Sterilization sustained release preparation containing bromothalonil and preparation method thereof

Abstract

The invention relates to the technical field of pesticide slow release, in particular to a bromothalonil-containing bactericidal slow-release preparation and a preparation method thereof. The preparation is composed of a double-shell core-shell slow-release microcapsule suspension, a dispersion stable component and a water-phase continuous phase, the microcapsule takes bromothalonil crystal particles as a core, dopamine hydrochloride is subjected to oxidative polymerization in an alkaline water phase and is deposited to form a polydopamine inner shell, a chitosan-sodium tripolyphosphate ionic crosslinking outer shell is constructed on the surface of the polydopamine inner shell, and the dispersion stable component and the water-phase continuous phase are subjected to cross-linking to form the double-shell core-shell slow-release microcapsule. Chitosan is combined with a polydopamine interface through hydrogen bonds and electrostatic interaction and is cross-linked and cured with sodium tripolyphosphate; the synergistic double-shell structure enables the system to maintain low viscosity under a high-solid-content processing condition and maintain integrity under pumping, spraying and high shearing, the encapsulation efficiency of 80-99% is achieved, and low-initial-stage burst release and long-acting slow release are both considered, so that the coupling contradiction among rheology controllability, interface stability and mechanical strength of a slow-release pesticide suspension system is relieved; the bactericidal composition is suitable for agricultural scenes requiring persistent sterilization.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pesticide slow-release technology, in particular to a bactericidal slow-release preparation containing chloronatron and a preparation method thereof. BACKGROUND

[0002] As a broad-spectrum halogenated nitrile fungicide, chloronatron has good control effect on various fungal diseases, but its low water solubility, easy photolysis and short persistence limit its application efficiency in the field. Traditional suspension or emulsion formulations are sprayed by dispersing with surfactants, but there are problems such as initial burst leading to waste of efficacy and environmental load, insufficient persistence requiring frequent application, poor dispersion stability in high temperature and humidity environment, etc. Microcapsule slow-release technology is considered an effective way to solve the above contradictions, which regulates the release rate of active ingredients through the barrier effect of shell material. However, the existing pesticide microcapsule technology faces three coupled contradictions: first, the rheological contradiction between high solid content formula requirements and low viscosity processing window, high solid content can increase the content of effective ingredients but leads to rapid increase of system viscosity affecting pumping and spraying; second, the interface construction contradiction between dispersion stability and high encapsulation rate and low burst target, enhancing particle surface charge or steric hindrance can improve dispersion stability but may weaken the shell density; third, microcapsules need to maintain structural integrity under high shear conditions such as pumping and spraying, but too rigid shell will delay the initial release and affect the speed of effect.

[0003] There have been many attempts at pesticide slow-release microcapsules in the prior art. For example, Chinese patent CN108094283A discloses a polyurea microcapsule suspension agent, which forms a polyurea shell layer on the surface of pesticide droplets through interfacial polymerization, but this method requires the use of organic solvents and the shell thickness is difficult to accurately control. Chinese patent CN109770394A discloses a chitosan-sodium alginate complex coacervation method for preparing pesticide microcapsules, which utilizes the biocompatibility of polysaccharide materials to achieve slow release, but the complex coacervation system is sensitive to pH and lacks mechanical strength, and is easily broken under high shear conditions. The above technologies have not effectively solved the coupled contradictions between high solid content and low viscosity processing window, interface stability and high encapsulation rate, and mechanical strength and release rate. As a biomimetic material, polydopamine can spontaneously oxidize and polymerize under alkaline conditions and deposit on the surface of various materials, with excellent interfacial adhesion properties. In recent years, it has been applied to the surface modification of functional materials, but its application to the surface construction of pesticide nanoparticles to form a slow-release shell and further composite with chitosan ion cross-linking layer to form a double-shell cooperative structure to meet the above three technical requirements has not been reported. SUMMARY

[0004] The purpose of this invention is to provide a bactericidal sustained-release formulation containing bromodiphenyl ether and its preparation method, which solves the rheological contradiction of existing sustained-release pesticide suspension systems in which it is difficult to simultaneously achieve high solids content and low viscosity processing window, the contradiction of interface and shell construction in which it is difficult to simultaneously satisfy dispersion stability and anti-settling and high encapsulation efficiency and low burst release, and the coupling contradiction between the structural integrity of microcapsules and the initial release effect under high shear conditions such as pump spraying. Thus, it achieves controllable sustained release and sustained bactericidal effect of bromodiphenyl ether based on manufacturability and shelf stability.

[0005] This invention achieves the above objectives through a dual-shell synergistic design. The inner polydopamine shell is only 3-15 nanometers thick, and is deposited in situ on the surface of nanoscale bromocyanuric acid crystal particles by utilizing the oxidative polymerization properties of dopamine under alkaline conditions. This ultrathin rigid shell provides both an initial encapsulation barrier for the particles and a functionalized surface rich in amino and phenolic hydroxyl groups. The outer chitosan-sodium tripolyphosphate ionic crosslinked shell forms a three-dimensional network structure through electrostatic crosslinking of chitosan cations and sodium tripolyphosphate anions. This flexible hydrogel shell forms an interfacial bond with the inner polydopamine shell through hydrogen bonds and electrostatic interactions. The dual-shell synergistic mechanism is as follows: the polydopamine inner shell provides rigid support and interfacial anchoring, while the chitosan outer shell provides hydrophilic dispersion stability and a sustained-release barrier. The strong interfacial bond between the two layers ensures that the shell does not detach under high shear conditions, while the controllable swelling properties of the outer hydrogel achieve a balance between initial moderate release and subsequent sustained release.

[0006] A bactericidal sustained-release formulation containing bromodiphenyl ether, wherein the bactericidal sustained-release formulation comprises the following components based on 100 parts by weight of the total mass of the bactericidal sustained-release formulation: (a) A core-shell sustained-release microcapsule suspension, comprising 5-90 parts by weight, wherein the solid content of the core-shell sustained-release microcapsule suspension is 5-60 wt%, and wherein the core-shell sustained-release microcapsule suspension comprises: (a1) Core-shell particles, wherein the core of the core-shell particles is a bromoacrylonitrile crystal particle and the shell is a polydopamine shell layer, wherein the polydopamine shell layer is formed by the oxidative polymerization of dopamine hydrochloride in an alkaline aqueous phase and deposition on the surface of the bromoacrylonitrile crystal particle; (a2) The outer chitosan-sodium tripolyphosphate ion-crosslinked shell is formed by crosslinking chitosan with sodium tripolyphosphate ions, and the polydopamine shell and the chitosan are bonded to each other through at least one of hydrogen bonding and electrostatic interaction. (b) A dispersion stabilizing component, in the form of 0.1-15 parts by weight, wherein the dispersion stabilizing component is selected from two or more of sodium dodecyl sulfate, Tween 80, sodium lignosulfonate, sodium polyacrylate, and sodium carboxymethyl cellulose; (c) an aqueous continuous phase, wherein the aqueous continuous phase comprises water; Among them, the sum of (a), (b), and (c) is 100 parts by weight; The core-shell sustained-release microcapsules of the bactericidal sustained-release formulation are obtained from the following intermediates, which include intermediate I, intermediate II and intermediate III. Intermediate I is the dispersion of bromodimethalin crystal particles, intermediate II is the dispersion obtained after forming the polydopamine shell on the surface of the bromodimethalin crystal particles of intermediate I, and intermediate III is the core-shell sustained-release microcapsule suspension obtained after forming the chitosan-sodium tripolyphosphate ion crosslinked shell on the outer layer of intermediate II.

[0007] Furthermore, the bromobenzonitrile crystal particle dispersion in the core-shell particles is intermediate I, and the preparation of intermediate I includes the following steps: A1. Raw materials: bromobenzonitrile, water and a dispersion stabilizing component are provided, wherein the dispersion stabilizing component comprises at least two chemicals selected from sodium dodecyl sulfate, Tween 80, sodium lignosulfonate, sodium polyacrylate, and sodium carboxymethyl cellulose; A2. Formulation: Based on 100 parts by mass of bromodiphenyl ether, the total mass of the dispersing and stabilizing components is 0.5-10 parts, and the mass of water is 165-900 parts, so that the solid content of the slurry before grinding is 10-40 wt%. A3. Steps: Under air atmosphere and normal pressure, premix the bromodiphenyl ether, the water, and the dispersion stabilizing component under mechanical stirring for 10-60 min; add zirconium dioxide grinding beads as grinding media, the zirconium dioxide grinding beads having a particle size of 0.1-0.5 mm; perform wet grinding at 10-35 ℃ for 0.5-6 h; A4. End point: Stop grinding when the median particle size D50 of the resulting dispersion reaches 0.2-0.8 µm; A5. Post-processing: Remove grinding beads and degas using sieving or separation equipment; A6. Quality control: The total solids content of intermediate I is 10-40 wt%, the pH is 5.0-8.0, and the median particle size D50 is 0.2-0.8 µm.

[0008] Furthermore, the core-shell particle is intermediate II, and the preparation of intermediate II includes the following steps: B1. Raw materials: Provide intermediate I, dopamine hydrochloride, tris(hydroxymethyl)aminomethane, pH adjuster and water, wherein the pH adjuster is selected from one or two of the following: hydrochloric acid aqueous solution with a concentration of 0.1-2.0 mol / L and sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L; B2. Proportioning: Based on 100 parts of bromodiphenyl ether in intermediate I, the mass of dopamine hydrochloride is 0.2-10 parts; the tris(hydroxymethyl)aminomethane is prepared into an aqueous solution with a concentration of 10-50 mmol / L; the amount of the tris(hydroxymethyl)aminomethane aqueous solution used is 300-1000 parts.

[0009] B3. Step: At 20-30 ℃, in air atmosphere, and under normal pressure, adjust the pH of the tris(hydroxymethyl)aminomethane aqueous solution to 8.0-8.8 using the pH adjuster; add the intermediate I and stir; then add the dopamine hydrochloride and continue stirring for 1-6 h, so that the dopamine hydrochloride is oxidized and polymerized under alkaline conditions and deposited on the surface of the bromoacrylonitrile crystal particles to form the polydopamine shell layer; B4. Endpoint: The thickness of the polydopamine shell in intermediate II is 3-15 nm, and the mass of the polydopamine is 0.2-10 wt% of the mass of the bromobenzonitrile. B5. Post-treatment: Remove free components from the aqueous phase by washing, centrifugation or membrane separation, then replenish with water and adjust the solid content; B6. Quality control: The pH of intermediate II is 7.5-8.5, the solid content of intermediate II is 10-40 wt%, and the free dopamine residue is 0.01-0.5 wt%.

[0010] Furthermore, the precursor solution required for the outer chitosan crosslinking network includes a chitosan solution and a sodium tripolyphosphate solution, and the preparation of the chitosan solution and the sodium tripolyphosphate solution includes the following steps: C1. Raw materials: Chitosan, acetic acid, water, sodium tripolyphosphate, and an aqueous solution of sodium hydroxide with a concentration of 0.1-2.0 mol / L are provided; C2. Proportioning: Based on 1000 parts by weight of water, the acetic acid comprises 5-30 parts by weight, and the chitosan comprises 2-20 parts by weight; based on 1000 parts by weight of water, the sodium tripolyphosphate comprises 0.5-10 parts by weight. C3. Steps: At 20-40 ℃, in an air atmosphere and under normal pressure, add the acetic acid to water and stir, add the chitosan and stir for 1-12 h to obtain a chitosan solution, and adjust the pH of the chitosan solution to 3.5-5.5; dissolve the sodium tripolyphosphate in water and adjust the pH to 8.0-10.5 using the sodium hydroxide aqueous solution to obtain a sodium tripolyphosphate solution; C4. Endpoint: No visible undissolved matter was found in the chitosan solution, and no visible precipitate was found in the sodium tripolyphosphate solution; C5. Post-treatment: The chitosan solution and the sodium tripolyphosphate solution are degassed and filtered respectively; C6. Quality control: The chitosan solution has a solid content of 0.2-2.0 wt%, and the sodium tripolyphosphate solution has a solid content of 0.05-1.0 wt%.

[0011] Furthermore, the core-shell sustained-release microcapsule is intermediate III, and the preparation of intermediate III includes the following steps: D1. Raw materials: Provide intermediate II, chitosan solution and sodium tripolyphosphate solution, pH adjuster and sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L, wherein the pH adjuster is selected from one or two of hydrochloric acid aqueous solution with a concentration of 0.1-2.0 mol / L and acetic acid aqueous solution with a concentration of 0.1-2.0 mol / L; D2. Proportioning: Based on 100 parts of bromodiphenyl ether in intermediate II, the mass of chitosan is 5-80 parts, the mass of sodium tripolyphosphate is 0.5-80 parts, and the mass ratio of chitosan to sodium tripolyphosphate is 1:0.05-1:1. The required amount of solution is calculated based on the solid content of the chitosan solution and the solid content of the sodium tripolyphosphate solution, so that the crosslinking process can be stirred and dropwise dispersion can be achieved; D3. Steps: At 15-35 ℃, in air atmosphere, and under normal pressure, add intermediate II to the chitosan solution and stir for 10-60 min; while maintaining the pH of the system at 4.0-6.5, add the sodium tripolyphosphate solution dropwise to the mixture over 10-120 min and continue stirring for 30-180 min to form an ionic cross-linked shell; then adjust the pH of the system to 6.0-8.0 using the 0.1-2.0 mol / L sodium hydroxide aqueous solution to obtain a microcapsule suspension; D4. Endpoint: The median particle size D50 of the obtained microcapsules was 1-10 µm, and the encapsulation efficiency of bromodiphenyl ether was 80-99%. D5. Post-treatment: Washing or membrane separation is used to reduce the free inorganic salt content in the aqueous phase, and water is used to make up the solid content to 5-60 wt%. D6. Quality control: The pH of the microcapsule suspension is 6.0-8.0, the median particle size D50 is 1-10 µm, and the encapsulation efficiency is 80-99%.

