An adjuvant composition for film-coated suspensions, film-coated suspensions and methods of making the same

Abstract

This invention provides an adjuvant composition for film-sealing suspensions, a film-sealing suspension, and its preparation method, belonging to the field of pesticide technology. By mass parts, the adjuvant composition for film-sealing suspensions in this invention comprises: 0-3 parts of cationic small molecule surfactant, 0.01-3 parts of anionic small molecule surfactant, 0-5 parts of solid thickener, 0-5 parts of stabilizer, 7-20 parts of emulsifier, and 40-80 parts of oil phase medium; the cationic small molecule surfactant and the solid thickener are not both 0, and when the cationic small molecule surfactant is 0, the solid thickener includes a cationic solid thickener. The film-sealing suspension prepared by the method of this invention has good storage stability and can form a stable S / O / W (oil-in-water emulsion) or S / S / O / W (oil-in-water emulsion) emulsion in water, exhibiting good storage stability and dispersibility, which is beneficial for improving efficacy.

Description

Technical Field

[0001] This invention relates to the field of pesticide technology, and in particular to an adjuvant composition for film-sealing suspensions, a film-sealing suspension, and a method for preparing the same. Background Technology

[0002] Oil suspensions are highly dispersed and stable suspensions of one or more active pesticide ingredients (at least one of which is a solid technical) in a non-aqueous dispersion medium. They can be used after dilution with an organic dispersion medium or water. The composition of oil suspensions generally includes the technical, dispersant, emulsifier, thickener, stabilizer, and dispersion medium. Oil suspensions are highly adaptable and are an important supplement to water-based and granular formulations. Many water-sensitive pesticides can be formulated into this type of product. Furthermore, they can use environmentally friendly solvents such as pure natural vegetable oils, methylated vegetable oils, and mineral oils as dispersion media, exhibiting good environmental compatibility and producing no dust during production and use, making them green and environmentally friendly. Traditional oil suspensions typically use anionic and nonionic surfactants, which generally suffer from poor storage stability, easily leading to stratification and crusting during storage. Moreover, their poor dispersibility in water during use often results in oil-pesticide separation, significantly hindering the development of oil suspensions. Summary of the Invention

[0003] The purpose of this invention is to provide an adjuvant composition for membrane-sealing suspensions, a membrane-sealing suspension, and a method for preparing the same. The membrane-sealing suspension prepared by the method of this invention has good storage stability and can form a stable S / O / W (oil-in-water emulsion) or S / S / O / W (oil-in-water emulsion) with drug (solid) in water. The product has good storage stability and good dispersibility, which is beneficial to improving drug efficacy.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides an additive composition for membrane-sealing suspending agents, comprising the following components in parts by weight: 0-3 parts cationic small molecule surfactant, 0.01-3 parts anionic small molecule surfactant, 0-5 parts solid thickener, 0-5 parts stabilizer, 7-20 parts emulsifier, and 40-80 parts oil phase medium; The cationic small molecule surfactant and the solid thickener are not both 0, and when the cationic small molecule surfactant is 0, the solid thickener includes a cationic solid thickener.

[0005] Preferably, the cationic small molecule surfactant includes a quaternary ammonium salt type cationic surfactant; the quaternary ammonium salt type cationic surfactant includes one or more of octyldecyl dimethyl ammonium halide, bis(octadecyl)dimethyl ammonium halide, bis(decyl)dimethyl ammonium halide, bis(tetradecyl)dimethyl ammonium halide, bis(hexadecyl)dimethyl ammonium halide, bis(dodecyl)dimethyl ammonium halide, dodecyltrimethyl ammonium halide, octadecyltrimethyl ammonium halide, and hexadecyltrimethyl ammonium halide; the halide ion in the quaternary ammonium salt type cationic surfactant is a chloride ion or a bromide ion.

[0006] Preferably, the anionic small molecule surfactant comprises one or more of sodium dodecyl sulfate, sodium lauryl sulfate, sodium oleate, sulfonates, triethanolamine oleate, and stearates; the sulfonates comprise one or more of sodium dioctyl succinate sulfonate, sodium α-alkenyl sulfonate, sodium dodecylbenzene sulfonate, calcium dodecylbenzene sulfonate, sodium fatty acid methyl ester sulfonate, and sodium hexadecyl sulfonate; and the stearates comprise one or more of sodium stearate, aluminum stearate, zinc stearate, calcium stearate, and magnesium stearate.

[0007] Preferably, the solid thickener includes one or more of organic bentonite, inorganic bentonite, silica, and magnesium aluminum silicate; the stabilizer includes, but is not limited to, citric acid and / or urea.

[0008] Preferably, the emulsifier comprises one or more of triphenylethylphenol polyoxyethylene ether, castor oil polyoxyethylene ether, calcium dodecylbenzenesulfonate, triphenylethylphenol polyoxyethylene polyoxypropylene ether, alkylphenol polyoxyethylene ether, cashew phenol polyoxyethylene ether, and fatty alcohol polyoxyethylene ether; the triphenylethylphenol polyoxyethylene ether is a 601 series emulsifier; the castor oil polyoxyethylene ether is an EL-10 series emulsifier or an EL-20 series emulsifier; the calcium dodecylbenzenesulfonate is a 500# calcium salt series emulsifier; the triphenylethylphenol polyoxyethylene polyoxypropylene ether is a 1601 series emulsifier; the alkylphenol polyoxyethylene ether comprises one or more of OP-10, OP-7, OP-4, DP-10, DP-7, and DP-4; and the fatty alcohol polyoxyethylene ether comprises one or more of AEO-9, AEO-7, AEO-5, and AEO-3.

[0009] Preferably, the oil phase medium includes one or more of methyl oleate, epoxidized soybean oil, corn oil, and soybean oil.

