Suspension concentrate acylhydrazone apyrase inhibitor formulation

Abstract

The present disclosure provides a formulation comprising an aqueous suspension of a first active compound having the structure: The present invention relates to a formulation comprising a dispersant, a freezing point depressant, and a buffer or partially neutralized base such that the pH of the formulation is between about 6 and 11. The formulation comprises particles of a first active compound having a volume-weighted median particle size of greater than 0.01 to 20 microns as measured by light scattering. The formulation may also include a viscosity modifier, a biocide, an antifoaming agent, a surfactant, and / or an agriculturally active compound such as a miticide, antibacterial agent, fungicide, herbicide, insecticide, molluscicide, or nematicide, or a combination thereof. Agricultural compositions comprising the formulation and methods of using the same are also disclosed.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to suspension concentrate acylhydrazone apyrase inhibitor formulations and methods of use thereof, particularly in the treatment of pathogen-susceptible crops. [Background technology]

[0002] Crops are plagued by a variety of pathogens worldwide. Pathogens, such as insects, mites, nematodes, weeds, and fungi, have developed a range of mechanisms to survive pesticides, for example, by sequestering, exporting, or detoxifying them. There is a need for formulations that enhance the efficacy of pesticides by blocking certain resistance mechanisms. Summary of the Invention [Means for solving the problem]

[0003] Provided herein is a formulation comprising an aqueous suspension of a first active compound having the structure: [ka] Disclosed are formulation embodiments that include a dispersing agent, a freezing point depressant, and a buffer or partially neutralized base such that the pH of the formulation is about 6 to 11. The formulation includes particles of a first active compound having a volume-weighted median particle size of greater than 0.01 to 20 microns as measured by light scattering. The formulation may also include a viscosity modifier, a biocide, an antifoaming agent, a surfactant, and / or an agriculturally active compound such as a miticide, antibacterial agent, fungicide, herbicide, insecticide, molluscicide, or nematicide, or a combination thereof.

[0004] Also disclosed herein are embodiments of agricultural compositions suitable for agricultural use. The agricultural composition includes water and the disclosed formulation, and also contains an agriculturally active compound. The agriculturally active compound can be provided by the disclosed formulation, or can be added to the agricultural composition in addition to the formulation or a combination thereof.

[0005] Further disclosed are methods for using the formulations, or agricultural compositions comprising the formulations, to control agricultural pathogens such as fungi.

[0006] The foregoing and other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0007] I. Terminology The following explanations of terms and methods are provided to more fully describe the present disclosure and to guide those skilled in the art in practicing the present disclosure. The singular forms "a," "an," and "the" refer to one or more, unless the context clearly dictates otherwise. The term "or" refers to any single element of listed alternative elements or a combination of two or more elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "including A or B" means "including A, B, or A and B," excluding additional elements. All references cited herein, including patents and patent applications, are incorporated by reference in their entirety unless otherwise specified.

[0008] Unless otherwise indicated, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, and the like used in the specification or claims should be understood to be modified by the term "about." Thus, unless implicitly or explicitly indicated otherwise, the numerical parameters given are approximations and may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. When directly and explicitly distinguishing an embodiment from the prior art discussed, the numbers of the embodiments are not approximations unless the word "about" is explicitly recited.

[0009] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0010] "Administering" refers to any suitable mode of administration for controlling pathogens, such as fungal pathogens, and includes treatment of existing crops, produce, seeds, soil, or combinations thereof.

[0011] "In combination with" refers to the administration of the compounds either simultaneously in a single administration, or sequentially in two or more different administrations that may be separated in any way, time, place, or manner.

[0012] "Control," with respect to a pathogen, such as a fungal pathogen, means blocking, inhibiting, and / or eradicating the pathogen and / or preventing the pathogen from damaging the crop. In one embodiment, control refers to reducing one or more pathogens, such as fungi, to undetectable levels, or reducing or suppressing the pathogen to an acceptable level as determined by one skilled in the art (e.g., a crop grower). Determining an acceptable level of pathogen reduction is based on numerous factors, including the crop, the pathogen, the severity of the pathogen, use limitations, economic thresholds, and other factors known to one skilled in the art.

[0013] As used herein, the terms "enhancer" and "potentiator" refer to a compound(s) disclosed herein that enhances the effectiveness of a pesticide. Without being limited by theory, the enhancer compounds disclosed herein may function by blocking one or more pathways by which pathogens, such as fungal pathogens, avoid the toxicity of pesticides, such as by detoxifying, sequestering, or transporting them. In certain embodiments, the compounds inhibit the activity of the enzyme apyrase, which leads to the enhancement, potentiation, or potentiation of pesticides, such as acaricides, antimicrobials, fungicides, herbicides, insecticides, molluscicides, and / or nematicides. For example, when an enhancer or potentiator is used in conjunction with a fungicide, the combination of the potentiator and fungicide enhances the fungicidal effect of the fungicide, and / or as a result of the activity of the potentiator, fungi that have previously been resistant to the fungicide become susceptible to the fungicide. In most cases, these enhancers or potentiators do not themselves inhibit the growth of the pathogen, such as a fungus, and do not have a deleterious effect on organisms that are (or may be) infected with the pathogen.

[0014] As used herein, the term "treatment" refers to a method used to administer or apply an effective amount of a disclosed compound or a formulation thereof to a target area of ​​a field and / or plant. Treatment methods can include, but are not limited to, aerosol spray, pressure spray, direct watering, chemical solution irrigation, spraying, and immersion. Target areas of a plant can include, but are not limited to, leaves, roots, stems, buds, flowers, fruits, plant seeds, and plant bulbs, including bulbs, corms, rhizomes, tubers, root nodules, and rhizophores. Treatment can include methods in which a plant is treated in one area (e.g., the root zone or foliage) and another area of ​​the plant is protected (e.g., the foliage is treated when the disclosed compound is applied to the shoots when applied to the root zone or foliage).

[0015] As used herein, the term "suspension concentrate" or "SC" refers to a liquid formulation containing a stable suspension of an active ingredient in an aqueous fluid. The suspension concentrate can be stored as a formulation and provided to the market and / or end user without further processing. In actual use, the suspension concentrate is prepared for application by the end user. Typically, the suspension concentrate is mixed with water in the end user's spray tank to the appropriate dilution for the particular application. The dilution may vary depending on the crop, pathogen, time of year, geography, local regulations, and degree of infestation, among other factors. Once appropriately diluted, the formulation can be applied, such as by spraying.

[0016] II. Preparations A common goal for agricultural product formulators is to maximize the biological activity of active ingredients. This is particularly difficult with aqueous suspension concentrates, because the solid state of the active ingredient tends to limit its bioavailability. However, it is generally not possible to predict whether a particular active ingredient will have good biological activity when delivered as an aqueous suspension concentrate. Without being limited by theoretical understanding, factors that can determine biological activity include: solubility in water (including how it changes with temperature, salinity, and pH at the application site), solubility in hydrophobic domains (including within the waxy leaf cuticle and any micellar surfactant domains), crystal lattice energy, the density of active ingredient crystals and their associated tendency to sediment, the existence of crystalline polymorphs and metastable states, diffusibility in water, the ability of the active ingredient to diffuse through the plant cuticle, the location of the active ingredient's site of action, and the required concentration of the active ingredient at that site. To overcome the limitations of biological activity, a large number of modifications are potentially discoverable by formulators, and many of these modifications have interdependent effects (meaning that testing each of them separately does not adequately inform about the consequences of altering each simultaneously), making it impractical to explore the entire experimental space.

[0017] Among the formulations tested during the work described in this disclosure, the inventors discovered that aqueous suspensions of (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide generally exhibited low biological activity. Furthermore, they discovered that controlling the particle size within a specific size range in formulations containing the required ingredients described below significantly improved biological activity.

[0018] A general requirement for agricultural product formulators is to achieve acceptable stability, both in terms of chemical stability (meaning that no significant chemical degradation of the active ingredient occurs) and physical stability (meaning that the product remains similar to the product at the time of manufacture in commonly available product containers stored under conditions commonly found in the supply chain, and that the product is suitable and convenient for use by the end user). Whether a particular active ingredient is susceptible to chemical degradation is unpredictable due to the large number of factors that can determine its behavior. These include the solubility of the active ingredient in any liquid phases present (including the hydrophobic phase of any surfactant micellar structure), the presence in those liquid phases of chemical species that can catalyze degradation, any tendency of the active ingredient to undergo autocatalysis, whereby degradation products accelerate further reactions, the presence of chemical bonds within the active ingredient that are susceptible to cleavage, and the effect of neighboring groups on their susceptibility. Physical stability also must be evaluated empirically, but it is known in the art that certain small-scale laboratory tests can often adequately represent larger-scale behavior in commercial applications.

[0019] Among the formulations tested during the work described in this disclosure, the inventors discovered that an aqueous suspension of (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide had unacceptable chemical stability. It was further discovered that formulations containing the necessary ingredients described below could achieve acceptable chemical stability by controlling the pH within a specific range. Furthermore, it was discovered that formulations containing the necessary ingredients described below have sufficient physical stability and remain suitable for use when subjected to stress testing at elevated temperatures, including temperatures that commercial products may experience during shipping, storage, and use.

[0020] Disclosed herein is an aqueous suspension formulation comprising a first active compound, also referred to herein as "Compound 1," having the following structure: [ka]

[0021] In some embodiments, the aqueous suspension formulation further comprises a dispersant, a freezing point depressant compound, a buffer and / or a partially neutralized base, and water.

[0022] In some embodiments, the aqueous suspension formulation is a suspension concentrate suitable for dilution, such as by an end user.

[0023] In some embodiments, at least a portion of the first active compound is present as a suspension in the aqueous suspension formulation. In some embodiments, the first active compound or a portion thereof is the only suspending material in the aqueous suspension formulation. In other embodiments, additional suspending components are present in the formulation in addition to the first active compound. In any embodiment, the total amount of suspending material is greater than 5% by weight, e.g., greater than 5% to 70%, 10% to 70%, 10% to 60%, 15% to 60%, 15% to 50%, or 15% to 40% of the total suspended solid material in the formulation. In some embodiments, the additional suspending component can include an inert filler. Suitable fillers are particulate solids that do not affect biological activity, such as clays, minerals, salts, diatomaceous earth, silica, alumina, cementitious materials, starches, wood flour, and other natural materials, such as plant-based, animal-based, or microbial-based materials.

[0024] In any embodiment, the suspension particles, such as particles of the first active compound, have a volume-weighted median particle size, as measured by light scattering, of 0.01 microns to 40 microns, e.g., 0.01 microns to 30 microns, 0.01 microns to 25 microns, 0.01 microns to 20 microns, 0.01 microns to 15 microns, 0.01 microns to 10 microns, 0.01 microns to 5 microns, or 0.01 microns to 2 microns, or 1 micron to 20 microns, e.g., 1 micron to 15 microns, e.g., 2 microns to 10 microns, or 4 microns to 8 microns. Furthermore, when the formulation includes additional suspension materials, such as those disclosed herein, any such additional suspension materials can also have a particle size, as measured by light scattering, as disclosed above for the first active compound.

