A method for preparing monodisperse solid-phase synthesis support resin microspheres

Abstract

This invention discloses a method for preparing uniformly sized solid-phase synthetic carrier resin microspheres. The method involves uniformly mixing a certain amount of monomer, crosslinking agent, and initiator to prepare an oil phase solution; uniformly mixing a certain amount of water and dispersant to prepare an aqueous phase solution; introducing the prepared oil and aqueous phases into a uniformly sized resin synthesis device; the oil phase solution flowing out of the device at a certain flow rate and temperature; and the aqueous phase solution flowing out of the device at a certain flow rate and temperature. Due to the flow rate difference between the oil and aqueous phase solutions, the aqueous phase solution disperses the oil phase solution into uniformly sized oil droplets, which are suspended in the aqueous phase solution and flow into a curing tank along with it. The curing tank is placed under specific curing conditions to solidify the uniformly sized oil droplets into uniformly sized spheres; the aqueous phase solution is filtered out, and the spheres are then washed and dried to finally obtain uniformly sized resin microspheres.

Description

Technical Field

[0001] This invention belongs to the field of functional polymer material manufacturing, specifically relating to a method for preparing uniformly sized solid-phase synthetic carrier resin microspheres. Background Technology

[0002] Solid-phase synthesis, a key technology in drug synthesis, has been widely applied in pharmaceutical research and development, such as the development of peptide and nucleic acid drugs, since its inception in the 1960s, due to its advantages such as mild reaction conditions, simple product separation and purification, and the ability to achieve automated continuous synthesis. In solid-phase synthesis, the solid-phase synthesis carrier resin serves as the immobilization carrier and reaction site for the reactants. Its performance directly determines the efficiency of the synthesis reaction, product purity, reaction compatibility, and potential for large-scale application, making it a core foundational material for the industrialization of solid-phase synthesis technology.

[0003] Currently, the widely used solid-phase synthetic carrier resin in the industry has specifications such as a crosslinking degree of 1-2% and particle size specifications of 100-200 mesh (75-150µm) and 200-400 mesh (35-75µm). The particle size is non-uniform and has a wide distribution. The main production process of solid-phase synthetic carrier resin involves first producing resin microspheres through suspension polymerization, then sieving the resin microspheres to the target particle size (also called white spheres or base spheres), such as 100-200 mesh and 200-400 mesh. Then, active functional groups are grafted onto the resin microspheres to prepare the solid-phase synthetic carrier resin. Because suspension polymerization cannot produce resin microspheres with uniform particle size, sieving is usually required. Sieving not only wastes material and results in low yield, but also leads to a wide particle size distribution of the sieved resin microspheres, making it difficult to achieve uniform particle size. Therefore, it is also difficult to achieve uniform particle size in the solid-phase synthetic carrier resin prepared based on these resin microspheres. In solid-phase synthesis reactions, solid-phase synthesis carrier resins with non-uniform particle sizes have large differences in particle size, resulting in significant differences in specific surface area. This leads to high mass transfer resistance during the reaction, poor reaction repeatability, and affects the quality of the reaction products. Therefore, the preparation of solid-phase synthesis carrier resin microspheres with uniform particle size is of great significance for optimizing solid-phase synthesis reactions and for the vigorous development of the pharmaceutical research and development field. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention discloses a method for preparing uniform solid-phase synthesis carrier resin microspheres. The method uses a spraying device to prepare solid-phase synthesis carrier resin microspheres with uniform particle size, thereby improving the uniformity of the resin microspheres and helping to improve the product quality of the solid-phase synthesis reaction.

[0005] A uniform particle solid-phase synthetic carrier resin microsphere is formed by suspending and solidifying an oil phase solution containing monomers and crosslinking agents in an aqueous phase solution containing a dispersant; the degree of crosslinking of the resin microsphere is 1-2%, the particle size is 35-300 μm, and the uniformity coefficient is 1-1.2.

