Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
  • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
  • A01N25/10—Macromolecular compounds
• • 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
  • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
  • A01N25/12—Powders or granules
• • 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
  • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
  • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
  • A01N41/10—Sulfones; Sulfoxides
• • 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
• • 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
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/88—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with three ring hetero atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5192—Processes

Definitions

• the present invention relates to new, solid active substance formulations comprising solid active substances, dispersants and polymers which together form a finely divided, predominantly amorphous mixture, a process for their preparation and their use for applying the biologically active substances contained.
• Müller et al., Pharm. Ind. 61, No. 1: 74-78 (1999) describes how, by grinding crystalline active ingredients in high-pressure homogenizers to give so-called nanosuspensions, the dissolution rate by increasing the surface area, by increasing saturation solubility, and by Shortening the diffusion distance can be improved.
• G.G. Liversidge et al., Int. J. Pharm. 125: 91 (1995) describes in a similar way that an improvement in the dissolution rate of crystalline active substances can be achieved by grinding in ball mills to form finely divided suspensions.
• New, powdered active ingredient formulations consist of at least one active substance which is solid at room temperature, at least one dispersant, at least one polymer and optionally additives
• Active ingredient, dispersant and polymer form a predominantly amorphous mixed phase.
• these particles can also be embedded in a carrier.
• Predominantly amorphous means that more than half, preferably more than 70% of the active ingredient is amorphous in the formulation according to the invention. Conversely, as a measure of the amorphous state, the degree of crystallinity can be determined in a simple manner known to the person skilled in the art using differential thermal calorimetry (DSC).
• DSC differential thermal calorimetry
• the invention relates to a method for producing amorphous mixtures based on crystalline active substances, in particular active substance formulations based on crystalline active substances, with the steps
• a displacement agent 2 in particular a liquid 2, in which less than 1% by weight of the active ingredient A) dissolves and which can be mixed with the solvent 1 and which causes the active ingredient A) to precipitate, as solution F ,
• a polymer B) especially water-soluble predominantly amorphous polymers, particularly preferably selected from the series: dextrans, dextrins, gum arabic, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, polyaspartic acid and alginates for the solution from step a) and / or to solution F) from step b).
• step e) Removing the solvents from the mixture by in particular freeze-drying, spray drying or spray granulation.
• Mixing is preferably carried out in accordance with step d) and, if appropriate, formation of a turbulent flow through a pressure gradient over the mixing nozzle, by stirring or by ultrasound treatment of the mixed streams.
• the viscosity of solutions E) and F) is kept in particular less than 100 mPas.
• the displacement means 2 can in particular be water or an aqueous solution of an acid, a base or a salt.
• the solvent 1 can preferably be a low molecular weight organic solvent, in particular one selected from the series of short-chain alcohols with 1 to 10 carbon atoms, such as e.g. Methanol, ethanol, 2-propanol, the short-chain glycols, e.g. Ethylene glycol, 1,2-propylene glycol, the short-chain ketones with 3 to 10 carbon atoms, e.g. Acetone, 2-butanone, carboxylic acids, such as e.g. Acetic acid, ether, e.g. Diethyl ether, tetrahydrofuran or methyl tert-butyl ether, esters such as e.g.
• short-chain alcohols with 1 to 10 carbon atoms such as e.g. Methanol, ethanol, 2-propanol
• the short-chain glycols e.g. Ethylene glycol, 1,2-propylene glycol
• the short-chain ketones with 3 to 10 carbon atoms e
• Methyl acetate, ethyl acetate or methyl formate heterocyclic amines such as e.g. Pyridines, formamides such as e.g. Dimethylformamide, or also n-methylpyrrolidone or dimethyl sulfoxide or an aqueous solution of a base or an acid.
• heterocyclic amines such as e.g. Pyridines, formamides such as e.g. Dimethylformamide, or also n-methylpyrrolidone or dimethyl sulfoxide or an aqueous solution of a base or an acid.
• formamides such as e.g. Dimethylformamide
• n-methylpyrrolidone or dimethyl sulfoxide or an aqueous solution of a base or an acid.
