CN104327120A - Riboflavin sodium phosphate compound injection and preparing method thereof - Google Patents
Riboflavin sodium phosphate compound injection and preparing method thereof Download PDFInfo
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- CN104327120A CN104327120A CN201410514866.4A CN201410514866A CN104327120A CN 104327120 A CN104327120 A CN 104327120A CN 201410514866 A CN201410514866 A CN 201410514866A CN 104327120 A CN104327120 A CN 104327120A
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- riboflavin
- sodium phosphate
- phosphate compound
- riboflavin sodium
- acid
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- SGIABBWBGLKPQF-DCBWTQNWSA-N Cc(c(C)c1)cc(N2C[C@@H](C(C(COPO)O)O)O)c1N=C(C(N1)=O)C2=NC1=O Chemical compound Cc(c(C)c1)cc(N2C[C@@H](C(C(COPO)O)O)O)c1N=C(C(N1)=O)C2=NC1=O SGIABBWBGLKPQF-DCBWTQNWSA-N 0.000 description 1
Abstract
The invention aims to provide a riboflavin sodium phosphate compound, a riboflavin sodium phosphate compound injection and a preparation method thereof. The riboflavin sodium phosphate having a novel crystal structure is better in stability, is reduced in phosphorylation reaction time during a synthetic process and is increased in yield. The riboflavin sodium phosphate compound is suitable for preparing a medicinal composition since the riboflavin sodium phosphate compound is uniform in particle size, is excellent in stability and is high in yield. The riboflavin sodium phosphate compound can be prepared into various known dosage forms, such as a freeze-dried powder needle, an injection and the like.
Description
Technical field
The present invention relates to a kind of compound injection liquid and preparation method thereof, particularly relate to a kind of Riboflavin sodium phosphate compound injection liquid and preparation method thereof.
Background technology
Riboflavin has another name called Lin Suanna Vitamin B2 Sodium Phosphate, is to maintain the necessary a kind of water-soluble vitamins of body eubolism, is the moiety of the important prothetic group of enzyme systems many in body, participates in energy metabolism and the substance metabolism of body.If body lacks riboflavin, will have influence on normal oxygenizement in organism, cause substance metabolism disorderly, make body occur a series of illness, serious will cause body dead.In view of riboflavin has extensive and important physiological function, the World Health Organization is classified as one of six large indexs of the growth of appraiser's bulk-growth and nutritional status.
Riboflavin sodium phosphate is one of important derivatives of riboflavin, and its physiological action and riboflavin are substantially identical, the main medicine as the various VB2 deficiency disease for the treatment of, food enrichment or fodder additives.Much research shows, riboflavin and derivative thereof also have diuresis, anti-cancer, reducing blood-fat and improve the effects such as heart function.Compared with riboflavin, the solubleness of riboflavin sodium phosphate in water increases greatly, is easily absorbed by body, can be made into the injection liquid etc. of compound VB2 preparation, eye drops and concentration stabilize clinically, and use convenient, range of application is more extensive.
The production of riboflavin sodium phosphate adopts chemical synthesis usually, namely in organic solvent, makes riboflavin and phosphorus oxychloride reaction generate FMN(riboflavin-5-phosphoric acid), then with NaOH solution neutralization, more after filtration, washing, drying and other steps obtains finished product.This technique seems very simple, but byproduct of reaction is more, reacts more wayward, cause the yield of riboflavin sodium phosphate lower, and the reaction times is also longer.
Application number is disclose a kind of riboflavin sodium phosphate crystalline compounds in the Chinese patent of 201110110744. 5, have 1. 5 crystal water, the X-ray powder diffraction that described riboflavin sodium phosphate crystalline compounds uses Cu-K u radionetric survey to obtain is 6. 1 at 2 θ
0, 11. 2
0, 13. 4
0, 14. 8
0, 19. 7
0, 20. 8
0, 23. 9
0, 24. 5
0, 26. 9
0, 27. 7
0, 29. 1
0, 31. 0
0with 31. 6
0show characteristic peak.Its X-ray powder diffraction figure is shown in Fig. 1.
Summary of the invention
The object of the present invention is to provide a kind of Riboflavin sodium phosphate compound, Riboflavin sodium phosphate compound injection liquid and preparation method thereof.The Riboflavin sodium phosphate compound crystalline structure that the present invention obtains there occurs change compared with the riboflavin sodium phosphate in the past reported, specifically sees the collection of illustrative plates shown in Fig. 1 and Fig. 2.The riboflavin sodium phosphate of the novel crystalline structure that the present invention obtains has better stability, and phosphorylation reaction time shorten in building-up process, productive rate also rises to some extent.
