Prozeb nano-suspension

Abstract

The invention belongs to the field of nano-pesticides, and relates to a propineb nano-suspension with a particle size of less than 100 nanometers and a preparation method of the propineb nano-suspension. According to the invention, two or three components are diluted and mixed with water to form the propineb nano suspension with the size of less than 100 nanometers. The preparation method comprises the following steps: under the condition that the stirring speed is not less than the effective stirring speed, adding the diluent of the component I into the diluent of the component II, or adding the diluent of the component II into the diluent of the component I; the propineb compound nano suspension is formed.

Description

Propineb Nanosuspension

Technical field

[0001] The invention belongs to the field of nano pesticides, and particularly relates to the preparation of nano suspensions with particle sizes less than 100 nanometers. [Background Technology]

[0002] Improving pesticide efficacy is one of the key approaches to reducing pesticide use, and developing nanopesticides is the best approach. Nanopesticides, which originated in the early 2000s, use nanotechnology to reduce the particle size in pesticide formulations and achieve nanodispersion. A nanometer (nm) is a unit of length, with 1 nm being one billionth of a meter and one millionth of a millimeter. Simply put, nanopesticides are pesticide formulations whose particle sizes are at the nanometer level during application. For both effectiveness and stability, a particle size of less than 100 nm is ideal, with smaller being the best. Currently, the particle size of traditional pesticide formulations is larger than microns. If the particle size is reduced to the corresponding nanometer size, a 1,000-fold reduction in particle size, the number of particles could theoretically increase by a billion times, and the surface area by a thousand times. This is the rationale for the development of nanopesticides.

[0003] In April 2019, on its 100th anniversary, the International Union of Pure and Applied Chemistry listed "nanopesticides" as the top of its "Top Ten Chemical Innovations That Will Change the World." Nanopesticides, based on their higher delivery efficiency and improved absorption, can address the major challenges of traditional pesticide formulations: environmental pollution, pesticide accumulation in organisms, and the significant increase in pest and disease resistance. They can significantly reduce pesticide usage. Therefore, nanopesticides have become a key development technology for the next generation of pesticide formulations.

[0004] Propineb is a nonspecific, multi-site fungicide developed by Bayer in Germany and a major product after propineb. Because it contains no manganese ions, its molecular structure differs from other mancozeb fungicides. The addition of a methyl group to the toxic group enhances the molecule's hydrophobicity and biological activity. This unique molecular structure and fungicidal properties make it less likely to develop resistance. Propineb shares characteristics with other mancozeb fungicides, all acting as preventative protective fungicides. However, propineb boasts a broader spectrum of activity, more stable efficacy, and superior fungicidal effectiveness. Its mechanism of action is to selectively target fungal cell walls and protein synthesis, inhibiting spore infiltration and germination, as well as mycelial growth, leading to deformation and death. Furthermore, propineb contains zinc, which is easily absorbed by crops, promoting growth and improving fruit quality.

[0005] The chemical name of propineb is poly(1,2-propylenedithiocarbamate)zinc. Its chemical structure is shown in formula (1). The pure product is a white powder with a slightly distinctive odor and decomposes above a melting point of 150°C. Because it is a polyvalent metal salt, its solubility in water and common organic solvents is extremely low. Its solubility in water (20°C) is <0.01 g / L. Its solubility in organic solvents (g / L): toluene, hexane, and dichloromethane are all <0.1. Only dimethylformamide and dimethyl sulfoxide have a solubility >200. It is stable under dry conditions and decomposes under moist, acidic, and alkaline conditions.

[0006] Propineb is a foliar fungicide with a protective effect. It kills conidia and developing conidia by contact. It can be used on most crops, including fruit trees, tea trees, vegetables, flowers, Chinese medicinal herbs, potatoes, and rice, to control a variety of diseases. It is particularly effective against leaf spot, leaf blotch, downy mildew, phytophthora, anthracnose, rust, and leaf spot. It has a protective effect on zinc-sensitive crops such as rice. For many years, Bayer has actively promoted the use of Propineb in China under the trade name Antaishan (70% Propineb wettable powder). Currently, over 50 pesticide companies in China produce Propineb alone, primarily as a wettable powder, with some producing water-dispersible granules. At least 100 companies also produce combinations of Propineb with other pesticides, using the same dosage form as the single agent. Since the active ingredient content in these preparations is too high, up to 70% to 80%, the space for adding dispersants and auxiliary components is limited, and the particles are in close contact with each other, which makes it easy for the particles to aggregate and crystallize, resulting in a larger particle size.

[0007] Propineb can be combined with a variety of pesticides to form a variety of compound preparations to increase the effectiveness of disease control. However, regardless of whether it is used alone or in combination, due to its physical properties - it is insoluble in water and organic solvents - its main dosage forms are traditional wettable powders and water-dispersible granules. According to the existing level of pesticide formulation processing technology, the minimum size of the pesticide particles in its preparations is usually more than a few microns, and the largest ones are more than ten microns or even dozens of microns. The large size of Propineb pesticide particles is not conducive to the effectiveness of the drug. In addition, a certain degree of drug resistance has been generated by years of large-scale use. The current usage per unit area is large, usually 750g to 2250g of active ingredient / hm2. 2 Therefore, how to improve its efficacy and reduce its dosage per unit area has become an important part of the research on the formulation type of this pesticide variety.

[0008] The preparation process of the existing single-dose formulation of propineb is to first synthesize the original drug and then process the formulation. The specific steps include: (1) original drug synthesis. It is divided into two steps: the first step is to synthesize propineb acid with 1,2-propylenediamine and CS2, and then neutralize it with alkali to form a salt to obtain propineb ammonium or propineb sodium or propineb potassium. The second step is to react propineb ammonium or propineb sodium or propineb potassium with zinc salt to obtain propineb. The propineb ammonium or propineb sodium or propineb potassium synthesized in the first step is water-soluble and can be dissolved in water. It then undergoes a metal ion exchange reaction with zinc salt to obtain block or granular precipitated propineb. The precipitated propineb is neither soluble in water nor in organic solvents, and needs to be separated, washed, and dried to obtain propineb original drug. (2) Preparation processing. The preparation is processed using solid propineb original drug as raw material. Usually, crushing, grinding, mixing and other processes are required to obtain propineb preparation. The above-mentioned preparation process from propineb, propineb, or propineb requires the addition of corresponding production equipment and workshops, such as filters, dryers, crushers, grinders, and mixers, as well as corresponding production processes and processing techniques. It can be seen that the process from synthesizing water-soluble propineb, propineb, or propineb to processing it into a solid dosage form of propineb is both lengthy and energy-intensive.

[0009] Existing technology: Chinese invention patent CN201711490378.4 "Preparation method of nano-mancozeb" discloses a nano-mancozeb powder dosage form.

[0010] The traditional process flow for preparing mancozeb technical and processing it into wettable powder is shown in Figure 1.

[0011] [Summary of the invention]

[0012] Prior application: PCT / CN2022 / 139831

[0013] One of the purposes of the above invention is to overcome the shortcomings of the prior art and provide a new idea and method for preparing a mancozeb powder dosage form that is different from the prior art. Through the dilution process with water, mancozeb (or mancozeb, mancozeb potassium) reacts with mancozeb salt and zinc salt to produce mancozeb, thereby providing a water-soluble and transparent mancozeb nanosuspension that can be directly used for spraying.

[0014] The mancozeb nano suspension of the above invention can be loaded into a pesticide spraying device for spraying.

[0015] The innovative ideas of the present invention are as follows:

[0016] Propinemium, sodium, or potassium are water-soluble ammonium salts, dispersed as monomolecules in water as one component. The zinc salts that react with them are also dispersed as monomolecules and metal ions in water as the other component. When the two interact, they easily form a propineb structure. Since zinc ions are polyvalent metal ions, the resulting propineb may actually be a complex structure, rather than the commonly assumed salt structure. Because this is an ionic reaction, the reaction is relatively fast. By controlling the addition rate of a particular component and the stirring speed during mixing, nanocrystals of propineb can be produced.

[0017] Under controlled stirring conditions, an aqueous solution of one component (e.g., a zinc salt) is added to an aqueous solution of another component (e.g., propineb). By controlling the addition rate and stirring speed, nanoparticles of propineb can be generated, forming a nano-suspension of propineb.

