CN114805863A - Polymer microsphere and preparation method thereof - Google Patents
Polymer microsphere and preparation method thereof Download PDFInfo
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- CN114805863A CN114805863A CN202210601374.3A CN202210601374A CN114805863A CN 114805863 A CN114805863 A CN 114805863A CN 202210601374 A CN202210601374 A CN 202210601374A CN 114805863 A CN114805863 A CN 114805863A
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- 229920000642 polymer Polymers 0.000 title claims abstract description 120
- 239000004005 microsphere Substances 0.000 title claims abstract description 94
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000002245 particle Substances 0.000 claims abstract description 36
- 238000009826 distribution Methods 0.000 claims abstract description 27
- 239000006185 dispersion Substances 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 230000005686 electrostatic field Effects 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- -1 poly (arylene sulfide Chemical compound 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 10
- 230000005611 electricity Effects 0.000 claims description 8
- 230000003068 static effect Effects 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 239000002270 dispersing agent Substances 0.000 claims description 7
- 239000002612 dispersion medium Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001125 extrusion Methods 0.000 claims description 6
- 239000011521 glass Substances 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000012360 testing method Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 230000010355 oscillation Effects 0.000 claims description 4
- 230000000007 visual effect Effects 0.000 claims description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 53
- 229920000747 poly(lactic acid) Polymers 0.000 description 19
- 239000004626 polylactic acid Substances 0.000 description 19
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 239000008213 purified water Substances 0.000 description 6
- 238000002791 soaking Methods 0.000 description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000001788 irregular Effects 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910001514 alkali metal chloride Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000004020 conductor Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910001963 alkali metal nitrate Inorganic materials 0.000 description 1
- 229910052936 alkali metal sulfate Inorganic materials 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000010041 electrostatic spinning Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/10—Energy storage using batteries
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
Abstract
The invention discloses a polymer microsphere and a preparation method thereof. The distribution coefficient of the grain diameter of the polymer microsphere is less than or equal to 0.8; the structure of the repeating unit of the polymer is shown as the formula (I). The polymer microsphere has narrow particle size distribution, low coefficient of variation and regular spheroidal structure.
Description
Technical Field
The invention relates to a polymer microsphere and a preparation method thereof.
Background
Polylactic acid is a polyester polymer obtained by polymerizing lactic acid serving as a main raw material, and is a novel biodegradable material. The polylactic acid microspheres mean that polylactic acid exists in the form of microspheres. The polylactic acid microspheres can be used as drug carriers and have wide research and application in the field of drug controlled release. The polylactic acid microspheres are used as a drug carrier, and can control the release speed of the drug so as to achieve the effects of long-acting slow release, increased drug targeting, reduced toxic and side effects and improved curative effect.
CN108315828A discloses a method for preparing polylactic acid microspheres. Drying the high molecular polymer, placing the dried high molecular polymer in a metal needle cylinder, heating to convert the high molecular polymer from a solid state into a molten liquid state, adjusting spinning voltage and spinning distance, and spinning. The polylactic acid microspheres prepared by the method are mutually adhered and have irregular shapes.
CN104945640A discloses a preparation method of polylactic acid microspheres. Dissolving polylactic acid into a mixed organic solvent to obtain a polylactic acid solution; preparing a string bead-shaped polylactic acid fiber membrane from a polylactic acid solution by using an electrostatic spinning technology; and soaking the obtained beaded polylactic acid fiber membrane in an alkaline solution to obtain the polylactic acid microspheres. The polylactic acid microspheres obtained by the method have irregular structures and wide particle size distribution.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a polymer microsphere with a narrow particle size distribution and a regular spheroidal structure. Furthermore, the polymer microspheres of the present invention have a small distribution coefficient and a small coefficient of variation in particle size. The invention also aims to provide a preparation method of the polymer microspheres, and the polymer microspheres prepared by the method have narrow particle size distribution and regular spheroidal structures. Furthermore, the polymer microspheres prepared by the method have small distribution coefficient and variation coefficient of particle size.
