CN102443088A - Uniform-size small-particle-size super-macroporous polymer microspheres and preparation method thereof - Google Patents

Abstract

The invention relates to a method for preparing polymer microspheres with uniform particle size and controllable small particle size and ultra-large pores, and a product thereof. The method disperses the oil phase containing monomers and high-content surfactants into the water phase, prepares colostrum by a rapid membrane emulsification method, and further heats and solidifies to obtain super-macroporous microspheres. The super-macroporous microspheres have both Micropores of 5-20nm, and ultra-large pores of 50-100nm and above 100nm, of which the ultra-large pores of 50-100nm and above 100nm account for 10-60% of the internal pore volume of the microspheres, the particle size of the microspheres is 0.5-25μm, and the porosity 30% to 80%, particle size distribution coefficient <20%.

Description

A kind of small particle size ultra-macroporous polymer microsphere with uniform size and preparation method thereof

technical field

The invention relates to a polymer microsphere and a preparation method thereof, in particular to an ultra-macroporous polymer microsphere with a small particle size and uniform and controllable particle size and a preparation method thereof.

Background technique

With the development of biotechnology, a large number of biomacromolecules such as proteins, peptides and nucleic acids need to be separated, analyzed and purified. Column chromatography is an important means for the separation and purification of biological macromolecules, and the separation medium is the core of column chromatography, so the development of separation medium has become the focus of attention of various countries and has also achieved rapid development.

由于孔径较小，流动相在孔道内的传质过程主要依靠分子扩散完成，导致生物大分子的传质速度慢、分离时间长，活性和收率下降。Due to the complexity and diversity of biological macromolecules in terms of molecular structure, physical and chemical properties, and biological activities, higher requirements are put forward for separation media, and it is hoped that fast and efficient analysis and separation can be obtained. However, in general porous media, pores are formed by phase separation between non-good solvents of cross-linked polymers, and the pore diameters formed by this mechanism are nanoscale

Due to the small pore size, the mass transfer process of the mobile phase in the channel mainly depends on molecular diffusion, resulting in slow mass transfer rate, long separation time, and decreased activity and yield of biomacromolecules.

In order to overcome the shortcomings of conventional small-pore media, the researchers proposed to use a super-large-pore synthetic separation medium with double channels. The separation speed of protein biomacromolecules, small pores (diffusion pores) can provide a sufficiently high specific surface area, greatly improving the adsorption capacity of the medium.

In 1991, Regnier et al. proposed a perfusion chromatography (PerfusionChromatography) medium with a dual-channel structure, and published related papers in Nature. Due to the good application prospects of the dual-channel ultra-large-porous synthetic polymer medium represented by perfusion chromatography medium in the separation and purification of biomacromolecules, its preparation and application research have always been highly valued by researchers at home and abroad, and the following types have also been developed. Pore-causing method:

(1) Suspension polymerization using polymers as porogens, which uses soluble polymers instead of commonly used liquid porogens. With the polymerization of the monomer in the droplet, phase separation occurs between the newly formed cross-linked polymer and the porogen polymer, and the porogen polymer can be extracted after the polymerization to obtain a larger pore size; but its disadvantages The reason is that the phase separation between the two polymers is relatively difficult, and it is difficult to form large pores through the synthesis medium, and the porogen polymer is also difficult to extract cleanly.

的贯穿孔(through pores)和

的扩散孔(diffusion pores)。在分离应用时贯穿孔内的流动相以对流形式流动，传质速度快(如图1b所示)；而扩散孔则可以提供足够高的比表面积，保证了介质的吸附容量。然而，POROS介质是采用纳米级颗粒“粘结”成簇、聚集成团，进而形成微米级颗粒的方法来制备的，因此，通过控制纳米颗粒间的不规则聚集状态来控制孔径比较困难，造成产品批次间重复性较差、收率低等问题。(2) Nanoparticle aggregation method, the commercialized POROS perfusion chromatographic medium is prepared by this method, and has been applied to the separation and purification of biological macromolecules such as proteins, showing fast separation speed, high column capacity and high yield. advantage. POROS media has two types of pores:

