Precise synthesis method of polymethacrylate polymer

Abstract

The invention discloses a precise synthesis method of a polymethacrylate polymer. The reaction process is regulated and controlled by using a magnetic oscillation environment, so that the technical defects of limited mass and heat transfer, non-uniform dispersion of a catalyst and an initiator, low structure control precision and the like caused by increase of system viscosity in the existing polymethacrylate polymer synthesis process are overcome; the narrowing of molecular weight distribution of the polymer, accurate control of the block structure and the like are realized, and the method has a wide application prospect in autonomous controllable preparation of high-end medicinal polymer materials.

Description

Technical Field

[0001] This invention belongs to the field of polymer material synthesis technology, and in particular relates to a precise synthesis method for polymethacrylate polymers. Background Technology

[0002] Polymethacrylate polymers, as a key class of pH-responsive pharmaceutical polymers, rely heavily on precise molecular structure parameters, including molecular weight distribution, block sequence arrangement, and composition ratios, for their applications in drug delivery, sustained-release formulations, and other biopharmaceutical fields. Currently, the precise synthesis of polymethacrylate polymers primarily employs atom transfer radical polymerization (ATRP) technology. In ATRP systems, both macromolecular initiators and traditional free radical initiators are typically introduced simultaneously. These two initiators play distinctly different but indispensable roles: the traditional free radical initiator generates free radicals to maintain catalytic activity, while the macromolecular initiator serves as the anchoring starting point for chain growth, jointly ensuring the efficient initiation and precise control of the polymerization reaction.

[0003] However, during the preparation of polymethacrylate polymers, the viscosity of the system increases sharply as the reaction progresses, which can easily lead to serious mass and heat transfer limitations. I. Uneven heat transfer induces side reactions: The coupling of exothermic polymerization and high viscosity can create "hot spots" in local areas of the reactor (such as near the agitator) (temperature fluctuations can reach ±5℃), leading to side reactions such as chain growth deactivation and explosive polymerization, which destroys the controllability of polymerization; II. Mass transfer limitation exacerbates viscosity increase: The viscosity of the system increases exponentially with the conversion rate. The formation of chain entanglement and local high concentration areas (such as monomer / free radical aggregation) will further reduce the fluidity of the system, resulting in a sharp drop in mass transfer efficiency and stagnation of the reaction rate in the later stage. III. Uneven distribution of active species disrupts synchronicity: Catalytic systems (e.g., Cu) 2+ / Cu + The free radicals generated by ligand complexes, macromolecular initiators and traditional free radical initiators are prone to uneven spatial distribution due to limited mass transfer (forming "free radical rich regions" and "catalyst aggregation regions"), resulting in significant differences in chain growth rates. Ultimately, this manifests as defects such as broadened molecular weight distribution (PDI), block ratios deviating from the design value (error > 5%), and unstable polymerization kinetics.

[0004] In existing technologies, mass and heat transfer enhancement in ATRP polymerization largely relies on mechanical stirring and ultrasonic assistance, but these methods have significant limitations: mechanical stirring can only improve macroscopic mixing and cannot affect the microscopic distribution of catalytic components / free radicals; moreover, it easily leads to excessive local shearing at high viscosity, exacerbating catalyst aggregation and local enrichment of macromolecular initiators. Ultrasonic assistance has limited depth of action and is prone to inducing free radical chain termination side reactions, making it difficult to achieve precise control of the polymerization process. Furthermore, the uniformity of catalyst dispersion and the effective contact efficiency between macromolecular initiators and free radicals in the ATRP system directly affect the stability of active species concentration and the synchronicity of chain growth; existing enhancement methods cannot effectively solve these problems in high-viscosity systems.

[0005] Therefore, developing a new technology that can simultaneously achieve heat transfer homogenization, mass transfer enhancement, and uniform distribution of active species at the microscale is of great scientific significance and industrial application value for improving the structural control precision of polymethyl methacrylate polymers. Summary of the Invention

[0006] To address at least some of the technical problems in the prior art, the present invention provides a method for the precise synthesis of polymethacrylate polymers. Specifically, the present invention includes the following:

[0007] A first aspect of the present invention provides a method for the precise synthesis of polymethacrylate polymers, comprising the following steps: (1) Mix methacrylate monomers, macromolecular initiators, small molecule free radical initiators, catalysts, chain transfer agents and solvents to obtain the initial reaction system; (2) The initial reaction system is reacted in a magnetic oscillation environment at 40-90℃ for 4-72 h to obtain the polymethyl methacrylate polymer.

[0008] In some embodiments, according to the precise synthesis method of polymethacrylate polymers of the present invention, the molar ratio of the macromolecular initiator, the small molecule free radical initiator, the catalyst, the chain transfer agent and the monomer is (0.5-1.5):(0.5-2.0):(0.05-0.20):(0.20-0.80):(20-200).

[0009] In some embodiments, the precise synthesis method for polymethacrylate polymers according to the present invention includes, wherein the methacrylate monomers include at least one of methyl methacrylate, ethyl methacrylate, dimethylaminoethyl methacrylate, and hydroxyethyl methacrylate.

[0010] In some embodiments, the precise synthesis method for polymethacrylate polymers according to the present invention includes a macromolecular initiator comprising a PEG-Br compound.

[0011] In some embodiments, the precise synthesis method for polymethacrylate polymers according to the present invention includes, wherein the small molecule free radical initiator comprises at least one selected from azobisisobutyronitrile, azobisisoheptanenitrile, benzoyl peroxide, and di-tert-butyl peroxide.

