Spirotetramat nano suspending agent and preparation method thereof

Abstract

The invention provides a spirotetramat nano suspending agent, which comprises the following components relative to the total mass of the nano suspending agent: (a) 1 to 50 percent, preferably 5 to 40 percent, of spirotetramat; (b) 0.1-10%, preferably 1-5%, of a wetting dispersant, and the wetting dispersant is polyoxyethylene sorbitan fatty acid ester; (c) 0.1 to 3 percent, preferably 0.1 to 1 percent, of a thickening agent, and the thickening agent is xanthan gum; (d) water, and (e) optionally added other auxiliary agents. Meanwhile, the invention also provides a preparation method of the spirotetramat nano suspending agent, and the spirotetramat nano suspending agent prepared by the invention has good particle size stability and suspension rate stability.

Description

Technical Field

[0001] This invention relates to spirotetramat nano-suspension and a method for preparing spirotetramat nano-suspension. Background Technology

[0002] The advantages of combining pesticide formulations with nanotechnology are that it significantly improves efficacy, reduces dosage, enhances the precision of targeting organisms, reduces the impact on non-target organisms and the environment, and promotes the rapid degradation of pesticides, reducing residues. This is beneficial for protecting the ecological balance and improving crop safety, and is one of the key technologies for promoting green agricultural development.

[0003] Spirotetramat is a highly effective broad-spectrum insecticide and acaricide, renowned for its unique bidirectional systemic activity, high efficacy, broad spectrum, and long-lasting effect. Spirotetramat has a broad insecticidal spectrum and can be used to control various piercing-sucking pests on crops, such as aphids, spider mites, thrips, psyllids, mealybugs, whiteflies, and scale insects.

[0004] Non-patent literature 1 describes the development of a 100 g / L spirotetramat nano-suspension using a two-stage wet milling method. The formulation consists of: 9.7% spirotetramat technical grade (100% concentration), 3% Atlox 4913, 5% Emulson AG TRST, 4% Ethylan NS-500LQ, 5% glycerol, 0.1% xanthan gum, 0.5% magnesium aluminum silicate, 0.15% Kathon, 0.1% T205, and deionized water to make up to 100%. This formulation requires the synergistic effect of three wetting and dispersing agents to control particle size increase, and the combination of two thickeners to improve suspension stability.

[0005] Non-patent literature 1: Zhang Xiaobing, Wang Jianwei, Wang Weichang, Zhao Baochen, Formulation and efficacy evaluation of 100g / L spirotetramat nano-suspension, World Pesticides, 2023, 45, 36-40. Summary of the Invention

[0006] This application provides a novel spirotetramat nano-suspension agent containing specific wetting and dispersing agents and thickeners.

[0007] This application also provides an improved process for preparing spirotetramat nano-suspension. The present invention simplifies the process by using a single type of wetting and dispersing agent instead of the complex combinations of wetting and dispersing agents used in existing formulations. Furthermore, the inventors of this application discovered during the preparation process that adding a thickener too early would cause the liquid to become viscous, preventing the movement between the grinding beads and thus reducing the grinding effect. The present invention prevents this phenomenon during the grinding process by delaying the addition time of the thickener and using a single thickener instead of a combination of thickeners.

[0008] Specifically, the present invention provides:

[0009] (1) Spirotetracycline nano-suspension, which, relative to the total mass of the nano-suspension, comprises:

[0010] (a) 1-50%, preferably 5-40%, of spirotetramat;

[0011] (b) 0.1-10%, preferably 1-5%, of a wetting and dispersing agent, wherein the wetting and dispersing agent is polyoxyethylene dehydrated sorbitan fatty acid ester;

[0012] (c) 0.1-3%, preferably 0.1-1%, of a thickener, wherein the thickener is xanthan gum;

[0013] (d) Water, and

[0014] (e) Other optional adjuvants.

[0015] (2) According to the nano-suspension agent described in (1) above, wherein the average degree of polymerization of the wetting and dispersing agent polyoxyethylene dehydrated sorbitan fatty acid ester is 1 to 200, more preferably 1 to 100, further preferably 1 to 50, and even more preferably 1 to 30.

