WO2010087736A1 - Disinfectant and a method for the production thereof - Google Patents

Abstract

The invention relates to chemical engineering, in particular, to disinfectants used for disinfection in medicine, veterinary science, construction and the food industry. The invention also relates to methods for producing disinfectants, in particular, to processes for producing biocidal compositions based on polyguanidine derivatives. A polyhexamethylene hydrochloride-based disinfectant is proposed, characterised in that it contains polyhexamethylene hydrochloride polymer as an active compound, which polymer has a mean molecular mass of 1200 Da and is produced by heating polyhexamethylene hydrochloride with a mean molecular mass of 2000 Da to a temperature of 100-110°C in the presence of transition metal salts. The method for producing the disinfectant involves heating polyhexamethylene hydrochloride with a mean molecular mass of 2000 Da to a temperature of 100-110°C for 3-6 hours in the presence of transition metal salts with a concentration of 0.1-0.5 mass %. The thus produced agent exhibits high antifungicidal activity and a high level of safety in use.

Description

 DISINFECTANT AND METHOD FOR PRODUCING IT

Technical field

The invention relates to the field of chemical technology, namely to disinfectants used for disinfection in medicine, veterinary medicine, construction and the food industry and methods for their preparation, in particular, to a technology for producing biocidal compositions based on polyguanidine derivatives.

State of the art

At present, guanidine derivatives, combining good biocidal properties with relative low toxicity, are one of the most promising disinfectant groups (GB 821113, 1959; SU 1184296, 1983, P.A. Gembitsky Synthesis of Metacid, Chem. Prom. 1984, JY ° 2, p. 18-19; SU 1687261,1991) The interest in them is largely due to the fact that they are much more effective and safer than quaternary ammonium compounds, surfactants (catamine, roccal, septabic), phenol derivatives and chlorine-based disinfectants preparations.

That is, an effective disinfectant is obtained by dissolving quaternary ammonium salts in the presence of guanidine

SUBSTITUTE SHEET (RULE 26) new followed by isolation of the obtained product (RU 2282463,2005)

On an industrial scale, in particular, chlorhexidine "(l, 6-bis (4,4-chlorophenoxy-bigyanidohexine), (US 2830006, 1967); low molecular weight polyhexamethylene-biguanidine" Vantotsil "(DE 2437844, 1982 ); "cosmocyl" CQ (US 4,587,266, 1986) and several others. Syntellins — biguanidine with guanidine moieties at the ends of long chain alkylene diradicals, for example, l-6-dihydro-aniding hexane (SU 1336491) also have fungicidal properties. .

Among the derivatives of guanidine, the most known are salts of polyhexamethy-lenganidine (PHMF) with acids, in particular, hydrochloride (PHMG-X), proposed to combat bacterial contamination, as well as compositions based on it (SU 944290, 1981, DE 2318137, 1973 ; RU 2052453, 1993; RU 2331470, 2006; RU 2122866, 1998; RU 2282463, 2005; RU 2275193, 2004; RU2165268, 2000, etc.).

Currently, the preparation of PHMG-X is carried out, as a rule, by polycondensation of dicyandiamide (DCDA) with ammonium chloride (XA), and then with hexamethylenediamine (HMDA). At the same time, the final product (Metacid, Polisept, BIOP-1 preparations) contains, in the form of impurities, an intermediate-forming guanidine hydrochloride (HCH) and melamine derivatives - amelide and ameline. (Gembitsky P.A., Limanov V.E. et al. Journal of Applied Chemistry, 1975, 48, p. 1833; Gembitsky P.A., Boksha L.F., Zhuk D.S. // Chem. industry, 1984, N, p. 82; Safonov G.A., Gembitsky P.A., Rodionov A.V. // Chem. prom., 1989, N 12, p. 1478).

Known (SU 1616898, 1990) is the technology for the production of PHMG by polycondensation of crude guanidine hydrochloride (GHC) and hexamethylenediamine (HMDA) by heating in a melt at 18O ⁰ C in for 2.5 hours, followed by a temperature increase to 24O ⁰ C and heating at this temperature for 5 hours. Moreover, GHC is prepared immediately before its use in a separate reactor in a melt at 200 ⁰ C from dicyandiamide (DCDA) and ammonium chloride.

