MXPA97005518A - Synergistic antimicrobial composition of n - [(dichlorofluoromethyl) thi] -n ', n'-dimethyl-n-phenyl-sulfamide and compounds of alquilguanid - Google Patents

Abstract

Synergistic antimicrobial combinations comprising N - [(dichlorofluoromethyl) thio] -N ', N'-dimethyl-N-phenylsulfamide, and an alkylguanidine compound, preferably dodecylguanidine hydrochloride, are described. Methods for inhibiting microbial growth using these synergistic antimicrobial combinations are also described

Description

ANTI-KYROBIAN SYNERGISTIC COMPOSITION OF N- [(DICHLOROFLUOROMETHYL) UNCLE] -N ', N' -DIMETHYL-N-PHENYL-SULFAMIDE AND ALOUILGUANIDINE COMPOUNDS The present invention relates to synergistic antimicrobial compositions which are generally useful for inhibiting microbial growth in any side where such microbial growth is found, for example, in aqueous systems related to a common variety of industrial applications. More particularly, the present invention relates to the synergistic mixtures of N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide and alkylguanidine compounds. The methods for employing them are also described. Both N- [(dichlorofluoromethyl) thio] -N ', N 1 -dimethyl-N-phenylsulfamide, referred to herein as N-phenylsulfamide, and the alkylguanidine compounds, such as dodecylguanidine hydrochloride (DGH), are known individually as agents antimicrobial The unexpected encounter of the present invention is that when they are used in combination they are synergistic. As used herein, the terms "synergistic" and "synergistic" refer to instances wherein the efficacy of a composition comprising two or more biocides, such as N-phenylsulfamide and DGH, exceeds the sum of the efficiencies of the individual components taken individually. In this way, using a synergistic biocide combination can be allowed to employ a low total biocide concentration or the performance of an enhanced antimicrobial effect at a comparable dose. The alkylguanidine compounds, including docecilguanidine hydrochloride, are known for their antimicrobial properties. For example, the mineral acid or salts of monocarboxylic acid of alkylguanidine compounds and their use as antimicrobial agents are described in U.S. Patent Nos. 2,867,562, 2,906,595, 3,116,326, 3,142,615, 3,143,459, 3,264,172 and 3,628,941. The acid salts of docecilguanidine are the best known and commonly used compounds of the kind. The Japanese Extract, Publication Number JP52007435, describes the use of 2, 3, 5, 6-tetrachloro-4- (methylsulfonyl) pyridine together with N-dimethyl-N 1 -phenyl- (fluorodichloromethylthio) sulfamide to protect electronic printed circuit boards from bacterial and fungal growth. The synergistic combination of N-phenylsulfamide and DGH, however, is not taught or suggested in the art. The phrases "antimicrobial", "biocide" and "antimicrobial growth inhibition", as used herein, refer to the killing, inhibition, or control of the growth of bacteria, yeast, fungi and / or algae . A significant number of industries have experienced serious adverse effects from the activity of such biological growth in the raw materials, which they use, in their process waters or in various components of their manufacturing processes, and in the finished products which produce . Such industries include the paint industry, wood, textile, cosmetics, leather, tobacco, leather coatings, clothing, paper, pulp, plastics, fuel, oil, elastic rubber and machine industries. It is contemplated that the synergistic mixture of N-phenylsulfamide and alkylguanidine compounds as described herein, and methods for using same, will be useful in virtually any aqueous system or in any article or product of manufacture in which inhibition. of microbial growth is desired, absent compatibility problems. Suggested applications of the synergistic antimicrobial combinations of the present invention include, for example: inhibiting the growth of bacteria and fungi in aqueous paints, adhesives, latexes, emulsions, inks and bonding cements; preserve the wood, preserve the cutting of oils and metals that work with fluids; control the bacteria and fungi that produce sludge, including fungi and yeasts, in the paper and pulp industries and cooling towers; as a drip or spray treatment for textiles and skin to prevent the growth of fungi; as a component of anti-biofouling paints to prevent the adhesion of biofouling organisms; protect paint films, especially outdoor paints, from fungal attack which occurs during the weathering of the paint film; protect processing equipment from sludge deposits during the manufacture of cane sugar and beet; prevent the accumulation and deposits of microorganisms in scrubbing systems or air scrubbers and in fresh industrial water supply systems; control the contamination of microorganisms in closed cycles and recirculating water cooling systems; control the contamination and deposits of microorganisms in fluid mud and field oil injection, and in the secondary processes of oil recovery; prevent the growth of fungi and bacteria in paper coating processes which can adversely affect the quality of the paper coating; control the growth and deposits of fungi and bacteria during the manufacture of various specialties of cardboard boxes, for example, cardboard and cardboard box particles; prevent discoloration of sapwood coloration on fresh wood cuts of various types; control the growth of bacteria and fungi in suspensions of clays and pigments of various types which are manufactured for subsequent use in paper coating and paint manufacturing and which are susceptible to degradation by microorganisms during storage and transportation; as a vigorous surface disinfectant to prevent the growth of fungi and bacteria on walls, floors, etc .; in pools to prevent the growth of algae; and to control the growth of bacteria and fungi in various cosmetic products. It is contemplated that the synergistic mixture of the present invention will be useful in various types of non-aqueous systems such as wells. The synergistic antimicrobial composition described in the present invention is particularly applicable to the control of sludge in papermaking processes. The control of bacteria and fungi in pulp and paper manufacturing water systems which contain aqueous dispersions of papermaking fiber in various consistencies is especially important. The uncontrolled accumulation of sludge produced by the accumulation of bacteria and fungi can cause production of inferior quality, production