CA1116512A - Aqueous antimicrobial composition having improved stability - Google Patents
Aqueous antimicrobial composition having improved stabilityInfo
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- CA1116512A CA1116512A CA000342819A CA342819A CA1116512A CA 1116512 A CA1116512 A CA 1116512A CA 000342819 A CA000342819 A CA 000342819A CA 342819 A CA342819 A CA 342819A CA 1116512 A CA1116512 A CA 1116512A
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Abstract
ABSTRACT OF THE DISCLOSURE
Aqueous antimicrobial compositions which com-prise a halogenated amide antimicrobial, such as 2,2--dibromonitrilopropionamide, a water miscible organic solvent such as a straight chain polyalkylene glycol (e.g., polyethylene glycol 200) or an ether thereof (e.g., a mono- or di-lower alkyl and/or phenyl ether) and water and which have improved stability are obtained by ensuring that such compositions are substantially free of glycols having a molecular weight of less than 70 and of salts of organic acids. The resulting improved compositions exhibit reduced rates of decompo-sition of the halogenated amide antimicrobial relative to the corresponding aqueous compositions containing salts of organic acids and/or glycols having a molecular weight of less than 70.
Aqueous antimicrobial compositions which com-prise a halogenated amide antimicrobial, such as 2,2--dibromonitrilopropionamide, a water miscible organic solvent such as a straight chain polyalkylene glycol (e.g., polyethylene glycol 200) or an ether thereof (e.g., a mono- or di-lower alkyl and/or phenyl ether) and water and which have improved stability are obtained by ensuring that such compositions are substantially free of glycols having a molecular weight of less than 70 and of salts of organic acids. The resulting improved compositions exhibit reduced rates of decompo-sition of the halogenated amide antimicrobial relative to the corresponding aqueous compositions containing salts of organic acids and/or glycols having a molecular weight of less than 70.
Description
~l AQUf :OUS ANT I M I CROB I AL COMPOS I T I ON
HAV I NG I MPROVED STAB I L I TY
This invention relates to aqueous halogenated amide antimicrobial compositions having improved stability and to processes for their preparation.
Halogenated amides such as 2,2-dibromonitrilo-propionamide are useful as antimicrobials in various applications. Certain halogenated amides are useful in the finishing of textiles, and others are useful as slimicides in aqueous systems such as paper pulp and cooling towers and as sterilizing agents for dry cleaning fluids.
In the storage, shipment and use of halogenated amide antimicrobial agents, it has hereto~ore been suggested to employ such antimicrob1al agent in the form of a li~uid concentrate composition wherein the halogenated amide is dissolved either iIl a straight chain pc~lyalkylene glycol ox in a mixture of such glycol with up to 20 weight percent water on a total weight basis. Unfortu-nately, however, ~he presence of wa~er in such compositionshas been found to accelerate the decomposition of the halogena-ted amide therein and, indeed, at water contents 18,497A-F
above 20 weight percent the stability of the halogenated amide in the resultlng aqueous compositions has been reported to be entirely unsatisfactory. Thus, in order to obtain adequate stability for most purposes, it has heretofore been generally necessary to either resort to essentially anhydrous liquid concentrate compositions or to at least limit the water content of such compositions to less than 20 weight percent on a total weight basis.
Similarly, it has also been necessary either to essentially exclude water from the ingredients used in the preparation of such compositions or at least to substantially limit the water content of such ingredients.
In view of the foregoing, it is highly desir-able to provide a means of reducing the adverse impact of water upon the aforementioned liquid compositions and to thereby provide (a) aqueous halogenated amide antimicrobial compositions having improved stability and (b) an economical process for the preparation of sui~ably stable aqueous halogenated amide antimicrobial compositions. Moreover, it is especially desirable to provide such aqueous halo-genated amide antimicrobial compositions (and preparation processes therefor3 which have acceptable stability of the halogenated amide antimicrobial therein even at water contents in excess of 20 weight percent based on the total weight of such aqueous antimicrobial composition.
This invention provides an aqueous antimicrobial composition having improved stability (a) which is sub-stantially free of glycols having a molecular weight of less than 70 and of salts of organic acids; ~b) which has a pH of from 2 to ~; and ( 5 ) which comprises:
(1~ an alpha-halogenated amide antimicrobial compound of the formula:
~8,497A-F -2-~3-Br 0 ~1 ~ C - ~ - N - (R)2 X
wherein:
X is hydrogen, halogen or a cyano radical;
each R group is independently hydrogen, a monovalent saturated hydrocarbon radical or an inertly substituted monovalent saturated hydrocarbon radical or the two R groups are jointly a divalent saturated hydrocarbon radical or an inertly substituted divalent saturated hydro-caxbon radical which, taken with the adjacent lS nitrogen atom, forms a heterocyclic ring having from 4 to 10 ring members; and Rl is a cyano radical or an amido radical of the formula:
~C~N~R)2 wherein R is as hereinbe:Eore defined;
HAV I NG I MPROVED STAB I L I TY
This invention relates to aqueous halogenated amide antimicrobial compositions having improved stability and to processes for their preparation.
Halogenated amides such as 2,2-dibromonitrilo-propionamide are useful as antimicrobials in various applications. Certain halogenated amides are useful in the finishing of textiles, and others are useful as slimicides in aqueous systems such as paper pulp and cooling towers and as sterilizing agents for dry cleaning fluids.
In the storage, shipment and use of halogenated amide antimicrobial agents, it has hereto~ore been suggested to employ such antimicrob1al agent in the form of a li~uid concentrate composition wherein the halogenated amide is dissolved either iIl a straight chain pc~lyalkylene glycol ox in a mixture of such glycol with up to 20 weight percent water on a total weight basis. Unfortu-nately, however, ~he presence of wa~er in such compositionshas been found to accelerate the decomposition of the halogena-ted amide therein and, indeed, at water contents 18,497A-F
above 20 weight percent the stability of the halogenated amide in the resultlng aqueous compositions has been reported to be entirely unsatisfactory. Thus, in order to obtain adequate stability for most purposes, it has heretofore been generally necessary to either resort to essentially anhydrous liquid concentrate compositions or to at least limit the water content of such compositions to less than 20 weight percent on a total weight basis.
Similarly, it has also been necessary either to essentially exclude water from the ingredients used in the preparation of such compositions or at least to substantially limit the water content of such ingredients.
In view of the foregoing, it is highly desir-able to provide a means of reducing the adverse impact of water upon the aforementioned liquid compositions and to thereby provide (a) aqueous halogenated amide antimicrobial compositions having improved stability and (b) an economical process for the preparation of sui~ably stable aqueous halogenated amide antimicrobial compositions. Moreover, it is especially desirable to provide such aqueous halo-genated amide antimicrobial compositions (and preparation processes therefor3 which have acceptable stability of the halogenated amide antimicrobial therein even at water contents in excess of 20 weight percent based on the total weight of such aqueous antimicrobial composition.
This invention provides an aqueous antimicrobial composition having improved stability (a) which is sub-stantially free of glycols having a molecular weight of less than 70 and of salts of organic acids; ~b) which has a pH of from 2 to ~; and ( 5 ) which comprises:
(1~ an alpha-halogenated amide antimicrobial compound of the formula:
~8,497A-F -2-~3-Br 0 ~1 ~ C - ~ - N - (R)2 X
wherein:
X is hydrogen, halogen or a cyano radical;
each R group is independently hydrogen, a monovalent saturated hydrocarbon radical or an inertly substituted monovalent saturated hydrocarbon radical or the two R groups are jointly a divalent saturated hydrocarbon radical or an inertly substituted divalent saturated hydro-caxbon radical which, taken with the adjacent lS nitrogen atom, forms a heterocyclic ring having from 4 to 10 ring members; and Rl is a cyano radical or an amido radical of the formula:
~C~N~R)2 wherein R is as hereinbe:Eore defined;
(2) a water miscible organic sol~ent in an amount sufficient to dissolve said alpha halogenated amide, said solvent being selected from the group con-sisting of polyalkylene glycols and ethers thereof; and ~3) water in an amount greater than 20 weight percent based upon the total weight of the aqueous anti-microbial composition. Such composition typically has a p~ of from 2 to 5 (preferably from 3 to 4), is substan-tially free of glycols having a molecular weight of less than 70 and of salts of organic acids and comprises:
18,497A-F -3-~4-(1) a water miscible organic solvent;
(2) water; and
18,497A-F -3-~4-(1) a water miscible organic solvent;
(2) water; and
(3) a halogenated amide antimicrobial.
~ particularly beneficial feature of the instant invention is that the substantial exclusion or elimination of the aforementioned impurities (iOe., the glycols having a molecular weight of less than 70 and/or salts of organic acids~ from the aqueous antimicrobial compositions hereof generally provides suitably stable aqueous haloge-nated amide antimicrobial compositions even at watercontents in excess of 20 weight percent based upon the total weight of such composition.
In another aspect, this invention provides an improved process for preparing the aqueous antimicrobial composition of Claim 1 which process (1~ is conducted under conditions which are substantially free o~ glycols having a molecular weight of less than 70 and of salts of organic acids and (23 comprises the steps of:
(a) preparing the alpha-halogenated amide antimicrobial by the acid catalyzed reaction of th~ corresponding nonhalogenated amide with halogen in aqueous solution at a temperature of less than 40 DC and at a hydrogen halide concent~ation which is less than 20 weight percent on a total weight basis but which is sufficient to catalyze the reaction;
(b) dissolving the resulting aqueous reaction mixture in the water miscible organic solvent; and 18,497A-F -4-(c) adjusting the pH of the reaction mixture or the organic solvent solution thereof such that the aqueous antimicrobial com position has a pH of from 2 to 5.