[0016] (3) The nano-suspension agent described in (1) or (2) above, wherein the wetting and dispersing agent, polyoxyethylene dehydrated sorbitan fatty acid ester, is a Tween series, preferably polyoxyethylene dehydrated sorbitan monooleate.

[0017] (4) The nano-suspension agent according to any one of (1) to (3) above further contains an antifoaming agent, the content of which is preferably 0.01 to 0.5% of the total mass of the nano-suspension agent, more preferably 0.01 to 0.1%; the antifoaming agent is preferably dimethyl silicone oil.

[0018] (5) The nano-suspension agent according to any one of (1) to (4) above further contains a preservative, the content of which is preferably 0.01 to 10% of the total mass of the nano-suspension agent, more preferably 0.1 to 1%; the preservative is preferably Kathon or ethylparaben.

[0019] (6) The nano-suspension agent according to any one of (1) to (5) above further contains an antifreeze agent, the content of which is preferably 1 to 5% of the total mass of the nano-suspension agent, more preferably 1 to 3%; the antifreeze agent is preferably propylene glycol or glycerol.

[0020] (7) The nano-suspension according to any one of (1) to (6) above, based on the total mass of the nano-suspension, contains 5 to 40% spirotetramat, 1 to 5% wetting and dispersing agent, 0.1 to 1% thickener, and the remainder water and other optional additives.

[0021] Preferably, the optional additives are one or more selected from defoamers, preservatives, and antifreeze agents.

[0022] (8) The method for preparing spirotetramat nano-suspension according to any one of (1) to (7) above, characterized in that it includes the following steps:

[0023] (S1) Mix the spirotetramat technical, wetting and dispersing agent and water, stir evenly, and grind;

[0024] (S2) Add thickener and other optional additives, and continue mixing until homogeneous to obtain spirotetramat nano suspension.

[0025] (9) According to the preparation method described in (8) above, wherein in step (S1), the particle size is ground to below 1000 nm.

[0026] (10) According to the preparation method described in (9) above, wherein in step (S2), the mixture is homogeneous by secondary grinding.

[0027] The beneficial effects of this invention are:

[0028] (1) Reduce the types of ingredients in the formula and simplify the process.

[0029] (2) The selected single-type wetting and dispersing agent is more compatible with spirotetramat, which is beneficial to reduce the particle size of spirotetramat and shorten the grinding time.

[0030] (3) By using a thickener instead of the thickener combination and changing its addition time, the grinding effect was improved and the suspension rate reached more than 98.5%.

[0031] (4) Promotes the absorption of spirotetramat and improves its efficacy. Attached Figure Description

[0032] Figure 1 The X-ray powder diffraction (XRD) patterns of the spirotetramat nano-suspension and the spirotetramat technical prepared in Example 1 of this application are shown.

[0033] Figure 2 This is a SEM image of the spirotetramat nano-suspension prepared in Example 1 of this application.

[0034] Figure 3 This is a SEM image of spirotetramat technical grade.

[0035] Figure 4 This is a schematic diagram of the particle size distribution of the spirotetramat nano-suspension prepared in Example 1 of this application. Detailed Implementation

[0036] In this application, unless otherwise specified, "%" refers to the percentage content by mass. The percentage content of spirotetramat is a percentage content converted from whole numbers. The term "about" means ±10%, preferably ±5%.

[0037] The active ingredient spirotetramat in the nano-suspension of this invention is a known compound that can be prepared by known methods or obtained commercially. The content of the active ingredient spirotetramat in the nano-suspension is 1-50%, preferably 5-40%.

[0038] In the nano-suspension of the present invention, the polyoxyethylene dehydrated sorbitan fatty acid ester used as a wetting and dispersing agent is preferably a Tween series, such as Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 80 (i.e., polyoxyethylene dehydrated sorbitan monooleate), Tween 81, Tween 85, etc., with Tween 80 being the most preferred.

[0039] The average degree of polymerization of the polyoxyethylene dehydrated sorbitan fatty acid ester is preferably 1-200, more preferably 1-100, further preferably 1-50, and even more preferably 1-30.

