Segmented pH-controlled polyethylene glycol derivative modified superparamagnetic ferrite nanoparticle ligand exchange method and system

Abstract

The invention relates to the technical field of nano composite material production, in particular to a segmented pH-controlled polyethylene glycol derivative modified superparamagnetic ferrite nanoparticle ligand exchange method and system. According to the segmented pH-controlled ligand exchange method for the polyethylene glycol derivative modified superparamagnetic ferrite nano-particles, the initial state of a reaction system for preparing the polyethylene glycol derivative modified superparamagnetic ferrite nano-particles, the stage reaction time and the stage pH target are controlled; the injection volumes and the injection rates of the buffer systems in different stages are determined according to the acid-base properties, the concentrations and the volumes of different polyethylene glycol derivative modifications and superparamagnetic ferrite nanoparticle ligands under the conditions of the concentrations of hydrogen ions and hydroxyl ions of different buffer systems, and a system capable of realizing the method is designed. By optimizing the ligand exchange process, the preparation capacity is improved, the modification efficiency is improved, particle aggregation is inhibited, and hydrophobic ligand residues are reduced.

Description

Technical Field

[0001] The invention relates to the technical field of nanocomposite material production, and in particular to a segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange method and system. Background Art

[0002] High-temperature thermal decomposition is an existing technology for preparing superparamagnetic ferrite nanoparticles. The synthesized superparamagnetic ferrite nanoparticles have a low defect rate and excellent crystallinity. However, the surface of the superparamagnetic ferrite nanoparticles synthesized by this method is usually coated with long-chain fatty acids or fatty amines such as oleic acid, oleylamine, and erucic acid. These hydrophobic substances often need to be replaced by surface-modified hydrophilic ligands. The unique properties of polyethylene glycol derivatives enable them to provide superparamagnetic ferrite nanoparticles with excellent water solubility, stability and biocompatibility. One of the existing technologies for modifying polyethylene glycol derivatives on superparamagnetic ferrite nanoparticles is the ligand exchange method, which replaces the original long-chain fatty acids or fatty amines through the coordination reaction between the hydrophilic ligands of polyethylene glycol derivatives with strong coordination ability and the metal ions on the surface of superparamagnetic ferrite nanoparticles.

[0003] Prior Art 1 In "Ultrastable Iron Oxide Nanoparticle Colloidal Suspensions Using Dispersants with Catechol-Derived Anchor Groups" Esther Amstad, Torben Gillich, Idalia Bilecka, Marcus Textor, Erik Reimhult, Nano Letters , Vol 9 / Issue 12, 2009, 9, 12, 4042–4048, discloses that the use of phenolic derivatives with irreversible binding affinity as amphiphilic solvents can promote the surface modification of ferrite nanoparticles. Prior art 2 is “Electron Doping in Bottom-Up Engineered Thermoelectric Nanomaterials through HCl-Mediated Ligand Displacement”, Maria Ibáñez, Rachel J. Korkosz, Zhishan Luo, Pau Riba, Doris Cadavid, Silvia Ortega, Andreu Cabot, Mercouri G. Kanatzidis, J. Am. Chem. Soc.2015, 137, 12, 4046–4049, discloses the removal of carboxylic acid while controlling the concentration of chloride ions through HCl-mediated ligand replacement.

[0004] The existing method of preparing polyethylene glycol derivative-modified inorganic nanoparticles by ligand exchange has the following problems when used to prepare polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles: First, the yield is low. The steric hindrance effect between the original long-chain fatty acids or fatty amines on the surface of the nanoparticles and the polyethylene glycol derivatives hinders the contact between the polyethylene glycol derivatives and the surface of the superparamagnetic ferrite nanoparticles. The reaction concentration is far lower than the saturation concentration, the reaction time is long, the single batch production scale is limited, and the production efficiency is low. Second, hydrophobic ligands remain. The existing ligand exchange method is limited by steric hindrance and reaction equilibrium, resulting in insufficient degree of substitution. Third, acid treatment induces agglomeration. The existing technology uses hydrochloric acid to strip oleic acid from the surface of upconversion nanoparticles, which requires acid treatment in advance. Direct acid treatment of superparamagnetic ferrite nanoparticles will destroy the surface stability of the superparamagnetic ferrite nanoparticles, causing aggregation and sedimentation.