S Typically, the pH of the reaction mixture (following the reaction and before dissolution in the organic solvent) is adjusted to a value of from 5 -to 7 (preferably from 5.5 to 6.5) so that the composition resulting after dissolution in the oxganic solvent has a pH of from 2 to 5 (preferably from 3 to 4). The particular reagent employed to achieve the aforementioned pH adjustment in such step is not particularly critical. However, as a general rule, alkali metal or alkaline earth metal car-bonates or bicarbonates (especially sodium carbonate~ are advantageously employed.
As used herein, the term "water miscible" means that the organic solvent is soluble in water (i.e., mixes or blends uniformly with water) at least to the degree required to achieve the desired solvent to water ratio in the aqueous composition and preferably the organic solvent is soluble in water in all proportions.
The terms "antimicrobial compound" and "halo-genated amide antimicrobial" are used interchangeably herein and refer to halogenated amides which function as biocides ~i.e., compounds which inhibit the growth of, or kill, microorganisms such as bacteria, molds, slimes, fungi, etc.).
The phrase "substantially free of glycols having a molecular weight of less than 70 and of salts of organic acids" means that the composition contains less than 1.0 (preferably less than 0.5) weight percent of 18,4g7A-F -5-such glycO15 and less than 0.1 (preferably less than 0.05~ weight percent of such salts, bo-th percentages being on a total weight basis.
Th~ aqueous antimicrobial compositions of the invention are useful as slimicides in aqueous systems such as paper pulping processes and cooling towers and as sterilizing agents for dry cleaning fluids. Such compo-sitions exhibit improved stability toward decomposition of the halogenated amide antimicrobial for extended periods under a wide variety of storage, packaging and handling conditions. They are easily handled and can be employed in the above applications pursuant to conventional techniques.
The indicated process for preparing -the aqueous antimicrobial composition is advantageous in that suitably stable compositions can be prepared without separation of the halogenated amide antimicrobial from the aqueous medium in which it was prepared.
Halogenated amide antimicrobials employed in the practice of this invention are alpha-haloamides;
that is, compounds which contain an amide functionality (i.e., a moiety of the formula -C(O)-N ) and which have at least one halogen atom on a carbon atom located adjacent to (i.e., in the alpha position relative to) the carbonyl group (i.e., the -C(O~- group) of such amide functionality. Advantageously, such halogenated amide antimicrobials are halogenated nitrilopropion-amides or halogenated malonic diamides having the for~ula:
18,497A-F -6--7~
Br O
"
Rl C - C - N - (R)2 wherein:
X is hydrogen, halogen or a cyano radical, i.e., -C-N (preferably hydrogen, chlorine or bromine);
each R group is independently hydrogen, a monovalent "saturated hydrocarbon radical" or an inertly substituted monovalent "saturated hydrocarbon radical"
or the two R groups are, jointly, a divalent "saturated hydrocarbon radical", or an inertly substituted divalent "saturated hydrocarbon radical", which, taken with the adjacent nitrogen atom, forms a heterocyclic riny having from 4 to 10 ring members; and Rl is a cyano radical (i.e., -C--N) or an amido radical having the formula:
"
C-N~R)2 wherein R is as hereinbefore define~. (Preferably, R
is a cyano radical.) As used herein, the term "saturat2d hydro-carbon radical" refers to a hydrocarbon radical which is ~ree from aliphatic carbon to carbon unsaturation.
Thus, such term includes radicals such as alkyl, cyclo-alkyl, aryl, alkylaryl, arylalkyl, cycloalkylaryl, etc., and excludes radicals such as alkenyl, cyclo-alkenyl, and alkynyl.
18,4g7A-F -7-. _, J.~ r~
As used herein, the term "inertly substituted saturated hydxocarbon radical" refers to a "saturated hydrocarbon radical" having one or more chain linkage or substituent which is "inert" in the sense that such chain linkage or substituent does not readily react with the ingredients of the agueous antimicrobial com-position. Suitable inertly substituted saturated hydrocarbon radicals thus include, for example, halo-alkyl, haloaryl., halocycloalkyl, aminoalkyl, ainino-aryl, ami.nocycloalkyl, hydroxyalkyl, hydroxyaryl,hydroxycycloalkyl, cyanoalkyl, cyanoaryl, and cyano-cycloalkyl.
The aforementioned halogenated amide antimi-crobials of the formula I thus include brominated nitrilopropionamides (i.e., compounds of the formula I
wherein R1 is a cyano radical~, such as 2-bromo-3--nitrilopropionamide, 2-bromo-2,3-dinitrilopropionamide, 2,2-dibromo-3-nitrilopropionamide, N-(n butyl)-2-bromo--3 nitrilopropionamide; N,N-dimethyl-2,2-dibromo-3~
-nitrilopropionamide, 2-chloro-2-bromo-3-nitrilopropion-amide, N-(n-propyl)-2-iodo-2-bromo-3-nitrilopropionamide, N-methyl-N-ethyl-2~fluoro-2-bromo-~-nitrilopropionamide, N-phenyl-2-cyario-~-bromo-3-nitrilopropionamide, N-cyclohexyl-2,2-dibromo-3-nitrilopropionamide, N-benzyl-Z5 -2-bromo-3-nitrilopropionamide, and N-(2,2-dibromo-3--nitrilopropionoyl)piperidine.
The aforementioned halogenated amide anti-microbials of the formula I also include mono and di-bromomalonic diamides (i.e., compounds of the formula I wherein R1 is an amido radical as hereinbefore described), such as 2-bromomalonic diamide, 2,2-dibromo-l~alonic diamide, N-methyl~N'-ethyl-2-chloro-2-bromo-malonic diamide, and N-phenyl-2-iodo-2-~romomalonic diamide.
189497A~F -~-.-- ~ ~ - r -~
- 9~-.
Among the aforementioned halogenated amide antimicrobials, those wherein, in the formula I, R1 is a cyano radical, X is hydrogen, chlorine or ~romine and each R is independently hydrogen, lower alkyl (e.g., an alkyl group of from 1 to 6 carbon atoms) or phenyl are preferred (especially those of the formula I
wherein each R independently is hydrogen or methyl and X is hydrogen or bromine). Such preferred halogenated amide antimicrobials include 2-bromo-3-nitrilopropion-amide, 2,2-dibromo-3-nitrilopropionamide, N-methyl-2~
-bromo-3-nitrilopropionamide, N-phenyl-2-bromo-2-chloro -3-nitrilopropionamide, N-methyl-2,2-dibromo-3-nitrilo-propionamide, N,N-dimethyl-2-bromo-3-nitrilopropionamide, N,N-diethyl-~,2-dibromo-3-nitrilopropionamide, and N,N-dimethyl-~,2-dibromo-3-nitrilopropionamide.
Also of particular interest are the dibromi-nated nitrilopropionamides (i.e., the halogenated amide antimicrobials of the formula I wherein X is bromine and R1 is cyano) wherein each R independently is hydrogen, lower alkyl or phenyl. Such compounds include 2,2--dibromo-3-nitrilopropionamide, N-(n-butyl)-2,2-dibromo---3~nitrilopropionamide, N,N-dimethy1-2,2-dibromo-3-nitrilopropionamide, and N-phenyl-N-methyl-2,2-dibromo--3-nitrilopropionamide; especially 2,2-dibromo-3-nitril-opropionarnide.
The aqueous antimicrobial compositions of theinvention normally contain from 1 to 25 percent, and more typically, from 5 to 20 percent, by weight of the hereinbefore described halogenated amide antimicrobial based upon the total weight of the composition. However, the prior art problem of decomposition of the halogenated amide antimicrobials in the presence of the aforementioned impurities (i.e., glycols having a molecular weight of 18,497A-F ~9-less than 70 and/or salts of organic acids) has been observed to be more pronounced when the aqueous compo-sitions contain less than 20 percent by weight of the antimicrobial on a total weight basis. Thus, aqueous antimicrobial compositions ~hich, by virtue of the rel-atively more pronounced benefits obtained by exclusion of such impurities, are of particular interest comprise from l to 15, preferably from 1 to lO, most preferably from 1 to 5, weight percent of the totaI composition.
In the composition of this invention, the aforementioned halogenated amide antimicrobial is dis-solved in a mixture of water and a water miscible organic solvent. Suitable organic solvents include any water miscible organic solvent in which the halogenated amide antimicrobial is at least partially soluble. Preferably, the organic solvent is one in which -the halogenated amide antimicrob1al is soluble at normal room temperature (i.e., from 20 to 25C~ to the extent of at least 5 parts by weight of the antimicrobial in 95 parts by weight of the solvent. The most preferred water miscible organic solvents are those in which the antimicrobial is soll~le to the extent of at least 10 [especially at leas~
20) parts by weight of the antimicrobial in 80 parts by weight of thP solvent at normal room tempPratures (i.e., ~5 from 20 to 2~C).
