Resin microspheres, and methods of making and using the same

Abstract

The application discloses resin microspheres, a preparation method and application thereof. The method is improved in view of a dispersing agent used in a seed microsphere preparation process, and can effectively ensure the size uniformity of the obtained seed microspheres. In combination with improvement in a seed microsphere swelling process, finally, the prepared resin microspheres have a polydispersity coefficient of 1-1.2 and a particle size of 4-9 microns.

Description

TECHNICAL FIELD

[0001] The present application relates to a seed microsphere and a resin microsphere, and simultaneously provides a preparation method and application of the seed microsphere and the resin microsphere. BACKGROUND

[0002] The micrometer-sized styrene-divinylbenzene resin microsphere is a new type of functional material, has the advantages of good sphericity, large specific surface area, and easy surface modification, and is one of the fillers available for chromatographic columns such as ion chromatography and liquid chromatography. When used as a chromatographic column filler, the crosslinking degree and the uniformity of the particle size of the resin microsphere are important factors affecting the chromatographic separation effect. The crosslinking degree is required to be at least not less than 25%, and a higher crosslinking degree can ensure that the resin microsphere is not easy to swell and dissolve in organic matter, and can withstand a larger pressure; and a certain range of particle size (usually 4-10 microns) is generally required to be selected.

[0003] The seed swelling method is one of the ideal methods for preparing monodisperse porous polymer microspheres at present, and the seed swelling polymerization system is usually composed of seed microspheres (or seed droplets), a swelling aid, monomers (or monomer droplets), a dispersed phase, an initiator, and a stabilizer. In order to prepare crosslinked porous microspheres, a crosslinking agent and a porogen are also required. The specific method is to first introduce the swelling aid into the seed microspheres to activate the seed microspheres, then add the monomers to continue swelling, add the stabilizer after the swelling is completed, and then polymerize by heating, and finally centrifuge the polymerization system, and the obtained particles are extracted with a suitable solvent to obtain the porous polymer microspheres.

[0004] However, the existing method usually has the following problems when preparing the micrometer-sized styrene-divinylbenzene resin microsphere:

[0005] Firstly, in the preparation process, if the prepared resin microspheres have a particle size suitable for use as chromatographic column fillers, or have relatively good uniformity, the prepared resin microspheres usually have the problem of too low crosslinking degree (generally less than 10%). When the crosslinking degree is too low, the resin microspheres have many internal pores, which may bring about a large specific surface area, but the resin microspheres have poor pressure resistance and are easy to collapse;

[0006] For example, the patent application No. 201110230790.9 discloses a preparation method of vinyl pyrrolidone and divinyl benzene monodisperse microspheres - swelling copolymerization method, the polystyrene microsphere seeds are prepared by dispersion polymerization method, N-vinyl pyrrolidone, acrylic acid and other comonomers are introduced in the swelling copolymerization process to prepare the corresponding copolymer microspheres. The preparation process of the method has the following problems: (1) the solution dropping time is long (2-11h), and the solution dropped in this process may be solidified or react in advance, and there are problems such as deterioration, in addition, there are problems of inconvenient operation and difficult control; (2) the operability control problem mentioned above also affects the stability of the product properties under the same conditions and different batches, that is, the reproducibility of the microspheres prepared by the method is not good; (3) the particle size of the microspheres synthesized by this method is concentrated in 20-80μm, and the crosslinking degree is not high enough, which is difficult to meet the requirements of chromatographic packing.

[0007] Secondly, in the preparation process, if the prepared resin microspheres have a high crosslinking degree, the particle size of the resin will gradually increase during the increase of the crosslinking degree, and the particle size dispersion of the resin will become larger, resulting in poor uniformity.

[0008] Therefore, it is of great research value and application prospect to prepare porous resin microspheres with high crosslinking degree, large particle size and uniform particle size. SUMMARY

[0009] 1. Problem to be solved

[0010] Based on the preparation method of the existing porous polymer microspheres, it is impossible to prepare the porous polymer microspheres with high crosslinking degree, controllable particle size and uniformity, one of the purposes of the present application is to provide a preparation method of resin microspheres, which can improve the particle size uniformity and crosslinking degree of the obtained product at the same time by using seed swelling polymerization method

[0011] Based on one of the purposes of the present application, the present application also provides resin microspheres and particle groups thereof, and chromatographic packing and chromatographic column based on the particle groups of the resin microspheres.

[0012] 2. Technical scheme

[0013] In order to solve the above problems, the technical scheme adopted by the present application is as follows:

[0014] [1] According to the purpose of the present application, the present application provides a preparation method of resin microspheres,

[0015] including the following steps:

[0016] A. Seed microsphere synthesis stage

[0017] A1 Preparation of raw material phase one:

[0018] The raw phase one includes a solvent; and,

[0019] at least two types of dispersants;

[0020] A2 preparing raw phase two:

[0021] The raw phase two includes styrene, and an initiator;

[0022] A3 seed microsphere synthesis:

[0023] The raw phase two is added to the raw phase one, and after the addition is completed, the reaction is carried out at 60-80°C for 4-24h, to obtain seed microspheres; preferably, the reaction is carried out at 65-75°C for 4-24h, to obtain seed microspheres;

[0024] B. Seed microsphere swelling stage

[0025] B1 preparing raw phase three:

[0026] The raw phase three includes seed microspheres, and an emulsifier;

[0027] B2 preparing raw phase four:

[0028] The raw phase four includes styrene, divinylbenzene, a porogen, an emulsifier, an initiator, and a surfactant.

[0029] B3 seed microsphere swelling one:

[0030] The raw phase three is added to the raw phase four, swelled, and reacted;

[0031] The addition is carried out for N times, and N is an integer ≥2.

[0032] [1.1] The method for preparing resin microspheres according to any one of the embodiments of the first aspect of the object of the present application, in the A1, the raw phase one includes two types of dispersants, type one and type two;

[0033] The dispersant of type one is selected from any one or two of polyvinylpyrrolidone, polyvinyl alcohol, wherein the molecular weight of the polyvinyl alcohol is ≥10000;

[0034] The dispersant of type two is selected from any one or several of polyacrylic acid, polyvinyl alcohol, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyapatite, wherein the molecular weight of the polyvinyl alcohol is <10000.

[0035] [1.2] The method for preparing resin microspheres according to any one of the embodiments of the first aspect of the object of the present application, the mass ratio of the amounts of the dispersants of type one and type two is (10-13):(0.5-1.5).

[0036] [1.3] The method for preparing resin microspheres according to any one of the first aspect of the object of the present application, A. seed microspheres synthesis stage, the emulsifier includes any one or several of sodium dodecyl benzene sulfonate, sodium dodecyl sulfate;

[0037] The initiator includes any one or several of azobisisobutyronitrile, azobisisoheptyl nitrile, dimethyl azobisisobutyrate, benzoyl peroxide, dibenzoyl peroxide.

[0038] [1.4] The method for preparing resin microspheres according to any one of the first aspect of the object of the present application, in the A. seed microspheres synthesis stage, the mass ratio of styrene, initiator, dispersant, solvent is (30-80):(1-3):(5-10):(300-600).

[0039] [1.5] The method for preparing resin microspheres according to any one of the first aspect of the object of the present application, in the A3, the temperature when the raw phase is added is not more than 50 degrees Celsius, preferably the temperature when the raw phase is added is 30-50℃; after the addition of the raw phase one or the raw phase two is completed, the temperature is raised, and the total reaction stage is entered, the temperature of the total reaction stage is 60-80℃, preferably the temperature is 65-75℃, and the total reaction time is 4-24h.

[0040] [1.6] The method for preparing resin microspheres according to any one of the first aspect of the object of the present application, the addition in the A3 is carried out for N times, and N is an integer greater than or equal to 2;

[0041] The addition process includes:

[0042] The temperature when the addition is not more than 50℃, preferably the temperature when the addition is 30-50℃; the interval time between the previous batch addition and the next batch addition is 10-120min.

[0043] [1.7] The method for preparing resin microspheres according to any one of the first aspect of the object of the present application,

[0044] The raw phase two is added to the raw phase one in N times;

[0045] After the addition of the raw phase two is completed, the temperature is raised, and then at least one temperature raising-temperature holding treatment is carried out, so that the temperature is raised to 60-80℃, and reacted at 60-80℃ for 4-24h; preferably reacted at 65-75℃ for 4-24h;

[0046] The temperature raising-temperature holding treatment, the temperature is raised (the temperature raising rate is not more than 10℃ / h), and the temperature holding time of each time is 10-120min.