[0010] This invention provides a method for preparing a membrane-sealing suspension based on the above-described additive composition for membrane-sealing suspensions, comprising the following steps: The cationic small molecule surfactant, solid thickener, active ingredient, stabilizer, and oil phase medium are mixed and ground to obtain the first mixture; The first mixture is mixed with an anionic small molecule surfactant to obtain a second mixture; The second mixture is mixed with an emulsifier to obtain the membrane-sealed suspension.

[0011] Preferably, the solid thickener in the film-sealed suspension contains 0-5% by mass, and the technical grade drug contains 1-50% by mass; the technical grade drug is a polar technical grade drug, including but not limited to one or more of cyclosulfonamide, nicosulfuron, mesotrione, benzoxazine, atrazine, mesosulfuron-methyl, penoxsulam, cyhalofop-butyl, terbufos, chlorantraniliprole, thiamethoxam, and bromuconamide.

[0012] Preferably, the preparation method of the first mixture includes the following steps: mixing a cationic small molecule surfactant, a solid thickener and a portion of an oil phase medium and pre-grinding to obtain a premix; mixing the mixture, the active ingredient, the stabilizer and the remaining oil phase medium and re-grinding to obtain the first mixture; The oil phase medium constitutes 30-70% of the total mass of the oil phase medium; the pre-grinding and regrinding are performed by sand milling; the particle size of the premix is ​​<1μm, the particle size of the first mixture is <5μm, and the particle size of the second mixture is <5μm.

[0013] The present invention provides a membrane-sealed suspension prepared by the method described in the above technical solution.

[0014] Beneficial Effects: The membrane-sealing suspension additive composition provided by this invention, by weight, comprises the following components: 0-3 parts cationic small molecule surfactant, 0.01-3 parts anionic small molecule surfactant, 0-5 parts solid thickener, 0-5 parts stabilizer, 7-20 parts emulsifier, and 40-80 parts oil phase medium; the cationic small molecule surfactant and solid thickener are not both zero, and when the cationic small molecule surfactant is zero, the solid thickener includes a cationic solid thickener. In this invention, the cationic small molecule surfactant and / or solid thickener provide cations, which, when combined with anionic small molecule surfactants, ensure good storage stability of the prepared membrane-sealing suspension. Furthermore, it forms a stable S / O / W emulsion or S / S / O / W emulsion upon contact with water, exhibiting good emulsification and dispersibility, resulting in good product storage stability and improved efficacy.

[0015] This invention also provides a method for preparing a film-sealing suspension based on the aforementioned adjuvant composition. In this invention, a cationic small-molecule surfactant and / or a solid thickener are first adsorbed onto the surface of the drug, and then an anionic small-molecule surfactant with opposite charge is added for secondary adsorption, thereby achieving the adsorption of both anions and cations (positive and negative ions) onto the surface of the drug. Due to the strong electrostatic attraction between anions and cations, the two oppositely charged reagents are firmly adsorbed onto the surface of the drug and hardly desorb or fall off. Therefore, an S / O (oil-in-drug / solid) interfacial film or an S / S / O (oil-in-solid-in-drug / solid) interfacial film composed of a mixture of two oppositely charged reagents can be formed on the surface of the drug. Then, under the action of an emulsifier, a bilayer is formed (i.e., a film layer formed by a small molecule surfactant and a solid thickener, and a film layer formed by an emulsifier). The resulting membrane-encapsulated suspension can form a stable S / O / W emulsion (with the addition of a cationic small molecule surfactant and no thickener) or an S / S / O / W emulsion (with the addition of a cationic small molecule surfactant and a thickener) when placed in water. Under a microscope, it appears as spherical oil droplets or irregularly shaped oil droplets (the specific shape depends on the particle size and shape of the drug). It has good emulsification and dispersibility, good product storage stability, and is conducive to improving drug efficacy. Attached Figure Description

[0016] Figure 1 A high-powered photograph of the water surface of the sample (the film-sealed suspension prepared in Example 1) on a glass slide; Figure 2 A low-magnification photograph of the water surface of the sample (the film-sealed suspension prepared in Example 1) on a glass slide; Figure 3 A high-powered photograph of the bottom of the sample (the film-sealed suspension prepared in Example 1) on a glass slide; Figure 4 A high-powered photograph of the water surface of the sample (the film-sealed suspension prepared in Example 2) on a glass slide; Figure 5 A low-power photograph of the sample (the film-sealed suspension prepared in Example 2) on a glass slide at the water surface; Figure 6 A high-powered photograph of the water surface of the sample (the film-sealed suspension prepared in Example 3) on a glass slide; Figure 7 A low-power photograph of the water surface of the sample (the film-sealed suspension prepared in Example 3) on a glass slide; Figure 8 A high-powered photograph of the bottom of the sample (the film-sealed suspension prepared in Example 3) on a glass slide; Figure 9 A high-powered photograph of the water surface of the sample (the film-sealed suspension prepared in Example 4) on a glass slide; Figure 10High magnification image of the bottom of the sample (the film-sealed suspension prepared in Example 4) on the glass slide (standing time approximately 5 minutes). Figure 11 High magnification image of the bottom of the sample (the film-sealed suspension prepared in Example 4) on the glass slide (standing time approximately 30 min). Figure 12 A high-powered photograph of the water surface of the sample (the film-sealed suspension prepared in Example 5) on a glass slide; Figure 13 A low-magnification photograph of the water surface of the sample (the film-sealed suspension prepared in Example 5) on a glass slide; Figure 14 A high-powered photograph of the bottom of the sample (the film-sealed suspension prepared in Example 5) on a glass slide; Figure 15 A high-powered photograph of the bottom of the sample (the film-sealed suspension prepared in Comparative Example 1) on a glass slide; Figure 16 A low-powered photograph of the bottom of the sample (the film-sealed suspension prepared in Comparative Example 1) on a glass slide; Figure 17 A high-powered photograph of the bottom of the sample (the film-sealed suspension prepared in Comparative Example 2) on a glass slide; Figure 18 This is a low-powered photograph of the bottom of the sample (the film-sealed suspension prepared in Comparative Example 2) on a glass slide. Detailed Implementation

[0017] This invention provides an additive composition for membrane-sealing suspending agents, comprising the following components in parts by weight: 0-3 parts cationic small molecule surfactant, 0.01-3 parts anionic small molecule surfactant, 0-5 parts solid thickener, 0-5 parts stabilizer, 7-20 parts emulsifier, and 40-80 parts oil phase medium; The cationic small molecule surfactant and the solid thickener are not both 0, and when the cationic small molecule surfactant is 0, the solid thickener includes a cationic solid thickener.