Advantageously, the organic solvent is a poly-alkylene glycol or an ether thereof, especially a normally liquid straight chain polyalkylene glycol or a mono- or di-lower saturated hydrocarbyl ether thereof wherein the term "saturated hydrocarbyl" refers to a monovalent saturated hydrocarbon radical as hereinbefore defined.
lB,497A-F -10-Generally, such polyalkylene glycols and poly-alkylene glycol ethers have a weight average molecular weight (Mw~ of from 75 to 1000. Such average molecular weights are hereinafter designated for the particular glycols involved by placing a numeral representing the weight average molecular weight after the glycol name.
of particular interest in the practice of the invention are the polyalkylene glycols of the ethylene, trimethylene or tetramethylene series and the mono- and di-lower (e.g., containing from 1 to 6 carbon atoms) saturated hydrocarbyl ethers thereof. Such particularly advantageous solvents thus include polyethylene glycols, trimethylene glycols, tetramethylene glycols and the mono- and di-lower saturated hydrocarbyl (e.gO, lower alkyl and phenyl) ethers of such glycols. Examples of such glycols and ethers include 1,4-butanediol, tri-ethylene glycol, polyethylene glycol 200, tetraethylene glycol, polyethylene glycol 400, diethylene glycol dimethyl ether, diethylene glycol phenyl ether, diethylene glycol ethyl phenyl ether, polytrimethylene glycol 200, diethylene glycol, triethylene glycol methyl ether and polyethylene glycol 600.
Preferably, the polyalkylene glycol or ether ingredient is a polyethylene glycol, or a mixture of polyethylene glycols, having Mw of from 175 to 250. Most preferably the polyalkylene glycol ingredient is poly-ethylene glycol 200.
As has been noted, this invention is based upon the discovery that the prior art problem of pronounced halogenated amide antimicrobial decomposition in aqueous li~uid concentrate compositions is attributable to the 18,497A-F
presence of certain impurities which have been present in the water miscible organic solvents typically employed in the prior art aqueous halogenated amide antimicrobial compositions. Specifically, such impurities are glycols having a molecular weight of less than 70 and/or salts of organic acids such as ammonium salts or alkali metal or alkaline earth metal (e.g., sodium, potassium or calcium), salt:s of organic acids (e.g., mono- and polycarboxylic acids) such as acetic acid, propionic acid, butyric acid, adipic acid, citric acid, etc. Conse~uently, since such impurities are commonly found in varying amounts in unpurified commercial grades of the aforementioned poly-alkylene glycols and polyalkylene glycol ethers, care must be exercised in the practice of this invention either to employ grades of such ylycols or ethers which have previously been purified to remove such impurities or to first purify (e.g., by distillation, etc.) the less pure commercial grades to remove such impurities prior to use in the instant invention. In short, it is a requirement in the practice of this invention that the aforementioned water miscible organic solvent be substantially free (e.g., contain less than l.0, preferably less than 0.5, weiyht percent based upon the weight of solvent) of glycols having a molecular weight of less than 70 and that such solvent also be substantially free (e.g., contain less than O.l, prefera~ly less than 0.05, weight percent based upon the weight of solvent) of salts of organic acids.
The amount of the aforementioned water miscible organic solvent employed in the practice of the invention is not particularly critical so long as a sufficient amount is employed to prevent precipitation of the halo~
genated amide antimicrobial during shipping, storage and 18,497A-F -12-use of the aqueous antlmicrobial composition. The amount of the organic solvent employed will thus depend upon such factors as the solubility of the halogenated amide antimicrobial in the organic solvent, the desired con-centration of the halogenated amide antimicrobial in thecomposition, and the like. However, as a general rule, the organic solvent constituies from 5 to 90, preferably from 10 to 80, more preferably from 25 to 75, most pre-ferably from 35 to 70, percent by weight of the total antimicrobial composition.
The amount of water contained by the aqueous antimicrobial composition of the invention is likewise not particularly critical to the practice of the inven-tion and, as a general rule, the compositions of the invention employ water in an amount of from 5 to 90 weight percent based upon the total weight of the a~ueous antimicrobial composition. However, as has been previously noted, the aforementioned prior art problem of accelerated halogenated amide antimicrobial decomposition under agueous conditions is generally more pronounced in compo-sitions having relatively large water contents and has been observed to be especially severe at water contents of greater than 20 weight percent based upon the total weight of the aqueous composition. Thus, the stability benefits obtained by the practice of this invention (i.e., by elimination of the aforementioned impurities~
are relatively greater in compositions having relatively large water contents. Accordingly, compositions in which the practice of this invention is especially advantageous ~ontain water in an amount of from 10 to 85 (pre~ferably from 15 to 70, more preferably from gxeater than 20 up to 60 and most preferably from 25 to 50) weight percent based upon the total weight o the aqueous antimicrobial 18,497A-F -13-composition and, indeed, a particularly beneficial aspect of the instant invention is that it permits obtention of aqueous compositions having suitable skability even at water contents in excess of 20 weight percent based upon the total weight of such aqueous antimicrobial composition.
In addition to the hereinbefore described ingredients, the aqueous antimicrobial compositions can optionally contain other ingredients. Such other inyre-dients can be inert in the sense that they neither inhibit nor accelerate decomposition of the halogenated amide.
Alternatively, such other ingredients can be of a t~pe which either accelerate or inhibit decomposition of the halogenated amide antimicrobial.
Thus, for example, the aqueous antimicrobial composition of the invention can optionally contain stabilizing ingredients such as acids or anhydrides (e.g., acetic acid, ethylenediaminetetraacetic acid, succinic acid, succinic anhydride, glycolic acid, etc.);
carbamoyl or sulfamoyl compounds (e.g., N-methyl urea, N,N-diethyl urea, biuret, sulfamide, oxamide, N,N-dimethyl-formamide, caprolactam, N-methyl-2-pyrrolidone, dimethyl-hydantoin, succinimide, etc.); cyclic ethers ~e.g., 1,4 dioxane, tetrahydrofuran, sym-trio~ane, N-methyl morpholine, etc.~; aldehydes (e.g., formaldehyde, para-formaldehyde, vanillin, etc.~; ~uaternary ammonium orphosphonium salts (e.g., methyl triphenyl phosphonium bromide, n-C12-C18 alkyl dimethyl benzyl ammonium chloride, etc.); and azine or nitrile com~ounds ~e.g., cyanuric àcid, 2~chloro-4,6-bis(ethylamino)-s-triazine, cyanoguanidine, succinonitrile, etc.). When such optional stabilizing ingredients are employed, they are generally used in an amount sufficient to measurably reduce the decomposition 18,497A-F -14-rate of the halogenated amide antimicrobial in the aqueous antimicrobial composition (i.e., in a stabilizing amount).
Such reduction in the halogenated amide antimicrobial decomposition is, of course, relative to the decomposition rate encountered with a corresponding aqueous composition in the absence of stabilizer under the same test conditions and such reduction is deemed to be "measurable" if it is detectible ~and reproducible) by the iodometric test method which is described hereinafter in conjunction with the working examples. Advantageously, such optional stabilizing ingredients, when used, are employed in an amount sufficient to reduce by at least 20 (preferably at least 30 and most preferably at least 40) percent the amount of the halogenated amide antimicrobial which decomposes during 15 days (preferably 30 days) at 50C
based upon the amount of decomposition which occurs under the same conditions in the absence of the stabilizing ingredient. While the amount of optional stabilizing ingredient required to accomplish the desired degree of stabilization in a given instance can vary, as a general rule, the optional stabilizing ingredient, if employed, will constitute between 0.05 and 10, preferably between 0.1 and 5, most preferably between 0.5 and 2, percent by weight of the total composition.
The aforementioned optional stabili2ing ingre-dients are not generally required for suitable stability in the compositions of the invention since such compo-sitions are free from the destabilizing effects of the hereinbefore described impurities. However, in those instances wherein the compositions of the invention comprise other destabilizing ingredients or impurities, it is preferable that such compositions also comprise one or more of the aforementioned optional stabilzing ingre-dients in addition to being substantially free from the 18,497A-F ~15-aforementioned impurities. Thus, for example, when the composition o~ -the invention is prepared pursuan-t to the hereinafter described process ~in which the aqueous reaction medium of the halogenated amide preparation reaction forms part of the aqueous composition), the resulting aqueous halogenated amide composition will generally contain halide salts (e.g., alkali metal or alkaline earth metal halides such as sodium bromide, sodium chloride, potassium chloride, potassium bromide, calcium bromide, calcium chloride, etc.). Such halide salts are generated in the halogenated amide preparation process and have also been found to adversely affect the stability of the halogenated antimicrobial in the aqueous liquid concentrate compositions thereof. Accordingly, when the compositions of the invention contain such halide salts (from the aforementioned process or from some other source), it is beneficial (and therefore preferred) to also employ the aforementioned optional stabilizing ingredients in such compositions.
The order of combination of the hereinbefore described ingredients is not critical to the practice of the invention. However, when the aforementioned optional stabilizing ingredients are employed, it is generally desirable to avoid prolonged exposure of the antimicrobial compound to the water in the composition prior to addition of such stabili2ing ingredient thereto. Similarly, it is generally desira~le, in order to re-tain optimum antimicrobial activity, to prepaxe, store, transport and handle the compositions of the invention at the lowest practicable temperature (normally ambient kemperature).
