CN101721838B - Method for separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester - Google Patents
Method for separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester Download PDFInfo
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- CN101721838B CN101721838B CN2009101550169A CN200910155016A CN101721838B CN 101721838 B CN101721838 B CN 101721838B CN 2009101550169 A CN2009101550169 A CN 2009101550169A CN 200910155016 A CN200910155016 A CN 200910155016A CN 101721838 B CN101721838 B CN 101721838B
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- vitamin
- polyethylene glycol
- acid esters
- tpgs
- dibasic acid
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 42
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 41
- 239000011709 vitamin E Substances 0.000 title claims abstract description 37
- 229940046009 vitamin E Drugs 0.000 title claims abstract description 37
- 229930003427 Vitamin E Natural products 0.000 title claims abstract description 36
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 235000019165 vitamin E Nutrition 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 13
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 title claims abstract description 13
- -1 succinate diester Chemical class 0.000 title claims abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 14
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims description 43
- 150000002148 esters Chemical class 0.000 claims description 43
- 239000002245 particle Substances 0.000 claims description 14
- 238000000926 separation method Methods 0.000 claims description 14
- 150000003900 succinic acid esters Chemical class 0.000 claims description 14
- GMWTXQKKRDUVQG-WOPPDYDQSA-N 4-amino-5-bromo-1-[(2r,3s,4s,5r)-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(Br)=C1 GMWTXQKKRDUVQG-WOPPDYDQSA-N 0.000 claims description 13
- 239000012141 concentrate Substances 0.000 claims description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 abstract description 53
- 239000002904 solvent Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000005526 G1 to G0 transition Effects 0.000 abstract 2
- 239000000284 extract Substances 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000003480 eluent Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000009471 action Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- MSCCTZZBYHQMQJ-AZAGJHQNSA-N Tocopheryl nicotinate Chemical compound C([C@@](OC1=C(C)C=2C)(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC1=C(C)C=2OC(=O)C1=CC=CN=C1 MSCCTZZBYHQMQJ-AZAGJHQNSA-N 0.000 description 1
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 230000008542 thermal sensitivity Effects 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 125000002640 tocopherol group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention discloses a method for separating a vitamin E polyethylene glycol succinate monoester from a vitamin E polyethylene glycol succinate diester. The method takes octadecyl silane bonded silica of which the grain diameter is of between 5 and 100 mu m as a stationary phase, takes a mixture of acetonitrile and isopropanol as a mobile phase, takes the mixture of vitamin E polyethylene glycol succinate of which the monoester content is of between 20 and 80 percent as a raw material, and adopts a simulated moving bed chromatographic system to separate TPGS monoester and TPGS diester of which the purity and the yield are both over 98 percent. Because simulated moving bed chromatography is a continuous operating process, the method has the advantages of high degree of automation, high efficiency, low consumption of the stationary phase and a solvent, and suitability of industrial production.
Description
Technical field
The present invention relates to chemical separation technology, especially relate to a kind of separation method of vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester.
Background technology
Vitamin E polyethylene glycol succinic acid ester (Tocopheryl Polyethylene Glycol Succinate, TPGS) being a kind of mixture, is by VE-succinate and different molecular weight polyethylene glycol (PEG400～PEG 2000) esterification and obtain.From the principles of chemistry, may generate two kinds of products of monoesters and dibasic acid esters.The TPGS that mentions now is commonly referred to be the vitamin E polyethylene glycol monoesters, and on structure, it had both contained the lipophilic group of vitamin E, contained the hydrophilic radical of polyethylene glycol long chain again, thereby has the character of surfactant.Because amphotericity and the good water-solubility of TPGS are good nonionic surface active agent for lipophilic substance.When itself and insoluble drug form micella or emulsion,, thereby improve bioavilability with the absorption of significantly increasing medicament in stomach and intestine.TPGS has the structure of Renascin, helps also to prevent that by the modification to the tocopherol structure tocopherol is oxidized, increases its stability.TPGS is as the carrier of solubilizer, sorbefacient, emulsifying agent, plasticizer and slightly water-soluble and fat-soluble medicine transmission system, as the carrier of administration in the carrier of solid dispersions, dosing eyes, the nasal cavity etc., be used widely at medicine and pharmacology, cosmetics and field of food.