• the aforementioned solvents can each be used alone or in a mixture.
• a carrier selected from the series talc, polyethylene glycol, modified starch or high molecular weight sugar, optionally also further polymer B), in each case based on the total weight the formulation.
• Active ingredient A) can be any active ingredient which is sparingly soluble in pure water; its proportion in the finished formulation is 0.5-50% by weight, preferably 5-30% by weight, based on the mixture.
• Dispersant C) or mixture of dispersants are selected specifically for the active ingredient.
• the proportion of the sum of the amount of all dispersants C) in relation to the amount of active compound A) is 0.1 times to 5 times, preferably 0.25 to 3 times, particularly preferably 0.5 times up to 2 times.
• the proportion of the sum of the polymers B) in the finished formulation is 5-90% by weight, preferably 10-80% by weight, particularly preferably 15-75% by weight.
• Suitable dispersants C) can be found in a simple manner known to the person skilled in the art, for example by considering the sedimentation behavior. For this purpose, crystalline or amorphous active ingredient is ground and suspended in equal parts with a selection of dispersants in water (for example 0.2 g of active ingredient in each case with 0.2 g of dispersant in 15 ml of water). The suspension is then redispersed by treatment with ultrasound and the effect of the dispersant is observed on the basis of the sedimentation behavior. Suitable dispersants C) are distinguished by the fact that they greatly delay or prevent the sedimentation of the particulate active ingredient A).
• a dispersant C) is suitable, for example, that the sedimentation up to 30 min. prevented.
• the selection of the dispersants C) to be tested can be restricted in advance by considering the electrochemical interface potential of the active ingredient A) in an aqueous environment and by considering the expected interactions of the dispersant with the active ingredient molecule.
• Suitable dispersants C) for the mixtures according to the invention are all customary nonionic, anionic, cationic and zwitterionic substances with the surface-active properties which are customarily used in formulations. These substances include reaction products of fatty acids, fatty acid esters, fatty alcohols, fatty amines, alkylphenols or alkylarylphenols with ethylene oxide and / or propylene oxide, as well as their sulfuric acid esters, phosphoric acid monoesters and phosphoric acid di-esters, as well as alkyl sulfonates, alkyl sulfates, aryl sulfates, Alkylaryl sulfates, alkyl ether sulfates, alkylaryl ether sulfates, tetra-alkyl ammonium halides, trialkylaryl ammonium halides, alkyl aryl ethoxylates, sorbitan ethoxylates and alkyl amine sulf
• the dispersants C) can be used individually or in a mixture. Reaction products of castor oil with ethylene oxide in a molar ratio of 1:20 to 1:60, reaction products of Cg-C20 alcohols with ethylene oxide in a molar ratio of 1: 5 to 1:50, reaction products of fatty amines with ethylene oxide in a molar ratio of 1: 2 to 1 may also be mentioned : 20, reaction products of 1 mol of phenol with 2 to 3 mol of styrene and 10 to 50 mol of ethylene oxide, reaction products of Cg-Ci2-alkylphenols with ethylene oxide in a molar ratio of 1: 5 to 1:30, alkyl glycosides, Cg-Cig-alkylbenzenesulfonic acid salts, such as Calcium, monoethanolammonium, diethanolammonium and triethanolammonium salts.
• nonionic dispersants C are the products known under the names Pluronic PE 10 100 and Pluronic F 68 (from BASF) and Atlox 4913 (from Uniqema). Tristyrylphenyl ethoxylates are also suitable.
• dispersants C) include copolymers of ethylene oxide and propylene oxide, reaction products of tristyrylphenol with ethylene oxide and / or propylene oxide, such as tristyrylphenol ethoxylate with an average of 24 ethylene oxide groups, tristyrylphenol ethoxylate with an average of 54 ethylene oxide groups or tristyrylphenol ethoxylate propoxylate with an average of 6 ethylene oxide and 8 propylene oxide groups, furthermore phosphated or sulfated tristyrylphenol ethoxylates, such as phosphated tristyrylphenol ethoxylate with an average of 16 ethylene oxide groups, sulfated tristyrylphenol ethoxylate with an average of 16 ethylene oxide groups or ammonium salt of phosphated tristyrylphenol -ethoxylate with an average of 16 ethylene oxide groups, also lipoids, such as phospholipid sodium glycolate or lecithin, and also liguinsulfonates.
