Preparation method of monodisperse high-molecular polymeric filler

Abstract

The invention discloses a preparation method of a monodisperse high-molecular polymer filler, which comprises the following steps: synthesizing seed microspheres with uniform particle size by a dispersion polymerization method, and preparing porous microspheres with required size and aperture by a two-step seed swelling method. In the preparation process, the selection, the mixing mode, the reaction temperature, the reaction time, the material proportion and the like of all the raw materials are accurately controlled, for example, the mass ratio of the dispersing agent to the vinyl monomer is (5-20)%: 1, and the like. A particle size control and pore size distribution model is also introduced to assist in controlling the product performance. The preparation method is simple in process, controllable in process and easy for industrial large-scale production. The obtained monodisperse polymer chromatographic filler has the advantages of accurately adjustable particle size and pore size, good monodispersity, good sphericity and narrow pore size distribution, can be widely applied to the fields of biochemistry, catalytic carriers, drug carriers and the like, effectively overcomes the defects of the traditional chromatographic filler, and meets the requirements of the market on high-performance chromatographic filler.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of high molecular materials, and particularly relates to a preparation method of monodisperse high molecular polymer filler. BACKGROUND

[0002] In the field of high molecular materials and chromatographic separation, chromatographic fillers play a crucial role. With the development of related technologies, the performance requirements of chromatographic fillers are increasingly improved. Traditional sugar microspheres and silica gel fillers have once dominated the market, but they each have obvious defects. Although sugar microspheres have high loading capacity and are easy to modify, they have poor size uniformity and poor pressure resistance, which greatly limits their application range. Although silica gel fillers are low in cost, easy to modify and resistant to high pressure, they have poor chemical stability and obvious limitations when facing the analysis of basic compounds. Therefore, developing high molecular chromatographic fillers with better performance has become an urgent need for the development of the industry.

[0003] At present, there are various methods for preparing high molecular polymer microspheres, each having advantages and disadvantages. Polymer microspheres prepared by emulsion polymerization have small particle sizes; although microspheres with large particle sizes can be prepared by suspension polymerization, the particle size distribution is wide, and screening is needed when used, which increases the application cost and difficulty; although 1-10 mu m microspheres with monodisperse and uniform sizes can be synthesized by dispersion polymerization, surfactants and stabilizers are left after the reaction, which affects the purity of the polymer and may affect its application in some fields with high purity requirements; the emerging SPG membrane emulsification method has unique advantages in preparing micron-sized monodisperse polymer microspheres and can accurately control the particle size, but the technology is difficult to control, and the equipment cost is high, which is not conducive to large-scale industrial production; although 5-20 mu m monodisperse and uniform microspheres can be synthesized by seed swelling method, and various structure microspheres can be prepared, but the accurate control of particle size and pore size still needs to be improved.

[0004] Based on the above background, it is urgent to develop a method for preparing monodisperse polymer chromatographic fillers with simple preparation method, controllable reaction process, easy industrial production, and effective solution to the problems of poor monodispersity and uneven pore size distribution of polymer microspheres. Such a method not only overcomes the shortcomings of existing preparation technologies, but also meets the growing market demand and promotes the further development of related fields. SUMMARY

[0005] In order to overcome the shortcomings and deficiencies of the prior art, the present application provides a preparation method of monodisperse high molecular polymer filler.

[0006] The technical scheme adopted by the present application is a preparation method of monodisperse high molecular polymer filler, which comprises the following steps:

[0007] S1: Select the raw materials required for the dispersion polymerization process, mix the set dispersant and reaction solvent in a certain proportion, use ultrasonic method to promote the uniform dispersion of the two, set the ultrasonic frequency between 350-370 Hz, control the ultrasonic time for 30 min, to form a stable dispersion system; mix the specific monomer with vinyl group and the specific initiator in proportion, use electric stirring method, control the stirring speed in the range of 110-130 rpm, and the stirring time is 30 min, so that the two are fully mixed and uniform;

[0008] S2: Put the mixed and uniform reaction system in S1 into the reaction device, heat under constant temperature conditions, accurately control the reaction temperature at 70℃, and set the reaction duration for 24 h. In this process, the vinyl monomer polymerizes under the action of the initiator to generate seed microspheres with uniform particle size;

[0009] S3: After the reaction in S2 is completed, take out the product containing seed microspheres from the reaction device, wash the product with water and alcohol to remove the impurities remaining in the product; after washing, further separate the impurities by positive pressure filtration to preliminarily purify the seed microspheres; dry the purified seed microspheres and store them;

[0010] S4: Perform the activation step of seed swelling, select the set swelling agent, mix the seed microspheres stored in S3 with the swelling agent in a certain mass ratio, use ultrasonic emulsification method, control the ultrasonic power at 1800-2200 W, and continuously act for 12-24 h in a temperature environment of 25-40℃, so that the surface and internal structure of the seed microspheres are activated;

[0011] S5: After activation, perform the swelling step, prepare an emulsified mixture as a swelling monomer by mixing the second monomer, crosslinking agent, porogen, initiator and SDS solution in a specific proportion; mix the seed microspheres activated in S4 with the swelling monomer, use ultrasonic emulsification method again, control the ultrasonic power at 1800-2200 W, and continuously swell at a temperature of 25-40℃ for 12-24 h, so that the seed microspheres further absorb the swelling monomer and swell in volume;

[0012] S6: After swelling is completed, increase the temperature of the reaction system to initiate the polymerization of the system, control the polymerization temperature at 65-80℃, and set the polymerization reaction duration for 12-36 h; after the reaction is completed, extract the porogen from the product, and then perform filtration, washing and drying operations to obtain monodisperse polymer microspheres, and further process to obtain the required monodisperse polymer chromatography packing material.