[0012] Furthermore, the median particle size D50 of the bromodiphenyl ether crystal particles is 0.2-0.8 µm, the thickness of the polydopamine shell is 3-15 nm, and the median particle size D50 of the core-shell sustained-release microcapsules is 1-10 µm, with a bromodiphenyl ether encapsulation efficiency of 80-99% for the core-shell sustained-release microcapsules; The bactericidal sustained-release formulation contains 1-40 parts by weight of bromodiphenyl ether, and the weight of the core-shell sustained-release microcapsules is not less than the weight of the bromodiphenyl ether, wherein the bromodiphenyl ether is 1,2-dibromo-2,4-dicyanobutane.

[0013] Furthermore, the dispersion stabilizing component comprises at least one of sodium dodecyl sulfate and Tween 80, and at least one of sodium lignosulfonate, sodium polyacrylate, and sodium carboxymethyl cellulose.

[0014] Furthermore, the aqueous continuous phase also includes an antifreeze plasticizing component, which is selected from one or both of glycerol and propylene glycol, and is present in a quantity of 0.5-15 parts by weight.

[0015] As a concept of this invention, the dual-shell synergistic structure design is mainly used to enhance the rheological controllability, dispersion stability, and synergistic optimization of sustained-release formulations within the high-solids processing window. Specifically, the inner polydopamine shell is constructed based on the principle of biomimetic mineralization. Dopamine hydrochloride undergoes oxidative polymerization in a weakly alkaline environment, and the resulting polydopamine oligomers and nanoparticles spontaneously adsorb onto the surface of bromobenzoic acid crystal particles through hydrogen bonds, gradually depositing to form a dense shell with controllable thickness. This inner shell is only 3-15 nanometers thick, accounting for a very small proportion of the total microcapsule size, but its rigid aromatic structure imparts initial mechanical strength to the particles. At the same time, the surface of the shell is rich in catechol, amino, and other active groups, providing multiple anchoring points for subsequent chitosan deposition. The construction of the outer chitosan-sodium tripolyphosphate (TTPP) ionic cross-linked shell utilizes the electrostatic attraction between the positive charge of the protonated amino groups on the chitosan molecular chain and the sodium tripolyphosphate anion. Under weakly acidic conditions, the dropwise addition of TTPP induces the chitosan molecular chain to cross-link and solidify on the surface of the core-shell particles, forming a three-dimensional network hydrogel structure. The outer shell and inner polydopamine layer are bonded at the interface through hydrogen bonding between the chitosan amino groups and the polydopamine phenolic hydroxyl groups, electrostatic interactions between chitosan and polydopamine, and potential hydrophobic interactions, ensuring that the double shell does not delaminate during high-shear pumping and spraying. The synergistic mechanism of the double shell allows the microcapsules to maintain low-viscosity suspension rheological properties within a solid content range of 5-60 wt%. The outer hydrophilic chitosan provides charge repulsion and steric hindrance stability, inhibiting microcapsule sedimentation and aggregation. Simultaneously, the double shell achieves an encapsulation rate of 80-99% for bromodiphenyl ether, and the synergistic effect of the inner rigid barrier and the outer hydrogel swelling and controlled release achieves a balance between initial low burst release and long-term sustained release.

[0016] This invention also discloses a method for preparing a bactericidal sustained-release formulation containing bromodiphenyl ether, comprising the following steps: S1. Provides intermediate II, chitosan solution, sodium tripolyphosphate solution, pH adjuster, and sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L, wherein intermediate II is a bromobenzoic acid crystal particle dispersion with a polydopamine shell on the surface, and the pH adjuster is selected from one or two of hydrochloric acid aqueous solution with a concentration of 0.1-2.0 mol / L and acetic acid aqueous solution with a concentration of 0.1-2.0 mol / L; S2. Based on 100 parts of bromodiphenyl ether in intermediate II, the mass of chitosan is 5-80 parts, the mass of sodium tripolyphosphate is 0.5-80 parts, and the mass ratio of chitosan to sodium tripolyphosphate is 1:0.05-1:1. S3. At 15-35 °C, in air atmosphere, and under normal pressure, intermediate II is added to the chitosan solution and stirred for 10-60 min; while maintaining the pH of the system at 4.0-6.5, the sodium tripolyphosphate solution is added dropwise to the mixture over 10-120 min and stirring is continued for 30-180 min to form an ionic cross-linked shell; subsequently, the pH of the system is adjusted to 6.0-8.0 using the sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L to obtain a suspension of intermediate III; S4. The suspension of intermediate III is mixed evenly with the dispersion stabilizing component and the aqueous continuous phase to obtain a bactericidal sustained-release formulation containing bromodiphenyl ether.

[0017] Furthermore, the degree of deacetylation of the chitosan in step S3 is 75-95%.

[0018] Furthermore, the premixing in A3 is carried out by mechanical stirring, and the mechanical stirring speed is 300-1500 r / min.

[0019] Furthermore, the wet grinding in A3 is carried out using a stirred bead mill, the mass ratio of the zirconium dioxide grinding beads to the slurry before grinding is 1-10:1, and the stirring speed of the bead mill is 800-3000 r / min.

[0020] Furthermore, the median particle size D50 in A4 is determined using a laser particle size analyzer.

[0021] Furthermore, in A5, a sieve with a pore size of 100-500 µm is used to remove the grinding beads, and the degassing is performed using vacuum degassing with a vacuum degree of 5-40 kPa absolute pressure and a degassing time of 5-30 min.

[0022] Furthermore, the solid content in A6 was determined by drying at 105 °C to constant weight, and the pH was determined using a pH meter at 25 °C.

[0023] Furthermore, after adding intermediate I to B3, the pH of the system is measured and adjusted to 8.0-8.8 using the pH adjuster, and the pH of the system is maintained at 8.0-8.8 during the reaction.

[0024] Furthermore, the stirring in B3 is mechanical stirring, with a stirring speed of 300-1500 r / min.

[0025] Furthermore, the thickness of the polydopamine shell in B4 was determined by transmission electron microscopy.

[0026] Furthermore, B5 is prepared by centrifugation and washing to remove free components. The centrifugation conditions are 3000-20000 g, the centrifugation time is 5-30 min, and the number of repetitions is 1-5.

[0027] Furthermore, the residual amount of free dopamine in B6 was determined by HPLC, and the residual amount of free dopamine accounted for 0.01-0.5 wt% of the total solid mass of intermediate II.

[0028] Furthermore, the chitosan solution in C3 is prepared by mechanical stirring at a speed of 300-1500 r / min.

[0029] Furthermore, the degassing in C5 is vacuum degassing, with a vacuum degree of 5-40 kPa absolute pressure, a degassing time of 5-30 min, and a filter pore size of 50-200 µm.

[0030] Furthermore, the solid content in C6 is determined by drying at 100-105 °C to constant weight.

[0031] Furthermore, in D3, a pH meter is used to monitor the pH of the system online, and the pH of the system is maintained at 4.0-6.5 by adding the pH adjuster.

[0032] Furthermore, the dropping rate of the sodium tripolyphosphate solution in D3 is 0.05-10 mL / min.

[0033] Furthermore, the stirring in D3 is mechanical stirring, with a stirring speed of 300-1500 r / min.

[0034] Furthermore, the D5 is washed by centrifugation to reduce the content of free inorganic salts. The centrifugation conditions are 500-5000 g, the centrifugation time is 5-30 min, and the number of repetitions is 1-5 times until the conductivity of the supernatant is less than or equal to 5 mS / cm.

[0035] Furthermore, the mixing in S4 is mechanical stirring, with a mixing temperature of 15-35 ℃, a mixing time of 10-60 min, and a stirring speed of 300-1500 r / min.

[0036] As another aspect of this invention, a three-step intermediate route is employed to enhance the quality controllability and process robustness of the double-shell microcapsule preparation process. The core of this method lies in decoupling the complex double-shell construction process into three intermediate stages with clearly defined quality control nodes. Each stage has clearly defined endpoint criteria and quality control indicators to ensure batch-to-batch stability of the final product performance. In intermediate stage I, bromocyanidin crystals are pulverized to a median particle size of 0.2-0.8 micrometers using wet milling. This nanoscale size ensures both the uniformity of subsequent shell coating and the final microcapsule size within the suitable spraying range of 1-10 micrometers. The combined use of dispersing and stabilizing components during milling synergistically provides electrostatic repulsion and steric hindrance stability, inhibiting the agglomeration and regeneration of nanoparticles. In the intermediate II stage, polydopamine is deposited in situ in a weakly alkaline tris(hydroxymethyl)aminomethane buffer solution. By controlling the amount of dopamine hydrochloride (0.2-10 parts), the reaction temperature (20-30 degrees Celsius), the pH (8.0-8.8), and the reaction time (1-6 hours), the thickness of the polydopamine shell can be precisely controlled within the range of 3-15 nanometers. This ultrathin shell does not excessively increase the microcapsule size, and the residual amount of free dopamine is reduced to 0.01-0.5 wt% through subsequent washing to avoid its interference with the cross-linking of the outer layer. In intermediate stage III, a chitosan ion-crosslinked shell is constructed under weakly acidic conditions using a dropwise addition method. By controlling the amount of chitosan (5-80 parts), sodium tripolyphosphate (0.5-80 parts), crosslinking pH (4.0-6.5), drop rate (0.05-10 mL / min), and crosslinking time (30-180 minutes), the shell thickness and crosslinking density can be adjusted to achieve a balance between encapsulation efficiency (80-99%) and sustained-release performance. Finally, adjusting the pH to 6.0-8.0 terminates the crosslinking reaction and imparts suitable storage stability to the product. The advantage of the three-step method compared to the one-step method is that each intermediate can be independently characterized and quality controlled. In case of anomalies, the problematic step can be quickly located and parameters adjusted, significantly improving the yield and batch consistency of industrial production.

[0037] The synergistic mechanism of the components in the double-shell structure of this invention is as follows: Bromhexanil crystal particles act as the functional core, providing bactericidal activity. Their nanoscale size of 0.2-0.8 micrometers ensures a high specific surface area to promote bactericidal contact after release and provides a suitable substrate for uniform shell coating. The polydopamine inner shell is tightly bound to the bromhexanil crystal surface through van der Waals forces and possible hydrogen bonds. This rigid aromatic shell, though thin (3-15 nanometers) in thickness, is dense and provides a certain barrier to water molecule penetration, significantly reducing initial burst release. Simultaneously, the catechols and amino groups abundant on the polydopamine surface provide multiple anchoring sites for the outer chitosan layer. The chitosan-sodium tripolyphosphate ion-crosslinked outer shell forms an interface with the inner layer through hydrogen bonding between the protonated amino groups of chitosan and the phenolic hydroxyl groups of polydopamine, electrostatic interactions between chitosan and polydopamine, and potential hydrophobic interactions. This multi-layered interaction ensures that the double shell does not delaminate under high shear conditions. The hydrophilicity of the outer hydrogel network endows the microcapsules with excellent dispersion stability, and its controllable swelling properties achieve a sustained-release barrier function. Water molecules must first permeate and swell the outer hydrogel before diffusing through the inner polydopamine barrier to dissolve and release bromobenzonitrile. This dual barrier synergistically achieves sustained release. In the dispersion stabilizing components, sodium dodecyl sulfate or Tween 80 provides interfacial activity to reduce interfacial tension, while sodium lignosulfonate, sodium polyacrylate, or sodium carboxymethyl cellulose provides charge repulsion and thickening stability. The multi-component compound can synergistically optimize suspension rheology and anti-sedimentation properties.

[0038] Beneficial technical effects 1. This invention effectively resolves the rheological contradiction between high solids content and low viscosity processing window in slow-release pesticide suspension systems through a dual-shell synergistic structure design. The inner polydopamine shell is only 3-15 nanometers thick, while the hydrophilicity and charge stability of the outer chitosan ion-crosslinked shell enable the microcapsules to maintain low viscosity suspension rheology within a solids content range of 5-60 wt%, making them suitable for pumping, filling, and spraying operations. Compared to traditional single-shell microcapsules, they exhibit lower viscosity at the same solids content, significantly improving the processing window width and manufacturing efficiency.

[0039] 2. The strong interfacial bonding mechanism of the double-shell interface in this invention endows the microcapsules with excellent mechanical strength and structural integrity. Multiple interfacial bonds formed between polydopamine and chitosan through hydrogen bonds and electrostatic interactions ensure that the shells of the microcapsules do not detach or break under high shear conditions such as pumping and spraying. Experiments show that after high-speed stirring at 5000 r / min for 30 minutes, the encapsulation efficiency of the microcapsules remains above 75%, while the encapsulation efficiency of traditional composite microcapsules with weak interfacial bonding drops to below 40% under the same conditions. This invention significantly improves the robustness of sustained-release formulations in practical applications.

[0040] 3. The dual-barrier sustained-release mechanism of this invention achieves a balance between low initial burst release and long-lasting sustained release. The inner rigid polydopamine shell acts as a barrier to water molecule penetration, while the controllable swelling properties of the outer hydrogel network provide an adjustable sustained-release barrier. The synergistic effect of the two shells controls the cumulative release rate of bromodiphenyl ether at 15-46% in 24 hours and reaches 60-90% in 96 hours. Compared with the burst release rate of more than 80% in 24 hours of shell-less suspensions, this invention significantly prolongs the bactericidal effect, reduces the frequency of application by 30-50%, and reduces environmental impact.

[0041] 4. This invention employs a three-step intermediate preparation method, with clearly defined quality control indicators and endpoint criteria for each stage to ensure batch-to-batch stability of the final product performance. Intermediates I, II, and III are controlled by median particle size, shell thickness, and encapsulation efficiency as core quality control parameters, respectively. In industrial production, the standard deviation of encapsulation efficiency between batches can be controlled within 3%, significantly better than the batch fluctuations exceeding 10% of traditional one-step methods, thus improving the quality controllability and commercial feasibility of sustained-release formulations.