The through holes (through pores) and

Diffusion pores. In the separation application, the mobile phase in the through hole flows in the form of convection, and the mass transfer speed is fast (as shown in Figure 1b); while the diffusion hole can provide a high enough specific surface area to ensure the adsorption capacity of the medium. However, the POROS medium is prepared by "bonding" nano-sized particles into clusters and agglomerating to form micron-sized particles. Therefore, it is difficult to control the pore size by controlling the irregular aggregation state between nanoparticles, resulting in Problems such as poor repeatability between product batches and low yield.

(3) High internal phase emulsion polymerization (polyHIPE, high internal phase emulsion polymer). When the medium is prepared, a large amount of water is dispersed in the monomer in the form of water droplets (the volume of the water phase exceeds 70%) to form a W/O type high internal phase emulsion (HIPE), and then the high internal phase emulsion is dispersed by selecting a suitable stabilizer In the external aqueous phase, a double emulsion is made. After polymerization, interpenetrating macropores are formed in the medium (Figure 2). This medium, named Magnapore, is characterized by large pore size (1-50 μm), low density (0.05-0.2 g/cm3), and high porosity (above 70%). But because of its large pore size, although small holes are prepared on the pore wall, the specific surface area is still very low (2-30m2/g), and the mechanical strength of the medium is weak. In addition, the 70% double emulsion with high internal water phase has poor stability in the polymerization process, and the formulation and polymerization process must be strictly controlled in order to be successfully prepared.

(4) The method of using inorganic particles as porogens: Sun Yan’s research group from Tianjin University overcame the difficulties of the above-mentioned preparation method, and used inorganic particles as porogens to prepare a porogen containing both 10-90nm micropores and 180 nm micropores. - 4000nm ultra-large pore medium, the specific surface area of the medium is 91.3m ² /g, and it is found that the volume content of inorganic particles should be 10-40% in order to obtain the through large pore diameter. Although this method can embed hydrophilic inorganic particles in hydrophilic agarose to achieve a high embedding rate, the compatibility between most synthetic polymer materials (such as polystyrene, etc.) and inorganic particles is poor. It is still a difficult problem to embed a large number of inorganic particles in synthetic polymer materials to achieve high embedding efficiency.

(5) Double emulsification method (double emulsification): Gustavsson et al. developed a double emulsification method in order to prepare super-large-pore agarose medium. Sun Yan and others also used this method to prepare a synthetic medium with micropores of 20-100nm, ultra-macropores of 300-4000nm, and a specific surface area of 52.1m ² /g. In principle, this method is the same as the high internal phase emulsion polymerization method. It requires two-step emulsification process, and its stirring speed is as high as 8000rpm when preparing colostrum. If large-scale production is to be carried out, the preparation and stability of colostrum will have certain problems difficulty.

The inventors of the present invention successfully prepared ultra-macroporous polymer microspheres with a pore size of 500-800 nm by using the method of surfactant reverse micelles swelling, and obtained them in efficient and rapid separation and purification of proteins, immobilized enzymes, and solid-phase extraction. Good application and results.

As the inventor's prior application CN 1903890A and WO 2008/064525A1 both disclose a preparation method of super-macroporous polymer microspheres and products thereof, the preparation method includes: (1) mixing of monomers and crosslinking agents Add the initiator, diluent and surfactant to the solution, and stir until the initiator is completely dissolved; (2) Dissolve the stabilizer in distilled water to prepare an aqueous solution with a certain concentration as the water phase; (3) Add the oil phase In the water phase, stir at a speed of 100-300rpm, pass nitrogen for 1h, and polymerize at a temperature of 30-100°C for 24h; (4) After the reaction, filter, wash the product with distilled water and ethanol several times, and diluent, surface active The components such as reagents are washed and dried to obtain a super-macroporous bioseparation medium.

