U.S. patent application number 16/705404 was filed with the patent office on 2020-04-09 for nematicidal aqueous suspension concentrate compositions.
This patent application is currently assigned to Monsanto Technology LLC. The applicant listed for this patent is Monsanto Technology LLC. Invention is credited to Yiwei Ding, Shaun Raj Selness, Urszula J. Slomczynska.
Application Number | 20200107548 16/705404 |
Document ID | / |
Family ID | 50883972 |
Filed Date | 2020-04-09 |
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United States Patent
Application |
20200107548 |
Kind Code |
A1 |
Ding; Yiwei ; et
al. |
April 9, 2020 |
NEMATICIDAL AQUEOUS SUSPENSION CONCENTRATE COMPOSITIONS
Abstract
Provided herein are aqueous suspension concentrate compositions
comprising biologically active 3,5-disubstituted-1,2,4-oxadiazoles
or salts thereof that are useful, for example, in the control of
nematodes.
Inventors: |
Ding; Yiwei; (Creve Coeur,
MO) ; Selness; Shaun Raj; (Chesterfield, MO) ;
Slomczynska; Urszula J.; (Ballwin, MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Monsanto Technology LLC |
St. Louis |
MO |
US |
|
|
Assignee: |
Monsanto Technology LLC
St. Louis
MO
|
Family ID: |
50883972 |
Appl. No.: |
16/705404 |
Filed: |
December 6, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16143771 |
Sep 27, 2018 |
10499645 |
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16705404 |
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14096793 |
Dec 4, 2013 |
10117434 |
|
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16143771 |
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61733239 |
Dec 4, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A01N 43/50 20130101;
A01N 25/02 20130101; A01N 37/46 20130101; A01N 37/42 20130101; A01N
43/56 20130101; A01N 43/653 20130101; A01N 37/36 20130101; A01N
25/04 20130101; A01N 43/82 20130101; A01N 43/82 20130101; A01N
25/00 20130101; A01N 37/46 20130101; A01N 37/50 20130101; A01N
43/653 20130101; A01N 51/00 20130101; A01N 25/04 20130101; A01N
37/46 20130101; A01N 37/50 20130101; A01N 43/653 20130101; A01N
51/00 20130101 |
International
Class: |
A01N 43/82 20060101
A01N043/82; A01N 25/04 20060101 A01N025/04; A01N 43/50 20060101
A01N043/50; A01N 43/653 20060101 A01N043/653; A01N 37/36 20060101
A01N037/36; A01N 25/02 20060101 A01N025/02; A01N 37/42 20060101
A01N037/42; A01N 43/56 20060101 A01N043/56; A01N 37/46 20060101
A01N037/46 |
Claims
1. A nematicidal aqueous suspension concentrate composition, the
composition comprising: a continuous aqueous phase comprising a
dispersant component comprising a primary anionic dispersant and a
secondary non-ionic dispersant; and a dispersed solid particulate
phase comprising a nematicidal component, the nematicidal component
selected from the group consisting of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole,
3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,
3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,
5-(furan-2-yl)-3-phenyl-1,2,4-oxadiazole, or a salt thereof;
wherein the median size of solid particulates in the dispersed
solid particulate phase is less than about 10 .mu.m.
2. The composition of claim 1 wherein the nematicidal component is
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
3. The composition of claim 1 wherein the nematicidal component is
3-phenyl-5-(furan-2-yl)-1,2,4-oxadiazole.
4. The composition of claim 1 wherein the composition is
storage-stable at 25.degree. C. for at least about 1 week.
5. The composition of claim 1 wherein the nematicidal component
comprises at least about 10% by weight of the composition.
6. The composition of claim 1 wherein the median size of the solid
particulates in the dispersed solid particulate phase is less than
about 5 .mu.m.
7. The composition of claim 1 wherein the mean size of the solid
particulates in the dispersed solid particulate phase is less than
about 20 .mu.m.
8. The composition of claim 1 wherein the dispersed solid
particulate phase has a polydispersity index is less than about
10.
9. The composition of claim 1 wherein the primary anionic
dispersant comprises a dispersant selected from the group
consisting of alkyl sulfates, alcohol sulfates, alcohol ether
sulfates, alpha olefin sulfonates, alkylaryl ether sulfates,
arylsulfonates, alkylsulfonates, alkylaryl sulfonates,
sulfosuccinates, mono- or diphosphate esters of polyalkoxylated
alkyl alcohols or alkyl phenols, mono- or disulfosuccinate esters
of alcohols or polyalkoxylated alkanols, alcohol ether
carboxylates, and phenol ether carboxylates.
10. The composition of claim 9 wherein the primary anionic
dispersant comprises an alkylaryl sulfonate.
11. The composition of claim 1 wherein the dispersant component
comprises from about 0.5% to about 20% by weight of the
composition.
12. The composition of claim 10 wherein the secondary non-ionic
dispersant comprises a dispersant selected from the group
consisting of sorbitan esters, ethoxylated sorbitan esters,
alkoxylated alkylphenols, alkoxylated alcohols, block copolymer
ethers, and lanolin derivatives.
13. The composition of claim 12 wherein the secondary non-ionic
dispersant comprises an alkyl ether block copolymer.
14. The composition of claim 1 wherein the ratio of primary
dispersant to secondary dispersant, on a weight basis, is from
about 1:1 to about 10:1.
15. The composition of claim 1 further comprising at least one of
an anti-freeze agent, an antifoam agent, a stabilizer component, a
biocidal agent, a viscosity modifying agent, or a combination
thereof.
16. The composition of claim 1 wherein the pH of the composition is
from about 5 to about 9.
17. The composition of claim 1 wherein the composition further
comprises an organic solvent component.
18. The composition of claim 17 wherein the organic solvent
component comprises a paraffinic hydrocarbon solvent comprising
predominantly linear or branched hydrocarbons.
19. A method of preparing the nematicidal composition of claim 1,
the method comprising: mixing the nematicidal component, the
dispersant component, and water to form an aqueous suspension; and
wet milling the aqueous suspension to produce a milled suspension
having a reduced particle size.
20. A method for protecting the roots of a plant against damage by
a nematode, the method comprising applying the nematicidal
composition of claim 1 to the soil surrounding the root zone of a
plant.
21. A method for protecting a seed and/or the roots of a plant
grown from the seed against damage by a nematode, the method
comprising treating a seed with a seed treatment composition, the
seed treatment composition comprising the nematicidal composition
of claim 1.
22. The method of claim 21 wherein the seed is an unsown seed.
23. The method of claim 21 wherein the seed is of a transgenic
plant.
24. The method of claim 21 wherein the seed is of corn, soybean, or
cotton.
25. A seed that has been treated by a method as set forth in claim
20.
26. The composition of claim 1 wherein the composition further
comprises a crystallization inhibitor.
27. The composition of claim 26 wherein the crystallization
inhibitor is selected from the group consisting of acrylic
copolymers, polyethylene glycol, polyethylene glycol hydrogenated
castor oil, and combinations thereof.
28. The composition of claim 1 further comprising at least one
additional pesticide selected from the group consisting of: an
insecticide or an additional nematicide selected from the group
consisting of carbamates, diamides, macrocyclic lactones,
neonicotinoids, organophosphates, phenylpyrazoles, pyrethrins,
spinosyns, synthetic pyrethroids, tetronic and tetramic acids; a
fungicide selected from the group consisting of aromatic
hydrocarbons, benzimidazoles, benzthiadiazole, carboxamides,
carboxylic acid amides, morpholines, phenylamides, phosphonates,
quinone outside inhibitors, thiazolidines, thiophanates, thiophene
carboxamides, triazoles; and an herbicide selected from the group
consisting of ACCase inhibitors, acetanilides, AHAS inhibitors,
carotenoid biosynthesis inhibitors, EPSPS inhibitors, glutamine
synthetase inhibitors, PPO inhibitors, PS II inhibitors, and
synthetic auxins.
29. The composition of claim 28 wherein the additional pesticide
comprises an insecticide or an additional nematicide selected from
the group consisting abamectin, aldicarb, aldoxycarb, bifenthrin,
carbofuran, chlorantraniliporle, chlothianidin, cyfluthrin,
cyhalothrin, cypermethrin, deltamethrin, dinotefuran, emamectin,
ethiprole, fenamiphos, fipronil, flubendiamide, fosthiazate,
imidacloprid, ivermectin, lambda-cyhalothrin, milbemectin,
nitenpyram, oxamyl, permethrin, spinetoram, spinosad,
spirodichlofen, spirotetramat, tefluthrin, thiacloprid,
thiamethoxam, and thiodicarb.
30. The composition of claim 28 wherein the additional pesticide
comprises a fungicide selected from the group consisting
acibenzolar-S-methyl, azoxystrobin, benalaxyl, bixafen, boscalid,
carbendazim, cyproconazole, dimethomorph, epoxiconazole, fluopyram,
fluoxastrobin, flutianil, flutolanil, fluxapyroxad, fosetyl-Al,
ipconazole, isopyrazam, kresoxim-methyl, mefenoxam, metalaxyl,
metconazole, myclobutanil, orysastrobin, penflufen, penthiopyrad,
picoxystrobin, propiconazole, prothioconazole, pyraclostrobin,
sedaxane, silthiofam, tebuconazole, thifluzamide, thiophanate,
tolclofos-methyl, trifloxystrobin, and triticonazole.
31. The composition of claim 28 wherein the additional pesticide
comprises an herbicide selected from the group consisting of
acetochlor, clethodim, dicamba, flumioxazin, fomesafen, glyphosate,
glufosinate, mesotrione, quizalofop, saflufenacil, sulcotrione, and
2,4-D.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/143,772 filed Sep. 27, 2018, which is a continuation of U.S.
application Ser. No. 14/096,793, filed Dec. 4, 2013, issued as U.S.
Pat. No. 10,117,434, and claims the benefit of U.S. provisional
Application No. 61/733,239, filed Dec. 4, 2012, the entire
disclosures of which are incorporated herein by reference.
FIELD
[0002] Provided herein are aqueous suspension concentrate
compositions comprising biologically active
3,5-disubstituted-1,2,4-oxadiazoles or salts thereof that are
useful, for example, in the control of nematodes.
BACKGROUND
[0003] Nematodes are active, flexible, elongate organisms that live
on moist surfaces or in liquid environments, including films of
water within soil and moist tissues within other organisms. Many
species of nematodes have evolved to be very successful parasites
of plants and animals and, as a result, are responsible for
significant economic losses in agriculture and livestock.
[0004] Plant parasitic nematodes can infest all parts of the plant,
including the roots, developing flower buds, leaves, and stems.
Plant parasites can be classified on the basis of their feeding
habits into a few broad categories: migratory ectoparasites,
migratory endoparasites, and sedentary endoparasites. Sedentary
endoparasites, which include root knot nematodes (Meloidogyne) and
cyst nematodes (Globodera and Heterodera), can establish long-term
infections within roots that may be very damaging to crops.
[0005] There is an urgent need in the industry for effective,
economical, and environmentally safe methods of controlling
nematodes. Continuing population growth, famines, and environmental
degradation have heightened concern for the sustainability of
agriculture.
[0006] Recently, a class of 3,5-disubstituted-1,2,4-oxadiazoles has
been shown to exhibit potent, broad spectrum nematicidal activity.
See generally U.S. Pat. No. 8,435,999 and U.S. Pat. No. 8,017,555,
the contents of which are expressly incorporated herein by
reference. The 3,5-disubstituted-1,2,4-oxadiazoles disclosed in
U.S. Pat. No. 8,435,999 and U.S. Pat. No. 8,017,555 are generally
characterized by low water solubility.
[0007] Two-phase suspension concentrates, which comprise solid
particles of a compound suspended in an aqueous medium, are
generally known in the art. In the context of seed treatment
applications, suspension concentrates are known to offer several
potential advantages, including high active loading, ease of
handling, and reduced toxicity and flammability associated with
solvents. The suspension concentrate compositions known in the art,
however, are also prone to instability and settling upon storage,
and may not provide a uniform distribution of the active nematicide
compound in a manner that enhances bioavailability.
[0008] To be effective for use as a seed treatment composition, a
nematicidal suspension concentrate desirably satisfies several key
requirements. The nematicidal active ingredient must be effectively
incorporated into a suspension having commercially acceptable
storage stability. The suspension should exhibit acceptable storage
stability over a wide temperature range and even where the
nematicidal active ingredient is present in a high loading, which
reduces the required volume of the composition and, therefore,
reduces the expense of storage and shipping. The nematicidal active
ingredient must also be amenable to transfer from the suspension
concentrate to the surface of the seed, such that the desired
loading can be efficiently achieved. Moreover, following
application to the seed, it may be desirable for the nematicidal
active ingredient to effectively migrate from the seed surface to
the root zone of the surrounding soil.
[0009] Accordingly, there remains a need in the art to develop
compositions that enable the efficient use of the above-mentioned
potent and effective 3,5-disubstituted-1,2,4-oxadiazole nematicidal
compounds in large-scale, commercial agricultural applications,
particularly in seed treatment applications, to protect against
nematode infestations.
SUMMARY OF THE INVENTION
[0010] In one aspect, the present invention is therefore directed
to a nematicidal aqueous suspension concentrate composition,
wherein the composition comprises a continuous aqueous phase
comprising a dispersant component, and a dispersed solid
particulate phase comprising a nematicidal component, the
nematicidal component comprising a
3,5-disubstituted-1,2,4-oxadiazole compound or a salt thereof,
wherein the median size of solid particulates in the dispersed
solid particulate phase is less than about 10 .mu.m.
[0011] In one embodiment, the present invention is directed to a
nematicidal aqueous suspension concentrate composition as described
above, wherein the nematicidal component comprises a compound of
Formula (I) or a salt thereof,
##STR00001##
[0012] wherein A is selected from the group consisting of phenyl,
pyridyl, pyrazyl, oxazolyl and isoxazolyl, each of which can be
optionally independently substituted with one or more substituents
selected from the group consisting of halogen, CF.sub.3, CH.sub.3,
OCF.sub.3, OCH.sub.3, CN, and C(H)O; and C is selected from the
group consisting of thienyl, furanyl, oxazolyl and isoxazolyl, each
of which can be optionally independently substituted with one or
more substituents selected from the group consisting of F, Cl,
CH.sub.3, and OCF.sub.3.