[0042] 5. The shell materials used in this invention, polydopamine and chitosan, are both natural or biomimetic materials with good biocompatibility. Their degradation products are environmentally friendly and have lower ecological risks compared to petroleum-based shell materials such as polyurea and polyamide. This aligns with the trend of green development in pesticide formulations and is suitable for disease control needs in environmentally sensitive areas or agricultural scenarios with high requirements for ecological risk control. Attached Figure Description

[0043] Figure 1 The Fourier transform infrared spectra of Example 1, Comparative Example 2, chitosan, and polydopamine are superimposed.

[0044] Figure 2 The Fourier transform infrared spectra of Example 1, Comparative Example 2, chitosan, and polydopamine are magnified comparison images.

[0045] Figure 3 The image shows a comparison of the N 1s X-ray photoelectron spectra of Example 1 and Comparative Example 2.

[0046] Figure 4 The bar charts show the nitrogen component percentages of Example 1 and Comparative Example 2 based on the XPS N 1s peak decomposition results.

[0047] Figure 5 This is a waterfall plot of X-ray photoelectron spectroscopy depth profile from Example 1.

[0048] Figure 6 This is a thermal map of the depth intensity distribution of the X-ray photoelectron spectrum in Example 1.

[0049] Figure 7 This is a superimposed image of liquid chromatography-ultraviolet detection of Example 1 and Comparative Example 7. Detailed Implementation

[0050] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Example 1

[0051] This embodiment provides a bactericidal sustained-release formulation containing bromodiphenyl ether. Based on a total mass of 100 parts by weight of the bactericidal sustained-release formulation in this embodiment, the bactericidal sustained-release formulation containing bromodiphenyl ether comprises the following components: 30 parts by weight of core-shell sustained-release microcapsules (30 wt% solid content), 7 parts by weight of dispersion stabilizing component, 5 parts by weight of antifreeze plasticizing component, and 58 parts by weight of aqueous continuous phase.

[0052] The core-shell sustained-release microcapsule of this embodiment includes: a core-shell particle, wherein the core of the core-shell particle is a bromoacrylonitrile crystal particle, and the shell is a polydopamine shell layer, which is formed by the oxidative polymerization of dopamine hydrochloride in an alkaline aqueous phase and deposition on the surface of the bromoacrylonitrile crystal particle; and an outer chitosan-sodium tripolyphosphate ion-crosslinked shell layer, which is formed by the crosslinking of chitosan and sodium tripolyphosphate ions, and the polydopamine shell layer and chitosan are bonded to each other through hydrogen bonding and electrostatic interaction.

[0053] The dispersion stabilizing component in this embodiment is 7 parts by weight, selected from 3 parts by weight of sodium dodecyl sulfate and 4 parts by weight of sodium lignosulfonate. The antifreeze plasticizing component in this embodiment is 5 parts by weight of glycerol. The aqueous continuous phase in this embodiment includes water, which is 58 parts by weight.

[0054] Intermediate I: refers to the bromoacrylonitrile crystal particle dispersion obtained by wet grinding.

[0055] Intermediate II (core-shell particles): refers to the dispersion obtained after a polydopamine shell is deposited on the surface of the bromoacrylonitrile crystal particles.

[0056] Intermediate III (core-shell sustained-release microcapsules): refers to the core-shell sustained-release microcapsule suspension obtained after further forming a chitosan-sodium tripolyphosphate ion cross-linked shell on the outer layer of intermediate II.

[0057] Bactericidal sustained-release preparations: refer to suspension formulations composed of core-shell sustained-release microcapsules, dispersible and stable components, and an aqueous continuous phase.

[0058] In this embodiment, the bromocyanidin crystal particle dispersion in the core-shell particles is intermediate I. The preparation of intermediate I includes the following steps: A1. Raw materials: Bromochloronitrofurazone, water, and a dispersion and stabilizing component are provided. The dispersion and stabilizing component contains two chemicals selected from sodium dodecyl sulfate and sodium lignosulfonate. A2. Proportioning: Based on 100 parts by mass of bromodiphenyl ether, the total mass of the dispersing and stabilizing components is 5 parts, including 2 parts sodium dodecyl sulfate, 3 parts sodium lignosulfonate, and 500 parts water, so that the mass ratio of bromodiphenyl ether to water in the slurry before grinding is 1:5; A3. Procedure: Under air atmosphere and normal pressure, bromodiphenyl ether, water, and dispersion stabilizing components were premixed for 35 min under mechanical stirring at a speed of 800 r / min. Zirconia grinding beads with a particle size of 0.3 mm and a mass ratio of zirconia grinding beads to the unmixed slurry of 5:1 were added as the grinding medium. Wet grinding was then performed at 22 ℃ using a stirred bead mill for 3 h at a stirring speed of 2000 r / min. A4. Endpoint: Grinding was stopped when the median particle size D50 of the resulting dispersion reached 0.5 µm. The median particle size D50 was determined using a laser particle size analyzer. A5. Post-treatment: Remove grinding beads through a sieve with a pore size of 300 µm, and perform vacuum degassing at a vacuum degree of 20 kPa absolute pressure for 15 min; A6. Quality control: The total solid content of intermediate I is 25 wt%, determined by drying at 105 ℃ to constant weight. The pH is 6.5, determined by pH meter at 25 ℃. The median particle size D50 is 0.5 µm.

[0059] In this embodiment, the core-shell particle is intermediate II, and the preparation of intermediate II includes the following steps: B1. Raw materials: Provide intermediate I, dopamine hydrochloride, tris(hydroxymethyl)aminomethane, pH adjuster, and water. The pH adjuster is selected from a 1.0 mol / L aqueous solution of hydrochloric acid and a 1.0 mol / L aqueous solution of sodium hydroxide. B2. Proportioning: Based on 100 parts by mass of bromodiphenyl ether in intermediate I, and 5 parts by mass of dopamine hydrochloride; prepare an aqueous solution of tris(hydroxymethyl)aminomethane with a concentration of 30 mmol / L, using 500 parts of the tris(hydroxymethyl)aminomethane aqueous solution; B3. Procedure: Under normal temperature, air atmosphere, and atmospheric pressure, the pH of the tris(hydroxymethyl)aminomethane aqueous solution was adjusted to 8.4 using a pH adjuster; intermediate I was added and stirred, and the pH of the system was measured and adjusted to 8.4 using a pH adjuster after the addition of intermediate I; then dopamine hydrochloride was added and stirred continuously for 3.5 h, allowing dopamine hydrochloride to oxidize and polymerize under alkaline conditions and deposit on the surface of bromoacrylonitrile crystal particles to form a polydopamine shell. The stirring was mechanical, with a stirring speed of 900 r / min, and the pH of the system was maintained at 8.4 during the reaction. B4. Endpoint: The thickness of the polydopamine shell in intermediate II was 9 nm, determined by transmission electron microscopy, and the mass of polydopamine was 5 wt% of the mass of bromodiphenyl ether. B5. Post-treatment: The free components in the aqueous phase were removed by centrifugation washing at 10,000 g for 15 min, repeated 3 times. Then, water was added to make up the solids and the solid content was adjusted to 25 wt%. B6. Quality control: The pH of intermediate II is 8.0 and the free dopamine residue is 0.25 wt%. The free dopamine residue is determined by HPLC and accounts for 0.25 wt% of the total solid mass of intermediate II.

[0060] The precursor solution required for the outer chitosan crosslinking network in this embodiment includes a chitosan solution and a sodium tripolyphosphate solution. The preparation of the chitosan solution and the sodium tripolyphosphate solution includes the following steps: C1. Raw materials: Chitosan, acetic acid, water, sodium tripolyphosphate, and a 1.0 mol / L aqueous solution of sodium hydroxide are provided; C2. Proportioning: Based on 1000 parts by weight of water, acetic acid comprises 17 parts by weight, and chitosan comprises 10 parts by weight; based on 1000 parts by weight of water, sodium tripolyphosphate comprises 5 parts by weight. C3. Procedure: At 30 ℃, in an air atmosphere and under normal pressure, acetic acid was added to water and stirred. Chitosan was then added and stirred for 6 h to obtain a chitosan solution. The pH of the chitosan solution was adjusted to 4.5. The chitosan solution was prepared by mechanical stirring at a speed of 900 r / min. Sodium tripolyphosphate was dissolved in water and the pH was adjusted to 9.2 using sodium hydroxide aqueous solution to obtain a sodium tripolyphosphate solution. C4. Endpoint: No visible undissolved matter was found in the chitosan solution, and no visible precipitate was found in the sodium tripolyphosphate solution; C5. Post-treatment: The chitosan solution and sodium tripolyphosphate solution were degassed and filtered separately. The degassed solution was vacuum degassed at an absolute pressure of 20 kPa for 15 min, and the filter pore size was 100 µm. C6. Quality control: The solid content of chitosan solution is 1.0 wt%, and the solid content of sodium tripolyphosphate solution is 0.5 wt%. The solid content is determined by drying at 105 ℃ to constant weight.

[0061] The core-shell sustained-release microcapsule in this embodiment is intermediate III. The preparation of intermediate III includes the following steps: D1. Raw materials: The above-prepared intermediate II, the above-prepared chitosan solution and sodium tripolyphosphate solution, pH adjuster, and a 1.0 mol / L sodium hydroxide aqueous solution are provided. The pH adjuster is selected from a 1.0 mol / L hydrochloric acid aqueous solution. D2. Proportion: Based on 100 parts by mass of bromochloronitrile in intermediate II, 40 parts by mass of chitosan, and 20 parts by mass of sodium tripolyphosphate, with the mass of sodium tripolyphosphate not exceeding the mass of chitosan; D3. Procedure: At 25 °C, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 35 min. While maintaining the system pH at 5.2, sodium tripolyphosphate solution was added dropwise to the mixture over 60 min, and stirring continued for 100 min to form an ionic cross-linked shell. The system pH was monitored online using a pH meter, and a pH adjuster was added to maintain the system pH at 5.2. The dropping rate of the sodium tripolyphosphate solution was determined based on the total amount and dropping time. Stirring was mechanical at a speed of 900 r / min. Subsequently, the system pH was adjusted to 7.0 using a 1.0 mol / L sodium hydroxide aqueous solution to obtain the microcapsule suspension. D4. Endpoint: The median particle size D50 of the obtained microcapsules was 5 µm, and the encapsulation efficiency of bromodiphenyl ether was 90%. The encapsulation efficiency was calculated using the following formula: the percentage of encapsulation efficiency equals m_total minus m_free divided by m_total and then multiplied by 100%, where m_total is the total mass of bromodiphenyl ether in the microcapsule suspension, and m_free is the mass of bromodiphenyl ether in the separated aqueous phase. Both m_total and m_free were determined by HPLC. D5. Post-treatment: Centrifugation was used to reduce the free inorganic salt content in the aqueous phase. The centrifugation conditions were 2500 g and 15 min, repeated 3 times, until the conductivity of the supernatant was less than or equal to 5 mS / cm, and then water was added to make up the solid content to 30 wt%. D6. Quality control: The pH of the microcapsule suspension is 7.0, the median particle size D50 is 5 µm, the encapsulation efficiency is 90%, and the solid content is 30 wt%.

[0062] In this embodiment, the median particle size D50 of the bromodiphenyl ether crystal particles is 0.5 µm, the thickness of the polydopamine shell is 9 nm, and the median particle size D50 of the core-shell sustained-release microcapsules is 5 µm, with a bromodiphenyl ether encapsulation rate of 90%. The content of bromodiphenyl ether in the bactericidal sustained-release formulation is 8.2 parts by weight, and the weight of the core-shell sustained-release microcapsules is not less than 30 parts by weight of 8.2 parts by weight of bromodiphenyl ether, wherein the bromodiphenyl ether is 1,2-dibromo-2,4-dicyanobutane.

[0063] The dispersion stabilizing component in this embodiment includes sodium dodecyl sulfate and sodium lignosulfonate.

[0064] The preparation method of the bactericidal sustained-release formulation containing bromodiphenyl ether in this embodiment includes the following steps: S1. Provides intermediate II, chitosan solution, sodium tripolyphosphate solution, pH adjuster, and a 1.0 mol / L aqueous solution of sodium hydroxide, wherein intermediate II is a bromocyanide crystal particle dispersion with a polydopamine shell on the surface, and the pH adjuster is selected from a 1.0 mol / L aqueous solution of hydrochloric acid; S2. Based on 100 parts of bromobenzonitrile in intermediate II, the mass of chitosan is 40 parts, the mass of sodium tripolyphosphate is 20 parts, and the mass ratio of chitosan to sodium tripolyphosphate is 1:0.5; S3. At 25 °C, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 35 min; while maintaining the pH of the system at 5.2, sodium tripolyphosphate solution was added dropwise to the mixture over 60 min and stirring was continued for 100 min to form an ionic cross-linked shell; subsequently, the pH of the system was adjusted to 7.0 using a 1.0 mol / L sodium hydroxide aqueous solution to obtain a suspension of intermediate III; S4. The suspension of intermediate III was mixed evenly with the dispersion stabilizing component and the aqueous continuous phase to obtain a bactericidal sustained-release formulation containing bromodiphenyl ether. The mixing was carried out by mechanical stirring at a temperature of 25 °C for 35 min and a stirring speed of 900 r / min.

[0065] In the preparation method, the degree of deacetylation of chitosan in step S3 is 85%.

[0066] The core-shell structure of intermediate II in this embodiment was characterized by transmission electron microscopy, and the surface elemental composition of intermediate II was characterized by X-ray photoelectron spectroscopy. The Zeta potentials of intermediates I, II, and III in this embodiment were determined by electrophoretic light scattering to characterize the surface charge changes during shell formation. The sustained-release performance of the bactericidal sustained-release formulation containing bromodifenac in this embodiment was characterized by a release test, which included measuring the amount of bromodifenac released in an aqueous medium at a specified temperature and obtaining a release curve.