[0013] Further, the reaction solvent is one or a combination of n-butanol solution, ethanol solution, and isopropanol solution. When multiple solvents are mixed, the volume ratio of alcohol to water in the solvent must be in the range of 90-100:0-10. The dispersant is one of polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol. The initiator is one of potassium persulfate, ammonium persulfate, benzoyl peroxide, and azobisisobutyronitrile. The monomer with vinyl groups is styrene.

[0014] Furthermore, the mass ratio of the dispersant to the vinyl monomer needs to be controlled within the range of 5%-20%:1; the mass ratio of the initiator to the vinyl monomer should be within the range of 1%-4%:1; and the amount of the vinyl monomer should account for 10-30% of the total weight of the reaction system.

[0015] Furthermore, in the S4 activation step, the seed is a non-crosslinked polystyrene microsphere, and the swelling agent is one or a combination of dibutyl phthalate (DBP), chloroform, and toluene; the mass ratio of the swelling agent to the seed is set in the range of 10-100:1.

[0016] Further, in the S5 swelling step, the second monomer is one or more combinations of methyl methacrylate (MMA), styrene (St), glycidyl methacrylate (GMA), and hydroxyethyl methacrylate (HEMA); the crosslinking agent is divinylbenzene (DVB) or ethylene glycol dimethacrylate (EGDMA); the porogen is one or more combinations of toluene, cyclohexanol, n-heptane, dodecanol, and linear polystyrene; the initiator is benzoyl peroxide (BPO) or azobisisobutyronitrile (AIBN); and the mass ratio of the second monomer to the seed is 2-20:1.

[0017] Furthermore, in the S5 swelling step, the mass ratio of the crosslinking agent to the vinyl monomer is 0.1-5:1; the mass ratio of the porogen to the vinyl monomer is 0.5-2:1; and the mass ratio of the initiator to the vinyl monomer is 5%-30%:1.

[0018] Furthermore, a particle size control model is introduced: Where D is the particle size of the final prepared monodisperse polymer chromatographic packing material, D0 is the initial particle size of the seed microspheres, and m sw For the mass of the swelling agent, m s m is the mass of the seed microspheres. cm m is the total mass of the crosslinking agent and the pore-forming agent. vmThe mass of the vinyl monomer is denoted as k1, and k2 is the particle size control coefficient. The value of k1 ranges from 0.01 to 0.05, and the value of k2 ranges from 0.005 to 0.02. This model is based on the influence of the mass of swelling agent, crosslinking agent, pore-forming agent and vinyl monomer on the final filler particle size during the preparation process.

[0019] Furthermore, an aperture distribution model is constructed: Where P(d) represents the probability distribution function for pore size d, μ is the average pore size, σ is the standard deviation of the pore size distribution, and m ca For the quality of the pore-forming agent, m vm m is the mass of the vinyl monomer. cm For the quality of the crosslinking agent, The function f(x,y) = 1 + 0.5x - 0.2y is related to the mass ratio of porogen and crosslinker. This model takes into account the mass ratio of porogen and crosslinker to vinyl monomer and is used to describe the pore size distribution of monodisperse polymer chromatographic packing.

[0020] Furthermore, during the S1 mixing process, when multiple reaction solvents are used, the solvent mixing uniformity is measured by the mixing uniformity coefficient M. Among them, V i Let C be the volume of the i-th solvent. i Let be the concentration of the i-th solvent, n be the number of solvent types, and the mixing uniformity coefficient M must satisfy the range of 0.95-1.05.

[0021] Furthermore, during the S6 polymerization reaction, the polymerization rate is expressed by the reaction rate model R6. p =k p ×[M]×[I] 0.5 Monitoring and regulation are carried out, among which R p k is the polymerization rate. p [M] represents the polymerization rate constant, [I] represents the monomer concentration, and [I] represents the initiator concentration. In this preparation method, the polymerization rate is maintained within the range of 0.01-0.05 mol / (L·s) by real-time monitoring of monomer and initiator concentrations and adjusting reaction conditions according to this model.

[0022] Beneficial Effects: This invention proposes a method for preparing monodisperse polymeric fillers. This method synthesizes seed microspheres through a specific dispersion polymerization process. First, the dispersant and reaction solvent are ultrasonically mixed, then the vinyl monomer and initiator are electrically stirred and mixed. The reaction is carried out under precisely controlled temperature and time to ensure the uniformity of the seed microsphere particle size. The subsequent two-step seed swelling method, through strict control of the conditions of each step of activation, swelling, and polymerization initiation, such as the selection of swelling agents and swelling monomers, and parameters such as reaction temperature and time, produces monodisperse polymeric chromatographic fillers with excellent performance in particle size and pore size control. The introduced particle size control model and pore size distribution model, based on the influence of the mass ratio of each raw material on particle size and pore size, make the preparation process more scientific and precise, allowing for flexible adjustment of the filler's particle size and pore size distribution characteristics according to actual needs. For example, by adjusting the mass ratio of swelling agent, crosslinking agent, porogen, and vinyl monomer, particle size and pore size can be effectively controlled. During the reaction, the mixing uniformity coefficient is used to monitor the mixing effect of the reaction solvent to ensure a stable reaction environment; the polymerization reaction rate model is used to monitor and control the polymerization reaction rate to ensure smooth reaction. The monodisperse polymer chromatographic packing material finally prepared has the characteristics of good monodispersity, good sphericity and narrow pore size distribution. It can be widely used in many fields such as protein separation, biomedicine, standard metrology, and chemical catalysis, providing a high-quality material basis for the development of related industries. This method effectively solves many problems existing in traditional chromatographic packing materials, such as poor size uniformity and poor pressure resistance of sugar microspheres, and poor chemical stability and poor acid and alkali resistance of silica packing materials. Attached Figure Description

[0023] Figure 1 This is a flowchart illustrating the overall steps of the present invention. Detailed Implementation

[0024] It should be noted that, unless otherwise specified, the embodiments and features in the embodiments of this application can be combined with each other. The following describes the application in further detail with reference to the accompanying drawings and specific embodiments.

