CN102127217A - Method for synthesizing polysorbate 80(I) for injection - Google Patents
Method for synthesizing polysorbate 80(I) for injection Download PDFInfo
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Abstract
The invention discloses a method for synthesizing polysorabte 80 (I) for injection. In the method, the mixture of sorbierite, sorbitan I and sorbitan II serving as a raw material is polymerized with epoxy ethane to obtain polyoxyethylene (20) sorbitol anhydride, and the polyoxyethylene (20) sorbitol anhydride is esterified with high-purity oleic acid; and refining, sterilization and pyrogen removal are performed on the esterification product to obtain a product. The method comprises the following steps of: (1) performing dehydration on a part of a sorbitol raw material in the presence of an acid catalyst in vacuum and purifying to obtain the sorbitan I; (2) further performing dehydration on sorbitol or crystalline mother liquor for preparing the sorbitol serving as a raw material, distilling under reduced pressure and purifying to obtain the sorbitan II; (3) performing addition polymerization on the mixture of the sorbierite, the sorbitan I and the sorbitan II and epoxy ethane to obtain the polyoxyethylene (20) sorbitol anhydride; and (4) reacting the polyoxyethylene (20) sorbitol anhydride with the high-purity oleic acid under the reaction of an esterification catalyst to obtain the polysorabte 80 (I). By adopting the method, the liquid chromatogram of the saponification liquor of the polysorabte 80 (I) contains three clear main product peaks, and does not contain other impurity peaks; and the polysorabte 80 (I) has the advantages of high purity, stable and controllable process and quality meeting the using requirement on a preparation for injection.
Description
Technical field
The present invention relates to a kind of chemical industry synthetic method, be specifically related to a kind of synthetic method of Tween-80 (I) of injection.
Background technology
Tween-80 (I), also claim polyoxyethylene (20) sorbitan monooleate, it is a kind of hydrophilic nonionogenic tenside, because it has hydrotropy effect preferably, when the injection of preparation insoluble drug, be commonly used for solubility promoter, emulsifying agent and stablizer.
The synthetic method of (I) of bibliographical information has following two kinds usually:
Method one: dehydration and esterification take place in sorbyl alcohol and oleic acid simultaneously under the basic catalyst effect, obtain sorbitan monooleate, with about 20 molfraction ethylene oxide condensation reaction, obtain Tween-80 (I) again.
Method two: sorbyl alcohol is dehydration earlier under acidity or basic catalyst effect, obtains anhydrous sorbitol, obtains sorbitan monooleate with the oleic acid esterification again, and last and about 20 molfraction ethylene oxide condensation reaction obtains Tween-80 (I).
Aforesaid method has the common drawback of following several respects:
The one, in the aforesaid method sorbyl alcohol in the dehydration reaction process except that producing an anhydrous sorbitol and two anhydrous sorbitols (Isosorbide), produce many dehydrations of intramolecularly and intermolecular dehydration reaction simultaneously, produce a large amount of sorbyl alcohol polymkeric substance (glucosides), content is more than 8% usually; These sorbyl alcohol polymkeric substance further produce undesirable ether-ether class product with reactions such as lipid acid, oxyethane, and content is about 10%.
The 2nd, oleic content has only 70 ~ 80% usually in the used oleic acid of aforesaid method, other also contains undesirable other lipid acid such as comprising tetradecanoic acid, palmitinic acid, Zoomeric acid, stearic acid, linolic acid, linolenic acid, these lipid acid and anhydrous sorbitol, polysorbate, reacting ethylene oxide produce undesirable ether-ether class product, and content is 20 ~ 30%.
The 3rd, sorbitan monooleate is with ethylene oxide polymerization the time, and the micro-moisture polymerization in oxyethane and the system produces the low-molecular-weight polyoxyethylene glycol of by product, and content is more than 3% usually;
The 4th, in producing the process of sorbitan monooleate, have a spot of unreacted oleic acid, when carrying out Polysorbate 80 (I) that the oxyethane addition reaction obtains again, will contain 2 ~ 3% polyoxyethylene oleate in the product;
The 5th, aforesaid method synthetic Polysorbate 80 (I) shade deviation, for yellow to pale brown look, do not meet the injection service requirements;
The 6th, the working substance content of wishing only is 60-70%, and there are limitation in by product and foreign matter content height on pharmaceutical application, do not meet the injection service requirements;
The 7th, the production operation poor plasticity, quality product is wayward.
The untoward reaction that some different traditional Chinese medicine injections take place in clinical use, mostly with use inferior quality, low-purity, not meet the Polysorbate 80 of injecting service requirements relevant.As seen, provide the synthetic method of a kind of Polysorbate 80 (injection) (I) to become very urgent scientific research task.
The patent of invention that the applicant has successively applied for two related productss before this, 200910035922.5) and " synthetic method of polysorbate-80 for injection " (application number: 201010255409X) that is: " synthetic method of high-purity polysorbate ester 80 " (application number:, by aforesaid method synthetic Polysorbate 80, its purity is greatly improved, quality product reaches requirement, the quality of injection stage easily to be controlled and good stability easily, uses as injection supplementary material to have foreseeable, clinical safety in utilization.Require especially traditional medicine Injectio service requirements but reach injection, still need further research and improvement.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of injection Polysorbate 80 (I).Injection sorb ester-80(I) be: the oxyethane addition polymerization product anhydrous sorbitol Soxylat A 25-7 (20) (V) of mixture (IV) and about 20 moles of multiples, with the mixture that is mainly oleic lipid acid (oleic acid content is greater than 90%) partial esterification.Low by method synthetic Tween-80 of the present invention (I) by-products content, purity is high, process stabilizing, controlled, quality satisfy especially traditional Chinese medicine service requirements of injection, clinical safety in utilization is more reliable.
