WO2001017667A1

WO2001017667A1 - Method of preparing metal oxide particles

Info

Publication number: WO2001017667A1
Application number: PCT/US2000/040848
Authority: WO
Inventors: Timothy J. Barder
Original assignee: Eichrom Technologies, Inc.
Priority date: 1999-09-09
Filing date: 2000-09-08
Publication date: 2001-03-15
Also published as: AU1106801A; WO2001017667A8

Abstract

A method of making colloidal metal oxide particles and metal oxide-coated silica particles is disclosed. This method comprises agitating an aqueous composition comprising a solvent-insoluble seed particle material having a diameter of about 0.1 νm to about 10 νm and a solvent-soluble metal compound to form a dispersion of the solvent-insoluble seed particle material and a solvent-soluble metal compound to form a dispersion of the solvent-insoluble seed particle material in a solution of metal ions. A base is admixed with the dispersion to provide a metal oxide coating on the solvent-insoluble seed particle material to thereby form a particle suspension of metal oxide-coated aggregated seed particles. The particle suspension is typically agitated to form metal oxide-coated seed particles and a colloid containing metal oxide particles, recovered without agitation or used as prepared.

Description

METHOD OF PREPARING METAL OXIDE PARTICLES

Description

Technical Field

The invention relates to a method of preparing a metal oxide particle. More particularly, the invention contemplates the preparation of metal oxide-coated particles and colloidal metal oxide particles that are more particularly a colloidal iron oxide particles.

Background of the Invention United States Patent No. 5,492,814 to eissleder discloses methods of making monocrystalline iron oxide nanoparticles . In one method, ferric chloride was mixed with an aspartate or citrate solution containing dextran, and the mixture dissolved at 90°C. Sodium hydroxide was added to raise the pH value of the solution, at which point black iron oxide particles precipitated.

Sonication was performed at 90°C and the precipitate was resuspended. The resulting slurry was centrifuged, and the supernate decanted. The slurry was then dissolved in a dispersion solution at 80°C and adjusted to a pH value of 8. The iron oxide particles were then ultracentrifuged, sonicated, separated on a Sephadex^® column, ultraconcentrated and dialyzed. In a present tense method, ferric chloride and dextran are dissolved in water. Sodium hydroxide is added at 1°C to 30°C, preferably 5°C to 10°C, until a dark green dispersion is formed. The dark green solution is heated to 90°C, turning the solution to a black-brown. The solution is cooled to

4°C, and the pH value is adjusted to 7.0-8.0. The pH adjustment step is said to be very important and determines the yield of monocrystalline iron oxide particles. If the pH is not adjusted, polycrystalline particles will form. The solution is then optionally sonicated in an ice bath. The sample is centrifuged, then subjected to column fractionation, reverse osmosis or ultrafiltration to remove polycrystalline particles. Pooled fractions are then dialyzed.

Schoepf et al . [BioTechniques 24:642-651 (1998) ] provide another method for preparing monocrystalline iron oxide nanoparticles . Ferric chloride and dextran were mixed in water. Chilled, concentrated ammonium hydroxide was added drop-wise until a pH value of 10.0 was obtained. The solution was heated to 70°C for 45 minutes and allowed to cool to 20°C overnight. Free dextran was removed by diafiltration, and monocrystalline iron oxide particles were recovered by size-fractionation ultrafiltration using hollow-fiber membrane cartridges with 0.1 μm pore size. United States Patent No. 5,196,267 to

Barder et al . discloses a process for producing microspheres of silica having a uniform size of about 0.1 to 10 microns and a surface coating comprising a metal . The process comprises combining a hydrolyzable silica precursor, such as tetraalkoxy silanes or alkyl alkoxysilances, with alcohol (such as methanol, ethanol , propanol , butanol or pentanol) , ammonia, and water to form two liquid phases. Silica microspheres are formed by the hydrolysis of the silica precursor. A second solution of a soluble compound of at least one metal selected from the group consisting of noble metals, transition metals, rare earth metals and representative metals is added to the solution containing the silica microspheres. The silica microspheres are contacted with the second solution for a period of time sufficient to deposit a coating of soluble metal compounds on the silica microspheres . The coated microspheres are then recovered. Disclosed soluble metal compounds include acetates, alkoxides, carboxylates, nitrates, chlorides and acetylacetonoates of the metals Al , Ti , Cr, Co, Ni, Cu, Y, Zr, Ru, Rh, Pd, Ag, Sn, Pt , Hg, Ce, Pr, Sm, Er, La, Nd and Ta . A surface-coated silica microsphere made by these processes is also disclosed.

United States Patent No. 5,648,124 to Sutor discloses a process for preparing magnetically responsive microparticles comprising heterocoagulating electrically charged, magnet responsive material with electrically charged core particles, wherein the electrically charged material and the electrically charged core particles are oppositely charged. The disclosed processes require the use of a polymeric dispersant such as polyacrylic acid, polyethyleneimine and/or polymethacrylic acid. United States Patent No. 4,339,241 to Massart discloses magnetic fluids (ferrofluids) consisting essentially of a surfactant-free aqueous solution of polyoxoanions of Fe(II) and at least one metal with an oxidation degree II selected from transition metals (iron, cobalt, manganese, copper and nickel) . The patent also discloses a method of producing such a magnetic fluid, comprising a base, an amount of the appropriate metal salt to form a gel, subjecting the gel to cation exchange, and separating the thus obtained gel.

