WO2024221052A1 - Fungicide suspension concentrate - Google Patents

Abstract

A method of preparing aqueous suspension concentrate of prothioconazole, the method comprising: providing a liquid solution of prothioconazole comprising a non- volatile solvent for the prothioconazole; and combining the liquid solution with an aqueous phase precipitant, under conditions of high shear mixing, to form an aqueous mixture and cause the prothioconazole to precipitate, thereby forming a suspension comprising precipitated particles of prothioconazole in the aqueous mixture.

Description

Fungicide Suspension Concentrate

Priority cross-reference

[0001] The present application claims priority from Australian provisional patent application No. 2023901225 filed on 26 April 2023 and from Australian provisional patent application No. 2023903398 filed on 25 October 2023, the contents of which should be considered to be incorporated into this specification by this reference.

Technical field

[0002] The present invention relates to the fungicide prothioconazole (2-(2RS)-2- (1 -chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl-2H-1 ,2,4-triazole-3 (4H)- thione) and in particular to compositions containing prothioconazole and methods for their preparation.

Background of invention

[0003] Prothioconazole is a systemic fungicide which is used in a range of applications including crop protection. Prothioconazole has a unique toxophore among the triazole class of fungicides. Its effective fungicidal properties are attributed to its ability to inhibit the CYP51 A1 enzyme which is required in biosynthesis of ergosterol, a key component in the cell membrane of fungi. Prothioconazole has been found to provide good control of almost all wheat fungal diseases, such as powdery mildew, banded sclerotial blight, leaf spot, rust disease, sclerotinia rot, net blotch, leaf spot and the like on wheat and barley, can also prevent and treat soil-borne diseases of rape and peanut, such as sclerotinia, and control main leaf surface diseases, such as grey mould (also referred to as Botrytis grey mould), black spot, brown spot, black shank, sclerotinia, rust disease and the like.

[0004] Despite its effectiveness as a fungicide, the poor solubility of prothioconazole in water (water solubility 300 mg/L at 20⁹C) and many common solvents and problems of chemical and physical stability present a significant challenge to formulators.

[0005] US patent 5,789,430 discloses prothioconazole and proposes a range of formulation types such as solutions, emulsifiable concentrates, emulsions, foams, suspensions, wettable powders, pastes, soluble powders, dusts and granules. The compositions examined are aqueous dispersions of prothioconazole in a solvent which is N-methylpyrrolidone or acetone.

[0006] US Patent 8,658,680 explains that prothioconazole is subject to chemical degradation, and that aqueous microdispersions become chemically unstable, particularly when diluted prior to use. Losses of ten to fifteen percent by weight of the active ingredient over time are said to have been reported, particularly in low concentration formulations. The stability of composition is said to be improved by the addition of sulphur compounds. However, US 1 1 ,425,903 recognises that due to regulatory guidelines on the use of sulfur compounds the stabilisation of prothioconazole formulations with sulfur compounds is often found to be ineffective. US 1 1 ,425,903 instead reports that transition metal salts such as copper sulfate improve stability.

[0007] US201 10144172 relates to a DMSO crystalline solvate of prothioconazole and to a method of forming amorphous prothioconazole in which the crystalline form is melted and cooled at a defined rate to produce amorphous particles of size D50 in the range 20 to 200 microns.

[0008] US 2018/0360042 recognises that stabilisation of prothioconazole formulations with sulfur compounds cannot be applied to emulsion concentrates and proposes emulsion concentrates in which the storage stability of prothioconazole is said to be significantly improved by use of an N,N-dimethyl fatty amide solvent such as N,N- dimethyl 9-decenamide which is renowned for its high solvency power.

[0009] N,N-dimethyl fatty amides are reported in US 20200093131 to have the disadvantage that they can only be prepared via a technically complex olefin metathesis step and comprise unwanted metal impurities which may catalyse the decomposition of prothioconazole. To address this problem US 20200093131 proposes using a range of 9-decenoate derivatives such as the 9-decenoate amide of dimethylaminopropylamine. The mixture is used to prepare a range of composition types including emulsion concentrates, water dispersible granules and aqueous suspension concentrates. [0010] Suspension concentrates are disclosed in US 20200093131 which are prepared by pre-comminuting prothioconazole in a colloid mill, followed by wet grinding with the addition of water and adjuvants including the 9-decenoate derivative.

[0011] A further problem of formulating prothioconazole is the tendency of particles in suspension to grow as a result of the phenomenon of Ostwald ripening. EP206131 1 addresses this problem by forming an oil-in-water microemulsion containing a dispersed solution of the pesticide in a volatile organic solvent in which the particles of dispersed solution of pesticide are of no more than 30 nanometres and then removing the volatile organic solvent to provide nanoparticles of the pesticide.

[0012] There is a need for a suspension concentrate of prothioconazole and methods for preparation which address these problems and allow concentrates of prothioconazole to provide effective fungicide activity.

[0013] A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that the document or matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims.

Summary

[0014] The invention provides a suspension concentrate of prothioconazole formed by precipitation from a liquid solution of prothioconazole comprising a non-volatile solvent. The liquid solution of prothioconazole is combined with an aqueous phase, which acts as a non-solvent for the dissolved prothioconazole, under conditions of high shear mixing to induce precipitation of particles of prothioconazole from the liquid solution and form a suspension concentrate in the aqueous mixture. The precipitated particles of prothioconazole may thus have one or more favourable properties such as a small particle size, narrow polydispersity index, predominantly amorphous solid form, and stability in the suspension concentrate.

[0015] The non-volatile solvent is typically destined to remain present in the suspension concentrate until its end use for fungicidal control, optionally as a useful adjuvant or second agrochemical active in the suspension concentrate. Since the nonvolatile solvent is thus never separated from the precipitated prothioconazole particles, there is no need to use a volatile solvent that can be removed by drying. Indeed, volatile components such as conventional organic solvents are typically undesirable components of aqueous suspension concentrates for fungicidal application.

[0016] Accordingly, there is provided a method of preparing an aqueous suspension concentrate of prothioconazole, the method comprising: providing a liquid solution of prothioconazole comprising a non-volatile solvent for the prothioconazole; and combining the liquid solution with an aqueous phase precipitant, under conditions of high shear mixing, to form an aqueous mixture and cause the prothioconazole to precipitate, thereby forming a suspension concentrate comprising precipitated particles of prothioconazole in the aqueous mixture.

[0017] The non-volatile solvent for prothioconazole is preferably miscible with the aqueous phase precipitant. Miscibility provides rapid mixing and precipitation of fine particles of prothioconazole.

[0018] Preferably the precipitate is formed in the presence of a water-soluble stabiliser which may be present in the liquid solution of prothioconazole (optionally as the non-volatile solvent), in solution in the aqueous phase precipitant or both in the liquid solution of prothioconazole and the aqueous phase precipitant.

[0019] It is preferred in order to provide a particularly stable suspension concentrate that the liquid solution of prothioconazole is at an elevated temperature when combined with the aqueous phase and the aqueous phase is at a lower temperature, typically less than the melting temperature of prothioconazole and preferably in the range of 5^SC to 60^sC such as 5^SC to 50^sC or 5^SC to 40^sC.

[0020] In some embodiments, the precipitated particles of prothioconazole are of diameter, D90, of no more than 1 micron. In some embodiments, the precipitated particles of prothioconazole are of diameter, Dz, of from 100 to 800 nanometres, preferably 100 nanometres to 500 nanometres. In some embodiments, the precipitated particles of prothioconazole have a polydispersity index (Pdl) of no more than 0.6, preferably no more than 0.5.

[0021] In some embodiments, the concentration of prothioconazole in the suspension concentrate is at least 10 g/L of the suspension concentrate. Preferably, the concentration of prothioconazole is at least 50 g/L of the suspension concentrate, such as at least 100 g/l, at least 150 g/L, at least 200 g/L, or at least 250 g/L, or in the range of 5 g/L to 500 g/L such as 10 g/L to 400 g/L, 50 g/L to 400 g/L, 100 g/L to 300 g/L or 150 g/L to 400 g/L of the suspension concentrate.

[0022] In some embodiments, the liquid solution of prothioconazole is formed at an elevated temperature below the melting point of prothioconazole.

[0023] In some embodiments, the liquid solution is at an elevated temperature when combined with the aqueous phase precipitant. The elevated temperature may be less than the melting point of prothioconazole. The elevated temperature may be in the range of 60^sC to 130^sC, such as in the range of 70^sC to 130^sC. The non-volatile solvent may be a liquid or solid at ambient temperature and a liquid at the elevated temperature, wherein the prothioconazole is insoluble or poorly soluble in the non-volatile solvent at ambient temperature and soluble in the non-volatile solvent at the elevated temperature. The aqueous phase precipitant may be cooler than the liquid solution when the liquid solution is combined with the aqueous phase precipitant. Suitably, the aqueous phase precipitant is at a temperature no more than 60^sC, preferably no more than 50^sC, most preferably no more than 40°C.

[0024] In some embodiments, the non-volatile solvent, if it has a normal boiling point, has a normal boiling point of at least 170^sC, preferably at least 200°C.

[0025] In some embodiments, the prothioconazole precipitates in the presence of a water-soluble stabiliser initially present in the liquid solution of prothioconazole, the aqueous phase precipitant or in both of the liquid solution of prothioconazole and the aqueous phase precipitant. The water-soluble stabiliser is optionally present in the liquid solution of prothioconazole as the non-volatile solvent.

[0026] In some embodiments, the water-soluble stabiliser is selected from a water- soluble polymer, a surfactant, and combinations thereof. In some embodiments, the water-soluble stabiliser comprises a non-ionic surfactant.

[0027] In some embodiments, the prothioconazole precipitates in the presence of a water-soluble stabiliser comprising one or more selected from homopolymers of, or copolymers prepared from two or more of, monomers selected from: vinyl alcohol, acrylic acid, methacrylic acid, acrylamide, methacrylamide, acrylamide methylpropane sulphonates, aminoalkyl acrylates, aminoalkyl methacrylates, hydroxyethylacrylate, hydroxyethylmethylacrylate, vinyl pyrrolidone, vinyl imidazole, vinyl amines, vinyl pyridine, ethylene glycol and other alkylene glycols, ethylene oxide and other alkylene oxides, ethyleneimine, styrenesulphonates, ethylene glycol acrylates and ethylene glycol methacrylates.

[0028] In some embodiments, the prothioconazole precipitates in the presence of a water-soluble stabiliser selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone and polyalkylene glycols including block and random copolymers such as poloxamers and comb graft copolymers, styrene-acrylic acid copolymers, ethoxylated copolyester copolymers such as ethoxylated acrylic, methacrylic copolymers and surfactants.

[0029] In some embodiments, the prothioconazole precipitates in the presence of a water-soluble stabiliser which is a surfactant having an HLB of at least 9, preferably at least 10, such as 10 to 20, or 10 to 15. The surfactant may comprise at least one nonionic surfactant selected from the group consisting of alkoxylated fatty alcohols, alkoxylated fatty acids, alkoxylated fatty amines, alkoxylated alkylphenols, polysorbates and poloxamers.

[0030] In some embodiments, the prothioconazole precipitates in the presence of a water-soluble stabiliser comprising a non-ionic ethoxylated surfactant. In some embodiments, the prothioconazole precipitates in the presence of a water-soluble stabiliser selected from a fatty alcohol ethoxylate, a fatty acid ethoxylate, a poly(meth)acrylate ethoxylate, a polysorbate (i.e. an alkoxylated sorbitan alkyl esters), a polyalkylene oxide ethoxylate such as a polypropylene oxide ethoxylate (i.e. a polypropylene oxide polyethylene oxide block co-polymer, including poloxamers). In some embodiments, the prothioconazole precipitates in the presence of a fatty alcohol ethoxylate.