[0040] In the nano-suspension of the present invention, the content of the wetting and dispersing agent is 0.1-10%, preferably 1-5%.

[0041] In the nano-suspending agent of the present invention, the content of the thickener is 0.1-3%, preferably 0.1-1%.

[0042] In the nano-suspension agent of the present invention, the water can be tap water, deionized water, purified water or distilled water, preferably deionized water or purified water.

[0043] The nano-suspension of this invention may further contain other adjuvants or excipients permitted for use in pesticides, specifically including preservatives, antifreeze agents, and defoamers. Those skilled in the art can rationally select and use these adjuvants or excipients as needed.

[0044] In some embodiments, the nano-suspension of the present invention contains a preservative, the content of which is preferably 0.01 to 10%, more preferably 0.1 to 1%.

[0045] In some specific implementations, Kathon or ethylparaben are used as preservatives.

[0046] In some embodiments, the nano-suspension of the present invention contains an antifreeze agent, preferably in a content of 1-5%, more preferably 1-3%.

[0047] In some specific implementations, propylene glycol or glycerol is used as an antifreeze agent.

[0048] When foam appears in the nano-suspension, an antifoaming agent can be added to remove it. The amount of antifoaming agent should be just enough to produce only a small amount of foam when stirred; too much antifoaming agent will increase the particle size of the nano-suspension of this invention.

[0049] In some embodiments, the content of the defoamer is preferably 0.01 to 0.5%, more preferably 0.01 to 0.1%.

[0050] In some specific implementations, dimethyl silicone oil is used as a defoamer.

[0051] Nano-suspensions containing the four components as described in (a) to (d) above, nano-suspensions consisting essentially of these components, and nano-suspensions consisting of these components are all included within the scope of this invention.

[0052] In some specific embodiments, the nano-suspension of the present invention comprises, is substantially composed of, or is composed of: 5-40% spirotetramat, 1-5% wetting and dispersing agent, 0.1-1% thickener, and the remainder being water and other optional additives.

[0053] In some specific embodiments, the nano-suspension of the present invention comprises, is substantially composed of, or is composed of the following components: 5-40% spirotetramat, 1-5% wetting and dispersing agent, 0.1-1% thickener, 0.1-1% preservative, 0.01-0.1% defoamer, 1-3% antifreeze agent, and the remainder water.

[0054] The present invention also provides a method for preparing spirotetramat nano-suspension, comprising the following steps: (S1) mixing and stirring spirotetramat technical, wetting and dispersing agent and water evenly, and grinding; (S2) adding thickener and other optional additives, and continuing to mix evenly to obtain spirotetramat nano-suspension.

[0055] In some specific embodiments, the particles are ground to a size of less than 1000 nm in step (S1).

[0056] In some specific implementations, in step (S2), the mixture is homogenized by secondary grinding.

[0057] In some specific embodiments, 5-40% spirotetramat, 1-5% wetting and dispersing agent, and water are mixed and stirred evenly, then grinding beads are added to grind the particles to a size below 1000 nm; 0.1-1% thickener is added, and grinding is continued until the mixture is uniform, thus obtaining spirotetramat nano-suspension.

[0058] In some more specific embodiments, 5-40% spirotetramat, 1-5% wetting and dispersing agent, 0.01-0.1% defoamer and water are mixed and stirred evenly, and then grinding beads are added to grind the particles to a size below 1000 nm; 0.1-1% thickener, 0.1-1% preservative, and 1-3% antifreeze are added, and grinding is continued until the mixture is uniform, thus obtaining spirotetramat nano-suspension.

[0059] In some more specific embodiments, the grinding beads are zirconium oxide grinding beads.

[0060] The spirotetramat nano-suspension of this invention has low unit dosage and fast-acting effect on target crops. Its systemic dose in crops after 1 hour exceeds the systemic dose of ordinary suspensions after 5 hours.