Paramagnetic and superparamagnetic (magnet responsive) iron oxide particles have been used to separate a variety of biological molecules using magnetic fields. Martin and Mitchell [Analytical Chem . News & Features, 322A-327A (May 1, 1998)] report that superparamagnetic nanoparticles of Fe3θ4 of 5 to 100 nm in diameter can be used to separate cells, proteins, or nucleic acid molecules (e.g., DNA or RNA) by selectively binding the biological material of interest to a magnetic particle, then using a magnetic field to separate the bound material from the surrounding matrix. A common application is immunospecific cell separation. Magnetic particles are coated with a monoclonal antibody directed to a cell-specific antigen. The antibody-coated particles are then mixed with a sample containing the cells of interest. The antibody-coated particles bind to the cell- specific antigen, and the cells are collected by exposing the sample to a magnetic field. This technique has been used to separate lymphocytes and tumor cells. Martin and Mitchell, Analytical Chem . News & Features , 322A-327A (May 1, 1998) . Colloidal magnetic dextran iron particles have been used for negative selection of rare cell types. Thomas, T.E., Biomedical Products 10:50-52 (1998) . Tetrameric antibody complexes comprising mouse IgG monoclonal antibodies held together by two rat anti -mouse IgG monoclonal antibodies are used in the assay. One of the mouse antibodies recognizes a cell surface antigen present on most cells but absent on the cells of interest. The other mouse antibody recognizes the dextran portion of the colloidal magnetic dextran iron particle. A cell sample is admixed with the tetrameric antibody complex and magnetic dextran iron particles. The treated sample is then passed through a magnetic field. Unwanted cells are bound by the magnetic field, whereas desired cells pass through to be collected. This technique has been used to separate primitive hematopoetic progenitor cells and dendritic cells from peripheral blood or bone marrow, basophils from peripheral blood, circulating epithelial tumor cells from bone marrow, peripheral blood, pleural effusions, or peritoneal effusions, and human cells from a murine/human chimera. Id . Schoepf et al . [BioTechniques 24:642-651

(1998) ] report the use of dextran-coated monocrystalline iron oxide nanoparticles (MION) to study lymphocyte adhesion and trafficking in vivo . . Lymphocytes were labeled by endocytosis of the superparamagnetic particles. The labeled lymphocytes adhered to human epithelial cells similar to unlabeled cells, and labeled lymphocyte trafficking was studied using MRI following injection of the labeled lymphocytes into rats. MRI detected accumulation of the cells in spleen, lymph nodes and liver. Id . As suggested by this research, superparamagnetic Fe3©4 particles are also useful as MRI contrast agents. Martin et al . , Analytical Chem . News & Features, 322A-327A (May 1, 1998) .

Metal oxide-coated particles, such as MagneSil™ paramagnetic particles (Promega Corp., Madison, WI) comprising a nearly 1:1 ratio of silicon dioxide to magnetite, are used for DNA purification. The MagneSil™ particles bind nucleic acids in solution, and the bound nucleic acids can be separated from the surrounding medium by use of a magnetic field.

In order to accommodate these varied uses for metal oxide particles and metal oxide-coated particles, there is a need for an efficient method of preparing these metal oxide and metal oxide-coated particles. There is also a need for the ability to control the magnetic properties of metal oxide particles, so that one can reproducibly prepare magnet-responsive or non-responsive metal oxide particles. There is a further need for a method to prepare metal oxide particles of different colors, to accommodate various assays based on visualization of colored reaction products. The processes of the invention provide such methods.

Brief Summary of the Invention

In one aspect, the invention contemplates a method of preparing metal oxide particles and metal oxide-coated seed particles comprising the following steps. A hydroxyl group-containing solvent composition comprising a solvent-insoluble seed particle having a diameter of about 0.1 μm to about 10 μm such as a silica particle, and preferably non- porous silica spheres, and a solvent-soluble metal compound is agitated to form a dispersion of the solvent-insoluble particle in a solution of metal ions. A base is admixed with the dispersion of seed solvent-insoluble particle in a solution of metal ions to provide a metal oxide coating on the particle to thereby form a metal oxide-coated aggregate seed particle suspension. The aggregate particle suspension is agitiated, preferably by sonication, to form a colloid containing metal oxide particles and a precipitate containing metal oxide-coated seed particles. Where only metal oxide-coated seed particles are desired, the agitation step is omitted. These reactions and admixing steps are typically carried out at ambient room temperature and pressure. In a preferred embodiment, the metal compound is ferric chloride, ferrous chloride, or a mixture of both. Alternatively, the metal compound is cobaltous acetate. Preferred seed particles are non-porous silica spheres.

Preferably, the base is ammonium hydroxide. Alternatively, the base is ethanolamine .

In preferred embodiments, the metal oxide particle is magnet responsive. Similarly, in further preferred embodiments, the metal oxide-coated particle is magnet responsive.

In a preferred embodiment where a magnet - responsive (paramagnetic) particle is desired, the base is admixed with the dispersion at a rate sufficient to provide a black color to the dispersion; in laboratory conditions, that addition takes place over a period of about 2 hours. In a preferred embodiment where a non-magnet-responsive particle is desired, the base is admixed with the dispersion at a rate sufficient to provide an ochre color to the dispersion; in laboratory conditions, that addition takes place over a period of greater than about 6 hours .

