WO2001021671A1

WO2001021671A1 - Amphoteric water-soluble poly(amine) derivatives

Info

Publication number: WO2001021671A1
Application number: PCT/US2000/040954
Authority: WO
Inventors: James Vincent Gruber
Original assignee: Union Carbide Chemicals and Plastics Technology LLC
Current assignee: Union Carbide Chemicals and Plastics Technology LLC
Priority date: 1999-09-20
Filing date: 2000-09-20
Publication date: 2001-03-29
Anticipated expiration: 2002-03-20
Also published as: AU1254801A

Abstract

Poly(amine)s substituted with oxirane carboxylic acids, e.g., epoxysuccinic acid, are disclosed. The poly(amine)s derivatives ca n be prepared in a covalently bonded or ionically bonded form. Methods for preparing the poly(amine)s derivatives are disclosed a s well as compositions containing the derivatives and uses for the derivatives.

Description

AMPHOTERIC WATER-SOLUBLE POLY(AMINE) DERIVATIVES

Field of the Invention

The present invention relates to derivatives of poly (amines), and more specifically relates to oxirane, carboxylic acid derivatives of synthetic, amine-containing polymers.

Background of the Invention

Amphoteric, water-soluble polymers are unique chemical species which are capable of carrying different molecular formal charges depending on the pH of the solution in which they are dissolved. The behavior of an amphoteric molecule, especially a polymer, can be represented schematically by the diagram below:

Y^" M

R N⁺ (A) CQ₂H - ^* R ⁺ (A) C0₂ ^" ■ " R N (A) CO '_:2

R' R' R'

II III

$

Increasing pH As an amphoteric polymer is brought from an acidic medium into a basic medium, it passes through three distinct regions, I-III. In region I, the basic amino group is protonated which causes the amine group to carry a positive (i.e. cationic) charge which is known as an ammonium ion. The cationic amine has, non-covalently associated with it, a counter ion, Y-, which effectively counterbalances the positive charge of the ammonium ion. As the pH is increased into region II, the ammonium ion may, but does not necessarily, become stabilized by the deprotonated carboxylic acid group which carries an overall negative (i.e. anionic) charge. If this happens, the amphoteric species now has an overall neutral charge because the positive ammonium ion is counterbalanced by the negative carboxylate ion which effectively cancels out the charge of the molecule. In this region, the molecule is said to be zwitterionic. As the pH is further increased into region III, the ammonium ion becomes deprotonated and the amphoteric molecule is dominated by the overall anionic charge of the carboxylate ion. The anionic charge of the carboxylate ion in region III is non-covalently coordinated with a positive counter ion, M⁺, which helps to neutralize the anionic charge of the molecule.

Amphoteric polymers made by copolymerization of an anionic monomer and a cationic monomer have been known since at least 1951. For example, researchers at Cornell University (Wagner, H.L. et al. J. Phys. Colloid Chem. 1951, 55, 1512.) reported the preparation of an amphoteric polymer by copolymerization of vinylpyridine and acrylic acid as shown below:

This was followed shortly by work from Dow Chemical (Turner, A. et al. J. Polym. Sci. 1957, 23, 533.) wherein, amphoteric copolymers were made by polymerizing cationic N-dimethylaminoethyl acrylate and various acidic acrylate monomers, such as acrylic acid as shown below:

Since the publication of these scientific works, amphoteric polymers have become well known in various applications. For example, amphoteric copolymers of the general structure shown below, known under the tradename Amphomer™ and by the

International Cosmetic Ingredients (INCI) designation: Octylacrylamide/acrylates/ butylaminoethylmethacrylate copolymers, have been employed extensively as hair fixative resins (see for example, Lochhead, R.Y. et al. Cosmet. Toilet. 1993, 108, 95 or Dallal, J.A. et al. In: Hair and Hair Care, Johnson, D.H. Ed., Marcel Dekker, New York, 1997, 105.). U.S. Pat. No. 4,402,977, issued Sept. 6, 1983, and WO 97 12596 published April 10, 1997 describe a variety of amphoteric polymers, including the Amphomer polymers described above, which are said to help improve the substantivity of anionic polymers to the skin and hair.

Copolymers which are subtle modifications of the general structure shown above for Amphomer are disclosed in U.S. Pat. No. 4,552,670, issued Nov. 12 , 1985, U.S. Pat. No. 4,505,828, issued March 19,1985, U.S. Pat. No. 4,431,548, issued Feb 14, 1984, U.S. Pat. No. 4,392,917, issued July 12, 1983, U.S. Pat. No. 4,363,886, issued Dec. 14, 1983 and U.S. Pat. No. 4,330,450, issued May 18,1982. These polymers are formed by self-inverting emulsion polymerization and are said to be especially useful in papermaking, sewage treatment and oil- well drilling muds. U.S. Pat. No. 4,075,131, issued Feb 21, 1978, discloses that polymers like those above are effective in conditioning shampoos where they lend stability to the shampoo, especially in the presence of strongly anionic surfactants in which typical cationic, conditioning polymers are said to form insoluble surfactant/polymer aggregates.

Copolymers of the general structure shown below,

known under the tradename, Diaformer™ and by the INCI designation: Methacryloyl ethyl betaine/methacrylates copolymer, have been employed as hair fixative resins (see, Lochhead, R.Y. et al. Cosmet. Toilet. 1993, 108, 95.). Also, copolymers of the general structure shown below:

known under the tradename Merquat™ and by the INCI designations: Polyquaternium-22 (without the pendent formamide group [i.e z=0]) and Polyquaternium-39 (with the pendent formamide group) (see for example, Lochhead, R.Y. et al. Cosmet. Toilet. 1993, 108, 95. and Dallal, J.A. et al. In Hair and Hair Care, Johnson, D.H. Ed., Marcel Dekker, New York, 1997, 105.) have been employed extensively as hair fixatives, and static fly-away control agents for hair care products and as conditioners for skin and hair care products. U.S. Pat. No. 5,650,383, issued July 22, 1997, discloses that combinations of amphoteric polymers with structures such as those described above can, in combination with silicone polymers, be effective hair conditioning materials when delivered from shampoos.

