Pesticide composition

Abstract

The present invention provides a water-based suspension formulation containing racemic crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, which has good storage stability. [Solution] A water-based suspension formulation containing a specific amount of a cocrystal of a racemic mixture of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and water.

Description

Technical Field

[0001] The present invention relates to a composition containing 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide.

Background Art

[0002] It is known that 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide is a compound useful as a fungicide (see, for example, Patent Document 1). Also, an agricultural composition containing crystals of the R-form of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide is known (see, for example, Patent Document 2).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] Water-based suspension concentrates (SCs) containing racemic crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide sometimes underwent changes in physical properties, such as increased viscosity and crystal particle growth, during storage after manufacturing. Increased viscosity negatively affects the fluidity of the suspension, making it difficult to discharge from the container and reducing ease of use during pesticide application. Furthermore, crystal particle growth can cause nozzle clogging in sprayers, leading to uneven pesticide application. [Means for solving the problem]

[0005] The inventors have found that a water-based suspension formulation containing racemic crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide exhibits good storage stability, meaning that physical properties are less likely to change during storage, when it contains a specific amount of cocrystals of the racemic mixture of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and water.

[0006] The present invention includes the following embodiments. [1] A liquid composition comprising crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, at least one surfactant, and water, wherein the crystals are suspended in water, The aforementioned crystals include a racemic crystal of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, The aforementioned liquid compositions contain less than 13% by weight of a cocrystal of a racemic mixture of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and water. [2] The liquid composition according to [1], wherein the total content of racemic crystals and cocrystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide in the liquid composition is 45% by weight or less. [3] The liquid composition according to [1] or [2], wherein the crystal comprises the R-form crystal of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, and the total content of the racemic crystal, the R-form crystal, and the cocrystal in the liquid composition is 5% by weight or more. [4] A liquid composition according to any one of [1] to [3], comprising 0.1% by weight or more of the cocrystal. [5] A liquid composition according to any one of [1] to [4], wherein the Dv90 of the crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and the particles of the cocrystal are 15 μm or less. [6] A liquid composition according to any of [1] to [5] that satisfies (A) below. (A) The particle size increase rate calculated by the following formula (1) is 75 or less. Particle size increase rate (%) = (D2 - D1) / D1 × 100 (1) (In formula (1), D1 represents the Dv90 of the crystalline particles contained in the liquid composition before storage at 40°C for 10 weeks, and D2 represents the Dv90 of the crystalline particles contained in the liquid composition after storage at 40°C for 10 weeks.) [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a water-based suspension formulation containing 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide that has good storage stability. [Brief explanation of the drawing]

[0008] [Figure 1] This figure shows the powder X-ray diffraction pattern of a racemic mixture of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and water as a cocrystal. The vertical and horizontal axes represent diffraction intensity (unit: cps) and diffraction angle 2θ (unit: °), respectively. [Figure 2] This figure shows the crystal structure of a cocrystal of the racemic mixture of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and water. [Modes for carrying out the invention]

[0009] The liquid composition of the present invention (hereinafter referred to as "the present invention composition") comprises crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide (hereinafter referred to as "the compound"), at least one surfactant, and water, wherein the crystals are suspended in water. A formulation in which a solid pesticide active compound is suspended in water is called a suspension concentrate (SC), and the present invention composition is a suspension concentrate.

[0010] The composition of the present invention includes, as crystals of the compound, racemic crystals of the compound. Racemic crystals of the compound are described in Japanese Patent Publication No. 2021-121587, etc., and can be produced by known methods, for example, the method described in Japanese Patent Publication No. 2021-121587.

[0011] The composition of the present invention contains 0.3% by weight or more of racemic crystals of the compound, based on 100% by weight of the composition of the present invention. Specific examples of the content of racemic crystals of the compound in the composition of the present invention include 0.3% by weight or more, 0.7% by weight or more, 45% by weight or less, 40% by weight or less, 36% by weight or less, 35% by weight or less, and 31% by weight or less. Other specific examples of the content of racemic crystals of the compound in the composition of the present invention include 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, and 30% by weight.

