CN103483601B - Preparation method for polymeric nanometer microsphere - Google Patents
Preparation method for polymeric nanometer microsphere Download PDFInfo
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- CN103483601B CN103483601B CN201310319385.3A CN201310319385A CN103483601B CN 103483601 B CN103483601 B CN 103483601B CN 201310319385 A CN201310319385 A CN 201310319385A CN 103483601 B CN103483601 B CN 103483601B
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- LPNBBFKOUUSUDB-UHFFFAOYSA-N Cc(cc1)ccc1C(O)=O Chemical compound Cc(cc1)ccc1C(O)=O LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 1
- RZOKQIPOABEQAM-UHFFFAOYSA-N Cc(nc1)ccc1C(O)=O Chemical compound Cc(nc1)ccc1C(O)=O RZOKQIPOABEQAM-UHFFFAOYSA-N 0.000 description 1
- HNTZKNJGAFJMHQ-UHFFFAOYSA-N Cc1ncccc1C(O)=O Chemical compound Cc1ncccc1C(O)=O HNTZKNJGAFJMHQ-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a preparation method for a polymeric nanometer microsphere. The preparation method comprises the following steps: with trithiocarbonate represented by a formula (I) as a chain transferring agent, carrying out RAFT living polymerization to synthesize a gradient copolymer; dissolving the gradient copolymer in an organic solvent and then adding water to form a polymeric micelle solution, wherein the organic solvent and water are intermiscible; and adding the polymeric micelle solution into an aqueous solution of an inorganic salt and carrying out solvent displacement so as to obtain the polymeric nanometer microsphere, wherein a volume ratio of the polymeric micelle solution to the aqueous solution of the inorganic salt is 0.01 to 1. The polymeric nanometer microsphere prepared by using the method has good stability and uniformity, narrow particle size distribution and photoresponse characteristics and the surface of the microsphere is rich in carboxyl groups, thereby facilitating application of the polymeric nanometer microsphere as a good carrier for drugs and proteins. Moreover, the method provided by the invention has the advantages of simpleness, easy practicability, good repeatability, low energy consumption, extensive applicability and easy realization of industrialization.
Description
Technical field
The present invention relates to polymeric material field, particularly the preparation method of polymer nano-microspheres in.
Background technology
Polymer nano-microspheres refers to that size is less than 100nm, the polymer microballoon be evenly distributed.In recent years because polymer nano-microspheres is in electron device engineering, especially nanosecond medical science is as the using value in the field such as pharmaceutical carrier, immunodiagnosis for biomedical engineering, and its preparation method receives much concern.
It is the common approach preparing polymer microballoon by monomer polymerization.But nanosecond medical science a lot of field general requirement nano microsphere system not containing tensio-active agent and so on small molecular weight impurity and particle diameter is less than 100nm.Emulsifier-free emulsion polymerization and precipitation polymerization are easily combined into macroparticle due to the primary particle poor stability of initial reaction stage, are therefore generally used for the mono-dispersion microballoon that preparation size is greater than 100 nanometers.Although letex polymerization is widely used in prepare Nano microsphere, but inevitably containing the complete monomer of unreacted and excessive emulsifying agent in system, aftertreatment is loaded down with trivial details.The patent No. is the emulsion polymerisation process that the Chinese patent of CN101703914A discloses a kind of improvement, but still unavoidably needs in system to add tensio-active agent.Complicated and the technique of the process involved by polymer microballoon preparing narrow dispersion additionally by monomer polymerization is difficult to control.
To be the U.S. Patent Publication of US005133908A and US005118528A a kind of by the polymkeric substance synthesized for the patent No. by dissolving--and the technique of nanoprecipitation prepares the method for Nano microsphere.Do not need to add tensio-active agent for microballoon by nanoprecipitation legal system, and it is simple for process, energy consumption is low, suitability is wide.In the organic solvent that polymer dissolution is normally dissolved each other with water in by its preparation process, then polymers soln is added to the water then to vapor away organic solvent or polymers soln is dialysed in water and carrys out replacement solvent.Due to the change of solvent property in solvent exchange process, the configuration of polymkeric substance is collapsed into a solid bead by random coil thus realizes the preparation of Nano microsphere.But research shows (Soft Matter, 2011,7,1581-1588; Langmuir, 2009,25,1970-1979) owing to lacking enough stability, the standby Nano microsphere of nanoprecipitation legal system generally can only exist by the very narrow regional stability of in " solvent-precipitation agent-polymkeric substance " ternary phase diagrams one.Therefore in nanoprecipitation legal system is for the detailed process of Nano microsphere, Macrodilution is needed, especially for the solid content very low (being less than 0.1%) that the polymkeric substance that polystyrene or polymethylmethacrylate are very hydrophobic is like this final, and distribution of sizes is quite uneven.