The technical scheme of finishing the foregoing invention task is, a kind of synthetic method of injection Polysorbate 80 is characterized in that, step is as follows:
Adopt sorbyl alcohol, with high purity one anhydrous sorbitol (II) and high purity two anhydrous sorbitols (Isosorbide) (III) by mass percentage 0 ~ 20%:20 ~ 80% to mix the mixture (IV) that obtains be raw material, in the described mixture (IV): the active principle quality total content of sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitols (Isosorbide) is greater than 99%; " 20 moles of multiples " of oxyethane copolymerization is meant " about 20 moles of multiples " in polyoxyethylene (20) sorbitol anhydride (V), is specially 17 ~ 24 moles of multiples; Used oleic acid is high purity oleic acid, and its oleic acid content is greater than 90%;
⑴ be raw material with the sorbyl alcohol, intramolecularly part dehydration under the effect of an acidic catalyst and vacuum state, 1 mole of fluid loss, dehydration product dilute with water post neutralization, filtration, concentrate an anhydrous sorbitol crude product, an anhydrous sorbitol crude product obtains a highly purified anhydrous sorbitol (II) through three crystallizations in lower alcohol;
⑵ be raw material with the sorbyl alcohol, intramolecularly part dehydration under the effect of an acidic catalyst and vacuum state, 2 moles of fluid losses; Or removing the enriched material behind free solvent and the water under the crystalline mother solution vacuum of collecting in the step (1), under the effect of an acidic catalyst and vacuum state, further carry out the dehydration of intramolecularly part, about 1 mole of fluid loss; The dehydration product is through neutralization, filtration, concentrated that two anhydrous sorbitol crude products, two anhydrous sorbitol crude products obtain highly purified two anhydrous sorbitols (III) through underpressure distillation;
⑶ the mixture (IV) that obtain after mixing by a certain percentage with sorbyl alcohol, high purity one anhydrous sorbitol (II) and high purity two anhydrous sorbitols (III) under the effect of basic catalyst with the oxyethane addition polymerization, obtain polyoxyethylene (20) sorbitol anhydride (V), wherein the consumption of oxyethane is 17 ~ 24 times of described mixture (IV) mole number;
⑷ polyoxyethylene (20) sorbitol anhydride (V) and high purity oleic acid are re-refined in reaction under the esterifying catalyst effect, obtain the Polysorbate 80 (I) of injection after the sterilization, depyrogenation.
Described sorbyl alcohol is the product that commercially available pharmaceutical grade Neosorb or liquid sorbitol (content common 70%) dewater through physics, and sorbitol content is greater than 99%;
An anhydrous sorbitol and two anhydrous sorbitols (Isosorbide) total content be greater than 99% in described high purity one anhydrous sorbitol (II), and an anhydrous sorbitol content is greater than 96%.
In described highly purified two anhydrous sorbitols (III) two anhydrous sorbitols (Isosorbide) and an anhydrous sorbitol total content greater than 99% and one anhydrous sorbitol content greater than 96%.
Described mixture (IV) is obtained than mixing by certain mass by sorbyl alcohol, high purity one anhydrous sorbitol (II) and high purity two anhydrous sorbitols (Isosorbide) (III), and its mass percent is 0 ~ 20%:20 ~ 80%:20 ~ 60%; Be preferably 5 ~ 15%:30 ~ 70%:25 ~ 55%; Be preferably 7 ~ 13%:40 ~ 60%:30 ~ 45%; The active principle total content of sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitols (Isosorbide) is greater than 99% in the mixture (IV).
The mass ratio of institute's polymeric oxyethane and mixture (IV) is 1:0.14 ~ 0.20 in described polyoxyethylene (20) sorbitol anhydride (V), is preferably 1:0.15 ~ 0.18, is preferably 1:0.16 ~ 0.17.
Described preparation high purity one anhydrous sorbitol (II) and the used an acidic catalyst of high purity two anhydrous sorbitols (Isosorbide) (III) are sulfuric acid, phosphoric acid, phosphorous acid or tosic acid; Or the acid salt of sulfuric acid, phosphoric acid, phosphorous acid, or be rich in the solid acid of hydrogen proton; The add-on of an acidic catalyst is 0.5 ~ 1.5% of a sorbyl alcohol quality, is preferably 0.8 ~ 1.2%;
50 ~ 180 ℃ of dehydration temperature of reaction, vacuum tightness are 700 ~ 759mmHg.
The process for purification of described high purity one anhydrous sorbitol (II) is for carrying out repeatedly crystalline method in low-alcohol solution.Be preferably in repeatedly crystallization in the methanol solution.
The process for purification of described high purity two anhydrous sorbitols (Isosorbide) (III) is the method that rectification under vacuum is purified.
