The method of obtaining a disinfectant

 

(57) Abstract:

The invention relates to the production of antimicrobial agents, in particular, can be used for disinfection treatment, prevent the formation of fungi and other undesirable microorganisms in the premises, equipment, food industry, veterinary medicine, medicine, can also be used to protect foods, as additives in paints, varnishes, vodoemulsionnye compositions. The method involves reacting dicyandiamide and hexamethyleneimine when heated. The reaction is carried out by heating a mixture of the diamine dihydrochloride and dicyandiamide for 5 h at 150oC, then the temperature was raised to 170oWith and heat the mixture at 170oC. Then the resulting product is distilled presidenial aqueous solution of sodium or potassium. The method provides improved disinfectant properties by increasing bactericidal target product 3 times while reducing its toxicity 2-5 times depending on the specific product. 2 C. p. F.-ly, 5 PL.

The invention relates to disinfectants for different objects, preimushestvenno competitive antimicrobial and disinfectant substances, in particular to prevent the formation of fungi and other unwanted micro-organisms on the walls, building structures, equipment, inventory, overalls, as well as for antimicrobial protection of food products: can be used as antimicrobial additives in paints, varnishes, water-emulsion paint formulations in medicine, veterinary science and in everyday life.

Currently in the domestic market there are no environmentally friendly, low-toxic domestic disinfectants, industry, agriculture and households used traditional chlorine-based tools (bleach, bleach, sodium hypochlorite solution) flawed in terms of toxicity, environmental safety, durability over time, in addition, traditional chlorine or chlorine-containing disinfectants are corrosive in contact with them equipment, create a risk to human health, the environment, are of limited validity; imported materials similar action has not been sufficiently studied, the effect of their long-term effects are not known, in addition, because of the high cost they are virtually inaccessible for agricultural enterprises (Desinfecte. 176 C.).

It is known that the guanidine antiseptics are widely used in the world, because they are much more effective Quaternary ammonium compounds (QAC), surfactants (ketamine, Rockall, satanika), phenol derivatives and chloractive disinfectants. They are stable and non-aggressive, do not form toxic degradation products. The best of them are 1,6-bis(4,4-chlorphenoxamine-hexyne)-"chlorhexidine" (or "Hibotan"), synthesized by the firm IC-AI (U.S. patent N 2830006, MKI 167-30); low-molecular polyhexamethyleneguanidine "vantocil" (patent UK N 702268, 115243, 1963; patent Germany N 2437844, 1982); "cosmocil CQ (U.S. patent, N 4587266, 1986).

It is also known that chlorhexidine is used as a disinfectant in the form of salts (mainly in the form of soluble gluconate) is widely recommended and abroad in the form of solutions, ointments, powders as an effective disinfectant surgery to combat hospital-acquired infections, treatment of skin diseases and domestic purposes (Davis, G. E. Francis J. Martin, Rose E. H. , Brit. J. Pharmacol., 1956, g. 192; Gillespic W. A., Zawbyry E. // Sancet 1960, p. 87).

Antifungal properties have also entellina - biguanidine with guanidinium groups at the ends of dinosaur. (a.c. USSR N 1336491).

However, prolonged antimicrobial activity and low toxicity, volatility have polymeric guanidine compounds that can form on the printed surface of the biocidal film-preserving for a long time the above effect.

The invention relates to the production of polymeric guanidine antimicrobial drug (antiseptic) polyhexamethyleneguanidine (phmg-hydrochloride) with reduced toxicity and high antimicrobial properties for use in food industry, medicine, veterinary medicine, and everyday life.

You know getting pgmg-hydrochloride by polycondensation of dicyandiamide (DCDA) with ammonium chloride (HA), and then with hexamethylenediamine were (HMDA). The intermediate formed guanidine hydrochloride (HCH) contains as impurities derivatives of cyanuric acid or melamine) - Amelia and Amelin.

From these impurities GGH not cleared and they are present in the final product (drugs "Metacid", Polisept, bir-1). (Gembicki P. A., Estuaries C. E., and others, Journal of applied chemistry, 1975, 48, S. 1833; Gembicki P. A., Boksha L. F., beetle D. C. //Chem. industry, 1984, No. 2, S. 82; Safonov, A., Gembicki P. A., Rodionov A. C. ANO for antimicrobial treatment and disinfection of work areas (walls, sexes) in the meat and dairy industry; as an additive in water-based paints and lime mortars (Kuznetsova L. S., A. Snezhko,, Borisov, H. S., Rozantsev E., Antimicrobial drug bir-1 /Dairy, 1997, No. 7, S. 16 - 17).