[0025] A. First Active Compound The aqueous suspension formulation includes a first active compound, (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide, in an amount sufficient so that, when diluted for use, the first active compound is present in an amount sufficient to enhance the effectiveness of one or more agriculturally active compounds that may be applied in combination with the first active compound. In some embodiments, the aqueous suspension formulation includes 0.5% to 60% or more by weight of the first active compound, e.g., 1% to 60%, 5% to 55%, 10% to 50%, 10% to 45%, or 15% to 40% by weight of the first active compound.

[0026] In certain embodiments, the aqueous suspension formulation comprises at least 15% by weight, e.g., 15% to 60% by weight, 15% to 50% by weight, or 15% to 40% by weight, of the first active compound.

[0027] In other embodiments, the aqueous suspension formulation comprises less than 15% by weight of the first active compound, e.g., 0.5% to less than 15% by weight, 1% to less than 15% by weight, 5% to less than 15% by weight, or 10% to less than 15% by weight. In such embodiments, the formulation may further comprise additional suspending materials, e.g., inert fillers, to bring the total amount of suspending materials, as disclosed herein, to at least 10% by weight.

[0028] B. Dispersants In some embodiments, the dispersant is a high molecular weight dispersant having a molecular weight of 400 daltons or greater, such as 400 daltons to 2,000,000 daltons, or 500 daltons to 1,000,000 daltons, or 750 daltons to 750,000 daltons, or 750 daltons to 500,000 daltons, or 1,000 daltons to 250,000 daltons, or 1,000 to 100,000 daltons.

[0029] In some embodiments, the composition comprises 0.1% to 15% or more by weight of dispersant, e.g., 0.5% to 15% by weight, 0.5% to 12% by weight, or 1% to 10% by weight.

[0030] In any embodiment, the dispersant can be selected from an anionic dispersant, a cationic dispersant, a non-ionic dispersant, or a combination thereof. In some embodiments, the dispersant is or includes an anionic dispersant. In other embodiments, the dispersant is or includes a non-ionic dispersant. In any embodiment, the dispersant can be a low metal content dispersant, such as a low sodium dispersant, a low calcium dispersant, a low potassium dispersant, or a combination thereof, or a low metal content non-ionic dispersant, such as a low sodium non-ionic dispersant, a low calcium non-ionic dispersant, a low potassium non-ionic dispersant, or a combination thereof.

[0031] In any embodiment, the dispersant may be selected from one or more of the following: homopolymer dispersants, such as, but not limited to, polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, polystyrene sulfonate, polyvinyl sulfonate, polyethyleneimine, or combinations thereof; Random or statistical copolymers, such as, but not limited to, polyethylene glycol / polyisobutylene succinate, vinylpyrrolidone / vinylcaprolactam, or combinations thereof; Block copolymers, such as, but not limited to, polyethylene oxide / polypropylene oxide, fatty acid / polyethylene oxide, polyethoxylated alcohols, polyethoxylated diamines, or combinations thereof; Naphthalenesulfonic acid formaldehyde condensate, lignosulfonates, ethoxylated lignosulfonates, Or any combination thereof.

[0032] C. Freezing point-depressing compounds A freezing point depressant is a compound that depresses the freezing point of a formulation compared to the freezing point of a similar formulation without the freezing point depressant. Depressing the freezing point can improve the usefulness of a formulation by allowing it to be used at lower temperatures and / or by improving the physical stability of the formulation when subjected to temperature changes or freeze-thaw cycles. In certain embodiments, the freezing point depressant helps maintain viscosity by providing improved stability under freeze-thaw conditions. In some embodiments, the freezing point depressant is a glycol, a sugar, a water-soluble salt, or a combination thereof. The glycol can be ethylene glycol, propylene glycol, glycerol, dipropylene glycol, tripropylene glycol, or a combination thereof. In certain embodiments, the freezing point depressant is or comprises propylene glycol.

[0033] The sugar may be a water-soluble sugar or polysaccharide. In some embodiments, the sugar has a molecular weight of 1,000 daltons or less, for example, between 180 and 1,000 daltons. The sugar may be selected from ribose, xylose, glucose, fructose, mannose, sucrose, maltose, isomaltose, trehalose, xylitol, mannitol, sorbitol, dextrose, galactose, lactose, maltodextrin, saccharose, or a combination thereof.

[0034] The water-soluble salt may be any water-soluble salt suitable for use in agricultural formulations, typically a non-toxic water-soluble salt. In some embodiments, the water-soluble salt is a halide, nitrate, sulfate, or phosphate. In some embodiments, the water-soluble salt is a salt of lithium, sodium, potassium, magnesium, calcium, ammonium, or aluminum. Also, in certain embodiments, the water-soluble salt may be selected from fluorides, chlorides, iodides, nitrates, sulfates, or phosphates of lithium, sodium, potassium, magnesium, calcium, ammonium, or aluminum.

[0035] In any embodiment, the freezing point depressant, and the amount thereof, is selected to depress the freezing point of the aqueous suspension formulation below the freezing point of water, i.e., below 0° C. In some embodiments, the amount of freezing point depressant is sufficient to obtain a freezing point of the aqueous suspension formulation below −1° C., e.g., below −2° C., below −3° C., below −4° C., or below −5° C., as measured by rheology, such as by using a rheometer, and as known to those skilled in the art. In some embodiments, the freezing point of the formulation is 0° C. to −1° C., 0° C. to −2° C., −1° C. to −3° C., −2° C. to −4° C., −3° C. to −5° C., −4° C. to −6° C., −5° C. to −7° C., −5° C. to −8° C., −5° C. to −9° C., or −5° C. to −10° C.

[0036] In some embodiments, the aqueous suspension formulation comprises from greater than zero to 25% or more by weight of a freezing point depressant compound, for example, from 1% to 25% by weight, or from 5% to 20% by weight of a freezing point depressant compound.

[0037] D. Buffers and / or Partially Neutralized Bases The buffer and / or partially neutralized base is selected to achieve the desired pH of the aqueous suspension formulation, which in some embodiments is from 6 or less to 11 or more, e.g., 7-11, 7-10.5, 6-10, 6-9, or 6-8.

[0038] The buffer and / or partially neutralized base can be any buffer and / or base suitable for use in agricultural applications. In some embodiments, the buffer is a phosphate, phthalate, CHES, phosphonate, sulfonate, or borate, or a combination thereof. In some embodiments, the buffer is a phosphate buffer, and in other embodiments, the buffer is a borate buffer. In one embodiment, the buffer comprises a phthalate.

[0039] In other embodiments, the buffer and / or the partially neutralized base comprises an amino alcohol, such as ethanolamine, diethanolamine, triethanolamine, or a combination thereof, however, in alternative embodiments, the buffer and / or the partially neutralized base does not comprise an amino alcohol.

[0040] E. Optional Additional Ingredients In some embodiments, the formulation may further comprise one or more additional ingredients, such as a viscosity modifier, a biocide, an antifoaming agent, a low molecular weight surfactant, an agriculturally active compound, or a combination thereof.

[0041] In some embodiments, the formulation does not contain more than 0.1 wt. % of compounds containing primary amines, secondary amines, and / or tertiary amines, e.g., zero to 0.1 wt. % of such compounds, or zero wt. % of such compounds.

[0042] In some embodiments, the formulation does not contain more than 0.1% by weight of quaternary ammonium compounds, for example, zero to 0.1% by weight, or zero% by weight of such compounds.

[0043] In some embodiments, the formulation contains no more than 0.1 wt.% of any metal, metal ion, or combination thereof, in total, e.g., zero to 0.1 wt.%, zero to 0.05 wt.%, zero to 0.02 wt.%, zero to 0.005 wt.%, or zero to 0.002 wt.% total metals and / or metal ions. In some embodiments, the formulation contains no more than 0.002 wt.% of any metal, metal ion, or combination thereof, in total, selected from Group 1 or Group 2 of the Periodic Table, e.g., zero to 0.002 wt.%.

[0044] i. Viscosity modifier In some embodiments, the formulation includes a viscosity modifier. In some embodiments, the viscosity modifier is selected from a polysaccharide or a clay, or a combination thereof. The polysaccharide can be xanthan, gellan, agar, guar, cellulose, or a chemically modified form of a polysaccharide, or a combination thereof. The clay can be kaolin, attapulgite, bentonite, laponite, or a combination thereof. In some embodiments, the viscosity modifier is or includes xanthan. In some embodiments, the viscosity modifier is a combination of xanthan and a clay, such as xanthan and attapulgite and / or kaolin.

[0045] The viscosity modifier may be present in an amount of 0.01% to 15% by weight. In certain embodiments, the viscosity modifier is a polysaccharide or chemically modified polysaccharide, such as xanthan, gellan, agar, guar, or cellulose, or a combination thereof, in an amount of 0.01% to 0.5% by weight. In certain embodiments, the viscosity modifier is a clay, such as kaolin, attapulgite, bentonite, laponite, or a combination thereof, and is present in an amount of 0.1% to 15% by weight.

[0046] ii. Biocides In some embodiments, the formulation includes one or more biocides. The biocide may be selected to reduce or prevent breakdown of the formulation or one or more of its components. In some embodiments, the biocide is selected to reduce or prevent breakdown of viscosity modifiers and / or freezing point depressants, such as sugars and / or glycols. In some embodiments, the biocide is selected from benzisothiazolin-3-one, benzoic acid, 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methyl-phenol, 2-bromo-2-nitro-1,3-propanediol, butylhydroxyanisole, butylhydroxytoluene, potassium benzoate, propyl gallate, propyl hydroxybenzoate, sodium nitrite, or a combination thereof. In certain embodiments, the biocide is present in an amount of 0.01% to 0.1% by weight.

[0047] iii. Surfactants In some embodiments, the formulation includes a surfactant that is different from the dispersing agent. The surfactant may be a low molecular weight surfactant. The surfactant may have a molecular weight of 150 Daltons to less than 1,200 Daltons. And / or the surfactant may be present in the formulation in an amount of 0.1% to 10% by weight.

[0048] The surfactant can be an anionic surfactant, a cationic surfactant, a nonionic surfactant, a quaternary ammonium surfactant, a zwitterionic surfactant, or a combination thereof. In some embodiments, the surfactant is an anionic surfactant, a cationic surfactant, a nonionic surfactant, or a combination thereof.