[0013] In another embodiment, the present invention is directed to
a nematicidal aqueous suspension concentrate composition as
described above, wherein the nematicidal component comprises a
compound of Formula (II) or a salt thereof,
##STR00002##
[0014] wherein A is selected from the group consisting of phenyl,
pyridyl, pyrazyl, oxazolyl and isoxazolyl, each of which can be
optionally independently substituted with one or more substituents
selected from the group consisting of halogen, CF.sub.3, CH.sub.3,
OCF.sub.3, OCH.sub.3, CN, and C(H)O; and C is selected from the
group consisting of thienyl, furanyl, oxazolyl and isoxazolyl, each
of which can be optionally independently substituted with one or
more with substituents selected from the group consisting of F, Cl,
CH.sub.3, and OCF.sub.3.
[0015] Another aspect of the present invention is directed to
methods of preparing the nematicidal aqueous suspension concentrate
compositions described above. In one embodiment, the method
comprises mixing the nematicidal compound, the dispersant, and
water to form an aqueous suspension; and wet milling the aqueous
suspension to produce a milled suspension having a reduced particle
size.
[0016] Another aspect of the present invention is directed to
methods of protecting the roots of a plant against damage by a
nematode, the method comprising applying a nematicidal aqueous
suspension concentrate composition as described above the soil
surrounding the root zone of a plant.
[0017] Another aspect of the present invention is directed to
methods of protecting a seed and/or the roots of a plant grown from
the seed against damage by a nematode, the method comprising
treating a seed with a seed treatment composition, the seed
treatment composition comprising a nematicidal aqueous suspension
concentrate composition as described above.
[0018] Another aspect of the present invention is directed to a
seed that has been treated with a seed treatment composition, the
seed treatment composition comprising a nematicidal aqueous
suspension concentrate composition as described above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 depicts a representative photomicrograph of
polymorphic Form I of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
[0020] FIG. 2 depicts a representative photomicrograph of
polymorphic Form II of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
[0021] FIG. 3 depicts a sample cyclic differential scanning
calorimetry (DSC) thermogram from a cyclic DSC analysis conducted
on 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole at a cooling rate of
30.degree. C. per minute.
[0022] FIG. 4 depicts an X-ray diffraction (XRD) overlay of
polymorphic Forms I and II of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
[0023] FIGS. 5A and 5B depict XRD overlay results for polymorphic
Forms I and II of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole,
respectively.
[0024] FIG. 6 depicts the results of a powder XRD analysis of the
Form I polymorph of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
[0025] FIG. 7 depicts the results of a powder XRD analysis of the
Form II polymorph of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
[0026] FIG. 8 depicts a graphical XRD overlay of the competitive
slurry experiment between polymorphic Forms I and II of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
[0027] FIGS. 9A through 9C depict the relevant DSC thermograms for
polymorphic Form I, polymorphic Form II, and a mixture of
polymorphic Forms I and II, respectively, of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
[0028] FIG. 10 depicts the results of an XRD analysis on samples of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole material after 4 weeks
of storage.
[0029] FIG. 11 depicts the XRD overlays of Forms I, II and the
sample of Form II which showed signs of transformation to Form
I.
DETAILED DESCRIPTION OF THE INVENTION
[0030] Provided herein are aqueous suspension concentrate
nematicidal compositions comprising
3,5-disubstituted-1,2,4-oxadiazoles and having improved
effectiveness for seed treatment applications.
[0031] It has been discovered that the dispersibility of solid
particulates of these generally hydrophobic, nematicidal compounds
in an aqueous medium can be significantly increased through the
application of milling techniques that substantially reduce the
mean and median particle size characteristics of the dispersed
solid phase, and by employing selected dispersants. The reduced
size of the solid particulates enables the preparation of
storage-stable, high-load suspension concentrate compositions.
Increasing the aqueous dispersibility of these active nematicidal
agents is highly beneficial, particularly in agricultural
applications. For example, the compositions of the present
invention may be advantageously applied to seeds as a prophylactic
treatment against nematode infestation. Improved aqueous
dispersibility provides for a more effective dispersion and more
consistent loading of the nematicidal compound during initial
application of the composition to the seed. In addition, the
improved aqueous dispersibility provided by the present
compositions is beneficial during the post-planting stage, as it
allows the nematicide to more effectively disperse throughout the
hydrophilic environment in the soil surrounding the seed and,
subsequently, the root zone of the plant. Furthermore, it has been
discovered that by controlling the particle size distribution of
the nematicide particles as described herein, the adhesion
characteristics of the active compound on the surface of the seeds
allows for the efficient production of treated seeds having the
desired active loading, and later enhances the bioavailability of
the active compound in the soil.
[0032] The aqueous suspension concentrate nematicidal compositions
described herein are sometimes referred to herein as "suspension
concentrate compositions," or more briefly as "suspension
concentrates" or "the composition." The suspension concentrate
composition may also be referred to herein as a "seed treatment
composition," particularly in the context of seed treatment
applications.
[0033] Nematicide
[0034] The aqueous compositions described herein generally comprise
a nematicide component comprising one or more
3,5-disubstituted-1,2,4-oxadiazole compounds.
[0035] For example, in one embodiment, the nematicide component
comprises a compound of Formula I or a salt thereof,
##STR00003##
[0036] wherein A is selected from the group consisting of phenyl,
pyridyl, pyrazyl, oxazolyl and isoxazolyl, each of which can be
optionally independently substituted with one or more substituents
selected from the group consisting of halogen, CF.sub.3, CH.sub.3,
OCF.sub.3, OCH.sub.3, CN, and C(H)O; and C is selected from the
group consisting of thienyl, furanyl, oxazolyl and isoxazolyl, each
of which can be optionally independently substituted with one or
more substituents selected from the group consisting of F, Cl,
CH.sub.3, and OCF.sub.3.
[0037] In a more specific embodiment, the nematicide component
comprises a 3,5-disubstituted-1,2,4-oxadiazole of Formula Ia or a
salt thereof,
##STR00004##
[0038] wherein R.sub.1 and R.sub.5 are independently selected from
the group consisting of hydrogen, CH.sub.3, F, Cl, Br, CF.sub.3 and
OCF.sub.3; R.sub.2 and R.sub.4 are independently selected from the
group consisting of hydrogen, F, Cl, Br, and CF.sub.3; R.sub.3 is
selected from the group consisting of hydrogen, CH.sub.3, CF.sub.3,
F, Cl, Br, OCF.sub.3, OCH.sub.3, CN, and C(H)O; R.sub.7 and Rs are
independently selected from hydrogen and F; R.sub.9 is selected
from the group consisting of hydrogen, F, Cl, CH.sub.3, and
OCF.sub.3; and E is O, N or S. Typically, E is selected from the
group consisting of O and S.
[0039] In another embodiment, the nematicide component comprises a
compound of
[0040] Formula Ib or a salt thereof,
##STR00005##
[0041] wherein R.sub.1 and R.sub.5 are independently selected from
the group consisting of hydrogen, CH.sub.3, F, Cl, Br, CF.sub.3 and
OCF.sub.3; R.sub.2 and R.sub.4 are independently selected from the
group consisting of hydrogen, F, Cl, Br, and CF.sub.3; R.sub.3 is
selected from the group consisting of hydrogen, CH.sub.3, CF.sub.3,
F, Cl, Br, OCF.sub.3, OCH.sub.3, CN, and C(H)O; R.sub.5 is selected
from hydrogen and F; R.sub.6 and R.sub.9 are independently selected
from the group consisting of hydrogen, F, Cl, CH.sub.3, and
OCF.sub.3; and E is N, O or S. Typically, E is selected from the
group consisting of O and S.
[0042] In another embodiment, the nematicide component comprises a
3,5-disubstituted-1,2,4-oxadiazole of Formula II or a salt
thereof,
##STR00006##
[0043] wherein A is selected from the group consisting of phenyl,
pyridyl, pyrazyl, oxazolyl and isoxazolyl, each of which can be
optionally independently substituted with one or more substituents
selected from the group consisting of halogen, CF.sub.3, CH.sub.3,
OCF.sub.3, OCH.sub.3, CN, and C(H)O; and C is selected from the
group consisting of thienyl, furanyl, oxazolyl and isoxazolyl, each
of which can be optionally independently substituted with one or
more with substituents selected from the group consisting of F, Cl,
CH.sub.3, and OCF.sub.3.
[0044] In a more specific embodiment, the nematicide component
comprises a compound of Formula IIa or a salt thereof,
##STR00007##
[0045] wherein R.sub.1 and R.sub.5 are independently selected from
the group consisting of hydrogen, CH.sub.3, F, Cl, Br, CF.sub.3 and
OCF.sub.3; R.sub.2 and R.sub.4 are independently selected from the
group consisting of hydrogen, F, Cl, Br, and CF.sub.3; R.sub.3 is
selected from the group consisting of hydrogen, CH.sub.3, CF.sub.3,
F, Cl, Br, OCF.sub.3, OCH.sub.3, CN, and C(H)O; R.sub.7 and R.sub.5
are independently selected from hydrogen and F; R.sub.9 is selected
from the group consisting of hydrogen, F, Cl, CH.sub.3, and
OCF.sub.3; and E is N, O or S. Typically, E is selected from the
group consisting of O and S.
[0046] In another embodiment, the nematicide component comprises a
compound of Formula IIb or a salt thereof,
##STR00008##
[0047] wherein R.sub.1 and R.sub.5 are independently selected from
the group consisting of hydrogen, CH.sub.3, F, Cl, Br, CF.sub.3 and
OCF.sub.3; R.sub.2 and R.sub.4 are independently selected from the
group consisting of hydrogen, F, Cl, Br, and CF.sub.3; R.sub.3 is
selected from the group consisting of hydrogen, CH.sub.3, CF.sub.3,
F, Cl, Br, OCF.sub.3, OCH.sub.3, CN, and C(H)O; R.sub.5 is selected
from hydrogen and F; R.sub.6 and R.sub.9 are independently selected
from the group consisting of hydrogen, F, Cl, CH.sub.3, and
OCF.sub.3; and E is N, O or S. Typically, E is selected from the
group consisting of O and S.
[0048] In a preferred embodiment, the nematicidal component
comprises a 3,5-disubstituted-1,2,4-oxadiazole of Formula (Ia) or a
salt thereof. Non-limiting examples of species include
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole of Formula (Ia-i),
##STR00009##
3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole of Formula
(Ia-ii),
##STR00010##
3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole of
Formula (Ia-iii),
##STR00011##
[0049] and 5-(furan-2-yl)-3-phenyl-1,2,4-oxadiazole of Formula
(Ia-iv).
##STR00012##
[0050] In another embodiment, the nematicidal component comprises a
3,5-disubstituted-1,2,4-oxadiazole of Formula (Ib) or a salt
thereof. Non-limiting examples of species include
3-(4-bromophenyl)-5-(furan-3-yl)-1,2,4-oxadiazole of Formula
(Ib-i),
##STR00013##
and 3-(2,4-difluorophenyl)-5-(thiophen-3-yl)-1,2,4-oxadiazole of
Formula (Ib-ii).
##STR00014##
[0051] In another embodiment, the nematicidal component comprises a
3,5-disubstituted-1,2,4-oxadiazole of Formula (IIa) or a salt
thereof. Non-limiting examples of species include
3-(thiophen-2-yl)-5-(p-tolyl)-1,2,4-oxadiazole of Formula
(IIa-i),
##STR00015##
5-(3-chlorophenyl)-3-(thiophen-2-yl)-1,2,4-oxadiazole of Formula
(IIa-ii),
##STR00016##
and 5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-1,2,4-oxadiazole of
Formula (IIa-iii).
##STR00017##
[0052] Polymorphs of the Nematicidal Compounds
[0053] The aqueous suspension concentrate composition can comprise
any of the polymorphic forms of the nematicidal compounds described
herein.
[0054] Generally, polymorphism refers to the potential of a
chemical entity to exist in different three-dimensional
arrangements in the solid state. Different polymorphic forms of a
compound can have different physical properties, including:
solubility and dissolution rate; crystal shape; solid state
stability; batch-to-batch manufacturing reproducibility; stability;
ease of formulation; and bioavailability, among others. In deciding
which polymorph of a given compound is preferable for a specific
application, the relevant properties of each polymorph should be
determined and compared, so that the polymorph with the most
desirable combination of attributes can be selected for use.
[0055] For example, it has been discovered that the nematicidal
compound 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole, referred to
herein as the compound of Formula (Ia-i), exists in two distinct
polymorphic forms, referred to herein as Form I and Form II. Form I
is believed to be the thermodynamically stable form under ambient
conditions, while Form II is metastable at room temperature and
pressure. The polymorphs are enantiotropically related. The
transition temperature between the two forms is believed to be
approximately 102.degree. C., wherein Form I is the stable form
below the transition temperature, and Form II is the more
thermodynamically stable form above that temperature.
[0056] Form I is believed to correspond to a dry crystalline
polymorphic form of the compound. Generally, Form I does not appear
to be prone to hydrate formation. Microscopic evaluation of Form I
showed birefringent acicular to columnar shaped particles ranging
from approximately 50 to 100 microns in length. FIG. 1 shows the
representative photomicrograph at room temperature.
[0057] Form II is also believed to correspond to a dry crystalline
polymorphic form of the compound. Microscopic evaluation of Form II
showed birefringent acicular, columnar, and flake shaped particles
ranging from approximately 25 to 150 microns in length. FIG. 2
shows the representative photomicrograph at room temperature.
