WO2023023768A1

WO2023023768A1 - Highly loaded metalaxyl-m formulations

Info

Publication number: WO2023023768A1
Application number: PCT/AU2022/050995
Authority: WO
Inventors: Peter Vaughan; Andrew HORSFIELD
Original assignee: Adama Australia Pty Ltd
Current assignee: Adama Australia Pty Ltd
Priority date: 2021-08-25
Filing date: 2022-08-25
Publication date: 2023-03-02
Anticipated expiration: 2024-02-25
Also published as: GB2625025A; UY39910A; CR20240149A; AU2021221736A1; CO2024003878A2; AR126860A1; AU2022333651A1; GB202404186D0; EP4391803A4; EP4391803A1; ECSP24023952A

Abstract

The invention provides a stable, highly loaded metalaxyl-m soluble liquid formulation, having a metalaxyl-m loading of more than 480 g ai/L, a solvent and a surfactant. The formulation enables combinations with tank mix partners which increase choices compared to the prior art.

Description

Highly Loaded Metalaxyl-M Formulations

Technical Field

The invention relates to metalaxyl-m formulations. In particular, the invention is concerned with highly loaded metalaxyl-m formulations having a loading in excess of 480 g a i/L.

Background Art

Metalaxyl-m (methyl N-(methoxyacetyl)-N-(2,6-xylyl)-DL-alaninate) is also known as mefenoxam. Metalaxyl-m is a systemic phenylamide fungicide that inhibits protein synthesis in selected oomycete fungi, by interfering with the synthesis of ribosomal RNA.

Metalaxyl-m is the resolved isomer of metalaxyl and is the fungicidally active form. Uses for metalaxyl-m include: control of a wide range of foliar diseases e.g., Pseudopeonospora, Phytophthora, Bremia, usually in a co-formulation with a protectant fungicide; soil application as a solo treatment or mixtures for soil-borne pathogens which cause root and lower stem rots in a wide range of situations e.g., cereals, tree crops, vegetables, turf, ornamentals; seed treatments for systemic control of a range of Peronosporaceae, either solo or in mixtures.

Metalaxyl-m is marketed under a wide range of formulation types e.g., powder for dry seed treatment (DS), emulsifiable concentrates (EC), flowable concentrate for seed treatment (FS), granules (GR), suspension concentrates (SC), suspoemulsions (SE), soluble liquids (SL), water dispersible granules (WG) and wettable powders (WP).

To reduce the risk of fungicide resistant development and to enhance disease control, metalaxyl-m (or metalaxyl) is co-formulated with protectant/other fungicide modes of action such as mancozeb or other dithiocarbamates, strobilurins such as azoxystrobin, triazoles, fludioxonil, SDHIs (Succinate Dehydrogenase Inhibitors), copper, chlorothalonil, captan, folpet, propamocarb and others. Co-formulations containing metalaxyl-m and another fungicide can be convenient for end-users who only need to apply a single product to control target diseases. However, the majority of co-formulations contain a relatively low concentration of metalaxyl-m, such as less than 20% w/v or w/w. This is particularly the case with co-formulations with high rate protectant fungicides, such as copper, chlorothalonil or mancozeb, where the metalaxyl-m concentration is less than 10% w/w or w/v. Development of stable granular formulations of metalaxyl-m + protectant fungicides is technically challenging, with few high quality formulations available. Co-formulations of metalaxyl-m + protectant fungicides as wettable powders in water soluble packaging are also commercially available, however these are not preferred by end users due to issues with mixing, aging of the bags and inability to easily apply a specific dose.

Solo SL and EC formulations are available, however these formulations are only registered and used for soil or early season foliar applications. Additionally, existing formulations, such as the 480 SL or EC, contain >50% raw materials, including three or more different components such as acetophenone, nonylphenol polyglycol ether, y-butyrolactone, alkylbenzene sulphonates, tallow fatty amine polyethylene oxide, 2-heptanone, propylene glycol and/or anionic dispersing agent. Other SL formulations mentioned in Australian Patent No. 2015220796 rely on water as part of the formulation.