[0025] like Figure 1 As shown, a method for preparing a monodisperse polymer filler includes the following steps:

[0026] S1: Select the raw materials required for the dispersion polymerization process, mix the set dispersant and reaction solvent in a certain proportion, and use ultrasound to promote uniform dispersion of the two. The ultrasound frequency is set between 350-370Hz, and the ultrasound duration is controlled at 30min to form a stable dispersion system. Then, the specific monomer with vinyl groups is mixed with the specific initiator in a certain proportion. The stirring is carried out by electric stirring, and the stirring speed is controlled within the range of 110-130rpm for 30min to ensure that the two are fully mixed and uniform.

[0027] Specifically, in step S1 of the preparation of monodisperse polymer chromatographic packing material, the first step is to select and pretreat the raw materials. The mixing of the dispersant and the reaction solvent is a crucial initial step in this process. Taking polyvinylpyrrolidone as the dispersant and ethanol as the reaction solvent as an example, the two are mixed in a certain proportion and then treated with ultrasound. The ultrasound frequency is set at 350-370 Hz, and the ultrasound duration is 30 minutes; this parameter setting is significant. At this frequency and duration, the high-frequency vibration generated by ultrasound can break the original aggregation state between the dispersant and solvent molecules, allowing the dispersant to be uniformly dispersed in the solvent, forming a stable dispersion system. This is similar to stirring a mixed liquid at a specific frequency and time, allowing substances that are prone to clumping to be evenly distributed in the liquid, ensuring the homogeneity of subsequent reactions.

[0028] Next, the vinyl monomer and initiator were mixed. Styrene was used as the vinyl monomer and azobisisobutyronitrile (AIBN) as the initiator. An electric stirrer was used at 110-130 rpm for 30 minutes. These stirring conditions ensured sufficient contact between the monomer and initiator, allowing the initiator to be uniformly dispersed within the monomer. The stirring process is analogous to thoroughly mixing two different colored sands, ensuring each part is evenly distributed. Uniform mixing of the monomer and initiator is fundamental for the smooth progress of the subsequent polymerization reaction. Inhomogeneous mixing may lead to localized polymerization, resulting in microspheres with uneven particle size.

[0029] This series of operations creates favorable conditions for the subsequent polymerization reaction. A stable dispersion system ensures that each microsphere is in a basically consistent environment during the formation of seed microspheres, which is conducive to the formation of seed microspheres with uniform particle size; while the thorough mixing of monomers and initiators ensures that the polymerization reaction starts uniformly throughout the system, avoiding inconsistent reactions and guaranteeing the quality and performance of the seed microspheres.

[0030] S2: Place the uniformly mixed reaction system from S1 into a reaction apparatus and heat it under constant temperature conditions. The reaction temperature is precisely controlled at 70℃ and the reaction duration is set to 24h. During this process, the vinyl monomer undergoes polymerization under the action of the initiator to generate seed microspheres with uniform particle size.

[0031] Specifically, step S2 involves a polymerization reaction to generate seed microspheres based on the reaction system formed in step S1. The reaction system is placed in a reaction apparatus, with the reaction temperature strictly controlled at 70°C and the reaction time at 24 hours. The reaction temperature of 70°C is an optimal temperature determined through extensive experimental verification. At this temperature, the initiator decomposes at a suitable rate to generate free radicals, which then initiate the polymerization reaction of the vinyl monomers. If the temperature is too high, the initiator decomposes too quickly, making the reaction rate difficult to control and potentially leading to an overly vigorous polymerization reaction and a wider particle size distribution in the resulting microspheres. If the temperature is too low, the initiator decomposes slowly, the polymerization reaction proceeds too slowly, and the reaction may not even be complete, affecting the formation of seed microspheres.

[0032] A 24-hour reaction time is crucial for ensuring the polymerization reaction proceeds fully. During this period, the vinyl monomers continuously polymerize under the influence of free radicals generated by the initiator, gradually forming seed microspheres with a specific particle size. Taking the preparation of polystyrene seed microspheres as an example, in this process, styrene monomer molecules are linked together by chemical bonds, forming increasingly larger polymer molecular chains, which eventually aggregate into microspheres. As the reaction time progresses, the particle size of the microspheres gradually increases, and when the reaction has proceeded for 24 hours, the particle size of the microspheres essentially reaches the expected uniform size.

[0033] The seed microspheres generated in this step form the basis for the subsequent preparation of monodisperse polymer chromatographic packing materials, and their particle size uniformity directly affects the quality of the final product. Uniform seed microsphere particle size ensures consistent growth and change of the microspheres during subsequent swelling and polymerization processes, thus producing polymer chromatographic packing materials with good monodispersity. If the seed microsphere particle size is not uniform, the performance of the subsequently prepared chromatographic packing materials will also differ, affecting their effectiveness in practical applications.

[0034] S3: After the S2 reaction is completed, the product containing the seed microspheres is taken out from the reaction device and thoroughly washed with water and alcohol to remove residual impurities. After washing, the impurities are further separated by positive pressure filtration to achieve preliminary purification of the seed microspheres. Finally, the purified seed microspheres are dried and properly stored.

[0035] Specifically, step S3 mainly involves post-processing the product obtained after the S2 reaction. The product often contains unreacted raw materials, byproducts generated during the reaction, and other impurities. These impurities can affect the purity and performance of the seed microspheres, thus requiring washing and purification. The product is thoroughly washed with water and alcohol, for example, alternating between deionized water and anhydrous ethanol. Water can dissolve some water-soluble impurities, and alcohol can dissolve some organic impurities. Through repeated alternating washing, most impurities can be effectively removed.