Installed its high antimicrobial activity, prolonged effect of targeted antimicrobial action and the feasibility of use for disinfection of premises, equipment, external surfaces of the equipment.

It is known (Safonov, A. , Gembicki P. A., Kuznetsov O. Y., etc. a.c. N 1616898 BI N 48, 1990) that getting pgmg (polyhexamethyleneguanidine) carry out the polycondensation of the crude guanidine hydrochloride (HGH) and diamine (HMDA) when heated in the melt at 180oC for 2.5 h followed by raising the temperature to 240oC and heated at this temperature for 5 hours GGH receive immediately before its use in a separate reactor, and (in the melt at 200oC) of dicyandiamide (DCDA) and ammonium chloride (HA), which is the closest analogue.

A known method described in the next similar, the following is true:

- long process that proceeds in two stages, carried out in two osushestvlyaetsya as a separate stage in a separate reactor for 4 8 hours in the melt;

- is mandatory pre-uniform distribution of the two solid components by thorough mixing of ammonium chloride and dicyandiamide for 5 to 7 hours at 200oC. a lengthy Process, due to the presence in the reaction mixture of ammonium chloride requires special corrosion-resistant equipment (reactor);

- there is no final stage of purification of final product pgmg from residual unreacted components of the synthesis, including diamine (HMDA) with high toxicity (residual content in the product to 1%, 2nd hazard class according to GOST 12. 1.007-76, D50250 mg), the presence of certain allergic properties;

- the final product obtained in this way is a mixture of polymeranalogous different molecular weight, including low molecular weight, characterized by a relatively high toxicity and low antimicrobial activity, in addition, the finished product polyhexamethylene guanidine hydrochloride differs insufficient activity to mold fungi, yeast, actinomycetes, specific micro enterprises processing bioserie;

The objective of the invention to create a more effective, simple, less energy-intensive way of getting polyhexamethylene guanidine-hydrochloride and its derivatives with a high content of the active (primary) substance in the final product, a decrease in the content hygienically and environmentally regulated unsafe residual impurities in the products of synthesis, increased microbial activity and antiseptic properties.

The technical result is achieved by the fact that in addition enter the diamine dihydrochloride, mixed with dicyandiamide and hexamethylenediamine were at 150oC for 5 h with a subsequent increase to 170oC and heated at this temperature for 5 h, then the resulting tool periostat aqueous solution of potassium or sodium, as sodium salt using sodium chloride, sodium (potassium) salt of dehydracetic acid, or sodium citrate.

As a result, along with the simplification of the production technology, improved antimicrobial activity and reduce toxicity of the final product.

In the present case, the process proceeds infinite product eliminates the presence of undesirable impurities - HGH, Amelia and Amelina, the reaction of dicyandiamide and dihydrochloride a hexamethylenediamine were flowing more clearly and leads to the formation of the intermediate product - 1,3-biguanidines high purity. The interaction of this intermediate product with hexamethylenediamine were also proceeds at 150 - 170oC, gives half the emissions of ammonia and does not require very high temperatures (used in the near equivalent of 200 - 220oC).

In the absence of the finished form of the diamine dihydrochloride it can be derived from a diamine and hydrochloric acid in the same reactor in which the polycondensation is carried out. A small amount of water introduced with hydrochloric acid, does not prevent the normal flow of the process.

Obtained in this way polyhexamethylene guanidine hydrochloride (PMGM hydrochloride) may be subjected to additional purification by presidenial from aqueous solution by adding to it a solution of salts of sodium or potassium hydroxide, in particular sodium chloride. You get a concentrated aqueous solution of the pure drug (70%) and an aqueous solution of salts of sodium or potassium, in particular NaCl, in which impurities pass the final HMDA and nission purified preparation can be used as a commodity form of the drug or may be dehydrated to obtain a dry product.

The essence of the method of purification is to presideny of the drug from the aqueous solution with sodium chloride. Thus, the proposed method is not associated with the use of sophisticated equipment (e.g., dialysis units) or toxic reagents and solvents. The gradual addition of concentrated (50%) aqueous solution with stirring to 25% of the resultant solution of sodium chloride leads to the separation of the mixture into two layers: the upper - concentrated (70%) solution of high-molecular part pgmg-hydrochloride aqueous solution containing sodium chloride and all low molecular weight impurities of the original drug. Separated from the NaCl pgmg hydrochloride, optionally washed with 2 portions of fresh 15% NaCl solution and then dried or diluted to obtain 20% of saleable concentrate.

Research has shown that a 15% aqueous solution of NaCl soluble: biguanidines hydrochloride and other lower oligomers of guanidine.

