Improved dispersion polymerization method for preparing micron-sized polystyrene microspheres
Through the addition of regulators, dynamic solvent concentration control and oxygen introduction strategies, the problem of difficult to prepare large-sized monodispersed microspheres in traditional dispersion polymerization methods is solved, and the preparation of micron-scale polystyrene microspheres with good particle size uniformity and batch repeatability is achieved, which is suitable for the biochemistry and medical fields.
Patent Information
- Application Number
- CN202510784547.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-12
- Publication Date
- 2025-08-08
AI Technical Summary
It is difficult to prepare large-sized monodispersed microspheres with wider particle size distribution and difficult to control the coefficient of variation below 5%, resulting in unsatisfactory monodispersity and batch repeatability of the microspheres.
The strategies of adjusting agent addition, dynamic solvent concentration control and oxygen introduction are adopted to effectively increase and uniformity control of microsphere particle size by regulating the primary nuclear particle size and polymerization reaction conditions.
The micron-scale polystyrene microspheres with good particle size uniformity and coefficient of variation less than 5% are prepared. The process is simple and suitable for the preparation of microspheres of a variety of monomers, meeting the needs of the biochemistry and medical fields.
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Figure CN120441739A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of polymer material preparation, and specifically relates to a method for preparing monodisperse, high-yield micron-sized polystyrene (PS) microspheres by an improved dispersion polymerization method, which is suitable for application needs in the fields of biochemistry, medical treatment and medicine. Background Art
[0002] In recent years, demand for polystyrene (PS) microspheres has exploded in the biomedical, electronic information, and intelligent sensing sectors due to their excellent monodispersity and surface modifiability. With the in-depth application of artificial intelligence (AI) technology, the application of PS microspheres is experiencing revolutionary breakthroughs, further promoting their expansion into cutting-edge fields such as precision medicine, intelligent sensing, and high-throughput testing.
[0003] Due to the limitations of its reaction mechanism and kinetic characteristics, the traditional dispersion polymerization method is mainly suitable for the preparation of monodisperse microspheres with a diameter of less than 3 microns. When trying to prepare microspheres of larger sizes (diameter greater than 2 microns), the method faces significant process challenges: First, as the target particle size increases, the matching degree between the monomer diffusion rate and the polymerization rate in the reaction system decreases, which can easily lead to uneven growth of the microspheres; secondly, larger microspheres are more prone to secondary nucleation and particle agglomeration during the formation process; in addition, the dynamic equilibrium of the solvent-monomer-stabilizer system is more difficult to maintain. These factors together lead to a significant widening of the particle size distribution of the product. Even after process optimization, the coefficient of variation of the particle size is usually difficult to control below 5%, resulting in unsatisfactory monodispersity and batch repeatability of the microspheres. Summary of the Invention
[0004] This invention aims to address the technical challenge of producing large, monodisperse microspheres using traditional dispersion polymerization methods. To address the significant increase in the coefficient of variation when the microsphere diameter exceeds 3 microns, the present invention addresses the problem by regulating the nucleation mechanism and improving the traditional process through the following strategies:
[0005] 1. Regulator addition strategy: Introducing a regulator into the reaction system significantly improves the reaction medium's ability to dissolve the long polymer chains in the initial stages of the polymerization reaction. By regulating the dissolution-precipitation equilibrium, the particle size of the primary nucleus increases, thereby forming larger microspheres in the subsequent growth stage.
[0006] 2. Dynamic solvent concentration control strategy: Leveraging the dual properties of styrene as both a monomer and a regulator, the continuous flow of high-purity nitrogen allows for slow volatilization of the reaction solvent, maintaining a relatively stable styrene concentration in the system. This approach avoids the rapid consumption of styrene that can lead to a decrease in solubility in traditional processes, further promoting the stable growth of primary polymer chains and ultimately increasing the size of the microspheres.
[0007] 3. Oxygen Introduction Strategy: Oxygen, a typical polymerization inhibitor, acts by consuming free radicals to hinder the polymerization reaction. Controlled introduction of oxygen during the initial reaction phase can reduce free radical concentration, decrease the number of primary nuclei, and increase the primary nucleation particle size, effectively regulating the final particle size of polymer microspheres.