As has been noted, elimination of the herein-before described impurities ~i.e., glycols having a molecular weight of less than 70 and salts of organic 18,497A-F -16-5~
acids) from aqueous haiogenated amide antimicrobial compositions has been found to reduce the halogenated amide antimicrobial decomposition rate in a mixture of the aforementioned organic solvent and water. A par-ticularly beneficial result of such phenomenon (espe-cially when used in conjunction with the stabilizing phenomenon of the aforementioned optional stabilizing ingredients) is that suitably stable halogenated amide antimicrobial compositions can be prepared directly from a mixture of the antimicrobial and the aqueous reaction medium in which it was prepared. Specifically, separation of the halogenated amide antimicrobial from its aqueous reaction medium is conveniently eliminated by incorporating such reaction medium into the antimicrobial composition.
The adverse impact of the resulting presence of water which would otherwise occur is prevented by ensuring that the resulting composition is substantially free from the aforementioned impurities (for example, by employing ingredients such as solvents, etc., which are substantially free of such impurities) and preferably by also adding the aforementioned optional stabilizing ingredients.
The preparation of the halogenated amide anti-microbial can be accomplished in any convenient conventional manner. Thus, for example, the halogenated amide antimicro-bial can be prepared by the acid catalyzed reaction ofthe corresponding nonhalogenated amide (e.g., cyanoacetamide, malonic diamide and M-substituted derivatives thereof) with halogen (especially bromine) in aqueous solution, preferably at a temperature of less than 40C and preferably at a hydrogen halide (w-hich is a reaction by-product) concentration of less than 20 weight percent on a total weight basis.
18,497A-F -17--18~
Preferably, however, the initial step of such process is performed pursuant to an improved procedure which comprises introducing a water-soluble bromate into the agueous reaction medium.
After the halogenated amide antimicrobial has been prepared, the resulting rPaction mixture is dissolved in the hereinbefore described organic solvent. Such dissolution step is performed either before or after the optional but preferable addition of the aforementioned stabilizing ingredient and without isolation of the halogenated amide antimicro~ial from the aqueous reaction medium.
It is generally desirable to avoid prolonged exposure of the halogenated amide antimicrobial to the a~ueous reaction medium in the absence of the stabilizing ingredient ~if such ingredient is to be employed) in order to minimize decomposition of the halogenated amide product prior to stabilization. In addition, the pH
adjustment stèp is also desirably accomplished without prolonged delay since the decomposition rate of the halo~
genated amide antimicrobial is generally pH dependent and since such decomposition rate is typically minimized within the indicated pH range. In addition, since the rate of decomposition of the halogenated amide anti-microbial increases with increased temperature, it ispreferable to conduct the aforementioned individual proc~ss steps (and to store, transport and handle the resulting aqueous antimicrobial compositions) at am~ient temperature (e.g., from 20 to 25C) or less in order to avoid excessive decomposition of the antimicrobial during such operations.
18,497A-F ~18-The practice of the instant invention is further illustrated by the following examples. In such examples, all weight percentages are on a total weight basis unless otherwise indlcated.
Example 1 - Stable Aqueous Composition of 2,2-Dibromo--3-Nitrilopropionamide Employing Purified Tetraethylene ~lycol as the Solvent These experiments illustrate the des~abllizing effect of common impurities in a polyalkylene glycol solvent ~which commonly arise in the manufacture of such solvents~ upon 2,2-dibromo-3-nitrilopropionamide ~DBNPA) dissolved in a mixture of such solvent and water. Also illustrated is the improved DBNPA stability in a glycol-water solution wherein the glycol has been purified to remove substantially all of such impurities.
Control 1 .. .. . .
A 2.5 g portion of 2,2-dibromo-3-nitrilo-propionamide (DBNPA) is placed in a 2 ounce amber bottle.
To this is add~d a 23.75 g portion of water and a 23.75 g portion of a commercially available unpurified mixture of polyethylene glycols having a weight averaged mole-cular weight of about 200. Such polyethylene glycol mixture also contains an undetermined amount of residual unpolymerized ethylene glycol monomer (m~lecular weight = 62~ and an undetermined amount of sodium acetate resulting from neutralization of excess sodium hydroxide remaining following polym-erization of the ethylene glycol monomer.
_a~e~
In a second 2 ounce amber bottle is placed a 2.5 g portion of ~DNPA, a 23.75 g por-tion of water and a 23.75 g portion of purified tetraethylene glycol.
18,497A-F -19-~o--The purified tetraethylene glycol is substantially ~ree of ethylene glycol monomer and of salts resulting from sodium hydroxide neutralization in the polyethylene glycol manufacturing operation.
The contents of both of the ~ottles are mixed until all o the ingredients are dissolved. The dis-solution is accompanied by a temperature rise of 5C.
After the heat of dissolution has dissipated, the initial DBNPA content is verified by iodometry. The bottles are lQ then closed with a polyethylene lined cap and placed in a constant temperature oven at 50C for accelerated decom-position testing. The samples are removed after 19 days and the extent of DBIIPA decomposition is determined by iodometry. In such test method, an excess of potassium iodide (KI) is added to the antimicrobial composition and the amount of elemental iodine which has been liberated from the KI (via oxidation of the KI by the DBNPA) is determined by titration with a standard solution of sodium thiosulfate. The amount of DBNPA present in the composition tested is then calculated on the basis of the amount of elemental iodine liberated thereby. (It should be noted that since certain of the intermediate decom-position products of DBNPA are also oxidizing agents, the indicated test method does not, strictly speaking, provide an exact measure of DBNPA content. However, such test method does pro~-ide a measure of the amount of DBNPA
which has completely ~ecomposed to ~he ultimate non-oxidizing species and thus provides a relative measure of the stability of the DBNPA compositions tested.~
The resulLs of the aforementioned iodometric testing indicate that after 19 days at 50C the agueous antimicrobial composition of Example 1 (i.e., using the 18,497A-F -20-i;3 purified tetraethylene glycol solvent3 contains 90 per-cent of its original DBNPA content. In contrast, the composition of Control 1 (i.e., using the unpurified polyethylene glycol 200 solvent) contains only 74 per-cent of its original DBNPA content after the same timeperiod at 50C. Elimination of the indicated impurities from the solvent of Control 1 (to thereby provide the composition of Example 1) is thus observed to reduce the DBNPA decomposition by about 62 percent based upon that which occurs in the presence of such impurities, i.e., ~0.90-0.74).(1.00-0.74)] x 100% = 62%.
Examples 2 and 3 - Aqueous Solution of DBNPA in Purified Tetraethylene Glycol Prepared Directly from the Aqueous DBNPA Reaction Medium A ~6.0 g quantity (i.e., 0.3 mole) of commer-cial cyanoacetamide is dissolved in 95 ml of water and is then reacted with a 48 g portion (i.e., 0.3 mole) of bromine for half an hour at 22-26C. Thereafter, a 15.1 g portion of NaBrO3 (in the orm of a concentrated aqueous solution thereof) is slowly added to the reac-tion mixture over a 1~1/2 hour period while continuing the reaction at 22-26C. An additional 2.0 g portion of bromine is then added and the reaction is continued for an additional 2 hour period.
The p~ of the resulting reaction mixture is then adjusted to 6.0 with Na2CO3 and a 180 g portion of purified tetraethylene glycol (i.e., substantially free of glycols other than tetraethylene glycol and of salts of organic acids) is added to dissol~e ~he reaction mix-ture. The resultant solution has a pH of 3.5 and con-tains 19.3 weight percent DBNPA as determined by iodo-metric titration; representing a 98 percent yield of DBNPA.
18,497A-F 21-~2 One portion of the resulting reaction mixture solution (i.e~, the composition of Example 2~ is stored at 50C and analyzed for retained DBNPA after various storage intervals by iodometric titration. A second portion of the resulting reaction mixture solution is stabilized with 1 weight percent paraformaldehyde (thereby forming the composition of Example 3) and is analyzed (by iodometric titration) for retained DBNPA
content after various storage intervals at 50C.
In a similar fashion, comparative compositions (i.e., Controls 2 and 3) are prepared which correspond to the compositions o Examples 2 and 3, respectively, except that an unpurified mixture of polyethylene gly-cols (having a weight averaged molecular weight of 200 and containing an undetermined quantity of residual ethylene glycol monomer and neutralization salts;
probably sodium acetate) is employed as the solvent in place of the purified tetraethylene glycol of Examples 2 and 3. T~ese compositions are also analyzed by iodo-metric titration for retained DBNPA content after varioussto.rage intervals at 50C.
The retained DBNPA results for the compositions of Examples 2 and 3 and for the comparative compositions of Controls 2 and 3 aré presented in Table I below.
18,4~7A-F ~22-~23--~1 I ~ U~ ~ ~1 O ,/ I d' ~, U
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mh ~ o 18, 497A~F --24--~ ~ d~
~25-The results in Table I show that the compo-sitions employing the purified tetraethylene glycol retain more DBNPA after the same (or longer) storage intervals than do the corresponding compositions employing unpurified polyethylene glycol 200 as the solvent in place of the tetraethylene glycol. (Compare Examples 2 and 3, respectively, with Controls 2 and 3.) The benefits of employing paraformaldehyde as a stabili~er in conjunction with the use of the purified tetraethylene glycol solvent and the aqueous DBNPA
reaction medium is observed by comparin~ the retained DBNPA results for the composition of Example 3 with ~hose for the composition of Example 2. Specifically, such comparison illustrates that the use of such stabilizer in the embodiment employing the a~ueous antimicrobial reaction medium provides further improve-- ment in the antimicrobial stability.
