US3417184A - Biocidal compositions containing quaternary ammonium phenates and methods of use - Google Patents

Description

United States Patent 3,417,184 BIOCIDAL COMPOSITIONS CONTAINING QUATERNARY AMMONIUM PHENATES AND METHODS OF USE Reginald L. Wakeman, Philadelphia, Pa., and Joseph F. Coates, Washington, D.C., assignors to Millmaster Onyx Corporation, Jersey City, NJ., a corporation of New York No Drawing. Continuation-impart of application Ser. No. 292,764, July 3, 1963. This application Oct. 18, 1966, Ser. No. 587,415

9 Claims. (Cl. 424-258) ABSTRACT OF THE DISCLOSURE A method and compositions for external biocidal use, such as in shampoos and the like, which utilizes an effective amount of a quaternary ammonium phenate having the chemical structure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue of either phenol or substituted pthenol whose only acidic group is at least one hydroxyl group, the water solubility of the quaternary ammonium phenate being no greater than 3 parts by weight per 100 parts by Weight of solution at room temperature.

This invention relates to cosmetic compositions containing quaternary ammonium compounds therein, and it more particularly relates to such compositions wherein the quaternary ammonium compounds are N-alkyl isoquinolinium phenates or substituted phenates.

This is a continuation-in-part of co-pending application Ser. No. 292,764, filed July 3, 1963, now US. Patent 3,285,923 of Nov. 15, 1966.

The quaternary ammonium compounds suitable for use in the present compositions contain as the anionic portions any monohydric or polyhydric phenol which is free from carboxyl groups or sulfonic acid groups. The phenol may have one or more benzene rings or it may have condensed ring systems. Examples of such phenols are phenol itself; the isomeric cresols; xylenols; catechols; catechol ethers; resorcinols and alkylated resorcinols, such as hexyl resorcinol and phloroglucinol; isopropyl phenols; t butyl phenols; 4-methyl-6-t-butyl phenol; di-t-butyl-p-cresol; higher alkyl phenols such, for example, as octyl phenol and nonyl phenol, o-phenyl phenol, p-phenyl phenol, 2,2- methylene bis-4-ethyl-6-t-butyl phenol; derivatives of the foregoing compounds free from carboxyl and sulfonic acid groups; the various halo phenols; halo cresols; halo xylenols; halo catechols; and their analogs and homologs', methoxy phenols and higher alkoxy phenols together with corresponding alkylated homologs; amino phenols; bromo phenols and their corresponding methyl, polymethyl and alkyl homologs; nitro phenols, nitro cresols, nitro xylenols, esters of phenolic acids such as paracarbomethoxy phenol, paracarboethoxy phenol, paracarbo-butoxy phenol, and paraca'rbobenzoxy phenol; naphthol and the chloro naphthols, al-kl naphthols, amino naphthols and the like; hydroxy diphenyl, hydroxy diphenyl ether, hydroxy diphenylene oxide, 2,2'-dihydroxy-5,5'-dichloro diphenyl methane salicylaldehyde, and the like. In general, any phenolic compound may be employed which is free from carboxylic and sulfonic acid groups.

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The phenates are preferably prepared from their watersoluble salts such as their sodium, potassium or ammonium salts, or in the form of the free phenol if solubility relationships permit.

Quaternary ammonium compounds useful in this invention are higher alkyl isoquinolinium halides corresponding to the formula:

wherein X is a halogen atom such as bromine or chlorine, or a hydroxyl group and R is an alkyl radical having from 8 to 18 carbon atoms, preferably having 12 to 16 carbon atoms. Typical examples are lauryl isoquinolinium chloride, bromide or hydroxide, the corresponding myristyl and cetyl compounds, or mixtures thereof.

These compounds have a low water solubility generally not in excess of 3 parts by weight per parts of solution at room temperatures, so that they are especially useful in applications wherein the known water-soluble quaternary ammonium compounds are washed away or are physically incompatible or unsatisfactory because of their .high water-solubility. It is, of course, possible to promote water-solubility by the use of suitable solvents, coupling agents or dispersing agents. Furthermore, when an excess of either quaternary or phenolic compound is employed, the resultant compound may be soluble in aqueous solutions of the excess reactant.