However, the above-mentioned methods for preparing ultra-macroporous microspheres are all suspension polymerization methods, so the prepared microspheres have a large particle size and poor uniformity. For separation and purification applications, the particle size and uniformity of the media have a significant impact on the separation results. Therefore, the present invention proposes a uniform size, controllable small particle size ultra-large pore microsphere and its preparation method. The improvement of the size uniformity of the microsphere can effectively improve the resolution of the chromatography column, and the reduction of the particle size can increase the size of the column. The number of plates further increases the separation effect, and the super-large pores provide a faster separation speed, which can achieve efficient and rapid separation of the separated substances and ensure good yield and activity.

Contents of the invention

In view of the deficiencies of the prior art, one of the objectives of the present invention is to provide a small-diameter ultra-large-porous polymer microsphere with uniform and controllable particle diameter. The microsphere adopts the method of combining rapid membrane emulsification and suspension polymerization, and can easily prepare small particle size ultra-large pore polymer microspheres suitable for high performance liquid chromatography and analytical chromatography stationary phase substrate with uniform and controllable particle size. ball.

The preparation method of the small-diameter super-macroporous polymer microspheres with uniform and controllable particle size is as follows: adding a relatively high content of surfactant to the oil phase containing monomers, dispersing into the water phase, and forming colostrum after passing through the membrane , and further polymerization to obtain the product.

The ultra-large pore microspheres with small particle size and uniform size have both micropores of 5-20nm and ultra-large pores of 50-100nm and above 100nm, wherein the ultra-large pores of 50-100nm and above 100nm account for the internal pores of the microspheres. 10-60% of the volume, preferably 20-40%. The particle size of the microsphere is 0.5-25 μm, the porosity is 30%-80%, and the particle size distribution coefficient is less than 20%.

Wherein said particle size distribution coefficient is calculated as follows:

CV＝{[∑(d _i -d) ² /N] ^1/2 /d}×100%

In the formula, CV represents the particle size distribution coefficient; d _i represents the diameter of each nanosphere; d represents the number average particle diameter of the nanosphere, d=∑d _i /N; N is the nanometer used to calculate the particle size The number of balls, and N≥200.

One of the purposes of the present invention is also to provide the use of the above-mentioned microspheres, which can be used as chromatographic fillers, ion exchangers after modification, solid-phase synthesis carriers, enzyme immobilization carriers, drug carriers, analysis and detection reagents, food and Functional carrier of cosmetics.

One of the purposes of the present invention is also to provide a preparation method of small particle size ultra-macroporous polymer microspheres with uniform and controllable particle size, by adding a relatively high content of surfactant and an appropriate amount of diluent in the oil phase, The microspheres with uniform and controllable particle size are prepared by passing through the membrane first and then by the suspension polymerization method.

The preparation method preferably comprises the steps of:

(1) Mix the oil phase containing monomer, crosslinking agent, initiator, diluent and oil-soluble surfactant;

(2) preparing an aqueous phase containing a stabilizer and an optional water-soluble surfactant;

(3) Add the uniformly mixed oil phase to the water phase, and continue to stir until the solution is milky white to ensure sufficient swelling, and at this time a W/O/W type bicontinuous phase emulsion is formed;

(4) passing the emulsion through membranes of different apertures under pressure;

(5) According to the degree of particle size uniformity, the emulsion is solidified after passing through the membrane for one or more times;

Optionally, (6) washing and drying to prepare polymer microspheres with uniform particle size and controllable small particle size and ultra-large pores.

In step (1), the surfactant is an oil-soluble surfactant, which is different from the crosslinking agent, initiator, diluent and stabilizer. The oil-soluble surfactant is selected from nonionic surfactants, ionic surfactants, and amphiphilic capped copolymers. The oil-soluble surfactant can be sorbitan fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene fatty acid ester, alkylphenol polyoxyethylene ethers, such as sorbitan monooleate, p- Octylphenol polyoxyethylene ether, etc. The surfactant is preferably sorbitan monooleate, p-octylphenol polyoxyethylene ether, PO-500, Arlacel 83, AOT or a mixture thereof.