[0012] In some embodiments, the precise synthesis method for polymethacrylate polymers according to the present invention includes a catalyst comprising a transition metal salt.

[0013] In some embodiments, according to the precise synthesis method of polymethacrylate polymers of the present invention, the chain transfer agent comprises at least one selected from 2,2'-bipyridine, 4,4'-dinonyl-2,2'-bipyridine, tris(2-pyridylmethyl)amine, and N,N,N',N'',N''-pentamethyldiethylenetriamine.

[0014] In some embodiments, the precise synthesis method for polymethacrylate polymers according to the present invention includes a solvent comprising at least one selected from N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, isopropanol, methanol, ethanol, 1,4-dioxane, and tetrahydrofuran.

[0015] In some embodiments, according to the precise synthesis method of polymethacrylate polymers of the present invention, the magnetic field strength of the magnetic oscillation changes periodically with time, the peak value of the magnetic field strength is in the range of 0.05-2.0 T, and the frequency of the magnetic oscillation is in the range of 10-50 Hz.

[0016] In some embodiments, according to the precise synthesis method of polymethacrylate polymers of the present invention, the direction of the magnetic field during magnetic oscillation is parallel to or at 30°-90° to the axis of the reaction vessel.

[0017] In some embodiments, the precise synthesis method for polymethacrylate polymers according to the present invention involves periodic reversals of the magnetic field direction.

[0018] In some embodiments, the precise synthesis method for polymethacrylate polymers according to the present invention further includes a step of purifying the polymethacrylate polymer.

[0019] A second aspect of the present invention provides a polymethacrylate polymer obtained by the method described in the first aspect of the present invention.

[0020] A third aspect of the invention provides the use of the polymethacrylate polymers according to the second aspect of the invention in the preparation of pH-responsive pharmaceutical excipients, drug delivery carriers, or sustained-release formulations.

[0021] The beneficial technical effects of this invention include: 1. Simultaneously solving the challenges of mass and heat transfer and multi-component dispersion: This invention employs a magnetic oscillation process to regulate the synthesis reaction of polymethyl methacrylate polymers. Through the magneto-electric coupling effect, directional perturbations are generated at the microscale, which not only effectively breaks the local aggregation of reactant components in high-viscosity media and significantly enhances the heat and mass transfer of the polymerization system, but also optimizes the dispersion uniformity of free radicals generated by catalyst-ligand active complexes, macromolecular initiators, and traditional free radical initiators. This avoids the aggregation and deactivation of active centers and the local enrichment of initiators / free radicals, fundamentally solving the core technical bottleneck of high-viscosity reaction systems. At the same time, the synergistic mechanism between macromolecular initiators (e.g., PEG-Br) and traditional free radical initiators (e.g., AIBN) is clarified, ensuring the orderly progress of the polymerization reaction.

[0022] 2. Significantly improved structural control precision: Magnetic oscillation can precisely regulate the polymerization kinetics of the synthesis reaction of polymethyl methacrylate polymers, suppress uncontrolled chain growth and irreversible termination side reactions, and achieve synchronicity in the chain growth process; the polymethyl methacrylate polymers prepared by the method of this invention have extremely narrow molecular weight distribution (PDI≤1.08), and the experimental realized value of complex block structures has an error of less than 5% compared with the theoretical design value. The structural control precision is high and far superior to the products prepared by the conventional ATRP method (the conventional method has a PDI of ≥1.2).

[0023] 3. Strong process compatibility: The method of this invention is based on the optimization of the ATRP polymerization system. It does not require modification of existing polymerization equipment. The enhancement effect can be achieved simply by using an external device that can provide a magnetic oscillation environment. It has strong process compatibility and is easy to operate. It can be applied on a large scale to the synthesis of polymethyl methacrylate pharmaceutical polymers.

[0024] 4. Stable and reliable process, excellent product performance: The reaction conditions of this invention are mild, and key factors such as magnetic field parameters, temperature, and component ratio are easy to control. The coefficient of variation of product structural parameters in repeated experiments under the same process conditions is ≤3%, indicating good process stability. The prepared polymethyl methacrylate polymers not only have precise structures but also maintain excellent pH response performance, fully meeting the requirements for high-end pharmaceutical excipients. Attached Figure Description

[0025] Figure 1 A is a schematic diagram of a device that provides a magnetic oscillation environment, and B is a schematic diagram of magnetic field changes.

[0026] Figure 2An exemplary synthetic route for a polymethacrylate polymer is shown.

[0027] Figure 3 The monomer conversion rates of the exemplary reaction system of Example 1 at different times are shown.

[0028] Figure 4 The viscosity test results of the exemplary reaction system of Example 1 at different times are shown.

[0029] Figure 5 The zeta potential measurement results of the exemplary polymethacrylate polymer of Example 1 at different pH values ​​are shown.

[0030] Figure 6 The monomer conversion rates of the exemplary reaction system of Comparative Example 1 at different times are shown.

[0031] Figure 7 The viscosity test results of the exemplary reaction system of Comparative Example 1 at different times are shown.

[0032] Figure 8 The zeta potential measurement results of the exemplary polymethacrylate polymer of Comparative Example 1 at different pH values ​​are shown. Detailed Implementation

[0033] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0034] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that the upper and lower limits of the range and each intermediate value between them are specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0035] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention.

[0036] In this invention, the term "precise synthesis method" refers to a synthesis process that can control the molecular structure of polymers with high precision, so that the structural parameters of the final product (such as, but not limited to, molecular weight, molecular weight distribution, block sequence, composition ratio, etc.) strictly conform to the preset theoretical values ​​and with minimal error.