[0018] When the generated propineb nanoparticles are very small and few in number, they can temporarily exist stably in water. However, as propineb nanoparticles continue to form, the system will experience collisions, growth, and aggregation. When the size of the propineb nanoparticles approaches or even exceeds the wavelength of visible light, the system begins to exhibit an opalescent sheen and gradually becomes opaque. Combined with the effect of the grains' own gravity, they precipitate as large grains. To prevent this phenomenon, a polymer additive must be added to the system. Polymer additives are water-soluble polymers, typically non-crystalline polymers, that, when dissolved in water, exist as random coils. A random coil is a loose, spherical structure formed by the spontaneous coiling of water-soluble polymer chains. The inner core is composed of lipophilic and hydrophobic molecular backbones, while the outer core is composed of hydrophilic polar groups. At this point, when the propineb nanoparticles generated by the system are less than 100 nanometers in size, the shear force of mechanical stirring causes these water-insoluble propineb nanoparticles to disperse into the interior of the random coils, where they are supported by the random coils. This isolates and prevents further effective collision, crystallization, growth, precipitation, and settling of the nanoparticles. Therefore, the random coils formed by the water-soluble polymer additive disperse, suspend, stabilize, and protect the propineb nanoparticles. Because the random coils are uniformly dispersed in the aqueous phase, the propineb nanoparticles uniformly dispersed within the random coils are also uniformly dispersed in the aqueous phase. When the crystal size is below 100 nanometers, natural light passing through the solution is not significantly reflected or refracted, resulting in the system appearing clear and transparent and apparently water-soluble.

[0019] It's important to note that during the formation of nanopesticide crystals, the rate at which one of the two components of propineb is added to the other and the stirring speed of the aqueous polymer adjuvant solution affect the amount of reactants added to the aqueous phase per unit time and the uniform dispersion of the product. These factors are crucial factors influencing the size of the resulting nanopesticide crystals. Regarding the addition rate, if the target size of the precipitated nanopesticide crystals is less than 100 nanometers, the clarity and transparency of the system is the key criterion. This theoretical basis is that when the particle size is less than one-quarter of the lower limit of the visible light wavelength, significant refraction and reflection are avoided, and the system is therefore transparent. The wavelength of visible light ranges from 400 to 760 nanometers, and less than one-quarter is less than 100 nanometers. Conversely, if the system producing nanopesticide crystals is clear and transparent, it indicates that the resulting crystals are less than 100 nanometers in size.

[0020] To achieve this goal, the following points must be focused on:

[0021] ① The mixing speed of the two-component solution (i.e., the speed at which one component is added) should not be too fast. If the solution is added too quickly, the two components will be unevenly dispersed, leading to excessively high local concentrations. This will accelerate the formation of crystals, resulting in a large number of crystals. This can lead to aggregation between nanocrystals, which in turn increases the size of the crystals. If the system exhibits opalescence, it indicates that the crystals are already several hundred nanometers in size. Increasing opalescence, even to the point of opacity, indicates that the crystals are approaching or exceeding one micron in size. Therefore, the addition speed should be adjusted to maintain the system's transparency.

[0022] ② The stirring speed of the system should be appropriately increased. The stirring speed of the system is related to the formation and dispersion rate of propineb nanocrystals in the aqueous phase. Thorough stirring and better dispersion promote rapid formation and dispersion of nanocrystals, maintaining a stable dispersion of smaller particles and preventing aggregation. This is the only way to obtain small and uniform propineb nanocrystals. After the two-component solution is added, continue stirring for a while to ensure that the generated propineb nanocrystals are dispersed, suspended, and stable in the water-soluble polymer additive.

[0023] Explanation of terms

[0024] Tyndall effect: When a beam of light passes through a colloid, a bright "pathway" can be observed perpendicular to the incident light. This phenomenon, also known as the Tyndall effect, is essentially the scattering of light when propagating through a colloid. This phenomenon occurs primarily because the particle size of colloidal particles ranges from 1 to 100 nm, resulting in significant scattering of visible light when passing through a colloid, while true solutions exhibit very little scattering of light. Therefore, colloids exhibit a pronounced Tyndall effect, while true solutions with dispersed molecules exhibit almost no scattering. Consequently, the Tyndall effect is often used to distinguish colloidal solutions from true solutions.

[0025] A further explanation of the Tyndall effect is that when propagating light strikes particles in a solution, if the particles are larger than the wavelength of the incident light (400nm to 740nm) or many times larger, significant light reflection occurs. If the particles are smaller than the wavelength of the incident light, light scattering occurs, with the observed light waves radiating outward around the particles. This radiated light is called scattered light or opalescence. The Tyndall effect is essentially a phenomenon of light scattering, or opalescence. Since the particle radius of a true solution generally does not exceed 1nm, colloidal particles lie between solute particles and turbidity particles in a solution, with a particle size of 1 to 100nm. This is less than one-quarter the lower limit of the visible light wavelength. Therefore, visible light will be significantly scattered when passing through a colloid. However, since the molecules or ions in a true solution are even smaller, the intensity of the scattered light decreases significantly as the volume of the scattering particles decreases. Therefore, the scattering effect of true solutions on light is very weak. Furthermore, the intensity of scattered light increases with increasing particle concentration in the dispersed system. From this we can judge: when the observed solution is clear and transparent, it indicates that the particle size in the solution is less than 100nm, and the Tyndall phenomenon may occur; when the observed solution shows opalescence or the opalescence becomes increasingly heavier, it indicates that the particle size is greater than 100nm, and the particle size tends to become larger and larger; when the solution is turbid or even opaque, the particle size has increased to microns or above.

[0026] System: The term "system" refers to the suspension system formed by mixing two components under controlled addition rate and stirring during the preparation of the propineb nanosuspension of the present invention. The system is the target product, the nanosuspension, formed by mixing water, a precursor, a zinc salt, and a water-soluble polymer additive.

[0027] Component: A component is a composition comprising one or more ingredients. In principle, any ingredient used in this invention can constitute a component on its own. However, for ease of packaging, transportation, and use, the components should be simplified. The principles are: 1) the ingredients should not react with each other; 2) the number of components should not be too large.

[0028] Ingredients: The so-called ingredients refer to the raw materials used in the present invention, including water-soluble propionate salt, zinc salt, water-soluble polymer auxiliary agent and water.

[0029] Precursor: The so-called precursor refers to the parent substance used in the production reaction of the target product propineb, that is, water-soluble propineb salts, including propineb ammonium, propineb sodium, and propineb potassium.

[0030] Water-soluble polymer additives are macromolecular substances containing hydrophilic polar groups that are soluble in water. They are also called polymer surfactants or active agents. Water-soluble polymer additives can provide dispersion, suspension, emulsification, and stabilization. Based on the nature of the groups, they can be categorized as anionic, cationic, zwitterionic, and nonionic polymer additives.

[0031] Particle size: also known as particle size; refers to the size of the propineb crystals formed by the interaction of the precursor with the zinc salt under the dispersion of water-soluble polymer additives in the system. It also includes the particle size formed by other pesticide varieties compounded with it, and does not specifically refer to the microscopic morphological structure of the crystals.

[0032] Sub-100 nanometers: This is a statistical classification of pesticide particle sizes within a system. All pesticide particle sizes within a suspension exhibit a statistical distribution. Sub-100 nanometer nanosuspensions, as described herein, refer to suspensions where the peak value on the particle size distribution curve between the mass fraction of each fraction and its corresponding size is less than 100 nanometers. Measurements can be made using a Malvern laser nanoparticle size analyzer (UK), using the Number Statistical Method.

[0033] Stability period: This refers to the time that the nanosuspension remains transparent after preparation. To ensure the completion of the spraying operation, the stability period should be no less than 1 hour. The present invention proposes an hourly stability period, which means a stability period of between 1 and 10 hours.

[0034] Effective stirring speed: The so-called effective stirring speed refers to the ability, under a certain addition method, to disperse the nanocrystals generated in the system promptly when one component is added to another, by stirring at a speed no less than the effective stirring speed, preventing grain growth and aggregation, and preventing the grain size from increasing to several hundred nanometers. Transparency of the resulting solution is a sign of effective stirring.

[0035] Effective stirring: The addition of components and the stirring method and speed have a significant impact on the resulting liquid. Stirring methods include mechanical stirring, multi-point mechanical stirring, manual stirring, and multi-point manual stirring. Fast stirring speeds are associated with optimal results. If the resulting liquid is transparent, the stirring is considered effective. Otherwise, the stirring is considered ineffective.

[0036] Addition method: The so-called addition method includes adding component A to component B, component B to component A, or adding component A and component B to the system simultaneously. It also includes continuous addition, intermittent addition, trickle addition, dropwise addition, spray addition, and addition at a fixed position or a movable position. The best addition method is to mix and disperse the two components as quickly as possible.