[0058] Generally, the aqueous suspension concentrate composition
can comprise any of the polymorphic forms of the nematicidal
compounds described herein. For example, in one embodiment, the
suspension concentrate composition comprises polymorphic Form I of
the compound of Formula (Ia-i). In another embodiment, the
suspension concentrate composition comprises polymorphic Form II of
the compound of Formula (Ia-i). Mixtures of more than one polymorph
are also considered to be within the scope of the invention. For
example, in one embodiment, the suspension concentrate composition
comprises a mixture of polymorphic forms I and II of the compound
of Formula (Ia-i).
[0059] Concentration
[0060] The suspension concentrate composition in some embodiments
comprises at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about .sub.30%, at least about
.sub.35%, at least about 40%, at least about 45%, or at least about
50% by weight of the nematicide component comprising one or more
active nematicidal compounds as described above. In one embodiment,
the suspension concentrate composition comprises at least about 40%
by weight of the nematicide component. In some embodiments, the
suspension concentrate composition comprises at least about 45% by
weight of the nematicide component, or even higher (e.g., at least
about 50% by weight).
[0061] The suspension concentrate composition comprises the
nematicide component in a concentration of at least about 100 g/L,
at least about 200 g/L, at least about 250 g/L, at least about
.sub.300 g/L, at least about .sub.350 g/L, at least about 400 g/L,
at least about 450 g/L, at least about 500 g/L, at least about 550
g/L, at least about 600 g/L, at least about 650 g/L, or at least
about 700 g/L. The nematicide concentration ranges from about 400
g/L to about 700 g/L, from about 450 g/L to about 750 g/L, or from
about 450 g/L to about 700 g/L.
[0062] Particle Size
[0063] The suspension concentrate compositions of the present
invention comprise a continuous aqueous phase and a dispersed solid
phase comprising solid particulates of the nematicide component as
described herein. The solid nematicidal particulates have a
particle size distribution selected to enhance dispersibility of
the particles suspended in the composition and improve the
stability of the suspension concentrate composition.
[0064] It has been discovered, however, that further reductions in
particle size provide a number of benefits, including improved
adhesion characteristics of the 3,5-disubstituted-1,2,4-oxadiazole
compounds when the composition is applied as a seed treatment. The
particle size reduction described herein provides enhanced adhesion
of the nematicidal active ingredient to the seed surface when the
composition is applied as a seed treatment and thereby allows for
efficient production of treated seeds having a uniform active
loading. Furthermore, and without being bound to a particular
theory, it is believed that further reducing the particulate size
of the 3,5-disubstituted-1,2,4-oxadiazole compounds facilitates
improved dispersibility of the solid nematicidal active within the
aqueous environment of the root zone after planting the treated
seed in the soil. Dispersion of the nematicide throughout the
surrounding root zone helps prevent soil nematodes from coming into
contact with the seed and, later, the newly formed roots of the
plant emerging from the seed, and ultimately manifests as an
improvement in nematicidal efficacy (i.e., a reduction in plant
damage attributable to nematodes).
[0065] In the preparation of suspension concentrates, there are
considerable energy costs and time requirements associated with
reducing the particle size of the solid phase. These costs tend to
increase significantly as the particle size decreases. Accordingly,
efficient production of suspension concentrates must take into
account the additional costs and benefits associated with the
particle size reduction step.
[0066] Accordingly, the particle size characteristics of the
dispersed solid phase of the suspension concentrate composition
comprising the 3,5-disubstituted-1,2,4-oxadiazole compounds
described above are selected so as to not only provide a stable
suspension, but also to allow for efficient production of treated
seeds having a uniform active loading and enhanced nematicidal
efficacy. More particularly, the dispersed solid phase of the
suspension concentrate has a median particle size less than about
10 .mu.m, less than about 5 .mu.m, less than about 4 .mu.m, less
than about 3 .mu.m, less than about 2 .mu.m, or less than about 1
.mu.m. The suspension concentrate composition typically has a
median particle size falling within the range of from about 0.5
.mu.m to about 10 .mu.m, from about 1 .mu.m to about 5 .mu.m, from
about 1 .mu.m to about 4 .mu.m, from about 1 .mu.m to about 3
.mu.m, or from about 1 .mu.m to about 2 .mu.m. In some embodiments,
the median particle size falls within the range of from about 0.5
.mu.m to about 5 .mu.m, from about 0.5 .mu.m to about 4 .mu.m, from
about 0.5 .mu.m to about 3 .mu.m, from about 0.5 .mu.m to about 2
.mu.m, or from about 0.5 .mu.m to about 1 .mu.m. In one embodiment,
the median particle size falls within the range of from about 1
.mu.m to about 2 .mu.m.
[0067] The dispersed solid phase of the suspension concentrate
composition typically has a mean particle size less than about 20
.mu.m, less than about 10 .mu.m, less than about 5 .mu.m, less than
about 4 .mu.m, less than about 3 .mu.m, less than about 2 .mu.m, or
less than about 1 .mu.m. The mean particle size typically falls
within the range of from about 0.5 .mu.m to about 20 .mu.m, from
about 0.5 .mu.m to about 10 .mu.m, from about 1 .mu.m to about 5
.mu.m, from about 1 .mu.m to about 4 .mu.m, from about 1 .mu.m to
about 3 .mu.m, or from about 1 .mu.m to about 2 .mu.m. In some
embodiments, the mean particle size falls within the range of from
about 0.5 .mu.m to about 5 .mu.m, from about 0.5 .mu.m to about 4
.mu.m, from about 0.5 .mu.m to about 3 .mu.m, from about 0.5 .mu.m
to about 2 .mu.m, or from about 0.5 .mu.m to about 1 .mu.m.
[0068] The mean and/or median particle size of the solid
particulates in the dispersed phase can be determined by means
known in the art, including laser diffraction particle size
analysis. A non-limiting example of a suitable apparatus for
determining the particle size characteristics of the solid
particulates is a BECKMAN COULTER LS Particle Size Analyzer (model
LS 13 320).
[0069] The dispersed solid phase of the suspension concentrate
typically has a polydispersity index, defined as the arithmetic
mean particle size divided by the median particle size, of less
than about 10. In some embodiments, the polydispersity index is
less than about 5, less than about 2, or less than about 1.5. The
polydispersity index typically falls within the range of from about
1 to about 2.
[0070] Dispersant
[0071] The suspension concentrate composition additionally
comprises a dispersant component comprising one or more dispersants
selected to enhance dispersibility of the solid particles suspended
in the composition and improve the stability of the suspension
concentrate composition. The dispersant may be selected from
non-ionic dispersants, anionic dispersants, or cationic
dispersants.
[0072] In a preferred embodiment, the dispersant is anionic.
Examples of anionic dispersants include alkyl sulfates, alcohol
sulfates, alcohol ether sulfates, alpha olefin sulfonates,
alkylaryl ether sulfates, arylsulfonates, alkylsulfonates,
alkylaryl sulfonates, sulfosuccinates, mono- or diphosphate esters
of polyalkoxylated alkyl alcohols or alkyl phenols, mono- or
disulfosuccinate esters of alcohols or polyalkoxylated alkanols,
alcohol ether carboxylates, phenol ether carboxylates.
[0073] In one embodiment, the dispersant is an alkylaryl sulfonate.
Alkylaryl sulfonates have been found to be effective at forming a
stable aqueous suspension comprising the
3,5-disubstituted-1,2,4-oxadiazole compounds used in the practice
of the present invention, particularly at high concentrations of
the nematicidal active ingredient.
[0074] Non-limiting examples of commercially available anionic
dispersants include sodium dodecylsulfate (Na-DS, SDS), MORWET
D-425 (a sodium salt of alkyl naphthalene sulfonate condensate,
available from Akzo Nobel), MORWET D-500 (a sodium salt of alkyl
naphthalene sulfonate condensate with a block copolymer, available
from Akzo Nobel), sodium dodecylbenzene sulfonic acid (Na-DBSA)
(available from Aldrich), diphenyloxide disulfonate, naphthalene
formaldehyde condensate, DOWFAX (available from Dow),
dihexylsulfosuccinate, and dioctylsulfosuccinate, alkyl naphthalene
sulfonate condensates, and salts thereof
[0075] Examples of non-ionic dispersants include sorbitan esters,
ethoxylated sorbitan esters, alkoxylated alkylphenols, alkoxylated
alcohols, block copolymer ethers, and lanolin derivatives. In
accordance with one embodiment, the dispersant comprises an
alkylether block copolymer.
[0076] Non-limiting examples of commercially available non-ionic
dispersants include SPAN 20, SPAN 40, SPAN 80, SPAN 65, and SPAN 85
(available from Aldrich); TWEEN 20, TWEEN 40, TWEEN 60, TWEEN 80,
and TWEEN 85 (available from Aldrich); IGEPAL CA-210, IGEPAL
CA-520, IGEPAL CA-720, IGEPAL CO-210, IGEPAL CO-520, IGEPAL CO-630,
IGEPAL CO-720, IGEPAL CO-890, and IGEPAL DM-970 (available from
Aldrich); Triton X-100 (available from Aldrich); BRIJ S10, BRIJ
S20, BRIJ 30, BRIJ 52, BRIJ 56, BRIJ 58, BRIJ 72, BRIJ 76, BRIJ 78,
BRIJ 92V, BRIJ 97, and BRIJ 98 (available from Aldrich); PLURONIC
L-31, PLURONIC L-35, PLURONIC L-61, PLURONIC L-81, PLURONIC L-64,
PLURONIC L-121, PLURONIC 10R.sub.5, PLURONIC 17R.sub.4, and
PLURONIC 31R.sub.1 (available from Aldrich); Atlas G-5000 and Atlas
G-5002L (available from Croda); ATLOX 4912 and ATLOX 4912-SF
(available from Croda); and SOLUPLUS (available from BASF), LANEXOL
AWS (available from Croda).
[0077] Non-limiting examples of cationic dispersants include mono
alkyl quaternary amine, fatty acid amide surfactants, amidoamine,
imidazoline, and polymeric cationic surfactants.
[0078] The suspension concentrate composition comprises from about
0.5% about 20%, from about 0.5% to about 10%, from about 0.5% to
about 5%, or from about 0.5% to about 8% of the dispersant
component by weight. In one embodiment, the composition comprises
the dispersant in an amount of from about 0.5% to about 5% by
weight.
[0079] The suspension concentrate composition may comprise the
dispersant in a concentration of at least about 5 g/L, at least
about 10 g/L, at least about 15 g/L, at least about 20 g/L, at
least about 25 g/L, at least about 30 g/L, at least about 35 g/L,
at least about 40 g/L, at least about 45 g/L, or at least about 50
g/L. In some embodiments, the dispersant is present in a
concentration of from about 1 to about 100 g/L, from about 5 to
about 75 g/L, or more typically from about 20 to about 50 g/L.
[0080] In some embodiments, the suspension concentrate composition
comprises a dispersant component comprising a primary dispersant in
combination with one or more secondary dispersants. The secondary
dispersant may also be referred to herein as a wetting agent.
[0081] In one embodiment, the secondary dispersant is non-ionic
when used in conjunction with an ionic primary dispersant. For
example, in some embodiments, the dispersant component comprises a
mixture of an anionic primary dispersant (described above) and a
non-ionic (described above) secondary dispersant. In other
embodiments, the dispersant component comprises a mixture of a
cationic primary dispersant and a non-ionic secondary dispersant.
In accordance with another embodiment, it has been found that the
pairing of an anionic primary dispersant with a non-ionic secondary
dispersant, in particular, imparts improved stability to the
aqueous suspension concentrates described herein.
[0082] The secondary dispersant typically comprises from about
0.05% to about 10%, from about 0.5% to about 5%, from about 1% to
about 5%, from about 1% to about 4%, or from about 1% to about 2.5%
by weight of the composition.
[0083] The composition typically comprises a ratio of primary
dispersant to secondary dispersant, on a weight basis, of from
about 1:1 to about 10:1, from about 1:1 to about 5:1, and from
about 2:1 to about 3:1.
[0084] Dendrimers
[0085] In some embodiments, the composition may further comprise
one or more functionalized dendrimers to enhance the efficacy
and/or stability of the composition. Non-limiting examples of
classes of functionalized dendrimers include poly(amidoamine)
(PAMAM, Generations 0-7), poly(amidoamine-organosilicone)
(PAMAMOS), poly(propylene imidine) (PPI, Generations 0-5),
poly(benzylethers) (Frechet-type), Arobols (Newkome type),
poly(phenylacetylenes) and surface engineered dendrimers (e.g.
PEGylated dendrimers, glycodendrimers, peptide funtionalized
dendrimers, and galabiose-functionalized dendrimers). In some
embodiments, the dendrimers comprise at least about 0.1% and up to
10% or more, or from about 1% to about 10% by weight of the
composition.
[0086] Antifreeze Agents
[0087] In some embodiments, the composition may further comprise
one or more antifreeze agents. In one embodiment, the antifreeze
agent is an alcohol. Non-limiting examples of antifreeze agents
include ethylene glycol, propylene glycol, butanediol, pentanediol,
mannitol, sorbitol, and glycerol (glycerin).
[0088] The suspension concentrate composition may comprise the
antifreeze agent in a concentration of at least about 5 g/L, at
least about 10 g/L, at least about 15 g/L, at least about 20 g/L,
at least about 30 g/L, at least about 40 g/L, at least about 50
g/L, at least about 60 g/L, at least about 70 g/L, or at least
about 80 g/L. The antifreeze agent is typically present in a
concentration of from about 1 to about 150 g/L, from about 10 to
about 100 g/L, or more typically from about 20 to about 80 g/L.
[0089] Antifoam Agents
[0090] In some embodiments, the composition may further comprise
one or more antifoam agents. Examples of antifoam agents include
organosilicone or silicone-free compounds. Non-limiting examples of
commercially available antifoam products include Break-Thru 0E441
(available from Evonik), Break-Thru AF9905 (available from Evonik),
AGNIQUE DF 6889 (available from Cognis), AGNIQUE DFM 111S
(available from Cognis), BYK-016 (available from BYK), FG-10
antifoam emulsion (available from Dow Corning), 1520-US (available
from Dow Corning), 1510-US (available from Dow Corning), SAG 1538
(available from Momentive), and SAG 1572 (available from
Momentive).