[0037] In this invention, the term "magnetic oscillation environment" refers to a magnetic field environment in which both the magnetic field strength and direction change periodically over time.

[0038] Precise Synthesis Methods for Polymethacrylate Polymers One aspect of the present invention provides a method for the precise synthesis of polymethacrylate polymers, comprising the following steps: (1) Mix the raw materials containing methacrylate monomers, macromolecular initiators, small molecule free radical initiators (also known as "traditional free radical initiators"), catalysts, chain transfer agents and solvents to obtain an initial reaction system; (2) The initial reaction system is subjected to polymerization reaction in a magnetic oscillation environment to obtain the polymethacrylate polymer.

[0039] The molar ratio of the macromolecular initiator, traditional free radical initiator, catalyst, chain transfer agent, and monomer can be controlled within a suitable range. This allows the free radicals generated by the traditional free radical initiator to precisely maintain catalytic activity, the catalyst and chain transfer agent to efficiently coordinate and form active centers, and the macromolecular initiator to efficiently initiate chain growth, achieving a balance between catalytic activity, synchronous chain growth, and the synthesis of narrow-distribution products. In this invention, the molar ratio of the macromolecular initiator, traditional free radical initiator, catalyst, chain transfer agent, and monomer is 1:(0.5-2.0):(0.05-0.20):(0.20-0.80):(20-200), preferably 1:(0.6-1.9):(0.06-0.19):(0.25-0.75):(30-190), and even more preferably 1:(0.7-1.8):(0.06-0.19):(0.25-0.75):(30-190), and even more preferably 1:(0.7-1.8):(0.06-0.19):(0.25-0.75):(30-190). 0.07-0.18):(0.3-0.7):(40-180), further preferred is 1:(0.8-1.7):(0.08-0.17):(0.35-0.65):(50-170), more preferably 1:(1-1.4):(0.1-0.14):(0.35-0.55):(80-120), for example 1:1:0.1:0.35:80, 1:1.2: 0.1:0.35:80, 1:1.4:0.1:0.35:80, 1:1:0.12:0.35:80, 1:1.2:0.12:0.35:80, 1:1.4:0.12:0.35:80, 1:1:0.14:0.35:80, 1:1.2:0.14:0.35:80, 1:1.4:0.14:0.35:80, 1:1:0.1: The ratios can be 0.4:80, 1:1.2:0.1:0.45:80, 1:1.4:0.1:0.55:80, 1:1.2:0.1:0.35:90, 1:1.4:0.1:0.35:100, 1:1:0.1:0.35:110, 1:1.2:0.1:0.35:120, 1:1.2:0.12:0.48:100, or any ratio within the above ranges. In a preferred embodiment, the molar ratio of the macromolecular initiator, conventional free radical initiator, catalyst, chain transfer agent, and monomer is 1:1.2:0.12:0.48:100.

[0040] In this invention, the methacrylate monomers are not particularly limited, and examples include, but are not limited to, methyl methacrylate monomers, ethyl methacrylate monomers, dimethylaminoethyl methacrylate monomers, and hydroxyethyl methacrylate monomers. In a preferred embodiment, the methacrylate monomer is an ethyl methacrylate monomer, and more preferably, 2-(diisopropylamino)ethyl methacrylate (DIPAMA).

[0041] In this invention, the macromolecular initiator is not particularly limited, and examples include, but are not limited to, PEG-Br compounds, such as, but not limited to, polyethylene glycol monomethyl ether bromide (mPEG-Br) and bi-terminated polyethylene glycol (Br-PEG-Br). The molecular weight of the macromolecular initiator is not particularly limited and can be adjusted as needed, preferably 500-10000 Da, more preferably 800-9500 Da, further preferably 1000-9000 Da, even more preferably 1500-9000 Da, more preferably 2000-8500 Da, and even more preferably 2500-8000 Da, for example, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, and 8000 Da. In one specific implementation, the macromolecular initiator is polyethylene glycol monomethyl ether bromide (mPEG-Br) with a molecular weight of 5000 Da.

[0042] In this invention, the conventional free radical initiator is not particularly limited, and examples include, but are not limited to, azobisisobutyronitrile (AIBN), azobisisoheptanenitrile (AIBN), benzoyl peroxide, and di-tert-butyl peroxide. In a preferred embodiment, the conventional free radical initiator is azobisisobutyronitrile (AIBN).

[0043] In this invention, a macromolecular initiator serves as the anchoring starting point for chain growth. Under the action of a catalyst / ligand system, the terminal bromine atom is activated to generate an active free radical, initiating the chain growth reaction of the monomer and simultaneously determining the block structure basis of the polymer (such as the PEG-polymethyl methacrylate block structure). Traditional free radical initiators decompose at the reaction temperature to generate initial free radicals, which can rapidly reduce high-valence catalysts (such as Cu) in the system. 2+ →Cu + Traditional free radical initiators maintain a stable concentration of active catalytic species in the system, ensuring the continuous initiation of PEG-Br chain growth, rather than directly initiating a large number of chain-initiating reactions (avoiding PDI broadening). In a preferred embodiment, the macromolecular initiator and the traditional free radical initiator are added simultaneously to synergistically ensure the controllability of polymerization.

[0044] In this invention, the catalyst is not particularly limited, and examples include, but are not limited to, transition metal salts, such as, but not limited to, copper chloride, copper bromide, ferric chloride, and nickel bromide. In a preferred embodiment, the catalyst is copper bromide (CuBr2).