[0008] To achieve the above objectives, the present invention adopts the following technical solutions:
[0009] The raw materials used in the synthesis are: monomer is styrene (St), initiator is azobisisobutyronitrile (AIBN), stabilizer is polyvinylpyrrolidone K30, and regulator is a solubility parameter of 9.3±5 (cal / cm 3 ) 2 The solvent includes but is not limited to benzene, toluene, xylene, ethylbenzene, isopropyl alcohol, isobutyl alcohol, acetonitrile, methyl acetate, ethyl acetate, etc. The reaction medium is anhydrous ethanol or a mixed solvent of anhydrous ethanol / modifier.
[0010] The initiator is 0.5%-2% of the monomer mass; the monomer is 10%-100% of the total amount of the reaction solvent and the regulator; the stabilizer is 5%-20% of the monomer mass; the regulator is 0-20% of the reaction solvent; the stirring speed is 100-400 rpm; the reaction temperature is 60-75°C; and the reaction time is 12-48 hours.
[0011] (1) Micron-sized microspheres were prepared using the “regulator addition” strategy.
[0012] The monomers, initiator, stabilizer, and modifier components are soluble in ethanol to form a homogeneous system. The modifier content should not exceed 20% of the reaction medium (the combined volume of the modifier and ethanol solvent). An appropriate olive-shaped magnet is added to the reaction flask, and nitrogen is bubbled through for 30 minutes to remove oxygen from the mixed solvent. The reaction system is then sealed. The polymerization reaction is carried out in an oil bath with a magnetic stirrer. The stirring speed is adjusted between 100 and 400 rpm, and the temperature is gradually increased from room temperature to the target temperature for 12–48 hours. After the reaction is completed, the medium and other components are removed by washing, sedimentation, and filtration. The micron-sized polystyrene microspheres are then dried in a 40°C oven for 24 hours.
[0013] (2) Apply the “dynamic solvent concentration control” strategy to prepare micron-sized microspheres.
[0014] The monomers, initiator, stabilizer, and modifier components are soluble in ethanol to form a homogeneous system. The modifier content should not exceed 20% of the reaction medium (the combined volume of the modifier and ethanol solvent). A suitable olive-shaped magnet is added to the reaction flask, and the reaction system is kept open. High-purity nitrogen is introduced at a flow rate of 0–500 ml / min to remove oxygen and slowly remove the ethanol solvent. The polymerization reaction is carried out in an oil bath with a magnetic stirrer at a speed of 100–400 rpm. The temperature is gradually increased from room temperature to the target temperature for 12–48 hours. After the reaction, the medium and other components are removed by washing, sedimentation, and filtration, and the micron-sized polystyrene microspheres are dried in a 40°C oven for 24 hours.
[0015] (3) Apply the “oxygen introduction” strategy to prepare micron-sized microspheres.
[0016] The monomer, initiator, stabilizer and regulator components can be dissolved in ethanol to form a homogeneous system. The regulator content should not exceed 20% of the reaction medium (the sum of the volume of the regulator and the ethanol solvent). Add a suitable olive-shaped magnet to the reaction bottle, keep the reaction system open, and introduce an oxygen / nitrogen mixed gas or air at a flow rate of 0-200 ml / min. The polymerization reaction is carried out in an oil bath magnetic stirrer, the stirring speed is adjusted to 100-400 rpm, the temperature is gradually increased from room temperature to the target temperature, and the reaction is carried out for 12-48 hours. After the reaction is completed, the medium and other components are removed by washing, sedimentation, filtration, etc., and dried in an oven at 40°C for 24 hours to obtain micron-sized polystyrene microspheres, C v .
[0017] Preferably, the above-mentioned regulator has a solubility parameter of 9.3±5 (cal / cm 3 ) 2 Solvents include but are not limited to benzene, toluene, xylene, ethylbenzene, isopropyl alcohol, isobutyl alcohol, acetonitrile, methyl acetate, ethyl acetate, etc.
[0018] Preferably, the target temperature is 60-75°C, or a step-type temperature gradient within this range.
[0019] Preferably, the washing method is to wash with ethanol and deionized water in sequence to remove the upper liquid.