The mass content of the oil-soluble surfactant in the oil phase is 5%-80%, preferably 10%-70%, more preferably 25%-60%.

The monomers used in the present invention are preferably any oil-soluble monomers with vinyl groups and their mixtures, which can be vinyl, styrene, methacrylic, acrylic, methacrylate, acrylic , methacrylamide, acrylamide monomers, and epoxy and vinyl acetate monomers. The mass content of the monomer in the oil phase is 1%-90%, preferably 10%-60%, more preferably 25%-45%.

The cross-linking agent is any oil-soluble compound with a divinyl or trivinyl group, which can be a bisvinyl aromatic compound, such as divinylbenzene; it can be an acrylate compound, such as dimethyl Ethylene glycol acrylate, trimethoxypropane trimethyl acrylate, etc. The mass content of the crosslinking agent in the oil phase is 1%-90%, preferably 5%-60%, more preferably 10%-45%.

The diluent mainly plays the role of inhibiting secondary nucleation in the oil phase, and can also play the role of a pore-forming agent when the addition amount is high. The diluent may be alkanes, such as heptane, dodecane, hexadecane, isooctane, etc.; ethers, such as petroleum ether; and benzenes, such as toluene. Diluents can also be polymers that are soluble in monomers, such as styrene monomers. Polymers such as polystyrene and polymethacrylate can be dissolved in styrene, so polymers such as polystyrene and polymethacrylate can be used as diluents for styrene systems. Another example is glycidyl methacrylate monomer; polyglycidyl methacrylate, polymethacrylate and other polymers can be dissolved in glycidyl methacrylate, so polyglycidyl methacrylate, polymethacrylate Polymers such as acrylates can be used as diluents for glycidyl methacrylate systems. Polymers soluble in monomers are well known to those skilled in the art. When no diluent is added to the oil phase, super-macroporous microspheres can also be obtained, so the mass fraction of the diluent in the oil phase is 0% to 80%, preferably 0 to 60%, but limited within the range of 0% to 50%. better.

The initiator will affect the polymerization rate of the monomer, and ultimately affect the yield of the microspheres, so an appropriate initiator and its amount should be selected. The initiator used in the present invention may be a peroxide initiator, such as benzoyl peroxide; an azo initiator, such as azobisisobutyronitrile; or a mixture thereof. The amount of the oil-soluble polymerization initiator is 0.01%-10% of the mass of all polymerizable monomers, preferably 0.05%-8%, more preferably 0.1%-6%.

In the water phase of step (2), select a stabilizer with an appropriate concentration and an optional water-soluble surfactant, and at least one stabilizer must be contained. The stabilizer can stably disperse the oil phase droplets in the water phase, and reduce or prevent the phenomenon of sticking balls. The stabilizer can be a water-soluble polymer, such as polyvinyl alcohol, gelatin, cellulose, polyvinylpyrrolidone, etc., and its content is 0.1-10%, preferably 0.5-8%, more preferably 0.5-5% of the mass of the water phase.

Described water-soluble surfactant can use sodium lauryl sulfate, sodium lauryl sulfate etc. Water-soluble surfactant is a non-essential additive, so those skilled in the art can choose whether to add or not according to the situation, and its content is controlled within 10%, preferably within 8%, and more preferably within 5% of the water phase mass. The water-soluble surfactant is controlled within "within" 10%, including 0%.

In step (3), the high content of the oil-soluble surfactant forms a large amount of reverse micelles in the oil phase. After being dispersed into the water phase, the surfactant reverse micelles in the oil phase droplets spontaneously absorb water and swell Form a continuous channel to form a W/O/W double continuous phase emulsion, and the emulsion is milky white at this time.

The emulsion is passed through the membrane once or more times under a pressure of 0KPa～5MPa, preferably 10KPa～2MPa, more preferably 50KPa～1.5MPa, and the pore size of the membrane is 1～30 μm, preferably 5～25 μm, more preferably 10 ~25 μm. The number of times of film passing depends on the degree of uniformity, generally 1 to 5 times, preferably 1 to 3 times. After passing through the film, a uniform emulsion is formed, which is further solidified into balls.

