RU2540431C2 - Method of obtaining microcapsules of heterocyclic compounds of triazine series - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to field of microcapsulation of heterocyclic compounds of triazine series, applied in pharmaceutical industry and agriculture as pesticides. Method of obtaining microcapsules includes physical-chemical method of precipitation with non-solvent with application of polyvinyl alcohol as microcapsule envelope. Carbinol and acetone are used as non-solvent. Preparation E 472c is used as emulsifier.

EFFECT: application of invention simplifies the process of obtaining microcapsules, increase of preparation output by weight.

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Description

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

Previously known methods for producing microcapsules. So, in US Pat. 2092155, IPC A61K 047/02, A61K 009/16, published 10.10.1997, the Russian Federation proposed a method of microencapsulation of drugs based on the use of special equipment using ultraviolet radiation.

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

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

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

In US Pat. 2091071, IPC A61K 35/10, Russian Federation, published 09/27/1997, a method for producing the preparation by dispersion in a ball mill to obtain microcapsules is proposed.

The disadvantages of the proposed method is the duration of the process and the use of a ball mill, the use of which can lead to the destruction of microcapsules.

In US Pat. 2076765, IPC B01D 9/02, Russian Federation, published April 10, 1997. A method for producing dispersed particles of soluble compounds in microcapsules by crystallization from a solution is proposed, characterized in that the solution is dispersed in an inert matrix, cooled, and dispersed particles are obtained by changing the temperature.

The disadvantage of this method is the difficulty of execution: obtaining microcapsules by dispersion with subsequent change in temperature, which slows down the process.

In US Pat. 2101010, IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19, Russian Federation, published January 10, 1998. A chewing form of the drug with a taste masking having the properties of a controlled release of the drug contains microcapsules with a size of 100-800 microns in diameter and consists of a pharmaceutical core with crystalline ibuprofen and a polymer coating comprising a plasticizer flexible enough to withstand chewing. The polymer coating is a methacrylic acid based copolymer.

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

In US Pat. 2139046, IPC A61K 9/50, A61K 49/00, A61K 51/00. Russian Federation, published 10.10.1999 a method for producing microcapsules as follows. An oil-in-water emulsion is prepared from an organic solution containing dissolved mono-, di-, triglyceride, preferably tripalmitin or tristearin and, optionally, a therapeutically active substance, and an aqueous solution containing a surfactant, optionally a part of the solvent is evaporated, add the redispersing agent and the mixture are freeze dried. The freeze-dried mixture is then redispersed in an aqueous carrier to separate the microcapsules from organic residues, and the hemispherical or spherical microcapsules are dried.

The disadvantages of the proposed method are the complexity and duration of the process, the use of freeze-drying, which takes a lot of time and slows down the process of obtaining microcapsules.

In US Pat. 2159037, IPC A01N 25/28, A01N 25/30, Russian Federation, published November 20, 2000. A method for producing microcapsules by a polymerization reaction at the phase boundary containing a solid agrochemical material of 0.1-55 wt.% Suspended in an organic mixed with water liquid, 0.01-10 wt.% non-ionic dispersant, active at the phase boundary and not acting as an emulsifier.

The disadvantages of the proposed method: complexity, duration, the use of high shear mixer.

The article “Development of microencapsulated and gel-like products and materials for various industries”, Russian Chemical Journal, 2001, vol. XLV, No. 5-6, p.125-135 describes a method for producing microcapsules of drugs by gas-phase polymerization, as the authors of the article consider unsuitable the method of chemical coacervation from aqueous media for microencapsulation of drugs due to the fact that most of them are water soluble. The microencapsulation process by gas phase polymerization using n-xylylene includes the following main stages: evaporation of the n-xylylene dimer (170 ° C), its thermal decomposition in a pyrolysis furnace (650 ° C at a residual pressure of 0.5 mm Hg), transfer of reaction products to the “cold” polymerization chamber (20 ° C, residual pressure 0.1 mm Hg), deposition and polymerization on the surface of the protected object. The polymerization chamber is made in the form of a rotating drum, the optimum speed for coating the powder is 30 rpm. The thickness of the shell is regulated by the time of coating. This method is suitable for encapsulation of any solids (with the exception of prone to intense sublimation). The resulting poly-n-xylylene highly crystalline polymer, characterized by high orientation and tight packaging, provides a conformal coating.

The disadvantages of the proposed method are the complexity and duration of the process, the use of gas phase polymerization, which makes the method inapplicable for producing microcapsules of drugs in polymers of protein nature due to denaturation of proteins at high temperatures.

The article “Development of micro- and nanosystems for drug delivery”, Russian Chemical Journal, 2008, vol. LII, No. 1, pp. 48-57, presents a method for producing microcapsules with incorporated proteins, which does not significantly reduce their biological activity, carried out by the interfacial process crosslinking soluble starch or hydroxyethyl starch and bovine serum albumin (BSA) using terephthaloyl chloride. The proteinase inhibitor aprotinin, either native or with a protected active center, was microencapsulated when it was introduced into the aqueous phase. The flattened form of lyophilized particles indicates the preparation of microcapsules or particles of a reservoir type. Thus prepared microcapsules were not damaged after lyophilization and easily restored their spherical shape after rehydration in a buffer medium. The pH of the aqueous phase was decisive in the preparation of durable microcapsules in high yield.