decreased due to the slow time sequence and greater cleaning, increased use of raw material and increase in maintenance costs. The problem of sludge deposits is especially critical in light of the widespread use of closed pure water systems in the paper industry. Another important area in which the antimicrobial compositions of the present invention are particularly useful is in controlling the growth of bacteria and fungi in clay suspensions and pigments. These suspensions comprise various clays (e.g., kaolin) and pigments (e.g., calcium carbonate and titanium dioxide) and are usually manufactured in a location separate from the end use application. This means that they are generally transported and stored for later use at the application site. Due to the high quality standards for the paper and paint products in which the suspensions are used. It is essential that these suspensions of clay or pigments have a very low amount of microorganisms. In addition, the synergistic combination of the present invention and methods for using same have found particular utility in the control of deleterious effects of microorganisms in water or aqueous media. Systems which use circulating water or aqueous medium become infected with microorganisms and their effectiveness undergoes substantial deterioration, when deposits of microorganisms accumulate in the system. The tanks cover the walls of tanks and other containers and any equipment of machinery or processing which is used and creates obstructions in pipes and valves. The deposits also create discolorations and other imperfections in the products that are processed, forcing expensive arrests. Particularly important is the control of microorganisms in aqueous media where particles or fine particles are dispersed in the aqueous medium, for example, dispersed cellulosic fibers and fillers and pigments dispersed in papermaking, and pigments dispersed in the manufacture of paints. Accordingly, there is a substantial and very real need for antimicrobial compositions capable of effectively controlling and / or inhibiting microbial growth in industrial aqueous systems and in articles of manufacture. Due to the increase in environmental regulations, there is still an additional need to provide biocidal compositions having high antimicrobial effects which are effective at low doses than those historically employed. The use of decreased amounts of biocides has a favorable impact on the environment, and allows users to make significant cost savings. The present invention generally meets the needs described in the foregoing by providing synergistic antimicrobial combinations comprising N- [(dichlorofluoromethyl) thio] -N ", N '-dimethyl-N-phenylsulfamide and alkylguanidine compounds, particularly dodecylguanidine hydrochloride (DGH). The present invention also provides a method for inhibiting microbial growth in aqueous systems and articles of manufacture having a tendency for such growth comprising adding to the systems or applying to the articles an effective amount of a composition comprising: a) N- [(dichlorofluoromethyl) -thio] -N1, N '-dimethyl-N-phenylsulfamide; and b) an alkylguanidine. The term "effective amount" as used herein, refers to the amount of a composition comprising N-phenylsulfamide and an alkylguanidine compound necessary to achieve the desired level of inhibition or control of microbial growth in the aqueous system or in the article to be treated. The present invention is directed to a synergistic antimicrobial composition comprising: a) N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide; and b) an alkylguanidine compound, wherein the weight ratio of a) to b), in an active base, is in the range of about 1000: 1 to 1: 1000. The preferred alkylguanidine compound is dodecylguanidine hydrochloride (DGH). The present invention is further directed to a method for inhibiting microbial growth in an aqueous system or in a manufacturing article prone to such growth, the method comprising treating the system or article with an effective amount of an antimicrobial composition comprising: a) N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide and b) an alkylguanidine compound, wherein the weight ratio of a) ab) in an active base, is in the range of approximately 1000: 1 to 1: 1000. The term "alkylguanidine compound", as used herein, refers to any of the salts of mineral acids, salts of monocarboxylic acids, or other salts of alkylguanidine including but not limited to the salts of dodecylguanidine. According to the present invention, the weight ratios of the two components of the synergistic combination are dictated by the dose levels of each component which demonstrate synergism, based on the 100% active ingredient, in relation to each application of use. final. Typically, the weight ratio of component a), N-phenylsulfamide and component b), for example DGH, is in the range of about 1000: 1 to 1: 1000 in an active base, preferably of approximately 50: 1 to 1:50, more preferably from about 5: 1 to 1:13. However, as will be understood by an expert in the art, the synergistic weight ratio of the two components generally varies somewhat depending on the application and the organism that is controlled. For example, a high ratio of N-phenylsulfamide to DGH may be more effective in one application, while a high ratio of DGH to N-phenylsulfamide may be more effective in another application. The composition N-phenylsulfamide / DGH has been particularly effective against bacteria when employed in a weight ratio of between about 10: 1 and 2: 1. An effective amount of a synergistic combination of N-phenylsulfamide and DGH must be added to the aqueous system to be treated. At least 0.1 parts per million (ppm) is added, based on the weight of the water in the system being treated, of the synergistic combination described above. Preferably, between about 0.78 ppm and about 3 ppm of N-phenylsulfamide and between about 2 ppm and 10 ppm of DGH are added, based on the weight of water in the system being treated. This is suitable within the ordinary experience of one skilled in the art to determine the effective amount of biocide for a given system, based on the various parameters of the system including but not limited to system size, system pH, types of present organisms and the amount of control desired. Similarly, an effective amount of a synergistic combination of N-phenylsulfamide and DGH must be applied to the article of manufacture that is treated.