18,497A-F -25-
~ particularly beneficial feature of the instant invention is that the substantial exclusion or elimination of the aforementioned impurities (iOe., the glycols having a molecular weight of less than 70 and/or salts of organic acids~ from the aqueous antimicrobial compositions hereof generally provides suitably stable aqueous haloge-nated amide antimicrobial compositions even at watercontents in excess of 20 weight percent based upon the total weight of such composition.
In another aspect, this invention provides an improved process for preparing the aqueous antimicrobial composition of Claim 1 which process (1~ is conducted under conditions which are substantially free o~ glycols having a molecular weight of less than 70 and of salts of organic acids and (23 comprises the steps of:
(a) preparing the alpha-halogenated amide antimicrobial by the acid catalyzed reaction of th~ corresponding nonhalogenated amide with halogen in aqueous solution at a temperature of less than 40 DC and at a hydrogen halide concent~ation which is less than 20 weight percent on a total weight basis but which is sufficient to catalyze the reaction;
(b) dissolving the resulting aqueous reaction mixture in the water miscible organic solvent; and 18,497A-F -4-(c) adjusting the pH of the reaction mixture or the organic solvent solution thereof such that the aqueous antimicrobial com position has a pH of from 2 to 5.
S Typically, the pH of the reaction mixture (following the reaction and before dissolution in the organic solvent) is adjusted to a value of from 5 -to 7 (preferably from 5.5 to 6.5) so that the composition resulting after dissolution in the oxganic solvent has a pH of from 2 to 5 (preferably from 3 to 4). The particular reagent employed to achieve the aforementioned pH adjustment in such step is not particularly critical. However, as a general rule, alkali metal or alkaline earth metal car-bonates or bicarbonates (especially sodium carbonate~ are advantageously employed.
As used herein, the term "water miscible" means that the organic solvent is soluble in water (i.e., mixes or blends uniformly with water) at least to the degree required to achieve the desired solvent to water ratio in the aqueous composition and preferably the organic solvent is soluble in water in all proportions.
The terms "antimicrobial compound" and "halo-genated amide antimicrobial" are used interchangeably herein and refer to halogenated amides which function as biocides ~i.e., compounds which inhibit the growth of, or kill, microorganisms such as bacteria, molds, slimes, fungi, etc.).
The phrase "substantially free of glycols having a molecular weight of less than 70 and of salts of organic acids" means that the composition contains less than 1.0 (preferably less than 0.5) weight percent of 18,4g7A-F -5-such glycO15 and less than 0.1 (preferably less than 0.05~ weight percent of such salts, bo-th percentages being on a total weight basis.
Th~ aqueous antimicrobial compositions of the invention are useful as slimicides in aqueous systems such as paper pulping processes and cooling towers and as sterilizing agents for dry cleaning fluids. Such compo-sitions exhibit improved stability toward decomposition of the halogenated amide antimicrobial for extended periods under a wide variety of storage, packaging and handling conditions. They are easily handled and can be employed in the above applications pursuant to conventional techniques.
The indicated process for preparing -the aqueous antimicrobial composition is advantageous in that suitably stable compositions can be prepared without separation of the halogenated amide antimicrobial from the aqueous medium in which it was prepared.
Halogenated amide antimicrobials employed in the practice of this invention are alpha-haloamides;
that is, compounds which contain an amide functionality (i.e., a moiety of the formula -C(O)-N ) and which have at least one halogen atom on a carbon atom located adjacent to (i.e., in the alpha position relative to) the carbonyl group (i.e., the -C(O~- group) of such amide functionality. Advantageously, such halogenated amide antimicrobials are halogenated nitrilopropion-amides or halogenated malonic diamides having the for~ula:
18,497A-F -6--7~
Br O
"
Rl C - C - N - (R)2 wherein:
X is hydrogen, halogen or a cyano radical, i.e., -C-N (preferably hydrogen, chlorine or bromine);
each R group is independently hydrogen, a monovalent "saturated hydrocarbon radical" or an inertly substituted monovalent "saturated hydrocarbon radical"
or the two R groups are, jointly, a divalent "saturated hydrocarbon radical", or an inertly substituted divalent "saturated hydrocarbon radical", which, taken with the adjacent nitrogen atom, forms a heterocyclic riny having from 4 to 10 ring members; and Rl is a cyano radical (i.e., -C--N) or an amido radical having the formula:
"
C-N~R)2 wherein R is as hereinbefore define~. (Preferably, R
is a cyano radical.) As used herein, the term "saturat2d hydro-carbon radical" refers to a hydrocarbon radical which is ~ree from aliphatic carbon to carbon unsaturation.
Thus, such term includes radicals such as alkyl, cyclo-alkyl, aryl, alkylaryl, arylalkyl, cycloalkylaryl, etc., and excludes radicals such as alkenyl, cyclo-alkenyl, and alkynyl.
18,4g7A-F -7-. _, J.~ r~
As used herein, the term "inertly substituted saturated hydxocarbon radical" refers to a "saturated hydrocarbon radical" having one or more chain linkage or substituent which is "inert" in the sense that such chain linkage or substituent does not readily react with the ingredients of the agueous antimicrobial com-position. Suitable inertly substituted saturated hydrocarbon radicals thus include, for example, halo-alkyl, haloaryl., halocycloalkyl, aminoalkyl, ainino-aryl, ami.nocycloalkyl, hydroxyalkyl, hydroxyaryl,hydroxycycloalkyl, cyanoalkyl, cyanoaryl, and cyano-cycloalkyl.
The aforementioned halogenated amide antimi-crobials of the formula I thus include brominated nitrilopropionamides (i.e., compounds of the formula I
wherein R1 is a cyano radical~, such as 2-bromo-3--nitrilopropionamide, 2-bromo-2,3-dinitrilopropionamide, 2,2-dibromo-3-nitrilopropionamide, N-(n butyl)-2-bromo--3 nitrilopropionamide; N,N-dimethyl-2,2-dibromo-3~
-nitrilopropionamide, 2-chloro-2-bromo-3-nitrilopropion-amide, N-(n-propyl)-2-iodo-2-bromo-3-nitrilopropionamide, N-methyl-N-ethyl-2~fluoro-2-bromo-~-nitrilopropionamide, N-phenyl-2-cyario-~-bromo-3-nitrilopropionamide, N-cyclohexyl-2,2-dibromo-3-nitrilopropionamide, N-benzyl-Z5 -2-bromo-3-nitrilopropionamide, and N-(2,2-dibromo-3--nitrilopropionoyl)piperidine.
The aforementioned halogenated amide anti-microbials of the formula I also include mono and di-bromomalonic diamides (i.e., compounds of the formula I wherein R1 is an amido radical as hereinbefore described), such as 2-bromomalonic diamide, 2,2-dibromo-l~alonic diamide, N-methyl~N'-ethyl-2-chloro-2-bromo-malonic diamide, and N-phenyl-2-iodo-2-~romomalonic diamide.
189497A~F -~-.-- ~ ~ - r -~
- 9~-.
Among the aforementioned halogenated amide antimicrobials, those wherein, in the formula I, R1 is a cyano radical, X is hydrogen, chlorine or ~romine and each R is independently hydrogen, lower alkyl (e.g., an alkyl group of from 1 to 6 carbon atoms) or phenyl are preferred (especially those of the formula I
wherein each R independently is hydrogen or methyl and X is hydrogen or bromine). Such preferred halogenated amide antimicrobials include 2-bromo-3-nitrilopropion-amide, 2,2-dibromo-3-nitrilopropionamide, N-methyl-2~
-bromo-3-nitrilopropionamide, N-phenyl-2-bromo-2-chloro -3-nitrilopropionamide, N-methyl-2,2-dibromo-3-nitrilo-propionamide, N,N-dimethyl-2-bromo-3-nitrilopropionamide, N,N-diethyl-~,2-dibromo-3-nitrilopropionamide, and N,N-dimethyl-~,2-dibromo-3-nitrilopropionamide.
Also of particular interest are the dibromi-nated nitrilopropionamides (i.e., the halogenated amide antimicrobials of the formula I wherein X is bromine and R1 is cyano) wherein each R independently is hydrogen, lower alkyl or phenyl. Such compounds include 2,2--dibromo-3-nitrilopropionamide, N-(n-butyl)-2,2-dibromo---3~nitrilopropionamide, N,N-dimethy1-2,2-dibromo-3-nitrilopropionamide, and N-phenyl-N-methyl-2,2-dibromo--3-nitrilopropionamide; especially 2,2-dibromo-3-nitril-opropionarnide.
The aqueous antimicrobial compositions of theinvention normally contain from 1 to 25 percent, and more typically, from 5 to 20 percent, by weight of the hereinbefore described halogenated amide antimicrobial based upon the total weight of the composition. However, the prior art problem of decomposition of the halogenated amide antimicrobials in the presence of the aforementioned impurities (i.e., glycols having a molecular weight of 18,497A-F ~9-less than 70 and/or salts of organic acids) has been observed to be more pronounced when the aqueous compo-sitions contain less than 20 percent by weight of the antimicrobial on a total weight basis. Thus, aqueous antimicrobial compositions ~hich, by virtue of the rel-atively more pronounced benefits obtained by exclusion of such impurities, are of particular interest comprise from l to 15, preferably from 1 to lO, most preferably from 1 to 5, weight percent of the totaI composition.
