Process for the preparation of polyurethane capsules and capsules so obtained

Abstract

The present invention relates to a process for the preparation of polyurethane microparticles suspension encapsulating at least one active ingredient in eco-friendly microsystems. The present invention relates also to polyurethane microparticles suspension obtainable by the process of the invention and their use for delivering said active ingredient in agriculture.

Description

[0001] P024101WO-01 Notarbartolo & Gervasi S.p.A.

[0002] TITLE:

[0003] PROCESS FOR THE PREPARATION OF POLYURETHANE CAPSULES AND CAPSULES SO OBTAINED

[0004] ***** ***** *****

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to a process for the preparation of a suspension of polyurethane microparticles encapsulating hydrophobic active ingredient in eco-friendly microsystems.

[0007] The present invention relates also to polyurethane microparticles suspension obtainable by the process of the invention and their use for delivering said active ingredient in agriculture.

[0008] STATE OF THE ART

[0009] Microplastics is a general term indicating solid polymeric particles less than 5 mm in length according to the European Chemicals Agency (ECHA). Once in the environment, not biodegradable microplastics are accumulated in marine, freshwater, and terrestrial ecosystems which lead to a big impact on the wildlife as well as on the whole food chain.

[0010] Many species mistake microplastics for food, leading to ingestion and potential health problems such as starvation, suffocation, and entanglement as reported by different researchers in the last decades. Furthermore, in an environment dominated by particulate material, microplastics can alter soil chemistry and affect soil organisms’ fitness and function.

[0011] In the literature it is shown that microplastics are frequently detected also in human samples since people are potentially exposed to microplastics through oral intake, inhalation, and skin contact as common ways. The effects connected with their introduction in human body mainly consist of oxidative stress, DNA damage, organ dysfunction, metabolic disorder, immune response, neurotoxicity, as well as reproductive and developmental toxicity. In addition, epidemiological evidence suggests that a variety of chronic diseases may be related to microplastics exposure.P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0012] In light of the above, in 2023, the European Commission adopted a REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) restriction on microplastics intentionally added to products and a proposal for a Regulation on preventing plastic pellet losses to the environment.

[0013] The Ell aims to reduce microplastic releases by 30% by 2030. This will be achieved by

[0014] - reducing plastic pollution (as these degrade into microplastics),

[0015] - restricting the use of intentionally added microplastics to products, and

[0016] - reducing unintentional microplastic releases

[0017] The regulation defines synthetic polymer microplastic as: “polymers that are solid and which either are contained in particles and constitute at least 1 % by weight of those particles, or build a continuous surface coating on particles, where at least 1 % by weight of those particles fulfill either of the following conditions:

[0018] (a) All dimensions of the particles are equal to or less than 5 mm.

[0019] (b) The length of the particles is equal to or less than 15 mm and their length to diameter ratio is greater than 3.”

[0020] However, some exceptions are included, such as:

[0021] • degradable or water-soluble (>2 g / l) polymers and natural polymers that have not been chemically modified,

[0022] • biodegradable polymers, and

[0023] • polymers with no carbon atoms within their own structure.

[0024] Crop protection compounds, including herbicides, insecticides, fungicides, and plant nutrients are often encapsulated either in polymeric matrices or within a core-shell system in their formulation form to achieve one or more purposes listed below:

[0025] • obtaining an active ingredient-controlled release for optimum effectiveness, • retarding the losses of volatile components,

[0026] • protecting the active ingredient against light and oxidation,

[0027] • protecting either employers or final users from harmful or unpleasant materials,

[0028] • preventing premature chemical reactions with other mixture components,P024101WO-01 Notarbartolo & Gervasi S.p.A.

[0029] and

[0030] • reducing actives side effects such as crop toxicity and drifting.

[0031] Nowadays, synthetic polymers such as polyacrylates, polyamides, polyureas or polyurethanes represent the most common materials for encapsulating pesticides. Unfortunately, such materials lack of the required REACH characteristics described above, and the development of new environmentally friendly products is needed. Nevertheless, polyurethanes materials are still widely used in agrochemical industry since such polymer class possess unique attributes which make them ideal for entrapping specific active ingredients. These attributes include a wide range of physical and mechanical properties, chemical functionality, and diversity in specific polymer characteristics.

[0032] Looking at the prior knowledge, no methods have been described to obtain polyurethane microparticles from relatively harmless starting materials and having an adequate biodegradation profile.

[0033] WO 2021 / 260017 illustrates the process to produce microcapsules from NCO terminated polyester-polyol polyisocyanate prepolymer containing at least 2 isocyanate groups and a polyamine as reagent materials. However, polyesters are known to undergo hydrolysis after some time in the environment. In fact, the biodegradability of the examples shown in the document described that the maximum value reached for the products was 38.8%. This result is not in compliance with the Commission Regulation 2023 / 2055 of 25 September 2023 amending Annex XVII to Regulation (EC) No 1907 / 2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) as regards synthetic polymer microparticles. According to the above, a tested item is considered to meet the biodegradation requirement if 60% mineralization is measured as consumed O2 or evolved CO2.