[0049] In any embodiment, the anionic surfactant is a citrate, carbonate, phosphate, phosphonate, sulfate, or sulfonate.The anionic surfactant can be an ester of alcohol, alcohol alkoxylate (e.g., alcohol ethoxylate and / or alcohol propoxylate), tristyrylphenol ethoxylate, fatty acid, natural oil, or a combination thereof.In certain embodiments, the anionic surfactant is a citrate ester, carbonate ester, phosphate ester, phosphonate ester, sulfate ester, or sulfonate ester of alcohol, alcohol alkoxylate, tristyrylphenol ethoxylate, fatty acid, or natural oil, or any combination thereof.

[0050] The cationic surfactant can be an ethoxylated amine, for example, an ethoxylated amine of a natural oil, an alcohol, a fatty acid, or a combination thereof.

[0051] The nonionic surfactant can be an alkoxylate of an alcohol, a natural oil, or a combination thereof, for example, an ethoxylate and / or propoxylate of an alcohol, a natural oil, or a combination thereof.

[0052] The quaternary ammonium surfactant can include at least one chain having at least 6 carbon atoms, e.g., 6 to 20 carbon atoms, or 6 to 12 carbon atoms, attached to a quaternary ammonium head group.

[0053] Also, in some embodiments, the zwitterionic surfactant comprises a positively charged group, e.g., a quaternary ammonium group, and a negatively charged group, e.g., a carboxylic acid moiety, a sulfonic acid moiety, or a phosphate moiety. An example of a zwitterionic surfactant is cocamidopropyl betaine.

[0054] In certain embodiments, the surfactant is an anionic surfactant and may be selected from an alcohol, an alcohol ethoxylate, a tristyrylphenol ethoxylate, a fatty acid, or a natural oil, a phosphate ester, a phosphonate ester, a sulfate ester, or a sulfonate ester, or any combination thereof.

[0055] In other embodiments, the surfactant is a non-ionic surfactant and may be selected from alkoxylates of alcohols, natural oils, or combinations thereof.

[0056] With particular reference to surfactants, one skilled in the art will understand that an alkoxylate group (e.g., ethoxylate or propoxylate) can contain one or more alkoxy moieties (i.e., can be polyalkoxylated), such as from 1 to 200 or more alkoxy moieties, and in some embodiments, the alkoxylate group contains from 2 to 200 alkoxy groups, e.g., from 4 to 200, or from 4 to 150 alkoxy groups.

[0057] iv. Antifoaming agent In some embodiments, the formulation includes one or more antifoaming agents. The antifoaming agent may be selected to reduce or prevent foaming during manufacture, handling, and / or use of the formulation. In some embodiments, the antifoaming agent is an emulsion of silicone oil. In some embodiments, the antifoaming agent is present in an amount ranging from 0.01% to 1.0% by weight.

[0058] F. Agriculturally Active Compounds The disclosed formulation can further comprise agriculturally active compounds.In addition, or alternatively, the formulation can be used in combination with one or more agriculturally active compounds as part of the agricultural composition, which is typically applied to crops, the seeds that can be sown to produce crops, harvested produce, and / or the soil that crops are planted in or can be planted or sown in.The agricultural composition can be at least partially formed by diluting the disclosed formulation with suitable solvent or solvent mixture, for example, water.

[0059] Embodiments of the disclosed formulations are useful for enhancing the effectiveness of a variety of pesticides, including fungicides, antivirals, antibacterials, herbicides, insecticides / acaricides, molluscicides, nematicides, soil pesticides, plant control agents, synergists, fertilizers, and soil conditioners.

[0060] In one embodiment, the formulations of the present disclosure are useful for enhancing the germicidal effect of various germicides. Germicidal agents for use with the disclosed formulations are well known to those of skill in the art and include, but are not limited to, those listed by class in Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0061] Fungicides are more broadly classified by the Fungicide Resistance Task Force (FRAC) in the FRAC Code List 2022, reproduced in Schedule 1, which is incorporated herein by reference in its entirety.

[0062] In one embodiment, the disclosed formulations are used in combination with one or more compounds from a family or group set forth in Table 2, Appendix 1, or both. In certain embodiments, the formulations are used in combination with one or more fungicides listed in column 1 of Table 1.

[0063] In certain embodiments, the disclosed formulations include any of the following: cyproconazole, difenoconazole, fenbuconazole, flutriafol, mefentrifluconazole, metconazole, ipconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, morpholine, cyflufenamid, metrafenone, pyriophenone, strobilurin, copper ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, lime sulfur, ethylene bisdithiocarbamate, aromatic hydrocarbons, phthalimide, guaiaconazole ... In some embodiments, the fungicides may be used in combination with one or more of the fungicides selected from benzimidazoles, including imidazoles and triazoles such as cinnamic acid, polyoxins, furazinam, and thiazolidine, dicarboximides, phenylpyrroles, anilinopyrimidines, hydroxyanilides, carboxamides, phenylamides, phosphonates, cinnamic acids, oxysterol binding protein inhibitors (OSBPIs), triazole carboxamides, cymoxanil, carbamates, benzamides, demethylation-inhibiting piperazines, demethylation-inhibiting pyrimidines, and demethylation-inhibiting azoles.

[0064] Specific fungicides that may be potentiated by administration of an apyrase inhibitor when used in combination with the formulations disclosed according to the methods herein include copper, such as copper octoate, copper hydroxide, copper sulfate, myclobutanil, propiconazole, tebuconazole, epoxiconazole, difenoconazole, triticonazole, and prothioconazole.

[0065] In one embodiment, combined treatment with a selected fungicide and the disclosed formulations provides synergistic fungicidal activity against plant pathogenic fungi.

[0066] In one embodiment, the present disclosure provides compositions and methods for treating plants or plant seeds infected or at risk of infection with fungal pathogens. In one embodiment, the disclosed composition comprises a fungicide formulation, a disclosed formulation, and a phytologically acceptable carrier. In another embodiment, the fungicide and formulation are administered in separate compositions. In a further embodiment, agricultural or horticultural fungicides are used in combination with other compounds in addition to the disclosed formulation. Such other compounds may be administered in the same or separate compositions as the fungicide and / or formulation. Examples of other ingredients include known carriers used to formulate the formulation. Additional examples include conventionally known herbicides, insecticides / acaricides, nematicides, soil pesticides, plant control agents, synergists, fertilizers, soil conditioners, and animal feeds. In one embodiment, the inclusion of such other ingredients provides a synergistic effect on crop growth.

[0067] In one embodiment, the disclosed formulations are used to enhance the effectiveness of herbicides. Exemplary herbicides for use in combination with the formulations are known to those skilled in the art and include, but are not limited to, those listed in Appendix 2. By way of example, suitable herbicides for use in combination with the disclosed formulations include inhibitors of acetyl-CoA synthetase, inhibitors of acetolactate synthesis, inhibitors of microtubule polymerization, inhibitors of microtubule organization, auxin mimetics, photosynthesis inhibitors, deoxy-D-xylulose phosphate synthase inhibitors, enolpyruvylshikimate phosphate synthase inhibitors, phytoene desaturase inhibitors, glutamine synthetase inhibitors, dihydropteroate synthesis inhibitors, protoporphyrinogen oxidase inhibitors, cellulose synthesis inhibitors, uncouplers, hydroxyphenylpyruvate dioxygenase inhibitors, fatty acid thioesterase inhibitors, serine-threonine protein phosphatase inhibitors, solanesyl diphosphate synthase inhibitors, inhibitors of very long-chain fatty acid synthesis, homogentisate solanesyltransferase inhibitors, and lycopene cyclase inhibitors.

[0068] In one embodiment, the disclosed formulations are used to enhance the effectiveness of pesticides. Exemplary pesticides for use in combination with the disclosed formulations are known to those of skill in the art and include, without limitation, those listed in Appendix 3.

[0069] III. Method of Use of the Formulation. Embodiments of methods of using the disclosed formulations include diluting the formulation with a suitable diluent, such as water, to form an agronomic composition suitable for application to plants, plant parts, seeds, soil in which the plants are growing or will be growing, or soil in which the seeds have been or will be sown. The method may further include applying the agronomic composition to the plants, plant parts, seeds, soil in which the plants are growing or will be growing, or soil in which the seeds have been or will be sown.

[0070] In some embodiments, the disclosed formulations include one or more agriculturally active compounds, and the agricultural composition is formed by diluting the formulation with a suitable solvent, such as water, to a concentration suitable for agricultural use. Optionally, one or more additional agriculturally active compounds can be added before, during, and / or after diluting the formulation.

[0071] In other embodiments, the formulation does not include an agriculturally active compound, and the agricultural composition is formed by diluting the formulation with a suitable solvent, such as water, to a concentration suitable for agricultural use. In such embodiments, forming the agricultural composition may further include adding one or more agriculturally active compounds to the water before the formulation is added, at the same time as the formulation is diluted with water, and / or to the diluted mixture that later includes the formulation.

[0072] In certain non-limiting embodiments, the disclosed formulations are diluted for agricultural use in an amount sufficient to provide about 0.01 to about 80% by weight of the first active compound, or about 25% to about 55%, e.g., about 30% to about 50%, about 35% to about 45%, e.g., about 0.01, 0.05, 0.1, 0.5, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 4.0, 5.0, 7.5, 10, 20, 30, 40, 50, 55, 60, or 80% by weight of the final composition. In one embodiment, the first active compound is provided in the final diluted composition at about 0.01 to about 50% volume to volume, e.g., about 15% to about 50%, about 20% to about 45%, about 25% to about 40%, e.g., about 0.01, 0.05, 0.1, 0.5, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 4.0, 5.0, 7.5, 10, 15, 20, 30, 40 or 50%.

[0073] In some embodiments, the agriculturally active compound(s) are present in the agricultural composition at a concentration that is less than the concentration of the agriculturally active compound(s) recommended for use in the absence of a formulation disclosed herein, for example, in the absence of (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide.

[0074] In some embodiments, a method of making an agricultural composition includes adding a formulation disclosed herein to water in an amount sufficient to enhance the agriculturally active compound(s), and adding the agriculturally active compound(s) in an amount sufficient to achieve a concentration in the agricultural composition that is less than the concentration recommended for use in the absence of the disclosed formulation, e.g., in the absence of (E)-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide. One of ordinary skill in the art will understand that the disclosed formulation and the agriculturally active compound can be added to water sequentially in any order or substantially simultaneously to form the agricultural composition.

[0075] In any embodiment, the one or more agriculturally active compounds can be an agricultural or horticultural pesticide disclosed herein, such as an acaricide, antimicrobial, fungicide, herbicide, insecticide, molluscicide, or nematicide, or a combination thereof. In some embodiments, the method is for controlling or preventing fungal growth.