[0091] Buffer
[0092] In some embodiments, the composition may comprise a buffer
solution that helps maintain the pH within a desired range. It has
been discovered that, at a pH greater than about 10, wet milling
and/or ball milling the nematicidal compounds described herein
results in excessive clumping and/or agglomeration, making particle
size reduction difficult and potentially causing damage to the
milling equipment. As a result, a pH buffer is typically selected
to provide an aqueous suspension concentrate composition having a
pH of less than 10, typically from about 5 to about 9, more
typically from about 6 to about 8, and most typically about 7.
Buffer solutions suitable for a variety of pH ranges are generally
known in the art.
[0093] Stabilizer
[0094] In some embodiments, the composition may comprise a
thickener (referred to hereinafter as "stabilizer") component.
Examples of stabilizers include anionic polysaccharides and
cellulose derivatives. In some embodiments, the stabilizer
comprises a clay or a silica, or a colloidal hydrophilic silica.
Non-limiting examples of commercially available stabilizers include
KELZAN CC (available from Kelco), methyl cellulose,
carboxymethylcellulose and 2-hydroxyethylcellulose,
hydroxymethylcellulose, kaolin, and microcrystalline cellulose. A
non-limiting example of a commercially available colloidal
hydrophilic silica is AEROSIL (available from Evonik).
[0095] The stabilizer component typically comprises from about
0.05% to about 10% by weight of the composition. For example, in
some embodiments, the stabilizer component comprises from about
0.1% to about 5%, from about 0.1% to about 2%, or from about 0.1%
to about 1% by weight of the composition.
[0096] Crystallization Inhibitor
[0097] In some embodiments, the composition may comprise a
crystallization inhibitor. Exemplary crystallization inhibitors
include acrylic copolymers, polyethylene glycol, polyethylene
glycol hydrogenated castor oil and combinations.
[0098] The crystallization inhibitor component typically comprises
from about 1% to about 10% by weight of the composition.
[0099] Co-Solvent
[0100] In some embodiments, the composition may further comprise a
co-solvent in addition to water. Non-limiting examples of
co-solvents that can be used include, ethyl lactate, methyl
soyate/ethyl lactate co-solvent blends (e.g., STEPOSOL, available
from Stepan), isopropanol, acetone, 1,2-propanediol,
n-alkylpyrrolidones (e.g., the AGSOLEX series, available from ISP),
a petroleum based-oil (e.g., AROMATIC series and SOLVESSO series
available from Exxon Mobil), isoparaffinic fluids (e.g. ISOPAR
series, available from Exxon Mobil), cycloparaffinic fluids (e.g.
NAPPAR 6, available from Exxon Mobil), mineral spirits (e.g. VARSOL
series available from Exxon Mobil), and mineral oils (e.g.,
paraffin oil).
[0101] Non-limiting examples of preferred commercially available
organic solvents include pentadecane, ISOPAR M, and ISOPAR V and
ISOPAR L (available from Exxon Mobil).
[0102] Viscosity Modifying Agent
[0103] In some embodiments, the composition may further comprise
one or more viscosity modifying agents.
[0104] Examples of viscosity modifying agents include humic acid
salts, fulvic acid salts, humin, and lignin salts.
[0105] In one embodiment, the viscosity modifying agent is the
sodium or potassium salt of humic acid. Generally, a humic
substance is one produced by biodegradation of dead organic matter,
particularly dead plant matter (e.g., lignin). With respect to the
compositions of the present invention, it has been discovered that
compositions comprising a humic acid exhibit a lower viscosity than
similarly-loaded compositions in the absence of a humic acid.
Fulvic acids, which are humic acids of lower molecular weight and
higher oxygen content than other humic acids, are used in some
embodiments.
[0106] Additional Excipients
[0107] In some embodiments, composition comprises one or more
additional excipients that improve the adhesion of the composition
to the seed, provide a visual indication of successful coating
(e.g., coloring agents), or otherwise impart improved
characteristics to the coating.
[0108] Biocidal Agents
[0109] In some embodiments, the composition may further comprise
one or more biocidal agents. Typically, a biocidal component is
included to prevent fungal and/or bacterial growth within the
suspension concentrate composition, particularly when the
composition is placed into storage. Examples of biocidal agents
include dichlorophen or benzyl alcohol hemiformal based compounds,
benzoisothiazolinones and rhamnolipids. Non-limiting examples of
commercially available biocidal agents include ACTICIDE (available
from THOR), PROXEL (available from Arch Chemical), and ZONIX
(available from Jeneil).
[0110] Additional Active Ingredients
[0111] In some embodiments, the composition may be formulated,
mixed in a seed treater tank or combined on the seed by overcoating
with one or more additional active ingredients in combination with
the nematicidal 3,5-disubstituted-1,2,4-oxadiazoles described
herein.
[0112] The additional active ingredient may be, for example, an
additional pesticide. The pesticide may be, for example, an
insecticide, a fungicide, an herbicide, or an additional
nematicide.
[0113] Non-limiting examples of insecticides and nematicides
include carbamates, diamides, macrocyclic lactones, neonicotinoids,
organophosphates, phenylpyrazoles, pyrethrins, spinosyns, synthetic
pyrethroids, tetronic and tetramic acids. In particular embodiments
insecticides and nematicides include abamectin, aldicarb,
aldoxycarb, bifenthrin, carbofuran, chlorantraniliporle,
chlothianidin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin,
dinotefuran, emamectin, ethiprole, fenamiphos, fipronil,
flubendiamide, fosthiazate, imidacloprid, ivermectin,
lambda-cyhalothrin, milbemectin, nitenpyram, oxamyl, permethrin,
spinetoram, spinosad, spirodichlofen, spirotetramat, tefluthrin,
thiacloprid, thiamethoxam, and thiodicarb,
[0114] Non-limiting examples of useful fungicides include aromatic
hydrocarbons, benzimidazoles, benzthiadiazole, carboxamides,
carboxylic acid amides, morpholines, phenylamides, phosphonates,
quinone outside inhibitors (e.g. strobilurins), thiazolidines,
thiophanates, thiophene carboxamides, and triazoles. Particular
examples of fungicides include acibenzolar-S-methyl, azoxystrobin,
benalaxyl, bixafen, boscalid, carbendazim, cyproconazole,
dimethomorph, epoxiconazole, fluopyram, fluoxastrobin, flutianil,
flutolanil, fluxapyroxad, fosetyl-Al, ipconazole, isopyrazam,
kresoxim-methyl, mefenoxam, metalaxyl, metconazole, myclobutanil,
orysastrobin, penflufen, penthiopyrad, picoxystrobin,
propiconazole, prothioconazole, pyraclostrobin, sedaxane,
silthiofam, tebuconazole, thifluzamide, thiophanate,
tolclofos-methyl, trifloxystrobin, and triticonazole.
[0115] Non-limiting examples of herbicides include ACCase
inhibitors, acetanilides, AHAS inhibitors, carotenoid biosynthesis
inhibitors, EPSPS inhibitors, glutamine synthetase inhibitors, PPO
inhibitors, PS II inhibitors, and synthetic auxins, Particular
examples of herbicides include acetochlor, clethodim, dicamba,
flumioxazin, fomesafen, glyphosate, glufosinate, mesotrione,
quizalofop, saflufenacil, sulcotrione, and 2,4-D.
[0116] Additional actives may also comprise substances such as,
biological control agents, microbial extracts, natural products,
plant growth activators or plant defense agents. Non-limiting
examples of biological control agents include bacteria, fungi,
beneficial nematodes, and viruses.
[0117] In certain embodiments, the biological control agent can be
a bacterium of the genus Actinomycetes, Agrobacterium,
Arthrobacter, Alcaligenes, Aureobacterium, Azobacter, Beijerinckia,
Brevibacillus, Burkholderia, Chromobacterium, Clostridium,
Clavibacter, Comomonas, Corynebacterium, Curtobacterium,
Enterobacter, Flavobacterium, Gluconobacter, Hydrogenophage,
Klebsiella, Methylobacterium, Paenibacillus, Pasteuria,
Phingobacterium, Photorhabdus, Phyllobacterium, Pseudomonas,
Rhizobium, Serratia, Stenotrophomonas, Variovorax, and
Xenorhadbus,. In particular embodiments the bacteria is selected
from the group consisting of Bacillus amyloliquefaciens, Bacillus
cereus, Bacillus firmus, Bacillus, lichenformis, Bacillus pumilus,
Bacillus sphaericus, Bacillus subtilis, Bacillus thuringiensis,
Chromobacterium suttsuga, Pasteuria penetrans, Pasteuria usage, and
Pseudomona fluorescens.
[0118] In certain embodiments the biological control agent can be a
fungus of the genus Alternaria, Ampelomyces, Aspergillus,
Aureobasidium, Beauveria, Colletotrichum, Coniothyrium,
Gliocladium, Metarhisium, Muscodor, Paecilonyces, Trichoderma,
Typhula, Ulocladium, and Verticilium. In particular embodiments the
fungus is Beauveria bassiana, Coniothyrium minitans, Gliocladium
virens, Muscodor albus, Paecilomyces lilacinus, or Trichoderma
polysporum.
[0119] In further embodiments the biological control agents can be
plant growth activators or plant defense agents including, but not
limited to harpin, Reynoutria sachalinensis, jasmonate,
lipochitooligosaccharides, and isoflavones.
[0120] Methods of Preparation
[0121] Another aspect of the present invention is directed to
methods of preparing the nematicidal suspension concentrate
compositions described herein.
[0122] As described above, it has been discovered that significant
benefits in the aqueous dispersibility of
3,5-disubstituted-1,2,4-oxadiazoles can be obtained and other
advantages realized by reducing the particulate size of the solid
phase in the suspension concentrate composition. Generally, the
particulate size of the nematicide component may be reduced by any
method known in the art. In accordance with one preferred
embodiment, the particle size of the nematicide component is
reduced by wet milling. Additionally, air milling, high pressure
homogenization, spinning disc, grinding and solvent evaporation
techniques can be used to reduce the particle size of the
nematicide component.
[0123] Typically, the first step in the process comprises a
pre-milling step wherein the nematicidal component comprising one
or more active nematicidal compounds is combined with water and
agitated to form an aqueous suspension. Typically, the dispersant
is also added to the aqueous suspension prior to the particle size
reduction step and acts as a wet-milling aid. Other optional
components which may be added to the aqueous suspension before the
particle size reduction step include a secondary dispersant and/or
an antifreeze agent, each of which may be selected as described
above. Additionally, in one embodiment, a buffer solution is added
to the suspension prior to the particle size reduction step; as
discussed above, the pH of the suspension during the particle size
reduction step is preferably less than 10 in order to minimize
clumping and/or agglomeration of the solid particulates.
[0124] The aqueous suspension is then wet-milled to obtain a
suspension concentrate having the desired particle size
distribution as described above. The wet-milling process may be
carried out using techniques and apparatus known in the art. Ball
milling is a particularly preferred technique, wherein the aqueous
suspension is placed inside a rotating cylinder containing grinding
media. The grinding media are preferably selected from the group
consisting of stainless steel beads, zirconium beads, glass beads
and ceramic beads. Non-limiting examples of suitable ball milling
apparatus include a SIZEGVARI ATTRITOR milling system made by UNION
PROCESS, and a MINI ZETA II milling machine made by Netzsch.
[0125] The wet-milling step typically produces a fine suspension
comprising a dispersed solid phase having a particle size
distribution characterized by the median and mean particle sizes
and polydispersity index described above. Using laser diffraction
particle size analysis or other suitable means, the duration and
intensity of the wet-milling operation is controlled to provide a
suspension concentrate composition having the desired particle size
characteristics.
[0126] Following the particle size reduction, the milled aqueous
suspension may be combined with an optional stabilizer component
and/or one or more additional biocidal agents, each of which may be
selected as described above.
[0127] Storage Stability
[0128] In one embodiment, the aqueous suspension concentrate
composition described herein exhibits commercially acceptable
storage stability across a wide range of temperatures and
environmental conditions. In this context, storage stability is
generally defined as the absence of sedimentation and the lack of
any significant change in the rheological properties of the
composition (e.g., viscosity). Commercially acceptable storage
stability can be reliably achieved by selecting the various
components of the aqueous suspension concentrate, particularly the
primary dispersant, optional secondary dispersant, and/or optional
stabilizer component, in accordance with the respective embodiments
described in detail above. The suspension concentrate composition
may be storage-stable at 25.degree. C. for at least about 1 week,
at least about 2 weeks, at least about 1 month, at least about 2
months, at least about 3 months, at least about 6 months, at least
about 12 months or at least about 18 months.
[0129] Methods of Application
[0130] Another aspect of the present invention is directed to
methods for protecting the roots of a plant against damage by
nematodes.
[0131] Application to Seeds
[0132] In one embodiment, the method comprises protecting a seed,
and/or the roots of a plant grown from the seed, against damage by
a nematode by treating the seed with a seed treatment composition
described herein and diluted as necessary to attain the desired
nematicide compound loading on the treated seeds.
[0133] The methods described herein can be used in connection with
any species of plant and/or the seeds thereof. In preferred
embodiments, however, the methods are used in connection with seeds
of plant species that are agronomically important. In particular,
the seeds can be of corn, peanut, canola/rapeseed, soybean,
cucurbits, crucifers, cotton, beets, rice, sorghum, sugar beet,
wheat, barley, rye, sunflower, tomato, sugarcane, tobacco, oats, as
well as other vegetable and leaf crops. In some embodiments, the
seed is corn, soybean, or cotton seed. The seed may be a transgenic
seed from which a transgenic plant can grow and incorporate a
transgenic event that confers, for example, tolerance to a
particular herbicide or combination of herbicides, increased
disease resistance, enhanced tolerance to stress and/or enhanced
yield. Transgenic seeds include, but are not limited to, seeds of
corn, soybean and cotton.
