CN103113216B - Naproxen sodium crystal compound, medical composition and preparation method thereof - Google Patents
Naproxen sodium crystal compound, medical composition and preparation method thereof Download PDFInfo
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- CN103113216B CN103113216B CN201310086891.2A CN201310086891A CN103113216B CN 103113216 B CN103113216 B CN 103113216B CN 201310086891 A CN201310086891 A CN 201310086891A CN 103113216 B CN103113216 B CN 103113216B
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- naproxen sodium
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- naproxen
- sodium crystal
- crystal compound
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- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 title claims abstract description 67
- 229960003940 naproxen sodium Drugs 0.000 title claims abstract description 66
- 150000001875 compounds Chemical class 0.000 title claims abstract description 13
- 239000013078 crystal Substances 0.000 title abstract description 32
- 238000002360 preparation method Methods 0.000 title abstract description 23
- 239000000203 mixture Substances 0.000 title abstract description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000002347 injection Methods 0.000 abstract description 14
- 239000007924 injection Substances 0.000 abstract description 14
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000007787 solid Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 14
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 13
- 229960002009 naproxen Drugs 0.000 description 13
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000008227 sterile water for injection Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005262 decarbonization Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940072359 anaprox Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a naproxen sodium crystal compound and a medical composition comprising the naproxen sodium crystal compound, and in particular relates to a powder-injection and a preparation method thereof. The naproxen sodium crystal compound is superior to other marketed products in stability and solubility, high in purity, easy to industrialize and suitable for preparing pharmaceutical preparations, and in particular suitable for long-time storage.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to the good naproxen sodium crystal of a kind of stability and solubleness, the powder injection that comprises it and their preparation method.
Background technology
Naproxen sodium has very strong relieving inflammation and relaxing pain usefulness, and its main biological action is: (1) suppresses the activity of prostaglandin synthetase (cyclooxygenase, reductase enzyme, isomerase), reduces PGE
2synthetic, thereby reduce capillary permeability; (2) reduce lysosome activity, reduce scavenger cell and generate superoxide and bring into play anti-inflammatory action; (3) stimulate T to suppress cytoactive; (4) reduce sensitivity to pain.With Naproxen Base or Asprin, make positive control, quite the naproxen sodium of dosage is all better than reference substance to the inhibition of inflammation with to the mitigation of pain, and the time that drug effect occurs also shifts to an earlier date compared with reference substance.
Existing Anaprox, state's Extra Pharmacopoeia Martindale only has tablet to record, about its injection, rare production.Because injection has, absorb fast, rapid-actionly, be especially suitable for needing the patient of performance analgesia effect fast.Therefore develop the needs that naproxen sodium injection is also market, still, the stability study of naproxen sodium injection liquid proves, the aqueous stability of naproxen sodium is very poor, light, air (O
2), pH value has considerable influence to its stability, so need to solve its stability problem, obtain a kind of stable naproxen sodium and preparation thereof and seem particularly necessary at medicine industry production field.
Chinese patent ZL200810136233.9 discloses a kind of production technique of Naproxen Base, passes into ammonia or adds the alkaline matters such as ammoniacal liquor, salify at a certain temperature in Naproxen Base aqeous suspension, after crystallisation by cooling, filtration obtains Naproxen Base salt, then it is dissolved to acidifying again, obtains Naproxen Base.Wherein Naproxen Base salt is intermediate material, and it can not solve the problems referred to above that occur in pharmacy and medicine storage.
The inventor, in production practice, has found a kind of new naproxen sodium crystal, and its stability and solvability are all good, are suitable for injection.In order further to improve its stability, the inventor has been made into powder injection, has further improved its stability simultaneously.
Summary of the invention
The object of the present invention is to provide a kind of naproxen sodium crystalline compounds, this crystal stability and solubleness are good, meanwhile, the problem that the present invention also in use exists for current naproxen sodium, provides a kind of naproxen sodium powder injection that comprises described crystalline compounds and preparation method thereof.
Aspect first, the invention provides a kind of naproxen sodium crystalline compounds.