• Substances with wetting agent properties are also suitable.
• Alkylphenol ethoxylates, dialkyl sulfosuccinates such as diisooctyl sulfosuccinate sodium, lauryl ether sulfates and polyoxyethylene sorbitan fatty acid esters may be mentioned as preferred.
• Suitable polymers B) for use in formulations according to the invention are predominantly amorphous polymers which are readily soluble in water, especially highly polar polymers, in particular those with different polar functional groups.
• Dextrans, dextrans, gum arabic, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyaspartic acid and alginates are to be mentioned as such. Both individual polymers B) and any mixtures of said polymers B) can be considered.
• polyvinyl alcohol is understood to mean both water-soluble polymerization products of vinyl alcohol and water-soluble, partially saponified polymers of vinyl acetate, preferably with an acetate group content between 1 and 28%, particularly preferably with an acetate group content between 15 and 28%.
• Preferred is polyvinyl alcohol with an average molecular weight between 10,000 and 200,000, particularly preferred between 13,000 and 130,000.
• polyvinylpyrrolidone is to be understood as meaning vinylpyrrolidone-vinyl acetate copolymers with a number between 10,000 and 200,000, preferably between 24,000 and 55,000.
• suitable polymers can be found in the manner known to the person skilled in the art on the basis of the criterion of the most extensive miscibility.
• the glass transition points determined by differential thermoanalysis can be used to assess the miscibility. If there are separate amorphous phases, these are generally distinguished by separate glass transition points.
• a mixed phase can e.g. be identified with a glass transition point that lies between the glass transition points of the respective input materials.
• Another object of the invention is an amorphous mixture based on crystalline active ingredients, in particular active ingredient formulation, consisting of at least
• an active ingredient A which is usually crystalline at 50 ° C.
• a polymer B in particular selected from the series: dextrans, dextrins, gum arabic, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol , Polyaspartic acid and alginates
• a dispersing agent C in particular a nonionic , anionic cationic or zwitterionic surface-active compound
• the mixture has homogeneous primary particles of a mixture of substances A), B), C) with an average particle diameter of ⁇ 5 ⁇ m, preferably ⁇ 2 ⁇ m, particularly preferably ⁇ 1 ⁇ m, the active ingredient A) being here more than 50% is in the amorphous state.
• the dispersion aid C) is preferably selected from the series: reaction products of fatty acids, fatty acid esters, fatty alcohols, fatty amines, alkylphenols or alkylarylphenols with ethylene oxide and / or propylene oxide, and also their sulfuric acid esters, phosphoric acid, monoesters and phosphoric acid diesters, reaction products of ethylene oxide with propylene oxide alkylsulfonates , Alkyl sulfates, aryl sulfates, alkylaryl sulfates, alkyl ether sulfates, alkylaryl ether sulfates, tetraalkylammonium halides, trialkylarylammonium halides, alkylarylethoxylate, sorbitan ethoxylates and alkylamine sulfonates, alone or in any mixture.
• An active substance-containing mixture is preferred, characterized in that the active substance is selected from the range of crop protection agents, such as, for example, herbicides, fungicides, insecticides, acaricides, nematicides, bird repellants, plant nutrients and agents which improve soil structure.
• crop protection agents such as, for example, herbicides, fungicides, insecticides, acaricides, nematicides, bird repellants, plant nutrients and agents which improve soil structure.