[0012] The composition of the present invention may contain crystals of the R-isomer of the compound as crystals of the compound. Crystals of the R-isomer of the compound are described in International Publication No. 2014 / 103812, etc., and can be produced by known methods, for example, the method described in International Publication No. 2014 / 103812.

[0013] When the composition of the present invention contains crystals of the R-form of the compound, the composition of the present invention typically contains a total of 5% by weight or more of racemic crystals of the compound and R-form crystals of the compound, based on 100% by weight of the composition of the present invention. Specific examples of the total content of racemic crystals of the compound and R-form crystals of the compound in the composition of the present invention include 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more, 9% by weight or more, 10% by weight or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, 30% by weight or more, 35% by weight or more, 36% by weight or more, 39% by weight or more, 45% by weight or less, 42% by weight or less, 41% by weight or less, and 40% by weight or less. When the composition of the present invention contains crystals of the R-form of the compound, specific examples of the content of crystals of the R-form of the compound in the composition of the present invention include 4.8% by weight or more, 5% by weight or more, 9.6% by weight or more, 10% by weight or more, 25% by weight or more, 40% by weight or less, 38.8% by weight or less, and 35% by weight or less.

[0014] The composition of the present invention contains water. The water contained in the composition of the present invention is water used in the production of conventional pesticide formulations such as tap water, well water, and ion-exchanged water. Specific examples of the water content in the composition of the present invention include 40% by weight or more, 50% by weight or more, 70% by weight or less, and 60% by weight or less. Other specific examples of the water content in the composition of the present invention include 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, and 90% by weight.

[0015] The composition of the present invention contains a co-crystal of a racemic form of the present compound and water (hereinafter referred to as the present co-crystal). In the composition of the present invention, the present co-crystal is suspended in water. That is, the composition of the present invention is a liquid composition containing crystals of the present compound and the present co-crystal, and these crystals are suspended in water. A liquid composition in which crystals of the racemic form of the present compound are suspended in water is prepared, and the composition is stored at room temperature (about 10 °C to 30 °C) or a certain period (about 1 month or more) at a temperature higher than room temperature, whereby the present co-crystal is generated in the composition. <​​​​​​​​​​​​​​​​​​​​The crystallographic data for the single crystal of this cocrystal are shown in Table 1. In Table 1 below, a, b, and c are the edge lengths of the unit cell, and α, β, and γ are the angles of the unit cell.

[0018] [Table 1] <Single-crystal XRD analysis conditions> Single-crystal X-ray diffractometer: VM-SPIDER (manufactured by Rigaku Corporation) X-ray source: Cu-Kα (40kV, 30mA) Measurement temperature: -173℃ (100K) Solve:SHELXT Refinement: SHELXL

[0019] In other words, this cocrystal has the following lattice constants: a=18.39±0.01Å, b=12.90±0.01Å, c=7.46±0.01Å, α=90.00±0.01°, β=90.00±0.01°, γ=90.00±0.01°, and volume=1771±1Å 3 It has.

[0020] The composition of the present invention contains less than 13% by weight of the cocrystal relative to 100% by weight of the composition of the present invention. The cocrystal content in the composition of the present invention is less than 13% by weight, resulting in good storage stability. Specifically, the viscosity increase during storage is suppressed, maintaining fluidity, making it easy to discharge from containers and preventing problems when used as a pesticide. Furthermore, because the growth of crystal particles is suppressed in the composition of the present invention, the rate of increase in crystal particle size, as described later, is low, thereby preventing nozzle clogging of sprayers. The composition of the present invention also has the effect of preventing separation and caking during storage at low and high temperatures, and exhibits excellent dispersion stability when diluted with water. The cocrystal content in the composition of the present invention is preferably 7% by weight or less, 6.5% by weight or less, 6.4% by weight or less, less than 6.4% by weight, 6% by weight or less, 5.5% by weight or less, 5% by weight or less, 4% by weight or less, or 3% by weight or less. The content of the cocrystal in the composition of the present invention may be 0.1% by weight or more, and may be 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, 0.5% by weight or more, 0.6% by weight or more, or 0.7% by weight or more. Specific examples of the content of the cocrystal in the composition of the present invention include 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 1.5% by weight, 2% by weight, 2.5% by weight, 3% by weight, 3.5% by weight, 4% by weight, 4.5% by weight, 5% by weight, 5.5% by weight, 6% by weight, 6.1% by weight, 6.2% by weight, 6.3% by weight, 6.4% by weight, 6.5% by weight, 6.6% by weight, 6.7% by weight, 6.8% by weight, 6.9% by weight, and 7% by weight. Specific examples of the total content of racemic crystals and cocrystals of the compound in the composition of the present invention include 0.3% by weight or more, 0.7% by weight or more, 45% by weight or less, 40% by weight or less, 36% by weight or less, 35% by weight or less, and 31% by weight or less. Other specific examples of the total content of racemic crystals and cocrystals of the compound in the composition of the present invention include 0.3% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, and 45% by weight.When the composition of the present invention contains crystals of the R-form of the compound, specific examples of the total content of the racemic crystals of the compound and the R-form of the compound (hereinafter, these crystals may be collectively referred to as "the crystals") and the cocrystals in the composition of the present invention include 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more, 9% by weight or more, 10% by weight or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, 30% by weight or more, 35% by weight or more, 36% by weight or more, 39% by weight or more, 45% by weight or less, 42% by weight or less, 41% by weight or less, and 40% by weight or less.