[0037] Addition speed: After determining the addition method, control the amount of components added with the goal of achieving effective stirring.

[0038] Nanoemulsions, also known as nanoemulsions, are solutions of pesticide active ingredients dispersed in water with the help of additives to form nanosized latex particles. Nanoemulsions are clear and transparent, with particle sizes typically below 100 nm and thermodynamic stability.

[0039] One of the purposes of the present invention is to overcome the shortcomings of the existing technology and provide a new idea and method. By utilizing the process in which pesticide formulations are usually diluted with water when spraying using water as a dispersion medium, the present invention achieves the mixing and reaction of propineb (or propinena, propineb potassium) and a zinc salt (such as zinc sulfate) to produce propineb, thereby providing an apparently water-soluble and transparent propineb nanosuspension that can be directly used for spraying pesticide equipment.

[0040] The propineb nanosuspension described in this invention can be loaded into pesticide spraying equipment for immediate application. It primarily controls: downy mildew, black rot, red fire, and gray mold on grapes; scab and brown rot on apples and pears; leaf spot on stone fruits; wilt, phytophthora, downy mildew, Septoria leaf spot, and leaf mold on tomatoes; wilt and phytophthora on potatoes; downy mildew on tobacco; rust and leaf spot on ornamental plants; and rust, leaf spot, and downy mildew on vegetables. It can also be used on citrus trees, berry trees, tea trees, and rice. At the recommended dosage, it is safe for crops, including sensitive crops during their growth stages.

[0041] The propineb nano suspension of the present invention refers to a propineb nano suspension of less than 100 nanometers; the propineb nano suspension of less than 100 nanometers is formed by diluting and mixing at least two components with water:

[0042] Component A: water-soluble propine salt or water-soluble propine salt aqueous solution, water-soluble polymer auxiliary agent; the water-soluble propine salt is one of propine ammonium, propine sodium, propine potassium, or a mixture of at least two of them;

[0043] Component B: zinc salt or aqueous solution of zinc salt in a certain mass ratio;

[0044] The component B may be further added with a water-soluble polymer auxiliary agent to form an aqueous solution.

[0045] The water-soluble polymer auxiliary agent is a nonionic surfactant.

[0046] The ratio of the amount of the water-soluble polymer additive to the amount of dilution water is not greater than 1:1500; preferably, not greater than 1:1200; more preferably, not greater than 1:1000.

[0047] Nonionic surfactants may include water-soluble starch and its derivatives, water-soluble guar gum and its derivatives, polyoxypropylene-polyoxyethylene block copolymers, alkylaryl polyoxypropylene polyoxyethylene ethers, fatty alcohol polyoxyethylene ethers, fatty acid polyoxyethylene ethers, fatty amine polyoxyethylene ethers, castor oil polyoxyethylene ethers, Tween, alkyl polysaccharides, polyvinyl alcohol, polyvinyl pyrrolidone, etc. Preferably, polyoxypropylene-polyoxyethylene block copolymers, alkylaryl polyoxypropylene polyoxyethylene ethers, OP-10, fatty alcohol polyoxyethylene ethers, fatty acid polyoxyethylene ethers, castor oil polyoxyethylene ethers, Tween, alkyl polysaccharides, etc.

[0048] The zinc salt is selected from at least one of zinc sulfate, zinc acetate, zinc chloride and zinc nitrate.

[0049] Furthermore, the nano-suspension of propineb below 100 nanometers has a stable period of hours.

[0050] When propine salt and zinc salt are propine ammonium and zinc sulfate respectively, propine ammonium has two acid groups. Considering zinc ion as a divalent metal ion, it also has tetravalent coordination activity. The range of its molecular (molar) ratio is:

[0051] Propanol: Zinc sulfate = 1: 0.50-1.01

[0052] Preferably, propinephrine: zinc sulfate = 1: 0.90-1.00

[0053] In industrial production, the molar ratio of propineb:zinc sulfate is 1:1.01. A slight excess of zinc sulfate is used to ensure complete propineb reaction. It should be noted that the multivalent nature of zinc ions contributes to the water and solvent insolubility of the product, propineb, acting as a crosslinking agent. The present invention, however, utilizes the dilution process to complete the reaction between propineb and zinc sulfate. Excess zinc ions are detrimental to the dispersion and stability of the resulting propineb nanoparticles, so a molar ratio of zinc sulfate close to or equal to 1 is used in the present invention.

[0054] To reduce packaging and transportation costs, the specifications of each component of the preparation can be the same or different. In the case of a zinc salt aqueous solution as component B, a certain amount of a water-soluble polymer additive can be added. The added concentration should be such that component B does not become turbid, and is generally not more than 10%.

[0055] Propineb suspension below 100nm

[0056] In order to improve the efficacy of nano-scale propineb, the present invention needs to reduce its particle size as much as possible. The original intention of studying nanopesticides is to improve the efficacy of pesticides and reduce the amount of pesticides used. The particle size of traditional pesticide preparations is usually in the micron level. Reducing it to the corresponding nanometer size spans three orders of magnitude. When reducing it to different orders of magnitude, the number of particles increased is also different. For example, if the particle size of traditional preparations is reduced from 2μm to 200nm, 20nm, and 2nm respectively, theoretically, the number of particles will increase by 1000 (10 3 ), 1 million (10 6 ), 1 billion (10 9 ) times. Therefore, it can be seen that different reductions in particle size and increases in particle number lead to different effects on the efficacy of the drug. Therefore, in order to improve the efficacy of nanopesticides, the particle size should be reduced as much as possible.

[0057] To further enhance the efficacy of nano-scale propineb, the present invention aims to reduce its particle size to below 100 nm. This is based on two factors. First, a size below 100 nm is the minimum size required for nanomaterials in any one dimension. Second, pesticide particles between 1 and 100 nm form a colloidal solution, appearing water-soluble and clear. When a beam of light is shone upon the solution, a well-defined beam of light is observed, consistent with the description of the Tyndall phenomenon.

[0058] Concentration of suspension

[0059] In a less concentrated suspension, the number of particles below 100 nm is relatively high, which has little effect on transparency. This is the case for a system with a dosage of 1500 g / ha of propineb, when diluted with more than 50 kg of water.

[0060] In highly concentrated suspensions, the presence of fewer particles smaller than 100 nanometers can significantly impact transparency. For a system with a propineb dosage of 1500 grams per hectare, diluted with 20 kilograms of water, while the suspension may briefly become transparent, the high concentration makes it easier for particles to collide with each other, causing crystal growth and aggregation, significantly affecting the suspension's transparency stability.

[0061] The situation where the water consumption is between 20 and 50 kg is the transition period of the suspension concentration.

[0062] Stable period

[0063] The propineb suspension prepared by the present invention is a type of transparent, apparently water-soluble solution, but it is not a thermodynamically stable solution. Therefore, the time for the nano propineb suspension to remain transparent is not infinite, but rather there is a stable period. Considering the operating characteristics of the spraying operation, after the nano propineb suspension is prepared, the required operating time should be at least more than 1 hour, so the length of the stable period can be described in hours. Thus, the present invention proposes the concept of a "stable period" for nano-level propineb suspensions below 100nm. That is, the nano-level propineb suspensions below 100nm prepared by the present invention complete the spraying operation within the period when the solution remains transparent, and the stable period should reach at least 1 hour.

[0064] From the application perspective, the stable period can be further divided into four time periods: less than 1 hour, 1 to 5 hours, 5 to 10 hours, and more than 10 hours.

[0065] The spraying operation was completed within 1 hour, indicating that the nano-propineb suspension still maintained a transparent state, that is, the particle size was ensured to be still less than 100 nm.

[0066] Direct observation can be used to determine changes in the transparency and particle size of nano-propineb suspensions. During the stable period, the suspension remains transparent, with particle sizes less than 100 nm. When the suspension becomes unstable, opalescence first appears, indicating that the particles are beginning to increase in size. A faint opalescence indicates that the particles are beginning to exceed 100 nm. Increasing opalescence indicates that the particles have grown to several hundred nanometers. Further turbidity or even opacity indicates that the particles have grown to micrometers or above. Crystallization or precipitation indicates that the particles have reached millimeter levels.

[0067] The present invention is applicable to the observation of the stable period phenomenon of the propineb suspension of less than 100 nanometers at different hourly levels.