In one aspect, the invention provides a polymer microsphere, wherein the distribution coefficient of the particle size of the polymer microsphere is less than or equal to 0.8;
wherein, the distribution coefficient is obtained by adopting the following method:
testing by a laser particle sizer to obtain D of the polymer microsphere 10 、D 50 And D 90 And calculating according to the following formula to obtain the distribution coefficient:
coefficient of distribution ═ D 90 -D 10 )/D 50 ；
Wherein the structure of the repeating unit of the polymer is shown as the formula (I):
wherein R is 1 Selected from H or alkyl of C1-C6.
According to the polymer microsphere, the variation coefficient of the particle size of the polymer microsphere is preferably less than or equal to 15 percent;
wherein the variation coefficient of the particle size of the polymer microsphere is obtained by the following method:
placing the mixture of the polymer microspheres and water in a vortex oscillator to shake so that the polymer microspheres are uniformly distributed in the water to form a suspension; dropping the suspension on a glass slide under the oscillation condition, measuring the diameter of the polymer microspheres in the visual field under a video microscope, measuring 300-500 in an accumulated manner, calculating the average value and the standard deviation of the diameters of the polymer microspheres, and calculating the coefficient of variation of the diameters of the polymers according to the following formula:
coefficient of variation ═ (standard deviation/average) × 100%.
The polymer microspheres according to the present invention, preferably, said R 1 Is methyl.
The polymeric microspheres according to the present invention, preferably D of said polymeric microspheres 50 10 to 200 μm, D 10 5 to 190 μm, D 90 15 to 210 μm.
In another aspect, the present invention provides a method for preparing the above polymeric microspheres, comprising the steps of:
(1) forming the polymer solution into liquid drops under the action of an electrostatic field;
(2) allowing the liquid drops to enter a dispersion solution under stirring condition under the action of an electrostatic field to obtain polymer microspheres;
wherein the dispersing solution contains a dispersing agent with a repeating unit structure as shown in a formula (II):
wherein R is 2 Selected from H or alkyl of C1-C6.
According to the preparation method of the invention, preferably, the dispersion solution further contains a dispersion medium, and the mass volume ratio of the dispersing agent to the dispersion medium is 0.1-10 g/L.
According to the preparation method, the dispersion solution is preferably stirred by a stirring device, and the rotating speed of the stirring device is 50-2000 r/min.
According to the preparation method of the invention, preferably, the polymer solution comprises a polymer and a solvent, the mass volume ratio of the polymer to the solvent is 10-100 g/L, and the solvent is selected from one or more of dichloromethane, trichloromethane, acetone, tetrahydrofuran and hexafluoroisopropanol.
According to the production method of the present invention, preferably, the polymer solution is extruded through the end opening of the tube to form droplets under the action of the electrostatic field;
wherein the extrusion flow rate of the polymer solution is 0.01-0.08 mL/s, the inner diameter of the end opening of the tubular object is 0.06-1.19 mm, the distance between the end opening of the tubular object and the liquid surface of the dispersion solution is 1-15 cm, and the voltage of the electrostatic field is 1-30 kV.
According to the production method of the present invention, preferably, the dispersion solution is placed in a conductive container;
and connecting the positive electrode of the high-voltage static electricity generating device with the tubular object, and connecting the grounding wire of the high-voltage static electricity generating device with the conductive container so as to form an electrostatic field.
The polymer solution is delivered to the end of the tube at a low flow rate and a high voltage is applied to the end of the tube. Since the electrostatic charge is concentrated on the surface of the liquid suspended at the end opening of the tube, the mutual repulsion of the same charges elongates the liquid, which becomes conical at a suitable voltage and extrusion flow, and the liquid stream is generated at the tip of the cone and breaks up into numerous fine droplets. The liquid drops enter the dispersion solution, and the irregular liquid drops gradually recover to be spherical under the influence of the surface tension of the irregular liquid drops, so that the polymer microspheres with narrow particle size distribution and regular structures are obtained. In addition, the method can obtain the polymer microspheres with controllable particle size and low dispersion.
Drawings
FIG. 1 is a scanning electron micrograph of the polymeric microspheres obtained in example 1 at 80 times magnification.
FIG. 2 is a scanning electron micrograph of the polymeric microspheres obtained in example 1 at 200 times magnification.
FIG. 3 is a scanning electron micrograph of the polymeric microspheres obtained in example 1 magnified 800 times.