[0005] In order to increase the production capacity of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles while improving the modification efficiency, it is necessary to provide a ligand exchange method and system that can achieve protonation of surface hydrophobic ligands, reduce binding force, and achieve rapid stripping, while also avoiding superparamagnetic ferrite nanoparticle aggregation caused by excessive acidification, maintaining a dynamic balance between the polyethylene glycol derivative ligand and the surface of the superparamagnetic ferrite nanoparticles, and reducing hydrophobic ligand residues. Summary of the Invention

[0006] In order to solve the problems raised in the above-mentioned background technology, the present invention provides a segmented pH-controlled polyethylene glycol derivative modified superparamagnetic ferrite nanoparticle ligand exchange method and system, which takes the initial state of the reaction system for preparing polyethylene glycol derivative modified superparamagnetic ferrite nanoparticles, the stage reaction time, the stage pH target, and the hydrogen ion and hydroxide ion concentrations of different buffer systems as conditions, and determines the injection volume and injection rate of the buffer system in different stages according to the different polyethylene glycol derivative modifications and the acid-base properties, concentration, and volume of the superparamagnetic ferrite nanoparticle ligands themselves, optimizes the ligand exchange process, improves the preparation capacity, enhances the modification efficiency, inhibits particle aggregation, and reduces hydrophobic ligand residue.

[0007] To achieve the above objectives, the first aspect of the present invention provides a segmented pH-controlled ligand exchange method and system for polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles, comprising: S1, determine the initial state of the reaction system and the concentration of the polyethylene glycol derivative , the unit is , the volume is , the unit is , pH is , the concentration of superparamagnetic ferrite nanoparticles is , the unit is , the volume is , the unit is , the initial pH is ,satisfy, , the injection rate of polyethylene glycol derivative is constant , the unit is , the injection rate of superparamagnetic ferrite nanoparticles is constant at , the unit is , the injection rate of the buffer system in the initial stage, mid-stage and final stage , the unit is , the injection volume is , the unit is , ; S2, determine the reaction time and target pH of each stage. The reaction time of the initial stage is , the unit is , pH target is , the reaction time in the middle stage is , the unit is , pH target is , the reaction time at the end stage is , the unit is , pH target is ; S3, Determine the hydrogen ion concentration, hydrogen ion concentration of polyethylene glycol derivatives , the hydrogen ion concentration of superparamagnetic ferrite nanoparticles , the hydrogen ion concentration of the buffer system at the initial stage, mid-stage, and final stage and the hydrogen ion concentration of the pH target are: and , and , and , the units are ; S4, calculate the initial stage of the buffer system injection volume and injection rate, the initial stage of the buffer system injection volume According to the conservation of hydrogen ion species or charge balance calculation, the initial buffer system injection rate is , the unit is ; S5, calculate the buffer system injection volume and injection rate in the mid-stage, the buffer system injection volume in the mid-stage According to the conservation of hydrogen ion mass or charge balance calculation, the buffer system injection rate in the middle stage is , the unit is ; S6, calculate the buffer system injection volume and injection rate at the end stage, the buffer system injection volume at the end stage According to the conservation of hydrogen ion mass or charge balance calculation, the buffer system injection rate at the end stage is , the unit is ; S7, output control parameters, 、 、 The filling rate of the buffer system in the initial stage, mid-stage and final stage is used as the control parameter.

[0008] As a further description of the above technical solution: S4, calculating the injection volume of the buffer system in the initial stage, according to the conservation of hydrogen ion mass, satisfies: (1) in, is the hydrogen ion concentration of the buffer system in the initial stage, is the hydroxide ion concentration of the buffer system in the initial stage.

[0009] As a further description of the above technical solution: S5, calculating the injection volume of the buffer system in the mid-stage, according to the conservation of hydrogen ion mass, satisfies: (2) in, is the hydrogen ion concentration of the buffer system in the middle stage, is the hydroxide ion concentration of the buffer system in the middle stage, is the volume of the initial buffer system continuously injected in the middle stage, is the volume of polyethylene glycol derivative continuously infused in the mid-stage, is the volume of superparamagnetic ferrite nanoparticles continuously injected in the middle stage.

