RU2520970C1 - Method of obtaining poly-para-dioxanon - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: described is a method of obtaining poly-para-dioxanon in a monomer mass under the action of tin (II) octanoate in the presence of a co-initiator, which are introduced in the form of a solution in an organic solvent; the solvent is removed by vacuumisation, polymerisation is carried out with heating in nitrogen atmosphere; the obtained polymer is cooled, crushed and purified from the residual monomer; characterised by the fact that as the co-initiator used are glycidyl ethers and esters, benzene is used as the solvent, removal of the solvent is carried out at room temperature and pressure not more than 0.5 mm Hg, polymerisation is performed in a thin layer at 80°C, the polymer is cooled to room temperature and purified from the residual monomer by the monomer distillation under pressure of 0.1-0.5 mm Hg at 80°C for 12 hours or re-precipitation.

EFFECT: obtaining poly-para-dioxanon with logarithmic viscosity, suitable for monofilaments.

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Description

The invention relates to the polymerization of cyclic esters and relates to a method for producing poly-para-dioxanone (poly-1,4-dioxan-2-one) in the mass of monomer, which is a raw material for the production of surgical absorbable monofilaments and other long-term medical devices. Poly-para-dioxanone is a valuable biodegradable polymer, products based on it have high strength, flexibility and a long decomposition time. The most widespread surgical monofilament based on it, which have good manipulative properties and low sawing effect. In Russia, poly-para-dioxanone is not produced and the need for surgical suture material based on it is made up for by imported materials.

Poly-para-dioxanone is characterized by a molecular weight or, more often, a ratio of the logarithm of the specific viscosity to the concentration of the polymer solution in 1,1,1,3,3,3-hexafluoroisopropanol, tetrachloroethane or another suitable solvent. In foreign literature, such viscosity is referred to as "intrinsic viscosity", in Russian-language literature this characteristic is called the logarithmic viscosity [Ya. Rabek, Experimental Methods in Polymer Chemistry, M.: Mir, 1983, v.1, p.133, section 9.1.].

A poly-para-dioxanone suitable for forming surgical monofilaments should have a logarithmic viscosity of 2.0-2.5 dl / g. A polymer with a lower logarithmic viscosity does not have a sufficiently large molecular weight to form a strong monofilament. A polymer with a higher logarithmic viscosity has a high melt viscosity, resulting in the need for a high extrusion temperature, which leads to the destruction of the polymer and does not allow to obtain the thread of the required quality.

Obtaining poly-para-dioxanone is mainly carried out by the method of cationic polymerization in the presence of an initiator - Lewis acid.

A known method of producing poly-para-dioxanone by polymerization of para-dioxanone in bulk (monomer melt) under the action of alkyl, aralkyl, aryl, acyloxy, hydroxy and halogen derivatives of zinc, cadmium, mercury in a concentration of from 0.001% to 5% of the mass [US 3645941]. All manipulations are carried out in a dry box with an inert atmosphere, the reaction is carried out at a temperature of 100-200 ° C for 5-8 hours. The molecular weight of the obtained polymer is up to 4000 Daltons, which corresponds to a logarithmic viscosity of 0.1 dl / g. The disadvantages of the method include the use of expensive, unstable and toxic initiators, as well as the low molecular weight of the polymer. Similar disadvantages have the method of polymerization of para-dioxanone in bulk under the action of aluminum alkyl derivatives [US 3063 967].

A known method of producing poly-para-dioxanone in the mass of monomer under the action of zirconium acetylacetonate (ratio of monomer: initiator 7500: 1) at a temperature of 80 ° C for 3 days. The result is a polymer with a logarithmic viscosity of 0.71 DL / g All manipulations are also carried out in a dry box with an inert atmosphere [US 4052988]. The disadvantages of the method are the duration of the process and the low logarithmic viscosity of the polymer, which does not allow the use of the polymer for forming surgical monofilaments.

A known method of producing poly-para-dioxanone in the mass of a monomer with a high molecular weight and a logarithmic viscosity of up to 2.26 dl / g using tetraoctylene glycol titanate (ratio of monomer: initiator 13300: 1) at a temperature of 80 ° C and a polymerization time of 6 days [US 4052988 ]. The disadvantages of the method are the hydrolytic instability of the initiator and the duration of the process.

Tin (II) octanoate (FDA) approved by the Food and Drug Administration (FDA) for use as a food supplement is used as a stable, effective, and safe initiator of the polymerization of para-dioxanone. Macromol. Sci. 2002. V. C42. N. 3. P. 373-398]. When using tin (II) octanoate, a co-initiator is also introduced into the reaction system, usually hydroxyl-containing compounds, most often n-dodecanol.

A known method of producing poly-para-dioxanone in the mass of monomer under the action of tin (II) octanoate (monomer: initiator ratio 25000: 1) in the presence of n-dodecanol as a polymerization co-initiator (monomer: co-initiator ratio 946: 1), which is carried out in two stage. In the first stage, the reaction is carried out at a temperature of 110-95 ° C to a viscosity value of the reaction mass of 100-500 cP. In the second stage, the reaction mass is maintained at a temperature of 80 ° C for 4 days. The result is a polymer with a logarithmic viscosity of up to 8 dl / g. All operations are performed in a dry glove box with an inert atmosphere [US 6090908]. The disadvantages of the method include two-stage and the duration of the process.