[0034] Moreover, the examples within the document describe the use of aromatic polyisocyanate (i.e. MDI, pMDI, TDI) as preferred reagents which are classified as extremely toxic, sometimes lethal by inhalation, materials (EC regulation 1272 / 2008). The aforesaid issues may result in difficulties on product handling asP024101WO-01 Notarbartolo & Gervasi S.p.A.

[0035] well as a concern for soil and aquatic environment.

[0036] W02023 / 006234A1 relates to (amino)saccharide-based polyurea and / or polyurethane-based microcapsules intended for cosmetic applications. Anyway, no evidence about the efficacy of those microcapsules in crop protection has been demonstrated; furthermore, the inventors still describe the employment of toxic polyisocyanate as starting reagents.

[0037] It is a further object of the invention to provide improved biodegradable microspheres for use in agriculture having improved properties, such as improved stability and a controlled and tunable release of the active ingredients either having a high volatility or being low-melting compounds.

[0038] SUMMARY OF THE INVENTION

[0039] It has now been unexpectedly found by the present inventors that it is possible to produce microparticle suspensions (CS) suitable for agricultural use, comprising at least one active ingredient which is encapsulated within a biodegradable polyurethane shell.

[0040] The use of such microsphere permits the tuned and controlled delivery of active ingredients ensuring a long term formulation stability and excellent flowing behavior at the same time.

[0041] Therefore, the invention relates to a process for the preparation of a capsule suspension containing at least one polyurethane microparticle, wherein said at least one microparticle encapsulates at least one active ingredient, said process comprising the step of:

[0042] a) preparing an oil phase by dissolving the L-lysine ethyl ester diisocyanate in at least one active ingredient;

[0043] b) preparing an aqueous phase;

[0044] c) preparing an oil in water (O / W) emulsion by mixing the oil phase of step a) and aqueous phase of step b);

[0045] d) adding at least one acyclic polyol compound cross-linking agent to the O / W emulsion of step c);P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0046] e) obtaining a suspension of polyurethane microparticles encapsulating the at least one active ingredient of step a).

[0047] The inventors found out an inventive process that allows to obtain a polyurethane microparticles suspension, wherein the microcapsules encapsulate at least one active ingredient for a tuned delivery in agriculture.

[0048] In the present invention the terms capsule, microcapsule, microsphere, and microparticle are used to mean a particle made of a polymer and in the particle size range of 1- 1000 pm as measured by microscopy, laser diffraction and sieving methods.

[0049] Moreover, advantageously the process of the invention uses an eco-friendly polyurethane as an encapsulating agent in order to encapsulate very different crop protection agents. The use of an eco-friendly polyurethane core / shell system allows to avoid the use of microplastics and meet the requirements of the REACH restriction adopted by the European Commission.

[0050] The inventors faced with the problem of encapsulating very highly volatile liquid active ingredients and with active ingredients having a low solubilization rate, preferably less than 10 mg / L at 25°C.

[0051] The inventors advantageously found out the process for obtaining microspheres / microcapsules suitable for encapsulating highly volatile liquid active ingredients or low-melting compounds.

[0052] The microparticles so obtained are solid and very stable in an aqueous medium and can be delivered as a suspension according to the present invention.

[0053] In a preferred embodiment the inventors found a one-step polymerization method to provide improved polyurethane microparticles suspensions for use in agriculture having enhanced properties in terms of physical stability and user-handling characteristics.

[0054] Preferably the oil phase obtained in step a) is an oil phase comprising at least 70% of the at least active ingredient , more preferably at least 80% with respect to the total amount of the oil phase. In this preferred embodiment the active principle is in an advantageous amount and it is released more slowly by the final microparticle.P024101WO-01 Notarbartolo & Gervasi S.p.A.

[0055] In another aspect the invention relates to a suspension of polyurethane microparticles encapsulating the at least one active ingredient obtainable from the process of the invention.

[0056] In a preferred and advantageous embodiment, the invention relates to a suspension of polyurethane microparticles encapsulating the at least one active ingredient, wherein the at least one active ingredient is a highly volatile liquid compound, preferably clomazone.

[0057] The inventors advantageously found out a process for obtaining microparticles suitable for encapsulating highly volatile liquid active ingredients. The microparticles so obtained are solid and very stable.

[0058] In a very advantageous and preferred embodiment the active ingredient is clomazone.

[0059] The polyurethane microparticles suspensions encapsulating the at least one active ingredient obtainable by the process of the invention are suitable for delivering the active ingredients in agriculture field.

[0060] In a very advantageous and preferred embodiment the the active ingredient is clomazone.

