METHOD FOR PRODUCING STABLE DISPERSIBLE MAGNETIC IRON OXIDE SINGLE-CORE NANOPARTICLES, STABLE DISPERSIBLE MAGNETIC IRON OXIDE SINGLE-CORE NANOPARTICLES AND USES OF SAME

Abstract

The present invention relates to magnetic single-core nanoparticles, in particular stable dispersible magnetic single-core nanoparticles (e.g. single-core magnetite nanoparticles) having a diameter between 20 and 200 nm in varied morphology, and the continuous aqueous synthesis thereof, in particular using micromixers. The method is simple, quick and cost-effective to perform and is carried out without organic solvents. The single-core nanoparticles produced by the method form stable dispersions in aqueous media, i.e. not having a tendency to assemble or aggregate. In addition, the method offers the possibility of producing anisotropic, super-paramagnetic, plate-shaped nanoparticles which, due to their shape anisotrophy, are extremely suitable for use in polymer matrices for magnet field-controlled release of active substances.

Claims

1-19. (canceled)

20. A method for continuous production of stably dispersible, magnetic, single-core nanoparticles, which comprise iron oxide and have a diameter between 20 and 200 nm, comprising the steps of: a) preparing an aqueous solution comprising at least one base and at least one oxidant; b) preparing an aqueous solution comprising at least one iron salt and another iron salt which is different from the at least one iron salt and in a lower concentration; c) preparing an aqueous solution comprising at least one hydrophilic stabiliser; d) mixing the aqueous solution of a) and b) to form a mixture in a micromixer, Fe(OH).sub.2 being formed, which precipitates out of the solution and oxidises to form magnetic single-core nanoparticles comprising iron oxide; e) mixing the mixture from d) with the aqueous solution from c), wherein the at least one hydrophilic stabiliser bonds to the iron oxide; wherein, in a) to e), the temperature is controlled from 10 C. to 200 C., and wherein the stably dispersible, magnetic, single-core nanoparticles are produced.

21. The method according to claim 20, wherein, in step d), optionally also in step e), mixing takes place with a micromixer according to DIN EN ISO 10991:2010-03.

22. The method according to claim 20, wherein the micromixer comprises a multilamination micromixer, split-and-recombine micromixer and/or an impinging jet micromixer, the micromixer, optionally following the mixing region or mixing chamber, having an essentially non-tapering and/or essentially straight exit without abrupt change in direction and/or tapering in cross-section of fluid flow.

23. The method according to claim 20, wherein the hydrophilic stabiliser has at least one radical which bonds to the iron oxide.

24. The method according to claim 23, the radical or radicals link to the hydrophilic polymer.

25. The method according to claim 24, wherein the radical or radicals are selected from the group consisting of phenol radical, PO.sub.3 radical, histidine radical and sugar radical.

26. The method according to claim 25, wherein the stabiliser comprises a substance selected from the group consisting of: a) glycosidic flavonoids; b) phenols; c) phosphoric acid derivatives; d) triphosphate; e) polymers with more than 3 histidine radicals; f) hydrophilic polymers; and g) carboxylic acid or carboxylic anhydride.

27. The method according to claim 20, wherein the radical comprises a glycosidic flavonoid crosslinked covalently with a hydrophilic polymer.

28. The method according to claim 20, wherein, in a further step, the surface of the stabilised, magnetic, single-core nanoparticles is modified, wherein the modifier comprising a substance selected from the group consisting of: a) inorganic phosphates; b) hard materials; and c) PEG-silane, polylactide, polyvinylpyrrolidone, polyglycolide, or polycaprolactone, or a combination thereof.

29. The method according to claim 20, wherein the aqueous solution in any of a), b), and c) is prepared in demineralised and/or degassed water which has less than 50% of the oxygen dissolved in equilibrium at 20 C. and at atmospheric pressure.

30. The method according to claim 20, wherein incubation takes place before or after addition of the stabiliser for a time period of 1 sec. to 24 h in a temperature-controlled dwell loop.

31. The method according to claim 20, wherein, in a further step, the surface of the stabilised, magnetic, single-core nanoparticles is modified by a modifier comprising a substance selected from the group consisting of: a) inorganic oxides; b) inorganic phosphates; c) hard materials; d) organic polymers; and e) inorganic polymers.

32. The method according to claim 20, wherein the concentration a) of the base is 10 mM to 5 M; b) of the oxidant is 10 mM to 5 M; c) of the at least one iron salt is 10 mM to 5 M; and/or d) of the stabiliser is 1 mM to 5 M.

33. The method according to claim 20, wherein the molar concentration ratio a) of Fe.sup.2+ ions to OH.sup. ions is 4:1 to 1:8; b) of NO.sub.3.sup. ions to Fe.sup.2+ ions is 20:1 to 1:4; and/or c) of NO.sub.3.sup. ions to OH.sup. ions is 1:5 to 10:1.

34. The method according to claim 20, wherein the base comprises an alkali hydroxide and/or ammonium hydroxide.

35. The method according to claim 20, wherein the oxidant comprises a nitrate salt and/or HNO.sub.3, but not Fe(III) ions.

36. The method according to claim 20, wherein the at least one iron salt comprises an Fe(II) halogenide and/or Fe(II) sulphate.