[0031] In some embodiments, the weight ratio of prothioconazole to water-soluble stabiliser is in the range of 50:1 to 1 :5, such as in the range of 40:1 to 1 :5, or in the range of 10:1 to 1 :2. [0032] In some embodiments, the non-volatile solvent for prothioconazole comprises (or consists of) at least one selected from the group consisting of C2 to Ce glycols particularly ethylene glycol and propylene glycol; glycerol and mono- and di-Ci to C aliphatic esters thereof, mono esters of glycols such as the Ci to C4 esters of ethylene glycol and propylene glycol; polyethers including polyalkylene glycols such as PEG 200 to PEG 4000, Ci to C4 alkyl ethers of ethylene glycol and diethylene glycol, Ci to C4 alkyl esters of ethylene glycol and diethylene glycol, Ci to C4 ethers of propylene glycol and di-propylene glycol; surfactants such alkoxylated fatty alcohols preferably comprising a fatty-aliphatic alcohol portion of from 8 to 20 carbon atoms alkoxylated with 2 to 30 oxyalkylene units, polysorbates such as polysorbate 20,40, 60 and 80, alkoxylated fatty-alkyl amines such as C8 to C18 fatty alkyl amines alkoxylated with 2 to 30 alkoxy units, and mixtures thereof.

[0033] In some embodiments, the non-volatile solvent for prothioconazole comprises (or consists of) at least one selected from the group consisting of glycerol, propylene glycol, dipropylene glycol dimethyl ether, PEG 200-PEG4000, fatty alcohol polyethers such as Cs to C18 fatty alcohols alkoxylated with from 2 to 30 EG and/or PO units, Ci to Ce alkyl ethers alkoxylated with from 2 to 30 EO and/or PO units, alkoxylated fatty-alkyl amines such as Cs to C18 fatty alkyl amines alkoxylated with 2 to 30 alkoxy units, EO/PO block copolymer surfactants, alkoxylated sorbitan alkyl esters such as Polysorbate 20, 40, 60 and 80, poloxamers such as poloxamer 188, and mixtures thereof.

[0034] In some embodiments, the liquid solution of prothioconazole is introduced to the aqueous phase precipitant in a zone of high shear mixing within the aqueous phase precipitant, such as a high shear zone of a rotor stator high shear mixer.

[0035] In some embodiments, the non-volatile solvent is a solid at ambient temperature and has a melting point below the melting point of prothioconazole. In such embodiments, the non-volatile solvent may comprise a further agrochemical active.

[0036] In some embodiments, the non-volatile solvent comprises (or consists of) an adjuvant for the suspension concentrate, optionally selected from the group consisting of an antifreeze agent, a surfactant and a stabiliser for the precipitated particles of prothioconazole.

[0037] In some embodiments, the suspension concentrate further comprises additional agrochemicals in suspension or dissolved in the aqueous composition.

[0038] In some embodiments, the method further comprises adding a non-volatile adjuvant, optionally a thickener, to the suspension concentrate after precipitation of the prothioconazole and without removing the non-volatile solvent from the suspension concentrate.

[0039] In some embodiments, the precipitated particles of prothioconazole are not separated from the non-volatile solvent prior to end-use application of the prothioconazole as fungicide.

[0040] The method of the invention has an advantage of generally producing a suspension of prothioconazole particles which have a small and relatively uniform particle diameter (i.e. small particle size distribution). It is preferred that the particles of prothioconazole which are precipitated have a polydispersity index (Pdl) of no more than 0.6 and more preferably no more than 0.5.

[0041] In a further aspect the invention thus provides a prothioconazole suspension concentrate comprising solid particles of prothioconazole, generally in an amount of at least 5 g/L, preferably at least 10g/L, of the suspension concentrate. The solid particles of prothioconazole have an average particle diameter, Dz, of no more than 1 micron, preferably no more than 0.8 micron, more preferably no more than 0.7 micron and still more preferably no more than 0.5 micron, and a polydispersity index (Pdl) of no more than 0.6, preferably no more than 0.5. The prothioconazole particles are preferably predominantly amorphous.

[0042] In some embodiments, the prothioconazole is present in an amount of at least 50 g/L of suspension concentrate, such at least 100 g/L, for example at least 200 g/L such as 200 g/L to 600 g/L of suspension concentrate.

[0043] The prothioconazole suspension concentrate is typically a suspension of solid predominantly amorphous particles of prothioconazole which are preferably uncoated particles of diameter, D90, of no more than 2 micron, preferably D90 no more than 1 micron more preferably from 50 nanometres to 800 nanometres such as 50 nanometres to 500 nanometres or 100 to 500 nanometres.

[0044] In a further aspect the invention provides a suspension concentrate of prothioconazole comprising solid particles of prothioconazole of diameter, D90, no more than 1 micron, preferably no more than 800 nanometres such as 50 nanometres to 800 nanometres or 50 nanometres to 500 nanometres such as 100 to 500 nanometres and having a polydispersity index (Pdl) of no more than 0.6, preferably no more than 0.5. The prothioconazole particles are preferably predominantly amorphous.

[0045] In a further aspect there is provided a prothioconazole suspension concentrate composition formed by precipitation in an aqueous phase precipitant of prothioconazole from a hot solution of prothioconazole in a non-volatile solvent, wherein the non-volatile solvent is a solid at ambient temperature and provides a solvent for prothioconazole at an elevated temperature in the range of 60^sC to 130^sC, such as in the range of 70^sC to 130^sC.

[0046] In a further aspect there is provided a method of controlling fungal infection comprising applying to a plant or locus in which fungal infection is to be controlled a suspension concentrate comprising a suspension of solid particles of prothioconazole wherein the particles of prothioconazole are particles of diameter, D90, of no more than 2 microns, preferably no more than 1 micron. The particles of the precipitated prothioconazole preferably have a polydispersity index (Pdl) of no more than 0.6 and more preferably no more than 0.5. The suspension is typically applied to plants or the locus where fungal infection is to be controlled following dilution of the suspension concentrate with water.

[0047] In a further aspect there is provided a method of controlling fungal infection comprising: diluting an aqueous suspension concentrate of prothioconazole produced by the methods disclosed herein to produce a diluted suspension of prothioconazole; and applying the diluted suspension of prothioconazole to a plant or locus in which fungal infection is to be controlled. Typically, the non-volatile solvent remains present in the diluted suspension of prothioconazole when applied.

[0048] In a further aspect, there is provided a method of controlling fungal infection comprising preparing an aqueous suspension concentrate of prothioconazole by a method according to any embodiment disclosed herein; optionally diluting the aqueous suspension concentrate to produce a diluted suspension of prothioconazole; optionally adding one or more non-volatile adjuvants to the suspension concentrate after precipitation of the prothioconazole or to the diluted suspension; and applying the aqueous suspension concentrate or the diluted suspension to a plant or locus in which fungal infection is to be controlled, wherein the non-volatile solvent remains present in the aqueous suspension concentrate or the diluted suspension when applied to the plant or locus.

Brief Description of Drawings

[0049] Working Examples of the invention are described with reference to the attached drawings.

[0050] In the drawings:

[0051] Figure 1 is a schematic drawing of a method for preparation of a prothioconazole suspension concentrate in accordance with the invention.

[0052] Figure 2 is a graph showing the size distribution resulting from each or three repetitions of the method of the invention in accordance with Example 1 (prepared with GENAPOL X080 as the stabiliser in the aqueous phase) at the time of preparation.

[0053] Figure 3 is a graph showing the size distribution resulting from each or three repetitions of the method of the invention in accordance with Example 2 (prepared with GENAPOL X080 and ATLOX 4894 combination as the stabiliser in the aqueous phase) at the time of preparation.

[0054] Figure 4 shows the particle size distribution of three repetitions of a prothioconazole dispersion prepared in Example 14 with Tween 22 as solvent, Atlox 4894 as stabiliser 1 and Genapol X020 as stabiliser 2, at the time of preparation.

[0055] Figure 5 shows the particle size distribution of three repetitions of a prothioconazole dispersion prepared in Example 14 with Tween 22 as solvent, Atlox 4894 as stabiliser 1 and Genapol X020 as stabiliser 2, 48 days after preparation. [0056] Figures 6 shows the particle size distribution of three repetitions of a prothioconazole dispersion prepared in Example 14 with Tween 22 as solvent, Atlox 4894 as stabiliser 1 and Genapol X050 as stabiliser 2, at the time of preparation.

[0057] Figure 7 shows the particle size distribution of three repetitions of a prothioconazole dispersion prepared in Example 14 with Tween 22 as solvent, Atlox 4894 as stabiliser 1 and Genapol X050 as stabiliser 2, 42 days after preparation.

Detailed Description

[0058] Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of one or more other features, integers, steps or components, or group thereof.

[0059] The term “ambient temperature” used herein refers to temperature of the surrounding medium (typically the surrounding air temperature) and is generally in the range 0^aC to 30^sC. In relation to specific solubilities the ambient temperature refers to 20^sC. The term “elevated temperature” used herein refers to a temperature which is above ambient temperature, typically above 30°C.

[0060] The term “non-volatile” used herein refers to a material having a normal boiling point of at least 150^sC, such as at least 170°C, or at least 200^sC, optionally at least 250°C (i.e. at one atmosphere pressure), or which is a solid or liquid with no apparent normal boiling point (e.g. because it decomposes without boiling when heated). The non-volatile solvent may be a liquid or solid at ambient temperature and a liquid at the temperature at which the liquid solution is combined with the aqueous phase. The non-volatile solvent will typically dissolve the prothioconazole at the temperature at which the liquid solution is added to the aqueous phase, but the prothioconazole may be insoluble or poorly soluble in the non-volatile solvent at ambient temperature.

[0061] The term “poorly soluble”, in the context of a solubility in the non-volatile solvent, means a solubility of less than 10 g/L at 20°C.

[0062] The term “water-soluble” as used herein means a solubility in water of at least 10 g/L, preferably at least 20 g/L such as at least 30g/L of water at 20^sC. The term “miscible” is used herein as a synonym for “soluble”, i.e. , a mixture of the materials in the proportions used form a “true” solution, in which one material is molecularly dispersed in the other.

[0063] The term “water-insoluble” refers to a solubility of no more than 10 g/L at 20^sC, preferably no more than 5 g/L at 20^sC, such as no more than 2 g/L at 20^sC.

[0064] The term “precipitation” refers to the formation of discrete particles by means of precipitation of the active prothioconazole into an aqueous antisolvent from a solution of prothioconazole in solvent. The term does not in itself impose limitations on the mechanism of solids formation, and encompasses formation of both amorphous and crystalline solids. However, without limitation by theory, precipitation according to the present disclosure under conditions of high shear mixing is believed to be a process that allows the formation of dispersed particles within a medium by the rapid desolvation of a prothioconazole solute when the solvent solution of prothioconazole is added to a non-solvent under conditions that prevent macroscale phase separation.

[0065] The term “adjuvant” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning) and refers without limitation to an agent that modifies the effect of other agents and more particularly used to enhance the effectiveness of prothioconazole fungicide and/or other agents.

[0066] The term “solution” refers to a homogeneous mixture of a solid (such as prothioconazole) or solids dissolved in a liquid solvent. The prothioconazole solute is dissolved in the non-volatile solvent and in preferred embodiments the solution is free of other undissolved material. The solution may not form at ambient temperatures but requires heating, preferably without needing to exceed the melting point of prothioconazole, before the solution is free of undissolved material.

[0067] The suspension concentrate is generally storage stable, and in some embodiments may be stored and transported in the conventional manner without settling of the suspension. A viscosity modifier may be added to limit or avoid settling of high concentration suspension concentrates. Typically, the compositions are sufficiently physically stable to resist particle size growth such as from Ostwald ripening or agglomeration. The suspension concentrate composition at the point of use may be diluted by the end user, e.g. in a spray tank, and applied to the site where fungal control is required, such as to crops in which prophylaxis or control of existing fungal infection is required. The composition may be applied by any suitable means and spray application is useful.