[0010] As a further description of the above technical solution: S6, calculating the injection volume of the buffer system at the end stage, according to the conservation of hydrogen ion mass, satisfies: (3) in, is the hydrogen ion concentration of the buffer system at the end stage, is the hydroxide ion concentration of the buffer system at the end stage, is the volume of the buffer system continuously injected in the initial stage at the end stage, The volume of the buffer system continuously injected at the end of the mid-stage, is the volume of polyethylene glycol derivative continuously infused in the mid-stage, is the volume of superparamagnetic ferrite nanoparticles continuously injected in the middle stage.

[0011] As a further description of the above technical solution: said S4, calculating the injection volume of the buffer system in the initial stage according to the charge balance calculation, comprises the following steps: S401, calculate the ion concentration introduced by the buffer solution in the initial stage, satisfying: (4) in, is the positive ion concentration of the buffer solution in the initial stage, is the negative ion concentration of the buffer solution in the initial stage, is the weak acid concentration, is the conjugate base concentration, is the dissociation constant; S402, after correction based on charge balance calculation in the initial stage ,satisfy: (5) in, It is an anion of polyethylene glycol derivative, is the anion of ferrite nanoparticles; S403, according to the revised Calculate the initial stage ,satisfy: (6) As a further description of the above technical solution: said S5, calculating the injection volume of the buffer system in the mid-stage according to the charge balance calculation, comprises the following steps: S501, calculate the ion concentration introduced by the buffer solution in the mid-stage, satisfying: (7) in, is the positive ion concentration of the buffer solution during the mid-stage, is the buffer negative ion concentration in the mid-stage; S502, after correction based on charge balance calculation in the mid-stage ,satisfy: (8) S503, according to the revised Calculate the initial stage ,satisfy: (9) As a further description of the above technical solution: S6, calculating the injection volume of the buffer system at the end stage according to the charge balance, includes the following steps: S601, calculate the ion concentration introduced by the buffer solution at the end stage, satisfying: (10) in, is the positive ion concentration of the buffer solution at the end stage, is the negative ion concentration of the buffer solution at the end stage; S602, after correction based on charge balance calculation ,satisfy: (11) S603, according to the revised Calculation end stage ,satisfy: (12) The second aspect of the present invention is a segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange system, which is prepared using the above-mentioned segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange method, and is characterized in that it includes: a PEG derivative ligand storage tank, a superparamagnetic ferrite nanoparticle storage tank, an initial stage buffer system storage tank, a mid-stage buffer system storage tank, an end-stage buffer system storage tank, a metering pump, a static mixer, a tubular reactor, a flow valve, and a control module. It is characterized in that the PEG derivative ligand storage tank and the superparamagnetic ferrite nanoparticle storage tank are respectively connected to the static mixer through a metering pump liquid path, the static mixer is connected to the tubular reactor through a flow valve liquid path, the initial stage buffer system storage tank, the mid-stage buffer system storage tank, and the end-stage buffer system storage tank are connected to the tubular reactor through a metering pump liquid path, and the metering pump and the flow valve are electrically connected to the control module.

[0012] As a further description of the above technical solution: the tank bodies of the PEG derivative ligand storage tank, superparamagnetic ferrite nanoparticle storage tank, initial stage buffer system storage tank, mid-stage buffer system storage tank, and final stage buffer system storage tank are made of tetrafluoroethylene, and liquid level sensors are provided in the tank bodies.

[0013] As a further description of the above technical solution: a spiral pipe or a spoiler internal component is arranged inside the tubular reactor.

[0014] By promoting the surface modification of superparamagnetic ferrite nanoparticles with polyethylene glycol through segmented pH regulation, the effect of pH at different reaction stages on ligand exchange in the preparation of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles can be optimized. In the initial stage, hydrophobic ligand stripping is efficiently achieved, while the polyethylene glycol derivative quickly replaces the stripped holes. In the middle stage, the residual hydrophobic ligand is slowly stripped by changing and maintaining the appropriate pH target environment. In the final stage, the hydrophobic ligand can be neutralized by changing and maintaining the pH target environment of the reaction system, which is beneficial for subsequent purification. Compared with the existing technology, the present invention has the following beneficial technical effects: 1. The uniform mixing of the buffer system, polyethylene glycol derivative ligand, and superparamagnetic ferrite nanoparticles and the precise control of the pH of the reaction are achieved. The polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles produced have extremely low hydrophobic ligand residues, high product batch consistency, good production stability, and a relative standard deviation of less than 5%.

