Method of producing microcapsules of heterocyclic compounds of triazine series

FIELD: chemistry.

SUBSTANCE: invention provides a method of producing pesticide microcapsules via a nonsolvent deposition method, characterised by that the active substances used are heterocyclic compounds of the triazine series and the envelope is polyvinyl alcohol, which is deposited from an aqueous solution by adding butanol and isopropanol at 25°C as the nonsolvent.

EFFECT: simple process of producing microcapsules of a preparation in water-soluble polymers, high mass output.

3 ex

 

The invention relates to the field of microencapsulation of heterocyclic compounds, triazines, which are used in the pharmaceutical industry and agriculture as pesticides.

Previously known methods for producing microcapsules. Thus, in U.S. Pat. 2092155 IPC A61K 047/02, A61K 009/16 published 10.10.1997 Russian Federation proposed a method for microencapsulation of drugs, based on the use of special equipment use of irradiation with ultraviolet rays.

The disadvantages of this method are the duration of the process and the use of ultraviolet radiation, which can influence the formation of microcapsules.

In Pat. 2095055 IPC A61K 9/52, A61K 9/16, A61K 9/10 of the Russian Federation published 10.11.1997 method for obtaining a solid non-porous microspheres includes melting pharmaceutically inactive substance carrier, the dispersion of a pharmaceutically active substance in the melt in an inert atmosphere, spraying the resulting dispersion in the form of a mist in the freezing chamber under pressure, in an inert atmosphere at a temperature of from 15 to 50°C, and the separation of the obtained microspheres into fractions by size. The suspension is intended for administration by parenteral injection, contains an effective amount of these microspheres distributed the pharmaceutically acceptable liquid vector, and the pharmaceutically active substance is insoluble microspheres in a specified liquid medium.

Disadvantages of the proposed method: duration of the process, the use of special equipment.

In Pat. 2091071 IPC A61K 35/10 Russian Federation published 27.09.1997 method for obtaining the drug by dispersion in a ball mill to obtain microcapsules.

Disadvantages of the proposed method is the length of the process and application of ball mill, which can lead to the destruction of the microcapsules.

In Pat. 2076765 IPC B01D 9/02 Russian Federation published 10.04.1997 method for obtaining dispersed particles of soluble compounds in the microcapsules by crystallization from a solution, wherein the solution is dispersed in an inert matrix, cooled and, by changing the temperature, get dispersed particles.

The disadvantage of this method is the difficulty of execution:

obtaining microcapsules by dispersion with subsequent change of temperatures, which slows down the process.

In Pat. 2101010 IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19 Russian Federation published 10.01.1998 proposed chewable form of the drug with taste masking, having the properties of a controlled release drug product contains micro-capsules of the size of the rum 100-800 microns in diameter and consists of pharmaceutical kernel crystalline ibuprofen and polymer coating, including plasticizer, elastic enough to resist chewing. The polymer coating is a copolymer based on methacrylic acid.

The drawbacks of the invention: use of a copolymer based on methacrylic acid, as these polymer coatings can cause cancer; complexity; the duration of the process.

In Pat. 2139046 IPC A61K 9/50, A61K 49/00, A61K 51/00 Russian Federation published 10.10.1999 method for obtaining microcapsules as follows. Emulsion oil-in-water prepared from organic solution containing dissolved mono-, di-, triglyceride, preferably of tripalmitin or tristearin, and possibly therapeutically active substance, and an aqueous solution containing a surfactant, it is possible to evaporate part of the solvent, add redispersible agent and the mixture is subjected to drying by freezing. Subjected to drying by freezing the mixture is then dispersed in an aqueous medium to separate the particles from organic substances and a hemispherical or spherical microcapsules dried.

Disadvantages of the proposed method are the complexity and duration of the process, the use of drying by freezing, which takes time and slows down the process of production of microcapsules.