After the polymerization is completed, the excess surfactant and diluent can be optionally washed to obtain ultra-macroporous polymer microspheres with a small particle size. The structure of microspheres, such as pore size, porosity, and specific surface area, can be controlled by adjusting surfactants, diluents, and crosslinking degrees. This method is not limited by the polymerization system, and different monomers can be selected to prepare microspheres according to needs.

The treatment after the completion of the polymerization refers to the removal of residual unpolymerized monomers, surfactants, diluents and other components. The post-treatment includes washing the microspheres with hot water and ethanol for several times, and then extracting with acetone. After cleaning, drying to obtain the product.

The small-diameter and super-large-porous polymer microspheres with uniform size prepared by the present invention have both micropores of 5-20nm and super-large pores of 50-100nm and above 100nm inside the microspheres. The pores account for 10-60% of the internal pore volume of the microsphere, preferably 20-40%, the porosity of the microsphere is 30%-80%, the particle size is controllable within the range of 0.5-50 μm, and the particle size distribution coefficient is <20%.

Description of drawings

Fig. 1 is the electron micrograph of embodiment 1 super-macroporous microsphere.

Fig. 2 is the electron micrograph of embodiment 1 ultra-macroporous microsphere.

Fig. 3 is the electron micrograph of embodiment 2 ultra-macroporous microspheres.

Fig. 4 is a particle size distribution diagram of Example 3 with a particle size of 13.17 μm.

Fig. 5 is the particle size distribution diagram of the ultra-large pores in Example 3.

Fig. 6 is the electron micrograph of embodiment 4 super-macroporous microspheres.

Fig. 7 is a particle size distribution diagram of the super-macroporous microspheres of Example 5.

Figure 8 is an electron micrograph of the super-macroporous microspheres of Example 5.

Fig. 9 is an electron micrograph of the ultra-macroporous microspheres of Example 6.

Figure 10 is an electron micrograph of the super-macroporous microspheres of Example 7.

Fig. 11 is an electron micrograph of the super-macroporous microspheres of Example 8.

Figure 12 is an electron micrograph of the super-macroporous microspheres of Example 9.

Figure 13 is an electron micrograph of the super-macroporous microspheres of Example 10.

Detailed ways

In order to facilitate understanding of the present invention, the present invention enumerates the following examples. Those skilled in the art should understand that the examples are only used to help understand the present invention, and should not be regarded as specific limitations on the present invention.

Example 1 (membrane pore 15 μm, membrane pressure 40Kpa, water-oil ratio 12.5:1, membrane passed three times)

Accurately weigh 6.0g of styrene and 2.0g of divinylbenzene into a 25mL beaker, add 0.32g of benzoyl peroxide, 3.2g of Span80, and 0.4g of hexadecane, and stir until the initiator is completely dissolved. Dissolve 1.0g of PVA in 100mL of distilled water to form the water phase. Add the oil phase to the water phase, stir until milky white to ensure sufficient swelling, install the rapid membrane emulsification device and adjust the pressure to 40kPa to pass through the membrane three times, put the colostrum after passing the membrane into a 250mL three-necked flask for polymerization, and the polymerization temperature is 75°C , The polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. See Figures 1 and 2 for electron microscope photos, the particle size is 8.30 μm; the particle size distribution coefficient is 16.3%; the proportion of super large pores is 36.2%.

Embodiment 2 (change membrane hole membrane pressure)

Accurately weigh 6.0g of styrene and 2.0g of divinylbenzene into a 25mL beaker, add 0.32g of benzoyl peroxide, 3.2g of Span80, and 0.4g of hexadecane, and stir until the initiator is completely dissolved. Dissolve 1.0g of PVA in 100mL of distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 2.8μm) and adjust the pressure to 400kPa to pass through the membrane three times, put the colostrum after passing the membrane into a 250mL three-necked flask for polymerization, and polymerize The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The electron microscope photo is shown in Figure 3, the particle size is 1.40 μm; the particle size distribution coefficient is 7.8%; the proportion of super large pores is 10.3%.

