RU2552313C1 - Method of producing microcapsules of heterocyclic compounds of triazine series - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention provides a method of producing microcapsules by non-solvent addition, characterised by that the nucleus of the microcapsules is triazine pesticides and the shell is polyvinyl alcohol, which is deposited from an aqueous solution by adding, as the non-solvent at the beginning, a first precipitant - 5% acetic acid solution in acetone, and then acetone as a second precipitant at 25°C.

EFFECT: simpler and faster process of producing microcapsules of a preparation in water-soluble polymers and higher mass output.

3 ex

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. RF 2092155, IPC A61K 047/02, A61K 009/16, published on 10/10/1997, a method of microencapsulation of drugs based on the use of special equipment using ultraviolet radiation was proposed.

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. RF 2095055, IPC A61K 9/52, A61K 9/16, A61K 9/10, published 10.11.1997, a method for producing solid non-porous microspheres, which includes the melting of a pharmaceutically inactive carrier substance, dispersion of the pharmaceutically active substance in a melt in an inert atmosphere, spraying the obtained dispersion in the form of fog in a freezing chamber under pressure in an inert atmosphere at a temperature of from -15 to -50 ° C and separating 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. RF 2091071, IPC A61K 35/10, 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. RF 2076765, IPC B01D 9/02, 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. RF 2101010, IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19, published 01/10/1998, a chewing form of the drug with a taste masking having the properties of a controlled release of the drug is proposed, which contains microcapsules 100-800 microns in diameter and consists of a pharmaceutical core with crystalline ibuprofen and a polymer coating including 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. RF 2139046, IPC A61K 9/50, A61K 49/00, A61K 51/00, published on 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. RF 2159037, IPC A01N 25/28, A01N 25/30, published on 11/20/2000, a method for producing microcapsules by a polymerization reaction at the phase boundary 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 the articles 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 using the gas-phase polymerization method 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 is a 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 included proteins, which does not significantly reduce their biological activity, carried out by the process interfacial crosslinking of 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 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. RF 2173140, IPC A61K 009/50, A61K 009/127, 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 range 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. JP WO / 2010/137743, 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 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. RF 2165700, 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 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 as a precipitant in the preparation 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 stirred 1000 rpm. After dissolving the components of the reaction mixture until a clear solution forms, 15 ml of the first precipitant (5% solution of acetic acid in acetone) are slowly added dropwise very slowly and then 5 ml of acetone. 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 0.540 g of microcapsule powder. The yield was 90%.

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 stirred 1000 rpm. After dissolving the components of the reaction mixture until a clear solution forms, 15 ml of the first precipitant (5% solution of acetic acid in acetone) are slowly added dropwise very slowly and then 5 ml of acetone. 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 stirred 1000 rpm. After dissolving the components of the reaction mixture until a clear solution forms, 15 ml of the first precipitant (5% solution of acetic acid in acetone) are slowly added dropwise very slowly and then 5 ml of acetone. 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, 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, which 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 of producing microcapsules by non-solvent precipitation, characterized in that triazine pesticides are used as the microcapsule core, polyvinyl alcohol is used as a shell, which is precipitated from the aqueous solution by first adding the first precipitant as a non-solvent - 5% solution of acetic acid in acetone, and then acetone as a second precipitant at 25 ° C.