Detailed Description
The present invention will be further described with reference to the following specific examples, but the scope of the present invention is not limited thereto.
D 50 The particle size is expressed when the cumulative percentage of the particle size distribution of the polymer microspheres reaches 50%. D 50 Also referred to as "median diameter" or "median particle diameter".
D 90 The particle size is expressed when the cumulative percentage of the particle size distribution of the polymer microspheres reaches 90%.
D 10 The particle size is expressed when the cumulative percentage of the particle size distribution of the polymer microspheres reaches 10%.
The Coefficient of Variation (CV) is a statistic that measures the degree of Variation of each observed value.
< polymeric microspheres >
The distribution coefficient of the grain diameter of the polymer microsphere is less than or equal to 0.8. The structure of the repeating unit of the polymer is shown as the formula (I):
in the invention, the particle size dispersion coefficient is less than or equal to 0.8; preferably, the particle size dispersion coefficient is less than or equal to 0.5; more preferably, the particle size dispersion coefficient is 0.25 or less. The particle size dispersion coefficient can be more than or equal to 0.1. In some embodiments, the particle size dispersion factor is ≧ 0.2. The particle size dispersion coefficient is obtained by the following method:
testing by a laser particle sizer to obtain D of the polymer microsphere 10 、D 50 And D 90 And calculating according to the following formula to obtain the distribution coefficient:
coefficient of distribution ═ D 90 -D 10 )/D 50 ；
The variation coefficient of the grain diameter of the polymer microsphere is less than or equal to 15 percent; preferably, the coefficient of variation is less than or equal to 10%; more preferably, the coefficient of variation is 5.5% or less. The coefficient of variation can be more than or equal to 1%. In certain embodiments, the coefficient of variation is greater than or equal to 3%. The variation coefficient of the particle size of the polymer microsphere is obtained by the following method:
placing the mixture of the polymer microspheres and water in a vortex oscillator to shake so that the polymer microspheres are uniformly distributed in the water to form a suspension; dropping the suspension on a glass slide under the oscillation condition, measuring the diameter of the polymer microspheres in the visual field under a video microscope, measuring 300-500 in an accumulated manner, calculating the average value and the standard deviation of the diameters of the polymer microspheres, and calculating the coefficient of variation of the diameters of the polymers according to the following formula:
coefficient of variation ═ 100% x (standard deviation/mean).
The smaller the distribution coefficient and the smaller the variation coefficient, the better the uniformity of the particle size.
In the formula (I), R 1 Selected from H or alkyl of C1-C6. Preferably, R 1 Is selected from alkyl of C1-C3. More preferably, R 1 Is a methyl group. The alkyl group may be a straight chain alkyl group or a branched chain alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, 1-methyl-propyl, 2-methyl-propyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 1-ethyl-propyl, 2-ethyl-propyl, hexyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1-ethyl-butyl, 2-ethyl-butyl, 3-ethyl-butyl. According to one embodiment of the invention, the polymer is polylactic acid.
The number average molecular weight of the polymer can be 1000-500000 Da; preferably 10000-150000 Da; more preferably 50000-100000 Da.
The polymer microspheres of the present invention are spherical or spheroidal. The polymeric microspheres of the present invention are not pie-shaped or irregularly elliptical.
D of Polymer microspheres of the invention 50 10 to 200 μm. In certain embodiments, D 50 Is 40 to 50 μm. In other embodiments, D 50 Is 110 to 140 μm. D of Polymer microspheres 10 5 to 190 μm. In certain embodiments, D 10 Is 30 to 50 μm. In other embodiments, D 10 Is 100 to 120 μm. D of Polymer microspheres 90 15 to 210 μm. In certain embodiments, D 90 45 to 60 μm. In other embodiments, D 90 130 to 150 μm.
< preparation method of Polymer microspheres >
The preparation method of the polymer microsphere comprises the following steps: (1) a step of forming droplets; and (2) a step of forming polymer microspheres.
Step of forming liquid droplet
The polymer solution is formed into liquid drops under the action of an electrostatic field.