[0036] After cleaning, impurities are further separated using positive pressure filtration. Positive pressure filtration utilizes pressure difference to force liquid through a filter medium, while impurities are trapped on the filter medium. In this process, selecting a filter medium with an appropriate pore size is crucial; generally, a filter medium that can effectively trap impurities without causing significant loss of the seed microspheres is chosen. Positive pressure filtration further removes any remaining minute impurities after cleaning, improving the purity of the seed microspheres.

[0037] Finally, the purified seed microspheres were dried and properly stored. Drying removes residual moisture and solvent from the surface and interior of the seed microspheres, preventing deterioration or aggregation during storage. Proper storage protects the seed microspheres from external environmental influences such as dust and moisture. For example, the dried seed microspheres can be stored in a dry, sealed container in a cool, well-ventilated place. This series of post-processing steps results in seed microspheres with higher purity and better stability, providing high-quality raw materials for subsequent swelling and polymerization reactions.

[0038] S4: Activation step for seed swelling. Select the set swelling agent, mix the seed microspheres preserved in S3 with the swelling agent at a certain mass ratio, use ultrasonic emulsification, control the ultrasonic power at 1800-2200W, and continue to act for 12-24 hours at a temperature of 25-40℃ to activate the surface and internal structure of the seed microspheres, preparing for subsequent swelling.

[0039] Specifically, step S4 is the activation stage of seed swelling. Selecting a suitable swelling agent is crucial. Taking dibutyl phthalate (DBP) as an example, it is mixed with non-crosslinked polystyrene seed microspheres at a mass ratio of 10-100:1. The role of the swelling agent is to loosen the surface and internal structure of the seed microspheres, increasing their absorption capacity for subsequent swelling monomers. During the mixing process, ultrasonic emulsification is used, with the ultrasonic power controlled at 1800-2200W. Ultrasonic emulsification allows the swelling agent to be more evenly dispersed around the seed microspheres and promotes faster penetration into the interior of the seed microspheres, accelerating the activation process.

[0040] The activation temperature is controlled between 25-40℃, and the activation time is 12-24 hours. This temperature range and time setting are designed to ensure that the swelling agent can effectively act on the seed microspheres while avoiding damage to the structure of the seed microspheres due to excessively high temperatures or prolonged times. Within this temperature range, the swelling agent molecules have sufficient activity to interact with the molecular chains of the seed microspheres, making the microsphere structure looser. Over time, the swelling agent gradually penetrates into the interior of the microspheres, causing the microspheres to gradually expand in volume, increasing the number and size of pores on the surface and inside.

[0041] This activation step alters the physical and chemical properties of the seed microspheres, creating favorable conditions for the subsequent swelling process. Activated seed microspheres can more fully absorb the swelling monomers, resulting in more uniform and higher-performance polymer microspheres during the subsequent swelling and polymerization reactions, ultimately producing high-quality monodisperse polymer chromatographic packing material. Insufficient activation, however, leads to inadequate absorption of the swelling monomers by the seed microspheres, potentially resulting in uneven pore size distribution in the final product and affecting its application in chromatographic separation and other fields.

[0042] S5: After activation, a swelling step is performed. The second monomer, crosslinking agent, pore-forming agent, initiator, and SDS solution are prepared into an emulsion mixture in a specific ratio as the swelling monomer. The seed microspheres activated in S4 are mixed with the swelling monomer and then subjected to ultrasonic emulsification again. The ultrasonic power is controlled at 1800-2200W and the swelling is continued for 12-24 hours at a temperature of 25-40℃, so that the seed microspheres can further absorb the swelling monomer and achieve volume expansion.

[0043] Specifically, step S5 involves further swelling of the seed microspheres activated in step S4. First, a swelling monomer is prepared. This monomer is an emulsion mixture composed of a second monomer, a crosslinking agent, a porogen, an initiator, and an SDS solution in a specific ratio. Taking methyl methacrylate as the second monomer, divinylbenzene as the crosslinking agent, toluene as the porogen, and benzoyl peroxide as the initiator as an example, these substances are mixed in the specified ratio and then ultrasonically emulsified. The ultrasonic power is controlled at 1800-2200W, and the mixture is ultrasonically treated for a period of time to form a homogeneous emulsion system.

[0044] The activated seed microspheres were then mixed with the swelling monomer and allowed to swell continuously at 25-40℃ for 12-24 hours. During this process, the activated seed microspheres absorb the swelling monomer, further expanding their volume. The second monomer participates in the polymerization reaction of the microspheres during absorption, increasing the polymer content. The crosslinking agent forms a crosslinked structure inside the microspheres, enhancing their mechanical strength and stability. The presence of the pore-forming agent creates pores inside the microspheres, which are crucial for the separation performance of the chromatographic packing material. The initiator provides the initiation conditions for the subsequent polymerization reaction.

[0045] The swelling process is like "feeding" loosened seed microspheres with various nutrients, allowing them to grow and develop continuously. By precisely controlling the proportions of each component in the swelling monomer, the swelling temperature, and the time, the degree of swelling and the final structure of the microspheres can be effectively controlled. For example, increasing the proportion of cross-linking agent will increase the degree of cross-linking of the microspheres and enhance their mechanical strength, but may reduce their flexibility; adjusting the amount of pore-forming agent can change the pore size and distribution inside the microspheres. This step is crucial for preparing monodisperse polymer chromatographic packing materials with specific pore sizes and properties, directly affecting the quality and application effect of the final product.

