A crystalline form of thiamethoxam and its preparation method and use

Abstract

This invention relates to a crystalline form of thiamethoxam, its preparation method, and its uses. The crystalline form, as measured by CuKα radiation, exhibits characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 12.1°±0.2°, 14.8°±0.2°, 18.3°±0.2°, 26.0°±0.2°, and 28.2°±0.2°. The thiamethoxam crystalline form of this invention exhibits low hygroscopicity, good stability, high dissolution rate, better efficacy, and ease of storage, making it highly valuable for application.

Description

Technical Field

[0001] This invention relates to a crystal form of thiamethoxam, its preparation method, and its uses. Background Technology

[0002] Thiamethoxam (1,2-benzisothiazol-3-one, CAS No.: 2634-33-5) is a broad-spectrum, low-toxicity, and highly effective agricultural fungicide with both protective and curative effects. Thiamethoxam exhibits excellent inhibitory and control effects against both bacterial and fungal diseases in crops and is widely used for disease control in grain crops, fruits and vegetables, and cash crops.

[0003] Currently, thiamethoxam technical grade has low solubility in water, a slow dissolution rate, and no clear reports on its crystal form. CN101570519A describes a solution obtained by adjusting the pH of water to 5-6 with hydrochloric acid, followed by cooling to 0-5°C and drying to obtain a white (or slightly yellow) crystalline wet powder. CN111559986A describes crystallization by adding a complexing agent to acidic water. CN103204823A describes crystallization using a methanol / water or ethanol / water system with cooling to obtain crystals (snow-white granules). CN108794424A describes recrystallization using methanol.

[0004] Currently available thiamethoxam products, especially solid formulations, have difficulty in rapidly dissolving and dispersing their active ingredients during field application. This results in poor absorption and translocation by crop plants, leading to slow onset of action and weak overall antibacterial effect, which greatly reduces their effectiveness in controlling diseases in the field.

[0005] Crystal form is a core factor affecting pesticide solubility, dissolution rate, physicochemical stability, and bioavailability. Different crystal forms of the same pesticide technical material exhibit significant differences in physicochemical properties and efficacy. Therefore, developing a new crystal form with rapid dissolution and stable properties is of significant practical importance and application value for optimizing the quality of thiamethoxam products, improving field fungicidal effects, and expanding product application scenarios. Summary of the Invention

[0006] To address the above problems, this application provides a crystal form of thiamethoxam, the crystal form of which exhibits characteristic peaks at 2θ values ​​of 12.1°±0.2°, 14.8°±0.2°, 18.3°±0.2°, 26.0°±0.2°, and 28.2°±0.2° when measured by CuKα radiation.

[0007] Furthermore, the X-ray powder diffraction pattern of the crystal form measured by CuKα rays also has one or more characteristic peaks at 2θ values ​​of 21.2°±0.2°, 22.6°±0.2°, and 26.8°±0.2°.

[0008] Furthermore, the X-ray powder diffraction pattern of the crystal form measured by CuKα rays is as follows: Figure 1As shown.

[0009] Furthermore, the infrared spectrum of the crystal form is as follows: Figure 2 As shown.

[0010] Furthermore, the crystal form differential scanning calorimetry curve is as follows: Figure 3 As shown.

[0011] This application also provides a method for preparing the crystal form of the thiamethoxam described above, wherein the thiamethoxam is heated to 70~170℃ and dissolved in an organic solvent, and then cooled and crystallized at 1~40℃ / min to obtain the crystal form, wherein the organic solvent is not a fatty alcohol.

[0012] Preferably, the organic solvent is one or more selected from dimethyl sulfoxide, N-methylpyrrolidone, cyclohexanone, benzene, toluene, xylene, cyclohexane, methylcyclohexane, dichloroethane, and trimethylpentane.

[0013] Preferably, the temperature for heating is controlled at 80–140°C, and more preferably 90–110°C.

[0014] Preferably, the cooling rate is controlled at 5–20 °C / min, and more preferably 10–20 °C / min.

[0015] Specifically: After cooling to 15-25℃, crystals are grown for 1-2 hours, then separated and dried to obtain the crystal form.

[0016] This application also provides a formulation comprising the crystalline form of the thiamethoxam, wherein the formulation is selected from wettable powders, water-dispersible granules, water-soluble granules, or single or compound formulations. The formulation is a pesticide, antifungal agent, or fungicide.

[0017] This application also provides the use of the crystal form of the thiamethoxam, which is used to control bacterial or fungal diseases of crops, including bacterial angular leaf spot, canker, gray mold, cotton wilt, wheat scab, and rice sheath blight.