[0020] Preferably, the sedimentation agent is a mixed solution of ethanol / deionized water or glycerol / deionized water, wherein the ratio of ethanol or glycerol to deionized water is 0-100%, and the ratio is adjusted according to the particle size of the microspheres, and the sedimentation is carried out naturally, and the sedimentation time is 1-72 hours.
[0021] The technical features of the present invention are:
[0022] (1) This method improves upon the traditional dispersion polymerization method and is capable of producing polystyrene microspheres with a particle size greater than 2 μm. The preparation method is simple and easily scalable. Compared to the seed swelling method, the present invention offers a simple and efficient preparation process, eliminates the need for small-particle seeds, and allows for easy control of the particle size of the finished microspheres, effectively reducing production costs.
[0023] (2) The polystyrene microspheres prepared by the present invention have more controllable particle size methods. In addition to adjusting the content of styrene, initiator and stabilizer, the type and proportion of the regulator, the flow rate of high-purity nitrogen, the ratio and flow rate of oxygen / nitrogen mixed gas, etc. can also be adjusted. The adjustment method is more diversified and the range of polystyrene microsphere particle size control is wider.
[0024] (3) The surface of the microspheres prepared by the present invention is smooth and the sphericity is good. After washing, sedimentation, filtration and other steps, the coefficient of variation is less than 5%, which can meet the use requirements of most scenarios.
[0025] (4) The microsphere preparation method involved in the present invention is universal and is not only applicable to the controlled preparation of polystyrene microspheres, but also to the preparation of microspheres of other vinyl monomers such as methyl methacrylate (MMA).
[0026] (5) The microsphere size control strategy of the present invention can be selected from one or more of the three strategies and used simultaneously in the specific micron-sized microsphere synthesis process. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 : SEM morphology of microspheres prepared in Example 1 of the present invention (2.0 μm);
[0028] Figure 2 : SEM morphology of microspheres prepared in Example 2 of the present invention (3.2 μm);
[0029] Figure 3 : SEM morphology of microspheres prepared in Example 3 of the present invention (4.5 microns);
[0030] Figure 4 : SEM morphology of microspheres prepared in Example 4 of the present invention (5.0 μm);
[0031] Figure 5 : SEM morphology of microspheres prepared in Example 5 of the present invention (6.3 μm);
[0032] Figure 6 : SEM morphology of microspheres prepared in Example 6 of the present invention (8.0 microns). DETAILED DESCRIPTION
[0033] In order to better understand the technical solution of the present application, the technical solution of the present application will be described in detail below with reference to specific examples. The reagents, consumables, etc. used in the following examples, unless otherwise specified, can be obtained through commercial channels.
[0034] Example 1: Preparation of polystyrene microspheres with a diameter of 2.0 microns:
[0035] 0.24g AIBN was added to 20ml styrene and ultrasonically shaken for 5 minutes to completely dissolve the AIBN. The mixture was then added to 125ml anhydrous ethanol containing 3.2g polyvinylpyrrolidone K30. The stirring speed of the magnetic stirrer was set to 300rpm. High-purity nitrogen was introduced for 30 minutes and the reaction system was sealed. The reaction temperature was gradually raised from room temperature to 70°C and the reaction was continued for 24 hours. After the reaction was completed, the precipitate was washed three times with ethanol and deionized water. The separated precipitate was dried in an oven at 40°C for 24 hours to obtain polystyrene microspheres with a diameter of 2.0 microns. The conversion rate was 86%. v =1.6.
[0036] Example 2: Preparation of polystyrene microspheres with a diameter of 3.2 microns:
[0037] Weigh 0.16g of AIBN and add it to 16ml of styrene. Ultrasonicate for 5 minutes to completely dissolve the AIBN. Mix 4ml of xylene and 36ml of anhydrous ethanol evenly, and add 1g of polyvinylpyrrolidone K30 to dissolve it. Set the magnetic stirrer to 200rpm, introduce high-purity nitrogen for 30 minutes, and then seal the reaction system. The reaction temperature is gradually raised from room temperature to 70°C and reacted for 24 hours. After the reaction is completed, wash the precipitate three times with ethanol and deionized water in sequence. The separated precipitate is dried in a 40°C oven for 24 hours to obtain polystyrene microspheres with a diameter of 3.5 microns, with a conversion rate of 88%. v =3.4.