In Pat. 2159037 M IS TO A01N 25/28, A01N 25/30 Russian Federation published 20.11.2000 method for obtaining microcapsules polymerization reaction at the phase boundary, containing solid agrochemical material 0.1 to 55 wt.%, suspended in peremestivsheesya water organic liquid, from 0.01 to 10 wt.% non-ionic dispersant, active on the phase boundary and is not acting as an emulsifier.

Disadvantages of the proposed method: the complexity, duration, using wysokosciowe mixer.

In the article "Razrabotka microencapsulated and gel products and materials for various industries", Russian chemical journal, 2001, .XLV, No. 5-6, s-135 is described a method of producing microcapsules of drugs by the method of gas-phase polymerization, since the authors considered unsuitable method of chemical koatservatsii from aqueous media for microencapsulation of drugs due to the fact that most of them are water-soluble. The process of microencapsulation by the method of gas-phase polymerization using n-xylylene includes the following basic stages: evaporation dimer n-xylylene (170°C), thermal decomposition of it into the pyrolysis furnace (650°C at a residual pressure of 0.5 mm Hg), the transfer of the reaction products in the "cold" chamber of polymerization (20°C, the residual pressure of 0.1 mm Hg), the precipitation of the polymerization on the surface of the protected object. Luggage polymerization is performed in the form of a rotating drum, the optimal speed for powder coating 30 rpm, the Thickness of the shell is governed by the time of coating. This method is suitable for the encapsulation of any solids (except prone to intense sublimation). The resulting poly-n-xylylene vysokokritichnyh polymer with high orientation and dense packing, provides a conformal coating.

Disadvantages of the proposed method are the complexity and duration of the process, using the method of gas-phase polymerization, which makes the method inapplicable to obtain microcapsules of drugs in polymers protein nature due to the denaturation of proteins at high temperatures.

In the article "Development of micro - and nanosystems in drug delivery". Russian chemical journal, 2008, t.LII, No. 1, p.48-57 presents a method of obtaining microcapsules included with proteins, which does not significantly reduce their biological activity carried out by the process of interfacial crosslinking of soluble starch or hydroxyethylamine and bovine serum albumin (BSA) using terephthaloyl chloride. The proteinase inhibitor is Aprotinin, either native or protected with an active center was microcapsular in his introduction to the composition of the aqueous phase. Sleep is i.i.d. form liofilizovannyh particles indicates obtaining microcapsules or particles tank types. Thus prepared microcapsules were not damaged after lyophilization and easily restored its spherical shape after rehydration in a buffered environment. The pH value of the aqueous phase was crucial in obtaining a solid microcapsules with high output.

The disadvantage of the proposed method of producing microcapsules is the complexity of the process that leads to the reduction of the yield of microcapsules.

In Pat. 2173140 IPC A61K 009/50, A61K 009/127 Russian Federation published 10.09.2001 method for obtaining kremnijorganicheskih microcapsules using a rotary cavitation plants with high shear effort and powerful acoustic phenomena of sound and ultrasound range for dispersion.

The disadvantage of this method is the use of special equipment - rotary-quotational installation, which has ultrasonic action that affects the formation of microcapsules and can cause adverse reactions due to the fact that ultrasound destructive effect on the polymers of protein nature, therefore the proposed method is applicable when working with polymers of synthetic origin.

In Pat. WO/2010/137743 JP IPC A01N 25/28, A01N 51/00; A01P 7/04; B01J 3/16 published 02.12.2010 a method for the production of microcapsules containing pesticide compounds in the air of IRN the th acid, that delays the release timing of pesticide compounds in comparison with the conventional microcapsules. In the method of producing microcapsules includes;

1) maintaining a mixture of the pesticide compound with polyisocyanate from 20 to 60°C for 3 hours or more;

2) adding to the mixture of water containing polyols or polyamine, and preparations for the formation of liquid droplets in the water;

3) formation of a film of polyurethane or polyurea around the drops.

The disadvantages of these methods are the use of special equipment (rotary homogenizer), a multi-stage, which complicates the method of producing microcapsules and makes it long.