[0015] 2. The segmented buffer injection strategy of the present invention maintains the dispersion stability of nanoparticles by precisely controlling the pH change rate and buffer concentration.

[0016] 3. Through the hydrogen ion conservation or charge balance model, combined with automated control modules such as metering pumps and flow valves, real-time calculation and adjustment of buffer volume and rate are achieved, shortening the total reaction time. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings: Figure 1 This is a flow chart of a segmented pH-controlled ligand exchange method for polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles proposed by the present invention; Figure 2 This is a schematic structural diagram of a segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange system proposed by the present invention; In the figure: 1. PEG derivative ligand storage tank, 2. Superparamagnetic ferrite nanoparticle storage tank, 3. Initial stage buffer system storage tank, 4. Mid-stage buffer system storage tank, 5. End stage buffer system storage tank, 6. Metering pump, 7. Static mixer, 8. Tubular reactor, 9. Flow valve, 10. Control module. DETAILED DESCRIPTION

[0018] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention. Specific implementation method 1 Combine Figure 1 、 2 In one embodiment of the present invention, S1, the initial state of the reaction system is determined, and the volume is determined to be , the initial pH is ,satisfy, , the injection rate of dopamine-terminated polyethylene glycol derivatives is constant at , the injection rate of superparamagnetic ferrite nanoparticles is constant at , the injection rate of the buffer system in the initial stage, mid-stage and final stage , the injection volume is , ; S2, determine the reaction time and target pH of each stage. The reaction time of the initial stage is , pH target is , the reaction time in the middle stage is , pH target is , the reaction time at the end stage is , pH target is ; S3. Determine the hydrogen ion concentration of the dopamine-terminated polyethylene glycol derivative , the hydrogen ion concentration of superparamagnetic ferrite nanoparticles , the hydrogen ion concentration of the buffer system at the initial stage, mid-stage, and final stage and the hydrogen ion concentration of the pH target are: and , and , and , the units are ; S4, calculate the initial stage of the buffer system injection volume and injection rate, the initial stage of the buffer system injection volume According to the conservation of hydrogen ion mass, the injection rate of the buffer system in the initial stage is ,satisfy:

[0020]

[0021]

[0022] in, is the hydrogen ion concentration of the buffer system in the initial stage, is the hydroxide ion concentration of the buffer system in the initial stage.

[0023] S5, calculate the buffer system injection volume and injection rate in the mid-stage, the buffer system injection volume in the mid-stage According to the conservation of hydrogen ion mass, the injection rate of the buffer system in the middle stage is ,satisfy:

[0024]

[0025]

[0026]

[0027] in, is the hydrogen ion concentration of the buffer system in the middle stage, is the hydroxide ion concentration of the buffer system in the middle stage, is the volume of the initial buffer system continuously injected in the middle stage, is the volume of polyethylene glycol derivative continuously infused in the mid-stage, is the volume of superparamagnetic ferrite nanoparticles continuously injected in the middle stage.

[0028] S6, calculate the buffer system injection volume and injection rate at the end stage, the buffer system injection volume at the end stage According to the conservation of hydrogen ion mass, the buffer system injection rate at the end stage is ,satisfy:

[0029]

[0030]

[0031]

[0032]

[0033] in, is the hydrogen ion concentration of the buffer system at the end stage, is the hydroxide ion concentration of the buffer system at the end stage, is the volume of the buffer system continuously injected in the initial stage at the end stage, The volume of the buffer system continuously injected at the end of the mid-stage, is the volume of polyethylene glycol derivative continuously infused in the mid-stage, is the volume of superparamagnetic ferrite nanoparticles continuously injected in the middle stage.

[0034] S7, with 、 、 As the filling rate parameter of the buffer system in the initial stage, mid-stage and final stage.