[0021] The cocrystal contained in the composition of the present invention is quantified by powder XRD. Specifically, first, liquid compositions containing the cocrystal at different concentrations (e.g., 1%, 2%, 3%, and 5% by weight) and a fixed amount of internal standard material are prepared as calibration curve samples. Preferably, the calibration curve samples do not contain racemic crystals of the compound. Next, the calibration curve samples are measured by powder XRD (permeation method), and a calibration curve is created from the ratio of the area value of the peak derived from the cocrystal (e.g., a peak at 16.6°±0.1) to the area value of the peak derived from the internal standard material (peak area value of the cocrystal / peak area value of the internal standard material). Next, the internal standard material is added to a liquid composition in which the cocrystal content is unknown, and the measurement is performed in the same manner. Then, based on the created calibration curve, the content of the cocrystal in the liquid composition is calculated from the ratio of the area value of the peak derived from the cocrystal to the area value of the peak derived from the internal standard material.

[0022] In the composition of the present invention, the particle size (Dv90) of the racemic crystalline and co-crystalline forms of the compound suspended in water is preferably 15 μm or less, more preferably 11 μm or less, 10 μm or less, 9 μm or less, 8 μm or less, 7 μm or less, or 6 μm or less. If the composition of the present invention contains the R-form crystals of the compound, Dv90 represents the Dv90 of the crystals and co-crystalline forms. Dv90 is the particle size at which the cumulative frequency in the volume-based particle size distribution reaches 90%. The Dv90 of the crystalline particles contained in the composition of the present invention is measured using a laser diffraction particle size distribution analyzer. More specifically, the Dv90 of the crystalline particles is determined by wet measurement, which is a method of measuring the particle size distribution while the particles are dispersed in water.

[0023] The increase rate of Dv90 of the crystalline particles contained in the composition of the present invention is preferably 75% or less, more preferably 50% or less, 25% or less, 20% or less, 15% or less, 10% or less, 9% or less, 8% or less, or 7% or less. The increase rate of Dv90 (particle size increase rate) is calculated by the following formula (1). Particle size increase rate (%) = (D2 - D1) / D1 × 100 (1) In formula (1), D1 represents the Dv90 of the crystalline particles contained in the composition of the present invention before storage under predetermined conditions, and D2 represents the Dv90 of the crystalline particles contained in the composition of the present invention after storage under predetermined conditions. The predetermined conditions may be 2 weeks at 40°C, 4 weeks at 40°C, 6 weeks at 40°C, 8 weeks at 40°C, 10 weeks at 40°C, 1 month at 40°C, 2 months at 40°C, or 3 months at 40°C.