The closest in technical essence to the claimed method is a method for producing poly-para-dioxanone in the mass of monomer under the action of tin (II) octanoate (monomer ratio: initiator 25000: 1) in the presence of n-dodecanol as a polymerization co-initiator (monomer ratio: co-initiator 7692 : 1) [US 6448367] - the prototype. In a flask equipped with a mechanical stirrer, in a nitrogen atmosphere, para-dioxanone, a solution of tin (II) octanoate and n-dodecanol in toluene are placed. Toluene is removed by vacuum in two stages. In the first stage, the reaction mixture is evacuated for 60 minutes at a pressure of less than 1 mm Hg, room temperature and stirring. In the second stage, the mixture is evacuated with stirring and heating to 60 ° C. Upon reaching a temperature of 60 ° C, the vacuum is filled with nitrogen, after which the mixture is heated to 95 ° C. The polymerization is carried out in two stages. In the first stage, polymerization is carried out at a temperature of 95 ° C for 4 hours, while the process is carried out with stirring until the load on the mixer increases by 33% with respect to the load at the beginning of the process. In the second stage, the polymerization is carried out in the solid phase at a temperature of 80 ° C for 6 days without stirring. Then the reactor is cooled with liquid nitrogen, the polymer is removed, crushed and dried in vacuum for 12 hours at room temperature.

The residual monomer is distilled off at 63 ° C and 8 mm Hg. within 36 hours. The result is purified poly-para-dioxanone with a logarithmic viscosity of 2.51 dl / g. The disadvantages of the method are two-stage, the need for control of mixing and the duration of the process.

The objective of the invention is to develop a simple method for producing poly-para-dioxanone with a logarithmic viscosity of 2.0-2.5 dl / g, suitable for the manufacture of surgical monofilaments.

The problem is solved in that in the method for producing poly-para-dioxanone, simple and complex glycidyl ethers are used as a co-initiator, benzene is used as a solvent, the solvent is removed at room temperature and a pressure of not more than 0.5 mm Hg, polymerization carried out in a thin layer at 80 ° C, the polymer is cooled to room temperature and purified from the residual monomer by distillation of the monomer at a pressure of 0.1-0.5 mm RT.article and 80 ° C for 12 hours or reprecipitation.

The process is carried out by polymerization of para-dioxanone in the mass of monomer in the action of tin (II) octanoate (ratio of monomer: initiator 2500: 1) in the presence of a simple or complex glycidyl ether as a polymerization co-initiator. Glycidyl ether is used in an amount corresponding to the equimolar ratio of oxirane cycles and tin (II) octanoate. As a solvent for the introduction of tin (II) octanoate and a co-initiator, benzene is used instead of toluene as a lower boiling solvent. The process is carried out in a thin layer with a thickness of the reaction mass up to 1 cm, preferably not more than 0.5 cm, which allows polymerization without stirring.

In a flask in an atmosphere of nitrogen or air with a humidity of less than 30%, para-dioxanone and a solution of tin (II) octanoate and a simple or complex glycidyl ether in benzene are placed so that the thickness of the reaction layer does not exceed 1 cm. Then the flask is evacuated for 60 minutes at room temperature and pressure less than 0.5 mm Hg, filled with nitrogen, heated to 80 ° C and incubated for 24 hours. After that, the obtained polymer is crushed and purified by reprecipitation or distillation of the monomer at 80 ° C and a pressure of less than 0.5 mm Hg. within 12 hours. The result is purified poly-para-dioxanone with a logarithmic viscosity of 2.0-2.5 dl / g, which can be used to form surgical monofilaments.

The resulting polymers were analyzed by nuclear magnetic resonance spectroscopy on hydrogen and carbon nuclei using an automatic analyzer company Perkin Elmer and viscometry.

The method of obtaining poly-para-dioxanone is illustrated by the following examples.

Example 1

1.89 g of para-dioxanone and 0.1 ml of a solution containing 0.0030 g of tin (II) octanoate and 0.00166 g of diphenylolpropane diglycidyl ether (ED-20, EC = 20) in benzene are placed in a flask under a nitrogen atmosphere. . The thickness of the reaction layer is 0.5 cm. The flask is evacuated for 60 minutes at room temperature and a pressure of 0.5 mm Hg, then it is filled with nitrogen and heated to 80 ° C. The polymerization is considered to have begun when the temperature of the mixture reaches 80 ° C. The mixture was kept at the indicated temperature for 24 hours, then cooled to room temperature and ground. The obtained poly-para-dioxanone is purified from the residual monomer by reprecipitation from a solution of 1,1,1,3,3,3-hexafluoroisopropanol in ethyl acetate. After reprecipitation, the polymer is dried in vacuo at room temperature to constant weight. The result is a poly-para-dioxanone with a logarithmic viscosity of 2.45 dl / g