In specific embodiment, in the X-ray powder diffraction of described crystalline compounds, 2 θ diffraction angle have characteristic peak at 6.0 ± 0.2,7.4 ± 0.2,15.2 ± 0.2,16.0 ± 0.2,17.5 ± 0.1,17.8 ± 0.1,18.3 ± 0.2,19.9 ± 0.2,21.2 ± 0.2,22.6 ± 0.2,24.1 ± 0.2,25.3 ± 0.2,26.1 ± 0.2,27.0 ± 0.2,28.0 ± 0.2,29.0 ± 0.2,30.7 ± 0.2,31.9 ± 0.2 degree places.
In embodiment more specifically, the X-ray powder diffraction figure of described crystal as shown in Figure 1.
Aspect second, the invention provides the preparation method of described crystal, comprising: Naproxen Base is dissolved in tetrahydrofuran solution, filters; Filtrate is stirred at 30 ~ 40 ℃, drips the ethanolic soln of sodium hydroxide, and after having dropped to solid and separating out, concentrating under reduced pressure, has a large amount of solids to separate out; Solid collected by filtration, dry.
Aspect the 3rd, a kind of pharmaceutical composition is provided, comprise naproxen sodium crystalline compounds as above and pharmaceutically acceptable carrier.
In a specific embodiment, described pharmaceutical composition is powder injection, by described naproxen sodium crystalline compounds, sodium hydroxide and water, is made.
In yet another aspect, the invention provides the preparation method of described powder injection, comprising: the naproxen sodium of recipe quantity is placed in clean container, the sterilized water for injection that adds approximately 80% total consumption, is stirred to medicine and dissolves completely, adds gac, under room temperature, stir filtering decarbonization; With the sodium hydroxide solution of 0.1mol/L, regulate pH value to 9.3 ~ 9.6, add sterilized water for injection and be settled to full dose, now pH value is 9.0 ~ 9.5; Adopt filtering with microporous membrane to remove insoluble impurities; Adopt double-deck millipore filtration Entkeimung; Carry out centre product check, measure the content of naproxen sodium in liquid, check clarity and the pH value of liquid simultaneously; Filling, lyophilize, gland, full inspection, packing, warehouse-in.
Naproxen sodium crystal X-ray powder diffraction of the present invention adopts Switzerland X'TRA type X-ray diffractometer, and condition determination is copper target, tube voltage 40 kV, tube current 40mA, 10.00 °/min of sweep velocity, 3.00～50.00 ° of sweep limits.
Its x-ray diffraction pattern is shown in Fig. 1.Its TGA curve shows, sample is containing planar water and solvent.
For characteristics such as the solvability of further checking naproxen sodium crystal provided by the present invention, stability, the present invention has carried out solvability and stability experiment to it.
One, solvability
Commercially available naproxen sodium (purchased from Hubei Heng great Yi Hua company limited) and naproxen sodium crystal of the present invention (embodiment 1 preparation) are carried out to solubility experiment, and water is cooked solvent, measures its solubleness, the results are shown in Table 1.
The test of table 1 naproxen sodium dissolution of crystals
| ? | Weight | Solvent volume | Dissolving situation | Conclusion |
| Commercially available naproxen sodium | 1002.13 mg | 5 ml | Do not dissolve completely | Be difficult for molten |
| Naproxen sodium crystal | 1022.24 mg | 3 ml | Dissolve completely | Yi Rong |
As can be seen from Table 1, the solubleness of naproxen sodium crystal of the present invention has had significant improvement, is beneficial to and prepares injection.
Two, stability
1, exposure experiments to light
Commercially available naproxen sodium and naproxen sodium crystal (embodiment 1 preparation) are evenly shared to uncovered culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, detects, and contrast with the result of 0 day respectively at sampling in 5,10 days.The results are shown in Table 2 and 3.
Table 2 naproxen sodium crystal exposure experiments to light
The commercially available naproxen sodium exposure experiments to light of table 3
Note: 23～26 ℃ of temperature, relative humidity variations 56～62%
From upper table 2 and 3, can find out, compare with commercially available naproxen sodium, naproxen sodium crystal of the present invention is more stable under illumination condition.
2, high temperature test
Commercially available naproxen sodium and naproxen sodium crystal (embodiment 1 preparation) are positioned in sealing clean vial, are placed in 60 ℃ of thermostatic drying chambers, respectively at sampling in 5,10 days, detect, and contrast with the result of 0 day.The results are shown in Table 4 and 5.
The test of table 4 naproxen sodium crystal high-temperature
The commercially available naproxen sodium high temperature test of table 5
From upper table 4 and 5, can find out, compare with commercially available naproxen sodium, naproxen sodium crystal of the present invention is more stable under hot conditions.