In the composition of this invention, the aforementioned halogenated amide antimicrobial is dis-solved in a mixture of water and a water miscible organic solvent. Suitable organic solvents include any water miscible organic solvent in which the halogenated amide antimicrobial is at least partially soluble. Preferably, the organic solvent is one in which -the halogenated amide antimicrob1al is soluble at normal room temperature (i.e., from 20 to 25C~ to the extent of at least 5 parts by weight of the antimicrobial in 95 parts by weight of the solvent. The most preferred water miscible organic solvents are those in which the antimicrobial is soll~le to the extent of at least 10 [especially at leas~
20) parts by weight of the antimicrobial in 80 parts by weight of thP solvent at normal room tempPratures (i.e., ~5 from 20 to 2~C).
Advantageously, the organic solvent is a poly-alkylene glycol or an ether thereof, especially a normally liquid straight chain polyalkylene glycol or a mono- or di-lower saturated hydrocarbyl ether thereof wherein the term "saturated hydrocarbyl" refers to a monovalent saturated hydrocarbon radical as hereinbefore defined.
lB,497A-F -10-Generally, such polyalkylene glycols and poly-alkylene glycol ethers have a weight average molecular weight (Mw~ of from 75 to 1000. Such average molecular weights are hereinafter designated for the particular glycols involved by placing a numeral representing the weight average molecular weight after the glycol name.
of particular interest in the practice of the invention are the polyalkylene glycols of the ethylene, trimethylene or tetramethylene series and the mono- and di-lower (e.g., containing from 1 to 6 carbon atoms) saturated hydrocarbyl ethers thereof. Such particularly advantageous solvents thus include polyethylene glycols, trimethylene glycols, tetramethylene glycols and the mono- and di-lower saturated hydrocarbyl (e.gO, lower alkyl and phenyl) ethers of such glycols. Examples of such glycols and ethers include 1,4-butanediol, tri-ethylene glycol, polyethylene glycol 200, tetraethylene glycol, polyethylene glycol 400, diethylene glycol dimethyl ether, diethylene glycol phenyl ether, diethylene glycol ethyl phenyl ether, polytrimethylene glycol 200, diethylene glycol, triethylene glycol methyl ether and polyethylene glycol 600.
Preferably, the polyalkylene glycol or ether ingredient is a polyethylene glycol, or a mixture of polyethylene glycols, having Mw of from 175 to 250. Most preferably the polyalkylene glycol ingredient is poly-ethylene glycol 200.
As has been noted, this invention is based upon the discovery that the prior art problem of pronounced halogenated amide antimicrobial decomposition in aqueous li~uid concentrate compositions is attributable to the 18,497A-F
presence of certain impurities which have been present in the water miscible organic solvents typically employed in the prior art aqueous halogenated amide antimicrobial compositions. Specifically, such impurities are glycols having a molecular weight of less than 70 and/or salts of organic acids such as ammonium salts or alkali metal or alkaline earth metal (e.g., sodium, potassium or calcium), salt:s of organic acids (e.g., mono- and polycarboxylic acids) such as acetic acid, propionic acid, butyric acid, adipic acid, citric acid, etc. Conse~uently, since such impurities are commonly found in varying amounts in unpurified commercial grades of the aforementioned poly-alkylene glycols and polyalkylene glycol ethers, care must be exercised in the practice of this invention either to employ grades of such ylycols or ethers which have previously been purified to remove such impurities or to first purify (e.g., by distillation, etc.) the less pure commercial grades to remove such impurities prior to use in the instant invention. In short, it is a requirement in the practice of this invention that the aforementioned water miscible organic solvent be substantially free (e.g., contain less than l.0, preferably less than 0.5, weiyht percent based upon the weight of solvent) of glycols having a molecular weight of less than 70 and that such solvent also be substantially free (e.g., contain less than O.l, prefera~ly less than 0.05, weight percent based upon the weight of solvent) of salts of organic acids.
The amount of the aforementioned water miscible organic solvent employed in the practice of the invention is not particularly critical so long as a sufficient amount is employed to prevent precipitation of the halo~
genated amide antimicrobial during shipping, storage and 18,497A-F -12-use of the aqueous antlmicrobial composition. The amount of the organic solvent employed will thus depend upon such factors as the solubility of the halogenated amide antimicrobial in the organic solvent, the desired con-centration of the halogenated amide antimicrobial in thecomposition, and the like. However, as a general rule, the organic solvent constituies from 5 to 90, preferably from 10 to 80, more preferably from 25 to 75, most pre-ferably from 35 to 70, percent by weight of the total antimicrobial composition.
The amount of water contained by the aqueous antimicrobial composition of the invention is likewise not particularly critical to the practice of the inven-tion and, as a general rule, the compositions of the invention employ water in an amount of from 5 to 90 weight percent based upon the total weight of the a~ueous antimicrobial composition. However, as has been previously noted, the aforementioned prior art problem of accelerated halogenated amide antimicrobial decomposition under agueous conditions is generally more pronounced in compo-sitions having relatively large water contents and has been observed to be especially severe at water contents of greater than 20 weight percent based upon the total weight of the aqueous composition. Thus, the stability benefits obtained by the practice of this invention (i.e., by elimination of the aforementioned impurities~
are relatively greater in compositions having relatively large water contents. Accordingly, compositions in which the practice of this invention is especially advantageous ~ontain water in an amount of from 10 to 85 (pre~ferably from 15 to 70, more preferably from gxeater than 20 up to 60 and most preferably from 25 to 50) weight percent based upon the total weight o the aqueous antimicrobial 18,497A-F -13-composition and, indeed, a particularly beneficial aspect of the instant invention is that it permits obtention of aqueous compositions having suitable skability even at water contents in excess of 20 weight percent based upon the total weight of such aqueous antimicrobial composition.
In addition to the hereinbefore described ingredients, the aqueous antimicrobial compositions can optionally contain other ingredients. Such other inyre-dients can be inert in the sense that they neither inhibit nor accelerate decomposition of the halogenated amide.
Alternatively, such other ingredients can be of a t~pe which either accelerate or inhibit decomposition of the halogenated amide antimicrobial.
Thus, for example, the aqueous antimicrobial composition of the invention can optionally contain stabilizing ingredients such as acids or anhydrides (e.g., acetic acid, ethylenediaminetetraacetic acid, succinic acid, succinic anhydride, glycolic acid, etc.);
carbamoyl or sulfamoyl compounds (e.g., N-methyl urea, N,N-diethyl urea, biuret, sulfamide, oxamide, N,N-dimethyl-formamide, caprolactam, N-methyl-2-pyrrolidone, dimethyl-hydantoin, succinimide, etc.); cyclic ethers ~e.g., 1,4 dioxane, tetrahydrofuran, sym-trio~ane, N-methyl morpholine, etc.~; aldehydes (e.g., formaldehyde, para-formaldehyde, vanillin, etc.~; ~uaternary ammonium orphosphonium salts (e.g., methyl triphenyl phosphonium bromide, n-C12-C18 alkyl dimethyl benzyl ammonium chloride, etc.); and azine or nitrile com~ounds ~e.g., cyanuric àcid, 2~chloro-4,6-bis(ethylamino)-s-triazine, cyanoguanidine, succinonitrile, etc.). When such optional stabilizing ingredients are employed, they are generally used in an amount sufficient to measurably reduce the decomposition 18,497A-F -14-rate of the halogenated amide antimicrobial in the aqueous antimicrobial composition (i.e., in a stabilizing amount).
Such reduction in the halogenated amide antimicrobial decomposition is, of course, relative to the decomposition rate encountered with a corresponding aqueous composition in the absence of stabilizer under the same test conditions and such reduction is deemed to be "measurable" if it is detectible ~and reproducible) by the iodometric test method which is described hereinafter in conjunction with the working examples. Advantageously, such optional stabilizing ingredients, when used, are employed in an amount sufficient to reduce by at least 20 (preferably at least 30 and most preferably at least 40) percent the amount of the halogenated amide antimicrobial which decomposes during 15 days (preferably 30 days) at 50C
based upon the amount of decomposition which occurs under the same conditions in the absence of the stabilizing ingredient. While the amount of optional stabilizing ingredient required to accomplish the desired degree of stabilization in a given instance can vary, as a general rule, the optional stabilizing ingredient, if employed, will constitute between 0.05 and 10, preferably between 0.1 and 5, most preferably between 0.5 and 2, percent by weight of the total composition.
The aforementioned optional stabili2ing ingre-dients are not generally required for suitable stability in the compositions of the invention since such compo-sitions are free from the destabilizing effects of the hereinbefore described impurities. However, in those instances wherein the compositions of the invention comprise other destabilizing ingredients or impurities, it is preferable that such compositions also comprise one or more of the aforementioned optional stabilzing ingre-dients in addition to being substantially free from the 18,497A-F ~15-aforementioned impurities. Thus, for example, when the composition o~ -the invention is prepared pursuan-t to the hereinafter described process ~in which the aqueous reaction medium of the halogenated amide preparation reaction forms part of the aqueous composition), the resulting aqueous halogenated amide composition will generally contain halide salts (e.g., alkali metal or alkaline earth metal halides such as sodium bromide, sodium chloride, potassium chloride, potassium bromide, calcium bromide, calcium chloride, etc.). Such halide salts are generated in the halogenated amide preparation process and have also been found to adversely affect the stability of the halogenated antimicrobial in the aqueous liquid concentrate compositions thereof. Accordingly, when the compositions of the invention contain such halide salts (from the aforementioned process or from some other source), it is beneficial (and therefore preferred) to also employ the aforementioned optional stabilizing ingredients in such compositions.