[0006] The monomer is selected from one or more of styrene, acrylonitrile, vinyl acetate, methyl acrylate, glycidyl methacrylate, methyl methacrylate, p-chloromethylstyrene, and bromomethylstyrene.

[0007] The crosslinking agent is selected from one or more of divinylbenzene, dipropylenebenzene, ethylene glycol dimethacrylate, hexamethylenedimethacrylamide, divinylphenylmethane, glyceryl trimethacrylate, trimethylolpropane trimethacrylate, triallyl isocyanurate, 1,2,4-trivinylbenzene, and 1,3,5-trivinylbenzene.

[0008] The dispersant is selected from one or more of carboxymethyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, sodium polyacrylate, polyvinylpyrrolidone, sodium chloride, calcium carbonate, calcium phosphate, and surfactants.

[0009] The method for synthesizing uniform particle size solid-phase carrier resin microspheres includes the following steps:

[0010] (1) Mix the monomer, crosslinking agent and initiator evenly to prepare an oil phase solution;

[0011] (2) Mix water and dispersant evenly to prepare an aqueous solution;

[0012] (3) The oil phase solution and the aqueous phase solution are respectively introduced into a uniform particle resin synthesis device, wherein the uniform particle resin synthesis device is a spraying device or a microchannel reactor;

[0013] (4) Control the oil phase solution and the aqueous phase solution to flow out of the uniform particle resin synthesis device at a set flow rate and temperature respectively, and use the flow rate difference between the aqueous phase solution and the oil phase solution to disperse the oil phase solution into uniform oil phase droplets and suspend the oil phase droplets in the aqueous phase solution;

[0014] (5) The mixture containing the oil phase droplets is introduced into a curing tank, and the oil phase droplets are cured to form microspheres under the set curing conditions;

[0015] (6) The aqueous solution is removed by filtration, and the resin microspheres are obtained by washing and drying.

[0016] The initiator is selected from one or more of peroxide initiators and azo initiators;

[0017] The amount of the initiator added is 0.1-5.0 wt% of the total weight of the monomer and the crosslinking agent, preferably 1.0 wt%.

[0018] The mass concentration of the dispersant in the aqueous solution is 0.1-2.0 wt%, preferably 0.5 wt%.

[0019] The structural parameters of the uniform particle resin synthesis apparatus satisfy any of the following conditions:

[0020] Condition 1: When the uniform particle resin synthesis device is a spraying device, the spraying device includes a spraying needle, the inner diameter of which is 1-1000μm, preferably 40-60μm; the material of the spraying needle is stainless steel, silicon carbide or quartz glass.

[0021] Condition 2: When the uniform particle resin synthesis device is a microchannel reactor, the microchannel reactor contains microchannels with a diameter of 1-1000μm, preferably 40-60μm; the shape of the microchannels is heart-shaped, rhomboid, T-shaped or Y-shaped; the material of the microchannels is stainless steel, silicon carbide or quartz glass.

[0022] In step (4), the flow rate of the oil phase solution is 0.1-10 mL / min, preferably 0.1-0.5 mL / min; the flow rate of the aqueous phase solution is 0.5-100 mL / min, preferably 0.5-2.0 mL / min.

[0023] In step (4), the temperature at which the oil phase solution and the aqueous phase solution flow out of the uniform particle resin synthesis device is 20-40℃.

[0024] In step (5), the curing conditions are: curing temperature of 40-95℃, preferably 80-90℃; curing time of 1-15h, preferably 8-12h.

[0025] The particle size of the synthesized microspheres was controlled by adjusting the flow rates of the oil phase solution, the aqueous phase solution, and the concentration of the aqueous phase solution to achieve the desired value. During the control process, the desired microsphere particle size was calculated using the following formula:

[0026]

[0027] In the formula, D p It is the particle size of the microspheres, Q o It is the oil phase flow rate, Q w It is the water phase flow velocity, C w α represents the concentration of the aqueous phase, and β and K are the parameters to be fitted.