[0067] Features of Example 1: This example uses moderate parameter configurations. The core-shell sustained-release microcapsule content is 30 parts by weight, the median particle size of bromodiphenyl ether crystals is 0.5 µm, the polydopamine shell thickness is 9 nm, the microcapsule particle size is 5 µm, the encapsulation efficiency is 90%, the content of the dispersion stabilizing component is 7 parts by weight, and the antifreeze plasticizing component is 5 parts by weight of glycerol. This example uses a compound dispersion system of sodium dodecyl sulfate and sodium lignosulfonate, the grinding temperature is 22℃, the reaction pH is 8.4, the degree of deacetylation of chitosan is 85%, the mass ratio of chitosan to sodium tripolyphosphate is 2:1, and the final suspension has a solid content of 30%. The parameter combination of this example reflects a balance between stability and operability. The process conditions are mild and suitable for agricultural protection applications that require stable sustained-release performance and long storage periods, such as field crop disease control and long-term sterilization treatment in greenhouse cultivation systems. Example 2

[0068] This embodiment provides a bactericidal sustained-release formulation containing bromodiphenyl ether. Based on a total mass of 100 parts by weight of the bactericidal sustained-release formulation of this embodiment, the bactericidal sustained-release formulation containing bromodiphenyl ether comprises the following components: 20 parts by weight of core-shell sustained-release microcapsules (solid content 15 wt%), 3 parts by weight of dispersion stabilizing component, 2 parts by weight of antifreeze plasticizing component, and 75 parts by weight of aqueous continuous phase.

[0069] The core-shell sustained-release microcapsule of this embodiment includes: a core-shell particle, wherein the core of the core-shell particle is a bromoacrylonitrile crystal particle, and the shell is a polydopamine shell layer, which is formed by the oxidative polymerization of dopamine hydrochloride in an alkaline aqueous phase and deposition on the surface of the bromoacrylonitrile crystal particle; and an outer chitosan-sodium tripolyphosphate ion-crosslinked shell layer, which is formed by the crosslinking of chitosan and sodium tripolyphosphate ions, and the polydopamine shell layer and chitosan are bonded to each other through hydrogen bonding and electrostatic interaction.

[0070] The dispersion stabilizing component in this embodiment is 3 parts by weight, and the dispersion stabilizing component is selected from 1.5 parts by weight of sodium dodecyl sulfate and 1.5 parts by weight of sodium carboxymethyl cellulose. The antifreeze plasticizing component in this embodiment is 2 parts by weight of propylene glycol. The aqueous continuous phase in this embodiment includes water, which is 75 parts by weight.

[0071] In this embodiment, the bromocyanidin crystal particle dispersion in the core-shell particles is intermediate I. The preparation of intermediate I includes the following steps: A1. Raw materials: Bromochloronitrofurazone, water, and a dispersion and stabilizing component are provided. The dispersion and stabilizing component comprises two chemicals selected from sodium dodecyl sulfate and sodium carboxymethyl cellulose. A2. Formulation: Based on 100 parts by mass of bromocyanidin, the total mass of the dispersing and stabilizing components is 3 parts, including 1.5 parts sodium dodecyl sulfate, 1.5 parts sodium carboxymethyl cellulose, and 700 parts water, so that the solid content of the slurry before grinding is 12.5 wt%. A3. Procedure: Under air atmosphere and normal pressure, bromodiphenyl ether, water, and dispersion stabilizing components were premixed for 20 min under mechanical stirring at a speed of 500 r / min; zirconia grinding beads with a particle size of 0.2 mm were added as grinding media, and the mass ratio of zirconia grinding beads to the unground slurry was 3:1; wet grinding was performed at 15 ℃ using a stirred bead mill for 1.5 h at a stirring speed of 1200 r / min. A4. Endpoint: Grinding was stopped when the median particle size D50 of the resulting dispersion reached 0.3 µm. The median particle size D50 was determined using a laser particle size analyzer. A5. Post-treatment: Remove grinding beads through a 200 µm sieve, and perform vacuum degassing at a vacuum level of 10 kPa absolute pressure for 10 min; A6. Quality control: The total solid content of intermediate I is 15 wt%, which is determined by drying at 105 ℃ to constant weight. The pH is 5.5, which is determined by pH meter at 25 ℃. The median particle size D50 is 0.3 µm.

[0072] In this embodiment, the core-shell particle is intermediate II, and the preparation of intermediate II includes the following steps: B1. Raw materials: Provide intermediate I, dopamine hydrochloride, tris(hydroxymethyl)aminomethane, pH adjuster, and water. The pH adjuster is selected from a 0.5 mol / L aqueous solution of hydrochloric acid and a 0.5 mol / L aqueous solution of sodium hydroxide. B2. Proportioning: Based on 100 parts by mass of bromodiphenyl ether in intermediate I, and 2 parts by mass of dopamine hydrochloride; prepare an aqueous solution of tris(hydroxymethyl)aminomethane with a concentration of 20 mmol / L, using 700 parts of the tris(hydroxymethyl)aminomethane aqueous solution; B3. Procedure: At 23 °C, in air atmosphere, and under normal pressure, the pH of the tris(hydroxymethyl)aminomethane aqueous solution was adjusted to 8.2 using a pH adjuster. Intermediate I was added and stirred. After adding intermediate I, the pH of the system was measured and adjusted to 8.2 using a pH adjuster. Subsequently, dopamine hydrochloride was added and stirred continuously for 2 h, allowing dopamine hydrochloride to oxidize and polymerize under alkaline conditions and deposit on the surface of bromobenzonitrile crystal particles to form a polydopamine shell. The stirring was mechanical, with a stirring speed of 600 r / min, and the pH of the system was maintained at 8.2 during the reaction. B4. Endpoint: The thickness of the polydopamine shell in intermediate II was 5 nm, determined by transmission electron microscopy, and the mass of polydopamine was 2 wt% of the mass of bromodiphenyl ether. B5. Post-treatment: Free components in the aqueous phase were removed by centrifugation washing at 6000 g for 10 min, repeated twice. Water was then added to make up the solids content to 15 wt%. B6. Quality control: The pH of intermediate II is 7.7 and the free dopamine residue is 0.12 wt%. The free dopamine residue was determined by HPLC and accounted for 0.12 wt% of the total solid mass of intermediate II.

[0073] The precursor solution required for the outer chitosan crosslinking network in this embodiment includes a chitosan solution and a sodium tripolyphosphate solution. The preparation of the chitosan solution and the sodium tripolyphosphate solution includes the following steps: C1. Raw materials: Chitosan, acetic acid, water, sodium tripolyphosphate, and a 0.5 mol / L aqueous solution of sodium hydroxide are provided; C2. Proportioning: Based on 1000 parts by weight of water, 10 parts by weight of acetic acid and 5 parts by weight of chitosan; based on 1000 parts by weight of water, 2 parts by weight of sodium tripolyphosphate. C3. Procedure: At 25 °C, in an air atmosphere and under normal pressure, acetic acid was added to water and stirred. Chitosan was then added and stirred for 4 h to obtain a chitosan solution. The pH of the chitosan solution was adjusted to 4.0. The chitosan solution was prepared by mechanical stirring at a speed of 600 r / min. Sodium tripolyphosphate was dissolved in water and the pH was adjusted to 8.5 using sodium hydroxide aqueous solution to obtain a sodium tripolyphosphate solution. C4. Endpoint: No visible undissolved matter was found in the chitosan solution, and no visible precipitate was found in the sodium tripolyphosphate solution; C5. Post-treatment: The chitosan solution and sodium tripolyphosphate solution were degassed and filtered separately. The degassed solution was vacuum degassed at an absolute pressure of 10 kPa for 10 min, and the filter pore size was 80 µm. C6. Quality control: The solid content of chitosan solution is 0.5 wt%, and the solid content of sodium tripolyphosphate solution is 0.2 wt%. The solid content is determined by drying at 105 ℃ to constant weight.

[0074] The core-shell sustained-release microcapsule in this embodiment is intermediate III. The preparation of intermediate III includes the following steps: D1. Raw materials: The above-prepared intermediate II, the above-prepared chitosan solution and sodium tripolyphosphate solution, pH adjuster, and a 0.5 mol / L sodium hydroxide aqueous solution are provided. The pH adjuster is selected from a 0.5 mol / L hydrochloric acid aqueous solution. D2. Proportion: Based on 100 parts of bromochloronitrile in intermediate II, the mass of chitosan is 20 parts, and the mass of sodium tripolyphosphate is 10 parts, with the mass of sodium tripolyphosphate not exceeding the mass of chitosan; D3. Procedure: At 20 ℃, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 20 min. While maintaining the system pH at 4.5, sodium tripolyphosphate solution was added dropwise to the mixture over 30 min, and stirring continued for 60 min to form an ionic cross-linked shell. The system pH was monitored online using a pH meter, and a pH adjuster was added to maintain the system pH at 4.5. The dropping rate of the sodium tripolyphosphate solution was determined based on the total amount and dropping time. Stirring was mechanical at a speed of 600 r / min. Subsequently, the system pH was adjusted to 6.5 using a 0.5 mol / L sodium hydroxide aqueous solution to obtain the microcapsule suspension. D4. Endpoint: The median particle size D50 of the obtained microcapsules was 2.5 µm, and the encapsulation efficiency of bromodifenac was 85%. The encapsulation efficiency was calculated using the following formula: the percentage of encapsulation efficiency equals m_total minus m_free divided by m_total and then multiplied by 100%, where m_total is the total mass of bromodifenac in the microcapsule suspension, and m_free is the mass of bromodifenac in the separated aqueous phase. Both m_total and m_free were determined by HPLC. D5. Post-treatment: Centrifugation was used to reduce the free inorganic salt content in the aqueous phase. The centrifugation conditions were 1000 g and 10 min, repeated twice, until the conductivity of the supernatant was less than or equal to 5 mS / cm. Water was then added to bring the solid content to 15 wt%. D6. Quality control: The pH of the microcapsule suspension was 6.5, the median particle size D50 was 2.5 µm, the encapsulation efficiency was 85%, and the solid content was 15 wt%.

[0075] In this embodiment, the median particle size D50 of the bromodiphenyl ether crystal particles is 0.3 µm, the thickness of the polydopamine shell is 5 nm, and the median particle size D50 of the core-shell sustained-release microcapsules is 2.5 µm, with a bromodiphenyl ether encapsulation rate of 85%. The content of bromodiphenyl ether in the bactericidal sustained-release formulation is 2.5 parts by weight, and the weight of the core-shell sustained-release microcapsules is not less than 20 parts by weight of bromodiphenyl ether, wherein the bromodiphenyl ether is 1,2-dibromo-2,4-dicyanobutane.

[0076] The dispersion stabilizing component in this embodiment includes sodium dodecyl sulfate and sodium carboxymethyl cellulose.

[0077] The preparation method of the bactericidal sustained-release formulation containing bromodiphenyl ether in this embodiment includes the following steps: S1. Provides intermediate II, chitosan solution, sodium tripolyphosphate solution, pH adjuster, and a 0.5 mol / L aqueous solution of sodium hydroxide, wherein intermediate II is a bromocyanide crystal particle dispersion with a polydopamine shell on its surface, and the pH adjuster is selected from a 0.5 mol / L aqueous solution of hydrochloric acid; S2. Based on 100 parts of bromobenzonitrile in intermediate II, 20 parts of chitosan and 10 parts of sodium tripolyphosphate are present, with a mass ratio of chitosan to sodium tripolyphosphate of 1:0.5. S3. At 20 °C, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 20 min. While maintaining the pH of the system at 4.5, sodium tripolyphosphate solution was added dropwise to the mixture over 30 min and stirring continued for 60 min to form an ionic cross-linked shell. Subsequently, the pH of the system was adjusted to 6.5 using a 0.5 mol / L sodium hydroxide aqueous solution to obtain a suspension of intermediate III. S4. The suspension of intermediate III is mixed evenly with the dispersion stabilizing component and the aqueous continuous phase to obtain a bactericidal sustained-release formulation containing bromodimethalin. The mixing is performed by mechanical stirring at a temperature of 20 °C for 20 min and a stirring speed of 600 r / min.

[0078] In the preparation method, the degree of deacetylation of chitosan in step S3 is 80%.

[0079] The core-shell structure of intermediate II in this embodiment was characterized by transmission electron microscopy, and the surface elemental composition of intermediate II was characterized by X-ray photoelectron spectroscopy. The Zeta potentials of intermediates I, II, and III in this embodiment were determined by electrophoretic light scattering to characterize the surface charge changes during shell formation. The sustained-release performance of the bactericidal sustained-release formulation containing bromodifenac in this embodiment was characterized by a release test, which included measuring the amount of bromodifenac released in an aqueous medium at a specified temperature and obtaining a release curve.

[0080] Example 2 Features: This example employs a formulation design with low microcapsule content and high aqueous phase content. The core-shell sustained-release microcapsule content is 20 parts by weight, the aqueous continuous phase is 75 parts by weight, the median particle size of bromodiphenyl ether crystals is 0.3 µm, the polydopamine shell thickness is 5 nm, the microcapsule particle size is 2.5 µm, the encapsulation efficiency is 85%, the content of the dispersion stabilizing component is 3 parts by weight, and the antifreeze plasticizing component is 2 parts by weight of propylene glycol. This example uses a compound dispersion system of sodium dodecyl sulfate and sodium carboxymethyl cellulose, with a relatively low grinding temperature of 15°C, a reaction pH of 8.2, a chitosan deacetylation degree of 80%, a chitosan to sodium tripolyphosphate mass ratio of 2:1, and a final suspension solid content of 15%. The formulation of this example exhibits the characteristics of low viscosity and high fluidity. The finer crystal particles and microcapsule particle size are conducive to rapid dispersion and initial release, making it suitable for spray application scenarios requiring rapid onset of action, such as foliar spraying in facility agriculture, disease control in drip irrigation systems, and sterilization treatment in hydroponics. Example 3

[0081] This embodiment provides a bactericidal sustained-release formulation containing bromodiphenyl ether. Based on a total mass of 100 parts by weight of the bactericidal sustained-release formulation of this embodiment, the bactericidal sustained-release formulation containing bromodiphenyl ether comprises the following components: 65 parts by weight of core-shell sustained-release microcapsules (solid content 50 wt%), 12 parts by weight of dispersion stabilizing component, 10 parts by weight of antifreeze plasticizing component, and 13 parts by weight of aqueous continuous phase.

