CN113999181A - Eutectic crystal of tebuconazole and organic acid and preparation method and application thereof - Google Patents
Eutectic crystal of tebuconazole and organic acid and preparation method and application thereof Download PDFInfo
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- CN113999181A CN113999181A CN202111490416.2A CN202111490416A CN113999181A CN 113999181 A CN113999181 A CN 113999181A CN 202111490416 A CN202111490416 A CN 202111490416A CN 113999181 A CN113999181 A CN 113999181A
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- tebuconazole
- ethyl
- eutectic
- organic acid
- crystal
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- PXMNMQRDXWABCY-UHFFFAOYSA-N 1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol Chemical compound C1=NC=NN1CC(O)(C(C)(C)C)CCC1=CC=C(Cl)C=C1 PXMNMQRDXWABCY-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 239000005839 Tebuconazole Substances 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000013078 crystal Substances 0.000 title claims abstract description 35
- 150000007524 organic acids Chemical class 0.000 title claims abstract description 24
- 230000005496 eutectics Effects 0.000 title abstract description 72
- 239000001530 fumaric acid Substances 0.000 claims abstract description 40
- 239000001384 succinic acid Substances 0.000 claims abstract description 39
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 36
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 33
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000005985 organic acids Nutrition 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001228 spectrum Methods 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims description 4
- TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 claims description 4
- SHZIWNPUGXLXDT-UHFFFAOYSA-N ethyl hexanoate Chemical compound CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- BYEVBITUADOIGY-UHFFFAOYSA-N ethyl nonanoate Chemical compound CCCCCCCCC(=O)OCC BYEVBITUADOIGY-UHFFFAOYSA-N 0.000 claims description 4
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 claims description 4
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 2
- KBEBGUQPQBELIU-CMDGGOBGSA-N Ethyl cinnamate Chemical compound CCOC(=O)\C=C\C1=CC=CC=C1 KBEBGUQPQBELIU-CMDGGOBGSA-N 0.000 claims description 2
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 claims description 2
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 2
- KBEBGUQPQBELIU-UHFFFAOYSA-N cinnamic acid ethyl ester Natural products CCOC(=O)C=CC1=CC=CC=C1 KBEBGUQPQBELIU-UHFFFAOYSA-N 0.000 claims description 2
- VIMXTGUGWLAOFZ-UHFFFAOYSA-N ethyl 2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropane-1-carboxylate Chemical compound CCOC(=O)C1C(C=C(C)C)C1(C)C VIMXTGUGWLAOFZ-UHFFFAOYSA-N 0.000 claims description 2
- JJOYCHKVKWDMEA-UHFFFAOYSA-N ethyl cyclohexanecarboxylate Chemical compound CCOC(=O)C1CCCCC1 JJOYCHKVKWDMEA-UHFFFAOYSA-N 0.000 claims description 2
- 229940116333 ethyl lactate Drugs 0.000 claims description 2
- 229940117360 ethyl pyruvate Drugs 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 49
- 238000002844 melting Methods 0.000 abstract description 19
- 230000008018 melting Effects 0.000 abstract description 19
- 239000000575 pesticide Substances 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000011248 coating agent Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- 239000003814 drug Substances 0.000 description 22
- 239000000725 suspension Substances 0.000 description 19
- 238000012360 testing method Methods 0.000 description 17
- 239000008367 deionised water Substances 0.000 description 12
- 229910021641 deionized water Inorganic materials 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 241000209140 Triticum Species 0.000 description 10
- 235000021307 Triticum Nutrition 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- 239000004721 Polyphenylene oxide Substances 0.000 description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- NVVZQXQBYZPMLJ-UHFFFAOYSA-N formaldehyde;naphthalene-1-sulfonic acid Chemical compound O=C.C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 NVVZQXQBYZPMLJ-UHFFFAOYSA-N 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000000049 pigment Substances 0.000 description 6
- 229920000570 polyether Polymers 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010008 shearing Methods 0.000 description 6
- 229920002545 silicone oil Polymers 0.000 description 6
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 6
- 239000004299 sodium benzoate Substances 0.000 description 6
- 235000010234 sodium benzoate Nutrition 0.000 description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- 239000000230 xanthan gum Substances 0.000 description 6
- 229920001285 xanthan gum Polymers 0.000 description 6
- 229940082509 xanthan gum Drugs 0.000 description 6
- 235000010493 xanthan gum Nutrition 0.000 description 6
- 230000000295 complement effect Effects 0.000 description 5