[0061] Example

[0062] The present invention will be described in more detail below through embodiments, but the present invention is not limited to these embodiments. Any modifications and changes that do not depart from the spirit and scope of the present invention shall fall within the scope of the present invention.

[0063] In the following examples and comparative examples, the content of spirotetramat was determined by HPLC. The detection conditions were as follows: the instrument was a Wukong K2025 liquid chromatograph with a UV detector; the chromatographic column was a 5 μm hydrophilic ODS column (Venusil MP C18, Agela Technologied, equipped with a pre-column filter or guard column); the mobile phase was acetonitrile:water = 1:1 (V:V); the column temperature was 40℃; the flow rate was 1.0 mL / min; the wavelength was 210 nm; and the injection volume was 10 μL.

[0064] X-ray powder diffraction (XRD) pattern determination conditions: The diffractometer was a Smart Lab SE Advance, with Cu Kα radiation. The detector is a D / teX Ultra 250, with a scanning 2θ range of 5–40°.

[0065] Laser particle size analyzer: 90 Plus PALS particle size analyzer (Brookhaven Instruments Corporation).

[0066] Suspension rate testing: The test shall be conducted in accordance with the test method for suspension rate in GB / T 14825-2023.

[0067] Example 1

[0068]

[0069] Preparation method: Spirotetramatine, wetting and dispersing agent, defoamer and water are mixed and stirred evenly, zirconia grinding beads are added and ground to grind the particle size to below 1000nm; thickener, preservative and antifreeze are added, and grinding is continued until the mixture is uniform to obtain spirotetramatine nano suspension.

[0070] The X-ray diffraction (XRD) patterns of the spirotetramat nano-suspension and spirotetramat technical obtained in Example 1 are shown below. Figure 1 As shown. By Figure 1 It can be seen that the peak intensity of spirotetramat nano-suspension decreased while the peak width increased, which is consistent with the characteristics of nano-formulations. Meanwhile, the peak position remained unchanged, indicating that the crystal form of spirotetramat did not change.

[0071] Example 2 Screening of wetting and dispersing agents

[0072] Carboxypropyl methylcellulose, highly substituted hydroxypropyl cellulose, and sodium carboxymethyl cellulose were used instead of Tween 80 in Example 1 as wetting and dispersing agents, and the particle size of the suspension after grinding for different times was compared. The results are shown in Table 1 below.

[0073] Table 1. Relationship between grinding time and particle size when using different wetting and dispersing agents

[0074]

[0075] As shown in Table 1 above, using Tween 80 as a wetting and dispersing agent can minimize grinding time and increase production rate.

[0076] Example 3 examines the timing of thickener addition.

[0077] Components: Same as in Example 1.

[0078] Preparation method: Spirotetramatine, wetting and dispersing agent, defoamer, thickener and water are mixed and stirred evenly, zirconia grinding beads are added and ground to grind the particle size to below 1000nm; preservative and antifreeze are added, and grinding is continued until the mixture is uniform to obtain spirotetramatine nano suspension.

[0079] The effect of different addition times of thickener on the grinding effect was investigated, and the results are shown in Table 2 below.

[0080] Table 2. Effect of different thickener addition times on grinding efficiency

[0081]

[0082] As shown in Table 2 above, adding thickener at different times during the preparation process will affect the grinding effect. Grinding until the particle size reaches within 1000nm before adding thickener is beneficial to improving grinding efficiency.

[0083] Example 4: Stability Assessment

[0084] The product of Example 1 was placed at 54℃±2℃ for 0 days and 14 days to examine its high-temperature stability and suspension rate; it was placed at 0℃ for 0 days and 7 days to examine its low-temperature stability and suspension rate. The results are shown in Tables 3 and 4 below.

[0085] Table 3. High-temperature stability and suspension rate

[0086] Placement time Particle size / nm Dispersion coefficient Potential / mV Suspension rate / % 0 days 511.47±12.87 0.246±0.021 -24.69±0.91 99.9％ 14 days 660.45±16.28 0.254±0.022 -27.96±1.16 98.8％

[0087] Table 4. Low-temperature stability and suspension rate

[0088] Placement time Particle size / nm Dispersion coefficient Potential / mV Suspension rate / % 0 days 511.47±12.87 0.246±0.021 -24.69±0.91 99.9％ 7 days 534.96±109.97 0.180±0.067 -24.95±2.59 98.7％

[0089] As shown in Tables 3 and 4 above, the particle size of the product in Example 1 after high-temperature and low-temperature treatment is below 1000 nm, and the suspension rate is above 98.5%, indicating good stability.