[0018] In this invention, unless otherwise specified, all raw materials used are commercially available products well known to those skilled in the art or prepared using methods well known to those skilled in the art.

[0019] The membrane encapsulation suspension additive composition provided by this invention comprises 0-3 parts by weight of a cationic small molecule surfactant, specifically 0 parts (i.e., none), 0.01 parts, 0.05 parts, 0.1 parts, 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 1 part, 1.5 parts, 2 parts, or 2.5 parts. The cationic small molecule surfactant mentioned in this invention specifically refers to a cationic surfactant with a relative molecular mass ≤1000. As one embodiment of this invention, the cationic small molecule surfactant includes a quaternary ammonium salt type cationic surfactant; the quaternary ammonium salt type cationic surfactant includes one or more of octyldecyl dimethyl ammonium halide, bis(octadecyl)dimethyl ammonium halide, bis(decyl)dimethyl ammonium halide, bis(tetradecyl)dimethyl ammonium halide, bis(hexadecyl)dimethyl ammonium halide, bis(dodecyl)dimethyl ammonium halide, dodecyltrimethyl ammonium halide, octadecyltrimethyl ammonium halide, and hexadecyltrimethyl ammonium halide; the halide ion in the quaternary ammonium salt type cationic surfactant is a chloride ion or a bromide ion. Specifically, the cationic small molecule surfactant described in this invention can be one or more of the following: octyldecyl dimethyl ammonium chloride, octyldecyl dimethyl ammonium bromide, dioctadecyl dimethyl ammonium chloride (D1821), dioctadecyl dimethyl ammonium bromide, didecyl dimethyl ammonium chloride (D1021), didecyl dimethyl ammonium bromide, dodecyl trimethyl ammonium chloride, dodecyl trimethyl ammonium bromide, octadecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium bromide, hexadecyl trimethyl ammonium chloride, and hexadecyl trimethyl ammonium bromide. In the examples, D1821 or D1021 is specifically used.

[0020] Based on the mass fraction of the cationic small molecule surfactant, the membrane encapsulation suspension additive composition provided by the present invention comprises 0.01 to 3 parts of anionic small molecule surfactant, specifically 0.05 parts, 0.1 parts, 0.3 parts, 0.5 parts, 0.6 parts, 0.8 parts, 1 part, 1.2 parts, 1.5 parts, 1.8 parts, 2 parts, or 2.5 parts. The anionic small molecule surfactant mentioned in the present invention specifically refers to anionic surfactants with a relative molecular mass ≤1000. In one embodiment of the present invention, the anionic small molecule surfactant includes one or more of sodium dodecyl sulfate, sodium lauryl sulfate, sodium oleate, sulfonates, triethanolamine oleate, and stearates; the sulfonates include one or more of sodium dioctyl succinate sulfonate, sodium α-alkenyl sulfonate, sodium dodecylbenzene sulfonate, calcium dodecylbenzene sulfonate, sodium fatty acid methyl ester sulfonate, and sodium hexadecyl sulfonate; the stearates include one or more of sodium stearate, aluminum stearate, zinc stearate, calcium stearate, and magnesium stearate. In this embodiment of the invention, the anionic surfactant may specifically be a compound of sodium dioctyl succinate sulfonate, sodium α-alkenyl sulfonate, aluminum stearate, and zinc stearate, wherein the mass ratio of sodium dioctyl succinate sulfonate, sodium α-alkenyl sulfonate, aluminum stearate, and zinc stearate may be 1.8~2.2:1.8~2.2:0.8~1.2:0.8~1.2, specifically 2:2:1:1; or, the anionic surfactant may specifically be a compound of sodium dioctyl succinate sulfonate and calcium dodecylbenzenesulfonate, wherein the mass ratio of sodium dioctyl succinate sulfonate and calcium dodecylbenzenesulfonate may be 0.8~1.2:0.8~1.2, specifically 1:1.

[0021] In one embodiment of the present invention, when the cationic small molecule surfactant is D1821 or D1021, the anionic small molecule surfactant can be a compound of sodium dioctyl succinate sulfonate, sodium α-alkenyl sulfonate, aluminum stearate and zinc stearate, or it can be a compound of sodium dioctyl succinate sulfonate and calcium dodecylbenzene sulfonate. The mass ratio of the components in each compound is consistent with the above technical solution, and will not be repeated here.

[0022] Based on the mass fraction of the cationic small molecule surfactant, the membrane encapsulation suspending agent composition provided by the present invention includes 0 to 5 parts of solid thickener, specifically 0 parts (i.e., none added), 0.01 parts, 0.05 parts, 0.1 parts, 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, or 4.5 parts. The cationic small molecule surfactant and the solid thickener in the present invention are not both 0, and when the cationic small molecule surfactant is 0, the solid thickener includes a cationic solid thickener. In one embodiment of the present invention, the solid thickener includes one or more of organic bentonite, inorganic bentonite, silica, and magnesium aluminum silicate, specifically organic bentonite, silica, or magnesium aluminum silicate; wherein the organic bentonite is a cationic solid thickener, and the inorganic bentonite, silica, and magnesium aluminum silicate are non-cationic solid thickeners; when the solid thickener used includes organic bentonite, a cationic small molecule surfactant may or may not be added; when the solid thickener used is at least one of inorganic bentonite, silica, and magnesium aluminum silicate, a cationic small molecule surfactant needs to be added. In one embodiment of the present invention, the organobentonite can specifically be one or more of OR-10, OR-13, OR-14, and OR-19 organobentonite. Specifically, in the embodiments, it can be a compound of OR-10 and OR-19 organobentonite, or a compound of OR-13 and OR-19 organobentonite, or a compound of OR-14 and OR-19 organobentonite. The mass content of OR-19 organobentonite in each compound can be independently 80-90%, and more specifically 83-85%. The silica can be fumed silica. The magnesium aluminum silicate can be MAS-2 magnesium aluminum silicate. The present invention uses the above-mentioned types and amounts of solid thickeners, which helps to ensure excellent product stability. If the amount is too large, the product viscosity will be high, making it inconvenient to use; if the amount is too small, the product stability will be insufficient.

