CA1340151C - Production of coated inorganic magnetic particles - Google Patents

Abstract

A process for producing solid ceramic particles completely coated with a coating metal oxide different from metal oxides in the ceramic are disclosed. The coated ceramic particles have a diameter less than approximately 5 microns. The process for preparing such particles comprises:
i) forming an emulsion of an aqueous solution of salts of metal ions of the ceramic in a non-miscible liquid to provide aqueous particles;
ii) reacting the emulsion with NH3(g) to precipitate the ceramic particles;
iii) separating out from the reaction mixture the precipitate.
In the course of this process, the ceramic particles are coated by:
iv) a) introducing a colloid of fine particles of precursors of the coating metal oxide at a selected point in the process steps i) and iii), the selection being such to produce coated particles of a desired size and shape, or b) introducing a solution of the coating metal oxide precursors followed by a reaction with NH3(g) to precipitate the coating material onto the surface of the ceramic particles formed in step ii).

Description

13~0151 PRODUCTION OF COATED INORGANIC MAGNETIC PARTICLES
FIELD OF THE INVENTION
This invention relates to a process for producing individual solid ceramic particles each completely coated with a coating metal oxide of different composition than the metal oxides in the ceramic and to the characteristics of such produced particles.
BACKGROUND OF THE lNV~N'l'lON
A variety of techniques have been developed for the production of ceramic particles which involve the precipitation of a precursor of the powder from an aqueous solution containing the desired cations of the ceramic. In many of these techniques, the solution is mixed with a reagent which will precipitate the cations in the form of easily reducible compounds, such as hydroxides, carbonates, oxalate, etc. The precipitates are separated from the liquid and sintered to reduce them to the respective oxides. A technique, which is particularly advantageous in developing ceramic particles in the micrometer size or less, is disclosed in copending Canadian patent application Serial Number 544868-9, filed 19 August 1987 of which one of the two inventors is also coinventor of this application.
Other techniques for preparing ceramic powders are disclosed in French patent 2,054,131. The patent discloses the emulsification of an aqueous solution of the metallic salts which form the ceramic. The emulsion is treated to remove the liquid and calcine the resultant solid phase to produce the ceramic particles.
Considerable attention has also been given to the development of micron size particles for use in biological treatments. A particular area of interest is the development of magnetic particles agglomerated or individually coated with materials to which biological substances can adhere. Examples of magnetic particles for use in this manner are disclosed in United States _ 13~0151 patents 3,330,693; 4,152,210 and 4,343,901. European Patent Application 176,638 published April 9, 1986 also discloses the use of magnetic particles for the immobilization of biological protein. Several of these 5 patents contemplate coating of the magnetic core with a polymeric material, or agglomerating several particles in a suitable polymer such as disclosed in United States patent 4,343,901.
The use for magnetic materials in the biological field continues to increase, hence an increased demand for superior materials. Consider, for example, the use of such particles for immobilizing enzymes or antibodies. Separation of such materials from other non-magnetic solids by the use of a magnetic field 15 permits separations and concentrations which would be otherwise difficult or even impossible to perform.
Besides allowing separation of the support from suspended solids in the process liquids, the ease and power of magnetic collection permits the use of very 20 small support particles. In turn, this allows the use of non-porous particles, while still retaining a reasonable specific area for enzymes or antibodies.
Another advantage of such magnetic materials is their potential use in a magnetic stabilized fluid bed, 25 thereby presenting further options in continuous reactor systems.
From the noted patents, a variety of magnetic materials have been used in the preparation of magnetic support matrices including iron, nickel, cobalt, and 30 their oxides as well as composite materials such as ferrites. However, such supports suffer from some disadvantages. First, metal ions from uncoated metal or metal oxide surfaces may irreversibly inhibit some enzymes, particularly when the enzyme is attached 35 directly to the metal surface. Methods have been devised to attach the enzymes to the inorganic material with the aid of intermediate crosslinking agents and/or to coat the magnetic material with organic coatings as noted in United States patent 4,152,210, or inorganic coatings as noted in United States patent 4,343,901.
Such coatings, however, are not continuous and as a result do not prevent losses in enzyme activity.
Second, the magnetic materials used are mostly ferrimagnetic and as a result have a tendency to aggregate after one use, as a result of residual magnetic forces. For a magnetic enzyme support, complete dispersion of these aggregates would be desirable to realize the advantages of a non-porous support. This could be achieved by using various soft magnetic materials.~5 SUMMARY OF THE INVENTION
According to an aspect of the invention, a process for producing a solid ceramic particle completely coated with a coating metal oxide composition different from metal oxides in the ceramic is provided. The coated~0 ceramic particle has a diameter less than five microns and is prepared in accordance with the following steps:
