RU2559429C1 - Method of obtaining chitosan-based hydrogelling agent - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method includes a reaction of chitosan powder with diglycidyl ether of 1,4-buthanediol or diethyleneglycol in a medium of a water-alcohol solution of formic, acetic, citric, oxalic, succinic, glycolic or lactic acid with the content of chitosan disperse medium of 15÷25 wt %. The water content in the alcohol is supported at the level from 10 to 30 wt %. The molar ratio chitosan:acid is supported at the level from 1:0.7 to 1:1.5 and the molar ratio chitosan:diglucidyl ether from 10:1 to 100:1. After that a hydrogelling agent is extracted by filtering, washed with ethanol and dried.

EFFECT: invention makes it possible to obtain the chitosan hydrogelling agent capable of forming highly viscous gels when mixed with water by a simple method in a single stage with an increased content of the ready product in the reaction medium.

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Description

The invention relates to chemical technology, specifically to a method for producing a chitosan-based hydrogel, and specifically to a method for cross-covalent crosslinking of chitosan macromolecules to produce a product that forms highly viscous hydrogels when mixed with water, used as promising materials for biotechnological, biomedical and pharmacological purposes.

The most widespread for the production of chitosan hydrogels was the reaction of the amino groups of chitosan macromolecules with aldehydes of various structures, such as formaldehyde, acetaldehyde, glyoxal, glutaral and terephthalic aldehydes [Masri M. Chemical modifications unsoluble polymers, Polymer. Prepr. 1975, v. 16, N 2, p. 70]. Known methods for producing chitosan hydrogels by crosslinking chitosan macromolecules at amino groups with glutaraldehyde (HA) [R.A.A. Muzzarelly, G. Barontini, R. Rocehetti. Cross-linked modification of chitosan with glutaraldehyde, Biotechnol. Bioeng. 18, 1445, 1976], as well as GA followed by reduction of azomethine groups in the environment of NaF, NaBr, or NaSCN electrolytes [G.A.F. Roberts, K.E. Taylor The formation of gels by reaction of chitosan with glutaraldehyde, Macromol. Chem. 190, 951, 1989].

However, the cited publications only record the formation of visco-amorphous, dark-brown colored preparations and do not provide data on the isolation, purification, and identification of products that can form gels when mixed with water.

In the work of N.R. Kildeeva, T.V. Smotina, V.V. Nikonorov, V.I. Lozinsky, R.V. Ivanov, P.A. Permin. Hydrogels based on covalently cross-linked chitosan, 9th International Conference “Current Prospects in the Study of Chitin and Chitosan”, Staropol, October 13-17, 2008; VNIRO Materials, 2008. P. 23-27 describes the preparation of chitosan hydrogels from its 2% solution in 2% acetic acid at pH 5.6 as a result of covalent crosslinking of HA with a molar ratio of amino groups of chitosan: HA equal to 0.4, but also without isolation, purification and identification of hydrogel.

Patent RU 2099352 (prototype) proposes a method for producing a hydrogel former from chitosan by reacting chitosan with glutaraldehyde in acetate buffer at pH 3.5 ÷ 5.5, the ionic strength of the solution is 0.1 ÷ 0.5 and the molar ratio of glutaraldehyde and chitosan from 1: 6 to 1:15, recovery of the reaction product with sodium borohydride, followed by isolation of the hydrogel former by filtration, washing and drying.

Distinctive features of this method are the reaction of chitosan with glutaraldehyde under the above conditions, the restoration of the reaction product with sodium borohydride and the isolation of the hydrogel former in dry form as a result of filtration, washing and drying.

The main disadvantage of the prototype method is the relatively low concentration, about 0.7%, of the finished product in the reaction mixture.

The second disadvantage is that the process itself is a complex two-stage process, since the use of glutaraldehyde determines the need for an additional redistribution step associated with the restoration of the intermediate reaction product of chitosan with glutaraldehyde.

The reaction of transverse covalent crosslinking of chitosan macromolecules by polyfunctional epoxy compounds in aqueous solutions was used to obtain medical devices for treating wounds [RU 2249467, RU2467767]. However, the use of this reaction to obtain a chitosan hydrogel former is not currently known.

The invention is aimed at finding a relatively simple method for producing a chitosan-based hydrogel former with an increased concentration of the finished product in the reaction mixture.