[0068] Hourly stability period

[0069] From the perspective of spraying operations:

[0070] The stabilization time is about 1 hour, which is not enough for spraying operations; a stabilization period of more than 10 hours is of little significance for pesticide formulations. Even if the liquid pesticide is very stable, it is not conducive to storage and transportation due to the low content and large volume of the pesticide.

[0071] Therefore, the stabilization time is between 1 and 10 hours, and the spraying operations of most pesticide equipment can be completed easily within this time.

[0072] The hour-level stabilization period mentioned in the present invention refers to a stabilization time between 1 and 10 hours.

[0073] For the hourly stable period, further detailed division can be carried out.

[0074] The basic period for spraying operation is 1 to 5 hours; in most cases, the spraying equipment can complete the operation.

[0075] 5 to 10 hours is a sufficient period for spraying operations; it can be used to accommodate spraying operations that are delayed due to special circumstances.

[0076] Components and additives of propineb nanosuspension

[0077] Traditional single-dose propineb and binary compound formulations typically consist of only one component and can be sprayed after dilution with water. However, most pesticide particles are larger than microns in size. The present invention, in order to produce a nano-scale propineb suspension, employs at least two components. By diluting the mixture with water according to a specific method, a propineb suspension with a particle size of less than 100 nanometers can be obtained.

[0078] Taking the three-component model as an example, the following explanation is given.

[0079] Three-component basic scheme

[0080] The basic solution of the sub-100 nanometer-sized propineb suspension of the present invention is a system formed by the reaction of three components. They are:

[0081] Component A: It is composed of propinephrine, propinephrine sodium or propinephrine potassium solid or its aqueous solution, which is the precursor for generating propineb nanoparticles.

[0082] Component A can be propinephrine, propinephrine sodium, propinephrine potassium, or a mixture thereof. A single component or a mixture of two or three components can be solid, which is convenient to package and has a small packaging volume. It can be dissolved in water before use and dissolves quickly. However, an aqueous solution thereof can also be used and can be directly diluted with water to a certain volume before use.

[0083] Component B: It is composed of zinc salt solid or its aqueous solution in a certain proportion, which is the multivalent metal ion required to generate propineb nanoparticles.

[0084] Component B, the zinc salt is selected from at least one of zinc sulfate, zinc acetate, zinc chloride, and zinc nitrate. Component B can be in solid form, which reduces packaging volume; or in aqueous solution, which is limited by solubility and requires a certain volume specification.

[0085] Component C: It is composed of at least one surfactant, or its aqueous solution, which is an auxiliary agent that has the effects of dispersing, suspending and stabilizing the generated propineb nanoparticles.

[0086] Component C is an auxiliary agent composed of a water-soluble surfactant. The auxiliary agent serves to disperse, suspend, and stabilize the propineb nanoparticles generated in the system. The water-soluble surfactant can be selected from a polymer surfactant and a small molecule surfactant. Considering that the polymer surfactant is superior to the small molecule surfactant in dispersing, suspending, and stabilizing the particles, the polymer surfactant is preferred.

[0087] The ratio of the amount of water-soluble surfactant to the amount of water used for dilution is preferably not greater than 1:1000.

[0088] The polymer surfactant selected in the present invention is, considering the type of surfactant, a commonly used anionic surfactant, typically a monovalent metal salt or its ammonium salt. When an anionic surfactant in an aqueous solution encounters a polyvalent metal ion, it is displaced by the polyvalent metal ion, thereby losing its water solubility and precipitating in the water. Therefore, the present invention selects a nonionic surfactant as a water-soluble polymer auxiliary agent to suspend, disperse, and stabilize the propineb nanoparticles generated in the system.

[0089] The water-soluble polymer additive described in the present invention is selected from nonionic surfactants. Preferred are derivatives of polyoxyethylene polymers, such as block copolymers of polyoxyethylene and polyoxypropylene, fatty alcohol polyoxyethylene ethers, fatty acid polyoxyethylene ethers, fatty amine polyoxyethylene ethers, and vegetable oil polyoxyethylene ethers. Other additives include natural products such as water-soluble starch, cellulose, nonionic chitosan derivatives, dextrin, methyl ethyl cellulose, and polyol derivatives such as Tween and alkyl polyglycosides. Other additives include synthetic polymers such as polyvinyl alcohol and polyvinyl pyrrolidone. The water-soluble polymer additive described in the present invention is one or more of the above-mentioned nonionic surfactants.

[0090] In order to simplify the components and make the packaging, storage, transportation and dilution with water operation simpler, the above three-component system can be combined into two components.

[0091] Two-component improvement plan

[0092] One of the improvements of the present invention is a suspension of propineb below 100 nanometers, which has a stable period of hours and is generated by a mixed reaction of two components. They are:

[0093] Component A: An aqueous solution consisting of propineb (or sodium propineb, potassium propineb), a water-soluble polymer additive, and water. This solution is composed of a precursor for forming propineb crystals smaller than 100 nanometers and a water-soluble polymer surfactant that disperses, suspends, and stabilizes the product.

[0094] Component B is an aqueous solution composed of a certain proportion of zinc salt, a water-soluble polymer additive and water. The zinc salt is selected from zinc sulfate, zinc acetate, zinc chloride and zinc nitrate.

[0095] Due to the limited solubility of zinc salts in water, in order to minimize the capacity specifications of component B, it is necessary to limit the amount of water used. In addition, the aqueous solution of zinc salts is also affected by the amount of additives added, which also limits the amount of water-soluble polymer additives added to component B.

[0096] This improvement plan is to distribute the water-soluble polymer additive used into component A and component B. In view of several limitations of component B, there is an upper limit to the proportion of the water-soluble polymer additive in component B, unless the limitation of component B to a certain capacity is not taken into account.

[0097] Propaneb component ratio

[0098] The above two-component improvement solution includes two components:

[0099] Component A: Use propinephrine (or propinephrine sodium, propinephrine potassium), or an aqueous solution of propinephrine (propinephrine sodium, propinephrine potassium), and then add an auxiliary agent.

[0100] Component B: Dissolve zinc sulfate (or zinc acetate, zinc chloride, zinc nitrate) in water in a certain proportion; auxiliary agents may be added.

[0101] The amount of active ingredients in Component A and Component B is the basis for determining the composition of the two components. Propinenium (or propineb sodium, propineb potassium) in Component A is the precursor for the formation of nano-propineb and is the basis for determining the composition of Component B.

[0102] The present invention takes the case where 100 grams of propineb is required to be sprayed on 1 / 15 hectare of field as an example, and a two-component design is carried out based on the generation of 100 grams of propineb suspension with a particle size below 100 nm.

[0103] Component A requires propinephrine, propinephrine sodium, or propinephrine potassium, preferably propinephrine, as a precursor, approximately 90 grams. Based on the aforementioned principle for distributing additives between components A and B, the vast majority of the additives will be distributed in component A. If both components A and B are packaged in 500-gram quantities, the amount of water used is the amount after removing the propinephrine and additives.

[0104] For component B, the amount of inorganic zinc salt required to react with propinephrine is first determined. Zinc sulfate is preferred in the present invention. It is generally believed that zinc ions react with propinephrine, replacing ammonium ions to form a salt, generating a linear repeating structure or complex structure. Zinc ions also have tetravalent coordination ability and may also form a complex structure.

[0105] Existing literature indicates that in the synthesis of propineb, the molecular (molar) ratio of propineb to zinc ion is 1:1.00 to 1.05. Propineb has two ammonium groups, and zinc ion is a divalent metal ion, so the molecular molar ratio should be 1:1, with a slight excess to ensure complete reaction. Although zinc ion also has tetravalent coordination properties, elemental analysis of propineb samples revealed a zinc content close to the theoretical value of 22.8%, indicating that propineb (propylene bisdithiocarbamate) and zinc sulfate are bound in a 1:1 ratio.

[0106] In the present invention, when the mass of the precursor propineb is 90 g (0.346 mol, generating 100 g of propineb), the zinc salt used is zinc sulfate (anhydrate), and the mass of the same mole is 56.5 g. A mass slightly lower than this can also be used.

[0107] Distribution of additives between component A and component B

[0108] Component A mainly contains propinephrine (or dapoxetine, propinephrine potassium).