[0061] In a preferred and advantageous embodiment, the capsule suspension of the invention comprises as the active ingredient clomazone. In a more preferred and advantageous embodiment, the encapsulated clomazone is in amount from 10 to 60% w / w, preferably from 20 to 30% w / w with respect to the total amount of the formulation.

[0062] The water dispersible dry microparticles obtainable by the process of the invention are suitable for delivering the active ingredients in agriculture field.

[0063] Advantageously the microparticles of the invention allow a tuned and controlled release of the active ingredient, depending on the action of the active principle. In a further aspect, the present invention relates to the use of said polyurethane microparticles suspension in agriculture for delivering one or more active ingredients.

[0064] DETAILED DESCRIPTION OF THE INVENTIONP024101WO-01 Notarbartolo & Gervasi S.p.A.

[0065] Therefore, the invention relates to a process for the preparation of a microcapsule suspension containing at least one polyurethane microparticle, wherein said at least one microparticle encapsulates at least one active ingredient, said process comprising the step of:

[0066] a) preparing an oil phase by dissolving the L-lysine ethyl ester diisocyanate in at least one active ingredient;

[0067] b) preparing an aqueous phase;

[0068] c) preparing an oil in water (O / W) emulsion by mixing the oil phase of step a) and aqueous phase of step b);

[0069] d) adding at least one acyclic polyol compound cross-linking agent to the O / W emulsion of step c);

[0070] e) obtaining a suspension of polyurethane microparticles encapsulating the at least one active ingredient of step a).

[0071] In the present description the following terms and definitions will be used:

[0072] - “microparticle” means a particle made of a polymer and in the particle size range of 1- 1000 pm as measured by microscopy, laser diffraction and sieving methods and comprises in its definition the “microsphere” and “microcapsule”;

[0073] - the term “active ingredient” refers to any hydrophilic or hydrophobic chemical or biological component (ora combination thereof), the application of which causes or provide a beneficial and / or useful effect in agriculture including, but not limited to fertilizers and pesticides including acaricides, fungicides, herbicides, insecticides, and nematicides;

[0074] - “highly volatile liquid” means a liquid having a vapour pressure equal to or above 1 10’4mm Hg, and

[0075] - “low melting compound” is a compound that is in a liquid state below 70°C.

[0076] The microencapsulation procedure as it will be clear from the examples used in this process consists of interfacial polymerization. When compared with bulk polymerization, interfacial polymerization occurs at the interface of two immiscible phases. Hence a primary emulsion must be obtained prior to the encapsulation of the active ingredient in a solid matrix.P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0077] The process comprises the step a) of preparing an oil phase by dissolving the crosslinking agent L-lysine ethyl ester diisocyanate in at least one active ingredient. Preferably the at least one active ingredient is a highly volatile liquid active ingredient, a compound, solid or liquid, having a low solubilization rate, harmful compounds for workers and final users or compounds which need a controlled release.

[0078] More preferably, the at least one active ingredient can be selected from the group consisting of fertilizers, pesticides, comprising preferably acaricides, fungicides, herbicides, insecticides, and nematicides.

[0079] Specifically and preferably, the at least one active ingredient can be selected from the group consisting of

[0080] - an herbicide, preferably clomazone;

[0081] - a thiocarbamate herbicide, preferably triallate, diallate, butylate, cycloate, EPTC and molinate;

[0082] - a pyrethroid, preferably cyfluthrin, lambda-cyhalothrin, bifenthrin, permethrin and resmethrin;

[0083] - a dinitroaniline, preferably pendimethalin, trifluralin, ethalfluralin, , butralin, and benefin / benfluralin;

[0084] - a terpen and / or terpenoid, preferably d-limonene, azadirachtins, carvacrol, 1 ,8-cineole, anisole, limonene, [3-pinene, linalool, menthone, a-pinene, pulegone, myrcene eugenol, borneol, menthol, isomenthol, anethole, camphor, carvone, menthyl acetate, linalyl acetate, thymol, p-cymene, y-terpinene, a-terpineol, 4-terpineol, citronellol and geraniol and

[0085] - an essential oil, preferably cinnamon oil, citronella oil, clove oil, eucalyptus oil, lemongrass oil, mint oil, mint oil, orange oil, peppermint oil, rosemary oil and thyme oil- a chloracetamide: preferably metholachlor and dimethylnamide

[0086] - a carboxylic acid, preferably pelargonic acid

[0087] More preferably the at least one active ingredient is selected from the group consisting of:P024101WC-01 Notarbartolo & Gervasi S.p.A.

[0088] - an isoxazoline-derivate herbicide, still more preferably clomazone, bixolozone, pyroxasulfone, fenoxasulfone and even more preferably clomazone;

[0089] - a thiocarbamate herbicide, still more preferably triallate, diallate, butylate, cycloate, EPTC and molinate; and

[0090] - a pyrethroid, still more preferably cyfluthrin, lambda-cyhalothrin, bifenthrin, permethrin and resmethrin.