[0018] The technical solution of this invention has the following advantages:

[0019] The thiamethoxam crystal form prepared by this invention significantly improves the hydrophilicity of the technical grade drug, greatly increases the dissolution rate, has low hygroscopicity, good stability, and is convenient to store; it fundamentally solves the problems of slow dissolution, low bioavailability, and insufficient efficacy of traditional thiamethoxam technical grade drug, and has strong economic value. Attached Figure Description

[0020] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0021] Figure 1 XRPD image of the crystal form obtained in Example 1;

[0022] Figure 2 The infrared spectrum of the crystal form obtained in Example 1;

[0023] Figure 3 The image shows the differential scanning calorimetry (DSC) curve of the crystal form obtained in Example 1. Detailed Implementation

[0024] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are only used to explain the present invention and are not intended to limit the scope of protection of the present invention. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0025] The X-ray powder diffraction pattern described in this invention is obtained by using an X-ray powder diffractometer (XRD, Bruker D8 Advance, CuKα rays, λ = 0.15406 nm) to analyze the crystal form of raw materials and products. The tube voltage is 40 kV, the tube current is 40 mA, the scanning range is 2-40°, the step size is 0.02°, the scanning rate is 8° / min, and the scanning mode is continuous.

[0026] DSC analysis was performed using a Mettler Toledo TGA / DSC 2 instrument.

[0027] Example 1: Preparation of Thiamethoxam Crystal Form

[0028] Add 50g of thiamethoxam solid, 50g each of toluene and methylcyclohexane to a 500mL three-necked flask, heat to 100℃, and then cool to 20℃ at a rate of 15℃ / min. Maintain this temperature for 2 hours, filter, wash, and dry to obtain approximately 49.2g of thiamethoxam crystalline solid with a purity of 98.7%.

[0029] The XRPD image of the thiamethoxam crystal form obtained in this embodiment is shown below. Figure 1 The X-ray powder diffraction data are shown in Table 1 below.

[0030]

[0031] The infrared spectrum of the thiamethoxam crystal obtained in this embodiment is as follows: Figure 2 .

[0032] The differential scanning calorimetry (DSC) curve of the thiamethoxam crystal form obtained in this embodiment is shown below. Figure 3 .

[0033] Example 2: Preparation of thiamethoxam crystal form

[0034] 50g of thiamethoxam solid, 50g each of toluene and methylcyclohexane were added to a 500mL three-necked flask. The mixture was heated to 100°C and then cooled to 20°C at a rate of 10°C / min. The temperature was maintained for 2 hours. After filtration, washing, and drying, approximately 48.7g of thiamethoxam crystalline solid with a purity of 98.0% was obtained. X-ray powder diffraction analysis of the solid confirmed that its crystal structure was the same as that in Example 1.

[0035] Example 3: Preparation of thiamethoxam crystal form

[0036] 50g of thiamethoxam solid, 50g each of N-methylpyrrolidone and cyclohexanone were added to a 500 mL three-necked flask. The mixture was heated to 100°C and then cooled to 20°C at a rate of 15°C / min. The temperature was maintained for 2 hours. After filtration, washing, and drying, approximately 47.4g of thiamethoxam crystalline solid with a purity of 98.9% was obtained. X-ray powder diffraction analysis confirmed that the solid's crystal structure was identical to that of Example 1.

[0037] Example 4: Preparation of thiamethoxam crystal form

[0038] 50g of thiamethoxam solid, 50g each of toluene and N-methylpyrrolidone were added to a 500mL three-necked flask. The mixture was heated to 100°C and then cooled to 20°C at a rate of 15°C / min. The temperature was maintained for 2 hours. The mixture was then filtered, washed, and dried to obtain approximately 48.2g of thiamethoxam crystalline solid with a purity of 99.0%. X-ray powder diffraction analysis confirmed that the solid's crystal structure was identical to that of Example 1.

[0039] Example 5: Preparation of thiamethoxam crystal form

[0040] 50g of thiamethoxam solid, 50g each of trimethylpentane and cyclohexanone were added to a 500mL three-necked flask. The mixture was heated to 100°C and then cooled to 20°C at a rate of 15°C / min. The temperature was maintained for 2 hours. After filtration, washing, and drying, approximately 49.0g of thiamethoxam crystalline solid with a purity of 98.3% was obtained. X-ray powder diffraction analysis confirmed that the solid's crystal structure was identical to that of Example 1.

[0041] Test case

[0042] Test Example 1: Hygroscopicity Test

[0043] 10 mg of each of Example 1 and commercially available sample (Dr. E, Germany, batch number H1626248, i.e., the control drug group) were taken and the three groups were parallel. The hygroscopic weight gain experiment was carried out at 25°C and 90% relative humidity (after equilibration). The hygroscopicity of each sample was tested using a dynamic moisture adsorption (DVS) instrument and the average value was taken. The experimental results are shown in Table 2.