[0024] The composition of the present invention comprises at least one surfactant. Examples of surfactants include anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants, and mixtures thereof. Examples of anionic surfactants include sulfonates, sulfate esters, phosphate esters, carboxylates, salts of copolymers of vinyl compounds and carboxylic acid monomers, and mixtures thereof. Examples of sulfonates include (alkyl)naphthalene sulfonates and their formaldehyde condensates, alkylbenzene sulfonates, alkyldiphenyl ether disulfonates, α-olefin sulfonates, lignin sulfonates, polyoxyethylene alkylphenyl ether sulfonates, and dialkyl sulfosuccinates. Examples of sulfate esters include alkyl sulfates, polyoxyethylene alkyl ether sulfates, and polyoxyethylene alkylphenyl ether sulfates. Examples of phosphate esters include polyoxyethylene alkylaryl ether phosphates and polyoxyethylene tristyrylphenyl ether phosphates. Examples of carboxylates include fatty acid salts and polycarboxylates. Examples of salts of copolymers of vinyl compounds and carboxylic acid monomers include salts of copolymers of styrene and acrylic acid and salts of copolymers of diisobutylene and maleic acid. Examples of salts include calcium salts, sodium salts, potassium salts, and amine salts. Examples of nonionic surfactants include polyoxyethylene alkyl ethers, polyoxypropylene alkyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene distyrylphenyl ethers, polyoxyethylene tristyrylphenyl ethers, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene alkylamines, alkyl alkanolamides, polyoxyethylene polyoxypropylene block copolymers, alkyl polygcosides, acrylic copolymers, and mixtures thereof. Examples of cationic surfactants include alkylamine salts, quaternary ammonium salts, and mixtures thereof. Examples of amphoteric surfactants include alkyl betaines. The content of at least one surfactant in the composition of the present invention is preferably 3.0% by weight or more and 10% by weight or less. Specific examples of the content of at least one surfactant in the composition of the present invention include 2.0% by weight, 3.0% by weight, 4.0% by weight, 5.0% by weight, 6.0% by weight, 7.0% by weight, 8.0% by weight, 9.0% by weight, 10.0% by weight, 11.0% by weight, and 12.0% by weight.

[0025] Preferably, at least one surfactant contained in the composition of the present invention is a surfactant that inhibits the formation of the cocrystal (hereinafter referred to as "the surfactant"). In this specification, inhibiting the formation of the cocrystal means keeping the amount of the cocrystal formed, i.e., the amount of the cocrystal contained in the composition of the present invention, within a predetermined range (for example, less than 13% by weight). Preferably, the surfactant is a polymer surfactant. Examples of such polymer surfactants include polycarboxylates, salts of copolymers of vinyl compounds and carboxylic acid monomers, formaldehyde condensates of (alkyl)naphthalene sulfonates, polyoxyethylene polyoxypropylene block copolymers, acrylic copolymers, and mixtures thereof. Specific examples of the weight ratio of the racemic crystalline form of the compound to the surfactant contained in the composition of the present invention include 1:0.01 or higher, 1:0.02 or higher, 1:0.03 or higher, 1:0.04 or higher, 1:0.05 or higher, 1:0.1 or higher, 1:15 or lower, 1:14 or lower, 1:13 or lower, 1:10 or lower, 1:9 or lower, 1:8 or lower, 1:7 or lower, 1:6 or lower, 1:5 or lower, 1:4 or lower, 1:3 or lower, 1:2 or lower, 1:1 or lower, 1:0.9 or lower, 1:0.8 or lower, 1:0.7 or lower, 1:0.6 or lower, 1:0.5 or lower, and 1:0.35 or lower. Furthermore, when the composition of the present invention contains crystals of the R-form of the compound, specific examples of the weight ratio of the crystals to the surfactant contained in the composition of the present invention include 1:0.01 or more, 1:0.02 or more, 1:0.03 or more, 1:0.04 or more, 1:0.05 or more, 1:0.3 or less, and 1:0.2 or less.

[0026] The composition of the present invention may optionally contain other formulation aids. Examples of formulation aids include thickeners, antifreezes, defoamers, preservatives, and pH adjusters.

[0027] Examples of thickening agents include polysaccharides such as xanthan gum, gellan gum, guar gum, locust bean gum, gum arabic, carrageenan, pectin, and sodium alginate, as well as mineral powders such as colloidal hydrated aluminum silicate, colloidal hydrated magnesium silicate, magnesium aluminum silicate, and silica. When the composition of the present invention contains one or more thickening agents, their total amount is usually 0.1% by weight or more and 0.8% by weight or less based on 100% by weight of the composition of the present invention.