The disadvantage of the proposed method for producing microcapsules is the complexity of the process, which leads to a decrease in the output of microcapsules.

In US Pat. 2173140, IPC A61K 009/50, A61K 009/127, Russian Federation, published September 10, 2001. A method for producing silicon organolipid microcapsules using a rotary-cavitation unit with high shear forces and powerful sonar acoustic and ultrasonic dispersion ranges is proposed.

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

In US Pat. WO / 2010/137743, JP IPC A01N 25/28; A01N 51/00; A01P 7/04; B01J 13/16 published 02/12/2010 describes a method for producing microcapsules containing pesticidal compounds in a fatty acid ester, which delays the release of pesticidal compounds compared to conventional microcapsules. The method of obtaining microcapsules includes:

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

2) adding to the mixture water containing polyols or polyamines, as well as preparing the formation of liquid drops in water;

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

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

The closest method is the method proposed in US Pat. 2165700 Russian Federation IPC A01N 25/28, A01N 53/00, A01N 57/00, published April 27, 2001, which describes a method for producing microencapsulated insecticidal preparations, which consists in the following: solution of a mixture in an organic solvent consisting of natural lipids and organophosphorus and / or a pyrethroid insecticide in a weight ratio of 2-4: 1, dispersed in water to obtain the target product. Using the proposed method can significantly simplify the process of encapsulation of insecticides and provides high quality insecticidal preparation.

The disadvantage of the method proposed in US Pat. 2165700 is dispersion in an aqueous medium, which makes the proposed method not applicable for the preparation of microcapsules of water-soluble preparations in water-soluble polymers.

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

The solution of the technical problem is achieved by the method of producing microcapsules of heterocyclic compounds of the triazine series, characterized in that when the microcapsules are obtained by the physicochemical non-solvent precipitation method, two precipitants are used - carbinol and acetone, and polyvinyl alcohol as the shell of the microcapsules. The process of obtaining microcapsules is carried out using a magnetic stirrer. As an emulsifier, the preparation E472c is used, which is citric acid glycerides.

A distinctive feature of the proposed method is the use of two precipitants - carbinol and acetone - upon receipt of microcapsules by the physicochemical method of precipitation with a non-solvent and polyvinyl alcohol - as a shell of 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), the ratio of 1: 5.

To 10 g of a 5% aqueous solution of PVA add 0.1 g of metribuzin and 0.02 g of the preparation E472c as an emulsifier. The resulting mixture was placed on a magnetic stirrer for stirring at 1000 rpm. After dissolving the components of the reaction mixture until a clear solution forms, 5 ml of carbinol as the first precipitant is very slowly added dropwise, and then 10 ml of acetone as the second. The resulting suspension of microcapsules is left for 1 minute, then filtered on a 16 pore class Schott filter, washed several times with acetone, dried.

Received 564 g of microcapsule powder. The yield was 94%.

EXAMPLE 2. Obtaining microcapsules of propiconazole in polyvinyl alcohol (PVA), the ratio of 1: 5.

To 10 g of a 5% aqueous solution of PVA add 0.1 g of propiconazole and 0.02 g of the preparation E472c as an emulsifier. The resulting mixture was placed on a magnetic stirrer for stirring at 1000 rpm. After dissolving the components of the reaction mixture until a clear solution forms, 5 ml of carbinol as the first precipitant is very slowly added dropwise, and then 10 ml of acetone as the second. The resulting suspension of microcapsules is left for 1 minute, then filtered on a 16 pore class Schott filter, washed several times with acetone, dried.

0.558 g of microcapsule powder obtained. The yield was 93%.

EXAMPLE 3. Obtaining microcapsules of trebuconazole in polyvinyl alcohol (PVA), the ratio of 1: 5.

To 10 g of a 5% aqueous solution of PVA add 0.1 g of trebuconazole and 0.02 g of the preparation E472c as an emulsifier. The resulting mixture was placed on a magnetic stirrer for stirring at 1000 rpm. After dissolving the components of the reaction mixture until a clear solution forms, 5 ml of carbinol as the first precipitant is very slowly added dropwise, and then 10 ml of acetone as the second. The resulting suspension of microcapsules is left for 1 minute, then filtered on a 16 pore class Schott filter, washed several times with acetone, dried.

Received 0.546 g of microcapsule powder. The yield was 91%.

Thus, microcapsules of heterocyclic compounds of the triazine series were obtained. This technique is characterized by high yields, ease of execution using conventional laboratory equipment and is applicable both to the substances given in the examples and to any others that contain a triazine ring. In addition, using the described method it is possible to obtain microcapsules of triazine compounds, which will only be synthesized by organic chemists in the future. The proposed method is applicable to both the pharmaceutical and agricultural industries.

Claims (1)

 A method for producing microcapsules of heterocyclic compounds of the triazine series, characterized in that when precipitating the microcapsules by the physicochemical non-solvent precipitation method, two precipitants are used - carbinol and acetone, polyvinyl alcohol is used as the shell of the microcapsules, and the preparation E 472c is used as an emulsifier.