[0068] The precipitated particles present in the suspension concentrate are preferably predominantly amorphous. For example, the dried formulation typically has reduced melting endotherms indicating a significant amorphous character. The term “predominantly amorphous” is defined as a precipitated particle formulation that shows a near complete absence of needle-like, cubic or plate-like crystal structure when observed using scanning electron microscopy, displays low intensity X-ray scattering when studied by powder X-ray diffraction techniques or exhibits reduced melting endotherms corresponding to the fungicide when measured using differential scanning calorimetry. Low intensity X-ray scattering is <15%, preferably <10% and most preferably <5% of the counts that are observed from a wholly crystalline reference sample of prothioconazole. Reduced melting endotherms are <15%, preferably <10% and most preferably <5% of the enthalpy observed from a wholly crystalline reference sample of prothioconazole. Fungicidal particles may be isolated for microscopic observation by being sprayed onto a surface and subjected to rapid drying including freeze drying.

[0069] The particle diameter of the particles of prothioconazole in the suspension concentrate, which may be predominantly amorphous, is measured by laser diffraction and/or by dynamic light scattering. In particular, dynamic or static light scattering and laser diffraction may be used, typically using Malvern Zetasizer or Malvern Mastersizer™ instruments (e.g., Malvern Mastersizer™ 2000, available from Malvern Instruments, UK). In these laser diffraction and/or light scattering particle size measurements, preferably the particle diameter is measured or stated by volume (e.g. by stating the mean diameter by volume = the volume-weighted mean diameter) or by hydrodynamic diameter, otherwise known as the z-average or Dz. Generally, for particle size analysis, sphericity of the particles is assumed.

[0070] The particle diameter of the prothioconazole in the suspension concentrate is typically no more than 2 microns. The particles are preferably of diameter (D90) of no more than 1.5 microns, such as no more than 1 micron, no more than 0.8 micron, no more than 0.75 micron or no more than 0.5 micron. The particles are typically at least 0.075 microns, such as at least 0.1 or at least 0.5 microns. It may be advantageous to select a particle diameter range depending on the components of the composition such as the specific stabilisers or the conditions under which it is to be used. Examples of various particle diameter ranges include 50 to 1000 nanometres, 50 to 800 nanometres, 100 to 800 nanometres.

[0071] The liquid solution of prothioconazole is typically formed at a temperature below the melting point of prothioconazole which is 140^sC. It is preferred that the temperature of the liquid solution is no more than 130^sC such as from above 30^sC to 130^sC, more preferably 60^sC to 130^sC when formed.

[0072] Prothioconazole is poorly soluble in many solvents at room temperature and the invention may use non-volatile solvents in which prothioconazole is poorly soluble at room temperature but when heated to an elevated temperature of less than 140^sC, preferably no more than 130^sC such as in the range of above 30^sC to 130^sC, more preferably in the range of 40^sC to 130^sC or in the range of 60^sC to 130^sC, most preferably in the range of 70^sC to 130^sC, the prothioconazole is sufficiently soluble to form a liquid solution suitable to produce the required concentration of precipitate, and an acceptable amount of the non-volatile solvent, in the suspension concentrate. The non-volatile solvent may be a solid or liquid at room temperature and act as a solvent for prothioconazole at a temperature less than 140^sC, preferably no more than 130^sC such as 30^sC to 130^sC or 40^sC to 130^sC, more preferably 60^sC to 130^sC, most preferably 70^sC to 130^sC.

[0073] The liquid solution typically comprises non-volatile solvent as the predominant or only solvent component for solubilising the prothioconazole. The nonvolatile solvent is typically destined to remain present in the suspension concentrate until its end use via optional dilution and application for fungicidal control, preferably as a useful adjuvant or at least an acceptably benign component. Since the non-volatile solvent is thus not removed from the suspension concentrate or otherwise separated from the precipitated prothioconazole particles, there is no need to use a volatile solvent that can be removed by drying. Indeed, volatile components such as conventional organic solvents are typically undesirable components of aqueous suspension concentrates for fungicidal applications. In some embodiments, the liquid solution thus comprises no more than 20 wt.% of volatile solvent, such as no more than 10 wt.% of volatile solvent, e.g. no more than 5 % of volatile solvent, based on the total weight of the suspension concentrate. Preferably, the liquid solution is substantially free of volatile solvent. It will be appreciated that “volatile solvents” referred to herein are nonaqueous volatile solvents. Water is volatile but is not a solvent for prothioconazole, and is typically avoided in the liquid solution. Nevertheless, water may in principle be accommodated within the liquid solution, to the extent possible before it renders the prothioconazole insoluble, since the solution is precipitated into an aqueous [phase precipitant.

[0074] The non-volatile solvent for prothioconazole is typically water-soluble or water-dispersible and is preferably water soluble to provide complete dissolution of the non-volatile solvent into the aqueous phase precipitant. The presence of surfactants in the aqueous phase precipitant may help to dissolve less water soluble solvents.

[0075] The prothioconazole suspension concentrate may comprise a stabiliser which may be used in the method of the invention as part of the aqueous phase precipitant or part of the prothioconazole solution used in the precipitation process. Generally, it is preferred that the stabiliser is a component of the aqueous phase into which the prothioconazole solution is introduced under high shear. The stabiliser assists in stabilising the suspension during the high shear mixing process to assist in forming and stabilising a fine precipitate.

[0076] Accordingly, the aqueous phase precipitant may comprise a stabiliser for the precipitate of prothioconazole which assists in stabilising the precipitate in suspension and against particle growth. Preferred stabilisers are water-soluble polymers which may, for example, be selected from homopolymers of, or copolymers prepared from two or more monomers selected from: vinyl alcohol, acrylic acid, methacrylic acid, acrylamide, methacrylamide, acrylamide methylpropane sulphonates, aminoalkylacrylates, aminoalkyl-methacrylates, hydroxyethylacrylate, hydroxyethylmethylacrylate, vinyl pyrrolidone, vinyl imidazole, vinyl amines, vinyl pyridine, ethyleneglycol and other alkylene glycols, ethylene oxide and other alkylene oxides, ethyleneimine, styrenesulphonates, ethyleneglycolacrylates and ethyleneglycol methacrylate. In preferred embodiments the water-soluble polymer is selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone and polyalkylene glycols including block and random copolymers such as poloxamers and comb graft copolymers, styrene-acrylic acid copolymers, ethoxylated copolyester copolymers such as ethoxylated acrylic, methacrylic copolymers and surfactants.

[0077] Preferred stabilisers are surfactants which may be non-ionic, ionic or zwitterionic. Non-ionic surfactants are preferred, particularly polyalkoxylated non-ionic surfactants. Suitable surfactants include relatively hydrophilic surfactants, e.g. having a HLB value of greater than 9, preferably greater than 10. Examples of suitable stabiliser surfactants include alkoxylated fatty alcohols, alkoxylated fatty amines, alkoxylated alkylphenols, polysorbates, poloxamers, alkoxylated fatty alkyl esters (i.e. alkoxylated fatty acids), and polyoxyethylene/polyoxypropylene block copolymers. The hydrophilic-lipophilic balance (HLB) of a surfactant is a measure of its degree of hydrophilicity or lipophilicity, and is to be calculated by Griffin’s method (HLB = 20 x Mh I M where Mh is the molecular mass of the hydrophilic portion of the molecule, and M is the molecular mass of the whole molecule).

[0078] The alkoxylated fatty alcohols preferably comprise a fatty-aliphatic alcohol portion of from 8 to 20 carbon atoms alkoxylated with 2 to 30 oxyalkylene units. Suitable saturated and unsaturated fatty alcohols in particular may be selected from capryl alcohol, pelargonic alcohol, capric alcohol, isodecyl alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, or behenyl alcohol, oleyl alcohol, elaidyl alcohol, linoleyl alcohol, linolenyl alcohol, or erucyl alcohol.

[0079] In particular, unsaturated and saturated C10 to Ci6 fatty alcohols may be preferred. The fatty alcohols may preferably be selected from capric alcohol, lauryl alcohol, isotridecyl alcohol or myristyl alcohol. Specific examples of ethoxyated alcohols, optionally containing one or more propylene oxide units include the following surfactants:

Triton®X100 (Dow), having formula: t-CsH — CeH4 — (OCH2CH2)9-IOOH;

Tergitol®TMN100x (Dow), having formula: sec-Ci₂H25— (OCH₂CH2)IO-OH;

Antarox®863 (Rhodia), having formula: iso-Ci₃H₂7— (OCH2CH2CH2)— (OCH₂CH2)IO— OH;

Rhodasurf®870 (Rhodia), having formula: iso-Ci3H27 — (OCH2CH2)IO — OH; and

Genapol®X080 (Clariant), having formula: iso-Ci₃H₂7— (OCH₂CH2)8— OH

[0080] Suitable examples of polysorbate surfactants include polysorbate 20 and polysorbate 80 (sold under the Tween® brand).

[0081] Examples of poloxamers include poloxamer 188 and poloxamer 407.

[0082] The stabiliser, which may be present in the prothioconazole solution, the aqueous phase, or both, may comprise a single stabiliser component or mixture of stabiliser components. In some cases, a single stabiliser in the aqueous phase is suitable such as a single stabiliser selected from PVA, alkoxylated C10 to C16 fatty alcohols, alkoxylated fatty alkyl esters, polyoxyethylene/polyoxypropylene block copolymers and polysorbates. In some embodiments two or more stabilisers are present as a result of mixing of the prothioconazole solution and aqueous phase. Specific examples of such combinations include combinations of two or more surfactants selected from polysorbates (e.g. polysorbate 40, 60 or 80) such as Polysorbate 80 available under the tradename TWEEN 80, polyoxyethylene/polyoxypropylene block copolymer, poloxamers such as poloxamer 188 and poloxamer 407, alkoxylated polyol esters such as available under the trade name ATPLUS® UEP, and alkoxylated fatty alcohols (e.g. having fatty-aliphatic alcohol portion of from 8 to 20 carbon atoms alkoxylated with 2 to 30 oxyalkylene units) such as ATLOX® 4894, Genapol X020, Genapol X050 and Genapol X080.

[0083] The nature of the non-volatile solvent used in preparing the solution of prothioconazole is not narrowly critical provided the above discussed solubility of prothioconazole and aqueous phase solubility/miscibility is achieved without compromising the prothioconazole. The non-volatile solvent may comprise a single molecular component or a plurality of molecules. Non-volatile solvents allow effective formation of precipitate at an elevated temperature. Suitable non-volatile solvents may be selected to remain in the suspension concentrate without a requirement for removal or special requirements for storage and transport.

[0084] In some embodiments, the non-volatile solvent is selected from (i) an adjuvant for the suspension concentrate, and (ii) an agrochemical active. The nonvolatile solvent is thus not only suitable to remain present in the suspension concentrate until its end use via optional dilution and application as fungicide, but is selected to play a useful functional role in the suspension concentrate e.g. during storage, transportation, aqueous dilution or ultimate application for fungal control. The nonvolatile solvent thus plays a double role as (i) solvent for the prothioconazole in the precipitation process, and (ii) water-dispersible, preferably water-miscible, adjuvant or second agrochemical active in the suspension concentrate thus produced.

[0085] In some embodiments, the non-volatile solvent is an adjuvant for the suspension concentrate selected from an antifreeze agent, a surfactant (e.g. wetting agent, penetrant) and a stabiliser for the precipitated particles of prothioconazole (e.g. a water-soluble polymer).