The used catalyzer of described preparation anhydrous sorbitol Soxylat A 25-7 (20) (V) is a basic catalyst, is specially basic metal C1 ~ C4 alkoxy compound, alkalimetal hydride or alkali metal hydroxide; The add-on of described basic catalyst is 0.1% ~ 2.0% of mixture (IV) quality, is preferably 0.5% ~ 1.5%, is preferably 0.9 ~ 1.2%; The temperature of reaction of oxyethane and mixture (IV) is 90 ~ 170 ℃, is preferably 100 ~ 150 ℃, is preferably 110 ~ 120 ℃.
The synthetic used oleic purity of described Polysorbate 80 (injection) (I) is not less than 90%, is preferably and is not less than 95%, is preferably and is not less than 99%.
Described Polysorbate 80 (injection) (I) is synthetic, and dehydration polyoxyethylene (20) sorbitol anhydride (V) is 1:0.28 ~ 0.35 with oleic mass ratio, is preferably 1:0.30 ~ 0.33.
Described Polysorbate 80 (injection) (I) is synthetic, and used esterifying catalyst is sodium hydroxide, sodium phosphate, sodium dihydrogen phosphite, phosphorous acid, or tosic acid; The usage quantity of esterifying catalyst is polyoxyethylene (20) sorbitol anhydride (V) and 0.1 ~ 2.0% of oleic acid quality sum, is preferably 0.5 ~ 1.2%; Esterification reaction temperature changes to some extent with the difference of catalyst system therefor, is 80 ~ 240 ℃, is preferably 150 ~ 220 ℃; Reaction time of esterification is 6 ~ 12 hours.
Polysorbate 80 of the present invention (injection) synthetic method (I) has been compared following advantage with technology in the past:
One, the synthetic method of Tween-80 of the present invention (I), be used for synthesizing of subsequent handling by an anhydrous sorbitol and two anhydrous sorbitols being made with extra care mixes with an amount of sorbyl alcohol again as raw material after purifying, effectively removed glucosides wherein, glucosides content is 0, has guaranteed to be used for the working substance composition content of ethoxylation greater than 99%.
Two, synthesis step of the present invention has guaranteed that the intermediates polyoxyethylene oleate content (≤0.01%) that dissociates in polyethyleneglycol content (≤0.01%) and the finished product is lower.
Three, the used oleic acid of the present invention is high purity oleic acid, content content 〉=90%, other fatty acid ester product content lower (≤10%).
Four, the Polysorbate 80 purity height, lighter color (APHA≤50), the foreign matter content that obtain of the present invention is few, and good fluidity, congealing point are low, and quality product meets Chinese Pharmacopoeia and American-European developed country standards of pharmacopoeia fully.
Five, the synthetic Tween-80 (I) of the present invention has technological operation, the easier control of quality product, and technology, quality stability are better.
Six, the Polysorbate 80 that obtains of the present invention, its saponification liquor liquid-phase chromatographic analysis shows three main compositional characteristic peaks, does not have other impurity peaks.
Seven, synthetic Tween-80 of the present invention (I) carries out supersensitivity, blood vessel irritation and the hemolytic test of animal systemic administration, results suggest secure sample of the present invention is better than inventor's invention in early stage sample, can be used for especially traditional Chinese medicine of injection formulations.
Description of drawings
Fig. 1 is Polysorbate 80 of the present invention (injection) saponification liquor liquid chromatogram.
Embodiment
For better explanation the present invention, we enumerate the following example, but the present invention is not limited in following embodiment.
Synthesizing of embodiment 1 one dehydration anhydrous sorbitols
Embodiment 1.1 adds 1400g sorbyl alcohol (70%) in 2000 milliliters of there-necked flasks, 100 ~ 120 ℃ of vacuum hydro-extraction 3 hours.Cool to 80 ℃, add 50g 20% aqueous sulfuric acid, vacuum, dehydration reaction, vacuum tightness 750mmHg, 105 ~ 120 ℃ of dehydration temperaturres, 5 hours time; Aqueous sodium hydroxide solution with 20% is neutralized to neutrality, adds activated carbon decolorizing, filtration, vacuum-drying and obtains the anhydrous sorbitol crude product, and crude product is through liquid-phase chromatographic analysis, content 73.74%.With make 1,4-anhydrous sorbitol crude product 800g carries out primary crystallization, secondary crystal and three crystallizations with methanol mixed, three crystallized product content be 99.25%(wherein an anhydrous sorbitol content be 97.46%).
Embodiment 1.2 and embodiment 1.1 are basic identical, but following change is arranged, and with the phosphorous acid replacement 48ml20% aqueous sulfuric acid of 10g, the product content 99.21%(that obtains a wherein anhydrous sorbitol content is 97.28%).
Embodiment 1.3 and embodiment 1.1 are basic identical, but following change is arranged, and replace the 120ml20% aqueous sulfuric acid with the 10g tosic acid, and the product content 99.20%(that obtains a wherein anhydrous sorbitol content is 96.88%).
Embodiment 1.4 and embodiment 1.1 are basic identical, but following change is arranged, and used an acidic catalyst is a phosphoric acid, and add-on is 10g; 50 ~ 60 ℃ of temperature of reaction, vacuum tightness is 700mmHg, the product content 99.50%(that obtains wherein anhydrous sorbitol content is 97.32%).