[0023] Based on the mass fraction of the cationic small molecule surfactant, the membrane encapsulation suspension additive composition provided by the present invention includes 0-5 parts of stabilizer, more specifically 0.01-5 parts, and can be 0.1 parts, 0.3 parts, 0.5 parts, 0.8 parts, 1 part, 1.2 parts, 1.5 parts, 1.8 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, or 4.5 parts. As one embodiment of the present invention, the stabilizer includes citric acid and / or urea; when the stabilizer is citric acid and urea, the mass ratio of citric acid to urea can be 1-10:1, specifically 3:1, 5:1, or 8:1. The present invention selects the appropriate stabilizer according to the type of active ingredient; for example, when the active ingredient includes nicosulfuron, citric acid is preferably used as the stabilizer; when the active ingredient includes nicosulfuron, urea is preferably used as the stabilizer. The use of stabilizers of the above types and amounts in the present invention is beneficial to further improve the stability of the product.

[0024] Based on the mass fraction of the cationic small molecule surfactant, the membrane encapsulation suspension additive composition provided by the present invention includes 7 to 20 parts of emulsifier, specifically 8, 9, 10, 11, 12, 13, 14, 15, or 18 parts. As one embodiment of the present invention, the emulsifier includes one or more of triphenylethylphenol polyoxyethylene ether, castor oil polyoxyethylene ether, calcium dodecylbenzenesulfonate, triphenylethylphenol polyoxyethylene polyoxypropylene ether, alkylphenol polyoxyethylene ether, cashew nut phenol polyoxyethylene ether, and fatty alcohol polyoxyethylene ether. In one embodiment of the present invention, the triphenylethylphenol polyoxyethylene ether can specifically be a 601 series emulsifier; the castor oil polyoxyethylene ether can specifically be an EL-10 series emulsifier or an EL-20 series emulsifier; the calcium dodecylbenzenesulfonate can specifically be a 500# calcium salt series emulsifier; the triphenylethylphenol polyoxyethylene polyoxypropylene ether can specifically be a 1601 series emulsifier; the alkylphenol polyoxyethylene ether can specifically include one or more of octylphenol polyoxyethylene ether, nonylphenol polyoxyethylene ether, and dodecylphenol polyoxyethylene ether, and further can include one or more of OP-10, OP-7, OP-4, DP-10, DP-7, and DP-4; the fatty alcohol polyoxyethylene ether can specifically include isomeric decayl alcohol polyoxyethylene ether and / or isomeric tridecayl alcohol polyoxyethylene ether, and further can include one or more of AEO-9, AEO-7, AEO-5, and AEO-3. The present invention can adaptably employ different types of emulsifier formulations for different types of surfactant systems and oil phase media. In this embodiment of the invention, the emulsifier may specifically be a compound of tristyrylphenol polyoxyethylene ether (601) - castor oil polyoxyethylene ether (EL-10) - calcium dodecylbenzenesulfonate (500#), wherein the mass ratio of 601, EL-10 and 500# may be 2~5:2~5:3~6, specifically 4:4:5, 3:4:4 or 3:3:4; or, the emulsifier may specifically be a compound of tristyrylphenol polyoxyethylene polyoxypropylene ether (1601) - castor oil polyoxyethylene ether (EL-10) - calcium dodecylbenzenesulfonate (500#), wherein the mass ratio of 1601, EL-10 and 500# may be 2~5:2~5:3~6, specifically 3:3:4. The calcium dodecylbenzenesulfonate (500#) used in this embodiment of the invention is specifically a compound of calcium dodecylbenzenesulfonate and solvent oil. The present invention uses the above-mentioned types and amounts of emulsifiers to form S / O / W emulsions or S / S / O / W emulsions, which helps to ensure that the product has excellent stability. If too much or too little is used, a stable S / O / W emulsion or S / S / O / W emulsion cannot be formed.

[0025] Based on the mass fraction of the cationic small molecule surfactant, the membrane encapsulation suspension additive composition provided by the present invention comprises 40-80 parts of an oil phase medium, specifically 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, or 75 parts. As one embodiment of the present invention, the oil phase medium comprises one or more of methyl oleate, epoxidized soybean oil, corn oil, and soybean oil, specifically methyl oleate.

[0026] This invention provides a method for preparing a membrane-sealing suspension based on the above-described additive composition for membrane-sealing suspensions, comprising the following steps: The cationic small molecule surfactant, solid thickener, active ingredient, stabilizer, and oil phase medium are mixed and ground to obtain the first mixture; The first mixture is mixed with an anionic small molecule surfactant to obtain a second mixture; The second mixture is mixed with an emulsifier to obtain the membrane-sealed suspension.

[0027] This invention eliminates the need for high-molecular-weight surfactants (polymer surfactants). Instead, it utilizes cationic small-molecule surfactants and / or solid thickeners to provide cations, which are then combined with anionic small-molecule surfactants. This means that two oppositely charged reagents can form an S / O (oil-encapsulated drug / solid) interfacial film on the surface of the active pharmaceutical ingredient (e.g., a polar active pharmaceutical ingredient). Finally, the film-encapsulated suspension is prepared under the action of an emulsifier. For different types of active pharmaceutical ingredients, due to differences in density and surface properties, the adsorption amounts of the two oppositely charged reagents on the ingredient surface vary, and the maximum particle size of the active pharmaceutical ingredient required to form an S / O / W emulsion or an S / S / O / W emulsion also differs. This invention does not impose any specific limitations on the particle size of the active pharmaceutical ingredient. The preparation method of the film-encapsulated suspension described in this invention is described in detail below.