Since existing SL and EC formulations contain a higher concentration of hydrocarbon solvents, such as acetophenone and glycol ethers, they are less efficient due to the lower metalaxyl-m-to-solvent ratio. The water solubility of the solvents in existing <480 g a i/L SL or EC formulations is generally lower than methyl carbitol and as a result multiple solvents/surfactants/humectants are required to create a stable SL formulation, both incan and on dilution in water.

There is a need for a stable highly loaded metalaxyl-m soluble liquid formulation with more than 480 g ai/L.

The benefits of high concentration formulations can be observed through the entire supply chain including: less volume of raw materials to procure; fewer litres or kilograms to formulate; fewer drums, labels and caps required for the same quantity of active ingredient; less freight and storage from procurement of raw materials through to the end user; less volume for the end user to handle during mixing and application;

Fewer drums to dispose of post application; and more cost-effective formulations for the manufacturer.

Any improvement in the delivery of the active ingredient from synthesis through to the point of application can enhance the efficiency and improve profitability of the agricultural chemical industry.

Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art.

Summary of the Invention

Accordingly, the present invention provides a stable, high loaded metalaxyl-m soluble liquid formulation, having a metalaxyl-m loading of more than 480 g ai/L, a solvent and a surfactant.

Preferably, the formulation of the invention has a single solvent and a single surfactant.

In the formulation of the invention, the solvent is preferably a glycol ether, one nonlimiting example of which is methyl carbitol.

Metalaxyl-m tech can be produced as a viscous liquid with a purity >90%. The selection of methyl carbitol as the solvent enabled metalaxyl-m to dissolve, to create a stable and useable formulation with acceptable viscosity range at typical temperatures for transport, storage and during application. Additionally, to ensure the solution stability on dilution the solvent selected needs to be water soluble. On dilution in water, the methyl carbitol dissolves, along with the metalaxyl-m and surfactant, to produce a stable solution where all the components are completely dissolved.

It was unexpected that methyl carbitol would enable stable SL formulations at loadings above 480 g ai/L and even as much as 800 g ai/L or more. In the formulation of the invention, the surfactant may be any suitable surfactant. An example is a non-ionic block co-polymer available as Termul® 203.

In one embodiment, each of the raw materials, including the solvent and the surfactant, are completely water soluble at typical dilution rates in water.

In one embodiment, the formulation of the invention has a ratio of more than 1:1 for metalaxyl-m compared to other raw materials in the formulation.

The formulation of the invention may not require an anti-foaming agent.

The formulation of the invention may not require the addition of water as a continuous phase or as a solvent.

The viscosity of the formulation of the invention is preferably in the range of about 100 to about 600 cps at a temperature range of about 20°C to about 0°C.

The total solvent + surfactant loading in a preferred embodiment of the formulation of the invention is less than 25% of the formulation, which is about half the raw materials required to formulate prior art SL 480 g metalaxyl-m/L formulations.

It is preferred that the formulation of the invention is compatible with a range of fungicides.

The invention also provides a method of control for diseases using the formulation of the present invention, tank mixed with at least one fungicide or compound with antifungal/plant activator/systemic acquired resistance activity.

The ability to high load formulations of metalaxyl-m creates greater flexibility for end users to apply this product: for control of a wide range of foliar diseases in a tank mix with a protectant fungicide; soil application as a solo application or in mixtures for soil-borne pathogens; and seed treatments.

Existing typical co-formulations contain low concentrations of metalaxyl-m or metalaxyl mixed with a higher concentration of a protectant fungicide. Examples are provided in Table 1, below, showing metalaxyl-m and metalaxyl coformulations and examples of solo partner components currently or previously commercially available. Table 1

The ability to tank mix with a range of different fungicides provides many benefits, including: less total formulated product to apply per hectare, with reductions ranging from 9.7 to 58.3% less volume/weight required to apply the same dose as an embodiment of the present invention, identified as AD-AU-2011 below, + relevant partner fungicide; - ability to select alternative tank mix partners for AD-AU-2011; end-users frequently apply the partner fungicides for other diseases using solo products, therefore AD-AU-2011 eliminates the requirement for an additional coformulation containing the same Al and metalaxyl-m; and

If the partner Al has a more restricted use or is banned due to regulatory decisions, AD-AU-2011 can be tank mixed with an alternative partner.