[0091] In a preferred and advantageous embodiment, the at least one active ingredient is a highly volatile liquid compound or a low-melting compound.

[0092] Preferably the oil phase obtained in step a) is an oil phase comprising at least 90% of the at least active ingredient , more preferably at least 90% with respect to the total amount of the oil phase.

[0093] In a more preferred and advantageous embodiment, the at least one active ingredient is selected from the group consisting of clomazone, triallate and lambda-cyhalothrin.

[0094] The most preferred active ingredient is clomazone.

[0095] Clomazone, the common name for 2-(2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone, is an active ingredient in highly effective herbicides that are selective against perennial weeds, including grasses and broadleaves. Clomazone works by inhibiting the biosynthesis of carotenoids in the plant; a plant affected by clomazone exhibits progressive whitening with increased dosage. Herbicides containing clomazone are applied to the soil for control of weeds on beans, cabbage, cucumbers, cotton, melons, mint, peas, peppers, rice, soybeans, squash, sugarcane, sweet potatoes, tobacco and tuberous vegetables. Such herbicides are selective against perennial weeds, including grasses and broadleaves.

[0096] Clomazone is a highly volatile compound and therefore it is a problematic active ingredient.

[0097] The same can be repeated for bixolozone, that is a highly volatile liquid herbicide characterized by high vapor tension, hence a significant volatility. Lambda-cyhalothrin, common name of (RS)-alpha-cyano-3-phenoxybenzyl 3-(2-chloro-3,3,3-trifluoropropenyl)-2,2, -dimethylcyclopropanecarboxylate is a syntheticP024101WC-01 Notarbartolo & Gervasi S.p.A.

[0098] pyrethroid insecticide and acaricide used to control a wide range of pests in a variety of applications. Pests controlled include aphids, Colorado beetles and butterfly larvae. Crops on which it may be applied include cotton, cereals, hops, ornamentals, potatoes, vegetables, or others.

[0099] Triallate, IIIPAC name S-(2,3,3-trichloroprop-2-enyl) N,N-di(propan-2-yl) carbamothioate, belongs to the thiocarbamate chemical class. It is a pre-emergence selective herbicide used to control grass weeds in fields and pulse crops. It is used selectively to control wild oats, black grass, and annual meadow grass in barley, wheat, peas, lentils, rye, maize, beets, brassicas, carrots, and onions.

[0100] Triallate needs to be finely released from capsules to carry out a proper weed control with no side effect on crops therefore it is a problematic active ingredient.

[0101] Lambda-cyhalothrin, common name (RS)-alpha-cyano-3-phenoxybenzyl 3-(2-chloro-3,3,3-trifluoropropenyl)-2,2, -dimethylcyclopropanecarboxylate is a synthetic pyrethroid insecticide and acaricide used to control a wide range of pests in a variety of applications. Pests controlled include aphids, Colorado beetles and butterfly larvae. Crops on which it may be applied include cotton, cereals, hops, ornamentals, potatoes, vegetables, or others.

[0102] Lambda-cyhalothrin has a high toxicity degree and it is potentially lethal by inhalation and therefore it is a problematic active ingredient.

[0103] L-lysine ethyl ester diisocyanate, the cross-linking agent of step a) of the process of the invention, is dissolved in the at least one active ingredient in a weight ratio in the range from 1:2.5 to 1:10(w / w), preferably 1:5 (w / w), between L-lysine ethyl ester diisocyanate and the at least one active ingredient

[0104] In a preferred embodiment, the oil phase of step a) comprises the cross-linking agent L-lysine ethyl ester diisocyanate in the range from 5% to 50%, preferably from 7% to 17% (w / w) with respect to the total weight of the oil phase.

[0105] In a preferred embodiment the oil phase of step a) comprises the at least one active ingredient in an amount of at least 70%, preferably from 80% to 90% (w / w) with respect to the total weight of the oil phase.

[0106] Step a) can be carried out preferably in the optional presence of a catalyst.P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0107] When present, the catalyst is preferably selected from the group consisting of triethylamine, dibutyltin dilaurate, 1,4-diazabicyclo [2.2.2] octane, cobaltous stearate, triethylenediamine, stannous 2-ethylhexoate, more preferably it is triethylamine or 1,4-diazabicyclo [2.2.2] octane.

[0108] When present, the catalyst is preferably added in an amount in the range from 0.000000009% to 0.2, preferably 0.000001 to 0.1% (w / w) with respect to the oil phase of step a).

[0109] The process comprises the step b) of preparing an aqueous phase.

[0110] In step b) the aqueous phase is prepared preferably by adding an excipient selected from the group consisting of a wetting agent in water, an emulsifying agent, a dispersing agent and a preservative agent.