[0046] S6: After swelling is complete, the temperature of the reaction system is raised to initiate the polymerization reaction. The polymerization temperature is controlled at 65-80℃ and the polymerization reaction duration is set to 12-36h. After the reaction is completed, the product is treated with pore-forming agent extraction, and then filtered, washed and dried to finally obtain monodisperse polymer microspheres. Further processing is then performed to obtain the required monodisperse polymer chromatographic packing material.

[0047] Specifically, step S6 involves initiating the polymerization reaction and post-processing the product to obtain the final monodisperse polymer chromatographic packing material. After swelling is complete, the temperature of the reaction system is raised to 65-80℃ to initiate the polymerization reaction, with the polymerization time controlled between 12-36 hours. Within this temperature range, the initiator begins to decompose, generating free radicals. These free radicals initiate polymerization reactions of various components in the swollen monomers. As the polymerization reaction proceeds, the polymer molecular chains inside the microspheres continuously grow and cross-link, gradually stabilizing the microsphere structure and enhancing its mechanical properties.

[0048] After the polymerization reaction, the product needs to be treated with an extraction porogen. Taking tetrahydrofuran as the extraction agent as an example, the extraction process removes the porogen from the inside of the microspheres, thereby forming a porous structure within the microspheres. These pores are key to the efficient separation of monodisperse polymer chromatographic packing materials. After extraction, the product also needs to undergo post-processing operations such as filtration, washing, and drying. Filtration removes some large particulate impurities that may have been generated during the reaction; washing further removes residual extraction agent, unreacted monomers, and other impurities; drying removes moisture from the product, bringing it to a stable state.

[0049] Through this series of operations, the resulting monodisperse polymer chromatographic packing material exhibits excellent monodispersity, good sphericity, and narrow pore size distribution. For example, scanning electron microscopy reveals that the prepared microspheres have uniform particle size, smooth surfaces, and a pore size distribution concentrated within a specific range. This high-quality chromatographic packing material can be widely used in protein separation, biomedicine, metrology, and chemical catalysis, providing crucial material support for research and production in these fields. In the entire preparation process, step S6 is the key step in transforming the preliminary preparation and reaction results into the final product, playing a decisive role in the product's performance and quality.

[0050] Preferably, the reaction solvent is one or a combination of n-butanol solution, ethanol solution, and isopropanol solution. When multiple solvents are mixed, the volume ratio of alcohol to water in the solvent needs to be in the range of 90-100:0-10. The dispersant is one of polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol. The initiator is one of potassium persulfate, ammonium persulfate, benzoyl peroxide, and azobisisobutyronitrile. The vinyl monomer is styrene.

[0051] Specifically, the reaction solvent can be one or more of n-butanol solution, ethanol solution, and isopropanol solution, with a volume ratio of alcohol to water of 90-100:0-10. Taking ethanol solution as an example, in the preparation of seed microspheres, ethanol provides a suitable dispersion environment for the reaction. Its specific ratio with water ensures uniform dispersion of the dispersant, monomer, and initiator, promoting a uniform polymerization reaction. If the alcohol content is too high, it may lead to poor solubility of some substances; if the alcohol content is too low, the presence of water may affect the reaction activity. Dispersants such as polyvinylpyrrolidone can adsorb onto the surface of the seed microspheres, preventing the microspheres from agglomerating during the reaction and ensuring the monodispersity of the microspheres. Initiators such as azobisisobutyronitrile (AIBN) decompose at a specific temperature to generate free radicals, initiating the polymerization of vinyl monomers. Styrene is selected as the vinyl monomer because it is chemically active and can effectively polymerize to form polymer microspheres under the action of the initiator.

[0052] Preferably, the mass ratio of the dispersant to the vinyl monomer should be controlled within the range of 5%-20%:1; the mass ratio of the initiator to the vinyl monomer should be within the range of 1%-4%:1; and the amount of the vinyl monomer should account for 10-30% of the total weight of the reaction system.

[0053] Specifically, the mass ratio of dispersant to vinyl monomer should be 5%-20%:1. If the dispersant ratio is too low, it cannot fully encapsulate the microspheres, easily leading to microsphere aggregation; if the ratio is too high, excessive dispersant residue will affect product purity. For example, when the mass ratio of dispersant to styrene is 10%:1, the microsphere dispersion can be maintained well. The mass ratio of initiator to vinyl monomer should be 1%-4%:1, which affects the polymerization rate. If the ratio is too low, the reaction will be slow or even fail to polymerize completely; if the ratio is too high, the reaction rate will be too fast and difficult to control, easily causing the microsphere particle size distribution to widen. The amount of vinyl monomer should account for 10-30% of the total weight of the reaction system. If the amount is too small, fewer microspheres will be generated; if the amount is too large, the viscosity of the system will increase, the reaction will be difficult to control, and the quality of the microspheres will be affected.

[0054] Preferably, in the S4 activation step, the seed is a non-crosslinked polystyrene microsphere, and the swelling agent is one or a combination of dibutyl phthalate (DBP), chloroform, and toluene; the mass ratio of the swelling agent to the seed is set in the range of 10-100:1.

[0055] Specifically, in the seed swelling activation step, the seed type is specified as non-crosslinked polystyrene microspheres, and the swelling agent can be one or a combination of several of dibutyl phthalate (DBP), chloroform, and toluene, with a swelling agent to seed mass ratio of 10-100:1. Taking dibutyl phthalate as an example, it can penetrate into the interior of the non-crosslinked polystyrene microspheres, causing the microspheres to swell and increasing the internal space, creating conditions for the subsequent entry of swelling monomers. A suitable mass ratio is crucial; if the swelling agent is too little, the activation effect will be poor, and the microspheres will not absorb enough of the subsequent swelling monomers; if there is too much, it may lead to over-swelling or even rupture of the microspheres. For example, when the swelling agent to seed mass ratio is 50:1, it can effectively activate the seed microspheres, which is beneficial to subsequent reactions.