[0134] In one embodiment, the treatment composition is applied to
the seed prior to sowing the seed so that the sowing operation is
simplified. In this manner, seeds can be treated, for example, at a
central location and then dispersed for planting. This permits the
person who plants the seeds to avoid the complexity and effort
associated with handling and applying the seed treatment
compositions, and to merely handle and plant the treated seeds in a
manner that is conventional for regular untreated seeds.
[0135] The seed treatment composition can be applied to seeds by
any standard seed treatment methodology, including but not limited
to mixing in a container (e.g., a bottle or bag), mechanical
application, tumbling, spraying, immersion, and solid matrix
priming. Seed coating methods and apparatus for their application
are disclosed in, for example, U.S. Pat. Nos. 5,918,413, 5,891,246,
5,554,445, 5,389,399, 5,107,787, 5,080,925, 4,759,945 and
4,465,017, among others. Any conventional active or inert material
can be used for contacting seeds with the seed treatment
composition, such as conventional film-coating materials including
but not limited to water-based film coating materials.
[0136] For example, in one embodiment, a seed treatment composition
can be introduced onto or into a seed by use of solid matrix
priming. For example, a quantity of the seed treatment composition
can be mixed with a solid matrix material and then the seed can be
placed into contact with the solid matrix material for a period to
allow the seed treatment composition to be introduced to the seed.
The seed can then optionally be separated from the solid matrix
material and stored or used, or the mixture of solid matrix
material plus seed can be stored or planted directly. Solid matrix
materials which are useful in the present invention include
polyacrylamide, starch, clay, silica, alumina, soil, sand,
polyurea, polyacrylate, or any other material capable of absorbing
or adsorbing the seed treatment composition for a time and
releasing the nematicide of the seed treatment composition into or
onto the seed. It is useful to make sure that the nematicide and
the solid matrix material are compatible with each other. For
example, the solid matrix material should be chosen so that it can
release the nematicide at a reasonable rate, for example over a
period of minutes, hours, days, or weeks.
[0137] Imbibition is another method of treating seed with the seed
treatment composition. For example, a plant seed can be directly
immersed for a period of time in the seed treatment composition.
During the period that the seed is immersed, the seed takes up, or
imbibes, a portion of the seed treatment composition. Optionally,
the mixture of plant seed and the seed treatment composition can be
agitated, for example by shaking, rolling, tumbling, or other
means. After imbibition, the seed can be separated from the seed
treatment composition and optionally dried, for example by patting
or air drying.
[0138] The seed treatment composition may be applied to the seeds
using conventional coating techniques and machines, such as
fluidized bed techniques, the roller mill method, rotostatic seed
treaters, and drum coaters. Other methods, such as spouted beds may
also be useful. The seeds may be pre-sized before coating. After
coating, the seeds are typically dried and then transferred to a
sizing machine for sizing. Such procedures are generally known in
the art.
[0139] If the seed treatment composition is applied to the seed in
the form of a coating, the seeds can be coated using a variety of
methods known in the art. For example, the coating process can
comprise spraying the seed treatment composition onto the seed
while agitating the seed in an appropriate piece of equipment such
as a tumbler or a pan granulator.
[0140] In one embodiment, when coating seed on a large scale (for
example a commercial scale), the seed coating may be applied using
a continuous process. Typically, seed is introduced into the
treatment equipment (such as a tumbler, a mixer, or a pan
granulator) either by weight or by flow rate. The amount of
treatment composition that is introduced into the treatment
equipment can vary depending on the seed weight to be coated,
surface area of the seed, the concentration of the nematicide
and/or other active ingredients in the treatment composition, the
desired concentration on the finished seed, and the like. The
treatment composition can be applied to the seed by a variety of
means, for example by a spray nozzle or revolving disc. The amount
of liquid is typically determined by the assay of the formulation
and the required rate of active ingredient necessary for efficacy.
As the seed falls into the treatment equipment the seed can be
treated (for example by misting or spraying with the seed treatment
composition) and passed through the treater under continual
movement/tumbling where it can be coated evenly and dried before
storage or use.
[0141] In another embodiment, the seed coating may be applied using
a batch process. For example, a known weight of seeds can be
introduced into the treatment equipment (such as a tumbler, a
mixer, or a pan granulator). A known volume of seed treatment
composition can be introduced into the treatment equipment at a
rate that allows the seed treatment composition to be applied
evenly over the seeds. During the application, the seed can be
mixed, for example by spinning or tumbling. The seed can optionally
be dried or partially dried during the tumbling operation. After
complete coating, the treated sample can be removed to an area for
further drying or additional processing, use, or storage.
[0142] In an alternative embodiment, the seed coating may be
applied using a semi-batch process that incorporates features from
each of the batch process and continuous process embodiments set
forth above.
[0143] In still another embodiment, seeds can be coated in
laboratory size commercial treatment equipment such as a tumbler, a
mixer, or a pan granulator by introducing a known weight of seeds
in the treater, adding the desired amount of seed treatment
composition, tumbling or spinning the seed and placing it on a tray
to thoroughly dry.
[0144] In another embodiment, seeds can also be coated by placing
the known amount of seed into a narrow neck bottle or receptacle
with a lid. While tumbling, the desired amount of seed treatment
composition can be added to the receptacle. The seed is tumbled
until it is coated with the treatment composition. After coating,
the seed can optionally be dried, for example on a tray.
[0145] In some embodiments, the treated seeds may also be enveloped
with a film overcoating to protect the nematicidal coating. Such
overcoatings are known in the art and may be applied using
conventional fluidized bed and drum film coating techniques. The
overcoatings may be applied to seeds that have been treated with
any of the seed treatment techniques described above, including but
not limited to solid matrix priming, imbibition, coating, and
spraying, or by any other seed treatment technique known in the
art.
[0146] Application to Soil
[0147] In another aspect of the present invention, the nematicidal
treatment composition, diluted as necessary to attain the desired
nematicide compound loading, is directly applied to the soil
surrounding the root zone of a plant. The application may be
performed using any method or apparatus known in the art, including
pressurized spray application to the soil surface or injected in
the planting furrow, as well as chemigation via overhead sprinkler
or drip systems, transplant water treatments, and plant or root
dips prior to planting. The rates used for the suspension
concentrate formulations for soil application may require 0.5 to 2
kgs per hectare on a broadcast basis (rate per treated area if
broadcast or banded).
[0148] Treated Seeds
[0149] Another aspect of the present invention is directed to a
seed that has been treated with a nematicidal seed treatment
composition as described herein. Typically, the seed has been
treated with the seed treatment composition using one of the seed
treatment methods set forth above, including but not limited to
solid matrix priming, imbibition, coating, and spraying. The seed
may be of any plant species, as described above.
[0150] Typically, the treated seeds comprise the nematicidal
compound in an amount of at least about 0.05 mg/seed, more
typically from about 0.05 to about 1 mg/seed, and even more
typically from about 0.05 to about 0.5 mg/seed.
[0151] In some embodiments, wherein the composition comprises a
paraffinic hydrocarbon solvent, the loading of active ingredient
per treated seed can be significantly reduced without compromising
nematicidal efficacy. For example, when the seed treatment
composition comprises a paraffinic hydrocarbon solvent, the treated
seeds may comprise the nematicidal compound in an amount of less
than about 0.1 mg/seed, from about 0.01 to about 0.1 mg/seed, or
from about 0.02 to about 0.08 mg/seed.
[0152] The following examples are to be considered as merely
illustrative, and are not intended to limit the scope of this
invention.
EXAMPLES
[0153] Several active nematicidal compounds were combined with
selected dispersants and other excipients and used in preparation
of suspension concentrate compositions in the following examples.
The nematicidal compounds are identified in Table 1.
TABLE-US-00001 TABLE 1 Ia-i 3-phenyl-5-(thiophen-2-
yl)-1,2,4-oxadiazole ##STR00018## Ia-ii 3-(4-chlorophenyl)-5-
(furan-2-yl)-1,2,4- oxadiazole ##STR00019## Ia-iii
3-(4-chloro-2-methyl- phenyl)-5-(furan-2-yl)- 1,2,4-oxadiazole
##STR00020##
Example 1
Preparation of a Suspension Concentrate Comprising
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole (Ia-i)
[0154] A quantity of the nematicidal compound Ia-i (25.00 g) was
added to an aqueous solution of water (25.00 g), glycerin (2.15 g),
MORWET D-500 dispersant (0.32 g), and AGNIQUE DF 6889 antifoam
agent (0.05 g). The resulting mixture was milled with a SIZEGVARI
ATTRITOR milling system made by UNION PROCESS containing stainless
steel beads having a diameter of 1/8 inch in a 100 mL jacketed
metal container. The stirring speed was controlled by a VARIAC
variable autotransformer.
[0155] After milling the mixture for 1 hour 40 minutes at a speed
of 50v/140v, a white aqueous suspension (45.25 g) was collected.
The particle size characteristics of the suspension were analyzed
with a BECKMAN COULTER LS Particle Size Analyzer (model LS 13 320).
The results indicated a mean particle size of 4.896 .mu.m, with a
median particle size of 2.937 .mu.m. The suspension was determined
to contain 47.6% (w/w) of the Ia-i nematicide.
Example 2
Preparation of a Suspension Concentrate Comprising
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole (Ia-i)
[0156] A quantity of the nematicidal compound Ia-i (30.00 g) was
added to an aqueous solution of water (25.00 g), glycerin (3.00 g),
MORWET D-500 dispersant (0.60 g), and AGNIQUE DF 6889 antifoam
agent (0.05 g). The resulting mixture was milled with a SIZEGVARI
ATTRITOR milling system made by UNION PROCESS containing stainless
steel beads having a diameter of 1/8 inch in a 100 mL jacketed
metal container. The stirring speed was controlled by a VARIAC
variable autotransformer.
[0157] After milling the mixture for 1 hour 30 minutes at a speed
of 50v/140v, and an additional 2 hours 15 minutes at 40v/140v, a
white aqueous suspension (45.20 g) was collected. The suspension
was determined to contain 51.2% (w/w) of the Ia-i nematicide.
Example 3
Preparation of a Suspension Concentrate Comprising
3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole (Ia-ii)
[0158] A quantity of the nematicidal compound Ia-ii (34.00 g) was
added to an aqueous solution of water (25.00 g), glycerin (3.00 g),
MORWET D-500 dispersant (0.60 g), and AGNIQUE DF 6889 antifoam
agent (0.10 g). The resulting mixture was milled with a SIZEGVARI
ATTRITOR milling system made by UNION PROCESS containing stainless
steel beads having a diameter of 1/8 inch in a 100 mL jacketed
metal container. The stirring speed was controlled by a VARIAC
variable autotransformer.
[0159] After milling the mixture for 4 hours at a speed of
50v/140v, a white aqueous suspension (45.40 g) was collected. The
particle size characteristics of the suspension were analyzed with
a BECKMAN COULTER LS Particle Size Analyzer (model LS 13 320). The
results indicated a mean particle size of 4.58 .mu.m, with a median
particle size of 3.14 .mu.m. The suspension was determined to
contain 54.2% (w/w) of the Ia-ii nematicide.
Example 4
Preparation of a Suspension Concentrate Comprising
3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole
(Ia-iii)
[0160] A quantity of the nematicidal compound Ia-iii (34.00 g) was
added to an aqueous solution of water (25.00 g), glycerin (3.00 g),
MORWET D-500 dispersant (0.60 g), and AGNIQUE DF 6889 antifoam
agent (0.05 g). The resulting mixture was milled with a SIZEGVARI
ATTRITOR milling system made by UNION PROCESS containing stainless
steel beads having a diameter of 1/8 inch in a 100 mL jacketed
metal container. The stirring speed was controlled by a VARIAC
variable autotransformer.
[0161] After milling the mixture for 4 hours at a speed of
50v/140v, a white aqueous suspension (49.10 g) was collected. The
particle size characteristics of the suspension were analyzed with
a BECKMAN COULTER LS Particle Size Analyzer (model LS 13 320). The
results indicated a mean particle size of 3.217 .mu.m, with a
median particle size of 2.192 .mu.m. The suspension was determined
to contain 54.2% (w/w) of the Ia-iii nematicide.
Example 5
Preparation of a Suspension Concentrate Comprising
3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole (Ia-ii)
[0162] A quantity of the nematicidal compound Ia-ii (34.00 g) was
added to an aqueous solution of water (141.67 g), glycerin (17.00
g), and MORWET D-500 dispersant (3.40 g). The resulting mixture was
milled with a SIZEGVARI ATTRITOR milling system made by UNION
PROCESS containing stainless steel beads having a diameter of 1/8
inch in a 500 mL jacketed metal container. The stirring speed was
controlled by a VARIAC variable autotransformer.
[0163] After milling the mixture for 1 hour at a speed of 75v/140v,
a small amount of AGNIQUE DF 6889 antifoam agent (0.10 g) was
added. The mixture was then further stirred at 75v/140v for 45
minutes, and at 60v/140v for an additional 1 hour 45 minutes.
[0164] Following the milling process, a white aqueous suspension
(330.5 g) was collected from the container. The particle size
characteristics of the suspension were analyzed with a BECKMAN
COULTER LS Particle Size Analyzer (model LS 13 320). The results
indicated a mean particle size of 2.90 .mu.m, with a median
particle size of 1.74 .mu.m. The suspension was determined to
contain 52.8% (w/w) of the Ia-ii nematicide.
Example 6
Preparation of a Suspension Concentrate Comprising
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole (Ia-i)
[0165] A quantity of the nematicidal compound Ia-i (34.00 g) was
added to an aqueous solution of water (141.67 g), glycerin (17.00
g), and MORWET D-500 dispersant (3.40 g). The resulting mixture was
milled with a SIZEGVARI ATTRITOR milling system made by UNION
PROCESS containing stainless steel beads having a diameter of 1/8
inch in a 500 mL jacketed metal container. The stirring speed was
controlled by a VARIAC variable autotransformer.
[0166] After milling the mixture for 1 hour at a speed of 75v/140v,
a small amount of AGNIQUE DF 6889 antifoam agent (0.10 g) was
added. The mixture was then further milled at 75v/140v for 45
minutes and at 60v/140v for an additional 1 hour 45 minutes.