Generally, a solution of the synergistic antimicrobial combination described above having a concentration of at least 0.1 ppm is incorporated into, dispersed or placed in, or otherwise applied, for example, by submerging or subsidence, to the substrate that is treated in order to prevent the growth of bacteria, fungi, yeast and algae. Again, this is suitable within the ordinary experience of an artisan skilled in the art to determine the effective amount of the biocide to be applied to a given article of manufacture that is being treated and to determine the proper modes of application. The active ingredients of the synergistic antimicrobial compositions of the present invention can also be employed in various formulations: solids, including finely divided powders and granular materials; as well as liquids, such as solutions, emulsions, suspensions, concentrates, emulsifiable concentrates, thick suspensions and the like, depending on the application intention, and the desired formulation medium. In addition, when the synergistic antimicrobial combinations are liquid, they can be used clean or they can be incorporated in several formulations, both solid and liquid, as in adsorbate in suitable inert carriers such as talcs, clays, diatomaceous earths and the like, or water and various liquids organic compounds such as lower alkanols, kerosene, benzene, toluene, and other petroleum distilled fractions or mixtures thereof. N-Phenylsulfamide is commercially available in the form of an aqueous solution from Bayer Corporation, Pittsburgh, PA as Preventol AS2. The DGH is commercially available from Calgon Corporation, Pittsburg, PA in liquid form. One skilled in the art will understand that the antimicrobial synergistic combination described herein may be used in combination with other antimicrobial materials. For example, the combination can be combined with other fungicides and bactericides in appropriate concentrations and in appropriate instances to combine the action of each to obtain particularly useful results. Such combinations may find particular application in the preparation of germicidal soaps, in the production of cosmetics and aqueous coatings and in combating the accumulations of sludge in paper mills. It is clear that the synergistic antimicrobial combination of the present invention can be combined with other algicidal agents as well. According to the present invention there is further provided a method for inhibiting the growth of at least one of: bacteria, fungi, yeasts and algae. According to the methods of the present invention, this growth is inhibited in aqueous systems or in articles or products of manufacture prone to such growth. These methods comprise adding to the aqueous system or the treated article or product containing bacteria, yeasts and / or algae with an effective amount of a synergistic combination of N-phenylsulfamide and an alkylguanidine compound such as DGH. This addition can be carried out by simple addition of N-phenylsulfamide and DGH together as a single mixture, or by the addition of the two components separately. Such separate administration may be at the same time or at different times. It is believed that the net effect is the same - the system, item or product that is dealt with lately, will have incorporated into it or will have applied to it, the proper dose concentration of each component. In addition, it is believed that the compositions of the present invention are effective regardless of the method of application. For example, the antimicrobial compositions described herein may be added to a system that is treated by means of a lower level path, a continuous feeding practice, a semicontinuous feeding practice or through a rotary screen feed. All these feeding practices will be familiar to someone expert in ordinary art. Rotary screen feeding is particularly effective and therefore is a preferred way of employing the methods of the present invention. This type of feeding allows the user to monitor the concentration of microorganisms in the system and product, fed only when the concentrations of microorganisms increase. The user makes cost savings by feeding an effective amount of N-phenylsulfamide and DGH only when needed. As indicated in the above, the present invention is based on the discovery that the use of N-phenylsulfamide together with alkylguanidine compounds produces synergistic results and is effective for controlling the growth of bacteria, yeasts, fungi and algae in a variety of industrial applications and other applications. The utility of the synergistic antimicrobial combination described herein is derived from its both versatilities in numerous industries in which it can be applied, as well as the numerous microorganisms against which they are effective. In particular, the loss of large economies in papermaking operations caused by the accumulation of sludge of bacteria and fungi in various parts of the system can be eliminated to a significant degree by the use of the synergistic combination described herein. The superior antimicrobial activity of the synergistic antimicrobial combination of N-phenylsulfamide and DGH has been confirmed using standard laboratory techniques. The antimicrobial combination has been effective, for example, in the inhibition of bacterial growth which includes but is not limited to Klebsiella pneumoniae and Escherichia coli and has been found to be effective particularly against Pseudomonas aeruginosa. It is also believed that the combination is effective against other aerobic bacteria, such as Bacillus sp. , Staphlococcus sp., Flavobacterium sp. , Enterobacter sp., And Xanthomonas sp., Anaerobic bacteria, and other freshwater organisms such as filamentous bacteria, fungi, which include but are not limited to several species of Candida and Saccharomyces and white and rosy yeasts and several species of algae. EXAMPLES The following examples are indicated to illustrate the present invention and should not be construed to limit the invention in any way. The biocidal efficacy is demonstrated in microtiter tests of the antimicrobial composition of the present invention, subsequently. Three different strains of bacteria are used, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, as well as a mixture of these three strains.