[0035] The dopamine-terminated polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles obtained by the ligand exchange method of the present invention had a hydrodynamic DLS peak size of 8.7 nm, a concentrated size distribution, no agglomeration was detected, and an electron microscopy size of 3.0±0.37 nm, indicating good dispersibility. Gas chromatography analysis of the dopamine-terminated polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles obtained by the ligand exchange method of the present invention showed that the residual hydrophobic ligand after esterification did not exceed 0.35%. Compared with the dopamine-terminated polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles obtained by the ligand exchange method of the present invention with the same volume and concentration of reactants but without the ligand exchange method of the present invention, the residual hydrophobic ligand after esterification did not exceed 5.31%. Specific embodiment 2 Combine Figure 2 A specific embodiment of the present invention is a segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange system, which is prepared using the above-mentioned segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange method, comprising: a PEG derivative ligand storage tank 1, a superparamagnetic ferrite nanoparticle storage tank 2, an initial stage buffer system storage tank 3, a mid-stage buffer system storage tank 4, a final stage buffer system storage tank 5, a metering pump 6, a static mixer 7, a tubular reactor 8, a flow valve 9, and a control module 10, characterized in that the PEG derivative ligand storage tank 1 and the superparamagnetic ferrite nanoparticle storage tank 2 are respectively connected to the static mixer 7 through the metering pump 6 liquid path, the static mixer 7 is connected to the tubular reactor 8 through the flow valve 9 liquid path, the initial stage buffer system storage tank 3, the mid-stage buffer system storage tank 4, and the final stage buffer system storage tank 5 are connected to the tubular reactor 8 through the metering pump 6 liquid path, and the metering pump 6 and the flow valve 9 are electrically connected to the control module 10.

[0037] In this embodiment, the operator first inputs parameter values ​​into the control module 10, including: the concentration, volume, initial pH, and injection rate of the polyethylene glycol derivative, the concentration, volume, initial pH, and injection rate of the superparamagnetic ferrite nanoparticles, the reaction time and pH target of the initial stage, the reaction time and pH target of the mid-stage, and the reaction time and pH target of the final stage. The control module 10 calculates the buffer system injection rate of the initial stage, the buffer system injection rate of the mid-stage, and the buffer system filling rate of the final stage based on the above values. The control system operates based on the calculated buffer system injection rates of each stage and the input parameter values. The control module 10 controls the metering pump 6 connected to the PEG derivative ligand storage tank 1 and the superparamagnetic ferrite nanoparticle storage tank 2 to operate. The PEG derivative ligand in the PEG derivative ligand storage tank 1 and the superparamagnetic ferrite nanoparticles in the superparamagnetic ferrite nanoparticle storage tank 2 are injected into the PEG derivative ligand storage tank 1 through the metering pump 6. Entering the static mixer 7, the initial stage start time control module 10 opens the flow valve 9 and the connecting metering pump of the initial stage buffer system storage tank 3, and the mixed liquid of the polyethylene glycol derivative modified superparamagnetic ferrite nanoparticles and the initial stage buffer system liquid in the static mixer 7 are injected into the tubular reactor 8 for the initial stage reaction of ligand exchange. When the mid-stage start time control module 10 opens the connecting metering pump of the mid-stage buffer system storage tank 4, the mid-stage buffer system liquid is injected into the tubular reactor 8 to continue the ligand exchange. When the end stage start time control module 10 opens the connecting metering pump of the end stage buffer system storage tank 5, the end stage buffer system liquid is injected into the tubular reactor 8 to continue the ligand exchange. Until the end stage cutoff time, the control module 10 controls the metering pump 6 and the flow valve 9 to stop working, thereby ending a process of segmented pH-controlled polyethylene glycol derivative modified superparamagnetic ferrite nanoparticle ligand exchange preparation.

[0038] Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

[0039] Those skilled in the art will clearly understand that for the sake of convenience and brevity of description, only the division of the above-mentioned functional units and modules is used as an example for illustration. In actual applications, the above-mentioned functions can be distributed and completed by different functional units and modules as needed, that is, the internal structure of the system can be divided into different functional units or modules to complete all or part of the functions described above. The functional units and modules in the embodiments can be integrated into a single processing unit, or each unit can exist physically separately, or two or more units can be integrated into a single unit. The above-mentioned integrated unit can be implemented in the form of hardware or in the form of a software functional unit. In addition, the specific names of the functional units and modules are only for the purpose of distinguishing them from each other and are not intended to limit the scope of protection of this application. The specific working processes of the units and modules in the above-mentioned wireless terminal can refer to the corresponding processes in the aforementioned method embodiments and will not be repeated here.