[0082] The core-shell sustained-release microcapsule of this embodiment includes: a core-shell particle, wherein the core of the core-shell particle is a bromoacrylonitrile crystal particle, and the shell is a polydopamine shell layer, which is formed by the oxidative polymerization of dopamine hydrochloride in an alkaline aqueous phase and deposition on the surface of the bromoacrylonitrile crystal particle; and an outer chitosan-sodium tripolyphosphate ion-crosslinked shell layer, which is formed by the crosslinking of chitosan and sodium tripolyphosphate ions, and the polydopamine shell layer and chitosan are bonded to each other through electrostatic interaction.

[0083] The dispersion stabilizing component in this embodiment is 12 parts by weight, selected from 5 parts by weight of Tween 80, 4 parts by weight of sodium lignosulfonate, and 3 parts by weight of sodium polyacrylate. The antifreeze plasticizing component in this embodiment is 5 parts by weight of glycerol and 5 parts by weight of propylene glycol. The aqueous continuous phase in this embodiment includes water, which is 13 parts by weight.

[0084] In this embodiment, the bromocyanidin crystal particle dispersion in the core-shell particles is intermediate I. The preparation of intermediate I includes the following steps: A1. Raw materials: Bromochloronitrogen, water, and dispersion and stabilizing components are provided. The dispersion and stabilizing components contain three chemicals selected from Tween 80, sodium lignosulfonate, and sodium polyacrylate. A2. Formulation: Based on 100 parts by weight of bromodiphenyl ether, the total mass of the dispersing and stabilizing components is 7.5 parts, including 3 parts by weight of Tween 80, 2.5 parts by weight of sodium lignosulfonate, 2 parts by weight of sodium polyacrylate, and 250 parts by weight of water, so that the solid content of the slurry before grinding is 28.0 wt%. A3. Procedure: Under air atmosphere and normal pressure, bromodiphenyl ether, water, and dispersion stabilizing components were premixed for 50 min under mechanical stirring at a speed of 1200 r / min; zirconia grinding beads with a particle size of 0.4 mm were added as grinding media, and the mass ratio of zirconia grinding beads to the unground slurry was 8:1; wet grinding was performed at 30 ℃ using a stirred bead mill for 5 h at a stirring speed of 2800 r / min. A4. Endpoint: Grinding was stopped when the median particle size D50 of the resulting dispersion reached 0.7 µm. The median particle size D50 was determined using a laser particle size analyzer. A5. Post-treatment: Remove grinding beads through a sieve with a pore size of 400 µm, and perform vacuum degassing at a vacuum degree of 35 kPa absolute pressure for 25 min; A6. Quality control: The total solid content of intermediate I is 35 wt%, which is determined by drying at 105 ℃ to constant weight. The pH is 7.5, which is determined by pH meter at 25 ℃. The median particle size D50 is 0.7 µm.

[0085] In this embodiment, the core-shell particle is intermediate II, and the preparation of intermediate II includes the following steps: B1. Raw materials: Provide intermediate I, dopamine hydrochloride, tris(hydroxymethyl)aminomethane, pH adjuster, and water. The pH adjuster is selected from a 1.5 mol / L aqueous solution of hydrochloric acid and a 1.5 mol / L aqueous solution of sodium hydroxide. B2. Proportioning: Based on 100 parts by mass of bromodiphenyl ether in intermediate I, and 8 parts by mass of dopamine hydrochloride; prepare an aqueous solution of tris(hydroxymethyl)aminomethane with a concentration of 45 mmol / L, using 500 parts of the tris(hydroxymethyl)aminomethane aqueous solution; B3. Procedure: At 28 ℃, in air atmosphere, and under normal pressure, the pH of the tris(hydroxymethyl)aminomethane aqueous solution was adjusted to 8.7 using a pH adjuster; intermediate I was added and stirred, and the pH of the system was measured and adjusted to 8.7 using a pH adjuster after the addition of intermediate I; then dopamine hydrochloride was added and stirred continuously for 5 h, allowing dopamine hydrochloride to oxidize and polymerize under alkaline conditions and deposit on the surface of bromobenzonitrile crystal particles to form a polydopamine shell. The stirring was mechanical, with a stirring speed of 1300 r / min, and the pH of the system was maintained at 8.7 during the reaction. B4. Endpoint: The thickness of the polydopamine shell in intermediate II was 13 nm, determined by transmission electron microscopy, and the mass of polydopamine was 8 wt% of the mass of bromodiphenyl ether. B5. Post-treatment: Free components in the aqueous phase were removed by centrifugation washing at 15000 g for 25 min, repeated 4 times. Water was then added to adjust the solid content to 35 wt%. B6. Quality control: The pH of intermediate II is 8.3 and the free dopamine residue is 0.42 wt%. The free dopamine residue was determined by HPLC and accounted for 0.42 wt% of the total solid mass of intermediate II.

[0086] The precursor solution required for the outer chitosan crosslinking network in this embodiment includes a chitosan solution and a sodium tripolyphosphate solution. The preparation of the chitosan solution and the sodium tripolyphosphate solution includes the following steps: C1. Raw materials: Chitosan, acetic acid, water, sodium tripolyphosphate, and a 1.5 mol / L aqueous solution of sodium hydroxide are provided; C2. Proportioning: Based on 1000 parts by weight of water, acetic acid comprises 25 parts by weight, and chitosan comprises 16 parts by weight; based on 1000 parts by weight of water, sodium tripolyphosphate comprises 8 parts by weight. C3. Procedure: At 35 ℃, in an air atmosphere and under normal pressure, acetic acid was added to water and stirred. Chitosan was then added and stirred for 10 h to obtain a chitosan solution. The pH of the chitosan solution was adjusted to 5.2. The chitosan solution was prepared by mechanical stirring at a speed of 1200 r / min. Sodium tripolyphosphate was dissolved in water and the pH was adjusted to 10.0 using sodium hydroxide aqueous solution to obtain a sodium tripolyphosphate solution. C4. Endpoint: No visible undissolved matter was found in the chitosan solution, and no visible precipitate was found in the sodium tripolyphosphate solution; C5. Post-treatment: The chitosan solution and sodium tripolyphosphate solution were degassed and filtered separately. The degassed solution was vacuum degassed at an absolute pressure of 35 kPa for 25 min, and the filter pore size was 150 µm. C6. Quality control: The solid content of chitosan solution was 1.55 wt%, and the solid content of sodium tripolyphosphate solution was 0.79 wt%. The solid content was determined by drying at 105 ℃ to constant weight.

[0087] The core-shell sustained-release microcapsule in this embodiment is intermediate III. The preparation of intermediate III includes the following steps: D1. Raw materials: The above-prepared intermediate II, the above-prepared chitosan solution and sodium tripolyphosphate solution, pH adjuster, and a 1.5 mol / L sodium hydroxide aqueous solution are provided. The pH adjuster is selected from a 1.5 mol / L hydrochloric acid aqueous solution and a 1.5 mol / L acetic acid aqueous solution. D2. Proportion: Based on 100 parts by mass of bromocyanidin in intermediate II, 65 parts by mass of chitosan, and 60 parts by mass of sodium tripolyphosphate, with the mass of sodium tripolyphosphate not exceeding the mass of chitosan; D3. Procedure: At 30 ℃, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 50 min. While maintaining the system pH at 6.0, sodium tripolyphosphate solution was added dropwise to the mixture over 100 min, and stirring continued for 150 min to form an ionic cross-linked shell. The system pH was monitored online using a pH meter, and a pH adjuster was added to maintain the system pH at 6.0. The dropping rate of the sodium tripolyphosphate solution was determined based on the total amount and dropping time. Stirring was mechanical at a speed of 1200 r / min. Subsequently, the system pH was adjusted to 7.5 using a 1.5 mol / L sodium hydroxide aqueous solution to obtain the microcapsule suspension. D4. Endpoint: The median particle size D50 of the obtained microcapsules was 8 µm, and the encapsulation efficiency of bromodiphenyl ether was 95%. The encapsulation efficiency was calculated using the following formula: the percentage of encapsulation efficiency equals m_total minus m_free divided by m_total and then multiplied by 100%, where m_total is the total mass of bromodiphenyl ether in the microcapsule suspension, and m_free is the mass of bromodiphenyl ether in the separated aqueous phase. Both m_total and m_free were determined by HPLC. D5. Post-treatment: Centrifugal washing was used to reduce the free inorganic salt content in the aqueous phase. The centrifugation conditions were 4000 g, centrifugation time was 25 min, and the number of repetitions was 4, until the conductivity of the supernatant was less than or equal to 5 mS / cm, and water was added to make up the solid content to 50 wt%. D6. Quality control: The pH of the microcapsule suspension is 7.5, the median particle size D50 is 8 µm, the encapsulation efficiency is 95%, and the solid content is 50 wt%.

[0088] In this embodiment, the median particle size D50 of the bromodiphenyl ether crystal particles is 0.7 µm, the thickness of the polydopamine shell is 13 nm, and the median particle size D50 of the core-shell sustained-release microcapsules is 8 µm, with a bromodiphenyl ether encapsulation rate of 95%. The content of bromodiphenyl ether in the bactericidal sustained-release formulation is 27.9 parts by weight, and the weight of the core-shell sustained-release microcapsules is not less than 65 parts by weight of bromodiphenyl ether, which is 27.9 parts by weight of bromodiphenyl ether. Bromodiphenyl ether is 1,2-dibromo-2,4-dicyanobutane.

[0089] The dispersion stabilizing component of this embodiment includes Tween 80, and also includes sodium lignosulfonate and sodium polyacrylate.

[0090] The preparation method of the bactericidal sustained-release formulation containing bromodiphenyl ether in this embodiment includes the following steps: S1. Provides intermediate II, chitosan solution, sodium tripolyphosphate solution, pH adjuster, and a 1.5 mol / L aqueous solution of sodium hydroxide, wherein intermediate II is a bromobenzoic acid crystalline particle dispersion with a polydopamine shell on its surface, and the pH adjuster is selected from a 1.5 mol / L aqueous solution of hydrochloric acid and a 1.5 mol / L aqueous solution of acetic acid; S2. Based on 100 parts of bromobenzonitrile in intermediate II, the mass of chitosan is 65 parts, the mass of sodium tripolyphosphate is 60 parts, and the mass ratio of chitosan to sodium tripolyphosphate is 1:0.92; S3. At 30 ℃, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 50 min; while maintaining the pH of the system at 6.0, sodium tripolyphosphate solution was added dropwise to the mixture over 100 min and stirring was continued for 150 min to form an ionic cross-linked shell; subsequently, the pH of the system was adjusted to 7.5 using a 1.5 mol / L sodium hydroxide aqueous solution to obtain a suspension of intermediate III; S4. The suspension of intermediate III is mixed evenly with the dispersion stabilizing component and the aqueous continuous phase to obtain a bactericidal sustained-release formulation containing bromodimethalin. The mixing is performed by mechanical stirring at a temperature of 30 °C for 50 min and a stirring speed of 1200 r / min.

[0091] In the preparation method, the degree of deacetylation of chitosan in step S3 is 90%.

[0092] The core-shell structure of intermediate II in this embodiment was characterized by transmission electron microscopy, and the surface elemental composition of intermediate II was characterized by X-ray photoelectron spectroscopy. The Zeta potentials of intermediates I, II, and III in this embodiment were determined by electrophoretic light scattering to characterize the surface charge changes during shell formation. The sustained-release performance of the bactericidal sustained-release formulation containing bromodifenac in this embodiment was characterized by a release test, which included measuring the amount of bromodifenac released in an aqueous medium at a specified temperature and obtaining a release curve.

[0093] Example 3 Features: This example employs a high microcapsule content and high solids content formulation design. The core-shell sustained-release microcapsule content is 65 parts by weight, the aqueous continuous phase is 13 parts by weight, the median particle size of bromodiphenyl ether crystals is 0.7 µm, the polydopamine shell thickness is 13 nm, the microcapsule particle size is 8 µm, the encapsulation efficiency is 95%, the content of the dispersion stabilizing component is 12 parts by weight, and the antifreeze plasticizing component is a mixture of glycerol and propylene glycol, consisting of 10 parts by weight. This example uses a ternary compound dispersion system of Tween 80, sodium lignosulfonate, and sodium polyacrylate. The grinding temperature is relatively high at 30°C, the reaction pH is 8.7, the degree of deacetylation of chitosan is 90%, the mass ratio of chitosan to sodium tripolyphosphate is close to 1:1, and the final suspension has a solids content of 50%. The formulation in this embodiment features high active ingredient content, strong sustained-release properties, and excellent storage stability. The thicker polydopamine shell and dense chitosan cross-linked network provide long-lasting sustained-release capability, making it suitable for applications requiring long-lasting effects, such as seasonal protection against fruit tree diseases, wood preservation and mildew prevention, long-lasting sterilization of soil, and continuous antibacterial properties in industrial circulating water systems. Example 4

[0094] This embodiment provides a bactericidal sustained-release formulation containing bromodiphenyl ether. Based on a total mass of 100 parts by weight of the bactericidal sustained-release formulation of this embodiment, the bactericidal sustained-release formulation containing bromodiphenyl ether comprises the following components: 80 parts by weight of core-shell sustained-release microcapsules (solid content 55 wt%), 1.5 parts by weight of dispersion stabilizing component, 2 parts by weight of antifreeze plasticizing component, and 16.5 parts by weight of aqueous continuous phase.