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- 238000001144 powder X-ray diffraction data Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910017488 Cu K Inorganic materials 0.000 description 2
- 229910017541 Cu-K Inorganic materials 0.000 description 2
- 241000208125 Nicotiana Species 0.000 description 2
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 241000218176 Corydalis Species 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000008686 ergosterol biosynthesis Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003377 silicon compounds Chemical class 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention relates to the field of compound crystal forms, in particular to tebuconazole eutectic, a preparation method and application thereof, wherein the tebuconazole eutectic comprises the following components in percentage by weight: tebuconazole and organic acids; wherein the molar ratio of the tebuconazole to the organic acid is 10: 1-1: 10; the invention also provides a preparation method and application of the tebuconazole eutectic. According to the technical scheme, organic acids such as succinic acid or fumaric acid are used as eutectic formers and form eutectic with tebuconazole, so that the water-soluble organic acid eutectic crystal has the advantages of high melting point, high water solubility value and high water solubility rate, and is particularly suitable for being applied to the production process of pesticide preparations.
Description
Technical Field
The invention belongs to the technical field of compound crystal preparation, and particularly relates to a tebuconazole-organic acid eutectic crystal, and a preparation method and application thereof.
Background
Tebuconazole is a novel broad-spectrum triazole fungicide developed by Bayer company in Germany. Tebuconazole has the effect of inhibiting the ergosterol biosynthesis, can be quickly absorbed by the parts of plants with growth ability and mainly transferred to the top, so that tebuconazole has three functions of protection, treatment and eradication, and has wide bactericidal spectrum and long lasting period. Can be used for seed treatment or leaf surface spraying of important economic crops, and can effectively prevent and treat various rust diseases, powdery mildew, net blotch, root rot, scab, smut, seed-borne wheel spot, early rice sheath blight and the like of cereal crops
Despite the numerous advantages of tebuconazole as a novel fungicide, practical application still faces some challenges. The tebuconazole has poor water solubility, low melting point, poor crystallinity and easy agglomeration, which causes certain trouble to the practical application of the tebuconazole. Therefore, how to simply and effectively improve the physicochemical properties of tebuconazole is a very critical factor for further development and application of tebuconazole. The conventional method for changing the properties of the product usually needs to change the structure of the product or add an auxiliary agent, so that the cost is high and the effect is uncertain. In recent years, the pharmaceutical cocrystal technology has received attention from researchers because of its excellent properties in improving the physicochemical properties of drugs, improving the bioavailability of drugs, and prolonging the life of existing drugs. The pharmaceutical co-crystal is a new pharmaceutical entity formed by combining a pharmaceutical active ingredient with a co-crystal form through non-covalent bonds such as hydrogen bonds. The pharmaceutical co-crystal not only can improve the physicochemical property of the drug on the premise of not changing the covalent structure of the drug, but also can realize the combined medication at the molecular level, thereby being widely concerned by academia and industry.
Succinic acid is also known as succinic acid, is a compound widely applied to industries such as food, medicine and the like, has the characteristics of safety and environmental protection, is safe to human bodies and animals, has low cost, and is suitable for eutectic transformation of pesticide raw medicines. Fumaric acid is an organic acid present in nature, was first found in corydalis tuber, and is also present in various mushrooms and fresh beef. Fumaric acid is an excellent eutectic former, and has the advantages of high water solubility, low toxicity and the like. The applicant surprisingly finds that the tebuconazole-succinic acid eutectic and the tebuconazole-fumaric acid eutectic are prepared by combining tebuconazole and succinic acid or fumaric acid in a eutectic mode on the premise of not changing the covalent structure of the tebuconazole, the physicochemical properties of the tebuconazole can be effectively improved, the water solubility and the melting point of the tebuconazole are improved, the stability and the processability of the tebuconazole are enhanced, the biological activity of a preparation of the tebuconazole is greatly improved, and a certain promotion effect is realized on the further development and application of the tebuconazole.
