RU2439090C1 - Method of producing interpolymer complex - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention describes a method of producing an interpolymer complex via radical polymerisation of methacrylic acid on a polymer matrix - polyethylene glycol in the presence of a polymerisation initiator while heating in a solvent medium, characterised by that polymerisation is carried out at temperature 80-95C in the medium of an organic solvent - mixture of toluene and cyclohexane, taken in ratio 25-50 - 75-50 wt %, respectively, with molar ratio methacrylic acid: polyethylene glycol: solvent equal to 1:1:(6.5-13.5), followed by filtration and drying. ^ EFFECT: obtaining an interpolymer complex in form of a homogeneous finely dispersed powder with low residual monomer content and high output. ^ 1 cl

Description

The present invention relates to the field of polymer chemistry, namely, to a method for producing an interpolymer complex of polymethacrylic acid (PMAA) with polyethylene glycol (PEG). The PMAA-PEG interpolymer complex is used in medicine as a polymeric carrier designed to create sustained release drugs.

The authors of the invention were faced with the task of developing a method for producing an interpolymer complex, which would simultaneously allow it to be obtained in the form of a homogeneous finely divided powder, easily tableted in the presence of a drug source and practically containing no residual monomer (<0.15 wt.% According to TU 2219 -478-00208947-2007).

A known method of producing an interpolymer complex by mixing aqueous solutions of polyacrylic or polymethacrylic acid with polyethylene glycol at a molar ratio of 1: 1. The total concentration of polymers varies from 0.02 to 6 g per 100 g of water. Depending on the pH of the solution, the resulting interpolymer complex precipitates as a swollen precipitate or remains in a dissolved state (Bailey F.E. Journal of Polymer Science, 1964, v. 2, No. 2, p. 845-851).

The disadvantages of this method include the difficulty of isolating the interpolymer complex and the need to use dilute polymer solutions.

When the interpolymer complex precipitates, it can be separated by filtration, but upon drying it forms a continuous glassy mass, which must be crushed for further use. If the interpolymer complex remains in solution, then it can be isolated by freeze drying or spray drying. However, both of these methods are extremely energy-intensive and inefficient, which entails a significant increase in the cost of the final product.

There is also a method of producing an interpolymer complex of PMAA with PEG in solution for use as a gel carrier of prolonged subcutaneous injection drug substances (International Application WO 9535093, A61K 47/10, published on 12.28.1995).

According to this method, the interpolymer complex is obtained by mixing aqueous solutions of PEG and PMAA taken in an equimolar ratio, followed by the gradual addition of a 10 M hydrochloric acid solution to the resulting mixture. The released interpolymer complex is removed from the solution in the form of a rubbery wet mass and dissolved in anhydrous ethanol. The yield of the interpolymer complex is about 95 wt.%. For use, the resulting solution, containing about 1/3 of the water, is diluted to a ratio of ethanol: water = 1: 1 to reduce its viscosity for ease of administration through a syringe.

The described method allows to obtain an interpolymer complex of PMAA with PEG only in the form of a solution and is not technologically advanced for industrial production due to the need to use dilute aqueous solutions and the inability to obtain an interpolymer complex suitable for tabletting without additional processing to create sustained-release oral drugs.

The closest in technical essence to the claimed method is a method for producing an interpolymer complex by the method of matrix polymerization, which is described in the journal "High Molecular Compounds", 1972, v.14 (a), p.2462-2471. The interpolymer complex is obtained in an aqueous medium by polymerization of acrylic or methacrylic acid on a polymer matrix - polyethylene glycol - at a temperature of 45-50 ° C and with a molar ratio of acid: PEG: water: initiator equal to 1: 1: 1323.7-1582.8: 0 , 0089-0.0106. Potassium persulfate is used as an initiator. At the end of the polymerization process, the interpolymer complex remains in solution.

The main disadvantage of this method is the use of diluted reagents (working concentrations of MAK, AK and PEG are equal to 3.5-4.17 · 10 ^-2 mol / l or in terms of the maximum total concentration of the used reagents 0.54 wt.%), And the difficulty of isolating the finished product from the solution by freeze drying or spray drying. This method is very energy intensive and inefficient.

The aim of the invention is to obtain an interpolymer complex in the form of a homogeneous fine powder with a low residual monomer content and high yield.