The compounds may be prepared by mixing aqueous solutions of the quaternary ammonium salts with any of the aforementioned phenols, their analogs or homologs, or with a salt thereof. In the case of polyhydric phenols such, for example, as resorcinol, phloroglucinol or phrogallol, they may be employed in the form of their completely neutralized salts or in any desired degree of neutralization, i.e., mono, di, trisodium salts or the like.

After thoroughly mixing, the organic product layer is separated from the aqueous layer (as with a separatory funnel) since two distinct phases are formed. Separation may be facilitated by the addition of an organic solvent immiscible with water. The product layer may be washed with water to remove any residual by-product salt or unreacted materials. The solvent, if any, may be evaporated and the product air or "vacuum dried to a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solvent mixture in Which the starting materials are soluble will be satisfactory. Non-aqeuous solvents facilitate the separation of by-product inorganic salt and reduce the need for vacuum drying to get an anhydrous product. When a non-aqueous medium is employed, it is usually necessary to add a small amount of water to facilitate ionic reaction.

The product may be used, if desired, without drying since any entrapped water is irrelevant to the microbiological activity of the compounds. In other applications, removal of water may be essential for reasons not related to biological activity.

The products of this invention are particularly useful in that they provide a single chemical compound which has a broad spectrum of mi-crobiocidal activity, ai'finity and substantivity for hair and scalp which can be used for treatment of dermatological disorders of the scalp such, for example, as dandruff, In vitro tests show them to be especially active with respect to Pityrospo'rum ovale.

The microbiological activity of our compounds has been evaluated for microbiological stasis by the Standard Tube Dilution Test, the technique for which is common knowledge to those skilled in the art. A Difco Bacto CSMA Broth #0826 was used in the study. This test is used to determine the lowest concentration of microbiologioally active compounds which will inhibit the growth of the organism in question. For wide range of applications, the inhibition of growth rather than outright kill is satisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of the CSMA Broth in a test tube which is then sterilized in an autoclave. One cc. solution of the microbiologically active compound at an appropriate concentration is added to the test tube which is then inoculated with 0.1 cc. of a twenty-four hour old culture of the organism under study. The test tube is then incubated at 37 C. for forty-eight hours and observed for bacterial growth.

The same procedure is followed for fungi. In such tests, however, the tubes are incubated for fourteen days as a temperature suitable for optimum fungal growth, usually 25 C.

The invention is illustrated by, but not restricted to, the following examples:

EXAMPLE I A stock solution containing 10 weight percent of sodium pentachlorophene was prepared. An aliquot of the solution containing 0.030 equivalents of sodium pentachlorophenol was vigorously agitated while a chemically equivalent amount of a commercial grade of lauryl isoquinolinium bromide (Onyx Chemical Company; Isothan Q75) in the form of a 10 weight percent solution was slowly added. The mixture was then poured into a separatory funnel. The mixture separated into two phases. The organic product layer was removed and vacuum dried to yield a dark brown paste in 83% yield. The product was lauryl isoquinolinium pentachlorophenate.

EXAMPLE II A solution was prepared containing 10 weight percent of the sodium salt of chloro o-phenyl phenol. To a vigorously agitated aliquot of this solution containing 0.044 equivalent weights of the compound was added a chemically equivalent amount of a 10% solution of lauryl isoquinolinium bromide. The mixture was poured into a separatory funnel and shaken, after which it was allowed to stand until it separated into two phases The organic product layer, a brown oil, was drawn off and vacuum dried to yield a brown paste of lauryl isoquinolinium chloro o-phenyl phenate in 90 yield.

If desired, an equivalent amount of lauryl isoquinolinium chloride may be used instead of the bromide in the preceding examples.

EXAMPLE III Using techniques similar to that described in Example II, lauryl isoquinolinium compounds were obtained from the sodium salts of tetrachlorophenol, p-chloro m-cresol, p-chloro m-xylenol and from the disodium salts of hexachlorobisphenol and dichlorobisphenol. Yields were 93%, 88%, 89%, 90% and 70% respectively.