Except the size of Nano microsphere, homogeneity, the functional of Nano microsphere is also a very important aspect.In bio-medical field, usually need microsphere surface functionalization, thus give Nano microsphere some special character, as just can be used for pharmaceutical carrier, biosensor and protein synthesis analysis by carboxylated for microsphere surface.And the design of initiator when generally all needing to relate to Nano microsphere is surface-functionalized the chemical reaction or polymerization that surface modification is correlated with, preparation process is difficult to control, post-processing step is loaded down with trivial details, but is difficult to again only by nanoprecipitation method the Nano microsphere obtaining functionalisation of surfaces.
Summary of the invention
The technical problem that the present invention solves is the preparation method providing a kind of polymer nano-microspheres, the polymer nano-microspheres narrow diameter distribution that the method obtains, good stability and have response characteristics to light.
The invention discloses a kind of preparation method of polymer nano-microspheres, comprise the following steps:
(A) select the trithiocarbonate class shown in formula (I) as chain-transfer agent, by RAFT living polymerization composition gradient multipolymer;
(B) described gradient copolymer is dissolved in organic solvent, then add water, form polymer micelle solution; Described organic solvent and water dissolve each other;
(C) described polymer micelle solution is joined in the aqueous solution of inorganic salt, by solvent exchange, obtain polymer nano-microspheres; The volume ratio of the aqueous solution of described polymer micelle solution and inorganic salt is 0.01 ~ 1;
Wherein, Z is the group of end with carboxyl, and R is leavings group.
Preferably, in described step (A), the monomer of described RAFT living polymerization comprises the first monomer and second comonomer, and described first monomer is vinylbenzene or its derivative, and second comonomer is the compound of esters of acrylic acid, methyl acrylic ester or vinyl pyridine class.
Preferably, in described step (B), described organic solvent is one or more in acetone, the alcohol of C1 ~ C3, the organic acid of C1 ~ C8, tetrahydrofuran (THF), dioxane and DMF.
Preferably, in described step (B), described gradient copolymer mass body volume concentrations is in organic solvent 0.01% ~ 5%.
Preferably, in described step (B), in described polymer micelle solution, the mass percentage of water is 0.1% ~ 50%.
Preferably, in described step (C), described inorganic salt are sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate.
Preferably, in described step (C), the mass percentage concentration of described inorganic salt is 1 × 10
-3~ 5mmol/L.
Preferably, in described step (C), the mode of described displacement is volatilization or dialysis.
Preferably, in described step (A), described Z be carboxylic propyl group, carboxymethyl, propyloic, carboxylic butyl, phenylformic acid benzyl,
Preferably, in described step (A), described R is benzyl, the tertiary butyl ,-CH
2cN ,-C (CH
3)
2cH
2c (CH
3)
2,
Compared with prior art, the present invention is by RAFT living polymerization, trithiocarbonate class with carboxyl is connected to copolymerization end, again in the mixed solvent of organic solvent and water by this copolymer micelle, then copolymer micelle is formed nanoprecipitation in water, finally organic solvent being removed, making the surface of the carboxyl of multipolymer end all by urging the trithiocarbonate class with carboxyl to be connected to Nano microsphere, form polymer nano-microspheres.Because carboxyl has electrostatic repulsion, it is distributed in the surface of polymer micelle, this improves stability and the homogeneity of polymer nano-microspheres, its narrow diameter distribution.Due to a large amount of existence of carboxyl, be conducive to the good carrier of polymer nano-microspheres as medicine and protein.Secondly, because the surface of polymer nano-microspheres is also with C-S key, C-S key can rupture under UV-irradiation, and the stability of polymer nano-microspheres in aqueous dispersion reduces, form precipitation, therefore described polymer nano-microspheres has response characteristics to light to UV-light.3rd, the method for the invention does not need to add stablizer, and obtain polymer nano-microspheres content in dispersion system higher, quality volumn concentration can reach 0.01% ~ 5%, and monodispersity is also better than the conventional nano precipitator method.In addition, the method for the invention is simple, reproducible, and energy consumption is low, and suitability is wide, is easy to realize industrialization.