[0167] Following the milling process, a white aqueous suspension
(305.3 g) was collected from the container. The particle size
characteristics of the suspension were analyzed with a BECKMAN
COULTER LS Particle Size Analyzer (model LS 13 320). The results
indicated a mean particle size of 3.334 .mu.m, with a median
particle size of 2.071 .mu.m. The suspension was determined to
contain 52.8% (w/w) of the Ia-i nematicide.
Example 7
Effect of Milling Time on the Mean/Median Particle Size Diameter of
a Suspension Concentrate Comprising
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole (Ia-i)
[0168] A quantity of the nematicidal compound Ia-i (362.4 g) was
added to an aqueous solution of water (283.34 g), glycerin (34.00
g), and MORWET D-500 dispersant (6.80 g). The resulting mixture was
pre-milled with a dissolver apparatus at 1900 rpm for 20 minutes. A
portion of the resulting pre-milled slurry (60% of the total
volume) was added to a NETZSCH MINI ZETA II milling machine filled
with zirconium beads having a diameter of 1.6-2 mm. The slurry was
milled for 1 hour, after which a sample of the resulting white
slurry (250 g) was collected.
[0169] During the milling process, samples were periodically
extracted for analysis using a BECKMAN COULTER LS Particle Size
Analyzer (model LS 13 320). The resulting mean and median particle
diameters for each sample are summarized in Table 2 below:
TABLE-US-00002 TABLE 2 Milling Time (mins) Mean (.mu.m) Median
(.mu.m) Mean/Median 15 4.073 2.834 1.437 30 3.041 2.062 1.475 45
2.872 1.851 1.551 60 2.781 1.760 1.580
[0170] The final suspension was determined to contain 44.2% (w/w)
of the Ia-i nematicide. This example demonstrates that the mean
and/or median particle size of the formulation can be controlled as
a function of the total milling time.
Example 8
Preparation of Seed Treatment Compositions
[0171] Seed treatment compositions were prepared using the
suspension concentrate compositions prepared in Examples 2-4
above.
[0172] Composition 1: A seed treatment composition comprising the
nematicidal compound Ia-i was prepared by mixing a portion of the
composition prepared in Example 2 (8.00g) with CF CLEAR seed coat
polymer (0.30 g), BECKER-UNDERWOOD seed gloss (1.00 g), and
BECKER-UNDERWOOD red color coating (2.00 g).
[0173] Composition 2: A seed treatment composition comprising the
nematicidal compound Ia-iii was prepared by mixing a portion of the
composition prepared in Example 3 (18.40g) with CF CLEAR seed coat
polymer (0.69 g), BECKER-UNDERWOOD seed gloss (2.30 g), and
BECKER-UNDERWOOD red color coating (4.60 g).
[0174] Composition 3: A seed treatment composition comprising the
nematicidal compound Ia-ii was prepared by mixing a portion of the
composition prepared in Example 4 (18.40g) with CF CLEAR seed coat
polymer (0.69 g), BECKER-UNDERWOOD seed gloss (2.30 g), and
BECKER-UNDERWOOD red color coating (4.60 g).
Example 9
Treatment of Seeds with Nematicidal Compositions
[0175] Soybean seeds (2.2 kg) were added to a WILLY NIKLAUS GMBH
seed treating apparatus. The seeds were tumbled inside the treater
while a quantity of seed treatment formulation was added. To ensure
full dispersion of the treatment composition, seeds were allowed to
tumble for an additional 30 seconds before being collected.
[0176] The amount of seed treatment composition used in each
prepared sample was varied in accordance with the targeted amount
of active ingredient per seed. As shown in the table below, the
targeted amount ranged from 0.1 to 0.5 mg/seed for Ia-i, and from
0.1 to 1 mg/seed for Ia-iii and Ia-ii. The actual amount of active
ingredient per seed was analyzed upon removal from the seed
treatment apparatus. The results are summarized in the table below,
where the "Composition No." refers to the compositions 1-3 prepared
in Example 8.
TABLE-US-00003 TABLE 3 Targeted Actual Composi- Active Active
Amount of tion Active Loading Loading Composition No. Ingredient
(mg/seed) (mg/seed) (g) 1 Ia-i 0.1 0.07 0.98 1 Ia-i 0.3 0.22 2.94 1
Ia-i 0.5 0.37 4.90 3 Ia-ii 0.1 0.07 0.92 3 Ia-ii 0.3 0.25 2.77 3
Ia-ii 0.5 0.46 4.62 3 Ia-ii 0.0 0.83 9.24 2 Ia-iii 0.1 0.04 0.92 2
Ia-iii 0.3 0.21 2.77 2 Ia-iii 0.5 0.40 4.62 2 Ia-iii 0.0 0.65
9.24
[0177] The results indicate that, for each sample, a significant
portion of the active nematicidal ingredient added to the seed
treatment apparatus was successfully transferred to the seed.
Example 10
Preparation of Suspension Concentrate Compositions
[0178] An additional series of suspension concentrate compositions
were prepared using the procedures set forth below.
[0179] A stock buffer solution was prepared by adding anhydrous
monobasic potassium phosphate (9.361 g) and dibasic sodium
phosphate heptahydrate (32.732 g) to a 1 liter volumetric flask,
the balance of which was filled with deionized water. The flask was
shaken until the salts were fully dissolved, providing a clear
buffer solution with a pH of 7.
[0180] For each sample, a blank solution was then prepared by
combining MORWET D-425 dispersant, PLURONIC L-35 secondary
dispersant, propylene glycol, and a quantity of the stock buffer
solution as prepared above. The relative proportions of these
components in each sample, respectively, are provided in Table 4
below.
[0181] In the next step of the process, the blank solution was
mixed with a quantity of Ia-i nematicide and a small amount of
BYK-016 antifoam agent in a 1 liter beaker. The formulation was
then agitated with a Tekmar homogenizer at 9,000 rpm for 10 to 12
minutes, resulting in a slurry. The particle size of the pre-milled
slurry was measured with a BECKMAN COULTER LS Particle Size
Analyzer (model LS 13 320).
[0182] For formulation Sample A and Sample C the pre-milled slurry
was then added to a NETZSCH MINI ZETA II apparatus filled with
either glass or zirconium oxide beads (200 mL) equipped with
cooling water. After milling for 35 minutes, the resulting white
slurry was collected, and the particle size was measured as
described above. Formulation Sample B was pre-milled only to give a
median particle size of 5.8 .mu.m. The particle size can be reduced
further through optimization of the pre-milling process.
[0183] A stabilizer composition was prepared by adding KELZAN CC
stabilizing agent (4.00 g) and PROXEL GXL biocide (8.00 g) to
deionized water (388.00 g). After agitation with a mechanical
stirrer at room temperature for 30 minutes, a homogeneous viscous
liquid was obtained.
[0184] The milled slurry was then mixed with a stabilizer
composition in a 9:1 weight ratio to provide a flowable suspension
concentrate composition. A summary of three representative
composition samples prepared according to this process is provided
below:
TABLE-US-00004 TABLE 4 Sample A Sample B Sample C Ingredient (wt.
%) (wt. %) (wt. %) Ia-i 45.91 45.91 45.91 MORWET D-425 1.13 1.13
4.52 Propylene glycol 5.65 5.65 5.65 Water 35.99 35.99 32.60
BYK-016 0.31 0.31 0.31 PLURONIC L-35 0.06 0.06 0.06 Buffer solution
0.94 0.94 0.94 Stabilizer (1% solution) 10.00 10.00 10.00
[0185] As indicated above, the compositions prepared according to
this process were all able to achieve an active ingredient loading
of at least about 45% by weight. Each of the compositions was
measured to have an average median particle size of from 1.0 to 1.2
microns, with a polydispersity index (median/mean) of from 1.4 to
1.5. Each of the compositions was observed to be storage stable at
room temperature for more than three months.
[0186] The formulations can also be prepared with Netzch Mini Zeta
II milling machine via a pass mode. In a typical example, the
formulation was first pre-milled with a homogenizer and then added
to the milling machine. After the formulation was passed through
the milling machine, it was collected and then added to the milling
machine again. After passing through the milling machine at 3504
rpm three times, the formulation was collected and mixed with the
KELZAN stabilizer composition to give the final formulation. The
particle size of the formulation was measured before the stabilizer
was added. The formulations prepared by the multiple pass mode are
shown in Table 5. The particle sizes for these formulations are
shown in Table 6.
TABLE-US-00005 TABLE 5 Sample D Sample E Sample F Ingredient (wt.
%) (wt. %) (wt. %) Ia-i 47.79 47.79 47.79 MORWET D-425 2.26 2.26
2.26 ISOPAR M 2.26 2.26 -- humic acid, sodium 2.26 -- 2.26 salt
Propylene glycol 5.65 5.65 5.65 Water 39.06 41.32 41.32 BYK-016
0.31 0.31 0.31 PLURONIC L-35 0.06 0.06 0.06 Buffer solution 0.039
0.039 0.039 Stabilizer 0.10 0.10 0.10 composition
1,2-benzisothiazolin- 0.20 0.20 0.20 3-one
TABLE-US-00006 TABLE 6 Formulation Mean (.mu.m) Median (.mu.m)
Mean/Median Sample D 2.63 1.87 1.41 Sample E 2.80 1.93 1.45 Sample
F 2.37 1.62 1.46
Example 11
Differential Scanning Calorimetry Analysis
[0187] Eleven batches of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole (Ia-i) were
characterized for polymorphic form using differential scanning
calorimetry (DSC) analysis. DSC data were collected using a TA
INSTRUMENTS Q2000 DSC apparatus.
[0188] For each batch, samples in the mass range of 1 to 10 mg were
crimped in aluminum sample pans and scanned over a range of
25.degree. C. to about 120.degree. C., increasing at a rate of
2.degree. C. to 10.degree. C. per minute, and using a nitrogen
purge at 50 mL/min.
[0189] The melting point onset ranged from approximately
106.degree. C. to 108.degree. C., with enthalpy of fusion ranging
from approximately 108 to 122 J/g. The results are shown below in
Table 7. Enthalpy of fusion measurements were obtained on single
sample analysis using a relatively small sample size of
approximately 2 mg.
TABLE-US-00007 TABLE 7 DSC Analysis Summary Batch Melting Point
Onset Enthalpy of Fusion (J/g) A 107.0 C. 116.6 B 107.7 C. 117.1 C
107.3 C. 118.9 D 107.0 C. 119.4 E 107.4 C. 110.1 F 107.7 C. 121.7 G
107.0 C. 118.9 H 106.1 C. 107.5 I 106.7 C. 110.0 J 107.3 C. 108.7 K
107.9 C. 111.0
[0190] The thermal behavior of batch G was determined using
differential scanning calorimetry and thermogravimetric analysis.
The DSC thermogram exhibited a sharp melting endotherm with an
onset of 106.9.degree. C. and an enthalpy of fusion of 118.9
J/g.
[0191] Microscopic evaluation of lot G showed birefringent acicular
to columnar shaped particles, ranging in size from approximately 5
to 100 microns. FIG. 1 shows the representative
photomicrograph.
Example 12
Solvent Recrystallization
[0192] To perform the solvent-based portion of the polymorph
screen, the 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole test
material was recrystallized using various solvents under
approximately 240 different crystal growth conditions. The scale of
the recrystallization experiments was from approximately 0.5 mL to
15 ml. The crystal growth conditions were changed by using binary
gradient arrays of solvent mixtures and by changing the saturation
temperature, growth temperature and evaporation rate (rate of
supersaturation generation).
[0193] Saturated solutions were prepared by agitating excess (as
possible) test material in contact with the various solvent systems
at the saturation temperature. If solids did not completely
dissolve in the solvent, the mother liquor was separated from the
residual solids by filtration. The mother liquor was then heated
above the saturation temperature (overheated) to dissolve any
remaining solids. The temperature of each solution was then
adjusted to the growth temperature and a controlled nitrogen shear
flow was introduced to begin solvent evaporation.
[0194] The recrystallization conditions for the seven solvent based
panels used during the study are summarized in Table 8A. Each
recrystallization panel contained from 27 to 96 wells. The wells
within each panel contained different solvent compositions. Because
of the different solvent composition in each well, each well acted
as a different crystal growth experiment. The compositional solvent
matrices for the five recrystallization panels used during the
solvent-based portion of the polymorph screen are shown below in
Tables 8B through 8F, respectively. Based on the XRD analysis
carried out on the screening samples (see Example 18, below) a new
polymorph of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was
discovered in these experiments. The starting material was
designated as Form I, while the new polymorph was designated as
Form II.
TABLE-US-00008 TABLE 8A Summary of Recrystallization Panels Satura-
Over- N.sub.2 tion heat Growth Flow No. of Scale Temp. Temp. Temp.
Rate Panel Wells (mL) Solvent (.degree. C.) (.degree. C.) (.degree.