[0040] Those skilled in the art will appreciate that the units and algorithm steps of each example described in conjunction with the embodiments disclosed herein can be implemented in electronic hardware, or a combination of computer software and electronic hardware. Whether these functions are performed in hardware or software depends on the specific application and design constraints of the technical solution. Professional and technical personnel can use different methods to implement the described functions for each specific application, but such implementation should not be considered beyond the scope of the present invention.

[0041] In the embodiments provided by the present invention, it should be understood that the systems / terminal devices and methods shown can be implemented in other ways. For example, the system / terminal device embodiments described above are merely illustrative. For example, the division of the modules or units is merely a logical functional division. In actual implementation, there may be other division methods, such as multiple units or components can be combined or integrated into another system, or some features can be ignored or not executed. In addition, the mutual coupling or direct coupling or communication connection shown or discussed can be through some interfaces, and the indirect coupling or communication connection of the system or unit can be electrical, mechanical or other forms.

[0042] The units described as separate components may or may not be physically separate, and the components described as units may or may not be physical units, that is, they may be located in one place or distributed across multiple network units. Some or all of the units may be selected according to actual needs to achieve the purpose of the solution of this embodiment.

[0043] The embodiments described above are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention, and should all be included in the scope of protection of the present invention.

Claims

1. A segmented pH-controlled ligand exchange method for polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles, characterized in that: The following steps are involved: S1, determine the initial state of the reaction system and the concentration of the polyethylene glycol derivative , the unit is , the volume is , the unit is , pH is , the concentration of superparamagnetic ferrite nanoparticles is , the unit is , the volume is , the unit is , the initial pH is ,satisfy, , the injection rate of polyethylene glycol derivative is constant , the unit is , the injection rate of superparamagnetic ferrite nanoparticles is constant at , the unit is , the injection rate of the buffer system in the initial stage, mid-stage and final stage , the unit is , the injection volume is , the unit is , ; S2, determine the reaction time and target pH of each stage. The reaction time of the initial stage is , the unit is , pH target is , the reaction time in the middle stage is , the unit is , pH target is , the reaction time at the end stage is , the unit is , pH target is ; S3, Determine the hydrogen ion concentration, hydrogen ion concentration of polyethylene glycol derivatives , the hydrogen ion concentration of superparamagnetic ferrite nanoparticles , the hydrogen ion concentration of the buffer system at the initial stage, mid-stage, and final stage and the hydrogen ion concentration of the pH target are: and , and , and , the units are ; S4, calculate the initial stage of the buffer system injection volume and injection rate, the initial stage of the buffer system injection volume According to the conservation of hydrogen ion species or charge balance calculation, the initial buffer system injection rate is , the unit is ; S5, calculate the buffer system injection volume and injection rate in the mid-stage, the buffer system injection volume in the mid-stage According to the conservation of hydrogen ion mass or charge balance calculation, the buffer system injection rate in the middle stage is , the unit is ; S6, calculate the buffer system injection volume and injection rate at the end stage, the buffer system injection volume at the end stage According to the conservation of hydrogen ion mass or charge balance calculation, the buffer system injection rate at the end stage is , the unit is ; S7, output control parameters, 、 、 The filling rate of the buffer system in the initial stage, mid-stage and final stage is used as the control parameter.

2. The method for ligand exchange of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles with segmented pH control according to claim 1, characterized in that: In S4, the injection volume of the buffer system in the initial stage is calculated according to the conservation of hydrogen ion mass, which satisfies formula (1): （1） in, is the hydrogen ion concentration of the buffer system in the initial stage, is the hydroxide ion concentration of the buffer system in the initial stage.

3. The method for ligand exchange of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles with segmented pH control according to claim 1, characterized in that: In S5, the injection volume of the buffer system in the mid-stage is calculated based on the conservation of hydrogen ion mass, satisfying formula (2): （2） in, is the hydrogen ion concentration of the buffer system in the middle stage, is the hydroxide ion concentration of the buffer system in the middle stage, is the volume of the initial buffer system continuously injected in the middle stage, is the volume of polyethylene glycol derivative continuously infused in the mid-stage, is the volume of superparamagnetic ferrite nanoparticles continuously injected in the middle stage.

