Nanosuspension comprising zinc thiazole and kasugamycin

Abstract

A nanosuspension comprising zinc thiazole and kasugamycin. The mass ratio of zinc thiazole to kasugamycin in the suspension is 7:1, the particle size D90 of particles in the suspension is 0.40 micrometers to 0.80 micrometers, and the nanosuspension is prepared by means of first thoroughly mixing zinc thiazole technical material, kasugamycin technical material, an auxiliary agent required for the nanosuspension, and water, and then performing sand milling. In the nanosuspension comprising zinc thiazole and kasugamycin prepared as described above, the decomposition rate of kasugamycin is lower, and the nanosuspension comprising zinc thiazole and kasugamycin is suitable for maintaining a low decomposition rate for a long period of time in harsh environments.

Description

A nano-suspension containing thiamethoxam zinc and kasugamycin

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese Patent Application No. 202411989328.0, filed on December 31, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of pesticides, specifically to the field of fungicide pesticide formulations, and particularly relates to a nano-suspension containing thiamethoxam zinc and kasugamycin. Background Technology

[0004] In formulations containing kasugamycin, the high decomposition rate of kasugamycin has always been a technical problem that needs to be solved in the industry. The applicant of this invention has also been researching methods to reduce the decomposition rate of kasugamycin in previous studies.

[0005] Kasugamycin is an antibiotic with bactericidal activity. A high decomposition rate of kasugamycin leads to reduced efficacy, as its effectiveness depends on its stability and concentration in the body. A high decomposition rate prevents the maintenance of sufficient bactericidal effect. Furthermore, a high decomposition rate may necessitate increased dosage or frequency of application to achieve the desired control effect. This not only increases agricultural production costs but may also place greater pressure on the environment. The high decomposition rate also makes the drug more susceptible to degradation during storage and transportation. This necessitates stricter storage and transportation conditions, such as low temperature, protection from light, and moisture, to ensure drug effectiveness, undoubtedly increasing the difficulty and cost of storage and transportation. Finally, the high decomposition rate limits its application under certain specific conditions. For example, under high temperature, high humidity, or ultraviolet radiation, the decomposition rate of kasugamycin is faster, which may prevent the drug from achieving the expected control effect under these conditions. This limits the scope of application of kasugamycin and reduces its practicality in agricultural production.

[0006] Patent publication CN116058373A describes a product and method for reducing the decomposition rate of kasugamycin. To reduce this rate, the pH of the suspension needs to be adjusted to 4-6, and 0.5-3.0% of an antioxidant needs to be added. This effectively reduces the decomposition rate of kasugamycin. This is the applicant's previous research result, which solved the problem of high decomposition rate of kasugamycin, reducing the decomposition rate to below 5% after 14 hours of heat storage with acidity adjustment and the application of antioxidants. However, the use of antioxidants in this method increases the cost of preparing the kasugamycin-containing suspension, increases the variety of raw materials required, and further complicates the stability assurance of the formulation.

[0007] To further reduce the decomposition rate of kasugamycin and minimize or even eliminate the use of antioxidants, is there a more feasible method? In response, this invention conducts in-depth research on suspensions containing kasugamycin and zinc thiazole. The research found that by ensuring that the particle size in the suspension is within a certain range during the preparation process, a lower decomposition rate of kasugamycin can be achieved. Summary of the Invention

[0008] To solve the above-mentioned technical problems, the present invention provides a nano-suspension containing thiazolium zinc and kasugamycin. In the suspension, the mass ratio of thiazolium zinc to kasugamycin is 7:1. The suspension contains particles with a particle size D90 of 0.40 micrometers to 0.80 micrometers. The nano-suspension is prepared by first fully mixing thiazolium zinc technical, kasugamycin technical, suspension adjuvants and water, and then sand milling.

[0009] Preferably, in the above-mentioned suspending agent, the particle size D90 is 0.50 micrometers to 0.75 micrometers, and more preferably, the particle size D90 is 502 nanometers to 724 nanometers.

[0010] Preferably, in the above-mentioned nano-suspension, the sum of the mass of thiazolium zinc and kasugamycin accounts for 8-40% of the mass of the suspension, and more preferably, the sum of the mass of thiazolium zinc and kasugamycin accounts for 40% of the mass of the suspension.

[0011] Preferably, in the above-mentioned nano-suspension agent, the particles in the suspension agent are particles with thiazole zinc particles as the core.