[0076] Crops that can be treated include, but are not limited to, those affected by various pathogens, including bacteria, viruses, fungal pathogens, mites, nematodes, mollusks, weeds, or other pests, as known to those skilled in the art of agriculture. By way of example, such agricultural and horticultural crops that can be treated according to the present disclosure include, for example, cereals; vegetables; root vegetables; potatoes; fruit trees, such as banana trees, tea trees, coffee trees, or cocoa trees; grasses; turf; or cotton, including their harvests, whether genetically modified or not.

[0077] Agronomic compositions containing the disclosed formulations can be applied to plant parts such as leaves, stems, stems, flowers, buds, fruits, seeds, shoots, roots, tubers, tuberous roots, shoots, or stumps. The formulations can also be applied to improved varieties, cultivars, and mutant, hybrid, and genetically modified embodiments of these plants.

[0078] Agronomic compositions containing the disclosed formulations can be used as seed treatments, foliage applications, soil applications, or water applications to control a variety of diseases occurring in agricultural or horticultural crops, including flowers, turf, and pasture grasses.

[0079] Agricultural compositions containing the disclosed formulations are useful for enhancing the effectiveness of antimicrobial agents, for example, the disclosed formulations can be used in combination with antimicrobial agents to combat bacterial and viral infections.

[0080] Embodiments of the disclosed formulations are useful for enhancing the effectiveness of herbicides. For example, the disclosed formulations can be used in combination with one or more herbicides to control weeds or other unwanted vegetation.

[0081] Embodiments of the disclosed formulations are useful for enhancing the effectiveness of insecticides, for example, the disclosed formulations can be used in combination with one or more insecticides to control insect infestations.

[0082] Embodiments of the disclosed formulations are useful for enhancing the effectiveness of acaricides or miticides, for example, the disclosed formulations can be used in combination with one or more acaricides to control mites.

[0083] Embodiments of the disclosed formulations are useful for enhancing the effectiveness of molluscicides. For example, the disclosed formulations can be used in combination with one or more molluscicides to prevent slugs or snails from damaging crops.

[0084] Embodiments of the disclosed formulations are useful for enhancing the effectiveness of nematicides, for example, the disclosed formulations can be used in combination with one or more nematicides to prevent nematodes from interfering with crops.

[0085] Embodiments of the disclosed formulations are particularly useful for enhancing the effectiveness of fungicides against fungal pathogens of plants. Examples of pathogens that may be treated according to the present disclosure include, but are not limited to, Botrytis cinerea, Colletotrichum graminicola, Fusarium oxysporum, Sclerotiana sclerotiorum, Verticillium dahlia, Mycospharella gramincola, and Sphacelotheca reliana.

[0086] Botrytis cinerea is an airborne plant pathogen whose necrotrophic lifestyle affects over 200 crop hosts worldwide. The fungus primarily attacks dicotyledonous plant species, including important protein, oil, fiber, and horticultural crops, grapes, and strawberries; Botrytis also causes soft rot of fruits and vegetables during storage, transport, and marketing. Many classes of fungicides have failed to control Botrytis cinerea due to its genetic plasticity.

[0087] The genus Colletotrichum consists of approximately 600 species that infect over 3,200 species of monocotyledonous and dicotyledonous plants. Colletotrichum graminicola primarily infects corn (Zea mays), causing losses of approximately $1 billion annually in the United States alone (Connell et al., 2012).

[0088] Banana wilt disease, caused by the soil-borne pathogen Fusarium oxysporum f.sp. cubense, is a major threat to banana production worldwide. Currently, no fungicides are available to effectively control the disease once plants are infected (Peng J et al., 2014).

[0089] The mildew fungus Sclerotinia sclerotiorum is known to infect over 400 host species and is considered one of the most prolific plant pathogens. The majority of crop species affected are dicotyledons, as well as several agriculturally important monocotyledons. Some important crops affected by S. sclerotiorum include legumes (soybeans), most vegetables, stone fruits, and tobacco.

[0090] The ascomycete Verticillium dahliae is a soil-borne fungal plant pathogen that causes vascular wilt disease in a wide range of dicotyledonous host species. V. dahliae can cause severe yield and quality losses in cotton and other important crops, such as vegetables, fiber, fruit, nuts, trees, and ornamentals.

[0091] The ascomycete fungus Mycospharella grammingola (anamorph: Septoria tritici) is one of the most important foliar diseases of wheat leaves and occurs wherever wheat is grown. Yield losses due to this disease range from 25% to 50%, and are particularly high in Europe, the Mediterranean region, and East Africa. Infection by M. gramincola is initiated by airborne ascospores produced in residues from the previous year's crop. Primary infection usually occurs after seedling emergence in spring or autumn. Mature disease is characterized by necrotic lesions on the leaves and stems of infected plants.

[0092] The basidiomycete fungus Sphacelotheca reliana infects maize (Zea mays) systemically and causes head smut. Yield losses due to the disease are variable and directly depend on the incidence of the disease. The fungus overwinters as diploid teliospores in crop debris or soil. Floral structures transform into sporangia containing powdery teliospore masses, similar to the galls of common smut.

[0093] Examples of crops that may be treated using the presently disclosed compounds and compositions, as well as plant diseases (pathogens) that may be controlled, include, but are not limited to: Sugar beet: Brown spot (Cercospora beticola), Black root rot (Aphanomyces cochlioides), Root rot (Thanatephorus cucumeris), Thanatephorus cuumeris, Leaf rot (Thanatephorus cucumeris), and the like.

[0094] Peanuts: Mycosphaerella arachidis, Ascochyta sp., Puccinia arachidis, Pythium debaryanum, Alternaria alternata, Sclerotium rolfsii, Mycosphaerella berkeleyi, etc.

[0095] Cucumber: Powdery mildew (Sphaerotheca fuliginea), downy mildew (Pseudoperonospora cubensis), stem blight (Mycosphaerella melonis), wilt (Fusarium oxysporum), sclerotinia rot (Sclerotinia sclerotiorum), gray mold (Botrytis cinerea), anthracnose (Colletotrichum orbiculare), scab (Cladosporium cucumerinum), brown spot (Corynespora cassiicola), damping-off disease (Pythium debaryanum, Rhizoctonia solani Kuhn), Phomopsis root rot (Phomopsis sp.), bacterial spot (Pseudomonas syringae pv. Lechrymans), etc. Tomato: Gray mold (Botrytis cinerea), leaf mold (Cladosporium fulvum), late blight (Phytophthora infestans), Verticillium wilt (Verticillium albo-atrum, Verticillium dahliae), powdery mildew (Oidium neolycopersici), early blight (Alternaria solani), leaf mold (Pseudocercospora fuligena), etc.

[0096] Eggplant: Gray mold (Botrytis cinerea), black rot (Corynespora melongenae), powdery mildew (Erysiphe cichoracearum), leaf mold (Mycovellosiella nattrassii), Sclerotinia rot (Sclerotinia sclerotiorum), Verticillium wilt (Verticillium dahlia), Mycosphaerella blight (Phomopsis vexans), etc.

[0097] Strawberries: Botrytis cinerea, powdery mildew (Sphaerotheca humuli), anthracnose (Colletotrichum acutatum, Colletotrichum fragariae), Phytophthora cactorum, soft rot (Rhizopus stolonifer), fusarium wilt (Fusarium) oxysporum), verticillium wilt (Verticillium dahlia), etc.

[0098] Onion: Neck rot (Botrytis allii), gray mold (Botrytis cinerea), leaf blight (Botrytis squamosa), downy mildew (Peronospora destructor), Phytophthora porn, etc.

[0099] Cabbage: Clubroot disease (Plasmodiophora brassicae), soft rot (Erwinia carotovora), black rot (Xanthomonas campestris pv. campestris), bacterial black spot (Pseudomonas syringae pv. Maculicola, Pspv. alisalensis), dew blight (Peronospora parasitica), sclerotinia rot (Sclerotinia sclerotiorum), black spot (Alternaria brassicicola), gray mold (Botrytis cinerea), etc. Common beans: Sclerotinia rot (Sclerotinia sclerotiorum), gray mold (Botrytis cinerea), anthracnose (Colletotrichum lindemuthianum), angular spot (Phaeoisariopsis griseola), etc.

[0100] Apple: Powdery mildew (Podosphaera leucotricha), red mold (Venturia inaequalis), Monilinia disease (Monilinia mali), black spot (Mycosphaerella pomi), Valla rot (Valsa mali), Alternaria blotch (Alternaria mali), rust (Gymnosporangium yamadae), ring rot (Botryosphaeria berengeriana), anthracnose (Glomerella cingulata, Colletotrichum acutatum), leaf rot (Diplocarpon mali), fly spot (Zygophiala jamaicensis), sooty spot (Gloeodes pomigena), purple root rot (Helicobasidium mompa), gray mold (Botrytis cinerea), etc.

[0101] Apricot: Red mold (Cladosporium carpophilum), gray mold (Botrytis cinerea), brown rot (Monilinia mumecola), etc.

[0102] Persimmon: Powdery mildew (Phyllactinia kakicola), anthracnose (Gloeosporium kaki), angular leaf spot (Cercospora kaki), etc.

[0103] Peaches: Brown rot (Monilinia fructicola), red mold disease (Cladosporium carpophilum), Phomopsis rot (Phomopsis sp.), bacterial shot hole disease (Xanthomonas campestris pv.pruni), etc.

[0104] Almonds: Brown rot (Monilinia taxa), spot blotch (Stigmina carpophila), red mold (Cladosporium carpophilum), red leaf spot (Polystigma rubrum), alternaria blotch (Alternaria alternata), anthracnose (Colletotrichum gloeospoides), etc.

[0105] Yellow peach: Brown rot (Monilinia fructicola), anthracnose (Colletotrichum acutatum), black spot (Alternaria sp.), Monilinia kusanoi disease (Monilinia kusanoi), etc.

[0106] Grapes: Gray mold (Botrytis cinerea), powdery mildew (Uncinula necator), ripening rot (Glomerella cingulata, Colletotrichum acutatum), downy mildew (Plasmopara viticola), anthracnose (Elsinoe ampelina), brown spot (Pseudocercospora vitis), black rot (Guignardia bidwellii), white spot (Coniella castaneicola), rust (Phakopsora ampelopsidis), etc.

[0107] Pear: Red mold disease (Venturia nashicola), rust disease (Gymnosporangium asiaticum), black spot disease (Alternaria kikuchiana), ring rot disease (Botryosphaeria berengeriana), powdery mildew (Phyllactinia mali), Cytospora canker disease (Phomopsis fukushii), brown spot disease (Stempphylium vesicarium), anthracnose (Glomerella cingulata), etc.

[0108] Tea: Ring spot disease (Pestalotiopsis longiseta, P. theae), anthracnose disease (Colletotrichum theae-sinensis), net cake disease (Exobasidium reticulatum), etc.