Preferably, where both are formed, the metal oxide-coated seed particle is separated from the metal oxide colloid.

In a further preferred embodiment, a contemplated process comprises the additional step of recovering the metal oxide-coated particles. Alternatively, a process of the invention comprises the additional step of recovering the colloid comprising metal oxide particles. More preferably, both types of particle are recovered. Alternatively, the metal oxide-coated aggregate seed particles are recovered.

In another more preferred aspect, the present invention contemplates a method for preparing an iron oxide particle and an iron oxide-coated seed particle comprising the following steps. An aqueous composition comprising solvent-insoluble seed particles such as the preferred spherical silica spheres having a diameter of about 0.1 μm to about 10 μm and a solvent-soluble iron compound is agitated to form a dispersion of the solvent -insoluble seed particles in a solution of iron ions. A base is admixed with the dispersion of solvent-insoluble seed particles in a solution of iron ions to provide an iron oxide coating on the seed particles to thereby form a iron oxide-coated silica aggregate seed particle suspension. The aggregate seed particle suspension is then agitated, preferably by sonication, to form an aqueous colloid containing iron oxide particles and a precipitate containing iron oxide-coated silica seed particles. Preferably, the iron oxide-coated particle

(preferably silica particle) is separated from the colloid containing the iron oxide particle.

In a preferred embodiment, the process comprises the additional step of recovering the iron oxide-coated silica seed particles. Alternatively, the process comprises the further step of recovering the aqueous colloid containing the iron oxide particles. More preferably, both particle types are recovered. Alternatively, the metal oxide-coated aggregate seed particles are recovered.

The invention has several benefits and advantages. One advantage is the use of a solid support provides a better and larger surface area for formation of the colloidal particles. One benefit is that the process is simple and efficient .

Another advantage is that the colloidal product particles can be selectively made to be magnet-responsive or non-magnet-responsive . Another benefit is that the colloidal particles can have different colorific properties. Yet other advantages are that the metal oxide particles comprise readily functionalizable surfaces, are highly hydrophilic, contain no organic matrix components, and can bind a variety of molecules using electrostatic forces as well as traditional covalent binding. Still further benefits and advantages of the invention will be apparent to a person of ordinary skill in the art from the description that follows .

Detailed Description of the Invention

In one aspect, the invention provides a method of preparing a colloidal metal oxide particle and a metal oxide-coated seed particle. Exemplary metal oxides include iron oxide (Fe II or Fe III) , cobalt oxide, zirconium oxide, tin oxide, nickel oxide, chromium oxide, platinum oxide, silver oxide, antimony oxide, molybdenum oxide, erbium oxide and manganese oxide. As discussed before, iron oxide particles display magnetic, paramagnetic, or superparamagnetic; i.e., magnet responsive, properties. Conversely, iron oxide can be devoid of magnetic properties. Metal oxide particles can also have a distinctive color. For example, certain magnet- responsive iron oxides are very dark green-black or brown-black in color, whereas magnet -non-responsive iron oxide particles have a reddish ochre color. Nuances of hue aside, those two colors are usually referred to herein as black and ochre, respectively. Cobalt oxide particles have a blue-purple color.

Metal oxide particles, such as black or ochre iron oxide particles or blue-purple cobalt- containing particles, and metal oxide-coated silica particles can be used as discussed hereinbefore and can also be used as colorific markers for a lateral flow device. Magnetic particles can also be used where ferrofluids are used. For example, colorific metal oxide particles can be bound as by adsorption to an antibody and used in a sandwich-type assay for detection of an analyte antigen bound by the antibody as a complex. The presence of the bound analyte antigen (complex) is confirmed by visualization of the colorific metal oxide particle at a receptor region comprising bound capture moieties that specifically react with the complex.

One method of the invention utilizes a hydroxyl -containing solvent composition comprising solvent-insoluble seed particles having a diameter of about 0.1 μm to about 10 μm, preferably about 0.5 μm to about 1.5 μm, and a solvent-soluble metal compound. A hydroxyl -containing solvent includes water and C1-C3 monohydric alcohols. A preferred hydroxyl -containing solvent is water. Further preferred hydroxyl -containing solvents include ethanol , methanol, n-propanol and isopropanol . Exemplary solvent-insoluble particles include porous and non-porous silica and alumina as well as colloidal metal powders such as powdered iron. Spherical silica particles having a diameter of about 0.1 to about 10 μm are particularly preferred. Those particles are preferably non-porous. Hydroxyl -containing solvent -insoluble non- porous silica having a diameter of about 0.1 μm to about 10 μm useful as seed particles is available from Eichrom Industries, Inc. of Darien, IL and can be prepared as discussed in United States Patent No. 5,196,267 to Barder et al . A solvent-soluble metal compound is typically in the form of a metal salt, such as a metal chloride, metal acetate, metal nitrate, metal carbonate, metal oxalate, metal acetylacetonate and the like. Preferred solvent- soluble metal compounds are ferric chloride, ferrous chloride and cobaltous acetate. The hydroxyl -containing solvent composition comprising solvent-insoluble seed particles and a solvent-soluble metal compound is agitated to form a dispersion of the solvent- insoluble seed particles in a solution of the metal compound. Agitation can be by sonication, shaking, stirring or the like. The agitation is conducted so as to homogeneously disperse the particles and the solvent-soluble metal compound throughout the admixture .