[0056] Preferably, in the S5 swelling step, the second monomer is one or a combination of methyl methacrylate (MMA), styrene (St), glycidyl methacrylate (GMA), and hydroxyethyl methacrylate (HEMA); the crosslinking agent is divinylbenzene (DVB) or ethylene glycol dimethacrylate (EGDMA); the porogen is one or a combination of toluene, cyclohexanol, n-heptane, dodecanol, and linear polystyrene; the initiator is benzoyl peroxide (BPO) or azobisisobutyronitrile (AIBN); and the mass ratio of the second monomer to the seed is 2-20:1.

[0057] Specifically, the optional types of the second monomer, crosslinking agent, pore-forming agent, and initiator in the swelling step are clarified, and the mass ratio of the second monomer to the seed is 2-20:1. The second monomer, such as methyl methacrylate, can copolymerize with the polymer in the seed microspheres, altering the chemical composition and properties of the microspheres. The crosslinking agent, such as divinylbenzene, forms a crosslinked structure inside the microspheres, enhancing their mechanical strength and stability, making them less prone to deformation during subsequent use. The pore-forming agent, such as toluene, is removed after the polymerization reaction, thus forming pores inside the microspheres; these pores are crucial for the separation function of the chromatographic packing material. The initiator, such as benzoyl peroxide, initiates the polymerization reaction, solidifying the microsphere structure. The mass ratio of the second monomer to the seed affects the final performance of the microspheres; if the ratio is too low, the performance change is not significant; if the ratio is too high, it may lead to excessive crosslinking of the microspheres, affecting their flexibility and pore size distribution.

[0058] Preferably, in the S5 swelling step, the mass ratio of the crosslinking agent to the vinyl monomer is 0.1-5:1; the mass ratio of the porogen to the vinyl monomer is 0.5-2:1; and the mass ratio of the initiator to the vinyl monomer is 5%-30%:1.

[0059] Specifically, the mass ratios of crosslinking agent, porogen, initiator, and vinyl monomer in the swelling step are limited. The crosslinking agent to vinyl monomer mass ratio is 0.1-5:1, which determines the degree of crosslinking of the microspheres. Too low a degree of crosslinking results in poor mechanical strength of the microspheres; too high a degree results in overly hard and brittle microspheres. The porogen to vinyl monomer mass ratio is 0.5-2:1, controlling the size and number of pores inside the microspheres. A lower ratio results in fewer and smaller pores; a higher ratio results in more and larger pores, but may affect the strength of the microspheres. The initiator to vinyl monomer mass ratio is 5%-30%:1, affecting the rate and extent of the polymerization reaction. An appropriate ratio ensures a sufficient and stable reaction, avoiding excessively fast or slow reactions that could adversely affect the quality of the microspheres.

[0060] Preferably, a particle size control model is introduced: Where D is the particle size of the final prepared monodisperse polymer chromatographic packing material, D0 is the initial particle size of the seed microspheres, and m sw For the mass of the swelling agent, m s m is the mass of the seed microspheres. cm m is the total mass of the crosslinking agent and the pore-forming agent. vm Here, k represents the mass of the vinyl monomer, and k1 and k2 are particle size control coefficients, with k1 ranging from 0.01 to 0.05 and k2 ranging from 0.005 to 0.02. This model is based on the influence of the mass of swelling agent, crosslinking agent, pore-forming agent, and vinyl monomer on the final filler particle size during the preparation process. By adjusting the mass ratio of each material, the filler particle size can be effectively controlled according to this model.

[0061] Specifically, a particle size control model is introduced, based on the influence of the mass of materials such as swelling agents, crosslinking agents, pore-forming agents, and vinyl monomers on the final filler particle size. In actual preparation, the swelling agent causes the seed microspheres to expand, increasing the particle size; the crosslinking agent and pore-forming agent participate in the reaction, affecting the internal structure and volume changes of the microspheres, thus affecting the particle size. For example, when the amount of swelling agent increases, the microspheres absorb more swelling agent, and the particle size will increase; changes in the amount of crosslinking agent and pore-forming agent will adjust the degree of crosslinking and pore structure inside the microspheres, indirectly affecting the particle size. By adjusting the mass ratio of these materials, the particle size of the filler can be effectively controlled according to this model, preparing monodisperse polymer chromatography fillers with particle sizes that meet the requirements of different applications.

[0062] Preferably, a pore size distribution model is constructed: Where P(d) represents the probability distribution function for pore size d, μ is the average pore size, σ is the standard deviation of the pore size distribution, and m ca For the quality of the pore-forming agent, m vm m is the mass of the vinyl monomer. cm For the quality of the crosslinking agent, The function f(x,y) is related to the mass ratio of porogen and crosslinker, where f(x,y) = 1 + 0.5x - 0.2y. This model comprehensively considers the mass ratio of porogen and crosslinker to vinyl monomers and is used to describe the pore size distribution of monodisperse polymer chromatographic packings, which helps to accurately control the pore size distribution characteristics of the packings.

[0063] Specifically, the pore size distribution of monodisperse polymer chromatographic packing materials is described by comprehensively considering the mass ratio of porogens and crosslinkers to vinyl monomers. Porogens form pores inside the microspheres, while crosslinkers affect the crosslinking structure of the microspheres; changes in their mass ratio alter the size, shape, and distribution of the pores. For example, increasing the amount of porogen may increase the number and size of pores; increasing the amount of crosslinker improves the degree of crosslinking of the microspheres, potentially leading to a more uniform pore distribution or altering pore connectivity. This model allows for targeted adjustment of these material ratios during preparation, precisely controlling the pore size distribution characteristics of the packing material to meet the pore size requirements of different separation tasks.