The technical result is achieved by the fact that a method for producing a chitosan-based hydrogelling agent is proposed, which consists in reacting chitosan powder with diglycidyl ether of 1,4-butanediol or diethylene glycol in an aqueous-alcoholic solution of formic, acetic, citric, oxalic, amber, glycol or lactic acid when the chitosan content in the dispersion medium is 15 ÷ 25 wt.%, the water content in alcohol is from 10 to 30 wt.%, the molar ratio of chitosan: acid is from 1: 0.7 to 1: 1.5 and the molar ratio of chitosan: dglycidyl ether from 10: 1 to 100: 1, followed by isolation of the hydrogel former by filtration, washing with ethyl alcohol and drying.

The essence of the present invention lies in the fact that the process of producing a hydrogel forming agent is carried out under the conditions of a heterophasic reaction of chitosan powder (dispersed phase) with difunctional epoxy compounds in an aqueous-alcoholic acid solution (dispersion medium), during which acids and epoxy compounds diffuse into chitosan powder particles to form corresponding salts due to acid ionization of the amino groups of chitosan and, simultaneously, with the formation of cross-linked macromolecules due to the parallel flow th reaction covalent crosslinking of chitosan by reaction of epoxides with hydroxyl groups at C-6 carbon atom of the elementary unit of chitosan.

As a result, it was possible for the first time to synthesize, isolate and identify by the indicated reaction samples of dry powders of the target hydrogel former.

The claimed parameters for the content of chitosan powder in a dispersion medium, the water content in alcohol, the molar ratio of chitosan: acid and the molar ratio of chitosan: diglycidyl ether are determined by the following considerations.

The increase in the content of the dispersed phase in the suspension of more than 25 wt.% Leads to the production of a sedentary, difficult to mix reaction mass, which complicates the diffusion of the components of the dispersion medium into powder particles. The decrease in the content of the dispersed phase in the suspension below 15 wt.% Does not provide a high yield of the finished product.

When the water content in the alcohol is less than 10 wt.%, The diffusion rate of the components of the dispersion medium into powder particles is significantly reduced. With an increase in the water content in alcohol of more than 30 wt.%, Clumping of the powder occurs, which complicates the stages of filtration, washing and drying.

With a decrease in the molar ratio of chitosan: acid less than 1: 0.7, the finished product does not form a gel when mixed with water; with an increase in the molar ratio of more than 1: 1.5, a hydrogel is formed with an acidity of pH ≤ 4.0, which is unacceptably high for further use as materials for biotechnological, biomedical and pharmacological purposes.

An increase in the molar ratio of chitosan: diglycidyl ether more than 100: 1 leads to the formation of viscous solutions instead of gel when the finished product is mixed with water, and its decrease below 10: 1 leads to the formation of swollen, inactive agglomerates.

The achievement of the claimed technical result is confirmed by the following examples. The examples illustrate but do not limit the proposed technical solution.

To obtain a hydrogel forming agent, the given examples use food-grade acid-soluble chitosan with a degree of deacetylation of 90%, a molecular weight of 150-200 kDa, a particle size of 0.25-1.25 microns and a moisture content of 9.5%, manufactured by Bioprgress CJSC according to TU 9289-067 -00472121, rectified ethyl alcohol from Bazik food raw materials according to GOST R 51652-2000, purified water according to FS 42-2619-97, acetic acid 99.8%, Fluka, cat. No. 45731, code 131030 and diglycidyl ether of 1,4-butadiol 95%, Aldrich, cat. No. 220892, or L (+) - 90% lactic acid, Fluka, cat. No. 69785 and diglycidyl ether of diethylene glycol according to TU 2225-027-00203306-97.

Example 1. Obtaining a hydrogel forming agent with a water content in ethyl alcohol of 20 wt.% At a molar ratio of reagents equal to 1: 1 in acetic acid, 10: 1 in diglycidyl ether.

310.7 g of a pre-prepared solution containing 240 g of rectified ethyl alcohol, 53.7 g of water, 22.2 g (0.37 mol) of acetic acid and 7.87 g of (800 g) were poured into a 500 ml glass reactor equipped with a stirrer. 0.037 mol) of diglycidyl ether of 1,4-butanediol. 65.6 g (0.37 mol) of chitosan powder were poured into the solution. The resulting suspension contained chitosan, acetic acid and diglycidyl ether 1,4-butanediol in ethyl alcohol containing 20 wt.% Water, with a molar ratio of reagents equal to 1: 1 in acid and 10: 1 in diglycidyl ether. The calculated concentration of the finished product in the reaction mixture was 21.4%.