[0028] The application of the homogeneous solid-phase synthetic carrier resin microspheres in the preparation of solid-phase synthetic carriers.

[0029] The solid-phase synthesis carrier is used for the solid-phase synthesis of polypeptide drugs or nucleic acid drugs.

[0030] The beneficial effects of this invention are:

[0031] This invention abandons the traditional suspension polymerization method, employing a jetting device or microchannel reactor to precisely shear and dropletize the resin microspheres by utilizing the velocity difference between the water and oil phases. The prepared resin microspheres have a highly uniform particle size (uniformity coefficient of 1-1.2), completely eliminating the cumbersome sieving process in traditional methods, avoiding material waste, and significantly improving the production yield of microspheres.

[0032] Uniform microspheres ensure a high degree of consistency in the specific surface area of ​​the solid-phase synthesis carrier, effectively eliminating the problem of large mass transfer resistance caused by particle size differences, and significantly improving the repeatability and batch stability of solid-phase synthesis reactions.

[0033] When these uniformly sized resin microspheres are applied to the solid-phase synthesis of peptides or nucleic acid drugs, the reaction efficiency can be significantly improved. Experiments show that, compared with traditional heterogeneous carriers, the purity of peptides synthesized using the carrier of this invention can be increased to over 87%~94%, and the yield can reach over 97%, greatly promoting the industrialization process in the field of pharmaceutical research and development. Attached Figure Description

[0034] Figure 1 This is a process flow diagram of the present invention for preparing uniform solid-phase synthetic carrier resin microspheres;

[0035] Figure 2 This is a schematic diagram of the spraying device of the present invention: wherein, 1. oil phase solution storage tank; 2. aqueous phase solution storage tank; 3. oil phase solution inlet valve; 4. aqueous phase solution inlet valve; 5. spraying pipe; 6. curing tank; 7. spraying needle.

[0036] Figure 3 This is a schematic diagram of the microchannel reactor device of the present invention: wherein, 1. oil phase solution storage tank; 2. aqueous phase solution storage tank; 3. oil phase solution inlet valve; 4. aqueous phase solution inlet valve; 5. microchannel reactor; 6. solidification tank.

[0037] Figure 4 This is an electron microscope image of the solid-phase synthetic support resin microspheres prepared according to the present invention. Detailed Implementation

[0038] This invention discloses a method for preparing uniformly sized solid-phase synthetic carrier resin microspheres. The method involves uniformly mixing a certain amount of monomer, crosslinking agent, and initiator to prepare an oil phase solution; uniformly mixing a certain amount of water and dispersant to prepare an aqueous phase solution; introducing the prepared oil and aqueous phases into a uniformly sized resin synthesis device; the oil phase solution flowing out of the device at a certain flow rate and temperature; and the aqueous phase solution flowing out of the device at a certain flow rate and temperature. Due to the flow rate difference between the oil and aqueous phase solutions, the aqueous phase solution disperses the oil phase solution into uniformly sized oil droplets, which are suspended in the aqueous phase solution and flow into a curing tank along with it. The curing tank is placed under specific curing conditions to solidify the uniformly sized oil droplets into uniformly sized spheres; the aqueous phase solution is filtered out, and the spheres are then washed and dried to finally obtain uniformly sized resin microspheres. The method of the present invention can make the resin microspheres controllable and uniform in size, with a uniformity coefficient of 1 to 1.2. When solid-phase synthesis carriers prepared using resin microspheres with such uniform particle size are used in solid-phase synthesis, they are beneficial to improving the purity and yield of the synthesized products.

[0039] Some embodiments of this patent include the following technical solutions:

[0040] A method for preparing uniformly sized solid-phase synthetic support resin microspheres includes the following steps:

[0041] (1) Prepare a uniform particle resin synthesis device, which comprises a spraying device and a microchannel reactor. The spraying device includes an oil phase solution storage tank, an aqueous phase solution storage tank, a curing tank, an oil phase solution inlet valve, an aqueous phase solution inlet valve, a spraying pipe, and a spraying needle. The microchannel reactor includes an oil phase solution storage tank, an aqueous phase solution storage tank, a curing tank, an oil phase solution inlet valve, an aqueous phase solution inlet valve, and microchannels.