Accompanying drawing explanation
Fig. 1 is the schema that the present invention prepares polymer nano-microspheres;
Fig. 2 is the scanning electron microscope (SEM) photograph of polymer nano-microspheres prepared by the embodiment of the present invention 1;
Fig. 3 is the grain size distribution of polymer nano-microspheres prepared by the embodiment of the present invention 1;
Fig. 4 is the photoresponse figure of the polymer nano-microspheres of preparation in the embodiment of the present invention 3.
Embodiment
In order to understand the present invention further, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these describe just for further illustrating the features and advantages of the present invention, instead of limiting to the claimed invention.
The embodiment of the invention discloses a kind of preparation method of polymer nano-microspheres, comprise the following steps:
(A) select the trithiocarbonic acid ester compound shown in formula (I) as chain-transfer agent, by RAFT living polymerization composition gradient multipolymer;
(B) described gradient copolymer is dissolved in organic solvent, then add water, form polymer micelle solution; Described organic solvent and water dissolve each other;
(C) described polymer micelle solution is joined in the aqueous solution of inorganic salt, by solvent exchange, obtain polymer nano-microspheres; The volume ratio of the aqueous solution of described polymer micelle solution and inorganic salt is 0.01 ~ 1;
Wherein, Z is the group of end with carboxyl, and R is leavings group.
The present invention takes full advantage of the convenience that reversible addion-fragmentation chain transfer polymerization (RAFT) reacts, carboxyl is introduced the end of gradient copolymer, again in the mixed solvent of organic solvent and water by this copolymer micelle, then copolymer micelle is formed nanoprecipitation in water, finally organic solvent is removed, make the carboxyl of multipolymer end all by being connected to the surface of Nano microsphere with the trithiocarbonate class of carboxyl, the aqueous dispersion of the polymer nano-microspheres obtained.Described polymer nano-microspheres is the polymer nano-microspheres of a kind of photoresponse and functionalisation of surfaces.Detailed process is the schema that the present invention prepares polymer nano-microspheres see Fig. 1, Fig. 1.
In the present invention, first select the trithiocarbonate class shown in formula (I) as chain-transfer agent, by RAFT living polymerization composition gradient multipolymer.The monomer of described RAFT living polymerization comprises the first monomer and second comonomer, described first monomer is preferably vinylbenzene or derivatives thereof, be more preferably vinylbenzene, second comonomer is preferably acrylate, the compound of methacrylic ester or vinyl pyridine class, be more preferably vinylformic acid, methyl acrylate, ethyl propenoate, n-butyl acrylate, isobutyl acrylate, sec-butyl acrylate, n-propyl, cyclohexyl acrylate, 2-Hydroxy ethyl acrylate, 2-hydroxypropyl acrylate, methacrylic acid, methyl methacrylate, β-dimethyl-aminoethylmethacrylate, n-BMA, Propenoic acid, 2-methyl, isobutyl ester, the secondary butyl ester of methacrylic acid, n propyl methacrylate, 2-vinyl pyridine or 4-vinylpridine, most preferably be methyl acrylate, butyl methacrylate or 4-vinylpridine.Described first monomer and second comonomer can arbitrary combination, by RAFT living polymerization, obtain gradient copolymer.The condition of the present invention to described RAFT living polymerization is not particularly limited, and carries out according to condition well known to those skilled in the art, can thermal initiation or initiator initiation.Trithiocarbonate class described in described formula (I) is chain-transfer agent, i.e. RAFT reagent.Z described in formula (I) is the group of end with carboxyl, be preferably carboxylic propyl group, carboxymethyl, propyloic, carboxylic butyl, phenylformic acid benzyl,
described R is leavings group, the group being namely connected with S atom, can sloughing through RAFT living polymerization, is preferably benzyl, the tertiary butyl ,-CH
2cN ,-C (CH
3)
2cH
2c (CH
3)
2,
Described RAFT living polymerization composition gradient multipolymer is one kettle way, and technique is simple, more economically.Through RAFT living polymerization, the part of the trithiocarbonate class shown in formula I except leavings group is all connected to gradient copolymer end, makes gradient copolymer end with carboxyl and C-S key.