[0028] This invention involves mixing and grinding a cationic small-molecule surfactant, a solid thickener, a technical grade agent, a stabilizer, and an oil-phase medium to obtain a first mixture. In one embodiment of this invention, the mass content of the cationic small-molecule surfactant in the membrane-sealing suspension is 0-3%, specifically 0, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 1.5%, 2%, or 2.5%; the mass content of the solid thickener is 0-5%, specifically 0, 0.01%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, or 4.5%. This invention does not specifically limit the type or amount of the technical grade agent; all technical grades suitable for oil-based suspension formulations can be used in the preparation of the membrane-sealing suspension of this invention. In one embodiment of this invention, the technical grade agent includes at least one solid technical grade agent; that is, the technical grade agent in this invention can be one or more solid technical grades, or one or more liquid technical grades combined with one or more solid technical grades. This invention does not specifically limit this. In one embodiment of the present invention, the technical material is a polar technical material, including but not limited to one or more of the following: cyclosulfonamide, nicosulfuron, mesotrione, benzoxazine, atrazine, mesosulfuron-methyl, penoxsulam, cyhalofop-butyl, terbufos, chlorantraniliprole, thiamethoxam, and broflanilide. For example, it can be cyclosulfonamide or chlorantraniliprole, or it can be a nicosulfuron-atrazine compound, or it can be a nicosulfuron-mesotrione-atrazine compound. The present invention does not specifically limit this; in the embodiments of the present invention, when the polar active ingredient is a nicosulfuron-atrazine compound, the mass ratio of nicosulfuron to atrazine can be 2~4:18~22, specifically 3:20; when the polar active ingredient is a nicosulfuron-mesotrione-atrazine compound, the mass ratio of nicosulfuron, mesotrione and atrazine can be 2~4:6~8:18~22, specifically 3:7:20. As one embodiment of the present invention, the mass content of the active ingredient in the membrane-sealed suspension can be 3~50%, specifically 3%, 5%, 8%, 10%, 15%, 20%, 23%, 25%, 30%, 35%, 40%, 45% or 50%.

[0029] This invention does not impose special limitations on the mixing method and operating conditions of the cationic small molecule surfactant, solid thickener, active ingredient, stabilizer, and oil phase medium, as long as the components are uniformly mixed and dispersed. This invention also does not impose special limitations on the grinding method and operating conditions, as long as the desired particle size of the first mixture is obtained. The grinding can be sand milling; the particle size of the first mixture can be <5μm. During the mixing and grinding process of this invention, in the oil phase medium, the cationic small molecule surfactant and solid thickener are adsorbed onto the surface of the active ingredient, forming an S / O interface film or an S / S / O interface film.

[0030] This invention allows for the direct mixing and grinding of cationic small molecule surfactants, solid thickeners, active ingredients, stabilizers, and an oil-phase medium. The operation is convenient, and the mixing and grinding can also be performed in stages. Specifically, the preparation method of the first mixture may include the following steps: pre-grinding a mixture of cationic small molecule surfactants, solid thickeners, and a portion of the oil-phase medium to obtain a premix; and further grinding the mixture, active ingredient, stabilizer, and the remaining oil-phase medium to obtain the first mixture. In one embodiment of this invention, the portion of the oil-phase medium constitutes 30-70% of the total mass of the oil-phase medium, and more specifically, 50-60%. The amount of oil-phase medium in the membrane-sealing suspending agent is based on ensuring that the total mass of all raw materials is 100%. This invention does not impose any special limitations on the mixing method and operating conditions of the cationic small molecule surfactant, solid thickener and oil phase medium, as long as the components are mixed and dispersed evenly; this invention also does not impose any special limitations on the pre-grinding and regrinding methods and operating conditions, as long as the desired particle size of the premix and the first mixture is obtained (the finer the particle size, the better); the pre-grinding and regrinding can be sand milling; the particle size of the premix can be <1μm, and the particle size of the first mixture can be <5μm.

[0031] After obtaining the first mixture, the present invention mixes the first mixture with an anionic small molecule surfactant to obtain a second mixture. In one embodiment of the present invention, the mass content of the anionic small molecule surfactant in the membrane-sealing suspension is 0.01~3%, specifically 0.1%, 0.3%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2%, or 2.5%. The present invention does not have specific limitations on the mixing method and operating conditions of the first mixture and the anionic small molecule surfactant, as long as the components are uniformly mixed and dispersed; the first mixture and the anionic small molecule surfactant can be directly mixed to obtain the second mixture, or they can be further ground after mixing to obtain the second mixture; the present invention does not have specific limitations on the grinding method and operating conditions, as long as the desired particle size of the second mixture is obtained; the grinding can be sand milling; the particle size of the second mixture can be <5μm. During the mixing and grinding process described in this invention, anionic small molecule surfactants and cationic small molecule surfactants and / or solid thickeners are adsorbed onto the surface of the drug in the oil phase medium, forming an adsorption layer on the drug surface together, which provides a basis for the formation of a stable S / O interface film or S / S / O interface film.

[0032] After obtaining the second mixture, the present invention mixes the second mixture with an emulsifier to obtain the membrane-sealing suspension. In one embodiment of the present invention, the mass content of the emulsifier in the membrane-sealing suspension can be 7-20%, specifically 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 18%. The present invention does not have specific limitations on the mixing method and operating conditions of the third mixture and the emulsifier, as long as the components are uniformly mixed and dispersed; specifically, stirring can be used for mixing. During the mixing process described in the present invention, in the oil phase medium, the emulsifier forms a bilayer with the anionic small molecule surfactant and the cationic small molecule surfactant adsorption layer. Upon introduction into water, a stable S / O / W emulsion or S / S / O / W emulsion can be obtained.

[0033] The present invention provides a membrane-encapsulated suspension prepared by the preparation method described in the above technical solution.