[0086] As already disclosed herein, the non-volatile solvent is typically destined to remain in the suspension concentrate until its end use application as fungicide. The non-volatile solvent is thus preferably not a conventional organic solvent, most of which are too volatile, too toxic and/or too hazardous to remain present in the suspension concentrate, or are immiscible with water. In some embodiments, therefore, the nonvolatile solvent does not consist of (and preferably contains less than 10 wt.% of, most preferably does not contain) an organic solvent which is a Ci-Ce amide (e.g. dimethylformamide). In some embodiments, the non-volatile solvent does not consist of (and preferably contains less than 10 wt.% of, most preferably does not contain) a Ci-C₆ organic solvent selected from an aliphatic mono-alcohol, an aliphatic ketone, an aliphatic carboxylic acid, an aliphatic amide or lactam, and mixtures thereof. In some embodiments, the non-volatile solvent does not consist of (and preferably contains less than 10 wt.% of, most preferably does not contain) a C1-C10 solvent selected from an aliphatic mono-alcohol, an aliphatic ketone, an aliphatic carboxylic acid, an aliphatic amide or lactam, and mixtures thereof. As used herein, a mono-alcohol refers to an alcohol with only one -OH group. In some embodiments, the non-volatile solvent does not consist of (and preferably contains less than 10 wt.% of, most preferably does not contain) a Ci-Ce compound, or a C1-C10 compound.

[0087] Specific example of non-volatile solvents include at least one selected from the group consisting of C2 to Ce glycols particularly ethylene glycol and propylene glycol; glycerol and mono- and di-Ci to C18 aliphatic esters thereof, mono esters of glycols such as the Ci to C4 esters of ethylene glycol and propylene glycol; polyethers including polyalkylene glycols such as PEG 200 to PEG 4000, Ci to C4 alkyl ethers of ethylene glycol and diethylene glycol, Ci to C4 alkyl esters of ethylene glycol and diethylene glycol, Ci to C4 alkyl ethers of propylene glycol and di-propylene glycol; surfactants such as alkoxylated fatty alcohols preferably comprising a fatty-aliphatic alcohol portion of from 8 to 20 carbon atoms alkoxylated with 2 to 30 oxyalkylene units, polysorbates such as polysorbate 20, 40, 60 and 80, alkoxylated fatty-alkyl amines such as C8 to C18 fatty alkyl amines alkoxylated with 2 to 30 alkoxy units; and mixtures of any of these.

[0088] Glycols, glycerol, polyethers and their derivatives are useful as antifreeze adjuvants in suspension concentrates. Surfactant adjuvants are useful as stabilisers for the prothioconazole particles, as wetting agents and for other purposes known to those of skill in the art.

[0089] Particularly preferred non-volatile solvents are glycerol, propylene glycol, dipropylene glycol dimethyl ether, PEG 200-PEG4000, fatty alcohol polyethers such as Cs to C fatty alcohols alkoxylated with from 2 to 30 EG and/or PO units, Ci to Ce alkyl ethers alkoxylated with from 2 to 30 EO and/or PO units, alkoxylated fatty-alkyl amines such as Cs to C18 fatty alkyl amines alkoxylated with 2 to 30 alkoxy units, EO/PO block copolymer surfactants, alkoxylated sorbitan alkyl esters such as Polysorbate 20, 40, 60 and 80 such as those commercially available under TWEEN and SPAN trade names and alkoxylated fatty-alkyl amines such as the SYNPROLAM 35X15 brand surfactant.

[0090] It will be understood that the identity and amount of stabiliser present in the aqueous phase prior to addition of the solution of prothioconazole will depend on the amount of prothioconazole to be stabilised, and the amount and nature of the solvent present in the prothioconazole solution. In some cases, the solvent may provide a role in stabilising the prothioconazole precipitate formed on addition of the solution of prothioconazole to the aqueous phase in which case the amount of stabiliser in the aqueous phase may be reduced. The amount and nature of the solvent and stabiliser and the temperature of the solvent and aqueous phase may be selected having regard to provide effective stabilisation of the prothioconazole precipitate resulting from addition of the prothioconazole solution to the aqueous phase.

[0091] The method includes a step of combining the liquid solution of prothioconazole with an aqueous phase precipitant, under conditions of high shear mixing. A water-soluble stabiliser is preferably present in the solution of prothioconazole which is added to the aqueous phase precipitant, in the aqueous phase precipitant with which the prothioconazole is mixed or in both the prothioconazole solution and aqueous phase precipitant. The weight ratio of prothioconazole to stabiliser is typically in the range of 50:1 to 1 :5 more preferably a weight ratio of 40:1 to 1 :5.

[0092] The prothioconazole suspension concentrate which is formed in the aqueous mixture will generally comprise a surfactant wherein the weight ratio of prothioconazole to the surfactant is in the range of from 50:1 to 1 :5. In some embodiments the non-volatile solvent is or comprises a stabiliser, particularly a surfactant which is a stabiliser. The ratio of prothioconazole to stabiliser when present in the liquid solution may vary widely depending on the solubility of the prothioconazole at the chosen temperature and the presence of any stabiliser in the aqueous phase. Typical examples of the weight ratio of prothioconazole to stabiliser such as surfactant in the liquid solution may be in the range 20:1 to 1 :10, preferably 20:1 to 1 :5. The concentration of stabiliser in the prothioconazole liquid solution may be reduced by the use of non-volatile co-solvents such as glycerol, propylene glycol, dipropylene glycol or the like.

[0093] It is preferred that the aqueous phase precipitant to which the prothioconazole is added contains a stabiliser such as surfactant. In one set of embodiments the weight ratio of prothioconazole to stabiliser in the aqueous phase precipitant is in the range of 50:1 to 1 :5 such as 40:1 to 1 :1 . [0094] The invention provides a suspension concentrate of the fungicide prothioconazole. The suspension concentrate comprises a suspension of solid particles of prothioconazole formed by precipitation facilitated by high shear mixing of the liquid solution of prothioconazole with an aqueous phase precipitant. The concentration of prothioconazole in the suspension concentrate of prothioconazole is typically at least 5 g/L of the suspension concentrate. More preferably the concentration of prothioconazole will be at least 10 g/L of suspension concentrate. The concentration may depend on whether the composition is to be provided in a ready to use format or whether the suspension concentrate is to be provided in a relatively high concentration for dilution by the formulator or end user prior to use in fungal control. More concentrated forms may contain an amount of prothioconazole of at least 50 g/L of the suspension concentrate, such as at least 100 g/l , at least 150 g/L , at least 200 g/L, at least 250 g/L, at least 300 g/L or at least 400 g/L. Typically the concentration is in the range of 5 g/L to 700 g/L such as 10 g/L to 600 g/L, 50 g/L to 600 g/L, 100 g/L to 500 g/L or 150 g/L to 500 g/L.

[0095] The method of the invention allows the suspension formed by precipitation to be recirculated to progressively increase the concentration of prothioconazole in the suspension without inducing crystal growth or unduly reducing the stability of the suspension concentrate. This is particularly advantageous as it allows a concentrate to be prepared without the need for further solvent removal or isolation and resuspension of the suspended particles by methods such as freeze drying, spray drying or the like which add significantly to the cost of manufacture. In one set of embodiments the method is conducted using a batch of aqueous phase precipitant into which the liquid solution of prothioconazole is gradually introduced into a zone of high shear mixing within the aqueous phase until the desired concentration is achieved. In some embodiments the aqueous phase precipitant is held in a vessel and circulated through an auxiliary vessel provided with a high shear mixer such as a rotor stator, and the solution of prothioconazole is introduced into the aqueous phase precipitant into a zone of high shear mixing within the aqueous phase. In this way the concentration of prothioconazole may be increased until the desired concentration, such as within the range 5 g/L to 500 g/L, 50 g/L to 500 g/L, 100 g/l to 400 g/L or 200 g/L to 400 g/l is achieved. [0096] Surprisingly, we have found that a fast precipitation process of prothioconazole which occurs as the rapid separation of a solid particles from a good solvent environment of the solution, when added under high shear mixing, to a poor solvent aqueous environment, or precipitant, may occur without the substantial formation of crystalline material.

[0097] The fast precipitation leads to the creation of concentrated suspensions that are stable. The good solvent environment may be created by using a non-volatile solvent at ambient temperature or heating a non-volatile material that may or may not have agrochemical activity and is not considered to be a good solvent at ambient temperature to a temperature where the material acts as a solvent. In some embodiments, therefore, the non-volatile solvent is a liquid or solid at ambient temperature and a liquid at an elevated temperature, such as of at least 60°C, (at atmospheric pressure), wherein the prothioconazole is insoluble or poorly soluble in the non-volatile solvent at ambient temperature and soluble in the non-volatile solvent at the elevated temperature.

[0098] The liquid solution may be at an elevated temperature when combined with the aqueous phase precipitant, such as at least 30°C, at least 40°C, at least 50°C or at least 60°C. In some such embodiments, the temperature of the liquid solution is below the melting point of prothioconazole when combined with the aqueous phase precipitant, such as in the range of 30^sC to 130^sC, more preferably 60^sC to 130^sC, most preferably 70^sC to 130^sC.

[0099] In embodiments where the liquid solution is at elevated temperature, the aqueous phase precipitant is preferably at a lower temperature than the liquid solution when the two compositions are combined, typically less than the melting temperature of prothioconazole and preferably no more than 60^sC, no more than 50^sC, or no more than 40°C, such as in the range of 5^SC to 60^sC such as 5^SC to 50^sC or 5^SC to 40^sC. The aqueous phase precipitant may suitably be at or near ambient temperature.

[0100] In a preferred embodiment the method involves heating a non-volatile material that has known agrochemical activity and is not considered to be a good solvent at ambient temperature to a temperature where the material acts as a solvent for prothioconazole. The formation of a good solvent environment at elevated temperatures is preferably determined by the formation of a homogeneous liquid solution at a temperature below the melting point of prothioconazole and may be accomplished with solvents that are solid or liquid at ambient temperature.

[0101] Unlike controlled crystallisation processes where the particles are subject to Ostwald ripening and instabilities that are driven by the nucleation of large structures by seed crystals, precipitation according to the present disclosure may be repeatedly undertaken in a single vessel with an increasing concentration of precipitate during the process. The method therefore provides significant advantages over melt emulsification or melt dispersion processes involving, for example, mixing streams in a confined chamber under high shear conditions and removal of solidified emulsion particles. In melt emulsification processes short residence time in the chamber is considered critical to prevent liquid formation and subsequent bulk crystallisation or aggregation of crystals into large structures. In the method of the present invention the use of solutions of prothioconazole overcomes the difficulties of manipulating emulsions and removes the need to manage residence time as the behaviour of crystal suspensions is overcome by forming precipitates.

[0102] The formation of a liquid solution of prothioconazole in a good solvent environment has surprisingly been successful when using liquids which are a poor solvent for prothioconazole at ambient temperature but become a good solvent at elevated temperature such as at least 60^sC, preferably at least 70^sC, more preferably at least 80^sC such as 30^sC to 130^sC, more preferably 60^sC to 130^sC, most preferably 70^sC to 130^sC or using materials that are solid at ambient temperature, and therefore do not act as conventional solvents under ambient conditions but form a liquid solvent at or above their melting point. When using a solid or a liquid that is not a solvent at ambient temperature, the material may be or contain further actives which have agrochemical activity and therefore allow for two or more agrochemicals to be simultaneously precipitated.

[0103] In one aspect the invention comprises: dissolving prothioconazole in a non-volatile, water-soluble solvent to produce a liquid solution; combining the liquid solution with an aqueous phase precipitant, under conditions of high shear mixing, to precipitate particles of prothioconazole and form a suspension concentrate, optionally with the addition of one or more formulation adjuvants. The liquid solution may be at a temperature suitable to dissolve the prothioconazole and may be at a temperature less than the melting point of prothioconazole, such as 30^sC to 130^sC, more preferably 60^sC to 130^sC, most preferably 70^sC to 130^sC.

[0104] In a further embodiment the method comprises: dissolving prothioconazole in a non-volatile solvent comprising or consisting of a further agrochemical active which is a poor solvent for prothioconazole at ambient temperature, at an elevated temperature sufficient to form a hot solution of prothioconazole, which optionally contains a surfactant and/or polymer. combining the hot solution, preferably at a temperature less than the melting point of prothioconazole, with an aqueous phase precipitant with high shear mixing to precipitate particles of the prothioconazole in the resulting aqueous mixture and form a suspension concentrate of the particles in the aqueous mixture, optionally with the addition of one or more formulation adjuvants.