Each of these three bacteria is grown on standard method agar plates (STM), separately and incubated at 37 ° C for a period of between about 24-48 hours. The bacterium is then separated from its respective STM plates and suspended in 50 ml of double resistance trypticase broth (2XTSB) and incubated again at 37 ° C for 24 hours; each organism is incubated in a separate tissue culture flask. The 2XTSB is prepared by mixing approximately 30 grams of trypticase broth powder in approximately 1000 ml of deionized water, which has been sterilized by autoclaving. After the 24 hour incubation of each of the organism suspensions, the suspensions are diluted in a ratio of 1:10 with additional 2XTSB. The samples of each of the diluted cultures are then used in the microtiter test. To prepare the mixture of the three organisms, an equal amount, approximately 10 ml, of each of the diluted cultures are mixed together in a separate tissue culture flask. Samples of this mixture are then used in the microtiter tests. The DGX 8X stock solution is prepared by dissolving approximately 1.28 grams (g) of active DGH at 24.7% in approximately 100 ml of deionized water. A 4X reserve solution from DGH is prepared in the same way only by using 0.064 g of DGH. The DGH used in the examples is obtained from Calgon Corporation, Pittsburgh, PA, as Metasol® 600HF. An 8X stock solution of N-phenylsulfamide is prepared by dissolving about 3.2 g of about 10% active Preventol AS2 in about 16 ml of methanol and diluting the volume to about 100 ml with deionized water. A 4X stock solution of N-phenylsulfamide is prepared in the same manner only using 0.16 g of Preventol AS2 in about 4 ml of methanol. Preventol AS2, which is a 10% active aqueous solution of N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide, is obtained from Bayer Corporation, Pittsburgh, PA. 8 microtiter plates are used in the example, each microtiter plate has 8 lines, A-H, and 12 columns, 1-12. The amount of each biocide in each well of the eight plates is described later.