A base is then admixed with the dispersion of solvent -insoluble seed particles in a solution of metal compound to provide a metal oxide coating on the seed particles to thereby form a metal oxide- coated aggregate seed particle suspension (dispersion) . A base can be defined as a substance that accepts hydrogen ions, and raises the pH value of the dispersion above pH 7.0, and preferably to about 9 to about 10.

Bases are well known in the art, and include sodium hydroxide, potassium hydroxide, calcium hydroxide, methylamine, ethanolamine and the like. Admixture of the base with the suspension provides a metal oxide coating on the particles. Such a metal oxide-coated aggregate seed particle has a size of about 0.1 μm to about 10 μm when the preferred non-porous silica spheres are used. The metal oxide-coated aggregate seed particles are thus present in suspension, and settle when agitation is stopped. It has been surprisingly found that the magnet-responsiveness of iron oxide particles and iron oxide-coated particles can be predicted from the size of the particles and the rate at which the base is added. Thus, when magnet-responsive particles are desired, particles of about 1 μm to about 10 μm in size, or larger such as preferred 1.5 μm to about 10 μm particles, are used and the base is admixed with the dispersion at a rate sufficient to provide a black color to the dispersion. In laboratory conditions such as those discussed hereinafter, that addition typically takes place over a period of about 2 hours. Typically, the total amount of base is added in drop-wise manner so that the entire amount is delivered to the dispersion over a period of about 1.5 to 2.5 hours .

Where non-magnet-responsive iron oxide particles are desired, irrespective of the size of the particles, the base is admixed with the dispersion at a rate sufficient to provide an ochre color to the dispersion. In laboratory conditions such as those illustrated hereinafter, that addition is typically carried out in a drop-wise manner and takes place over a period of greater than about 6 hours. When particles of less than about 1 μm, and particularly at about 0.5 μm to about 0.2 μm, or less, are used, irrespective of the rate of addition of the base, non-magnet-responsive iron oxide particles are produced. This particle suspension is then agitated to form a colloid containing metal oxide particles and a precipitate containing metal oxide-coated seed particles. The admixing can be by sonnication, shaking, or both. Preferably, the admixing is by sonnication. Because of the nanoparticulate nature of the metal oxide particles, those particles are present as a colloid whose particles do not settle out when agitation is stopped, rather than as a settling suspension or dispersion. The metal oxide- coated seed particles, being of larger size, settle out of solution over time, and can be easily recovered upon decanting of the metal oxide particle colloid. The remaining recovered colloid comprises metal oxide particles.

It can also be advantageous to utilize the metal oxide-coated aggregate seed particles themselves, particularly when seed particles of less than about 1.0 μm, such as those of about 0.5 μm to about 0.2 μm are used. In this instance, the metal oxide-coated aggregate seed particles are not agitated, but are typically recovered, although they can also be utilized without further recovery as where they are used to adsorb antibodies for use as indicators in assays .

Aggregate and metal oxide-coated seed particles are different entities. Aggregate metal oxide-coated seed particles exhibit a rough surface of metal oxide agglomerates, whereas metal oxide- coated seed particles exhibit a smooth surface of metal oxide .

While not wishing to be bound by theory, a process of the invention is believed to require an excess of solvent-soluble metal compound such that an agglomeration of precipitated metal oxide and metal oxide-coated aggregate seed particles are formed. The agglomeration is then disrupted by agitation, such as by ultrasonication, to release metal oxide- coated particles and a finely dispersed (colloidal) suspension of metal oxide particles.

In another aspect, the above process can be conducted using as a starting material a metal oxide- coated seed particle rather than solvent-insoluble uncoated seed particles. In this process, the metal oxide-coated seed particles can be coated with a coating of the same metal oxide, or another metal oxide. Such a process can be repeated for multiple rounds, thus adding multiple layers of one or more metal oxides to the surface of the solvent-insoluble seed particles such as silica spheres.

The invention further contemplates an in si tu method of preparing metal oxide particles and metal oxide-coated particles. In this aspect of the invention, a hydrolyzable silica precursor is admixed with one or more hydroxyl -containing solvents (as discussed before) and a base. A hydrolyzable silica precursor is represented by the formula

R ₍4__n) Si (OR ' ) _n, where R and R' are each independently a C1-C4 (lower) alkyl group, and n is 2, 3 or 4. Representative hydrolyzable silica precursors include methyltrimethoxysilane, ethyltrimethoxysilane, tetramethoxysilane , tetraethoxysilane , tetrapropoxysilane , tetrabutoxysilane , tetraisopropoxysilane, tetraisobutoxysilane, and tetrasecbutoxysilane . A preferred hydrolyzable silica precursor is tetraethoxysilane. A solution comprising one or more hydroxyl - containing solvents and a base is provided. Preferably, the hydroxyl -containing solvent comprises a C1-C4 monohydric alcohol and water. A preferred C1-C4 monohydric alcohol is methanol . A preferred base is ammonium hydroxide.

The solution is then heated to about 30°C to about 60°C, preferably about 30°C to about 50°C, and more preferably to about 40°C. The hydrolyzable silane is then admixed with the heated solution to form a hydrolysis reaction solution. The hydrolysis reaction solution is agitated for a time period and under temperature and pH conditions sufficient to form a solvent -insoluble spherical silica particle- containing solution. The time period is preferably about 1 to about 3 hours, and more preferably about 1 hour. The temperature conditions are preferably from about 40°C to about 100°C, and more preferably from about 45°C to about 55°C. The pH conditions provide a solution with a pH value of about 5 to about 8, and more preferably a pH value of about 7.