[0105] In this embodiment the solvent may be liquid or solid at ambient temperature.

[0106] In another embodiment the method comprises: dissolving prothioconazole in an agrochemically active non-volatile solvent which is a poor solvent for prothioconazole at ambient temperature and a good solvent for prothioconazole at a temperature below the melting point of prothioconazole, at an elevated temperature sufficient to form a hot solution of prothioconazole which optionally contains at least a surfactant and/or polymer; and combining the hot solution at a temperature less than the melting point of prothioconazole and an aqueous phase precipitant with high shear mixing to precipitate particles of prothioconazole in the resulting aqueous mixture and form a suspension concentrate of the particles in the aqueous mixture, optionally with the addition of one or more formulation adjuvants. [0107] In one embodiment the method provides a mixture of two or more fungicides in the suspension concentrate. The method may involve addition of a liquid solution of one or more fungicides in addition to prothioconazole. For example, the liquid solution of prothioconazole may be formed by dissolving prothioconazole in a non-volatile solvent of a further fungicide at a temperature at which the prothioconazole is a solid and the further fungicide is a liquid. Alternatively, separate solutions of different agrochemicals may be introduced sequentially or simultaneously to the aqueous phase precipitant under high shear mixing conditions to provide a suspension concentrate comprising the mixture of prothioconazole and further agrochemical.

[0108] In one embodiment a liquid solution of prothioconazole is formed in an additional agrochemically active component, which is thus the non-volatile solvent. For example, the composition may contain one, two, three or more agrochemical actives.

[0109] Examples of additional materials may include fertiliser including nitrogenous fertiliser such as such as urea, pesticides such as: herbicides, particularly solid water-insoluble herbicides further fungicides such as other azole fungicides; insecticides; plant growth regulators; and nematicides.

[0110] Generally, the total pesticidally active component of the suspension concentrate composition will contain at least 20 wt%, preferably at least 50 wt% such as at least 70 wt% or at least 80 wt% of the total of prothioconazole.

[0111] The method comprises combining the liquid solution with an aqueous phase precipitant, optionally comprising a stabiliser such as a water-soluble polymer, under conditions of high shear mixing to precipitate the prothioconazole in the resultant aqueous mixture. The high shear condition may be provided by a range of mixers and homogenisers known in the art. The preferred conditions of high shear use a highspeed high shear mixer. [0112] Specific examples of high speed high sheer mixers include TURRAX T25, SILVERSON SL2 and LV1 MICROFLUIDIZER homogenisers.

[0113] The method may be conducted by introducing the liquid solution comprising prothioconazole into the aqueous phase precipitant with high shear mixing until the required concentration is achieved. Alternatively, the aqueous phase may be recirculated, for example from a batch of aqueous phase, through a vessel containing a high shear mixer to allow the gradual addition of liquid solution which may be continuous until the desired concentration is achieved. In general, the liquid solution comprising the prothioconazole is preferably introduced directly into the aqueous phase in or adjacent to a zone of high shear mixing, for example, into the high shear zone of a rotor stator type high shear mixer.

[0114] The method may include a step of adding a further non-volatile adjuvant to the suspension concentrate after precipitation of the prothioconazole and without removing the non-volatile solvent from the suspension concentrate. Suitable adjuvants for suspension concentrates are known to those of skill in the art, and include surfactants such as wetting agents, stickers, anti-freeze agents, humectants, dispersants, thickeners, anti-foam agents, drift control agents and the like. Such nonvolatile agents may supplement the non-volatile solvent as disclosed herein, which may itself function as an adjuvant in the suspension concentrate. The non-volatile solvent and the further adjuvant both typically remain present in the suspension concentrate until its end use for fungal control.

[0115] The suspension concentrate may include a thickener which is generally added following the formation of the suspension concentrate. Suitable thickeners for the present invention include polysaccharide gums such as xanthan gum, guar gum and ethoxylated dialkyl phenols and finely divided silicates and finely divided clays such as bentonite and attapulgite. The thickener is preferably present in the composition in 0.01 % to 2% by weight of the suspension concentrate composition, preferably 0.1 % to 2% by weight such as 0.1 % to 1 % by weight of the suspension concentrate composition Usually, the composition has a viscosity, at 20^sC, of at most 4000 mPa.s, e.g., from 100 to 4000 mPa.s, in particular from 100 to 3000 mPa.s, determined according to ASTM D 2196 by means of a Brookfield viscosimeter. [0116] The suspension concentrate may also comprise antifoam agents such as silicone antifoams. A silicone antifoam is commercially available under the Silfoam® SRE brand.

[0117] Usually, the composition has a viscosity, at 20^sC, of at most 4000 mPa.s, e.g., from 100 to 4000 mPa.s, in particular from 100 to 3000 mPa.s, determined according to ASTM D 2196 by means of a Brookfield viscosimeter.

[0118] The composition of the invention does not require the presence of mono- and or di-saccharides to provide a stable suspension of the particles of prothioconazole. The composition of the aqueous phase will generally contain no more than 5wt% of mono- and di-saccharides, preferably no more than 1 wt% mono- and disaccharides and is most preferably free of mono- and disaccharides.

[0119] An embodiment of the invention may be described with reference to Figure 1 of the drawings.

[0120] In the drawings Figure 1 shows a schematic representation of a manufacturing method for the suspension concentrate in which a liquid solution of prothioconazole is formed at a temperature of 80^sC to 130^sC in a heated vessel (10) with stirring and transferred by pump (30) via heated transfer line (20) (which maintains the temperature of the prothioconazole solution in the range 80^sC to 130^sC) to precipitation vessel (40) containing a stirred aqueous phase precipitant (50) at room temperature (such as 15^SC to 25^s) containing a dissolved surfactant such as an ethoxylated isotridecyl alcohol (such as GENAPOL X080), polysorbate 80 (such as TWEEN 80) or mixture of the two. The precipitation vessel (50) is provided with a high shear mixer (60) comprising a rotor-stator high shear mixing zone (70). The hot solution transfer line (20) from the pump (30) to the precipitation vessel (40) extends into or adjacent the high shear mixing zone (70) of high shear mixer (60). As a result, the hot solution is delivered from the end (80) of the transfer line (20) into the high shear mixing zone (70) to induce rapid precipitation of the prothioconazole and form a suspension concentrate.

[0121] The concentration of the suspended prothioconazole may be increased by continuously introducing the hot solution into the high shear zone (70) over a period of time to increase the precipitate concentration to the desired concentration such as at least 100 g/L. The aqueous phase (50) of the precipitation vessel may be supplemented with adjuvants, such as one or more of additional polymer, surfactant, antifoam and/or thickener contained in stirred adjuvant vessel (90) by transfer pump (100) via transfer line (1 10).

[0122] Despite the convenience of fungicidal suspension concentrate formulations their efficacy has generally been reported to be lower than for emulsifiable concentrates and solutions which each rely on high concentrations of powerful water immiscible solvents to solubilise the active ingredient.

[0123] For example, Xiao-xu Li et al.; J. Agric. Food Chem. 2020, 68, 1198-1206; (Fungicide Formulations Influence Their Control Efficacy by Mediating Physicochemical Properties of Spray Dilutions and Their Interaction with Target Leaves) compare the efficacy of pyraclostrobin fungicide formulations in the forms of emulsifiable concentrate (EC), suspension concentrate (SC), and microcapsules (MCs) in the control of fungal infestations in cucumber anthracnose. The conventional SC composition used includes a broad particle size distribution and relatively large particle size. The particle size distributions of pyraclostrobin EC, MCs, and SC are reported as 0.2- 1.97, 0.2-28.56, and 0.2-3.5 pm, respectively. The mean diameters of pyraclostrobin EC, SC, and MCs are reported as significantly different, being 0.91 , 1.69, and 4.72 pm, respectively.

[0124] The efficacy of the compositions was tested at a range of concentrations and shown to be highly dependent on concentration of active. Across the range of concentrations the efficacy of pyraclostrobin MCs (efficacy 87.37-95.12%) was reported to be significantly higher than those of EC (69.74-87.83%) which in turn was higher than SC (50.40-81 .11 %).

[0125] The paper also shows that pyraclostrobin EC and SC had significantly smaller particle sizes than pyraclostrobin MCs but crystalised on plant leaves to form larger crystals of blocklike crystallization morphology, whereas MCs remained as a sphere capsules. However, the crystal particles of pyraclostrobin SC were found to be concentrated in clusters, while those of MCs and EC were better dispersed.

[0126] The ability to form and maintain smaller and preferably amorphous particles (e.g. of diameter 50 to 1000 nanometres, particularly 100 to 500 nanometres) in suspension concentrates of the present invention is believed to be responsible for improved efficacy and stability of the prothioconazole suspension concentrate.

[0127] Without wishing to be bound by theory we consider the physicochemical characteristics of relatively small particles of low polydispersity, such as dissolution kinetics, significantly reduces the propensity for Ostwald ripening and also provides a significant enhancement in efficacy.

[0128] Ostwald ripening is a phenomenon observed in suspension concentrates which results from the change of an inhomogeneous structure over time. Small crystals or sol particles dissolve and redeposit onto larger crystals resulting in crystal growth and poor physical stability of the suspension concentrate. The uniformity of the small particle size (small polydispersity such as less than 0.6, preferably less than 0.5 and in many cases less than 0.3) is considered to significantly reduce the problem of Ostwald Ripening.

[0129] The relatively small particle size, amorphous character and low polydispersity are also considered to enhance the absorption of suspension concentrates on plant surfaces. The application to plant foliage which generally involves dilution with water and application (for example by spraying) onto plants, results in enhanced bioavailability of the prothioconazole as a result of enhanced dissolution kinetics of small particles, particularly for particles of diameter less than 1 micron such as 50 to 800 or 100 to 500 nanometres commonly resulting from the process of the present invention.

[0130] Dissolution rate of the active in droplets on the surface of plant foliage is significantly enhanced for particle compositions of high surface area. The Noyes- Whitney equation states that the rate of mass transfer of solute particles into the continuous phase (rate of dissolution) is equal to: dm/dt = DACs/h. where dm/dt = rate of mass transfer I rate of dissolution. D = diffusion coefficient. A= surface area of solute particles.

[0131] Further, while diffusion occurs first through the boundary layer about particles, which may control solubility, this diffusion is very significantly enhanced for particles of diameter less 1 micron so that boundary layer considerations are believed to also enhance solubility and bioavailability of the prothioconazole suspension concentrate prepared by the method of the present invention.

[0132] The suspension concentrate formed by the method of the invention has the stability to be stored and used without the need for drying and resuspension. However, in some embodiments the formation of a powder may be desirable for more concentrated storage and transport. We have found that the ‘Buchi’ B-290 type laboratory spray drying apparatus is suitable. The product form obtained from the preferred spray drying process is a powder. Generally, the suspension concentrate is prepared without the need for drying or solvent removal.

[0133] The invention will now be described with reference to an example which is provided for the purpose of further understanding embodiments of the invention but is not intended to limit the scope or applicability of the invention to the specific examples.

Examples

[0134] Examples 1-5

[0135] This Example demonstrates the preparation of the prothioconazole suspension concentrate in accordance with the process of the invention.

[0136] Prothioconazole and ATLOX 4894 added to a glass vessel at a 1 .85:1 ratio (2.5g Al and 1 .35 g ATLOX 4894 acting as a solvent).

[0137] The combination is heated until a clear, homogeneous solution is formed (below the melting point of prothioconazole (lit ref 140°C). Typical range of temperature < 130°C - but not limited to this). This hot solution is used with no extra additives.

[0138] A vessel containing 20mL of an aqueous solution of stabilisers set out in the Table 1 (typically but not limited to 2.5g of stabiliser in 20mL of water - 50wt% ratio with respect to prothioconazole) is prepared and weighed. Stock solutions of the stabilisers are made at a concentration of 125 mg/mL if a desired final mass of stabiliser of 2.5 g is required.