i) forming an emulsion of an aqueous solution of salts of metal ions of the ceramic in a non-miscible liquid to provide aqueous par-ticles;
ii) reacting the emulsion with a suitable reactant to precipitate the ceramic particles;
iii) separating out the precipitate; and iv) the ceramic particle being coated by introducing either:
a) colloid of fine particles of the coating metal oxide composition precursors at a selected point in process steps i) and iii);
or b) a solution of the coating metal oxide composition precursors followed by a second treatment with a suitable reactant to precipitate the coating material onto the surface of the ceramic particles formed in ii) The selected point in the process steps is determined by a desired size and shape of the coated ceramic particle.
According to another aspect of the invention, a coated ferrimagnetic particle has a diameter in the range of 0.1 to 5 micrometers and comprises a discrete core of a ferrimagnetic material coated with a metal oxide selected from the group consisting of A1203, Si02, Tio2~ Zr02, hydroxy-apatite and mixtures thereof. The coating weighs in the range of 5 to 50% of the core weight and provides a continuous coating over the entire surface of the core to prevent exposure of the core to surrounding media.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The process of this invention is applicable to the application of a suitable metal oxide coating on cores of various ceramic materials. The process is particularly suited for preparing coated particles which have diameters in the range of 5 micrometers and less and preferably in the range of 0.5 to 2 micrometers.
Depending upon the manner in which the process of this invention is carried out, various particle sizes can be produced having either a somewhat irregular shape or a smooth spherical shape. Normally, the particles, as produced by an aspect of the process of this invention having sizes in the range of 0.1 to less than 1 micrometer in size, are irregular in shape.
The process of this invention comprises three basic steps, i.e., emulsification, reaction and separation, with an additional step interposed amongst these basic steps at a point in the process sequence to produce coated particles of a desired size and shape. The three basic steps of the process are as follows.
In step (i) an emulsion of an aqueous solution of salts of metal ions of the desired ceramic core is developed in a non-miscible liquid to provide aqueous particles. Such salts of metal ions are generally referred to as precursors of the metal oxide coating composition when the coating material in the form of hydroxides are calcined to yield the desired oxides.
The non-miscible liquid may be of any suitable organic composition, such as an oil or a solvent. The art of preparing emulsions is well understood so that the selection of a suitable organic liquid is fully appreciated by those skilled in the art. As examples, the following oils, such a paraffin oil, and solvents, such as hexane, heptane, octane, toluene, etc., are particularly useful in the preparation of emulsions.
The emulsion of aqueous particles is developed to produce aqueous droplets in the size range of less than 25 micrometers and preferably less than 5 micrometers.
To promote the development of the emulsion, it is preferable to include a suitable surfactant.
Surfactants also lend stability to the emulsion once the desired aqueous particle size has been developed.
Surfactants are usually large molecules of the formula RX, where R is a hydrophobic group and X is a hydrophilic group. The hydrophobic group is usually a small low molecular weight group and may be cationic, anionic or nonionic. The hydrophobic group is usually a long chain hydrocarbon. As it is appreciated, surfactants are often classified by the ratio of the hydrophilic-lipophilic balance (HLB) number. HLB
numbers are determined empirically and range from 1 to 40. Surfactants having HLB numbers; i.e. less than lo, are considered to be hydrophobic emulsifiers to form water in oil emulsions. Hence for the preparation of 13401Sl the emulsion in step i), suitable hydrophobic emulsifiers having HLB numbers less than 10, such as sorbitan monooleate or Span 80 (ICI, UK) are used.
-~ The aqueous solutions, in this technique, are made by using distilled water of the purity required to avoid introduction of unwanted cations, the wanted cations being introduced in the form of suitable water soluble salts, e.g. nitrates, carbonates, acetates, etc. The fraction of the aqueous solution can be theoretically as high as 74% by volume which corresponds to the theoretical maximum volume that can be occupied by closely packed, uniform spherical particles. In practice, however, it is preferred to use a smaller fraction of about 30% to 50% by volume, since higher concentrations result in distortion from the spherical shape of the dispersed phase leading to non-uniformity in size of the resultant coated particles.
Step ii) of the process comprises treating the developed emulsion with a suitable reactant to precipitate the ceramic particles. This aspect of the process involves the chemical reaction of the salt ions in the solution in the water particles. This is usually done by a change in pH to produce suitable hydroxides which precipitate in the reaction media. Normally such reaction brings about a change in pH from acidic to alkaline of the aqueous droplets which causes the precipitation of the precursor salt as hydrates in the forms of very finely divided non-agglomerated solids whose surface bears the added solids of the sol. Such reaction takes place without breaking of the emulsion so that uniformity and discreteness of the developed particles is maintained. Such change in pH can be accomplished by bubbling ammonia through the emulsion or introducing ammonium hydroxide or a liquid amine, such as ethanolamine or hexamethylene diamine, into the emulsion. Other useful gases include C02 which may be * 1~a~