Disclosure of Invention
The invention aims to overcome the inconvenience in the preparation and storage processes of pesticide preparations caused by lower water solubility and lower melting point of tebuconazole in the prior art. According to the technical scheme, succinic acid or fumaric acid is used as a eutectic forming substance to form a eutectic with tebuconazole, so that the water-soluble organic silicon compound has the advantages of high melting point, high water solubility value and high water solubility rate, and is suitable for being applied to the production process of pesticide preparations.
In order to achieve the technical purpose, the invention provides the following technical scheme: a tebuconazole cocrystal comprising: tebuconazole and organic acids; wherein the molar ratio of the tebuconazole to the organic acid is 10: 1-1: 10; the organic acid is succinic acid or fumaric acid.
Further, the molar ratio of the tebuconazole to the organic acid is 2: 1-1: 2.
Further, the molar ratio of the tebuconazole to the organic acid is 1: 1-1: 2; the preferred molar ratio is 1: 1.
Further, when the organic acid is succinic acid, at least 4 of the following diffraction peaks given by 2 θ values are displayed in the spectrum: 6.901 ° ± 0.2, 8.404 ° ± 0.2, 12.874 ° ± 0.2, 16.707 ° ± 0.2, 17.808 ° ± 0.2, 18.627 ° ± 0.2, 20.566 ° ± 0.2, 22.117 ° ± 0.2, 23.052 ° ± 0.2, 23.813 ° ± 0.2, 25.079 ° ± 0.2, 26.181 ° ± 0.2, 28.735 ° ± 0.2, 30.438 ° ± 0.2, 31.790 ° ± 0.2, 33.494 ° ± 0.2.
Further, when the organic acid is fumaric acid, at least 4 of the following diffraction peaks given in 2 θ values are shown in the spectrum: 8.264 DEG + -0.2, 12.630 DEG + -0.2, 14.138 DEG + -0.2, 16.567 DEG + -0.2, 18.548 DEG + -0.2, 19.625 DEG + -0.2, 20.303 DEG + -0.2, 22.364 DEG + -0.2, 23.014 DEG + -0.2, 23.571 DEG + -0.2, 24.937 DEG + -0.2, 25.426 DEG + -0.2, 28.462 DEG + -0.2, 31.320 DEG + -0.2, 31.646 DEG + -0.2, 33.092 DEG + -0.2.
The preparation method of the eutectic comprises the steps of mixing tebuconazole and succinic acid or fumaric acid, adding an alcohol or ester solvent, stirring under heating or without heating, filtering, standing the filtrate, and collecting a solid as the eutectic.
Further, the heating condition is heating at 30-70 ℃;
the alcohol solvent is any one or a mixture of methanol, ethanol, propanol or butanol; preferably methanol or ethanol;
the ester solvent is any one or a mixture of more of ethyl acetate, methyl acetate, n-butyl acetate, n-amyl acetate, ethyl valerate, ethyl propionate, ethyl butyrate, ethyl lactate, ethyl nonanoate, triethyl phosphate, ethyl hexanoate, ethyl formate, ethyl cyclohexanecarboxylate, ethyl heptanoate, ethyl cinnamate, ethyl pyruvate and ethyl chrysanthemate; preferably ethyl acetate or ethyl propionate;
the solid-liquid ratio of the mixture of tebuconazole and organic acid to the solvent is (0.3-0.6) g, (5-10) mL.
The invention also discloses an agricultural preparation, which comprises an effective amount of tebuconazole cocrystal;
further, the composition also comprises an agriculturally acceptable preparation carrier or a preparation auxiliary agent.
The invention also discloses a method for controlling plant diseases, which comprises applying a bactericidal effective amount of tebuconazole cocrystal or agricultural preparation on plants and/or propagules thereof.
The invention also discloses the application of the tebuconazole cocrystal or the agricultural preparation in controlling plant diseases.