[0012] The solid component in the suspension is mainly thiazolium zinc particles. However, it is unknown whether kasugamycin will be coated or adsorbed on the surface of these particles during nano-sizing. During the preparation of the nano-suspension, as the thiazolium zinc particles gradually decrease in size, kasugamycin molecules may be coated or adsorbed onto the particle surface with the help of surfactants. Because kasugamycin is in molecular form in the suspension, even if it adheres to the surface of the thiazolium zinc particles, it cannot affect the particle size D90 data at the current measurement level. Therefore, even if kasugamycin molecules adhere to the particle surface, they cannot be measured. As the particle size of the thiazolium zinc particles further decreases, the adsorption or coating environment changes, leading to an environment unsuitable for the stability of kasugamycin, resulting in an increased decomposition rate. Based on the above analysis, the applicant believes that the particles in the suspension should not be simply considered as thiazolium zinc particles, but rather as particles with thiazolium zinc particles as the core.

[0013] Preferably, in the above-mentioned suspending agent, the required additives for the suspending agent include one or more of surfactants, thickeners, preservatives, defoamers, and antifreeze agents.

[0014] Preferably, in the above-mentioned suspending agent, the surfactant is selected from one or more of the following: polyether and polymer surfactants, sulfonate and condensate surfactants, ether and ester surfactants, resin and sulfate surfactants, and other types of surfactants.

[0015] Specifically, the polyether and polymer surfactants are selected from one or more of EO / PO block polyethers, polyacrylic acid graft copolymers, sodium salts of acrylic acid homopolymers, sodium salts of maleic acid-acrylic acid copolymers, acrylic acid-maleic anhydride copolymers, butenedioic acid-styrene copolymers, and polyoxyethylene-polyoxypropylene ether block copolymers. The sulfonate and condensate surfactants are selected from one or more of naphthalene sulfonic acid condensate sodium salts, phenol sulfonic acid condensate sodium salts, sodium methylnaphthalene sulfonate formaldehyde condensate, sodium methylene dinaphthalene sulfonate, sodium dioctyl sulfosuccinate, alkyl naphthalene sulfonate, lignin sulfonate, lignin and its derivative sulfonates, alkyl sulfonates, alkylbenzene ether sulfonates, aryl sulfonates, dodecylbenzene sulfonate, and styrene sulfonate polymers. The ether and ester surfactants are selected from one or more of sodium octenyl succinate starch, fatty alcohol polyoxyethylene ethers, polyoxyethylene fatty acids, and alkyl aryl polyethylene glycol ethers. The resin and sulfate surfactants are selected from one or more of alkylphenol formaldehyde resins, polyoxyethylene ether sulfates, lauryl alcohol polyoxyethylene polyoxypropylene ether sulfates, and fatty alcohol polyoxyethylene ether sulfates. Other surfactants are selected from alkylphenol polyoxyethylene ether sulfonates or fatty acid ethane adduct phosphates.

[0016] Preferably, in the above-mentioned suspending agent, the thickener is selected from one or more of xanthan gum, sodium carboxymethyl cellulose, polyvinyl alcohol, and magnesium aluminum silicate; the preservative is selected from one or more of phenyl salicylate, butylparaben, potassium sorbate, sodium benzoate, 2-methyl-4-isothiazolin-3-one, 5-chloro-2-methyl-4-isothiazolin-3-one, 1,2-benzisisothiazolin-3-one, 2-bromo-2-nitro-1,3-propanediol, and 3-iodo-2-propynyl-butylcarbamate; the defoamer is selected from one or more of silicone defoamer, GP polyether defoamer, GPE polyether defoamer, and GPES polyether defoamer; and the antifreeze is selected from one or more of ethylene glycol, propylene glycol, glycerol, isopropanol, and urea.

[0017] Preferably, the above-mentioned suspending agent does not contain antioxidants.

[0018] This invention also provides a method for reducing the decomposition rate of kasugamycin in a suspension of thiazolium zinc and kasugamycin. The method involves milling kasugamycin together with thiazolium zinc, suspending agents, and water during the preparation of the suspension. The milling process reduces the particle size of the solid particles to a D90 of 0.40 μm to 0.80 μm. Particularly preferred is milling to reduce the particle size to a D90 of 0.50 μm to 0.75 μm. Even more preferred is milling to reduce the particle size to a D90 of 502 nm to 724 nm.

[0019] Preferably, in the above method, the mass ratio of thiazolium zinc to kasugamycin is 7:1, and the sum of the masses of thiazolium zinc and kasugamycin accounts for 8-40% of the mass of the suspension. More preferably, the sum of the masses of thiazolium zinc and kasugamycin accounts for 40% of the mass of the suspension.

[0020] Preferably, the range of suspending agents required in the above method is the same as that required in the above suspending agent scheme.

