阅读说明：本技术 丙硫菌唑的稳定液体制剂 (Stable liquid formulations of prothioconazole ) 是由 亚历山大·科内利斯·范德拉恩 拉詹·希尔萨特 加德夫·拉耶尼肯特·施洛夫 维克拉姆·拉耶尼肯特 于 2018-05-11 设计创作，主要内容包括：本发明公开了一种制剂,该制剂包含丙硫菌唑和稳定量的过渡金属盐,任选地助农药,任选地两种助农药,其制备方法,其使用方法和包含其组分的试剂盒。(A formulation comprising prothioconazole and a stabilizing amount of a transition metal salt, optionally a co-pesticide, optionally two co-pesticides, methods of making the same, methods of using the same and kits comprising components thereof.)

1. A formulation comprising prothioconazole and a stabilizing amount of a transition metal salt.

2. The formulation of claim 1, wherein the transition metal salt is selected from the group consisting of transition metal salts of Cu, Fe, Zn, Mn, Co, and Ni.

3. The formulation of claim 1, wherein the prothioconazole is present in an amount of about 0.01% to about 30% by weight of the formulation.

4. The formulation of claim 1, wherein the transition metal salt is present in an amount of at least about 0.01% by weight of the formulation.

5. The formulation of claim 1, wherein the transition metal salt is selected from the group comprising: nitrates, carbonates, sulfates, halides and hydroxides of transition metals, wherein the transition metals are in a monovalent, divalent or trivalent state.

6. A method of preparing a formulation comprising dispersing prothioconazole and a stabilizing amount of a transition metal salt in an aqueous medium.

7. The method of claim 6, wherein the method comprises the steps of:

a) dispersing prothioconazole in water to prepare an aqueous dispersion of prothioconazole; and

b) dispersing a transition metal salt into the aqueous dispersion in an amount effective to keep the dispersion stable, wherein the transition metal salt is selected from the group consisting of transition metal salts including Cu, Fe, Zn, Mn, Co, and Ni.

8. A method of producing a stable liquid formulation of prothioconazole comprising the steps of:

a) dispersing prothioconazole in water to prepare an aqueous dispersion of prothioconazole;

b) dispersing a transition metal salt into the aqueous dispersion in an amount effective to maintain the aqueous dispersion stable, wherein the transition metal salt is selected from the group consisting of transition metal salts including Cu, Fe, Zn, Mn, Co, and Ni; and

c) introducing at least one booster pesticide into the aqueous dispersion

9. A formulation comprising prothioconazole, a stabilizing amount of a transition metal salt, and at least one co-pesticide.

10. The formulation of claim 9, wherein the co-pesticide is selected from the group comprising: dithiocarbamate fungicides, demethylation inhibitors, quinone outside inhibitors, succinate dehydrogenase inhibitors, and quinone inside inhibitors.

11. The formulation of claim 9, wherein the formulation comprises at least two co-pesticides.

12. The formulation of claim 9, wherein the co-pesticide is selected from the group comprising: dithiocarbamate fungicides, demethylation inhibitors, quinone outside inhibitors, succinate dehydrogenase inhibitors, and quinone inside inhibitors.

13. The formulation of claim 10, wherein the dithiocarbamate fungicide is mancozeb.

14. The formulation of claim 10, wherein the quinone outside inhibitor is selected from strobilurin fungicides.

15. A method of controlling pests, the method comprising applying to the pests or their habitat an effective amount of a formulation comprising prothioconazole and a stabilizing amount of a transition metal salt.

16. The method of claim 15, wherein the formulation is used as a fungicide.

17. The method of claim 15, wherein the formulation further comprises at least one co-pesticide.

18. A kit comprising a prothioconazole component and a component comprising a stabilizing amount of a transition metal salt.

19. The kit of claim 18, comprising instructions, said instructions comprising instructions to mix said components of said kit prior to use.

20. A kit comprising prothioconazole, a stabilizing amount of a transition metal salt, and at least one co-pesticide.

Technical Field

The present invention relates to stable agrochemical liquid formulations comprising prothioconazole.

Background

Fungi are one of the leading causes of crop loss worldwide, and thus fungicides are considered an important class of pesticides. Fungicides are a specific type of pesticide that is widely used to control fungal disease by inhibiting or killing the disease-causing fungi.

