Note: Descriptions are shown in the official language in which they were submitted.
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
1340151
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
1340151
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
- 1340151
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~
1340151
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
1340151
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
1340151
11
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.
EXAMPLE 1 - ALUMINA-COATED MAGNETIC PARTICLES
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.
EXAMPLE 2 - ALUMINA-COATED MAGNETIC PARTICLES
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
12
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.
EXAMPLE 3 - ZIRCONIA-COATED MAGNETIC PARTICLES
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
13
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.