Due to the adoption of the technology, compared with the prior art, the invention has the remarkable advantages that:
1) according to the technical scheme, succinic acid and fumaric acid are used as eutectic formers and form eutectic with tebuconazole, so that the eutectic has the advantages of high melting point, high water solubility value and high water solubility rate, particularly the melting point is increased to be more than 123 ℃, the water solubility is increased to be more than 52.40mg/L, the dissolution rate in water is greatly increased, the eutectic is suitable for being applied to the production process of pesticide preparations, and the inconvenience caused by the lower water solubility and the lower melting point of tebuconazole in the prior art in the preparation and storage processes of the pesticide preparations is solved;
2) according to the preparation method of the tebuconazole eutectic crystal, the solvent volatilization method and the cooling method are adopted to prepare the high-purity eutectic crystal, and PXRD, melting point measurement and other related characterization and dissolution rate test are performed on the eutectic crystal, so that the prepared tebuconazole-succinic acid and tebuconazole-fumaric acid eutectic crystal has high purity and crystallinity, can be kept stable for a long time without deterioration, is simple in preparation process and low in cost, and is suitable for large-scale production;
3) compared with the mixture of tebuconazole and/or organic acid, the tebuconazole-succinic acid eutectic and the tebuconazole-fumaric acid eutectic have better biological activity and are more suitable for being applied to pesticide preparations.
Drawings
FIG. 1 is a PXRD pattern of tebuconazole-succinic acid eutectic of the present invention;
FIG. 2 is a comparison graph of PXRD spectra of tebuconazole-succinic acid eutectic, tebuconazole and succinic acid of the invention;
FIG. 3 is a PXRD pattern of tebuconazole-fumaric acid eutectic of the present invention;
FIG. 4 is a comparison of PXRD patterns of tebuconazole-fumaric acid eutectic of the invention with tebuconazole and fumaric acid;
FIG. 5 is a graph showing the comparison of the dissolution rates of the tebuconazole-succinic acid eutectic crystal and tebuconazole in water;
FIG. 6 is a graph showing the comparison of the dissolution rate of the tebuconazole-fumaric acid eutectic crystal and tebuconazole in water.
Detailed Description
In order to make the technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments.
Example 1
The preparation method of the tebuconazole-succinic acid eutectic crystal is implemented according to the following steps:
putting 0.307g of tebuconazole raw material medicine and 0.118g of succinic acid into a round-bottom flask according to the molar ratio of 1:1, adding 5mL of methanol into the mixed powder, heating and stirring in a water bath kettle at 30 ℃ for 3h, filtering, standing the filtrate for 4 days to volatilize the solvent, and collecting solid phase substances to obtain the tebuconazole-succinic acid eutectic crystal. The test is carried out by using an X-ray diffractometer model D8 of German BRUKER company, the test conditions are that the Cu-Kalpha target tube voltage is 40kV, the tube current is 10mA, the scanning speed is 2 DEG/min, and the PXRD diffraction pattern of the product is shown in figure 1. As shown in fig. 2, compared with PXRD of tebuconazole-succinic acid eutectic, tebuconazole bulk drug and succinic acid bulk drug, it can be seen that the characteristic diffraction peak position and diffraction intensity of the tebuconazole-succinic acid eutectic are significantly changed, indicating that a new phase is generated.
In the embodiment, the yield of the tebuconazole-succinic acid eutectic crystal prepared by the cooling method is 85.5%. The prepared eutectic is white crystalline powder, has good chemical stability, can keep the framework structure of the crystal after being placed at room temperature for a long time, and does not have any deterioration phenomenon.
The melting point of the eutectic compound is measured to be 123 ℃ by using a Shanghai Jiaohan WRS-1C type melting point tester, and the melting point of the tebuconazole is 105 ℃, which shows that compared with the tebuconazole, the melting point of the tebuconazole in the eutectic is improved by 18 ℃, and the stability of the tebuconazole in a preparation is greatly promoted.