Embodiment 1.5 and embodiment 1.1 are basic identical, but following change is arranged: the add-on of described an acidic catalyst is 35g; 170 ~ 180 ℃ of temperature of reaction, vacuum tightness is 759mmHg, the product content that obtains be 99.12%(wherein an anhydrous sorbitol content be 97.18%).
Embodiment 1.6 and embodiment 1.1 are basic identical, but following change is arranged: the add-on of described an acidic catalyst is 75g, the product content that obtains be 99.26%(wherein an anhydrous sorbitol content be 97.38%).
Embodiment 1.7 and embodiment 1.1 are basic identical, but following change is arranged:
Used an acidic catalyst is a sodium pyrosulfate;
The add-on of described an acidic catalyst is 0.5% of a sorbyl alcohol quality;
50 ~ 60 ℃ of temperature of reaction, vacuum tightness are 700mmHg.
Embodiment 1.8 and embodiment 1.1 are basic identical, but following change is arranged:
Used an acidic catalyst is a SODIUM PHOSPHATE, MONOBASIC;
The add-on of described an acidic catalyst is 1.5% of a sorbyl alcohol quality;
170 ~ 180 ℃ of temperature of reaction, vacuum tightness are 759mmHg.
Embodiment 1.9 and embodiment 1.1 are basic identical, but following change is arranged:
Used an acidic catalyst is a sodium dihydrogen phosphite;
The add-on of described an acidic catalyst is 0.8% of a sorbyl alcohol quality.
Embodiment 1.10 and embodiment 1.1 are basic identical, but following change is arranged:
Used an acidic catalyst is the solid acid that is rich in the hydrogen proton;
The add-on of described an acidic catalyst is 1.2% of a sorbyl alcohol quality.
Synthesizing of embodiment 2 two anhydrous sorbitols
Embodiment 2.1 adds 1400g sorbyl alcohol (70%) in 2000 milliliters of there-necked flasks, 100 ~ 120 ℃ of vacuum hydro-extraction 3 hours.Cool to 80 ℃, add 50g 20% aqueous sulfuric acid, vacuum, dehydration reaction, vacuum tightness 750mmHg, 105 ~ 120 ℃ of dehydration temperaturres, 5 hours time; Continued to be warming up to 150 ~ 170 ℃ of dehydration reactions 6 hours, the aqueous sodium hydroxide solution with 20% is neutralized to neutrality, adds activated carbon decolorizing, filtration, vacuum-drying and obtains two anhydrous sorbitol crude products, and crude product is through liquid-phase chromatographic analysis, content 63.2%.Two anhydrous sorbitol crude products with making carry out underpressure distillation, and vacuum tightness 759mmHg collects 175 ~ 185 ℃ of cuts, is two anhydrous sorbitols (Isosorbide), its content be 99.86%(wherein two anhydrous sorbitol content be 97.58%).
Embodiment 2.2 and embodiment 2.1 are basic identical, but following change is arranged, and with the phosphorous acid replacement 48ml20% aqueous sulfuric acid of 10g, the product content 99.29%(that obtains wherein two anhydrous sorbitol content is 97.66%).
Embodiment 2.3 and embodiment 2.1 are basic identical, but following change is arranged, and replace the 120ml20% aqueous sulfuric acid with the 10g tosic acid, and the product content 99.050%(that obtains wherein two anhydrous sorbitol content is 96.17%).
Embodiment 2.4 and embodiment 2.1 are basic identical, but following change is arranged, and used an acidic catalyst is a phosphoric acid, and add-on is 10g; 50 ~ 60 ℃ of temperature of reaction, vacuum tightness is 700mmHg, the product content 99.20%(that obtains wherein anhydrous sorbitol content is 96.39%).
Embodiment 2.5 and embodiment 2.1 are basic identical, but following change is arranged: the add-on of described an acidic catalyst is 35g; 170 ~ 180 ℃ of temperature of reaction, vacuum tightness is 759mmHg, the product content that obtains be 99.45%(wherein two anhydrous sorbitol content be 96.48%).
Embodiment 2.6 and embodiment 2.1 are basic identical, but following change is arranged: the add-on of described an acidic catalyst is 75g, the product content that obtains be 99.86%(wherein two anhydrous sorbitol content be 97.89%).
Embodiment 2.7 and embodiment 2.1 are basic identical, but following change is arranged: will used sorbyl alcohol (70%) change the mother liquor mixture of collection among the embodiment 1 into, the product content that obtains be 99.55%(wherein two anhydrous sorbitol content be 98.28%).
Synthesizing of embodiment 3 Polysorbate 80s (injection)
Embodiment 3.1 adds initiator and is specially in etherifying reactor: 10g sorbyl alcohol, 55g one anhydrous sorbitol, 35g two anhydrous sorbitols, add 0.9g NaOH(or KOH) solid (catalyzer), with being warming up to 90 ℃ behind the nitrogen replacement, slowly add oxyethane 610g, under 110 ℃, 0.4MPa, react, no longer reduce to pressure, cooling discharge, with among 1.1g Glacial acetic acid and the 10g 600NS and absorption, vacuum hydro-extraction is filtered, and obtains polyoxyethylene (20) sorbitol anhydride, the survey hydroxyl value is 175.8mgKOH/g, colourity APHA＜20.