[0021] Beneficial effects of the present invention

[0022] The suspension containing thiamethoxam zinc and kasugamycin prepared by this invention exhibits a lower decomposition rate of kasugamycin and is suitable for maintaining a low decomposition rate for extended periods in harsh environments. Especially in harsh environments with prolonged high temperatures, kasugamycin maintains a low decomposition rate in the nano-suspension of this invention, as demonstrated by the fact that the decomposition rate of kasugamycin remains below 5% even after 28 days of heat storage. The low decomposition rate of kasugamycin in the nano-suspension of this invention is guaranteed by a particle size D90 of 0.40 μm to 0.80 μm, although the process of reducing the particle size to this range requires the continued presence of kasugamycin in the suspension.

[0023] The method for reducing the decomposition rate of kasugamycin in a suspension provided by this invention reduces the particle size of the particles in the suspension. During the reduction process, kasugamycin is present in the suspension. The suspension prepared in this way can ensure a lower decomposition rate of kasugamycin and also ensure the stability of the suspension quality. Detailed Implementation

[0024] The 95% thiamethoxam technical used in the following examples was produced by Zhejiang Xinong Chemical Co., Ltd., and the 70% kasugamycin technical was purchased from the market. The adjuvants used were also purchased from the market.

[0025] Example 1: Preparation of 40% Thiazole Zinc·Kasugamycin Suspension

[0026] Weigh out 1486.2g of 95% thiamethoxam technical grade (1400g), 286g of 70% kasugamycin technical grade (200g), 180g of acrylic acid-maleic anhydride copolymer, 40g of EO / PO block polyether, 180g of alkylbenzene ether sulfonate, 4g of sodium carboxymethyl cellulose, 2g of xanthan gum, 160g of ethylene glycol, 8g of sodium benzoate, 4g of silicone defoamer, and 60g of phosphoric acid, then add water to a final volume of 4000g.

[0027] After the above raw materials are stirred and dispersed evenly, they are fed into a sand mill for sand milling. A three-stage sand milling process is adopted. The first stage sand mill uses zirconia beads with a diameter of 1.0 mm as the sand milling medium and the sand milling time is 40 minutes. The second stage sand mill uses zirconia beads with a diameter of 0.5 mm as the sand milling medium and the sand milling time is 40 minutes. The third stage sand mill uses zirconia beads with a diameter of 0.1 mm as the sand milling medium.

[0028] Sample 1 was obtained after sand milling in the first-stage sand mill, sample 2 was obtained after sand milling in the second-stage sand mill, sample 3 was obtained 20 minutes after sand milling in the third-stage sand mill, and then sample 4, sample 5, sample 6, sample 7 and sample 8 were obtained at 30 minutes, 40 minutes, 60 minutes, 90 minutes and 150 minutes.

[0029] Example 2: Measurement of the decomposition rate of kasugamycin in suspension

[0030] The particle size of the suspension was measured using a wet laser particle size analyzer, with a Mastersizer 3000E instrument. Particle size was measured on the day the suspension sample was taken, and the D90 value was recorded in the results.

[0031] The method for calculating the decomposition rate of kasugamycin in suspensions is as follows: Kasugamycin content is detected on the day the suspension sample is taken, and the detected kasugamycin content is M1. Then, a 14-day heat storage experiment is conducted. After the 14-day heat storage experiment, the kasugamycin content is detected as M2. If the heat storage experiment continues, the kasugamycin content is detected as M3 after a 28-day heat storage experiment. The decomposition rate of kasugamycin is then calculated using the following formula:

[0032] The decomposition rate of kasugamycin after 14 days of heat storage = (M1-M2) / M1×100%

[0033] The decomposition rate of kasugamycin after 28 days of heat storage = (M1-M3) / M1 × 100%

[0034] The detection of kasugamycin content M1, M2 and M3 was carried out in accordance with the kasugamycin content detection method in the standard GB / T 34774-2017 Kasugamycin Aqueous Solution.

[0035] The particle size and kasugamycin content measurements of the eight samples in Example 1 before heat storage are shown in Table 1 below.

[0036] Table 1. Results of particle size and kasugamycin content in samples before heat storage.

[0037] As can be seen from the results in Table 1, the particle size D90 of the prepared 40% thiazolium zinc·kasugamycin suspension reached as small as 304 nm, and the kasugamycin content in all 8 samples met the requirement of a 10% fluctuation in mass content.

[0038] After measuring the above 8 samples before heat storage, heat storage was carried out at 54℃ for 14 days. After 14 days of heat storage, all 8 samples were qualified, and no stratification, clumping, or precipitation was observed. Cold storage tests were not conducted on the above 8 samples because kasugamycin is stable at low temperatures, and low temperatures will not cause it to decompose.