[0034] The present invention does not impose any special limitations on the specific method of using the membrane-sealed suspension, and its method of use can be the same as that of traditional oil suspension.

[0035] Unlike traditional oil suspensions, the film-sealed suspension (FSS) described in this invention specifically refers to an oil suspension that can spontaneously form an S / O / W (oil-in-water emulsion with drug / solid) or S / S / O / W (oil-in-water emulsion with solid-pharmaceutical emulsion) upon immersion in water. The challenge in obtaining this film-sealed suspension lies in the fact that to obtain a stable S / O / W emulsion, a stable S / O membrane or S / S / O membrane is required, while simultaneously ensuring the hydrophilic-lipophilic balance between the S / O (solid / oil) or S / S / O (solid / solid / oil) and O / W (oil / water) interfaces. If only one interface is well-balanced while the other is not, a stable S / O / W emulsion or S / S / O / W emulsion cannot be obtained. This invention successfully solves this problem by combining anionic small molecule surfactants and cationic small molecule surfactants and / or solid thickeners in a non-aqueous dispersion medium (i.e., an oil phase medium).

[0036] Specifically, traditional oil suspensions generally suffer from poor storage stability, leading to easy stratification and crusting. Furthermore, they often exhibit oil-pharmaceutical separation in water during use, failing to achieve proper suspension both during storage and upon immersion in water. Through extensive research and experimentation, the inventors discovered that the primary cause of these problems lies in the desorption of surfactants. Over time, the surfactants initially adsorbed onto the drug surface desorb and cannot return, resulting in crusting. By adjusting the surfactant formulation to ensure its firm adsorption onto the drug surface, forming a stable S / O (oil-encapsulated drug / solid) surfactant film or solid thickener microparticle layer (S / S / O), and then adding an emulsifier, a bilayer is formed on the drug surface. Upon immersion in water, a stable S / O / W emulsion or S / S / O / W emulsion is formed. This bilayer seals the drug surface, separating drug particles and preventing stratification and crusting. Therefore, the key to obtaining a stable S / O / W emulsion or S / S / O / W emulsion lies in whether a stable S / O interface film or S / S / O interface film can be formed. If a stable S / O interface film or S / S / O interface film cannot be formed, a stable S / O / W emulsion or S / S / O / W emulsion will not be obtained after being immersed in water.

[0037] This invention successfully solves this problem by employing a compounding technique of anionic small molecule surfactants, cationic small molecule surfactants, and / or solid thickeners. It should be noted that there is little research, both domestically and internationally, on mixed systems of anionic small molecule surfactants and cationic small molecule surfactants and / or solid thickeners with opposite ionic charges, and related research is limited to aqueous dispersion media. Furthermore, in the chemical industry, the general rule is that "anionic surfactants and cationic surfactants cannot be mixed, otherwise they lose their surface activity." This invention uses a compounding technique of anionic small molecule surfactants and cationic small molecule surfactants and / or solid thickeners in non-aqueous dispersion media. The strong electrostatic attraction between the two leads to a significant increase in the surface activity of the mixed system, far exceeding the surface activity achievable with nonionic-anionic surfactant mixtures. This allows for the stable formation of S / O or S / S / O interfacial films, laying the foundation for obtaining stable S / O / W or S / S / OW emulsions in water, thus achieving true suspension of the oil suspension.

[0038] Compared to traditional oil suspensions, the membrane-sealed suspension of this invention has the advantages of high suspension stability. It spontaneously forms S / O / W or S / S / O / W multiple emulsions upon entering water, resulting in uniform dispersion of the active pharmaceutical ingredient. This solves the problem of oil and drug separation and uneven drug distribution in traditional oil suspensions upon entering water. At the same time, by introducing cationic small molecule surfactants and / or solid thickeners to synergize with other components, the membrane-sealed suspension of this invention has excellent storage stability and dispersibility, which helps to improve its adhesion and spreading performance on the target surface, enhance its resistance to rain washout, and prolong the duration of drug efficacy.

[0039] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, not all of them. Essentially, all formulations capable of producing oil suspensions can be modified to use the technical solutions of this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0040] Unless otherwise specified, the following examples and comparative examples were conducted under normal temperature and pressure conditions; all raw materials used were commercially available products, of which organic bentonite was purchased from Beijing Jiuyan New Materials Technology Co., Ltd., with models OR-10, OR-13, and OR-19 respectively; magnesium aluminum silicate was purchased from Beijing Jiuyan New Materials Technology Co., Ltd., with model MAS-2; calcium dodecylbenzenesulfonate (500#) is a compound of calcium dodecylbenzenesulfonate and solvent oil, wherein the mass fraction of calcium dodecylbenzenesulfonate is 50%.

[0041] Examples 1-3 Solid thickener, active ingredient, stabilizer and oil phase medium are mixed and sand-milled in a sand mill to obtain the first mixture (particle size <5μm). The first mixture is mixed with anionic small molecule surfactant and then milled in a sand mill to obtain a second mixture (particle size <5μm). The second mixture is stirred and mixed with an emulsifier to obtain a membrane-sealed suspension.

[0042] Examples 4-5 A cationic small molecule surfactant, a solid thickener, and a portion of an oil phase medium (the mass of the oil phase medium is 60% of the total mass of the oil phase medium) are mixed and milled in a sand mill to obtain a premix (particle size <1μm). The premix, active ingredient, stabilizer, and remaining oil phase medium are mixed and then milled in a sand mill to obtain a first mixture (particle size <5μm). The first mixture is mixed with anionic small molecule surfactant and then milled in a sand mill to obtain a second mixture (particle size <5μm). The second mixture is stirred and mixed with an emulsifier to obtain a membrane-sealed suspension.

[0043] The types and amounts of raw materials used in the preparation of the membrane-sealing suspensions in Examples 1-5 are listed in Tables 1-5.