Recently, the use of amphoteric copolymers to improve shampoo formulations has been suggested. For example, U.S. Pat. No. 5,609,862, issued March 11, 1997, suggests that amphoteric copolymers, like the Merquat™ polymers above, can improve the conditioning properties of shampoos by replacing the cationic polymers which are typically employed. The amphoteric polymers are said to allow better deposition (i.e. conditioning) control by moderating the cationic character of the polymer. The amphoteric polymers are disclosed to have improved compatibility with anionic surfactants commonly used in shampoos and to offer styling (hair fixative) benefits. Such multifunctionality is commonly described for shampoos known as 2-in-l systems.

Likewise, Japanese application JP 08283127-A, published Oct. 29, 1996, discloses that hair shampoos containing Merquat-type amphoteric polymers offer improvements in shampoo foaming, improvements in the wet and dry hair feel and help to aid in preventing static fly-away in dry hair. Further, Japanese patent application JP 09020626-A1, published Jan. 21, 1997 discloses the use of amphoteric polymers in hair styling products where the polymers are said to provide good hair styling and hair cleansing properties.

U.S. Pat. No. 5,208,295, issued May 4, 1993, discloses that treatment of anhydride -containing polymers (known under the tradename Gantrez^®) with difunctional amines affords amphoteric polymers of the general structure: OR CON(R')(CH₂)_αN⁺H(R^")(R^"

C0₂ ^"

These polymers are disclosed to be effective hairspray fixative resins when delivered from alcohol-based aerosol hairsprays. U.S. Pat. No. 3,998,796, issued Dec. 21,1976, discloses that amphoteric polymers of the general structure:

are useful in water treatment as flocculants.

Amphoteric random copolymers such as described above are typically manufactured by carefully controlling the polymerization reaction and adding the various monomers in known measured amounts so that the molar ratios [i.e. (a,b,c,d,e); (n); (p,q) and (x,y,z)] are well established. In the hair fixative polymers, the anionic portion of the polymer typically helps control the glass transition temperature, T_g, of the polymer and the solubility of the polymer in aqueous mediums. The cationic portion of the amphoteric polymers helps to control deposition of the polymers onto skin and hair which are known to be physiologically anionic in nature.

Amphoteric graft copolymers are produced differently than the random copolymers discussed above. In graft copolymerization, a fully intact polymer is treated with a reactive reagent which covalently (i.e. permanently) attaches itself to some reactive site on the polymer backbone. Typically, these sites on the polymer include: hydroxyl (- OH), carboxyl (-COOH), amino (-NR₂), or sulfhydryl (-SH) groups.

Natural polymers, particularly polysaccharides, such as, for example, cellulose, starch and chitosan are conveniently amenable to grafting reactions. Often, these grafts afford polysaccharides with amphoteric characteristics. For instance, an amphoteric potato starch, known by the trade name Solanace™ and by the INCI designation: Potato Starch Modified, has been described (see, Pasapane, J. et al. Comet. Toilet. Manf. Worldwide 1996, 175). It has been disclosed that this particular amphoteric polysaccharide has unique thickening and emulsifying properties, particularly in personal care formulations of high alkalinity such as dyes and perms.

An amphoteric polysaccharide of the general structure shown below (has been disclosed by Zheng, G. et al. Polym. Inter. 1994, 34,

241 and Zheng, G. et al. Polym. 1996, 37, 1629.).

H

While specific industrial applications for this polymer were not discussed, the authors discuss that such polymers are finding applications as flocculants, polymeric catalysts, drug delivery vehicles, and separation membranes.

Chitosan, a naturally-occurring, amine-containing polysaccharide, lends itself nicely to graft reactions to afford amphoteric polysaccharides. Several amphoteric derivatives of chitosan are known in the art. For example, a review of the biological significance of amphoteric chitosans made by carboxyalkylation of chitosan has been published (see Muzzarelli, R.A.A. In Chitin and Chitosan, Skjak-Break, G., Anthonse, T., Sandford, P., Eds. Elsevier Applied Science, London 1989, 87.).

European patent application EP 718313-A3, published July 3, 1996, discloses amphoteric chitosan derivatives made by graft cyanomethylation and subsequent hydrolysis of the cyano groups to afford the corresponding amphoterics shown below:

These derivatives are suggested to have beneficial properties as sequestration agents, chelating agents, stabilizers in bleaching applications, moisturizing agents, repulsion agents and thickeners.

U.S. Pat. No. 5,597,811, issued January 28, 1997, discloses amphoteric polyglucosamines made by the reaction of the polyglucosamine salts with oxirane (i.e. epoxide) carboxylic acids as shown below:

The patent discloses many possible applications for this amphoteric polysaccharide, especially in personal care as a potential fixative, conditioning or thickening ingredient. In addition, the patent discloses that the chitosan requires swelling by reaction with carboxylic acid in order initiate the reaction with the epoxide.

Certain synthetic polymers also lend themselves nicely to graft reactions to afford amphoteric polymers. In the standard nomenclature for these polymers, one often finds the term 'polyampholyte' used to describe these graft polymers. Many of these amphoteric polymers have found usefulness in waste-water treatment and as metal sequestering agents. For instance, it has been reported that the reaction of poly(vinylpyridine) with various carboxylic acid olefins affords amphoteric graft copolymers (see Barboiu, V. et al. J. Polym. Sci. A Polym. Chem. 1995, 33, 389.).

U.S. Pat. No. 5,068,324, issued Nov. 26,1991, discloses complex amphoteric polymers made by graft reaction of epichlorohydrin, a toxic difunctional crosslinking agent, with the unusual monomers shown below:

The resultant crosslinked polymers are stated to be mild hair conditioning agents which lend anti-tangle and softening properties to the hair.

Siltech discloses in U.S. Pat. No. 5,073,619, issued Dec 17,1991, discloses that silicone polymers, which are known in the art as hair conditioning polymers, are further improved by grafting amphoteric monomers onto the silicone polymer backbone. The resultant amphoteric polymers are stated to be more non-irritating than their silicone precursors. The amphoteric moiety also helps to enhance surfactant foaming which the straight silicone polymers are noted to suppress.

WO 9638493-A1, published May 5, 1995, discloses amphoteric graft copolymers made by reacting poly(ethyleneimine) with various anionic grafting reagents to afford polymers of the general structure shown below;

R"

-(CH₂CH₂₇ ^■ N - -(CH₂CH₂N)-

R'=CO₂H, P(O)(OH)₂ R"=CH₂R^*, H

It is disclosed that these amphoteric polymers will have applications in waste water treatment and metal sequestering.

