RU2540063C1 - Method of obtaining microcapsules of heterocyclic compounds of 1,2,4-triazine series - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: in the process of obtaining microcapsules by a physical-chemical method of precipitation by means of a non-solvent, a heterocyclic compound is dissolved in DMSO, the obtained solution is transferred into a PVP water solution, the first precipitating agent - a mixture of acetic acid in acetone, containing octyl ether of acridonacetic acid (OeAAA) as SAS, is added, and after that, the second precipitating agent - a mixture of OeAAA in acetone is added, the obtained suspension is filtered, washed with acetone and dried.

EFFECT: realisation of the invention makes it possible to simplify the process of obtaining microcapsules and increase the output by weight.

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Description

The invention relates to the field of microencapsulation of heterocyclic compounds of the 1,2,4-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 on 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 11/10/1997 a method for producing solid non-porous microspheres includes melting a pharmaceutically inactive carrier substance, dispersing the pharmaceutically active substance in a melt in an inert atmosphere, spraying the resulting dispersion into 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 04/10/1997 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 10.01.1998 a chewing form of the drug with a taste masking having the properties of a controlled release of the drug contains microcapsules the 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 possibly a therapeutically active substance, and an aqueous solution containing a surfactant, possibly a portion of the solvent is evaporated, a redispersing agent is added the 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 11/20/2000 A method for producing microcapsules by a polymerization reaction at the interface, containing solid agrochemical material 0.1-55 wt.% Suspended in an organic liquid mixed with water, 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-aprotinin inhibitor, 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 value of the aqueous phase was decisive in obtaining durable microcapsules with 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 and ultrasonic sonar phenomena for dispersion 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 December 2, 2010 describes a method for producing microcapsules containing pesticidal compounds in a fatty acid ester, which delays the release time of pesticidal compounds compared to conventional microcapsules. In a way. receiving 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 on 04/27/2001, which describes a method for producing microencapsulated insecticidal preparations, which consists in the following: a 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 to the technical problem is achieved by the method of producing microcapsules of heterocyclic compounds of the triazine series, characterized in that upon receipt of the microcapsules by the physicochemical method of precipitation with a non-solvent, a mixture of acetone and acetic acid is used as the precipitator, and polyvinyl alcohol is used as the shell of the microcapsules, the production process is carried out without special equipment .

A distinctive feature of the proposed method is the use of a mixture of acetone with acetic acid (or water) as a precipitant in the preparation of microcapsules by the physicochemical method of precipitation with a non-solvent and polyvinylpyrrolidone (PVP) 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 PVP, the ratio of 1: 3

18 g of a 5% aqueous solution of PVP are placed in a 150 ml beaker, placed on a magnetic stirrer and stirring is started. 0.3 g of metribuzin is dissolved in 2 ml of DMSO with heating. The resulting solution was cooled and transferred dropwise into a solution of PVP. After the formation of an independent solid phase with 1,2,4-triazide, the first precipitant is poured (5% solution of acetic acid in acetone containing 0.2% octyl ester of acridonoacetic acid (OAAA) as a surfactant) in an amount of 50 ml, and then the second - 0 , 2% OAAA solution in 15 ml of acetone. The resulting suspension of microcapsules is filtered on a Schott filter and washed with acetone. Dry in a desiccator over calcium chloride.

1.1 g of microcapsule powder obtained. The yield was 91.67%.

EXAMPLE 2. Obtaining microcapsules of propiconazole in PVP, the ratio of 1: 3

18 g of a 5% aqueous solution of PVP are placed in a 150 ml beaker, placed on a magnetic stirrer and stirring is started. 0.3 g of propiconazole is dissolved in 2 ml of DMSO with heating. The resulting solution was cooled and transferred dropwise into a solution of PVP. After the formation of an independent solid phase with 1,2,4-triazide, the first precipitant is poured (5% solution of acetic acid in acetone containing 0.2% octyl ester of acridonoacetic acid (OAAA) as a surfactant) in an amount of 50 ml, and then the second - 0 , 2% OAAA solution in 15 ml of acetone. The resulting suspension of microcapsules is filtered on a Schott filter and washed with acetone. Dry in a desiccator over calcium chloride.

Received 1.05 g of microcapsule powder. The yield was 87.5%.

EXAMPLE 3. Obtaining microcapsules trebuconazole in PVP, the ratio of 1: 3

18 g of a 5% aqueous solution of PVP in benzene are placed in a 150 ml beaker, placed on a magnetic stirrer and stirring is started. 0.3 g of 1,2,4-triazide is dissolved in 2 ml of DMSO with heating, 1 ml of alcoholic 2% OC-20 solution is added. The resulting solution was cooled and transferred dropwise into a solution of PVP. After formation of an independent solid phase with 1,2,4-triazide, a precipitant is added 3 ml of water with OC-20.

The resulting suspension of microcapsules is filtered on a Schott filter and washed with acetone. Dry in a desiccator over calcium chloride.

Received 1.11 g of microcapsule powder. The yield was 92.5%.

Thus, microcapsules of heterocyclic compounds of the 1,2,4-triazine series were obtained. This technique is characterized by high yields, ease of execution, does not require special 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 that will only be synthesized by organic chemists in the future. The proposed method is applicable for both pharmaceutical and agricultural industries.

Claims (1)

 A method for producing microcapsules of 1,2,4-triazine heterocyclic compounds, characterized in that upon receipt of the microcapsules by physicochemical precipitation with a non-solvent, the heterocyclic compound is dissolved in DMSO, the resulting solution is transferred to an aqueous solution of PVP, the first precipitant is added - a mixture of acetic acid in acetone containing acridonoacetic acid octyl ester (OeAAA) as a surfactant, and then the second precipitant is a mixture of OeAAA in acetone, the resulting suspension is filtered off, washed with acetone and dried.