[0039] After 14 days of heat storage, small samples for particle size measurement and kasugamycin content measurement were taken from eight suspension samples and then heat-stored again. For the taken samples, the particle size D90 and kasugamycin content in the suspension were measured, and the decomposition rate of kasugamycin in each sample was calculated. The specific results are shown in Table 2 below.

[0040] Table 2. Results of particle size and kasugamycin content of suspension after 14 days of heat storage.

[0041] As can be seen from the results in Table 2 above, all eight samples after 14 days of heat storage met the requirement of a 10% fluctuation in quality, meaning that the kasugamycin content in all eight samples was within the range of 5 ± 0.5%, which is qualified. However, from the perspective of field efficacy requirements, the lower the decomposition rate, the better. In particular, the decomposition rate of kasugamycin in samples 3, 4, 5, 6, and 7 was less than 5%, which means that the decomposition rate of kasugamycin in suspensions with a particle size D90 of 434 nm to 979 nm was less than 5%. The particle size D90 range of suspensions of samples 4, 5, and 6, which had a kasugamycin decomposition rate of less than 2%, was between 525 nm and 688 nm.

[0042] Eight samples that underwent continued heat storage were observed for quality after a total storage time of 28 days. Some samples showed stratification, but the degree of stratification still met the requirements for qualified suspension concentrate. For the samples stored for 28 days, the particle size D90 and the content of kasugamycin were measured, and the decomposition rate of kasugamycin was calculated. The details are shown in Table 3 below.

[0043] Table 3. Results of particle size and kasugamycin content of suspension after 28 days of heat storage.

[0044] Table 3 shows that after 28 days of heat storage, the decomposition rate of kasugamycin in the 40% thiamethoxam zinc·kasugamycin suspension significantly increased, but the decomposition rates of samples 4, 5, and 6 remained below 5%. The particle size distribution (D90) before, after 14 days, and after 28 days of heat storage indicates that when the particle size (D90) of the suspension fluctuates between 502 nm and 724 nm, the decomposition rate of kasugamycin in the suspension can be well controlled, ensuring that the decomposition rate remains below 5% even under harsh conditions.

[0045] Example 3: Comparative Study Experiment

[0046] The above research revealed that the active ingredient of kasugamycin exists in a relatively stable environment of smaller particles within the nano-sized system of thiazole zinc and kasugamycin suspension (in this invention, this refers to a system with a particle size D90 of less than 1 micrometer). In this environment, the decomposition rate of kasugamycin is very low; when the particle size D90 is 400 to 700 nanometers, the decomposition rate of kasugamycin after 14 days of heat storage is less than 5%. If the low decomposition rate of kasugamycin is solely due to the presence of thiazole zinc particles with a particle size D90 of 400 to 700 nanometers in the system, then mixing a suspension of thiazole zinc particles with this particle size range with kasugamycin technical should achieve the desired reduction in decomposition rate. However, in practice, it is not feasible to test the decomposition effect of nanoparticles on kasugamycin by adding nano-thiazole zinc suspension to kasugamycin technical or formulations. This is because the quality of the mixture obtained by adding kasugamycin technical or formulations to nano-thiazole zinc suspension is unstable, or even substandard, and the mixture will separate after heat and cold storage. Mixing nano-thiazole zinc suspension and kasugamycin aqueous solution in a bucket mixing method is meaningless because this experiment simulates the field application process. Even if mixing the water-diluted solutions of the two formulations can reduce the decomposition rate of kasugamycin, it has no significance in the formulation production and transportation.

[0047] To investigate the relationship between reduced particle size of nano-thiazole zinc particles and decreased decomposition rate of kasugamycin, the following preparation scheme was designed: After the nano-thiazole zinc suspension was prepared, kasugamycin technical grade was added, followed by thorough mixing via sand milling to prepare a new suspension. The specific experimental procedure is as follows:

[0048] Suspension agent ingredients: 368.4g of 95% thiamethoxam zinc technical grade (350g by conversion), 45g of acrylic acid-maleic anhydride copolymer, 10g of EO / PO block polyether, 45g of alkylbenzene ether sulfonate, 1g of sodium carboxymethyl cellulose, 0.5g of xanthan gum, 40g of ethylene glycol, 2g of sodium benzoate, 1g of silicone defoamer, 15g of phosphoric acid, and water to 928.5g.