The spherical silica particle-containing solution is then admixed with a solvent-soluble metal compound to provide a metal oxide coating on the spherical silica to thereby form a metal oxide-coated aggregate particle suspension. Preferably, the solvent-soluble metal compound is admixed with water to form a metal ion solution. Preferably, the metal ion solution is admixed in a drop-wise manner into the silica-containing solution. Using laboratory conditions such as those discussed hereinafter, the metal ion solution is preferably admixed with the silica-containing solution over a time period of about 15 minutes to about 3 hours, and more preferably over a time period of about 30 minutes. In a preferred embodiment, additional base is added to the dispersion of silica and metal ions.

Where relatively small particles such as those having a diameter of less than about 1.0 μm such as the before-discussed particles having a diameter of about 0.5 μm to about 0.2 μm, the metal oxide-coated aggregate particles are themselves typically recovered. Where larger seed particles such as those having diameters of about 1.0 μm up to about 10 μm are used, the metal oxide-coated aggregate particles can be recovered and used as such, or those particles can be agitated to form colloidal metal oxide particles and metal oxide- coated seed particles. In that latter instance, the metal oxide-coated aggregate particle suspension discussed before is then agitated as by sonication to provide metal oxide-coated seed particles and a colloid of metal oxide particles.

United States Patent No. 5,196,267 does not disclose the use of iron oxide in the processes described, nor is the preparation of a colloid comprising a metal oxide described. Moreover, the method described therein does not disclose admixing a base with a dispersion of solvent -insoluble porous or non-porous spherical silica particles in a solution of metal ions to provide a metal oxide coating on the spherical silica to form a metal oxide-coated aggregate particle suspension, and thereafter, a metal oxide-coated particle suspension and a metal oxide particle-containing colloid. Still further, those disclosed processes do not teach the preparation of a magnet responsive metal oxide particles . On the other hand, the present invention provides a method of preparing metal oxide particles and metal oxide-coated particles by admixing solvent- insoluble seed particles such as silica spheres with a solvent-soluble metal compound. In one embodiment, a base is added at ambient room temperature.

Surprisingly, depending on the size of the solvent - insoluble spherical silica particles, the rate of addition of the base determines whether the resulting metal oxide particle metal oxide-coated seed particle is magnet-responsive or non-magnet -responsive . Metal oxide-coated aggregate particles are recovered, and the metal oxide-coated aggregate particles are agitated to form a colloid of metal oxide particles and metal oxide-coated silica seed particles. The method does not require excess heat, excess cooling, ultracentrifugation, column separation, ultraconcentration, reverse osmosis, diafiltration, ultrafiltration, dialysis or the use of dispersants. In contrast to other methods, the present invention provides a method that is efficient and economical. The following examples are offered to further illustrate, but not limit, the present invention.

Example 1 : Preparation of Colloidal Iron Particles Ten grams of processed non-porous silica, 1.5 ± 0.5 μm in size (Eichrom Industries Inc., Darien, IL) , were suspended in 250 mL distilled water. Ferric chloride (FeCl3-6H2θ; 2.9 grams) was added and the mixture sonicated for 30 minutes to completely disperse the silica. The dispersion was poured into a 5 L beaker and the volume increased to 2 L with distilled water. Ferrous chloride (FeCl2-4H2θ; 4.3 grams) was dissolved in 250 mL distilled water and added to the ferric ion/non- porous silica dispersion. The dispersion was stirred at 300 revolutions per minute using an A-310 impeller blade and a Cole-Parmer overhead stirrer.

Concentrated ammonium hydroxide (10 mL) was dissolved in 250 mL distilled water and the solution placed in a 250 mL separatory funnel. The ammonium hydroxide solution was added drop-wise to the dispersion so that complete addition occurred over a period of about 2 hours. The resulting suspension changed color from yellow to orange-brown to dark green-black during that time period. The suspension was stirred at 150 revolutions per minute for 30 minutes after complete addition of the ammonium hydroxide solution. The stir blade was removed and the beaker covered with plastic wrap and permitted to settle . The suspension was decanted and the precipitated solid of metal oxide-coated aggregate silica particles was washed three times with 2 L distilled water. The final wash was permitted to settle overnight (16 hours) , and the water decanted. The precipitated metal oxide-coated aggregate silica particles were placed in a 500 mL polypropylene bottle along with 200 mL of distilled water and sonicated for 40 to 60 minutes with intermittent shaking. The resulting suspension was permitted to settle over several days. A dark magnet -responsive mother liquor containing colloidal iron oxide particles was decanted from light brown magnet- responsive iron oxide-coated non-porous silica particles. The iron oxide-coated particles were washed three times in 250 mL distilled water.

A similar preparation was carried out using approximately 0.29 grams of ferric chloride and 0.43 grams of ferrous chloride with the above amount of non-porous silica. This reaction provided yellow- brown silica spheres and a colloid. The reaction was repeated three more times using the produced metal oxide-coated silica spheres to provide dark brown metal oxide-coated silica spheres that were very magnet -responsive .