[0028] Examples of antifreeze agents include ethylene glycol, diethylene glycol, glycerin, propylene glycol, and urea. When the composition of the present invention contains one or more antifreeze agents, their total amount is usually 3% to 10% by weight relative to 100% by weight of the composition of the present invention.

[0029] Examples of defoaming agents include silicone-based defoaming agents. When the composition of the present invention contains one or more defoaming agents, their total amount is usually 0.1% by weight or more and 0.4% by weight or less, based on 100% by weight of the composition of the present invention.

[0030] Examples of preservatives include isothiazolinone-based preservatives such as 2-n-octyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, 5-chloro-2-methyl-4-isothiazolin-3-one, and 1,2-benzisothiazolin-3-one; parabens (parahydroxybenzoic acid esters) such as methylparaben, ethylparaben, propylparaben, and butylparaben; and bronopol. When the composition of the present invention contains one or more preservatives, their total amount is usually 0.001% by weight or more and 0.5% by weight or less, based on 100% by weight of the composition of the present invention.

[0031] Examples of pH adjusting agents include carboxylic acids and their salts, such as citric acid, acetic acid, and sorbic acid, as well as phosphoric acid and its salts. When the composition of the present invention contains one or more pH adjusting agents, the total amount is usually 0.05% by weight or more and 0.5% by weight or less, based on 100% by weight of the composition of the present invention.

[0032] The composition of the present invention may contain one or more pesticide-active compounds other than the present compound. Examples of such pesticide-active compounds include insecticidal compounds, fungicidal compounds, herbicidal compounds, and plant growth-regulating compounds.

[0033] The composition of the present invention is produced by a conventional method for producing a suspension concentrate. For example, the production method involves adding racemic crystals of the compound, a surfactant, and optionally, R-form crystals and formulation aids to water, stirring with a stirrer to obtain a mixture, and then grinding the crystals of the compound in the mixture to a desired particle size using a wet grinder such as a bead mill. Another production method involves grinding the racemic crystals of the compound and optionally, R-form crystals of the compound to a desired particle size using a dry grinder such as a jet mill, and then adding the ground racemic crystals or crystals of the compound, a surfactant, and optionally, formulation aids to water, and stirring with a stirrer.

[0034] The composition of the present invention is used as a pesticide formulation to control plant diseases. The composition of the present invention exhibits excellent control effects against plant diseases such as soybean rust. The composition of the present invention is applied to plants or their growing environment by conventional methods of applying suspension concentrate. Examples of such application methods include soil application and foliar application. Soil application and foliar application are usually carried out by diluting the composition of the present invention with water to a desired application concentration and then spraying the resulting spray solution onto the soil or plants using a sprayer. The amount of spray solution is usually 10 L / ha to 10,000 L / ha, preferably 30 L / ha to 7,000 L / ha. The application rate of the composition of the present invention varies depending on the type of plant, the type and frequency of occurrence of the plant disease to be controlled, the timing of application, the method of application, the location of application, weather conditions, etc. However, the application rate of the racemic mixture of this compound is usually 10 g / ha to 2000 g / ha, preferably 30 g / ha to 1400 g / ha, and the application rate of the R-form of this compound is usually 10 g / ha to 1000 g / ha, preferably 30 g / ha to 700 g / ha. [Examples]

[0035] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0036] The materials used in the manufacturing example are shown below. Soprophor FLK (a mixture of 40% ethoxylated tristyrylphenol potassium phosphate and 60% propylene glycol, manufactured by Solvay) Morwet D-425 (formaldehyde condensate of alkylnaphthalene sulfonate sodium salt, manufactured by Noryon) Xiameter AFE-1530 Antifoam emulsion (30% silicone resin emulsion, manufactured by Dow) Proxel GXL (20% dipropylene glycol aqueous solution of 1,2-benzisothiazolin-3-one, manufactured by Arxada) Kelzan (xanthan gum, manufactured by CP Kelco) Veegum R (Magnesium Aluminum Silicate, manufactured by Vanderbilt Minerals, LCC) Propylene glycol (manufactured by Adeka)