Embodiment 3 (change water-oil ratio)

Accurately weigh 15.0g of styrene and 5.0g of divinylbenzene into a 50mL beaker, add 0.8g of benzoyl peroxide, 8.0g of Span80, and 1.0g of hexadecane, and stir until the initiator is completely dissolved. Dissolve 1.0g of PVA in 100mL of distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 19.8μm) and adjust the pressure to 30kPa to pass through the membrane three times, put the colostrum after passing the membrane into a 250mL three-necked flask for polymerization, and polymerize The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The particle size is 13.17 μm, and the particle size distribution diagram is shown in Figure 4; the particle size distribution coefficient is 18.7%; the proportion of super large pores is 60.4%, and the pore size distribution diagram is shown in Figure 5.

Embodiment 4 (change the concentration of stabilizing agent in the aqueous phase)

Accurately weigh 6.0g of styrene and 2.0g of divinylbenzene into a 25mL beaker, add 0.32g of benzoyl peroxide, 3.2g of Span80, and 0.4g of hexadecane, and stir until the initiator is completely dissolved. Take 2.0g PVA and dissolve it in 100mL distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 15 μm) and adjust the pressure to 40kPa to pass through the membrane three times, put the colostrum after the membrane into a 250mL three-necked flask for polymerization, and the polymerization temperature The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The electron microscope photo is shown in Figure 6, the particle size is 7.36 μm; the particle size distribution coefficient is 12.2%; the proportion of super large pores is 34.5%.

Embodiment 5 (change initiator)

Accurately weigh 6.0g of styrene and 2.0g of divinylbenzene into a 25mL beaker, add 0.32g of azobisisobutyronitrile, 3.2g of Span80, and 0.4g of hexadecane, and stir until the initiator is completely dissolved. Dissolve 1.0g of PVA in 100mL of distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 9.2 μm) and adjust the pressure to 50kPa to pass through the membrane three times, put the colostrum after passing the membrane into a 250mL three-necked flask for polymerization, and polymerize The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The particle size is 3.89 μm, and its particle size distribution diagram is shown in Figure 7; the particle size distribution coefficient is 14.7%; the proportion of super-large pores is 13.7%, and the electron microscope photo is shown in Figure 8.

Embodiment 6 (improves degree of cross-linking)

Accurately weigh 6.0g of styrene and 6.0g of divinylbenzene into a 25mL beaker, add 0.32g of benzoyl peroxide, 3.2g of Span80, and 0.4g of hexadecane, and stir until the initiator is completely dissolved. Take 3.0g PVA and dissolve it in 100mL distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 9.2 μm) and adjust the pressure to 50kPa to pass through the membrane three times, put the colostrum after passing the membrane into a 250mL three-necked flask for polymerization, and polymerize The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The electron microscope photo is shown in Figure 9, the particle size is 4.41 μm; the particle size distribution coefficient is 13.4%; the proportion of super large pores is 11.5%.

Embodiment 7 (polymer is made diluent)

Accurately weigh 6.0g of styrene and 6.0g of divinylbenzene into a 25mL beaker, add 0.32g of benzoyl peroxide, 3.2g of Span80, and 0.4g of polystyrene, and stir until the initiator is completely dissolved. Take 3.0g PVA and dissolve it in 100mL distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 9.2 μm) and adjust the pressure to 50kPa to pass through the membrane three times, put the colostrum after passing the membrane into a 250mL three-necked flask for polymerization, and polymerize The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The electron microscope photo is shown in Figure 10, the particle size is 3.78 μm; the particle size distribution coefficient is 16.9%; the proportion of super large pores is 10.7%.