In place of lauryl isoquinolinium in the foregoing examples, we may employ equivalent amounts of octyl or decyl isoquinolinium chloride or bromide; equivalent amounts of myristyl, cetyl or stearyl isoquinolinium chloride or bromide, and mixtures thereof.

These compounds, along with those of Examples I and II, are listed in Table I. This table shows their microbiological activity as well as their solubility in water. This microbiological activity was determined by the Standard Tube Dilution Test, described previously, using three different organisms, i.e., Staphylococcus aureus, Salmonella typlzosa and Aspergillus niger. All of the products were found to be microbiologically active with respect to these three organisms.

TABLE I.-PROPERTIES OF THE REACTION PRODUCTS OF SODIUM SALTS OF VARIOUS OHLORINATED PHENOLS WITH LAYRYL ISOQUINOLINIUM BROMIDE Reciprocal of Static Water Dilution of Product vs. Chlorinated Phenol Solubility (g,/100 g.Sol) S. a. S. t. A. n.

Pcntachlorophenol 0. 07 10 10 10 'Ietrachlorophenol 0. 06 10 10 10 Chloro o-phenyl phenol 0.009 10 10 10 Hexachlorobisphenol 0. 02 10 10 10 Dichlorobisphenol 0. 07 10 10 l0 EXAMPLE IV The product formed according to Example III by reaction of lauryl isoquinolinium bromide with the sodium salt of p-chloro-m-cresol and having a solubility of 0.03 part per 100 grams of water at room temperature was evaluated against three different fungi by the previously described Standard Tube Dilution Test, the following concentrations being found to be the effective static dilution levels:

Asperillus niger:1/75,000 Penicillium luteum:1/75,000 Pullularia pullulans:1/75,000

Similar static levels were found for the analogous product derived from the reaction of lauryl isoquinolinium bromide with the sodium salt of p-chloro-m-xylenol prepared by the method of Example III.

EXAMPLE V To a solution of 20 grams of the sodium salt of paracarbomethoxy-benzoate in 200 cc. of water was added, with stiring, a chemically equivalent amount of a 50% aqueous solution of lauryl isoquinolinium bromide.

The mixture was allowed to stand in a separatory funnel until it separated into two distinct layers. The lauryl isoquinolinium methyl p-hydroxy benzoate formed the lower layer. This lower layer was separated and vacuum dried to yield a dark brown paste in 88.3% yield.

In a similar way, paracarboalkoxy phenates wherein the alkoxy is ethoxy, propoxy, butoxy and benzoxy, were reacted with lauryl isoquinolinium bromide. The respective yields were 76%, 71% and 79%. All were dark brown pastes.

EXAMPLE VII A solution of 14 grams of the sodium salt of o-phenyl phenol in 250 cc. of water was prepared and mixed with 250 cc. of a 10% solution of lauryl isoquinolinium bromide. Two layers formed. The lower layer contained the lauryl isoquinolinium o-phenyl phenate. This layer was separated and vacuum dried to yield 18 grams of a solid brown product. This represented a 47% yield.

In a similar way the sodium salt of p-phenyl phenol gave a 45% yield of a brown paste when reacted with lauryl isoquinolinium bromide.

The sodium salt of p-cresol gave a 98% yield of a dark red paste when reacted with lauryl isoquinolinium bromide.

The sodium salt of phenol when reacted in aqueous solution with a chemically equivalent amount of lauryl isoquinolinium bromide gave a yield of a dark red paste.

5 EXAMPLE vur To 70 cc. of a 10% aqueous solution of lauryl isoquinolinium bromide in a 250 cc. separatory funnel was added 100 cc. of a 10% solution of the sodium salt of ditertiary .butyl p-cresol. These solutions were well mixed by vigorously shaking the separatory funnel. On standing, a dark red oil separated and formed the lower layer. This lower layer was drawn off into an evaporating dish and vacuum dried to give an 80% yield of lauryl isoquinolinium ditertiary butyl p-cresylate, a dark brown paste. The di(lauryl isoquinolinium) salt of bisphenol was also prepared.