[0047] [1.8] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, wherein the A. seed microspheres synthesis stage, the particle size of the prepared seed microspheres is 0.5-3 μm.

[0048] [1.9] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, wherein the A. seed microspheres synthesis stage, the particle size of the seed microspheres can be any value taken from any one of the following numerical ranges: 0.5-3 μm, 0.5-2.5 μm, 0.5-2 μm, 0.5-1.5 μm, 0.5-1 μm, 1-3 μm, 1-2.5 μm, 1-2 μm, 1-1.5 μm, 1.5-3 μm, 1.5-2.5 μm, 1.5-2 μm, 2-3 μm, 2-2.5 μm, 2.5-3 μm.

[0049] [1.10] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, wherein the A. seed microspheres synthesis stage, the prepared seed microspheres have a polydispersity coefficient of 1-1.2; preferably a polydispersity coefficient of 1.02-1.1.

[0050] [1.11] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, wherein the B. seed microspheres swelling stage, the emulsifier includes any one or several of sodium dodecyl benzene sulfonate, sodium dodecyl sulfate;

[0051] The initiator includes any one or several of azobisisobutyronitrile, azobisisoheptyl nitrile, dimethyl azobisisobutyrate, benzoyl peroxide, dibenzoyl peroxide;

[0052] The porogen includes any one or several of linear polystyrene, dibutyl phthalate, toluene, liquid paraffin, polyvinyl acetate; preferably the porogen includes any one or both of dibutyl phthalate and toluene.

[0053] [1.12] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, wherein in the B1, the mass percentage of the seed microspheres and the emulsifier is (0.5-2):(0.5-1.5).

[0054] [1.13] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, wherein in the B2, the raw phase four is added to the raw phase three for N times.

[0055] The raw phase four includes a first raw phase four and a second raw phase four.

[0056] [1.14] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, the mass percentage of styrene, divinylbenzene, porogen, emulsifier, initiator in the first raw material phase four is (1.5-3):(1-4):(1-2):(0.5-1.5):(0.5-1.5).

[0057] [1.15] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, the mass percentage of styrene, divinylbenzene, emulsifier, initiator in the second raw material phase four is (1.5-3):(1-4):(0.5-1.5):(0.5-1.5).

[0058] [1.16] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, the ratio of the use amount of the first raw material phase four to the third raw material phase is (1-2):(1-2); and / or,

[0059] The ratio of the use amount of the first raw material phase four to the second raw material phase four is (1-2):(1-2).

[0060] [1.17] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, in the B3, the first raw material phase four is added first, the addition is divided into N times, and N is an integer greater than or equal to 2; preferably N is an integer of 2-5;

[0061] Then the second raw material phase four is added, the addition is divided into N times, and N is an integer greater than or equal to 2; preferably N is an integer of 2-5.

[0062] [1.18] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, the process of adding the first raw material phase four comprises:

[0063] The temperature during the addition is not more than 50°C, preferably the temperature during the addition is 30-50°C; the interval time between the previous batch of addition and the next batch of addition is 10-120 min;

[0064] and / or,

[0065] In the B3, after the addition of the first raw material phase four is completed, swelling is carried out, and then reaction is carried out at 60-80°C for 4-24 h; preferably reaction is carried out at a temperature of 65-75°C for 4-24 h.

[0066] [1.19] The method for preparing the resin microspheres according to any one of the first aspect of the object of the present application, the process of adding the second raw material phase four comprises:

[0067] The temperature of the second raw material phase four in each batch is not more than 50℃, preferably the temperature of the second raw material phase four is 30-50℃ when added; the interval time between the addition of the previous batch and the addition of the next batch is 10-120min;

[0068] and / or,

[0069] After the addition of the previous batch is completed, the temperature is raised to 60-80℃ (preferably the temperature is 65-75℃), and the reaction is carried out for 10-120min, then the temperature is lowered to not more than 50℃ before the next batch is added, preferably the temperature is lowered to 30-50℃;

[0070] After the addition of the second raw material phase four is completed, swelling is carried out, and then the reaction is carried out at 60-80℃ for 4-24h; preferably the reaction is carried out at 65-75℃ for 4-24h.

[0071] [1.20] The method for preparing the resin microspheres according to any one of the embodiments of the first aspect of the object of the present application, the amount of the first raw material phase four in each batch accounts for 20-50wt% of the total amount of the first raw material phase four, calculated according to the mass of the first raw material phase four;

[0072] and / or,

[0073] The amount of the second raw material phase four in each batch accounts for 20-50wt% of the total amount of the second raw material phase four, calculated according to the mass of the second raw material phase four.

[0074] [1.21] The method for preparing the resin microspheres according to any one of the embodiments of the first aspect of the object of the present application, the particle size of the seed microspheres is 0.5-3μm, and the polydispersity index is 1-1.2; preferably the polydispersity index is 1.02-1.1.

[0075] The seed microspheres are prepared by the

seed microspheres and the method for preparing the same

[0076] [2] Based on the first aspect of the object of the present application, the second aspect of the present application provides

resin microspheres

[0077] [2.1] The resin microspheres according to any one of the embodiments of the second aspect of the object of the present application, the particle size of the resin microspheres is 4-9μm.

[0078] [2.2] The resin microspheres according to any one of the embodiments of the second aspect of the present application, the particle size of the resin microspheres can be any value taken from any one of the following ranges: 4-9 microns, 4-8 microns, 4-7 microns, 4-6 microns, 4-5 microns, 5-9 microns, 5-8 microns, 5-7 microns, 5-6 microns, 6-9 microns, 6-8 microns, 6-7 microns, 7-9 microns, 7-8 microns, 8-9 microns.

[0079] [2.3] The resin microspheres according to any one of the embodiments of the second aspect of the present application, the cross-linking degree of the resin microspheres is 30%-45%.

[0080] [2.4] The resin microspheres according to any one of the embodiments of the second aspect of the present application, the cross-linking degree of the resin microspheres can be any value taken from any one of the following ranges: 30-45%, 30-40%, 30-35%, 35-45%, 35-40%, 40-45%.

[0081] [2.5] The resin microspheres according to any one of the embodiments of the second aspect of the present application, the polydispersity coefficient of the resin microspheres is 1-1.2, preferably has a polydispersity coefficient of 1.02-1.1.

[0082] [2.6] The resin microspheres according to any one of the embodiments of the second aspect of the present application, the polydispersity coefficient of the resin microspheres can be any value taken from any one of the following ranges: 1-1.2, 1.01-1.1, 1.02-1.09, 1.02-1.07, 1.02-1.05, 1.023-1.035, 1.035-1.045, 1.035-1.055, 1.035-1.065, 1.035-1.075, 1.035-1.085, 1.035-1.097.

[0083] [3] Based on the first or second aspect of the present application, the third aspect of the present application provides a population of resin microspheres, which is prepared by any one of the above-mentioned methods.

[0084] [3.1] The population of resin microspheres according to any one of the embodiments of the third aspect of the present application, the population of resin microspheres comprises resin microspheres with a particle size of 4-9 microns, accounting for 92.6-97.3 wt%.

[0085] [3.2] The resin microsphere particle group according to any one of the embodiments of the third aspect of the object of the present application, the particle size of the resin microspheres can be any value taken from any one of the following numerical ranges: 4-9 microns, 4-8 microns, 4-7 microns, 4-6 microns, 4-5 microns, 5-9 microns, 5-8 microns, 5-7 microns, 5-6 microns, 6-9 microns, 6-8 microns, 6-7 microns, 7-9 microns, 7-8 microns, 8-9 microns.

[0086] [3.3] The resin microsphere particle group according to any one of the embodiments of the third aspect of the object of the present application, the resin microsphere particle group comprises resin microsphere particles with a crosslinking degree of 30%-45%.

[0087] [3.4] The resin microsphere particle group according to any one of the embodiments of the third aspect of the object of the present application, the crosslinking degree of the resin microspheres can be any value taken from any one of the following numerical ranges: 30-45%, 30-40%, 30-35%, 35-45%, 35-40%, 40-45%.

[0088] [3.5] The resin microsphere particle group according to any one of the embodiments of the third aspect of the object of the present application, the polydispersity coefficient of the resin microsphere particles contained in the resin microsphere particle group is 1-1.2, preferably has a polydispersity coefficient of 1.02-1.1.

[0089] [3.6] The resin microsphere particle group according to any one of the embodiments of the third aspect of the object of the present application, the polydispersity coefficient of the resin microsphere particles contained in the resin microsphere particle group can be any value taken from any one of the following numerical ranges: 1-1.2, 1.01-1.1, 1.02-1.09, 1.02-1.07, 1.02-1.05, 1.023-1.035, 1.035-1.045, 1.035-1.055, 1.035-1.065, 1.035-1.075, 1.035-1.085, 1.035-1.097.