The present invention is achieved through the following technical solutions:
A kind of Riboflavin sodium phosphate compound, its preparation method is as follows:
The pre-treatment of riboflavin: riboflavin is added in mixed acid solution, the quality of mixed acid solution is 6-10 times of riboflavin quality, the quality group of mixing acid becomes acetic acid: lactic acid=3-6:1, then 80-90 DEG C is heated to, 140-150 DEG C is warming up to after keeping 1-3 hour, removing mixing acid, dry, obtain pretreated riboflavin.
The pretreated riboflavin of 20-30 g, 3-10ml distilled water and phosphorus oxychloride is added successively, in 30-40 DEG C of reaction 30-35min after stirring in 100 ml acetonitriles; Then 70-90ml distilled water is added, be warming up to 60 DEG C of reaction 2h, then room temperature is cooled to, cross the insolubles filtered in reaction solution, in filtrate, add sodium hydroxide regulate pH to 5.5-6.1, stirring at room temperature reaction 15-20 min, filter, with the ethanolic soln washing leaching cake that volume fraction is 50%, drying is carried out to filter cake, obtains riboflavin sodium phosphate solid;
Described riboflavin and the mol ratio of phosphorus oxychloride are riboflavin: phosphorus oxychloride=1:4-5;
By 10g riboflavin sodium phosphate dissolution of solid in the distilled water of 700-800g, regulator solution pH is 5.5-6.5, at 20-25 DEG C in solution slowly at the uniform velocity pass into 800-1000ml NO
2, Ne, CO
2mixed gas, leave standstill 20-30min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 20-50ml, limit edged stirs, be cooled to 1-5 DEG C again, filter after leaving standstill 2-3 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains riboflavin phosphate sodium crystal after dry 2-5 h.
In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=(3-8): (0.2-1.1): (10-15), the interpolation flow velocity of mixed gas is 10-15 ml/min;
In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=(1-3): (2-5): (0.5-1), and the interpolation speed of mixing solutions is 0.5-1 ml/min;
Described stirring velocity is that 10-20 turns/min;
Riboflavin is slightly soluble in water, and in neutrality or acidic solution, heating is stable, and heat-resisting, resistance to oxidation.After riboflavin acetic acid and lactic acid are carried out pre-treatment by the present invention, then adopt phosphorus oxychloride to be phosphorylation agent, adopt sodium hydroxide to neutralize, can significantly shorten the phosphorylation reaction time, simultaneously obtained riboflavin sodium phosphate yield is high, steady quality.
The present invention, by adopting mixed gas and mixed solvent as precipitation agent, to the control of the crystallization conditions such as degree of supersaturation, pH value, interpolation speed, stirring velocity, obtains a kind of new riboflavin phosphate sodium crystal.The particle diameter of this crystal evenly, character is more stable.
The present invention, by changing the crystallization condition of riboflavin sodium phosphate, obtains a kind of new Riboflavin sodium phosphate compound, uses Cu-K alpha-ray to sample at 5-50
0scan in scope, X-ray powder diffraction characteristic peak 2 θ (± 0.2 obtained
0) be 7.02
0, 10.25
0, 14.25
0, 20.06
0, 23.15
0, 26.93
0.Its structural formula is as follows:
。
Riboflavin sodium phosphate crystalline compounds prepared by the present invention, due to the advantage that it has epigranular, has good stability, yield is high, is therefore applicable to prepare medicinal compositions, can be prepared into various known formulation, as freeze-dried powder, injection liquid etc.
accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of application number for riboflavin sodium phosphate crystalline compounds a kind of disclosed in the Chinese patent of 201110110744. 5.
Fig. 2 is the X-ray powder diffraction figure of the riboflavin sodium phosphate crystalline compounds that preferred version embodiment 5 of the present invention obtains.
Specific embodiment
Embodiment 1: a kind of Riboflavin sodium phosphate compound, its preparation method is as follows:
The pre-treatment of riboflavin: riboflavin is added in mixed acid solution, the quality of mixed acid solution is 8 times of riboflavin quality, the quality group of mixing acid becomes acetic acid: lactic acid=4:1, then 85 DEG C are heated to, keep being warming up to 145 DEG C after 2 hours, removing mixing acid, dry, obtain pretreated riboflavin.