[0042] (2) Mix the monomer, crosslinking agent and initiator evenly to prepare an oil phase solution;

[0043] (3) Mix water and dispersant evenly to prepare an aqueous solution;

[0044] (4) The oil phase solution and the aqueous phase solution are introduced into the uniform particle resin synthesis device respectively;

[0045] (5) Adjust the oil phase inlet valve so that the oil phase solution flows out from the uniform particle resin synthesis device at a certain flow rate and temperature;

[0046] (6) Adjust the inlet valve of the aqueous phase so that the aqueous phase solution flows out of the uniform particle resin synthesis device at a certain flow rate and temperature. When it flows through the channel in the uniform particle resin synthesis device, due to the flow rate difference between the aqueous phase solution and the oil phase solution, the oil phase solution is dispersed into uniform oil phase droplets by the aqueous phase solution and suspended in the aqueous phase solution. It then flows into the curing tank with the aqueous phase. By adjusting the flow rates of the aqueous phase and the oil phase, the particle size of the oil phase droplets is controlled to form uniform oil phase droplets.

[0047] (7) Place the curing tank under certain curing conditions to allow the oil phase droplets to solidify and form microspheres;

[0048] (8) Filter the aqueous solution, wash and dry it to obtain resin microspheres.

[0049] The inner diameter of the spray needle is 1~1000um, and the needle material is stainless steel, silicon carbide, or quartz glass.

[0050] The microchannels are defined as follows: the microchannel diameter is 1~1000um, the channel shape is heart-shaped, rhomboid, T-shaped or Y-shaped, and the channel material is stainless steel, silicon carbide or quartz glass.

[0051] The monomer is one or a mixture of styrene, acrylonitrile, vinyl acetate, methyl acrylate, glycidyl methacrylate, methyl methacrylate, p-chloromethylstyrene, and bromomethylstyrene.

[0052] The crosslinking agent is one or a mixture of divinylbenzene, dipropylenebenzene, ethylene glycol dimethacrylate, hexamethylenedimethacrylamide, divinylphenylmethane, glyceryl trimethacrylate, trimethylolpropane trimethacrylate, triallyl isocyanurate, 1,2,4-trivinylbenzene, and 1,3,5-trivinylbenzene.

[0053] The initiator is one or more of peroxide-based and azo-based initiators.

[0054] The dispersant is one or a mixture of carboxymethyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, sodium polyacrylate, polyvinylpyrrolidone, sodium chloride, calcium carbonate, calcium phosphate, and surfactant.

[0055] The resin microspheres have the following characteristics: crosslinking degree of 1~2%, particle size of 35~300um, and uniformity coefficient of 1~1.2.

[0056] The flow rates are as follows: the flow rate of the oil phase solution is 0.1~10 mL / min, and the flow rate of the oil phase solution is 0.5~100 mL / min.

[0057] The temperature is 20~40℃.

[0058] The curing conditions are 40~95℃ for 1~15 hours.