TABLE1 QUANTITY OF EACH BIOCIDE EM WELLS OF PLATES OF ICROTITULO 1-1-8 As illustrated in the table above, the amount of DGH in the wells of plates 1 and 5 and the amount of N-phenylsulfamide in the wells of plates 2 and 6 vary in the series of the serial dilution in the range of active of 400 ppm to the active of 0.78 ppm while the other concentrations of components are maintained at an active of 10 ppm; plates 3 and 7 represent the use of DGH alone, while plates 4 and 8 represent the use of N-phenylsulfamide alone. Plates 3 and 4, and 7 and 8 are used to determine the minimum amount of each biocide in which, when used alone, it can inhibit microbial growth. No biocide is added to the wells of column 12 on any of the plates, which represents an organism control, or a positive control. This positive control is run to ensure that organisms are able to grow in the provided environment. No bacteria are added to the wells of column 11 in any of the plates, which represents a control of the broth, or a negative control. This is done to ensure that there is no contamination of the plates. In each of the 8 microtitre plates Pseudomonas aeruginosa is added to lines A and B, Klebsiella pneumoniae to lines C and D, Escherichia coli to lines E and F and the mixture of the three bacteria to lines G and H Plates 1-4 are used to determine the minimum inhibition concentration (MIC) for each biocide combination against each strain of bacteria. The MIC is the minimum amount of biocide necessary to prevent growth in the well, with growth defined as a turbidity in the medium or a "granulate" of the cells which are outside the medium and are fixed in the bottom of the well . Plates 5-8 are then subcultured from plates 1-4, respectively, at 24 hours after the addition of the biocide. The subculture is carried out to determine the minimum biocide concentration (MBC). The MBC is the minimum concentration of the biocide that results in zero growth after subculturing and subsequent incubation. All microtiter plates including the MIC plates and the MBC plates are incubated for 24 hours at 37 ° C. After the 24 hour incubation period, the presence or absence of growth in each well of the plates is determined. Growth is determined in the microtiter plates with a Dynatech MR-5000 microplate reader, available from Dynatech Laboratories, Chantilly, VA, the use of which will be familiar to one having ordinary experience in the art. The presence or absence of growth in each well, together with the biocide concentration in each well, is then used to determine the synergistic properties of the biocide combinations. The synergistic properties are evaluated by determining the value of Kull, or the value of K; the K value is determined from each of the analyzed bacteria. The method to calculate the value of K is well known to those skilled in the art. In this example, the value of K is determined by the following formula: [DGH] In Combination + [N-phenylsulfamide] In Combination K = - [DGH] Only [N-phenylsulfamide] Only Where "[DGH] In Combination" means the concentration of DGH which, when used in combination with N-phenylsulfamide results in the inhibition of microbial growth; The "[N-phenylsulfamide] In Combination" means the concentration of N-phenylsulfamide in which, when used in combination with DGH, they cause the inhibition of microbial growth; The "[DGH] Solo" means the concentration of DGH which, when used alone, causes the inhibition of microbial growth; The "[N-phenylsulfamide] alone" means the concentration of N-phenylsulfamide which, when used alone, causes the inhibition of microbial growth; A value of K less than 1 indicates the synergy between the two biocides, a value of K greater than 1 indicates antagonism between the two biocides, and a value of K equal to 1 indicates an additive effect of the two biocides. The values of K determined for each of the organisms used in the example are recorded in Tables 2 to 5.