The pretreated riboflavin of 25 g, 8ml distilled water and phosphorus oxychloride is added successively, in 35 DEG C of reaction 33min after stirring in 100 ml acetonitriles; Then 80ml distilled water is added, be warming up to 60 DEG C of reaction 2h, then room temperature is cooled to, cross the insolubles filtered in reaction solution, in filtrate, add sodium hydroxide regulate pH to 5.8, stirring at room temperature reacts 18 min, filter, with the ethanolic soln washing leaching cake that volume fraction is 50%, drying is carried out to filter cake, obtains riboflavin sodium phosphate solid;
Described riboflavin and the mol ratio of phosphorus oxychloride are riboflavin: phosphorus oxychloride=1:4.5;
Differentiate the riboflavin sodium phosphate obtained by the method in " Chinese Pharmacopoeia " version in 2010, result is as follows:
(1) get the present embodiment synthetic product and be about 1mg, after the 100ml that adds water dissolves, solution shows faint yellow in transmitted light and has strong yellow-green fluorescence; Add hydrochloric acid or sodium hydroxide solution, namely fluorescence disappear.
(2) the present embodiment synthetic product is got, add phosphate buffered saline buffer (pH7.0) and make the solution containing 10 μ g in every 1ml, measure with ultraviolet visible spectrophotometry, have maximum absorption at the wavelength place of 267nm, 372nm and 444nm, have minimal absorption at the wavelength place of 240nm.
(3) the infrared Absorption collection of illustrative plates of the present embodiment synthetic product is consistent with the infrared spectra of riboflavin sodium phosphate standard substance.
(4) get the present embodiment synthetic product 0.5g, add nitric acid 10ml, evaporate to dryness in water-bath, blazing, the residue 5ml that adds water makes dissolving, and filter if desired, filtrate shows the identification of sodium salt.
Can determine that the present embodiment synthetic product is riboflavin sodium phosphate thus.
Embodiment 2: a kind of Riboflavin sodium phosphate compound, its preparation method is as follows:
The pre-treatment of riboflavin: riboflavin is added in mixed acid solution, the quality of mixed acid solution is 6 times of riboflavin quality, the quality group of mixing acid becomes acetic acid: lactic acid=3:1, then 80 DEG C are heated to, keep being warming up to 140 DEG C after 1 hour, removing mixing acid, dry, obtain pretreated riboflavin.
The pretreated riboflavin of 20g, 3ml distilled water and phosphorus oxychloride is added successively, in 30 DEG C of reaction 30min after stirring in 100 ml acetonitriles; Then 70ml distilled water is added, be warming up to 60 DEG C of reaction 2h, then room temperature is cooled to, cross the insolubles filtered in reaction solution, in filtrate, add sodium hydroxide regulate pH to 5.5, stirring at room temperature reacts 15 min, filter, with the ethanolic soln washing leaching cake that volume fraction is 50%, drying is carried out to filter cake, obtains riboflavin sodium phosphate solid;
Described riboflavin and the mol ratio of phosphorus oxychloride are riboflavin: phosphorus oxychloride=1:4;
All the other are with embodiment 1.
Embodiment 3: a kind of Riboflavin sodium phosphate compound, its preparation method is as follows:
The pre-treatment of riboflavin: riboflavin is added in mixed acid solution, the quality of mixed acid solution is 10 times of riboflavin quality, the quality group of mixing acid becomes acetic acid: lactic acid=6:1, then 90 DEG C are heated to, keep being warming up to 150 DEG C after 3 hours, removing mixing acid, dry, obtain pretreated riboflavin.
The pretreated riboflavin of 30 g, 10ml distilled water and phosphorus oxychloride is added successively, in 40 DEG C of reaction 35min after stirring in 100 ml acetonitriles; Then 90ml distilled water is added, be warming up to 60 DEG C of reaction 2h, then room temperature is cooled to, cross the insolubles filtered in reaction solution, in filtrate, add sodium hydroxide regulate pH to 6.1, stirring at room temperature reacts 20 min, filter, with the ethanolic soln washing leaching cake that volume fraction is 50%, drying is carried out to filter cake, obtains riboflavin sodium phosphate solid;
Described riboflavin and the mol ratio of phosphorus oxychloride are riboflavin: phosphorus oxychloride=1:5;
All the other are with embodiment 1.
Embodiment 4: a kind of Riboflavin sodium phosphate compound, its preparation method is as follows:
The pre-treatment of riboflavin: riboflavin is added in mixed acid solution, the quality of mixed acid solution is 5 times of riboflavin quality, the quality group of mixing acid becomes acetic acid: lactic acid=7:1, then 70 DEG C are heated to, keep being warming up to 160 DEG C after 4 hours, removing mixing acid, dry, obtain pretreated riboflavin.