[0109] Components A and B must be packaged separately because they react when mixed. If a two-component formulation is used, component A must contain an additive; otherwise, there's nowhere to store the additive, unless a separate additive is added as a dedicated third component. This complicates the packaging and dilution process. The addition of additives to component A requires that both propinephrine and the additive be soluble in water and miscible without precipitation or other instabilities. However, given the high content of propinephrine and the additive, their inherent viscosity makes handling difficult. Therefore, a certain amount of water must be added to dilute the mixture, reduce viscosity, and facilitate dilution. The amount of water added should minimize the overall mass of component A, while achieving these objectives, to reduce the resulting production, packaging, and transportation costs.

[0110] Component B is mainly zinc salt or its aqueous solution.

[0111] Component B can be a solid zinc salt, which should be dissolved in water before use. For convenience, aqueous solutions can be used. Due to their limited solubility, a certain amount of water is required. Adding or omitting additives is optional for two reasons: First, if a large amount of additive is added to Component B, it will form a film on the surface of the mixture of zinc salt, additive, and water, hindering the subsequent dilution process. Second, if the amount of additive in Component A is sufficient to suspend and disperse the generated propineb nanoparticles, additives can be omitted from Component B. However, if propineb is used for disease control in orchards with large tree canopies, the water consumption required for spraying is high, often reaching 200 kg / mu or more. If the amount of additive added to Component A is insufficient to support the dispersion and suspension of the generated propineb nanoparticles in such a large dilution water volume, an appropriate additive should be added to Component B to compensate for the insufficient additive in the dilution solution. However, the prerequisite is that the amount of additive added to the aqueous solution of zinc salt must ensure that the solution remains transparent and avoid condensation and film formation on the surface of the solution during storage. The mass concentration of the added additive is generally not higher than 10%.

[0112] Although both component A and component B can be increased in mass to address the above difficulties, increasing the dosage of the two components will undoubtedly increase production, packaging, and transportation costs. Taking all these factors into consideration, balancing the dosage of other components and product specifications to minimize the use of other ingredients (adjuvants, water) while maintaining the unit mass of propineb is an important factor to consider.

[0113] Water-soluble polymer additives

[0114] 1) The transparent propineb tank mix is ​​a ready-to-use propineb nano-suspension dispersion. A water-soluble polymeric additive with a dispersing effect is added to this solution, resulting in nano-sized propineb suspended in the polymeric additive solution. Because the particle size is less than 100 nanometers, the resulting nano-suspension solution is transparent and apparently water-soluble.

[0115] 2) The water-soluble polymer auxiliary agent with dispersing effect is an important component related to the size of the nano-crystals of propineb generated when the two components are diluted and mixed, as well as whether they can be evenly dispersed and stably suspended.

[0116] 3) Polymeric additives, also known as polymeric surfactants, generally refer to substances with a relative molecular mass greater than 10,000 and exhibiting surface activity. Compared to small-molecule surfactants, polymeric surfactants are less effective at reducing surface tension, but possess other special properties, such as dispersion, suspension, and viscosity enhancement. Polymeric surfactants can be classified by source into natural polymers and their derivatives and synthetic polymers. Polymeric surfactants possess a hydrophobic chain structure and hydrophilic functional groups, either at the end or at the side, such as hydroxyl, carboxyl, carboxymethyl, sulfonic acid, sulfate, phosphoric acid, and amino groups, making them water-soluble polymers. Water-soluble natural polymers and their derivatives include starch (linear), dextrin, and its various derivatives; water-soluble starch, oxidized starch, carboxymethyl starch, modified starch; cellulose and its derivatives; carboxymethyl cellulose; hydroxyethyl hydroxypropyl cellulose; carboxymethyl chitosan; modified guar gum; tea saponin; water-soluble humic acid; and sodium lignin sulfonate. Synthetic water-soluble polymers include polyvinyl alcohol, polyacrylic acid, polyacrylamide, polystyrene-maleic anhydride copolymer, and polyvinyl pyrrolidone. Since the backbone of synthetic water-soluble polymers is mostly carbon and not easily biodegradable, water-soluble natural polymers and their derivatives should be chosen as much as possible for environmental reasons to minimize the impact on the ecological environment.

[0117] 4) The reason for selecting polymeric additives in the present invention is to utilize the dispersing and suspending properties of water-soluble polymers in aqueous solutions. Water-soluble polymers with molecular weights in the tens of thousands, hundreds of thousands, or even hundreds of thousands typically have linear polymer chain structures and are soluble in water. When dissolved in water, linear polymers exhibit a large aspect ratio, but they do not appear as straight chains. Instead, due to the flexibility of the molecular chains, they exhibit a coiled state, or "random coil" morphology. The hydrophilic groups in the random coils tend to face the aqueous phase, while the lipophilic chains are coiled within the random coils. The size of the random coils depends on the relative molecular weight of the polymeric additive, its concentration, and the polymer chain structure. The larger the molecular weight, the larger the volume of the random coils formed by a single molecule. The more flexible the polymer chain, the easier it is to rotate internally, and the more stretched it is in the solvent, the larger the random coils. When the concentration of water-soluble polymers is high, random coils formed by different molecules tend to aggregate, resulting in a larger volume. Generally, when the molecular weight of a water-soluble polymer is in the tens or hundreds of thousands, the size of the resulting random coils is typically tens to hundreds of nanometers. If pesticide nanocrystals form in the system, based on the principle that similar structures dissolve (or are compatible), the lipophilic nanocrystals tend to enter the interior of the lipophilic random coils and become intercalated in different locations within the random coils. When the pesticide nanocrystals are smaller, more nanocrystals can be dispersed within the random coils. Therefore, water-soluble polymer adjuvants can disperse and stabilize the generated nanocrystals. Traditional pesticide suspension concentrates also utilize this principle, but their pesticide particles are micron-sized. Due to the large size of micron particles, suspension concentrates are generally opaque and subject to significant gravity, making their stability highly uncertain. When the size of pesticide particles is reduced by 2 to 3 orders of magnitude, the gravitational effect on the particles is much smaller. The same water-soluble polymer surfactant can obtain a more stable suspension and dispersion system, achieving apparent water solubility and transparent appearance.

[0118] 5) Water-soluble polymer additives, like small molecule surfactants, are classified into different types based on the nature of the active groups contained in the macromolecular chain. They mainly include anionic polymer additives, cationic polymer additives, zwitterionic polymer additives, and non-ionic polymer additives. These polymer additives carry active groups of different properties on the side groups or main chains. For example, anionic polymer additives carry acidic groups such as carboxyl groups, sulfonic acid groups, and sulfate groups, as well as monovalent metal salts. Examples include carboxymethyl starch, carboxymethyl cellulose, lignin sulfonates, humates, polyacrylic acid, and polystyrene-maleate. Cationic polymer additives carry basic groups or salts formed with acidic groups, such as chitosan (hydrochloride) and polyacrylamide, as well as polymers containing pyridine groups on the side groups and being quaternized. Amphoteric polymer additives are polymers that contain both anionic and cationic groups in their molecular structure, such as carboxymethyl chitosan and carboxymethyl cellulose. The simplest non-ionic polymer additives are polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymers, as well as various polyoxyethylene ethers with hydrophobic groups such as fatty alcohols, fatty acids, fatty amines, alkylphenols, aromatic phenols, and oil groups, such as Peregual series, OP series, Tween series, polyol series, ricinoleic acid series, alkyl polyglycosides, etc.

[0119] 6) Of the first three types of polymeric additives, anions and zwitterions contain acidic groups and corresponding metal ions in their molecules, while cations contain basic groups. The presence of these polar groups causes the anionic polymeric additives to react with the zinc sulfate metal ions during the reaction between propineb and zinc sulfate, forming a water-insoluble structure that precipitates. Meanwhile, the basic groups of cationic polymeric additives can react with the acidic groups of propineb, potentially disrupting the formation of propineb. Therefore, generally speaking, anionic, cationic, and zwitterionic polymeric additives cannot be used as water-soluble polymeric additives in the present invention.

[0120] 7) The water-soluble polymer additive with dispersing effect is used as the additive of the present invention. Only non-ionic polymer additives can be used as the additive of the present invention. The hydrophilic group of the non-ionic polymer additive is the random coil formed by polyoxyethylene ether, also known as "micelle". The outside of the random coil is hydrophilic, and the inside of the micelle is hydrophobic. The generated propineb nanoparticles enter the inside of the micelle, thereby achieving dispersion and stability.

[0121] 8) The propineb nanosuspension is produced directly by reacting the precursor propineb (or sodium or potassium) with a zinc salt during the dilution process prior to use. Because the active ingredient content is at spray concentration, it is relatively low, approximately 1.0 to 0.5 g / kg water (for example, if the active ingredient dosage of propineb is 100 g / mu, the sprayer uses 100 to 200 kg / mu of water, where an acre is 1 / 15 of a hectare, and the same applies hereinafter). The dispersion stability of the propineb nanosuspension can be adjusted by controlling the amount of polymer additives used.