[0090] [4] Based on any one of the first to third aspects of the object of the present application, the fourth aspect of the present application provides a

chromatographic packing material

[0091] [5] Based on any one of the first to fourth aspects of the object of the present application, the fifth aspect of the present application provides a

chromatographic column

[0092] Figure 1Resin microspheres prepared for Example 6A. DETAILED DESCRIPTION

[0093] The present disclosure can be more easily understood and further advantages and benefits can be obtained by reference to the following description and examples in conjunction with the accompanying drawings in which all figures are schematic, like elements are referred to with like reference numerals, and in which: It should be understood that the present disclosure is not limited to the particular products, methods, conditions or parameters described and / or shown herein, unless otherwise specified. Further, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, unless otherwise specified.

[0094] It should also be understood that, unless clearly indicated otherwise, certain features of the present disclosure can be described in the context of separate embodiments and can also be provided in combination with each other in a single embodiment. That is, unless explicitly incompatible or specifically excluded, each separate embodiment is considered combinable with any other embodiment, and such combinations are considered to represent another, different embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment can also be provided separately or in any subcombination, for the sake of brevity. Finally, while a particular embodiment can be described as part of a series of steps or part of a more general structure, each step or substructure can itself be considered an independent embodiment.

[0095] Unless otherwise indicated, it is to be understood that each individual element in a list and each combination of individual elements in that list is to be construed as a separate embodiment. For example, a list of embodiments recited as “A, B, or C” is to be construed as including the embodiments of “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0096] In the present disclosure, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a substance” is a reference to at least one of such a substance and equivalents thereof.

[0097] Terms including ordinal numbers such as “first” and “second” can be used to explain various components or fluids, but the components, fluids are not limited by the terms. Thus, the terms are used only to distinguish the component / fluid from another component / fluid without departing from the teaching of the present disclosure.

[0098] When items are described by using conjunctive terms such as “and / or” and the like, the description should be understood to include any one of the associated listed items as well as all combinations of one or more of the items.

[0099] Generally, use of the term“about” indicates approximations that can vary depending on the desired properties obtained through the disclosed subject matter and will be interpreted in a functionally dependent manner based on the context in which it is used. Accordingly, one of ordinary skill in the art will be able to interpret a degree of variance on a case-by-case basis. In some instances, the number of significant digits used in expressing a particular value can be representative of the degree of precision intended for determining the degree of variance allowed by the term“about.” In other instances, a range of values can be used to determine the degree of variance allowed by the term“about.” Further, all ranges in the present disclosure are inclusive and combinable, and a reference to a value in a range includes each value in the range.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application.

[0101] In order to make the technical solutions and advantages of the present application, the technical solutions in the embodiments of the present application will be described in detail below.

[0102] A. seed microspheres synthesis stage, the preparation method of the seed microspheres of the present application comprises the following steps:

[0103] A1 preparation of raw material phase one:

[0104] The raw material phase one comprises a solvent; and,

[0105] At least two types of dispersants;

[0106] A2 preparation of raw material phase two:

[0107] The raw material phase two comprises styrene, and an initiator;

[0108] A3 seed microspheres synthesis:

[0109] The raw material phase two is added to the raw material phase one for total reaction to obtain seed microspheres.

[0110] As the reaction monomer styrene, divinylbenzene (80wt%) in the raw material phase, it is preferable to carry out a deblocking treatment before use to remove the possible existing polymerization inhibitor of the reaction monomer. Generally, the styrene, divinylbenzene can be cleaned with sodium hydroxide solution to remove the polymerization inhibitor, and then the lower aqueous solution is separated out with a separatory funnel until the aqueous solution is neutralized to complete the cleaning

[0111] As the solvent in the raw material phase, the type is not particularly limited. For example, any one of water, ethanol, ethylene glycol methyl ether, etc. or any mixture of several as a solvent can be used;

[0112] The initiator in the raw material phase is not particularly limited in type. For example, any one of azobisisobutyronitrile, azobisisoheptyl nitrile, dimethyl azobisisobutyrate, benzoyl peroxide, dibenzoyl peroxide, or any mixture of several thereof can be used;

[0113] The selection of the type of dispersant in the raw material phase and the manner of use will affect the uniformity of the particle size of the resin microspheres formed, and therefore, in the present application, it is required that the dispersant in the raw material phase be composed of two different types, one selected from the types listed below as Type I and the other selected from the types listed below as Type II:

[0114] The dispersant of Type I is selected from any one of polyvinylpyrrolidone, polyvinyl alcohol (molecular weight ≥ 10000); for example, the molecular weight of the polyvinyl alcohol available on the market can be 47000, 57000, 66000, 89000, 98000, 130000, 145000, 205000;

[0115] The dispersant of Type II is selected from any one of polyacrylic acid, polyvinyl alcohol (molecular weight < 10000), ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyapatite; for example, the molecular weight of the polyvinyl alcohol available on the market can be 3200, 5000, 7000, 9000, 9900.

[0116] Furthermore, it should be further noted that in fact, the complexity of the dispersant will affect the ease of controlling the subsequent reaction, and therefore, in order to meet the requirements for the uniformity of the particle size of the resin microspheres formed and the easy control of the subsequent reaction, it is recommended that the dispersant combination type be composed of two different types, one from Type I and the other from Type II. For example, the following can be mentioned:

[0117] Dispersant combination type Type 1 Type 2 Ratio (mass ratio) 1 Polyvinylpyrrolidone Polyvinyl alcohol 15：1 2 Polyvinylpyrrolidone Acrylic acid 15：2 3 Polyvinyl alcohol Ethyl cellulose 7：1 4 Polyvinylpyrrolidone Hydroxypropyl methyl cellulose 8：1 5 Polyvinyl alcohol Hydroxypropyl methyl cellulose 7.5：1

[0118] Further, the addition amount of the styrene, initiator, dispersant, and solvent is calculated as a mass ratio of (30-80):(1-3):(5-10):(300-600); a more preferred ratio is (50-70):(1.5-2.5):(6.5-8.5):(400-550).

[0119] The process for preparing the raw material phase I can be referred to as follows: dissolve the dispersant in the solvent, during which nitrogen is introduced to expel oxygen, stir (the speed is controlled at 200-350 r / min) and maintain the temperature (30-50 degrees Celsius) stable, so that the solvent and the dispersant are fully mixed and uniform;

[0120] The reference process for preparing A2 raw material phase two is as follows: a certain amount of deblocked styrene is weighed, the initiator is added to the styrene monomer, stirred and dissolved, and uniformly dispersed; in order to make the initiator more easily dissolved in the styrene monomer, the styrene monomer can be placed in a beaker and heated in a water bath.

[0121] The reference process for preparing A3 seed microspheres is as follows: the raw material phase two prepared in step A2 is added to the raw material phase one prepared in step A1 (this process needs to keep the temperature at 30-50°C), and the temperature is raised (the temperature raising rate is not more than 10°C / h) to 60-80°C, accompanied by stirring during the process, and reacted at 60-80°C for 4-24h; after the reaction is completed, the obtained seed microspheres are washed by ultrasonic, centrifuged and dried using ethanol and acetone.

[0122] In further pursuit of the uniformity of the particle size and the crosslinking degree of the finally obtained seed microspheres, without considering the difficulty of the control accuracy of the reaction process, another reference process for preparing A3 seed microspheres is as follows:

[0123] The raw material phase two prepared in step A2 is added to the raw material phase one prepared in step A1 in N batches. Each batch of raw material phase two needs to keep the temperature at 30-50°C during the process of adding to the raw material phase one, accompanied by stirring;

[0124] According to the mass of the raw material phase two, the amount of each batch of raw material phase two accounts for 20-50wt% of the total mass of the raw material phase two; the interval time between the addition of the previous batch and the addition of the next batch is 10-120min.

[0125] After all batches of raw material phase two are added, the temperature is kept at the addition temperature for 10-120min, and then the temperature is raised and kept, and finally the temperature is raised to 60-80°C, and reacted at 60-80°C for 4-24h, and the reaction is completed. After the reaction is completed, the seed microspheres are obtained by ultrasonic washing, centrifugation and Soxhlet extraction to remove the porogen.