EXAMPLE IX To a 2.5% aqueous solution of the sodium salt of 4,4 thio bis (6-tertiary butyl o-cresol) was added a chemically equivalent amount of a 10% aqueous solution of lauryl isoquinolinium bromide. On standing, a red oil precipitated to form a separate lower layer. This lower layer was dried to give a 71.5% yield of lauryl isoquinolinum 4,4 thio bis (6-tertiary butyl o-cresylate).

EXAMPLE X To 60 cc. of a 10% aqueous solution of the sodium salt of mixed tertiary butyl phenols was added 134 cc. of a 10% aqueous solution of lauryl isoquinolinium bromide. The product layer was separated and dried to give a 76% yield of a lauryl isoquinolinium tertiary butyl phenolate, a dark red paste.

In a similar way aqueous solutions of the sodium salts of 2,2 methylene bis(4-methyl-6-tertiary butyl phenol) and 2,2 methylene bis (4-ethyl-6-tertiary butyl phenol) were reacted with lauryl isoquinolinium bromide to give essentially water insoluble salts in yields of 99% and 91%, respectively. The lauryl isoquinolinium salt of 2,6 ditertiary butyl alpha dimethyl amino phenol was also prepared.

EXAMPLE XI To a solution of 14 grams of the solution salt of salicylaldehyde in 200 cc. of water was added, with stirring, 379 cc. of a 10% solution of lauryl isoquinolinium bromide. The mixture was allowed to stand and two distinct layers formed. The product layer containing the lauryl isoquinolinium salt of salicylaldehyde was a red-brown oil with a density greater than water. It was separated and vacuum dried to yield a red paste in 79% yield.

EXAMPLE XII Using standard bacteriological methods described above, the products described in Examples V through XI were tested against Staphylococcus aureus, Salmonella typhosa and Aspergillus niger for biostasis, referred to respectively as S.a., S.t., and A.n. in the following table. Results of these tests are shown in the following Table II.

TABLE II Reciprocal of Static Dilution Lauryl Isoquinolim'um Reaction Product With of Product vs.

S. a. S. t. A. n.

Nonyl phenol 10 10 Para carbo methoxy phenol 10 10 Para carbo ethoxy phenol. 10 10 Para carbo propoxy phenoL 10 10 Para carbo butoxy phenoL 10 10 Para carbo benzoxy phenol" 10 10 o-Phenyl phenol 10 10 p-Phenyl phenol- 10 10 p-CresoL. 10 10 Phenol 10 10 Di-t-Butyl -Cresol 10 10 4,4 thio bis(6t-Butyl o-Cresol) 10 10 10 Mixed t-Butyl phenols 10 10 10 2,6 di-t-Butyl alpha dimethyl amino para cresol 10 10 10 2,2 methylene bis (l-methyl fi't-Butyl phenol) 10 10 10 2,2 methylene bis (at-ethyl t-G-butyl phenol) 10 10 10 Salieylaldehyde I 10 10 10 10 Bis phenol 6 EXAMPLE x111 A stock shampoo formulation was prepared as follows:

1 Percent Triethanolamine salt of lauryl sulfate 30 Laurie acid diethanolamine condensate 8 Ethoxylated lanolin 2 Water 60 A second solution was prepared of 20% by weight of lauryl isoquinolinium p-chloro m-xylenate in isopropanol.

This isopropanol solution was mixed with the stock shampoo formulation to give a finished product which contained 0.1 weight percent of lauryl isoquinolinium p chloro m-xylenate. The finished product is a clear, red, slightly viscous foamy liquid which was found effective for the control of dandruff. Any of the higher alkyl isoquinolinium phenolic derivatives listed in the preceding examples having microbiologically active properties may be used in sufficiently active amounts in place of the above Xylenate compound.

It is possible to formulate shampoo preparations by directly adding the desired lauryl isoquinolinium halide, for example, lauryl isoquinolinium bromide, together with a selected phenolic compound, such as p-chloro mxylenol or mixtures thereof, to the shampoo formulation.

The super amide was melted and was then added to the remaining ingredients which were then mixed at room temperature to provide the final product.