3, high wet test
Commercially available naproxen sodium and naproxen sodium crystal (embodiment 2 preparations) are evenly spread out to uncovered culture dish, and thickness≤5mm, is placed in room temperature (25 ℃ of left and right), relative humidity is in 90 ± 5% constant incubator, respectively at sampling in 5,10 days, detect, and contrast with the result of 0 day.The results are shown in Table 6 and 7.
The high wet test of table 6 naproxen sodium crystal
The high wet test of the commercially available naproxen sodium of table 7
From upper table 6 and 7, can find out, compare with commercially available naproxen sodium, naproxen sodium crystal of the present invention is more stable under super-humid conditions.
Experimental result shows, the naproxen sodium crystal that the present invention obtains is under illumination, high temperature and super-humid conditions, and the variation of its outward appearance and its related substances is all better than commercially available common naproxen sodium, is applicable to being prepared as pharmaceutical preparation, particularly powder injection.
Visible, naproxen sodium crystalline compounds of the present invention, has good solubility and good stability, is applicable to making pharmaceutical preparation standing storage.
Simultaneously, because the required solvent of naproxen sodium crystal preparation technology in the present invention is simple and amount is few, take Naproxen Base as the crystal purity of raw material gained better, stable yield, quality circulation ratio is good, and product purity is easy to control, and can well solve deficiency and problem in currently available technology, there is significant beneficial effect, be easy to suitability for industrialized production.
accompanying drawing explanation:
Fig. 1 is the X-ray powder diffraction pattern of naproxen sodium crystal of the present invention.
Embodiment
Below by embodiment, further illustrate the present invention.Embodiments of the invention are only for the present invention is described, rather than to formulation restriction of the present invention, on method of the present invention basis, simple modifications all belongs to the scope of protection of present invention.
embodiment 1: the preparation of naproxen sodium crystal
Get Naproxen Base 13.0 g and be placed in reaction flask, add tetrahydrofuran (THF) 100mL, fully stir, after 30min, dissolve completely, filter, drain, filtrate is transferred in the there-necked flask of 500mL, at 35 ℃, stirs, and drips the ethanolic soln (0.25 g/mL) of sodium hydroxide, while having solid to separate out, drip and finish, continue equality of temperature stirring reaction 0.5 h.Concentrating under reduced pressure reaction solution at 35 ℃, stops concentrating while having a large amount of solids to separate out, and is cooled to 15 ℃ of crystallization 4h, has a large amount of white solids to separate out.Suction filtration, filter cake washs and drains with tetrahydrofuran (THF).In 40 ℃ of decompressions (more than 0.09MPa), be dried to obtain white solid 12.4g, yield 86.7%.
Its X-ray powder diffraction figure as shown in Figure 1.
embodiment 2: the preparation of naproxen sodium crystal
Get Naproxen Base 20.0 g and be placed in reaction flask, add tetrahydrofuran (THF) 300mL, fully stir, after 30min, dissolve completely, filter, drain, filtrate is transferred in the there-necked flask of 500mL, at 30 ℃, stirs, and drips the ethanolic soln (0.25 g/mL) of sodium hydroxide, while having solid to separate out, drip and finish, continue equality of temperature stirring reaction 1 h.Concentrating under reduced pressure reaction solution at 35 ℃, stops concentrating while having a large amount of solids to separate out, and is cooled to 15 ℃ of crystallization 4h, has a large amount of white solids to separate out.Suction filtration, filter cake washs and drains with tetrahydrofuran (THF).Solid is dried to obtain white solid 18.8 g, yield 85.6% in 40 ℃ of decompressions (more than 0.09MPa).
The product of its x-ray powder and embodiment 1 is basic identical.
embodiment 3: the preparation of naproxen sodium crystal
Get Naproxen Base 100 g and be placed in reaction flask, add tetrahydrofuran (THF) 1200mL, fully stir, after 30min, dissolve completely, filter, drain, filtrate is transferred in the there-necked flask of 2000mL, at 35 ℃, stirs, and drips the ethanolic soln (0.25 g/mL) of sodium hydroxide, while having solid to separate out, drip and finish, continue equality of temperature stirring reaction 1 h.Concentrating under reduced pressure reaction solution at 35 ℃, stops concentrating while having a large amount of solids to separate out, and is cooled to 15 ℃ of crystallization 5h, has a large amount of white solids to separate out.Suction filtration, filter cake washs and drains with tetrahydrofuran (THF).Solid is dried to obtain white solid 91.1g, yield 82.8% in 40 ℃ of decompressions (more than 0.09MPa).