[0064] Preferably, during the S1 mixing process, when multiple reaction solvents are used, the solvent mixing uniformity is measured by the mixing uniformity coefficient M. Among them, V i Let C be the volume of the i-th solvent. i Let be the concentration of the i-th solvent, n be the number of solvent types, and the mixing uniformity coefficient M must be in the range of 0.95-1.05 to ensure that the reaction solvents are mixed uniformly and to provide a stable environment for subsequent reactions.

[0065] Specifically, the mixing uniformity coefficient is used to measure the mixing effect of multiple reaction solvents, and the mixing uniformity coefficient needs to meet the range of 0.95-1.05. When using multiple reaction solvents, such as ethanol and n-butanol, the properties of different solvents differ. If the mixing is not uniform, it will lead to different local compositions in the reaction system, affecting the uniformity of the polymerization reaction. For example, in the dispersion polymerization process, uneven solvent mixing may result in monomer concentrations that are too high or too low in some areas, causing inconsistent microsphere particle sizes. By monitoring the mixing uniformity coefficient, it is ensured that the solvents are fully mixed, providing a stable and uniform environment for subsequent reactions, and ensuring the quality and monodispersity of the seed microspheres.

[0066] Preferably, during the S6 polymerization reaction, the polymerization rate is determined by the reaction rate model R. p =k p ×[M]×[I] 0.5 Monitoring and regulation are carried out, among which R p k is the polymerization rate. p [M] represents the polymerization rate constant, [I] represents the monomer concentration, and [I] represents the initiator concentration. In this preparation method, the monomer concentration and initiator concentration are monitored in real time, and the reaction conditions are adjusted according to this model to keep the polymerization rate within the range of 0.01-0.05 mol / (L·s) to ensure that the polymerization reaction proceeds smoothly and the product with the expected performance is obtained.

[0067] Specifically, polymerization rate models are used to monitor and control the polymerization rate, keeping it within the range of 0.01-0.05 mol / (L·s). The polymerization rate has a significant impact on product quality. An excessively fast reaction rate may lead to rapid heat accumulation within the system, causing explosive polymerization, resulting in a wider particle size distribution and uneven structure of the microspheres. Conversely, an excessively slow reaction rate leads to low production efficiency and may result in incomplete reactions, affecting microsphere performance. For example, during the initiation of the polymerization reaction, by real-time monitoring of monomer and initiator concentrations and adjusting reaction temperature, stirring speed, and other conditions according to the model, the reaction rate is controlled within a suitable range to ensure stable polymerization and obtain monodisperse polymer chromatographic packing materials with stable performance and reliable quality.

[0068] A method for preparing a monodisperse polymer packing material has significant advantages and effectively overcomes many shortcomings of traditional chromatographic packing materials and existing preparation techniques.

[0069] From a process perspective, this method employs dispersion polymerization to synthesize seed microspheres, followed by a two-step seed swelling process to prepare the final product. The conditions for each step are clearly defined and controllable. For example, during dispersion polymerization, the dispersant and reaction solvent are ultrasonically mixed, and the vinyl monomers and initiator are mixed by electric stirring. The reaction temperature and time are precisely set to 70℃ and 24h, ensuring uniform seed microsphere particle size. Compared to traditional methods, dispersion polymerization avoids the problems of excessively small microsphere size in emulsion polymerization and the wide particle size distribution requiring sieving in suspension polymerization. It also solves the drawback of residual surfactants affecting purity in dispersion polymerization. In the seed swelling stage, the precise control of temperature, time, and the proportions of each material during activation and swelling ensures that the microspheres form an ideal structure in subsequent polymerization. This overcomes the shortcomings of existing technologies that struggle to precisely control microsphere particle size and pore size. For instance, while SPG membrane emulsification can precisely control particle size, it is technically complex and has high equipment costs, whereas this method offers a simpler and lower-cost preparation process.

[0070] In terms of product performance, the monodisperse polymer chromatographic packing material prepared by this method has significant advantages. By introducing particle size control and pore size distribution models, the particle size and pore size distribution characteristics of the packing material can be flexibly adjusted according to actual needs. For example, the microsphere particle size can be precisely controlled within the required range, and the pore size distribution is narrow, which is unmatched by traditional carbohydrate microspheres and silica gel packing materials. Carbohydrate microspheres have poor size uniformity and are not pressure resistant, while silica gel packing materials have poor chemical stability and are not resistant to acids and alkalis. In contrast, this polymer chromatographic packing material has good monodispersity, good sphericity, and narrow pore size distribution, and exhibits excellent chemical stability and pressure resistance. It can be widely used in protein separation, biomedicine, standard metrology, chemical catalysis, and other fields, greatly expanding its application scope.

[0071] In terms of reaction process control, the mixing uniformity coefficient is used to monitor the mixing effect of the reaction solvent, ensuring a stable reaction environment; the polymerization reaction rate model is used to monitor and regulate the polymerization reaction rate, ensuring the smooth progress of the reaction. This avoids product quality problems caused by unstable reaction conditions, overcomes the shortcomings of existing technologies in controlling the reaction process, and makes the preparation process more scientific and efficient, with more stable and reliable product quality, providing strong support for the development of related industries.