• Examples include bistrifluron, boramsulfuron, mesosulfuron-methyl, pyraclostrobin, pyriftalid, abamectin, AC 94,377, acequinocyl, acibenzolar-S-methyl, aclonifen, acrinathrin, AKH-7088, amidosulfuron, amitraz, anilafenos, anthra Azinphos-methyl, Azocyclotin, Azoxystrobin, Beflubutamid, Benalaxyl, Benazolin-ethyl, Benfluralin, Benomyl, Benoxacor, Bensulfuron-methyl, Bensultap, Benzobicyclon, Benzofenap, Benzoximate, Bifenazate, Bifenox, Bifenthrin, Bitertumol, Brertoxanol Bromadiolone, bromethalin, Bromobutide, bromoprop
• a mixture containing active ingredients characterized in that the active ingredient is selected from the range of agents for curing, alleviating or preventing diseases in humans or animals, such as acidosapeutics, analeptics / antihypoxaemics, analgesics / antirheumatics, anthelmintics, antiallergics and antianemics , antiarrhythmics, antibiotics / antiinfectives, Antider ⁇ entiva, antidiabetics, antidotes, antiemetics / antinauseants, anti-convulsants, Antiphasemorrhagi a, antihypertensive agents, hypoglycemics, antihypotensives, anti koagulantia, antifungals, antiparasitic agents, antiphlogistics, antitussives / expectorants, arteriosclerosis agents, bronchodilators / Antiasthmatics, Cholagoga and Bile duct therapeutics, cholinergics, cho
• Enzyme deficiency and Transport proteins fibrinolytics, geriatrics, gout agents, gynecologics, hepatics, hypnotics / sedatives, immunomodulators, cardiacs, coronary drugs, laxatives, lipid-lowering agents, local anesthetics / neural therapies, gastrointestinal agents, migraine drugs, muscle relaxants / calcium ophthalmic agents, ophthalmologics, ophthalmologics, ophthalmologics, ophthalmologics, ophthalmologics, ophthalmologics, ophthalmic drugs Psychotropic drugs, rhinologics / sinusitis agents, roborants / tonics, thyroid therapeutics, sex hormones and the like.
• the invention also relates to the use of the active substance-containing mixtures according to the invention or of the active substance-containing mixtures obtainable by the process for the preparation of active substance-containing suspensions in water or aqueous solvents as crop protection agents, for example as spraying agents or soil treatment agents, and for the production of pharmaceutical preparations, for example in oral dosage form.
• the method is preferably carried out according to the following principle:
• Solution E is mixed with solution F, the product thus obtained is largely dried.
• Solution E consists of a solvent 1, dissolved therein the active ingredient A), and optionally the dispersant C) and optionally the polymer B).
• Solution F a displacement agent (solvent 2), dissolved in the polymer, and optionally the dispersant.
• the solutions usually contain:
• Solution E solvent 1, active ingredient A) and dispersant C)
• Solution E solvent 1, active ingredient A), polymer B) and dispersant C)
• Solution F displacement agent 2, polymer B) and dispersant C)
• Displacement agent 2 is preferably water, but can also be any other liquid which is completely miscible with solvent 1 and in which the active ingredient A) dissolves poorly.
• Poor solubility here means a solubility of less than 1% by weight, preferably less than 0.1% by weight, particularly preferably less than 0.01% by weight.
• Suitable solvents 1 are all solvents which are miscible with the displacement agent 2. Particularly suitable solvents are those in which the active compound A) has a solubility greater than 1% by weight, preferably greater than 10% by weight.
• Mixing takes place, for example, by feeding solutions E and F uniformly and continuously to a mixing chamber.
• solutions E and F uniformly and continuously to a mixing chamber.
• it is advisable to generate violent turbulence for an intensive mixture. It is irrelevant whether the turbulence is generated by pressure loss in a mixing nozzle, by stirring, by ultrasound, or in any other way.
• the viscosity of both solutions is less than 100 mPas, preferably less than 50 mPas, particularly preferably less than 20 mPas. It is also advantageous if the difference in the viscosity of the two solutions is small. If necessary, the viscosity of the solutions can be adjusted by appropriately dividing the polymers B) between the two solutions or by diluting the solutions accordingly.
• the above-mentioned method can also be used to obtain a formulation by precipitating an active ingredient from its salt, which is present in aqueous solution.
• the active ingredient is an acid that is displaced from its salt by adding a stronger acid.
• the active ingredient can also be a base, which is displaced from its salt by adding a stronger base.