In the present invention, after obtaining described gradient copolymer, described gradient copolymer is dissolved in organic solvent, then adds water, form polymer micelle solution.Because the end of gradient copolymer is with carboxyl, carboxyl has wetting ability and electrostatic repulsion, and therefore in the process forming micella, carboxyl is distributed in the surface of polymer micelle.Described organic solvent and water dissolve each other, be preferably acetone, the alcohol of C1 ~ C3, the organic acid of C1 ~ C8, tetrahydrofuran (THF), dioxane and N, one or more in dinethylformamide, be more preferably in acetone, ethanol, acetic acid, tetrahydrofuran (THF), dioxane and DMF one or more.Described gradient copolymer mass body volume concentrations is in organic solvent preferably 0.01% ~ 5%, is more preferably 0.5% ~ 2%.In described polymer micelle solution, the mass percentage of water is preferably 0.1% ~ 50%, is more preferably 5% ~ 20%.
In the present invention, after obtaining polymer micelle, described polymer micelle solution is joined in the aqueous solution of inorganic salt, by solvent exchange, obtains polymer nano-microspheres.The volume ratio of the aqueous solution of described polymer micelle solution and inorganic salt is 0.01 ~ 1, is preferably 0.5 ~ 0.9.By solvent exchange, polymer micelle constantly shrinks formation microballoon, in containing the aqueous solution of inorganic salt, form the aqueous dispersion containing polymer nano-microspheres.In described aqueous dispersion, the quality volumn concentration of polymer nano-microspheres is preferably 0.01% ~ 5%.Described inorganic salt are preferably sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate.The mass percentage concentration of described inorganic salt is preferably 1 × 10
-3~ 5mmol/L.The mode of described displacement is preferably volatilization or dialysis, is more preferably volatilization.
Detect the polymer nano-microspheres obtained, its particle diameter is 20 ~ 80nm, dispersion coefficient PD.I<0.1.
Utilize UV-light to detect the response characteristics to light of described polymer nano-microspheres, in 254 ~ 365nm UV-irradiation after 5 ~ 7 minutes, namely described polymer nano-microspheres gets off from good dispersion state flocculating settling.
Trithiocarbonate class with carboxyl, by RAFT living polymerization, is connected to copolymerization end by the present invention, then by nanoprecipitation method, forms polymer nano-microspheres.Because carboxyl has electrostatic repulsion, it is distributed in the surface of polymer micelle, this improves stability and the homogeneity of polymer nano-microspheres, its narrow diameter distribution.Due to a large amount of existence of carboxyl, be conducive to the good carrier of polymer nano-microspheres as medicine and protein.Secondly, because the surface of polymer nano-microspheres is also with C-S key, C-S key can rupture under UV-irradiation, and the stability of polymer nano-microspheres in aqueous dispersion reduces, form precipitation, therefore described polymer nano-microspheres has response characteristics to light to UV-light.3rd, the method for the invention does not need to add stablizer, and obtain polymer nano-microspheres content in dispersion system higher, quality volumn concentration can reach 0.01% ~ 5%, and monodispersity is also better than the conventional nano precipitator method.In addition, the method for the invention is simple, reproducible, and energy consumption is low, and suitability is wide, is easy to realize industrialization.
In order to understand the present invention further, below in conjunction with embodiment, the preparation method to polymer nano-microspheres provided by the invention is described, and protection scope of the present invention is not limited by the following examples.
Embodiment 1
Nitrogen is passed into after 20 minutes in the reactor of drying, add styrene monomer and RAFT reagent S-1-carboxylic propyl group-S '-benzyl trithiocarbonate, monomer and RAFT reagent mol ratio are 300:1, which kind of catalyzer stirring and dissolving woulds you please clear and definite is once after, reactor is heated to 120 ° of C, react after 12 hours, to be joined in reactor by the methyl methacrylate of styrene monomer 2.5 times of equivalents with syringe pump and carry out copolyreaction, copolyreaction carries out 14 hours.Within first 6 hours, at the uniform velocity inject 8% of methyl methacrylate total amount, then by instantaneous for the methyl methacrylate of 65% injection, within last 8 hours, at the uniform velocity inject the methyl methacrylate of 27%, reaction terminates rear room temperature cooling precipitation, purified polymer.By nucleus magnetic hydrogen spectrum (
1h NMR) and gel permeation chromatography (GPC) gradient copolymer is characterized.The final molecular weight of polymkeric substance is 4.7 ten thousand, and molecular weight distribution is 1.38, and methyl methacrylate content is 43%.
