CN1616524A - Preparing magnetic high molecular microball by compound emulsion method - Google Patents
Preparing magnetic high molecular microball by compound emulsion method Download PDFInfo
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- CN1616524A CN1616524A CN 200310113439 CN200310113439A CN1616524A CN 1616524 A CN1616524 A CN 1616524A CN 200310113439 CN200310113439 CN 200310113439 CN 200310113439 A CN200310113439 A CN 200310113439A CN 1616524 A CN1616524 A CN 1616524A
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- microsphere
- macromolecular microsphere
- oil phase
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- 230000005291 magnetic effect Effects 0.000 title claims abstract description 92
- 150000001875 compounds Chemical class 0.000 title claims abstract description 17
- 238000004945 emulsification Methods 0.000 title claims abstract description 17
- 239000011806 microball Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 72
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 239000000839 emulsion Substances 0.000 claims abstract description 26
- 239000000126 substance Substances 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 230000001804 emulsifying effect Effects 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 239000003513 alkali Substances 0.000 claims abstract 2
- 239000004005 microsphere Substances 0.000 claims description 78
- 239000000178 monomer Substances 0.000 claims description 35
- 239000007864 aqueous solution Substances 0.000 claims description 30
- 239000006249 magnetic particle Substances 0.000 claims description 30
- 239000012071 phase Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006116 polymerization reaction Methods 0.000 claims description 19
- 239000012530 fluid Substances 0.000 claims description 18
- 229920000642 polymer Polymers 0.000 claims description 18
- 229910021645 metal ion Inorganic materials 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000012266 salt solution Substances 0.000 claims description 11
- 210000003022 colostrum Anatomy 0.000 claims description 9
- 235000021277 colostrum Nutrition 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000000935 solvent evaporation Methods 0.000 claims description 9
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- -1 iron ion Chemical class 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 238000007885 magnetic separation Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000000630 rising effect Effects 0.000 claims description 3
- 238000005842 biochemical reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229920002521 macromolecule Polymers 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 9
- 230000002209 hydrophobic effect Effects 0.000 claims 9
- 229920001519 homopolymer Polymers 0.000 claims 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 6
- 239000013543 active substance Substances 0.000 claims 4
- 230000008878 coupling Effects 0.000 claims 4
- 238000010168 coupling process Methods 0.000 claims 4
- 238000005859 coupling reaction Methods 0.000 claims 4
- 239000012670 alkaline solution Substances 0.000 claims 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 2
- 239000008367 deionised water Substances 0.000 claims 2
- 229910021641 deionized water Inorganic materials 0.000 claims 2
- 238000001035 drying Methods 0.000 claims 2
- 239000002994 raw material Substances 0.000 claims 2
- 230000003252 repetitive effect Effects 0.000 claims 2
- 238000005201 scrubbing Methods 0.000 claims 2
- 229910003321 CoFe Inorganic materials 0.000 claims 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims 1
- 229910017840 NH 3 Inorganic materials 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- 238000004220 aggregation Methods 0.000 claims 1
- 230000002776 aggregation Effects 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 229910001566 austenite Inorganic materials 0.000 claims 1
- 229910001429 cobalt ion Inorganic materials 0.000 claims 1
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 claims 1
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 230000005294 ferromagnetic effect Effects 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910001425 magnesium ion Inorganic materials 0.000 claims 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910000859 α-Fe Inorganic materials 0.000 claims 1
- 238000005406 washing Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 238000003759 clinical diagnosis Methods 0.000 abstract description 3
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 238000000926 separation method Methods 0.000 description 7
- 230000008961 swelling Effects 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000004793 Polystyrene Substances 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000001000 micrograph Methods 0.000 description 4
- 229920002223 polystyrene Polymers 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 3
- 229940088623 biologically active substance Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 2
- 229940044192 2-hydroxyethyl methacrylate Drugs 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 2
- 108010093096 Immobilized Enzymes Proteins 0.000 description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000593 microemulsion method Methods 0.000 description 2
- 238000005204 segregation Methods 0.000 description 2
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- XZKRXPZXQLARHH-UHFFFAOYSA-N buta-1,3-dienylbenzene Chemical compound C=CC=CC1=CC=CC=C1 XZKRXPZXQLARHH-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910001447 ferric ion Inorganic materials 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000011553 magnetic fluid Substances 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Images
Abstract
Magnetic high molecular microballoon is prepared through compound emulsifying process and has embedded magnetic grains accounting for 1-50 wt% of the microballoon, stable chemical property and acid and alkali resistance. The preparation process includes preparing two kinds of initial emulsion, mixing the two kinds of initial emulsion, compound emulsification, eliminating solvent, washing magnetic microballoon, and other steps. The present invention features the simultaneous generation and embedding of the magnetic grains. The microballoon size and magnetic grain content may be controlled. The magnetic microballoon may be used as carrier of enzyme, antibody and medicine in cell separate, clinical diagnosis, etc. The present invention has the features of simple process, high repeatability, low cost, etc.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to magnetic macromolecular microsphere that has magnetic and preparation method thereof.