Yet the existing commodity TPGS in market does not make detailed explanation for wherein composition and content, and this mainly is because as polymer, there is certain difficulty in it aspect separation.Composition is very complicated in the product that obtains after the reaction of VE-succinate and polyethylene glycol, except polymer this in having on the molecular weight certain distribution, also exist side reaction product---vitamin E polyethylene glycol butanedioic acid dibasic acid esters.The two structurally only differs a VE-succinate functional group, adds complicated molecular weight distribution, therefore separates to get up to be not easy very much.The commodity TPGS that is sold on the market, owing to wherein be mixed with dibasic acid esters, so monoesters purity is not high, approximately has only about 80%.The height of monoesters purity directly affects TPGS as surfactant and as the action effect of another supply form of vitamin E.In many documents, all not mentionedly after thoroughly being separated, TPGS re-uses, and some action effects of the TPGS that obtains under this situation are inapt.And there is certain degree of difficulty in another product that dibasic acid esters obtains as reaction because itself and monoesters separated fully, does not therefore also conduct a research well for the effect of dibasic acid esters itself and with the effect difference aspect of monoesters.Therefore, from the mixture of VE-succinate and polyethylene glycol product, both are separated and purify significant.
Almost do not report for the separation of the single dibasic acid esters of TPGS both at home and abroad at present, minority mentions that the method that the single dibasic acid esters of TPGS separates also mainly is to adopt the analysis and the separation method of column chromatography.U.S. Pat 20050163828 reported with analytic type HPLC the TPGS product content analyzed, owing to be the chromatographic system of analytic type, so treating capacity is very little, and separation costs is also very high, can't realize industrialization.Collnot has studied preparative liquid chromatography purification monoesters (E.-M.Collnot.Journal of Controlled Release, 2006,111:35-40), utilize C8 preparative chromatography post, methyl alcohol/acetonitrile, acetonitrile/isopropyl alcohol, three kinds of solvents of isopropyl alcohol carry out gradient elution purifying monoesters, but do not report, more do not mention the preparation and the purification of dibasic acid esters for the monoesters purity that obtains, yield.Still there is certain defective in preparative chromatography in addition, and is little as treating capacity, solvent cost is high, need gradient elution, and very big restriction is arranged on commercial Application.
It is strong that SMBC has separating power, device structure is little, be convenient to automatic control, and be particularly conducive to that to separate thermal sensitivity high and be difficult to advantage such as separation mixture, be applicable to and carry out the continuity large-scale industrial production, its introducing can improve the automatization level and the production efficiency of producing greatly under the prerequisite that guarantees separation purity and yield, and makes production environment obtain very large improvement.Owing to the complexity and the particularity of TPGS system composition, have not yet to see the report of relevant SMBC separating VE polyethylene glycol monomester succinate and dibasic acid esters.
Summary of the invention
The object of the present invention is to provide a kind of separation method of vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester, be to be raw material, adopt the SMBC method to isolate highly purified monoesters and dibasic acid esters with vitamin E polyethylene glycol succinic acid ester mixture (monoester content 20%～80%).
The technical solution used in the present invention is:
From the vitamin E polyethylene glycol succinic acid ester mixture, isolate vitamin E polyethylene glycol monomester succinate and dibasic acid esters, it is characterized in that: with particle diameter 5-100 μ m is fixedly phase of octadecylsilane chemically bonded silica conduct, mixture conduct with acetonitrile and isopropyl alcohol is flowed mutually, the vitamin E polyethylene glycol succinic acid ester mixture that with the monoester content is 20%-80% is a raw material, adopts the SMBC method to isolate highly purified monoesters and dibasic acid esters.
