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Claims for Patent: 4,695,393

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Claims for Patent: 4,695,393

Title: Magnetic particles for use in separations
Abstract:A process is provided for the preparation of magnetic particles to which a wide variety of molecules may be coupled. The magnetic particles can be dispersed in aqueous media without rapid settling and conveniently reclaimed from media with a magnetic field. Preferred particles do not become magnetic after application of a magnetic field and can be redispersed and reused. The magnetic particles are useful in biological systems involving separations.
Inventor(s): Chagnon; Mark S. (Lowell, MA), Groman; Ernest V. (Brookline, MA), Josephson; Lee (Arlington, MA), Whitehead; Roy A. (Hingham, MA)
Assignee: Advanced Magnetics Inc. (Cambridge, MA)
Application Number:06/744,435
Patent Claims: 1. A process for preparing magnetically-responsive particles which comprises:

(a) precipitating divalent and trivalent transition metal salts in base to form a precipitate;

(b) washing the precipitate in water to approximate neutrality;

(c) washing the precipitate in an electrolyte;

(d) suspending the washed precipitate in an organic solvent containing about 1% (V/V) water to form a mixture;

(e) adding an acidic solution of a silane monomer to the mixture of step (d);

(f) homogenizing the resultant mixture of steps (d) and (e) at high speed;

(g) adding to the homogenized mixture of steps (d), (e), and (f) a wetting agent, which agent is miscible in the organic solvent and water;

(h) heating the resultant mixture of steps (d), (e), (f), and (g) to a temperature which is: (i) at or above the boiling point of the organic solvent and the boiling point of water, such that the organic solvent and water are evaporated; (ii) below the boiling point of the wetting agent, such that the wetting agent is not evaporated; and (iii) sufficient to polymerize the silane monomer and to cause the resultant silane polymer to become adsorptively or covalently bound to the precipitate; and

(i) washing the wetting agent from the silanized precipitate, which precipitate comprises silane-coated magnetically-responsive particles with mean diameters between about 0.1.mu. and 1.5.mu. as measured by light scattering, a mass of the particles being dispersable in aqueous media to form an aqueous dispersion having (a) a fifty-percent-turbidity-decrease settling time of greater than about 1.5 hours in the absence of a magnetic field, and (b) a ninety-five-percent-turbidity-decrease separation time of less than about 10 minutes in the presence of a magnetic field, the magnetic field being applied to the aqueous dispersion by bringing a vessel containing a volume of the dispersion into contact with a pole face of a permanent magnet, the permanent magnet having a volume which is less than the volume of the aqueous dispersion in the vessel.

2. A process for preparing magentically-responsive particles which comprises:

(a) precipitating divalent and trivalent iron cations of divalent and trivalent iron salts in base to form a precipitate;

(b) washing the precipitate in water to approximate neutrality;

(c) washing the precipitate in an electrolyte;

(d) suspending the washed precipitate in an organic solvent containing about 1% (V/V) water to form a mixture;

(e) adding an acidic solution of a silane monomer to the mixture of step (d);

(f) homogenizing the resultant mixture of steps (d) and (e) at high speed;

(g) adding to the homogenized mixture of steps (d), (e), and (f) a wetting agent, which agent is miscible in the organic solvent and water;

(h) heating the resultant mixture of steps (d), (e), (f), and (g) to a temperature which is: (i) at or above the boiling point of the organic solvent and the boiling point of water, such that the organic solvent and water are evaporated; (ii) below the boiling point of the wetting agent, such that the wetting agent is not evaporated; and (iii) sufficient to polymerize the silane monomer and to cause the resultant silane polymer to become adsorptively or covalently bound to the precipitate; and

(i) washing the wetting agent from the silanized precipitate, which precipitate comprises silane-coated superparamagnetic particles with mean diameters between about 0.1.mu. and 1.5.mu. as measured by light scattering, a mass of the particles being dispersable in aqueous media to form an aqueous dispersion having (a) a fifty-percent-turbidity-decrease settling time of greater than about 1.5 hours in the absence of a magnetic field, and (b) a ninety-five-percent-turbidity-decrease separation time of less than about 10 minutes in the presence of a magnetic field, the magnetic field being applied to the aqueous dispersion by bringing a vessel containing a volume of the dispersion into contact with a pole face of a permanent magnet, the permanent magnet having a volume which is less than the volume of the aqueous dispersion in the vessel.