In reaction kettle of the esterification, add the above-mentioned polyoxyethylene of 400g (20) sorbitol anhydride, 128g oleic acid (95.6%) and 4.85gNaH
2PO
3(catalyzer), nitrogen blows drum down in 220 ℃ of stirring reaction 5h, reduce to room temperature, handle with discoloring clay and diatomite, filter, through 0.22 μ filter element filtering degerming depyrogenation, obtain Polysorbate 80 (injection), surveying hydroxyl value and be 72.5 mgKOH/g, saponification value and be 48.5 mgKOH/g, congealing point is 368.2mm for-8 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.2 and embodiment 3.1 are basic identical, but following change is arranged, mineral oil solution with the KH (or NaH) of 3.0g30% replaces 0.9g NaOH(or KOH) solid is as catalyst for etherification, the polyoxyethylene that obtains (20) sorbitol anhydride, the survey hydroxyl value is 174.6mgKOH/g, colourity APHA＜30; Replace NaH with phosphorous acid
2PO
3As esterifying catalyst, the Polysorbate 80 that obtains (injection), surveying hydroxyl value and be 72.1 mgKOH/g, saponification value and be 48.2 mgKOH/g, congealing point is 365.4mm for-9 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.3 and embodiment 3.1 are basic identical, but following change is arranged: the add-on of catalyst for etherification is 0.1% of an initiator quality; The mass ratio of oxyethane and initiator is 1:0.15; Oxyethane addition reaction temperature is 170 ℃, the polyoxyethylene that obtains (20) sorbitol anhydride, and the survey hydroxyl value is 165.4mgKOH/g, colourity APHA＜80; The used oleic acid content of esterification is 90.5%, the Polysorbate 80 that obtains (injection), and surveying hydroxyl value and be 69.6 mgKOH/g, saponification value and be 49.1 mgKOH/g, congealing point is 369.7mm for-8 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜50.
Embodiment 3.4 and embodiment 3.1 are basic identical, but following change is arranged: the add-on of etherification reaction basic catalyst be the initiator quality 2.0%, the mass ratio of oxyethane and initiator is that 1:0.20, oxyethane addition reaction temperature are 100 ℃, the polyoxyethylene that obtains (20) sorbitol anhydride, the survey hydroxyl value is 183.8mgKOH/g, colourity APHA＜80; The used oleic acid content of esterification is 99.3%, the Polysorbate 80 that obtains (injection), and surveying hydroxyl value and be 75.6 mgKOH/g, saponification value and be 48.0 mgKOH/g, congealing point is 363.4mm for-11 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜50.
Embodiment 3.5 and embodiment 3.1 are basic identical, but following change is arranged: the add-on of etherification reaction basic catalyst is 0.5% of an initiator quality; Temperature of reaction is 130 ℃, the polyoxyethylene that obtains (20) sorbitol anhydride, and the survey hydroxyl value is 176.2mgKOH/g, colourity APHA＜30; Esterification polyoxyethylene (20) sorbitol anhydride and oleic mass ratio are 1:0.30, the Polysorbate 80 that obtains (injection), and surveying hydroxyl value and be 73.9 mgKOH/g, saponification value and be 46.2 mgKOH/g, congealing point is 358.5mm for-10 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜50.
Embodiment 3.6 and embodiment 3.1 are basic identical, but following change is arranged: the add-on of etherification reaction basic catalyst is 1.2% of an initiator quality; The mass ratio of oxyethane and initiator is 1:0.17; Temperature of reaction is 150 ℃, the polyoxyethylene that obtains (20) sorbitol anhydride, and the survey hydroxyl value is 179.0mgKOH/g, colourity APHA＜30; Esterification polyoxyethylene (20) sorbitol anhydride and oleic mass ratio are 1:0.33, the Polysorbate 80 that obtains (injection), and surveying hydroxyl value and be 73.3 mgKOH/g, saponification value and be 50.6 mgKOH/g, congealing point is 359.7mm for-10 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.7 and embodiment 3.1 are basic identical, but following change is arranged, sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitol mass percents are respectively 7%, 60%, 33% in the etherificate initiator, the mass ratio of oxyethane and initiator is 1:0.17, obtain polyoxyethylene (20) sorbitol anhydride, the survey hydroxyl value is 172.7mgKOH/g, colourity APHA＜20; Esterification polyoxyethylene (20) sorbitol anhydride and oleic mass ratio are 1:0.35, the Polysorbate 80 that obtains (injection), and surveying hydroxyl value and be 70.3 mgKOH/g, saponification value and be 53.6 mgKOH/g, congealing point is 369.2mm for-12 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.8 and embodiment 3.1 are basic identical, but following change is arranged, sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitol mass percents are respectively 13%, 42%, 45% in the etherification reaction initiator, the mass ratio of oxyethane and initiator is 1:0.17, obtain polyoxyethylene (20) sorbitol anhydride, the survey hydroxyl value is 168.5mgKOH/g, colourity APHA＜20; Esterification polyoxyethylene (20) sorbitol anhydride and oleic mass ratio are 1:0.28, the Polysorbate 80 that obtains (injection), and surveying hydroxyl value and be 71.9 mgKOH/g, saponification value and be 45.2 mgKOH/g, congealing point is 374.2mm for-9 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.9 