[0139] The vessel is stirred using high shear mixing, typically a SILVERSON brand high shear mixer (but not limited to this) set to maximum rpm. The vessel is maintained at ambient temperature. [0140] The hot solution prepared above is pumped into the mixing zone of the high shear mixer, during which the “solvent” is dispersed into the aqueous solution. The hot solution is, therefore, rapidly diluted (leading to precipitation), cooled (leading to solidification) and subjected to high shear mixing (leading to the break-up of the flow and the formation of small solid particles of prothioconazole)

[0141] The vessel is reweighed after complete addition of the hot prothioconazole solution and additional water is added if required to ensure the target prothioconazole concentration (in this case 125 g/L in 20 mL final volume) is achieved.

[0142] It is important to note that some “solvents” may also act as additional stabilisers once dissolved into the aqueous solution.

[0143] Table 1 Stabiliser of Example:

[0144] GENAPOL X080 is a non-ionic surfactant containing Ci 1-14 iso alcohols (rich in isotridecyl alcohol) ethoxylated with about 8 EO units, sold by Clariant.

[0145] ATLOX 4894 is a non-ionic surfactant containing ethoxylated C12-15 alcohol having an HLB of about 16, sold by Croda Crop Care.

[0146] ATPLUS UEP is an alkoxylated polyol ester non-ionic surfactant comprising a C -unsaturated fatty acid ester with polyethylene glycol ether, combined with trimethylolpropane (3:1 ), sold by Croda Crop Care.

[0147] TWEEN 80 is a surfactant having the common name of Polysorbate 80 [polyoxyethylene (80) sorbitan monooleate]. [0148] Table 2

[0149] Data suggested that samples using GENAPOL X080 alone as the stabiliser or an ATLOX 4894 I GENAPOLX080 combination would provide samples that were >100 nm (in a preferred range of 100 to 500 nm).

[0150] The two samples for scale-up were therefore prepared for Example 1 and Example 2.

• Prothioconazole 125 g/L (concentration in final product)

• 50 wt% Al relative to stabilisers in the aqueous phase

• Solvent: ATLOX 4894 (present in both samples)

• Stabilisers GENAPOL X080 (Example 1 ) or GENAPOL X080 and ATLOX 4894 Example 2

[0151] Figure 2 shows the particle size distribution of the sample of Example 1 , prepared with GENAPOL X080 as the stabiliser in the aqueous phase, at the time of preparation.

[0152] Figure 3 shows the samples of Example 2, prepared with GENAPOL X080 and ATLOX 4894 combination as the stabiliser in the aqueous phase, at the time of preparation.

[0153] Example 5 Spring barley - Leaf scald - Glasshouse trial

[0154] Glasshouse trials refer to plant growth stages (abbreviated as GS). The growth stages referred to by number are well known to those involved in crop management and explanation of the growth stages are set out in the publication “Cereal Growth Stages” Grain Research & Development Corporation; ISBN 1 -875477; published September 2005. [0155] Objective

[0156] To test the efficacy of two experimental prothioconazole formulations against a commercial standard for Leaf Scald (Rhynchosporium) efficacy.

[0157] Formulations

[0158] PROLINE 275 275g ai/L Prothioconazole (Proline 275 is an emulsifiable concentrate of Prothioconazole at 275 g/L available from Bayer UK)

[0159] Example 2 Composition 125g ai/L Prothioconazole SC

[0160] Example 1 Composition 125g ai/L Prothioconazole SC

[0161] Examples 1 and 2 were prepared in accordance with the above procedure for Examples 1 and 2 with the volume increased to 200 ml.

[0162] Rates 24.75, 49.5, 99, 148.5, 198g ai/ha

[0163] Barley SY Tungsten

[0164] Application Timing GS13-14 (early seedling development stage with 3- 4 leaves unfurled)

[0165] Application Volume 200L/ha

[0166] Randomised Complete Block Design 5 Replicates

[0167] Methodology

5

[0168] Seedlings were inoculated with Rhynchosporium commune at 1 x10 spores/ml at 3-leaf stage.

[0169] Four barley seedlings per pot

[0170] Plants were sprayed at GS13-14 [3 days after inoculation] therefore represent a curative application.

[0171] Assessments - Leaf scald severity “% of Leaf Area Disease” (%LAD) @ 15

& 23 days after spraying (DAT) [0172] Analysis

[0173] Data was analysed using ANOVA and Factorial analysis of variance at P=0.05

[0174] Area under the disease progress curve was calculated and analysed from two assessment dates.

[0175] Acronyms

[0176] %LAD % Leaf Area Disease - An assessment of disease severity which defines the percentage area of leaves displaying symptoms

[0177] DAA Days after first treatment

[0178] ANOVA Analysis of variance - Comparison of treatment means

[0179] FAOV Factorial Analysis of Variance - Comparison of factor means and interactions between factors

[0180] LSD Least Significant Difference - Separation of means which satisfies condition that 5% probability of a Type I error

[0181] AUDPC Area Under the Disease Progress Curve - a measure of the total amount of disease over a period of time, which can be used to compare epidemics quantitatively

[0182] RESULTS

[0183] Phytotoxicity

[0184] No phytotoxicity observed throughout the trial.

[0185] Efficacy

[0186] There was no significant response to rate for Proline 15DAA but there was 23DAA.

[0187] There was a response to rate for Example 2 15DAA & 23DAA and generally more efficacious than Proline for each assessment timing and rate. [0188] There was a response to rate for Example 1 15DAA & 23DAA and generally more efficacious than Proline for 23DAA assessment timing and rate. Generally, response to rate 15DAA was similar to Proline.

[0189] Table 3 ANOVA - Barley %LAD Rhynchosporium commune

[0190] Averaged across rates, Proline was less efficacious than Example 1 and Example 2 compositions at 15DAA & 23DAA.

[0191] Example 2 was more efficacious than Example 1 composition15DAA but was less efficacious 23DAA.

[0192] AUDPC analysis confirms Example 1 and Example 2 compositions are more efficacious than Proline, but not significantly different to each other. [0193] Table 4 FAOV - Formulation

[0194] Averaged across formulations, there was a significant response to rate at 15DAA & 23DAA

[0195] Table 5 FAOV - Rate

[0196] Conclusions

[0197] All formulations significantly reduced disease severity at 15DAA & 23DAA.

[0198] Proline was less efficacious generally than Example 1 and Example 2

Compositions.

[0199] Example 2 was more efficacious than Example 1 at 15DAA, indicating that it may have faster action but assessment 23DAA indicates that Example 1 is more efficacious than Example 2. AUDPC analysis found no significant difference between these two formulations when averaged across rates. [0200] Example 6 Winter wheat - Powdery mildew- Glasshouse trial

[0201] Objective

[0202] To test the efficacy & crop safety of two experimental Prothioconazole microparticle formulations for curative control of Powdery Mildew (Blumeria graminis f. sp.) in Wheat

[0203] Formulations

[0204] PROLINE 275 275g ai/L Prothioconazole

[0205] Example 2 Compl 25g ai/L Prothioconazole SC

[0206] Example 1 comp 125g ai/L Prothioconazole SC

[0207] Rates 49.5, 99 & 198gai/ha

[0208] Wheat (Triticum aestivum) cv RGT Gravity

[0209] Application Timing GS21 -22 (1 -2 tillers)

[0210] Application Method OPS Sprayer delivering 200L/ha medium spray quality at 2.5 bar pressure

[0211] Randomised Complete Block Design 10 Replicates

[0212] Methodology

[0213] Six weeks prior to trial seed being sown twenty pots of cv RGT Gravity Wheat were sown & placed in glasshouse to facilitate development of natural infection of powdery mildew - these were used as inoculators.

[0214] When trial plant had emerged powdery mildew spores were manually spread onto trial plants (For non-inoculated Untreated control plants were covered in a polythene bag to prevent infection - these were kept on plants until final inspection.

[0215] Three wheat seeds per pot were planted & thinned to uniform size at GS11 - 12. [0216] Plants were sprayed at GS21 -22, therefore representing a curative application. (GS21 Main shoot & 1 tiller. GS22 is Main shoot & 2 tillers)

[0217] Assessments were made of Crop Phytotoxicity & Powdery Mildew Severity (% of whole plant Infected) @ 7, 14, 21 & 28 days after spraying (DAA).

[0218] Analysis

[0219] Data was analysed using ANOVA and Factorial analysis of variance at P=0.05.

[0220] The area under the disease progress curve was calculated and analysed from four assessment dates.

[0221] RESULTS

[0222] Phytotoxicity

[0223] No phytotoxicity was observed throughout the trial

[0224] Efficacy

[0225] Disease severity was assessed 7, 13, 20 & 28 days after treatment.

[0226] All formulations at all rates reduced the severity of disease at all assessment timings.

[0227] Response to each formulation at each rate were similar apart from the two instances noted below.

[0228] The Example 1 composition was less efficacious than Example 2 & PROLINE @ 198g ai/ha 20DAA.

[0229] The Example 2 composition was more effective than Example 1 @ 198g ai/ha AUDPC. [0230] Table 6 ANOVA - Severity - 17, 24, 30, 38DAA - Wheat Blumeria graminis f. sp.

[0231] Averaged across rates, there were no significant differences between formulations at any of the four assessment dates or when data was analysed for AUDPC.

[0232] Table 7 FAOV - Severity - Formulation - Wheat Blumeria graminis f.sp.

[0233] Averaged across formulations, there was no significant difference between formulations 7DAA.

[0234] Application at 49.5g ai/ha was less efficacious than the two higher rates 13DAA.

[0235] Application at 198g ai/ha was more efficacious than the two lower rates 20DAA. [0236] There was no significant difference between formulations 28DAA.

[0237] Area under the disease progress curve analysis showed that each of the rates are significantly different when averaged across all formulations.

[0238] Table 8 FAOV - Severity - Rate - Wheat Blumeria graminis f.sp.

[0239] Conclusions

[0240] Data was generated in glasshouse conditions for evaluation of level of control achieved with 2 microparticle formulations of Prothioconazole [Example 1 & Example 2] and compared to a commercial standard [Proline 275].

[0241] Treatments were applied to winter wheat which had disease present, so challenge was for control or eradication of existing disease.

[0242] Trial design was appropriate with adequate degrees of freedom and replication.

[0243] Disease pressure appeared to decline in the week leading to 20DAA and then increased in the week following. No conclusion can be drawn on the length of control for any of the three formulations tested, since all behaved similarly.

[0244] The response to rate was similar for all three formulations across the duration of the trial.

[0245] Compositions Example 1 , 2 and Proline provided similar levels of control at each rate across the duration of the trial. [0246] Composition Examples 1 and 2 did not provide more rapid control than Proline.

[0247] Composition Examples 1 and 2 provided similar lasting control to Proline.

[0248] Under the conditions tested, Compositions Examples 1 and 2 provided equivalent levels of control to Proline 275.

[0249] Example 7

[0250] A suspension concentrate of prothioconazole having a prothioconazole concentration of 125 g/L was prepared by the following procedure:

[0251] The chosen stabiliser#1 (1.11 g; see Table 9-10) was dissolved in H2O (1 OmL) and chosen stabiliser#2 (0.56g; see Tables 9-10) was dissolved in H2O (1 OmL) and both solutions were mixed overnight. Prothioconazole (2.5 g) was weighed into 40 mL vials along with Atlox 4894 LQ (1 ,35g) and then heated to 125 degC using a hotplate and Asynt heating insert. The antifoam Silfoam SRE (2-5 drops, 111.1 mg/ml) was added to the stabiliser mixture (Table 10), and the stabiliser mixture was stirred using Silversone SL2 high shear mixer before dissolved prothioconazole was pumped into the solution using a peristaltic pump. DLS characterisation was undertaken on samples diluted to 1 mg/mL in H2O after synthesis and 24 and 48 hours after.