[0059] Example 1

[0060] Adopting attachment Figure 2A jetting apparatus was used to prepare uniform solid-phase synthetic carrier resin microspheres. The jetting needle had an inner diameter of 50 μm and was made of stainless steel. 99% (w / w) styrene and 1% (w / w) divinylbenzene were mixed with 1% benzoyl peroxide by their total weight to prepare an oil phase solution. The aqueous phase solution was a 0.5% polyvinyl alcohol solution. The flow rate of the oil phase solution was adjusted to 0.2 mL / min by controlling the inlet valve of the oil phase solution and to 1 mL / min by controlling the inlet valve of the aqueous phase solution, thus preparing oil phase droplets. The oil phase droplets were then cured in a curing tank at 85℃ for 10 hours. After curing, the resin was filtered, washed, and dried to obtain resin microspheres with an average particle size of 98.2 μm. After modifying the resin microspheres, a solid-phase synthesis carrier 2-CTC resin with uniform particle size was prepared. 20g of the uniformly sized 2-CTC resin prepared above was used to synthesize polypeptide BPC157 (amino acid sequence of polypeptide BPC157: Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val). The specific solid-phase synthesis steps are as follows: (1) Swelling: 20g of the resin microspheres was used to prepare a solid-phase synthesis carrier 2-CTC resin with uniform particle size. 2-CTC resin was added to a solid-phase reaction column, and an appropriate amount of anhydrous dichloromethane (DCM) was added. The column was shaken and swollen for 30 minutes at room temperature. (2) Loading of the first amino acid: DCM solution of the first amino acid Fmoc-Val-OH and N,N-diisopropylethylamine (DIEA) was added and reacted at room temperature for 1 hour. (3) End-capping: A mixture of methanol and DIEA was added to perform an end-capping reaction to block the unreacted active sites on the resin. The resin was then washed alternately with DCM and N,N-dimethylformamide (DMF). (4) Peptide chain extension: 20% piperidine / DMF solution was added to remove the Fmoc protecting group. After washing, the next Fmoc-amino acid (Fmoc-Leu-OH), condensing agent (HBTU / HOBt) and DIEA were added to perform a condensation reaction. Repeat the cycle, sequentially adding the remaining amino acids according to the sequence of peptide BPC157; (5) lysis and precipitation: After the peptide chain synthesis is completed, use a lysis buffer containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (TIS) to lyse at room temperature for 2 hours. Filter and collect the lysis buffer, precipitate with ice-cold ether, centrifuge and dry to obtain crude peptide BPC157. At the same time, use the traditional solid-phase synthesis carrier 2-CTC resin, which has a particle size of 100~200 mesh and is non-uniform. Take 20g of this resin to synthesize peptide BPC157 as comparative example 1. Both Example 1 and Comparative Example 1 were solid-phase synthesized with peptide BPC157 under the same experimental conditions. The peptide purity and yield of Example 1 and Comparative Example 1 are shown in Table 1.

[0061] Table 1. Peptide purity and yield of Example 1 and Comparative Example 1

[0062] peptide BPC157 Example 1 Comparative Example 1 purity / % 87.16 83.67 Yield / % 97.34 49.90

[0063] As shown in Table 1, the solid-phase synthetic carrier resin with uniform particle size prepared by the spray method in Example 1 produced a peptide BPC157 with a purity of 87.16% and a yield of 97.34%. In contrast, the peptide BPC157 synthesized using a resin with non-uniform particle size in Comparative Example 1 had a purity of 83.67% and a yield of 49.90%. This indicates that the solid-phase synthetic carrier resin microspheres with uniform particle size prepared by the spray method have a good effect on improving the purity and yield of the synthesized peptide.

[0064] Example 2

[0065] Adopting attachment Figure 2 A jetting device was used to prepare uniform solid-phase synthetic carrier resin microspheres. The jetting needle had an inner diameter of 50 μm and was made of silicon carbide. 99% (w / w) styrene and 1% (w / w) divinylbenzene were mixed with 1% azobisisobutyronitrile (AIBN) of the total weight of the two to prepare an oil phase solution. The aqueous phase solution was a 0.5% polyvinyl alcohol solution. The flow rate of the oil phase solution was adjusted to 0.2 mL / min by controlling the inlet valve of the oil phase solution and to 1 mL / min by controlling the inlet valve of the aqueous phase solution, thus preparing oil phase droplets. The oil phase droplets were then cured in a curing tank at 85°C for 10 hours. After curing, the resin was filtered, washed, and dried to obtain resin microspheres with an average particle size of 98.2 μm. After modifying the resin microspheres, a solid-phase synthesis carrier 2-CTC resin with uniform particle size was prepared. 20g of the 2-CTC resin was used to synthesize polypeptide TB500 (amino acid sequence of polypeptide TB500: Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-COOH), as Example 2. Simultaneously, 20g of a conventional solid-phase synthesis carrier 2-CTC resin with a particle size of 100-200 mesh and non-uniform particle size was used to synthesize polypeptide TB500, as Comparative Example 2. Both Example 2 and Example 2 were performed under the same experimental conditions to synthesize polypeptide TB500 in a solid phase. The polypeptide purity and yield of Example 2 and Comparative Example 2 are shown in Table 1.