[0122] The amount of polymer additive used is related to the amount of propineb generated by the system and the amount of dilution water used. For example, if 100g of propineb is used per mu and the dilution water used is 100kg, 150kg, and 200kg, the active ingredient concentrations are 0.100%, 0.067%, and 0.05%, respectively. The polymer additive concentration should be at least 0.1% to 0.5%.

[0123] Testing has shown that the active ingredient particles in the propineb nanosuspension are approximately 10 to 60 nm in size. This nanosuspension remains stable for less than 8 hours, without precipitation or settling, and can be directly applied to various pesticide spraying equipment.

[0124] 9) The propineb nanosuspension is directly formed during the dilution process before spraying. It uses water-soluble propinebium, propineb sodium, or propineb potassium as a precursor, adds a polymeric adjuvant, and forms component A. A zinc salt aqueous solution, with or without a dispersant, forms component B. These components are mixed at a specific concentration and in a specific mixing pattern to produce the desired nanosuspension. This approach not only eliminates the synthesis and purification steps required by pesticide manufacturers to prepare propineb from propinebium or propineb sodium, but also eliminates the multi-step physical processing required by pesticide formulation manufacturers to convert propineb into existing formulations, such as wettable powders. The proposed solution can be directly applied to the plant protection sector of agricultural production, offering significant energy savings and environmental benefits, significantly reducing production costs, and producing a suspension dispersion with propineb particles less than 100 nm in size. Because the particle size is significantly smaller than that of existing solid formulations of propineb, the present invention maximizes its efficacy, significantly reducing pesticide usage and increasing its effectiveness.

[0125] FIG2 is a flow chart of the present invention for preparing a propineb nano suspension by diluting with water.

[0126] The key technologies of the present invention lie in the following aspects:

[0127] 1. The production process of nanopesticides

[0128] This innovative model and method for preparing nanosuspensions of water- and organic solvent-insoluble pesticides containing polyvalent metal ions has been proposed. By leveraging the need for dilution of the pesticide with water, the precursor of the target product is mixed with the corresponding metal salt. The rapid reaction of metal ions is exploited to control the mixing and stirring speeds of the reactants, resulting in a nanosuspension with a particle size of less than 100 nanometers for direct use. This method eliminates the chemical synthesis and purification steps required by pesticide manufacturers to prepare propineb from propinebium, propineb sodium, or propineb potassium, as well as the multi-step physical processing required by pesticide formulation manufacturers to convert propineb into the current wettable powder formulation. This innovative research approach, preparation model, and method are the most critical technologies of this invention. This key technology is not only suitable for compounding propineb with other fungicides, but is also applicable to the preparation of nanosuspensions of similar pesticides.

[0129] 2. Concentration of Propineb

[0130] The concentration of propineb generated in the diluted water by component A, primarily composed of propinebium or propineb sodium, and component B, primarily composed of a zinc salt, is controlled. Specifically, if the active ingredient, propineb, is used at a dosage of 100 g / mu, the concentration of propineb generated by the reaction of propinebium or propineb sodium with zinc sulfate is affected by the amount of water used for dilution. For example, the concentration of propinebium or propineb sodium should be controlled within the range of 0.09 to 0.045 g / kg, and the concentration of zinc sulfate should be controlled within the range of 0.07 to 0.0035 g / kg, corresponding to a water dosage of 100 to 200 kg. If the water dosage is too low, far less than 100 kg, for example, less than 20 kg, the resulting particles become larger and the transparency of the diluted solution deteriorates. This is because the higher the concentration of particles, the greater the probability of collisions to form larger particles, reducing stability and hindering the formation of particles smaller than 100 nm. If the water usage exceeds 200 kg, a transparent dilution solution can still be obtained, but the concentration of the dispersant in the components is significantly reduced, and the stability of the diluted solution will also deteriorate. Therefore, controlling the concentration of the final propineb—that is, controlling the amount of water used for dilution—is one of the key technologies for obtaining propineb nanosuspensions.

[0131] 3. Type and dosage of dispersant

[0132] Selecting the appropriate type and dosage of dispersant is another key technology for producing propineb nanosuspensions. However, when propineb ammonium or propineb sodium react with zinc salts in water to form propineb nanoparticles, the dispersion effect of large amounts of water and stirring alone cannot maintain the size of the newly formed propineb nanoparticles. This is because the particles dispersed in water are not static; they are constantly in motion, colliding with each other. These collisions lead to particle fusion, crystallization, and eventual precipitation. An effective way to prevent the size of the formed particles from increasing is to select the appropriate type and dosage of dispersant to ensure that the nanoparticles of the active ingredient are uniformly dispersed in the solution formed by the dispersant in water. These dispersants are primarily water-soluble polymers that dissolve in water. In water, these water-soluble polymers exist as random coils. The size of these random coils is much larger than that of the newly formed propineb particles, typically ranging from several hundred nanometers to larger than one micron, depending on the molecular weight and dosage. If the propineb nanoparticles produced at this point are smaller than 100 nanometers, for example, a few nanometers or a dozen nanometers, they can enter the interior of the random coils. To a certain extent, the random coils can prevent and slow down collisions between the particles, thereby improving the stability of the propineb nanoparticles. This is the role played by the addition of a dispersant.

[0133] However, there is a problem: water-soluble polymers come in many different types, and whether all of them can be used. The present invention has tested various types of water-soluble polymers and concluded that this is not the case. Among the numerous anionic surfactants, cationic surfactants, and nonionic surfactants, only nonionic polymer adjuvants currently offer the desired effect, such as alkyl alcohols, polyoxyethylene ethers of alkyl acids, polyoxypropylene-polyoxyethylene ethers of alkylaryls, OP-10, alkyl polyglycosides, castor oil polyoxyethylene ethers, and Tween-80. Of these, only a few combinations offer the best results. Anionic surfactants cannot be used because the reaction mechanism for forming propineb during dilution with water is essentially a process in which polyvalent metal ions replace ammonium or sodium ions, thereby forming salts or complexes. When anionic surfactants are used as dispersants, the polyvalent metal ions are likely to react with the sodium salts of the acidic groups in the dispersant in the same manner, causing the dispersant to precipitate out of its water-soluble state along with the generated propineb nanoparticles, thus failing to achieve the desired dispersion effect. The present invention does not exclude the special case where an individual cationic surfactant is optimally combined with an appropriate anionic or nonionic surfactant to dissolve in water without precipitation.

[0134] The present invention uses the important role of water-soluble polymer auxiliary agent and is self-evident.The present invention utilizes in the water dilution process, with water-soluble propinebium or propineb sodium or propineb potassium, with the zinc salt such as zinc sulfate that zinc ion is provided, mixes in a certain manner, by zinc ion and propinebium or propineb sodium or propineb potassium reaction in the mixing process, generates the propineb suspension of level below 100 nanometers.In system, if do not contain surfactant, especially do not contain water-soluble polymer surfactant, the nano-crystal grains that generate will constantly collide with each other, cause crystallization to grow up, assemble, until macroscopic precipitation occurs.When there is the water-soluble polymer surfactant of suitable kind and consumption in the system, the nano-crystal grains that generate will enter in the random coil that water-soluble polymer auxiliary agent forms, just can stop and delay collision, crystallization to grow up between the nano-crystal grain, thereby the propineb nano-crystal grains that generate are played to dispersion, suspension and stable effect.

[0135] The type and amount of the water-soluble polymer additive used in the present invention can be determined through experiments. The type of water-soluble polymer additive can be determined by conducting stability tests on different additives under fixed conditions and observing the effects. The additive type test includes a single dose of a water-soluble polymer additive or a compounded additive of two or more. The present invention will exemplify the types of different water-soluble polymer additives in the test examples. The determination of the amount of the water-soluble polymer additive will be based on meeting the following two conditions: First, the generated propineb nanosuspension must be transparent in appearance and apparent water-soluble, so as to ensure that the particle size is below 100nm; second, the stability time of this transparent nanosuspension is between 1 and 10 hours, at least between 1 and 5 hours.