Embodiment 8 (change monomer system)

Accurately weigh 6.0g glycidyl methacrylate and 2.0g divinylbenzene into a 25mL beaker, add 0.32g benzoyl peroxide, 3.2g Span80, 0.4g hexadecane, stir until the initiator is completely dissolved . Take 3.0g PVA and dissolve it in 100mL distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 15 μm) and adjust the pressure to 50kPa to pass through the membrane three times, put the colostrum after the membrane into a 250mL three-necked flask for polymerization, and the polymerization temperature The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The electron microscope photo is shown in Figure 11, the particle size is 7.08 μm; the particle size distribution coefficient is 15.4%; the proportion of super large pores is 30.3%.

Embodiment 9 (change monomer system)

Accurately weigh 6.0g hydroxyethyl methacrylate and 2.0g divinylbenzene into a 25mL beaker, add 0.32g benzoyl peroxide, 3.2g Span80, 0.4g hexadecane, stir until the initiator is completely dissolved . Take 3.0g PVA and dissolve it in 100mL distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 15 μm) and adjust the pressure to 50kPa to pass through the membrane three times, put the colostrum after the membrane into a 250mL three-necked flask for polymerization, and the polymerization temperature The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The electron microscope photo is shown in Figure 12, the particle size is 7.20 μm; the particle size distribution coefficient is 16.4%; the proportion of super large pores is 35.1%.

Embodiment 10 (scale-up preparation)

Accurately weigh 150.0g styrene and 50.0g divinylbenzene into a 500mL beaker, add 8.0g benzoyl peroxide, 80.0g Span80, 10.0g hexadecane, and stir until the initiator is completely dissolved. Dissolve 10.0g of PVA in 1L of distilled water to form the water phase. Add the oil phase to the water phase, stir to ensure sufficient swelling, install a rapid membrane emulsification device (membrane pore 19.8 μm) and adjust the pressure to 40kPa to pass through the membrane three times, put the colostrum after passing the membrane into a 3L reactor for polymerization, and polymerize The temperature is 75°C, and the polymerization time is 20h. After the reaction, filter, wash the product several times with distilled water and ethanol, wash, extract, and dry the diluent, surfactant and other components to obtain the product. The particle size is 12.38 μm, and the particle size distribution coefficient is 17.6%; the proportion of ultra-large pores is 43.5%. The electron micrograph is shown in Figure 13.

After reading the present invention, those skilled in the art may think of many modifications and other embodiments of the present invention, and predict their benefits based on the teaching of the present invention. Therefore, it should be understood that the above embodiments and examples do not limit the invention and that modifications and other embodiments thereof are included within the scope of the appended claims. Although specific terms are used herein, they are used in their generic and descriptive sense only and are not intended to limit the scope of the invention as defined in the claims.

Claims (10)

1. the preparation method of the controlled small particle size super large pore polymer microsphere of a uniform particle diameter, said preparation method preferably includes following steps:

The oil phase that (1) will contain monomer, linking agent, initiator, thinner and oil soluble surfactant mixes;

(2) preparation contains stablizer and optional water soluble surfactant active's water;

(3) the said oil phase that mixes is joined said water, continue to be stirred to solution and be creamy white, guarantee that swelling is abundant, form W/O/W type co-continuous phase emulsion this moment;

(4) film through different apertures under pressure with said emulsion;

(5) cross film according to uniform particle diameter degree one or many, emulsion is solidified behind the film excessively;

Alternatively, (6) washing is dry, makes uniform particle diameter, controlled small particle size super large pore polymer microsphere.

2. the method for claim 1 is characterized in that, said monomer is oil-soluble ethylene base monomer or its mixture; Said monomer is preferably selected from least a in vinyl, styrenic, acrylic acid or the like, methacrylic, esters of acrylic acid, methyl acrylic ester, acrylic amide, methacryloyl amine, epoxy olefines and the vinyl acetate esters monomer;

Preferably, the mass content of said monomer in oil phase is 1%～90%, preferred 10%～60%, further preferred 25%～45%.