C.) (psi) 1 34 15 Single/Binary 25 55 25 1.5 2 34 15 Single/Binary
25 NA 80 1.5 4 27 15 Binary 25 55 50 1.5 6 27 15 Binary 25 NA 65
1.5 7 96 0.5 Binary 25 50 40 2
TABLE-US-00009 TABLE 8B Recrystallization Panel 1 (Evaporated at
Room Temp) Well Solvent Sample ID XRD Form 1 methanol RC1-1 Form I
2 ethanol RC1-2 Form I 3 trifluoroethanol RC1-3 Form I 4 1-propanol
RC1-4 Form I 5 2-propanol RC1-5 Form I 6 1-butanol RC1-6 Form I 7
2-butanol RC1-7 Form I 8 water RC1-8 NA 9 dimethyl formamide RC1-9
Form I 10 dimethylacetamide RC1-10 Form I 11 butyl amine RC1-11
Form I 12 diisopropyl amine RC1-12 Form I 13 pyridine RC1-13 Form I
14 nitromethane RC1-14 Form I 15 acetone RC1-15 Form I 16 methyl
ethyl ketone RC1-16 Form I 17 isopropyl ether RC1-17 Form I 18
Ethyl acetate RC1-18 Form I 19 methyl tert butyl ether RC1-19 Form
I 20 isopropyl acetate RC1-20 Form I 21 tetrahydrofuran RC1-21 Form
I 22 acetonitrile RC1-22 Form I 23 methylene chloride RC1-23 Form I
24 chloroform RC1-24 Form I 25 toluene RC1-25 Form I 26 heptane
RC1-26 Form I 27 1,4 dioxane RC1-27 Form I 28 NMP RC1-28 NA/T 29
DMSO RC1-29 NA/T 30 xylene RC1-30 Form I 31 butyl acetate RC1-31
Form I 32 2-methyl tetrahydrofuran RC1-32 Form I 33 propylene
glycol RC1-33 NA/T 34 glycerol/pyridine (2:13) RC1-34 NA/T
TABLE-US-00010 TABLE 8C Recrystallization Panel 2 (Evaporated at
80.degree. C.) Well Solvent Sample ID XRD Form 1 methanol RC2-1
Form I + II 2 ethanol RC2-2 Form I 3 trifluoroethanol RC2-3 Form I
4 1-propanol RC2-4 Form I II 5 2-propanol RC2-5 Form I 6 1-butanol
RC2-6 Form I 7 2-butanol RC2-7 Form I + II 8 water/acetone
(7.5/7.5) RC2-8 Form I 9 DMF/1-butanol (7.5/7.5) RC2-9 Form II 10
DMA/IPE (7.5/7.5) RC2-10 Form II 11 butyl amine RC2-11 Form I 12
diisopropyl amine RC2-12 Form I +II 13 pyridine RC2-13 Form I 14
nitromethane RC2-14 Form I + II 15 acetone RC2-15 Form I 16 methyl
ethyl ketone RC2-16 Form II 17 isopropyl ether RC2-17 Form I 18
Ethyl acetate RC2-18 Form I + II 19 methyl tert butyl ether RC2-19
Form I 20 isopropyl acetate RC2-20 Form I + II 21 tetrahydrofuran
RC2-21 Form I 22 acetonitrile RC2-22 Form I + II 23 methylene
chloride RC2-23 Form I + II 24 chloroform RC2-24 Form I 25 toluene
RC2-25 Form I + II 26 heptane RC2-26 Form I + II 27 1,4 dioxane
RC2-27 Form I + II 28 NMP/MeOH (7.5/7.5) RC2-28 Form II 29
DMSO/EtOH (7.5/7.5) RC2-29 Form I 30 xylene RC2-30 Form I 31 butyl
acetate RC2-31 Form I + II 32 2-methyl tetrahydrofuran RC2-32 Form
I 33 PropGly/CHCl3 (7.5/7.5) RC2-33 Form I 34 glycerol/pyridine
(1:14) RC2-34 Form I
TABLE-US-00011 TABLE 8D Recrystallization Panel 4 (Evaporated at
50.degree. C.) Solvent Matrix and XRD Result for Recrystallization
Panel 4 Sample Ratio of Solvents Co/ Solvent ID 1 2 3 AntiSolvent
DMF A 12:3 7.5:7.5 3:12 1-butanol DMA B 12:3 7.5:7.5 3:12 IPE MEK C
12:3 7.5:7.5 3:12 EtOH NMP D 12:3 7.5:7.5 3:12 MeOH TFE E 12:3
7.5:7.5 3:12 Water Xylene F 12:3 7.5:7.5 3:12 IPA EtOAc G 12:3
7.5:7.5 3:12 2-butanol 1,4 dioxane H 12:3 7.5:7.5 3:12 Heptane DCM
I 12:3 7.5:7.5 3:12 Acetonitrile Sample XRD Form Co/ Solvent ID 1 2
3 AntiSolvent 5 A Form I Form Form 1-butanol I + II I + II DMA B
Form I Form II Form IPE I+ II MEK C Form Form I Form I EtOH I + II
NMP D Form II Form I Form I MeOH TFE E Form II Form I No sample
Water Xylene F Form I Form I Form I IPA EtOAc G Form I Form I Form
I 2-butanol 1,4 dioxane H Form I Form I Form I Heptane DCM I Form I
Form I Form I Acetonitrile
TABLE-US-00012 TABLE 8E Recrystallization Panel 6 (Evaporated at
65.degree. C.) Solvent Matrix and XRD Result for Recrystallization
Panel 6 Sample Ratio of Solvents Co/ Solvent ID 1 2 3 AntiSolvent
TFE A 12:3 7.5:7.5 3:12 Isopropyl Acetate 1-propanol B 12:3 7.5:7.5
3:12 MEK THF C 12:3 7.5:7.5 3:12 Chloroform Butylamine D 12:3
7.5:7.5 3:12 Toluene Diisopropyl- E 12:3 7.5:7.5 3:12 butyl acetate
amine Pyridine F 12:3 7.5:7.5 3:12 2-meth THF Nitromethane G 12:3
7.5:7.5 3:12 DMA Acetone H 12:3 7.5:7.5 3:12 NMP MTBE I 12:3
7.5:7.5 3:12 DMF Sample XRD Form Co/ Solvent ID 1 2 3 AntiSolvent
TFE A Form Form II Form Isopropyl I + II I + II Acetate 1-propanol
B Form Form Form I MEK I + II I +II THF C Form Form I Form I
Chloroform I + II Butylamine D Form I Form I Form I Toluene
Diisopropyl- E Form I Form Form I butyl acetate amine I +II
Pyridine F Form Form I Form I 2-meth THF I + II Nitromethane G Form
Form I Form I DMA I + II Acetone H Form Form I Amor- NMP I + II
phous/LC MTBE I Form I Form I Form I DMF
TABLE-US-00013 TABLE 8F Recrystallization Panel 7 (96 Well Plate,
Evaporated at 40.degree. C.) Nitro- Isopropyl 1,4 Pyridine methane
Acetone MEK EtOAc MTBE acetate THF DCM CHCl3 Toluene dioxane 1 2 3
4 5 6 7 8 9 10 11 12 A TFE Form I Form I Form II Form II Form I LC
NA NA Form I NA Form II Form I B 1- NA Form Form II NA Form I Form
I Form I NA NA LC Form II Form I propanol I + II C IPA NA Form II
Form II NA Form II NA Form I NA NA NA NA NA D 2- LC Form II Form II
NA Form I NA Form I NA NA NA NA NA butanol E DMF NA NA NA Form II
NA NA NA Form I Form II NA NA NA F DMA NA NA NA NA Form I NA NA NA
NA NA Form I NA G butyl- NA Form II NA NA NA Form I NA NA Form I NA
NA NA amine H Di- Form II Form I Form I NA NA NA NA NA NA NA NA NA
isopropyl amine
Example 13
Recrystallization from the Melt
[0195] Cyclic DSC analysis was performed on lot G (Form I) to
determine if 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole would
recrystallize from the melt as a different form (solvent-less
recrystallization). Experiments were performed by heating the
material above the melting temperature, then cooling the material
at a rate of 5.degree. C., 10.degree. C., 20.degree. C., 30.degree.
C., 40.degree. C. or 50.degree. C. per minute, followed by
reheating above the melting temperature. At the 5.degree. C. to
30.degree. C. per minute cooling rates, the first enthalpy of
fusion values (for the starting material) were approximately 120
J/g while the second values (for the melting of the solids obtained
after cooling the original melt) were approximately 100 J/g. There
was also a slight change in the melting point onset (approximately
0.5.degree. C.). It is believed that melting Form I, followed by
recrystallization, may result in the formation of Form II.
[0196] The results of the experiments performed at cooling rates of
40.degree. C. and 50.degree. C. per minute were unclear, and may
indicate that the experiment was uncontrolled under these
conditions.
[0197] FIG. 3 shows a sample cyclic DSC thermogram from the run
conducted at a cooling rate of 30.degree. C. per minute.
[0198] In a further experiment, approximately 300-400 mg of Form I
starting material was heated to melting in a forced air oven at
approximately 120.degree. C. for approximately 40 minutes. The
sample was slow cooled to room temperature, and XRD, DSC and proton
NMR analyses were performed on this sample. The XRD pattern was
different from the starting material (Form I) and was similar to
the Form II pattern. DSC exhibited a melting onset temperature of
107.8.degree. C. and enthalpy of fusion of 103.2 J/g.
Example 14
Grinding Analysis
[0199] Batches of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole
polymorphic Forms I and II were ground using a CRESCENT WIG-L-BUG
ball mill for 2 minutes at 4800 oscillations per minute (3.2 m/s)
in two separate experiments. Under these conditions, no
transformation was observed in Form I, while the Form II sample
transformed to Form I. FIG. 4 shows the XRD overlay of the milled
Form I and Form II samples and the reference patterns of Forms I
and II. The Form II used in this experiment was obtained by
recrystallization from the melt of Form I, as described in Example
14, above,
Example 15
Mechanical Pressure Analysis
[0200] Batches of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole
polymorphic Forms I and II were placed in a CARVER press and
compressed at approximately 15,000 psi for approximately 20 seconds
in two separate experiments. XRD analysis was performed on the
samples. The resulting XRD pattern matched the starting material in
both experiments, as shown in FIGS. 5A and 5B for Forms I and II,
respectively. The pressurized treatment did not reveal any changes
in the polymorphic form of the starting material in both
experiments. The Form II used in this experiment was obtained by
recrystallization from the melt of Form I, as described in Example
14, above.
Example 16
Non-Competitive Slurry Experiments
[0201] In addition to the solvent recrystallization experiments,
non-competitive slurry experiments were performed to search for new
solid-state forms of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole.
These experiments rely on solubility differences of different
polymorphic forms (if the compound exists in different polymorphic
forms). As such, only polymorphs having a lower solubility (that
is, are more stable) than the original crystalline form can result
from a noncompetitive slurry experiment.
[0202] Essentially, when a solid is mixed with solvent to create
slurry, a saturated solution eventually results. The solution is
saturated with respect to the polymorphic form dissolved. However,
the solution is supersaturated with respect to any polymorphic form
that is more stable (more stable forms have lower solubility) than
the polymorphic form initially dissolved. Therefore, any of the
more stable polymorphic forms can nucleate and precipitate from
solution. In addition, noncompetitive slurry experiments are often
useful in identifying solvents that form solvates with the
compound.
[0203] The slurry experiments were performed by exposing excess
supplied material to solvents and agitating the resulting
suspensions for several days at ambient temperature. The solids
were filtered using a WHATMAN Grade 1 apparatus (11 .mu.m pore
size) and analyzed by XRD to determine the resulting form(s). To
avoid possible desolvation or physical change after isolation, the
samples were not dried before X-ray analysis. A summary of
non-competitive slurry experiments is shown in Table 9.
TABLE-US-00014 TABLE 9 Vehicle Initial Form Duration Final Form
Methanol I 12 days I Ethanol I 12 days I Trifluoroethanol I 12 days
I 1-propanol I 12 days I Isopropyl alcohol I 12 days I 1-butanol I
12 days I 2-butanol I 12 days I water I 12 days I heptane I 12 days
I glycerol/water (1:10) I 12 days I propylene glycol/water (1:10) I
12 days I Isopropyl alcohol/water (1:1) I 12 days I ethanol II 7
days I trifluoroethanol II 7 days I 1-propanol II 7 days I
Isopropyl alcohol II 7 days I 1-butanol II 7 days I 2-butanol II 7
days I heptane II 7 days I glycerol/water (1:10) II 7 days I
propylene glycol/water (1:10) II 7 days I Isopropyl
alcohol/water(1:1) II 7 days I
[0204] Based on their X-ray scattering behavior, the slurry
experiments with Form I as the starting material resulted in Form I
after approximately 12 days of slurring (indicating no
transformation). The slurry experiments with Form II as the
starting material (obtained by recrystallization from the melt, as
set forth in Example 14, above) resulted in Form I after
approximately 7 days of slurring. These data indicate that Form I
is more stable than Form II at ambient temperature and pressure. No
new polymorphs, solvates, or hydrates were isolated in these
experiments.
Example 17
X-Ray Analysis of Screening Samples
[0205] Batches of solid 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole
polymorphs generated from the solvent based recrystallization
panels and from other means (slurry, recrystallization from melt in
an oven, etc.) were analyzed by powder XRD. To mitigate preferred
grain effects, a two dimensional detection system was used to
collect all the XRD screening data. The two dimensional detector
integrates along the concentric Debye cones which helps reduce
pattern variation. An example of the Debye cone integration using a
two dimensional detector is shown below. If bright spots appear in
the conical rings, it indicates strong preferred grain effects that
can lead to considerable variability in the observed diffraction
patterns including changes in peak intensities. Some samples of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole exhibited preferred
grain effects based on the appearance of the scattering
behavior.
[0206] The results of this analysis revealed the material exists as
two different polymorphs. The polymorphs were designated as Forms I
and II. A powder XRD analysis of the Form I polymorphs,
corresponding to the initial test samples, is set forth in FIG. 6.
A powder XRD analysis of the Form II polymorphs is set forth in
FIG. 7.
[0207] The initial test material was designated as Form I. The
resulting form designation for each individual (solvent-based)
recrystallization experiment is shown in Tables 7B through 7F,
above.
Example 18
Summary of Formation of Forms I and II
[0208] A number of different crystallization conditions were used
to produce the samples utilized in Examples 12 through 18, above.
Polymorphic Form I of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole
was obtained in approximately 50% of the experiments under various
crystallization conditions. Polymorphic Form II was obtained in
approximately 10% of the experiments also under various
crystallization conditions. Mixtures of Forms I and II were
obtained in approximately 11% of the experiments indicating that
the two polymorphs have a tendency to nucleate and grow
concomitantly. Form I appears to be the thermodynamically stable
form under ambient conditions based on the results of the non
competitive slurry experiment. The exact crystallization conditions
are shown in Tables 7A through 7F, above.