Triazoles are one of the largest classes of fungicides and have been found to be very effective as broad-spectrum fungicides. A particularly important triazole fungicide is 2- [2- (1-chlorocyclopropyl) -3- (2-chlorophenyl) -2-hydroxypropyl ] -2, 4-dihydro- [1,2,4- ] -triazole-3-thione, developed by the bayer process. The common name for such triazolinethione fungicides is prothioconazole. Prothioconazole is a sterol demethylation (ergosterol biosynthesis) inhibitor and is used agriculturally as a fungicide.

US5789430 discloses prothioconazole and its use as microbicide in plant protection. It is a systemic fungicide, and has protective, curative, eradicating and lasting effects. It is widely used for controlling diseases such as ocular spot (cercospora herpetiformis), fusarium ear blight (fusarium, micronosporium spot), leaf spot (septoria tritici, septoria glumae, pyrenophora, barley leaf spot, etc.), rust (puccinia) and powdery mildew (erysiphe graminis) by foliar application in wheat, barley and other crops. It is also used for seed dressing, for the control of Ustilago, tillering, Fusarium and Microsporum.

Prothioconazole is a water-insoluble active ingredient and can be formulated with organic solvents and emulsifiers (emulsifiable concentrates) or with aqueous dispersions and other inert ingredients. Emulsifiable concentrates are less desirable due to cost and adverse environmental effects on the use of organic solvents.

US 8658680 discloses that in aqueous dispersions prothioconazole degrades and is chemically unstable, especially when formulated at low concentrations, thereby reducing the shelf life of the formulation. Stability of the formulation is achieved by the addition of a sulfur-containing compound. Due to the strict guidelines of various regulatory agencies for the allowable limits of sulfur compounds in agricultural formulations, it is generally found to be ineffective in providing the required stability and maintaining the active ingredient content within acceptable limits.

The problems associated with the chemical and physical stability of formulations are exacerbated when it is desired to develop formulations containing more than one active ingredient. Formulation development becomes tricky if it is desired to combine water-insoluble prothioconazole with another water-insoluble active ingredient.

Therefore, it is challenging to develop a stable liquid formulation of prothioconazole, wherein the active ingredient of prothioconazole remains in the formulation even after prolonged storage.

Disclosure of Invention

Object of the Invention

It is an object of the present invention to provide stable agrochemical liquid formulations comprising prothioconazole.

It is another object of the present invention to provide a method for preparing a stable liquid formulation comprising prothioconazole wherein chemical degradation of prothioconazole can be prevented.

It is another object of the present invention to provide a liquid formulation comprising prothioconazole which does not degrade during prolonged storage.

It is another object of the present invention to provide a stable liquid formulation comprising prothioconazole and at least one co-pesticide.

The present invention satisfies at least one, and preferably all, of the above objects as will be apparent from the following description.

Detailed Description

The present invention provides stable liquid formulations comprising prothioconazole.

According to various regulatory requirements, the active ingredients present/claimed in a given formulation must not change beyond acceptable limits during storage to ensure the safety and desired performance of the particular active ingredient.

The inventors of the present invention have attempted to control the chemical degradation of prothioconazole in liquid formulations, especially in low concentration liquid formulations. The problem of chemical degradation of prothioconazole in liquid formulations is surprisingly solved by mixing it with a transition metal salt.

It has therefore surprisingly been found that stable liquid formulations of prothioconazole can be prepared by dispersing prothioconazole together with at least one transition metal salt.

Most surprisingly, it has been found that the inventive formulations of the present invention require a stabilizing amount of a transition metal salt to prevent chemical degradation of prothioconazole.

With respect to the present invention, the term "stable liquid formulation" refers to a physically and chemically stable liquid formulation. As used herein, the term "chemical stability" refers to a formulation containing one or more active ingredients wherein the active ingredients do not chemically degrade or decompose beyond acceptable limits. As used herein, the term "physical stability" refers to a formulation comprising one or more active ingredients wherein there is no significant layer separation or settling of solid particles during/after storage.

In some embodiments, the present invention provides stable liquid formulations of chemically and physically prothioconazole.

For the purposes of the present invention, prothioconazole means 2- [2- (1-chlorocyclopropyl) -3- (2-chlorophenyl) -2-hydroxypropyl ] -1, 2-dihydro-3H-1, 2, 4-triazole-3-thione, its isomers, mixtures of isomers and crystal modifications.

In some other embodiments, the present invention provides stable aqueous formulations of prothioconazole.

In certain other embodiments, the present invention provides stable aqueous dispersions of prothioconazole.