[0136] For a system formed by the mixed reaction of two components, the amount of adjuvant is distributed between component A and component B. Theoretically, if there is no capacity limit for the two components, the proportion of adjuvant in component A and component B can be arbitrarily distributed; if there is a packaging capacity limit for the two components, for example, for the use of the drug in a 1 / 15 hectare field (to produce 100 grams of propineb), component A and component B are required to be 500 grams each. Considering the large amount of water used to dissolve the zinc salt in component B and the poor solubility of this inorganic salt solution for the adjuvant, the amount of adjuvant added to component B will be greatly limited. In this way, the adjuvant distribution amount of the two components can be determined by the following formula:

[0137] Amount of adjuvant (组分A) =Total amount of additives-amount of additives (组分B)

[0138] In the case of a fixed capacity, the amount of additives added to component B can be determined by the situation after the additives are added to component B. When the system changes from transparent to turbid, it is the upper limit of the amount of additives added to component B.

[0139] The amount of additive used in the present invention is relative to the amount of water used for dilution. The larger the amount of dilution water used, the more additive used. The ratio of additive to dilution water should be at least 1:1200, and preferably within 1:1000.

[0140] 4. Feeding method

[0141] The method of addition is also a key factor influencing the performance of propineb nanosuspensions. Once the active ingredient content or concentration in the dilution solution is determined, the water consumption is also determined. How is the dilution water distributed? How much is used in Component A and Component B? How is the dilution process performed? These factors all affect the size and stability of the resulting propineb particles in the dilution solution. For example, if the water consumption is 100 kg, two issues arise:

[0142] First, how to distribute the amount of water used into the two components to form component A dilution and component B dilution?

[0143] Second, how is it added? Is the component A diluent added to the component B diluent, or is the component B diluent added to the component A diluent?

[0144] These issues all relate to the concentration of reactants at the moment the two components are mixed. For example, if propinephrine, propinephrine sodium, or propinephrine potassium is used as a diluent for component A, whether it contains a dispersant, and if so, the amount of dispersant, all of this affects the instantaneous concentration of the zinc salt-containing diluent for component B when it is added to the diluent for component A. Furthermore, the presence or absence of stirring also affects the dispersion of the instantaneous product. The general principle is that a high concentration of dispersant in the precursor (substrate component) promotes the dispersion and stability of nanoparticles, while stirring and effective stirring also promote the dispersion and stability of nanoparticles.

[0145] Preparation method of propineb nano suspension

[0146] The present invention adopts the following technical solutions:

[0147] Under the condition that the stirring speed is not less than the effective stirring speed, the component A dilution is added to the component B dilution, or the component B dilution is added to the component A dilution to form a propineb nano suspension.

[0148] The component A diluent and the component B diluent are aqueous solutions formed by diluting the following components A and B with water respectively;

[0149] Component A: water-soluble propine salt or water-soluble propine salt aqueous solution, water-soluble polymer auxiliary agent; the water-soluble propine salt is one of propine ammonium, propine sodium, propine potassium, or a mixture of at least two of them;

[0150] Component B: It is composed of a certain proportion of zinc salt solid or its aqueous solution.

[0151] The adding method, adding speed and stirring speed are controlled so that 100-nanometer propineb nanoparticles, that is, 100-nanometer propineb nanosuspension, are generated in the suspension.

[0152] Effective stirring speed

[0153] The so-called effective stirring speed refers to the process in which when one component is added to another component, the nanopesticide crystals generated in the mixed liquid can be dispersed in time by stirring at a speed not less than the effective stirring speed, without significant crystal aggregation, thus preventing the size of these crystals from increasing to hundreds of nanometers or micrometers.

[0154] Stirring method

[0155] Manual stirring: This is more suitable for most application scenarios; in this case, the stirring speed must meet the physiological requirements of manual stirring and cannot be too fast.

[0156] Mechanical stirring: In the field, it is difficult to have large containers equipped with stirring devices. If such conditions are available, the speed of large stirring equipment generally does not exceed 100 rpm. Mixing at a speed close to this is sufficient.

[0157] For manual stirring, the stirring speed should be consistent with the human body's physiological function. To obtain a stable target product, the material addition rate can be appropriately reduced. The material addition rate can be determined by observing the product's transparent state in the system.

[0158] Joining method and joining speed

[0159] To ensure that the added materials are uniformly fine and quickly dispersed upon entering the system, one component can be added to another continuously, intermittently, or dropwise. For dropwise addition, spraying with a manual sprayer, commonly available in rural areas, is the most effective method. The addition speed is determined by observing the transparency of the product within the system.

[0160] Traditional pesticide formulations sprayed with water as the dispersion medium typically require dilution or mixing of co-used pesticide formulations before spraying, a process commonly known as "tank mixing." The present invention utilizes this process to mix components A and B at specific concentrations, addition methods, and speeds, in the presence of a specific adjuvant—a dispersant—to directly produce a transparent, tank-mixed propineb nanosuspension suitable for on-site spraying.

[0161] Dilution water consumption

[0162] Current experimental data shows that around 30 kg is a reasonable starting range

[0163] Of course, this dilution water consumption is strongly related to our target stabilization period.

[0164] This is a multivariate problem, and the additives (composition, content) in the component may also have an impact.

[0165] The present invention aims to produce a propineb suspension with a transparency and stability period of 1 to 10 hours at a level below 100 nanometers. When the unit mass of the precursor (e.g., 90 grams of propineb) and the metal salt (manganese sulfate, zinc sulfate) reacting with it are fixed, factors that can affect the nanometer size and stability of the particles include the amount of dilution water, the amount of additives used, and the preparation method.

[0166] The amount of water used for dilution can affect the size and stability of the resulting nano-propineb particles. This is because the amount of water used as the dispersion medium affects the concentration of the propineb solution and zinc sulfate solution at the moment of contact, as well as the uniformity of dispersion. Consequently, this influences the resulting grain size, grain dispersion, and the chances of crystal aggregation and growth. The amount of additive used affects its concentration in the aqueous solution at different water levels, as well as the extent of its dispersion, suspension, and stabilization of the resulting nano-particles and the duration of their stability. Too little water will reach a limit. For example, when the dilution water amount is less than 20 kg, the stability time of the resulting transparent nano-propineb suspension is only about one hour, which is insufficient for spraying operations. Therefore, the dilution water amount should be increased.

[0167] The present invention selects the dilution water amount to be between 30 and 300 kilograms, preferably between 50 and 200 kilograms, for producing 100 grams of the target product, i.e., a propineb suspension with a transparent stability period of 1 to 10 hours at a level below 100 nanometers.

[0168] [Brief Description of the Figures]

[0169] Figure 1: a flow chart of the traditional process for preparing mancozeb technical and processing it into a wettable powder formulation;

[0170] Figure 2: Schematic diagram of the process for preparing a nano-suspension of Propineb (two components)

[0171] Figure 3: Schematic diagram of the process for preparing a nano-suspension of Propineb (three components)

[0172] [Implementation Method]

[0173] The method of the present invention for preparing a transparent propineb suspension of less than 100 nm in size comprises the following steps:

[0174] In the first step, component A and component B are diluted separately according to different water amounts and different dilution ratios to form component A dilution liquid and component B dilution liquid.

[0175] In the second step, under mechanical stirring (preferably) or manual stirring conditions, the stirring speed is not less than the effective stirring speed, and the diluted solution of component A is evenly added to the diluted solution of component B according to a certain addition method (continuous or intermittent pouring, dropwise addition, spraying, etc.); or the addition can be done in the reverse order.

[0176] The steps for the three-component protocol are as follows:

[0177] In the first step, component A' (or component C) and component B' are diluted respectively according to different water amounts and different dilution ratios to form a component A' (or component C) dilution solution and a component B' dilution solution.

[0178] In the second step, component C (or component A') is added to the dilution of component A' (or component C), and stirred and dispersed evenly to form a mixed dilution of component A' (component C) and component C (component A').

[0179] The third step is to uniformly add the component B' dilution to the mixed dilution of component A' and component C in a certain addition method (continuous or intermittent pouring, dropwise addition, spraying, etc.) under mechanical stirring (preferably) or manual stirring at a stirring speed not less than the effective stirring speed; or add in the reverse order.

[0180] Here are some examples:

[0181] Example 1

[0182] Propineb nanosuspension can be used to control early and late blight of tomatoes, early blight of potatoes, and downy mildew of cucumbers. The active ingredient dosage is approximately 100 grams per mu, and the dilution water requirement is generally 50 kilograms. To produce 100 grams of propineb, 90 grams of propinephrine are required.