Table 2 below sets out the equivalent rate of metalaxyl-m and partner fungicide to achieve the same dose per hectare as example co-formulations listed in Table 1: Table 2

As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises and "comprised", are not intended to exclude further additives, components, integers or steps.

Further aspects of the present invention described in the preceding paragraphs will become apparent from the following description, given by way of embodiments and/or examples.

Detailed Description of Preferred Embodiments

Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments and/or examples, it will be understood that the intention is not to limit the invention to those embodiments/examples. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention.

One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the features mentioned or evident from the text. All of these different combinations constitute various alternative aspects of the invention.

For the purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

Example 1: Highly Loaded Metalaxyl-M Formulation

By way of example, a highly loaded aqueous SL formulation containing a Metalaxyl-M concentration of about 800 g a i/L was prepared (AD-AU-2011).

Technical grade metalaxyl-M TGAC 91% min was obtained from Zhejiang Heben Pesticide & Chemicals Co, Ltd of China. The formulation components are as set out in Table 3: Table 3: Formulation Components

The suppliers of the excipients are detailed in Table 4: Table 4

AD-AU-2011 SL is formulated as a batch process. The method of formulation of the product including the sequence of operations to be followed is described below: 1. Charge the Methyl Carbitol into a suitable vessel equipped with a propeller type stirrer.

2. Commence stirring and add the Metalaxyl-M TGAC.

3 Continue stirring and add the molten Termul 203.

4. Stir for a further 20 mins and ensure complete homogeneity. Examine a sample against the specification and adjust with Methyl Carbitol as required.

Stability Testing

5000 mL of product was formulated as above. 2 x 250 mL samples were assigned to stability study and each was packaged in COEX HDPE containers with screw cap closure (commercial packaging material). Labels were attached to the assigned specimens in preparation for ambient and elevated temperature storage.

The specimens remained in their containers and were stored in an air-conditioned facility at approximately 21 °C for the period prior to ambient temperature and elevated temperature storage.

On the day of initiation of the accelerated storage trial, each of the specimens in their unopened containers were weighed on a top pan balance (Mettler PJ3600 Delta Range: SNR J29589) to determine a starting weight (for use as a comparison with weights at the conclusion of the storage period).

The sample designated for elevated temperature storage (Accelerated Stability sample TAS1) was placed into a thermostatically controlled oven (VWR Mini Incubator: SNR 0811V1169), heated to 54 ± 2 °C, for a period of 14 days. At the end of this period, the sample was removed from the oven and placed into a desiccation chamber to allow cooling to ambience.

The remaining AD-AU-2011 SL formulation sample (Time Zero sample T01) was stored at air-conditioned ambient temperatures (~21 °C) in a locked cabinet for the duration of the elevated temperature storage period.

A sample of AD-AU-2011 SL was prepared for low temperature stability testing by placing 100 mL formulation sample (TCD1) into a 100 mL ASTM D96 graduated centrifuge tube and storing it in a refrigerated cabinet (Esatto Model EBF93W: SNR 5G386) at a temperature of 0 °C ± 2 °C for a total of 7 days.

Table 5 sets out results for the ambient sample at time zero.

Table 6 sets out the results for the accelerated stability sample:

Table 7 sets out the results for the cold temperature stability sample:

Table 8 shows packaging stability:

Table 8: Packaging Stability

No observable degradation, deformation, discolouration or etching of the container or lid was evident after accelerated storage. No odour was detectable emanating from the seal. No appreciable weight difference was determined over the 14-day period for both ambient and 54 °C storage conditions.