The pretreated riboflavin of 15 g, 2ml distilled water and phosphorus oxychloride is added successively, in 50 DEG C of reaction 45min after stirring in 100 ml acetonitriles; Then 100ml distilled water is added, be warming up to 60 DEG C of reaction 2h, then room temperature is cooled to, cross the insolubles filtered in reaction solution, in filtrate, add sodium hydroxide regulate pH to 5.4, stirring at room temperature reacts 10 min, filter, with the ethanolic soln washing leaching cake that volume fraction is 50%, drying is carried out to filter cake, obtains riboflavin sodium phosphate solid;
Described riboflavin and the mol ratio of phosphorus oxychloride are riboflavin: phosphorus oxychloride=1:3;
All the other are with embodiment 1.
Embodiment 5: the obtained riboflavin sodium phosphate solid 10g of Example 1 is dissolved in the distilled water of 750g, and regulator solution pH is 6.0, at 22 DEG C in solution slowly at the uniform velocity pass into 900ml NO
2, Ne, CO
2mixed gas, leaves standstill 25 min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 35 ml, limit edged stirs, then is cooled to 3 DEG C, filters after leaving standstill 2.5 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains riboflavin phosphate sodium crystal after dry 3 h.
In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=5:0.6:13, the interpolation flow velocity of mixed gas is 12 ml/min;
In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=2:3:0.8, and the interpolation speed of mixing solutions is 0.7 ml/min;
Described stirring velocity is 15 turns/min;
Use Cu-K alpha-ray to the riboflavin phosphate sodium crystal obtained at 5-50
0scan in scope, X-ray powder diffraction characteristic peak 2 θ (± 0.2 obtained
0) be 7.02
0, 10.25
0, 14.25
0, 20.06
0, 23.15
0, 26.93
0.
Embodiment 6: the obtained riboflavin sodium phosphate solid 10g of Example 1 is dissolved in the distilled water of 700g, and regulator solution pH is 5.5, at 20 DEG C in solution slowly at the uniform velocity pass into 800 ml NO
2, Ne, CO
2mixed gas, leaves standstill 20min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 20ml, limit edged stirs, then is cooled to 1 DEG C, filters after leaving standstill 2 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains riboflavin phosphate sodium crystal after dry 2 h.
In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=3:0.2:10, the interpolation flow velocity of mixed gas is 10 ml/min;
In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=1:2:0.5, and the interpolation speed of mixing solutions is 0.5 ml/min;
Described stirring velocity is 10 turns/min;
All the other are with embodiment 5.
Embodiment 7: the obtained riboflavin sodium phosphate solid 10g of Example 1 is dissolved in the distilled water of 800g, and regulator solution pH is 6.5, at 25 DEG C in solution slowly at the uniform velocity pass into 1000ml NO
2, Ne, CO
2mixed gas, leaves standstill 30min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 50ml, limit edged stirs, then is cooled to 5 DEG C, filters after leaving standstill 3 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains riboflavin phosphate sodium crystal after dry 5 h.
In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=8:1.1:15, the interpolation flow velocity of mixed gas is 15 ml/min;
In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=3:5:1, and the interpolation speed of mixing solutions is 1 ml/min;
Described stirring velocity is 20 turns/min;
All the other are with embodiment 5.
Embodiment 8: the obtained riboflavin sodium phosphate solid 10g of Example 1 is dissolved in the distilled water of 900g, and regulator solution pH is 5.3, at 18 DEG C in solution slowly at the uniform velocity pass into 1100ml NO
2, Ne, CO
2mixed gas, leaves standstill 33min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 60 ml, limit edged stirs, then is cooled to 6 DEG C, filters after leaving standstill 1.5 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains riboflavin phosphate sodium crystal after dry 1 h.