37. The method according to claim 20, wherein the single-core nanoparticles are purified in a further step after step e).

38. A magnetic, single-core nanoparticles with a diameter between 20 and 200 nm, comprising iron oxide and at least one stabiliser, produced by the method according to claim 20.

39. The magnetic, single-core nanoparticles according to claim 38, wherein the single-core nanoparticles have the shape of a plate with a thickness of 2 to 20 nm.

Description

[0072] The subject according to the invention is intended to be explained in more detail with reference to the following Figures and examples, without wishing to restrict said subject to the specific embodiments illustrated here.

[0073] FIG. 1 shows a schematic representation of a method according to the invention. A first aqueous solution BO comprising a base and an oxidant is pumped via the pump A at a speed of 7 to 10 ml/min to the first micromixer M1. There, the first aqueous solution BO impinges on the second aqueous solution F which comprises at least one Fe(II) salt and, via the pump B at a speed of 1 to 1.5 ml/min, is pumped into the micromixer M1. In the micromixer M1, the first and second aqueous solution BO, F are mixed and the mixture is pumped into a temperature-controlled dwell loop V which has an inner diameter of approx. 0.5 mm-1.6 mm and a specific, predefined length. The length of the dwell loop V establishes the incubation time before the mixture is contacted with an aqueous solution comprising stabiliser. If plate-shaped nanoparticles are to be produced, the length of the dwell loop V is short (e.g. 2 m=>short incubation duration). If spherical nanoparticles are to be produced, the length of the dwell loop V is long (e.g. 50 m=>long incubation duration). After passing through the dwell loop, the mixture is guided into the micromixer M2. There the mixture impinges on the aqueous solution S comprising at least one stabiliser which is pumped into the micromixer M2 via the pump C at a speed of 2 to 3 ml/min. In the micromixer M2, hydrophilically-stabilised, iron oxide, single-core nanoparticles according to the invention which are further purified via an ultrafiltration module U are produced. Excess educts E (salts and excess stabiliser) are hence separated from the product EP (single-core nanoparticles).

[0074] FIG. 2 shows a TEM picture of nanoparticles produced according to the invention. In FIG. 2A, plate-shaped nanoparticles (diameter approx. 30 nm, thickness approx. 3 nm) are illustrated, which were produced with the help of a short dwell loop. FIG. 2B shows spherical to cuboid nanoparticles (diameter approx. 80 nm) which were produced with the help of a long dwell loop.

[0075] FIG. 3 shows a cryo-TEM picture of plate-shaped nanoparticles according to the invention. Tilting of the sample from FIG. 3B by 30 relative to the sample from FIG. 3A verifies the disc character of the nanoparticles (see the two single-core nanoparticles marked with arrows).

EXAMPLE 1PRODUCTION OF MAGNETIC, IRON OXIDE, SINGLE-CORE NANOPARTICLES IN DISC FORM

[0076] Starting solution BO: 60 mM NaOH, 54 mM NaNO.sub.3 in degassed and demineralised water; [0077] Starting solution F: 0.1 M FeCl.sub.2 in degassed water; [0078] Stabiliser solution S: 20 mM rutin hydrate in 60 mM NaOH.

[0079] All reaction solutions were preheated to 60 C., the reaction was effected at 60 C.

[0080] Pump A was operated with 10 ml/min, pump B with 1.5 ml/min and pump C with 3 ml/min. The dwell loop with inner diameter 0.5 mm was 2 m long. A micromixer was used which had the designation CPMM R300x12-SO made of polyetheretherketone. The disc-shaped single-core nanoparticles produced with this method are illustrated in FIG. 2A.

[0081] Particular features of these disc-shaped, magnetic particles are, in addition to the shape anisotropy, which enables magnetic switching, also the particular magnetic properties thereof, which is predestined in particular for use in (medical) imaging. Thus these particles have, for their potential application in magnetic particle imaging, as can be proved (measurement in a magnetic particle spectrometer), comparably good signal behaviour to the samples, used at present as gold standard with Resovist (Resovist comprises ferucarbotran, i.e. a colloidal, aqueous suspension of super-paramagnetic, iron oxide particles [mixture of magnetite Fe.sub.3O.sub.4 and maghemite -Fe.sub.2O.sub.3], which are covered with carboxydextran).

EXAMPLE 2PRODUCTION OF SINGLE-CORE NANOPARTICLES IN ESSENTIALLY SPHERICAL FORM OR CUBOID FORM

[0082] Starting solution BO: 60 mM NaOH, 54 mM NaNO.sub.3 in degassed water; [0083] Starting solution F: 0.1 M FeCl.sub.2 in degassed water; [0084] Stabiliser solution S: 20 mM rutin hydrate in 60 mM NaOH.

[0085] All reaction solutions were preheated to 60 C., the reaction was effected at 60 C.

[0086] Pump A was operated with 7 ml/min, pump B with 1.05 ml/min and pump C with 2.1 ml/min. The dwell loop with inner diameter 1/16 was 50 m long in this example. A micromixer was used with the designation CPMM R300x12-SO made of polyetheretherketone. The cuboid single-core nanoparticles with this method are illustrated in FIG. 2B.