Dissolve synthesizing the styrene/methacrylic acid methyl esters gradient copolymer obtained in acetone, concentration is 0.5%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 8%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 2mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until acetone volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.By scanning electron microscope (SEM) and dynamic light scattering (DLS), this microballoon is characterized.
Fig. 2 is the scanning electron microscope (SEM) photograph of polymer nano-microspheres prepared by the embodiment of the present invention 1, can see the Nano microsphere of regular spherical morphology in Fig. 2 in SEM image.
Fig. 3 is the grain size distribution of polymer nano-microspheres prepared by the embodiment of the present invention 1, and this Nano microsphere size uniform of DLS digital proof in Fig. 3, polydispersity index PD.I=0.011, mean diameter is 45nm.
Embodiment 2
Nitrogen is passed into after 20 minutes in the reactor of drying, add styrene monomer and RAFT reagent S-1-carboxylic propyl group-S '-benzyl trithiocarbonate, monomer and RAFT reagent mol ratio are 300:1, after stirring and dissolving, reactor is heated to 120 ° of C, react after 12 hours, to be joined in reactor by the methyl methacrylate of styrene monomer 2.5 times of equivalents with syringe pump and carry out copolyreaction, copolyreaction carries out 14 hours.Within first 6 hours, at the uniform velocity inject 8% of methyl methacrylate total amount, then by instantaneous for the methyl methacrylate of 65% injection, within last 8 hours, at the uniform velocity inject the methyl methacrylate of 27%, reaction terminates rear room temperature cooling precipitation, purifying, obtains gradient copolymer thing.
Be dissolved in tetrahydrofuran (THF) by described gradient copolymer, concentration is 0.5%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 10%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 2mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until tetrahydrofuran (THF) volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.It is 47nm that dynamic light scattering (DLS) result shows this microballoon mean diameter, and polydispersity index PD.I=0.055, dimensional homogeneity is good.
Embodiment 3
Nitrogen is passed into after 20 minutes in the reactor of drying, add styrene monomer and RAFT reagent S-1-carboxylic propyl group-S '-benzyl trithiocarbonate, monomer and RAFT reagent mol ratio are 300:1, after stirring and dissolving, reactor is heated to 120 ° of C, react after 12 hours, to be joined in reactor by the methyl methacrylate of styrene monomer 2.5 times of equivalents with syringe pump and carry out copolyreaction, copolyreaction carries out 14 hours.Within first 6 hours, at the uniform velocity inject 8% of methyl methacrylate total amount, then by instantaneous for the methyl methacrylate of 65% injection, within last 8 hours, at the uniform velocity inject the methyl methacrylate of 27%, reaction terminates rear room temperature cooling precipitation, purifying, obtains gradient copolymer thing.
Dissolved in acetone by described gradient copolymer, concentration is 1.5%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 6%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 20mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until acetone volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.It is 53nm that dynamic light scattering (DLS) result shows this microballoon mean diameter, and polydispersity index PD.I=0.082, dimensional homogeneity is good.
The photoresponse of embodiment 4 Nano microsphere is tested
By the Nano microsphere solution of preparation in embodiment 3, be configured to the solution that concentration is 5mg/mL, irradiate under 254nm ultraviolet lamp after 7 minutes and observe.Fig. 4 is the photoresponse experiment photo of the polymer nano-microspheres of preparation in enforcement 3.As shown in Figure 4, A is pre-irradiation polymer nano-microspheres solution, for being with the settled solution of blue-opalescent, B is UV-irradiation post-consumer polymer Nano microsphere solution, and become muddy, C is the polymer nano-microspheres solution after standing 2 hours, solution layering, upper strata is clear liquid, and lower floor is flocks.Verify the ultraviolet light response characteristic of this polymer nano-microspheres thus.
Embodiment 5
Nitrogen is passed into after 20 minutes in the reactor of drying, add styrene monomer and RAFT reagent S-1-carboxylic octyl group-S '-tertiary butyl trithiocarbonate, monomer and RAFT reagent mol ratio are 300:1, after stirring and dissolving, reactor is heated to 120 DEG C, react after 12 hours, to be joined in reactor by the methyl acrylate of styrene monomer 3 times of equivalents with syringe pump and carry out copolyreaction, copolyreaction carries out 16 hours.Within first 6 hours, at the uniform velocity inject 8% of methyl acrylate total amount, then by instantaneous for the methyl acrylate of 65% injection, within last 10 hours, at the uniform velocity inject the methyl acrylate of 27%, reaction terminates rear room temperature cooling precipitation, purified polymer.By nucleus magnetic hydrogen spectrum (
1hNMR) and gel permeation chromatography (GPC) gradient copolymer is characterized.The final molecular weight of polymkeric substance is 5.3 ten thousand, and molecular weight distribution is 1.22, and methyl acrylate content is 50%.