[0090] Comparative Example 1: Preparation of Spirotetracycline Nanoparticle Suspension from Non-Patent Literature

[0091]

[0092]

[0093] Preparation method: A two-stage wet grinding process was adopted. Spirotetracycline technical, wetting and dispersing agent, thickener, antifreeze, defoamer, preservative and water were mixed and pre-dispersed and sheared at 3000 rpm for 3-5 minutes using a high-speed shear mill. Then, zirconia grinding beads were added to the sheared mixture at a ball-to-material mass ratio of 1:1 and the mixture was transferred to a vibratory mill at 800 rpm for grinding. The particle size change was recorded in real time.

[0094] Comparative Example 2: Preparation of Spirotetramethrin Suspension

[0095]

[0096] Preparation method: Spirotetramat, wetting and dispersing agent, defoamer and deionized water are mixed and stirred evenly, then zirconia grinding beads are added and ground. When the particle size reaches 1-3 μm, thickener, preservative and antifreeze are added, and grinding is continued until the mixture is uniform to obtain spirotetramat suspension.

[0097] Example 5 Particle size investigation

[0098] (1) The particle size changes of the product of Example 1 and the product of Comparative Example 1 at different grinding times were measured using a laser particle size analyzer, as shown in Table 5 below.

[0099] Table 5. Relationship between product particle size and grinding time

[0100]

[0101] As shown in Table 5 above, the product using the formulation and preparation method of Example 1 has a faster particle size reduction rate and a better grinding effect.

[0102] (2) The product of Comparative Example 1 was further ground for 8-9 hours to prepare a nano-suspension product with a particle size similar to that of Example 1. The storage stability of the two products at room temperature was then investigated.

[0103] Table 6. Relationship between particle size and storage time

[0104]

[0105] As shown in Table 6 above, the nano-suspension prepared in Example 1 is more stable when stored at room temperature.

[0106] Example 6: Leaf Absorption Test

[0107] Leaves of the same species and growing conditions (with similar age, location, light intensity, size, thickness, and weight) were cut off with the petiole attached, weighed, and then soaked in 0.2 mg / mL suspension solutions of Example 1, Comparative Example 1, and Comparative Example 2, respectively. The leaves were repeatedly shaken to ensure full contact with the surrounding tissues, and then placed in petri dishes for incubation at room temperature. After 1, 3, and 5 hours, the leaves were removed and rinsed repeatedly under running tap water.

[0108] After washing, the leaves were chopped and placed in a 5 mL centrifuge tube. Two 5 mm zirconia grinding beads, 0.2 mL of 1 μg / mL nifedipine internal standard solution, and 1 mL of anhydrous ethanol were added. The mixture was ground at 40 Hz for 5–10 min to extract spirotetramat. After grinding, the mixture was centrifuged at 8000 rpm, and the supernatant was transferred to a 2 mL centrifuge tube. The supernatant was centrifuged again at 12000 rpm for 20 min at 4 °C, and the supernatant was collected again. 1 mL of water was added to precipitate chlorophyll. The supernatant was centrifuged again at 12000 rpm for 10 min at 4 °C, and the supernatant was collected again. After drying the supernatant, it was dissolved in 200 μL of mobile phase (50% acetonitrile), centrifuged at 12000 rpm for 10 min, and the supernatant was collected for HPLC analysis.

[0109] (1) Absorption rate of spirotetramat from cherry blossom leaves

[0110] Table 7. Absorption rate of spirotetramat from cherry blossom leaves (n=3)

[0111]

[0112] *Note: n represents the number of repetitions.