[0111] More preferably step b) can be carried out by adding to water at least one excipient selected from the group consisting of a wetting agent, an emulsifying agent, a dispersing agent, and a preservative agent and their mixture.

[0112] Preferably, the wetting agent of step b) is selected from the group consisting of sodium dioctylsulfosuccinate, sodium lauryl sulfate, alkylbenzene sulfonates, alkylphenolethocylates, polysorbates, polyether alcohols and polypropylene glycolethylene oxide condensates more preferably it is sodium dioctylsulfosuccinate. The wetting agent of step b) is preferably dissolved in water in a weight percentage (%) in the range from 1% to 10%, preferably 2.30% (w / w) with respect to the total weight of the aqueous phase.

[0113] Preferably, the emulsifying agent of step b) is selected from the group consisting of calcium lignosulphonate, tristyrylphenol phosphate, castor oil ethoxylate, sodium lauryl sulfate, alkylbenzene sulfonates, alkylphenolethocylates, polysorbates, polyether alcohols and polypropylene glycol-ethylene oxide condensates.

[0114] The emulsifying agent of step b) is added in water in a weight percentage (%) in the range from 1 % to 30%, preferably from 2.45% to 11.30% (w / w) with respect to the total weight of the aqueous phase.

[0115] Preferably, the dispersing agent of step b) is selected from the group consisting of xanthan gum dispersion, fatty acid esters and ethoxylated fatty acid esters, sodiumP024101WG-01 Notarbartolo & Gervasi S.p.A.

[0116] alkyl sulfosuccinates, allyloxybenzene sulfonates, poly(vinyl alcohol), guar gum and hydroxyethyl, more preferably it is a xanthan gum dispersion commercially available as AG RH 23 gel 2.7%.

[0117] The dispersing agent of step b) is added in water in a weight percentage (%) in the range from 1% to 20%, preferably from 2.74 to 11.64% (w / w) with respect to the total weight of the aqueous phase.

[0118] Preferably, the preservative agent of step b) is selected from the group consisting of 1 ,2-benzisothiazolin-3-one, sorbic acid, benzoic acid, propionic acid, parabens and benzalkonium chloride.

[0119] The preservative agent of step b) is added in water in a weight percentage (%) in the range from 0.05% to 0.3%, preferably 0.14% to 0.19% (w / w) with respect to the total weight of the aqueous phase.

[0120] The process comprises the step c) of preparing an oil in water (O / W) emulsion by mixing the oil phase of step a) and aqueous phase of step b); Preferably, the aqueous phase of step b) is added to the oil phase of step a) for preparing the oil in water (O / W) emulsion.

[0121] In the oil in water (O / W) emulsion, the above compounds are present preferably in the following amounts with respect to the total amount of the emulsion:

[0122] - L-lysine ethyl ester diisocyanate, the cross-linking agent of step a) is in an amount in the range from 1 to 7% (w / w), preferably from 2 to 5%, more preferably about 4.4% (w / w);

[0123] - the at least one active ingredient in the range from 5% to 50%, preferably from 15% to 45% (w / w);

[0124] when present, the catalyst is in an amount in the range from 0.000000009% to 0.2%, preferably 0.000001% to 0.1% (w / w);

[0125] - the wetting agent is in the range from 0.1% to 8%, preferably 6% (w / w);

[0126] - the emulsifying agent is in the range from 1% to 10%, preferably from 2% to 6% (w / w), more preferably from 2% to 4%;

[0127] - the dispersing agent is in the range from 0.5% to 10%, preferably from 1.0% to 5.0% (w / w);P024101WO-01 Notarbartolo & Gervasi S.p.A.

[0128] - the preservative agent is in the range from 0.01% to 1%, preferably about 0.1%(w / w).

[0129] Preferably, before step c) a pre-heating is carried out of the aqueous phase and the oil phase, independently from each other, more preferably at a temperature in the range from 20°C to 80°C, still more preferably at 50°C.

[0130] In an advantageous and preferred embodiment, the aqueous phase is poured dropwise into oil phase and homogenized. The homogenization can be carried out preferably with a speed in the range from 500 to 5000 rpm, more preferably at 900 rpm with a homogenizer known in the art.

[0131] The process comprises the step d) of adding at least one acyclic polyol compound cross-linking agent to the O / W emulsion of step c).

[0132] The at least one acyclic polyol cross-linking agent of step d) is preferably a water soluble polyol compound selected from the group consisting of glycerol, di(trimethylolpropane), 1 ,1 ,1-Tris(hydroxymethyl)propane, polyethylene glycols, ethylene glycol, propylene-1 ,3-diol and propylene-1 ,2-diol, and an aliphatic polyol containing an number of hydroxyl groups ranging from 2 to 10, preferably in the range from 3 to 6.

[0133] In an advantageous and preferred embodiment, the at least one acyclic polyol compound cross-linking agent of step d) is added to the O / W emulsion of step c) in a weight percentage (%) in the range from 1% to 14%, preferably in the range from 1 % to 6% (w / w) with respect to the total weight of the emulsion.