[0066] Table 2. Peptide purity and yield of Example 2 and Comparative Example 2

[0067] Peptide TB500 Example 1 Comparative Example 1 purity / % 94.67 92.89 Yield / % 64.30 42.70

[0068] As shown in Table 2, the solid-phase synthetic carrier resin with uniform particle size prepared by the spray method in Example 2 produced a polypeptide TB500 with a purity of 94.67% and a yield of 64.30%; while the polypeptide TB500 synthesized by the resin with non-uniform particle size in Comparative Example 2 had a purity of 92.89% and a yield of 42.70%. This indicates that the solid-phase synthetic carrier resin microspheres with uniform particle size prepared by the spray method have a good effect on improving the purity and yield of the synthesized polypeptide.

[0069] Example 3

[0070] Adopting attachment Figure 3 A microchannel reactor was used to prepare uniform solid-phase synthetic carrier resin microspheres. The microchannels had a diameter of 50 μm, a Y-shaped shape, and were made of quartz glass. 99% (w / w) styrene and 1% (w / w) divinylbenzene were mixed with 1% benzoyl peroxide (by weight of the total weight of the two) to form an oil phase solution. The aqueous phase solution was a 0.5% polyvinyl alcohol solution. The flow rate of the oil phase solution was adjusted to 0.2 mL / min by controlling the inlet valve, and the flow rate of the aqueous phase solution was adjusted to 1 mL / min by controlling the inlet valve, thus preparing oil phase droplets. These droplets were then cured in a curing tank at 85°C for 10 hours. The resin was then filtered, washed, and dried to obtain resin microspheres with an average particle size of 98.2 μm. After modifying the resin microspheres, a solid-phase synthesis carrier, 2-CTC resin, was prepared with uniform particle size. 20g of this 2-CTC resin was used to synthesize smegglutinin (smegglutinin amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly), as Example 3. Simultaneously, 20g of a conventional solid-phase synthesis carrier, 2-CTC resin, with a particle size of 100-200 mesh and non-uniform particle size, was used to synthesize smegglutinin, as Comparative Example 3. Both Example 3 and Comparative Example 3 were performed under the same experimental conditions for solid-phase synthesis of smegglutinin. The peptide purity and yield of Example 3 and Comparative Example 3 are shown in Table 1.

[0071] Table 3. Peptide purity and yield of Example 3 and Comparative Example 3

[0072] Smegglutide Example 1 Comparative Example 1 purity / % 41.87 23.46 Yield / % 82.44 30.70

[0073] As shown in Table 3, the solid-phase synthesis carrier resin with uniform particle size prepared using a microchannel reactor in Example 3 resulted in a smegglutinin synthesis with a purity of 82.44% and a yield of 41.87%. In contrast, the smegglutinin synthesized using a resin with non-uniform particle size in Comparative Example 3 had a purity of 23.46% and a yield of 30.70%. This indicates that the solid-phase synthesis carrier resin microspheres with uniform particle size prepared using a microchannel reactor have a good effect on improving the purity and yield of synthesized peptides.