The closest method is the method proposed in U.S. Pat. 2165700 Russian Federation IPC A01N 25/28, A01N 53/00, A01N 57/00 published 27.04.2001, which describes a method of obtaining a microencapsulated insecticide, which is as follows: the solution mixture in an organic solvent composed of natural lipids and organophosphorus and/or a PYRETHROID insecticide in the weight ratio of 2-4:1, was dispersed in water to obtain the desired product. Using the proposed method allows to significantly simplify the process of encapsulation of insecticides and provides high quality insecticide preparation.

The disadvantage of the method proposed in path one is by dispersing in an aqueous medium, what makes the proposed method applicable to the production of microcapsules of water-soluble drugs in water-soluble polymers.

The technical problem is to simplify the process of production of microcapsules of the drug in water-soluble polymers, increasing the yield by weight.

The solution of the technical problem is achieved by a method of producing microcapsules of heterocyclic compounds, triazines, wherein upon receipt of the microcapsules physico-chemical method for the deposition nerastvorim uses two precipitator - butanol and isopropanol, and as the shell of the microcapsules is polyvinyl alcohol, the retrieval process is carried out without special equipment.

A distinctive feature of the proposed method is the use of two precipitators butanol and isopropanol in obtaining microcapsules physico-chemical method for the deposition nerastvorim and polyvinyl alcohol as the shell of the microcapsules.

The result of the proposed method is to obtain microcapsules of pesticides at 25°C for 15 minutes.

Example 1 Obtaining microcapsules of metribuzin in polyvinyl alcohol (PVA), a ratio of 1:5

To 10 g of 5% aqueous solution of PVA added 0.1 g of metribuzin and 0.02 g of the drug Is as an emulsifier. The resulting mixture was put into a mixing about 1000/sec. After dissolution of the components is offering the reaction mixture until a clear solution is formed very slowly dropwise 5 ml of butanol as the first precipitator, and then 10 ml of isopropanol as the second. The resulting suspension of microcapsules leave on for 1 minute, then sucked on the filter SCHOTT 16 class then washed several times with isopropanol, dry.

Received 0,522 g of powder of microcapsules. The yield was 87%.

Example 2 Obtaining microcapsules of propiconazole in polyvinyl alcohol (PVA), a ratio of 1:5

To 10 g of 5% aqueous solution of PVA added 0.1 g of propiconazole and 0.02 g of the drug E472c as an emulsifier. The resulting mixture was put into a mixing about 1000/sec. After the dissolution of the components of the reaction mixture until a clear solution is formed very slowly dropwise 5 ml of butanol as the first precipitator, and then 10 ml of isopropanol as the second. The resulting suspension of microcapsules leave on for 1 minute, then sucked on the filter SCHOTT 16 class then washed several times with isopropanol and dried.

Received 0,522 g of powder of microcapsules. The yield was 87%.

Example 3 Obtaining microcapsules of tebuconazole in polyvinyl alcohol (PVA), a ratio of 1:5

To 10 g of 5% aqueous solution of PVA added 0.1 g of tebuconazole and 0.02 g of the drug E472c as an emulsifier. The resulting mixture was put into a mixing about 1000/sec. After the dissolution of the components of the reaction mixture until a clear solution is formed very slowly dropwise 5 ml of butanol as is, I can pay tithing precipitator, and then 10 ml of isopropanol as the second. The resulting suspension of microcapsules leave on for 1 minute, then sucked on the filter SCHOTT 16 class then washed several times with isopropanol and dried.

Received 0,528 g of powder of microcapsules. The yield was 88%.

Thus, the obtained microcapsules heterocyclic triazines. This technique is characterized by high yields, simple design, requires no special equipment and is applicable to both the examples of substances, and any others that contain triazine cycle. Additionally, the described method it is possible to obtain microcapsules compounds, triazines, which will only be synthesized by chemists organically in the future. The proposed method is applicable for pharmaceutical and agricultural industries.

The method of producing microcapsules of pesticides by precipitation with aristotelem, characterized in that the active substances are heterocyclic compounds triazines, as the shell - polyvinyl alcohol, which is precipitated from aqueous solution by adding as herstories butanol and isopropanol at 25 °C.



 

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