The disadvantage of this technology is the length and multiplicity of the process carried out in two reactors; obtaining the final product of PHMG containing about 1% of the mass of hexamethylenediamine, which is highly toxic and other impurities characterized by the presence of allergic properties. According to the authors (RU 2122866, 1998), the final product is a mixture of polymer homologs of different molecular weights, including low molecular weight, characterized by relatively high toxicity and reduced antimicrobial activity. In addition, the final product, polyhexamethylene guanidine hydrochloride, is characterized by insufficient activity against mold, yeast, actinomycetes, as well as by the specific microflora of enterprises processing bio-raw materials, and does not have a wide spectrum of antimicrobial activity at hygienically normalized doses. A known method of producing a disinfectant in the form of a derivative of polyhexamethylene guanidine, which is a chloride of polyhexamethylene guanidine, by polycondensation in a melt of guanidine hydrochloride and hexamethylene diamine (RU 1616898, 1990). Guanidine hydrochloride is pre-synthesized by fusion of dicyandiamide and ammonium chloride at a temperature of 180 ⁰ C, and the hexamethylene diamine melt with a temperature of about 5O ⁰ C is provided in an amount ensuring its molar ratio to guanidine hydrochloride of 1.0-0.85, and 2.5 g of guanidine hydrochloride are introduced into the melt uniformly with constant stirring. hours. One- temporarily with the introduction of hexamethylenediamine, the mixture is heated to 18 ^{0 0} C. Upon completion of the supply of hexamethylenediamine, the mixture is heated to a temperature of 240 ⁰ C and thermostated at this temperature for 5 hours. To improve the disinfection properties, the resulting preparation is alkylated with dodecyl chloride (RU2142452, 1998)

A disadvantage of the polymer product obtained in this way is the high content of water-insoluble fraction, insufficient bactericidal activity and weak reactivity of the functional end groups of the macromolecule.

The known technology for the production of polymeric analogue of PGMG-X, which includes thermal polycondensation of hexamethylenediamine and guanidine hydrochloride in two stages. At the first stage, the process is conducted until the ammonia evolution is completed, at the second stage, additional amounts of hexamethylenediamine are introduced into the melt. (RU2258696, 2004). The resulting product contains two additional terminal amino groups, has a lower degree of polymerization compared to the preparation obtained by traditional technology, from 14 to 45 and a molecular weight of from 2700 to 8200. The drug has shown effectiveness in controlling bacteria, but its antifungicidal effect not high enough. Known compositions containing PHMG, nonionic surfactants, alcohol, urea, complexon, perfume and water (RU 2275193, 2004). The tool has low toxicity, but not effective against fungi. However, studies have shown that existing technologies for the production of PHMG-X lead to the formation of a sufficiently toxic mixture due to the presence of a significant amount of impurities in its composition. In this case, the use of A position based on PGMG-X for controlling molds requires sufficiently high concentrations of the active principle (up to 7% of the mass).

Known technologies for the production of PHMG-X, including its purification by reprecipitation in a 25% solution of sodium chloride (RU 2122866, 1998).

The disadvantages of this technology include insufficiently complete purification of the preparation from impurities associated with the relatively low solubility of these salts in water, and a rather high salting-out concentration of NaCl for PHMG chloride (-14%). (RU 2172748, 2001).

Closest to the claimed technical essence is the technology consisting in heating a mixture of HMDA dihydrochloride and dicyandiamide for 5 hours at 150-170 ° C, followed by reprecipitation of the obtained product from a 15-25% solution of sodium or potassium salts (RU 2122866 , 1998).

The disadvantage of this method is the need to use large quantities of metal chlorides, as well as the lack of effectiveness of the method, in connection with which, as a rule, the resulting product is reprecipitated in several stages to achieve the effect. In addition, it does not carry out sufficiently effective purification from melanin.

Thus, existing technologies are aimed at reducing toxicity and increasing the effectiveness, mainly of antibacterial activity, of disinfectants. In this case, as a rule, studies go along the path of increasing the molecular weight of the polymer, isolating from it unreacted starting or intermediate products, or creating compositions based on the active principle by introducing additional ingredients into it. At the same time, the problem of obtaining a drug that is more effective, in particular, with increased antifungicidal properties, is safe when it is used, remains very relevant.

SUMMARY OF THE INVENTION

The technical problem solved by the author was the creation of a disinfectant (DS) based on PHMG, characterized by higher antifungicidal activity and less toxicity to humans. The basis of the task was the assumption that the traditional opinion about the increase in the biocidal activity of drugs of this type with an increase in their molecular weight is far from true in all cases. In the course of experiments on thermocatalytic destruction of PHMG-X in the presence of transition metal salts, it was possible to obtain a relatively low molecular weight polymer composition of PHMG-X, which has enhanced antifungicidal properties while reducing the toxicity of DS against higher mammals due to more complete cleaning of the final product from toxic impurities or due to their binding to non-toxic compounds.

The technical result was achieved by creating a new PHMG polymer composition with a molecular weight of 1200-1400 Da by thermocatalytic destruction of the PHMG-X polymer with a molecular weight of 1900-2100 Da or more, obtained by traditional technology. The new DS, which received the code name "MltIdez" (certificate for the trademark JCH 36OO58, received in the name of the applicant), is obtained by heating the industrially produced PGMG-X at a temperature of 95-11O ⁰ C for 3-6 hours in the presence of 0.1-0.5% transition metal salts (SPM). As salts, base metals used their sulfates or chlorides, for example, nickel chloride, manganese sulfate or ferrous iron.