It has also been disclosed that synthetic, amphoteric copolymers can be made by graft reaction of poly (allylamine) with activated halo- acetic acid as shown below:

(see Naka, K. et al. Polym. Bull. 1995, 35, 659 and Naka, K. et al. J. Polym. Sci. A. Polym Chem. 1996, 34, 1003.) It is suggested that these materials are being developed for metal sequestering and for use, in particular, in the manufacture of metal superconducting ceramics. A majority of the amphoteric graft copolymers are made by the reaction of some type of activated acetic acid derivative, i.e XCH2CO2H, where X is typically a chlorine or bromine leaving group an amine-containing polymer. Such activated a-haloacetic acid reagents are considered highly toxic and corrosive because hydrolysis of the reagent affords the corresponding acid, i.e. hydrochloric or hydrobromic acid as a by-product. In addition, because of the extraordinary reactivity of these activated reagents, controlling reaction stoichiometry can be a challenge. For instance, reaction of chloroacetic acid with poly(allylamine) can afford three potential amphoteric derivatives shown below, the relative amounts of which can be difficult to control and predict.

Also, if chloroacetic acid is used to make a grafted amphoteric polymer from a polymeric backbone which has multiple reactive sites, a mixture of various regioisomers will necessarily result. For example, the reaction of chloroacetic acid with chitosan affords N,O- carboxymethylchitosan as shown below.

Japanese patent JP 8059471, issued Dec. 2, 1981, describes the reaction of epoxysuccinic acid with poly(aminoalkyl silsesquioxanes), which are silicone based polymers. However, the patent does not disclose or suggest the possible graft reaction of epoxy acids, like epoxysuccinic acid, with synthetic amine containing polymers such as poly (allylamine) or poly(vinylamine).

Summary of the Invention

The present invention provides synthetic, amine-containing polymers (hereinafter referred to as "poly(amine)") which are substituted with oxirane carboxylic acids, such as, for example, epoxysuccinic acid.

By the present invention, it is now possible to provide synthetic, water-soluble, amphoteric, polymeric derivatives both in the covalently bonded and ionically bonded form. Moreover, the amphoteric polymers of the present invention can contain multiple functional groups. As a result, these derivatives can have enhanced reactivity, e.g., as metal chelating agents, as well as, enhanced performance in many industrial applications, especially, the cosmetic and pharmaceutical industries.

Detailed Description of the Invention

The poly(amine)s of the present invention are comprised of homo-, co-, or terpolymers in which some portion of the polymer contains an amino-functional monomer. The amine functionality of the polymer of the present invention must be ionically reactive or covalently reactive with the oxirane carboxylic acids of the present invention. As such, the poly(amine)s may be comprised of monomers possessing either a primary amine, RNH₂, a secondary amine, R^NH or a tertiary amine, RiRaRsN, and mixtures thereof but not a quaternary amine, RiR2R3R4N⁺, unless the amine is a quaternary ammonium salt of either a primary, secondary or tertiary amine [where Rj, R2, R3 and R4 are typically alkyl, aryl, alyl-aryl, cyclic, straight chain, branched chain, saturated or unsaturated hydrocarbon groups.]

Principal poly(amine)s, suitable for the present invention include, for example, poly(allylamine) available as the hydrochloride salt from Aldrich Chemical Co (Milwaukee, WI) or poly(vinylamine) as described, for example, by Reynolds, D.D. and Kenyon, W.O. in J. Am. Chem. Soc. 1947, 69, 911, and U.S. Pa. No. 5,491,199 issued Feb. 13, 1996 and incorporated herein as reference. Secondary poly(amine)s suitable for the present invention include, for example, poly(ethyleneimine) available from Aldrich Chemical Co. Tertiary poly(amine)s suitable for the present invention include, for example, poly(4-vinylpyridine) available from Aldrich Chemical Co. Preferred for the composition of the present invention are primary amine- containing polymers. Especially preferred is poly (allylamine).

When the poly(amine)s of the present invention are copolymeric or terpolymeric, the additional monomers comprising the co-, or terpolymer can be anionic, cationic, amphoteric, nonionic, hydrophobic or hydrophilic, such monomers being known to those skilled in the art. In addition, the polymer can be a co-, or terpolymer which contains more than one oxirane -reactive, amine-containing monomer as described above. Amine-containing copolymers useful for the composition of the present invention include, for example, Copolymer 845^® (a copolymer comprised of polyvinylpyrrolidone and dimethylaminoethyl methacrylate) available from ISP (Fort Wayne, NJ). Amine-containing terpolymers useful for the composition of the present invention include, for example, Amphomer^® ( a terpolymer comprised of octylacrylamide, tert-butylaminoethyl methacrylate and various acrylic acid monomers) available from National Starch and Chemical Co., (Bridgewater, NJ).

The poly(amine)s of the present invention do not necessarily have to be of an organic nature. Inorganic polymers which contain oxirane-reactive, amine-containing functionality can also be employed in the object of the present invention. Such inorganic polymers might include, for example silicone or silica polymers which have been further derivatized by amine-containing functional reagents. Such an inorganic, poly (amine) might include, for example, aminopropylsilanized silica gel, available from Regis Technologies (Morton Grove, IL), or amodimethicone, available from General Electric (Pittsfield, MA).

The molar amount of the amine in the poly(amine)s of the present invention is not critical to the present invention and vary widely depending on the polymer starting material.

Typically the molecular weight of the poly(amine)s is from about 1000 grams per gram mole to about 2,000,000 grams per gram mole. Preferably, the molecular weight of the poly(amine)s is from about 2000 grams per gram mole to about 1,000,000 grams per gram mole. More preferably, the molecular weight of the poly(amine)s is from about 3000 grams per gram mole to about 800,000 grams per gram mole. As used herein, the term "molecular weight" means weight average molecular weight. Methods for determining the weight average molecular weight of the amine-containing polymers of the present invention are known to those skilled in the art. Typical methods include, for example, light scattering, intrinsic viscosity and gel permeation chromatography. The determination of weight average molecular weight by gel permeation chromatography is preferred in accordance with the present invention. Additionally, those skilled in the art will recognize that the poly(amine)s of the present invention can be crosslinked with any of a number of amine reactive crosslinking agents including, for example, formaldehyde, epichlorohydrin, or other difunctional crosslinking agents, or by functional crosslinking with an amine-reactive metal ion, such as, for example copper (II) ions. Such crosslinking reactions can modify the observed molecular weight of the polymer to afford molecular weights greater than 2,000,000 grams per gram mole.