[0037] Manufacturing Example 1 Mix 35 parts by weight of crystals of the R-form of this compound (hereinafter referred to as R-form crystals), 4 parts by weight of crystals of the racemic mixture of this compound (hereinafter referred to as racemic crystals), 4 parts by weight of Soprophor FLK, 1 part by weight of Morwet D-425, 0.1 parts by weight of Xiameter AFE-1530 Antifoam emulsion, and water in an amount that makes up to 81.3 parts by weight in total to obtain a mixture. Then, wet grind the mixture using a horizontal bead mill (DYNO-MILL KDL, WILLY A.BACHOFEN AG Maschinenfabrik) to obtain a slurry. Mixing 0.3 parts by weight of Proxel GXL, 0.2 parts by weight of Kelzan, 0.4 parts by weight of Veegum R, 5 parts by weight of propylene glycol, 0.1 parts by weight of Xiameter AFE-1530 antifoam emulsion, and 20.7 parts by weight of water and stirring for 2 hours yields a mixture containing a thickening agent (hereinafter referred to as "thickening mixture 1"). The slurry and the thickening mixture 1 are mixed to obtain a liquid composition (hereinafter referred to as composition 1).

[0038] Manufacturing Example 2 A liquid composition (hereinafter referred to as Composition 2) is obtained by following the procedure of Production Example 1, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 3 parts by weight and 2 parts by weight, respectively.

[0039] Manufacturing Example 3 A liquid composition (hereinafter referred to as Composition 3) is obtained by following the procedure of Production Example 1, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 2 parts by weight and 3 parts by weight, respectively.

[0040] Manufacturing Example 4 A liquid composition (hereinafter referred to as Composition 4) is obtained by following the procedure of Production Example 1, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 1 part by weight and 4 parts by weight, respectively.

[0041] Manufacturing Example 5 Except for changing the amounts of R-form crystals and racemic crystals to 40 parts by weight and 0.3 parts by weight, respectively, a liquid composition (hereinafter referred to as Composition 5) is obtained by following the procedure of Production Example 1.

[0042] Manufacturing Example 6 A liquid composition (hereinafter referred to as Composition 6) is obtained by following the procedure of Production Example 5, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 3 parts by weight and 2 parts by weight, respectively.

[0043] Manufacturing example 7 A liquid composition (hereinafter referred to as Composition 7) is obtained by following the procedure of Production Example 5, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 2 parts by weight and 3 parts by weight, respectively.

[0044] Manufacturing Example 8 A liquid composition (hereinafter referred to as Composition 8) is obtained by following the procedure of Production Example 5, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 1 part by weight and 4 parts by weight, respectively.

[0045] Manufacturing Example 9 Except for changing the amounts of R-form crystals and racemic crystals to 32 parts by weight and 10 parts by weight, respectively, a liquid composition (hereinafter referred to as Composition 9) is obtained by following the procedure of Production Example 1.

[0046] Manufacturing Example 10 A liquid composition (hereinafter referred to as Composition 10) is obtained by following the procedure of Production Example 9, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 3 parts by weight and 2 parts by weight, respectively.

[0047] Manufacturing Example 11 Except for changing the amounts of Soprophor FLK and Morwet D-425 to 2 parts by weight and 3 parts by weight, respectively, a liquid composition (hereinafter referred to as Composition 11) is obtained by following the procedure of Production Example 9.

[0048] Manufacturing Example 12 A liquid composition (hereinafter referred to as Composition 12) is obtained by following the procedure of Production Example 9, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 1 part by weight and 4 parts by weight, respectively.

[0049] Manufacturing Example 13 Except for changing the amounts of R-form crystals and racemic crystals to 25 parts by weight and 20 parts by weight, respectively, a liquid composition (hereinafter referred to as Composition 13) is obtained by following the procedure of Production Example 1.

[0050] Manufacturing Example 14 A liquid composition (hereinafter referred to as Composition 14) is obtained by following the procedure of Production Example 13, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 3 parts by weight and 2 parts by weight, respectively.