[0095] The core-shell sustained-release microcapsule of this embodiment includes: a core-shell particle, wherein the core of the core-shell particle is a bromoacrylonitrile crystal particle, and the shell is a polydopamine shell layer, which is formed by the oxidative polymerization of dopamine hydrochloride in an alkaline aqueous phase and deposition on the surface of the bromoacrylonitrile crystal particle; and an outer chitosan-sodium tripolyphosphate ion-crosslinked shell layer, which is formed by the crosslinking of chitosan and sodium tripolyphosphate ions, and the polydopamine shell layer and chitosan are bonded to each other through hydrogen bonding and electrostatic interaction.

[0096] The dispersion stabilizing component in this embodiment is 1.5 parts by weight, selected from sodium dodecyl sulfate (0.8 parts by weight) and Tween 80 (0.7 parts by weight). The antifreeze plasticizing component in this embodiment is 2 parts by weight of glycerol. The aqueous continuous phase in this embodiment includes water, which is 16.5 parts by weight.

[0097] In this embodiment, the bromocyanidin crystal particle dispersion in the core-shell particles is intermediate I. The preparation of intermediate I includes the following steps: A1. Raw materials: Bromochloronitrofurazone, water, and dispersion and stabilizing components are provided. The dispersion and stabilizing components contain two chemicals selected from sodium dodecyl sulfate and Tween 80. A2. Formulation: Based on 100 parts by mass of bromocyanidin, the total mass of the dispersing and stabilizing components is 1.2 parts, including 0.6 parts by mass of sodium dodecyl sulfate, 0.6 parts by mass of Tween 80, and 200 parts by mass of water, so that the solid content of the slurry before grinding is 33.2 wt%. A3. Procedure: Under air atmosphere and normal pressure, bromodiphenyl ether, water, and dispersion stabilizing components were premixed for 40 min under mechanical stirring at a speed of 800 r / min; zirconia grinding beads with a particle size of 0.15 mm were added as grinding media, and the mass ratio of zirconia grinding beads to the unground slurry was 5:1; wet grinding was performed at 25 ℃ using a stirred bead mill for 4 h at a stirring speed of 2000 r / min. A4. Endpoint: Grinding was stopped when the median particle size D50 of the resulting dispersion reached 0.72 µm. The median particle size D50 was determined using a laser particle size analyzer. A5. Post-treatment: Remove grinding beads through a sieve with a pore size of 300 µm, and perform vacuum degassing at a vacuum degree of 20 kPa absolute pressure for 15 min; A6. Quality control: The total solid content of intermediate I is 37 wt%, determined by drying to constant weight at 105 ℃. The pH is 6.5, determined by pH meter at 25 ℃. The median particle size D50 is 0.72 µm.

[0098] In this embodiment, the core-shell particle is intermediate II, and the preparation of intermediate II includes the following steps: B1. Raw materials: Provide intermediate I, dopamine hydrochloride, tris(hydroxymethyl)aminomethane, pH adjuster, and water. The pH adjuster is selected from a 1.0 mol / L aqueous solution of hydrochloric acid and a 1.0 mol / L aqueous solution of sodium hydroxide. B2. Proportioning: Based on 100 parts by mass of bromodiphenyl ether in intermediate I, the mass of dopamine hydrochloride is 8.5 parts; prepare an aqueous solution of tris(hydroxymethyl)aminomethane with a concentration of 30 mmol / L, and use 500 parts of the tris(hydroxymethyl)aminomethane aqueous solution; B3. Procedure: At 25 ℃, in air atmosphere, and under normal pressure, the pH of the tris(hydroxymethyl)aminomethane aqueous solution was adjusted to 8.4 using a pH adjuster; intermediate I was added and stirred, and the pH of the system was measured and adjusted to 8.4 using a pH adjuster after the addition of intermediate I; then dopamine hydrochloride was added and stirred continuously for 4 h, allowing dopamine hydrochloride to oxidize and polymerize under alkaline conditions and deposit on the surface of bromobenzonitrile crystal particles to form a polydopamine shell. The stirring was mechanical, with a stirring speed of 900 r / min, and the pH of the system was maintained at 8.4 during the reaction. B4. Endpoint: The thickness of the polydopamine shell in intermediate II was 12 nm, determined by transmission electron microscopy, and the mass of polydopamine was 8.5 wt% of the mass of bromodiphenyl ether. B5. Post-treatment: The free components in the aqueous phase were removed by centrifugation washing at 10,000 g for 15 min, repeated 3 times. Then, water was added to make up the solids and the solid content was adjusted to 37 wt%. B6. Quality control: The pH of intermediate II is 8.0 and the free dopamine residue is 0.38 wt%. The free dopamine residue was determined by HPLC and accounted for 0.38 wt% of the total solid mass of intermediate II.

[0099] The precursor solution required for the outer chitosan crosslinking network in this embodiment includes a chitosan solution and a sodium tripolyphosphate solution. The preparation of the chitosan solution and the sodium tripolyphosphate solution includes the following steps: C1. Raw materials: Chitosan, acetic acid, water, sodium tripolyphosphate, and a 1.0 mol / L aqueous solution of sodium hydroxide are provided; C2. Proportioning: Based on 1000 parts by weight of water, acetic acid comprises 18 parts by weight, and chitosan comprises 17 parts by weight; based on 1000 parts by weight of water, sodium tripolyphosphate comprises 7 parts by weight. C3. Procedure: At 30 ℃, in an air atmosphere and under normal pressure, acetic acid was added to water and stirred. Chitosan was then added and stirred for 8 h to obtain a chitosan solution. The pH of the chitosan solution was adjusted to 4.5. The chitosan solution was prepared by mechanical stirring at a speed of 900 r / min. Sodium tripolyphosphate was dissolved in water and the pH was adjusted to 9.5 using sodium hydroxide aqueous solution to obtain a sodium tripolyphosphate solution. C4. Endpoint: No visible undissolved matter was found in the chitosan solution, and no visible precipitate was found in the sodium tripolyphosphate solution; C5. Post-treatment: The chitosan solution and sodium tripolyphosphate solution were degassed and filtered separately. The degassed solution was vacuum degassed at an absolute pressure of 20 kPa for 15 min, and the filter pore size was 100 µm. C6. Quality control: The solid content of chitosan solution was 1.66 wt%, and the solid content of sodium tripolyphosphate solution was 0.69 wt%. The solid content was determined by drying at 105 ℃ to constant weight.

[0100] The core-shell sustained-release microcapsule in this embodiment is intermediate III. The preparation of intermediate III includes the following steps: D1. Raw materials: The above-prepared intermediate II, the above-prepared chitosan solution and sodium tripolyphosphate solution, pH adjuster, and a 1.0 mol / L sodium hydroxide aqueous solution are provided. The pH adjuster is selected from a 1.0 mol / L hydrochloric acid aqueous solution. D2. Proportion: Based on 100 parts by mass of bromocyanidin in intermediate II, 70 parts by mass of chitosan, and 65 parts by mass of sodium tripolyphosphate, with the mass of sodium tripolyphosphate not exceeding the mass of chitosan; D3. Procedure: At 25 °C, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 40 min. While maintaining the system pH at 5.5, sodium tripolyphosphate solution was added dropwise to the mixture over 80 min, and stirring continued for 120 min to form an ionic cross-linked shell. The system pH was monitored online using a pH meter, and a pH adjuster was added to maintain the system pH at 5.5. The dropping rate of the sodium tripolyphosphate solution was determined based on the total amount and dropping time. Stirring was mechanical at a speed of 900 r / min. Subsequently, the system pH was adjusted to 7.2 using a 1.0 mol / L sodium hydroxide aqueous solution to obtain the microcapsule suspension. D4. Endpoint: The median particle size D50 of the obtained microcapsules was 8.5 µm, and the encapsulation efficiency of bromodifenac was 96%. The encapsulation efficiency was calculated using the following formula: the percentage of encapsulation efficiency equals m_total minus m_free divided by m_total and then multiplied by 100%, where m_total is the total mass of bromodifenac in the microcapsule suspension, and m_free is the mass of bromodifenac in the separated aqueous phase. Both m_total and m_free were determined by HPLC. D5. Post-treatment: Centrifugation was used to reduce the free inorganic salt content in the aqueous phase. The centrifugation conditions were 2500 g and 15 min, repeated 3 times, until the conductivity of the supernatant was less than or equal to 5 mS / cm, and then water was added to make up the solid content to 55 wt%. D6. Quality control: The pH of the microcapsule suspension was 7.2, the median particle size D50 was 8.5 µm, the encapsulation efficiency was 96%, and the solid content was 55 wt%.

[0101] In this embodiment, the median particle size D50 of the bromodiphenyl ether crystal particles is 0.72 µm, the thickness of the polydopamine shell is 12 nm, and the median particle size D50 of the core-shell sustained-release microcapsules is 8.5 µm, with a bromodiphenyl ether encapsulation rate of 96%. The content of bromodiphenyl ether in the bactericidal sustained-release formulation is 32.9 parts by weight, and the weight of the core-shell sustained-release microcapsules is not less than 80 parts by weight of bromodiphenyl ether, which is 32.9 parts by weight of bromodiphenyl ether. Bromodiphenyl ether is 1,2-dibromo-2,4-dicyanobutane.

[0102] The dispersion stabilizing components in this embodiment include sodium dodecyl sulfate and Tween 80.

[0103] The preparation method of the bactericidal sustained-release formulation containing bromodiphenyl ether in this embodiment includes the following steps: S1. Provides intermediate II, chitosan solution, sodium tripolyphosphate solution, pH adjuster, and a 1.0 mol / L aqueous solution of sodium hydroxide, wherein intermediate II is a bromocyanide crystal particle dispersion with a polydopamine shell on the surface, and the pH adjuster is selected from a 1.0 mol / L aqueous solution of hydrochloric acid; S2. Based on 100 parts of bromobenzonitrile in intermediate II, the mass of chitosan is 70 parts, the mass of sodium tripolyphosphate is 65 parts, and the mass ratio of chitosan to sodium tripolyphosphate is 1:0.93; S3. At 25 °C, in air atmosphere, and under normal pressure, intermediate II was added to the chitosan solution and stirred for 40 min; while maintaining the pH of the system at 5.5, sodium tripolyphosphate solution was added dropwise to the mixture over 80 min and stirring was continued for 120 min to form an ionic cross-linked shell; subsequently, the pH of the system was adjusted to 7.2 using a 1.0 mol / L sodium hydroxide aqueous solution to obtain a suspension of intermediate III; S4. The suspension of intermediate III was mixed evenly with the dispersion stabilizing component and the aqueous continuous phase to obtain a bactericidal sustained-release formulation containing bromodiphenyl ether. The mixing was carried out by mechanical stirring at a temperature of 25 °C for 35 min and a stirring speed of 900 r / min.

[0104] In the preparation method, the degree of deacetylation of chitosan in step S3 is 90%.

[0105] The core-shell structure of intermediate II in this embodiment was characterized by transmission electron microscopy, and the surface elemental composition of intermediate II was characterized by X-ray photoelectron spectroscopy. The Zeta potentials of intermediates I, II, and III in this embodiment were determined by electrophoretic light scattering to characterize the surface charge changes during shell formation. The sustained-release performance of the bactericidal sustained-release formulation containing bromodifenac in this embodiment was characterized by a release test, which included measuring the amount of bromodifenac released in an aqueous medium at a specified temperature and obtaining a release curve.

[0106] Features of Example 4: This example employs a design with a high microcapsule content and a low dispersion stabilizing component content close to the formulation limit. The core-shell sustained-release microcapsule content is 80 parts by weight, the dispersion stabilizing component content is 1.5 parts by weight, the aqueous continuous phase is 16.5 parts by weight, and the antifreeze plasticizing component is 2 parts by weight of glycerol. In this example, the median particle size of bromoacrylonitrile crystals is 0.72 µm, the solid content of the slurry before grinding is 37%, the zirconium dioxide grinding beads have a small particle size of 0.15 mm, the polydopamine shell thickness is 12 nm, the amount of dopamine hydrochloride is 8.5 parts, the microcapsule particle size is 8.5 µm, the encapsulation efficiency is 96%, the mass ratio of chitosan to sodium tripolyphosphate is close to 1:1, and the final suspension has a solid content of 55%. This embodiment uses the minimum compounding amount of sodium dodecyl sulfate and Tween 80, and the degree of deacetylation of chitosan is 90%, which reflects the extremely high loading of active ingredients and the ultra-long sustained-release capability. It is suitable for professional application scenarios with extremely high requirements for the concentration of active ingredients and the duration of effect, such as long-term protection against diseases of high-value economic crops, seed coating treatment, disinfection of nursery substrates, anti-mildew and antibacterial treatment of building materials, and sterilization treatment of oilfield water injection systems.

[0107] Comparative Example 1: It is basically the same as Example 1, except that the content of core-shell sustained-release microcapsules is 3 parts by weight, the content of aqueous continuous phase is 85 parts by weight, and the amount of other components and preparation conditions remain unchanged.

[0108] Comparative Example 2: Essentially the same as Example 1, except that a high-solids formulation system was used for comparison: the core-shell sustained-release microcapsule suspension used Intermediate III (30 wt% solids) obtained in Example 1. Based on a total mass of 95 parts by weight for components excluding the aqueous continuous phase (core-shell sustained-release microcapsule suspension, dispersion stabilizing component, and antifreeze plasticizing component), the core-shell sustained-release microcapsule suspension comprised 83 parts by weight, the dispersion stabilizing component comprised 7 parts by weight, and the antifreeze plasticizing component comprised 5 parts by weight; subsequently, the aqueous continuous phase was added to bring the total to 100 parts by weight (i.e., 5 parts by weight of the aqueous continuous phase); other preparation conditions remained unchanged.

[0109] Comparative Example 3: It is basically the same as Example 1, except that dopamine hydrochloride is not added in the preparation of intermediate II, and a polydopamine shell is not formed on the surface of the bromodiphenyl ether crystal particles. Intermediate I is directly used for subsequent chitosan-sodium tripolyphosphate cross-linking shell coating. The amount of other components and preparation conditions remain unchanged.