[0134] Preferably, after the addition of the at least one acyclic polyol compound crosslinking agent to the O / W emulsion in step d), the resulting emulsion is heated and kept under magnetic stirring.

[0135] In an advantageous and preferred embodiment, the stirring is carried out preferably at a temperature in the range from 20°C to 10°C, preferably at 60°C, more preferably with a speed in the range from 200 to 500 rpm for 4 hours, still more preferably at 400 rpm for 4 hours with a stirrer known in the art.

[0136] The process comprises the step e) of obtaining a polyurethane microparticles suspensions encapsulating the at least one active ingredient of step a).P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0137] Preferably, in step e) the emulsion of step d) is slowly cooled at room temperature and it is stirred.

[0138] The process of the invention allowed the encapsulation of very highly volatile liquid active ingredients and having a low solubilization rate.

[0139] The process of the invention advantageously permits the encapsulation of one or more active ingredients with a loading in the range from 25 to 95% (w / w), preferably from 30 to 90% (w / w) with respect to the total weight of the microparticle.

[0140] In the preferred and advantageous embodiment wherein the active ingredient is clomazone, the encapsulated clomazone is in amount from 30 to 95 % (w / w), preferably from 40 to 95 % (w / w) with respect to the total weight of the m icroparticle. The use of an eco-friendly polyurea matrix allows to avoid the use of microplastics and meet the requirements of the REACH restriction adopted by the European Commission.

[0141] In another aspect, the invention relates to a suspension of polyurethane microparticles encapsulating the at least one active ingredient obtainable from the process of the invention.

[0142] In a preferred and advantageous embodiment, the invention relates to a suspension of polyurethane microparticles encapsulating the at least one active ingredient, wherein the at least one active ingredient is a highly volatile liquid compound, preferably clomazone.

[0143] Advantageously the suspension of the invention comprises a microcapsule capable to release an amount of the at least one active ingredient in the range from 1 to 100%, with respect to the whole amount of the microcapsule suspension.

[0144] The inventors advantageously found out a process for obtaining microparticles suitable for encapsulating highly volatile liquid active ingredients. The microparticles so obtained are solid and very stable. In a very advantageous and preferred embodiment the active ingredient is clomazone.

[0145] The polyurethane microparticles suspensions encapsulating the at least one active ingredient obtainable by the process of the invention are suitable for delivering one or more active ingredients in agriculture field.P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0146] Advantageously the microparticles suspension of the invention allows a tuned and controlled release of the active ingredient, depending on the action of the active principle.

[0147] Preferably, the polyurethane microparticle has a D50 in the range from 1 pm to 40 pm, more preferably 1-15 pm and D90 in the range from 10 pm to 100 pm, more preferably from 15 pm to 40 pm as measured by a laser diffraction analyzer (more preferably analyzer Malvern 3000, Malvern Panalytical, Malvern, UK).

[0148] In a further aspect, the present invention relates to the use of said polyurethane microparticles suspension encapsulating the at least one active ingredient in agriculture for delivering one or more active ingredients.

[0149] EXPERIMENTAL PART

[0150] Example 1 : Preparation of the suspension of microparticles of the invention The microencapsulation procedure used consisted of interfacial polymerization. When compared with bulk polymerization, interfacial polymerization occurs at the interface of two immiscible phases. Hence a primary emulsion must be obtained prior clomazone encapsulation.

[0151] L-Lysine ethyl ester diisocyanate (VWR, Milano, Italy) was dissolved in Clomazone (Sipcam Oxon, Mezzana Bigli, Italy), this mixture represented the oil phase of the primary emulsion. The aqueous phase was obtained by dissolving 6 g of sodium dioctylsulfosuccinate (Geropon SDS, Solvay, Ospiate di Bollate, Italy) in 75.1 ml of deionized water. The two phases were pre-heated at 50°C, then the aqueous phase was poured dropwise into the dispersed phase and homogenized by an Ultraturrax T50, (IKA, Staufen, Germany) at 900 rpm to obtain a O / W emulsion. Afterwards, an aqueous solution containing 3.0 g of glycerol as cross-linking agent and triethylamine (0.1 g) at the aforementioned emulsion and kept under stirring at 400 RPM and 60°C for 4h. Lastly, the temperature was dropped down at room temperature whereas the sample have been stirring overnight to obtain a capsule suspension. Axanthan gum dispersion (AG RH 23 gel 2,7% (w / w), Azelis, Antwerp, Belgium) and the preservative agent 1 ,2-benzisothiazolin-3-one, (Proxel GXL, Antwerp, Belgium) were added after microcapsule maturation occurred.P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0152] The composition is reported in Table 1.

[0153] Table 1. O / W primary emulsion composition

[0154]

[0155] The loading of clomazone was found to be 18.8% (w / w) of the whole formulation by HPLC.