The poly(amine)s of the present invention should be, but do not necessarily have to be, water-soluble. Water-soluble polymers are defined herein as those polymers in which at least 1.0 gram and preferably 2.0 grams dissolve in 100 grams of water at 25°C at a pH of about 7. Water solubility facilitates the reaction of the amine- containing polymers with the oxirane carboxylic acids of the present invention. However, even poly(amine)s which are not water-soluble may be made to react with the oxirane carboxylic acids of the present invention. Such reactions might occur, for example, some other suitable solvent in which both the poly(amine) and the oxirane carboxylic acid can be dissolved. The preferred solvent for the present invention is water. In addition, the reaction of the poly(amine) with the oxirane carboxylic acids of the present invention may occur in a solvent-free, molten or gaseous phase.

The oxirane carboxylic acids suitable for use in accordance with the present invention, contain an epoxide group, at least one acid group and have from about 3 to 18 carbon atoms, or more, per molecule. Preferably, the oxirane carboxylic acid contains from 3 to 6 carbon atoms per molecule, and more preferably is a dicarboxylic acid. Other preferred oxirane carboxylic acids include cis-epoxysuccinic acid and rαns-epoxysuccinic acid, with cis-epoxysuccinic acid being especially preferred. Methods for the preparation of oxirane carboxylic acids suitable for use in accordance with the present invention are known to those skilled in the art. In addition, such materials are commercially available.

In accordance with the present invention the oxirane carboxylic acid is preferably substituted onto the amine of the poly(amine). Preferably, an effective amount of oxirane carboxylic acid is substituted onto the poly(amine) to achieve the desired properties of the amphoteric polymer derivative. As used herein, the term "molar substitution", also referred to as "(MS)", means the moles of oxirane carboxylic acid substituted on the poly(amine) per mole of reactive amine-containing monomer unit. Preferably, the amine-containing derivatives of the present invention have a MS of from about 0.03 to 3.0 and more preferably from about 0.2 to 1.0 moles of the oxirane carboxylic acid per mole of reactive amine monomer unit.

Quite advantageously in accordance with the present invention, the oxirane carboxylic acid derivatives can be prepared in either the salt form, i.e., ionically bonded, or in the covalently bonded form. The covalently bonded amine-containing derivatives of the present invention can be represented by the following schematic:

where Ri, or Ri and R₂, or R_1; R₂ and R3 are either H, alkyl or aryl, or some portion of the poly (amine) polymer backbone. The ionically bonded poly(amine) of the present invention can be represented by the following structure:

The ionically bonded structure is not amphoteric because the carboxylic acid group is not attached to the poly(amine) in a permanent fashion. In addition, Ri, R₂ or R3, or combinations of these may represent further substituent group modifications to the polymer backbone such as, for example, hydroxyalkyl groups (e.g. hydroxyethyl or hydroxypropyl groups), carboxyalkyl groups (e.g. carboxymethyl groups), amide groups (e.g. succinyl groups), or other alkyl or aryl substituents. These other substituent groups may be introduced prior to or subsequent to the reaction of the poly(amine) with the epoxysuccinic acid.

While it may be true that the parent poly(amine)s may or may not be water-soluble, it is an object of the present invention that the resulting oxirane carboxylic acid-modified amphoteric polymers (herein referred to as either "amphoteric polymer", "amphoteric derivative" or "poly (amine) derivative") are water soluble. However, water solubility of the amphoteric polymers will be dependent on the pH in which the polymers are dissolved. As disclosed below, at certain acidic pHs, the amphoteric polymers of the present invention can become water insoluble. Solubility will also be influenced by the degree of substitution of the oxirane carboxylic acid onto the poly (amine). Such techniques for adjusting solubility are known to those skilled in the art.

In addition, the above-described amphoteric polymers can be further modified to contain other substituent groups, such as, ethers (e.g. hydroxyethyl or hydroxypropyl ether groups, or 3-(trimethyl- ammonium chloride)-2-hydropropyl or 3-(dimethyloctadecylammonium chloride)-2-hydroxypropyl ether groups), amine reactive groups (for example methyl, ethyl or propylchloride), or amide groups (e.g. succinyl or acetyl groups), ester groups (e.g. acetate groups), carboxyalkyl groups (e.g. carboxymethyl groups). These other substituent groups may be introduced prior to or subsequent to the reaction with the acid, or introduced simultaneously by reaction of the amine-containing polymer with the acid and other derivatizing reagents. Likewise, the amine-containing polymer may contain functional groups, such as, for example, hydroxyl, carboxylic acid, or other reactive groups in addition to the amine groups.

The ionically bonded, or ammonium salt form of the poly(amine) which utilizes the oxirane carboxylic acid as the anionic counter ion can be prepared in accordance with known methods for preparing such polymeric ammonium salts. In general, if the salt is prepared under heterogeneous conditions, the poly (amine) can be slurried (i.e. dispersed, but not dissolved) in a non-solvent. Such a non-solvent might be, for example, a solitary solvent, or it might be a combination of solvents. If the polymeric ammonium salt is formed under homogeneous conditions, the poly(amine) is dissolved in a solvent in which the oxirane carboxylic acid is also soluble, the two components are mixed and the salt forms in situ.

Typical solvent materials include for example, water, ketones, such as acetone, alcohols such as methanol, ethanol, N-propanol, isopropanol, t-butanol, and various other solvents such as, for example, acetonitrile, tetrahydrofuran, dioxane, 2-ethoxyethanol, dimethoxy ethane, and the like. Then, the oxirane carboxylic acid is added to the slurry or solution in an amount of from about a 0.03 to 5 fold excess , preferably about a 0.1 to 3 fold excess, most preferably about a 0.1 to 1.5 fold excess of the desired degree of substitution. The addition of the oxirane carboxylic acid is preferably conducted in the liquid phase at a temperature of from about room temperature to 100°C, more preferably from about 35 to 80°C, and most preferably, from about 45 to 75°C. The pressure at which the oxirane carboxylic acid is introduced is not critical and typically ranges from about 0 to 1000 psig. Typical reaction times for preparing the salt range from about 30 minutes to 5 hours preferably from about 30 minutes to 2 hours, and more preferably from about 30 minutes to 1 hour.

