WO2002009125A1

WO2002009125A1 - Spherical, magnetic sio2 particles with an adjustable particle and pore size and an adjustable magnetic content, method for producing them and use of sio2 particles of this type

Info

Publication number: WO2002009125A1
Application number: PCT/EP2001/008392
Authority: WO
Inventors: Detlef Müller-Schulte; Rainer Fischer
Original assignee: Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
Priority date: 2000-07-21
Filing date: 2001-07-20
Publication date: 2002-01-31
Also published as: AU2001279770A1; DE10035953A1

Abstract

The invention relates to a method for producing magnetic SiO2 particles, comprising the following steps: a) alkoxysilanes are dispersed in water, acid-catalytically hydrolyzed and condensed to form an SiO2 hydrosol; b) a magnetic particle-sol mixture is produced by adding magnetic particles, for example usual magnetic particles, magnetic colloids and/or ferrofluids to the SiO2 hydrosol; c) dispersing the magnetic particle-sol mixture in an organic solvent which is immiscible with water; and d) adding a base to the magnetic particle-sol mixture during or after the dispersion in the organic solvent in order to form a gel.

Description

Spherical, magnetic SiQ _g particles with adjustable particle and pore size and adjustable magnetic content, process for their production and use of such SiQ ₂ particles

The present invention relates to magnetic Si0 ₂ particles with adjustable pore and particle size and adjustable magnetic content, a process for their preparation and their use. Such Si0 ₂ particles are used in particular in the field of purification and analysis, in particular of biomolecules and as a carrier for biocatalysts, for example in the field of biotechnology, as an adsorber, for example in the field of medicine or as a stimulus-response gel.

Si0 ₂ gels of various origins have long been known as chromatography media, but their use specifically for nucleic acid purification was only recognized and in the early eighties DE 32 11 309 AI described. The particles listed there are pure Si0 ₂ gels, which are used exclusively in acid chromatography.

Silanized iron oxide particles for the immobilization of enzymes are known from US 4,152,210 A. Also for the purpose of enzyme immobilization, US 4,343,901 describes ferromagnetic particles which are produced by a sol-gel technique.

PCT EP97 / 04828 describes 50-150 nm large monodisperse magnetic particles which consist of an SiO ₂ core which receives magnetic properties by coating with iron oxide. Subsequent silanization of the iron oxide layer enables the particles to bind nucleic acids. ^■

Magnetic Si0 hybrid paste particles, consisting of a polystyrene core onto which magnetite and subsequently an Si0 ₂ layer are polymerized, are known from PCT / US 95/12988. The particles are used for antibody and cell separation.

Iron oxide particles coated with colloidal SiO ₂ are disclosed in US Pat. No. 4,280,918 A.

Goetz et al. (Biotechn. & Bioengineering, Vol. 37, 614, 1991) describe 20 to 100 μm large magnetic SiO ₂ gel particles capable of enzyme immobilization, which are generated by electrostatic coating of nickel powders with SiO ₂ sols. In a similar way, Homola and Lorenz (IEEE Transaction on Magnetics, Vol. 22, 716, 1986) described electrostatic coating of SiO _P particles on Fe ₂ 0 ₃ particles for the production of magnetic storage media. ben.

Colloidal metal particles for use in immunoassay are described in the application PCT / US97 / 03886.

US Pat. No. 5,320,944 A discloses 0.2-3 .mu.m magnetic particles which obtain magnetic properties by coating a polymer particle with iron oxides. By further coating the particles with silanes, nylon or polystyrene, antibodies can then be coupled to the particles for use in the immunoassay. WO 99/13993 discloses the production of an optical sensor in the form of a glass or transparent polymer support on which noble metal colloids are applied to improve the binding of the effector molecules for use in immunoassays.

The synthesis of silica gels for gel permeation chromatography, which are grafted with cerium (IV) initiation with vinyl monomers in order to suppress non-specific protein adsorption, is known from PCT / EP94 / 01378.

Organosilanized colloidal Si0 ₂ gel particles as biological separating media are disclosed 4,927,749 A and US 4,927,750 A and WO 99/36359 in the ^'US, wherein the stability of the colloids, and manner of silanization in the foreground, magnetic particles contain a magnetic core material and are coated with an inorganic oxide are disclosed in EP 0 343 934 AI. Polymer particles which are coated with a further polymer layer containing a magnetic material, on which a third layer for interaction ω co t P »

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closing silanization can come into direct contact with the analyte solution. This poses a serious problem in nucleic acid analysis e.g. in the context of the polymerase chain reaction ("PCR"), since the polymerases used in the PCR can be deactivated in contact with iron compounds. In the case of the magnetic particles known from the prior art, furthermore, no special procedural measures are specified which lead to a targeted setting of the pore size, a parameter which has a decisive influence on the efficiency of the purification of nucleic acid.

The methods known from the prior art for producing the magnetic particles are fundamentally very complex and require a manufacturing process that takes several hours.

Starting from this prior art, it is an object of the present invention to provide magnetic SiO ₂ particles, processes for their production and use of such particles, in which no labor-intensive and time-consuming coating techniques are required and the particle size, pore large and the magnetic portion can be set in a targeted manner.

This object is achieved by the method for producing magnetic Si0 ₂ particles according to claim 1, particles according to claim 68 or 69 and by the use according to claim 74. Advantageous developments of the method according to the invention and of the particles according to the invention are given in the respective dependent claims.

The starting point of the invention are prepolymers in the form of Si0 ₂ hydrosols, which are mixed with magnetic colloids or magnetic particles and then polycondensed into spherical polymer particles in the heterogeneous phase.

Magnetic particles in the sense of the present invention are understood here to mean conventional magnetic particles, magnetic colloids and / or ferrofluids, with “colloids * or“ ferrofluids * by definition all magnetic nanoparticles which, either with or without the addition of a stabilizer, surfactant or emulsifier, form a stable aqueous form colloidal dispersion.