bubbled through the solution. By virtue of forming bicarbonates, the pH is shifted from acid to basic to form the desired hydroxides.
Step (iii) of the process includes in the separation of the precipitated particles from the emulsion. This may include a dewatering step which can be accomplished in a suitable water trap followed by spray drying, distillation optionally under vacuum, freeze drying, etc. Subsequent to this separation step It is understood that the solids are subjected to a heat treatment to convert the hydroxides to the oxides in forming the desired ceramic. This entails heating the solids at temperatures ranging between 500~C to 1000 ~ C .
The objective, however, of this invention is to coat the ceramic core as developed in the above process steps. Depending upon when the coating composition is introduced to the above steps, a variation in particle size and shape can be achieved. The step of introducing the ceramic coating material in the form of a sol is carried out at a point in steps i) and iii). The composition of the coating is introduced in the form of a colloid of fine particles of the coating metal oxide or oxides at the selected point in process steps i) and iii). If the metal oxide coating is in the form of an aqueous solution, then the solution is introduced in step ii) to coat the precipitate.
The colloid of fine particles of the coating metal oxide may be developed in accordance with well known colloidal processing techniques. For example, a solution of the metal salt may be neutralized with aqueous ammonia, aged and then peptized with nitric acid to a pH of approximately 2 to form colloids having a particle size in the range of 10 to 50 nanometers.
According to an aspect of the invention, the colloidal particles of the coating metal oxide may be -. 13~0151 added to the aqueous solution of salts of the metal ions of the ceramic in step i). In that case, the finely dispersed solids added to the salt solution stabilize the emulsion and as a result, very fine particles of the order of 1 micrometer can be obtained. This phenomena of stabilization of emulsion by finely dispersed solids is well known. In this situation, the surface of the colloid can be modified by the controlled absorption of some surface active agents, such as sodium dodecyl sulfate, HLB greater than 10, which make the particles hydrophobic and therefore preferentially wettable by the oil phase.
The coating material can also be introduced after step ii). In that instance, the coating material can be in the form of colloids suspended in an aqueous solution or in the form of an aqueous solution containing the respective cation or mixture of cations. Wetting of the emulsion droplets by such coatings is preferred by rendering the droplet surface hydrophilic. This is achieved by the addition of a surfactant having a high HLB value, for example, aliphatic polyethers, such as ~, ~ Antarox C0 530TM having an HLB number of 10.8.
Coating thickness can be adjusted by re-emulsifying the dispersion to produce a second emulsion using the previously noted Sorbitan monooleate surfactant in the non-miscible solvent such as n-heptane.
According to another aspect of the process, after the coating material is introduced in the form of a solution, the second emulsion may be reacted with a suitable reactant as previously indicated to precipitate the coated ceramic particles. After the particles are calcined, this process produces smooth spherical particles having a diameter in the range of 0.5 to 5 micrometers and preferably in the range of 0.5 to 2 micrometer.
~q. k Depending on the size of the colloidal particles used for coating the ceramic core, it has been found that the resultant continuous coating normally has a thickness in the range of 10 to 50 nanometers.
In biological applications, it is apparent that with the minute particles it is essential that each particle be completely coated with an inert metal oxide to avoid contamination of the biological media with the inner potentially toxic core which normally has some form of magnetic property.
Suitable magnetic cores include lithium ferrite, nickel ferrite, barium ferrite or any other magnetic oxides. It is appreciated, however, that several other forms of ceramic cores may be developed which may or may not have magnetic properties. They include alumina silica, zirconium oxide, titanium oxide and any other metal oxide. Suitable coatings may be alumina, silica, zirconia, titania, mixtures thereof or any other metal oxide as well as any composite such as hydroxy-apatite.
As previously noted, particles of such minute size can have significant application in the biotechnology field, particularly particles which have para-magnetic and ferrimagnetic cores. These particles can be used as supports for immobilized enzymes, antibodies, antigens and other bioactive materials for use in industrial processes, affinity purification, therapeutics and diagnostics. The current practice, for example, in the industrial production of lactose-free milk is to add the enzyme B-galactosidase to milk in a conventional stir tank reactor and then allow a specific reaction time to elapse. Following this, the milk is pasteurized which destroys the enzyme in the process. On the other hand if the enzyme were immobilized on a magnetic particle, such as provided by this invention, it could be recovered by a magnetic separation and reused. The process of this invention is capable of producing coated _. 1340151 particles having cores of a ferrite composition which are incapable of generating a magnetic field. Hence any re-use would not result in particle aggregation which is associated with ferrous materials due to retained magnetic properties of the ferrimagnetic composition.
The use of these magnetic particles in such a process significantly improves the economics of the process.
Other considerations include new therapies which have been developed for the treatment of diseases, such as childhood leukemia. Current experimental treatments include the use of magnetite, impregnated polystyrene beads which are coated with bioactivations.
Biomaterials specifically recognize and bind to the surface of the leukemic cells thus allowing the separation of diseased and healthy cells. The healthy cells are reintroduced into the patient after all of his/her remaining bone marrow cells have been destroyed through aggressive chemotherapy. The problem with the existing technology is that the magnetic particles currently used in this type of therapy are quite large, that is, in the range of 5 micrometers or more.
Unfortunately, smaller particles of this composition are ineffective due to surface roughness. On the other hand, the coated ceramic particles of this invention are smooth and small for this application, that is, in the range of 1 to 2 micrometers and will overcome the problems of the larger, rougher, magnetic impregnated beads.
The particles produced, according to this invention, are also useful in diagnostic tests. For example, in the examination of blood, there are usually several centrifugation steps involved to separate the various fractions including cells, platelets, serum and plasma. If magnetic particles coated with the appropriate immobilized bioactive materials were used, virtually all centrifugation steps could be eliminated which opens the way for the development of rapid automated blood diagnostic equipment. This would considerably lower costs of the diagnosis and increase the speed of testing.
Aspects of the invention will now be demonstrated by way of the following Examples.