[0109] Citrus fruits: Red mold (Elsinoe fawcettii), blue mold (Penicillium italicum), common green mold (Penicillium digitatum), gray mold (Botrytis cinerea), melanose disease (Diaporthe citri), canker disease (Xanthomonas campestris pv. Citri), powdery mildew (Oidium sp.), etc. Wheat: Powdery mildew (Blumeria graminis f.sp. tritici), Fusarium head blight (Gibberella zeae), Red rust (Puccinia recondita), Brown snow rot (Pythium iwayamai), Pink snow rot (Monographella nivalis), Eyespot (Pseudocercosporella herpotrichoides), Leaf scorch (Septoria tritici), Leaf blight (Leptosphaeria nodorum), Small snow rot (Typhula incarnata), Large snow rot (Myriosclerotinia borealis), Damping-off (Gaeumannomyces graminis), Ergot (Claviceps purpurea), Smut (Tilletia caries), Pungent slump (Telletia caries), Naked smut (Ustilago nuda), etc.

[0110] Barley: Leaf spot disease (Pyrenophora graminea), net spot disease (Pyrenophora teres), leaf spot disease (Rhynchosporium secalis), smut disease (Ustilago tritici, U. nuda), etc.

[0111] Rice: Blast (Pyricularia oryzae), sheath rot (Rhizoctonia solani), bacnae (Gibberella fujikuroi), brown spot (Cochliobolus miyabeanus), damping-off (Pythium graminicola), bacterial leaf blight (Xanthomonas oryzae), bacterial seedling damping-off (Burkholderia plantarii), brown stripe (Acidovorax avenae), bacterial grain rot (Burkholderia glumae), Cercospora leaf spot (Cercospora oryzae), false blast (Ustilaginoidea virens), rice brown spot (Alternaria alternata, Curvularia intermedia), rice grain discoloration (Alternaria padwickii), pink rice grain discoloration (Epicoccum purpurascens), etc.

[0112] Tobacco: Sclerotinia rot (Sclerotinia sclerotiorum), powdery mildew (Erysiphe cichoracearum), Phytophthora rot (Phytophthora nicotianae), etc.

[0113] Tulips: Gray mold (Botrytis cinerea), etc.

[0114] Sunflower: Downy mildew (Plasmopara halstedii), Sclerotinia rot (Sclerotinia sclerotiorum), etc.

[0115] Bentgrass: Snow mold (Sclerotinia borealis), large patch (Rhizoctonia solani), brown patch (Rhizoctonia solani), dollar spot (Sclerotinia homoeocarpa), blight (Pyricularia sp.), Pythium wilt (Pythium aphanidermatum), anthracnose (Colletotrichum graminicola), etc.

[0116] Orchard grass: Powdery mildew (Erysiphe graminis), etc.

[0117] Soybean: Purple stain disease (Cercospora kikuchii), downy mildew (Peronospora manshurica), Phytophthora rot (Phytophthora sojae), rust (Phakopsora pachyrhizi), Sclerotinia rot (Sclerotinia sclerotiorum), anthracnose (Colletotrichum truncatum), gray mold (Botrytis cinerea), Sphaceloma scab (Elsinoe glycines), melanose (Diaporthe phaseolorum var. sojae), etc.

[0118] Potatoes: phytophthora infestans, early blight (Alternaria solani), scarf disease (Thanaphorus cucumeris), Verticillium wilt (Verticillium albo-atrum, V. dahlia, V. nigrescens, etc.).

[0119] Banana: Panama disease (Fusarium oxysporum), Sigatoka disease (Mycosphaerella fijiensis, M. musicola), etc.

[0120] Rapeseed: Sclerotinia rot (Sclerotinia sclerotiorum), root rot (Phoma lingam), black spot (Alternaria brassicae), etc.

[0121] Coffee: Rust (Hemileia vastatrix), anthracnose (Colletotrichum coffeanum), leaf spot (Cercospora coffeicola), etc.

[0122] Sugarcane: Brown rust (Puccinia melanocephala), etc.

[0123] Corn: Zonate spot (Gloeocercospora sorghi), rust (Puccinia sorghi), southern rust (Puccinia polysora), Smit disease (Ustilago maydis), brown spot (Cochliobolus heterostrophus), northern leaf blight (Setosphaeria turcica), etc.

[0124] Cotton: Seedling damping-off (Pythium sp.), rust (Phakopsora gossypii), sour rot (Mycosphaerella areola), anthracnose (Glomerella gossypii), etc.

[0125] IV. Method of making the formulation. The disclosed formulations can be made by methods known to those skilled in the art. In some embodiments, the method includes providing a first active compound, a dispersant, a freezing point depressant, a buffer and / or a partially neutralized base, and water, and forming a formulation. Optionally, a viscosity modifier, a surfactant, a biocide, an antifoaming agent, and / or an agriculturally active compound may also be added. In some embodiments, the solid materials in the mixture are mixed with a first portion of water, optionally in the presence of a dispersant, a freezing point depressant, a buffer and / or a partially neutralized base, and crushed, such as by bead stirring, until the solid particles reach the desired size for the formulation. In other embodiments, the solid material, such as the first active compound, can be ground to a suitable size or provided in such a size before being added to the water or formulation.

[0126] Additional ingredients, including additional water and / or buffer and / or partially neutralized base, can be added to obtain the desired pH and concentration. Those skilled in the art will understand that optional ingredients such as dispersants, freezing point depressants, and buffer and / or partially neutralized base, as well as viscosity modifiers, surfactants, biocides, antifoam agents, and / or agriculturally active compounds, can be added in any suitable or convenient order.

[0127] In one embodiment, the order of adding the ingredients is the first portion of water, the freezing point depressant, the dispersant, the small molecule surfactant (if present), the antifoaming agent (if present), the buffer and / or the partially neutralized base, the first active compound, the viscosity modifier (if present), the biocide (if present), and the remainder of the water to obtain the desired concentration of the formulation. Typically, the mixture is milled after the first active compound is added, for example, to reduce the particle size of the first active compound to the desired size. In some embodiments, the mixture is milled after the first active compound is added and before any additional ingredients are added. In one embodiment, the order of adding the ingredients can be the first portion of water, followed by the freezing point depressant, the dispersant, the small molecule surfactant (if present), and the antifoaming agent (if present), in any order. Then, a pH adjuster, such as a buffer and / or the partially neutralized base, is added, followed by the first active compound. The mixture can then be milled. The viscosity modifier (if present) and / or biocide (if present) may then be added, followed by the remainder of the water.

[0128] In any embodiment, additional buffers, acids, bases, and / or partially neutralized bases may be added to adjust the final pH of the formulation. [Example]

[0129] V. Working Examples Example 1 Preparation of stable aqueous suspension concentrates [ka] 2.5 g of the first active compound is placed in a 100 mL glass beaker along with 0.5 g of dispersant Tamol SN, 1 g of propylene glycol, 0.006 g (10 mM) of boric acid powder buffer, 5 g of water, optionally 0.05 g of low molecular weight surfactant Surfonic L24-7, and optionally 0.01 g of antifoaming agent SAG 1572. 30 g of 2 mm diameter glass beads are added, and the suspension is milled using a mechanical stirrer to a median diameter of less than 1.5 microns as measured with a Malvern Mastersizer 3000. 0.5 g of a pregel containing 2% xanthan polysaccharide and 2% biocide Acticide B20 is added to the suspension concentrate, and the mechanical stirrer is operated for an additional 10 minutes. The pH is adjusted to 9.0 using 2% phosphoric acid or 1 M sodium hydroxide, as needed. Water is added as needed to achieve a final concentration of 25% by weight of Compound B. The suspension concentrate is collected by sieving through glass beads.

[0130] Example 2 Improved biological efficacy Samples are prepared according to the methods described herein, such as in Example 1 above, except that the grinding conditions are adjusted to obtain different particle sizes for the various samples. The samples are tested for bioactivity in combination with a commercial disinfectant. The degree of pathogen control is expected to be particle size dependent.

[0131] Example 3 Acceptable chemical stability Samples are prepared according to the methods described herein, such as in Example 1 above, except that the pH is adjusted so that each sample has a different pH. The chemical stability of the samples is evaluated by storing the samples at elevated temperatures and periodically measuring the remaining concentration of the active ingredient by HPLC. Reference samples are stored at lower temperatures and are also tested at the same time points. Results are expected to show acceptable chemical stability within a specific pH range.

[0132] Example 4 Acceptable chemical stability Samples are prepared according to the methods described herein, such as in Example 1 above, except that certain sub-samples are spiked with low concentrations of certain components, including primary amines, secondary amines, tertiary amines, quaternary amines, or alkali metals. Chemical stability is evaluated as described in Example 3 above. Results are expected to indicate that certain components accelerate chemical degradation and should be excluded from the formulations of the invention.

[0133] Example 5 Acceptable physical stability Several liters of formulation are prepared according to the methods described herein, such as in Example 1 above, except that some formulation components are substituted for others so that the components of the composition still fall within the compositional ranges set forth above in Section II. Subsamples are stored at several different temperatures and periodically evaluated for pH, viscosity, appearance, sedimentation, and syneresis. The formulation is expected to have excellent physical stability.

[0134] Example 6 Chemical stability as a function of pH A standard solution of compound 1 was prepared in dimethyl sulfoxide at a concentration of 500 μM. 2 μL of the standard solution and 198 μL of PBS pH 4.5 or PBS pH 7.4 were added to a glass vial to obtain a final concentration of 5 μM. The setup was performed in duplicate. The vials were incubated at 37°C in a water bath at 60 rpm and sampled at the indicated time points: 0, 2, 4, 6, and 24 hours. For each time point, the incubation was terminated with 1000 μL of cold acetonitrile containing an internal analytical reference standard. The samples were vortexed for 1 minute and then centrifuged at 2500 g for 10 minutes at room temperature. A 200 μL aliquot of the supernatant was used for LC-MS / MS analysis.

[0135] The remaining amounts of Compound 1 in the samples incubated in PBS buffer at pH 4.5 for 0, 2, 4, 6, and 24 hours were 100%, 62.3%, 33.7%, 29.2%, and 3.1%, respectively. The remaining amounts of Compound 1 in the samples incubated in PBS buffer at pH 7.4 for 0, 2, 4, 6, and 24 hours were 100%, 112.4%, 96.2%, 97.8%, and 91.1%, respectively.

[0136] These results indicate rapid degradation under mildly acidic conditions, with an apparent half-life of slightly more than 2 hours at 37°C. Because the aqueous solubility of compound 1 is less than 5 μM total concentration in this experiment, the actual rate of degradation in solution is very rapid, with an estimated half-life of less than 1 hour. Stability is superior at pH 7.4 compared to acidic conditions.