The introduction of salts in a smaller amount or at a lower temperature does not allow the complete purification of PHMG from impurities, the use of higher concentrations, as a rule, is not required and it is advisable to use only with an increased amount of contaminants in the initial product.

As a result of this action, an upper layer is formed containing various high molecular weight impurities, in particular, transition metal complexes with melamine, dicyanediimide, guanidine hydrochloride (GHC) and hexamethylenediamine (HMDA).

Brief Description of the Drawings

In FIG. l shows the data of mass spectroscopy of the industrially produced drug Metacid.

Figure 2 shows the data of mass spectroscopy of the claimed drug, shot under the same conditions.

Options for implementation. Industrial applicability

The drug "MiltiDez" is prepared as follows. Example 1. In a tank containing 60 liters of water heated to 70-80 ⁰ C, containing 0.3% iron chloride, 60 kg of crystals of the industrial preparation Metacid with a molecular weight of 1962 Yes are poured and heated to a temperature of 105 ± 5 ° C and incubated for 4 hours at periodic automatic topping of VQDA as it boils. Then the formed upper layer will be removed, and the resulting the product is slowly cooled, after which the water concentration is adjusted to 50%, receiving a disinfectant “Teflex-concentrate”. The resulting polymer has a molecular weight of 1284 Da. The results of mass spectroscopy are presented in figure 2. Example 2. In an autoclave containing 60 liters of water heated to 70-80 ° C, containing 0.5% manganese sulfate, 60 kg of crystals of the industrial preparation POLISEPT with a molecular weight of 2100 Da are poured and heated to a temperature of 110 ± 5 ° C and maintained 3 hours with periodic automatic topping up of water as it boils. After which the formed upper layer is removed, the resulting product is slowly cooled. The resulting polymer has a molecular weight of 1408 ± 30 Da

Example 3. In a tank containing 60 liters of water heated to 70-8O ⁰ C, containing 0.1% nickel chloride, 60 kg of crystals of the industrial preparation BIOP-1 with a molecular weight of 1942 ± 50 Da are poured and heated to a temperature of 110 ± 15 ° C and can withstand 6 hours with periodic automatic topping up of water as it boils. After which the formed upper layer is removed, the resulting product is slowly cooled. The resulting polymer has a molecular weight of 1202 ± 30 Da

Example 4. Evaluation of antibacterial and antifungicidal properties was carried out using the following procedure as cellulose test objects.

Bleached pulp was cut into squares of 1 square cm and sterilized at 180 ^° C for 60 minutes. In the experiment, reference strains of E. col, S. aureus and Vas.subtilisvaraut used for testing the quality of disinfectants, as well as the strain of Asp.piger fungus, pcs. N ° 23, were used. Working solutions of the preparations were prepared immediately before use. Preparations 24 hours before the start of the experiment were applied to sterile test objects at the rate of 0.1 ml of a 0.2% solution per test object. In this case, the drugs were tested, according to examples 1-3.

The strains of E. col and S. aureus were grown on meat-peptone broth at 37 ° C for 18-24 hours, and B. subtiles in the same conditions -48 hours.

A. piger was grown on Saburo-aar at 37 ^° C for 48 hours, and then at 22 ° C for another 48 hours. A working suspension of microorganisms was prepared by successive 10-fold dilutions of the initial suspension with a concentration of 10 ⁹ CFU / test object. When conducting experiments, the workload was 10 ⁶ CFU per test object.

As a control, untreated test objects were used. Two exposures were used - 1 and 24 hours. After exposure, test objects with sterile tweezers were transferred into test tubes with meat-peptone broth and incubated in an incubator. The results showed that within 30 days after treatment with the claimed preparations, no colonization was observed in any of the treated objects. In the control, seedlings were tested one day after the start of cultivation.

Example 5. Under the conditions of example 4, reference strains of bacteria and fungi Asp.piger and Repicillum were prepared. The drugs were introduced into the culture in the form of specified quantities in sterile saline. After incubation at room temperature for 1 hour, the number of viable microorganisms in the test and control tubes was determined. The test results are shown in table 3. Tab. 3 Activity of copolymers in relation to test objects

Example 5. In the Department of Biological Research, Scientific Research Institute of Chemistry, INGU, the disinfectant "Polycept" and the biocidal agent "MiltiDez" manufactured by ZAO Soft-Protectop, St. Petersburg, were tested for fungicidal activity. The fungal test cultures used are: Aspergillus oruzae, A. piger A. terreus, Chetotium globusum, Rasilomus sarito, Repillium fisulosum, P. chorosumum, P. trichorium.

Fungicidal activity was determined according to GOST 9.049-91 (Method 2). The test period was 14 days.