[0126] For the temperature raising-keeping treatment, the general reference raising speed is not more than 10°C / h, for example, the raising speed is 2°C / h, 3°C / h, 4°C / h, 5°C / h, 6°C / h, 7°C / h, 8°C / h, 9°C / h;

[0127] The reference keeping treatment temperature is 50°C, 53°C, 55°C, 57°C, 60°C, 62°C, 65°C, 67°C, 70°C, 73°C, etc.

[0128] The reference heat treatment time is 5 min, 8 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, 65 min, 70 min, 75 min, 80 min, 85 min, 90 min, 95 min, 100 min, 105 min, 110 min, 115 min, 120 min, etc.

[0129] For example, when all batches of raw material phase two are added at 40℃, and the heat preservation at 40℃ is continued for half an hour, the following reference temperature rising-heat preservation process is performed: rising to 50℃ at a speed gradient of 10℃ / h, heat preservation at 50℃ for half an hour, and then rising to 60℃ at a speed gradient of 10℃ / h, heat preservation at 60℃ for half an hour.

[0130] After the above reference temperature rising-heat preservation process is completed, the following example can be used for subsequent processing: rising to 75℃ at a speed gradient of 10℃ / h, reaction at 75℃ for 20h, and then ultrasonic washing, centrifugation, and Soxhlet extraction to remove the porogen to obtain the final seed microspheres.

[0131] Finally, based on the preparation method provided by the present application, the present application can also provide seed microspheres, and the particle size of the prepared seed microspheres is 0.5-3μm.

[0132] B. Resin microsphere synthesis, the preparation method of the resin microspheres of the present application comprises the following steps:

[0133] B1 Preparation of raw material phase three:

[0134] The raw material phase three comprises seed microspheres and an emulsifier.

[0135] B2 Preparation of raw material phase four:

[0136] The preparation of raw material phase four comprises styrene, divinylbenzene, a porogen, an emulsifier, and an initiator.

[0137] B3 Swelling of seed microspheres:

[0138] The raw material phase three and the raw material phase four are added and swelled for the total reaction.

[0139] The addition is performed for N times, and N is an integer greater than or equal to 2.

[0140] The emulsifier in the raw material phase is not particularly limited. For example, any one of sodium dodecylbenzenesulfonate, sodium dodecyl sulfate, etc., or any mixture of several thereof can be used as an emulsifier.

[0141] The kind of the porogen in the raw material phase is not particularly limited. For example, any one of linear polystyrene, dibutyl phthalate, toluene, liquid paraffin, polyvinyl acetate, or several kinds of any mixture can be used as the porogen; and from the perspective of improving the stability of the system during the reaction, the porogen preferably includes dibutyl phthalate and toluene, but does not include linear polystyrene, liquid paraffin, and polyvinyl acetate.

[0142] Further, in the B1, the mass percentage of the seed microspheres and the emulsifier is (0.5-2):(0.5-1.5); and a more preferred ratio is (0.8-1.6):(0.8-1.2).

[0143] In the B2, the mass percentage of the seed microspheres, styrene, divinylbenzene, the porogen, the emulsifier, and the initiator is (0.5-2):(1.5-3):(1-4):(1-2):(0.5-1.5):(0.5-1.5); and a more preferred ratio is (0.8-1.6):(2-2.5):(1.5-3):(1.2-1.8):(0.8-1.2):(0.6-1.2).

[0144] The process for preparing the raw material phase three in the B1 can be as follows: a certain amount of the prepared seed microspheres is added to an aqueous solution containing the emulsifier, and then ultrasonic dispersion and stirring are performed.

[0145] The process for preparing the raw material phase four in the B2 can be as follows: styrene, divinylbenzene, the porogen, and the initiator are added to an aqueous solution containing the emulsifier, and then ultrasonic emulsification is performed for 30-60 min at a temperature of 20-40°C.

[0146] The process for swelling the seed microspheres in the B3 can be as follows: the raw material phase four prepared in the step B2 is added to the raw material phase three prepared in the step B1 in N batches. The temperature is maintained at 30-50°C during the addition of each batch of the raw material phase four to the raw material three, and stirring is performed at the same time.

[0147] According to the mass of the raw material phase four, the mass ratio of the amount of each batch of the raw material phase four to the total amount of the raw material phase four is 20-50 wt%; and the interval time between the addition of the previous batch and the addition of the next batch is 10-120 min.

[0148] After the addition of all batches of the raw material phase four is completed, the temperature is increased (at a rate of no more than 10°C / h) to 60-80°C, and the reaction is performed at 60-80°C for 4-24 h; after the reaction is completed, ultrasonic washing, centrifugation, and Soxhlet extraction are performed to remove the porogen, and the final resin microspheres are obtained.

[0149] In the meantime, when considering the uniformity of the particle size of the final obtained resin microspheres and the crosslinking degree, the process for preparing the fourth raw phase B2 can be as follows:

[0150] The fourth raw phase is divided into a first raw phase four and a second raw phase four; and,

[0151] The ratio of the amount of the first raw phase four to the third raw phase is (1-2):(1-2);

[0152] The ratio of the amount of the first raw phase four to the second raw phase four is (1-2):(1-2). Wherein,

[0153] The first raw phase four comprises styrene, divinylbenzene, porogen, emulsifier, initiator, and the mass percentage of the styrene, divinylbenzene, porogen, emulsifier, and initiator is (1.5-3):(1-4):(1-2):(0.5-1.5):(0.5-1.5);

[0154] The second raw phase four comprises styrene, divinylbenzene, emulsifier, and initiator, and the mass percentage of the styrene, divinylbenzene, emulsifier, and initiator is (1.5-3):(1-4):(0.5-1.5):(0.5-1.5).

[0155] In addition, on the basis of the above-mentioned process for preparing the fourth raw phase B2, another process for swelling the seed microspheres B3 can be as follows:

[0156] The first raw phase four prepared in step B2 is added to the third raw phase prepared in step B1 in N batches. In the process of adding the first raw phase four to the third raw phase, the temperature is kept at 30-50°C, and stirring is performed during the process;

[0157] According to the mass of the first raw phase four, the mass ratio of the amount of each batch of the first raw phase four to the total amount of the first raw phase four is 20-50wt%; the interval time between the addition of the previous batch and the addition of the next batch is 10-120min.

[0158] After the addition of all batches of the first raw phase four is completed, the temperature is kept at the addition temperature for 8-16h, and then the temperature is increased to 60-80°C, and the reaction is performed at 60-80°C for 2-4h. After the reaction is completed, the second raw phase four is added.

[0159] The adding process of the second raw material phase four can be referenced as follows: the second raw material phase four prepared in step B2 is added into the raw material phase three prepared in step B1 in N batches. During the adding process of each batch of the second raw material phase four into the raw material phase three, the temperature is kept at 30-50℃, and stirring is performed during the process;

[0160] After the adding of the second raw material phase four in the previous batch into the raw material phase three is completed, and before the adding of the second raw material phase four in the next batch into the raw material phase three is started, the time interval is 10-120 min; and during the time interval, the temperature increasing-temperature keeping-temperature decreasing process is performed to ensure that the temperature during the adding of each batch of the second raw material phase four is at 30-50℃. The process is repeated until the adding of all batches of the second raw material phase four is completed;

[0161] Finally, the temperature is increased (the temperature increasing rate is not more than 10℃ / h) to 60-80℃, and the swelling reaction is performed at 60-80℃ for 4-24 h; after the reaction is completed, the porogen is removed by ultrasonic washing, centrifugation and Soxhlet extraction to obtain the final resin microspheres. Finally, the particle size of the prepared resin microspheres is 4-9 μm.

[0162] For the temperature increasing-temperature keeping-temperature decreasing process, the temperature increasing rate can be referenced as not more than 10℃ / h, for example, the temperature increasing rate is 2℃ / h, 3℃ / h, 4℃ / h, 5℃ / h, 6℃ / h, 7℃ / h, 8℃ / h, 9℃ / h;

[0163] The temperature keeping process can be referenced as keeping the temperature at any temperature selected from 60-80℃, for example, 65℃, 67℃, 70℃, 73℃, etc.

[0164] The temperature keeping time can be referenced as keeping the temperature for any time selected from 5-60 min, for example, 5 min, 8 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, etc.

[0165] For example, when the adding of the second raw material phase four in the previous batch is completed at 40℃, and the temperature keeping process at 40℃ is continued for half an hour, the temperature increasing-temperature keeping-temperature decreasing process can be referenced as follows: the temperature is increased to 70℃ at a rate of 5℃ / h, the temperature is kept at 70℃ for half an hour, and then the temperature is decreased to 40℃.