The Si0 ₂ sols are produced by the known sol-gel processes by hydrolysis of alkoxysilanes with the aid of dilute mineral acids or organic-based acids. Hydrochloric acid or carboxylic acids such as acetic acid, iron acid or propionic acid are used as mineral acids. To obtain the Si0 ₂ sols, the alkoxysilanes are dispersed in water and hydrolyzed by adding acid. Silicic acid orthoesters of aliphatic alcohols can be used as alkoxysilanes, preferably methyl, ethyl or propyl esters being used individually or as mixtures. As a result, condensation to low-polymer Si0 ₂ hydrosols takes place, which gradually lead to more or less viscous sols or gels through further polycondensation. This sol-gel process is generally carried out at lower temperatures, preferably with ice cooling. In order to better mix the heterogeneous silane-water phase, the reaction is carried out in an ultrasonic bath or with the aid of an ultrasonic sonotrode. Depending on the composition, sonication times of 5 to 30 minutes are sufficient, with the Cd ω b ρ> cπ o cπ o cπ o cπ

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Λ ⁴ Φ Φ P ⁴ P P- .J Λ • 03 P li Φ P ¹ li Φ <! H> P φ φ 1 φ 01

0 P cn ro P o P »n J P & P- P p- (0 cn P P p-

HP CΛ Φ O CΛ P ⁴ <t? J P- d PJ uq 03 P- P φ N 1 Ω • ^' Hi S P- H Ω o O Φ Φ p H sq φ P d ι-i Λ ⁴ PJ d P ⁴ od = Φ g 1 TJ H 1 PJ PJ 01 ιΩ 03 O: O tP d

P- l-i H "H 1 01 φ 1 1 P P-

1 1 1 3 1 1 01 a P

b) formation of defined polymer droplets in the

Disperse in suitable organic solvents.

As soon as the silane suspension is homogenized by hydrolysis in the first production step, the sol can be used for further particle production. However, immediate use of the brine is not absolutely necessary, since the brine, depending on the acid concentration and sol preparation, maintain a fluid consistency over several days and can still be processed after days.

In the second process step, a magnetic colloid or ferrofluid is added to the sol. By definition, “colloids” or “ferrofluids” include all magnetic nanoparticles which form a stable aqueous-colloidal dispersion either with or without the addition of a stabilizer, surfactant or emulsifier. Magnetic and transition metal oxides, ferrites or other nanoparticulate compounds which are either ferro-, ferri- or superparamagnetic in nature are suitable as magnetic nanoparticles. The production of such colloids or ferrofluids is described in manifold ways in: US 4,628,037; BR 1 439 031, EP 0275 285 AI, US 3,917,538 A; US 4,827,945 A; US 4,329,241 A.

The main criterion for the selection of suitable colloids or ferrofluids is their compatibility with the Si0 ₂ sol, ie the colloid must not flocculate or agglomerate in contact with the sol phase. Ferrofluids that enter into a homogeneous dispersion with the sols are those that contain either charged surfactants, for example in the form of aromatic or aliphatic sulfides. co co cπ O Cπ o cπ Cn

P ¹ TJ H aa P ¹ $, a H d H ¹ a HN CΛ φ 03 Φ P- <! S rt 3 tr Hi IS! P ⁴ Hi

• o Φ O d Φ Φ φ Φ Φ OP p: Φ P "s: P = P- Φ P o Φ P- P φ H Φ P" d P ¹ p- po tr <l H Hi & o li 03 P- 03 Hi uq d 01 Φ P- d P • rt P- ι-i Ω P- P. H ^ p: 01 rt Ω HP d P- H Φ lΩ. P rt P ^J Φ Hi W 03 H Φ £ a Ξ H << 03 HP Ω P Φ P ⁴ rt 03 p P p N d H, Φ - d iQ ι-id P ⁴ rt a rt Ω Φ tu φ Φ φ O 03 - PP ⁴ rt ι-i Φ p:

P- • <Φ d P- s, P 03 Φ φ P- P- P ii P ⁴ 3 Φ a P tr P- 1 P Φ NPP d

PH P. H aao PP ⁴ rt a P aa O φ _^ - »P- P- Φ P- a P- 03 Dd CΛ rt PP • H

PP ⁴ Φ PP a Φ Φ a P- d 3 P tr rt H 01 Φ o ι-i P φ P <rt Φ o P ¹ d: HHP Φ PPH Φ Φ ι-i P Φ a rt rt • P ¹ P Λ ⁴ o P- CΛ aa Λ ⁴ P- ω φ a 3 aa Φ li Ω uq a <! Ül Φ 3 • • <N rt P o φ

Φ OP "P P- <! PP P- rt rt c- P ⁴ P Φ o rt P P- a O TJ r_ P- HH

HP ⁴ Φ w P Φ 03 s Φ φ φ tr Φ P tl P rt P- t? D tu PO: pi: <H3 P 'Ω P- o P a H s: PPHP a Φ Φ rt NP ⁴ S rt φ P P rt 03 P "Φ φ PP ⁴ <l

> M N TJ t, Φ «uq rt rt a H H Φ J d P Φ rt o Cπ Φ d P" P P 01 Φ P

P ¹ • 03 ιΩ Φ H o P Hi φ P- H 03 NP o uq ≤ uq P »01 03 rt PP d 03 01 rt uq öd φ HP a P- * Φ Φ P Φ Ω Ω Φ P" rt o P 01 o Ω Φ rt uq P CΛ P- φ h Φ

P- ö • da Φ rt ι-i P> P ⁴ P ⁴ d tr φ φ φ HP ⁴ Ω OΛ Φ uq da PP "

P φ d P d P o Hi P «rt d: lΩ. Φ PH rt a uq Φ P ⁴ P "P> P 03 tr Φ d 0

P P- P a P • P- Φ rt o 03 rt Hi Φ O Φ Hi P- P Ji><i 03 P 03 P- a et rr P uq 03 uq a - • * Ξ s: 03 Φ P- φ ö TJ H p: a • co φ rt * • P- a φ li p: a Ξ h- ¹ P- pj: P- PP P- da P ⁴ P- Φ P> s: HP Ω Φ h

<1 P] <rt aa Φ o HP ⁴ uq a P ι-i P- Φ S rt P <£> U3 P- Hi PHP ⁴

Φ P o φ N Φ P tr H P- a H φ W Φ Φ Ω Ω ι-i P P- a <s £) φ P tsi 3 03 P

HH li H ¹ HPN aa Φ o rt 03 t P ⁴ Φ uq uq o P »OP ⁴ φ d P P- P ¹

Hi 3 ≤ P- P Ξ Φ 03 P CΛ Ω p rt 03 P φ tr P ¹ ~ -— CO d HPP "d. P P-

PS TJ m Ω O »P σ a PP ⁴ 03 Φ uq φ φ Φ» • Φ uq Ω a TJ uq o <1 PP ⁴ tr a Λ ¹ d H uq P ⁴ rt 03 Φ rt P- o P ¹ PJ PP ⁴ PP ⁴ P ⁴ φ M o P- d