[0045] In this invention, the chain transfer agent is not particularly limited, and examples include, but are not limited to, 2,2'-bipyridine, 4,4'-dinonyl-2,2'-bipyridine, tris(2-pyridylmethyl)amine, and N,N,N',N'',N''-pentamethyldiethylenetriamine. In a preferred embodiment, the chain transfer agent is tris(2-pyridylmethyl)amine (TPMA).

[0046] In this invention, the solvent is not particularly limited, and examples include, but are not limited to, N,N-dimethylformamide (DMF), dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, isopropanol, methanol, ethanol, 1,4-dioxane, tetrahydrofuran, etc. When two or more solvents are used, the ratio between the solvents is not particularly limited and can be adjusted as needed.

[0047] The precise synthesis method for polymethacrylate polymers of the present invention can improve polymerization reaction performance, such as, but not limited to, monomer conversion rate, degree of polymerization, product structure accuracy, polymer dispersibility index, impurity residue, reaction controllability, and process stability.

[0048] In this invention, the synthesis reaction is carried out in a magnetically oscillating environment to improve the reaction performance of the polymethacrylate polymer synthesis reaction. In a preferred embodiment, the magnetically oscillating environment refers to a non-static magnetic field environment. This invention has found through research that periodically perturbing the charged / paramagnetic components (such as Cu) within the system... 2+ / Cu + -Ligand complexes) can form continuous heat transfer channels at the microscale, break chain entanglement and local aggregation, and homogenize the distribution of active species, thereby precisely solving the core bottleneck of high viscosity in the ATRP reaction.

[0049] To maximize mass and heat transfer while avoiding excessive magnetic field strength that could lead to oxidative deactivation of active species in the catalyst, thereby improving the reaction performance of polymethyl methacrylate polymer synthesis, the peak value and frequency of the magnetic field strength in the magnetic oscillation environment can be controlled within a suitable range. In this invention, the peak magnetic field strength of the magnetic oscillation environment is 0.05-2.0 T, preferably 0.06-1.5 T, even more preferably 0.07-1 T, further preferably 0.08-0.8 T, more preferably 0.09-0.6 T, and even more preferably 0.1-0.5 T, for example 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, and 0.5 T, and the frequency is 10-50 Hz, preferably 12-48 Hz, even more preferably 14-46 Hz, further preferably 16-44 Hz, more preferably 18-42 Hz, and even more preferably 20-40 Hz, for example 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40 Hz. In a preferred embodiment, the peak magnetic field strength of the magnetic oscillation environment is 0.3 T, and the frequency is 30 Hz.

[0050] In a preferred embodiment, the magnetic oscillation environment is formed by a magnetic oscillation device (e.g., a controlled oscillating magnetic field generator), which is configured to output an oscillating magnetic field with adjustable intensity and frequency. The direction of the magnetic field is parallel to the axis of the reaction vessel or at a preset angle (30°-90°), thereby ensuring that the magnetic field acts uniformly on the entire reaction system and achieves directional perturbation at the microscale.

[0051] In this invention, the temperature and reaction time of the polymerization reaction are not particularly limited. To improve the reaction performance of the synthesis reaction of polymethyl methacrylate polymers, the temperature of the polymerization reaction can be controlled at 40-90°C, preferably 45-85°C, even more preferably 50-80°C, further preferably 55-80°C, and more preferably 60-80°C, for example 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80°C. The reaction time is 4-72 h, preferably 5-60 h, even more preferably 6-50 h, further preferably 7-40 h, more preferably 8-30 h, and more preferably 8-20 h, for example 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 h.

[0052] In a preferred embodiment, the polymerization reaction is carried out in an inert gas atmosphere (e.g., but not limited to nitrogen, argon, etc.).

[0053] In a preferred embodiment, the method for precise synthesis of polymethyl methacrylate polymers of the present invention further includes a step of purifying the polymethyl methacrylate polymer. The purification is not particularly limited and can be performed using methods known in the art, such as, but not limited to, precipitation, washing, and drying of the polymethyl methacrylate polymer. In a more preferred embodiment, the purification includes dissolving the reaction product in an excess solvent (e.g., but not limited to, tetrahydrofuran, 1,4-dioxane, etc.), dialyzing with an aqueous solution (e.g., but not limited to, distilled water, purified water, reverse osmosis water, etc.), and lyophilizing to obtain the polymethyl methacrylate polymer.

[0054] The present invention also provides a method for improving the reaction performance of ATRP, which includes the step of carrying out the ATRP reaction in a magnetically oscillating environment.

[0055] In a preferred embodiment, the method for improving the ATRP response performance includes: (1) The raw materials containing methacrylate monomers, macromolecular initiators, free radical initiators, catalysts, chain transfer agents and solvents are mixed to obtain an initial reaction system; (2) The initial reaction system is subjected to polymerization reaction in a magnetic oscillation environment to obtain the polymethacrylate polymer.

[0056] Polymethacrylate polymers One aspect of the present invention provides a polymethacrylate polymer obtained by the method described herein. The polymethacrylate polymer of the present invention has a molecular weight distribution (PDI) not higher than 1.08, an experimental value for the block structure with an error of <5% compared to the theoretical design value, preferably <4%, more preferably <3%, even more preferably <2.6%, and low impurity residue (e.g., Cu not higher than 0.32 ppm). 2+ (Residual amount), and has a stable pH response function.

[0057] In existing synthesis techniques for polymethacrylate polymers, the conventional ATRP method (analytical non-magnetic reinforcement) typically produces polymers with a wide molecular weight distribution, with a PDI generally above 1.2 and difficult to stably fall below 1.10. This invention, by introducing a controlled oscillating magnetic field during polymerization, effectively optimizes the mass and heat transfer behavior in the reaction system, significantly improving the dispersion uniformity of active species and the synchronization of chain growth, thereby achieving precise control of the polymer structure (e.g., a molecular weight distribution PDI of up to 1.069).