[0166] After the temperature increasing-temperature keeping-temperature decreasing process is completed, the adding of the second raw material phase four in the next batch can be continued at 40℃, and the process is repeated until the adding of the second raw material phase four in the last batch is completed, and then the temperature keeping process at 40℃ is continued for half an hour;

[0167] Finally, the temperature is raised (at a rate of no more than 5°C / h) to 70°C, and the total reaction is carried out at 70°C for 4-24 h; after the reaction is completed, the porogen is removed by ultrasonic washing, centrifugation, and Soxhlet extraction to obtain the final resin microspheres.

[0168] Based on the preparation method provided by the present application, the present application can also provide resin microsphere particles: the particle size of the resin microsphere particles is 4-9 μm; and / or,

[0169] The crosslinking degree of the resin microsphere particles is 30%-45%.

[0170] Based on the preparation method provided by the present application, the present application can also provide a resin microsphere particle group: the resin microsphere particle group comprises resin microsphere particles with a particle size of 4-9 μm, and the proportion is 92.6-97.3 wt%; and / or,

[0171] The resin microsphere particle group comprises resin microsphere particles with a crosslinking degree of 30%-45%; and / or,

[0172] The polydispersity coefficient of the resin microsphere particles contained in the resin microsphere particle group is 1-1.2, and the preferred polydispersity coefficient is 1.023-1.097.

[0173] Based on the preparation method provided by the present application, the present application can also provide a chromatographic packing material: the chromatographic packing material comprises the resin microsphere particles and / or the resin microsphere particle group prepared by any of the above methods.

[0174] Based on the preparation method provided by the present application, the present application can also provide a chromatographic column: the chromatographic column comprises the resin microsphere particles and / or the resin microsphere particle group, and / or the chromatographic packing material prepared by any of the above methods.

[0175] Example 1

[0176] Deblocking treatment:

[0177] After washing the styrene and divinylbenzene with 1M sodium hydroxide solution for three times, the pH of the washing solution approaches neutrality.

[0178] Raw phase one: 350 mL of ethanol, 100 mL of water, and 100 mL of ethylene glycol methyl ether were added to a 1000 mL three-necked flask, which was placed in a water bath to keep the water temperature at 40°C, and stirring was started at a speed of 200 r / min. After stirring for 5 minutes, 9 g of polyvinylpyrrolidone and 0.6 g of polyvinyl alcohol (molecular weight 5000) were weighed and added to the mixed solution;

[0179] Raw material phase II: 85g of the de-blocked styrene was weighed into a beaker, and 2.5g of azobisisobutyronitrile was weighed and added to the weighed styrene. The beaker was placed in a water bath at 50 degrees, and a glass rod was used to stir to dissolve the azobisisobutyronitrile;

[0180] Seed microsphere (seed ball) synthesis: the water temperature was kept at 40 degrees Celsius, and the prepared raw material phase II was added to the three-necked flask containing raw material phase I, with stirring at a speed of 350 r / min during the addition. After the addition was completed, the temperature was kept at 40 degrees Celsius for half an hour, then the temperature was increased to 45 degrees Celsius, and kept at 45 degrees Celsius for half an hour, then the temperature was increased to 50 degrees Celsius, and kept at 50 degrees Celsius for half an hour, then the temperature was increased-kept (each time the temperature was increased by 5 min, and then kept for half an hour) until 75 degrees Celsius, and the reaction was carried out at 75 degrees Celsius for 20 hours.

[0181] After the reaction was completed, centrifugation was performed, and ethanol and acetone were used for washing three times. During the washing process, after the addition of ethanol / acetone, ultrasonic dispersion was performed for 5 minutes, and then the sample was placed in a centrifuge for centrifugation at a speed of 3000 r / min for 2 min.

[0182] The washed small balls were transferred to a petri dish and dried in an oven, with the oven temperature set to 60 degrees Celsius. The dried small balls were placed in a self-sealing bag for storage to prevent water absorption.

[0183] The average particle size of the prepared seed microspheres (seed ball-1) was 1.9 μm; the polydispersity coefficient was 1.029.

[0184] Example 2

[0185] De-blocking treatment:

[0186] After washing the styrene and divinylbenzene with 1M sodium hydroxide solution three times, the pH of the washing solution was close to neutral.

[0187] Raw material phase I: 350mL of ethanol, 100mL of water, and 100mL of ethylene glycol methyl ether were added to a 1000mL three-necked flask, which was placed in a water bath to maintain a water temperature of 40 degrees Celsius. The stirring was turned on at a speed of 200 r / min. After stirring for 5 minutes, 7g of polyvinylpyrrolidone and 1g of polyvinyl alcohol (molecular weight 5000) were weighed and added to the mixed solution.

[0188] Raw material phase II: 85g of the de-blocked styrene was weighed into a beaker, and 2.1g of azobisisobutyronitrile was weighed and added to the weighed styrene. The beaker was placed in a water bath at 50 degrees to dissolve the azobisisobutyronitrile;

[0189] Seed microspheres (seed ball) synthesis: keep the water temperature at 40 degrees Celsius, add the prepared raw material phase two to the three-necked flask containing raw material phase one, with stirring at a speed of 400 r / min during the process, after the addition is completed, keep the temperature at 40 degrees Celsius for half an hour, then heat to 45 degrees Celsius, keep the temperature at 45 degrees Celsius for half an hour, continue to heat to 50 degrees Celsius, keep the temperature at 50 degrees Celsius for half an hour, continue to heat-keep (each time the heating amplitude is 5 min, then keep for half an hour), until 75 degrees Celsius, react for 20 h at 75 degrees Celsius.

[0190] After the reaction is completed, centrifugation is performed, and ethanol and acetone are used for washing three times. During the washing process, after adding ethanol / acetone, ultrasonic dispersion is performed for 5 minutes, and then the centrifuge is used for centrifugation at a speed of 3000 r / min for 2 min.

[0191] The washed small balls are transferred to a surface dish and dried in an oven, and the oven is set to 60 degrees Celsius. The dried small balls are placed in a self-sealing bag for storage to prevent water absorption.

[0192] The particle size of the prepared seed microspheres (seed ball-2) is 2.3 μm; the polydispersity coefficient is 1.039.

[0193] Example 3 (seed ball-3)

[0194] Deblocking treatment:

[0195] After washing the styrene and divinylbenzene three times with 1M sodium hydroxide solution, the pH of the washing solution approaches neutrality.

[0196] Raw material phase one: 350 mL of ethanol, 100 mL of water, and 60 mL of ethylene glycol methyl ether are added to a 1000 mL three-necked flask, which is placed in a water bath to keep the water temperature at 40 degrees Celsius, and stirring is started at a speed of 200 r / min. After stirring for 5 minutes, 8 g of polyvinylpyrrolidone and 0.9 g of hydroxypropyl methyl cellulose are weighed and added to the mixed solution.

[0197] Raw material phase two: 85 g of deblocked styrene is weighed and placed in a beaker, and 2.5 g of azobisisobutyronitrile is weighed and added to the styrene. The beaker is placed in a 50-degree water bath to dissolve the azobisisobutyronitrile;

[0198] Seed microspheres (seed ball) synthesis: keep the water temperature at 40 degrees Celsius, add the prepared raw material phase two to the three-necked flask containing raw material phase one, with stirring at a speed of 400 r / min during the process, after the addition is completed, keep the temperature at 40 degrees Celsius for half an hour, then heat to 45 degrees Celsius, keep the temperature at 45 degrees Celsius for half an hour, continue to heat to 50 degrees Celsius, keep the temperature at 50 degrees Celsius for half an hour, continue to heat-keep (each time the heating amplitude is 5 min, then keep for half an hour), until 75 degrees Celsius, react for 20 h at 75 degrees Celsius.

[0199] After the reaction is completed, centrifugation is performed, and ethanol and acetone are used for washing three times. During the washing process, after adding ethanol / acetone, ultrasonic dispersion is performed for 5 minutes, and then the centrifuge is used for centrifugation at a speed of 3000 r / min for 2 min.

[0200] The washed small balls are transferred to a surface dish and dried in an oven, and the oven is set to 60 degrees Celsius. The dried small balls are placed in a self-sealing bag for storage to prevent water absorption.

[0201] The prepared seed microspheres (seed ball-3) have a particle size of 2.2 μm and a polydispersity coefficient of 1.076.

[0202] Example 4 (seed ball-4)

[0203] Deblocking treatment:

[0204] After washing the styrene and divinylbenzene three times with 1M sodium hydroxide solution, the pH of the washing solution approaches neutrality.