& g O: H a N H P- P 03 TJ s: O P a * - "• Φ rt P P

P "PP uq H 3 P Ω PP ¹ PP p, Φ P P- TJ rt a P ¹ Φ ^ PKO 3 d rt

PP d Φ Ω 03 PPP ⁴ 03 O: aa "H Ω HP ⁴ Hi Φ ii <! D 03 ι-i P Ω P-

Ω J ι-i Ω PP ⁴ Ω Ω φ 03 P- d Φ a φ Φ H CΛ O oi rt φ uq P ⁴ 03

CΛ P o P ⁴ P ⁴ P ⁴ P 3 wd φ HPO rt HH ID «P ⁴ P Φ PP Ω

OO «Φ P Φ o PP Ω Φ a Φ PC VO o P- Pd Φ; * r P ⁴

H • a 03 o P- P ¹ tu HP ⁴ ι rt P ⁴ TJ J-> P 03 d »PP ^ p- o rt o Φ

Ω Φ <i P- OP ¹ P rt φ φ li P * Φ Φ 1 Ω 03 φ PP af P ⁴ 03 φ a P- 3

P ⁴ P- P- φ P <Hi Φ P 03 3 oa 3 uq Ü P ¹ P ⁴ uq rt P> o PP φ P Φ 01 pn φ PP Ω o PPP rt P P- dp φ 3 o H TJ OP ⁴ \ Ω P- P • H Ω Φ P s ^• <d: P ⁴ P- Ω da HPP o O aa Φ U> Φ PP ⁴ HP tr φ a P ⁴ a 03 P- P- Ω uq Φ P p 3 P ⁴ Φ Φ cn Ji> rt φ Hi H σ 01 Φ N tr

PJP Φ Φ φ Φ P Ω uq tr P ⁴ P P- φ p P TJ π H Φ ^• - rt PHP o P- o uq o Ω H s 03 PP ⁴ φ N Φ rt P -— rt HPP ¹ NP «Φ P

PP "Φ P tr w tr Φ 03 sa rt Φ rt 's OO a * la tr P ¹ PP" 1 d 03 o 01 φ << rt Φ uq tsi P ¹ s • P- H) rt l ιΩ Λ S! Φ φ • and P- Φ • P "P d rt P" P "p: rt 03 P P- P. D P Φ C a P d H φ φ 03 • P s: P- d

TJ rt rt P φ • rt uq PP ^ 1 P ¹ o P- P Ω 3 03 Ω _^ - _^ da Φ uq o Φ li

P • <φ rt P- P a 01 φ co a> a φ TJ rt P ⁴ a Φ P ⁴ • _^ -. P P. Φ P- P Φ p, H TJ ^ o Φ Φ N Ω P p: Φ d Φ P ⁴ P- li H TJ Cd a Pd a P a P ⁴ P rt 0 TJ Hi CD P rt h CD p ⁴ 1 c Ul Hi n Cfl P- D. o 0 H- J H- P- ro CD pj:

P- P ¹ O Φ KK Hi Φ P ¹ uq P- 01 d P- P «φ P" O Sö 03 POH φ

W 1 01 rt 1 Ξ Φ CΛ P φ H Ω Ω HP φ o tr • Ω Φ Φ tr o rt P φ rt P- P- P "pj: d P ⁴ P ⁴ Ω P ¹ P Φ P P- P a Φ P ⁴ 1 rt

P- ¹ Φ 1 φ 1 d P Φ P ⁴ • 1 P 1 1 P- HP 1

1 1 a 1 Φ 1 φ

which generally have a particle size of 0.05 to 3 μm and are used in the field of biomolecule purification are known from the prior art: PCT / EP96 / 02398, J. Appl. Polymer Sci., Vol 50, 765, (1993) / Anal. Biochem., Vol 128, 342, 1983,

US 4,654,267 A; J. Cell Sei., Vol 56, 157, 1982; Proc. Natl. Acad. Sci., Vol. 78, 579, 1981, DE 35 08 000 AI; Magnetic particles of this type are also commercially offered under the name Dyna-beads, BioMag, Estapor, M-PVA, AGOWA, BioBeads or SPHERO. are registered trademarks.

These magnetic particles are used in an analogous manner to the colloids or ferrofluids for the production of the Si0 ₂ particles according to the invention.

The magnetic-colloid-sol mixture is dispersed in an organic solvent with stirring in the subsequent step. Suitable dispersants are solvents which are immiscible with water and which form either emulsions or dispersions. It has surprisingly been found that, above all, organic solvents lead to a stable dispersion which have a distribution coefficient of> 2. According to Laane et al. (in "Biocatalysis in Organic Media", Laane et al. Ed., Elsevier, Amsterdam, pp 65, 1987) the logarithm of the distribution coefficient is defined in a standard octanol-water two-phase system. Solvents that fulfill these properties are, for example, chloroform, trichlorethylene, 1.1.1-trichloroethane, hexane, petroleum ether, toluene, carbon tetrachloride, heptane, octane. Mixtures of the above solvents, which have a density of approx. 1 g / cm ³ . o ω to P ¹ P>

Cπ o cπ o cπ o cπ

founded. The low viscosity enables the synthesized magnetic particles to be separated from the reaction mixture within a few seconds using a commercially available hand magnet. This separation step, however, takes up to a few hours when using vegetable oils, followed by extensive washing processes with organic solvents, which are necessary to remove the residual oil from the magnetic particles. In the present process, however, the solvents used can be easily recovered by redistillation. The volume ratios of organic phase to hydrosol are generally 8: 1 to 30: 1 and 2: 1 to 4: 1 in relation to the volume ratio of sol to magnetic colloid. The weight percentage of the magnetic

Solids in the sol approach is between 10-55%. The possibility of the simple and targeted adjustment of the magnetic portion by simply adding the magnetic colloid, which distinguishes this method from the prior art, opens up a wide range of applications, which is the mere separation of biomolecules and nucleic acids or biomolecule analysis, as in W098 / 12712 ; DE 32 11 309 AI; US 5,320,944 A; U.S. 4,927,749 A; US 4,927,750 A; WO 99/36359, PCT / FR97 / 00912, goes far. This applies, for example, to the use of the magnetic particles as biocatalysts in biotechnological fermentation processes, as a protein encapsulation matrix, as a "stimulus-response" gel or as an adsorber in hemoperfusion. These additional applications result from the fact that with the aid of the methods and products according to the invention, biomolecules such as enzymes or proteins are both encapsulated in the sol-gel matrix by simple admixing to the sol approach and also via active groups, as will be explained below the Si0 ₂ carrier can be covalently coupled. co ω t P ¹ cπ o tπ o Cn Cπ