The polymer solution of the present invention comprises a polymer and a solvent. In certain embodiments, the polymer solution is comprised of a polymer and a solvent. The specific structure of the polymer is as described above. The solvent may be selected from one or more of dichloromethane, trichloromethane, acetone, tetrahydrofuran or hexafluoroisopropanol. Preferably, the solvent is selected from one or more of dichloromethane or trichloromethane. More preferably, the solvent is dichloromethane. The mass volume ratio of the polymer to the solvent in the polymer solution is 10-100 g/L; preferably 20-80 g/L; more preferably 40 to-60 g/L. The polymer may be added to the solvent and stirred to form a polymer solution. This enables the polymer solution to have appropriate viscosity and surface tension, facilitating the formation of polymer microspheres.
In certain embodiments, the polymer solution is extruded through an end opening of the tube, and the polymer solution extruded from the end opening forms droplets under the influence of an electrostatic field. Examples of tubes include, but are not limited to, needles, capillaries, and the like. The tube of the present invention is formed of a conductive material so that an electrostatic field can be formed. According to one embodiment of the invention, the tube is a needle. The needle may be a needle of a microsyringe. The inner diameter of the end opening of the tubular object can be 0.06-1.19 mm.
The voltage of the electrostatic field can be 1-30 kV; preferably 2-10 kV; more preferably 2-4 kV. According to one embodiment of the present invention, the tube is connected to a positive electrode of a high voltage static electricity generating device, and a ground line of the high voltage static electricity generating device is connected to a conductive container containing the dispersion solution, thereby forming an electrostatic field. The high-voltage static electricity generating device can be a high-voltage static electricity generator. Such a voltage is advantageous for forming uniform droplets of the polymer solution.
The extrusion flow rate of the polymer solution is 0.01-0.08 mL/s; preferably 0.03-0.06 mL/s. The extrusion flow rate can be controlled by a syringe pump. According to one embodiment of the invention, the flow rate of the polymer solution extruded from the needle is controlled by a micro-syringe pump.
The distance between the opening at the end part of the tubular object and the liquid level of the dispersion solution is 1-15 cm; preferably 2-10 cm; more preferably 2 to 4 cm. This helps to form relatively uniform droplets.
Step of Forming Polymer microspheres
The liquid drops enter into the dispersion solution under the action of an electrostatic field to obtain the polymer microspheres.
The dispersion liquid contains a dispersant and a dispersion medium, wherein the structure of the repeating unit is shown as the formula (II):
in the formula (II), R 2 Selected from H or alkyl of C1-C6. Preferably, R 2 Selected from H or alkyl of C1-C3. More preferably, R 2 Is hydrogen. The alkyl group may be a straight chain alkyl group or a branched chain alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, 1-methyl-propyl, 2-methyl-propyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 1-ethyl-propyl, 2-ethyl-propyl, hexyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1-ethyl-butyl, 2-ethyl-butyl, 3-ethyl-butyl. According to one embodiment of the present invention, the polymer having the repeating unit structure represented by formula (II) is polyvinyl alcohol. The number average molecular weight of the polymer containing the repeating unit structure shown in the formula (II) can be 25000-220000 Da; preferably 25000 to-150000 Da; more preferably 25000 to 100000 Da. This helps to form polymeric microspheres with a uniform particle size distribution.
The dispersion medium of the present invention may be water. The mass volume ratio of the dispersing agent to the dispersing medium can be 0.1-10 g/L; preferably 1-8 g/L; more preferably 3 to 6 g/L. This helps to form polymer microparticles of uniform particle size.
The dispersion solution of the present invention may further include an alkali metal salt. In certain embodiments, the dispersion solution is comprised of a dispersant having a repeating unit structure as shown in formula (II), an alkali metal salt, and a dispersion medium. The alkali metal salt may be selected from one or more of alkali metal sulfate, alkali metal chloride or alkali metal nitrate; preferably, the alkali metal salt is an alkali metal chloride. The alkali metal element in the alkali metal salt can be selected from one or more of lithium, sodium and potassium; preferably, the alkali metal element in the alkali metal salt is sodium. This can increase the conductivity of the dispersion solution.
The dispersion solution of the present invention is placed in a conductive container. The conductive container may be a container made of a conductive material capable of containing a dispersion solution. According to one embodiment of the invention, the conductive container is a stainless steel beaker.