In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=9:1.2:8, the interpolation flow velocity of mixed gas is 16 ml/min;
In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=4:1:1.2, and the interpolation speed of mixing solutions is 0.4 ml/min;
Described stirring velocity is 22 turns/min;
Embodiment 9: a kind of Riboflavin sodium phosphate compound injection liquid, it is made up of Riboflavin sodium phosphate compound 5-10mg and water for injection 2-5mL; Preparation method adds injection liquid water in a reservoir, stir in ultrasonic dissolution instrument and make to dissolve completely, Citric Acid-Sodium Citrate buffer salt system is adopted to regulate liquid PH value to 5.5, add Riboflavin sodium phosphate compound, in ultrasonic dissolution instrument, make medicine dissolution, stir, liquid is through the gac cellulose acetate ultrafiltration composite membrane filtration under diminished pressure of 0.22 μm of micropore, sampling censorship, measures outward appearance, color and luster, clarity, after qualified; Liquid filters through the microporous bilayer polyacrylonitrile ultrafiltration film of 0.2 μm; Filling, fill nitrogen, sealing by fusing, 121 DEG C of tunnel-type hot air circulation microwaves sterilizing 8 minutes, the inspection of cooling back light, packaging, inspection, get product.
The technical parameter of described Riboflavin sodium phosphate compound is as follows: use Cu-K alpha-ray to sample at 5-50
0scan in scope, X-ray powder diffraction characteristic peak 2 θ (± 0.2 obtained
0) be 7.02
0, 10.25
0, 14.25
0, 20.06
0, 23.15
0, 26.93
0; Its structural formula is as follows:
；
The preparation method of described Riboflavin sodium phosphate compound is with embodiment 2;
The method of purification of described Riboflavin sodium phosphate compound is: the obtained riboflavin sodium phosphate solid 10g of Example 2 is dissolved in the distilled water of 700g, and regulator solution pH is 5.5, at 20 DEG C in solution slowly at the uniform velocity pass into 800 ml NO
2, Ne, CO
2mixed gas, leaves standstill 20min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 20ml, limit edged stirs, then is cooled to 1 DEG C, filters after leaving standstill 2 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains riboflavin phosphate sodium crystal after dry 2 h.
In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=3:0.2:10, the interpolation flow velocity of mixed gas is 10 ml/min;
In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=1:2:0.5, and the interpolation speed of mixing solutions is 0.5 ml/min;
Described stirring velocity is 10 turns/min;
Embodiment 10: a kind of Riboflavin sodium phosphate compound injection liquid, its preparation method is: add injection liquid water in a reservoir, stir in ultrasonic dissolution instrument and make to dissolve completely, Citric Acid-Sodium Citrate buffer salt system is adopted to regulate liquid PH value to 6.0, add Riboflavin sodium phosphate compound, medicine dissolution is made in ultrasonic dissolution instrument, stir, liquid is through the gac cellulose acetate ultrafiltration composite membrane filtration under diminished pressure of 0.22 μm of micropore, sampling censorship, measure outward appearance, color and luster, clarity, after qualified; Liquid filters through the microporous bilayer polyacrylonitrile ultrafiltration film of 0.2 μm; Filling, fill nitrogen, sealing by fusing, 121 DEG C of tunnel-type hot air circulation microwaves sterilizing 8 minutes, the inspection of cooling back light, packaging, inspection, get product.
The preparation method of described Riboflavin sodium phosphate compound is with embodiment 1;
The method of purification of described Riboflavin sodium phosphate compound is with embodiment 5;
All the other are with embodiment 9.
Embodiment 11: a kind of Riboflavin sodium phosphate compound injection liquid, its preparation method is for add injection liquid water in a reservoir, stir in ultrasonic dissolution instrument and make to dissolve completely, Citric Acid-Sodium Citrate buffer salt system is adopted to regulate liquid PH value to 6.5, add Riboflavin sodium phosphate compound, medicine dissolution is made in ultrasonic dissolution instrument, stir, liquid is through the gac cellulose acetate ultrafiltration composite membrane filtration under diminished pressure of 0.22 μm of micropore, sampling censorship, measure outward appearance, color and luster, clarity, after qualified; Liquid filters through the microporous bilayer polyacrylonitrile ultrafiltration film of 0.2 μm; Filling, fill nitrogen, sealing by fusing, 121 DEG C of tunnel-type hot air circulation microwaves sterilizing 8 minutes, the inspection of cooling back light, packaging, inspection, get product.
The preparation method of described Riboflavin sodium phosphate compound is with embodiment 3;
The method of purification of described Riboflavin sodium phosphate compound is: the obtained riboflavin sodium phosphate solid 10g of Example 3 is dissolved in the distilled water of 800g, and regulator solution pH is 6.5, at 25 DEG C in solution slowly at the uniform velocity pass into 1000ml NO
2, Ne, CO
2mixed gas, leaves standstill 30min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 50ml, limit edged stirs, then is cooled to 5 DEG C, filters after leaving standstill 3 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains riboflavin phosphate sodium crystal after dry 5 h.