03 t IV 01 tr. , z T 03 rV tsi Ω IV P l-i φ a ü tr <Φ o uq öd N l_l. Ω IV N 03 Hi N

Ω Φ φ Ω P- N ii dp: Φ cd OO: P "O P- Φ P Φ o P- Φ P d φ P ⁴ dd Ω P- d

P ⁴ PP ⁴ P ⁴ 03 • ι-i P rt P- p ö 03 H) PH P- P σ 03 03 uq Φ P uq P ⁴ PH s: ii z öd IV IV NP ύP p P ¹ 03 rt ad φ Cπ φ φ 01 P ⁴ P a Φ li P-

P- N rt P- N • N rt a H ¹ Φ ö H Φ d Ω P- P ¹ pt rt PZ, O: 01 Φ 01 P- φ Td

P z Φ P d Φ P- P- P- ü d P- P- P- P ⁴ a φ • • Φ tr IS Φ P ⁴ • P φ rt ii P- a P- ad O φ Ω P ¹ ι- i Ω P a H Φ to PP »P- rt P- Φ rt rt rt X

P- 03 TJ P- to H uq PP ⁴ φ Ω P ⁴ φ 03 P- u cπ <i 03 s: 01 H ö NN Φ P- uq Ω P uq o rt φ Φ tu P- ϊ Φ H Φ Φ tr Φ tr Ξ P- φ φ d rt ZP φ

IV P ⁴ o IV ι-i P φ a P tr Go m P "P- td P- o φ φ a P = ii

Φ φ TJ φ o PH P- tr P- CΛ NP "Φ P- 03 P ⁴ 03 * _* li z. P- Φ P ⁴ S d

P- P o P- o 1 a _^ ~. 01 φ Φ 03 <! rt Ξ P- p, Φ p: a N P- CD Q P- ö HPP rt H rt o 1 "3 P- Λ rt 03 Ω Φ d Ω 01 HP ¹ HP ¹ Φ • P Φ P P- Φ uq uq

Φ ro rt d Φ P ¹ Φ uq OP ⁴ ii PP ⁴ rt d .. rt t 3 P öd a uq P "Φ φ PP

P o P- d H op: P φ Hi a W Φ PPO • • φ tr 3 01 a φ ao P ^• . HPP a PP Φ O a P ¹ uq • P- dp P- "PZ P- φ rt φ

P- d P a 3 PP ^• pd uq Φ P ⁴ • P ¹ Φ P ¹ 01 03 P- P Ö ≥; P "p: Hi a TJ P

3 PP P- X Ω p P P- li a ii Pi d ι-i 01 uq H p- P 01 P ⁴ a Φ öd Φ P a M ι-3 P © P ⁴ * - * uq uq Φ Φ Φ α OP φ Φ φ Φ Φ o P "d 01 P oi H 3 öd P- Φ Φ 03 PP P- co uq PP tu d rt P rt 01 rt P

Φ cπ rt P- φ a 01 tr P öd 03 a> 03 rV o tr ¹ ≥; P Φ uq Φ φ Ü P- uq

H o: P "H Φ P- φ Φ CΛ Φ cn P TJ rt P s: O: P 01 cn P P d IV P

Φ o rt Ω Hi 3 3 P 03 J 01 o P- tr rt ι-i P- 03 p: 03 rt φ Öd TJ N ι-i Φ Φ p- P ⁴ O P- a O d Ω P Φ Φ P ⁴ OO Φ tP d HO: P ii O d Ω rt

Ω a Φ P rt TPP ⁴ P ⁴ 1 φ a P- Φ NPHPOP t? 03 O Φ uq t P P-

P ⁴ 3 Φ P ao P ⁴ a ii ii Ir ¹ Φ P 03 Φ N P- uq PP g Φ NP ¹ P 3 cn

H uq Φ Φ rt P Φ uq p: O: tSJ d Φ φ tP 03 d uq P "Φ P P Φ tr tr P-

P uq ι-i H P- o P H φ P fl φ rt P Φ φ P P o IV S> P- Φ 03 z Ω

P- P ⁴

OP "φ O: MPP a 03 ι-i V Φ P- Φ a Hi P ⁴ CΛ P fe * d POP ¹ Ω H Φ

PM cn öo P- Φ 1 Φ p: d 3 rt rt rjd: HO g uq uq P- P P- a Hi P ⁴ a P uq rt φ Ω CΛ P "Hi rt P P- Φ Φ 03 PP ¹ Ir ¹ P Φ PPN 03 dd: d

00 φ PP ⁴ rt 01 Φ Φ uq rt ι-i uq P- li O: O d IV Φ rt PP ⁴ P P- CΛ o 3 P ¹ tr P d: P- φ rt 03 Φ rt CΛ a PP ¹ 03 P 2 PP uq li uq 3 P- o Φ rt Φ 9 rt r P <! P Φ TJ uq PO P- 01 P- d P- P- a <! rt a rt 03 o

1 P- 03 N ao P ¹ Φ φ H "P Φ d P" Φ Ω φ PPH 03 φ p. P a <J

P> P rt ZHH P- li ii 1 HP Hl 03 P ⁴ uq uq ^ ap: HP tr Φ P- o Φ 1 oo a φ P- Φ 1 Ω z φ r? P d: t, öd φ rt rt Φ 03 P P. rt σ oa PP ⁴ 03 P ⁴ JP ⁴ TJ Φ 01 P- tr P d PPP <! a P- N z φ P- P- P uq ISI P- or tP rt Ω d ld Φ PP 03 03 φ PP 03 tr φ d PP ¹ PO TJ φ P rt 03 ι- (P ⁴ P P- P, a IV PH aa P- P "ι-i li P- a P do tS P Φ TJ c ⁴ Ω Pl Φ Φ uq P σ rt Φ 0: rt <01 p: s: Ω a Ω Φ HP ⁴ uq P Φ

P ⁴ Φ P- P 03 N P- P- rt PNOP <a TJ d P * Φ P ⁴ Φ P ⁴ rt P- P 03 left

3 P- P P- oi IV P Φ P P "O Φ P Hl P- P s: H •> 03 01 p P" 01

P- TJ P ¹ Φ TJ Φ J TJ φ z φ 03 <P 03 ii rt Ω a P rt o φ tr φ Φ p-

P d: Ω d = P- φ φ P σt φ rt P "Φ uq J d P • H P- H o

P ⁴ P ⁴ d P ⁴ 03 P ii 1 ii uq o P s: τι P- φ rt Φ Ω P IV rt <! P Hi P

Φ li φ p li rt ii uq a uq P- Φ Φ Φ H • P- uq P ⁴ a <! d = ι-io φ P

Hi uq P uq uq d tr P- Φ H tr tr P ⁴ P ü ro li t P CD ro 0 H 0: PP ⁴

N φ uq Φ Φ P Φ φ P d rt P- φ μ- 1 H Hl Φ α Φ ι-f H N TJ öd P> d

Φ 1 H 1 1 uq P- ii • P 03 H uq O P- P- ^ l P- ro 1 Φ Hi CΛ P Φ d O: rt l φ H 03 Φ OPPH 1 Φ 03 P a uq 1 φ a Φ 1