[0137] Example 7 Long-term chemical stability as a function of pH Method: An aqueous suspension concentrate was prepared with the following composition: 30 wt% Compound 1, 2.5 wt% tristyrylphenol ethoxylate surfactant, 2.0 wt% ethylene oxide-propylene oxide block copolymer dispersant, 5.0 wt% propylene glycol cryoprotectant, 0.1 wt% silicone oil antifoam, and 52.4 wt% distilled water. After 2 hours of grinding, 8.0 wt% viscosity modifier gel containing 2.0% xanthan and 1.0% biocide in water was added. Aliquots of this suspension were adjusted to pH 6, 7, and 8 with 10 wt% sulfuric acid, pH 10 borate buffer, and 10 wt% sodium hydroxide, respectively. Three samples were subdivided and stored at room temperature (RT, approximately 25°C) and 38°C. A control sample was stored at 0°C for reference. Aliquots were periodically withdrawn and diluted with acetonitrile for analysis by HPLC.

[0138] Results: After 1 and 9 months at RT, the amount of compound 1 remaining in the pH 6 sample was 99% and 86%, respectively. After 1 and 9 months at 38°C, the amount of compound 1 remaining in the pH 6 sample was 103% and 94%, respectively. After 1 and 9 months at RT, the amount of compound 1 remaining in the pH 7 sample was 103% and 76%, respectively. After 1 and 9 months at 38°C, the amount of compound 1 remaining in the pH 7 sample was 104% and 89%, respectively. After 1 and 9 months at RT, the amount of compound 1 remaining in the pH 8 sample was 99% and 102%, respectively. After 1 and 9 months at 38°C, the amount of compound 1 remaining in the pH 6 sample was 99% and 103%, respectively.

[0139] These results demonstrate that aqueous suspensions of Compound 1 are chemically unstable at neutral or acidic pH but stable at pH 8. Furthermore, there is a slight tendency for faster degradation at RT than at 38°C, which, without being limited to any particular theory, may be the result of a complex relationship between apparent solubility and temperature in this formulation. Because Compound 1 is much more soluble in the hydrophobic internal phase of surfactant micelles than in the aqueous phase, and because surfactant micelles undergo phase changes as a function of temperature, the amount of Compound 1 in solution decreases with increasing temperature due to micelle instability and a slower overall rate of degradation. Nevertheless, pH is an important factor in the aqueous stability of Compound 1.

[0140] Example 8 Physical and chemical stability as a function of buffer Methods: An aqueous suspension was prepared as described in Example 7, subdivided into three aliquots, and adjusted to pH 6, 7, and 8, respectively. Each aliquot was further divided into three, and each set of material was stored at 0° C., 25° C., and 38° C. After 6 months of storage, the pH of all aliquots was measured.

[0141] Results: Formulations initially with a pH of 6 decreased to pH 3.64, 2.86, and 2.84 when stored at 0°C, 25°C, and 38°C, respectively. Formulations initially with a pH of 7 decreased to pH 5.06, 4.35, and 3.90 when stored at 0°C, 25°C, and 38°C, respectively. Formulations initially with a pH of 8 decreased to pH 7.55, 6.95, and 5.80 when stored at 0°C, 25°C, and 38°C, respectively.

[0142] These results indicate that in the absence of a buffer to stabilize the pH, aqueous suspensions of Compound 1 become more acidic over time as a result of chemical degradation of Compound 1. Example 7 above demonstrates that the rate of degradation is greater at neutral or low pH; therefore, degradation is autocatalytic in the sense that the more Compound 1 degrades, the lower the pH, and the faster the degradation occurs. A buffer is useful for maintaining a stable pH (which aids the viscosity modifier's function of preventing settling) and minimizing chemical degradation. As will be understood by those skilled in the art of formulation, the amount of buffer will depend on the amount of Compound 1 and the specifics of the other ingredients present in the formulation and can be routinely determined by those skilled in the art.

[0143] Example 9 Physical stability at low temperatures as a function of cryoprotectant Methods: Two aqueous suspensions were prepared as described in Example 7, except that one sample contained 5% by weight of propylene glycol cryoprotectant and the other did not, with the remainder consisting of water. The samples were subjected to two freeze-thaw cycles by alternately storing them in a freezer below -4°C and at room temperature. Viscosity was measured using a Brookfield rotating spindle viscometer.

[0144] Results: Both samples remained uniform in appearance without significant settling or syneresis during the short time frame of this experiment. The viscosity of the sample without propylene glycol was 480 mPa before the freeze-thaw cycle and 1100 mPa after. The viscosity of the sample with propylene glycol was 420 mPa both before and after the freeze-thaw cycle.

[0145] The cryoprotectant propylene glycol inhibits the formation of structures in the liquid phase (structures here being molecular aggregates of species present in aqueous solution) which would otherwise result in unacceptably high viscosity, making the formulation unsuitable for pumping and convenient use by the end user.

[0146] Example 10 Effectiveness as a function of granularity Methods: Aqueous suspension concentrates containing 30% by weight of Compound 1 were prepared as described in Example 7, except that milling conditions were controlled to achieve a range of particle sizes. Specifically, milling was performed using ceramic grinding media in a water-jacketed, stirred vessel for various milling times. Samples were diluted with water and bioassays were conducted in greenhouses using Compound 1 at 20 ppm in paired combinations with one of the commercial fungicides: Amistar (0.03 L / ha), Imtrex (0.35 L / ha), Proline (0.125 L / ha), or Balaya (0.2 L / ha). Each paired combination was used to challenge four commercially important pathogenic fungi: Botrytis cinerea (on tomato plants), Zymoseptoria tritici (on wheat plants), Puccinia triticina (on wheat plants), and Phakopsora pachyrhizi (on soybean cultivar Siverka). Seeds were grown in a mixture of Petersfild horticultural compost (75% medium grade peat, 12% screened sterilized loam, 3% medium grade vermiculite, 10% abrasive grain (5mm screened, no lime), 1.5 kg PG mix per m³, lime to pH 5.5-6.0, and a wetting agent (Vitax Ultrawet Seeds were sown 1-2 cm deep in 9 cm diameter pots using 200 ml / m³ of water and germinated / grown under a 16-hour day / 8-hour night light regime at 23°C. Plants were treated 2-3 weeks after sowing, when they were at the BBCH11 growth stage (when the first pair of true leaves (single leaves) had developed). Using a track sprayer, plants were treated with commercial fungicides and Compound 1 at a water volume of 200 L / ha. 24 hours after treatment, plants were inoculated with the appropriate fungus (pathogen). Four replicates were used for each fungicide, pathogen, and formulation combination. When disease symptoms were fully manifested, 7-20 days (depending on the pathogen), each plant was evaluated for percent disease control. Appropriate controls, including "inoculation checks," were used in all experiments; plants were inoculated with specific pathogens to assess disease levels. Each commercial fungicide was also tested alone as part of each treatment; this served as the "control" basis for evaluating experimental compounds.The percent disease control for each treated plant was calculated as the average disease severity of the inoculated but untreated plants ("check") minus the average disease severity of the treated plants, divided by "check." The percent synergy for each formulation plus fungicide combination (test combination) was calculated as the disease control of the fungicide-only treated plants ("control") minus the disease control of the test combination, divided by 100% minus "control." Synergy represents the amount of benefit achieved by adding Compound 1 formulation to the fungicide and is expressed as a percentage of the maximum effect that can be achieved. Thus, 100% means complete disease control, and 0% means the combination had no effect.

[0147] result: The particle sizes of the ground samples were measured using a laser light scattering instrument, and the volume weighted median particle sizes were 1.0, 7.0, and 15 microns, respectively. For simplicity, these samples will be referred to as A1, B7, and C15 in the following discussion.

[0148] Zymoseptoria tritici: There was no consistent synergy with Amistar; with Imtrex, synergy was 28%, 28%, and 4.6% for A1, B7, and C15, respectively; with Proline, synergy was 26%, 25%, and 61% for A1, B7, and C15, respectively; and with Balaya, synergy was 51%, 40%, and 36% for A1, B7, and C15, respectively.

[0149] Phakopsora pachyrhizi: With Amistar the synergy was 30% for A1, no synergy for B7 or C15, with Imtrex and Proline there was no significant synergy, and with Balaya it was 40%, 33% and 20% for A1, B7 and C15, respectively.

[0150] There was no significant synergy with Puccinia triticina:Amistar, 29%, 3%, and no synergy with Imtrex for A1, B7, and C15, respectively, and no significant synergy with Proline or Balaya.

[0151] Botrytis cinerea: There was no significant synergy with Amistar, Imtrex had 18%, 6% and no synergy with A1, B7 and C15, respectively, Proline had 33%, 14 and 10% synergy with A1, B7 and C15, respectively, and Balaya had no significant synergy.

[0152] Conclusion: In these greenhouse assays, it is clear that in some cases, no synergistic effect was observed between Compound 1 and fungicides in controlling some pathogens. This could be because, for example, the use rate of the commercial fungicide in that particular test was too low or too high relative to the severity of plant disease caused by the inoculated pathogen, so that the addition of Compound 1 would not produce any measurable benefit or there would be no opportunity to further improve disease control beyond already high levels. In some cases, the mode of action and detoxification of the fungicide against that pathogen in a particular test may not involve the enzyme regulated by Compound 1 and therefore may not be suitable for synergistic effects with an apyrase inhibitor. These results without synergy can be discounted for the purpose of evaluating the effect of particle size on efficacy.

[0153] If there is a synergistic effect, and the results are grouped by fungicide, the following can be highlighted: a) In combination with Imtrex, B7 is always superior to C15, and A1 is either essentially identical to B7 (one case) or superior to B7 (three cases) (i.e., A1 > B7 > C15). b) In combination with Balaya, B7>C15. c) In combination with Amistar, there is a synergistic effect only against Phakopsora pachyrhizus, and here too there is a clear trend of A1>B7>C15. d) In combination with Proline, in one case A1>B7>C15, and in another case C15>A1=B7.

[0154] If there is a synergistic effect, and instead the results are grouped by pathogen, the following can be highlighted: a) Against Zymoseptoria tritici, A1=B7>C15 for Imtrex, C15>A1=B7 for Proline, and A1>B7>C15 for Balaya. b) Against Phakopsora pachyrhizi, only A1 had a synergistic effect in Amistar, whereas A1 > B7 > C15 in Balaya. c) Against Puccinia triticina, A1>B7>C15 for Imtrex. d) Against Botrytis cinerea, A1>B7>C15 for both Imtrex and Proline

[0155] Within this set of experiments, there is one clear counterexample of Proline against Zymoseptoria tritici (based on a possible outlier in C15), but the other seven examples establish a pattern. Overall, suspension concentrates with a median particle size of 1 micron are more biologically effective than suspension concentrates with a median particle size of 7 microns, which in turn are more biologically effective than suspension concentrates with a median particle size of 15 microns. This pattern is valid for all pathogens tested here. Of the fungicides tested, efficacy is most consistent with Imtrex and Balaya, although there are also examples with both other fungicides.