3. The process of claim 2 wherein the divalent and trivalent iron salts are FeCl.sub.2 and FeCl.sub.3.

4. The process of claim 2 wherein the divalent and trivalent iron cations are used in an Fe.sup.2+ /Fe.sup.3+ ratio of about 4/1 to about 1/2.

5. The process of claim 2 wherein the washings are performed by redispersing the precipitate in water and electrolyte and magnetically collecting the precipitate between washings.

6. The process of claim 2 wherein the organic solvent is methanol and the wetting agent is glycerol.

7. The process of claim 2 wherein the solution of silane monomer is made acidic with orthophosphorus acid or glacial acetic acid.

8. The process of claim 2 wherein said silane polymer is formed from a silane monomer selected from the group consisting of p-aminophenyltrimethoxysilane, 3-aminopropyltrimethoxysilane, N-2-aminoethyl-3-aminopropyltrimethoxysilane, n-dodecyltriethoxysilane, and n-hexyltrimethoxysilane.

9. A process for preparing magnetically-responsive particles which comprises:

(a) precipitating FeCl.sub.2 and FeCl.sub.3 in an Fe.sup.2+ /Fe.sup.3+ ratio of about 2/1 with sodium hydroxide to form a precipitate;

(b) washing the precipitate in water to approximate neutrality by redispersing and magnetically separating the precipitate;

(c) washing the precipitate in a sodium chloride solution by redispersing and magnetically separating the precipitate;

(d) suspending the washed precipitate in methanol containing about 1% (V/V) water to form a mixture;

(e) adding an acidic solution of a silane monomer to the mixture of step (d);

(f) homogenizing the resultant mixture of steps (d) and (e) at high speed;

(g) adding glycerol to the homogenized mixture of steps (d), (e), and (f);

(h) heating the resultant mixture of steps (d), (e), (f), and (g) to a temperature in the range from about 160.degree. C. to about 170.degree. C. to evaporate water and organic solvent and to polymerize the silane monomer such that the glycerol is not evaporated, and the resultant silane polymer becomes adsorptively or covalently bound to the precipitate; and

(i) washing glycerol from the silanized precipitate, which precipitate comprises magnetically responsive particles comprising superparamagnetic iron oxide cores generally surrounded by a coat of polymeric silane to which molecules can be covalently coupled, the iron oxide cores including a group of crystals of iron oxide, the particles individually having a mean diameter between about 0.1.mu. and about 1.5.mu. as measured by light scattering and a surface area as measured by nitrogen gas adsorption of at least about 100m.sup.2 /gm, a mass of the particles being dispersable in aqueous media to form an aqueous dispersion having (a) a fifty-percent-turbidity-decrease settling time of greater than about 1.5 hours in the absence of a magnetic field, and (b) a ninety-five-percent-turbidity-decrease separation time of less than about 10 minutes in the presence of a magnetic field, the magnetic field being applied to the aqueous dispersion by bringing a vessel containing a volume of the dispersion into contact with a pole face of a permanent magnet, the permanent magnet having a volume which is less than the volume of the aqueous dispersion in the vessel.

10. The process of claim 9 wherein the silane monomer is selected from the group consisting of p-aminophenyltrimethoxysilane, 3-aminopropyltrimethoxysilane N-2-aminoethyl-3-aminopropyltrimethoxysilane, n-dodecyltriethoxysilane, and n-hexyltrimethoxysilane.

11. The process of claims 1, 2 or 9 wherein the acidic solution of the silane monomer is an acidic aqueous solution.

12. The process of claim 1, 2 or 9 wherein the acidic solution of the silane monomer is an acidic organic solution.
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