Example 2
The preparation method of the tebuconazole-succinic acid eutectic crystal is implemented according to the following steps:
placing 3.070g of tebuconazole raw material medicine and 1.180g of succinic acid into a round-bottom flask according to the molar ratio of 1:1, adding 30mL of methanol into the mixed powder, heating in a water bath at 50 ℃ and stirring for 3h, filtering while hot, cooling the filtrate to room temperature, and collecting solid phase substances to obtain tebuconazole-succinic acid eutectic crystal. The measurement was carried out using an X-ray diffractometer model D8 from BRUKER, Germany under the conditions of a Cu-K.alpha.target tube voltage of 40kV, a tube current of 10mA, and a scanning speed of 2 DEG/min, and the PXRD diffraction pattern of the product was the same as that of example 1. The melting point was the same as in example 1.
Example 3
The preparation method of the tebuconazole-fumaric acid eutectic crystal is implemented according to the following steps:
putting 0.307g of tebuconazole raw material medicine and 0.116g of fumaric acid into a round-bottom flask according to the molar ratio of 1:1, adding 5mL of methanol into the mixed powder, heating and stirring in a water bath kettle at 30 ℃ for 3h, filtering, standing the filtrate for 4 days to volatilize the solvent, and collecting solid phase substances to obtain the tebuconazole-fumaric acid eutectic. The test is carried out by using an X-ray diffractometer model D8 of German BRUKER company, the test conditions are that the Cu-Kalpha target tube voltage is 40kV, the tube current is 10mA, the scanning speed is 2 DEG/min, and the PXRD diffraction pattern of the product is shown in figure 3. As shown in fig. 4, when compared with PXRD of tebuconazole-fumaric acid eutectic, tebuconazole bulk drug and fumaric acid bulk drug, the characteristic diffraction peak position and diffraction intensity of the tebuconazole-fumaric acid eutectic are significantly changed, indicating that a new phase is generated.
In this example, the yield of the tebuconazole-fumaric acid eutectic prepared by the cooling method is 87.5%. The prepared eutectic is white crystalline powder, has good chemical stability, can keep the framework structure of the crystal after being placed at room temperature for a long time, and does not have any deterioration phenomenon.
The melting point of the eutectic compound is 152 ℃ and the melting point of the tebuconazole is 102 ℃ by using a Shanghai Jiaohan WRS-1C type melting point tester, which shows that compared with the tebuconazole, the melting point of the tebuconazole in the eutectic is improved by 50 ℃, and the stability of the tebuconazole in a preparation is greatly promoted.
Example 4
The preparation method of the tebuconazole-succinic acid eutectic crystal is implemented according to the following steps:
placing 3.070g of tebuconazole bulk drug and 1.160g of fumaric acid in a round bottom flask according to the molar ratio of 1:1, adding 30mL of methanol into the mixed powder, heating in a water bath at 50 ℃, stirring for 3h, filtering while hot, cooling the filtrate to room temperature, and collecting a solid phase substance to obtain the tebuconazole-fumaric acid eutectic. The measurement was carried out using an X-ray diffractometer model D8 from BRUKER, Germany under the conditions of a Cu-K.alpha.target tube voltage of 40kV, a tube current of 10mA, and a scanning speed of 2 DEG/min, and the PXRD diffraction pattern of the product was the same as that of example 3. The melting point was the same as in example 3.
Example 5
Solubility test of tebuconazole-succinic acid eutectic:
the dissolution rates of the tebuconazole-succinic acid eutectic sample and tebuconazole are respectively measured in water by an excess powder dissolution rate method. Respectively placing excess tebuconazole-succinic acid eutectic sample and tebuconazole sample with equal weight into 2 eggplant-shaped flasks with 100mL, placing the eggplant-shaped flasks into a water bath kettle, simultaneously adding 20mL of water and starting timing, wherein the water bath temperature is 15 +/-0.5 ℃. The test lasted 180 minutes, and 0.5mL was sampled at 1, 2, 3, 4, 5, 10, 15, 30, 60, 120, 180 minutes, with the results shown in FIG. 5.
As can be seen from the figure, the maximum solubility of the tebuconazole-succinic acid eutectic in water is 62.40mg/L which is higher than 32.25mg/L of tebuconazole, which indicates that the pharmaceutical eutectic can improve the solubility of the tebuconazole, and the research result provides scientific basis for improving the bioavailability of the tebuconazole and further playing the bactericidal effect of the tebuconazole under the low-temperature condition.