The dispersion solution is preferably a dispersion solution in a stirred state. The rotating speed of a device for stirring the dispersion solution can be 50-2000 r/min; preferably 400-120 r/min; more preferably 600 to 900 r/min. The means for stirring the dispersion solution may be a magnetic stirrer or mechanical stirring.
The droplets form spheres in the dispersion solution; shaping the spherical object to obtain a shaped spherical object; removing impurities on the surface of the shaped ball, and drying to obtain the polymer microsphere.
And volatilizing the solvent in the ball to shape the ball. The dispersion solution may be continuously stirred to volatilize the solvent.
The impurities on the surface of the shaped ball-shaped object can be removed by adopting a cleaning and soaking mode. The cleaning and soaking can be repeated for a plurality of times, for example, 3-5 times. The solvent used for washing and soaking may be water.
The drying may be freeze vacuum drying.
The following raw materials are introduced:
the number average molecular weight of the polylactic acid is: 50000-100000 Da.
The number average molecular weight of the polyvinyl alcohol is: 25000 to 100000 Da.
The test method is described below:
d of Polymer microspheres 50 、D 10 And D 90 ：
Taking a proper amount of polymer microspheres, adding 50mL of purified water, starting the stirring function of a circulating sample injector of a laser particle size analyzer (LS609, Europe and America Instrument Co., Ltd.), uniformly dispersing the polymer microspheres in the purified water, setting parameters such as refractive index of the polymer and the like, and starting the test. Checking the D of the polymer microspheres according to the test report 50 、D 10 And D 90 。
The distribution coefficient of the diameters of the polymer microspheres is calculated by adopting the following formula:
coefficient of distribution ═ D 90 -D 10 )/D 50
The coefficient of variation is obtained by the following method: taking a proper amount of polymer microspheres, adding 5mL of purified water, and placing the mixture in a vortex oscillator for shaking to ensure that the polymer microspheres are uniformly distributed in the purified water to form a suspension. Under the oscillation condition, the suspension is dropped on a glass slide, the glass slide is placed under a video microscope (H series, Dongguan optical instrument), the glass slide is amplified to a proper time, the diameters of the microspheres in a visual field are sequentially measured, the cumulative number of the measurements is 300-500, the average value and the standard deviation of the particle size of the polymer microspheres are calculated, and the variation coefficient of the polymer microspheres is obtained according to the formula (standard deviation/average value) multiplied by 100%.
Example 1
The positive electrode of a high-voltage electrostatic generator was connected to the needle of a microsyringe containing a polymer solution (consisting of 3g of polylactic acid and 100mL of methylene chloride), and the ground lead of the high-voltage electrostatic generator was connected to the side wall of a stainless steel beaker containing a dispersion solution (consisting of 5g of polyvinyl alcohol and 1L of purified water) to form an electrostatic field of 6 kV. The distance between the tip of the needle of the microsyringe and the surface of the dispersion solution was 3 cm. The polymer solution is extruded out through a needle of a microsyringe, and the extrusion flow rate of the polymer solution is controlled to be 0.05mL/s by a micro-injection pump, so that the polymer solution forms droplets under the action of an electrostatic field.
Stirring the dispersion by using a magnetic stirrer, wherein the rotating speed of the magnetic stirrer is 1000 r/min. The liquid drops enter the dispersion solution in a stirring state under the action of an electrostatic field to form spheres.
After the polymer solution was completely extruded, the dispersion solution was continuously stirred to volatilize methylene chloride and to set the spheres.
The dispersion solution containing the shaped spheres was filtered and the shaped spheres were collected. And cleaning and soaking the collected shaped spheres by using purified water, repeating the steps of cleaning and soaking for 4 times, and then freezing and drying in vacuum to obtain the polymer microspheres.
The properties of the resulting polymeric microspheres are shown in table 1.
Example 2
The procedure of example 1 was repeated, except that the dispersion solution contained 8g of polyvinyl alcohol, the electrostatic field voltage was 15kV, the distance between the tip of the needle of the microsyringe and the liquid surface of the dispersion solution was 4cm, and the rotational speed of the magnetic stirrer was 1500 rpm. The properties of the resulting polymeric microspheres are shown in table 1.