[0058] The present invention also provides the use of the polymethacrylate polymers in the preparation of pH-responsive pharmaceutical excipients, drug delivery carriers or sustained-release formulations.

[0059] Example 1 This embodiment exemplifies a method for the precise synthesis of polymethacrylate polymers.

[0060] 1. Magnetic oscillation device 1.1 Core Components A schematic diagram of the magnetic oscillation device in this embodiment is shown below. Figure 1 As shown in A, the core component consists of a motor, a belt, and a ring magnetic pole assembly; rare earth permanent magnet materials are alternately arranged along the circumference on the inner side of the ring magnetic pole assembly, and the number of magnetic poles is ≥6 sets.

[0061] 1.2 Working Method The motor drives the annular magnetic pole assembly to rotate at a constant speed via a belt. During rotation, the N / S poles periodically alternate passing through the reaction vessel (located in the central region of the magnetic pole assembly), forming an oscillating radial magnetic field. A schematic diagram of the magnetic field change is shown below. Figure 1 As shown in B. The oscillating magnetic field is a continuous magnetic field that can generate an extremely low induced electric field, and the magnetic field strength and frequency are adjustable.

[0062] 2. Synthesis Method (1) Reaction system preparation: In a 500 mL three-necked flask, the following were added sequentially: 2.13 g (0.01 mol, 100 parts by weight ratio) of monomer 2-(diisopropylamino)ethyl methacrylate (DIPAMA), 0.50 g (0.0001 mol, 1 part by weight ratio, molar ratio with monomer = 1:100) of macromolecular chain initiator polyethylene glycol monomethyl ether bromide (mPEG-Br, molecular weight 5000 Da), 0.0198 g (0.00012 mol, 1.2 parts by weight ratio, molar ratio with PEG-Br = 1.2:1) of traditional free radical initiator azobisisobutyronitrile (AIBN), and 0.0027 g (0.000012 mol, 1.2 parts by weight ratio, molar ratio with PEG-Br = 1.2:1) of catalyst copper bromide (CuBr2). The following components were added: 0.0148 g (0.000048 mol, calculated as 0.48 parts by weight, with a molar ratio of 0.12 to PEG-Br = 0.12:1), 0.0148 g (0.000048 mol, calculated as 0.48 parts by weight, with a molar ratio of 0.48 to PEG-Br = 0.48:1), and 40 mL (0.000048 mol, calculated as 0.48 parts by weight, with a molar ratio of 0.48 to PEG-Br = 1), N,N-dimethylformamide (DMF):isopropanol (IPA) = 1:1. The mixture was stirred until all components were completely dissolved, forming a homogeneous initial ATRP reaction system. The core component ratio was PEG-Br:AIBN:CuBr2:TPMA:DIPAMA = 1:1.2:0.12:0.48:100, where mPEG-Br acts as a chain initiator to anchor the chain growth starting point, AIBN generates free radicals to maintain catalytic activity, and CuBr2 coordinates with TPMA to form an active center, synergistically ensuring the controllability of polymerization.

[0063] (2) Magnetic oscillation device setup: Place the three-necked flask in an oscillating magnetic field generator with adjustable magnetic field strength. The magnetic field direction is parallel to the flask axis, and the magnetic field frequency is preset to 30 Hz.

[0064] (3) Polymerization reaction implementation: The reaction system was heated to 70°C and purged with nitrogen for 30 min to completely remove oxygen and moisture from the system; the magnetic oscillation device was started and the magnetic field strength was adjusted to 0.3 T. The reaction was maintained at this temperature, magnetic field parameters and nitrogen protection conditions for 48 h; during the reaction, samples were taken at 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h respectively. The monomer conversion rate was monitored by gas chromatography (GC) and the viscosity change of the system was monitored by rheometer.

[0065] (4) Post-processing of product: After the reaction is completed, the reaction solution is poured into an excess of tetrahydrofuran (500 mL) to dissolve it. The solution is dialyzed with distilled water and then freeze-dried to obtain the poly[2-(diisopropylamino)ethyl methacrylate] block copolymer product.

[0066] 3. Product testing 3.1 Aggregation Process The monomer conversion rates at different time points (2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h) during the reaction were measured by GC and were 30.2%, 55.7%, 73.1%, 84.3%, 89.1%, 90.5%, and 90.8%, respectively. The monomer conversion rate tended to stabilize after 12 h of reaction, and the final conversion rate reached over 90%. The viscosity of the system gradually increased with the reaction. The viscosity at each time point was measured by rheometer as 7.8 mPa•s, 16.3 mPa•s, 29.5 mPa•s, 37.2 mPa•s, 43.8 mPa•s, 46.5 mPa•s, and 47.2 mPa•s, respectively. The overall viscosity change was stable, with no local sudden increase.

[0067] 3.2 Product Structure GPC analysis showed that the number-average molecular weight (Mn) of the 12-h product was 6920 Da, the weight-average molecular weight (Mw) was 7460 Da, and the molecular weight distribution (PDI) was 1.078, exhibiting an extremely narrow molecular weight distribution. ¹H-NMR analysis revealed that the molar ratio of the PEG-DIPAMA blocks was 1:97.5, with an error of only 2.5% compared to the theoretical design ratio (1:100), demonstrating excellent precision in block structure control.