In one embodiment, an aqueous dispersion of prothioconazole is provided, wherein the prothioconazole does not degrade beyond acceptable limits.

Accordingly, in some embodiments, the present invention provides formulations comprising prothioconazole and a transition metal salt.

In some embodiments, the presence of the transition metal salt controls the degradation of prothioconazole in the aqueous dispersion.

In certain other embodiments, chemical stabilization of prothioconazole is achieved by the presence of a transition metal salt in the aqueous dispersion.

In some embodiments, the present invention provides aqueous formulations of prothioconazole wherein the prothioconazole is present at low concentrations.

In one embodiment of the inventive formulation of the present invention, prothioconazole is present in an amount of about 0.01% to about 30% by weight of the formulation. Preferably, the prothioconazole is present in the formulation in an amount of about 0.1% to about 20% by weight of the formulation.

In one embodiment, transition metal salts useful for stabilizing prothioconazole include salts of transition metals including Cu, Fe, Zn, Mn, Co, and Ni.

In certain embodiments, examples of transition metal salts include nitrates, carbonates, sulfates, halides, and hydroxides, wherein the transition metal is in a monovalent, divalent, or trivalent state.

In one embodiment, the transition metal salt is selected from, but not limited to, copper nitrate, copper nitrite, copper sulfite, copper sulfate, copper carbonate, copper chloride, copper bromide, copper iodide, copper fluoride, copper hydroxide, iron nitrate, iron nitrite, iron carbonate, iron chloride, iron bromide, iron iodide, iron fluoride, iron hydroxide, zinc nitrate, zinc nitrite, zinc sulfate, zinc sulfite, zinc carbonate, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, zinc hydroxide, manganese nitrate, manganese sulfite, manganese carbonate, manganese chloride, manganese bromide, manganese iodide, manganese fluoride, manganese hydroxide, cobalt nitrate, cobalt nitrite, cobalt sulfite, cobalt sulfate, cobalt carbonate, cobalt chloride, cobalt bromide, cobalt iodide, cobalt fluoride, cobalt hydroxide, copper sulfate, copper carbonate, copper chloride, copper nitrite, copper sulfite, copper sulfate, copper carbonate, copper chloride, copper bromide, copper, Nickel nitrate, nickel nitrite, nickel sulfite, nickel sulfate, nickel carbonate, nickel chloride, nickel bromide, nickel iodide, nickel fluoride, and nickel hydroxide.

In some embodiments, an effective amount of a transition metal salt is needed to maintain chemical stability to prothioconazole.

In another embodiment, the transition metal salt is present in a stabilizing amount to prevent chemical degradation of prothioconazole.

In another embodiment, the stabilizing amount of the transition metal salt is at least 0.01% by weight of the formulation.

In certain other embodiments, the transition metal salt is present in an amount of at least about 0.01% by weight of the formulation.

In certain other embodiments, the transition metal salt is present in an amount from about 0.01% to about 10% by weight of the formulation.

The inventive formulation of the present invention further comprises at least one co-pesticide.

In some embodiments, the co-pesticide is selected from, but not limited to, herbicides, insecticides, insect growth regulators, nematicides, termiticides, molluscicides, bactericides, insect repellents, animal repellents, antimicrobials, fungicides, disinfectants, and sanitizers.

In some preferred embodiments, the co-pesticide is selected from the group consisting of fungicides, antimicrobials, and insecticides.

In some more preferred embodiments, the co-pesticide is selected from fungicides.

In some most preferred embodiments, the fungicide is selected from, but is not limited to, dithiocarbamate fungicides, demethylation inhibitors, off-quinone inhibitors, succinate dehydrogenase inhibitors, and in-quinone inhibitors.

In one embodiment, the dithiocarbamate fungicide comprises a dithiocarbamate molecular moiety and is selected from the group consisting of amobam, arsonium, thiram oxide, morbus, thiabendazole, copper oxychloride, disulfiram, ferbam, metam, sodium metiram, acetonitrile, thiram, arsone, ziram, dazomet, thioneb, metiram, mancopper, mancozeb, maneb, metiram, zineb, and zineb.

In a preferred embodiment, the dithiocarbamate fungicide is mancozeb.

In another embodiment, the quinone outside inhibitor is selected from strobilurin fungicides.

In another embodiment, the strobilurin fungicide is selected from, but is not limited to, azoxystrobin, kresoxim-methyl, picoxystrobin, pyraclostrobin and trifloxystrobin.