[0074] Example 4

[0075] Optimization and control of operating conditions in the synthesis of resin microspheres:

[0076] To control particle size during microsphere synthesis, this patent constructs a correlation between experimental conditions and particle size, used to prepare microspheres with the desired particle size. The correlation is constructed based on the following approach:

[0077] In this synthesis process, the oil phase, as the dispersed phase, enters the aqueous phase, while the aqueous phase, as the continuous phase, exerts shearing, compression, and carrying effects on the oil phase droplets. The oil phase continues to enter the droplets before they break apart. Therefore, the higher the oil phase flow rate Q0, the greater the volume of oil phase entering the droplets before breakup, resulting in a larger final droplet volume. On the other hand, the aqueous phase flow rate Q... w The larger the droplet size, the stronger the compression and shearing forces exerted by the water phase on the neck of the oil phase droplet, making the droplet more prone to premature breakage and resulting in a smaller final droplet volume. The droplet volume can be understood as consisting of two parts: 1. the base volume determined by the device structure, injection needle, or microchannel size; 2. the volume of the oil phase that continues to enter the droplet before breakage. The droplet volume can be written as:

[0078]

[0079] Wherein: V d V0 is the volume of the oil phase droplet; α is the volume of the base droplet; and α is the strength of the effect of the flow rate ratio on the droplet volume.

[0080] Dispersant concentration C in aqueous solution w This affects the droplet formation process. Generally, increasing the concentration of the aqueous dispersant alters the viscosity of the aqueous phase, the interfacial tension between oil and water, improves the dispersion stability of oil droplets in the aqueous phase, and makes droplets more prone to breakup and smaller size. Therefore, at the same Q0 and Q... w Below, aqueous phase concentration C w The higher the concentration, the easier it is for droplets to form smaller sizes. To incorporate the effect of aqueous phase concentration into the model, a concentration correction term is defined:

[0081]

[0082] β represents the strength of the effect of aqueous phase concentration on droplet breakup and stabilization processes. The droplet volume expression can be rewritten as:

[0083]

[0084] After the droplets solidify in the curing tank, they form approximately spherical microspheres. For spherical particles, their volume is related to the cube of the particle size.

[0085] The particle size of microspheres can be written as:

[0086]

[0087] K is a coefficient.

[0088] Based on Example 1, the experimental results were fitted by adjusting the flow rates of the aqueous and oil phases and the concentration of the aqueous solution, and then verified using test results under other conditions. The results are as follows:

[0089] The fitted data are:

[0090] Cw Qo Qw Experimental value of Dp Predicted value 0.5 0.2 1 98um 99.3435 um 1.5 0.05 0.8 72 um 67.3359 um 3 0.4 2 83 um 75.5434 um 5 0.6 3 59 um 69.6763 um

[0091] Parameters K=54.9853, α=41.8450, β=1.4176, mean percentage error 8.7320%.

[0092] The following two sets of data were used for verification, and the results are as follows:

[0093] Cw Qo Qw Experimental value of Dp Predicted value 1 0.3 4 72 um 72.5616 um 2 0.25 6 52 um 62.3013 um

[0094] The average percentage error is 10.2950%.

[0095] As can be seen, the data in this patent, based on two experimental datasets, has good prediction accuracy for obtaining microsphere particle size, with an overall average percentage error of about 8-10%, which can effectively guide precise synthesis.

Claims

1. A uniform particle solid phase synthesis support resin microsphere, characterized by, The resin microspheres are formed by suspending and solidifying an oil phase solution containing monomers and crosslinking agents in an aqueous phase solution containing dispersants; the degree of crosslinking of the resin microspheres is 1-2%, the particle size is 35-300 μm, and the uniformity coefficient is 1-1.

2.

2. The uniform particle solid phase synthesis support resin microsphere of claim 1, wherein, The monomer is selected from one or more of styrene, acrylonitrile, vinyl acetate, methyl acrylate, glycidyl methacrylate, methyl methacrylate, p-chloromethylstyrene, and bromomethylstyrene. The crosslinking agent is selected from one or more of divinylbenzene, dipropylenebenzene, ethylene glycol dimethacrylate, hexamethylenedimethacrylamide, divinylphenylmethane, glyceryl trimethacrylate, trimethylolpropane trimethacrylate, triallyl isocyanurate, 1,2,4-trivinylbenzene, and 1,3,5-trivinylbenzene.