Example 2 : Preparation of Colloidal Iron Particles Ten grams of processed non-porous silica,

1.5 + 0.5 μm in size (Eichrom Industries, Darien, IL) , were suspended in 250 mL distilled water. Ferric chloride (FeCl3 ^• 6H2O; 2.9 grams) was added and the mixture sonicated for 30 minutes to completely disperse the silica. The dispersion was poured into a 5 L beaker and the volume increased to 2 L with distilled water. Ferrous chloride (FeCl2 ^• 4H2O ; 4.3 grams) was dissolved in 250 mL distilled water and added to the ferric ion/non-porous silica dispersion. The dispersion was stirred at 300 revolutions per minute using an A-310 impeller blade and a Cole- Parmer overhead stirrer. Concentrated ammonium hydroxide (10 mL) was dissolved in 250 mL distilled water and the solution placed in a 250 mL separatory funnel. The ammonium hydroxide solution was added drop-wise to the dispersion so that complete addition occurred over a period of about 6 hours. The resulting suspension changed color from yellow to orange-brown to dark green-black to reddish ochre over that time period. The suspension was stirred at 150 revolutions per minute for 30 minutes after complete addition of the ammonium hydroxide solution. The stir blade was removed, the beaker covered with plastic wrap and composition permitted to settle.

The suspension was decanted and the precipitated, solid, metal oxide-coated aggregate silica particles were washed three times with 2 L distilled water. The final wash-containing solid was permitted to settle overnight (16 hours) , and the water decanted. The precipitated solid was placed in a 500 mL polypropylene bottle along with 200 mL of distilled water and sonicated for 40 to 60 minutes with intermittent shaking. The resulting suspension was permitted to settle over several days. An ochre colored mother liquor containing colloidal iron oxide particles was decanted from yellow, iron oxide-coated non-porous silica particles. The yellow iron oxide- coated particles were washed three times in 250 mL distilled water and were not magnet-responsive .

Example 3: Preparation of Cobalt Oxide-coated

Silica Particles

Methanol (1.5 L) , 250 mL distilled water and 230 mL concentrated ammonium hydroxide were mixed in a 4 L glass beaker. Using an A-310 impeller blade and a Cole-Parmer overhead stirrer, the mixture was stirred at 150 revolutions per minute. The mixture was then heated to 40°C, and 100 mL of tetraethoxide silane (TEOS) were added. The solution was permitted to stir for 1 hour at 45°C to 55°C. The composition was sampled, and the silica spheres were found to have diameters of about 100 nm. The stirring rate was then increased to 300 revolutions per minute, and a solution of 2.0 grams of cobaltous (Co (II)) acetate -4 H2O dissolved in 200 mL distilled water was prepared. This cobaltous acetate solution was then added to the suspension in drop-wise manner over a period of about 30 minutes. Optionally, 5.0 mL ethanolamine dissolved in 50 mL distilled water was also added to the suspension. The resulting blue- purple suspension was removed from the heat and permitted to settle. The supernate was decanted and discarded, and the cobalt oxide-coated aggregate silica particles were washed three times in 2L distilled water.

Example 4: Preparation of Magnet-non-responsive Iron Oxide-coated Silica Particles Methanol (1.5 L) , 250 mL distilled water and 230 mL concentrated ammonium hydroxide were mixed in a 4 L glass beaker. Using an A-310 impeller blade and a Cole-Parmer overhead stirrer, the mixture was stirred at 150 revolutions per minute. The mixture was then heated to 40°C, and 100 mL of tetraethoxide silane (TEOS) were added. The solution was permitted to stir for 1 hour at room temperature (about 22°C) . The composition was sampled, and the silica particles produced were found to have diameters of about 200 nm. The stirring rate was then increased to 300 revolutions per minute, and the solution heated to 90°C with intermittent addition of distilled water to maintain a total volume of between 2.0 and 2.5 L. The pH value of the solution was monitored and the suspension was permitted to cool to 40°C when the pH value was about 7.0. About one-third of the volume of the composition was removed and placed into a 5 L flask and the volume brought to about 2 L with distilled water. Ferric chloride (FeCl3"6H2θ; 2.9 grams) was added and the mixture sonicated for 30 minutes to completely disperse the silica. Ferrous chloride (FeCl2 • 4H2O ; 4.3 grams) was dissolved in 250 mL distilled water and added to the ferric chloride/ spherical silica dispersion. The dispersion was stirred at 300 revolutions per minute using an A-310 impeller blade and a Cole-Parmer overhead stirrer.

Concentrated ammonium hydroxide (10 mL) was dissolved in 250 mL distilled water and the solution placed in a 250 mL separatory funnel. The ammonium hydroxide solution was added drop-wise to the dispersion so that complete addition occurred over a period of about 6 hours and in other studies over 1.5 to 2 hours. In each instance, the resulting suspension changed color from yellow to orange-brown to dark green-black to reddish ochre during that time period. The suspension was stirred at 150 revolutions per minute for 30 minutes after complete addition of the ammonium hydroxide solution. The stir blade was removed and the beaker covered with plastic wrap and permitted to settle.

The suspension was decanted and the precipitated solid of metal oxide-coated aggregate silica particles was washed three times with 2 L distilled water. The final wash was permitted to settle overnight (16 hours) , and the water decanted. Reddish-ochre non-magnet -responsive iron oxide-coated spherical silica particles were recovered. The iron oxide-coated particles were washed three times in 250 mL distilled water.