In one embodiment, the demethylating fungicide is selected from triazole fungicides.

In another embodiment, the triazole fungicide is selected from, but is not limited to, cyproconazole, flusilazole, flutriafol, metconazole, myclobutanil, propiconazole, tebuconazole, and tetraconazole.

In one embodiment, the succinate dehydrogenase inhibitor is selected from the group consisting of benzovindiflupyr, bixafen, fluxapyroxad, furametpyr, isopyrazam, penflufen, penthiopyrad, pyriflufen, boscalid, thifluzamide, carboxin, oxycarboxin, meturam, fluopyram, iprodione, mefenoxam, fuberidazole, and mefenapyr.

Thus, in certain embodiments, there is provided a stable liquid formulation comprising prothioconazole, a stabilizing amount of a transition metal salt, and a dithiocarbamate fungicide.

In certain preferred embodiments, a stable liquid formulation is provided comprising prothioconazole, a stabilizing amount of a transition metal salt, and mancozeb.

In certain embodiments, the formulations of the present invention further comprise at least two co-pesticides.

In one embodiment, the co-pesticide is selected from the group consisting of dithiocarbamate fungicides, demethylation inhibitors, quinone outside inhibitors, succinate dehydrogenase inhibitors, and quinone inside inhibitors.

In a preferred embodiment, the co-pesticide is selected from dithiocarbamate fungicides and quinone external inhibitors.

In another embodiment, the quinone outside inhibitor is selected from strobilurin fungicides.

In another embodiment, the strobilurin fungicide is selected from, but is not limited to, azoxystrobin, kresoxim-methyl, picoxystrobin, pyraclostrobin and trifloxystrobin.

Accordingly, in certain embodiments, a stable liquid formulation is provided comprising prothioconazole, a stabilizing amount of a transition metal salt, a dithiocarbamate fungicide, and a strobilurin fungicide.

In one embodiment, a stable liquid formulation is provided comprising prothioconazole, a stabilizing amount of a transition metal salt, mancozeb, and azoxystrobin.

In another embodiment, a stable liquid formulation is provided comprising prothioconazole, a stabilizing amount of a transition metal salt, mancozeb, and kresoxim-methyl.

In another embodiment, a stable liquid formulation is provided comprising prothioconazole, a stabilizing amount of a transition metal salt, mancozeb, and picoxystrobin.

In another embodiment, a stable liquid formulation is provided comprising prothioconazole, a stabilizing amount of a transition metal salt, mancozeb, and pyraclostrobin.

In another embodiment, a stable liquid formulation is provided comprising prothioconazole, a stabilizing amount of a transition metal salt, mancozeb, and trifloxystrobin.

According to the present invention, there is provided a method for producing a stable liquid formulation of prothioconazole.

In a preferred embodiment, the liquid formulation is an aqueous formulation.

In one embodiment, a method of chemically stabilizing prothioconazole in an aqueous formulation is provided.

In another embodiment, a method of chemically stabilizing a low concentration aqueous formulation of prothioconazole is provided.

In some other embodiments, a method of chemically stabilizing an aqueous dispersion of prothioconazole is provided.

In another embodiment, a method is provided for chemically stabilizing an aqueous dispersion of prothioconazole by effecting interaction between the prothioconazole and a transition metal salt.

In one embodiment, a method is provided for producing a stable liquid formulation of prothioconazole comprising the steps of:

a) dispersing prothioconazole in water to prepare an aqueous dispersion of prothioconazole; and

b) dispersing a transition metal salt into the aqueous dispersion in an amount effective to maintain the dispersion stable, wherein the transition metal salt is selected from the group consisting of transition metal salts including Cu, Fe, Zn, Mn, Co, and Ni.

In certain other embodiments, the transition metal salt used in the method may be selected from the group consisting of nitrates, carbonates, sulfates, halides, and hydroxides.

In some embodiments, an effective amount of a transition metal salt is needed to maintain chemical stability to prothioconazole during stabilization of prothioconazole.

In some other embodiments, the transition metal salt is present in an amount of at least about 0.01% by weight of the formulation during stabilization of prothioconazole.

In certain other embodiments, the transition metal salt is required in an amount of from about 0.01% to about 10% by weight of the formulation.

In some embodiments, the formulations according to the present invention may be provided as different formulation types selected from suspending agents, suspended emulsions, microdispersions, microemulsions or dilutable dispersions.

In certain embodiments, the formulations of the present invention comprise a continuous aqueous phase.