[0252] Table 9

, Mass ,,, „_z „ . , Ratio (wrt , , ,

Chemical , , Wt% Ratio (wrt Al) , , Vol

(g) solvent)

Prothioconazole 2.5 60 1 1.85

Atlox 4894 1.35 - 0.54 1

Stabiliser#l 1.11 27 0.66 1.2 10

Stabilised 0.56 13 0.34 0.63 10

“Wt%” - weight percent of the composition.

“Ratio - (wrt” - means weight ratio with respect to the component referred to in the parentheses. [0253] Table 10

Solvent StabiliserWl Stabiliser#

Atlox 4894 LQ Genapol X080 Genapol X080

Atlox 4894 LQ Genapol X080 Atlox 4894 LQ

Atlox 4894 LQ Pluronic F68 Genapol X050

Atlox 4894 LQ Pluronic F68 Genapol X020

[0254] Pluronic F68 is a non-ionic surfactant which is a polyoxyethylenepolyoxypropylene block copolymer (a poloxamer), with an HLB of 29.

[0255] GENAPOL X050 is a non-ionic surfactant containing Ci 1-14 iso alcohols (rich in isotridecyl alcohol) ethoxylated with about 5 EO units, sold by Clariant.

[0256] GENAPOL X020 is a non-ionic surfactant containing Ci 1-14 iso alcohols (rich in isotridecyl alcohol) ethoxylated with about 2 EO units, sold by Clariant.

[0257] The resulting suspension concentrate had the following particle size (Dz) and polydispersity index (Pdl) properties shown in Tables 11 to 14.

[0258] Table 11

Sample day Dz (nm) Pdl

Pluronic F68: X020 0 225 ± 3 0.267 ± 0.009

Pluronic F68: X020 1 355 ± 3 0.299 ± 0.026

Pluronic F68: X020 2 432 ± 60 0.370 ± 0.119

[0259] Table 12

Sample day Dz (nm) Pdl

Pluronic F68: X050 0 234 ± 5 0.231 ± 0.012

Pluronic F68: X050 1 333 ± 34 0.308 ± 0.073

Pluronic F68: X050 2 315 ± 5 0.285 ± 0.014 [0260] Table 13

Sample day Dz (nm) Pdl

X080: X080 0 639 1 41 0.740 1 0.081

X080: X080 1 6341 124 0.833 1 0.206

X080: X080 2 435 1 42 0.861 1 0.097

[0261] Tablei 4

Sample day Dz (nm) Pdl

X080: Atlox4894 0 3141 3 0.553 1 0.012

X080: Atlox4894 1 352 1 2 0.561 1 0.013

X080: Atlox4894 2 5341 25 0.999 1 0.002

[0262] Example 8

[0263] Further suspension concentrates of prothioconazole at 125 g/L were prepared according to the previous Example 7 using the components and amounts shown in the following Tables 15 and 16.

[0264] Table 15

Mass , , Ratio (wrt

Chemical , . Wt% Ratio (wrt Al) , . Vol

(g) solvent)

Prothioconazole 2.5 70 1 1.85

Atlox 4894 1.35 - 0.54 1

Stabiliser#! 0.71 20 0.66 1.2 10

Stabilised 0.36 10 0.34 0.63 10 [0265] Table 16

Solvent Stabiliser#l Stabiliser#2

Atlox 4894 LQ Genapol X080 Genapol X080

Atlox 4894 LQ Genapol X080 Atlox 4894 LQ

Atlox 4894 LQ Pluronic F68 Genapol X050

Atlox 4894 LQ Pluronic F68 Genapol X020

[0266] The particle size (Dz) and polydispersity index (Pdl) were determined for the samples over 2 days and a shown in Tables 17 to 20 below.

[0267] Table 17

Sample day Dz (nm) Pdl

Pluronic F68: X020 0 180 ± 2 0.195 ± 0.016

Pluronic F68: X020 1 244 ± 1 0.276 ± 0.033

Pluronic F68: X020 2 235 ± 3 0.338 ± 0.022

[0268] Table 18

Sample day Dz (nm) Pdl

Pluronic F68: X050 0 245 ± 3 0.313 ± 0.032

Pluronic F68: X050 1 376 ± 18 0.387 ± 0.024

Pluronic F68: X050 2 367 ± 4 0.475 ± 0.043

[0269] Table 19

Sample day Dz (nm) Pdl

X080: X080 0 638 ± 136 0.875 ± 0.115

X080: X080 1 253 ± 3 0.344 ± 0.006

X080: X080 2 450 ± 10 0.336 ± 0.029 [0270] Table 20

Sample day Dz (nm) Pdl

X080: Atlox4894 0 218 ± 1 0.374 ± 0.014

X080: Atlox4894 1 194 ± 2 0.257 ± 0.018

X080: Atlox4894 2 199 ± 4 0.284 ± 0.017

[0271] Example 9

[0272] The process of Example 8 was repeated using the components and amounts set out in the following tables to form a suspension concentrate containing prothioconazole at a concentration of 175g/L using the compositions shown in the Tables 21 and 22 below.

[0273] Table 21

Ratio (wrt Chemical Mass (g) Tw% Ratio (wrt Al) , . Vol

^& solvent)

Prothioconazole 2.5 50 1 1.85

Atlox 4894 1.35 - 0.54 1

Stabiliser#l 0.71 33 0.66 1.2 10

Stabilised 0.36 17 0.34 0.63 10

“Wt%” - weight percent

“Ratio - (wrt... .)” - means weight ratio with respect to the component referred to.

[0274] Table 22

Solvent Stabiliser#! Stabiliser#2

Atlox 4894 LQ Genapol X080 Genapol X080

Atlox 4894 LQ Genapol X080 Atlox4894

[0275] The particle size (Dz) and polydispersity index (Pdl) were determined for the samples over 2 days and a shown in Tables 23 and 24 below. [0276] Table 23

Sample day Dz (nm) Pdl

X080: X080 0 209 ± 11 0.297 ± 0.030

X080: X080 1 225 ± 4 0.418 ± 0.002

X080: X080 2 192 ± 8 0.320 ± 0.015

[0277] Table 24

Sample day Dz (nm) Pdl

X080: Atlox4894 0 327 ± 8 0.943 ± 0.022

X080: Atlox4894 1 593 ± 33 0.588 ± 0.016

X080: Atlox4894 2 541 ± 8 0.589 ± 0.040

[0278] Example 10

[0279] The general process of Example 7 was repeated to form a suspension concentrate containing prothioconazole at a concentration of 225g/L using the compositions shown in the Tables 25 and 26 below.

[0280] Table 25

Chemical Mass (g) Wt% Ratio (wrt Al) Ratio (wrt

solvent)

Prothioconazole 2.5 50 1 1.85

Atlox 4894 1.35 - 0.54 1

Stabiliser#! 0.71 33 0.66 1.2 10

Stabilised 0.36 17 0.34 0.63 10 [0281] Table 26

Solvent StabilizerWl Stabiliser#

Atlox 4894 LQ Genapol X080 Genapol X080

Atlox 4894 LQ Genapol X080 Atlox 4894 LQ

[0282] The particle size (Dz) and polydispersity index (Pdl) were determined for the samples over 2 days and a shown in Tables 27 and 28 below.

[0283] Table 27

Sample day Dz (nm) Pdl

X080: X080 0 257 ± 14 0.504 ± 0.026

X080: X080 1 199 ± 8 0.257 ± 0.003

X080: X080 2 197 ± 13 0.310 ± 0.047

[0284] Table 28

Sample day Dz (nm) Pdl

X080: Atlox4894 0 308 ± 17 0.593 ± 0.188

X080: Atlox4894 1 436 ± 22 0.739 ± 0.122

X080: Atlox4894 2 529 ± 34 0.682 ± 0.168

[0285] Example 11

[0286] Further suspension concentrates of prothioconazole at 125 g/L were prepared according to the Example 7 using the components and amounts shown in the following Tables 29 and 30. [0287] Table 29

Chemical Mass (g) Wt% Ratio (wrt Al) Ratio (wrt solvent) Vol

Prothioconazole 2.5 50 1 1.85

Atlox 4894 1.35 - 0.54 1

Stabiliser#! 0.71 33 0.66 1.2 10

Stabilised 0.36 17 0.34 0.63 10

[0288] Table 30

Solvent Polymer Stabiliser

Atlox 4894 LQ Tween 80 Brij 78

Atlox 4894 LQ Atlox 4894 Genapol X080

Atlox 4894 LQ Brij 78 Brij 78

[0289] Brij 78 is a nonionic surfactant containing polyoxyethylene (23) lauryl ether (solid at room temperature).

[0290] The particle size (Dz) and polydispersity index (Pdl) were determined for the samples over 2 days and a shown in Tables 31 to 32 below.

[0291] Table 31

Sample day Dz (nm) Pdl

Atlox 4894: X080 0 104 ± 1 0.232 ± 0.007

Atlox 4894: X080 1 133 ± 5 0.249 ± 0.009

Atlox 4894: X080 2 127± 3 0.284 ± 0.015 [0292] Table 32

Sample day Dz (nm) Pdl

Tween80: Brij 78 0 15 ± 1 0.156 ± 0.013

[0293] Table 33

Sample day Dz (nm) Pdl

Brij 78: Brij 78 0 154 ± 22 0.506 ± 0.027

Brij 78: Brij 78 1 115 ± 9 0.338 ± 0.066

Brij 78: Brij 78 4 163 ±1 0.447 ± 0.021

[0294] Example 12

[0295] A summary of results for the general process with differing combinations of solvents and stabilisers is summarised in Table 34 below:

0296] Table 34

_ , ^ , ... .. Dz nm Pdl Dz (nm) Pdl Dz (nm) Pdl

Solvent StabihserWl Stabihser#2 %AI Cone. Of Al . . , * , * . . day 0 day 0 day 1 day 1 day 2 day 2

Atlox4894LQ Pluronic F68 GenapolX050 60 125 g/L 234 0.231 333 0.308 315 0.285

Atlox4894LQ Pluronic F68 GenapolX020 60 125 g/L 225 0.267 355 0.299 432 0.370

Atlox4894LQ Genapol X080 GenapolX080 70 125 g/L 638 0.875 253 0.344 450 0.336

Atlox4894LQ Genapol X080 Atlox4894LQ 70 125 g/L 218 0.374 195 0.257 199 0.284

Atlox4894LQ Pluronic F68 Genapol X050 70 125 g/L 245 0.313 376 0.387 367 0.475

Atlox4894LQ Pluronic F68 Genapol X020 70 125 g/L 180 0.195 244 0.276 235 0.338

Atlox4894LQ Genapol X080 Genapol X080 50 175 g/L 209 0.297 225 0.418 192 0.320

Atlox4894LQ Genapol X080 Genapol X080 50 225 g/L 256 0.504 199 0.257 197 0.310

Atlox4894LQ Pluronic F68 Genapol X050 50 125 g/L 259 0.279 293 0.267 299 0.244

Atlox4894LQ Pluronic F68 Genapol X020 50 125 g/L 251 0.272 273 0.250 277 0.257

Atlox4894LQ Genapol X080 Genapol X080 50 125 g/L 422 0.259 446 0.264 251 0.302

Atlox4894LQ Genapol X080 Atlox4894LQ 50 125 g/L 185 0.336 179 0.234 189 0.280

Atlox4894LQ Atlox4894 Genapol X080 50 125 g/L 105 0.232 133 0.249 127 0.284

Atlox4894LQ Brij 78 Brij 78 50 125 g/L 154 0.506 115 0.338 163 0.447

Atlox4894 Tween 80 Brij 78 50 125 g/L 15 0.156

[0297] Example 13

[0298] A range of chemicals were screened for use as solvents for prothioconazole in the process of the invention. The screen allows the identification of excipients that can act as solvents in a “hot precipitation” process of the invention.