[0110] Comparative Example 4: It is basically the same as Example 1, except that sodium tripolyphosphate solution is not added in the preparation of intermediate III. Only chitosan solution is used to physically adsorb and coat intermediate II without forming an ionic cross-linked shell. The amount of other components and preparation conditions remain unchanged.

[0111] Comparative Example 5: It is basically the same as Example 1, except that the median particle size D50 of the bromoacrylonitrile crystal particles is 0.15 µm, which is obtained by extending the wet grinding time to 8 hours. The amount of other components and the preparation conditions remain unchanged.

[0112] Comparative Example 6: It is basically the same as Example 1, except that the median particle size D50 of the bromoacrylonitrile crystal particles is 1.2 µm, which is obtained by shortening the wet grinding time to 0.5 hours. The amount of other components and preparation conditions remain unchanged.

[0113] Comparative Example 7: Basically the same as Example 1, except that only 2 parts by weight of sodium dodecyl sulfate was used as the dispersion stabilizing component, and sodium lignosulfonate was not used. The amounts of other components and preparation conditions remained unchanged.

[0114] Comparative Example 8: It is basically the same as Example 1, except that the antifreeze and plasticizing component glycerol is not added, the aqueous continuous phase is adjusted to 63 parts by weight, and the amounts of other components and preparation conditions remain unchanged.

[0115] Performance testing: Test Subject: Bromhexanil-containing bactericidal sustained-release formulations prepared in the examples and comparative examples. Test Objective: To evaluate the cumulative release rate and sustained-release performance of bromhexanil. Test Principle: Bromhexanil is gradually released from microcapsules in a constant-temperature aqueous medium. The cumulative release rate is calculated by periodically sampling and determining the concentration of bromhexanil in the aqueous phase. Experimental Method: 10 mL of a 5 wt% solid content formulation suspension was placed in 100 mL of deionized water and magnetically stirred at 25±1 ℃ (300 r / min). Samples of 3 mL were taken at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and an equal volume of fresh medium was added. After centrifugation, the supernatant was used to determine the bromhexanil concentration using high-performance liquid chromatography (HPLC, mobile phase: methanol-water 70:30 v / v, detection wavelength: 254 nm, C18 column), and the cumulative release rate was calculated. Key parameters: temperature 25±1 ℃, stirring rate 300 r / min, initial solid content 5 wt%, sampling time points 12. Data processing: the cumulative release percentage is equal to the sum of the release amounts at each time point divided by the total loading amount multiplied by 100%. Release curves are plotted and a release kinetic model (such as the Higuchi model or the Korsmeyer-Peppas model) is fitted. The release rate constant and half-release time t50 are calculated.

[0116] Test Subject: Core-shell sustained-release microcapsules (intermediate III) prepared in the examples and comparative examples. Test Objective: To determine the encapsulation efficiency of bromodifenacin and evaluate the integrity and encapsulation effect of the microcapsule shell. Test Principle: The microcapsules and aqueous phase were separated by centrifugation, and the total bromodifenacin and free bromodifenacin were determined separately to calculate the encapsulation efficiency. Experimental Method: 2 g of the microcapsule suspension (solid content approximately 30 wt%) was placed in a centrifuge tube, diluted with deionized water to 20 mL, and centrifuged at 25 ℃ and 5000 g for 15 min. 5 mL of the supernatant was collected, and the concentration of free bromodifenacin (mfree) was determined by HPLC (mobile phase methanol-water 70:30 v / v, detection wavelength 254 nm, C18 column). Separately, 0.2 g of the original suspension was placed in a 50 mL volumetric flask, methanol was added, and the mixture was ultrasonically disrupted for 30 min before being brought to volume. The mixture was filtered through a 0.22 µm filter membrane, and the concentration of total bromodifenacin (mtotal) was determined by HPLC. Key parameters: Centrifugation conditions: 5000 g, 15 min; ultrasonic disruption: 30 min; HPLC detection wavelength: 254 nm. Data processing: Encapsulation percentage equals (mtotal - mfree) / mtotal × 100%. Each sample was measured in triplicate, and the average value was taken. Standard deviation <2%.

[0117] Test Subjects: Bromhizobium crystalline particle dispersions (Intermediate I), core-shell particle dispersions (Intermediate II), and core-shell sustained-release microcapsule suspensions (Intermediate III and final formulation) prepared in the examples and comparative examples. Test Objective: To determine the particle size distribution and median particle size D50, and to evaluate the particle size variation and dispersion uniformity at each preparation stage. Test Principle: Laser diffraction method; particle size distribution is calculated by measuring the scattering angle and intensity of the laser light by the particles. Experimental Method: The sample was diluted to a suitable concentration (10-20% opacity) and added to the dispersion cell of a laser particle size analyzer (e.g., Malvern Mastersizer 3000). Deionized water was used as the dispersion medium. After ultrasonic dispersion for 2 min, the sample was measured at 25 °C. The refractive index was set to 1.55 (bromhizobium) / 1.45 (water), and the measurement range was 0.01-3500 µm. Each sample was measured three times. Key parameters: shading 10-20%, ultrasonic time 2 min, test temperature 25 ℃, refractive index 1.55 / 1.45. Data processing: Automatically outputs median particle size D50, D10, D90 and particle size distribution curves, and calculates the span Span=(D90-D10) / D50 to evaluate the distribution width.

[0118] Test Subjects: Dispersion systems of intermediates I, II, and III at each preparation stage. Test Objective: To determine the Zeta potential, characterizing the changes in particle surface charge and dispersion stability during shell formation. Test Principle: Electrophoretic light scattering method. Under an applied electric field, charged particles undergo electrophoretic motion, and the Zeta potential is calculated by measuring the electrophoretic mobility. Experimental Method: An appropriate amount of sample was diluted to approximately 0.1 wt% solids and added to the folded capillary electrophoresis pool of a Zeta potential analyzer (e.g., Malvern Zetasizer NanoZS). Measurements were taken at 25 ℃ with no pH adjustment (maintaining the original system pH). Each sample was automatically measured three times, with 11 sub-cycles per measurement. Key Parameters: Dilution solids content 0.1 wt%, test temperature 25 ℃, equilibration time 120 s, number of measurements 3 × 11. Data Processing: The average and standard deviation of the Zeta potential (mV) were automatically output. Zeta potential change curves for intermediates I → II → III were plotted to evaluate the effect of shell coating on surface charge.

[0119] Test subject: Bromodiclofenac-containing bactericidal sustained-release formulations prepared in the examples and comparative examples. Test purpose: To evaluate the stability of the formulations under different storage conditions, including appearance, viscosity, pH, particle size change and active ingredient retention rate. Test principle: The long-term storage process is simulated by accelerated aging test, and key quality indicators are tested periodically. Experimental method: The formulations are dispensed into 100mL polyethylene bottles and sealed. They are stored in the dark at three temperatures of (0±2)℃, (25±2)℃ and (54±2)℃ respectively. Samples are taken at 0, 7, 14 and 28 days for testing: (1) Appearance: Visual inspection for layering, precipitation and clumping; (2) Viscosity: NDJ-5S rotational viscometer, rotation speed 60 r / min, 25 ℃; (3) pH: pH meter, 25 ℃; (4) Median particle size D50: laser particle size analyzer; (5) Active ingredient content: Bromodiclofenac content is determined by HPLC. Key parameters: Storage temperature 0 / 25 / 54 ℃; sampling time points 0, 7, 14, and 28 days; 3 parallel samples. Data processing: Calculate the rate of change of each indicator relative to the initial value; effective ingredient retention rate = (Ct / C0) × 100%.

[0120] Test objects: Intermediate II (bromodiphenyl ether crystal particles with a polydopamine shell) and Intermediate III (core-shell sustained-release microcapsules). Test objective: To characterize the surface elemental composition and chemical state using X-ray photoelectron spectroscopy (XPS), and to verify the formation of the polydopamine shell and the chitosan-sodium tripolyphosphate cross-linked shell. Test principle: X-rays excite inner-shell electrons of the sample surface atoms to generate photoelectrons. The elemental type and chemical state are identified by measuring the photoelectron binding energy. Experimental method: After freeze-drying, the samples were pressed into pellets and fixed on the sample stage. The full-spectrum and high-resolution spectra of C 1s, N 1s, O 1s, and P 2p were measured using an XPS photoelectron spectrometer (e.g., Thermo Fisher ESCALAB250Xi, Al Kα source 1486.6 eV) under ultra-high vacuum (<10^-7 Pa). The charge effect was corrected with C 1s = 284.8 eV. The scan range was 0-1200 eV, and the energy step was 0.1 eV. Key parameters: Excitation source Al Kα 1486.6 eV, vacuum degree <10^-7 Pa, energy resolution <0.5 eV. Data processing: High-resolution spectra were fitted using XPS Peak software to calculate the atomic percentages of surface elements and N / C and P / N ratios, verifying the shell chemical composition.

[0121] Figure 1 For FTIR (full spectrum 4000–400 cm⁻¹) -1 The infrared spectrum overlay was obtained, and the characterization method was Fourier transform infrared spectroscopy. The comparison samples were Example 1, Comparative Example 2, chitosan, and polydopamine. The fixed parameters were a wavenumber range of 4000 cm⁻¹. -1 Up to 400 cm-1 Transmittance was plotted on the vertical axis, using the same coordinate scale and data processing method, with the sample category as the variable parameter. Example 1 exhibited composite characteristics in the characteristic absorption ranges of chitosan and polydopamine, and compared to Comparative Example 2, showed a more significant enhancement in chitosan-related absorption characteristics (including changes in the chitosan-inherent amide nitrogen / residual acetyl-related range). This can be used to corroborate that chitosan-related components are more fully covered / bound on the sample surface, thus supporting the correctness of the scheme.

[0122] Figure 2 For FTIR (magnification region 1800–1400 cm⁻¹) -1 The infrared spectra of the samples were magnified and compared. The characterization method was Fourier transform infrared spectroscopy. The comparison samples were Example 1, Comparative Example 2, chitosan, and polydopamine. The fixed parameters were a wavenumber range of 1800 cm⁻¹. -1 Up to 1400 cm -1 Transmittance is displayed on the vertical axis, using the same magnification window and normalization method, with the variation parameter representing the sample category. In Example 1, the peak shape and intensity in the amide-related absorption region are more prominent than in Comparative Example 2, and the peaks show enhanced consistency with the chitosan characteristic region. This indicates a more pronounced signal response from the nitrogen-containing functional groups associated with chitosan and more complete interfacial binding, demonstrating that the structural design of Example 1 has a verifiable spectroscopic response in the key functional group region, thus supporting the correctness of the scheme.

[0123] Figure 3 The XPS N 1s spectra are compared between Example 1 and Comparative Example 2. The characterization method was X-ray photoelectron spectroscopy. The comparison samples were Example 1 and Comparative Example 2. Fixed parameters included the binding energy range of 394 eV to 406 eV, the same peak decomposition model, the same background processing method, and the same coordinate scale for displaying the original and fitted total spectra. The variable parameter was the sample category. In Example 1, the N 1s spectrum showed a relatively higher proportion of amide nitrogen components, and the fitted total spectrum matched the original spectrum well. This indicates a significant increase in the nitrogen proportion in the amide-containing environment and self-consistent chemical state distribution. This suggests that Example 1 had a higher proportion of nitrogen chemical environment signals related to the inherent amide nitrogen / residual acetyl groups on the chitosan surface, which can be used to corroborate more complete chitosan-related shell coverage, thus supporting the correctness of the scheme.

[0124] Figure 4 is a comparative bar chart of nitrogen component proportions based on XPS N 1s peak decomposition results. The characterization method is the statistical analysis of component proportions based on XPS N 1s peak decomposition results. The comparison samples are Example 1 and Comparative Example 2. The fixed parameters are the same component definition and the same peak area normalization calculation method. The vertical axis represents the percentage of amide nitrogen, and the variable parameter is the sample category. The amide nitrogen proportion of Example 1 is 42.5%, while that of Comparative Example 2 is 5.2%. This shows that Example 1 significantly improves the amide nitrogen proportion, proving that the surface chemical modification of Example 1 is more effective and consistent with the conclusion of the spectrum fitting, thus supporting the correctness of the scheme.

[0125] Figure 5 The XPS depth profile waterfall (Example 1) was characterized using X-ray photoelectron spectroscopy depth profiling. The sample was from Example 1. Fixed parameters included a binding energy range of 394 eV to 406 eV, the same spectral processing method, and the display of signals at different depths in a staggered manner. Variations were achieved using sputtering time from 0 s to 30000 s. The overall signal gradually decreased with increasing sputtering time while maintaining consistent spectral shape, indicating that nitrogen-containing chemical states were mainly enriched at the surface and gradually weakened inwards. Furthermore, no abrupt changes in chemical state types were observed, demonstrating that Example 1 formed an effective functional surface layer with a stable structure, supporting the correctness of the proposed scheme.

[0126] Figure 6 This is a depth intensity distribution heatmap of XPS depth profiling (Example 1). The characterization method is two-dimensional visualization of the X-ray photoelectron spectroscopy depth profiling results. The sample is Example 1. Fixed parameters are: horizontal axis binding energy range of 394 eV to 406 eV, vertical axis sputtering time range of 0 s to 30000 s, and the same intensity mapping rule. The varying parameters are sputtering time and binding energy position. The heatmap shows that the intensity is higher in the surface region and continuously decreases with increasing depth. The main intensity distribution band is consistent with the N1s characteristic region, proving that the functional nitrogen-containing signal has a clear depth gradient and repeatable energy distribution characteristics, thus supporting the correctness of the scheme.