In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=8:1.1:15, the interpolation flow velocity of mixed gas is 15 ml/min;
In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=3:5:1, and the interpolation speed of mixing solutions is 1 ml/min;
Described stirring velocity is 20 turns/min.
Comparative example 1: according to Authorization Notice No. for the preparation method of a kind of Riboflavin sodium phosphate compound disclosed in the Chinese patent embodiment 1 of CN 102260291 B is: add 20ml water in 1000m1 three-necked bottle, 250m1 tetrahydrofuran (THF) and 48 grams of riboflavin stirring and dissolving resulting mixtures, be cooled to 5-10 DEG C, slowly add the 100m1 sodium-metaphosphate aqueous solution (20.4 grams of sodium-metaphosphates are dissolved in 100m1 water), temperature controls at 28-30 DEG C, finish, be warming up to 40 DEG C, reaction 2-3 hour, stopped reaction, be cooled to 15-25 DEG C, reaction solution is poured in large beaker, add 250m1 water, cooling is noted while stirring, removing insolubles.10% sodium hydroxide solution is added in filtrate, pH value is regulated to be 9, stirring at room temperature 0.5 hour, suction filtration, mother liquor hydrochloric acid adjusts PH to 5-6, suction filtration, obtains white solid, with 50% a small amount of alcohol flushing, again by the ethanol of molten for product 95%, filter, crystallizing and drying obtains orange/yellow solid 59. 2 grams, and yield is 92%.Adopt efficient liquid phase chromatographic analysis, its purity is 98.5 % simultaneously.
Test example 1: the yield calculating riboflavin sodium phosphate in embodiment 1-4, and its yield and phosphorylation reaction time and comparative example 1 are contrasted, the results are shown in Table 1.
Table 1 yield and phosphorylation reaction time compare
As can be seen from Table 1, embodiment 1-3(parameters is all in the scope of technical solution of the present invention) the yield of riboflavin sodium phosphate all more than 92%, higher than comparative example 1, but the phosphorylation reaction time of embodiment 1-3 be only 0.5 hours, substantially reduce the reaction times.Embodiment 4(parameters is all outer in the scope of technical solution of the present invention) its yield is only 71.8%.
Test example 2: riboflavin sodium phosphate crystal stability is investigated
1) influence factor test
The riboflavin phosphate sodium crystal that embodiment 5 and embodiment 8 obtain is prepared into injection liquid according to currently known methods, specification is by riboflavin 2ml:5mg, then carry out high temperature test, high humidity test and strong illumination test according to the regulation in " Chinese Pharmacopoeia " version in 2010, result is respectively in table 2 and table 3.
Table 2 embodiment 5 riboflavin sodium phosphate influence factor test-results
Table 3 embodiment 8 riboflavin sodium phosphate influence factor test-results
As can be seen from table 2 and table 3, embodiment 5(preferred version of the present invention) injection of sodium phosphate ribvoflavin proterties, visible foreign matters and particulate matter etc. that obtained riboflavin phosphate sodium crystal is made all do not change, pH value, particulate matter and content are very little, and embodiment 8(various process parameters is all outer in the scope of technical solution of the present invention) although the injection of sodium phosphate ribvoflavin proterties made of obtained riboflavin phosphate sodium crystal and particulate matter are without considerable change, but content significantly declines, and visible foreign matters, pH value have part to exceed the regulation of pharmacopeia; This illustrates that the preparation made by riboflavin sodium phosphate utilizing the inventive method to obtain has good stability.
2) accelerated test
Each 3 batches of ratios according to riboflavin sodium phosphate crystalline compounds 5g and N.F,USP MANNITOL 20g of riboflavin sodium phosphate crystalline compounds that difference Example 6 and embodiment 8 obtain, freeze-dried powder is made by currently known methods, then carry out accelerated test according to the regulation in " Chinese Pharmacopoeia " version in 2010, the results are shown in Table 4 and table 5.
Table 4 embodiment 6 riboflavin sodium phosphate accelerated test result
Table 5 embodiment 8 riboflavin sodium phosphate accelerated test result
As can be seen from table 4 and table 5, riboflavin sodium phosphate powder pin proterties, visible foreign matters and particulate matter etc. within acceleration period that the riboflavin phosphate sodium crystal that embodiment 6 obtains is made all do not change, pH value, particulate matter and content are very little, and the riboflavin sodium phosphate powder pin that the obtained riboflavin phosphate sodium crystal of embodiment 8 is made proterties, pH value, visible foreign matters, particulate matter, content when 6th month acceleration period all exceed the standard of States Pharmacopoeia specifications; This illustrates that the preparation made by riboflavin sodium phosphate utilizing the inventive method to obtain has good stability.