TABLE 2 VALUES OF "K" OF THE PLATE 1 MIC- TABLE 3 VALUES OF "K" OF THE PLATE 2f IC TABLE 4"K" VALUES OF THE PLATE 5 f MBC1 TABLE 5 VALUES OF "K" OF LAPLACA6 ÍMBC.

As seen from the results of Tables 2-5, the synergy is demonstrated against the total of the three organisms analyzed, as well as the mixture of these three organisms.

Claims (16)

1. CLAIMS 1. A synergistic antimicrobial combination characterized in that it comprises: a) N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide; and b) an alkylguanidine compound; wherein the weight ratio of a) to b), on an active basis, is in the range of between about 1000: 1 and 1: 1000.
2. 2. The combination according to claim 1, characterized in that the weight ratio of a) to b) is in the range of between about 5: 1 and 1:13.
3. 3. The combination, according to claim 1, characterized in that the alkylguanidine compound is dodecylguanidine hydrochloride.
4. 4. The combination, according to claim 2, characterized in that the alkylguanidine compound is dodecylguanidine hydrochloride.
5. 5. A method for inhibiting microbial growth in an aqueous system which comprises adding to the system an effective amount of a synergistic antimicrobial combination characterized in that it comprises: a) N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl- N-phenylsulfamide; and b) an alkylguanidine compound; wherein the weight ratio of a) to b), on an active basis, is in the range of between about 1000: 1 and 1: 1000.
6. 6. The method according to claim 5, characterized in that the weight ratio of a) to b) is in the range between approximately 5: 1 and 1: 13.
7. 7. The method, in accordance with the claim 6, characterized in that the alkylguanidine compound is dodecylguanidine hydrochloride.
8. 8. The method, in accordance with the claim 5, characterized in that the N- [(dichlorofluoromethyl) thio] -N1, N'-dimethyl-N-phenylsulfamide and the alkylguanidine compound are aggregated together as an individual composition to the system to be treated.
9. 9. The method, in accordance with the claim 5, characterized in that the N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide and the alkylguanidine compound are separately added to the system to be treated.
10. The method, according to claim 5, characterized in that at least 0.1 ppm of the synergistic antimicrobial composition is added to the system to be treated.
11. 11. The method, in accordance with the claim 7, characterized in that between about 0.78 ppm and 3 ppm of N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide and between about 2 ppm and 10 ppm of dodecylguanidine hydrochloride are added to the system to be treaty.
12. 12. A method for inhibiting microbial growth in an article of manufacture which comprises applying to the article an effective amount of a synergistic antimicrobial combination characterized in that it comprises: a) N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl -N-phenylsulfamide; and b) an alkylguanidine compound; wherein the weight ratio of a) to b), on an active basis, is in the range of between about 1000: 1 and 1: 1000.
13. The method, according to claim 12, characterized in that the weight ratio of a) to b) is in the range of between about 5: 1 and 1:13.
14. The method, according to claim 12, characterized in that the alkylguanidine compound is dodecylguanidine hydrochloride.
15. 15. The method according to claim 12, characterized in that the N- [(dichlorofluoromethyl) thio] -N ', N' -dimethyl-N-phenylsulfamide and the alkylguanidine compounds are applied together as an individual composition to the article to be treated.
16. 16. The method according to claim 12, characterized in that the N- [(dichlorofluoromethyl) thio] -N1, N'-dimethyl-N-phenylsulfamide and the alkylguanidine compound are applied separately to the article to be treated.