and embodiment 3.1 are basic identical, but following change is arranged, sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitol mass percents are respectively 20%, 40%, 40% in the etherification reaction initiator, the mass ratio of oxyethane and initiator is 1:0.17, obtain polyoxyethylene (20) sorbitol anhydride, the survey hydroxyl value is 179.7mgKOH/g, colourity APHA＜20; The dosage of esterification catalyst system therefor is polyoxyethylene (20) sorbitol anhydride (V) and 0.5% of oleic acid quality sum, the Polysorbate 80 that obtains (injection), surveying hydroxyl value and be 73.9 mgKOH/g, saponification value and be 47.8 mgKOH/g, congealing point is 365.4mm for-9 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.10 and embodiment 3.1 are basic identical, but following change is arranged, sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitol mass percents are respectively 15%, 30%, 55% in the etherification reaction initiator, the mass ratio of oxyethane and initiator is 1:0.17, obtain polyoxyethylene (20) sorbitol anhydride, the survey hydroxyl value is 161.7mgKOH/g, colourity APHA＜20; The dosage of esterification catalyst system therefor is polyoxyethylene (20) sorbitol anhydride (V) and 1.2% of oleic acid quality sum, the Polysorbate 80 that obtains (injection), surveying hydroxyl value and be 66.8 mgKOH/g, saponification value and be 48.8 mgKOH/g, congealing point is 367.6mm for-9 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.11 and embodiment 3.1 are basic identical, but following change is arranged, sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitol mass percents are respectively 5%, 70%, 25% in the etherification reaction initiator, obtain the anhydrous sorbitol Soxylat A 25-7, the survey hydroxyl value is 178.5mgKOH/g, colourity APHA＜20; The dosage of esterification catalyst system therefor is polyoxyethylene (20) sorbitol anhydride (V) and 1.2% of oleic acid quality sum, the Polysorbate 80 that obtains (injection), surveying hydroxyl value and be 76.8 mgKOH/g, saponification value and be 47.1 mgKOH/g, congealing point is 359.6mm for-10 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.12 and embodiment 3.1 are basic identical, but following change is arranged, sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitol mass percents are respectively 0%, 80%, 20% in the etherification reaction initiator, the mass ratio of oxyethane and initiator is 1:0.17, obtain polyoxyethylene (20) sorbitol anhydride, the survey hydroxyl value is 179.0mgKOH/g, colourity APHA＜20; The dosage of esterification catalyst system therefor is polyoxyethylene (20) sorbitol anhydride (V) and 2.0% of oleic acid quality sum, the Polysorbate 80 that obtains (injection), surveying hydroxyl value and be 77.2 mgKOH/g, saponification value and be 47.3 mgKOH/g, congealing point is 361.5mm for-10 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜30.
Embodiment 3.13 and embodiment 3.1 are basic identical, but following change is arranged, sorbyl alcohol, an anhydrous sorbitol and two anhydrous sorbitol mass percents are respectively 20%, 20%, 60% in the etherification reaction initiator, the mass ratio of oxyethane and initiator is 1:0.2, obtain polyoxyethylene (20) sorbitol anhydride, the survey hydroxyl value is 183.5mgKOH/g, colourity APHA＜20; The dosage of esterification catalyst system therefor is polyoxyethylene (20) sorbitol anhydride (V) and 0.1% of oleic acid quality sum, 240 ℃ of esterification reaction temperatures, the Polysorbate 80 that obtains (injection), surveying hydroxyl value and be 79.2 mgKOH/g, saponification value and be 47.1 mgKOH/g, congealing point is 369.9mm for-8 ℃, viscosity
2/ s, glucosides content are zero, colourity (APHA)＜50.
Embodiment 3.14 and embodiment 3.1 are basic identical, but following change is arranged, and esterification reaction temperature is 150 ℃, and reaction time of esterification is 10h.
Embodiment 3.15 and embodiment 3.1 are basic identical, but following change is arranged:
The used basic catalyst of etherification reaction is a sodium methylate;
The add-on of basic catalyst is 0.1% of an anhydrous sorbitol quality;
The mass ratio of oxyethane and initiator is 1:0.15; Oxyethane addition reaction temperature is 120 ℃.
Embodiment 3.16 and embodiment 3.1 are basic identical, but following change is arranged:
The add-on of etherification reaction basic catalyst is 0.9% of an initiator quality;
The mass ratio of oxyethane and initiator is 1:0.16; Oxyethane addition reaction temperature is 130 ℃.
Embodiment 3.17 and embodiment 3.1 are basic identical, but following change is arranged:
The add-on of etherification reaction basic catalyst is 1.2% of an initiator quality;
The mass ratio of oxyethane and initiator is 1:0.17; Oxyethane addition reaction temperature is 150 ℃.
Embodiment 3.18 and embodiment 3.1 are basic identical, but following change is arranged:
The add-on of etherification reaction basic catalyst is 0.1% of an initiator quality;
Oxyethane addition reaction temperature is 170 ℃.
Embodiment 3.19 and embodiment 3.1 are basic identical, but following change is arranged:
The add-on of etherification reaction basic catalyst is 2.0% of an initiator quality;
Oxyethane addition reaction temperature is 100 ℃.