[0068] 3.3 Product Function Transmission electron microscopy (TEM) revealed that the nanoparticles exhibited distinct spherical morphology at pH 7.4 and disintegrated into polymer chains (invisible under TEM) at pH 4.0. The zeta potential, measured by a potentiometer, was +28.3 mV at pH 2.0, +15.7 mV at pH 4.0, -3.2 mV at pH 7.4, and -8.5 mV at pH 9.0. The charge characteristics changed significantly with pH, ​​meeting the requirements for pH-responsive pharmaceutical materials.

[0069] 3.4 Process stability In addition, three parallel experiments were conducted, and the Mn values ​​of the products were measured to be 6920 Da, 6810 Da, and 7050 Da, with a coefficient of variation of 1.52%; the PDI values ​​were 1.078, 1.085, and 1.069, with a coefficient of variation of 0.72%; and the final monomer conversion rates were 89.1%, 87.6%, and 90.2%, with a coefficient of variation of 1.43%. There were significant differences in the coefficients of variation of each parameter, and the coefficient of variation of conversion rate was significantly higher than that of PDI, which is consistent with the actual situation that the conversion rate is more affected by mass transfer fluctuations in the polymerization reaction.

[0070] 3.5 Residual Impurities ICP-MS analysis showed that Cu in the product 2+ The residue level was 0.32 ppm, which is far below the heavy metal residue limit (≤1 ppm) in pharmaceutical materials and meets pharmaceutical standards.

[0071] Table 1. Parameters of poly(diisopropylamino)methacrylate, Example 1 Table 2. Parameters of poly(diisopropylamino)methacrylate in three parallel experiments in Example 1 Example 2 This embodiment illustrates the effect of different magnetic field parameters on the structure of ATRP products.

[0072] 1. Synthesis Method Using the same core ratio of reaction system as in Example 1 (PEG-Br:AIBN:CuBr2:TPMA:DIPAMA=1:1.2:0.12:0.48:100) and basic reaction conditions (temperature 70℃, polymerization reaction time 12 h, nitrogen purging 30 min), only the extreme values ​​of magnetic field strength (0.05 T, 0.1 T, 0.3 T, 0.5 T, 1.0 T, 2.0 T) and frequency (5 Hz, 10 Hz, 30 Hz, 50 Hz, 100 Hz) of the magnetic oscillation device were changed to prepare 11 groups of poly[2-(diisopropylamino)ethyl methacrylate] block copolymer samples (including the product of Example 1).

[0073] 2. Experimental Results 2.1 Aggregation Process The final monomer conversion rates of each group of samples were measured by GC, ranging from 65.8% to 89.1%, corresponding to actual degrees of polymerization of 66-89. The conversion rates did not show a linear change. The conversion rate increased significantly when the magnetic field strength was around 0.3 T (0.1-0.5 T) (from 72.3% to 89.1%), while the conversion rate dropped sharply when the magnetic field strength was greater than 1.0 T (78.5% at 1.0 T and only 65.8% at 2.0 T). The frequency effect showed that the conversion rate was stable above 80% in the 10-50 Hz range, and the conversion rate dropped rapidly below 10 Hz or above 50 Hz (68.2% at 5 Hz and 71.3% at 100 Hz). Example 1 (0.3 T, 30 Hz) had the highest conversion rate, reaching 89.1%.

[0074] 2.2 Product Structure The structural parameters of the products were detected by GPC. The Mn range was 6380-6920 Da, the Mw range was 6850-7460 Da, and the PDI range was 1.078-1.245. The PDI of Example 1 was the lowest (1.078). When the magnetic field parameters deviated from the optimal value, the PDI increased significantly. In particular, the PDI of the group with a magnetic field strength of 2.0 T and a frequency of 100 Hz exceeded 1.24, and the molecular weight distribution became significantly wider. The block structure error was detected by ¹H-NMR and ranged from 2.5% to 8.3%. The error of Example 1 was the smallest (2.5%). The errors of other parameter groups were all above 3%, and the errors of some extreme parameter groups exceeded 7%.

[0075] 2.3 Product Function The Zeta potential of the product in the pH=7.4 buffer solution was detected and ranged from -2.5 mV to -6.1 mV. The Zeta potential of the parameter group in Example 1 was -3.2 mV, which showed the best stability. When the magnetic field strength was >1.0 T or the frequency was >50 Hz, the fluctuation amplitude of the Zeta potential increased sharply (the fluctuation amplitude of the 2.0 T, 100 Hz group reached 3.6 mV).

[0076] 3. Conclusion Comparative analysis of the data shows that there is a clear optimal parameter range for magnetic oscillation enhancement (intensity 0.1-0.5 T, frequency 10-50 Hz). When the parameters deviate from this range, the polymerization performance does not decrease uniformly, but exhibits a non-equilibrium characteristic of "stable before the threshold and sudden drop after the threshold". Among them, 0.3 T and 30 Hz used in Example 1 are the optimal parameter points. Under this condition, the polymerization reaction has the strongest controllability and the product structure precision and functional stability are the best.

[0077] Table 3. Effects of different magnetic field strengths on the parameters of poly(diisopropylamino)methacrylate. Table 4. Effects of different magnetic field frequencies on the parameters of poly(diisopropylamino)methacrylate. Comparative Example 1 This comparative example illustrates the reaction performance testing method and results of the conventional ATRP method.

[0078] 1. Synthesis Method Using the exact same reaction system configuration as in Example 1 (strictly following the ratio of PEG-Br:AIBN:CuBr2:TPMA:DIPAMA=1:1.2:0.12:0.48:100) and reaction conditions (temperature 70℃, reaction time 12 h, nitrogen purging for 30 min), except that the magnetic oscillation device was not activated (conventional mechanical stirring was used at a stirring rate of 300 r / min), a comparative sample of poly[2-(diisopropylamino)ethyl methacrylate] block copolymer was prepared.