Example 5 : Procedure for making Colloidal and Coated Composite Particles 1. Suspend 10 g of processed 1.5 ± 0.1 μm non-porous silica (NPS) particles in 250 ml of distilled water.

2. Add 2.9 grams (0.011 moles) of ferric chloride [FeCl₃ • 6 H₂0] and sonicate mixture of silica and ferric ion solution for 30 minutes to completely disperse the silica. Intermittent shaking may be necessary to effect good dispersion.

3. Pour dispersed mixture into a 5 L beaker and bring volume to 2 L with distilled water.

4. Dissolve 4.3 g (0.022 moles) of ferrous chloride [FeCl₂ • 4 H₂0] in 250 mL of distilled water and add to the yellow ferric ion/NPS particle suspension. 5. Using an A-310 impeller blade and a Cole-Parmer™ overhead stirrer, stir mixture at 300 rpm.

6. Dissolve 10 mL of concentrated NHOH in

250 mL of distilled water and place in a 250 mL separatory funnel .

7. Begin to add NH₄0H solution drop-wise so that complete addition occurs over a period of 2 hours .

8. The suspension progresses in color from yellow to orange-brown to dark green-black.

9. The suspension is stirred at 150 rpm for 30 minutes after complete NH₄OH addition.

10. Remove stir-blade and cover the beaker with Saran^® wrap, and permit the green-black solids to settle.

11. Decant the liquid, and resuspend green-black solids in 2 L of distilled water 3 times.

12. Permit the last resuspension to settle for at least 16 hours and decant the water phase.

13. Resuspend solid in 250 mL of distilled water in a 500 mL polypropylene bottle and sonicate for 40-60 minutes with intermittent shaking. 14. Permit the suspension to settle over several days and decant off colloidal suspension.

15. Wash remaining settled light brown solid 3 times with distilled water by settling and decanting off supernatant. The resulting 1.5 μm diameter particles are a composite of a solid silica core with a metal (iron) oxide coating.

Using this procedure both the colloidal and the composite material are highly magnet responsive.

Following the same general procedure as outlined above, an extensive series of studies was carried out changing certain conditions and constituents in the reaction mix. The table below highlights these changes for colloidal particles (except along with the mole ratios of the various constituents in these reactions. These mole ratios are based on the actual moles of material outlined in the procedure above; e.g. the reaction above is 2 moles Fe (II) : lmole Fe(III). The resulting colloidal suspensions, unless otherwise stated, are indefinitely stable.

Except where noted, the non ferrous metal ions used were all hydrated chloride salts readily available commercially.

* These data are for 1.5μ spheres that were coated, recovered and coated again for a total of four coatings.

Each of the patents and articles cited herein is incorporated by reference. The use of the article "a" or "an" is intended to include one or more .

From the foregoing, it will be observed that numerous modifications and variations can be effected without departing from the true spirit and scope of the present invention. It is to be understood that no limitation with respect to the specific examples presented is intended or should be inferred. The disclosure is intended to cover by the appended claims modifications as fall within the scope of the claims.

Claims

WHAT IS CLAIMED:

1. A method for preparing a metal oxide particle colloid and a metal oxide-coated seed particle comprising the steps of:

(a) agitating an aqueous composition comprising solvent -insoluble seed particles having a diameter of about 0.1 μm to about 10 μm and a solvent -soluble metal compound to form a dispersion of said solvent-insoluble seed particles in a solution of metal ions;

(b) admixing a base with said dispersion to provide a metal oxide aggregate on said seed particles and thereby form a suspension of aggregated metal oxide-coated seed particles; and

(c) agitating said aggregated metal oxide- coated seed particle suspension to form a metal oxide particle colloid and metal oxide-coated seed particles .

2. The method of claim 1 wherein said metal compound is selected from the group consisting of a salt of iron(II), iron(III), cobalt (II), nickel (II), chromium (IV) and mixtures thereof.

3. The method of claim 1 wherein said metal compound is a salt of iron(II), iron(III), or a mixture thereof .

4. The method of claim 1 wherein said metal oxide-coated seed particles are separated from said colloid.

5. The method of claim 1 comprising the further step of recovering said metal oxide-coated seed particles.

6. The method of claim 1 comprising the further step of recovering said colloid.

7. A method for preparing an iron oxide particle colloid and iron oxide-coated silica seed particles comprising the steps of:

(a) agitating an aqueous composition comprising solvent -insoluble silica seed particles having a diameter of about 0.1 μm to about 10 μm and a solvent-soluble iron compound to form a dispersion of said solvent -insoluble silica seed particles in a solution of iron ions;

(b) admixing a base with said dispersion to provide an iron oxide coating on said silica seed particles to thereby form an aggregated iron oxide- coated silica seed particle suspension; and

(c) agitating said aggregated iron oxide- coated silica seed particle suspension to form an iron oxide particle colloid and iron oxide-coated silica seed particles.

8. The method of claim 7 wherein said base is ammonium hydroxide.

9. The method of claim 7 wherein said base is ethanolamine.

10. The method of claim 7 wherein said iron oxide colloid particle is magnet responsive.

11. The method of claim 7 wherein said base is admixed with said dispersion at a rate sufficient to provide a black color to said dispersion.