Embodiment 3.20 and embodiment 3.1 are basic identical, but following change is arranged:
Esterifying catalyst is NaOH, and the add-on of esterifying catalyst is 0.5% of polyoxyethylene (20) sorbitol anhydride and an oleic acid quality sum;
Embodiment 3.21 and embodiment 3.1 are basic identical, but following change is arranged:
Catalyst for esterification reaction is Na
3PO
4, the add-on of esterifying catalyst is 1.2% of polyoxyethylene (20) sorbitol anhydride and an oleic acid quality sum.
Embodiment 3.22 and embodiment 3.1 are basic identical, but following change is arranged:
Catalyst for esterification reaction is a phosphorous acid, and the add-on of esterifying catalyst is 0.5% of polyoxyethylene (20) sorbitol anhydride and an oleic acid quality sum.
Embodiment 3.23 and embodiment 3.1 are basic identical, but following change is arranged:
Catalyst for esterification reaction is a tosic acid, and the add-on of esterifying catalyst is 2.0% of polyoxyethylene (20) sorbitol anhydride and an oleic acid quality sum.
Polysorbate 80 (injection) saponification liquor liquid chromatography detecting method
Testing goal: testing product purity.
Detecting instrument: Tianjin, island LC-20AT liquid chromatograph, RID-10A type refractive power parallax detector.
Experiment condition
Chromatographic column: Aminex HPX-87H ion Exclusion Column(7.8 * 300mm)
Column temperature: 55 ℃ of constant temperature;
Moving phase: 0.5 ‰ aqueous sulfuric acids; Flow velocity: 0.60mL/min;
Sample size: 10 μ L.
Experimental technique
Take by weighing 1g Polysorbate 80 sample and place the 100mL Erlenmeyer flask, add the 20mL20g/L sodium hydrate methanol solution, install reflux condensing tube, backflow saponification reaction 35min in 80 ℃ of water-baths after reaction finishes, removes prolong, adds 50mL water, shakes up.Aqueous hydrochloric acid with 5% transfers to neutral slant acidity with solution, extracts in separating funnel with the 20mL normal heptane, detects water.
Claims (10)
1. the synthetic method of the Polysorbate 80 of an injection (I), the Polysorbate 80 of described injection (I) is the ethoxy compound and the oleic partial esterification products of sorbyl alcohol and dehydration product thereof, it is characterized in that synthesis step is as follows:
With the sorbyl alcohol is raw material, intramolecularly part dehydration under the effect of an acidic catalyst and vacuum state, and 1 mole of fluid loss loses
Aquatic products thing dilute with water post neutralization, filtration, concentrate an anhydrous sorbitol crude product, an anhydrous sorbitol crude product obtains a highly purified anhydrous sorbitol (II) through three crystallizations in lower alcohol;
⑵ be raw material with the sorbyl alcohol, intramolecularly part dehydration under the effect of an acidic catalyst and vacuum state, 2 moles of fluid losses; Or removing the enriched material behind free solvent and the water under the crystalline mother solution vacuum of collecting in the step (1), under the effect of an acidic catalyst and vacuum state, further carry out the dehydration of intramolecularly part, about 1 mole of fluid loss; The dehydration product is through neutralization, filtration, concentrated that two anhydrous sorbitol crude products, two anhydrous sorbitol crude products obtain highly purified two anhydrous sorbitols (III) through underpressure distillation;
⑶ the mixture (IV) that obtain after mixing by a certain percentage with sorbyl alcohol, high purity one anhydrous sorbitol (II) and high purity two anhydrous sorbitols (III) under the effect of basic catalyst with the oxyethane addition polymerization, obtain polyoxyethylene (20) sorbitol anhydride (V), wherein the consumption of oxyethane is 17 ~ 24 times of described mixture (IV) mole number;
⑷ polyoxyethylene (20) sorbitol anhydride (V) and high purity oleic acid are re-refined in reaction under the esterifying catalyst effect, obtain the Polysorbate 80 (I) of injection after the sterilization, depyrogenation.
2. the synthetic method of the Polysorbate 80 of injection according to claim 1 (I) is characterized in that, used an acidic catalyst is sulfuric acid, phosphoric acid, phosphorous acid or tosic acid among step ⑴ and the step ⑵; Or the acid salt of sulfuric acid, phosphoric acid, phosphorous acid, or be rich in the solid acid of hydrogen proton; In the dehydration product and used neutralizing agent be alkali metal hydroxide or alkaline carbonate.
3. the synthetic method of the Polysorbate 80 of injection according to claim 1 (I) is characterized in that, the add-on of an acidic catalyst described in the step ⑴ is 0.5 ~ 1.5% of a sorbyl alcohol quality; 50 ~ 180 ℃ of intramolecularly dehydration temperature of reaction, vacuum tightness are 700 ~ 759mmHg; The used lower alcohol of described crystallization is methyl alcohol or ethanol; Tc is 0 ~ 40 ℃;
In high purity one anhydrous sorbitol (II) of gained, an anhydrous sorbitol (II) is not less than 99% with two anhydrous sorbitols (III) content sum after three crystallizations, and wherein an anhydrous sorbitol (II) mass content is not less than 96%.