3) test of long duration
Each 3 batches of ratios according to riboflavin sodium phosphate crystalline compounds 5g and N.F,USP MANNITOL 20g of riboflavin sodium phosphate crystalline compounds that difference Example 7 and embodiment 8 obtain, freeze-dried powder is made by currently known methods, then carry out test of long duration according to the regulation in " Chinese Pharmacopoeia " version in 2010, the results are shown in Table 6 and table 7.
Table 6 embodiment 7 riboflavin sodium phosphate long-term test results
Table 7 embodiment 8 riboflavin sodium phosphate long-term test results
As can be seen from table 6 and table 7, the riboflavin sodium phosphate powder pin made of the obtained riboflavin phosphate sodium crystal of embodiment 7 index such as proterties, visible foreign matters, particulate matter, pH value, particulate matter and content within the test of long duration phase all meets States Pharmacopoeia specifications, and the riboflavin sodium phosphate powder pin that the obtained riboflavin phosphate sodium crystal of embodiment 8 is made proterties, pH value, visible foreign matters, particulate matter, content when 12nd month test of long duration phase all exceed the standard of States Pharmacopoeia specifications; This illustrates that the preparation made by riboflavin sodium phosphate utilizing the inventive method to obtain has good stability.
Claims (7)
1. a Riboflavin sodium phosphate compound injection liquid, is characterized in that: be made up of Riboflavin sodium phosphate compound 5-10mg and water for injection 2-5mL.
2. a kind of Riboflavin sodium phosphate compound injection liquid as claimed in claim 1, is characterized in that: the technical parameter of described Riboflavin sodium phosphate compound is as follows: use Cu-K alpha-ray to sample at 5-50
0scan in scope, X-ray powder diffraction characteristic peak 2 θ (± 0.2 obtained
0) be 7.02
0, 10.25
0, 14.25
0, 20.06
0, 23.15
0, 26.93
0; Its structural formula is as follows:
。
3. a kind of Riboflavin sodium phosphate compound injection liquid as claimed in claim 2, it is characterized in that: the preparation method of described Riboflavin sodium phosphate compound is: the 1) pre-treatment of riboflavin: riboflavin is added in mixed acid solution, the quality of mixed acid solution is 6-10 times of riboflavin quality, the quality group of mixing acid becomes acetic acid: lactic acid=3-6:1, then 80-90 DEG C is heated to, 140-150 DEG C is warming up to after keeping 1-3 hour, removing mixing acid, drying, obtains pretreated riboflavin; 2) in 100 ml acetonitriles, the pretreated riboflavin of 20-30g, 3-10ml distilled water and tripoly phosphate sodium STPP is added successively, in 30-40 DEG C of reaction 30-35min after stirring; Then 70-90ml distilled water is added, be warming up to 60 DEG C of reaction 2h, then room temperature is cooled to, cross the insolubles filtered in reaction solution, in filtrate, add sodium hydroxide regulate pH to 5.5-6.1, stirring at room temperature reaction 15-20 min, filter, with the ethanolic soln washing leaching cake that volume fraction is 50%, drying is carried out to filter cake, obtains Riboflavin sodium phosphate compound A; Described riboflavin and the mol ratio of tripoly phosphate sodium STPP are riboflavin: tripoly phosphate sodium STPP=1:4-5.
4. a kind of Riboflavin sodium phosphate compound injection liquid as claimed in claim 3, it is characterized in that: the preparation method of described Riboflavin sodium phosphate compound is: the 1) pre-treatment of riboflavin: riboflavin is added in mixed acid solution, the quality of mixed acid solution is 8 times of riboflavin quality, the quality group of mixing acid becomes acetic acid: lactic acid=4:1, then be heated to 85 DEG C, keep being warming up to 145 DEG C after 2 hours, removing mixing acid, drying, obtains pretreated riboflavin; 2) in 100 ml acetonitriles, the pretreated riboflavin of 25g, 8ml distilled water and phosphorus oxychloride is added successively, in 35 DEG C of reaction 33min after stirring; Then 80ml distilled water is added, be warming up to 60 DEG C of reaction 2h, then room temperature is cooled to, cross the insolubles filtered in reaction solution, in filtrate, add sodium hydroxide regulate pH to 5.8, stirring at room temperature reacts 18 min, filter, with the ethanolic soln washing leaching cake that volume fraction is 50%, drying is carried out to filter cake, obtains Riboflavin sodium phosphate compound A; Described riboflavin and the mol ratio of phosphorus oxychloride are riboflavin: phosphorus oxychloride=1:4.5.