[0044] Table 1. Types and amounts of raw materials used in the preparation of the membrane-sealing suspension in Example 1

[0045] Table 2. Types and amounts of raw materials used in the preparation of the membrane-sealing suspension in Example 2.

[0046] Table 3. Types and amounts of raw materials used in the preparation of the membrane-sealing suspension in Example 3.

[0047] Table 4. Types and amounts of raw materials used in the preparation of the membrane-sealing suspension in Example 4.

[0048] Table 5. Types and amounts of raw materials used in the preparation of the membrane-sealing suspension in Example 5.

[0049] Comparative Example 1 This comparative example is a typical oil suspension formulation, without the combined use of anionic and cationic small molecule surfactants. The specific formulation, by mass percentage, is as follows: 4% nicosulfuron, 6% mesotrione, 20% atrazine, 5% calcium dodecylbenzenesulfonate (500#), 2% castor oil polyoxyethylene ether (EL-20), 3% octylphenol polyoxyethylene ether (OP-10), 3% octylphenol polyoxyethylene ether (OP-4), 0.6% M5 (purchased from Zibo Shenlang New Material Technology Co., Ltd.), 1.5% M4 (purchased from Zibo Shenlang New Material Technology Co., Ltd.), 0.3% organobentonite (a mixture of OR-10 and OR-19 organobentonite in a mass ratio of 1:5), 0.5% silica, and the balance being methyl oleate.

[0050] The specific preparation steps are as follows: Mix the above components and grind them in a sand mill to obtain an oil suspension (particle size <5μm).

[0051] Comparative Example 2 This comparative example is a typical oil suspension formulation, without the combined use of anionic and cationic small molecule surfactants. The specific formulation by mass percentage is as follows: 8% nicosulfuron, 5% calcium dodecylbenzenesulfonate (500#), 2% castor oil polyoxyethylene ether (EL-20), 3% octylphenol polyoxyethylene ether (OP-10), 3% octylphenol polyoxyethylene ether (OP-4), 1.2% organobentonite (a mixture of OR-10 and OR-19 organobentonite in a mass ratio of 1:5), 2% silica, and the balance being methyl oleate.

[0052] The specific preparation steps are as follows: Mix the above components and grind them in a sand mill to obtain an oil suspension (particle size <5μm).

[0053] Test Example 1 The stability of the membrane-sealed suspensions prepared in each embodiment and the oil suspensions prepared in each comparative example were tested. Specifically, at room temperature (25°C), 1.0 mL of membrane-sealed suspension and oil suspension were added to a beaker containing 100.0 mL of water, stirred and mixed, and a small amount of emulsion was taken from the middle of the beaker, spread evenly on a glass slide, and then observed under a microscope. The high-power objective used was a 40x objective lens, and the low-power objective used was a 10x objective lens.

[0054] Figures 1-3 These are microscopic images of the membrane-sealing suspension (8% cyclosulfonone) prepared in Example 1 after being immersed in water. Figure 1 This is a high-powered photograph of the upper surface of the sample (i.e., the water surface) on a glass slide. Figure 2 This is a low-power photograph of the water surface of a sample on a glass slide. Figure 3 This is a high-magnification photograph of the bottom of the sample on the glass slide (i.e., the bottom of the water, corresponding to the upper surface of the glass slide). The results show that the film-encapsulated suspending agent prepared in Example 1 exhibits a stable suspension state in water.

[0055] Figure 4 and Figure 5 These are microscopic images of the membrane-sealing suspension (10% chlorantraniliprole) prepared in Example 2 after being immersed in water. Figure 4 This is a high-powered photograph of the water surface of a sample on a glass slide. Figure 5 This is a low-magnification photograph of the sample on a glass slide at the water surface. The results show that the membrane-sealed suspension prepared in Example 2 exhibits a stable suspension state in water.

[0056] Figures 6-8 These are microscopic images of the membrane-sealing suspension (10% nicosulfuron) prepared in Example 3 after being immersed in water. Figure 6 This is a high-powered photograph of the water surface of a sample on a glass slide. Figure 7This is a low-power photograph of the water surface of a sample on a glass slide. Figure 8 This is a high-powered photograph of the bottom of the sample on a glass slide. The results show that the film-encapsulated suspending agent prepared in Example 3 exhibits a stable suspension state in water.

[0057] Figures 9-11 These are microscopic images of the membrane-sealing suspension (30% nicosulfuron, i.e., 3% nicosulfuron + 7% mesotrione + 20% atrazine) prepared in Example 4 after being immersed in water. Figure 9 This is a high-powered photograph of the water surface of a sample on a glass slide. Figure 10 This is a high-powered photograph of the bottom of the sample on the glass slide (standing time approximately 5 minutes). Figure 11 This is a high-powered photograph of the bottom of the sample on a glass slide (after standing for approximately 30 minutes). The results show that the film-encapsulated suspension prepared in Example 4 exhibits oil-coated particles that float on the water surface. Even when they sink to the bottom, they remain oil-coated; the higher the coating rate, the better the stability. Figure 10 The emulsion is not clear when the standing time is short, but it is still possible to tell that the surface of the particles is coated with oil. Figure 11 After standing for a long time, the emulsion exhibits a clear coating.

[0058] Figures 12-14 These are microscopic images of the membrane-sealing suspension (10% nicosulfuron) prepared in Example 5 after being immersed in water. Figure 12 This is a high-powered photograph of the water surface of a sample on a glass slide. Figure 13 This is a low-power photograph of the water surface of a sample on a glass slide. Figure 14 This is a high-powered photograph of the bottom of the sample on a glass slide. The results show that the film-encapsulated suspending agent prepared in Example 5 exhibits a stable suspension state in water.

[0059] Figure 15 and Figure 16 Microscopic images of the oil suspension (30% nicosulfuron, i.e., 4% nicosulfuron + 6% mesotrione + 20% atrazine) prepared in Comparative Example 1 after being immersed in water. Figure 15 This is a high-powered photograph of the bottom of the sample on a glass slide. Figure 16 This is a low-power photograph of the bottom of the sample on a glass slide. The oil suspension product prepared in Comparative Example 1 showed precipitation almost immediately upon initial observation, i.e., oil-drug separation occurred upon contact with water. The photograph after contact with water is shown below. Figure 15 and Figure 16 As shown, it sinks quickly to the bottom after entering the water, while there are almost no particles on the surface.