[0205] Raw material phase one: 350 mL of ethanol, 100 mL of water, and 60 mL of ethylene glycol methyl ether are added to a 1000 mL three-necked flask, which is placed in a water bath to keep the water temperature at 40 degrees Celsius, and stirring is started at a speed of 200 r / min. After stirring for 5 minutes, 7.5 g of polyvinyl alcohol (molecular weight 89000) and 1 g of hydroxypropyl methyl cellulose are weighed and added to the mixed solution.

[0206] Raw material phase two: 85 g of deblocked styrene is weighed and placed in a beaker, and 2.5 g of azobisisobutyronitrile is weighed and added to the styrene. The beaker is placed in a 50-degree water bath to dissolve the azobisisobutyronitrile;

[0207] Synthesis of seed microspheres (seed pellets): Maintaining the water temperature at 40 degrees Celsius, the prepared raw material phase II was added to a three-necked flask containing raw material phase I, with stirring during the process. The stirring speed was 400 r / min. After the addition was completed, the temperature was maintained at 40 degrees Celsius for half an hour, then the temperature was increased to 45 degrees Celsius and maintained at 45 degrees Celsius for half an hour. The temperature was then increased to 50 degrees Celsius and maintained at 50 degrees Celsius for half an hour. The temperature was then increased and maintained (each increase was 5 minutes, followed by a half-hour maintenance) until the temperature reached 75 degrees Celsius. The reaction was carried out at 75 degrees Celsius for 20 hours.

[0208] After the reaction was complete, the mixture was centrifuged and washed three times each with ethanol and acetone. The washing process was as follows: after adding ethanol / acetone, the mixture was ultrasonically dispersed for 5 minutes, and then centrifuged at 3000 rpm for 2 minutes.

[0209] Transfer the washed balls to a petri dish and dry them in an oven at 60 degrees Celsius. Store the dried balls in a resealable bag to prevent moisture absorption.

[0210] The prepared seed microspheres (seed ball-3) have a particle size of 1.9 μm and a polydispersity index of 1.091.

[0211] Comparative Example 1

[0212] This comparative example is basically the same as Example 3, except that:

[0213] Comparative Sample-1: 8g of polyvinylpyrrolidone was weighed from raw material phase one and added to the mixed solution. Hydroxypropyl methylcellulose was not added. The rest was the same as in Example 3. Finally, the particle size of the prepared seed microspheres (comparative sample-1) was 2.4μm and the polydispersity index was 1.232.

[0214] Comparative Sample-2: 0.9g of hydroxypropyl methylcellulose was weighed from raw material phase one and added to the mixed solution. No more polyvinylpyrrolidone was added. The rest was the same as in Example 3. Finally, the particle size of the prepared seed microspheres (comparative sample-2) was 6.6μm and the polydispersity index was 1.319.

[0215] Comparative Sample-3: 11g of polyvinylpyrrolidone and 0.9g of hydroxypropyl methylcellulose were weighed from raw material phase one and added to the mixed solution, and the rest was the same as in Example 3; finally, the particle size of the prepared seed microspheres (comparative sample-3) was 1.8μm and the polydispersity index was 1.205.

[0216] Comparison Sample-4:

[0217] In raw phase one-1, take half amount of solvent mixed solution of ethanol, water, ethylene glycol methyl ether (350 mL of ethanol, 100 mL of water, 100 mL of ethylene glycol methyl ether), and weigh 8 g of polyvinylpyrrolidone into the mixed solution in the manner of example 3;

[0218] In raw phase one-2, take the other half amount of solvent mixed solution of ethanol, water, ethylene glycol methyl ether (350 mL of ethanol, 100 mL of water, 100 mL of ethylene glycol methyl ether), and weigh 0.9 g of hydroxypropyl methyl cellulose into the mixed solution in the manner of example 3;

[0219] The preparation of raw phase two is the same as example 3;

[0220] Seed microsphere (seed ball) synthesis: in the manner of example 3, the prepared raw phase two is added to the three-necked flask containing raw phase one-1, with stirring at a speed of 350 r / min during the addition, and after the addition is completed;

[0221] Start the temperature programming in the manner of example 3, control the stirring speed, and add raw phase one-2 in stages before each temperature increase, and the rest is the same as example 3; finally, the prepared seed microspheres (comparative sample-3) have a particle size of 2.0 μm and a polydispersity coefficient of 1.174.

[0222] Example 5

[0223] In this example, the seed microspheres prepared in the example, i.e. seed ball-1, are used for the preparation of resin microspheres. The specific steps are as follows:

[0224] Raw phase three: 150 mL of ultrapure water is added to a 500 mL three-necked flask, 1.5 g of sodium dodecyl sulfonate is weighed into the water, and stirring is started at a speed of 200 r / min. After the sodium dodecylbenzenesulfonate is dissolved, 3 g of seed balls are weighed into the solution.

[0225] The three-necked flask is ultrasonically treated for 40 min to disperse the seed balls uniformly. The three-necked flask containing the seed balls is placed in a water bath to maintain a temperature of 40 degrees Celsius, and mechanical stirring is used at a speed of 350 r / min.

[0226] Raw phase four:

[0227] First portion: 1 g of sodium dodecyl sulfate is weighed into 100 mL of water, 4 g of styrene, 8 g of divinylbenzene (purity 80%), 2 mL of dibutyl phthalate, and 2 mL of toluene are added, the liquid is observed under a microscope after ultrasonic dispersion, until no obvious oil droplets are observed, then 1.5 g of benzoyl peroxide and 0.4 g of azobisisobutyronitrile are added, and the mixture is ultrasonically dispersed uniformly.

[0228] Second: 0.5 g of sodium dodecyl sulfate was weighed into 50 mL of water, 2 g of styrene was added, 4 g of divinylbenzene (purity 80%) was added, and ultrasonic dispersion was performed. The liquid was observed under a microscope until no obvious oil droplets were observed. Then, 0.7 g of benzoyl peroxide was added and uniformly dispersed by ultrasonic dispersion.

[0229] Seed microsphere swelling: 40 mL of the first portion of raw phase four was added to raw phase three, and after stirring for 10 minutes, 30 mL of the first portion of raw phase four was added to raw phase three, and after stirring for half an hour, the remaining 30 mL of the first portion of raw phase four was added, and swelling was performed for 12 h;

[0230] After the swelling was completed, the temperature was increased to 70 degrees Celsius, and the reaction was performed for 2 h;

[0231] Then, the temperature was decreased to 50 degrees Celsius;

[0232] 20 mL of the second portion of raw phase four was continuously added, and after stirring for 10 minutes at 50 degrees Celsius, the temperature was increased to 70 degrees Celsius and the reaction was performed for half an hour; then the temperature was decreased to 50 degrees Celsius, 10 mL of the second portion of raw phase four was added, and after maintaining at 50 degrees Celsius for 10 minutes, the temperature was increased to 70 degrees Celsius and the reaction was performed for half an hour; the foregoing process was repeated until the addition of the second portion of raw phase four was completed.

[0233] After the addition of the second portion of raw phase four was completed, the temperature was increased to 70 degrees Celsius, and the reaction was performed for 10 h, and the heating was stopped.

[0234] After multiple washing and extraction with ethanol, drying was performed at 50 degrees Celsius until a constant weight was obtained. The particle size of the resin microspheres was measured to be 4.3 μm, the polydispersity coefficient was 1.037, and the crosslinking degree was 41%.

[0235] Example 6

[0236] In this example, seed microspheres prepared in the example, i.e., seed ball-2, were used to prepare resin microspheres. The specific steps are as follows:

[0237] Raw phase three: 150 mL of ultrapure water was added to a 500 mL three-necked flask, 1.5 g of sodium dodecyl sulfonate was weighed into the water, and stirring was started at a speed of 200 r / min. After the sodium dodecylbenzenesulfonate was dissolved, 2.5 g of seed balls were added to the solution.

[0238] The three-necked flask was ultrasonically dispersed for 40 min to uniformly disperse the seed balls. The three-necked flask containing the seed balls was placed in a water bath, and the temperature was maintained at 40 degrees Celsius. Mechanical stirring was used, and the stirring speed was 400 r / min.

[0239] Raw phase four:

[0240] The first portion: take 1 g of sodium dodecyl sulfonate into 100 mL of water, add 3.5 g of styrene, 7 g of divinyl benzene (purity 65%), 2 mL of dibutyl phthalate, 2 mL of toluene, ultrasonic dispersion, take the liquid to observe under a microscope, until no obvious oil droplets. Then add 1.2 g of benzoyl peroxide, 0.3 g of azobisisobutyronitrile, ultrasonic dispersion is uniform.