[0079] 2. Experimental Results 2.1 Aggregation Process The monomer conversion rates at different reaction times (2 h, 4 h, 6 h, 8 h, 12 h) were measured by GC and were 18.5%, 40.2%, 62.3%, 73.1%, and 78.5%, respectively, corresponding to actual degrees of polymerization of 19-79 and total molecular weights of approximately 9053-21851 Da. Compared with the conversion rates at the same time points in Example 1 (30.2%, 55.7%, 73.1%, 84.3%, 89.1%), the largest difference in conversion rate was observed in the early stage (2-4 h) (15.5 percentage points), while the difference narrowed in the later stage (8-12 h) (4.6 percentage points), demonstrating the kinetic law of insufficient mass transfer efficiency in the early stage and a slower reaction rate in the later stage of the conventional stirring system. The system viscosity was measured at each time point as 11.2 mPa•s, 23.7 mPa•s, 40.5 mPa•s, 47.8 mPa•s, and 54.3 mPa•s, respectively. The viscosity values ​​of mPa•s were all higher than those of Example 1 at the same time, indicating that the viscosity of the conventional stirring system accumulated faster and the mass transfer resistance problem was more prominent.

[0080] 2.2 Product Structure GPC analysis revealed that the product had a molecular weight distribution of 6760 Da for Mn, 7820 Da for Mw, and 1.157 for PDI. Compared to the PDI of Example 1 (1.078), the molecular weight distribution broadened by 7.7 percentage points, a significantly larger increase than the change in Mn (which decreased by only 2.4%). This indicates that uneven mass transfer led to a decrease in the synchronicity of chain growth. 1H-NMR analysis showed that the molar ratio of the PEG-DIPAMA blocks was 1:94.7, with an error of 5.3% compared to the theoretical design ratio (1:100). This represents a 112% increase in error compared to the error of Example 1 (2.5%). The increase in error was significantly higher than the increase in conversion rate, highlighting that uneven mass transfer has a more critical impact on the control of block structure.

[0081] 2.3 Product Function The zeta potential was measured by a potentiometer (3 parallel experiments), and the values ​​were: +24.5 mV at pH=2.0 (coefficient of variation 2.8%), +12.3 mV at pH=4.0 (coefficient of variation 3.6%), -4.8 mV at pH=7.4 (coefficient of variation 7.2%), and -10.2 mV at pH=9.0 (coefficient of variation 2.9%). Compared with Example 1, the potential fluctuation amplitude was significantly increased under neutral and alkaline conditions, and the functional stability decreased, showing differentiated characteristics.

[0082] 2.4 Process stability In addition, three parallel experiments were conducted, and the Mn values ​​of the products were measured to be 6760 Da, 6950 Da, and 6640 Da, with a coefficient of variation of 2.35%; the PDI values ​​were 1.156, 1.172, and 1.148, with a coefficient of variation of 0.98%; and the final monomer conversion rates were 78.5%, 76.8%, and 79.2%, with a coefficient of variation of 1.62%. The coefficients of variation for all parameters were higher than those in Example 1 (Example 1: Mn coefficient of variation 1.52%, PDI coefficient of variation 0.72%, conversion coefficient of variation 1.43%).

[0083] 2.5 Residual Impurities ICP-MS analysis showed that Cu in the product 2+ The residual amount was 0.92 ppm, which is 142% higher than the 0.38 ppm in Example 1. This is because the catalyst particles aggregated more severely due to conventional stirring, and the increase in residual amount was significantly higher than the changes in other indicators.

[0084] 3. Conclusion Compared to conventional mechanical stirring, magnetic oscillation enhancement exhibits a non-uniform effect on the polymerization reaction. The improvement in early-stage conversion rate, block structure control precision, and catalyst dispersion uniformity is more significant (all increases > 10%), while the improvement in later-stage conversion rate and functional stability under alkaline conditions is relatively weak (increase < 5%). Specifically, it can reduce the product PDI by 7.7 percentage points and increase the final monomer conversion rate by 13.5 percentage points (an increase of 17.2%, corresponding to an increase in degree of polymerization of approximately 14), Cu... 2+ The residual amount was reduced by 58.7%, which significantly improved the controllability of the polymerization reaction, the precision of the product structure and the stability of the process, highlighting the core technological advantages of magnetic oscillation enhancement.

[0085] Table 5. Molecular weight and molecular weight distribution of ethyl poly-2-(diisopropylamino)methacrylate, Comparative Example 1 Table 6. Parameters of different batches of poly-2-(diisopropylamino)methacrylate in Comparative Example 1 Comparative Example 2 This comparative example illustrates the testing methods and results for the polymerization performance of ATRP under dynamic magnetic field, static magnetic field, and unreinforced conventional magnetic field.

[0086] 1. Experimental Grouping The reaction system configuration was exactly the same as in Example 1 (strictly following the ratio of PEG-Br:AIBN:CuBr2:TPMA:DIPAMA=1:1.2:0.12:0.48:100, with mPEG-Br molecular weight of 5000 Da) and reaction conditions (temperature 70℃, reaction time 12 h, nitrogen purging for 30 min). Three groups of experiments were set up: unenhanced conventional ATRP group: only natural diffusion, without any magnetic field enhancement; static magnetic field group: a fixed intensity magnetic field (magnetic induction intensity 0.3 T) was generated using a permanent magnet; dynamic magnetic field group: the oscillating magnetic field of Example 1 (0.3 T, 30 Hz).