[0156] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be construed as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. The inventors therefore claim as their invention all that comes within the spirit and scope of these claims. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10

Claims

1. 1. A formulation comprising an aqueous suspension of a first active compound having the structure: 【Chemistry 4】 a dispersant; and A freezing point depressant; a buffer or a partially neutralized base such that the pH of the formulation is about 6 to 11; The formulation, wherein the particles of the first active compound have a volume weighted median particle size of greater than 0.01 to 20 microns as measured by light scattering.

2. 10. The formulation of claim 1, wherein the formulation comprises from 0.5% to about 60% by weight of the first active compound.

3. 3. The formulation of claim 1 or claim 2, wherein the formulation comprises 15% to 40% by weight of the first active compound.

4. 3. The formulation of claim 1 or claim 2, wherein the formulation comprises less than 15% by weight of the first active compound, and the formulation further comprises an inert filler such that the total amount of suspended material in the formulation is at least 10% by weight.

5. A formulation according to any one of claims 1 to 4, wherein the formulation comprises from 0.1% to 15% by weight of the dispersing agent.

6. A formulation according to any one of claims 1 to 5, wherein the formulation comprises from 1% to 10% by weight of the dispersing agent.

7. 7. The formulation of any one of claims 1 to 6, wherein the dispersing agent has a molecular weight of from 400 Daltons to 2,000,000 Daltons.

8. 8. The formulation of any one of claims 1 to 7, wherein the dispersing agent has a molecular weight of from 1,000 Daltons to 100,000 Daltons.

9. The formulation of any one of claims 1 to 8, wherein the dispersant is an anionic dispersant, a cationic dispersant, a non-ionic dispersant, or a combination thereof.

10. 10. The formulation of claim 9, wherein the dispersant is an anionic dispersant.

11. 10. The formulation of claim 9, wherein the dispersant is a non-ionic dispersant.

12. 10. The formulation of any one of claims 1 to 9, wherein the dispersant is selected from a homopolymer dispersant, a random or statistical copolymer, a block copolymer, or a combination thereof.

13. 10. The formulation of any one of claims 1 to 9, wherein the dispersing agent is selected from polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, polystyrene sulfonate, polyvinyl sulfonate, polyethyleneimine, polyethylene glycol / polyisobutylene succinate, vinylpyrrolidone / vinyl caprolactam, polyethylene oxide / polypropylene oxide, fatty acid / polyethylene oxide, polyethoxylated alcohols, polyethoxylated diamines, naphthalene sulfonic acid formaldehyde condensates, lignosulfonates, ethoxylated lignosulfonates, or combinations thereof.

14. 14. The formulation of any one of claims 1 to 13, wherein the formulation comprises from greater than zero to 25% by weight of the freezing point depressant.

15. 15. The formulation of any one of claims 1 to 14, wherein the formulation comprises 5% to 20% by weight of the freezing point depressant.

16. 16. The formulation of any one of claims 1 to 15, wherein the freezing point depressant is a glycol, a sugar, a water-soluble salt, or a combination thereof.

17. 17. The formulation of claim 16, wherein the sugar has a molecular weight of 180 to 1,000 daltons.

18. the glycol is ethylene glycol, propylene glycol, glycerol, dipropylene glycol, tripropylene glycol, or a combination thereof; the sugar is ribose, xylose, glucose, fructose, mannose, sucrose, maltose, isomaltose, trehalose, xylitol, mannitol, sorbitol, dextrose, galactose, lactose, maltodextrin, saccharose, or a combination thereof; 18. The formulation of claim 16 or claim 17, wherein the water-soluble salt is a fluoride, chloride, iodide, nitrate, sulfate or phosphate salt of ammonium, lithium, sodium, potassium, magnesium, calcium or aluminum, or a combination thereof.

19. 19. The formulation of claim 18, wherein the freezing point depressant is propylene glycol.

20. 20. The formulation of any one of claims 1 to 19, wherein the freezing point depressant is selected to depress the freezing point of the formulation below 0°C.

21. 21. The formulation of any one of claims 1 to 20, wherein the freezing point depressant is selected to depress the freezing point of the formulation to below -5°C.

22. 22. The formulation of any one of claims 1 to 21, wherein the buffer or partially neutralized base results in a pH of the formulation of between 7 and 10.

5.

23. 23. The formulation of any one of claims 1 to 22, wherein the buffer or partially neutralized base provides a pH of the formulation of about 6 to about 8.

24. 24. The formulation of any one of claims 1 to 23, wherein the buffer and / or partially neutralized base is any buffer and / or base suitable for use in agricultural applications.

25. 25. The formulation of any one of claims 1 to 24, wherein the buffer is a phosphate, phthalate, CHES, phosphonate, sulfonate, or borate, or a combination thereof.

26. 26. The formulation of claim 25, wherein the buffer is a phosphate buffer or a borate buffer.

27. 27. The formulation of any one of claims 1 to 26, wherein the volume weighted median particle size of the first active compound is less than about 15 microns as measured by light scattering.

28. 28. The formulation of claim 27, wherein the volume weighted median particle size of the first active compound is less than about 7 microns as measured by light scattering.

29. 28. The formulation of claim 27, wherein the volume weighted median particle size of the first active compound is greater than 0.01 to 10 microns as measured by light scattering.

30. 28. The formulation of claim 27, wherein the volume weighted median particle size of the first active compound is greater than 0.01 to 5 microns as measured by light scattering.

31. 28. The formulation of claim 27, wherein the volume weighted median particle size of the first active compound is greater than 0.01 to 2 microns as measured by light scattering.

32. 28. The formulation of claim 27, wherein the volume weighted median particle size of the first active compound is about 1 micron or less as measured by light scattering.

33. 28. The formulation of claim 27, wherein the volume weighted median particle size of the first active compound is about 1 micron as measured by light scattering.

34. 28. The formulation of claim 27, wherein the volume weighted median particle size of the first active compound is less than about 1 micron as measured by light scattering.

35. 35. The formulation of any one of claims 1 to 34, wherein the formulation further comprises a viscosity modifier.

36. 36. The formulation of claim 35, wherein the viscosity modifier is selected from polysaccharides, chemically modified polysaccharides, and / or clays.

37. the polysaccharide is xanthan, gellan, agar, guar, cellulose, or a combination thereof; 37. The formulation of claim 36, wherein the clay is kaolin, attapulgite, bentonite, laponite, or a combination thereof.

38. 38. A formulation according to any one of claims 35 to 37, wherein the viscosity modifier is present in an amount of from 0.01% to 15% by weight.

39. the viscosity modifier is a polysaccharide or a chemically modified polysaccharide in an amount of 0.01% to 0.5% by weight; or 39. The formulation of claim 38, wherein the viscosity modifier is a clay and is present in an amount of 0.1% to 15% by weight.

40. A formulation according to any one of claims 1 to 39, wherein the formulation further comprises a biocide.

41. 41. The formulation of claim 40, wherein the biocide is selected from benzisothiazolin-3-one, benzoic acid, 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methyl-phenol, 2-bromo-2-nitro-1,3-propanediol, butylated hydroxyanisole, butylated hydroxytoluene, potassium benzoate, propyl gallate, propyl hydroxybenzoate, sodium nitrite, or combinations thereof.

42. 42. A formulation according to any one of claims 1 to 41, wherein the formulation further comprises from 0.1% to 10% by weight of a surfactant.

43. 43. The formulation of claim 42, wherein the surfactant has a molecular weight of from 150 to less than 1,200 daltons.

44. 44. The formulation of claim 42 or claim 43, wherein the surfactant is an anionic surfactant, a cationic surfactant, a nonionic surfactant, a quaternary ammonium surfactant, a zwitterionic surfactant, or a combination thereof.

45. the anionic surfactant is a citrate, carbonate, phosphate, phosphonate, sulfate, or sulfonate ester of an alcohol, an alcohol ethoxylate, a tristyrylphenol ethoxylate, a fatty acid, or a natural oil, or any combination thereof; the cationic surfactant is an ethoxylated amine of a natural oil, an alcohol, a fatty acid, or a combination thereof; or 45. The formulation of claim 44, wherein the nonionic surfactant is a polyethoxylate and / or polypropoxylate of an alcohol, a natural oil, or a combination thereof.

46. 46. ​​A formulation according to any one of claims 1 to 45, wherein the formulation further comprises an antifoaming agent.

47. 47. The formulation of claim 46, wherein the antifoaming agent is an emulsion of silicone oil.

48. 48. A formulation according to claim 46 or claim 47, wherein the anti-foaming agent is present in an amount of from 0.01% to 1% by weight.

49. A formulation according to any one of claims 1 to 48, further comprising an agriculturally active compound.

50. 50. The formulation of claim 49, wherein the agriculturally active compound is an acaricide, antimicrobial, fungicide, herbicide, insecticide, molluscicide, or nematicide, or a combination thereof.

51. 50. The formulation of claim 49, wherein the agriculturally active compound is a fungicide.

52. The agriculturally active compound is a benzimidazole fungicide, a dicarboximide fungicide, a phenylpyrrole fungicide, an anilinopyrimidine fungicide, a hydroxyanilide fungicide, a carboxamide fungicide, a phenylamide fungicide, a phosphonate fungicide, a cinnamate fungicide, an OSBPI fungicide, a triazolecarboxamide fungicide, a Group 27 fungicide, a carbamate fungicide, a benzamide fungicide, a demethylation inhibitor fungicide, a piperazine fungicide, a pyrimidine fungicide, an imidazole fungicide, or a triazole fungicide.

52. The formulation of claim 51, wherein the fungicide is selected from a group consisting of a morpholine fungicide, a Group U6 fungicide, a Group 50 fungicide, a Qol strobilin fungicide, a quinoline fungicide, an inorganic fungicide, a copper fungicide, a sulfur fungicide, a lime sulfur fungicide, an ethylene bisdithiocarbamate (EBDC) fungicide, an EBDC fungicide, an aromatic hydrocarbon fungicide, a chloronitrile fungicide, a phthalimide fungicide, a guanidine fungicide, a Qil fungicide, a polyoxin fungicide, a Group 29 fungicide, a thiazolidine fungicide, or a combination thereof.