Isolation of the polymeric ammonium salt will depend on the method of salt formation. If the salt is formed under heterogeneous conditions, the resulting products can be isolated by filtration and purified by washing or extraction. If the salt is prepared under homogeneous conditions, isolation will typically require either precipitation through the use of a non-solvent, or the product can be isolated as a solid by freeze-drying or spray-drying, both techniques being familiar to those skilled in the art.

Although the polymeric ammonium salts prepared in accordance with the present invention can be used for virtually all known applications for which polymeric ammonium salts, for example, are used, including but not limited to biomedical applications, such as burn treatment and topical medical formulations for rashes and fungal infections, the polymeric ammonium salts of the present invention can also be utilized as reactive intermediates in the preparation of amphoteric covalent derivatives of poly(amine)s.

The covalently bonded amphoteric polymers of the present invention can be made in accordance with methods known to those skilled in the art provided that the oxirane carboxylic acid is reactive under the conditions of the process. Preferably, however, the covalently bonded amphoteric polymers of the present invention are prepared the following procedure.

The starting material is preferably a poly(amine) or polymeric ammonium salt made from a variety of acids including, but not limited to, formic, acetic, N-acetylglycine, acetylsalicylic, fumaric, glycolic, iminodiacetic, itaconic, DL-lactic, maleic, DL-malic, nicotinic, 2- pyrrolidone-5-carboxylic, salicylic, succinamic, succinic, ascorbic, aspartic, glutamic, glutaric, malonic, pyruvic, sulfonyldiacetic, thioactetic, and thioglycolic acids, as well various mineral acids including, but not limited to, hydrochloric, sulfuric, phosphoric, etc. Preferred poly(amines) or polymeric ammonium salts include, for example, poly(allylamine) or its hydrochloride salt or cis-epoxysuccinic acid salt, made as described above, or poly(vinylamine) or its hydrochloride or cis-epoxysuccinic acid salt, prepared in accordance witht he procedures outlined in U.S. Pat. No. 5,491,199, issued Feb. 13, 1996.

The base employed to make the covalent amphoteric derivative should be soluble in the reaction solvent, and those skilled in the art will recognize that the chosen base should be of a more organic nature if the reaction solvent is organic. Such bases include, for example, sodium methoxide, ter -butyllithium, lithium diisopropylamide, triethylamine or other organic bases known to those skilled in the art. The selection of the proper base requires that the base not be so reactive as to hydrolyze the oxirane carboxylic acid before it has had a chance to react with the poly (amine). The concentration of the caustic in the medium is typically from about 1 to 50 weight percent, preferably from about 2 to 25 weight percent, and more preferably, from about 3 to 10 weight percent caustic, i.e., dilute caustic medium. The amount of caustic added should be sufficient to neutralize the carboxylic acid groups of the oxirane carboxylic acid to be introduced subsequently, as well as, the acid groups present if a polymeric ammonium salt is employed as the starting polymer.

After neutralization, the reaction mixture contains the neutralized poly(amine) at a pH of from about 7 to 14, e.g., from about 7.7-14, preferably from about 9.0-12. Those skilled in the art will recognize that pH is a meaningless term outside of an aqueous environment. Consequently, reactions run in strictly organic solvents, or in predominantly organic solvents will require careful control of the caustic stoichiometry to achieve the desired reaction results. If the epoxysuccinic acid salt of the poly(amine) is employed as the starting polymer, the minimum requirement of 3 equivalents of caustic can be reduced because, in this case, a portion of the salt has already been neutralized by the poly (amine). The addition of the poly (amine) or its ammonium salt is done under stirring conditions for a time period of from about 1-3 hours and preferably about 1 hour. The temperature and pressure used during this initial step to neutralize the poly(amine) are typically from about room temperature to 100 °C and atmospheric pressure, repectively, although neither temperature nor pressure is critical for this step.

After the dissolution of the polymer in the dilute caustic medium an appropriate amount of the oxirane carboxylic acid is added to the poly(amine)-containing reaction mixture as required to achieve the desired molar substitution of the oxirane carboxylic acid onto the poly (amine). Typically, the amount of oxirane carboxylic acid introduced will range from about 0.5 to 5 moles, and more preferably from about 0.5 to 3 moles of oxirane carboxylic acid per mole of amine in the monomer unit. Those skilled in the art will recognize that the amount of oxirane carboxylic acid required to be added to conduct the covalent substitution will be lower in the case where the oxirane carboxylic acid salt is used as a starting material. The covalent substitution is accomplished by maintaining the mixture at a temperature of less than about 200 °C, preferably from about 30 to 150 °C and more preferably from about 80 to 100 °C, e.g., by heating. The pressure to affect the substitution is not critical, provided however, that it is preferred to maintain the reaction in the liquid phase. The reaction is conducted for a time period of from about 1-48 hours and more typically from about 8-24 hours. The progress of the reaction can be monitored by any number of analytical techniques known to those skilled in the art. Especially preferred is the use of Fourier-transform infrared spectroscopy or gas chromatography. Especially preferred is the use of gas chromatography where one can monitor the disappearance of the oxirane carboxylic acid.

In a preferred embodiment of the invention, the reaction mixture, is then neutralized with an acid such as, for example, acetic acid, lactic acid, tartaric acid or similar acids, or the with a mineral acid such as, for example, hydrochloric acid. If an organic base is used in the reaction, it is preferred that the residual base be hydrolyzed by water prior to neutralization of the reaction mixture to minimize the exothermic heat of neutralization. In an especially preferred embodiment, if the reaction is run in an aqueous medium, advantage can be taken of the inherent nature of the amphoteric polymer to become water-insoluble when the pH of the of the reaction mixture is such that the amphoteric polymer becomes zwitterionic. The resulting zwitterionic polymer will typically precipitate out of the reaction medium and isolation of the resulting polymer can easily be accomplished by filtration. The amphoteric polymer will typically precipitate at a pH of from about 1.0 to 7.0, more preferably from about 2.0 to 5.0. The resulting solid polymer can be filtered in the usual fashion. The amphoteric polymer can be washed with additional aqueous solvent to further purify the polymer. If such isolation is not desired, the polymer can be precipitated from the homogeneous reaction mixture by addition of a non-solvent. The isolated solid polymer can then be washed with additional non-solvent to further purify it.