• the solvent is the aqueous base / acid corresponding to the active ingredient, which dissolves the active ingredient by salt formation.
• the displacement agent is the aqueous solution of the stronger acid / base, which displaces the active ingredient from its salt.
• the acids that can be used include, for example, HC1, H 2 SO 4 , HNO 3 , or HF.
• the bases that can be used include, for example, NaOH, KOH, Ba (OH) 2 , or Ca (OH) 2 .
• the drying of the suspension obtained can be carried out in a manner known per se by e.g. Freeze drying, spray granulation and in particular spray drying take place.
• a carrier before drying, which combines the nanoparticulate active substance particles into macroscopic particles.
• the amount of carrier is conveniently 10-30% by weight of the finished formulation.
• a suitable carrier is selected in a manner known per se and can be, for example, a mixture of talc and a polyethylene glycol, an additional polymer B) such as modified starch, or high molecular weight sugar. In a simple manner, the carrier can also be an excess of one of the polymers used for stabilization.
• the carrier which is useful for better handling, can be added before mixing in one or both of the solutions mentioned above, or after mixing, before the fine-particle suspension is added.
• the powdered active ingredient formulations according to the invention consist of individual primary particles which essentially consist of a homogeneous mixture of the active ingredient, the dispersant and the polymer.
• the particles are predominantly in the amorphous state and have an average diameter in the nanometer range.
• the average particle diameter is generally between 20 and 2,000 nm, preferably between 50 and 1,000 nm.
• the formulations according to the invention are redispersible powders which consist of finely divided active ingredient particles and which are optionally embedded in a carrier.
• the powder formulations according to the invention are stable even after prolonged storage (e.g. 1 year). They can be converted into homogeneous suspensions with a primary particle size of less than 5 ⁇ m by stirring in water, or they release the finely divided active ingredient particles after contact with body fluids.
• the application rate of the powder formulations according to the invention can be varied within a substantial range. It depends on the active substances present and their content in the formulations.
• Active ingredients can be used in a particularly advantageous manner with the aid of the powder formulations according to the invention.
• the active ingredients contained are readily bio-available and develop a biological effectiveness that is significantly better than that of conventional formulations in which the active components are in a crystalline state.
• FIG. 1 The invention is explained in more detail below using FIG. 1 as an example.
• FIG. 1 shows a diagram of an apparatus suitable for carrying out the method. Examples
• FIG. 1 An apparatus, the schematic representation of which is shown in FIG. 1, is preferably used to carry out the method according to the invention. Mean in this figure
• Solution E is placed in storage container 1 and, if necessary, adjusted to the desired temperature for better solubility or to reduce the viscosity.
• Temperature can be any temperature, preferably between 20 ° C and the boiling point of the solvent, but can also be higher, for which purpose the corresponding pressure is set in storage container 1.
• Solution F is placed in tank 2 and, if necessary, adjusted to the desired temperature for better solubility or to reduce the viscosity.
• Temperature can be any temperature, preferably between 20 ° C and the boiling point of the displacement agent, but can also be higher, for which purpose the corresponding pressure is set in container 2.
• the pumps 3 for increasing the pressure should work as pulsation-free as possible, gear pumps are favorable. Pumps with pulsation are also possible, provided the pulsation is reduced by an appropriate expansion tank.
• a pressure loss across the mixing chamber of 10-12 bar is sufficient for mixing, with viscosities greater than 20 mPas it is advantageous to increase the pressure loss across the mixing chamber to 30-50 bar. Larger pressures are also possible.
• the collecting container 5 can be operated discontinuously and continuously. In the case of discontinuous operation, the collecting container can either be empty or filled with the desired additives before the start of the test.
• the additives can also from template 6 with With the help of the Förde ⁇ umpe 7 together with the nanodisperse suspension from the mixing chamber 4 to the collecting container 5 are supplied.
• the residence time of the suspension in the collecting container 5 should be chosen to be as short as possible. A dwell time of less than 30 minutes is preferred, preferably less than 10 minutes.
• the nanodisperse suspension from the mixing chamber 4 can also be fed directly into the dryer 9 if no further additives are added.