1 03 ι-i 1 Φ H 1 1 Φ 03 Φ rt P 3 03 1 1

co co b to ρ> p »Cπ o Cn O Cπ o π

a 03 P α 53 03 TJ N 03 a rt a N TJ rt σ <! P P- öd a tr H IV uq 3 a P Φ J cn

P- z

Ω P- P- P- d P d Ω P- p- Φ P- ¹ • P Pd o Φ PP Φ d: Φ Φ O: Φ P- Φ Φ H d = Ω φ φ P ⁴ Ω Φ rt HPP ⁴ φ p:> öd P- ^ li P 03 03 f H? v P- PH rt

• P 03 NP ⁴ P ⁴ n li P ⁴ ι-i Hi rt uq Φ ι-i P Ω rt o HP tr P- PPP Φ HZ a

CΛ p: rt Ω P- P P- H CΛ Φ d P- P- P ¹ to P d Φ 03 J a P P- φ Z> tu d <! P- Φ

P- PP ⁴ M rt IV a • <li IV a co IV p: uq 03 cn ii P- P uq P φ H Ό P uq OPP o IV P Φ o φ Φ φ 03 P * 1 φ & o P> φ rt o PP φ rt d H IV P- P rt ro H a rt

1 d 3 rt PP ¹ HO rt O Φ P- ¹ QP ¹ rt P ¹

• P P P * X Φ P

Hi P- a a O φ Φ uq P- d

HZP ⁴ aoo P ¹ φ

PJ ada 01 P- CΛ P uq P- P ⁴ 03 & PP uq P

03 P- tr H 3 tr P- Φ Φ TJ X • <3 ω ω 01 Φ 03 φ Φ P o Φ P P tv

PH a P = a Ω Φ N P- Φ φ 01 HP ⁴ Ω P- P- o uq Ω HP TJ

% S <H 3 uq S uq Φ

P- uq PP ⁴ ω z rt 03 Φ P- P- rt Ω o Φ P ⁴ Φ d = PP Φ o uq d: PP P- P3

Φ Φ 03 • Ω <! 03 H a P ⁴ φ Φ rt P-

Φ n rt P φ tr d TJ φ uq

Φ P- P "a rt Φ li t P ⁴ O 03 Φ φ o • <Pd d P- H s N Ω PP ⁴ ZPP rt PP φ P-

P- tu s uq fe ¹ P- ti P rt IV TJ P ¹ J a P uq - - φ P ¹ V rt o ≥! o P- ao Φ φ d PP ¹

3 P Φ o 03 p P- P d O: * o O d a P a P- rt P- a d P Ω N P rt φ Ω

P- φ li ap: p- Hi Φ S ι-i P h P "XX P. φ Hi P- Ω o Φ ^ PP ⁴ sa Φ TJ H <l P ⁴ rt H 01 P- d P Φ tr φ fa Hi 3 ^ 3 ^» Ω ö rt d: φ P ⁴ PPPP ¹ φ Φ P tP PP rt o Φ rt Hi ι-io Φ rt p: P φ 1 P ⁴ Pd i P d φ P p, 03 d HPP tr Φ P- CD 1 <! PP d li d rt H 03 03 φ p><uq P- φ z 03 03 03 rt P-

03 Φ HN 03 o Φ P ¹ P φ PP ⁴ O d Ω o P- a 3 P o Φ PP φ Φ Ω μ- P Cπ P-

03 P ¹ P- or PP p ^j a li uq> TJ tr P ⁴ -JP P- p- Z ι-3 PP 01 P- 11 P ⁴ a IV o 3 od Φ a tr Ω P ¹ • <03 φ a φ rt P- P dp: CΛ 03 Φ Φ ao rt PP li Φ 03 o Pd P ⁴ 03> aa P ¹ rt 3 P ¹ φ p: iz; rt d P- Φ P P- PP ¹ Φ o öd

P- a uq d ι-i rt P TJ Φ Ω P ¹ Φ P- rt P- P- -J ≥! IV 01 uq d N n OP Φ H 1 Φ rt Φ P P- li o P ⁴ IV 03 p: p, rt 03 3 d P φ Φ IV rt φ P- • ΪP CΛ IV t ii d P. uq rt tr XP s: << rt P- d Ω IO H IV rt PH, P ¹ P 1 P Φ d O: J o φ

Φ o 3 do * <rt PP "o P ⁴ 3 P- P ⁴ op: P- 3 Φ Z TJ α P 03 P Φ • P-

P- PP a P- P- P 1 1 Ω PX o φ Φ φ <£> uq φ o φ P- φ o PS! P- TJ P uq φ o Ω φ li P φ oi 03 ι-3 P ⁴ 3 P- X rt H Φ P- P φ a PH al "i P Φ 03 φ Φ Φ o P ⁴ rt> H ii o ii P = d H P- 1-1 ^■ P ⁴ rt tr HP P- 01 P- 03 a Φ rt cn P- PP \ -> o Φ doa rt d tr p: 03 PP ω O Φ 3 φ 03 03 φ p : Φ p. P- cn Φ Ω 03 <!

01

PP CΛ P- Φ H cn uq P φ P P- XP 03 X ω p: Ω P- P d P IV φ PP ⁴ P- 03 ro O

Hl Φ P- φ P Φ rt Φ d PP ¹ * <Φ P od P ⁴ 03 li J Φ PP ⁴ oo P d = P o 03 P P- K Pi P ⁴ P- pj 03 rt PHP, Φ rt P Φ 11 P ¹ P

> 3 P a tr 3 ^{^} - 'P ⁴ P 03 O rt P Φ φ PP P- P "tsi P Ω Φ P d P o PP ¹

1 φ P P- P- o

P d 1 P-

IV P d H ii uq JV d rt P ⁴ P Hl rt ad rt P ⁴ PP 01 P d 03 TJ uq H CΛ P- P- 03 φ d P o P • Φ Q d P ⁴ Φ P- Hi Φ P tr P Cn