The amphoteric polymer of the invention can be used directly upon completion of the reaction or after neutralization or after partial or complete isolation of the amphoteric derivative from the reaction product mixture. Accordingly, the reaction product comprises a composition containing from about 0.05 to 99 weight percent of the amphoteric derivative and from about 0.05 to 99 weight percent of an organic acid by-product from the reaction. These acids are typically the acids from the polymeric ammonium salt starting material and from the oxirane carboxylic acid. Often, the acids are selected from the group consisting of tartaric acid, lactic acid, acetic acid, glycolic acid, pyrrolidone carboxylic acid or salts thereof and mixtures of these acids or salts or both. Depending upon the extent of isolation of the amphoteric derivative, the composition may further comprise from about 0.1 to 90 weight percent, often from about 10 to 80 weight percent water based on the total weight of the composition. Typically, the composition comprises from about 0.1 to 70 weight percent of the amphoteric polymer, from about 0.01 to 15 weight percent of the above mentioned acids and from about 15 to 99.8 weight percent water.

Residual by-products from the reaction may include, for example, the sodium salt of the initial polymeric ammonium salt starting material, residual inorganic salts, e.g., NaCl, KC1, NaOH and the like, and residual tartaric acid. Tartaric acid is a non-toxic, naturally occurring hydroxy acid. An advantage of starting the reaction with polymeric ammonium oxirane carboxylic acid salt, is the presence of the corresponding acid, e.g., tartaric acid, as a residual byproduct at completion of the reaction. By employing poly(amine) epoxysuccinate, for example, initially in the reaction, the problem of additional residual organic acids is minimized and the major contaminants become the innocuous inorganic salts. Under such conditions, the product might be manufactured and used as a solution containing the acid salts.

When further purification of the amphoteric polymer is desired, a variety of options known to those skilled in the art are available. If the poly(amine) derivative is isolated as a solid, it can be dissolved and reprecipitated by either the above mentioned described methods, i.e. pH manipulation, or by addition of a non-solvent. In addition, another more preferred method is to purify the polymer by passing the neutralized reaction product mixture through a membrane. Such membrane separations include, for example, ultra filtration, micro filtration, reverse osmosis, nano filtration, dialysis or electrodialysis. Details concerning such membrane technology are known to those skilled in the art.

The final product can be concentrated and used as a solution or dried to a powder by lyophilization, spray drying, drum drying or any of a number of additional methods of drying such aqueous solutions known those skilled in the art. The poly(amine) derivatives of the present invention can be described as a substituted polymeric aminoacid, an anionic ethoxylated poly (amine), a polymeric alpha- hydroxy acid or an amphoteric poly(amine) dicarboxylic acid.

Additionally, those skilled in the art will recognize that the amphoteric polymers of the present invention can be further modified with any of a number of amine-, carboxy or hydroxy-reactive crosslinking agents including, but not limited to formaldehyde, epichlorohydrin, or other difunctional crosslinking agents, or by functional crosslinking using a polyvalent metal ion, such as for example, calcium, aluminum or copper which crosslinks the amphoteric polymer through ionic interactions with the dicarboxylate functionality or the amine functionality of the amphoteric polymer. In addition, those skilled in the art will recognize that the derivative of the present invention can be made to form polyelectrolyte complexes with other charged or non-charged synthetic or natural polymers such as, for example chitosan, carboxymethyl cellulose, polyacrylic acid, poly(allylamine), poly(vinylamine), poly(vinylpyridine) or polyethyleneimine or the like. Furthermore, those skilled in the art will recognize that the amphoteric polymers of the present invention can be further modified by standard reactions known to those skilled in the art including, but not limited to formation of carboxylic acid salts (e.g. sodium or potassium), carboxylate esters, amides, or anhydrides, and amine salts made by acidification of the amphoteric derivative with any of a variety of organic or mineral acids (e.g HC1, H3PO4, acetic, gly colic, lactic or pyrrolidone carboxylic).

The poly(amine) derivatives of the present invention will have a variety of uses, including, but not limited to, neutraceuticals, pharmaceuticals, cosmetics and therapeutics, as well as, in various industrial applications including, for example, water treatment, detergents, or adsorption, metal complexation, paper flocculation, textile sizing, membrane applications such as food coatings and gas separations, as solid supports for chromatographic stationary phases, hydrogels, and as polymeric components in polyelectrolyte complexes.

A preferred end-use application for poly(amine) derivatives of the present invention is as a component in a personal care composition, e.g., skin creams, lotions, cleansing products, conditioners, hairsprays, mousses, gels and the like, which comprises the poly(amine) derivative and other personal care ingredients. As used herein, the term "personal care ingredients" includes, but is not limited to, active ingredients, such as, for example, spermicides, virucides, analgesics, anesthetics, antibiotic agents, antibacterial agents, antiseptic agents, vitamins, corticosteroids, antifungal agents, vasodilators, hormones, antihistamines, autacoids, kerolytic agents, anti-diarrhea agents, anti- alopecia agents, anti-inflammatory agents, glaucoma agents, dry-eye compositions, wound healing agents, anti-infection agents, and the like, as well as solvents, diluents and adjuvants such as, for example, water, ethyl alcohol, isopropyl alcohol, higher alcohols, glycerine, propylene glycol, sorbitol, preservatives, surfactants, menthol, eucalyptus oil, other essential oils, fragrances, viscosity adjusters and the like. Such personal care ingredients are commercially available and known to those skilled in the art.

The amount of the poly(amine) derivatives present in the personal care composition will vary depending upon the particular care composition. Typically, however, the personal care composition will comprise from about 0.1 to 99 weight percent of the poly (amine) derivative of the present invention.

Typical formulations may contain, for example, 90 weight percent of the poly(amine) derivative. Often, the concentration of the poly(amine) derivative in the personal care composition will range from about 0.5 to 50 weight percent, and more often from about 0.5 to 10 weight percent based on the personal care composition.

Typical cleansing systems may contain water and a surfactant, like ammonium lauryl sulfate and ammonium laureth sulfate and, auxiliary surfacts like lauramide DEA or coco betaines, thickening agents like NaCl, hydroxypropyl cellulose or PEG- 120 methyl glucose dioleate, pH adjusters like citric acid or triethylamine and a chelating agent like tetrasodium EDTA. Likewise, bar soaps may contain surfactants like tallowate or cocoate and a feel modifier like glycerin.

Typical areosol and non-areosol hairsprays may contain a solvent like a low molecular weight alcohol and, or water, a propellent like dimethylether or a hydrocarbon, a resin like poly(vinylpyrrolidone)/vinyl acetate copolymer and, or poly(vinylmethacrylate)/methacrylate copolymer, a plasticizer like dimethicone copolyol and a neutralizing agent like aminomethyl propanol.