• the temperature of the drying is based on the boiling points of the solvent and the displacement agent. Drying can be carried out at normal pressure or negative pressure. A temperature of less than 80 ° C. is usually chosen, preferably less than 50 ° C. Drying can also be done by freeze drying.
• Polyvinylpyrrolidone K30 (CAS No. 9003-39-8, FLUKA)
• Fluoxastrobin (5, 6-dihydro-1, 4,2-dioxazine-3-yl) (2 - ((6- (2-chloropheroxy) -5-fluoro-4-pyrimidinyl) -oxy) -phenyl) 4nethanone-o-methyl oximes
• Soprophor® 3D-33 phosphoric acid-mono-diester mixture of a tristyrylphenol ethoxylate, approx. 16 EO (from Rhodia)
• Prothioconazoles 2- [2- (l-chlorocyclopropyl) -3- (2-chlorophenyl) -2-hydroxypropyl] -l, 2-dihydro-3H-l, 2,4-triazole-3-thione sodium hydroxide solution, NaOH aqueous sulfuric acid, H 2 SO aqueous
• Solution E 12 g of N2- (l, l-dimethyl-2-methylsulfonylethyl) -3-iodo-Nl- ⁇ 2-methyl-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl ⁇ phthalamide, 12 g alkyl polyglycoside Glucopon ⁇ 600 CS UP are dissolved in 54 g N-methylpyrrolidone at 20 ° C.
• Solution F 12 g polyvinylpyrrolidone K30, 12 g polyvinyl alcohol Mowiol ⁇ 3-83 are dissolved in 198 g demineralized water at ambient conditions.
• Solution E is fed to the mixing chamber at 10 kg / h, solution F at 32 kg / h and mixed turbulently, so that a mixing ratio of 1 / 3.2 is established.
• the suspension is collected in a beaker without any other additives.
• the suspension obtained has an average diameter of the suspended primary particles of 0.94 ⁇ m (measurement by laser diffraction)
• the suspension is dropped into liquid nitrogen, the solid obtained is freeze-dried.
• An amorphous product is obtained according to DSC measurements.
• Solution E 12 g of N2- (l, l-dimethyl-2-methylsulfonylethyl) -3-iodo-Nl- ⁇ 2-methyl-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl ⁇ phthalamide, 12 g alkyl polyglycoside Glucopon ⁇ 600 CS UP are dissolved in 54 g N-methylpyrrolidone at ambient conditions.
• Solution F 12 g polyvinylpyrrolidone K30, 12 g polyvinyl alcohol Mowiol ⁇ 3-83 are dissolved in 198 g demineralized water at ambient conditions.
• Solution E is fed to the mixing chamber at 12 kg / h, solution F at 35 kg / h, so that a mixing ratio of 1 / 2.92 is achieved.
• the suspension is collected in a beaker and mixed with 24g PLURAFAC ® LF 132 plasticizer and 24g Mowiol ⁇ 3-83 polyvinyl alcohol.
• the suspension is quenched in liquid nitrogen and freeze-dried.
• An amorphous product is obtained according to DSC.
• a sample is stored for 2 weeks at 54 ° C, the sample remains in the amorphous state according to the DSC measurement.
• Solution E 12 g of N2- (l, l-dimethyl-2-methylsulfonylethyl) -3-iodo-Nl- ⁇ 2-methyl-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl ⁇ phthalamide, 12 g alkyl polyglycoside Glucopon ⁇ 600 CS are dissolved in 54 g N-methylpyrrolidone at ambient conditions.
• Solution F 12 g polyvinylpyrrolidone K30, 12 g polyvinyl alcohol Mowiol ⁇ 3-83 are dissolved in 330 g demineralized water at ambient conditions.
• Solution E is fed to the mixing chamber at 7 kg / h, solution F at 40 kg / h, so that a mixing ratio of 0.175 / 1 is established.
• the suspension is collected in a beaker without any other additives.
• the suspension obtained has an average diameter of 0.95 ⁇ m (laser diffraction)
• the suspension obtained is quenched in liquid nitrogen and freeze-dried.