The reaction mixture was vigorously stirred at room temperature for 5 hours. The dispersed phase was filtered off, washed with 100 ml of rectified ethyl alcohol and dried in vacuum at a temperature of 45-50 ° C.

In one step, a hydrogel suspension was obtained, from which, by filtration, washing and drying, the target product was isolated in quantitative (calculated) yield, capable of forming a gel with a dynamic viscosity of 2040 centipoise at a concentration of 1.0 wt% in water.

Similarly, the target hydrogel was obtained when the water content in ethanol was 10 wt.% And 30 wt.% With a molar ratio of reagents equal to 1: 0.7 and 1: 1.3 in acid, 40: 1 and 100: 1 in diglycidyl ether.

The data are summarized in Table 1: “The main properties of the obtained chitosan hydrogel forming samples depending on the conditions of the heterophasic reaction in the medium of an aqueous-alcoholic solution of acetic acid using diglycidyl ether 1,4-butanediol as a crosslinking reagent”.

Example 2. Obtaining a hydrogel forming agent with a water content in ethyl alcohol of 20 wt.% At a molar ratio of reagents equal to 1: 1 in lactic acid, 40: 1 in diglycidyl ether.

310.7 g of a pre-prepared solution containing 240 g of rectified ethyl alcohol, 53.7 g of water, 37.0 g (0.37 mol) of lactic acid and 3.45 g of (500 g) were poured into a 500 ml glass reactor equipped with a stirrer. 0.00925 mol) of diethylene glycol diglycidyl ether. 65.6 g (0.37 mol) of chitosan powder were poured into the solution. The resulting suspension contained chitosan, lactic acid and diethylene glycol diglycidyl ether in 80 wt.% Ethanol with a molar ratio of chitosan: lactic acid and chitosan: diethylene glycol diglycidyl ether equal to 1: 1 and 40: 1, respectively. The calculated concentration of the finished product in the reaction mixture was 23.4%.

The reaction mixture was vigorously stirred at room temperature for 5 hours. The precipitate was filtered off, washed with 100 ml of rectified ethyl alcohol and dried in vacuum at a temperature of 45-50 ° C.

In one step, a hydrogel suspension was obtained, from which, by filtration, washing and drying, the target product was isolated in quantitative (calculated) yield, capable of forming a gel with a dynamic viscosity of 1230 centipoise at a concentration of 1.0 wt% in water.

Similarly, the target hydrogel was obtained when the water content in ethanol was 10 wt.% And 30 wt.% With a molar ratio of reagents equal to 1: 0.7 and 1: 1.3 in acid, 10: 1 and 100: 1 in diglycidyl ether.

The data are summarized in Table 2: "The main properties of the obtained samples of chitosan hydrogel forming agent depending on the conditions of the heterophasic reaction in the medium of an aqueous-alcoholic solution of lactic acid using diethylene glycol diglycidyl ether as a crosslinking reagent."

As can be seen from the presented examples, the nature of the acid does not significantly affect the achievement of a technical result. The important thing is that all the claimed acids provide ionization of the amino groups of chitosan.

Thus, the invention opens up the possibility of producing a chitosan hydrogel under the conditions of a heterophasic reaction of chitosan with difunctional epoxy compounds in the environment of water-alcohol solutions of acids, capable of forming highly viscous gels when mixed with water. The process of obtaining is relatively simple, as it is carried out in one stage with a high content of finished products in the reaction medium. The obtained hydrogel forming agent is of interest as a biopolymer base for the development of innovative materials for biotechnological, biomedical and pharmacological purposes.

Claims (1)

A method of producing a chitosan-based hydrogel former, which consists in reacting chitosan powder with diglycidyl ether of 1,4-butanediol or diethylene glycol in an aqueous-alcoholic solution of formic, acetic, citric, oxalic, succinic, glycolic or lactic acid with a chitosan content of dispersion medium 15 ÷ 25 wt.%, the water content in alcohol from 10 to 30 wt.%, the molar ratio of chitosan: acid from 1: 0.7 to 1: 1.5 and the molar ratio of chitosan: diglycidyl ether from 10: 1 to 100: 1 followed by hydrogeo Browser by filtration, washing with ethyl alcohol and drying.