The product of its x-ray powder and embodiment 1 is basic identical.
embodiment 4: the preparation of naproxen sodium crystal
Get Naproxen Base 50 g and be placed in reaction flask, add tetrahydrofuran (THF) 80mL, fully stir, after 30min, dissolve completely, filter, drain, filtrate is transferred in the there-necked flask of 500mL, at 35 ℃, stirs, and drips the ethanolic soln (0.25 g/mL) of sodium hydroxide, while having solid to separate out, drip and finish, continue equality of temperature stirring reaction 0.5 h.Concentrating under reduced pressure reaction solution at 35 ℃, stops concentrating while having a large amount of solids to separate out, and is cooled to 15 ℃ of crystallization 4h, has a large amount of white solids to separate out.Suction filtration, filter cake washs and drains with tetrahydrofuran (THF).Solid is dried to obtain white solid 46.7g, yield 85.0% in 40 ℃ of decompressions (more than 0.09MPa).
The product of its x-ray powder and embodiment 1 is basic identical.
embodiment 5: the preparation of naproxen sodium composition
Prescription:
Naproxen sodium (C
14h
13naO
3) 275g (being equivalent to Naproxen Base 250g)
The sodium hydroxide solution of 0.1mol/L is appropriate
Water for injection adds to 2000mL
Make altogether 1000 bottles of dried frozen aquatic productses
Preparation:
According to recipe quantity, take naproxen sodium, naproxen sodium is placed in clean container, add the sterilized water for injection of approximately 80% total consumption, be stirred to medicine and dissolve completely, add 0.1% (g/mL) injection gac, under room temperature, stir filtering decarbonization after 30min; With the sodium hydroxide solution of 0.1mol/L, regulate pH value to 9.3 ~ 9.6, add sterilized water for injection and be settled to full dose, now pH value is 9.0 ~ 9.5; Adopt the filtering with microporous membrane of 0.45 μ m, remove insoluble impurities; Adopt the millipore filtration Entkeimung of double-deck 0.22 μ m; Carry out centre product check, measure the content of naproxen sodium in liquid, check clarity and the pH value of liquid simultaneously; Filling, lyophilize, gland, full inspection, packing, warehouse-in.
embodiment 6: the preparation of naproxen sodium composition
Prescription:
Naproxen sodium (C
14h
13naO
3) 200 g
The sodium hydroxide solution of 0.1mol/L is appropriate
Water for injection adds to 1750mL
Make altogether 1000 bottles of dried frozen aquatic productses
Preparation method is with embodiment 5.
embodiment 7: the preparation of naproxen sodium composition
Prescription:
Naproxen sodium (C
14h
13naO
3) 300g
The sodium hydroxide solution of 0.1mol/L is appropriate
Water for injection adds to 3000mL
Make altogether 1000 bottles of dried frozen aquatic productses
Preparation method is with embodiment 5.
Claims (1)
1. a naproxen sodium crystalline compounds, its X-ray powder diffraction figure as shown in Figure 1.
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| CN201310086891.2A CN103113216B (en) | 2013-03-18 | 2013-03-18 | Naproxen sodium crystal compound, medical composition and preparation method thereof |
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Application publication date: 20130522 Assignee: SHANDONG PKU HIGH-TECH HUATAI PHARMACEUTICAL Co.,Ltd. Assignor: Ning Hui Contract record no.: 2014370000212 Denomination of invention: Naproxen sodium crystal compound, medical composition and preparation method thereof Granted publication date: 20141210 License type: Common License Record date: 20141226 |
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Effective date of registration: 20240423 Address after: Room 202, East Building C, Headquarters Center, No. 23 Guangfu East Street, Houtang Community, Jiangbei Street, Dongyang City, Jinhua City, Zhejiang Province, 322100 Patentee after: Zhejiang Zhongyan Pharmaceutical Technology Co.,Ltd. Country or region after: China Address before: Room 202, Study Abroad Building, No. 129 Fuzhou North Road, Shibei District, Qingdao City, Shandong Province, 266034 Patentee before: Ning Hui Country or region before: China |