Dissolve synthesizing the styrene/acrylic methyl esters gradient copolymer obtained in acetone, concentration is 0.5%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 12%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 2mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until acetone volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.Characterizing microballoon mean diameter by dynamic light scattering (DLS) is 50nm, and polydispersity index PD.I=0.042, dimensional homogeneity is good.
Embodiment 6
Nitrogen is passed into after 20 minutes in the reactor of drying, add styrene monomer and RAFT reagent S-1-carboxylic propyl group-S '-isopropyl itrile group trithiocarbonate, monomer and RAFT reagent mol ratio are 300:1, after stirring and dissolving, reactor is heated to 120 ° of C, react after 12 hours, the butyl methacrylate of styrene monomer 2 times of equivalents to be joined in reactor with syringe pump and carry out copolyreaction, copolyreaction carries out 12 hours.Within first 4 hours, at the uniform velocity inject 10% of butyl methacrylate total amount, then by instantaneous for the butyl methacrylate of 65% injection, within last 8 hours, at the uniform velocity inject the butyl methacrylate of 25%, reaction terminates rear room temperature cooling precipitation, purified polymer.By nucleus magnetic hydrogen spectrum (
1h NMR) and gel permeation chromatography (GPC) gradient copolymer is characterized.The final molecular weight of polymkeric substance is 4.2 ten thousand, and molecular weight distribution is 1.28, and butyl methacrylate content is 39%.
Dissolve synthesizing the styrene/methacrylic acid butyl ester gradient copolymer obtained in acetone, concentration is 0.5%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 6%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 2mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until acetone volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.Characterizing microballoon mean diameter by dynamic light scattering (DLS) is 50nm, and polydispersity index PD.I=0.042, dimensional homogeneity is good.
Embodiment 7
Nitrogen is passed into after 20 minutes in the reactor of drying, add initiator Diisopropyl azodicarboxylate (AIBN), styrene monomer and RAFT reagent S-1-carboxylic propyl group-S '-isopropyl itrile group trithiocarbonate, monomer, RAFT reagent and AIBN mol ratio are 7500:5:1, after stirring and dissolving, reactor is heated to 60 ° of C, react after 12 hours, to be joined in reactor by the 4-vinylpridine of styrene monomer 2.5 times of equivalents with syringe pump and carry out copolyreaction, copolyreaction carries out 15 hours.Within first 6 hours, at the uniform velocity inject 10% of 4-vinylpridine total amount, then by instantaneous for the 4-vinylpridine of 65% injection, within last 9 hours, at the uniform velocity inject the 4-vinylpridine of 25%, reaction terminates rear room temperature cooling precipitation, purified polymer.By nucleus magnetic hydrogen spectrum (
1h NMR) and gel permeation chromatography (GPC) gradient copolymer is characterized.The final molecular weight of polymkeric substance is 6.1 ten thousand, and molecular weight distribution is 1.32, and 4-vinylpridine is 45%.
Be dissolved in tetrahydrofuran (THF) by synthesizing the vinylbenzene/4-vinylpridine gradient copolymer obtained, concentration is 0.5%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 5%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 2mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until acetone volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.Characterizing microballoon mean diameter by dynamic light scattering (DLS) is 60nm, and polydispersity index PD.I=0.059, dimensional homogeneity is good.
Embodiment 8
In the reactor of drying, pass into nitrogen after 20 minutes, add styrene monomer and RAFT reagent, the Z group in described RAFT reagent is
r is
styrene monomer and catalyst molar ratio are 300:1, after stirring and dissolving, reactor is heated to 120 ° of C, reacts after 12 hours, to be joined in reactor by the methyl methacrylate of styrene monomer 2.5 times of equivalents with syringe pump and carry out copolyreaction, copolyreaction carries out 14 hours.Within first 6 hours, at the uniform velocity inject 8% of 2-hydroxypropyl acrylate total amount, then by instantaneous for the 2-hydroxypropyl acrylate of 65% injection, within last 8 hours, at the uniform velocity inject the 2-hydroxypropyl acrylate of 27%, reaction terminates rear room temperature cooling precipitation, purifying, obtains gradient copolymer.