[0127] Figure 7 This is a superimposed HPLC-UV chromatogram (Example 1 vs. Comparative Example 7), characterized by HPLC-UV detection. The comparison samples were Example 1 and Comparative Example 7. Fixed parameters included retention time range of 0 min to 30 min, UV absorbance as the detection signal, the same chromatographic display scale, and the same processing method. The variable parameter was the sample category. Example 1 showed a more concentrated main peak and lower impurity peak signals, while Comparative Example 7 exhibited more pronounced impurity peak responses near and after the main peak. This indicates that Example 1 had a higher proportion of the main component and fewer degradation or byproducts, demonstrating that the method can improve sample purity and suppress impurity formation, thus supporting the correctness of the method.

[0128] As can be seen from the performance of the examples and comparative examples in Table 1, Examples 1-4 achieved excellent sustained-release performance and stability through the double-shell structure design of core-shell sustained-release microcapsules. Among them, the half-release times (t50) of Examples 3 and 4 reached 98.5 hours and 105.8 hours, respectively, which were significantly longer than those of the comparative examples. The cumulative release rate after 24 hours was controlled at a low level of 16-18%, and the cumulative release rate after 96 hours was 61-65%, exhibiting typical sustained-release characteristics. The encapsulation efficiency of the examples was generally higher than that of the comparative examples. The encapsulation efficiency of Examples 3 and 4 reached over 95%, which is attributed to the polymerization... The synergistic effect of the dopamine shell and the chitosan-sodium tripolyphosphate cross-linked shell; Comparative Example 1, due to its low microcapsule content (3 parts by weight), showed a significant decrease in sustained-release effect, with a 24-hour release rate as high as 82.6%, a half-release time of only 8.2 hours, and an encapsulation efficiency of 72.3%; Comparative Examples 3 and 4, lacking either a polydopamine shell or an ionic cross-linked shell, respectively, exhibited significantly deteriorated sustained-release performance, with half-release times of 15.6 and 18.3 hours, and encapsulation efficiencies of 76.8% and 68.2%, respectively, demonstrating the importance of the dual-shell structure for sustained-release performance and encapsulation stability; Examples 54 After 28 days of accelerated aging at ℃, the retention rate of active ingredients was higher than 94%, with Example 4 reaching 98.3%, while the retention rate of Comparative Examples 1-7 was 78-89%, indicating that the double-shell structure significantly improved storage stability. Zeta potential data showed that the absolute values ​​of Examples 3 and 4 were higher than -32 mV, and the high surface charge density was beneficial to dispersion stability. However, the absolute value of the Zeta potential of Comparative Example 3 dropped to -18.5 mV due to the lack of a polydopamine shell, resulting in decreased dispersion stability.

[0129] Table 1 Performance Comparison of Examples and Comparative Examples

[0130] 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 it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A bactericidal sustained-release formulation containing bromodiphenyl ether, characterized in that, Based on 100 parts by weight of the total mass of the bactericidal sustained-release formulation, the bactericidal sustained-release formulation containing bromodiphenyl ether comprises the following components: (a) A core-shell sustained-release microcapsule suspension, comprising 5-90 parts by weight, wherein the solid content of the core-shell sustained-release microcapsule suspension is 5-60 wt%, and wherein the core-shell sustained-release microcapsule suspension comprises: (a1) Core-shell particles, wherein the core of the core-shell particles is a bromoacrylonitrile crystal particle and the shell is a polydopamine shell layer, wherein the polydopamine shell layer is formed by the oxidative polymerization of dopamine hydrochloride in an alkaline aqueous phase and deposition on the surface of the bromoacrylonitrile crystal particle; (a2) The outer chitosan-sodium tripolyphosphate ion-crosslinked shell is formed by crosslinking chitosan with sodium tripolyphosphate ions, and the polydopamine shell and the chitosan are bonded to each other through at least one of hydrogen bonding and electrostatic interaction. (b) A dispersion stabilizing component, in the form of 0.1-15 parts by weight, wherein the dispersion stabilizing component is selected from two or more of sodium dodecyl sulfate, Tween 80, sodium lignosulfonate, sodium polyacrylate, and sodium carboxymethyl cellulose; (c) an aqueous continuous phase, wherein the aqueous continuous phase comprises water; Among them, the sum of (a), (b), and (c) is 100 parts by weight; The core-shell sustained-release microcapsules of the bactericidal sustained-release formulation are obtained from the following intermediates, which include intermediate I, intermediate II and intermediate III. Intermediate I is the dispersion of bromodimethicone crystal particles, intermediate II is the dispersion obtained after forming the polydopamine shell on the surface of the bromodimethicone crystal particles of intermediate I, and intermediate III is the core-shell sustained-release microcapsule suspension obtained after forming the chitosan-sodium tripolyphosphate ion crosslinked shell on the outer layer of intermediate II.

2. The bactericidal sustained-release formulation containing bromodiphenyl ether as described in claim 1, characterized in that, The bromochloronitrile crystal particle dispersion in the core-shell particles is intermediate I, and the preparation of intermediate I includes the following steps: A1. Raw materials: bromobenzonitrile, water and a dispersion stabilizing component are provided, wherein the dispersion stabilizing component comprises at least two chemicals selected from sodium dodecyl sulfate, Tween 80, sodium lignosulfonate, sodium polyacrylate, and sodium carboxymethyl cellulose; A2. Formulation: Based on 100 parts by mass of bromodiphenyl ether, the total mass of the dispersing and stabilizing components is 0.5-10 parts, and the mass of water is 165-900 parts, so that the solid content of the slurry before grinding is 10-40 wt%. A3. Steps: Under air atmosphere and normal pressure, premix the bromodiphenyl ether, the water, and the dispersion stabilizing component under mechanical stirring for 10-60 min; add zirconium dioxide grinding beads as grinding media, the zirconium dioxide grinding beads having a particle size of 0.1-0.5 mm; perform wet grinding at 10-35 ℃ for 0.5-6 h; A4. End point: Stop grinding when the median particle size D50 of the resulting dispersion reaches 0.2-0.8 µm; A5. Post-processing: Remove grinding beads and degas using sieving or separation equipment; A6. Quality control: The total solids content of intermediate I is 10-40 wt%, the pH is 5.0-8.0, and the median particle size D50 is 0.2-0.8 µm.

3. The bactericidal sustained-release formulation containing bromodiphenyl ether as described in claim 1, characterized in that, The core-shell particle is intermediate II, and the preparation of intermediate II includes the following steps: B1. Raw materials: Provide intermediate I, dopamine hydrochloride, tris(hydroxymethyl)aminomethane, pH adjuster and water, wherein the pH adjuster is selected from one or two of the following: hydrochloric acid aqueous solution with a concentration of 0.1-2.0 mol / L and sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L; B2. Proportion: Based on 100 parts of bromodiphenyl ether in intermediate I, the mass of dopamine hydrochloride is 0.2-10 parts; The tris(hydroxymethyl)aminomethane is prepared into an aqueous solution with a concentration of 10-50 mmol / L, and the amount of the tris(hydroxymethyl)aminomethane aqueous solution used is 300-1000 parts; B3. Step: At 20-30 ℃, in air atmosphere, and under normal pressure, adjust the pH of the tris(hydroxymethyl)aminomethane aqueous solution to 8.0-8.8 using the pH adjuster; add the intermediate I and stir; then add the dopamine hydrochloride and continue stirring for 1-6 h, so that the dopamine hydrochloride is oxidized and polymerized under alkaline conditions and deposited on the surface of the bromoacrylonitrile crystal particles to form the polydopamine shell layer; B4. Endpoint: The thickness of the polydopamine shell in intermediate II is 3-15 nm, and the mass of the polydopamine is 0.2-10 wt% of the mass of the bromobenzonitrile. B5. Post-treatment: Remove free components from the aqueous phase by washing, centrifugation or membrane separation, then replenish with water and adjust the solid content; B6. Quality control: The pH of intermediate II is 7.5-8.5, the solid content of intermediate II is 10-40 wt%, and the free dopamine residue is 0.01-0.5 wt%.

4. The bactericidal sustained-release formulation containing bromodiphenyl ether as described in claim 1, characterized in that, The precursor solution required for the outer chitosan crosslinking network includes a chitosan solution and a sodium tripolyphosphate solution. The preparation of the chitosan solution and the sodium tripolyphosphate solution includes the following steps: C1. Raw materials: Chitosan, acetic acid, water, sodium tripolyphosphate, and an aqueous solution of sodium hydroxide with a concentration of 0.1-2.0 mol / L are provided; C2. Proportioning: Based on 1000 parts by weight of water, the acetic acid comprises 5-30 parts by weight, and the chitosan comprises 2-20 parts by weight; based on 1000 parts by weight of water, the sodium tripolyphosphate comprises 0.5-10 parts by weight. C3. Steps: At 20-40 ℃, in an air atmosphere and under normal pressure, add the acetic acid to water and stir, add the chitosan and stir for 1-12 h to obtain a chitosan solution, and adjust the pH of the chitosan solution to 3.5-5.5; dissolve the sodium tripolyphosphate in water and adjust the pH to 8.0-10.5 using the sodium hydroxide aqueous solution to obtain a sodium tripolyphosphate solution; C4. Endpoint: The chitosan solution contained no visible undissolved matter, and the sodium tripolyphosphate solution contained no visible precipitate; C5. Post-treatment: The chitosan solution and the sodium tripolyphosphate solution are degassed and filtered respectively; C6. Quality control: The chitosan solution has a solid content of 0.2-2.0 wt%, and the sodium tripolyphosphate solution has a solid content of 0.05-1.0 wt%.

5. The bactericidal sustained-release formulation containing bromodiphenyl ether as described in claim 1, characterized in that, The core-shell sustained-release microcapsule is intermediate III, and the preparation of intermediate III includes the following steps: D1. Raw materials: Provide intermediate II, chitosan solution and sodium tripolyphosphate solution, pH adjuster and sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L, wherein the pH adjuster is selected from one or two of hydrochloric acid aqueous solution with a concentration of 0.1-2.0 mol / L and acetic acid aqueous solution with a concentration of 0.1-2.0 mol / L; D2. Proportion: Based on 100 parts of bromodiphenyl ether in intermediate II, the mass of chitosan is 5-80 parts, the mass of sodium tripolyphosphate is 0.5-80 parts, and the mass ratio of chitosan to sodium tripolyphosphate is 1:0.05-1:

1. D3. Steps: At 15-35 ℃, in air atmosphere, and under normal pressure, add intermediate II to the chitosan solution and stir for 10-60 min; while maintaining the pH of the system at 4.0-6.5, add the sodium tripolyphosphate solution dropwise to the mixture over 10-120 min and continue stirring for 30-180 min to form an ionic cross-linked shell; then adjust the pH of the system to 6.0-8.0 using the 0.1-2.0 mol / L sodium hydroxide aqueous solution to obtain a microcapsule suspension; D4. Endpoint: The median particle size D50 of the obtained microcapsules was 1-10 µm, and the encapsulation efficiency of bromodiphenyl ether was 80-99%. D5. Post-treatment: Washing or membrane separation is used to reduce the free inorganic salt content in the aqueous phase, and water is used to make up the solid content to 5-60 wt%. D6. Quality control: The pH of the microcapsule suspension is 6.0-8.0, the median particle size D50 is 1-10 µm, and the encapsulation efficiency is 80-99%.

6. The bactericidal sustained-release formulation containing bromodiphenyl ether as described in claim 1, characterized in that, The median particle size D50 of the bromodiphenyl ether crystal particles is 0.2-0.8 µm, the thickness of the polydopamine shell is 3-15 nm, and the median particle size D50 of the core-shell sustained-release microcapsules is 1-10 µm, with a bromodiphenyl ether encapsulation efficiency of 80-99% for the core-shell sustained-release microcapsules; The bactericidal sustained-release formulation contains 1-40 parts by weight of bromodiphenyl ether, and the weight of the core-shell sustained-release microcapsules is not less than the weight of the bromodiphenyl ether, wherein the bromodiphenyl ether is 1,2-dibromo-2,4-dicyanobutane.

7. The bactericidal sustained-release formulation containing bromodiphenyl ether as described in claim 1, characterized in that, The dispersion stabilizing component comprises at least one of sodium dodecyl sulfate and Tween 80, and at least one of sodium lignosulfonate, sodium polyacrylate, and sodium carboxymethyl cellulose.

8. The bactericidal sustained-release formulation containing bromodiphenyl ether as described in claim 1, characterized in that, The aqueous continuous phase further includes an antifreeze and plasticizing component, which is selected from one or both of glycerol and propylene glycol, and is present in a quantity of 0.5-15 parts by weight.

9. A method for preparing a bactericidal sustained-release formulation containing bromodiphenyl ether as described in any one of claims 1-8, characterized in that, Includes the following steps: S1. Provides intermediate II, chitosan solution, sodium tripolyphosphate solution, pH adjuster, and sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L, wherein intermediate II is a bromocyanide crystal particle dispersion with a polydopamine shell on the surface, and the pH adjuster is selected from one or two of hydrochloric acid aqueous solution with a concentration of 0.1-2.0 mol / L and acetic acid aqueous solution with a concentration of 0.1-2.0 mol / L; S2. Based on 100 parts of bromodiphenyl ether in intermediate II, the mass of chitosan is 5-80 parts, the mass of sodium tripolyphosphate is 0.5-80 parts, and the mass ratio of chitosan to sodium tripolyphosphate is 1:0.05-1:

1. S3. At 15-35 °C, in air atmosphere, and under normal pressure, intermediate II is added to the chitosan solution and stirred for 10-60 min; while maintaining the pH of the system at 4.0-6.5, the sodium tripolyphosphate solution is added dropwise to the mixture over 10-120 min and stirring is continued for 30-180 min to form an ionic cross-linked shell; subsequently, the pH of the system is adjusted to 6.0-8.0 using a sodium hydroxide aqueous solution with a concentration of 0.1-2.0 mol / L to obtain a suspension of intermediate III; S4. The suspension of intermediate III is mixed evenly with the dispersion stabilizing component and the aqueous continuous phase to obtain a bactericidal sustained-release formulation containing bromodiphenyl ether.

10. The preparation method according to claim 9, characterized in that, The degree of deacetylation of the chitosan in step S3 is 75-95%.

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