Example 6
Solubility test of tebuconazole-fumaric acid cocrystal:
the dissolution rates of the tebuconazole-fumaric acid eutectic sample and tebuconazole are respectively measured in water by an excess powder dissolution rate method. Respectively placing an excessive tebuconazole-fumaric acid eutectic sample and a tebuconazole sample with equal weight into 2 eggplant-shaped flasks of 100mL, placing the eggplant-shaped flasks into a water bath kettle, simultaneously adding 20mL of water and starting timing, wherein the water bath temperature is 15 +/-0.5 ℃. The test lasted 180 minutes, and 0.5mL was sampled at 1, 2, 3, 4, 5, 10, 15, 30, 60, 120, 180 minutes, with the results shown in FIG. 6.
As can be seen from the figure, the maximum solubility 52.40mg/L of the tebuconazole-fumaric acid eutectic in water is higher than 32.25mg/L of tebuconazole, which indicates that the pharmaceutical eutectic can improve the solubility of the tebuconazole, and the research result provides scientific basis for improving the bioavailability of the tebuconazole and further playing the bactericidal effect of the tebuconazole under the low-temperature condition.
Example 7
Seed treatment test of tebuconazole-succinic acid eutectic:
1) the preparation of the suspending seed coating agent containing tebuconazole-succinic acid eutectic crystal comprises the following steps:
adding 60g of naphthalenesulfonic acid formaldehyde polymer sodium salt, 20g of PO/EO block polyether, 10g of sodium lauryl sulfate, 5g of silicone oil, 50g of propylene glycol and 2g of sodium benzoate into 500g of deionized water, stirring uniformly, adding 83g of tebuconazole-succinic acid eutectic crystal (molar ratio is 1:1) and 60g of pigment, stirring uniformly, shearing at high speed, sanding by a wet method until the particle size is qualified, finally adding 10g of polyacrylic emulsion, 2g of xanthan gum and deionized water to complement 1000g, stirring uniformly, and filtering to obtain the suspended seed coating agent.
2) Preparing a suspension seed coating agent containing tebuconazole and succinic acid:
adding 60g of naphthalenesulfonic acid formaldehyde polymer sodium salt, 20g of PO/EO block polyether, 10g of sodium lauryl sulfate, 5g of silicone oil, 50g of propylene glycol and 2g of sodium benzoate into 500g of deionized water, stirring uniformly, then adding 60g of tebuconazole, 23g of succinic acid and 60g of pigment, stirring uniformly, carrying out high-speed shearing, then carrying out wet sanding until the particle size is qualified, finally adding 10g of polyacrylic emulsion, 2g of xanthan gum and deionized water to complement 1000g, stirring uniformly, and filtering to obtain the suspension seed coating agent.
3) Preparation of tebuconazole-containing suspension seed coating agent:
adding 60g of naphthalenesulfonic acid formaldehyde polymer sodium salt, 20g of PO/EO block polyether, 10g of sodium lauryl sulfate, 5g of silicone oil, 50g of propylene glycol and 2g of sodium benzoate into 500g of deionized water, stirring uniformly, then adding 60g of tebuconazole and 60g of pigment, stirring uniformly, then carrying out high-speed shearing, then carrying out wet sanding until the particle size is qualified, finally adding 10g of polyacrylic emulsion, 2g of xanthan gum and deionized water to complement 1000g, stirring uniformly, and filtering to obtain the suspension seed coating agent.
4) Seed treatment test:
1kg of wheat seeds (tobacco grower 21, available on the market) and 15mL of liquid medicine (suspension seed coating agent 0.5g + clear water) containing the tebuconazole-succinic acid eutectic suspension seed coating agent are uniformly mixed, a control group 1 is that 1kg of wheat seeds and 15mL of liquid medicine (suspension seed coating agent 0.5g + clear water) containing the tebuconazole-succinic acid suspension seed coating agent are uniformly mixed, a control group 2 is that 1kg of wheat seeds and 15mL of liquid medicine (suspension seed coating agent 0.5g + clear water) containing the tebuconazole-suspension seed coating agent are uniformly mixed, a control group 3 is that 1kg of wheat seeds and 15mL of clear water are uniformly mixed, and the treated seeds are all placed in a ventilated place to be dried.