Dissolved in acetone by described gradient copolymer, concentration is 1%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 6%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 2mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until acetone volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.It is 53nm that dynamic light scattering (DLS) result shows this microballoon mean diameter, and polydispersity index PD.I=0.072, dimensional homogeneity is good.
Embodiment 9
In the reactor of drying, pass into nitrogen after 20 minutes, add styrene monomer and RAFT reagent, the Z group in described RAFT reagent is
r is
styrene monomer and catalyst molar ratio are 300:1, after stirring and dissolving, reactor is heated to 120 ° of C, reacts after 12 hours, to be joined in reactor by the methyl methacrylate of styrene monomer 2.5 times of equivalents with syringe pump and carry out copolyreaction, copolyreaction carries out 14 hours.Within first 6 hours, at the uniform velocity inject 8% of vinylformic acid total amount, then by instantaneous for the vinylformic acid of 65% injection, within last 8 hours, at the uniform velocity inject the vinylformic acid of 27%, reaction terminates rear room temperature cooling precipitation, purifying, obtains gradient copolymer.
Be dissolved in tetrahydrofuran (THF) by described gradient copolymer, concentration is 2%(w/v), then dropwise add deionized water under agitation, stirring velocity is 300rpm, and final water-content is 6%(w/w).
Above-mentioned gradient copolymer micellar solution joined with vigorous stirring in the sodium bicarbonate aqueous solution of equivalent 20mmol/L, stirring velocity is 600rpm.Uncovered continuation stirring 48 hours, until acetone volatilizees completely can obtain polymer nano-microspheres aqueous dispersion.It is 53nm that dynamic light scattering (DLS) result shows this microballoon mean diameter, and polydispersity index PD.I=0.057, dimensional homogeneity is good.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.
To the above-mentioned explanation of the disclosed embodiments, professional and technical personnel in the field are realized or uses the present invention.To be apparent for those skilled in the art to the multiple amendment of these embodiments, General Principle as defined herein can without departing from the spirit or scope of the present invention, realize in other embodiments.Therefore, the present invention can not be restricted to these embodiments shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (9)
1. a preparation method for polymer nano-microspheres, comprises the following steps:
(A) select the trithiocarbonic acid ester compound shown in formula (I) as chain-transfer agent, by RAFT living polymerization composition gradient multipolymer; The monomer of described RAFT living polymerization comprises the first monomer and second comonomer, and described first monomer is vinylbenzene or its derivative, and second comonomer is the compound of esters of acrylic acid, methyl acrylic ester or vinyl pyridine class;
(B) described gradient copolymer is dissolved in organic solvent, then add water, form polymer micelle solution; Described organic solvent and water dissolve each other;
(C) described polymer micelle solution is joined in the aqueous solution of inorganic salt, by solvent exchange, obtain polymer nano-microspheres; The volume ratio of the aqueous solution of described polymer micelle solution and inorganic salt is 0.01 ~ 1;
Wherein, Z is the group of end with carboxyl, and R is leavings group.
2. preparation method according to claim 1, it is characterized in that, in described step (B), described organic solvent is one or more in acetone, the alcohol of C1 ~ C3, the organic acid of C1 ~ C8, tetrahydrofuran (THF), dioxane and DMF.
3. preparation method according to claim 1, is characterized in that, in described step (B), described gradient copolymer mass body volume concentrations is in organic solvent 0.01% ~ 5%.
4. preparation method according to claim 1, is characterized in that, in described step (B), in described polymer micelle solution, the mass percentage of water is 0.1% ~ 50%.
5. preparation method according to claim 1, is characterized in that, in described step (C), described inorganic salt are sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate.
6. preparation method according to claim 5, is characterized in that, in described step (C), the mass percentage concentration of described inorganic salt is 1 × 10
-3~ 5mmol/L.
7. preparation method according to claim 1, is characterized in that, in described step (C), the mode of described displacement is volatilization or dialysis.
8. preparation method according to claim 1, is characterized in that, in described step (A), described Z be carboxylic propyl group, carboxymethyl, propyloic, carboxylic butyl, phenylformic acid benzyl,
9. preparation method according to claim 1, is characterized in that, in described step (A), described R is benzyl, the tertiary butyl ,-CH
2cN ,-C (CH
3)
2cH
2c (CH
3)
2,
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