This goal is achieved by the fact that in the method for producing an interpolymer complex by radical polymerization of methacrylic acid on a polymer matrix - polyethylene glycol - in the presence of a polymerization initiator when heated in a solvent medium, the polymerization is carried out at a temperature of 80-95 ° C in an organic solvent - a mixture of toluene with cyclohexane taken in a ratio of 25-50 ÷ 75-50 wt.%, respectively, with a molar ratio of methacrylic acid: polyethylene glycol: solvent equal to 1: 1: (6.5-13.5), followed by filter drying and drying.

Benzoyl peroxide, azobisisobutyronitrile, tert-butyl peroxyisobutyrate, etc. can be used as a radical initiator of polymerization.

The invention is illustrated by the following examples of specific performance.

Example 1

9.5 g (0.216 mole) of polyethylene glycol (PEG), 18.66 g (0.216 mole) of MAA, 60.5 g (0.658 mol) of toluene, 187.8 g are charged into a reactor equipped with a stirrer, a thermometer and a reflux condenser. (2.236 mol) cyclohexane.

Turn on the stirrer and heat the contents of the reactor to 75 ° C. At this temperature, 0.086 g (0.000355 mol) of benzoyl peroxide dissolved in 2.4 ml (2.08 g, 0.023 mol) of toluene are charged. Then the reaction mixture is heated to 80 ° C. Polymerization takes 3 hours. The precipitated polycomplex is filtered off and dried at 70-75 ° C and reduced pressure for 5-7 hours.

A finely dispersed amorphous white powder is obtained with an average particle size of ~ 1 micron and a bulk density of 170 g / cm ³ .

The output of the polycomplex is 27.0 g (95.8 wt.%). The content of residual monomer MAK 0.05 wt.%.

The determination of the residual content of methacrylic acid was carried out in accordance with TU 2219-478-00208947-2007 by gas-liquid chromatography with the introduction of an internal standard.

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

Example 2

The method is carried out analogously to example 1. Download 9.5 g (0.216 mole base) of polyethylene glycol (PEG), 18.66 g (0.216 mole) of MAA, 45.9 g (0.5 mole) of toluene and 112 g (1.33 mole) of cyclohexane, heated to 75 ° C, 0.059 g (0.000324 mol) of benzoyl peroxide dissolved in 2.4 ml (2.08 g, 0.023 mol) of toluene are added. The mixture is heated to 82 ° C. The process takes 3 hours. Obtain 27.5 g (97.6 wt.%) Of the polycomplex with a residual monomer MAK content of 0.01 wt.%.

The conditions for obtaining the interpolymer complex and its properties are given in the table.

Example 3

Carried out analogously to example 1. Download 9.5 g (0.216 mole base) of polyethylene glycol (PEG), 18.66 g (0.216 mole) of MAA, 65.6 g (0.713 mole) of toluene and 101.5 g (1.21 mole ) cyclohexane, heated to 75 ° C and injected with 0.061 g (0.00025 mol) of benzoyl peroxide dissolved in 2.4 ml (2.08 g, 0.023 mol) of toluene. The mixture is heated to 84 ° C. The process takes 3 hours. Obtain 27.3 g (97.0 wt.%) Polycomplex with a residual monomer MAK of 0.06 wt.%).

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

Example 4

Carry out analogously to example 1. Download 9.5 g (0.216 mole) of polyethylene glycol (PEG), 18.66 g (0.216 mol) of MAA, 59.5 g (0.657 mole) of toluene and 61.6 g (0.734 mole) of cyclohexane , heated to 75 ° C, and 0.047 g (0.00019 mol) of benzoyl peroxide dissolved in 2.4 ml (2.08 g, 0.023 mol) of toluene are added. The mixture is heated to 86 ° C. The process takes 3 hours. Obtain 27.4 g (97.4 wt.%) Polycomplex with a residual monomer MAK of 0.06 wt.%.

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

Example 5

Carried out analogously to example 1. Download 9.5 g (0.216 mole) of polyethylene glycol (PEG), 18.66 g (0.216 mole) of MAK, 126.9 g (1.377 mol) of toluene and 128 g (1.39 mol) of cyclohexane , heated to 75 ° C, and 0.086 g (0.000355 moles) of benzoyl peroxide in 2.4 ml (2.08 g, 0.023 moles) of toluene are added. The mixture is heated to 95 ° C. The process takes 3 hours. Obtain 27.5 g (97.6 wt.%) Of the polycomplex with a residual monomer MAK content of 0.05 wt.%.