EXAMPLE XV A hair cream-rinse was prepared as follows:

Percent Polyethylene glycol 200 monostearate 3 Lauryl isoquinolinium paracresylate 1-4 Water to make 100%.

The monostearate was melted and was then mixed at [room temperature with the remaining ingredients to form the final product.

EXAMPLE XVI A liquid germicidal hand-cleaning soap was prepared according to the basic formula for Medicinal Soft Soap presented on page 646 of the Sixteenth Revision of the Pharmacopeia of the United States of America.

650 grams of the soap paste was dissolved in 200 grams of alcohol plus 20 grams of oil of lavender with agitation until it became homogeneous.

10 grams of lauryl isoquinolinium nonyl phenate was dissolved in grams of alcohol. This was added to the soap solution until the tincture was homogeneous. After aging for twenty-four hours, the solution was clarified by filtration, and adjusted to make grams by the addition of alcohol.

This was used as a pre-surgical hand-scrubbing soap, and was tested as such by the Price Technique for Determining Degermation of the Skin as described in Antiseptics, Disinfectants, Fungicides, and Chemical and Physical Sterilization edited by George F. Reddish (Lea and Febiger, 1957) pages 101-102. It was found to be equal to or better than a soap containing 2% of hexachlorophene.

7 EXAMPLE xvrr A foot powder was prepared by coating kaolin with 0.11% lauryl isoquinolinium phenate from an ethyl al cohol solution. The coated material was then dried and 10% thereof mixed with 90% talc.

It is to be understood that all the aforementioned percentages are by Weight unless otherwise stated.

Examples XIII, XIV, XV and XVI disclose specific foaming, detergent and solubilizing agents. However, this is only for the purpose of illustration, it being understood that any feasible agents of these types can be used within the scope of the present invention.

Obviously, many modifications of the present invention are possible in the light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

The invention claimed is:

1. A biocidal method of treating human living tissue which comprises externally applying to said tissue a biocidally elTective amount of a quaternary ammonium phenate having the structure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue of a member of the group consisting of phenol and substituted phenol whose only acidic group is at least one hydroxyl group, the water solubility of said quaternary ammonium phenate being not greater than 3 parts by weight per 100 parts of solution at room temperature.

2. The method of claim 1 wherein the phenate is applied to the hair.

3. The method of claim 1 wherein the phenate is applied to a foot.

4. The method of claim 1 wherein the phenate is applied in a liquid carrier.

5. The method of claim 1 wherein the phenate is applied as a powder.

6. A hair shampoo consisting essentially of a liquid carrier and a biocidally efiFective amount of a quaternary ammonium phenate have the structure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue of a member of the group consisting of phenol and substituted phenol whose acidic group is at least one hydroxyl group, the water solubility of said quaternary ammonium phenate being not greater than 3 parts by weight per parts of solution at room temperature.

7. The shampoo of claim 6 wherein the liquid carrier contains an effective amount of a detergent and foaming agent.

8. The shampoo of claim 6 wherein the liquid carrier contains an efiective amount of a solubilizer for the quaternary ammonium phenate.

9. A skin-treating powder consisting essentially of a biocidally effective amount of a quaternary ammonium phenate having the structure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue of a member of the group consisting of phenol and substituted phenol whose only acidic group is at least one hydroxyl group, the water solubility of said quaternary ammonium phenate being not greater than 3 parts by weight per 100 parts of solution at room temperature mixed with a solid pulverulent carrier.

References Cited UNITED STATES PATENTS 2,223,142 11/1940 Weirich l67--58 2,250,480 7/1941 Gump 260-619 2,255,694 9/1941 Beale 16758 2,524,738 10/1950 Snell 167-58 2,668,136 2/1954 Winkle 167-58 2,783,279 2/1957 Chiddix 260--6l9 2,961,375 11/1960 Shaw 167-58 FOREIGN PATENTS 809,655 2/1959 Great Britain. 809,689 3/1959 Great Britain.

ALBERT T. MEYERS, Primary Examiner.

V. C. CLARKE, Assistant Examiner.

U.S. C1. X.R.