Technical background
Magnetic macromolecular microsphere is meant by appropriate means magnetic-particle to be embedded in the polymer microsphere and forms the microballoon with certain magnetic responsiveness and special construction.It is a kind of new function polymer composite that grows up in the later stage seventies 20th century.On the one hand, it has the characteristic of polymer microsphere, can make polymer microsphere surface have multiple functional group by chemical reactions such as copolymerization, surface modifications, thereby can be in conjunction with multiple biologically active substance; On the other hand, it has magnetic again, can be fast under externally-applied magnetic field and other do not have the separating substances of magnetic, and energy expenditure is little.Therefore, magnetic macromolecular microsphere has a wide range of applications in the fields such as contrast medium of biomedical (clinical diagnosis, targeted drug), cytology (cellular segregation), immobilized enzyme, affine separation and magnetic resonance image (MRI) as new functional macromolecule material.
At present, the preparation method of existing magnetic macromolecular microsphere has four kinds in document and the patent: monomer polymerization method
[1,2,3], the activation swelling method
[4,5], the interface sedimentation
[6,7], the reverse microemulsion method
[8,9](1) monomer polymerization method, with magnetic fluid or magnetic small-particle be dispersed in make mixing solutions in macromolecular solution or the monomer after, this mixing solutions and water are mixed and made into O/W type (oil-in-water-type) emulsion, adopt then to take out and desolvate or the method for polymerization single polymerization monomer obtains solidified microsphere.Its shortcoming is that the affinity between magnetic-particle and the macromolecular material is poor, and the wetting ability of magnetic-particle is strong, at monomer polymerization or take out when desolvating, the magnetic small-particle escapes into surface and outer aqueous phase easily, not only embedding rate is low, and microsphere surface adsorbing a large amount of magnetic-particles, is difficult to wash-out, be used for that biologically active substance separates or fixedly the time, influence the activity of biologically active substance.(2) activation swelling method, the activation swelling method of Ugelstad proposition in 1993 is the better method of the preparation magnetic macromolecular microsphere of hitherto reported.Concrete steps are after preparing poly-(vinylbenzene-2-hydroxyethyl meth acrylate) microballoon of single-size with emulsion polymerization, to make bigger microballoon with swelling method more then.Then, vinylbenzene is nitrated, utilize the affinity interaction of nitro and iron ion again, make microballoon absorb the ferrous iron and the ferric ion aqueous solution.After the microballoon that has adsorbed iron ion separated, mix, make the iron ion in the microballoon be converted to Fe with basic solution
3O
4Particle and being deposited in the microballoon.But problems such as length consuming time, reactions steps are many, severe reaction conditions that this method exists, thus cause cost too high, therefore limited magnetic macromolecular microsphere in biochemical industry, medicine industry and application clinically.(3) interface sedimentation makes the magnetic small-particle of positively charged be adsorbed on electronegative polymer microsphere surface earlier, and then plates one deck macromolecular material on its surface.Because a polymer microsphere surface can only adsorb one deck magnetic-particle, the embedding amount of magnet is very low.(4) reverse microemulsion process, in redox or thermal initiation system, to hydrophilic monomers such as third rare amides and acrylic acid or the like, the molysite that adds emulsifying agent, initiator, linking agent, different valence state, control is reflected in certain scope that feeds intake, directly synthetic magnetic macromolecular microsphere with superparamagnetism of a step in reverse micro emulsion.But this method only is applicable to hydrophilic monomer, the particle diameter of microballoon also smaller (below 200nm), and reaction conditions is also wayward.In sum, existing preparation method only is applicable to laboratory or Small Scale Industry production, therefore, is necessary to develop the new method for preparing magnetic macromolecular microsphere, in the hope of the higher magnetic macromolecular microsphere of preparation cost performance.