[0241] The second portion: take 0.5 g of sodium dodecyl sulfonate into 50 mL of water, add 1.2 g of styrene, 2.3 g of divinyl benzene (purity 80%), ultrasonic dispersion, take the liquid to observe under a microscope, until no obvious oil droplets. Then add 0.4 g of benzoyl peroxide, ultrasonic dispersion is uniform.

[0242] Seed microsphere swelling: add 40 mL of the first portion of raw material phase four into raw material phase three, stir for 10 minutes, then add 30 mL of the first portion of raw material phase four into raw material phase three, stir for half an hour, then add the remaining 30 mL of the first portion of raw material phase four, swell for 12 h;

[0243] After the swelling is completed, the temperature is raised to 70 degrees Celsius, and the reaction is carried out for 2 h;

[0244] Then, the temperature is lowered to 50 degrees Celsius;

[0245] Continue to add 20 mL of the second portion of raw material phase four, stir for 10 minutes at 50 degrees Celsius, then raise the temperature to 70 degrees Celsius and react for half an hour; then lower the temperature to 50 degrees Celsius, add 10 mL of the second portion of raw material phase four, maintain for 10 minutes at 50 degrees Celsius, then raise the temperature to 70 degrees Celsius and react for half an hour; repeat the foregoing process until the raw material phase four is added completely.

[0246] After the raw material phase four is added completely, the temperature is raised to 70 degrees Celsius, and the reaction is carried out for 10 h, and the heating is stopped.

[0247] After washing with ethanol for multiple times, extract, dry at 50 degrees Celsius until the weight is constant, and resin microspheres 6-A are obtained.

[0248] In addition, sample resin microspheres 6-B, resin microspheres 6-C, and resin microspheres 6-D are also respectively prepared in the same manner as the resin microspheres 6-A. The properties of the finally obtained samples are as shown in Table 1.

[0249] Average particle diameter μm Polydispersity coefficient Degree of crosslinking Resin microspheres 6-A 5.3 1.046 38％ Resin microspheres 6-B 5.5 1.049 37％ Resin microspheres 6-C 5.4 1.039 36％ Resin microspheres 6-D 5.3 1.043 37％

[0250] Comparative Example 2

[0251] Comparative sample-5-A:

[0252] The preparation of raw material phase three is the same as that in Example 6;

[0253] The preparation of raw material phase four is the same as that in Example 6;

[0254] Swelling of seed microspheres:

[0255] The first portion of raw material phase four was added dropwise to raw material phase three at 40 degrees Celsius, and the whole dropwise addition took 5 hours. Then the temperature was raised to 45 degrees Celsius, and the temperature was maintained at 45 degrees Celsius for 8 hours.

[0256] After the swelling was completed, the temperature was raised to 70 degrees Celsius, and the reaction was carried out for 2 hours.

[0257] Then, the temperature was lowered to 50 degrees Celsius, and the second portion of raw material phase four was continuously added dropwise, and the whole dropwise addition took 5 hours. Then, the temperature was maintained at 50 degrees Celsius for 5 hours.

[0258] After the swelling was completed, the temperature was raised to 70 degrees Celsius, and the reaction was carried out for 5 hours. Then, the heating was stopped, and resin microspheres comparative sample-5-A was obtained.

[0259] In addition, comparative sample-5-B, comparative sample-5-C, and comparative sample-5-D were respectively prepared in the same way as comparative sample-5-A. The properties of the finally obtained samples are shown in Table 2.

[0260]

[0261]

[0262] Comparative sample-6: basically the same as example 6, except that the seed microspheres were replaced by comparative sample-1 in comparative example 1. Finally, the average particle size of the resin microspheres was measured to be 5.6 μm, the polydispersity coefficient was 1.328, and the crosslinking degree was 34%.

[0263] Comparative sample-7: basically the same as example 6, except that the seed microspheres were replaced by comparative sample-2 in comparative example 1. Finally, the average particle size of the resin microspheres was measured to be 21 μm, the polydispersity coefficient was 1.394, and the crosslinking degree was 28%.

[0264] Comparative sample-8: basically the same as example 6, except that the seed microspheres were replaced by comparative sample-3 in comparative example 1. Finally, the average particle size of the resin microspheres was measured to be 4.2 μm, the polydispersity coefficient was 1.228, and the crosslinking degree was 37%.

[0265] Comparative sample-9: basically the same as example 6, except that the seed microspheres were replaced by comparative sample-4 in comparative example 1. Finally, the average particle size of the resin microspheres was measured to be 4.8 μm, the polydispersity coefficient was 1.227, and the crosslinking degree was 34%.

[0266] Example 7

[0267] Seed microspheres prepared in the examples, i.e. seed-3 of Example 3, were used in the preparation of the resin microspheres in this example. The specific steps are as follows:

[0268] Raw material phase three: 150 mL of ultrapure water was added to a 500 mL three-necked flask, 1.5 g of sodium dodecyl sulfonate was weighed into the water, and stirring was started at a speed of 200 r / min. After the sodium dodecyl benzene sulfonate was dissolved, 3 g of seed spheres were weighed into the solution.

[0269] The three-necked flask was sonicated for 40 min to disperse the seed spheres-3 uniformly. The three-necked flask containing the seed spheres was placed in a water bath to maintain a temperature of 40 degrees Celsius, and mechanical stirring was used at a speed of 350 r / min.

[0270] Raw material phase four:

[0271] First portion: 1 g of sodium dodecyl sulfate was weighed into 100 mL of water, 4 g of styrene, 8 g of divinyl benzene (purity 80%), 2 mL of dibutyl phthalate, and 2 mL of toluene were added, and ultrasonic dispersion was performed. The liquid was observed under a microscope until no obvious oil droplets were present, and then 1.5 g of benzoyl peroxide and 0.4 g of azobisisobutyronitrile were added and ultrasonic dispersion was performed.

[0272] Second portion: 0.5 g of sodium dodecyl sulfate was weighed into 50 mL of water, 2 g of styrene and 4 g of divinyl benzene (purity 80%) were added, and ultrasonic dispersion was performed. The liquid was observed under a microscope until no obvious oil droplets were present. Then 0.7 g of benzoyl peroxide was added and ultrasonic dispersion was performed.

[0273] Swelling of the seed microspheres: 40 mL of the first portion of raw material phase four was added to raw material phase three, and stirring was performed for 10 min. Then 30 mL of the first portion of raw material phase four was added to raw material phase three, and stirring was performed for half an hour. Then the remaining 30 mL of the first portion of raw material phase four was added, and swelling was performed for 12 h.

[0274] After the swelling was complete, the temperature was increased to 70 degrees Celsius, and reaction was performed for 2 h.

[0275] Then, the temperature was decreased to 50 degrees Celsius.

[0276] 20 mL of the second portion of raw material phase four was continuously added, and stirring was performed at 50 degrees Celsius for 10 min. Then the temperature was increased to 70 degrees Celsius, and reaction was performed for half an hour. Then the temperature was decreased to 50 degrees Celsius, 10 mL of the second portion of raw material phase four was added, and stirring was performed at 50 degrees Celsius for 10 min. Then the temperature was increased to 70 degrees Celsius, and reaction was performed for half an hour. The foregoing process was repeated until the addition of raw material phase four was complete.

[0277] After the addition of raw material phase four was complete, the temperature was increased to 70 degrees Celsius, and reaction was performed for 10 h. Heating was stopped.

[0278] The seed microspheres were washed with ethanol several times and dried at 50°C until the weight was constant. The size of the resin microspheres was 4.8 μm, the polydispersity coefficient was 1.113, and the cross-linking degree was 39%.

[0279] Example 8

[0280] In this example, the seed microspheres prepared in the examples, i.e. the seed microspheres-4 of Example 4, were used to prepare the resin microspheres. The specific steps were as follows:

[0281] Raw phase three: 150 mL of ultrapure water was added to a 500 mL three-necked flask, 1.5 g of sodium dodecyl sulfonate was weighed and added to the water, and stirring was started at a speed of 200 r / min. After the sodium dodecyl benzene sulfonate was dissolved, 3 g of seed microspheres were weighed and added to the solution.

[0282] The three-necked flask was ultrasonically treated for 40 min to uniformly disperse the seed microspheres-4. The three-necked flask containing the seed microspheres was placed in a water bath to maintain a temperature of 40°C, and mechanical stirring was used at a speed of 350 r / min.