[0044]

[0045] The results showed that the thiamethoxam crystal obtained in Example 1 of the present invention had no obvious moisture absorption and its stability was good; Examples 1-5 had similar moisture absorption test results, and the moisture absorption of commercially available products was worse than that of Example 1.

[0046] Test Example 2: Stability Test

[0047] The thiamethoxam crystalline solid obtained in Example 1 was stored at different temperatures and humidity levels for 60 days. Two sets of experiments were set up at each temperature with 50% and 75% humidity, and the changes in its crystal form were measured again.

[0048]

[0049] The thiamethoxam crystalline solid obtained in Example 1 was placed at 25°C and stored in dark and light (natural light) environments for 60 days respectively. Its crystal form change was measured again, and the total impurity change was detected by HPLC area normalization method.

[0050]

[0051] The results showed that the thiamethoxam crystal form was stable, and there was no obvious crystal transformation phenomenon during normal storage. The content of the active ingredient decreased slightly under natural light, but the degradation was not significant. Commercially available products showed obvious degradation.

[0052] Test Example 3: Solubility Test.

[0053] Refer to NY / T 1860.22-2016 "Test Guidelines for the Determination of Physicochemical Properties of Pesticides - Part 23: Solubility in Water".

[0054] The results showed that at 25℃, the saturated solubility of thiamethoxam in water was 1.4 g / L compared to the original drug group; the saturated solubility of the crystalline thiamethoxam of the present invention was 2.6 g / L, representing an 85.7% increase in solubility and a significant improvement in solubility performance.

[0055] Test Example 4: Formulation preparation, dissolution rate test, and field efficacy test.

[0056] Dissolution rate test method:

[0057] Accurately weigh 2.0000g of the sample to be tested and place it in a constant-temperature dissolution vessel. Quickly add constant-temperature ultrapure water and start stirring, simultaneously starting the timer. Accurately take 5mL samples at each preset time point of 1 minute, 3 minutes, 5 minutes, 10 minutes, 15 minutes, and 30 minutes. Immediately after sampling, filter the sample rapidly using a 0.22μm aqueous filter membrane. Perform high-performance liquid chromatography (HPLC) analysis on the filtrate and calculate the cumulative dissolution rate of the active ingredient at each time point.

[0058] Field efficacy testing methods:

[0059] The experimental plots were selected from fields with uniform soil fertility, consistent water and fertilizer management, and uniform natural disease occurrence. There were no pesticide residues from the previous period, and the environmental conditions such as temperature, humidity, and light were suitable for disease occurrence during the experiment.

[0060] The application method is conventional foliar spraying. The application time is at the early stage of disease onset, and the application is once every 7 days, for a total of 2 applications.

[0061] The investigation method involved setting up three replicate plots in each group of experiments. Fifty healthy plants were randomly selected from each plot. The number of diseased plants and the severity of the disease were investigated at 7 days and 14 days after the second application of the pesticide. The disease index and control effect were calculated using the following formula:

[0062] Disease index = ×100

[0063] Prevention and control effect (%) = ×100

[0064] Field control trial of wheat scab: The test subject was wheat (Yangmai 16 variety) from Weinan, Shaanxi Province, and the target disease was wheat scab. The test dosage was 45g / mu of pesticide in each group, diluted with 30kg of water and sprayed evenly.

[0065] Field control trial of citrus canker: test subject - mandarin orange, target disease is citrus bacterial canker; test dosage - each group of agents diluted 1500 times and sprayed evenly, covering the entire plant leaves and fruit.

[0066] Field control trial of bacterial angular leaf spot: The test subject was greenhouse cucumber, and the target disease was bacterial angular leaf spot of cucumber; the test dosage was 40g / mu of pesticide per group, diluted with 30kg of water for spraying.

[0067] 1. Preparation of water-dispersible granules and their field control efficacy against wheat scab.

[0068] Commercially available / Crystal form of this invention (Example 1): 30% thiamethoxam technical grade, 3% lignin sulfonate, 3% alkyl polyoxyethylene sulfonate, 3% silica, 10% sodium sulfate, 0.1% polyvinyl alcohol, and 100% kaolin.

[0069] The dissolution rate results are shown in Table 5. The commercially available thiamethoxam crystal form dissolves slowly in the early stage and has a delayed release effect, and it still cannot be completely dissolved after 30 minutes. However, the new crystal form of the present invention (Example 1) has a significantly improved thiamethoxam release rate. Nearly 90% of the active ingredients can be rapidly dissolved in 5 minutes, and it is basically completely dissolved in 15 minutes. The cumulative dissolution rate at 10 minutes is 32.3 percentage points higher than that of the traditional crystal form, the cumulative dissolution rate at 15 minutes is 30.1 percentage points higher than that of the traditional crystal form, and the cumulative dissolution rate at 30 minutes is 27.4 percentage points higher than that of the traditional crystal form.