A precursor salt solution was made up of ferric nitrate and lithium nitrate in distilled water in a proportion that would result in lithium ferrite, LiFe508, after drying and decomposition, the solution comprising 1010 g/L Fe(N03)3.9H20 and 34.5 g/L LiNo3. A
sol of colloidal pseudoboehmite was prepared by techniques well known in the art of sol-gel techniques, peptized with nitric acid and treated with sodium dodecyl sulfate. This sol was transferred into the salt solution in proportion that would result in a ratio Al203/LiFe508 of 0.05.
The resulting sol solution was then emulsified in n-heptane, the emulsion consisting of 30% by volume of the aqueous solution, 70% by volume of n-heptane and including 5% by volume of Span 80 as a surfactant and using a Brinkmann homogenizer as an emulsator. Ammonia gas was then bubbled through the emulsion until the pH
had increased to about 10 to 11. The water and heptane were removed by spray drying and the resulting powder was calcined at 700~C for 2 hours to result in an unagglomerated magnetic powder size distribution 0.1 to 0.5 micrometers. The TEM photomicrograph of the powder indicates that the particles are relatively irregular in shape. The thickness of the alumina coating is, however, relatively uniform at 10 to 20 nanometers.

In the previous example, the alumina sol was added before emulsification of the salt solution. In the present example, this procedure was modified as the - 13401~1 alumina was added to the emulsified salt solution; the solution containing ferric nitrate and lithium nitrate was emulsified in n-heptane, and treated with ammonia until the pH had increased to 10 to 11. An alumina sol, similar to that of the previous example, in which 5% by volume of Antarox CO 530 had been added, was transferred into the emulsion in proportion that would result in a ratio A1203/LiFes08 of 20%. The mix was ultrasonically dispersed and then emulsified again in n-heptane in the ratio by volume of 50%, using 2% by volume of Span 80 as the surfactant. The water was subsequently removed by refluxing the emulsion in a "Dean Stark" moisture trap.
After the removal of the organic phase in the spray drier, the powder was calcined at 700~C for 2 hours.
The calcined powders that resulted had a particle size in the range less than 1 micrometer, were spherical with a core of magnetic lithium ferrite in an alumina shell.

The process described in the previous example was modified to produce zirconia coated magnetic particles.
In the present example, the reacted core emulsion was coated with a solution of zirconia oxychloride in which 2% by volume of Antarox CO 530 had been added. The target ratio of Zr02/LiF508 was 15%. The mix was ultrasonically dispersed and then emulsified again in n-heptane in the ratio by volume of 50%, using 2% by volume of Span 80 as the surfactant. Ammonia gas was again bubbled through the emulsion until the pH had increased to about 10 to 11. Subsequent treatments were the same as in the previous example. A
photomicrograph obtained under the scanning electron microscope shows that the resulting submicron particles obtained are of spherical shape with a smooth surface and have a diameter in the range of 0.5 to 2 micrometers.