The order of combination of the hereinbefore described ingredients is not critical to the practice of the invention. However, when the aforementioned optional stabilizing ingredients are employed, it is generally desirable to avoid prolonged exposure of the antimicrobial compound to the water in the composition prior to addition of such stabili2ing ingredient thereto. Similarly, it is generally desira~le, in order to re-tain optimum antimicrobial activity, to prepaxe, store, transport and handle the compositions of the invention at the lowest practicable temperature (normally ambient kemperature).
As has been noted, elimination of the herein-before described impurities ~i.e., glycols having a molecular weight of less than 70 and salts of organic 18,497A-F -16-5~
acids) from aqueous haiogenated amide antimicrobial compositions has been found to reduce the halogenated amide antimicrobial decomposition rate in a mixture of the aforementioned organic solvent and water. A par-ticularly beneficial result of such phenomenon (espe-cially when used in conjunction with the stabilizing phenomenon of the aforementioned optional stabilizing ingredients) is that suitably stable halogenated amide antimicrobial compositions can be prepared directly from a mixture of the antimicrobial and the aqueous reaction medium in which it was prepared. Specifically, separation of the halogenated amide antimicrobial from its aqueous reaction medium is conveniently eliminated by incorporating such reaction medium into the antimicrobial composition.
The adverse impact of the resulting presence of water which would otherwise occur is prevented by ensuring that the resulting composition is substantially free from the aforementioned impurities (for example, by employing ingredients such as solvents, etc., which are substantially free of such impurities) and preferably by also adding the aforementioned optional stabilizing ingredients.
The preparation of the halogenated amide anti-microbial can be accomplished in any convenient conventional manner. Thus, for example, the halogenated amide antimicro-bial can be prepared by the acid catalyzed reaction ofthe corresponding nonhalogenated amide (e.g., cyanoacetamide, malonic diamide and M-substituted derivatives thereof) with halogen (especially bromine) in aqueous solution, preferably at a temperature of less than 40C and preferably at a hydrogen halide (w-hich is a reaction by-product) concentration of less than 20 weight percent on a total weight basis.
18,497A-F -17--18~
Preferably, however, the initial step of such process is performed pursuant to an improved procedure which comprises introducing a water-soluble bromate into the agueous reaction medium.
After the halogenated amide antimicrobial has been prepared, the resulting rPaction mixture is dissolved in the hereinbefore described organic solvent. Such dissolution step is performed either before or after the optional but preferable addition of the aforementioned stabilizing ingredient and without isolation of the halogenated amide antimicro~ial from the aqueous reaction medium.
It is generally desirable to avoid prolonged exposure of the halogenated amide antimicrobial to the a~ueous reaction medium in the absence of the stabilizing ingredient ~if such ingredient is to be employed) in order to minimize decomposition of the halogenated amide product prior to stabilization. In addition, the pH
adjustment stèp is also desirably accomplished without prolonged delay since the decomposition rate of the halo~
genated amide antimicrobial is generally pH dependent and since such decomposition rate is typically minimized within the indicated pH range. In addition, since the rate of decomposition of the halogenated amide anti-microbial increases with increased temperature, it ispreferable to conduct the aforementioned individual proc~ss steps (and to store, transport and handle the resulting aqueous antimicrobial compositions) at am~ient temperature (e.g., from 20 to 25C) or less in order to avoid excessive decomposition of the antimicrobial during such operations.
18,497A-F ~18-The practice of the instant invention is further illustrated by the following examples. In such examples, all weight percentages are on a total weight basis unless otherwise indlcated.
Example 1 - Stable Aqueous Composition of 2,2-Dibromo--3-Nitrilopropionamide Employing Purified Tetraethylene ~lycol as the Solvent These experiments illustrate the des~abllizing effect of common impurities in a polyalkylene glycol solvent ~which commonly arise in the manufacture of such solvents~ upon 2,2-dibromo-3-nitrilopropionamide ~DBNPA) dissolved in a mixture of such solvent and water. Also illustrated is the improved DBNPA stability in a glycol-water solution wherein the glycol has been purified to remove substantially all of such impurities.
Control 1 .. .. . .
A 2.5 g portion of 2,2-dibromo-3-nitrilo-propionamide (DBNPA) is placed in a 2 ounce amber bottle.
To this is add~d a 23.75 g portion of water and a 23.75 g portion of a commercially available unpurified mixture of polyethylene glycols having a weight averaged mole-cular weight of about 200. Such polyethylene glycol mixture also contains an undetermined amount of residual unpolymerized ethylene glycol monomer (m~lecular weight = 62~ and an undetermined amount of sodium acetate resulting from neutralization of excess sodium hydroxide remaining following polym-erization of the ethylene glycol monomer.
_a~e~
In a second 2 ounce amber bottle is placed a 2.5 g portion of ~DNPA, a 23.75 g por-tion of water and a 23.75 g portion of purified tetraethylene glycol.
18,497A-F -19-~o--The purified tetraethylene glycol is substantially ~ree of ethylene glycol monomer and of salts resulting from sodium hydroxide neutralization in the polyethylene glycol manufacturing operation.
The contents of both of the ~ottles are mixed until all o the ingredients are dissolved. The dis-solution is accompanied by a temperature rise of 5C.
After the heat of dissolution has dissipated, the initial DBNPA content is verified by iodometry. The bottles are lQ then closed with a polyethylene lined cap and placed in a constant temperature oven at 50C for accelerated decom-position testing. The samples are removed after 19 days and the extent of DBIIPA decomposition is determined by iodometry. In such test method, an excess of potassium iodide (KI) is added to the antimicrobial composition and the amount of elemental iodine which has been liberated from the KI (via oxidation of the KI by the DBNPA) is determined by titration with a standard solution of sodium thiosulfate. The amount of DBNPA present in the composition tested is then calculated on the basis of the amount of elemental iodine liberated thereby. (It should be noted that since certain of the intermediate decom-position products of DBNPA are also oxidizing agents, the indicated test method does not, strictly speaking, provide an exact measure of DBNPA content. However, such test method does pro~-ide a measure of the amount of DBNPA
which has completely ~ecomposed to ~he ultimate non-oxidizing species and thus provides a relative measure of the stability of the DBNPA compositions tested.~
The resulLs of the aforementioned iodometric testing indicate that after 19 days at 50C the agueous antimicrobial composition of Example 1 (i.e., using the 18,497A-F -20-i;3 purified tetraethylene glycol solvent3 contains 90 per-cent of its original DBNPA content. In contrast, the composition of Control 1 (i.e., using the unpurified polyethylene glycol 200 solvent) contains only 74 per-cent of its original DBNPA content after the same timeperiod at 50C. Elimination of the indicated impurities from the solvent of Control 1 (to thereby provide the composition of Example 1) is thus observed to reduce the DBNPA decomposition by about 62 percent based upon that which occurs in the presence of such impurities, i.e., ~0.90-0.74).(1.00-0.74)] x 100% = 62%.
Examples 2 and 3 - Aqueous Solution of DBNPA in Purified Tetraethylene Glycol Prepared Directly from the Aqueous DBNPA Reaction Medium A ~6.0 g quantity (i.e., 0.3 mole) of commer-cial cyanoacetamide is dissolved in 95 ml of water and is then reacted with a 48 g portion (i.e., 0.3 mole) of bromine for half an hour at 22-26C. Thereafter, a 15.1 g portion of NaBrO3 (in the orm of a concentrated aqueous solution thereof) is slowly added to the reac-tion mixture over a 1~1/2 hour period while continuing the reaction at 22-26C. An additional 2.0 g portion of bromine is then added and the reaction is continued for an additional 2 hour period.
The p~ of the resulting reaction mixture is then adjusted to 6.0 with Na2CO3 and a 180 g portion of purified tetraethylene glycol (i.e., substantially free of glycols other than tetraethylene glycol and of salts of organic acids) is added to dissol~e ~he reaction mix-ture. The resultant solution has a pH of 3.5 and con-tains 19.3 weight percent DBNPA as determined by iodo-metric titration; representing a 98 percent yield of DBNPA.
18,497A-F 21-~2 One portion of the resulting reaction mixture solution (i.e~, the composition of Example 2~ is stored at 50C and analyzed for retained DBNPA after various storage intervals by iodometric titration. A second portion of the resulting reaction mixture solution is stabilized with 1 weight percent paraformaldehyde (thereby forming the composition of Example 3) and is analyzed (by iodometric titration) for retained DBNPA
content after various storage intervals at 50C.
In a similar fashion, comparative compositions (i.e., Controls 2 and 3) are prepared which correspond to the compositions o Examples 2 and 3, respectively, except that an unpurified mixture of polyethylene gly-cols (having a weight averaged molecular weight of 200 and containing an undetermined quantity of residual ethylene glycol monomer and neutralization salts;
probably sodium acetate) is employed as the solvent in place of the purified tetraethylene glycol of Examples 2 and 3. T~ese compositions are also analyzed by iodo-metric titration for retained DBNPA content after varioussto.rage intervals at 50C.