[0087] 2. Experimental Results 2.1 Polymerization Kinetics and Conversion Rate Traditional group without reinforcement: The monomer conversion rate was 78.5% after 12 h of reaction, and only increased by 4.6 percentage points in the 8-12 h stage. The rate slowed down in the later stage due to the increase in viscosity. Static magnetic field group: The conversion rate reached 82.3% at 12 h (3.8 percentage points higher than the unenhanced group), and improved by 6.2 percentage points in the 8-12 h stage (slightly improving mass transfer in the later stage); Dynamic magnetic field group: The conversion rate reached 89.1% after 12 hours (6.8 percentage points higher than that of the static magnetic field group), and continued to improve by 4.8 percentage points in the 8-12 hour stage, with no obvious rate stagnation throughout the process.

[0088] Conclusion: Static magnetic fields slightly improve the conversion rate compared to traditional stirring, but the effect is limited; dynamic magnetic fields do not require additional stirring and can achieve more efficient mass transfer through magnetic field oscillation, with a significant advantage in conversion rate.

[0089] 2.2 Product structural accuracy Unreinforced conventional group: PDI=1.157, block structure error=5.3%, Mn=6760Da (error 2.5%); Static magnetic field group: PDI=1.128 (0.029 narrower than the unreinforced group), block structure error=4.6% (0.7 percentage points lower), Mn=6840Da (error 1.3%); Dynamic magnetic field group: PDI=1.078 (0.050 narrower than static magnetic field group), segmental structure error=2.5% (2.1 percentage points lower), Mn=6920Da (error 0.25%).

[0090] Conclusion: Static magnetic fields can only slightly improve structural precision, while dynamic magnetic fields, through directional perturbation of catalytic complexes, significantly improve chain growth synchronicity, resulting in structural precision far exceeding that of static magnetic fields and the unreinforced group.

[0091] 2.3 Process stability The unenhanced conventional group: the coefficient of variation for Mn in 3 parallel experiments was 2.35%, the coefficient of variation for PDI was 0.98%, and the coefficient of variation for conversion rate was 1.62%. Static magnetic field group: Mn coefficient of variation = 2.18% (0.17 percentage points lower than the unenhanced group), PDI coefficient of variation = 0.85%, conversion rate coefficient of variation = 1.46%; Dynamic magnetic field group: Mn coefficient of variation = 1.52% (more uniform structure compared to static magnetic field group), PDI coefficient of variation = 0.72%, conversion rate coefficient of variation = 1.43%.

[0092] 3. Conclusion Static magnetic fields slightly improve stability, but the effect is not significant; dynamic magnetic fields have better stability in core indicators (PDI, block error) and stronger overall process controllability.

[0093] Table 7. Parameters of poly(diisopropylamino)methacrylate in each group of Comparative Example 2 Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for the precise synthesis of polymethacrylate polymers, characterized in that, Includes the following steps: (1) The raw materials containing methacrylate monomers, macromolecular initiators, small molecule free radical initiators, catalysts, chain transfer agents and solvents are mixed to obtain an initial reaction system; (2) The initial reaction system is reacted in a magnetic oscillation environment at 40-90℃ for 4-72 h to obtain the polymethyl methacrylate polymer.

2. The method for precise synthesis of polymethacrylate polymers according to claim 1, characterized in that, The molar ratio of the macromolecular initiator, small molecule free radical initiator, catalyst, chain transfer agent and monomer is 1:(0.5-2.0):(0.05-0.20):(0.20-0.80):(20-200).

3. The method for precise synthesis of polymethacrylate polymers according to claim 1, characterized in that, The methacrylate monomers include at least one of methyl methacrylate, ethyl methacrylate, dimethylaminoethyl methacrylate, and hydroxyethyl methacrylate.

4. The method for precise synthesis of polymethacrylate polymers according to claim 1, characterized in that, The macromolecular initiator includes PEG-Br compounds; the small molecule radical initiator includes at least one of azobisisobutyronitrile, azobisisoheptanenitrile, benzoyl peroxide, and di-tert-butyl peroxide; the catalyst includes a transition metal salt.

5. The method for precise synthesis of polymethacrylate polymers according to claim 1, characterized in that, The chain transfer agent includes at least one of 2,2'-bipyridine, 4,4'-dinonyl-2,2'-bipyridine, tris(2-pyridylmethyl)amine, and N,N,N',N'',N''-pentamethyldiethylenetriamine.

6. The method for precise synthesis of polymethacrylate polymers according to claim 1, characterized in that, The solvent includes at least one selected from N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, isopropanol, methanol, ethanol, 1,4-dioxane, and tetrahydrofuran.

7. The method for precise synthesis of polymethacrylate polymers according to claim 1, characterized in that, The magnetic field strength of the magnetic oscillation changes periodically over time, with the peak value of the magnetic field strength in the range of 0.05-2.0 T, and the frequency of the magnetic oscillation in the range of 10-50 Hz.

8. The method for precise synthesis of polymethacrylate polymers according to claim 1, characterized in that, The direction of the magnetic field during magnetic oscillation is parallel to the axis of the reaction vessel or at an angle of 30°-90°. Preferably, the direction of the magnetic field undergoes periodic reversals.

9. A polymethacrylate polymer, characterized in that, It is obtained by the method described in any one of claims 1-8.

10. The use of the polymethacrylate polymer according to claim 9 in the preparation of pH-responsive pharmaceutical excipients, drug delivery carriers or sustained-release formulations.

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