12. The method of claim 7 wherein said base is admixed with said dispersion at a rate sufficient to provide an ochre color to said dispersion.

13. The method of claim 7 wherein said iron oxide-coated silica seed particles are separated from said iron oxide particle colloid.

14. The method of claim 7 further comprising the step of recovering said iron oxide- coated silica seed particles.

15. The method of claim 7 further comprising the step of recovering said iron oxide particle colloid.

16. The method of claim 7 wherein said solvent-soluble iron compound is a mixture of iron(II)and iron(III) salts.

17. The method of claim 16 wherein said iron (II) salt is present in excess over said iron (III) salt in said mixture of iron salts.

18. The method of claim 7 wherein said silica seed particles are non-porous silica seed particles .

19. A method for preparing a magnet responsive iron oxide particle colloid and magnet responsive iron oxide-coated silica particles comprising the steps of:

(a) agitating an aqueous composition comprising solvent -insoluble non-porous silica having a diameter of about 1.0 μm to about 10 μm and a solvent -soluble iron compound that is a mixture of iron (II) and iron(III) salts in which the iron(II) salt is in excess over the iron (III) salt to form a dispersion of said solvent -insoluble non-porous silica in a solution of mixed iron ions;

(b) admixing a base with said dispersion at a rate sufficient to provide a black color to said dispersion to provide a magnet responsive iron oxide coating on said non-porous silica to thereby form a black-colored aggregated iron oxide-coated silica particle suspension; and

(c) agitating said black-colored aggregated iron oxide-coated silica particle suspension to form a magnet responsive iron oxide particle colloid and paramagnetic iron oxide-coated silica particles.

20. The method of claim 19 wherein said mixture of solvent -soluble iron compound contains a molar ratio of iron(II) to iron(III) salts of about 3:2 to about 5:1.

21. The method of claim 19 wherein said non-porous silica has a diameter of about 1.5 μm to about 10 μm.

22. The method of claim 19 wherein said black-colored aggregated iron oxide-coated silica particle suspension is agitated by sonication.

23. The method of claim 19 wherein said black-colored iron oxide-coated silica particles are separated from said black-colored iron oxide particle colloid.

24. The method of claim 19 further comprising the step of recovering said black-colored iron oxide-coated silica particles.

25. A method for preparing aggregated metal oxide-coated seed particles comprising the steps of:

(a) agitating an aqueous composition comprising solvent -insoluble seed particles having a diameter of about 0.1 μm to about 0.5 μm and a solvent -soluble metal compound to form a dispersion of said solvent -insoluble seed particles in a solution of metal ions; and

(b) admixing a base with said dispersion to provide a metal oxide aggregate on said seed particles and thereby form a suspension of aggregated metal oxide-coated seed particles.

26. The method of claim 25 wherein said metal compound is selected from the group consisting of a salt of iron(II), iron(III), cobalt (II), nickel (II), chromium(IV) and mixtures thereof.

27. The method of claim 25 wherein said metal compound is a salt of iron(II), iron(III), or a mixture thereof .

28. The method of claim 25 comprising the further step of recovering said aggregated metal oxide-coated seed particles.

29. A method for preparing aggregated iron oxide-coated silica seed particles comprising the steps of :

(a) agitating an aqueous composition comprising solvent -insoluble silica seed particles having a diameter of about 0.1 μm to about 10 μm and a solvent -soluble iron compound to form a dispersion of said solvent -insoluble silica seed particles in a solution of iron ions; and

(b) admixing a base with said dispersion to provide an iron oxide coating on said silica seed particles to thereby form an aggregated iron oxide- coated silica seed particle suspension.

30. The method of claim 29 wherein said base is ammonium hydroxide.

31. The method of claim 29 wherein said base is ethanolamine.

32. The method of claim 29 wherein said base is admixed with said dispersion at a rate sufficient to provide a black color to said dispersion.

33. The method of claim 29 wherein said base is admixed with said dispersion at a rate sufficient to provide an ochre color to said dispersion.

34. The method of claim 29 further comprising the step of recovering said aggregated iron oxide-coated silica seed particles.

35. The method of claim 29 wherein said solvent-soluble iron compound is a mixture of iron(II)and iron(III) salts.

36. The method of claim 35 wherein said iron (II) salt is present in excess over said iron

(III) salt in said mixture of iron salts.

37. The method of claim 29 wherein said silica seed particles are spherical non-porous silica seed particles.

38. Aggregated metal oxide-coated seed particles comprising aqueous solvent -insoluble seed particles having a diameter of about 0.1 μm to about 10 μm having a metal oxide aggregate coating thereon.

39. The aggregated metal oxide-coated seed particles of claim 38 wherein said seed particles have a diameter of about 1.0 μm to about 10 μm.

40. The aggregated metal oxide-coated seed particles of claim 38 wherein said seed particles have a diameter of less than about 1.0 μm to about 0.1 μ .

41. The aggregated metal oxide-coated seed particles of claim 40 wherein said seed particles have a diameter of about 0.5 μm to about 0.2 μm.

42. The aggregated metal oxide-coated seed particles of claim 38 wherein the metal of said metal oxide is selected from the group consisting of a salt of iron, cobalt, nickel, chromium and mixtures thereof .

43. The aggregated metal oxide-coated seed particles of claim 38 that are magnet responsive.

44. The aggregated metal oxide-coated seed particles of claim 38 that are magnet non-responsive.