Example 2

Example 2 completely repeats example 1, but the purification of poly-para-dioxanone from the residual monomer is carried out by distillation of the monomer at 80 ° C and a pressure of 0.5 mm Hg. Art. within 12 hours. The result is a poly-para-dioxanone with a logarithmic viscosity of 2.46 dl / g

Example 3

1.89 g of para-dioxanone and 0.1 ml of a solution containing 0.0030 g of tin (II) octanoate and 0.00111 g of vinyl glycidyl ether in benzene are placed in a flask under a nitrogen atmosphere. The flask is evacuated for 60 minutes at room temperature and a pressure of 0.1 mm Hg, then it is filled with nitrogen and heated to 80 ° C. The polymerization and purification are carried out analogously to example 1. The result is a polymer with a logarithmic viscosity of 2.09 DL / g

Example 4

Example 4 completely repeats example 1, but to initiate the polymerization using a solution containing 0.0030 g of tin (II) octanoate and 0.00055 g of glycidol. The result is a polymer with a logarithmic viscosity of 2.05 DL / g

Example 5

Example 5 completely repeats example 1, but to initiate the polymerization using a solution containing 0.0030 g of tin (II) octanoate and 0.00096 g of n-butyl glycidyl ether. The result is a polymer with a logarithmic viscosity of 2.44 DL / g

Example 6

Example 6 completely repeats example 1, but to initiate the polymerization using a solution containing 0.0030 g of tin (II) octanoate and 0.00055 g of glycidyl orthophthalate. The result is a polymer with a logarithmic viscosity of 2.01 DL / g

Example 7

Example 7 fully repeats Example 1, but to initiate the polymerization, a solution containing 0.0030 g of tin (II) octanoate and 0.00064 g of ethylene glycol diglycidyl ether is used. The result is a polymer with a logarithmic viscosity of 2.03 DL / g

Example 8

Example 8 completely repeats example 1, but to initiate the polymerization using a solution containing 0.0030 g of tin (II) octanoate and 0.00115 g of diethylene glycol diglycidyl ether (DEG-1, EC = 27). The result is a polymer with a logarithmic viscosity of 2.51 DL / g

Example 9

Example 9 completely repeats example 1, but to initiate the polymerization using a solution containing 0.0030 g of tin (II) octanoate and 0.00075 g of diglycidyl ether 1,4-butanediol. The result is a polymer with a logarithmic viscosity of 2.53 DL / g

Example 10

9.45 g of para-dioxanone and 0.1 ml of a solution containing 0.0150 g of tin (II) octanoate and 0.0083 g of diphenylolpropane diglycidyl ether (ED-20, EC = 20) in benzene are placed in a flask under nitrogen atmosphere. . The polymerization and purification are carried out analogously to example 1. The result is a polymer with a logarithmic viscosity of 2.46 DL / g

The obtained poly-para-dioxanone is formed at 145 ° C on a laboratory plunger extruder with a die diameter of 2 mm, the resulting monofilament is subjected to orientation drawing at 80 ° C. The result is a monofilament with a diameter of 0.24 mm and a breaking force in a simple node 13H.

Table 1 The results of the polymerization of para-dioxanone under the action of tin (II) octanoate (2500: 1) in the presence of various glycidyl ethers, Т = 80 ° С, τ = 24 h Example Glycidyl ether FROM
(monomer: glycerol ether) Viscosity log., Dl / g one diphenylolpropane diglycidyl ether 1250: 1 2.45 3 vinyl glycidyl ether 2500: 1 2.09 four glycidol 2500: 1 2.05 5 n-butyl glycidyl ether 2500: 1 2.44 6 diglycidylorthophthalate 1250: 1 2.01 7 ethylene glycol diglycidyl ether 1250: 1 2.03 8 diethylene glycol diglycidyl ether 1250: 1 2,51 9 diglycidyl ether 1,4-butanediol 1250: 1 2,53

Thus, the proposed method provides obtaining suitable for molding surgical monofilaments of poly-para-dioxanone with a logarithmic viscosity of 2.0-2.5 dl / g during polymerization in a single stage without multi-day exposure. Advantages of the method are also the absence of the need for mixing the reaction mass, evacuation during heating, and the use of a nitrogen current during distillation of the residual monomer. In addition, cooling the polymer after polymerization to room temperature instead of cooling with liquid nitrogen eliminates the step of drying the polymer in vacuo to remove condensate.

Claims (1)

The method of producing poly-para-dioxanone in the mass of monomer under the action of tin (II) octanoate in the presence of a co-initiator, which is introduced as a solution in an organic solvent, the solvent is removed by vacuum and polymerization is carried out by heating in a nitrogen atmosphere, the obtained polymer is cooled, crushed and purified from residual monomer, characterized in that simple and complex glycidyl ethers are used as a co-initiator, benzene is used as a solvent, the solvent is removed at room temperature temperature and pressure of not more than 0.5 mm Hg, polymerization is carried out in a thin layer at 80 ° C, the polymer is cooled to room temperature and the residual monomer is purified by distillation of the monomer at a pressure of 0.1-0.5 mm Hg. and 80 ° C for 12 hours or reprecipitation.