3. The uniform particle size solid-phase synthetic carrier resin microspheres according to claim 1, characterized in that, The dispersant is selected from one or more of carboxymethyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, sodium polyacrylate, polyvinylpyrrolidone, sodium chloride, calcium carbonate, calcium phosphate, and surfactants.

4. A method for preparing uniform-particle solid-phase synthetic carrier resin microspheres as described in any one of claims 1-3, characterized in that, Includes the following steps: (1) Mix the monomer, crosslinking agent and initiator evenly to prepare an oil phase solution; (2) Mix water and dispersant evenly to prepare an aqueous solution; (3) The oil phase solution and the aqueous phase solution are respectively introduced into a uniform particle resin synthesis device, wherein the uniform particle resin synthesis device is a spraying device or a microchannel reactor; (4) Control the oil phase solution and the aqueous phase solution to flow out of the uniform particle resin synthesis device at a set flow rate and temperature respectively, and use the flow rate difference between the aqueous phase solution and the oil phase solution to disperse the oil phase solution into uniform oil phase droplets and suspend the oil phase droplets in the aqueous phase solution; (5) The mixture containing the oil phase droplets is introduced into a curing tank, and the oil phase droplets are cured to form microspheres under the set curing conditions; (6) The aqueous solution is removed by filtration, and the resin microspheres are obtained by washing and drying.

5. The method according to claim 4, characterized in that, The initiator is selected from one or more of peroxide initiators and azo initiators; The amount of the initiator added is 0.1-5.0 wt% of the total weight of the monomer and the crosslinking agent, preferably 1.0 wt%. The mass concentration of the dispersant in the aqueous solution is 0.1-2.0 wt%, preferably 0.5 wt%.

6. The method according to claim 4, characterized in that, The structural parameters of the uniform particle resin synthesis apparatus satisfy any of the following conditions: Condition 1: When the uniform particle resin synthesis device is a spraying device, the spraying device includes a spraying needle, the inner diameter of which is 1-1000μm, preferably 40-60μm; the material of the spraying needle is stainless steel, silicon carbide or quartz glass. Condition 2: When the uniform particle resin synthesis device is a microchannel reactor, the microchannel reactor contains microchannels with a diameter of 1-1000μm, preferably 40-60μm; the shape of the microchannels is heart-shaped, rhomboid, T-shaped or Y-shaped; the material of the microchannels is stainless steel, silicon carbide or quartz glass.

7. The method according to claim 4, characterized in that, In step (4), the flow rate of the oil phase solution is 0.1-10 mL / min, preferably 0.1-0.5 mL / min; the flow rate of the aqueous phase solution is 0.5-100 mL / min, preferably 0.5-2.0 mL / min. In step (4), the temperature at which the oil phase solution and the aqueous phase solution flow out of the uniform particle resin synthesis device is 20-40℃. In step (5), the curing conditions are: curing temperature of 40-95℃, preferably 80-90℃; curing time of 1-15h, preferably 8-12h.

8. The method according to claim 4, characterized in that, The particle size of the synthesized microspheres was controlled by adjusting the flow rate of the oil phase solution, the flow rate of the aqueous phase solution, and the concentration in the aqueous phase solution to make it meet the expected value. During the control process, the expected microsphere particle size is calculated using the following formula: ； where D p is the microsphere diameter, Q o is the oil phase flow rate, Q w is the water phase flow rate, C w is the water phase concentration, and a, β, K are parameters to be fitted.

9. The application of the uniform particle size solid-phase synthetic support resin microspheres as described in any one of claims 1-3 in the preparation of solid-phase synthetic supports.

10. The application according to claim 9, characterized in that, The solid-phase synthesis carrier is used for the solid-phase synthesis of polypeptide drugs or nucleic acid drugs.

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