Example 3
The same procedure as in example 1 was repeated, except that the polylactic acid content in the polymer solution was 5g, the electrostatic field voltage was 3kV, the distance between the tip of the needle of the microsyringe and the liquid surface of the dispersion solution was 2cm, and the rotational speed of the magnetic stirrer was 800 r/min. The properties of the resulting polymeric microspheres are shown in table 1.
TABLE 1
| Serial number | D 50 (μm) | D 10 (μm) | D 90 (μm) | Coefficient of distribution | Coefficient of variation |
| Example 1 | 46.864 | 40.470 | 53.691 | 0.282 | 6.35％ |
| Example 2 | 25.950 | 20.695 | 30.657 | 0.384 | 14.42％ |
| Example 3 | 123.051 | 110.657 | 137.217 | 0.216 | 5.21％ |
The present invention is not limited to the above-described embodiments, and any variations, modifications, and substitutions which may occur to those skilled in the art may be made without departing from the spirit of the invention.
Claims (10)
1. The polymer microsphere is characterized in that the distribution coefficient of the particle size of the polymer microsphere is less than or equal to 0.8;
wherein, the distribution coefficient is obtained by adopting the following method:
testing by a laser particle sizer to obtain D of the polymer microsphere 10 、D 50 And D 90 And calculating according to the following formula to obtain the distribution coefficient:
coefficient of distribution ═ D 90 -D 10 )/D 50 ；
Wherein the structure of the repeating unit of the polymer is shown as the formula (I):
wherein R is 1 Selected from H or alkyl of C1-C6.
2. The polymer microsphere of claim 1, wherein the coefficient of variation of the particle size of the polymer microsphere is less than or equal to 15%;
wherein the variation coefficient of the particle size of the polymer microsphere is obtained by the following method:
placing the mixture of the polymer microspheres and water in a vortex oscillator to shake so that the polymer microspheres are uniformly distributed in the water to form a suspension; dropping the suspension on a glass slide under the oscillation condition, measuring the diameter of the polymer microspheres in the visual field under a video microscope, measuring 300-500 in an accumulated manner, calculating the average value and the standard deviation of the diameters of the polymer microspheres, and calculating the coefficient of variation of the diameters of the polymers according to the following formula:
coefficient of variation ═ (standard deviation/average) × 100%.
3. The polymeric microsphere of claim 1, wherein R is 1 Is methyl.
4. The polymeric microsphere of claim 1, wherein the poly (arylene sulfide)D of the Complex microspheres 50 10 to 200 μm, D 10 5 to 190 μm, D 90 15 to 210 μm.
5. The method for preparing the polymeric microspheres according to any one of claims 1 to 4, comprising the steps of:
(1) forming the polymer solution into liquid drops under the action of an electrostatic field;
(2) allowing the liquid drops to enter a dispersion solution under stirring condition under the action of an electrostatic field to obtain polymer microspheres;
wherein the dispersing solution contains a dispersing agent with a repeating unit structure as shown in a formula (II):
wherein R is 2 Selected from H or alkyl of C1-C6.
6. The method according to claim 5, wherein the dispersion solution further contains a dispersion medium, and the mass-to-volume ratio of the dispersant to the dispersion medium is 0.1 to 10 g/L.
7. The method according to claim 5, wherein the dispersion solution is stirred by a stirring device at a rotation speed of 50 to 2000 r/min.
8. The preparation method according to claim 5, wherein the polymer solution comprises a polymer and a solvent, the mass volume ratio of the polymer to the solvent is 10-100 g/L, and the solvent is one or more selected from dichloromethane, chloroform, acetone, tetrahydrofuran and hexafluoroisopropanol.
9. The method according to claim 5, wherein the polymer solution is extruded through an end opening of the tube to form droplets under the action of an electrostatic field;
wherein the extrusion flow rate of the polymer solution is 0.01-0.08 mL/s, the inner diameter of the end opening of the tubular object is 0.06-1.19 mm, the distance between the end opening of the tubular object and the liquid surface of the dispersion solution is 1-15 cm, and the voltage of the electrostatic field is 1-30 kV.
10. The production method according to claim 9, wherein the dispersion solution is placed in a conductive container;
and connecting the positive electrode of the high-voltage static electricity generating device with the tubular object, and connecting the grounding wire of the high-voltage static electricity generating device with the conductive container so as to form an electrostatic field.
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