[0060] Figure 17 and Figure 18 Microscopic images of the oil suspension (8% nicosulfuron) prepared in Comparative Example 2 after being immersed in water. Figure 17This is a high-powered photograph of the bottom of the sample on a glass slide. Figure 18 This is a low-power photograph of the bottom of the sample on a glass slide. The oil suspension product prepared in Comparative Example 2 also exhibits poor storage stability; oil-drug separation occurs immediately after being added to water and shaken. The photograph of this product after immersion in water is shown below. Figure 17 and Figure 18 As shown, it sinks quickly to the bottom after entering the water, while there are almost no particles on the surface.

[0061] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A composition of additives for membrane-sealing suspending agents, comprising, by weight parts: 0-3 parts cationic small molecule surfactant, 0.01-3 parts anionic small molecule surfactant, 0-5 parts solid thickener, 0-5 parts stabilizer, 7-20 parts emulsifier, and 40-80 parts oil phase medium; The cationic small molecule surfactant and the solid thickener are not both 0, and when the cationic small molecule surfactant is 0, the solid thickener includes a cationic solid thickener.

2. The composition of additives for membrane-sealing suspending agents according to claim 1, characterized in that, The cationic small molecule surfactant includes quaternary ammonium salt cationic surfactants; the quaternary ammonium salt cationic surfactants include one or more of octyldecyl dimethyl ammonium halide, bis(octadecyl)dimethyl ammonium halide, bis(decyl)dimethyl ammonium halide, bis(tetradecyl)dimethyl ammonium halide, bis(hexadecyl)dimethyl ammonium halide, bis(dodecyl)dimethyl ammonium halide, dodecyltrimethyl ammonium halide, octadecyltrimethyl ammonium halide, and hexadecyltrimethyl ammonium halide; the halide ion in the quaternary ammonium salt cationic surfactant is a chloride ion or a bromide ion.

3. The composition of additives for membrane-sealing suspending agents according to claim 1, characterized in that, The anionic small molecule surfactant includes one or more of sodium dodecyl sulfate, sodium lauryl sulfate, sodium oleate, sulfonates, triethanolamine oleate, and stearates; the sulfonates include one or more of sodium dioctyl succinate sulfonate, sodium α-alkenyl sulfonate, sodium dodecylbenzene sulfonate, calcium dodecylbenzene sulfonate, sodium fatty acid methyl ester sulfonate, and sodium hexadecyl sulfonate; the stearates include one or more of sodium stearate, aluminum stearate, zinc stearate, calcium stearate, and magnesium stearate.

4. The composition of additives for membrane-sealing suspending agents according to claim 1, characterized in that, The solid thickener includes one or more of organic bentonite, inorganic bentonite, silica, and magnesium aluminum silicate; the stabilizer includes, but is not limited to, citric acid and / or urea.

5. The composition of additives for membrane-sealing suspensions according to claim 1, characterized in that, The emulsifier includes one or more of triphenylethylphenol polyoxyethylene ether, castor oil polyoxyethylene ether, calcium dodecylbenzenesulfonate, triphenylethylphenol polyoxyethylene polyoxypropylene ether, alkylphenol polyoxyethylene ether, cashew nut phenol polyoxyethylene ether, and fatty alcohol polyoxyethylene ether; the triphenylethylphenol polyoxyethylene ether is a 601 series emulsifier; the castor oil polyoxyethylene ether is an EL-10 series emulsifier or an EL-20 series emulsifier; the calcium dodecylbenzenesulfonate is a 500# calcium salt series emulsifier; the triphenylethylphenol polyoxyethylene polyoxypropylene ether is a 1601 series emulsifier; the alkylphenol polyoxyethylene ether includes one or more of OP-10, OP-7, OP-4, DP-10, DP-7, and DP-4; and the fatty alcohol polyoxyethylene ether includes one or more of AEO-9, AEO-7, AEO-5, and AEO-3.

6. The composition of additives for membrane-sealing suspending agents according to claim 1, characterized in that, The oil phase medium includes one or more of methyl oleate, epoxidized soybean oil, corn oil, and soybean oil.

7. A method for preparing a membrane-sealing suspension based on the auxiliary composition for membrane-sealing suspension according to any one of claims 1 to 6, comprising the following steps: The cationic small molecule surfactant, solid thickener, active ingredient, stabilizer, and oil phase medium are mixed and ground to obtain the first mixture; The first mixture is mixed with an anionic small molecule surfactant to obtain a second mixture; The second mixture is mixed with an emulsifier to obtain the membrane-sealed suspension.

8. The method according to claim 7, characterized in that, The solid thickener in the film-sealed suspension contains 0-5% by mass, and the technical grade drug contains 1-50% by mass; the technical grade drug is a polar technical grade drug, including but not limited to one or more of the following: cyclosulfonamide, nicosulfuron, mesotrione, benzoxazine, atrazine, mesosulfuron-methyl, penoxsulam, cyhalofop-butyl, terbufos, chlorantraniliprole, thiamethoxam, and bromuconamide.

9. The method according to claim 7 or 8, characterized in that, The preparation method of the first mixture includes the following steps: mixing a cationic small molecule surfactant, a solid thickener and a portion of an oil phase medium and pre-grinding to obtain a premix; mixing the mixture, the active ingredient, the stabilizer and the remaining oil phase medium and re-grinding to obtain the first mixture; The oil phase medium constitutes 30-70% of the total mass of the oil phase medium; the pre-grinding and regrinding are performed by sand milling; the particle size of the premix is ​​<1μm, the particle size of the first mixture is <5μm, and the particle size of the second mixture is <5μm.

10. The membrane-sealed suspension prepared by the method according to any one of claims 7 to 9.

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