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

Example 6 (prototype).

The following are examples 7-18 for comparison.

Example 7

In a reactor equipped with a stirrer, a thermometer and a reflux condenser, a solution of 9.5 g (0.216 mole) of PEG, 18.66 g (0.216 mole) of MAA and 0.059 g (0.00024 mole) of benzoyl peroxide in 160 g (1 , 7 moles) of toluene. Turn on the stirrer and heat the contents of the reactor to 110 ° C. The process takes 3 hours. The resulting polycomplex is filtered off, washed with toluene and dried under reduced pressure. The output of the polycomplex is 26.2 g (93.0 wt.%). The residual monomer MAK content of 0.45 wt.%.

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

Example 8

Carry out analogously to example 7. In a reactor equipped with a stirrer, thermometer and reflux condenser, load a solution of 9.5 g (0.216 mole) of PEG, 18.66 g (0.216 mole) of MAA and 0.059 g (0.00024 mole) of benzoyl peroxide in 202 g (2.4 mol) of cyclohexane, heated to 80 ° C. The process is carried out for 4 hours. The resulting polycomplex is filtered off, washed with cyclohexane and dried at 75-80 ° C for 6 hours. Obtain 25.6 g (91.0 wt.%)) With a residual monomer MAK content of 0.2 wt.%.

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

Example 9

Carry out analogously to example 7. In a reactor equipped with a stirrer, thermometer and reflux condenser, load a solution of 9.5 g (0.216 mole) of PEG, 18.66 g (0.216 mole) of MAA and 0.059 g (0.00024 mole) of benzoyl peroxide in 188 g (2.4 mol) of benzene, heated to 80 ° C. The process is carried out in 4.5 hours. The resulting polycomplex is filtered off, washed with benzene and dried under reduced pressure. 26.4 g (93.8 wt.%) Are obtained with a residual MAK monomer content of 0.5 wt.%.

The conditions for obtaining the interpolymer complex and its properties are given in the table.

Example 10

Carry out analogously to example 7. In a reactor equipped with a stirrer, thermometer and reflux condenser, load a solution of 9.5 g (0.216 mole) of PEG, 18.66 g (0.216 mole) of MAA and 0.059 g (0.00024 mole) of benzoyl peroxide in 160 g (2.76 mol) of acetone, heated to 55 ° C. The process is carried out for 7 hours. The resulting polycomplex is filtered off, washed with acetone and dried. Obtain 26.3 g (93.5 wt.%) With a residual monomer MAK content of 0.38 wt.%.

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

Example 11-17.

The composition of the solvent, synthesis conditions and properties of the finished product are shown in the table.

Example 18

The method is carried out analogously to example 2. Download 9.5 g (0.216 mole base) of polyethylene glycol (PEG), 18.66 g (0.216 mole) of MAA, 45.9 g (0.5 mole) of toluene and 112 g (1.33 mole) of cyclohexane, heated to 75 ° C, 0.059 g (0.00024 mol) of benzoyl peroxide dissolved in 2.4 ml (0.023 mol) of toluene are added and the reaction mixture is kept at 82 ° C for 3 hours. Get 25.9 g (92.0 wt.%) Polycomplex with a residual monomer MAK of 0.03 wt.%.

The conditions for obtaining the interpolymer complex and its properties are shown in the table.

A method of obtaining an interpolymer complex and its properties No. p / p Polymerization Conditions The total duration of the synthesis, hour Yield, wt.% Residual monomer, wt.% Solvent, wt.% Temperature ° C The molar ratio of components POPPY PEG Solvent one 2 3 four 5 6 7 8 9 According to the invention one Toluene 25 Cyclohexane 75 80 one one 13.5 3.0 95.8 0.05 2 Toluene 30 Cyclohexane 70 82 one one 8.6 3.0 97.6 0.01 3 Toluene 40 Cyclohexane 60 84 one one 9.0 3.0 97.0 0.06 four Toluene 50 Cyclohexane 50 86 one one 6.5 3.0 97.4 0.06 5 Toluene 50 Cyclohexane 50 95 one one 13.5 3.0 97.6 0.05 For comparison 6 According to the prototype Water 100 45-50 one one 1323.7-1582.8 7 Toluene 100 BY one one 7.9 3.0 93.0 0.45 8 Cyclohexane 100 80 one one 11.0 4.0 91.0 0.20 9 Benzene 100 80 one one 11.0 4,5 93.8 0.50