[0070]

[0071] Table 6 shows the efficacy against wheat scab. For wheat scab, the novel crystalline formulation of this invention exhibits significantly better short-term and long-term control efficacy than commercially available products, with an average efficacy increase of 7.7 percentage points and a relative improvement rate of 42.7%.

[0072]

[0073] 2. Preparation of wettable powder and its efficacy in preventing citrus canker.

[0074] Commercially available / Crystal form of this invention (Example 1): 30% thiamethoxam technical grade, 5% naphthalene sulfonate, 3% styrene-phenol polyoxyethylene ether phosphate, 2% sodium dodecyl sulfate, 4% silica, and kaolin to make up to 100%.

[0075] The dissolution rate test results were similar to those of the water-dispersible granules.

[0076] The efficacy of the new crystalline formulation against citrus canker is shown in Table 7. The new crystalline formulation showed excellent efficacy against citrus canker, with an improvement of 14.6 percentage points compared to the average efficacy of commercially available formulations, representing a relative improvement of 53.7%.

[0077]

[0078] 3. Preparation of soluble granules and field control efficacy results for bacterial angular leaf spot.

[0079] Commercially available / Crystal form of the present invention (Example 1): 30% thiamethoxam technical grade, 10% urea as a solubilizing agent, 4% polycarboxylate as a dispersant, 2% sodium dodecylbenzenesulfonate as a wetting agent, and anhydrous sodium sulfate as a water-soluble carrier to bring the total to 100%.

[0080] The dissolution rate test results were similar to those of the water-dispersible granules.

[0081] Table 8 shows the field control of bacterial angular leaf spot. For bacterial diseases, the new crystalline formulation of the agent has significant advantages, with an average control efficacy increase of 11.6 percentage points and a relative improvement rate of 40.9%, effectively solving the problems of slow dissolution and low bioavailability of thiamethoxam technical.

[0082]

[0083] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these modifications all fall within the protection scope of the present invention.

Claims

1. A crystalline form of thiamethoxam, characterized in that: The X-ray powder diffraction pattern of the crystal form, measured by CuKα rays, has characteristic peaks at 2θ values ​​of 12.1°±0.2°, 14.8°±0.2°, 18.3°±0.2°, 26.0°±0.2°, and 28.2°±0.2°.

2. The crystal form of thiamethoxam according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystal form measured by CuKα rays also has one or more characteristic peaks at 2θ values ​​of 21.2°±0.2°, 22.6°±0.2°, and 26.8°±0.2°.

3. The thiamethoxam crystal form according to claims 1 to 2, characterized in that: The X-ray powder diffraction pattern of the crystal form, measured by CuKα rays, is shown in Figure 1.

4. The thiamethoxam crystal form according to claims 1 to 2, characterized in that: The infrared spectrum of the crystal form is shown in Figure 2.

5. The thiamethoxam crystal form according to claims 1 to 2, characterized in that: The differential scanning calorimetry curve of the crystal form is shown in Figure 3.

6. A method for preparing the crystal form of thiamethoxam according to claims 1 to 5, characterized in that: Thiamethoxam is heated to 70-170°C and dissolved in an organic solvent, and then cooled at 1-40°C / min to crystallize and obtain the crystal form. The organic solvent is not a fatty alcohol.

7. The preparation method according to claim 6, characterized in that: The organic solvent is one or more selected from dimethyl sulfoxide, N-methylpyrrolidone, cyclohexanone, benzene, toluene, xylene, cyclohexane, methylcyclohexane, dichloroethane, and trimethylpentane.

8. The preparation method according to claim 6, characterized in that: The temperature for heating is controlled to be 80–140°C, and more preferably 90–110°C.

9. The preparation method according to claim 6, characterized in that: The cooling rate is controlled at 5–20 °C / min, and more preferably 10–20 °C / min.

10. The preparation method according to any one of claims 6 to 9, characterized in that: After cooling to 15-25℃, crystals are grown for 1-2 hours, then separated and dried to obtain the crystal form.

11. A formulation, characterized in that, The formulation comprises the crystal form of thiamethoxam as described in any one of claims 1 to 5, the formulation is selected from wettable powder, water-dispersible granules, water-soluble granules, single or compound formulations, and the formulation is a pesticide formulation, antifungal agent or fungicide.

12. Use of a crystal form of thiamethoxam according to any one of claims 1 to 5, characterized in that: The crystalline form of the thiamethoxam is used to control bacterial or fungal diseases of crops, including bacterial angular leaf spot, canker, gray mold, cotton wilt, wheat scab, and rice sheath blight.

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