[0209] Table 10 shows a summary of the results obtained in all the
experiment panels in this study. Note that Panels 1, 2, 4, 6, and 7
are described in Example 13, above. Panel 3 corresponds to the
recrystallization from the melt as set forth in Example 14, above.
Panels 5 and 8 correspond to the noncompetitive slurry experiments
conducted with respect to Form I and Form II, respectively, in
Example 17, above.
TABLE-US-00015 TABLE 10 No. of Mix of Experi- Form Form Forms I No
Panel No. ments I II and II Result Panel 1 34 29 0 0 5 Panel 2 34
17 4 13 0 Panel 3 (Melt) 5 0 3 0 2 Panel 4 27 19 3 4 1 Panel 5 Form
1 12 12 0 0 0 NC Slurry Panel 6 27 16 1 9 1 Panel 7 96 well 96 19
14 1 62 Panel 8 Form 2 10 10 0 0 0 NC Slurry Total 245 122 25 27 71
% of total 100% 50% 10% 11% 29%
Example 19
Competitive Slurry Experiments
[0210] In addition to the solvent recrystallization experiments, a
competitive slurry experiment was also performed to determine the
most stable polymorphic form of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole. These experiments rely
on the solubility differences of different polymorphic forms. As
such, only polymorphic forms (and solvates) having a lower
solubility (more stable) than the form initially dissolved can
result from a competitive slurry experiment.
[0211] Essentially, when a solid is dissolved in a (slurry)
solvent, a saturated solution eventually results. The solution is
saturated with respect to the polymorphic form dissolved. However,
the solution is supersaturated with respect to any polymorphic form
that is more stable (more stable forms have lower solubility) than
the polymorphic form initially dissolved. Therefore, any of the
more stable polymorphic forms can nucleate and precipitate from
solution. In addition, competitive slurry experiments are often
useful in identifying solvents that form solvates with the API.
[0212] The slurry experiment was performed by exposing excess
material of Forms I and II to a small volume of neat solvent and
agitating the resulting suspensions for several days at ambient
temperature. The solids were filtered and analyzed by XRD to
determine the resulting form. To avoid possible desolvation or
physical change after isolation, the sample was not dried before
x-ray analysis. Table 11 shows the results of the competitive
slurry experiment.
TABLE-US-00016 TABLE 11 Initial Forms Slurry Final Form (XRD)
Solvent Duration (XRD) I & II Isopropyl alcohol 1 week I
[0213] The thermal data obtained above was used to calculate an
approximate value for the transition temperature of conversion of
Forms I and II using methods known in the art. The value obtained
using this method was approximately 102.degree. C. Based on these
calculations, Form I is expected to be the stable form below this
temperature and Form II above it. This is another characteristic of
an enantiotropic polymorphic relationship.
[0214] A graphical XRD overlay of the competitive slurry experiment
is depicted in FIG. 8.
Example 20
Estimation of Transition Temperature
[0215] Polymorphic Forms I and II of
3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole, as well as a 50/50
mixture thereof, were analyzed by DSC at a slow heating rate of
2.degree. C. per minute, with similar sample sizes. The melting
temperatures and enthalpy of fusion data are shown in Table 12,
below. These data indicate that Form I has a lower melting
temperature and a higher enthalpy of fusion. Form II has a higher
melting temperature and a lower enthalpy of fusion. In accordance
with the Heat of Fusion Rule, this indicates that Form I and II
have an enantiotropic relationship. FIGS. 9A through 9C show the
relevant DSC thermograms for Form I, Form II, and a mixture of
Forms I and II, respectively.
[0216] The thermal data using the procedure set forth above was
used to calculate an approximate value for the transition
temperature of conversion of Forms I and II, resulting in an
estimated transition temperature value of 102.degree. C. Based on
these calculations, Form I is expected to be the stable form below
this temperature, while Form II is expected to possess greater
thermodynamic stability above that temperature. This further
indicates that Forms I and II exhibit an enantiotropic polymorphic
relationship.
TABLE-US-00017 TABLE 12 Onset Maximum Enthalpy of Fusion Sample ID
(.degree. C.) (.degree. C.) (J/g) Batch G Form I 106.9 107.9 117.9
54478-21-4 Form II 108.0 108.8 98.3 50/50, Form I/II 108.0 108.0,
108.8 114.6
Example 21
Storage Stability of Polymorphs
[0217] To determine the storage stability and/or hydrate formation
of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole Form I material
during storage at ambient conditions, samples were monitored in two
static humidity chambers. In these studies, samples were stored in
open Petri dishes in chambers containing saturated salt solutions
to maintain the relative vapor pressure. Solutions of saturated
potassium chloride (84% RH) and sodium chloride (75% RH) salts at
ambient temperature were used.
[0218] FIG. 10 shows the XRD pattern of the samples stored at 75
and 84% RH after 4 weeks of storage. As indicated in the figure,
Form I does not form a hydrate and appears to be thermodynamically
stable over time at ambient conditions.
[0219] In contrast, samples of Form II stored in a scintillation
vial in a hood under ambient conditions showed signs of
transformation to Form I when analyzed by XRD after approximately 6
days of storage. FIG. 11 shows the XRD overlays of Forms I, II and
the sample of Form II which showed signs of transformation to Form
I.
Example 22
Soybean Cyst Nematode Assay
[0220] Formulations were tested for nematicidal activity against
soybean cyst nematode (SCN) in an SCN cup assay.
[0221] The formulations were prepared as follows:
[0222] Preparation of the phosphate buffer solution: To a 1 L
volumetric flask were added potassium phosphate monobasic anhydrous
(9.329 g) and sodium phosphate dibasic heptahydrate (32.756 g). DI
water was added to the flask to the mark and it was inverted 15
times to give a clear solution.
[0223] Preparation of Formulation Blank A: To a 2 L beaker were
added MORWET D-425 (43.6 g), DI water (1,386.9 g), the phosphate
buffer solution (36.3 g), propylene glycol (217.7 g), and PLURONIC
L-35 (2.2 g). The mixture was stirred with a spatula to give a
brown solution.
[0224] Preparation of Formulation Blank B: To a 2 L beaker were
added MORWET D-425 (174.3 g), DI water (1,256.0 g), the phosphate
buffer solution (36.3 g), propylene glycol (217.8 g), and PLURONIC
L-35 (2.1 g). The mixture was stirred with a spatula to give a dark
brown solution.
[0225] Preparation of the KELZAN stabilizer solution: To a 1 L
beaker were added KELZAN CC (4.060 g), PROXEL GXL (7.978 g), and DI
water (388.273 g). The mixture was then agitated with a Melton
mechanical stirrer (model CM -100) at 2,000 rpm for 30 minutes to
give a viscous liquid.
[0226] Preparation of Suspension Concentrate Formulation 3: To a 2
L beaker were added Formulation Blank A (497.3 g), Compound Ia-i
(521.4 g), and BYK-016 (3.6 g). The mixture was stirred with a
spatula to give a slurry. The mixture was placed in an ice bath and
a Tekmar T554 homogenizer (model TR-10) was used for the
pre-milling. During the pre-milling, the slurry (1022.3 g) was
agitated with the homogenizer at 9,000 rpm for 12 mins. An Eiger
mill (model M250) was filled with zirconium oxide beads with an
average diameter of 0.3-0.4 mm. Nearly half of the pre-milled
slurry (501.4 g) was then added to the Eiger mill and was milled
with a speed of 5000 rpm in recycle mode at room temperature. After
30 minutes, the resulting white liquid formulation (412.4 g) was
collected and mixed with KELZAN stabilizer solution (45.8 g) to
give the final formulation (458.2 g). The particle size of the
formulation was analyzed with a Beckman Coulter particle size
analyzer (Model LS 13 320) before the stabilizer was added.
[0227] Preparation of Suspension Concentrate Formulation 4: The
pre-milled slurry (501.4 g) from the suspension concentrate
formulation above was also milled with the same Eiger mill filled
with zirconium oxide beads with an average diameter of 0.3-0.4 mm.
After milling for 120 minutes, the resulting white liquid
formulation (408.5 g) was collected and mixed with KELZAN
stabilizer solution (45.4g) to give the final formulation (453.9
g). The particle size of the formulation was also analyzed with a
Beckman Coulter particle size analyzer (Model LS 13 320) before the
stabilizer was added.
[0228] Preparation of Suspension Concentrate Formulation 5: To a 1
L beaker were added Formulation Blank B (383.3 g), Compound Ia-i
(261.1 g), and BYK-016 (2.5 g). The mixture was stirred with a
spatula to give a slurry. The mixture was placed in an ice bath and
a Tekmar T554 homogenizer (model TR-10) was used for the
pre-milling. During the pre-milling, the slurry was agitated with
the homogenizer at 9,000 rpm for 10 mins. The milling was divided
into two stages. Both Netzsch Mini Zeta II filled with glass beads
with an average diameter of 0.8-1 mm and Eiger mill (model M250)
filled with zirconium oxide beads with an average diameter of
0.1-0.2 mm were used in the milling. In the first stage, the slurry
was passed through the Netzsch miller three times and the miller
was operated at 3,504 rpm for each pass. In the second stage, the
slurry was passed through the Eiger miller ten times and the
milling was operated at 5,000 rpm. A white liquid (452.1 g) was
collected and part of the white liquid (349.0 g) mixed with the
KELZAN stabilizer solution(38.8 g) to give the final formulation
(387.8 g). The particle size of the formulation was also analyzed
with a Beckman Coulter particle size analyzer (Model LS 13 320)
before the stabilizer was added.
[0229] Preparation of Suspension Concentrate Formulation 6: To an 8
dram vial were added MORWET D-425 (0.714 g), DI water (3.75 g), the
phosphate buffer solution (0.147 g), ISOPAR M (1.45 g), propylene
glycol (0.898 g), PLURONIC L-35 (0.009 g), Compound Ia-i (7.315 g),
and BYK-016 (0.067 g). The mixture was stirred followed by addition
of 3 mm diameter stainless steel beads (14 mL). The vial was capped
and placed on a US Stoneware roller (Ser. No. CK-11009) and rotated
at a speed setting of 50. After 2 days the slurry (5.903 g) was
collected and mixed with the KELZAN stabilizer solution (0.660 g)
to give the final formulation (6.563 g). The particle size of the
formulation was analyzed with a Beckman Coulter particle size
analyzer (Model LS 13 320) before the stabilizer was added.
[0230] Table 13 below depicts the compositions of each formulation
used for seed treatment in the SCN efficacy assay.
TABLE-US-00018 TABLE 13 Composition of Formulation for Seed
Treatment Ia-i Commercial Compound Form- Form- Seed Ia-i ulation
ulation Treatment Water Rate Treatment Ia-i (g) (g) (g) (mg/seed) 1
NA N/A N/A N/A N/A 2 NA 0 1.557 0.64 N/A 3A 3 0.36 0 0.64 0.05 3B 3
2.16 0 1.01 0.3 4A 3 0.36 1.557 0.64 0.05 4B 3 2.16 1.557 1.01 0.3
5A 4 0.36 0 0.64 0.05 5B 4 2.16 0 1.01 0.3 6A 4 0.36 1.557 0.64
0.05 6B 4 2.16 1.557 1.01 0.3 7A 5 0.45 0 1.21 0.05 7B 5 2.73 0
1.16 0.3 8A 5 0.45 1.557 1.21 0.05 8B 5 2.73 1.557 1.16 0.3 9A 6
0.36 0 0.64 0.05 9B 6 2.16 0 1.01 0.3 10A 6 0.36 1.557 0.64 0.05
10B 6 2.16 1.557 1.01 0.3
[0231] SCN Efficacy Assay
[0232] A4630 soybean plants were grown in cups filled with full
strength Murashige & Skoog basal salts fertilizer (Phytotech
Cat. No. 201080-52) followed by 180 ml of 20:80 soil/sand mixture
(sterile St. Charles sand and US 10 soil premixed by Hummert). A
Gustafson Batch Modular Coater (BMC) Treater was used to the treat
the soybean seeds with the formulations as described in Table
13.
[0233] The untreated seed and treated seed were placed on top of
20:80 soil and pushed 1/2 inch deep into the soil. The cups were
placed in the growth chamber and the soil was misted with water to
saturation. Propagation domes were placed over the cups until the
seeds had germinated (about 3 to 5 days). Conditions in the growth
chamber were as follows: 28.degree. C., 60% relative humidity, and
16 h/14 h day/night periods, with 347.mu. Einsteins of light.
[0234] Ten days after planting, soybean cyst inoculum (2.times.500
.mu.L, 5000 eggs/cup) was delivered into the soil on two sides of
the soybean plant. The plants were grown for an additional 5 weeks
after inoculation and watered as needed with overhead watering.
[0235] The efficacy of the formulations was determined by
harvesting plants (45 days) and counting cysts. Table 14
demonstrates the bioefficacy against SCN at 50 .mu.g/seed and 300
.quadrature..mu.g/seed.
TABLE-US-00019 TABLE 14 Treat- Particle Rate Cyst Counts ment Size
(.mu.m) (mg/seed) Mean Std Dev Std Err Mean 1 N/A 227 159 65 2 N/A
337 205 84 3A 0.8 0.05 149 80 33 3B 0.3 67 47 19 4A 0.8 0.05 247
244 100 4B 0.3 92 106 43 5A 0.48 0.05 146 55 22 5B 0.3 90 58 24 6A
0.48 0.05 203 193 79 6B 0.3 57 71 29 7A 0.065 0.05 137 86 35 7B 0.3
150 55 25 8A 0.065 0.05 176 101 41 8B 0.3 86 70 29 9A 1.7 0.05 147
97 40 9B 0.3 80 89 36 10A 1.7 0.05 92 63 28 10B 0.3 76 64 26
[0236] When introducing elements of the present invention or the
preferred embodiments(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0237] In view of the above, it will be seen that the several
objects of the invention are achieved and other advantageous
results attained.
[0238] As various changes could be made in the above products and
methods without departing from the scope of the invention, it is
intended that all matter contained in the above description and the
associated drawings shall be interpreted as illustrative and not in
a limiting sense.
* * * * *