Desirable magnetic macromolecular microsphere microballoon should have following characteristics: magnetic-particle has superparamagnetism; The microspherulite diameter homogeneous; Microballoon contains quantity of magnetism height; Chemical stability is good, and magnetic-particle does not have leakage, and is pollution-free; The physical strength height; Good biocompatibility; Technology is simple, good reproducibility, is easy to large-scale production, and price is low.
To the introduction of prior preparation method, be not difficult to find out that the microballoon that does not have a kind of method preparation in the existing method can reach the requirement of desirable microballoon by above, this has also limited the application of magnetic macromolecular microsphere in medical treatment and bioseparation.The invention provides a kind of novel preparation method---compound emulsion method, in the hope of reach the preparation desirable magnetic macromolecular microsphere requirement, thereby produce great economic benefit and social benefit.
Reference:
1、J.C.Daniel，J.L.Schuppiser，M.Tricot，US?Patent?4,358,388(1982)
2, Li Xiaohong, Ding Xiaobin, Sun Zonghua, functional polymer journal, 1,73 (1995)
3, official's moon is put down Liu Huizhou, An Zhentao, Ke Jiajun, old family a large bell Chinese patent 98124516.1 (1998)
4、J.Ugelstad，P.Stenstad，L.Kilaas，Blood?Puri.，11，349(1993)
5、J.Ugelstad，P.C.Mork，R.Schmid，T.Ellingsen，A.Berg，Polymer?International，30，157(1993)
6、K.Furusawa，K.Nagashima，C.Anzai，Kobunshi?Eonbunshu，50，337(1993)
7、S.James，WO?Patent，96/37131(1996)
8, Wang Lei, Deng Yonghua, A Deer Hammett Euler Sa, wide Chinese patent 01126181.1 (2001) of mansion longevity
9, Deng Yonghui, Wang Lei, Yang Wuli, wide, the high chemical journal of Elaissari Abdelhamid of mansion longevity, 24 (5), 920, (2003)
Summary of the invention
The invention provides a kind of preparation method of novel magnetic macromolecular microsphere.This method adopts the emulsion legal system to be equipped with magnetic macromolecular microsphere, and the mass ratio that the magnetic-particle of microballoon institute embedding accounts for whole microballoon is 1-50%, and chemical property is stable, acid and alkali-resistance.The washing of the preparation that its main technique flow process is two kinds of colostric fluids, the mixing of colostric fluid, emulsionization, removal of solvents, magnetic microsphere etc.Concrete preparation method is: the metal ion aqueous solution is dispersed in polymers soln or the monomer solution, obtains W
11/ O type colostric fluid; In addition alkaline aqueous solution is dispersed in another polymers soln or the monomer solution, obtains W
12/ O type colostric fluid; Two kinds of colostric fluids are mixed, obtain (W
11+ W
12The compound colostric fluid of)/O; Should compound colostric fluid mix with outer water and be prepared into (W
11+ W
12)/O/W
2Emulsion; At last, intensification polymerization or remove organic solvent and moisture content, the limit makes magnetic-particle generate the limit it is embedded in the polymer microsphere.The invention is characterized in does not need prepared beforehand magnetic-particle or polymer microsphere; outer water rotating speed and outer water stabiliser content were controlled when microspherulite diameter can be by emulsion, and magnetic content can be controlled by the concentration of interior aqueous phase solute and the ratio of interior water and oil phase.This magnetic microsphere can be used as the carrier of enzyme, antibody, medicine, is used for cellular segregation, clinical diagnosis, target medicine carrier, immobilized enzyme, affine separation etc.The present invention has characteristics such as method is simple, good reproducibility, cost is low, microspherulite diameter is controlled, magnetic content is controlled.