A kind of separation method of vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester may further comprise the steps:
(1) the vitamin E polyethylene glycol succinic acid ester mixture is dissolved in mobile phase, concentration is 1mg/mL～300mg/mL;
(2) from simulated moving bed chromatography system, tell vitamin E polyethylene glycol succinic acid ester monoesters and dibasic acid esters solution;
(3) vitamin E polyethylene glycol succinic acid ester monoesters and dibasic acid esters solution concentrate respectively, steam desolventize after, obtain purity and yield and all be higher than 98% vitamin E polyethylene glycol succinic acid ester monoesters and dibasic acid esters.
The total pillar number of described SMBC is 4～32, and every district pillar number is 1～8.
The described volume ratio that flows middle mutually acetonitrile and isopropyl alcohol is 30: 70～70: 30.
The operating temperature of described simulated moving bed chromatography system is 0～50 ℃.
The beneficial effect that the present invention has is:
Using simulated moving bed chromatographic separation process, is raw material with the mixture of TPGS monoester content 20～80%, adopts simulated moving bed chromatography system, isolates purity and yield all greater than 98% TPGS monoesters and dibasic acid esters.Because SMBC is a continued operation process, so the consumption of the automaticity height of this method, efficient height, fixing phase and solvent is low, is fit to suitability for industrialized production.
Description of drawings
Accompanying drawing is the SMBC schematic diagram.
The specific embodiment
The method of isolating monoesters and dibasic acid esters from the TPGS mixture is:
1. adopt SMBC (SMB) system, this system comprises sampling pump, wash-out liquid pump, extracts pump, puies forward surplus pump, rotary valve and chromatographic column, as shown in drawings.There are 4 districts in the SMB system, every district 1～8 root chromatogram column, and feeding liquid is from injecting between 2 districts and 3 districts, and weak absorbed component (raffinate) is collected between 3 districts and 4 districts, and strong absorbed component (extract) is collected between 1 district and 2 districts, and eluent is from injecting between 4 districts and 1 district.At regular intervals, sample introduction liquid switches to next root chromatogram column outlet (as accompanying drawing dotted arrow indication position) with eluent inlet, extract and the moving flow direction mutually of raffinate outlet while longshore current.
2. the fixing selection that reaches the phase that flows mutually of chromatographic column
Fixing is octadecylsilane chemically bonded silica mutually, particle diameter 5～100 μ m, and more little helping more of particle diameter separates.Flowing is acetonitrile and isopropyl alcohol mixed solvent mutually, volume ratio 30: 70～70: 30.
3. separating step
Contain TPGS monoesters, dibasic acid esters and small amount of impurities in the TPGS mixture.Mixture is dissolved in mobile phase, and concentration is 1mg/mL～300mg/mL; The total pillar number of SMBC is 4～32, and every district pillar number is 1～8; The operating temperature of system is 0～50 ℃.Through simulation moving-bed separation, obtain highly purified TPGS dibasic acid esters from the extract outlet, obtain highly purified TPGS monoesters from the raffinate outlet.Desolventize through concentrating to steam again, just obtain TPGS monoesters and dibasic acid esters finished product after the drying.
Embodiment 1:
Simulated moving bed chromatography system
C9812 (Nore, Germany), assemble 8 root chromatogram columns (ID 1 * 15cm), 2 in every district, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, particle diameter 50 μ m.Flow be mutually acetonitrile/aqueous isopropanol (50/50, v/v), 35 ℃ of temperature.The sample that charging is used is TPGS 1000 mixed liquors, concentration: 200mg/ml, and wherein monoester content is 68.3%, dibasic acid esters content is 31.4%.
A, operating condition:
Sample introduction flow velocity: UF=1ml/min
Eluent flow rate: UD=5.7ml/min
Raffinate flow velocity: U
R=3.0ml/min
Extract flow velocity: U
E=3.7ml/min
Switching time: t
s=144s
B, check analysis:
Analyze raffinate and extract composition with HPLC.TPGS monoesters purity is 98.2% in the raffinate, and yield is 99.2%; TPGS dibasic acid esters purity is 99.5% in the extract, and yield is 99.6%.