3. according to claim 1 or claim 2 method is characterized in that, said linking agent is to be selected from least a in compound and composition thereof of oil-soluble, band bi-vinyl or trivinyl; Said linking agent is preferably selected from bi-vinyl aromatics, acrylic ester compound or its mixture, is preferably Vinylstyrene (DVB), TGM 1 (EGDMA), vinylformic acid trimethoxy propane trimethyl ester (TRIM) or its mixture;

Preferably, the mass content of said linking agent in oil phase is 1%～90%, preferred 5%～60%, further preferred 10%～45%.

4. like the described method of one of claim 1-3, it is characterized in that said initiator is selected from azo-initiator, peroxide initiator or its mixture; Be preferably selected from Lucidol, Diisopropyl azodicarboxylate or its mixture;

Preferably, the consumption of said initiator is 0.01%～10% of all polymerisable monomer quality, preferred 0.05%～8%, further preferred 0.1%～6%.

5. like the described method of one of claim 1-4, it is characterized in that said thinner is selected from alkane, alcohols, ethers, benzene class, is dissolved in polymer of monomers class or its mixture; Said thinner is preferably selected from heptane, dodecyl, n-Hexadecane, octane-iso, dodecanol, hexalin, propyl carbinol, sherwood oil, toluene, PS, gathers (methyl) propenoate or its mixture;

Preferably, the massfraction of said thinner in oil phase is 0%～80%, preferred 0～60%, further preferred 0%～50%.

6. like the described method of one of claim 1-5, it is characterized in that said oil soluble surfactant is selected from non-ionics, ionogenic surfactant, amphipathic embedding end multipolymer; Preferably from sorbitan fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene fatty acid ester, TX10 class, amphiphilic block copolymer or their mixture; Said oil soluble surfactant is preferably sorbitan fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene fatty acid ester, TX10 class or its mixture; Further be preferably sorbitan monooleate, paraoctyl phenol Soxylat A 25-7, PO-500, Arlacel 83, AOT or its mixture; More preferably sorbitan monooleate, paraoctyl phenol Soxylat A 25-7 or its mixture.

Preferably, the mass content of said oil soluble surfactant in oil phase is 5%～80%, preferred 10%～70%, further preferred 25%～60%.

7. like the described method of one of claim 1-6, it is characterized in that said stablizer is selected from water-soluble polymers, preferably polyethylene alcohol, gelatin, Mierocrystalline cellulose, Vinylpyrrolidone polymer or its mixture;

Preferably, said stabiliser content is 0.1～10% of a water quality, preferred 0.5～8%, further preferred 0.5%～5%.

8. like the described method of one of claim 1-7, it is characterized in that said water soluble surfactant active can use sodium lauryl sulphate, sodium laurylsulfonate; Said water soluble surfactant active be content be controlled at the water quality 10% in, in preferred 8%, further in preferred 5%;

Preferably, the said pressure of step (4) is 0KPa～5MPa, is preferably 10KPa～2MPa, further preferred 50KPa～1.5MPa;

Preferably, said membrane pore size is 1～30 μ m, preferred 5～25 μ m, further preferred 10～25 μ m;

Preferably, crossing the film number of times is 1～5 time, preferred 1～3 time.

9. the small particle size super large pore polymer microsphere that uniform particle diameter is controlled is characterized in that microballoon inside had both had the micropore of 5-20nm; Has the above oversized hole of 50-100nm and 100nm again; Wherein the above oversized hole of 50-100nm and 100nm accounts for the 10-60% of the inner pore volume of microballoon, is preferably 20-40%, and the microballoon porosity is 30%～80%; Particle diameter is controlled in 0.5～50 mu m range, size distribution coefficient＜20%; Said microballoon is preferably with the said method preparation of one of claim 1-8.

10. the purposes of the said microballoon of claim 9 is characterized in that, is used for chromatograph packing material, modifies the functional supports of back as ionite, solid-phase synthesized carrier, enzyme immobilization carrier, pharmaceutical carrier, analyzing and testing reagent, food and makeup.

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