[0156] Particle size analyses were obtained by a laser diffraction analyzer (Malvern 3000, Malvern Panalytical, Malvern, UK) using water as dispersing medium, D50 and D90 obtained were 5.6 and 14.4 pm respectively.

[0157] The release of clomazone from the microparticles were analyzed by dispersing a known weight of powder in a fixed volume of hexane, the amount of released active ingredient was obtained by calculating the difference between the initial loading value and the clomazone amount measured in the supernatant normalized by the microparticle concentration after 1, 5, 15, 30 and 60 minutes. Results are shown in Table 2.

[0158] Table 2. Clomazone releasing profile

[0159]

[0160] Table 2. Clomazone releasing profileP024101WC-01 Notarbartolo & Gervasi S.p.A.

[0161] Suspensibility was analyzed as per the method mentioned for agricultural applications as per CIPAC handbook. 2.5 g sample of the formulation was weighed in a 100 ml beaker and 50 ml of water was added to it. The material was stirred, and the suspension obtained was allowed to remain for 4 minutes in a water bath at temperature of 30 C. Suspension was taken into a 250 ml cylinder with additional quantity of water and maintained up to the 250 ml mark. The cylinder was stoppered and inverted 30 times and kept undisturbed for 30 minutes. After 30 minutes, upper portion 225 ml (9 / 10) of the material was removed by siphon. Suspension remaining at base of the cylinder is transferred to a petri-dish, by rinsing with distilled water and dried to constant weight. Suspensibility was estimated by the following equation:

[0162]

[0163] where a is the mass of sample taken for analysis and b is the mass of sample remaining at bottom of the cylinder. The value obtained was 99.0%.

[0164] The suspension viscosity was measured by transferring 50 ml of sample in a 100 ml beaker at 20°C. The value was obtained by a Brookfield Ametek DV-1+ Viscometer (IIRAI S.p.A., Milan, Italy) using a LV spindle #6 at shear rate of 12 rpm. the resulting viscosity was 800 cPs.

[0165] The pH value was obtained by pouring 1g of formulation in 100 ml of water under magnetic stirring. And it resulted in 5.8.

[0166] Residual evaluation was performed by the “wet sieve method” described in CIPAC Handbook. Analysis of Technical and Formulated Pesticides”. The found residual amount employing both a 45 and 150 pm sieves was 0.02 and 0.05% respectively. Finally, the formulation density resulted 1,0812 g / ml.

[0167] Example 2: Preparation of the suspension of microparticles of the invention A further suspension of microcapsules containing clomazone as encapsulated active ingredient was obtained following the procedure described in example 2 with some modifications.P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0168] A mixture of tristyrylphenol phosphate and castor oil ethoxylate has been used as emulsifying agents whereas dibutyltin dilaurate was added in the oily phase as catalyst. A preservative agent 1 ,2-benzisothiazolin-3-one, (Proxel GXL, Antwerp, Belgium) was added after microcapsule maturation occurred.

[0169] Table 3 shows the amount as %w / w of each component of the formulation of the suspension.

[0170] Table 3. O / W emulsion composition

[0171]

[0172] The loading of clomazone within the whole formulation was found to be 19.6% (w / w) by HPLC considering the whole formulation.

[0173] Particle size analyses of D50 and D90 resulted 14.1 and 50.0 pm, respectively as measured by a laser diffraction analyzer (Malvern 3000, Malvern Panalytical, Malvern, UK) using water as dispersing medium.

[0174] Release profile is shown in Table 4.

[0175] Table 4. Clomazone releasing profile

[0176]

[0177] P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0178]

[0179] Example 3: Preparation of the microparticle of the invention containing bixlozone

[0180] A suspension of microcapsules containing bixlozone (2-(2,4-Dichlorobenzyl)-4,4-dimethylisoxazolidin-3-one) as encapsulated active ingredient was also obtained. Bixlozone is a highly volatile liquid herbicide characterized by a high vapor tension, hence a significant volatility. The need to achieve an active ingredient controlled release for optimum effectiveness as well as the reduction of side effects such as crop toxicity and drifting is necessary. The sample has been obtained following the procedures described in example 2. Table 5 shows the amount as %w / w of each component of the suspension formulation.

[0181] Table 5. O / W emulsion composition

[0182]

[0183] The loading of Carvaclor within the capsule suspension was found to be 19.9% (w / w) of the whole formulation by HPLC. Particle size analyses of D50 and D90 resulted 15.2 and 43.0 pm respectively as measured by a laser diffraction analyzer (Malvern 3000, Malvern Panalytical, Malvern, UK) using water as dispersing medium.