[0051] Manufacturing Example 15 A liquid composition (hereinafter referred to as Composition 15) is obtained by following the procedure of Production Example 13, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 2 parts by weight and 3 parts by weight, respectively.

[0052] Manufacturing Example 16 A liquid composition (hereinafter referred to as Composition 16) is obtained by following the procedure of Production Example 13, except that the amounts of Soprophor FLK and Morwet D-425 are changed to 1 part by weight and 4 parts by weight, respectively.

[0053] Manufacturing Example 17 Except for changing the amounts of R-form crystals and racemic crystals to 38.8 parts by weight and 2.5 parts by weight, respectively, a liquid composition (hereinafter referred to as Composition 17) was obtained according to the procedure of Production Example 1.

[0054] Manufacturing Example 18 A liquid composition (hereinafter referred to as Composition 18) was obtained by following the procedure of Production Example 17, except that the amounts of Soprophor FLK and Morwet D-425 were changed to 3 parts by weight and 2 parts by weight, respectively.

[0055] Manufacturing example 19 A liquid composition (hereinafter referred to as Composition 19) was obtained by following the procedure of Production Example 17, except that the amounts of Soprophor FLK and Morwet D-425 were changed to 2 parts by weight and 3 parts by weight, respectively.

[0056] Manufacturing Example 20 A liquid composition (hereinafter referred to as Composition 20) was obtained by following the procedure of Production Example 17, except that the amounts of Soprophor FLK and Morwet D-425 were changed to 1 part by weight and 4 parts by weight, respectively.

[0057] Manufacturing Example 21 Except for not using R-form crystals, changing the amount of racemic crystals to 40 parts by weight, and changing the amounts of Soprophor FLK and Morwet D-425 to 2.5 parts by weight each, a liquid composition (hereinafter referred to as Composition 21) was obtained by following the procedure of Production Example 1.

[0058] Manufacturing Example 22 A liquid composition (hereinafter referred to as Composition 22) was obtained by following the procedure of Production Example 21, except that the amounts of Soprophor FLK and Morwet D-425 were changed to 2 parts by weight and 3 parts by weight, respectively.

[0059] Manufacturing Example 23 A mixture was obtained by mixing 9.6 parts by weight of R-crystals, 30.3 parts by weight of racemic crystals, 4 parts by weight of Soprophor FLK, 1 part by weight of Morwet D-425, 0.1 parts by weight of Xiameter AFE-1530 Antifoam emulsion, and water in an amount that made up to 81.3 parts by weight in total. The mixture was then wet-milled using a horizontal bead mill (DYNO-MILL KDL, WILLY A.BACHOFEN AG Maschinenfabrik) to obtain a slurry. A mixture containing a thickening agent (hereinafter referred to as "thickened mixture 2") was obtained by mixing 0.2 parts by weight of Proxel GXL, 0.2 parts by weight of Kelzan, 0.4 parts by weight of Veegum R, 5 parts by weight of propylene glycol, 0.1 parts by weight of Xiameter AFE-1530 antifoam emulsion, and 20.8 parts by weight of water and stirring for 2 hours. The slurry and the thickening mixture 2 were mixed to obtain a liquid composition (hereinafter referred to as composition 23).

[0060] Manufacturing Example 24 A liquid composition (hereinafter referred to as Composition 24) was obtained by following the procedure of Production Example 23, except that the amounts of Soprophor FLK and Morwet D-425 were changed to 3 parts by weight and 2 parts by weight, respectively.

[0061] Manufacturing Example 25 Except for changing the amounts of R-form crystals and racemic crystals to 4.8 parts by weight and 35.2 parts by weight, respectively, a liquid composition (hereinafter referred to as Composition 25) was obtained by following the procedure of Production Example 23.

[0062] Manufacturing example 26 A liquid composition (hereinafter referred to as Composition 26) was obtained by following the procedure of Production Example 25, except that the amounts of Soprophor FLK and Morwet D-425 were changed to 3 parts by weight and 2 parts by weight, respectively.

[0063] Manufacturing example 27 Except for not using R-form crystals, changing the amount of racemic crystals to 40 parts by weight, and changing the amounts of Soprophor FLK and Morwet D-425 to 3 parts by weight and 2 parts by weight, respectively, a liquid composition (hereinafter referred to as Composition 27) was obtained by following the procedure of Production Example 23.