The invention provides a kind of method of quick, efficient, magnetic content controllable preparation magnetic macromolecular microsphere, this method is different from all methods of having reported fully.
Description of drawings:
The preparation flow synoptic diagram of Fig. 1 magnetic macromolecular microsphere.
Magnetic macromolecular microsphere suspended state in water when no magnetic field of Fig. 2 embodiment 1 preparation.
Separating effect after the placement of magnetic macromolecular microsphere in the magnetic field of 2000T of Fig. 3 embodiment 1 preparation.
The light micrograph of the magnetic macromolecular microsphere of Fig. 4 embodiment 1 preparation.
The light micrograph of the magnetic macromolecular microsphere of Fig. 5 embodiment 2 preparations.
The light micrograph of the magnetic macromolecular microsphere of Fig. 6 embodiment 3 preparations.
The light micrograph of the magnetic macromolecular microsphere of Fig. 7 embodiment 4 preparations.
Specific embodiments
The purpose of this invention is to provide a kind of method of quick, efficient, magnetic content controllable preparation magnetic macromolecular microsphere, this method is different from all methods of having reported fully.Its preparation flow as shown in Figure 1.
Concrete steps:
(1) with metal ion salt solution W
11Mixed with oil phase O, make W
11The colostric fluid that/O type is stable.
Oil phase is polymer organic solution or prepolymer organic solution or monomer and initiator, and surfactant mixtures.
(2) identical with (1), with alkaline aqueous solution W
12Make W
12The colostric fluid that/O type is stable.
(3) with W
11/ O and W
12/ O mixes, and generates (W
11+ W
12The colostric fluid that)/O type is stable.
(4) with (W
11+ W
12)/O is added to the outer water W with certain rotational speed
2In (containing stablizer), be prepared into (W
11+ W
12)/O/W
2The type emulsion.
(5) if contain monomer in the oil phase, double emulsion under agitation feeds N
2Protection heats up, and makes monomer polymerization.
(6) organic solvent in the method removal oil phase of employing intensification or decompression and the moisture of interior aqueous phase.Since the rising of organic solvent evaporation and system temperature in polymerization or the oil phase, W
11Drop and W
12Droplet collision merges, W
11Metal ion salt solution in the drop and W
12Alkaline aqueous solution in the drop generation magnetic-particle that reacts.Owing to polymerization and solvent evaporation, oil phase is solidified into microballoon simultaneously, thereby generates magnetic macromolecular microsphere.
(7) add ethanol or water washing three times, utilize magnetic separation technique, magnetic macromolecular microsphere is separated, carry out vacuum-drying again, obtain product.
In the existing report method, monomer polymerization method is at first to prepare magnetic-particle, the refabrication microballoon; Interface sedimentation and activation swelling method are at first to prepare the nano level microballoon, generate magnetic-particle at microsphere surface again, prepare magnetic macromolecular microsphere as the seed microballoon at last; The reverse microemulsion method is to adopt w/o type (water-in-oil-type) microemulsion, only is suitable for hydrophilic monomer or polymkeric substance.And the compound emulsion method that the present invention uses is different from existing all methods, it is characterized in that the limit generates magnetic-particle, and the limit makes emulsion solidify balling-up, thereby magnetic-particle is embedded in the polymer microsphere.
Present method is used compound emulsion method; it is characterized in that before the polymerization or solvent evaporation before; metal ion salt solution liquid grain and alkaline aqueous solution liquid grain are independent respectively to be existed; after the polymerization or take out and desolvate and during moisture; two kinds of liquid grains mix, and cause the biochemical reaction of metal ion salt solution drop and alkaline aqueous solution drop hybrid concurrency to generate magnetic-particle, simultaneously because monomer polymerization or solvent evaporation; oil phase is solidified into microballoon, thereby generates magnetic macromolecular microsphere.Present method can be controlled magnetic content and reach the requirement of high embedding amount.