53. The agriculturally active compound is selected from the group consisting of benomyl, thiabendazole, thiophanate methyl, iprodione, vinclozolin, fludioxonil, cyprodinil, pyrimethanil, fenhexamid, fenpyrazamine, boscalid, carboxin, fluopyram, flutolanil, fluxapyroxad, impirfluxam, isofetamide, oxycarboxin, penthiopyrad, pydiflumetofen, solatenol (benzovindiflupyr), Mefenoxam, metalaxyl, oxadixyl, aluminum tris, phosphorous acid, dimethomorph, mandipropamide, oxathiapiproline, ethaboxam, cymoxanil, propamocarb, fluopicolide, triforine, fenarimol, imazalil, triflumizole, cyproconazole, difenoconazole, fenbuconazole, flutriafol, mefentrifluconazole, metconazole, ipconazole, micropig 52. The formulation of claim 51, wherein the fungicide is selected from the group consisting of benzophenone, propiconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, piperaline, spiroxamine, cyflufenamid, metrafenone, pyriophenone, azoxystrobin, famoxadone, fenamidone, fluoxastrobin, kresoxim-methyl, mandestrobin, picoxystrobin, pyraclostrobin, trifloxystrobin, quinoxyfen, Bordeaux, copper ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, calcium polysulfide, mancozeb, maneb, metiram, ferbam, thiram, ziram, dicloran (DCNA), etridizole, pentachloronitrobenzene, chlorothalonil, captan, dodine, cyazofamid, polyoxin, fluazinam, flutianil, or combinations thereof.

54. An agricultural composition comprising water and the formulation of any one of claims 1 to 53.

55. 55. The agricultural composition of claim 54, wherein the composition comprises from 0.01% to 10% by weight of the formulation of any one of claims 1 to 54.

56. 56. The agricultural composition of claim 54, wherein the formulation is a formulation of any one of claims 1 to 55, and the agricultural composition further comprises an agriculturally active compound.

57. 57. The agricultural composition of claim 56, wherein the formulation of any one of claims 1 to 51 is present in the agricultural composition in an amount sufficient to enhance the biological effect of the agriculturally active compound such that the total amount of the agriculturally active compound in the agricultural composition applied to a crop or agricultural product is lower than would typically be required and / or recommended to produce the same biological effect in a composition that does not include the formulation of any one of claims 1 to 51.

58. 58. The agricultural composition of claim 56 or claim 57, wherein the agriculturally active compound is an acaricide, antimicrobial, fungicide, herbicide, insecticide, molluscicide, or nematicide, or a combination thereof.

59. 59. The agricultural composition of claim 58, wherein the agriculturally active compound is a fungicide.

60. The agriculturally active compound is selected from the group consisting of benzimidazole fungicides, dicarboximide fungicides, phenylpyrrole fungicides, anilinopyrimidine fungicides, hydroxyanilide fungicides, carboxamide fungicides, phenylamide fungicides, phosphonate fungicides, cinnamate fungicides, OSBPI fungicides, triazolecarboxamide fungicides, Group 27 fungicides, carbamate fungicides, benzamide fungicides, demethylation inhibitor fungicides, piperazine fungicides, pyrimidine fungicides, imidazole fungicides, triazole fungicides, 59. The agricultural composition of claim 58, wherein the fungicide is selected from a morpholine fungicide, a Group U6 fungicide, a Group 50 fungicide, a Qol strobilin fungicide, a quinoline fungicide, an inorganic fungicide, a copper fungicide, a sulfur fungicide, a lime sulfur fungicide, an ethylene bisdithiocarbamate (EBDC) fungicide, an EBDC fungicide, an aromatic hydrocarbon fungicide, a chloronitrile fungicide, a phthalimide fungicide, a guanidine fungicide, a Qil fungicide, a polyoxin fungicide, a Group 29 fungicide, a thiazolidine fungicide, or a combination thereof.

61. The agriculturally active compound is selected from the group consisting of benomyl, thiabendazole, thiophanate methyl, iprodione, vinclozolin, fludioxonil, cyprodinil, pyrimethanil, fenhexamid, fenpyrazamine, boscalid, carboxin, fluopyram, flutolanil, fluxapyroxad, impirfluxam, isofetamide, oxycarboxin, penthiopyrad, pydiflumetofen, solatenol (benzovindiflupyr), metronidazole, methylparaben ... Fenoxam, metalaxyl, oxadixyl, aluminum tris, phosphorous acid, dimethomorph, mandipropamid, oxathiapiproline, ethaboxam, cymoxanil, propamocarb, fluopicolide, triforine, fenarimol, imazalil, triflumizole, cyproconazole, difenoconazole, fenbuconazole, flutriafol, mefentrifluconazole, metconazole, ipconazole, myclobutanil , propiconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, piperaline, spiroxamine, cyflufenamid, metrafenone, pyriophenone, azoxystrobin, famoxadone, fenamidone, fluoxastrobin, kresoxim-methyl, mandestrobin, picoxystrobin, pyraclostrobin, trifloxystrobin, quinoxyfen, Bordeaux, cupric ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, calcium polysulfide, mancozeb, maneb, metiram, ferbam, thiram, ziram, dicloran (DCNA), etridizole, pentachloronitrobenzene, chlorothalonil, captan, dodine, cyazofamid, polyoxin, fluazinam, flutianil, or combinations thereof.

62. 62. A method of using the agricultural composition of any one of claims 54 to 61, comprising applying the agricultural composition to a plant, a plant part, a seed, the soil in which a plant is growing or will grow, or the soil in which a seed has been sown or will be sown.

63. 62. A method of controlling or preventing fungal growth, the method comprising applying the agricultural composition of any one of claims 59 to 61 to a site having fungal growth or at risk of developing fungal growth.

64. 1. A method for controlling or preventing fungal growth, comprising: diluting the formulation of any one of claims 1 to 53 with water to form a diluted mixture; applying the diluted mixture to an area having fungal growth or at risk of developing fungal growth.

65. 65. The method of claim 64, wherein the formulation is a formulation of any one of claims 1 to 53, and diluting the formulation further comprises adding an agriculturally active compound.

66. 53. The method of claim 52, wherein adding the agriculturally active compound comprises adding an amount of the agriculturally active compound that is less than the amount of the agriculturally active compound recommended for use in the absence of the formulation of any one of claims 1 to 51.

67. The agriculturally active compound is selected from the group consisting of benzimidazole fungicides, dicarboximide fungicides, phenylpyrrole fungicides, anilinopyrimidine fungicides, hydroxyanilide fungicides, carboxamide fungicides, phenylamide fungicides, phosphonate fungicides, cinnamate fungicides, OSBPI fungicides, triazolecarboxamide fungicides, Group 27 fungicides, carbamate fungicides, benzamide fungicides, demethylation inhibitor fungicides, piperazine fungicides, pyrimidine fungicides, imidazole fungicides, triazole fungicides, mol 67. The method of claim 65 or claim 66, wherein the fungicide is selected from a folin fungicide, a Group U6 fungicide, a Group 50 fungicide, a Qol strobilin fungicide, a quinoline fungicide, an inorganic fungicide, a copper fungicide, a sulfur fungicide, a lime sulfur fungicide, an ethylene bisdithiocarbamate (EBDC) fungicide, an EBDC fungicide, an aromatic hydrocarbon fungicide, a chloronitrile fungicide, a phthalimide fungicide, a guanidine fungicide, a Qil fungicide, a polyoxin fungicide, a Group 29 fungicide, a thiazolidine fungicide, or a combination thereof.

68. The agriculturally active compound is selected from the group consisting of benomyl, thiabendazole, thiophanate methyl, iprodione, vinclozolin, fludioxonil, cyprodinil, pyrimethanil, fenhexamid, fenpyrazamine, boscalid, carboxin, fluopyram, flutolanil, fluxapyroxad, impirfluxam, isofetamide, oxycarboxin, penthiopyrad, pydiflumetofen, solatenol (benzovindiflupyr), mef Enoxam, metalaxyl, oxadixyl, aluminum tris, phosphorous acid, dimethomorph, mandipropamid, oxathiapiproline, ethaboxam, cymoxanil, propamocarb, fluopicolide, triforine, fenarimol, imazalil, triflumizole, cyproconazole, difenoconazole, fenbuconazole, flutriafol, mefentrifluconazole, metconazole, ipconazole, myclobutanil, propranolol 67. The method of claim 65 or claim 66, wherein the fungicide is selected from lopiconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, piperaline, spiroxamine, cyflufenamid, metrafenone, pyriophenone, azoxystrobin, famoxadone, fenamidone, fluoxastrobin, kresoxim-methyl, mandestrobin, picoxystrobin, pyraclostrobin, trifloxystrobin, quinoxyfen, Bordeaux, copper ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, calcium polysulfide, mancozeb, maneb, metiram, ferbam, thiram, ziram, dicloran (DCNA), etridizole, pentachloronitrobenzene, chlorothalonil, captan, dodine, cyazofamid, polyoxin, fluazinam, flutianil, or combinations thereof.

69. 62. Use of the agricultural composition according to any one of claims 54 to 61 for application to a plant, a plant part, a seed, the soil in which a plant is growing or will grow, or the soil in which a seed has been or will be sown.

70. 62. Use of the agricultural composition of any one of claims 54 to 61 to control or prevent fungal growth in a site having or at risk of developing fungal growth.

71. 10. The formulation of claim 1, wherein the particles of the first active compound have a volume-weighted median particle size of less than about 15 microns as measured by light scattering.

72. 10. The formulation of claim 1, wherein the particles of the first active compound have a volume-weighted median particle size of less than about 7 microns as measured by light scattering.

73. 10. The formulation of claim 1, wherein the particles of the first active compound have a volume-weighted median particle size of about 1 micron or less as measured by light scattering.

74. 10. The formulation of claim 1, wherein the pH of the formulation is greater than about 7.

75. 10. The formulation of claim 1, wherein the pH of the formulation is greater than about 7.

4.

76. 10. The formulation of claim 1, wherein the pH of the formulation is greater than about 8.

77. 62. A method for protecting crops from pests, the method comprising applying a formulation according to any one of claims 1 to 53 or an agricultural composition according to any one of claims 54 to 61 to a plant, a plant part, a seed, the soil in which a plant is growing or will grow, or the soil in which a seed has been or will be sown, or a combination thereof.

78. 78. The method of claim 77, further comprising applying a pesticide to the plant, the plant part, the seed, the soil in which the plant is growing or will grow, or the soil in which the seed has been or will be sown, or a combination thereof.

79. 79. The method of claim 78, wherein the effectiveness of the pesticide is enhanced by the formulation or agricultural composition.

80. 79. The method of claim 78, wherein the formulation or agricultural composition has a synergistic effect when combined with the pesticide.

81. 81. The method of any one of claims 77 to 80, wherein the formulation or composition is applied to an area having fungal growth or at risk of developing fungal growth.

82. 82. The method of any one of claims 78 to 81, wherein the pesticide comprises a fungicide.

83. 83. The method of claim 82, wherein the disinfectant comprises Imtrex, Balaya, Amistar, Proline, or a combination thereof.

84. 83. The method of claim 82, wherein the fungicide is used to treat tomato plants.

85. 83. The method of claim 82, wherein the fungicide is used to treat wheat.

86. 83. The method of claim 82, wherein the fungicide is used to treat soybean plants.

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