Referring to part 16 of pesticide field efficacy test guidelines: the bactericide for preventing and treating wheat root rot (NY/T1464.16-2007) performs the rate of emergence investigation, and the experimental result is that: the germination rate of the tebuconazole-succinic acid eutectic test group is 91.50%, the germination rate of the control 1 group is 89.58%, the germination rate of the control 2 group is 90.31%, and the germination rate of the control 3 group is 90.78%.
Example 8
Seed treatment test of tebuconazole-fumaric acid cocrystal:
1) preparation of a suspending seed coating agent containing tebuconazole-fumaric acid eutectic:
adding 60g of naphthalenesulfonic acid formaldehyde polymer sodium salt, 20g of PO/EO block polyether, 10g of sodium lauryl sulfate, 5g of silicone oil, 50g of glycerol and 2g of sodium benzoate into 500g of deionized water, stirring uniformly, adding 82.6g of tebuconazole-fumaric acid eutectic crystal (molar ratio is 1:1) and 60g of pigment, stirring uniformly, shearing at high speed, sanding by a wet method until the particle size is qualified, finally adding 10g of polyacrylic emulsion, 2g of xanthan gum, supplementing 1000g of deionized water, stirring uniformly, and filtering to obtain the suspended seed coating.
2) Preparation of a suspension seed coating agent containing tebuconazole and fumaric acid:
adding 60g of naphthalenesulfonic acid formaldehyde polymer sodium salt, 20g of PO/EO block polyether, 10g of sodium lauryl sulfate, 5g of silicone oil, 50g of glycerol and 2g of sodium benzoate into 500g of deionized water, stirring uniformly, then adding 60g of tebuconazole, 22.6g of fumaric acid and 60g of pigment, stirring uniformly, carrying out high-speed shearing, then carrying out wet sanding until the particle size is qualified, finally adding 10g of polyacrylic emulsion, 2g of xanthan gum and deionized water to complement 1000g, stirring uniformly, and filtering to obtain the suspended seed coating agent.
3) Preparation of tebuconazole-containing suspension seed coating agent:
adding 60g of naphthalenesulfonic acid formaldehyde polymer sodium salt, 20g of PO/EO block polyether, 10g of sodium lauryl sulfate, 5g of silicone oil, 50g of glycerol and 2g of sodium benzoate into 500g of deionized water, stirring uniformly, then adding 60g of tebuconazole and 60g of pigment, stirring uniformly, then carrying out high-speed shearing, then carrying out wet sanding until the particle size is qualified, finally adding 10g of polyacrylic emulsion, 2g of xanthan gum and deionized water to complement 1000g, stirring uniformly, and filtering to obtain the suspension seed coating agent.
4) Seed treatment test:
1kg of wheat seeds (tobacco grower 21, sold in the market) and 15mL of liquid medicine (suspension seed coating agent 0.5g + clear water) containing the tebuconazole-fumaric acid eutectic suspension seed coating agent are uniformly mixed, a contrast group 1 is formed by uniformly mixing 1kg of wheat seeds and 15mL of liquid medicine (suspension seed coating agent 0.5g + clear water) containing the tebuconazole-fumaric acid suspension seed coating agent, a contrast group 2 is formed by uniformly mixing 1kg of wheat seeds and 15mL of liquid medicine (suspension seed coating agent 0.5g + clear water) containing the tebuconazole suspension seed coating agent, a contrast group 3 is formed by uniformly mixing 1kg of wheat seeds and 15mL of clear water, and the treated seeds are all placed in a ventilated place to be dried.
Referring to part 16 of pesticide field efficacy test guidelines: the bactericide for preventing and treating wheat root rot (NY/T1464.16-2007) performs the rate of emergence investigation, and the experimental result is that: the emergence rate of the tebuconazole-fumaric acid eutectic test group is 92.25%, the emergence rate of the control group 1 is 90.13%, the emergence rate of the control group 2 is 90.74%, and the emergence rate of the control group 3 is 91.75%.