[0049] After the above raw materials are thoroughly mixed and dispersed, they are fed into a sand mill for sand milling. A three-stage sand milling process is adopted. The first-stage sand mill uses zirconia beads with a diameter of 1.0 mm as the sand milling medium and the sand milling time is 40 minutes. The second-stage sand mill uses zirconia beads with a diameter of 0.5 mm as the sand milling medium and the sand milling time is 40 minutes. The third-stage sand mill uses zirconia beads with a diameter of 0.1 mm as the sand milling medium (consistent with the sand milling conditions in Example 1).

[0050] Samples D4, D5, and D6, each weighing 185.7 g, were collected at 30, 40, and 60 minutes after the start of grinding in the third-stage sand mill. Then, 14.3 g of 70% kasugamycin technical grade was added to each sample, and the mixture was milled using 1.0 mm diameter zirconia beads as the milling medium. After milling for 40 minutes, a suspension of 40% thiamethoxam zinc·kasugamycin was obtained.

[0051] In the above operations, the purpose of obtaining samples D4, D5 and D6 is to study the possible reasons for the low decomposition rate of kasugamycin in samples 4, 5 and 6 in Example 2. Therefore, the sampling time of the thiazole zinc suspension used in samples D4, D5 and D6 is the same as the sampling time of the 40% thiazole zinc·kasugamycin suspension in samples 4, 5 and 6 in Example 2.

[0052] The particle size D90 and kasugamycin content of samples D4, D5, and D6 were measured before heat storage. After 14 days of heat storage, all three samples showed stratification and no longer met the quality standards for suspension concentrates. Even so, the particle size D90 and kasugamycin content of the three samples were measured again after 14 days of heat storage. The results are shown in Table 4 below.

[0053] Table 4. Particle size, kasugamycin content, and decomposition rate of the control suspension after 14 days of heat storage.

[0054] Based on the quality of the heat-stored suspension samples D4, D5, and D6, it is not feasible to prepare the thiazolium zinc suspension first and then add kasugamycin technical to re-prepare the suspension. From the decomposition rate of kasugamycin in Table 4, the smaller particle size of thiazolium zinc in the suspension is not the sole reason for the low decomposition rate of kasugamycin. In other words, the smaller particle size in the suspension environment is not the only reason for the low decomposition rate of kasugamycin. Or, there is no direct correlation between the smaller particle size of thiazolium zinc in the suspension and the reduced decomposition rate of kasugamycin. One cannot conclude that the low decomposition rate of kasugamycin is solely due to the presence of smaller thiazolium zinc particles in the suspension, excluding the suspension preparation process. Rather, it requires that kasugamycin remain present in the suspension throughout the process of reducing the particle size of thiazolium zinc.

[0055] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent modifications made based on the content of the present invention specification, or direct or indirect applications in related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A nano-suspension containing thiazolium zinc and kasugamycin, wherein the mass ratio of thiazolium zinc to kasugamycin in the suspension is 7:1, the suspension contains particles, the particle size D90 of which is 0.40 μm to 0.80 μm, and the nano-suspension is prepared by first thoroughly mixing thiazolium zinc technical, kasugamycin technical, suspension adjuvants and water and then sand milling.

2. The nano-suspending agent according to claim 1, characterized in that, The particle size D90 is 0.50 micrometers to 0.75 micrometers.

3. The nano-suspending agent according to claim 2, characterized in that, The particle size D90 ranges from 502 nm to 724 nm.

4. The nano-suspending agent according to claim 1, characterized in that, The combined mass of thiazoxazole zinc and kasugamycin accounts for 8-40% of the mass of the suspension.

5. The nano-suspending agent according to claim 4, characterized in that, The combined mass of thiazoxazole zinc and kasugamycin accounts for 40% of the mass of the suspension.

6. A method for reducing the decomposition rate of kasugamycin in a suspension of thiazolium zinc and kasugamycin, wherein the method involves, during the preparation of the suspension, kasugamycin, thiazolium zinc, suspending agent, and water are milled together until the particle size of the solid particles is reduced to a particle size D90 of 0.40 micrometers to 0.80 micrometers.

7. The method according to claim 6, characterized in that, The solid particles are ground until the particle size is reduced to a particle size D90 of 0.50 micrometers to 0.75 micrometers.

8. The method according to claim 6, characterized in that, The particle size of the solid particles was reduced to 502 nm to 724 nm by sand milling.

9. The method according to claim 6, characterized in that, The mass ratio of thiazolium zinc to kasugamycin is 7:1, and the sum of the masses of thiazolium zinc and kasugamycin accounts for 8-40% of the mass of the suspension.

10. The method according to claim 6, characterized in that, The combined mass of thiazoxazole zinc and kasugamycin accounts for 40% of the mass of the suspension.

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