Method for production of concentrates of preferably water-soluble active agents

Abstract

The invention relates to a method for production of concentrates of water-soluble active agents, wherein, in a waterless method using solid active agents as starting materials, the crystals of an active agent are uniformly distributed in a first organic solvent to which a dispersing agent is added, the viscosity of the solution thus obtained is adjusted as applicable by a suitable auxiliary agent, a polymer creator is added to the solution thus obtained, in a second organic solvent as applicable, wherein the viscosity of either the solution to be added or the solution to be obtained is adjusted by the addition of a suitable auxiliary agent, and a crosslinking agent having at least two functional groups in a third organic solvent is given to the obtained solution, wherein the viscosity of either the added or obtained solution is in turn adjusted by the addition of a suitable auxiliary agent and the polymer creator is selected from the group comprising low-viscosity polymethylene-polyphenylisocyanate, preferably having an average NCO content of 25-35, particularly preferably 30-32%, and mixtures thereof.

Claims

1. A method for the preparation of concentrates of a water-soluble active agent comprising: distributing crystals of an active agent in a first organic solvent or solvents in a water-free process using solid active agents as a starting material with addition of a dispersant to obtain a solution; adding a polymer forming agent to the solution in a water-free process, wherein the polymer forming agent is a polymethylene polyphenyl isocyanate; and adding a crosslinking agent having at least two functional groups to the solution in a water-free process, either before or after the addition of the polymer forming agent, wherein the crosslinking agent is an at least bifunctional crosslinking agent for an isocyanate (NCO) group that is or comprises triethanolamine (TEA) and is added in an at least a stoichiometric amount; wherein concentrates of a water-soluble active agent are prepared.

2. The method of claim 1, wherein the polymer forming agent is comprised in an organic solvent that is different from the first organic solvent or solvents.

3. The method of claim 1, wherein the polymethylene polyphenyl isocyanate with low viscosity has a medium NCO content of 25-35%.

4. The method of claim 3, wherein the polymethylene polyphenyl isocyanate with low viscosity has a medium NCO content of 30-32%.

5. The method of claim 1, wherein the crosslinking agent is comprised in an organic solvent that is different from the first organic solvent or solvents.

6. The method of claim 1, wherein the viscosity of the solution is adjusted by adding a suitable auxiliary at any point in the method.

7. The method of claim 1, wherein the active agent is selected from the group consisting of a biologically active agent, insecticidal agent, herbicidal agent, fungicidal agent, acaricidal agent, algaecidal agent, microbicidal agent, microbistatic agent, rodenticidal agent, antibiotic agent, repellent, attractant, pheromone, fragrance and flavor.

8. The method of claim 1, wherein the dispersant is a graft polymer of polyvinyl pyrrolidone and an alkylation group of 4 to 30 carbon atoms.

9. The method of claim 1, wherein the first organic solvent or solvents is selected from the group consisting of an ester of plant oil, terpene hydrocarbon, aliphatic or aromatic hydrocarbon, and ether or ester of a natural or technical aliphatic or aromatic alcohol in branched or unbranched form.

10. The method of claim 9, wherein at least one solvent used is selected from the group consisting of a methyl ester or ethylhexyl ester of a medium chain saturated or mono- or polyunsaturated fatty acid having 8 to 16 carbon atoms without any reactive hydroxyl group or orange terpene.

11. The method of claim 1, wherein the preparation further comprises that it takes place at a temperature between 10 and 80° C.

12. The method of claim 11, wherein the preparation further comprises that it takes place at a temperature between 40 and 60° C.

13. The method of claim 1, further defined as occurring at a temperature at which the organic solvent or solvents have such a low vapor pressure that under reaction conditions no potentially explosive atmosphere is formed.

14. A powder or granule, comprising concentrates of a water-soluble active agent obtainable by the method of claim 1.

15. The method of claim 1, wherein the dispersant is a graft polymer of polyvinyl pyrrolidone and an alkylation group of 16 carbon atoms.

Description

EXAMPLE 1

Basics

(1) In the following steps a coating of Acetamiprid-crystals with a hydrophobic layer of polyurethane is described: I. 50 g of dry-milled Acetamiprid with an average particle size d50 of 5-6 μm is dispersed into a solution of 142 g Radia® 7118 (methyl laurate) of Oleon NV (NL) and 2.9 g Agrimer® AL 22 (an alkylated polyvinylpyrrolidone) of ISP International Specialty Products (US) at room temperature with a high shear mixer and then heated to 50° C. II. A mixture consisting of 9.4 g Voranate® M 220 (polymethylene polyphenyl isocyanate) of The Dow Chemical Company (US) and 3.5 g Surfadonee® LP 300 (linear N-alkyl-2-pyrrolidone) of ISP International Specialty Products (US) is then slowly added dropwise to the dispersion and then the mixture is stirred for 10 minutes. III. A solution is prepares from 3.7 g of triethanolamine (TEA) and 9.4 g Surfadonee® LP 300 and this is very slowly added dropwise over a period of about 60 minutes. IV. For a sufficient reaction rate, the temperature is kept between 50 and 60° C. After about 10 minutes, the reaction begins to start and the solution begins to thicken. In order to avoid an excessive thickening of the suspension during the coating reaction, the solution isd stirred vigorously with an Ultra Turrax® homogenizer of IKA Werke GmbH & Co. KG (DE). Inadequate stirring during the reaction leads to the formation of polymer lumps, which may result in a non-homogeneous coating. V. Then the dispersion is stirred for 2 further hours at 50° C. and then cooled again to room temperature.