03

P "P rt P tr H d φ oi Pt rt 03 PPX uq H d H Ω HP P- ι-i tr P φ uq tπ φ uq H rt PP p: o ¹ o Φ a • <σ Hl d P ⁴ Φ tr P φ Φ Φ n φ 3 n 1

01 d rt d P Hi rt P H 3 o 03 a P- rt Φ φ IV z P φ rt P- C

IV P 01 P- Φ a φ H P- P a P- φ Φ t TJ P- Λ Hi P ¹

Hl 01 H- li H TJ tr PPP rt P n rt φ O ooo Ω IV φ p: rt P d P Φ rt P Φ P 03 rt φ φ Φ Φ P ⁴ rt 03 HS 53 φ IV P,

XHP ⁴ φ ° d φ HPPP Φ PP t Pi 03 uq NP j PP tda ^• p

• 3 Φ ti P CΛ Ω d • Φ Ω P CΛ H 03 PP P- φ d rt uq 03 P P- P Φ 1 H tr 3 Φ P- P ⁴ 01 \ -> P ⁴ co P- P- d. , P CΛ

0 Ω 3 l-J • P Ω rt a n

IV P- PO: P o rt 03 P "1 s: o Pl PP [P P- P ⁴ p: Φ P ⁴ Hi Φ P ^•

0: P ¹

H ¹ IQ P3 N> S H- H- n C vo. p rt O &> rt, ds

P tr φ P "P ⁴ 1 3 d Ω rt Φ φ 1 p: P- P-

P g ö S Φ P • e

P rt P φ P ⁴

P Φ P- P- 03 1 P ⁴ Φ & o uq P tr o 1 P a HP tr P- N l P • uq ii Φ ö H

Φ 1 Ω _* o Φ ι-i Φ φ d Φ 1 a Φ 1 P p: φ 1 P-

Φ ö Φ uq

R PP rt P ⁴ öd 1 rt 1 PH 03 11 PP Ω 1 P 1 P- li

• • 1 1 1 1 s> P ⁴ Φ 1

of the general formula X- (CH ₂ ) _n -Si- (OR) ₃ , where X is a halogen, cyano, NH ₂ or mercapto radical, n = 1-6, preferably 3, R is an alkyl or trialkysilyl Rest or H mean to be implemented. Ligands in the form of peptides, proteins or enzymes can be covalently coupled to the supports modified in this way for the separation according to the affinity principle or for use as biocatalysts. There are several options for this:

1. Protein and other ligands can be coupled directly to the halogen-substituted supports by simple incubation.

2. Protein ligands can be covalently bound with the amino group-substituted magnetic particles using dialdehydes.

3. Amino-substituted Si0 ₂ carriers are first reacted using succinic anhydride and the carboxyl groups formed are then activated, for example with carbodiimides. Protein ligands can be coupled directly to the activated groups.

4. Binding of protein and other ligands via the oxirane group of the epoxy-substituted Si0 ₂ particles described above.

In an analogous manner to the proteins, amino-functionalized nucleic acids of any kind can also be coupled to the Si0 ₂ support using the methods described.

Without going into further detailed explanations this

To include couplings and modifications, which, inter alia, in "Scientific and Clinical Applications of Magnetic Carriers", Häfeli et al. (Ed.), Plenum Press, New York, 1997, and Shriver-Lake in "Immunized Biomolecules in Analysis", T. Cass and FS Ligler ed., Oxford University Press, 1998, are believed to be a person skilled in the art knows the special reaction methods well and can therefore basically use the description. The described embodiments are therefore in no way to be interpreted as limiting disclosures.

In addition to the possibility of producing magnetic particles from pure Si0 ₂ gel, it was surprisingly shown that the magnetic particles can also be produced by mixing Si0 ₂ sols with synthetic, semisynthetic or natural organic polymers. With regard to the changed morphology and the chemical reaction behavior compared to the pure Si0 ₂ gels, there is a modified one

Range of properties that opens up an expansion of the application framework. This relates in particular to the application in the field of purification of high molecular nucleic acids and the separation of proteins. The polymer mixture leads to hybrid polymers which partially combine both the chemical-physical properties of the organic polymers and those of the SiO ₂ gels. Specifically, the hybrid particles' adsorption behavior towards proteins, the mechanical strength and the base stability are worth mentioning.

Suitable copolymers are largely those polymers which are water-soluble and compatible with the SiO ₂ sols, ie which can form homogeneous mixtures without phase separation. The pro Products and their targeted use in selected biochemical and biotechnological areas are preferred those polymers that enable a targeted modification of the morphological structure with regard to a surface enlargement as well as with regard to the pore structure.

Polymers that are preferred as additives are, for example, polyvinyl alcohol, polyacrylic acid, polyamino acids, polysaccharides, proteins or polyvinylpyrrolidone. According to the invention, usually 0.5-5% aqueous polymer solutions are used, which are mixed with the SiO ₂ sols before the dispersion process. The volume fraction of the organic polymer solutions in the sol phase is between 5 and 25%. Polymers with a molecular weight of 15,000 to 250,000 are usually used.

With regard to the separation of proteins, the use of the predominantly very hydrophilic polymers also offers the possibility of largely suppressing the unspecific adsorption behavior which is very pronounced in pure silica gels.

The addition of the organic polymers to the sol approach does not fundamentally change the procedure described above for the production of pure Si0 ₂ particles.

Some examples of methods and Si0 ₂ particles according to the invention are described below.

example 1

A mixture of 55 ml tetraethoxylsilane and 15 ml 0.05 M HCI are in an ultrasonic bath for 25 min. sonicated under ice cooling. 20 ml of the SiO ₂ sol, which has a viscosity of 36 cp at 20 ° C., are mixed with 5 ml of a magnetic colloid, which according to the specification by Shinkai et al. (Biocatalysis, Vol 5, 61, 1991) by oxidation of a 0.6 molar iron (II) salt solution using 0.3 M Na nitrite. The suspension obtained is introduced into 280 ml of 1.1.1-trichloroethane in which 0.5% by volume of Tween 80 and 0.8% by volume of Prisorine have been dissolved. The batch is dispersed with stirring (1800 rpm) for a few seconds, 10 ml of 1% ammonia solution are then added, and the dispersion is stirred for a further 3 seconds. After 5 minutes, the magnetic particles are separated from the suspension using a hand magnet and washed three times with approx. 50 ml of ethanol and water. Magnetic particles with a particle size of 20-60 µm are obtained. After 12 hours of incubation in water, the particles are washed several times with water and then dried in vacuo for several hours to constant weight. The particles have an average pore size of 24 nm. The magnetic particles obtained can be used according to the known methods for the purification of nucleic acids.