The above-mentioned embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the scope of the present invention should be defined by the claims, and equivalents including technical features of the claims, i.e., equivalent modifications within the scope of the present invention.
Claims (10)
1. A tebuconazole cocrystal, characterized by comprising: tebuconazole and organic acids; wherein the molar ratio of the tebuconazole to the organic acid is 10: 1-1: 10; the organic acid is succinic acid or fumaric acid.
2. A co-crystal according to claim 1, wherein the molar ratio of tebuconazole to organic acid is 2:1 to 1: 2.
3. The co-crystal according to claim 2, wherein the molar ratio of tebuconazole to organic acid is 1:1 to 1: 2; the preferred molar ratio is 1: 1.
4. Co-crystal according to any of claims 1 to 3, characterized in that the organic acid, when succinic acid, shows in the spectrum at least 4 of the following diffraction peaks given in 2 θ values: 6.901 ° ± 0.2, 8.404 ° ± 0.2, 12.874 ° ± 0.2, 16.707 ° ± 0.2, 17.808 ° ± 0.2, 18.627 ° ± 0.2, 20.566 ° ± 0.2, 22.117 ° ± 0.2, 23.052 ° ± 0.2, 23.813 ° ± 0.2, 25.079 ° ± 0.2, 26.181 ° ± 0.2, 28.735 ° ± 0.2, 30.438 ° ± 0.2, 31.790 ° ± 0.2, 33.494 ° ± 0.2.
5. A co-crystal according to any of claims 1 to 3, wherein the organic acid is fumaric acid and exhibits in the spectrum at least 4 of the following diffraction peaks given in 2 Θ values: 8.264 DEG + -0.2, 12.630 DEG + -0.2, 14.138 DEG + -0.2, 16.567 DEG + -0.2, 18.548 DEG + -0.2, 19.625 DEG + -0.2, 20.303 DEG + -0.2, 22.364 DEG + -0.2, 23.014 DEG + -0.2, 23.571 DEG + -0.2, 24.937 DEG + -0.2, 25.426 DEG + -0.2, 28.462 DEG + -0.2, 31.320 DEG + -0.2, 31.646 DEG + -0.2, 33.092 DEG + -0.2.
6. A process for the preparation of the co-crystal according to claim 1, characterized in that tebuconazole is mixed with succinic acid or fumaric acid, an alcohol or ester solvent is added, the mixture is stirred with or without heating and then filtered, and the filtrate is left to stand and the solid is collected as the co-crystal.
7. The method according to claim 6, wherein the heating condition is heating at 30 to 70 ℃;
the alcohol solvent is any one or a mixture of methanol, ethanol, propanol or butanol; preferably methanol or ethanol;
the ester solvent is any one or a mixture of more of ethyl acetate, methyl acetate, n-butyl acetate, n-amyl acetate, ethyl valerate, ethyl propionate, ethyl butyrate, ethyl lactate, ethyl nonanoate, triethyl phosphate, ethyl hexanoate, ethyl formate, ethyl cyclohexanecarboxylate, ethyl heptanoate, ethyl cinnamate, ethyl pyruvate and ethyl chrysanthemate; preferably ethyl acetate or ethyl propionate;
the solid-liquid ratio of the mixture of tebuconazole and organic acid to the solvent is (0.3-0.6) g, (5-10) mL.
8. An agricultural formulation comprising an effective amount of the tebuconazole co-crystal of any one of claims 1 to 5; preferably, the composition also comprises an agriculturally acceptable preparation carrier or a preparation auxiliary agent.
9. A method for controlling plant diseases, which comprises applying a fungicidally effective amount of a tebuconazole cocrystal according to any one of claims 1 to 5 or an agricultural formulation according to claim 8 to a plant and/or propagule thereof.
10. Use of tebuconazole co-crystal of any one of claims 1 to 5 or agricultural formulation of claim 8 for controlling plant diseases.
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| 吴正红: "《药剂学》", pages: 379 - 380 * |
| 高占彪: "《定西主要农作物病虫害综合防治技术》", 31 December 2018, pages: 382 - 380 * |
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