[0299] The cited melting point of prothioconazole is 140 °C. Cited melting point have been taken from Pesticide Properties Database (herts.ac.uk).

[0300] Method:

• Weigh out 2.5 g of active, and 1 .35 mg of ‘solvent’ (The ratio has been set with an “wt excess” of active - 1 .85 active: 1 solvent et ratio)

• Heat slowly in a small vial covered in tin foil, using a hot plate equipped with an Asynt heating block, to 10°C below the cited melting point of the active.

• If the ‘solvent’ is able to dissolve the active, then this is a potential solvent to use in the scale up precipitation.

[0301] The solvents shown in Table 35 were shown to be useful solvents for prothioconazole, as determined by their ability to form a homogeneous solution in the above test.

[0302] Table 35

[0303] Prothioconazole was not successfully dissolved in the solvents shown in Table 36 in the screening test.

[0304] Table 36

[0305] Solvents identified in Table 35 were tested in the process of the invention to form suspension concentrates.

[0306] Example 14

[0307] Following the identification of suitable solvents in Example 13 (See Table 35), a stabiliser screening process was undertaken using a hot precipitation method. Stabilisers as shown in Table 37 were evaluated.

[0308] Table 37

[0309] Each screening experiment targeted a final prothioconazole concentration of 125 g/L (in water excluding stabilisers) and a composition of 50:33:17 wt%, prothioconazole: stabiliser 1 : stabiliser 2.

[0310] Stabilisers 1 (1 .65 g) and 2 (0.85 g), selected from those shown in Table 37, were rolled in tap water (50 mg/mL) overnight to ensure dissolution. The stabiliser solutions were combined in a tall 50 mL beaker along with several drops of a 10 wt% Silfoam SRE solution to act as an anti-foam. The beaker and solution were weighed, and the mass noted. This mixture was then mixed with a Silverson L5S mixer at full speed (10,000 to 10,800 rpm).

[0311] Simultaneously, prothioconazole (2.5 g) was heated to ca. 135 °C with a solvent (1 .35 g) in a 40 mL vial using a hot plate equipped with an Asynt heating block, until the mixture became a fully homogeneous solution. The solvents were selected from those shown in Table 35.

[0312] The prothioconazole solution was then transferred to the stabiliser mixture, stirring under high sheer, using a peristaltic pump and a Masterflex Viton tubing. The resulting dispersion was then mixed under high shear for 9 minutes. Once 9 minutes had elapsed the sample was re-weighed, and the water lost during addition of the hot solution was replenished.

[0313] An aliquot of the dispersion was then diluted to 1 g/L and characterised by dynamic light scattering (DLS). The dispersion was then stored on a bench top under ambient conditions whilst aliquots were taken for DLS over time to determine stability along with visual assessment of the sample.

[0314] Dispersions were determined to be successful by the following criteria:

• No sedimentation present, or any sedimentation is easily redispersed by shaking by hand.

• No crystals present in the DLS sample.

• DLS screening criteria is met (Dz particle size <1000 nm and Pdl <0.5). [0315] Some stabiliser combinations comprising PVPK30, Pluronic F68 or HMPC as the main stabiliser component (stabiliser 1 ) failed to produce satisfactory dispersions under these criteria, regardless of the solvent choice, indicating that these materials are less suitable as stabilisers.

[0316] The combinations shown in Table 38 met the success criteria upon initial preparation and for storage periods between 1 and 7 days.

[0317] Table 38

[0318] The combinations shown in Table 39 met the success criteria upon initial preparation and for storage periods of greater than 7 days, and are thus particularly preferred compositions. [0319] Table 39

[0320] Figures 4 and 5 show the particle size distribution of the samples of the prothioconazole dispersion prepared with Tween 22 as solvent, Atlox 4894 as stabiliser 1 and Genapol X020 as stabiliser 2, at the time of preparation and after 48 days storage respectively.

[0321] Figures 6 and 7 show the particle size distribution of the samples of the prothioconazole dispersion prepared with Tween 22 as solvent, Atlox 4894 as stabiliser 1 and Genapol X050 as stabiliser 2, at the time of preparation and after 42 days storage respectively.

[0322] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is understood that the invention includes all such variations and modifications which fall within the spirit and scope of the present invention.

Claims

Claims

1 . A method of preparing an aqueous suspension concentrate of prothioconazole, the method comprising: providing a liquid solution of prothioconazole comprising a non-volatile solvent for the prothioconazole; and combining the liquid solution with an aqueous phase precipitant, under conditions of high shear mixing, to form an aqueous mixture and cause the prothioconazole to precipitate, thereby forming a suspension concentrate comprising precipitated particles of prothioconazole in the aqueous mixture.

2. The method of claim 1 , wherein the particles of prothioconazole are of diameter, D90, of no more than 1 micron.

3. The method of any one of the previous claims, wherein the particles of prothioconazole are of diameter, Dz, of from 100 to 800 nanometres.

4. The method of any one of the previous claims, wherein the particles of prothioconazole have a polydispersity index (Pdl) of no more than 0.6.

5. The method of any one of the previous claims, wherein the concentration of prothioconazole in the suspension concentrate is at least 50 g/L of the suspension concentrate.

6. The method of any one of the previous claims, wherein the liquid solution of prothioconazole is formed at an elevated temperature below the melting point of prothioconazole.

7. The method of any one of the previous claims, wherein the liquid solution is at an elevated temperature below the melting point of prothioconazole when combined with the aqueous phase precipitant.

8. The method of claim 7, wherein the non-volatile solvent is a liquid or solid at ambient temperature and a liquid at the elevated temperature, wherein the prothioconazole is insoluble or poorly soluble in the non-volatile solvent at ambient temperature and soluble in the non-volatile solvent at the elevated temperature.

RECTIFIED SHEET (RULE 91)

9. The method of claim 7 or claim 8, wherein the aqueous phase precipitant is cooler than the liquid solution when the liquid solution is combined with the aqueous phase precipitant wherein the aqueous phase precipitant is at a temperature no more than 60^sC.

10. The method of any one of the previous claims, wherein the non-volatile solvent for prothioconazole is water-soluble.

11 . The method of any one of the previous claims, wherein the non-volatile solvent, if it has a normal boiling point, has a normal boiling point of at least 170^sC.

12. The method of any one of the previous claims, wherein the prothioconazole precipitates in the presence of a water-soluble stabiliser initially present in the liquid solution of prothioconazole, the aqueous phase precipitant or in both of the liquid solution of prothioconazole and the aqueous phase precipitant.

13. The method of claim 12, wherein the water-soluble stabiliser is present in the liquid solution of prothioconazole as the non-volatile solvent.

14. The method of any one of the previous claims, wherein the prothioconazole precipitates in the presence of a water-soluble stabiliser comprising one or more selected from homopolymers of, or copolymers prepared from two or more of, monomers selected from: vinyl alcohol, acrylic acid, methacrylic acid, acrylamide, methacrylamide, acrylamide methylpropane sulphonates, aminoalkyl acrylates, aminoalkyl methacrylates, hydroxyethylacrylate, hydroxyethylmethylacrylate, vinyl pyrrolidone, vinyl imidazole, vinyl amines, vinyl pyridine, ethylene glycol and other alkylene glycols, ethylene oxide and other alkylene oxides, ethyleneimine, styrenesulphonates, ethylene glycol acrylates and ethylene glycol methacrylates.

15. The method of any one of the previous claims, wherein the prothioconazole precipitates in the presence of a water-soluble stabiliser selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone and polyalkylene glycols including block and random copolymers such as poloxamers and comb graft copolymers, styrene-acrylic acid copolymers, ethoxylated copolyester copolymers such as ethoxylated acrylic, methacrylic copolymers and surfactants.

RECTIFIED SHEET (RULE 91)

16. The method of any one of the previous claims, wherein the prothioconazole precipitates in the presence of a water-soluble stabiliser which is a surfactant having an HLB of at least 9.

17. The method of claim 16, wherein the surfactant comprises at least one non-ionic surfactant selected from the group consisting of alkoxylated fatty alcohols, alkoxylated fatty acids, alkoxylated fatty amines, alkoxylated alkylphenols, polysorbates and poloxamers.

18. The method of any one of claims 12 to 17, wherein the weight ratio of prothioconazole to water-soluble stabiliser is in the range of 50:1 to 1 :5.

19. The method of any one of the previous claims, wherein the non-volatile solvent for prothioconazole comprises at least one selected from the group consisting of C2 to Ce glycols; glycerol and mono- and di-Ci to C18 aliphatic esters thereof, mono esters of glycols; polyethers, Ci to C4 alkyl ethers of ethylene glycol and diethylene glycol, Ci to C4 alkyl esters of ethylene glycol and diethylene glycol, Ci to C4 ethers of propylene glycol and di-propylene glycol; alkoxylated fatty alcohols, polysorbates, alkoxylated fatty-alkyl amines, and mixtures thereof.

20. The method of any one of the previous claims, wherein the non-volatile solvent for prothioconazole comprises at least one selected from the group consisting of glycerol, propylene glycol, dipropylene glycol dimethyl ether, PEG 200-PEG4000, fatty alcohol polyethers, Ci to Ce alkyl ethers alkoxylated with from 2 to 30 EG and/or PO units, alkoxylated fatty-alkyl amines alkoxylated with 2 to 30 alkoxy units, EO/PO block copolymer surfactants, alkoxylated sorbitan alkyl esters, poloxamers, and mixtures thereof.

21. The method of any one of the previous claims, wherein the liquid solution of prothioconazole is introduced to the aqueous phase precipitant in a zone of high shear mixing of a rotor stator high shear mixer within the aqueous phase precipitant.

22. The method of any one of the previous claims, wherein the non-volatile solvent is a solid at ambient temperature and has a melting point below the melting point of prothioconazole.

RECTIFIED SHEET (RULE 91)

23. The method of claim 22, wherein the non-volatile solvent comprises a further agrochemical active.

24. The method of any one of claims 1 to 22, wherein the non-volatile solvent comprises an adjuvant for the suspension concentrate selected from the group consisting of an antifreeze agent, a surfactant and a stabiliser for the precipitated particles of prothioconazole.

25. The method of any one of the previous claims, wherein the suspension concentrate further comprises additional agrochemicals in suspension or dissolved in the aqueous composition.

26. The method of any one of the previous claims, further comprising adding a nonvolatile adjuvant to the suspension concentrate after precipitation of the prothioconazole and without removing the non-volatile solvent from the suspension concentrate.

27. The method of any one of the previous claims, wherein the precipitated particles of prothioconazole are not separated from the non-volatile solvent prior to end-use application of the prothioconazole as fungicide.

28. A prothioconazole suspension concentrate composition formed by precipitation in an aqueous phase precipitant of prothioconazole from a hot solution of prothioconazole in a non-volatile solvent, wherein the non-volatile solvent is a solid at ambient temperature and provides a solvent for prothioconazole at an elevated temperature in the range of 60^sC to 130^sC.

29. A prothioconazole suspension concentrate composition comprising solid particles of prothioconazole of diameter, (Dz), of no more than 1 micron, wherein the solid particles of prothioconazole have a polydispersity index (Pdl) of no more than 0.6.

30. The prothioconazole suspension concentrate of claim 29, wherein the prothioconazole is present in an amount of at least 50 g/L of suspension concentrate.

31 . A method of controlling fungal infection, the method comprising: preparing an aqueous suspension concentrate of prothioconazole by a method according to any one of claims 1 to 27;

RECTIFIED SHEET (RULE 91) optionally diluting the aqueous suspension concentrate to produce a diluted suspension of prothioconozole; optionally adding one or more non-volatile adjuvants to the suspension concentrate after precipitation of the prothioconazole or to the diluted suspension; and applying the aqueous suspension concentrate or the diluted suspension to a plant or locus in which fungal infection is to be controlled, wherein the non-volatile solvent remains present in the aqueous suspension concentrate or the diluted suspension when applied to the plant or locus.

RECTIFIED SHEET (RULE 91)