Embodiment 2:
Simulated moving bed chromatography system
C9812 (Nore, Germany), assemble 24 root chromatogram columns (ID 1 * 15cm), 6 in every district, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, particle diameter 5 μ m.Flow be mutually acetonitrile/aqueous isopropanol (70/30, v/v), 0 ℃ of temperature.The sample that charging is used is TPGS 400 mixed liquors, concentration: 20mg/ml, and wherein monoester content is 20.1%, dibasic acid esters content is 79.8%.
A, operating condition:
Sample introduction flow velocity: U
F=1ml/min
Eluent flow rate: U
D=8.18ml/min
Raffinate flow velocity: U
R=3.2ml/min
Extract flow velocity: U
E=5.9ml/min
Switching time: t
s=180s
B, check analysis:
Analyze raffinate and extract composition with HPLC.TPGS monoesters purity is 99.9% in the raffinate, and yield is 99.9%; TPGS dibasic acid esters purity is 99.7% in the extract, and yield is 99.9%.
Embodiment 3:
Simulated moving bed chromatography system
C9812 (Nore, Germany), assemble 32 root chromatogram columns (ID 1 * 15cm), 8 in every district, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, particle diameter 20 μ m.Flow be mutually acetonitrile/aqueous isopropanol (50/50, v/v), 50 ℃ of temperature.The sample that charging is used is TPGS 400 mixed liquors, concentration: 300mg/ml, and wherein monoester content is 55.1%, dibasic acid esters content is 44.6%.
A, operating condition:
Sample introduction flow velocity: U
F=2ml/min
Eluent flow rate: U
D=21.2ml/min
Raffinate flow velocity: U
R=9.19ml/min
Extract flow velocity: U
E=14.0ml/min
Switching time: t
s=60s
B, check analysis:
Analyze raffinate and extract composition with HPLC.TPGS monoesters purity is 98.9% in the raffinate, and yield is 99.9%; TPGS dibasic acid esters purity is 99.8% in the extract, and yield is 99.9%.Every liter of fixing phase per hour can be produced monoesters 4.5g, and dibasic acid esters 3.7g, every production 1g monoesters consume the moving phase of 0.97 up-flow, and every production 1g dibasic acid esters consumes the moving phase of 11 up-flows.
Embodiment 4:
Simulated moving bed chromatography system
C9812 (Nore, Germany), assemble 16 root chromatogram columns (ID 1 * 15cm), 4 in every district, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, particle diameter 50 μ m.Flow be mutually acetonitrile/aqueous isopropanol (50/50, v/v), 40 ℃ of temperature.The sample that charging is used is TPGS 600 mixed liquors, concentration: 50mg/ml, and wherein monoester content is 70.4%, dibasic acid esters content is 29.4%.
A, operating condition:
Sample introduction flow velocity: U
F=2ml/min
Eluent flow rate: U
D=21.2ml/min
Raffinate flow velocity: U
R=9.19ml/min
Extract flow velocity: U
E=14.0ml/min
Switching time: t
s=60s
B, check analysis:
Analyze raffinate and extract composition with HPLC.TPGS monoesters purity is 98.9% in the raffinate, and yield is 99.9%; TPGS dibasic acid esters purity is 99.8% in the extract, and yield is 99.9%.
Embodiment 5:
Simulated moving bed chromatography system
C9812 (Nore, Germany), assemble 16 root chromatogram columns (ID 1 * 15cm), 4 in every district, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, particle diameter 100 μ m.Flow be mutually acetonitrile/aqueous isopropanol (30/70, v/v), 30 ℃ of temperature.The sample that charging is used is TPGS 2000 mixed liquors, concentration: 85mg/ml, and wherein monoester content is 58.7%, dibasic acid esters content is 40.1%.
A, operating condition:
Sample introduction flow velocity: U
F=1.2ml/min
Eluent flow rate: U
D=5.1ml/min
Raffinate flow velocity: U
R=2.9ml/min
Extract flow velocity: U
E=3.3ml/min
Switching time: t
s=216s
B, check analysis:
Analyze raffinate and extract composition with HPLC.TPGS monoesters purity is 98.7% in the raffinate, and yield is 99.8%; TPGS dibasic acid esters purity is 98.6% in the extract, and yield is 99.8%.