[0184] . Release profiles is shown in Table 6.P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0185] Table 6. Bixlozone releasing profile

[0186]

[0187] Example 4: Preparation of the microparticle of the invention containing lambda cyhalothrin

[0188] A suspension of microcapsules containing lambda cyhalothrin as encapsulated active ingredient was produced. Lambda cyhalothrin is a pyrethroid insecticide harmful to humans because of its severe side effects. The encapsulation of lambda cyhalothrin in a confined system is mandatory in several manufacturing processes to protect either employers or final users. The sample has been obtained following the procedures described in example 2. Glycerol was replaced by 1 ,1 ,1-Tris(hydroxymethyl)propane as cross-linking agent. Table 7 shows the amount as %w / w of each component of the formulation.

[0189] Table 7. O / W emulsion composition

[0190]

[0191] P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0192] The loading of lambda cyhalothrin within the whole formulation was found to be 38.8% (w / w) of the whole formulation by HPLC.

[0193] Particle size analysis results showed values of 7.9 and 21.1 pm for D50 and D90 respectively as measured by a laser diffraction analyzer (Malvern 3000, Malvern Panalytical, Malvern, UK) using water as dispersing medium.

[0194] Results are shown in Table 8.

[0195] Table 8. Lambda cyhalothrin Tech releasing profile

[0196]

[0197] Example 5: Preparation of the microparticle of the invention containing triallate A suspension of microcapsules containing triallate as encapsulated active ingredient was obtained following the procedure described in the example 3. Triallate is a herbicide belonging to the thiocarbamate class and it needs to be finely released from capsules to carry out a proper weed control with no side effect. The sample has been obtained following the procedures described in example 2. Glycerol was replaced by di(trimethylolpropane) as cross-linking agent. Table 9 shows the amount as %w / w of each component of the formulation.

[0198] Table 9. O / W emulsion composition

[0199]

[0200] P024101WG-01 Notarbartolo & Gervasi S.p.A.

[0201]

[0202] The loading of triallate within whole formulation was found to be 19.5% (w / w) of the whole formulation by HPLC.

[0203] Particle size analysis results showed values of 7.9 and 21.1 pm for D50 and D90 respectively as measured by a laser diffraction analyzer (Malvern 3000, Malvern Panalytical, Malvern, UK) using water as dispersing medium.

[0204] Results are shown in Table 10.

[0205] Table 10. Triallate Tech releasing profile

[0206]

Claims

P024101WG-01 Notarbartolo & Gervasi S.p.A.CLAIMS1. A process for the preparation of a suspension containing at least one polyurethane microparticle, wherein said at least one microparticle encapsulates at least one active ingredient, said process comprising the step of:a) preparing an oil phase by dissolving the L-lysine ethyl ester diisocyanate in at least one active ingredient;b) preparing an aqueous phase;c) preparing an oil in water (O / W) emulsion by mixing the oil phase of step a) and aqueous phase of step b);d) adding at least one acyclic polyol compound cross-linking agent to the O / W emulsion of step c);e) obtaining a suspension of polyurethane microparticles encapsulating the at least one active ingredient of step a).

2. The process of claim 1 , wherein the oil phase obtained by step a) is an oil phase comprising at least 70% of at least one active ingredient, preferably at least 80% with respect to the total amount of the oil phase.

3. The process of claim 1 or claim 2, wherein the at least one active ingredient is a very highly volatile liquid active ingredients or is a low-meting compound.

4. The process of anyone of claims 1 to 3, wherein the at least one active ingredient is selected from the group consisting of fertilizers, pesticides, comprising preferably acaricides, fungicides, herbicides, insecticides, and nematicides.

5. The process of claim 4, wherein the at least one active ingredient is clomazone.

6. The process of anyone of claims 1 to 5, wherein in step b) the aqueous phase is prepared by adding at least one excipient selected from the group consisting of a wetting agent in water, an emulsifying agent, a dispersing agent and a preservative agent.

7. The process of anyone of claims 1 to 6, wherein the at least one acyclic polyol cross-linking agent of step d) is a water soluble polyol compound selected from the group consisting of glycerol, di(trimethylolpropane), 1,1,1-Tris(hydroxymethyl)propane, polyethylene glycols, ethylene glycol, propylene-1 ,3-P024101WG-01 Notarbartolo & Gervasi S.p.A.diol and propylene-1 ,2-diol, and an aliphatic polyol containing an number of hydroxyl groups ranging from 2 to 10, preferably in the range from 3 to 6.

8. The process of anyone of claim 1 to 6, wherein the loading of at least one active ingredient is in the range from 25 to 95% (w / w), preferably from 30 to 90% (w / w) with respect to the total weight of the microparticle.

9. A suspension of polyurethane microparticles encapsulating the at least one active ingredient obtainable from the process of anyone of claims 1 to 7.

10. The suspension of polyurethane microcapsules according to claim 8, wherein the at least one active ingredient is a highly volatile liquid compound, preferably clomazone11. A use of the suspension of clam 9 or claim 10 in agriculture for delivering at least one active ingredient.

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