Example 2

A mixture consisting of 25 ml of the sol prepared according to Example 1 and 8 ml of a magnetite colloid, which according to the instructions of Khalafalla and Reimers (Br-Pat. 1 439 03 1) from an iron (III) - / iron ( II) salt solution (molar ratio 2: 1) obtained by ammonia precipitation are in

300 ml of toluene, in each of which 2% by volume Pripol 1009 and Tween 20 are solved using an Ultra-Turrax at 12,000 rpm. dispersed. After adding 12 ml of 3% ammonia solution, dispersion is continued for a further 2 seconds. Separation and processing follow as in Example 1. Magnetic particles with a particle size of 1-4 .mu.m and a Magnetil content of 3.8% by weight are obtained.

Example 3

A suspension consisting of 50 ml of tetramethoxylsilane and 20 ml of 0.3 M HC1 is for 5 min. sonicated in an ultrasonic bath. 20 ml of the thus obtained

Sols which have a viscosity of 48 cP are mixed with 8 ml of the magnetite colloid produced according to Example 2 and 2 ml of a 2.5% strength polyvinyl alcohol solution (molar mass = 224,000). The suspension is then dispersed with stirring (1600 rpm) in 320 ml of hexane containing 0.5% by volume of Estol SMO 3685. 10 ml of 1% ammonia solution are added during the dispersing process, and stirring is continued for 4 seconds. Separation and processing of the magnetic particles obtained is carried out analogously to Example 1. Carriers with a size of 80-150 μm and an average pore size of 58 ran are produced. The separated magnetic particle fraction is washed 5 times with dried toluene after each magnetic separation and then after 12 hours

Add 50 ml of toluene and 0.85 g of 3-aminopropyltriethoxysilane boiled under reflux. The magnetic particles are separated magnetically again and washed 3 times each with toluene and chloroform. This is followed by drying in a vacuum for several hours. The amino-modified product is then treated with 6% glutaraldehyde Solution in 25 ml 0.1 M Na carbonate buffer, pH 9.2, reacted for 3 hours at 35 ° C. It is then washed thoroughly with 0.1 M phosphate buffer, pH 7.2. The aldehyde-functionalized magnetic particles obtained are suspended in 15 ml of 0.1 M phosphate buffer. 2 ml of the suspension are separated magnetically and incubated in 2 ml of 0.1M IM phosphate buffer, pH 7.2, in which 1.2 mg of streptavidin are dissolved. After reaction for 6 hours at 35 ° C., the product is washed five times with phosphate buffer. In order to saturate remaining aldehyde groups, the magnetically separated product is incubated in 5 ml of 0.2 M ethanolamine at room temperature over a period of 5 hours. The magnetic particles which are subsequently washed several times with phosphate buffer can be used directly by the known methods for binding biotinylated nucleic acids or biotinylated proteins.

Claims

claims

1. A process for the production of magnetic Si0 ₂ particles by a) dispersing alkoxysilanes in water, hydrolyzing them under acid catalysis and condensing them to form a Si0 ₂ hydrosol, b) producing magnetic particles and sols containing the Si0 ₂ hydrosol, for example magnetic particles conventional magnetic particles, magnetic colloids and / or ferrofluids can be mixed in, c) the magnetic particle-sol mixture is dispersed in a water-immiscible organic solvent and d) the magnetic particle-sol mixture during or after the dispersion in the organic solvent for gel formation, a base is added.

2. The method according to the preceding claim, characterized in that vegetable oils or organic solvents as a solvent a distribution coefficient greater than 2 or mixtures of these are used.

3. The method according to any one of the preceding claims, characterized in that as the solvent chloroform, trichlorethylene, 1.1.1.-

Trichloroethane, hexane, petroleum ether, toluene, carbon tetrachloride, heptane, octane or mixtures of these can be used.

4. The method according to any one of the preceding claims, characterized in that the viscosity of the Si0 ₂ hydrosol is adjusted such that the Si0 ₂ particles produced have a predetermined diameter.

5. The method according to any one of the preceding claims, characterized in that the viscosity of the Si0 ₂ hydrosol is adjusted between 5 cp and 500 cp.

6. The method according to claim 4 or 5, characterized in that for the production of Si0 ₂ - particles with a diameter of less than 100 to the viscosity of the sol is set to less than 40 cp.

7. The method according to claim 4 or 5, thereby indicates that the viscosity of the sol is adjusted to greater than 40 cp for the production of SiO ₂ particles with a diameter of greater than 200 μm.

8. The method according to any one of the preceding claims, characterized in that the dispersion of hydrosol, magnetic particles, organic solvent and base is stirred mechanically.

9. The method according to the preceding claim, characterized in that the dispersion is stirred for about 2 to 5 seconds.

10. The method according to any one of the two preceding claims, characterized in that the dispersion is stirred at such a speed that a predetermined diameter of the Si0 ₂ particles is achieved.

11. The method according to the preceding claim, characterized in that the dispersion is stirred at 800 - 1800 U / min.

12. The method according to claim 51, characterized in that the dispersion is stirred at 5000-20000 U / min.

13. The method according to any one of the preceding claims, characterized in that aliphatic alcohols are used as alkoxysilanes.

14. The method according to claim 13, characterized in that methyl, ethyl and / or propyl esters are used as esters.

15. The method according to any one of the preceding claims, characterized in that dilute acids and / or organic-based acids are added to the alkoxysilanes for acid catalytic hydrolysis.

16. The method according to any one of the preceding claims, characterized in that hydrochloric acid, formic acid or propionic acid are added to the alkoxysilanes for acid catalytic hydrolysis.

17. The method according to any one of the preceding claims, characterized in that mineral acids with a concentration between 0.02 and 1 mol / liter are added for acid catalytic hydrolysis.

18. The method according to any one of the preceding claims, characterized in that mineral acids are added in a volume fraction of 15 to 35% in the dispersion for acid catalytic hydrolysis.

19. The method according to any one of the preceding claims, characterized in that for acid catalytic hydrolysis mineral acids are added to a volume fraction of 20 to 28% in the dispersion.

20. The method according to any one of the preceding claims, characterized in that for acid catalytic hydrolysis monocarboxylic acids as pure Acids are added.

21. The method according to any one of the preceding claims, characterized in that for acid catalytic hydrolysis monocarboxylic acids are added to a volume fraction of 15 to 30% in the dispersion.

22. The method according to any one of the preceding claims, characterized in that the acid concentration in the dispersion is adjusted such that the Si0 ₂ particles produced have a predetermined pore size.