Embodiment 1:
Get the PSt (polystyrene) of 0.9g and the Span85 (Witconol AL 69-66) of 2.0g, be dissolved in the 40ml toluene, form oil phase O, be divided into two parts again.Add W in the portion
11(0.1ml concentration is the FeCl of 0.50mol/l
3The aqueous solution and 0.2ml concentration are the FeCl of 0.50mol/l
2The aqueous solution), add W in another part
12(0.3ml concentration is the NaOH aqueous solution of 2.0mol/l).Stir certain hour with the emulsification clarifixator respectively, rotating speed is 9000 rev/mins, two parts of emulsions is mixed again, and forms stable compound colostrum (W
11+ W
12)/O.Prepare outer water W
2(H
2O 225g, polyvinyl alcohol 1.5g), with outer water W
2Stir with stirring arm, rotating speed is 400 rev/mins.With the compound colostrum (W that has prepared
11+ W
12)/O slowly pours the outer aqueous phase in the stirring into, forms emulsion (W
11+ W
12)/O/W
2, continue under field conditions (factors) to stir 1hr, be warming up to 65 ℃ again and stir 6hr, separation in externally-applied magnetic field, washing, vacuum-drying at last promptly gets product.During no externally-applied magnetic field, product is scattered in the water, microballoon can suspend in water, as shown in Figure 2; When externally-applied magnetic field is 0.2T, microballoon can with the water sharp separation, as shown in Figure 3.The photo of magnetic macromolecular microsphere as shown in Figure 4, magnetic-particle is embedded in the polymer microsphere well, does not have leakage phenomenon.
Embodiment 2:
Get the PSt (polystyrene) of 0.9g and the Aracel83 (sorbitan sesquioleate) of 2.6g, be dissolved in the 40ml methylene dichloride (DCM), form oil phase O, be divided into two parts again.Add W in the portion
11(0.1ml concentration is the CoCl of 2.0mol/l
2The aqueous solution and 0.1ml concentration are the FeCl of 2.0mol/l
2The aqueous solution and 0.2ml concentration are the FeCl of 0.2mol/l
3The aqueous solution), add W in another part
12(0.4ml concentration is the NaOH aqueous solution of 6.0mol/l).Use supersound method emulsification certain hour respectively.Again two parts of emulsions are mixed, form compound colostrum (W
11+ W
12)/O.Prepare outer water W
2(H
2O 225g, polyvinyl alcohol 1.5g), outer water is stirred with stirring arm, rotating speed is 500 rev/mins.With the compound colostrum (W that has prepared
11+ W
12)/O slowly pours the outer aqueous phase in the stirring into, forms emulsion (W
11+ W
12)/O/W
2Again the emulsion emulsion is warming up to 84 ℃, stirs 4hr with 200 rev/mins rotating speeds, separation in externally-applied magnetic field, washing, vacuum-drying at last promptly gets product.The photo of magnetic macromolecular microsphere as shown in Figure 5, magnetic-particle is embedded in the polymer microsphere well, does not have leakage phenomenon.
Embodiment 3:
Get the St (vinylbenzene) and the multipolymer (ratio is 9: 1) of HEMA (2-hydroxyethyl meth acrylate) and the HCO10 (Crodaret) of 2.4g of 0.6g, the toluene and the 17ml methylene dichloride (DCM) that add 23ml again stir 2hr, form oil phase O, be divided into two parts again.Add W in the portion
11(0.10ml concentration is the Fe of 0.52mol/l
2(SO
4)
3The aqueous solution and 0.10ml concentration are the FeSO of 0.52mol/l
4The aqueous solution and 0.2mol/l concentration are the MgCl of 0.26mol/l
2The aqueous solution), add W in another part
12(0.4ml concentration is the NaOH aqueous solution of 6mol/l).Use homogeneous emulsifying machine emulsification certain hour respectively, rotating speed is 7500 rev/mins, uses ultrasonic emulsification emulsification certain hour again, two parts of emulsions is mixed again and mixes, and forms compound colostrum (W
11+ W
12)/O.Prepare outer water W
2(H
2O 225g, polyvinyl alcohol 1.5g), outer water is stirred with stirring arm, rotating speed is 400 rev/mins.With the compound colostrum (W that has prepared
11+ W
12)/O slowly pours the outer aqueous phase in the stirring into, forms emulsion (W
11+ W
12)/O/W
2, stir 2.0hr down at 30 ℃, 60 ℃ are stirred 2.0hr down, and 85 ℃ are stirred 3.0hr down, and the mixing speed of emulsion emulsion is 200 rev/mins.Separation in externally-applied magnetic field, washing, vacuum-drying at last promptly gets product.The photo of magnetic macromolecular microsphere as shown in Figure 6, magnetic-particle is embedded in the polymer microsphere well, does not have leakage phenomenon.