13401~1 Although preferred embodiments of the invention have been described herein in detail, it will be understood by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims.

Claims (22)

1. In a process for producing a completely coated ceramic particle with a coating metal oxide composition different from metal oxide compositions of said ceramic, said coated ceramic particle having a diameter less than 5 microns, the steps of:
i) forming an emulsion of an aqueous solution of salts of metal ions of said ceramic in a non-miscible liquid to provide aqueous particles;
ii) reacting said emulsion with a suitable reactant to precipitate said ceramic particles;
iii) separating out said precipitate; and iv) said ceramic particle being coated by introducing either:
a) a colloid of fine particles of a coating metal oxide composition precursors at a selected point in said process steps i) and iii), said selected point in said process steps being determined by a desired size and shape of said coated ceramic particle; or b) a solution of the coating metal oxide composition precursor after step ii) followed by a second treatment with a suitable reactant to precipitate the coating material onto the surface of the ceramic particles formed in step ii).

2. A process of claim 1 wherein said selected point in said process steps comprises adding said colloid to said aqueous solution of salts of metal ions of said ceramic in step i) before emulsifying said solution in the presence of a surfactant for promoting development of said emulsion.

3. A process of claim 2 wherein said surfactant has an HLB number less than 10.

4. A process of claim 1, wherein said selected point in said process steps comprises dispersing said colloid in with said precipitated ceramic particles produced by step ii) and re-emulsifying said dispersion before step iii) in the presence of a suitable surfactant to promote development of a second emulsion.

5. A process of claim 4, wherein said surfactant used in the re-emulsification step has an HLB number greater than 10.

6. A process of claim 2, wherein step iii) comprises drying said coated precipitated particles and calcining said coated particles to provide irregular shaped particles having a mean diameter in the range of 0.1 to 0.5 micrometers.

7. A process of claim 5, wherein step iii) comprises drying said second emulsion to yield coated particles and calcining said coated particles to provide smooth spherical particles having a diameter less than 1 micrometer.

8. A process of claim 7, wherein step i) a surfactant is provided to promote development of said emulsion, said surfactant having an HLB number less than 10.

9. A process of claim 1, wherein said reactant of step ii) is a solution of ammonia hydroxide or liquid amines to cause precipitation of said aqueous particles.

10. A process of claim 9 wherein said amine is selected from the group consisting of ethanolamine and hexamethylene diamine.

11. A process of claim 1, wherein said reactant of step ii) is gaseous NH3 or CO2.

12. A process of claim 1, wherein said ceramic metal oxides are selected from the group consisting of lithium ferrite, barium ferrite and nickel ferrite.

13. A process of claim 1, wherein said coating metal oxide is selected from the group consisting of Al2O3, SiO2, TiO2, ZrO2, hydroxy-apatite and mixtures thereof.

14. A process of claim 1 wherein step iv) sub b) after introduction of said solution of coating metal oxide composition, said solution with said precipitated ceramic particles is re-emulsified in the presence of a suitable surfactant to promote development of a second emulsion.

15. A process of claim 14 wherein said surfactant used in said re-emulsification step has an HLB number greater than 10.

16. A process of claim 14 wherein said suitable reactant used in step iv) sub b) is a solution of ammonia hydroxide or a suitable amine.

17. A process of claim 14 wherein said suitable reactant used in step iv) sub b) is gaseous NH3 or CO2.

18. A process of claim 17 wherein step iii) comprises drying said coated particles of step iv) sub b) and calcining said coated particles to provide smooth spherical particles having a diameter in the range of 0.5 to 5 micrometers.

19. A coated ferrimagnetic particle having a diameter in the range of 0.1 to 5 micrometers and comprising a discrete core of magnetic material coated with a metal oxide selected from the group consisting of Al2O3, SiO2, TiO2, ZrO2, hydroxy-apatite and mixtures thereof, said coating weighing in the range of 5% to 50% of said core weight and providing a continuous coating over the entire surface of said core to prevent exposure of said core to surrounding media.

20. A particle of claim 19 having a diameter in the range of 0.5 to 2 micrometers and being spherical in shape with smooth surfaces.

21. A particle of claim 19, wherein said coating thickness is in the range of 10 to 20 nanometers for particles ranging in size from 0.1 to 0.5 micrometer in mean diameter.

22. A particle of claim 19, 20 or 21 wherein said magnetic material is lithium ferrite.