4. The method for ligand exchange of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles with segmented pH control according to claim 1, characterized in that: In S6, the injection volume of the buffer system at the end stage is calculated according to the conservation of hydrogen ion mass, which satisfies formula (3): （3） in, is the hydrogen ion concentration of the buffer system at the end stage, is the hydroxide ion concentration of the buffer system at the end stage, is the volume of the buffer system continuously injected in the initial stage at the end stage, The volume of the buffer system continuously injected at the end of the mid-stage, is the volume of polyethylene glycol derivative continuously infused in the mid-stage, is the volume of superparamagnetic ferrite nanoparticles continuously injected in the middle stage.

5. The method for ligand exchange of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles with segmented pH control according to claim 1, characterized in that: In S4, the injection volume of the buffer system in the initial stage is calculated based on the charge balance, including the following steps: S401, calculate the ion concentration introduced by the buffer solution in the initial stage, satisfying formula (4): （4） in, is the positive ion concentration of the buffer solution in the initial stage, is the negative ion concentration of the buffer solution in the initial stage, is the weak acid concentration, is the conjugate base concentration, is the dissociation constant; S402, after correction based on charge balance calculation in the initial stage , satisfying formula (5): （5） in, It is an anion of polyethylene glycol derivative, is the anion of ferrite nanoparticles; S403, according to the revised Calculate the initial stage , satisfying formula (6): （6）。 6. The method for ligand exchange of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles with segmented pH control according to claim 1, characterized in that: In S5, the buffer system injection volume in the mid-stage is calculated based on the charge balance, including the following steps: S501, calculate the ion concentration introduced by the buffer solution in the mid-stage, satisfying formula (7): （7） in, is the positive ion concentration of the buffer solution during the mid-stage, is the buffer negative ion concentration in the mid-stage; S502, after correction based on charge balance calculation in the mid-stage , satisfying formula (8): （8）； S503, according to the revised Calculate the initial stage , satisfying formula (9): （9）。 7. The method for ligand exchange of polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticles with segmented pH control according to claim 1, characterized in that: In S6, the buffer system injection volume at the end of the calculation is calculated based on the charge balance, including the following steps: S601, calculate the ion concentration introduced by the buffer solution at the end stage, satisfying formula (10): （10） in, is the positive ion concentration of the buffer solution at the end stage, is the negative ion concentration of the buffer solution at the end stage; S602, after correction based on charge balance calculation , satisfying formula (11): （11） S603, according to the revised Calculation end stage , satisfying formula (12): （12）。 8. A segmented pH-controlled PEG derivative-modified superparamagnetic ferrite nanoparticle ligand exchange system, used to perform the segmented pH-controlled PEG derivative-modified superparamagnetic ferrite nanoparticle ligand exchange method according to any one of claims 1 to 7, characterized in that: include: A PEG derivative ligand liquid storage tank, a superparamagnetic ferrite nanoparticle liquid storage tank, an initial stage buffer system liquid storage tank, a mid-stage buffer system liquid storage tank, a final stage buffer system liquid storage tank, a metering pump, a static mixer, a tubular reactor, a flow valve, and a control module. The PEG derivative ligand liquid storage tank and the superparamagnetic ferrite nanoparticle liquid storage tank are respectively connected to the static mixer via a metering pump liquid path, the static mixer is connected to the tubular reactor via a flow valve liquid path, the initial stage buffer system liquid storage tank, the mid-stage buffer system liquid storage tank, and the final stage buffer system liquid storage tank are connected to the tubular reactor via a metering pump liquid path, and the metering pump and the flow valve are electrically connected to the control module.

9. The segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange system according to claim 8, characterized in that: The PEG derivative ligand storage tank, superparamagnetic ferrite nanoparticle storage tank, initial stage buffer system storage tank, mid-stage buffer system storage tank, and final stage buffer system storage tank are made of tetrafluoroethylene, and liquid level sensors are provided in the tanks.

10. The segmented pH-controlled polyethylene glycol derivative-modified superparamagnetic ferrite nanoparticle ligand exchange system according to claim 8, characterized in that The tubular reactor is provided with a spiral pipe or a spoiler internal component.

Images