[0183] Component ratio: The component ratio, dilution water volume, water distribution, addition sequence and method, and test results are listed in the following table:

[0184] How to do it:

[0185] Dilute and dissolve component A and component B in 50 kg of water at a ratio of 2 / 3 and 1 / 3, respectively. While stirring, add the diluted component B to the diluted component A in a continuous stream to obtain a transparent nano-suspension of propineb. The suspension should be stable for 3 hours.

[0186] Example 2

[0187] Propineb nanosuspension can be used to control apple leaf spot disease. The active ingredient dosage is 200 grams per mu, and the dilution water dosage is generally 200 kilograms. 180 grams of propineb are required to produce 200 grams of propineb.

[0188] Component ratio: The component ratio, dilution water volume, water distribution, addition sequence and method, and test results are listed in the following table:

[0189] How to do it:

[0190] Component A and component B were diluted and dissolved in a ratio of 4 / 5 and 1 / 5 of 200 kg of dilution water, respectively. While stirring, the diluted component B solution was added to the diluted component A solution by continuous spraying to obtain a transparent nano-suspension of propineb, which was stable for 5 hours.

[0191] Example 3

[0192] Propineb nanosuspension can be used to control black scab in pear trees. The active ingredient dosage is 300 grams per mu, and the dilution water requirement is generally 300 kilograms. Propineb requires 270 grams of propineb to produce 300 grams.

[0193] Component ratio: The component ratio, dilution water volume, water distribution, addition sequence and method, and test results are listed in the following table:

[0194] How to do it:

[0195] Component C and component B' were diluted and dissolved in a ratio of 4 / 5 and 1 / 5 of 300 kg of dilution water, respectively, to produce a component C dilution solution and a component B' dilution solution, respectively. Component A' was then added to the component C dilution solution and stirred to disperse uniformly, forming a mixed dilution solution of components C and A'. While stirring, the component B' dilution solution was continuously sprayed into the mixed dilution solution of components C and A', resulting in a transparent nano-suspension of propineb, which remained stable for 4 hours.

[0196] Example 4

[0197] Propineb nanosuspension can be used to control corn leaf spot. The active ingredient dosage is about 100 grams per mu, and the dilution water requirement is generally 30 kilograms. 90 grams of propineb are required to produce 100 grams of propineb.

[0198] Component ratio: The component ratio, dilution water volume, water distribution, addition sequence and method, and test results are listed in the following table:

[0199] How to do it:

[0200] Dilute and dissolve component A and component B in 40 kg of water at a ratio of 2 / 3 and 1 / 3, respectively. While stirring, continuously spray the diluted component B solution into the diluted component A solution to produce a transparent nano-suspension of propineb. The suspension is stable for 3.5 hours.

[0201] Example 5

[0202] Propineb nanosuspension can be used to control rice flax spot disease. The active ingredient dosage is about 70 grams per mu, and the dilution water requirement is generally 30 kilograms. To produce 70 grams of propineb, 63 grams of propinephrine are required.

[0203] Component ratio: The component ratio, dilution water volume, water distribution, addition sequence and method, and test results are listed in the following table:

[0204] How to do it:

[0205] Dilute and dissolve component A and component B in 40 kg of water at a ratio of 2 / 3 and 1 / 3, respectively. While stirring, continuously spray the diluted component B into the diluted component A to produce a transparent nano-suspension of propineb. Stable for 3 hours.

[0206] Example 6

[0207] Propineb nanosuspension can be used to control anthracnose and scab in citrus trees. The active ingredient dosage is 100 grams per mu, and the dilution water requirement is generally 200 kilograms. 90 grams of propineb are required to produce 100 grams of propineb.

[0208] Component ratio: The component ratio, dilution water volume, water distribution, addition sequence and method, and test results are listed in the following table:

[0209] How to do it:

[0210] Component C and component B' were diluted and dissolved in a ratio of 4 / 5 and 1 / 5 of 200 kg of dilution water, respectively, to produce a component C dilution solution and a component B' dilution solution, respectively. Component A' was then added to the component C dilution solution and stirred to disperse uniformly, to produce a mixed dilution solution of components C and A'. While stirring, the component B' dilution solution was continuously sprayed into the mixed dilution solution of components C and A', to produce a transparent propineb nanosuspension with a stable time of 4.5 hours.

Claims

1. A propineb nano suspension, characterized in that: The propineb nano suspension is a propineb nano suspension with a size of less than 100 nanometers. The propineb nano suspension with a size of less than 100 nanometers is formed by diluting and mixing two components with water: Component A: water-soluble propine salt or water-soluble propine salt aqueous solution, water-soluble polymer auxiliary agent; the water-soluble propine salt is one of propine ammonium, propine sodium, propine potassium, or a mixture of at least two of them; Component B: zinc salt or aqueous solution of zinc salt in a certain mass ratio.

2. The propineb nano suspension according to claim 1, wherein The nano-suspension of propineb below 100 nanometers has a stable period of hours.

3. The propineb nano suspension according to claim 1, wherein The component B is added with a water-soluble polymer auxiliary agent and water to form an aqueous solution.

4. The propineb nano suspension according to claim 1, wherein The water-soluble polymer auxiliary agent is a nonionic surfactant.

5. The propineb nano suspension according to claim 1, wherein The ratio of the amount of the water-soluble polymer additive to the amount of water used for dilution is not greater than 1:1200.

6. The propineb nano suspension according to claim 4, wherein The nonionic surfactant is at least one of the following options: water-soluble starch and its derivatives, water-soluble guar gum and its derivatives, polyoxypropylene-polyoxyethylene block copolymer, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, OP-10, alkylarylphenol polyoxypropylene polyoxyethylene ether, castor oil polyoxyethylene ether, alkyl polysaccharide, Tween, and polyvinyl alcohol.

7. The propineb nanosuspension according to any one of claims 1 to 6, characterized in that The zinc salt is selected from at least one of zinc sulfate, zinc acetate, zinc chloride and zinc nitrate.

8. [Corrected 21.12.2023 according to Rule 91] The nanosuspension of propineb according to claim 7, characterized in that When the propine salt and the zinc salt are propinephrine and zinc sulfate respectively, the mass ratio thereof is in the range of propinephrine: zinc sulfate = 1: 0.50-1.01, preferably, propinephrine: zinc sulfate = 1: 0.90-1.

00.

9. A propineb nano suspension, characterized in that: The propineb nano suspension is a propineb nano suspension with a size of less than 100 nanometers. The propineb nano suspension with a size of less than 100 nanometers is formed by diluting and mixing three components with water: Component A: consisting of solid propinemium and / or propinem sodium and / or propinem potassium, or a solid aqueous solution of propinemium and / or propinem sodium and / or propinem potassium; Component B: composed of zinc salt solid or its aqueous solution in a certain proportion; Component C: consists of at least one water-soluble surfactant, or its aqueous solution.

10. The propineb nano suspension according to claim 9, wherein The ratio of the amount of the water-soluble surfactant to the amount of dilution water is not greater than 1:1200.

11. The propineb nano suspension according to claim 9, wherein The nano-suspension of propineb below 100 nanometers has a stable period of hours.

12. The propineb nano suspension according to claim 9, wherein The component B is composed of an inorganic zinc salt or its aqueous solution.

13. The propineb nanosuspension according to claim 12, characterized in that The zinc salt is selected from at least one of zinc sulfate, zinc acetate, zinc chloride and zinc nitrate.

14. The propineb nano suspension according to claim 9, wherein The water-soluble surfactant is a high-molecular surfactant and / or a small-molecular surfactant.

15. The propineb nanosuspension according to claim 14, characterized in that The polymer surfactant is selected from nonionic surfactants.

16. The propineb nanosuspension according to claim 15, characterized in that The nonionic surfactant is selected from derivatives of polyoxyethylene polymers, water-soluble starch, cellulose, nonionic derivatives of chitosan, dextrin, methyl ethyl cellulose, chitosan with a deacetylation degree of about 50%, and polyol derivatives such as Tween and alkyl polyglycoside; or selected from synthetic polymer products such as polyvinyl alcohol and polyvinyl pyrrolidone.

17. A method for preparing the propineb nanosuspension according to claims 1 to 8; adding the diluted component A to the diluted component B under the condition that the stirring speed is not less than the effective stirring speed; Alternatively, the component B dilution is added to the component A dilution to form a propineb nanosuspension; The component A dilution solution and the component B dilution solution are aqueous solutions formed by diluting component A and component B with water, respectively.

18. The preparation method according to claim 17, wherein The method of adding one component to another component is one of the following four methods: continuous addition, intermittent addition, dropwise addition, and spray addition.

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