5. a kind of Riboflavin sodium phosphate compound injection liquid as claimed in claim 3, it is characterized in that: the method for purification of described Riboflavin sodium phosphate compound is: be dissolved in the distilled water of 700-800g by 10g Riboflavin sodium phosphate compound A, regulator solution pH is 5.5-6.5, at 20-25 DEG C in solution slowly at the uniform velocity pass into 800-1000ml NO
2, Ne, CO
2mixed gas, leave standstill 20-30min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 20-50ml, limit edged stirs, be cooled to 1-5 DEG C again, filter after leaving standstill 2-3 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains Riboflavin sodium phosphate compound after dry 2-5 h; In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=3-8:0.2-1.1:10-15, the interpolation flow velocity of mixed gas is 10-15 ml/min; In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=1-3:2-5:0.5-1, and the interpolation speed of mixing solutions is 0.5-1 ml/min; Described stirring velocity is that 10-20 turns/min.
6. a kind of Riboflavin sodium phosphate compound injection liquid as claimed in claim 5, it is characterized in that: the method for purification of described Riboflavin sodium phosphate compound is: be dissolved in the distilled water of 750g by 10g Riboflavin sodium phosphate compound A, regulator solution pH is 6.0, at 22 DEG C in solution slowly at the uniform velocity pass into 900ml NO
2, Ne, CO
2mixed gas, leaves standstill 25 min, then slowly at the uniform velocity add ethyl acetate, ether and ethylene glycol mixing solutions 35 ml, limit edged stirs, then is cooled to 3 DEG C, filters after leaving standstill 2.5 h, filter cake volume fraction is the ethylene glycol washing of 30%, obtains Riboflavin sodium phosphate compound after dry 3h; In described mixed gas, the volume ratio of each component is NO
2: Ne:CO
2=5:0.6:13, the interpolation flow velocity of mixed gas is 12 ml/min; In described mixing solutions, the volume ratio of each component is ethyl acetate: ether: ethylene glycol=2:3:0.8, and the interpolation speed of mixing solutions is 0.7 ml/min; Described stirring velocity is 15 turns/min.
7. a kind of Riboflavin sodium phosphate compound injection liquid described in claim 1 or 2 or 6, is characterized in that: preparation method often props up in Riboflavin sodium phosphate compound injection liquid to contain Riboflavin sodium phosphate compound 5-10mg, often props up containing water for injection 2-5mL; Its preparation process is: add injection liquid water in a reservoir, stir in ultrasonic dissolution instrument and make to dissolve completely, Citric Acid-Sodium Citrate buffer salt system is adopted to regulate liquid PH value to 5.5-6.5, add Riboflavin sodium phosphate compound, in ultrasonic dissolution instrument, make medicine dissolution, stir, liquid is through the gac cellulose acetate ultrafiltration composite membrane filtration under diminished pressure of 0.22 μm of micropore, sampling censorship, measures outward appearance, color and luster, clarity, after qualified; Liquid filters through the microporous bilayer polyacrylonitrile ultrafiltration film of 0.2 μm; Filling, fill nitrogen, sealing by fusing, 121 DEG C of tunnel-type hot air circulation microwaves sterilizing 8 minutes, the inspection of cooling back light, packaging, inspection, get product.
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| CN116925144A (en) * | 2023-07-28 | 2023-10-24 | 广东嘉亨新材料有限公司 | Halogen-free flame retardant, preparation method thereof and prepared flame-retardant fiber |
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2014
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Non-Patent Citations (1)
| Title |
|---|
| 国家药典委员会: "核黄素磷酸钠注射液", 《中华人民共和国药典》, 31 December 2000 (2000-12-31), pages 706 * |
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|---|---|---|---|---|
| CN116925144A (en) * | 2023-07-28 | 2023-10-24 | 广东嘉亨新材料有限公司 | Halogen-free flame retardant, preparation method thereof and prepared flame-retardant fiber |
| CN116925144B (en) * | 2023-07-28 | 2024-02-09 | 广东嘉亨新材料有限公司 | Halogen-free flame retardant, preparation method thereof and prepared flame-retardant fiber |
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