[0038] Example 3: Preparation of polystyrene microspheres with a diameter of 4.5 microns:
[0039] 0.4 g AIBN and 2.6 g polyvinylpyrrolidone K30 were weighed and added to a double-necked reaction flask, followed by the addition of 40 ml styrene and 80 ml anhydrous ethanol. The mixture was stirred evenly under a magnetic stirring condition of 200 rpm. The reaction system was kept open and high-purity nitrogen was introduced at a rate of 100 ml / min. The reaction temperature was gradually raised from room temperature to 70°C and the reaction was carried out for 24 h. After the reaction was completed, the precipitate was washed three times with ethanol and deionized water in sequence. Finally, the precipitate was separated and dried in an oven at 40°C for 24 h to obtain polystyrene microspheres with a diameter of 4.5 μm. The conversion rate was 87%, and C v =2.6.
[0040] Example 4: Preparation of polystyrene microspheres with a diameter of 5.0 microns:
[0041] 0.26g AIBN was added to 26ml styrene and ultrasonically shaken for 5min to completely dissolve the AIBN. It was then added to 60ml anhydrous ethanol dissolved with 1.7g polyvinyl pyrrolidone K30 and stirred evenly at a stirring speed of 200rpm. The reaction system was kept open and the reaction temperature was gradually raised from room temperature to 70°C. After the reaction was completed for 30h, the precipitate was washed 3 times with ethanol and deionized water in sequence. After natural sedimentation in an ethanol / deionized water mixed solution (volume ratio 1:1), the supernatant was poured out and the sedimentation was repeated until the upper liquid was clear. The separated precipitate was dried in an oven at 40°C for 24h to obtain polystyrene microspheres with a diameter of 6.0 microns, with a conversion rate of 73%, C v =3.2.
[0042] Example 5: Preparation of polystyrene microspheres with a diameter of 6.0 microns:
[0043] 0.9g AIBN was added to 88ml styrene, ultrasonically shaken for 5min to completely dissolve AIBN, and then added to 160ml anhydrous ethanol dissolved with 5.8g polyvinyl pyrrolidone K30, stirred evenly at a stirring speed of 200rpm, and the reaction system was kept open. The reaction temperature was gradually raised from room temperature to 60°C, reacted for 1h, and then raised to 70°C and reacted for 30h. After the reaction was completed, the precipitate was washed 3 times with ethanol and deionized water in sequence, and naturally settled in an ethanol / deionized water mixed solution (volume ratio 1:1) and the supernatant was poured out. The sedimentation was repeated until the upper liquid was clear. The separated precipitate was dried in an oven at 40°C for 24h to obtain polystyrene microspheres with a diameter of 6.0 microns, with a conversion rate of 65%, C v =2.2.
[0044] Example 6: Preparation of polystyrene microspheres with a diameter of 8.0 microns:
[0045] 0.4g AIBN was added to 40ml styrene and ultrasonically shaken for 5min to completely dissolve the AIBN. Then, it was added to 100ml anhydrous ethanol / acetonitrile mixed solution (anhydrous ethanol: acetonitrile = 19:1) dissolved with 2.6g polyvinyl pyrrolidone K30, and stirred evenly at a stirring speed of 200rpm. The reaction system was kept open, and the reaction temperature was gradually raised from room temperature to 60°C, reacted for 1h, and then raised to 70°C and reacted for 30h. After the reaction was completed, the precipitate was washed 3 times with ethanol and deionized water in sequence, and naturally settled in an ethanol / deionized water mixed solution (volume ratio 2:1). The supernatant was poured out and the sedimentation was repeated until the upper liquid was clear. The separated precipitate was dried in an oven at 40°C for 24h to obtain polystyrene microspheres with a diameter of 8.0 microns, with a conversion rate of 70%, C v =4.2.
[0046] The formula for calculating "conversion rate" is as follows:
[0047]
[0048] The coefficient of variation is calculated as follows:
[0049]
[0050] Where: σ is the standard deviation of the microsphere diameter;
[0051] μ is the ratio of the average value of the microsphere diameter;
[0052] The sample size for calculating the coefficient of variation of microsphere diameters was 500.
[0053] The above examples show that the present invention can be used to prepare polystyrene microspheres with a particle size greater than 2 microns, which have a smooth surface and uniform size.