(2) In order to determine the level or the quality of the coating, the prepared dispersion is dispersed into a liquid water-based building protection film in such an amount that the content of Acetamiprid in the finished film is 2 g/kg.

(3) 4 g of this liquid film, corresponding to 8 mg coated Acetamiprid are then extracted in 100 ml of water and the content of acetamiprid is determined with HPLC-UV.

(4) The following results were determined.

(5) TABLE-US-00001 Acetamiprid in Extraction time solution mg/100 mol Acetamiprid dissolved 30 minutes 1.04 13% 24 hours 2.40 30% 48 hours 2.64 33%  7 days 2.96 37%

(6) According to literature Acetamiprid has normally a solubility of 400 mg/100 ml at 20° C. From the results listed in the table above it becomes clear that the solubility was reduced significantly by the coating of the crystals.

EXAMPLE 2

Regulation of the Hydrophobization by the Amount of Polymer Forming Agent

(7) In this example, the amount of polymer forming agent is doubled compared with Example 1, furthermore the coating was carried out in orange terpene as solvent. I. 50 g of ground Acetamiprid with an average particle size of 5-6 μm is dispersed into a solution consisting of 135 g of orange terpene and 2.5 Agrimer® AL 22 at room temperature using a high shear mixer and then the solution is heated up to 45° C. II. 25.2 g Voranate® M 220 are mixed with 25.2 g Citrofol® B1 (acetyltributyl citrate) of Jungbunzlauer (AT) and slowly added dropwise to the dispersion. III. 9.2 g of triethanolamine are slowly added dropwise under high shear mixing of the dispersion over a period of 60 minutes. The dispersion is constantly agitated. IV. The reaction is completed when the solution does not thicken any more when the mixing is stopped. This is the case after further 30 minutes of stirring. V. After the end of the reaction the dispersion is stirred for 2 hours at 40° C.

(8) The quality of the coating was examined using the same method as described in Example 1.

(9) TABLE-US-00002 Acetramiprid in Extraction time solution mg/100 ml Acetamiprid dissolved 30 Minutes 0.40  5% 24 Hours 0.72  9% 48 Hours 0.80 10%  7 Days 1.20 15%

(10) In this case, the doubling of the polymer also results in a doubling of the hydrophobization of the crystals of the active agent. It can also be demonstrated by this example that the coating works in another solvent medium.

EXAMPLE 3

Definition of the Quantity Range

(11) Here, the amount of polymer forming agent is reduced by 50% compared to Example 1.

(12) This experiment is carried out corresponding to example 1. However, the amount of Voranate M 220® is reduced from 9.2 g to 4.6 g and the amount of triethanolamine is reduced from 3.7 g to 1.85 g.

(13) Quality tests as described in example 1 and 2 revealed that after 30 minutes already 100% of the Acetamiprid is dissolved. Therefore the coating is insufficient.

EXAMPLE 4

Definition of the Temperature Range

(14) Amounts and reagents correspond to those of example 1, but here the entire batch is cooled to keep the temperature during the coating process constantly under 15° C. The result of this is that the reaction starts only after 2 hours and proceeds very slowly. Besides the solution thickens very much in spite of intensive stirring, so that a compact paste is produced.

(15) The reason for this behavior is the increasing viscosity of the dispersion at low temperatures, causing the particles to clump together. Therefore, dispersion media with low viscosity are preferred for carrying out the coating at low temperatures.

(16) The quality of the obtained capsule is very similar to that of Example 1.

EXAMPLE 5

Effect of Changing the Cross-Linking Agent

(17) The same production method as in example 1 was chosen but using diethanolamine instead of triethanolamine as a crosslinking agent. The resulting high increase in viscosity of the solution during the coating process leads to a rather doughy mass. Crystals are not sufficiently coated with the polymer.

(18) Quality tests as described for example 1 and 2 revealed that already after 30 minutes 80% of the Acetamiprid is dissolved.