• Solution E 60 g fluoxastrobin, 40 g acetone, 45 g Soprophor® 3D-33
• Solution F 45 g Polyvinylpyrrolidone K30, 45 g Ffl-CAP ⁇ 100, 345 g demineralized water
• Solution E is fed to the mixing chamber at 5.7 kg / h, solution F at 15.3 kg / h, so that a mixing ratio of 1 / 2.68 is established.
• the suspension is collected in a beaker without any other additives.
• the suspension obtained is quenched in liquid nitrogen and freeze-dried.
• An amorphous product is obtained according to the DSC measurement.
• Example 4 The procedure was as in Example 4, but based on a different mixing ratio and other additives.
• Solution E 49.5 g fluoxastrobin, 100.5 g acetone, 37.1 g Soprophor® 3D-33
• Solution F 37.1 g of polyvinylpyrrolidone K30, 123.8 g of Mowiol ⁇ 3-83, 774.6 g of fully demineralized water
• Solution E is fed into the mixing chamber at 5.7 kg / h, solution B at 27 kg / h, so that a mixing ratio of 1 / 4.74 is achieved.
• the suspension obtained has an average diameter of 0.30 ⁇ m (LKS)
• the suspension is collected in a beaker and mixed with a solution of 198 g Genapol ⁇ C 100 plasticizer and 594 g water.
• the suspension is quenched in liquid nitrogen and freeze-dried.
• Another active ingredient was used:
• Prothioconazole melting point 140 ° C. Another method was used for the precipitation from the salt of the active ingredient.
• Solution E 25 g prothioconazole, 44 g sodium hydroxide solution 10% by weight, 12.5 g Soprophor® 3D-33, diluted to 250 ml with deionized water.
• Solution F 49 g sulfuric acid 10% by weight, 25 g polyvinylpyrrolidone K30, 25 g Mowiol ⁇ 3-83, diluted to 250 ml with deionized water.
• Solution E is fed to the mixing chamber at 5 1 h, solution B at 5 1 / h and mixed turbulently, so that a volumetric mixing ratio of 1/1 is established.
• the suspension is collected in a beaker without any other additives.
• the suspension obtained is quenched in liquid nitrogen and freeze-dried.
• the insecticidal activity of the formulations from Preparation Examples 1-3 can be demonstrated in the biological test of the xylem-systemic activity.
• Live maize plants (2-3 leaves) were transferred from the soil to 20 ml test tubes.
• an application zone was delimited with a fat barrier.
• 30 ml of a 417 ppm active ingredient spray solution were applied with a pipette, which corresponds approximately to an application rate of 250 g active ingredient / ha.
• the part of the leaf above the application zone was cut off and divided into two parts, a proximal and a distal. These leaf parts were placed in petri dishes (filled with 4 ml of 1% agar) together with 3 L2 larvae of Spodoptera frugiperda. After three and five days, feeding and mortality were evaluated. After three days, the larvae were fed untreated corn leaves.
• Leaves were used that were cut off in the fully developed state from golden Delicious apple trees.
• the cuticles were isolated in such a way that leaf disks marked and punched out with dye were first filled by vacuum infiltration with a pectinase solution (0.2 to 2% strength) buffered to a pH value between 3 and 4, sodium azide was then added and the leaf disks treated in this way were left to stand until the original leaf structure had dissolved and the non-cellular cuticle had become detached.
• the cuticles were placed with tweezers in the middle on the edges of the diffusion cells, which were coated with silicone grease, and sealed with a ring that was also greased.
• the arrangement was chosen so that the morphological outside of the cuticles was directed outwards, ie towards the air, while the original inside was facing the inside of the diffusion cell.
• the diffusion cells were filled with water or with a mixture of water and solvent.
• Spray liquor A (according to the invention)
• Spray liquor B conventional suspension concentrate of the fungicidal active ingredient stated in Example 3 in 1 liter of water. Active substance content 1,000 ppm
• CIPAC water was used in each of the spray liquors.
• test results are shown in the following table.
• the figures given are average values from 8 measurements.

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