The presence of fungicidal activity was judged by the formation of a zone of inhibition of growth of test cultures around the test substance, which was placed in the wells in an agarized Chapek-Doks medium. The disinfectant "Polycept" was tested in the following concentrations: 1: 9; 1: 99.

The biocidal agent MeltiDez was tested as a 1% solution. ^one

The test results showed the following. The drug "MeltiDez" has a pronounced fungicidal effect in relation to the studied test cultures of fungi - the radius of the zone of inhibition of growth of micromycetes around the test substance was 6 mm.

“Polyscept” had fungicidal activity in diluting the initial preparation in the ratio 1: 9 - the radius of the zone of inhibition of micromycete growth around the test substance was 7 mm. With a dilution of 1: 99, a fungicidal effect was not found.

Example 7. A study of the fungicidal activity of the agent obtained according to Example 2 was carried out on the example of mold fungi of the genera Asregargillus, Repicillium, Cladosrium in relation to the starting material and its ten-fold dilutions of 0.01%, 0.001%. Pure mushroom cultures were grown on Saburo medium. For the preparation of suspensions, three to five-day-old cultures of molds were used. The study was performed by a cup disc diffusion method. On the surface of standard Petri dishes with nutrient medium was sown (0, 1 ml of the main suspension) using a spatula. Disks made of filter paper with a diameter of 6 mm, impregnated with 0.01 ml of various ten-fold dilutions of the test drug are applied to the seeded surface. One disc had one disc. Incubated for 5 days at a temperature of 20 -37 ⁰ C. The criterion for evaluating antimicrobial activity was the presence and diameter of the zone of complete absence of growth of molds around discs soaked with dilutions of the preparation. The effect of the drug was evaluated according to a 4-point system: “0” - continuous growth of microorganisms under the disk “+” - weak inhibition of growth of microorganisms under the disk

“++” - complete inhibition of the growth of microorganisms under the disk “; +++” - diameter of the complete inhibition of the growth of microorganisms 8–9 mm

"++++" ~ diameter of complete inhibition of the growth of microorganisms 10-11 mm or more

Research results.

Пример 8. Испытания средства <<lV-yльтиДeз>> в на токсичность, проведенные в Аккредитованном испьпагельном лабораторном центре показали., что дезинфицирующее средство по параметрам острой токсичности относится: к IV классу мало опасных веществ при введении в желудок (LD₅₀ для мышей составляет > 5000 мг/кг массы тела) ГОСТ 12.1.007-76 к V классу практически нетоксичных веществ при введении в брюшную полость (LD_5O Для крыс - более 1000 мг/кг массы тела) Классификация Сидорова К.К. к ГV классу мало опасных веществ при нанесении на неповрежденную кожу (LD₅₀ для мышей - более^ОО мг/кг массы тела) ГОСТ 12.1.007-76 к ГV классу мало опасных веществ при ингаляционном воздействии концентрата Классификация химических дезинфицирующих веществ по степени летучести (2O⁰C).

Example 8. The toxicity tests of the << lV-yltIdez >> c agent at the Accredited Spanish Laboratory Center showed that the disinfectant, according to the parameters of acute toxicity, refers to: Class IV contains few hazardous substances when introduced into the stomach (LD ₅₀ for mice is > 5000 mg / kg body weight) GOST 12.1.007-76 to class V practically non-toxic substances when introduced into the abdominal cavity (LD _5O For rats - more than 1000 mg / kg body weight) Classification Sidorova K.K. GV class low hazardous substances when applied to intact skin (LD ₅₀ for mice - more than ОО mg / kg body weight) GOST 12.1.007-76 GV class low hazardous substances when inhaled by concentrate Classification of chemical disinfectants by volatility ( 2O ⁰ C).

The tool with a single and multiple exposure does not have a local irritant effect on the skin.

The tool has a slight irritating effect on the mucous membrane of the eyes (rabbits). The product does not have sensitizing activity.

Claims

CLAIM 1. A disinfectant based on polyhexamethylene hydrochloride, characterized in that as an active principle it contains a polyhexamethylene hydrochloride polymer with an average molecular weight of 1200 Da, obtained by heating polyhexamethylene hydrochloride with an average molecular weight of 2000 Da to a temperature of 100-110 ⁰ C in the presence of transition metal salts . 2. A method of producing a disinfectant by processing industrial polyhexamethylene hydrochloride at elevated temperature in the presence of salts, characterized in that the polyhexamethylene hydrochloride with an average molecular weight of 2000 Da is heated to a temperature of 100-11O ⁰ C for 3-6 hours in the presence of transition salts metals in a concentration of 0.1-0.5% wt. 3. The method according to claim 2, characterized in that iron sulfate is used as the salt. 4. The method according to claim 2, characterized in that iron chloride is used as the salt.