one 2 3 four 5 6 7 8 9 10 Acetone 100 55 one one 12.8 7 90.15 0.38 eleven Toluene 20 Cyclohexane 80 80 one one 10,4 3.0 85.0 0.20 12 Toluene 70 Cyclohexane 30 86 one one 8.8 3.0 93.5 0.36 13 Toluene 30
Benzene 70 82 one one 10.0 3.0 92.5 0.50 fourteen Toluene 30
Acetone 70 58 one one 11.3 3.0 59.0 0.35 fifteen Acetone 30
Benzene 70 56 one one 11.5 3.0 55.0 0.40 16 Benzene 30 Cyclohexane 70 80 one one 11.0 3.0 92.0 0.15 17 Acetone 30 Cyclohexane 70 56 one one 11.5 3.0 54.0 0.25 eighteen Toluene 30 Cyclohexane 70 75 one one 8.6 3.0 92.0 0,03

From the data in the table it follows that the proposed method allows to obtain an interpolymer complex in the form of a fine powder with a residual monomer MAK content of 0.01-0.06 wt.% And a yield of 95.8-97.6 wt.%. (see examples 1-5). An interpolymer complex with this yield and quality can only be obtained in a mixture of toluene and cyclohexane solvents taken in a ratio of 25-50 ÷ 75-50 wt.%, Respectively, at a temperature of 80-95 ° C and a molar ratio of methacrylic acid: polyethylene glycol: solvent 1: 1: (6.5-13.5).

The synthesis of the PMAA interpolymer complex with PEG in the environment of individual organic solvents, such as toluene, benzene, cyclohexane or acetone, allows the interpolymer complex to be obtained in the form of a finely dispersed powder, but of significantly lower quality and with a lower yield. The content of residual monomer in it is 0.20-0.50 wt.%, Which makes it unsuitable for use as a polymer carrier for drugs with prolonged action. The yield of the complex is 90.15-93.80 wt.%, Which is also lower than by the proposed method (see examples 7-10).

Obtaining interpolymer complex in a mixture of toluene and cyclohexane, but in ratios outside the claimed reduces the yield of the interpolymer complex to 85.0-93.5 wt.% And increases the content of residual monomer to 0.20-0.36 wt.% (See examples 11-12).

The synthesis of the polymer complex in a medium of a mixture of organic solvents other than the claimed does not allow to achieve the desired result. The yield of the complex is 54.0-93.5 wt.%, And the content of residual monomer 0.15-0.50 wt.% (See examples 13-17).

The polymerization of MAK on PEG according to the proposed method is carried out at a temperature of 80-95 ° C. Lowering the polymerization temperature reduces the yield of the interpolymer complex (see Example 18). The upper limit of the synthesis temperature is limited by the boiling point of the solvent mixture used.

The molar ratio of the components of methacrylic acid: polyethylene glycol equal to 1: 1, was selected in accordance with the requirements of the polymer carrier of the drug in order to ensure the necessary film strength and speed of release of the drug. The molar ratio of solvent, methacrylic acid and polyethylene glycol is 1: 1: (6.5-13.5). To carry out the process in more dilute solutions, when the ratio is greater than 13.5, is uneconomical. At a lower solvent ratio, when the ratio is less than 6.5, the quality of the interpolymer complex deteriorates, since in the process of its preparation the aggregation of the complex occurs and its uniformity is violated.

Claims (1)

A method of obtaining an interpolymer complex by radical polymerization of methacrylic acid on a polyethylene glycol polymer matrix in the presence of a polymerization initiator when heated in a solvent medium, characterized in that the polymerization is carried out at a temperature of 80-95 ° C in an organic solvent - a mixture of toluene with cyclohexane taken in the ratio 25- 50 ÷ 75-50 wt.%, Respectively, with a molar ratio of methacrylic acid: polyethylene glycol: solvent equal to 1: 1: (6.5-13.5), followed by filtration and drying.