A method for the analytical determination of diamine in pgmg-hydrochloride (deposition of polymer nitrate of barium, and then thin-layer chromatography) found that the content of this toxic monomer different is missing.

Instead of a 25% aqueous solution of sodium chloride, you can use a 25% solution of sodium salt of dehydroretinol or 25% solution of sodium citrate (sodium salt of citric acid). In this case, the cleaning presidenial occurs according to the same scheme: the gradual addition of concentrated (50%) aqueous solution pgmg-hydrochloride with stirring to 25% of the resultant solution of sodium salt of dehydracetic acid or sodium citrate leads to the separation of the mixture into two layers: the upper - concentrated (70%) solution of high-molecular pgmg-dehydrate or pgmg-citrate and lower (15%) aqueous solution containing sodium chloride and all low-molecular-weight impurity source pgmg-hydrochloride.

Separated from the NaCl solution of high molecular weight product is dried or diluted with water to obtain the necessary marketable concentrate.

Practical implementation of the invention is illustrated by the following examples.

Example 1. The diamine dihydrochloride (HMDA) 0.019 kg dicyandiamide (DCDA) 0,0085 kg, hexamethylenediamine were (HMDA) 0,0116 kg thoroughly mixed in a conical heat-resistant glass flask with a capacity of 0.1 liter Flask with a mixture immersed in SUP>C, and then the mixture is kept for 5 h at 170oC. While the mixture was continuously stirred until the process is complete, which is determined by the termination of the allocation of ammonia. Then once the product is cooled, dissolved in 0.05 l of hot water when heated, and then with continuous stirring enter 0.05 l of a 25% aqueous solution of sodium chloride, disable running the mixer, stand 20 to 30 minutes, after which the mixture is stratified into two layers. Separating the upper layer representing a concentrated solution of the finished product from the bottom layer of saline solution containing impurities; then the upper layer was washed with fresh portions 15% aqueous solution of NaCl, dried to constant weight at 80oC and crushed, the finished product is examined for the content of the basic substance, antimicrobial activity, the residual diamine, determine the molecular weight of characteristic viscosity.

Example 2. 0,015 kg HMDA placed in a flask of 100 ml, then added to the flask with 10 ml of 36% HCl, and then the resulting solution is injected under stirring 0,085 kg DCD.

Then the flask is put in an oil bath and the mixture is heated with stirring at 120oC to pnii filing HMDA the mixture is heated to 150oC and incubated for 5 h, the mixture is continuously stirred, then heated the mixture to 170oC and maintain the melt at this temperature for 5 hours the Mixture will continue to alter. Then the method is carried out as in example 1.

Example 3. The method according to example 2 is carried out on pilot plant pilot reactor designs SKB A.V.Topchiev Institute of petrochemical synthesis Russian Academy of Sciences.

In the reactor is injected 11.5 kg shredded HMDA include a mixer, mix, then when the mixer is injected portions through the dispenser 10 l of 36% HCl. Then include the heating of the reactor and heat the mixture to 120oC and distilled 5 l of water received from HCl. Then under stirring portions through the dispenser into the reactor enter 8,5 kg DCD and 11.5 kg HMDA, heat the mixture after the introduction of components up to 150oC and kept at this temperature for 5 h with stirring, then heated to melt 170oC and kept at this temperature for 5 hours under stirring of the melt until the process is complete the termination of allocation of NH3.

Then the melt is cooled to 50 - 40oC, is injected through the dispenser 40 l of water and when the stirrer is then injected portions 40 l 25% salt; the stirrer was switched off, the mixture shall hexamethylenebiguanide-hydrochloride and the lower layer 15% NaCl solution containing impurities. Then through the bottom fitting of the reactor is separated drain 15% NaCl solution; the remaining concentrate the finished product is polyhexamethylene guanidine-hydrochloride, washed twice by stirring with a 15% NaCl solution, then turn off the mixer, stand the mixture for 20 to 30 minutes, after which the system is divided into two layers and then the method is carried out as in example 1.

Example 4. Portion 435 g pgmg-hydrochloride obtained according to example 2, are dissolved in 600 ml of water and the resulting solution was added under stirring to a solution of 400 dehydrate sodium in 1 liter of water. The reaction mixture after completion of mixing of stratified into two layers. Top water containing NaCl (1300 ml) and bottom - polymer. Separated in a separating funnel bottom layer and dried to constant weight at a temperature of 80oC. To the obtained dehydroacetate of guanidine (drug GIS) determine the minimum inhibiting concentration for E. coli, toxicity and maintenance of hygienically regulated components of the reaction.