Storage Stability Analysis Methods

Relevant test parameters for soluble concentrate (SL) formulations are given in Section 4, Table 18 of the APVMA Guidelines for the Generation of Storage Stability Data for Agricultural Chemical Products (Version 3, 24 February 2020). An outline summary of each method employed follows:

Appearance, Physical State & Colour

These tests are performed visually and are described in descriptive terms.

Odour

This test is performed organoleptically and involves the use of descriptive terms. Density Anton Paar DMA 48 Density Meter

The Anton Paar density meter calculates the density of liquids and gases based on an electronic measurement of the frequency of oscillation of a U-tube containing the sample at a specified temperature. pH CIPAC MT 75.3

The pH value of the neat formulation is determined by means of a pH meter and electrode system.

Solution Stability CIPAC MT 41

The sample is diluted and allowed to stand for 18 h at 20 °C. At the end of this time a notation is made if there is any separated material.

Persistent Foam CIPAC MT 47.2

The sample is diluted in a measuring cylinder of standard dimensions which is inverted 30 times and the amount of foam created and remaining after certain times is measured.

Cold Temperature Stability of Liquid Formulations CIPAC MT 39.3

A sample is maintained at 0 ± 2 °C for 7 days and the volume and nature of any separated material is recorded.

Active Constituent Content - QChem Laboratories Analytical Method QCM-229.01

The R-Metalaxyl enantiomer (Metalaxyl-M) is separated & determined by reversed phase chiral high performance liquid chromatography using UV detection and external standardisation. The method is appropriately validated as per the APVMA Guidelines for the Validation of Analytical Methods for Active Constituents and Agricultural Products (Revision 1, July 1 2014).

Observation of Packaging Stability

A sample of the product in a container of the same material and construction to that of the marketed product is weighed and then maintained at 54 C for a period of 14 days. Any loss or gain in weight is recorded and the container examined, recording observations of any significant interaction with the formulation.

In conclusion, the new SL formulation L performs excellently in all requisite tests. Example 2: Field Trials

Field Trial 1

A field trial was conducted in grape cv. Cabernet sauvignon at Langhorne Creek in South Australia. The trial evaluated AD-AU-2011 with a range of tank mix partners and compared with standard co-formulations including Axiom MZ and Ridomil Gold Plus (Table 9).

All fungicides were applied four times, at E-L 15, E-L 20, E-L 26 and E-L 31 in a spray volume of 1000 to 1700 L/ha.

All treatments were safe to the crop, with no phytotoxicity observed. Assessments of downy mildew leaf infection (Table 10) at 55 and 78 days after the final application demonstrated that:

AD-AU-2011 applied with Penncozeb provided similar control to Axiom MZ,

AD-AU-2011 applied with different copper formulations provided similar control to Ridomil Gold Plus, - AD-AU-2011 applied with Polyram, Cavalry or MCW 296 provided similar control of downy mildew.

Table 9. Products evaluated in grapes at Langhorne Creek

Table 10. Downy mildew leaf severity in grape cv. Cabernet sauvignon

DAA = Days after application

Means followed by the same letter are not significantly different (P = 0.05, Duncan's) Field Trial 2

A field trial was conducted in grape cv. Merlot at Faraday in Victoria. The trial evaluated AD-AU-2011 with a range of tank mix partners and compared with standard coformulations including Axiom MZ and Ridomil Gold Plus (Table 11).

All fungicides were applied three times, at BBCH 57, 70 and 75 in a spray volume of 800 to 1000 L/ha. All treatments were safe to the crop, with no phytotoxicity observed. Assessments of downy mildew bunch severity (Table 12) at 32 days after the final application demonstrated that:

AD-AU-2011 applied with Penncozeb provided similar control to Axiom MZ, - AD-AU-2011 applied with different copper formulations provided similar control to Ridomil Gold Plus,

AD-AU-2011 applied with Polyram, Cavalry or MCW 296 provided similar control of downy mildew.