Embodiment 6:
Simulated moving bed chromatography system
C9812 (Nore, Germany), assemble 16 root chromatogram columns (ID 1 * 15cm), 4 in every district, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, particle diameter 10 μ m.Flow be mutually acetonitrile/aqueous isopropanol (40/60, v/v), 20 ℃ of temperature, the sample that charging is used is TPGS 1200 mixed liquors, concentration: 1mg/ml, wherein monoester content is 79.7%, dibasic acid esters content is 20.0%.
A, operating condition:
Sample introduction flow velocity: U
F=1.5ml/min
Eluent flow rate: U
D=4.3ml/min
Raffinate flow velocity: U
R=2.0ml/min
Extract flow velocity: U
E=3.8ml/min
Switching time: t
s=180s
B, check analysis:
Finished product is analyzed with HPLC and is obtained that TPGS monoesters purity is 98.9% in the raffinate, and yield is 99.2%; TPGS dibasic acid esters purity is 99.3% in the extract, and yield is 99.3%.
Embodiment 7:
Among the embodiment 1, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, and particle diameter is used 80 μ m instead.The sample that charging is used is TPGS 1000 mixed liquors, concentration: 100mg/ml, and composition and content are identical with example 1.Adopt the processing step identical with embodiment 1.
Finished product is analyzed with HPLC and is obtained that TPGS monoesters purity is 98.0% in the raffinate, and yield is 99.8%; TPGS dibasic acid esters purity is 98.6% in the extract, and yield is 99.7%.
Embodiment 8:
Among the embodiment 1, the fixing of filling is octadecylsilane chemically bonded silica mutually in the chromatographic column, and particle diameter is used 10 μ m instead.The sample that charging is used is TPGS 1000 mixed liquors, concentration: 10mg/ml, and composition and content are identical with example 1.Adopt the processing step identical with embodiment 1.
Finished product is analyzed with HPLC and is obtained that TPGS monoesters purity is 99.0% in the raffinate, and yield is 99.2%; TPGS dibasic acid esters purity is 99.3% in the extract, and yield is 99.7%.
Embodiment 9:
Among the embodiment 1, simulated moving bed chromatography system assemble 12 root chromatogram columns (ID 1 * 15cm), every district 3 root chromatogram columns, chromatographic column is fixing, and to reach particle diameter mutually identical with example 1.The sample that charging is used is TPGS 1000 mixed liquors, concentration: 200mg/ml, and composition and content are identical with example 1.Other all adopts the processing step identical with embodiment 1.
A, operating condition:
Sample introduction flow velocity: U
F=1ml/min
Eluent flow rate: U
D=4.2ml/min
Raffinate flow velocity: U
R=2.4ml/min
Extract flow velocity: U
E=2.8ml/min
Switching time: t
s=180s
B, check analysis:
Finished product is analyzed with HPLC and is obtained that TPGS monoesters purity is 99.3% in the raffinate, and yield is 99.8%; TPGS dibasic acid esters purity is 99.6% in the extract, and yield is 99.4%.
Embodiment 10:
Among the embodiment 1, simulated moving bed chromatography system assemble 4 root chromatogram columns (ID 1 * 15cm), every district 1 root chromatogram column, chromatographic column is fixing, and to reach particle diameter mutually identical with example 1.The sample that charging is used is TPGS 1000 mixed liquors, concentration: 200mg/ml, and composition and content are identical with example 1.Other all adopts the processing step identical with embodiment 1.
A, operating condition:
Sample introduction flow velocity: U
F=1ml/min
Eluent flow rate: U
D=4.8ml/min
Raffinate flow velocity: U
R=2.0ml/min
Extract flow velocity: U
E=3.8ml/min
Switching time: t
s=200s
B, check analysis:
Finished product is analyzed with HPLC and is obtained that TPGS monoesters purity is 98.2% in the raffinate, and yield is 98.7%; TPGS dibasic acid esters purity is 98.6% in the extract, and yield is 99.0%.