[0283] Raw phase four:

[0284] First portion: 1 g of sodium dodecyl sulfate was weighed and added to 100 mL of water, 4 g of styrene, 8 g of divinyl benzene (purity 80%), 2 mL of dibutyl phthalate, and 2 mL of toluene were added, and ultrasonic dispersion was performed. The liquid was observed under a microscope until no obvious oil droplets were present, and then 1.5 g of benzoyl peroxide and 0.4 g of azobisisobutyronitrile were added and ultrasonically dispersed.

[0285] Second portion: 0.5 g of sodium dodecyl sulfate was weighed and added to 50 mL of water, 2 g of styrene and 4 g of divinyl benzene (purity 80%) were added, and ultrasonic dispersion was performed. The liquid was observed under a microscope until no obvious oil droplets were present. Then, 0.7 g of benzoyl peroxide was added and ultrasonically dispersed.

[0286] Swelling of the seed microspheres: 40 mL of the first portion of raw phase four was added to raw phase three, and stirring was performed for 10 min. Then, 30 mL of the first portion of raw phase four was added to raw phase three, and stirring was performed for half an hour. Then, the remaining 30 mL of the first portion of raw phase four was added, and swelling was performed for 12 h.

[0287] After the swelling was completed, the temperature was increased to 70°C, and reaction was performed for 2 h.

[0288] Then, the temperature was decreased to 50°C.

[0289] Continue to add 20 mL of the second portion of raw phase four, after stirring at 50 degrees Celsius for 10 minutes, increase the temperature to 70 degrees Celsius and react for half an hour; then reduce the temperature to 50 degrees Celsius, add 10 mL of the second portion of raw phase four, maintain at 50 degrees Celsius for 10 minutes, then increase the temperature to 70 degrees Celsius and react for half an hour; repeat the foregoing process until the raw phase four is added completely.

[0290] After the raw phase four is added completely, increase the temperature to 70 degrees Celsius and react for 10 hours, then stop heating.

[0291] After extraction by washing with ethanol for multiple times, dry at 50 degrees Celsius until the weight is constant. The particle size of the resin microspheres is measured to be 4.3 μm, the polydispersity index is 1.127, and the crosslinking degree is 36%.

[0292] Example 9

[0293] In this example, the seed microspheres prepared in the example, i.e., seed-1, are used to prepare resin microspheres. The specific steps are as follows:

[0294] Raw phase three: add 150 mL of ultrapure water into a 500 mL three-necked flask, weigh 1.5 g of sodium dodecyl sulfonate and add into the water, turn on the stirring, and the stirring speed is 200 r / min. After the sodium dodecyl sulfonate is dissolved, weigh 3 g of seed balls and add into the solution.

[0295] Ultrasonic the three-necked flask for 40 minutes to make the seed balls uniformly dispersed. Put the three-necked flask containing the seed balls into a water bath and maintain the temperature at 40 degrees Celsius, and use mechanical stirring with a stirring speed of 350 r / min.

[0296] Raw phase four:

[0297] First portion: weigh 1 g of sodium dodecyl sulfate and add into 100 mL of water, add 4 g of styrene, 9 g of divinylbenzene (purity 80%), 2.5 mL of dibutyl phthalate, and 2 mL of toluene, ultrasonic disperse, take the liquid to the microscope to observe until there are no obvious oil droplets, then add 1.5 g of benzoyl peroxide and 0.4 g of azobisisobutyronitrile, and ultrasonic disperse uniformly.

[0298] Second portion: weigh 0.5 g of sodium dodecyl sulfate and add into 50 mL of water, add 2 g of styrene and 4.5 g of divinylbenzene (purity 80%), ultrasonic disperse, take the liquid to the microscope to observe until there are no obvious oil droplets, then add 0.7 g of benzoyl peroxide and ultrasonic disperse uniformly.

[0299] Seed microsphere swelling: add 40 mL of the first portion of raw phase four into raw phase three, stir for 10 minutes, then add 30 mL of the first portion of raw phase four into raw phase three, stir for half an hour, then add the remaining 30 mL of the first portion of raw phase four, and swell for 12 hours;

[0300] After the swelling is completed, the temperature is raised to 70 degrees Celsius and the reaction is carried out for 2 hours;

[0301] Then, the temperature is lowered to 50 degrees Celsius;

[0302] The second 20 mL of raw material phase four is continuously added, after stirring for 10 minutes at 50 degrees Celsius, the temperature is raised to 70 degrees Celsius and the reaction is carried out for half an hour; then the temperature is lowered to 50 degrees Celsius, 10 mL of the second raw material phase four is added, after maintaining for 10 minutes at 50 degrees Celsius, the temperature is raised to 70 degrees Celsius and the reaction is carried out for half an hour; the foregoing process is repeated until the raw material phase four is added completely.

[0303] After the raw material phase four is added completely, the temperature is raised to 70 degrees Celsius and the reaction is carried out for 10 hours, and the heating is stopped.

[0304] After the extraction with ethanol is carried out for several times, drying is carried out at 50 degrees Celsius until the weight is constant. It is measured that the resin microsphere particle size is 4.1 μm, the polydispersity coefficient is 1.046, and the crosslinking degree is 43%.

Claims

1. A method for producing a resin microsphere, characterized by, The method comprises the following steps: A. Seed microsphere synthesis stage A1 preparing raw phase one, which comprises solvent, and two types of dispersants, type one and type two; The amount ratio of the type one and type two dispersants is (10-13):(0.5-1.5); The type one dispersant is selected from any one or both of polyvinylpyrrolidone and polyvinyl alcohol, wherein the molecular weight of the polyvinyl alcohol is ≥10000; The type two dispersant is selected from any one or several of polyacrylic acid, polyvinyl alcohol, ethyl cellulose, hydroxypropyl methyl cellulose and hydroxyapatite, wherein the molecular weight of the polyvinyl alcohol is <10000; A2 preparing raw phase two, which comprises styrene and initiator; A3 seed microsphere synthesis, adding the raw phase two to the raw phase one, and after the addition is completed, reacting at 60-80℃ for 4-24h to obtain seed microspheres; B. Seed microsphere swelling stage B1 preparing raw phase three, which comprises seed microspheres and emulsifier; B2 preparing raw phase four, which comprises styrene, divinylbenzene, porogen, emulsifier, initiator and surfactant; and the raw phase four comprises first raw phase four and second raw phase four; The amount ratio of the first raw phase four to raw phase three is (1-2):(1-2); and the amount ratio of the first raw phase four to the second raw phase four is (1-2):(1-2); B3 seed microsphere swelling one, adding, swelling and reacting the raw phase three and the raw phase four, specifically comprising: First, adding the first raw phase four, which is divided into N times, wherein N is an integer ≥2; after the previous addition is completed, the temperature is raised to 60-80℃ for reaction, and then the temperature is lowered to below 50℃ for the next addition; after the addition of the first raw phase four is completed, swelling is performed, and then reacting at 60-80℃ for 4-24h; Then, adding the second raw phase four, which is divided into N times, wherein N is an integer ≥2; after the previous addition is completed, the temperature is raised to 60-80℃ for reaction, and then the temperature is lowered to below 50℃ for the next addition; after the addition of the second raw phase four is completed, swelling is performed, and then reacting at 60-80℃ for 4-24h.

2. The method for producing a resin microsphere according to claim 1, characterized by, In the A, the mass ratio of styrene, initiator, dispersant and solvent is (30-80):(1-3):(5-10):(300-600).

3. The method for producing a resin microsphere according to claim 2, characterized by, In the B1, the mass percentage of seed microspheres and emulsifier is (0.5-2):(0.5-1.5).

4. The method for producing a resin microsphere according to any one of claims 1 to 3, characterized by, In the B2, the mass percentage of styrene, divinylbenzene, porogen, emulsifier and initiator in the first raw phase four is (1.5-3):(1-4):(1-2):(0.5-1.5):(0.5-1.5); and / or, the mass percentage of styrene, divinylbenzene, emulsifier and initiator in the second raw phase four is (1.5-3):(1-4):(0.5-1.5):(0.5-1.5).

5. Resin microsphere particles, characterized in that, The resin microsphere particles are prepared by the method of any one of claims 1-4, and the particle size of the resin microsphere particles is 4-9 µm.

6. The resin microsphere particle according to claim 5, characterized by The specific surface area of the resin microspheres is 40 to 100 m 2 / g.

7. The resin microsphere particle according to claim 5 or 6, characterized by The cross-linking degree of the resin microsphere particles is 30%-45%.

8. Chromatography packing or chromatography column, characterized in that, The chromatographic packing or chromatographic column comprises the resin microsphere particles prepared by the method of any one of claims 1-4, and / or the resin microsphere particles of any one of claims 5-7.

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