Typical creams may contain an oil like mineral oil, water, an emulsifier like methyl glucose sesquistearate or PEG-20 methyl glucose sesquistearate, a feel modifier like isopropyl palmitate or PEG- 20 methyl glucose distearate, a polyhydridic alcohol like methyl gluceth-20 and a stabilizer like carbomer.

Typical mousses may contain a solvent like water and, or alcohol, a surfactant like oleth-10, a feel modifier like isopropyl palmitate and a resin like polyquaternium-10 or poly(vinylmethacrylate)/methacrylate copolymer.

Typical gels may contain a viscosifying agent like carbomer, a solvent like water and, or alcohol, a styling resin like poly(vinylmethacrylate)/vinylmethacrylate copolymer, a neutralizing agent like aminomethyl propanol and a feel modifier like methyl gluceth-20

Further details concerning the ingredients, amounts of ingredients and preparation methods of personal care compositions such as described above are known to those skilled in the art.

The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims which follow.

The following ingredients were used in the examples:

Ingredient Source

Sodium Hydroxide Baker Chemical,

Philipsburg, NJ

Poly (ally lamine)hydrochloride Polysciences, Inc.,

Warrington, PA Ingredient Source cis-Epoxysuccinic acid TCI America, Portland OR Hydrochloric acid Baker Chemical, Philipsburg, NJ

N-Vinylformamide Aldrich Chemical Co., Milwaukee, WI

i-Butylperoxybenzoate Aldrich Chemical Co., Milwaukee, WI

Ethyl Acetate Fisher Scientific, Fair Lawn, NJ

2-Propanol Fisher Scientific, Fair Lawn, NJ

Poly(ethyleneimine) Polysciences, Inc., Warrington, PA

Examples 1-3

Formation of Poly{[N-(2',3'-dicarboxy-3'- hydroxy)ethyl] allylamine}

In a 500 ml, 3-necked roundbottom flask equipped with a reflux condenser, a thermometer and an overhead stirrer was placed 2160 grams of a 5 wt % NaOH solution. To this was added 50 grams (0.54 moles) of poly(allylamine)hydrochloride and the mixture was stirred at room temperature until the polymer dissolved. To the homogeneous reaction mixture was added 142 grams (1.08 mole, 2.0 eq) of cis- epoxyscccinic acid (ESA) and the reaction was brought to a gentle reflux for 48 hrs.

The resulting clear, homogeneous solution was cooled to room temperature and the pH was adjusted to 3.0 using 6 M HC1, whereupon, a white precipitate of zwitterionic poly{[N-(2',3'-dicarboxy- 3'-hydroxy)ethyl] allylamine} appeared. The white solid was filtered and subsequently redispersed in 5 wt% NaOH solution. The product was allowed to redissolve and was reprecipitated by adjustment of the solution pH to 3.0 with more 6 M HC1. The product was filtered and allowed to air dry. Proton NMR examination in D2O indicated that the poly(allylamine) had reacted with 1 molar equivalent of the epoxide.

Examples 2 and 3 were run in an identical fashion but with 0.75 and

0.50 molar equivalents of ESA employed, respectively. The Proton

NMR chemical shifts (from TMS) and the calculated and actual combustion analysis data are compiled in Table 1.

Table 1.

NMR Chemical Shifts and Combustion Analysis for Examples 1-3. ^{a b}

3.8 ppm

a) Figure shows proton NMR chemical shifts (from TMS salt internal standard) characteristic for epoxide-substituted amine.

b) Combustion analysis theoretical values are based on calculated monomer molar percentages derived from NMR analysis.

Examples 4-5

Formation of PolvUN-(2 3^,-dicarboxy-3^,- h vdroxy)ethyl1 vinylamine}

Synthesis

In a 1 liter glass resin kettle with a 4-necked clamped kettle top equipped with an overhead stirrer, a reflux condenser and two addition funnels under a nitrogen blanket, was placed 279 grams of ethyl acetate (EtOAc), 22.5 grams of N-vinylformamide and 0.97 grams of t-butylperoxybenzoate. This mixture was refluxed for 15 minutes while an addition funnel was charged with 330 grams of EtOAc and 177.5 grams of N- vinylformamide. This mixture was slowly added to the refluxing kettle mixture over a 4 hour period.

The second addition funnel was charged with 26.5 grams of EtOAc and 0.20 grams of t-butylperoxybenzoate and 2 hours into the reflux of the kettle mixture, this additional peroxide was added concomitantly with the monomer addition over a two hour period. Upon complete addition of the peroxide, the funnel was recharged with an additional 37 grams of EtOAc and 0.50 grams of t- butylperoxybenzoate and this mixture was added to the kettle mixture over a three hour period. The reaction mixture was than heated an additional 5 hours at reflux.

The reaction mixture was cooled to room temperature, whereupon, the solid poly[N-(vinylformamide)] was isolated by filtration, rinsed with additional pure EtOAc and dried. The reaction afforded 100 grams of crude poly[N-(vinylforamide)]. Molecular weight analysis by GPC on a Hydrogel column using poly(vinylpyrrolidone) standards indicated the poly(vinylformamide) had a weight average molecular weight M_w of approximately 313,000 and a polydispersity of 16.3. Proton NMR analysis in D2O confirmed the structure of the poly [N-(vinylforamide)] .

Synthesis of Poly(vinylamine) hydrochloride: In a 500 ml, 4- necked roundbottom flask equipped with a reflux condenser, an overhead stirrer and a thermometer was placed 1080 grams of a 5 wt% NaOH solution and 100 grams of the poly[(N-vinylformamide)] described above. The mixture was heated to reflux for 24 hrs. Upon completion of the heating, the reaction mixture was cooled to room temperature and the pH of the reaction mixture was adjusted to 3.0 using 6M HC1. The reaction mixture was then concentrated under vacuum into a thick syrup and the poly(vinylamine) hydrochloride was precipitated by addition of 2-propanol. The crude product was examined by NMR in D₂O where it was found to be comprised of approximately 86 mole % NH2 groups and 14 mole % NHC(0)H groups.