In certain other embodiments, the formulations of the present invention comprise a discontinuous organic phase.

According to the present invention there is provided a process for the production of a stable liquid formulation of prothioconazole comprising prothioconazole, a stabilizing amount of a transition metal salt and at least one co-pesticide.

In certain other embodiments, there is provided a method of producing a stable liquid formulation of prothioconazole comprising the steps of:

a) dispersing prothioconazole in water to prepare an aqueous dispersion of prothioconazole;

b) dispersing a transition metal salt into the aqueous dispersion in an amount effective to keep the aqueous dispersion stable, wherein the transition metal salt is selected from the group consisting of transition metal salts including Cu, Fe, Zn, Mn, Co, and Ni; and

c) introducing at least one co-pesticide into the aqueous dispersion.

In some embodiments, steps (b) and (c) may be performed in any order.

In certain embodiments, the co-pesticide is introduced as an aqueous dispersion or solution in a suitable solvent.

In some embodiments, a suitable solvent is water.

In some embodiments, the method includes solvents commonly used in agricultural formulations.

In certain other embodiments, suitable solvents that may be used in the process include, but are not limited to, alcohols, ketones, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, amide solvents vegetable oils, derivatives or mixtures thereof.

The stable liquid formulation of the present invention may optionally include other agrochemically acceptable excipients. Examples are surfactants such as dispersants, wetting agents, emulsifiers, suspending agents, defoamers, penetrants, antioxidants, stabilizers, pH adjusters, fertilizers, rheology modifiers or thickeners, inert substances, and combinations thereof.

In one embodiment, surfactants that may be used as wetting and/or dispersing agents include sulfosuccinates, naphthalene sulfonates, sulfates, phosphate esters, sulfated alcohols, alkylbenzene sulfonate polycarboxylates, polynaphthalenesulfonates, phenol sulfonic acid condensates, lignosulfonates, methyl oleoyl taurates, and polyvinyl alcohols. In addition, other surfactants known in the art may be used without departing from the scope of the invention.

In one embodiment of the invention, the composition may comprise a pH adjusting agent. Suitable pH adjusting agents include buffers. Examples are alkali metal salts of weak inorganic or organic acids.

In one embodiment of the invention, the composition comprises a rheology modifier (or thickener). Suitable compounds are all those compounds which are customarily used in agrochemical compositions. Examples include bentonite, attapulgite, polysaccharides, xanthan gum and kelzan gum.

In another embodiment of the invention, the composition comprises an antifreeze agent. Suitable antifreeze agents are liquid polyols, such as ethylene glycol, propylene glycol or glycerol.

In another embodiment of the invention, the composition comprises an antifoaming agent selected from the group consisting of non-silicone or silicone-based antifoaming agents.

Furthermore, the present invention provides a method for controlling pests, which comprises applying an effective amount of the stable liquid prothioconazole formulation according to the invention to the pests or their habitat.

In one embodiment, a method of controlling pests is provided, the method comprising applying an effective amount of a stable liquid formulation of prothioconazole, the formulation comprising prothioconazole and a stabilizing amount of a transition metal salt.

In one embodiment, the stable liquid formulation of the present invention is used as a fungicide.

In another embodiment, there is a method of controlling harmful fungi comprising applying a fungicidally effective amount of a stable liquid formulation of prothioconazole comprising prothioconazole and a stabilizing amount of a transition metal salt.

In some embodiments, the formulations according to the present invention may be used for pest control on plants, plant parts, seeds, seedlings or soil.

In some embodiments, a method of controlling pests is provided, the method comprising applying to the pests or their habitat a stable liquid formulation of an effective amount of prothioconazole, the formulation comprising prothioconazole, a stable amount of a transition metal salt and a co-pesticide.

In some other embodiments, a stable liquid formulation comprising prothioconazole, a stabilizing amount of a transition metal salt, and a co-pesticide is used as a fungicide.

The formulations of the present invention may be sold as a pre-mixed composition or kit of parts, such that the individual components of the formulation may be mixed prior to spraying.

Accordingly, in one aspect, the present invention provides a kit comprising a prothioconazole component and a component comprising a stabilizing amount of a transition metal salt.

In one embodiment, the components of the indicator kit are mixed prior to use.

Thus, in this embodiment, the kit of the invention further comprises instructions.

In another embodiment, a kit comprises prothioconazole, a stabilizing amount of a transition metal salt, and at least one co-pesticide.

The invention will now be illustrated by the following examples.