EXAMPLE 6

Effect of Changing the Solvent

(19) In this experiment an attempt was made to coat the Acetamiprid crystals using a different vegetable oil ester, ethylhexyl oleate (Radia® 7331 of the company Oleon) as solvent. Due to insufficient miscibility and likely reaction of the polymer forming agent with this solvent there was no sufficient coating of the crystals and the attempt had to be stopped.

EXAMPLE 7

Coating of Acetamiprid With 18.89 G of Polymer/100 G Acetamiprid

(20) This test is based on the basics of Example 1, wherein the steps are as set forth therein. The slightly higher temperature of 60° C. is chosen.

(21) TABLE-US-00003 Component Quantity Radia ® 7118 509.0 g Agrimer ® AL 22 10.3 g Heat up to 60° C. - Ground Acetamiprid @ 98.0% 180.0 g Disperse with Ultra Turrax ® - Premix of polymer forming agents (see below) 47.5 g Add slowly, stir for 10 min - Premix crosslinker (see below) 44.3 g Add slowly over 30 min, stir vigorously - Hold temperature for 1 h at 60° C. - Radia ® 7118 80.0 g Allow to cool to room temperature and stir overnight - Total 871.0 g

(22) TABLE-US-00004 Quantity Polymer forming agent Premix Surfadonee ® LP 300 10.3 g Voranate ® M220 34.0 g Total 44.3 g Crosslinker Premix Surfadone ® LP 300 34.0 g Triethanolamine (TEA) @ 100.0% 13.4 g Total 47.5 g

EXAMPLE 8

Coating of Acetamiprid With 9.44 G Polymer/100 G Acetamiprid

(23) The amounts of polymer forming agent premix and crosslinker premix were cut in half compared with example 7, therefore the calculated amount of coating was cut in half as well.

(24) TABLE-US-00005 Component Quantity Radia ® 7118 554.9 g Agrimer ® AL 22 10.3 g Heat up to 60° C. - Ground Acetamiprid 98.0% 180.0 g Disperse at Turrax ® - Premix polymer forming agent (see below) 23.73 g Add slowly, stir for about 10 minutes Premix crosslinker (see below) 22.1 g Add slowly within 15 min - Keep temperature for 1 h at 60-65° C. - Radia ® 7118 80.0 g Allow to cool to room temperature and stir overnight - Total 871.0 g

(25) TABLE-US-00006 Quantity Polymer forming agent Premix Surfadonee ® LP 300  5.1 g Voranate ® M220 17.0 g Total 22.1 g Crosslinkers Premix Surfadonee ® LP 300 17.0 g Triethanolamine (TEA) @ 100.0%  6.7 g Total 23.7 g

(26) The example of U.S. Pat. No. 5,911,923 B1 was carried out for comparative purposes, however the obtained dispersion of microcapsules in the solvent used according to U.S. Pat. No. 5,911,923 B1 (a mixture of toluene, ethyl acetate and soybean oil), proved not to be stable, furthermore the obtained microcapsules exhibited only a low wall thickness, therefore the active agent could diffuse quickly through it. When using the solvent preferably used according to the invention a significant improvement was obtained already. Example 9 shows the method according to U.S. Pat. No. 5,911,923 B1 using the preferred solvent according to the invention (but without the use of diamines as a cross-linking agent) with an already substantially improved encapsulation of the active agent used.

EXAMPLE 9

Coating of Acetamiprid With 18.89 g of Polymer/100 g of Acetamiprid)

(27) In this experiment a diol was used (in this case propylene glycol) instead of the amino alcohol preferred according to the invention, wherein the polymerization reaction is conducted in the presence of a polymerization catalyst. Here 1,4-diazabicyclo[2.2.2]octane serves as catalyst, which is commonly used in the preparation of polyurethanes. The calculated coating thickness is the same as in example 7.

(28) TABLE-US-00007 Component Quantity Radia ® 7118 512.2 g Agrimer ® AL 22 10.3 g Heat to 60-65° C. - Ground Acetamiprid @ 98.0% 180.0 g Disperse well at Turrax ® - Premix polymer forming agent (see below) 44.30 g Add slowly and stir for about 10 minutes - Crosslinker catalyst premix (see below) 44.3 g Add slowly dropwise at 60-65° C. - Total 791.0 g Yield 791.0 ml

(29) TABLE-US-00008 Quantity Polymer forming agent Premix Surfadone ® LP 300 10.3 g Voranate ® M220 34.0 g Total 44.3 g Yield 44.3 ml Crosslinker Catalyst Premix Surfadone ® LP 300 34.0 g Propylene glycol 9.5 g DABCO 0.8 g Total 44.3 g Yield 44.3 ml

EXAMPLE 10

Comparative Example, Not According to the Invention, Typical Micro-Encapsulation According to the O/W Emulsion Process For Obtaining 16.00 G Of Polymer/100 G of Acetamiprid

(30) This is a typical way of drug encapsulation not according to the invention, as it would be carried out by someone skilled in the art on the basis of published literature. In the process the active substance Acetamiprid is dissolved in a water-immiscible solvent (organic phase) and emulsified in an aqueous medium (water phase), wherein the disadvantage is that the water already solves part of the Acetamiprid during emulsification. Polyisocyanate was used as encapsulating polymer, which engages with a diamine as cross-linking agent in surface polymerization and thus forms a shell of polyurea.