[0072] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various equivalent changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a monodisperse polymer filler, characterized in that, The method includes: S1: Select the raw materials required for the dispersion polymerization process, mix the set dispersant and reaction solvent in a certain proportion, and use ultrasound to promote uniform dispersion of the two. The ultrasound frequency is set between 350-370Hz, and the ultrasound duration is controlled at 30min to form a stable dispersion system. Mix the specific monomer with vinyl group and the specific initiator in a certain proportion, and use electric stirring to control the stirring speed in the range of 110-130rpm for 30min to ensure that the two are fully mixed and uniform. S2: Place the uniformly mixed reaction system from S1 into a reaction apparatus and heat it under constant temperature conditions. Precisely control the reaction temperature at 70°C and set the reaction duration to 24 hours. During this process, the vinyl monomer undergoes polymerization under the action of the initiator to generate seed microspheres with uniform particle size. S3: After the S2 reaction is completed, remove the product containing the seed microspheres from the reaction apparatus, and wash the product thoroughly with water and alcohol to remove residual impurities. After washing, use positive pressure filtration to further separate the impurities, so that the seed microspheres are initially purified. Dry the purified seed microspheres and store them. S4: The seed swelling activation step is carried out. The set swelling agent is selected, and the seed microspheres preserved in S3 are mixed with the swelling agent at a certain mass ratio. The mixture is then subjected to ultrasonic emulsification with ultrasonic power controlled at 1800-2200W. The mixture is kept at a temperature of 25-40℃ for 12-24 hours to activate the surface and internal structure of the seed microspheres. S5: After activation, a swelling step is performed. The second monomer, crosslinking agent, pore-forming agent, initiator, and SDS solution are prepared into an emulsion mixture in a specific ratio as the swelling monomer. The seed microspheres activated in S4 are mixed with the swelling monomer and then subjected to ultrasonic emulsification again. The ultrasonic power is controlled at 1800-2200W and the swelling is continued for 12-24 hours at a temperature of 25-40℃, so that the seed microspheres can further absorb the swelling monomer and expand in volume. S6: After swelling is complete, the temperature of the reaction system is raised to initiate the polymerization reaction. The polymerization temperature is controlled at 65-80℃ and the polymerization reaction duration is set to 12-36h. After the reaction is completed, the product is treated with pore-forming agent extraction, and then filtered, washed and dried to obtain monodisperse polymer microspheres. Further processing is then performed to obtain the required monodisperse polymer chromatographic packing material.

2. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, The reaction solvent is one or a combination of n-butanol solution, ethanol solution, and isopropanol solution. When multiple solvents are mixed, the volume ratio of alcohol to water in the solvent must be in the range of 90-100:0-10. The dispersant is one of polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol. The initiator is one of potassium persulfate, ammonium persulfate, benzoyl peroxide, and azobisisobutyronitrile. The monomer with vinyl groups is styrene.

3. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, The mass ratio of the dispersant to the vinyl monomer needs to be controlled within the range of 5%-20%:1; the mass ratio of the initiator to the vinyl monomer should be within the range of 1%-4%:1; and the amount of the vinyl monomer should account for 10-30% of the total weight of the reaction system.

4. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, In the S4 activation step, the seed is a non-crosslinked polystyrene microsphere, and the swelling agent is one or a combination of dibutyl phthalate (DBP), chloroform, and toluene; the mass ratio of the swelling agent to the seed is set in the range of 10-100:

1.

5. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, In the S5 swelling step, the second monomer is one or a combination of methyl methacrylate (MMA), styrene (St), glycidyl methacrylate (GMA), and hydroxyethyl methacrylate (HEMA); the crosslinking agent is divinylbenzene (DVB) or ethylene glycol dimethacrylate (EGDMA); the porogen is one or a combination of toluene, cyclohexanol, n-heptane, dodecanol, and linear polystyrene; the initiator is benzoyl peroxide (BPO) or azobisisobutyronitrile (AIBN); and the mass ratio of the second monomer to the seed is 2-20:

1.

6. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, In the S5 swelling step, the mass ratio of the crosslinking agent to the vinyl monomer is 0.1-5:1; the mass ratio of the porogen to the vinyl monomer is 0.5-2:1; and the mass ratio of the initiator to the vinyl monomer is 5%-30%:

1.

7. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, Introducing a particle size control model: Where D is the particle size of the final prepared monodisperse polymer chromatographic packing material, D0 is the initial particle size of the seed microspheres, and m sw For the mass of the swelling agent, m s m is the mass of the seed microspheres. cm m is the total mass of the crosslinking agent and the pore-forming agent. vm The mass of the vinyl monomer is denoted as k1, and k2 is the particle size control coefficient. The value of k1 ranges from 0.01 to 0.05, and the value of k2 ranges from 0.005 to 0.

02. This model is based on the influence of the mass of swelling agent, crosslinking agent, pore-forming agent and vinyl monomer on the final filler particle size during the preparation process.

8. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, Construct an aperture distribution model: Where P(d) represents the probability distribution function for pore size d, μ is the average pore size, σ is the standard deviation of the pore size distribution, and m ca For the quality of the pore-forming agent, m vm m is the mass of the vinyl monomer. cm For the quality of the crosslinking agent, The function f(x,y) = 1 + 0.5x - 0.2y is related to the mass ratio of porogen and crosslinker. This model takes into account the mass ratio of porogen and crosslinker to vinyl monomer and is used to describe the pore size distribution of monodisperse polymer chromatographic packing.

9. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, In the S1 mixing process, when multiple reaction solvents are used, the solvent mixing uniformity is measured by the mixing uniformity coefficient M. Among them, V i Let C be the volume of the i-th solvent. i Let be the concentration of the i-th solvent, n be the number of solvent types, and the mixing uniformity coefficient M must be in the range of 0.95-1.

05.

10. The method for preparing a monodisperse polymer filler according to claim 1, characterized in that, In the S6 polymerization reaction, the polymerization rate is expressed by the reaction rate model R6. p =k p ×[M]×[I] 0.5 Monitoring and regulation are carried out, among which R p k is the polymerization rate. p [M] represents the polymerization rate constant, [I] represents the monomer concentration, and [I] represents the initiator concentration. In this preparation method, the polymerization rate is maintained within the range of 0.01-0.05 mol / (L·s) by real-time monitoring of monomer and initiator concentrations and adjusting reaction conditions according to this model.

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