The retained DBNPA results for the compositions of Examples 2 and 3 and for the comparative compositions of Controls 2 and 3 aré presented in Table I below.
18,4~7A-F ~22-~23--~1 I ~ U~ ~ ~1 O ,/ I d' ~, U
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IU~ ~ ~1rl ~ O
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., ~r~ -rl O
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h ~1 rl @) ~ Il) O rq ao ~ ~ ~
O~ ~ ~ ~ td ta td ~ ~ V rl U~
va).~s 'l æ ~ ~,~
m ~ a~ , , ~ ~ N
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mh ~ o 18, 497A~F --24--~ ~ d~
~25-The results in Table I show that the compo-sitions employing the purified tetraethylene glycol retain more DBNPA after the same (or longer) storage intervals than do the corresponding compositions employing unpurified polyethylene glycol 200 as the solvent in place of the tetraethylene glycol. (Compare Examples 2 and 3, respectively, with Controls 2 and 3.) The benefits of employing paraformaldehyde as a stabili~er in conjunction with the use of the purified tetraethylene glycol solvent and the aqueous DBNPA
reaction medium is observed by comparin~ the retained DBNPA results for the composition of Example 3 with ~hose for the composition of Example 2. Specifically, such comparison illustrates that the use of such stabilizer in the embodiment employing the a~ueous antimicrobial reaction medium provides further improve-- ment in the antimicrobial stability.
18,497A-F -25-
Claims (12)
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An aqueous antimicrobial composition (a) which is substantially free of glycols having a molecular weight of less than 70 and of salts of organic acids; (b) which has a pH of from 2 to 5; and (c) which comprises:
(1) an alpha-halogenated amide antimicrobial compound of the formula:
wherein:
X is hydrogen, halogen or a cyano radical;
each R group is independently hydrogen, a monovalent saturated hydrocarbon radical or an inertly substituted monovalent saturated hydrocarbon radical or the two R groups are jointly a divalent saturated hydrocarbon radical or an inertly substituted divalent saturated hydro-carbon radical which, taken with the adjacent nitrogen atom, forms a heterocyclic ring having from 4 to 10 ring members; and 18,497A-F -26-R1 is a cyano radical or an amido radical of the formula:
wherein R is as hereinbefore defined;
(2) a water miscible organic solvent in an amount sufficient to dissolve said alpha-halogenated amide, said solvent being selected from the group con-sisting of polyalkylene glycols and ethers thereof; and (3) water in an amount greater than 20 weight percent based upon the total weight of the aqueous anti-microbial composition.
(1) an alpha-halogenated amide antimicrobial compound of the formula:
wherein:
X is hydrogen, halogen or a cyano radical;
each R group is independently hydrogen, a monovalent saturated hydrocarbon radical or an inertly substituted monovalent saturated hydrocarbon radical or the two R groups are jointly a divalent saturated hydrocarbon radical or an inertly substituted divalent saturated hydro-carbon radical which, taken with the adjacent nitrogen atom, forms a heterocyclic ring having from 4 to 10 ring members; and 18,497A-F -26-R1 is a cyano radical or an amido radical of the formula:
wherein R is as hereinbefore defined;
(2) a water miscible organic solvent in an amount sufficient to dissolve said alpha-halogenated amide, said solvent being selected from the group con-sisting of polyalkylene glycols and ethers thereof; and (3) water in an amount greater than 20 weight percent based upon the total weight of the aqueous anti-microbial composition.
2. The composition of Claim 1 wherein the water miscible organic solvent is a normally liquid straight chain polyalkylene glycol or a mono- or di-lower saturated hydrocarbyl ether thereof.
3. The composition of Claim 2 wherein the polyalkylene glycol or ether thereof is a normally liquid, straight chain polyalkylene glycol of the ethylene, trimethylene or tetramethylene series or a mono- or di-lower alkyl or phenyl ether thereof.
4. The composition of Claim 3 wherein the polyalkylene glycol or ether thereof has a weight average molecular weight of from 75 to 1000.
5. The composition of Claim 1 wherein, in the halogenated amide antimicrobial compound:
X is hydrogen, bromine or chlorine;
18,497A-F -27-each R group is independently hydrogen, a mono-valent saturated hydrocarbon radical or an inertly substituted monovalent saturated hydrocarbon radical; and R1 is a cyano radical.
X is hydrogen, bromine or chlorine;
18,497A-F -27-each R group is independently hydrogen, a mono-valent saturated hydrocarbon radical or an inertly substituted monovalent saturated hydrocarbon radical; and R1 is a cyano radical.
6. The composition of Claim 1 wherein the halogenated amide antimicrobial compound is 2,2-dibromo--3-nitrilopropionamide.
7. The composition of Claim 1 wherein the water miscible organic solvent is tetraethylene glycol and the halogenated amide antimicrobial compound is 2,2-dibromo-3-nitrilopropionamide.
8. The composition of Claim 1 wherein:
(a) the halogenated amide antimicrobial com-pound constitutes from 5 to 20 weight percent of the total composition;
(b) the water constitutes from greater than 20 up to 60 weight percent of the total composition;
(c) the water miscible organic solvent con-stitutes from 25 to 75 weight percent of the total composition; and (d) the composition contains less than 1.0 weight percent, based upon the total weight of the composition, of glycols having a molecular weight of less than 70 and less than 0.1 weight percent, based upon the total weight of the composition, of salts of organic acids.
18,497A-F -28-
(a) the halogenated amide antimicrobial com-pound constitutes from 5 to 20 weight percent of the total composition;
(b) the water constitutes from greater than 20 up to 60 weight percent of the total composition;
(c) the water miscible organic solvent con-stitutes from 25 to 75 weight percent of the total composition; and (d) the composition contains less than 1.0 weight percent, based upon the total weight of the composition, of glycols having a molecular weight of less than 70 and less than 0.1 weight percent, based upon the total weight of the composition, of salts of organic acids.
18,497A-F -28-
9. A process for preparing the aqueous antimicrobial composition of Claim 1 which process (1) is conducted under conditions which are substan-tially free of glycols having a molecular weight of less than 70 and of salts of organic acids and (2) com-prises the steps of:
(a) preparing the alpha-halogenated amide antimicrobial by the acid catalyzed reaction of the corresponding non-halogenated amide with halogen in aqueous solution at a temperature of less than 40°C and at a hydrogen halide concen-tration which is less than 20 weight percent on a total weight basis but which is sufficient to catalyze the reaction;
(b) dissolving the resulting aqueous reaction mixture in the water miscible oryanic solvent; and (c) adjusting the pH of the reaction mixture or the organic solvent solution thereof such that the aqueous antimicrobial com-position has a pH of from 2 to 5.
(a) preparing the alpha-halogenated amide antimicrobial by the acid catalyzed reaction of the corresponding non-halogenated amide with halogen in aqueous solution at a temperature of less than 40°C and at a hydrogen halide concen-tration which is less than 20 weight percent on a total weight basis but which is sufficient to catalyze the reaction;
(b) dissolving the resulting aqueous reaction mixture in the water miscible oryanic solvent; and (c) adjusting the pH of the reaction mixture or the organic solvent solution thereof such that the aqueous antimicrobial com-position has a pH of from 2 to 5.
10. The process of Claim 9 which further comprises a step of adding to the reaction mixture, or to the solution thereof in the water miscible organic solvent, a stabilizing amount of one or more stabilizing ingredients selected from the group consisting of acids, anhydrides, carbamoyl compounds, sulfamoyl compounds, cyclic ethers, aldehydes, quaternary ammonium compounds, quaternary phosphonium compounds, azine compounds and nitrile compounds.
18,497A-F -29-
18,497A-F -29-
11. The process of Claim 9 wherein a water-soluble bromate is introduced to the aqueous reaction medium during the acid catalyzed reaction to prepare the halogenated amide antimicrobial and the pH of the reaction or the organic solvent solution thereof is adjusted by the addition of an alkali metal, or an alkaline earth metal, carbonate or bicar-bonate such that the aqueous antimicrobial composition has a value of from 3 to 4.
12. The process of Claim 11 wherein:
(1) the halogenated amide antimicrobial is 2,2-dibromo-3-nitrilopropionamide and the halogen is bromine;
(2) the water miscible organic solvent is tetraethylene glycol; and (3) the stabilizing ingredient is parafor-maldehyde, caprolactam, succinimide or ethylenediaminetetraacetic acid.
18,497A-F -30-
(1) the halogenated amide antimicrobial is 2,2-dibromo-3-nitrilopropionamide and the halogen is bromine;
(2) the water miscible organic solvent is tetraethylene glycol; and (3) the stabilizing ingredient is parafor-maldehyde, caprolactam, succinimide or ethylenediaminetetraacetic acid.
18,497A-F -30-
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000342819A CA1116512A (en) | 1979-12-31 | 1979-12-31 | Aqueous antimicrobial composition having improved stability |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000342819A CA1116512A (en) | 1979-12-31 | 1979-12-31 | Aqueous antimicrobial composition having improved stability |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1116512A true CA1116512A (en) | 1982-01-19 |
Family
ID=4115937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000342819A Expired CA1116512A (en) | 1979-12-31 | 1979-12-31 | Aqueous antimicrobial composition having improved stability |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1116512A (en) |
-
1979
- 1979-12-31 CA CA000342819A patent/CA1116512A/en not_active Expired
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