[0054] The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiment. Any modifications, equivalent replacements, improvements, etc. made by ordinary technicians in this field based on the contents disclosed by the present invention should be included in the protection scope recorded in the claims.
Claims
1. A method for preparing micron-sized polystyrene microspheres by an improved dispersion polymerization method, characterized in that: The raw materials are styrene, stabilizer, regulator, initiator and reaction medium, wherein the initiator accounts for 0.5%-2% of the monomer mass; the monomer accounts for 10%-100% of the total amount of the reaction solvent and regulator; the stabilizer accounts for 5%-20% of the monomer mass; the regulator accounts for 0-20% of the reaction solvent; the stirring speed is 100-400 rpm; the reaction temperature is 60-75°C, or a step-type temperature gradient within this range; and the reaction time is 12-48 hours. During the synthesis of micron-sized microspheres, one or more of a regulator addition strategy, a dynamic solvent concentration control strategy, or an oxygen introduction strategy is used simultaneously; After the reaction is completed, the reaction emulsion is added to a centrifuge tube, centrifuged at an appropriate speed, and the upper solution is discarded. Ethanol is added and centrifuged for 3-5 times, and then centrifuged and washed 3-5 times with deionized water. Then, a suitable sedimentation agent is used to precipitate multiple times or a suitable filter membrane is used to filter. The washed / precipitated / filtered microspheres are placed in an oven at 40°C and dried for 24 hours to obtain micron-sized polystyrene microspheres.
2. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: The regulator addition strategy includes the following steps: ultrasonically dissolving a certain amount of initiator in styrene, adding the solution to a mixed reaction solution containing a certain proportion of regulator and stabilizer, stirring the mixed solution at a certain speed, introducing high-purity nitrogen for 30 minutes to remove oxygen from the solution, then sealing the reaction system, gradually raising the temperature from room temperature to the reaction temperature, and stopping the reaction after an appropriate reaction time. The dynamic solvent concentration control strategy involves the following steps: ultrasonically dissolving a certain amount of initiator in styrene, adding the solution to a mixed reaction solution containing a certain proportion of a regulator and a stabilizer, stirring the mixed solution at a certain speed, maintaining an open system, and continuously introducing high-purity nitrogen at a certain flow rate. The temperature is gradually raised from room temperature to the reaction temperature, and the reaction is terminated after an appropriate reaction time. The oxygen introduction strategy comprises the following reaction steps: ultrasonically dissolving a certain amount of initiator in styrene, adding the solution to a mixed reaction solution containing a certain proportion of a regulator and a stabilizer, stirring the mixed solution evenly at a certain speed, keeping the system open, and continuously introducing a certain flow rate and concentration of oxygen / nitrogen mixed gas or air, gradually raising the temperature from room temperature to the reaction temperature, and stopping the reaction after an appropriate reaction time.
3. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: The initiator was azobisisobutyronitrile, which was purified by recrystallization from ethanol.
4. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: The stabilizer is polyvinylpyrrolidone K30.
5. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: The solubility parameter of the modifier is 9.3±5 (cal / cm 3 ) 2 Solvents include but are not limited to benzene, toluene, xylene, ethylbenzene, isopropyl alcohol, isobutyl alcohol, acetonitrile, methyl acetate, and ethyl acetate.
6. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: High-purity nitrogen gas is continuously introduced into the open system at a certain flow rate of 0-500 ml / min.
7. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: An oxygen / nitrogen mixed gas or air is continuously introduced into the open system at a certain flow rate of 0-200 ml / min.
8. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: An oxygen / nitrogen mixed gas is continuously introduced into the open system at a certain flow rate, and the oxygen concentration thereof is 0-100%.
9. The method for preparing micron-sized polystyrene microspheres by dispersion polymerization according to claim 1, characterized in that: The sedimentation agent is a mixed solution of ethanol / deionized water or glycerol / deionized water, wherein the ratio of ethanol or glycerol to deionized water is 0-100%. The ratio is adjusted according to the particle size of the microspheres. The sedimentation time is 1-72 hours, depending on the volume of the microspheres.
10. The method according to claim 1 is universal and is also applicable to the preparation of microspheres of methyl methacrylate (MMA) and other vinyl monomers.