Embodiment 4:
Get the BPO (benzoyl peroxide) of DVB (Vinylstyrene), 0.03g of St (vinylbenzene), 0.1g of 0.8g and the Span85 of 2.0g, be dissolved in the 40ml toluene, form oil phase O, be divided into two parts again.Add W in the portion
11(0.1ml concentration is the FeCl of 0.50mol/l
3The aqueous solution and 0.2ml concentration are the FeCl of 0.50mol/l
2The aqueous solution), add W in another part
12(0.3ml concentration is the NaOH aqueous solution of 2.0mol/l).Stir certain hour with the emulsification clarifixator respectively, rotating speed is 9000 rev/mins, two parts of emulsions is mixed again, and forms stable compound colostrum (W
11+ W
12)/O.Prepare outer water W
2(H
2O 225g, polyvinyl alcohol 1.5g), with outer water W
2Stir with stirring arm, rotating speed is 400 rev/mins.With the compound colostrum (W that has prepared
11+ W
12)/O slowly pours the outer aqueous phase in the stirring into, forms emulsion (W
11+ W
12)/O/W
2, at N
2Protection continues to stir 1hr down, is warming up to 75 ℃ again and stirs 8hr, and separation in externally-applied magnetic field, washing, vacuum-drying at last promptly gets product.The photo of magnetic macromolecular microsphere as shown in Figure 7, magnetic-particle is embedded in the polymer microsphere well, does not have leakage phenomenon.
Claims (20)
1, a kind of method for preparing magnetic macromolecular microsphere is characterized in that adopting compound emulsion method to prepare the polymer microsphere that inside comprises magnetic-particle, and wherein the quality of magnetic-particle accounts for 0.5%～50% of microballoon total mass.
2, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1 is characterized in that the kind of magnetic-particle comprises ferric oxide (γ-Fe
2O
3, Fe
3O
4); Ferrite (CoFe
2O
4, MgFe
2O
4) wait the magnetic-particle of various available chemical methods preparations.
3, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1 is characterized in that magnetic-particle is generated by the salts solution and the alkaline solution generation chemical reaction of one or more metal ions such as iron ion, magnesium ion, cobalt ion.
4, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1, it is characterized in that magnetic-particle comprises ferromagnetic particle and supperparamagnetic particles, its magnetic property can be by the concentration of interior aqueous phase metal ion and alkaline solution, both ratios and the rate-controlling of desolvating.
5, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1, the size that it is characterized in that magnetic-particle are 1nm～1 μ m, and the size of polymer microsphere is 100nm～800 μ m.
6, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1 is characterized in that polymkeric substance in the described magnetic macromolecular microsphere can be the mixture of mixture, the multipolymer of homopolymer, multipolymer, homopolymer, also can be the mixture of homopolymer and multipolymer.Wherein, homopolymer is the polymkeric substance that a kind of hydrophobic monomer forms; Multipolymer is the multipolymer that one or more hydrophobic monomers and one or more hydrophilic monomers form, and the total mass ratio of hydrophobic monomer and hydrophilic monomer is between 2: 8 to 10: 0.
7, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1 is characterized in that using polymkeric substance or prepolymer also can use monomer to be raw material as raw material.
8, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1, when it is characterized in that using polymkeric substance or prepolymer as feedstock production, concrete preparation flow is as follows;
(1) polymkeric substance or prepolymer are dissolved in the organic solvent (containing tensio-active agent) with other additive, are prepared into oil phase O;
(2) with metal ion salt solution W
11Mix with oil phase O (containing polymkeric substance, organic solvent, tensio-active agent), use one or both method couplings of sonioation method or homogenizing emulsifying method, make W
11The colostric fluid that/O type is stable;
(3) identical with (2), with alkaline aqueous solution W
12(sodium hydroxide, potassium hydroxide, ammoniacal liquor, pyridine etc.) are distributed in the oil phase, make W
12The colostric fluid that/O type is stable;
(4) with W
11/ O and W
12Two kinds of colostric fluids of/O mix, and form (W
11+ W
12The mixed type colostric fluid that)/O type is stable;
(5) with (W
11+ W
12)/O is added to the outer water W that stirs with given pace
2In (containing stablizer), be prepared into (W
11+ W
12)/O/W
2The type double emulsion;
The organic solvent in one or more method couplings removal oil phases such as (6) employing intensification, decompression and the moisture of interior water also make the prepolymer polymerization, since the organic solvent evaporation in the oil phase and the rising of system temperature, W
11Drop and W
12Droplet collision merges, W
11Metal ion salt solution in the drop and W
12Alkaline aqueous solution hybrid concurrency in the drop is given birth to reaction and is generated magnetic-particle, because solvent evaporation is dissolved in the macromolecule aggregation in the oil phase organic solvent, microballoon solidifies simultaneously, thereby generates magnetic macromolecular microsphere.
(7) utilize magnetic separation technique to separate magnetic microsphere, and with ethanol and deionized water repetitive scrubbing isolate and drying, obtain the magnetic macromolecular microsphere of finished product.
9, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 1, when it is characterized in that using monomer as feedstock production, concrete preparation method is as follows;
(1) monomer and initiator thereof and solvent, tensio-active agent, linking agent are mixed, be dissolved in the organic solvent, be prepared into oil phase O;
(2) with metal ion salt solution W
11O mixes with oil phase, uses one or both method couplings of sonioation method or homogenizing emulsifying method, makes W
11The colostric fluid that/O type is stable;
(3) identical with (2), with alkaline aqueous solution W
12(sodium hydroxide, potassium hydroxide, ammoniacal liquor, pyridine etc.) are distributed in the oil phase, make W
12The colostric fluid that/O type is stable;
(4) with W
11/ O and W
12Two kinds of colostric fluids of/O mix, and generate (W
11+ W
12The mixed type colostric fluid that)/O type is stable;
(5) with (W
11+ W
12)/O is added to the outer water W that stirs with given pace
2In (containing stablizer), be prepared into (W
11+ W
12)/O/W
2The type double emulsion;
(6) stir double emulsion, at N
2Under the protection, heating up makes decomposition of initiator, trigger monomer polymerization;
The organic solvent in one or more method couplings removal oil phases such as (7) employing intensification, decompression and the moisture of interior water.Since the organic solvent evaporation in monomeric polymerization, the oil phase and the rising of system temperature, W
11Drop and W
12Droplet collision merges, W
11Metal ion salt solution in the drop and W
12Alkaline aqueous solution hybrid concurrency in the drop is given birth to reaction and is generated magnetic-particle, and this step also can merge with step (6);
(8) utilize magnetic separation technique to separate magnetic microsphere, and with ethanol and deionized water repetitive scrubbing isolate and drying, obtain the magnetic macromolecular microsphere of finished product.
10, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that described emulsion structure is (W
11+ W
12)/O/W
2Before polymerization or the solvent evaporation, metal ion salt solution and alkaline aqueous solution are independent respectively to be existed, polymerization or take out is desolvated and during moisture, two kinds of drops merge, and cause the biochemical reaction of metal ion salt solution drop and alkaline aqueous solution drop hybrid concurrency to generate magnetic-particle, simultaneously because polymerization or solvent evaporation, oil phase is solidified into microballoon, thereby generates magnetic macromolecular microsphere.
11, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 8 is characterized in that described polymkeric substance and prepolymer can be the mixtures of mixture, the multipolymer of homopolymer, multipolymer, homopolymer, also can be the mixture of homopolymer and multipolymer.Wherein, homopolymer is the polymkeric substance that a kind of hydrophobic monomer forms; Multipolymer is the multipolymer that one or more hydrophobic monomers and one or more hydrophilic monomers form, and the total mass ratio of hydrophobic monomer and hydrophilic monomer is between 2: 8 to 10: 0.
12, a kind of method for preparing magnetic macromolecular microsphere as claimed in claim 9, it is characterized in that described monomer is the mixture of hydrophobic monomer or hydrophobic monomer and hydrophilic monomer, the total mass ratio of hydrophobic monomer and hydrophilic monomer is between 2: 8 to 10: 0.
13, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that the metal ion in the described metal ion salt solution is Fe
2+, Fe
3+, Co
2+, Mg
2+Wait one or more can generate the metal ion of magnetic substance with the alkaline solution reaction.
14, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that described alkaline aqueous solution comprises NaOH, KOH, NH
3H
2O, Na
2CO
3, NaHCO
3, various alkaline aqueous solutions such as pyridine, organic amine the mixing solutions of one or more alkaline aqueous solutions.
15, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that described alkali OH
-With the mol ratio of metal ion sum be 10: 1 to 1: 10.
16, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that the tensio-active agent in the oil phase is one or more oil soluble nonionic surface active agent, and the mass content in oil phase is 0.1%～25%.
17, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that the oil phase and the ratio of outer water are 1: 1～1: 2000, and the ratio of interior water and oil phase is 1: 1～1: 100.
18, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that described colostrum preparation method is various emulsion processes such as supersound method, emulsification homogeneous method, mechanical mixing method.
19, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that described emulsion preparation method comprises various emulsion processes such as mechanical mixing method, emulsification homogeneous method.
20, a kind of as claimed in claim 8 or 9 method for preparing magnetic macromolecular microsphere is characterized in that the described method of desolvating comprises normal pressure intensification volatilization, normal pressure and temperature volatilization, decompression extracting the whole bag of tricks such as (vacuum extraction).
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100443508C (en) * | 2006-09-28 | 2008-12-17 | 上海交通大学 | Process for preparing functional high molecule composite micro ball with quick magnetic field responsiveness |
| CN100457094C (en) * | 2006-03-08 | 2009-02-04 | 中山大学 | Preparing process of biodegradable capsule loading medicine and nano magnetic particle |
| CN1973832B (en) * | 2006-10-24 | 2010-05-12 | 中山大学 | Biodegradable nanometer medicine capsule with CT trace effect and its preparation process |
| CN1943565B (en) * | 2006-10-24 | 2010-05-26 | 中山大学 | Biological degradable nano medicinal capsule with MRI tracer effect and its preparing method |
| CN104558353A (en) * | 2014-11-04 | 2015-04-29 | 华文蔚 | Method for preparing magnetic polymer microspheres by multiple emulsion method |
-
2003
- 2003-11-11 CN CN 200310113439 patent/CN1276006C/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100457094C (en) * | 2006-03-08 | 2009-02-04 | 中山大学 | Preparing process of biodegradable capsule loading medicine and nano magnetic particle |
| CN100443508C (en) * | 2006-09-28 | 2008-12-17 | 上海交通大学 | Process for preparing functional high molecule composite micro ball with quick magnetic field responsiveness |
| CN1973832B (en) * | 2006-10-24 | 2010-05-12 | 中山大学 | Biodegradable nanometer medicine capsule with CT trace effect and its preparation process |
| CN1943565B (en) * | 2006-10-24 | 2010-05-26 | 中山大学 | Biological degradable nano medicinal capsule with MRI tracer effect and its preparing method |
| CN104558353A (en) * | 2014-11-04 | 2015-04-29 | 华文蔚 | Method for preparing magnetic polymer microspheres by multiple emulsion method |
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|---|---|
| CN1276006C (en) | 2006-09-20 |
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