Synthesis of Poly{[N-(2', 3'-dicarboxy-3'-hydroxy)- ethyljυinylamine}: In a 500 ml, 3-necked roundbottom flask equipped with an overhead stirrer and a reflux condenser was placed 744 grams of a 5 wt % NaOH solution and 25 grams of the poly(vinylamine) hydrochloride isolated above. To this homogeneous mixture was added 41.5 grams of cis-epoxysuccinic acid and the mixture was heated to reflux for 30 hrs. The resulting tan, homogeneous reaction mixture was cooled to room temperature and the pH of the solution was adjusted to 4.7 using 6M HC1. The zwitterionic poly{[N-(2',3'- dicarboxy-3'-hydroxy)ethyl]vinylamine} precipitated from the solution and the product was isolated by filtration. Repeated reprecipitations afford analytically useful material. Example 5 was run similarly except 50 grams of the ESA was employed. The proton NMR and combustion data for the products of Example 4 and 5 are summarized in Table 2.

Table 2.

Proton NMR Chemical Shifts and Combustion Data for Examples 4 and 5.^{a b}

standard) characteristic for epoxide-substituted amine.

Example β

hydroxy)ethyll ethyleneiminel

In a 500 ml, 3-necked roundbottom flask equipped with an overhead stirrer, a reflux condenser and a thermometer was placed 480 grams of a 5 wt% NaOH solution followed by addition of 5.0 grams of poly(ethyleneimine). The polymer was allowed to dissolve and 32 grams of cis-epoxysuccinic acid was added. The resulting homogeneous reaction mixture was heated to reflux for 48 hrs. Upon completion of the heating cycle, the mixture was cooled to room temperature, and the pH was adjusted to 4.5 with 6M HC1. The poly{[N-(2',3'-dicarboxy-3'- hydroxy)ethyl]ethyleneimine} precipitated as a pale yellow powder. The product was collected by filtration and further purified to a fine white powder by repeated reprecipitations. Proton and Carbon NMR were run to confirm the reaction of the epoxide onto the poly(ethyleneimine) backbone. Results of the NMR work and resulting combustion analysis of the product are shown in Table 3. Table 3.

Proton NMR and Combustion Data for Example 6.^{a b}

2.7 ppm

Ex. # "/o 7o 7o 7o theo act Htheo H act Nthe Nact

0.74 0.26 52.06 35.11 9.81 5.83 26.18 11.21 a) Figure shows proton NMR chemical shifts (from TMS salt internal standard) characteristic for epoxide-substituted amine. b) Combustion analysis theoretical values are based on calculated monomer molar percentages derived from NMR analysis.

Although the invention has been described with respect to specific aspects, those skilled in the art will recognize that other aspects of the invention are intended to be included in the scope of the claims which follow.

Claims

Claims:

1. A derivative of a synthetic, amine-containing polymer having primary, secondary or tertiary amine groups wherein at least one of said primary, secondary or tertiary amine groups is substituted with an oxirane carboxylic acid in an amount from about 0.05 to 3.0 moles of said oxirane carboxylic acid per mole of amine-containing monomer unit.

2. The derivative of claim 1 wherein the amine-containing polymer is selected from the group consisting of poly(allylamine), poly(vinylamine), poly(ethyleneimine) or poly(vinylpyridine), and derivatives thereof.

3. The derivative of claim 1 wherein the amine-containing polymer has a weight average molecular weight of from about 1000 grams per gram mole to 2,000,000 grams per gram mole.

4. The derivative of claim 1 wherein the amine-containing polymer is a copolymer polymerized from an amine-containing monomer and at least one additional monomer which may be amphoteric, cationic, anionic, hydrophobic or hydrophilic.

5. The derivative of claim 1 wherein the amine-containing polymer has at least one reactive functional group in addition to said amine group.

6. The derivative of claim 1 wherein the oxirane carboxylic acid has from about 3 to 6 carbon atoms per molecule.

7. The derivative of claim 1 wherein the oxirane carboxylic acid is a dicarboxylic acid.

8. The derivative of claim 7 wherein the oxirane carboxylic acid is selected from the group consisting of cis-epoxysuccinic acid, £rc s-epoxysuccinic and mixtures thereof.

9. The derivative of claim 1 wherein the molar substitution of the oxirane carboxylic acid is from about 0.2 to 1.0 mole of oxirane carboxylic acid per mole of amine-containing monomer unit.

10. The derivative of claim 1 wherein the oxirane carboxylic acid is ionically bonded or covalently bonded to the amine-containing polymer.

11. Poly {N- [(2'-hydroxy-2\ 3'-dicarboxy)ethyl] allylamine} having a molar substitution of from about 0.2 to 1.0 mole of (2'- hydroxy-2',3'-dicarboxy)ethyl groups per amine-containing monomer unit.

12. Poly{N-[(2'-hydroxy-2',3'-dicarboxy)ethyl]vinylamine} having a molar substitution of from about 0.2 to 1.0 mole of (2'- hydroxy-2',3'-dicarboxy)ethyl groups per amine-containing monomer unit.

13. Poly{N-[(2'-hydroxy-2',3'-dicarboxy)ethyl]ethyleneimine} having a molar substitution of from about 0.2 to 1.0 mole of (2'- hydroxy-2',3'-dicarboxy)ethyl groups per amine-containing monomer unit.

14. Poly{N-[(2'-hydroxy-2',3'-dicarboxy)ethyl]vinylpyridine} having a molar substitution of from about 0.2 to 1.0 mole of (2'- hydroxy-2',3'-dicarboxy)ethyl groups per amine-containing monomer unit.

15. A composition comprising:

(i) from about 0.05 to 99.95 weight percent of the derivative of claim 1; and

(ii) from about 0.05 to 99.95 weight percent of an organic acid selected from the group consisting of tartaric acid, lactic acid, acetic acid, glycolic acid, pyrrolidone carboxylic acid or salts thereof, and mixtures of said acids or salts or both.

16. The composition of claim 15 further comprising from about 1 to 90 weight percent water based on the total weight of the composition.

17. The composition of claim 15 comprising:

(i) from about 0.1 to 70 weight percent of the compound of claim 1; (ii) from about 0.1 to 15 weight percent of an organic acid selected from the group consisting of tartaric acid, lactic acid, acetic acid, glycolic acid, pyrrolidone carboxylic acid or salts thereof, and mixtures of said acids or salts or both; and (iii) from about 15 to 99.8 weight percent water.

8. A personal care composition comprising: (i) the derivative of claim 1; (ii) at least one personal care ingredient; and (iii) water.