Example 5. A portion of the drug 708 g, obtained in example 3, are dissolved in 300 ml of water by heating to 80oC and add the resulting solution with stirring to a solution is through the funnel, dried at 80oC to constant weight and analyzed. Bottom layer - 1200 ml represents a 20% aqueous NaCl solution and impurities - low molecular weight compounds.

Adding dihydrochloride of hexamethylendiamine (dihydrochloride of HMDA) dicyandiamide (DCDA) and hexamethylenediamine were (HMDA) in a molar ratio of greater than 1 : 1 : 1 is accompanied by the formation of the gel, which clogs the equipment. The target product loses its ability to dissolve in water and cannot be used as a water-soluble antimicrobial drug and disinfectant. The ratio of the dihydrochloride of HMDA to DCD and HMDA less than 1 : 1 : 1 leads to the deterioration of the antimicrobial properties of the product, increasing its toxicity.

The process of obtaining the target product at temperatures below 150oC is difficult, no selection of NH3when identifying the final products the presence of the target product was not detected.

Increasing the process temperature over 170oC is accompanied by a decrease in molecular weight of the target product, leads to the deterioration of the antimicrobial characteristics of the target product and its hygienic characteristics.

In table 1 before the mu and the known methods.

The structure of the resulting hydrochloride polysaccharides and its derivatives is confirmed by the results of IR spectroscopy.

Toxicity to warm-blooded animals (LD50for phmg-hydrochloride and its derivatives, obtained by the proposed method 2500 - 4000 mg/kg (LD50Pgmg-hydrochloride obtained according to the method, 1000 mg/kg (table 1).

Determination of antibacterial, antidrogas and antifungal activity obtained disinfectants based on pgmg was carried out using serial dilutions of the studied compounds on liquid nutrient media using mycopathologia broth for bacteria and liquid environment Saburo for fungi and yeast. In each tube was placed to 7.0 ml of culture medium, 2.5 ml of the appropriate dilution of the investigated disinfectant and 0.5 ml of microbial cells in a nutrient medium. Tubes with bacterial cells were incubated in the incubator for 24 h at 37oC, yeast cells and fungi - in the 28oC for 5 and 7 days.

The results are shown in table 2.

Disinfecting activity of the studied compounds was also studied for their ability to inhibit the growth of a dispute Plesneva in the tested solutions were wet discs of filter paper with a diameter of 25 mm and was laid to lawns with cultures of fungi and yeast.

As the test cultures were studied mushroom spores Penicillinus chrysogemum, Aspergillius niger. , mucor heterosporum, and yeast Torulopsis Sp., Saccharamyces cerevisiae.

Spore suspensions were prepared by flushing water dispute two weeks jamb of a given culture. The concentration of the dispute is brought up to 1 - 2 million/ml and was applied with a spatula on a solid medium Saburo in Petri dishes. On the formed lawns laid out disks of filter paper soaked in 1% solution of the compounds. Cups were placed in a thermostat with T = 28oC, the area of suppression of fungal spores and yeasts was observed after 5 and 7 days of incubation.

The research results are summarized in table 3.

Determination of minimum inhibitory concentration and concentration, completely suppresses the growth of microorganisms, for the studied compounds were also carried out on an automated analyzer "Bioskin" (Finland), allowing to determine the cell survival of microorganisms on the change of transmittance under cultivation in liquid nutrient media. Used the program "Bioscreen", version 4.1, with the following parameters: the volume of the growth medium in the measuring cell 400 Ál, no filters, time of cultivation - 20 h for bacteria and 72 the changes are distributed on the device kootam for a given program. The research results are mathematically processed by a special program on an IBM - compatible PC.

The results are shown in table 4 and 5.

Thus, from the data presented in tables 1 - 5, it follows that the claimed method in comparison with the prototype provides improved antimicrobial activity and disinfectant properties, by increasing bactericidal target product in 3 to 4 times, increasing the range of its validity, the reduction in the target product content hygienically regulated products, for example, diamine 10 times, which will increase the hygienic purity of the announced products and to significantly expand the range of their actions.

1. The method of obtaining a disinfectant, including the interaction of dicyandiamide and diamine by heating, characterized in that it further impose the diamine dihydrochloride, mixed with dicyandiamide and hexamethylenediamine were at 150oC for 5 h with a subsequent increase to 170oWith and heated at this temperature for 5 h, then the resulting tool periostat aqueous solution of sodium or potassium.

2. The method according to p. 1, wherein thesimulation diamine with hydrochloric acid.

3. The method according to p. 1, characterized in that as the sodium salt using sodium chloride or sodium salt dehydracetic acid, or sodium citrate.

 

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