[0113] As shown in Table 7 above, the absorption rate of the product in Example 1 on cherry blossom leaves is much higher than that of the products in Comparative Examples 1 and 2. Since the lethal effect of a drug on pests is usually linearly related to the natural logarithm of the drug concentration in plant leaves (PD ~ lnPK), and the natural logarithm ratio of drug concentration is consistent with the efficacy, it can be inferred that, at the same dosage, the efficacy of the product in Example 1 is approximately 1.47 times that of the product in Comparative Example 1, and the efficacy of the product in Example 1 is approximately 2.17 times that of the product in Comparative Example 2.

[0114] (2) Absorption rate of spirotetramat from maple leaves

[0115] Table 8. Absorption rate of spirotetramat from maple trees (n=6)

[0116]

[0117] *Note: n represents the number of repetitions.

[0118] As shown in Table 8 above, the absorption rate of the product in Example 1 on maple leaves is higher than that of the product in Comparative Example 1, and much higher than that of the product in Comparative Example 2. Since the efficacy is usually linearly related to the natural logarithm of the drug concentration in plant leaves (PD ~ lnPK), and the ratio of the natural logarithm of the drug concentration is consistent with the efficacy, it can be inferred that at the same dosage, the efficacy of the product in Example 1 is approximately 1.11 times that of the product in Comparative Example 1, and the efficacy of the product in Example 1 is approximately 1.43 times that of the product in Comparative Example 2.

Claims

1. Spirotetracycline nano-suspension, comprising, relative to the total mass of the nano-suspension: (a) 1-50%, preferably 5-40%, of spirotetramat; (b) 0.1-10%, preferably 1-5%, of a wetting and dispersing agent, wherein the wetting and dispersing agent is polyoxyethylene dehydrated sorbitan fatty acid ester; (c) 0.1-3%, preferably 0.1-1%, of a thickener, wherein the thickener is xanthan gum; (d) Water, and (e) Other optional adjuvants.

2. The nano-suspension agent according to claim 1, wherein the average degree of polymerization of the wetting and dispersing agent polyoxyethylene dehydrated sorbitan fatty acid ester is 1-200, more preferably 1-100, further preferably 1-50, and even more preferably 1-30.

3. The nano-suspension agent according to claim 1 or 2, wherein the wetting and dispersing agent, polyoxyethylene dehydrated sorbitan fatty acid ester, is a Tween series, preferably polyoxyethylene dehydrated sorbitan monooleate.

4. The nano-suspension agent according to any one of claims 1 to 3, further comprising an antifoaming agent, the content of which is preferably 0.01 to 0.5% of the total mass of the nano-suspension agent, more preferably 0.01 to 0.1%; the antifoaming agent is preferably dimethyl silicone oil.

5. The nano-suspension agent according to any one of claims 1 to 4, further comprising a preservative, the content of which is preferably 0.01 to 10% of the total mass of the nano-suspension agent, more preferably 0.1 to 1%; the preservative is preferably Kathon or ethylparaben.

6. The nano-suspension agent according to any one of claims 1 to 5, further comprising an antifreeze agent, the content of which is preferably 1 to 5% of the total mass of the nano-suspension agent, more preferably 1 to 3%; the antifreeze agent is preferably propylene glycol or glycerol.

7. The nano-suspension agent according to any one of claims 1 to 6, based on the total mass of the nano-suspension agent, comprises 5 to 40% spirotetramat, 1 to 5% wetting and dispersing agent, 0.1 to 1% thickener, and the remainder being water and other optional additives. Preferably, the optional additives are one or more selected from defoamers, preservatives, and antifreeze agents.

8. The method for preparing the spirotetramat nano-suspension according to any one of claims 1 to 7, characterized in that, Includes the following steps: (S1) Mix the spirotetramat technical, wetting and dispersing agent and water evenly, and then grind them; (S2) Add thickener and other optional additives, and continue mixing until homogeneous to obtain spirotetramat nano suspension.

9. The preparation method according to claim 8, wherein in step (S1), the particle size is ground to below 1000 nm.

10. The preparation method according to claim 9, wherein in step (S2), the mixture is homogenized by secondary grinding.

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