[0064] Preservation test 80 mL of the liquid composition was transferred to a glass bottle and sealed. The glass bottle was then placed in a constant temperature bath and maintained at 40°C for a predetermined period (10 weeks or 3 months). After that, the glass bottle was removed from the constant temperature bath and the particle size, viscosity, powderiness, and amount of the cocrystal were measured.

[0065] Particle size measurement The particle sizes of the main crystals and cocrystals contained in each liquid composition were measured by wet measurement using a laser diffraction particle size distribution analyzer (Mastersizer 2000, Malvern Panalytical). Dv10, Dv50, and Dv90 represent the particle sizes at which the cumulative frequency of each particle size distribution is 10%, 50%, and 90%, respectively, based on volume.

[0066] Viscosity measurement The viscosity of each liquid composition was measured using a Type B viscometer (Viscometer RB-85L, manufactured by Toki Sangyo Co., Ltd.) at 25°C, using spindle No. 2, and at a rotation speed of 6 rpm.

[0067] Measurement of powderiness The powderiness of each liquid composition was measured by a wet method using a sieve with a mesh size of 75 μm, in accordance with CIPAC MT185.

[0068] Measurement of the amount of this cocrystal contained in the liquid composition Calibration curve preparation samples were prepared, each containing 18% by weight of the R-form crystal of the compound as an internal standard, and 1%, 2%, 3%, and 5% by weight of the co-crystal. Calibration curves were then created. Each liquid composition was analyzed by powder XRD (permeation method), and the ratio of the peak area value of 16.6°±0.1 derived from the co-crystal to the peak area value of 17.7°±0.1 derived from the R-form crystal of the compound was determined. Based on the previously prepared calibration curve, the amount of co-crystal contained in the liquid composition was calculated. The analysis conditions for powder XRD are shown below. <Powder XRD analysis conditions> Powder X-ray diffractometer: Aeris (manufactured by Spectris Corporation) Measurement method: Transmission method (film) X-ray output: Cu-Kα, 40kV, 15mA Scanning range: 15.5°~19.5° Measurement temperature: room temperature In Tables 3 and 4, the notation "Not detected" means that no peak of 16.6°±0.1 was observed.

[0069] [Table 2]

[0070] [Table 3]

[0071] [Table 4]

[0072] In Table 4, if the Dv90 measured after 10 weeks of storage at 40°C is less than the value measured before storage, the Dv90 is considered unchanged, and the rate of increase is expressed as 0.

[0073] [Table 5]

[0074] The fluidity of composition 27 was inferior to that of compositions 23 to 26, making it difficult to discharge from the container. Furthermore, the powderiness of composition 27 was higher than that of compositions 23 to 26, raising concerns about nozzle clogging in sprayers.

Claims

1. A liquid composition comprising crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, at least one surfactant, and water, wherein the crystals are suspended in water, The crystals include a racemic crystal of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide. The liquid composition is a liquid composition containing less than 13% by weight of a racemic cocrystal of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and water.

2. The liquid composition according to claim 1, wherein the total content of racemic crystals and cocrystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide in the liquid composition is 45% by weight or less.

3. The liquid composition according to claim 1 or 2, wherein the crystal comprises the R-form crystal of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, and the total content of the racemic crystal, the R-form crystal, and the cocrystal in the liquid composition is 5% by weight or more.

4. The liquid composition according to any one of claims 1 to 3, comprising 0.1% by weight or more of the aforementioned cocrystal.

5. The liquid composition according to any one of claims 1 to 4, wherein the Dv90 of the crystals of 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide and the particles of the cocrystal are 15 μm or less.

6. A liquid composition according to any one of claims 1 to 5, satisfying (A) below. (A) The particle size increase rate calculated by the following formula (1) is 75 or less. Particle size increase rate (%) = (D2 - D1) / D1 × 100 (1) (In formula (1), D1 represents the Dv90 of the crystalline particles contained in the liquid composition before storage at 40°C for 10 weeks, and D2 represents the Dv90 of the crystalline particles contained in the liquid composition after storage at 40°C for 10 weeks.)

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