Table 11. Products evaluated in grapes at Faraday, Victoria

Table 12. Downy mildew bunch severity in grape cv. Merlot

DAA = Days after application

Means followed by the same letter are not significantly different (P = 0.05, Fisher's LSD)

Field Trial 3

A field trial was conducted in grapes at Stanthorpe in Queensland. The trial evaluated AD- AU-2011 with a range of tank mix partners and compared with standard co-formulations including Axiom MZ and Ridomil Gold Plus (Table 13). All fungicides were applied seven times as a dilute application.

All treatments were safe to the crop, with no phytotoxicity observed. Assessments of defoliation from downy mildew (Table 14) at 28 days after the final application demonstrated that:

AD-AU-2011 applied with Unizeb provided similar control to Axiom MZ,

AD-AU-2011 applied with different copper formulations provided similar control to Ridomil Gold Plus,

AD-AU-2011 applied with Polyram, Cavalry or MCW 296 provided similar control of downy mildew. Table 13. Products evaluated in grapes at Stanthorpe, Queensland

Table 14. Defoliation in grapes due to downy mildew

DAA = Days after application Means followed by the same letter are not significantly different (P = 0.05, Fisher's LSD)

Field Trial 4

A field trial was conducted in turf at Brisbane in Queensland. The trial evaluated AD-AU- 2011 as a solo application for pythium control in comparison with the standard formulation, Triumph. All fungicides were applied three times using a hand boom.

All treatments were safe to turf, with no phytotoxicity observed. Assessments of the area under disease progress curve (Table 15) demonstrated that AD-AU-2011 provided equivalent control compared to the standard fungicide, Triumph. Table 15. Pythium control in turf

AUDPC = area under disease progress curve

Means followed by the same letter are not significantly different (P = 0.05, Duncans test)

Industrial Applicability

The highly loaded metalaxyl-m soluble liquid formulation of the invention provides a stable formulation having a much higher concentration than prior art formulations. The formulation of the invention enables a broad choice of mixtures with tank mix partners, being at least equivalent with prior art fungicides.

Claims

1. A stable, highly loaded metalaxyl-m soluble liquid formulation, having a metalaxyl- m loading of more than 480 g ai/L, a solvent and a surfactant.

2. The formulation of claim 1, wherein the loading of metalaxyl-m is about 800 g ai/L.

3. The formulation of claim 1 or 2, which has a single solvent and a single surfactant.

4. The formulation of any one of claims 1 to 3, wherein the solvent is a glycol ether.

5. The formulation of claim 4, wherein the solvent is methyl carbitol.

6. The formulation of any one of claims 1 to 5, wherein the surfactant is a non-ionic block co-polymer.

7. The formulation of claim 6, wherein the surfactant is Termul® 203.

8. The formulation of any one of claims 1 to 7, wherein the solvent and the surfactant are completely water soluble at typical dilution rates in water.

9. The formulation of any one of claims 1 to 8, wherein the ratio of metalaxyl-m to other raw materials in the formulation is more than 1:1.

10. The formulation of any one of claims 1 to 9 which does not require an antifoaming agent.

11. The formulation of any one of claims 1 to 10 which does not require the addition of water as a continuous phase or as a solvent.

12. The formulation of any one of claims 1 to 11, wherein the viscosity of the formulation is in the range of about 100 to about 600 cps at a temperature range of about 20°C to about 0°C.

13. The formulation of any one of claims 1 to 12, wherein total solvent and surfactant loading is less than 25% of the formulation.

14. A method of control of a disease using the formulation of any one of claims 1 to 13, tank mixed with at least one fungicide or compound with antifungal/plant activator/systemic acquired resistance activity.

15. The method of claim 14, wherein the formulation is tank mixed with one or more tank mix partners chosen from: copper, chlorothalonil, metiram, mancozeb and folpet.

16. The method of claim 14 or 15, wherein the disease is downy mildew.

17. The method of claim 16, when used to control downy mildew in grapes.

18. A method of control for a disease using the formulation of any one of claims 1 to 13, wherein the formulation is used solo, without an active ingredient tank mix partner.

19. The method of claim 18, wherein the disease is pythium.

20. The method of claim 19, when used to control pythium in turf.