(31) TABLE-US-00009 Component Quantity Water phase @ 50° C. 939 g Oil phase @ 60° C. 610 g Ethylenediamine solution 20% strength 17 g Encapsulate with Turrax ® - Stir for 2 h at 50° C. - Silfoam ®SRE, antifoam of Wacker Chemie AG, DE An antifoaming agent 15.1 g Glucopon ®215 UP BASF (DE) a non-ionic surfactant 56 g the rest was left out Proxel ® GXL from Lonza (IT), a biocide 4.0 g Citric acid 7.9 g Demineralized water 126.6 g Rhodopol ® of Brenntag (AT), Xanthan gum 23 at 2% 183 g Total 1958 g Yield 1958 ml

(32) TABLE-US-00010 Oil phase Quantity Purasolv ® EHL, 2-ethylhexyl-L-lactate 395 g Voranate ® M 220 16 g Acetamiprid 100 g Purasolv ® EHL 99 g Total 610 g Yield 610 ml

(33) TABLE-US-00011 Water phase Quantity Demineralized water 713 g Silfoam (TM) SRE 0.5 g Agrimer ® AL-10 LC 11.9 g Glucopon ® 215 UP 3.7 g PVP K-30 ®′ water-soluble polyvinylpyrrolidone 32 g Silfoam ® SRE, antifoam 0.3 g Demineralized water 178 g Total 939 g Yield 939 ml

(34) The last 4 examples 7 to 10 will now be compared for their encapsulating quality. For this purpose the liquid building protection film which was already mentioned in the quality control of example 1 and 2 with a content of 2 g/kg Acetamiprid is prepared and dried. The dried film is then extracted with 100 ml of water and the amount of Acetamiprid dissolved in the water is analytically determined over time.

QUALITY CONTROL OF EXAMPLE 7

Embodiment of the Invention With Tea and 18.89 G of Polymer/100 G Acetamiprid

(35) TABLE-US-00012 Weighed Acetamiprid sample Content in the in solution Dissolved Extraction time [g] film [g/kg] [mg/100 ml] Acetamiprid 30 Minutes 6.4 2.2 1.085 8% 24 Hours 6.4 2.2 1.8 13% 48 Hours 6.4 2.2 2.2 16%

QUALITY CONTROL OF EXAMPLE 8

Embodiment of the Invention With Tea; 9.44 G of Polymer/100 G Acetamiprid

(36) TABLE-US-00013 Weighed Acetamiprid sample Content in the in solution Dissolved Extraction time [g] film [g/kg] [mg/100 ml] Acetamiprid 30 Minutes 5.7 2 10.5 92% 24 Hours 5.7 2 10.5 92% 48 Hours 5.7 2 — —

QUALITY CONTROL OF EXAMPLE 9

Embodiment With Diol and Dabco; 18.89 G of Polymer/100 G Acetamiprid

(37) TABLE-US-00014 Weighed Acetamiprid sample Content in the in solution Dissolved Extraction time [g] film [g/kg] [mg/100 ml] Acetamiprid 30 Minutes 5.4 2.1 5.3 47% 24 Hours 5.4 2.1 5.7 50% 48 Hours 5.4 2.1 6.2 55%

QUALITY CONTROL OF EXAMPLE 10

Comparative Example (Embodiment Not According to the Invention With Emulsifying Process, 16.00 G of Polymer/100 G Acetamiprid)

(38) TABLE-US-00015 Weighed Acetamiprid sample Content in the in solution Dissolved Extraction time [g] film [g/kg] [mg/100 ml] Acetamiprid 30 Minutes 5.3 2.1 10 90% 24 Hours 5.4 2.1 — — 48 Hours 5.4 2.1 — —

(39) It can be seen clearly here that in the embodiment of the coating according to the invention the active ingredient is released much more slowly than in a traditional, non-inventive embodiment. If Acetamiprid is used as an active agent a solution delay which is suitable for the purpose of the building protection film occurs, starting with an amount of about 19 g polymer forming agent per 100 g Acetamiprid. Cutting the amount of polymer forming agent in half does not lead to a suitable solution delay any more as shown in Example 3 and 8.

(40) The optimum quantity of polymer forming agent for specific application depends inter alia on the shape and average particle size of the coating substrate and it is up to the expert to determine it by means of calculations and experiments for the individual purpose.