Claims (2)
1. the separation method of a vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester, from the vitamin E polyethylene glycol succinic acid ester mixture, isolate vitamin E polyethylene glycol monomester succinate and dibasic acid esters, it is characterized in that: with particle diameter is fixedly phase of 5-100 μ m octadecylsilane chemically bonded silica conduct, mixture conduct with acetonitrile and isopropyl alcohol is flowed mutually, the vitamin E polyethylene glycol succinic acid ester mixture that with the monoester content is 20%-80% is a raw material, adopts the SMBC method to isolate monoesters and dibasic acid esters; May further comprise the steps:
(1) the vitamin E polyethylene glycol succinic acid ester mixture is dissolved in mobile phase, concentration is 1mg/mL～300mg/mL;
(2) from simulated moving bed chromatography system, tell vitamin E polyethylene glycol succinic acid ester monoesters and dibasic acid esters solution;
(3) vitamin E polyethylene glycol succinic acid ester monoesters and dibasic acid esters solution concentrate respectively, steam desolventize after, obtain purity and yield and all be higher than 98% vitamin E polyethylene glycol succinic acid ester monoesters and dibasic acid esters;
The total pillar number of described SMBC is 4～32, and every district pillar number is 1～8;
The operating temperature of described simulated moving bed chromatography system is 0～50 ℃.
2. the separation method of a kind of vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester according to claim 1 is characterized in that: described flow mutually in the volume ratio of acetonitrile and isopropyl alcohol be 30: 70～70: 30.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN102766266B (en) * | 2012-07-18 | 2013-09-25 | 浙江大学 | Method for extracting and separating vitamin E polyethylene glycol succinic acid monoester and diester |
| CN102924555A (en) * | 2012-10-22 | 2013-02-13 | 浙江大学 | Method for preparing 24-dehydrocholesterol through separation of simulated moving bed chromatography |
| CN109254102B (en) * | 2017-07-14 | 2022-02-15 | 上海联陆实业股份有限公司 | High performance liquid detection method for water-soluble vitamin E derivatives |
| CN107474238A (en) * | 2017-08-15 | 2017-12-15 | 武汉桀升生物科技有限公司 | A kind of method of separating VE polyethylene glycol mono succinate dibasic acid esters |
| CN109422873B (en) * | 2017-09-04 | 2022-12-27 | 广东东阳光药业有限公司 | Post-treatment method of vitamin E succinic acid polyethylene glycol ester |
| CN112920152A (en) * | 2019-12-06 | 2021-06-08 | 中国科学院大连化学物理研究所 | High-efficiency preparation chromatographic method for removing zearalenone from natural vitamin E |
| CN111751480B (en) * | 2020-07-16 | 2021-06-15 | 北京理工大学 | Application of vitamin E polyethylene glycol succinate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050163828A1 (en) * | 2003-10-27 | 2005-07-28 | Bernard Bobby L. | Tocopheryl polyethylene glycol succinate articles and process for preparing TPGS articles |
| CN101220018A (en) * | 2008-01-24 | 2008-07-16 | 浙江大学 | Method for separating single tocopherol from mixed tocopherol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050163828A1 (en) * | 2003-10-27 | 2005-07-28 | Bernard Bobby L. | Tocopheryl polyethylene glycol succinate articles and process for preparing TPGS articles |
| CN101220018A (en) * | 2008-01-24 | 2008-07-16 | 浙江大学 | Method for separating single tocopherol from mixed tocopherol |
Non-Patent Citations (2)
| Title |
|---|
| Eva-Maria Collnot. et al.Influence of vitamin E TPGS poly(ethylene glycol) chain length on apical.《Journal of Controlled Release》.2006,第111卷(第1-2期),第35-40页. * |
| Jingyuan Wang. et al.LC Separation and Quantification of Tocopheryl Polyethylene Glycol Succinate and Tocopheryl Acid Succinate in TPGS Reaction Mixture.《CHROMATOGRAPHIA》.2009,第70卷(第3/4期),第551-555页. * |
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