4. the synthetic method of the Polysorbate 80 of injection according to claim 1 (I) is characterized in that, the add-on of an acidic catalyst described in the step ⑵ is 0.5 ~ 1.5% of sorbyl alcohol quality or a mother liquor enriched material quality; Intramolecularly dehydration temperature of reaction is 50 ~ 180 ℃, and vacuum tightness is 700 ~ 759mmHg; 100 ~ 200 ℃ of the temperature of two anhydrous sorbitol crude product underpressure distillation, vacuum tightness are 700 ~ 759mmHg;
In high purity two anhydrous sorbitols (III) of gained, two anhydrous sorbitols (III) are not less than 99% with an anhydrous sorbitol (II) content sum after the underpressure distillation, and wherein two anhydrous sorbitols (III) mass content is not less than 96%.
5. according to the synthetic method of the Polysorbate 80 (I) of the described injection of one of claim 1 ~ 4, it is characterized in that, sorbyl alcohol, high purity one anhydrous sorbitol (II) and high purity two anhydrous sorbitols (III) mix in the mixture (IV) that obtains, and the quality compound percentages of sorbyl alcohol, an anhydrous sorbitol (II) and two anhydrous sorbitols (III) is 0 ~ 20%:20 ~ 80%:20 ~ 60%; The used basic catalyst of the addition polymerization of described mixture (IV) and oxyethane is basic metal C1 ~ C4 alkoxy compound, alkalimetal hydride or alkali metal hydroxide; The add-on of described basic catalyst is 0.1% ~ 2.0% of mixture (IV) quality; The mass ratio of described oxyethane and mixture (IV) is that 1:0.14 ~ 0.20 or mol ratio are 17 ~ 24; The temperature of reaction of oxyethane and mixture (IV) is 90 ~ 170 ℃.
6. the synthetic method of the Polysorbate 80 of injection according to claim 5 (I), it is characterized in that, described sorbyl alcohol, high purity one anhydrous sorbitol (II) and high purity two anhydrous sorbitols (III) mix in the mixture (IV) that obtains, and the quality compound percentages of sorbyl alcohol, an anhydrous sorbitol (II) and two anhydrous sorbitols (III) is 5 ~ 15%:30 ~ 70%:25 ~ 55%; The add-on of the basic catalyst that the addition polymerization of described mixture (IV) and oxyethane is used is 0.5% ~ 1.5% of mixture (IV) quality; The mass ratio of described oxyethane and mixture (IV) is that 1:0.15 ~ 0.18 or mol ratio are 18 ~ 22; The temperature of reaction of oxyethane and mixture (IV) is 100 ~ 150 ℃;
Gained polyoxyethylene (20) sorbitol anhydride (V) hydroxyl value is 155 ~ 185 mgKOH/g, colourity APHA≤150.
7. the synthetic method of the Polysorbate 80 of injection according to claim 6 (I), it is characterized in that, described sorbyl alcohol, high purity one anhydrous sorbitol (II) and high purity two anhydrous sorbitols (III) mix in the mixture (IV) that obtains, and the quality compound percentages of sorbyl alcohol, an anhydrous sorbitol (II) and two anhydrous sorbitols (III) is 7 ~ 13%:40 ~ 60%:30 ~ 45%; The add-on of the basic catalyst that the addition polymerization of described mixture (IV) and oxyethane is used be mixture (IV) quality be 0.9 ~ 1.2%; The mass ratio of oxyethane and mixture (IV) is that 1:0.16 ~ 0.17 or mol ratio are 19 ~ 21; The temperature of reaction of oxyethane and mixture (IV) is 110 ~ 120 ℃;
Gained polyoxyethylene (20) sorbitol anhydride (V) hydroxyl value is 160 ~ 180 mgKOH/g, colourity APHA≤120.
8. according to the synthetic method of the Polysorbate 80 (I) of the described injection of one of claim 1 ~ 7, it is characterized in that described oleic purity is not less than 90%; Polyoxyethylene (20) sorbitol anhydride (V) is 1:0.28 ~ 0.35 with oleic mass ratio; Used esterifying catalyst is sodium hydroxide, sodium phosphate, sodium dihydrogen phosphite, phosphorous acid, or tosic acid; The usage quantity of esterifying catalyst is anhydrous sorbitol Soxylat A 25-7 (V) and 0.1 ~ 2.0% of oleic acid quality sum; Esterification reaction temperature is 80 ~ 240 ℃; Reaction time of esterification is 6 ~ 12 hours.
9. the synthetic method of the Polysorbate 80 of injection according to claim 8 (I) is characterized in that, described polyoxyethylene (20) sorbitol anhydride (V) is 1:0.30 ~ 0.33 with oleic mass ratio; The usage quantity of esterifying catalyst is anhydrous sorbitol Soxylat A 25-7 (V) and 0.5 ~ 1.2% of oleic acid quality sum; Esterification reaction temperature is 150 ~ 220 ℃.
10. the resulting product of synthetic method according to the Polysorbate 80 (I) of the described injection of one of claim 1 ~ 9 has following feature:
⑴ colourity (APHA)≤50;
⑵ glucosides content is 0;
⑶ good fluidity, viscosity V
25(mm
2/ s): 350-400;
⑷ congealing point is low, congealing point :≤-5 ℃;
⑸ oleic acid content 〉=90% during lipid acid is formed;
⑹ polyoxyethylene oleate content≤0.01%;
⑺ saponification liquor liquid-phase chromatographic analysis shows three groups of principal constituent characteristic peaks clearly, does not have other impurity peaks;
⑻ safety in utilization especially Chinese medicine preparation safety in utilization is further improved.
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