibuprofen of embodiment 1,2,3 preparations is not seen considerable change.
2, accelerated test
The arginine (s)-ibuprofen of embodiment 1,2,3 preparations is simulated listing respectively as sample pack, in 40 ℃ ± 2 ℃, under the condition of relative humidity 75% ± 5%; Placed 6 months, respectively at 1,2; Sampling on time in 3,6 months is carried out each item and is measured; The result shows: accelerated test condition held 6 months, and each item index of the arginine (s)-ibuprofen of embodiment 1,2,3 preparations and comparison in 0 day, no considerable change.
3, the long-term placement
The arginine (s)-ibuprofen of embodiment 1,2,3 preparations is packed as sample simulation listing, and in 25 ± 2 ℃, the condition held of relative humidity 60 ± 10% is respectively at 0; 3,6,9,12; Sampling on time in 18,24,36 months is carried out each item and is measured; The result shows: product is test of long duration condition held 9 months, each item index of the arginine (s)-ibuprofen of embodiment 1,2,3 preparations and comparison in 0 day, no considerable change.
Claims (9)
1. the preparation method of an arginine (s)-ibuprofen comprises step: (S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 50 ℃～60 ℃, stir down; Slowly drip the L-l-arginine continuously, 10min～20min dropwises, and keeps 50 ℃～60 ℃ to continue stirring reaction 2 hours～3.5 hours; Leave standstill 25min～35min, be cooled to 18 ℃～30 ℃ again, suction filtration; Get crystal, obtain white crystal after washing, the drying, promptly get arginine (s)-ibuprofen.
2. the preparation method of arginine (s)-ibuprofen according to claim 1 is characterized in that, (S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 50 ℃; Stir down, slowly drip the L-l-arginine continuously, 10min dropwises, and keeps 50 ℃ to continue stirring reaction 2 hours; Leave standstill 25min, be cooled to room temperature again, suction filtration gets crystal; Wash 3 times, drying obtains white crystal, promptly gets arginine (s)-ibuprofen.
3. the preparation method of arginine (s)-ibuprofen according to claim 1 is characterized in that, (S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 55 ℃; Stir down, slowly drip the L-l-arginine continuously, 15min dropwises, and keeps 55 ℃ to continue stirring reaction 2.5 hours; Leave standstill 30min, be cooled to room temperature again, suction filtration gets crystal; Wash 3 times, drying obtains white crystal, promptly gets arginine (s)-ibuprofen.
4. the preparation method of arginine (s)-ibuprofen according to claim 1 is characterized in that, (S)-ibuprofen is dissolved in ethanol or the aqueous ethanolic solution, is heated to 60 ℃; Stir down, slowly drip the L-l-arginine continuously, 20min dropwises, and keeps 60 ℃ to continue stirring reaction 3.5 hours; Leave standstill 35min, be cooled to room temperature again, suction filtration gets crystal; Wash 3 times, drying obtains white crystal, promptly gets arginine (s)-ibuprofen.
5. according to the preparation method of each described arginine (s)-ibuprofen of claim 1～4, it is characterized in that the alcoholic acid concentration expressed in percentage by volume is 80%～95% in the described aqueous ethanolic solution.
6. the preparation method of arginine (s)-ibuprofen according to claim 5 is characterized in that, the alcoholic acid concentration expressed in percentage by volume is 90%～95% in the described aqueous ethanolic solution.
7. according to the preparation method of each described arginine (s)-ibuprofen of claim 1～4, it is characterized in that washing used washings is that concentration expressed in percentage by volume is 95% ethanol or absolute ethyl alcohol.
8. according to the preparation method of each described arginine (s)-ibuprofen of claim 1～4, it is characterized in that described exsiccant temperature is 65 ℃～70 ℃.
9. according to the preparation method of each described arginine (s)-ibuprofen of claim 1～4, it is characterized in that the described exsiccant time is 4 hours～6 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617330A (en) * | 2012-03-15 | 2012-08-01 | 合肥科大生物技术有限公司 | Method for preparing ibuprofen arginine salt |
| CN102854263A (en) * | 2012-08-31 | 2013-01-02 | 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 |
| CN109521117A (en) * | 2018-12-07 | 2019-03-26 | 成都倍特药业有限公司 | A kind of detection method of the ibuprofen injection in relation to substance |
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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 | Method for preparing dexibuprofen arginine 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20090083667A (en) * | 2008-01-30 | 2009-08-04 | 대화제약 주식회사 | Method for preparing dexibuprofen arginine salt |
| 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 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617330A (en) * | 2012-03-15 | 2012-08-01 | 合肥科大生物技术有限公司 | Method for preparing ibuprofen arginine salt |
| 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 |
| CN102854263A (en) * | 2012-08-31 | 2013-01-02 | 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 |
| 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 |
| CN109521117A (en) * | 2018-12-07 | 2019-03-26 | 成都倍特药业有限公司 | A kind of detection method of the ibuprofen injection in relation to substance |
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| CN102344360B (en) | 2014-05-14 |
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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. |