23. The method according to the preceding claim, characterized in that for the production of Si0 ₂ particles with a pore size greater than about 30 nm, the acid concentration to greater

0.15 mol / liter is set.

24. The method according to claim 22, characterized in that for the production of Si0 ₂ particles with a pore size less than about 30 nm, the acid concentration is set to less than 0.15 mol / liter

25. The method according to any one of the preceding claims, characterized in that the condensation of the alkoxysilanes in step a) is carried out at low temperatures.

26. The method according to the preceding claim, characterized in that the condensation of the alkoxysilanes in step a) is carried out with ice cooling.

27. The method according to any one of the preceding claims, characterized in that the aqueous dispersion of alkoxysilanes is sonicated at least temporarily with ultrasound during step a).

28. The method according to any one of the preceding claims, characterized in that the aqueous dispersion of alkoxysilanes is sonicated during step a) for about 5 to 30 minutes

29. The method according to any one of the preceding claims, characterized in that for the production of a magnetic particle-sol mixture the Si0 ₂ - hydrosol magnetic particles in the form of magnetic table colloids, in particular colloids of magnetic nanoparticles, ferrofluids, in particular fluids with magnetic nanoparticles, and / or generally magnetic nanoparticles.

30. The method according to the preceding claim, characterized in that magnetite, transition metal oxides, ferrites and / or other nanoparticulate, ferro-, ferri- or superparamagnetic compounds are admixed as magnetic nanoparticles.

31. The method according to any one of the preceding claims, characterized in that stabilizers, surfactants and / or emulsifiers are added to the magnetic particles to form a stable aqueous colloidal dispersion of the magnetic particles in the Si0 ₂ hydrosol.

32. The method according to any one of the preceding claims, characterized in that ferrofluids are added as magnetic particles, which form a homogeneous dispersion with the Si0 ₂ hydrosol,

33. Method according to one of the preceding claims. before, characterized in that ferrofluids containing charged surfactants, aromatic or aliphatic sulfonic acid derivatives and / or aliphatic carboxylic acids are mixed in as magnetic particles.

34. The method according to any one of the preceding claims, characterized in that magnetic particles are added which have a solid and / or u n l o s l i c h e polymer shell.

35. The method according to the preceding claim, characterized in that magnetic particles are added which have a polymer shell containing or consisting of polyvinyl acetate, polyvinyl alcohol, dextran, polyacrolein, polystyrene, albumin and / or alginate.

36. The method according to any one of the preceding claims, characterized in that the magnetic particles have a diameter between 0.05 microns and 3 microns.

37. The method according to any one of the preceding claims, characterized in that the magnetic particles are mixed in such a way that Volume ratio of hydrosol to magnetic particles is between 2: 1 and 4: 1 and / or the weight fraction of the magnetic particles in the magnetic colloid-sol mixture is between 10% and 55%.

38. The method according to any one of the preceding claims, characterized in that the magnetic particle-sol mixture is dispersed in a water-immiscible organic solvent for 1 to 5 seconds.

39. The method according to any one of the preceding claims, characterized in that the magnetic particle-sol mixture is dispersed in an organic solvent which is immiscible with water and forms emulsions or dispersions.

40. The method according to any one of the preceding claims, characterized in that surface-active substances, emulsifiers and / or surfactants are added to the solvent.

41. The method according to the preceding claim, characterized in that the solvent as surface-active substances polyglycerol esters, Polyethylene glycol castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, alkylphenylpolyethylene glycol derivatives, block copolymers from castor oil derivatives, propylene oxide / ethylene oxide block copolymers, modified polyesters, poly ethylene glycol ether copolymers, polyoxypropylene-sorbitan-ethylene copolymers , Polyethylene glycols, polyoxyethylene derivatives, polyoxyethylene alcohol derivatives, polyhydroxy fatty acid-polyethylene glycol block copolymers are added.

42. The method according to one of the two preceding claims, characterized in that the proportion of surface-active substances, emulsifiers and / or surfactants in the organic solvent is between 0.1% by volume and 25% by volume.

43. The method according to any one of the three preceding claims, characterized in that the surface-active substances, emulsifiers and / or

Surfactants can be added to a concentration in the dispersion between 0.1 and 15% by volume or% by weight.

44. The method according to the preceding claim, characterized in that the surface-active substances, emulsifiers and / or surfactants are added to a concentration in the dispersion of between 0.5 and 6% by volume or% by weight.

45. The method according to any one of the preceding claims, characterized in that the solvent is added such that the volume ratio of solvent to hydrosol is between 5: 1 and 30: 1, preferably between 8: 1 and 30: 1.

46. The method according to any one of the preceding claims, characterized in that the base in process step d) is added in a concentration so that the Si0 ₂ particles produced have a predetermined pore size.

47. The method according to the preceding claim, characterized in that for the production of Si0 particles with a pore size greater than about 30 nm, the final concentration of the base added is between 1 and 3%.

48. The method according to claim 46, characterized in that the final concentration of the base added is between 6 and 25% for the production of Si0 ₂ particles having a pore size of less than approximately 30 nm.

49. The method according to any one of the preceding claims, characterized in that 7Λmmoniak is added as the base.

50. The method according to the preceding claim, characterized in that the ammonia is used in the form of a 1% to 12% aqueous solution.

51. Method according to one of the preceding claims, characterized in that sodium hydroxide solution (NaOH) is used as the base.

52. The method according to the preceding claim, characterized in that the sodium hydroxide solution is used in the form of a 0.05 to 0.1 molar solution.

53. The method according to any one of the preceding claims, characterized in that the volume ratios of the added base and the hydrosol are between 1: 2 and 1: 4.

54. The method according to any one of the preceding claims, characterized in that the magnetic Si0 ₂ particles, optionally with a hand magnet, are removed from the dispersion and optionally cleaned.

55. The method according to the preceding claim, characterized in that the magnetic Si0 ₂ particles removed from the dispersion are washed one or more times with alcohol and / or water.

56. The method according to any one of the two preceding claims, characterized in that the Si0 ₂ particles removed from the dispersion and optionally purified in an aqueous medium be kept.

57. The method according to any one of the preceding claims, characterized in that the Si0 ₂ particles are reacted with alkoxysilanes and / or substituted alkoxysilanes, epoxy-substituted alkoxysilane, 3-glycidyloxypropyltrimethoxysilane and / or 3-glycidyloxypropylmethyldiethoxysilane and then a nucleo - Phile opening of the oxirane ring is carried out by means of tertiary or secondary alkylamines.

58. The method according to the preceding claim, characterized in that the Si0 ₂ particles with epoxy-substituted alkoxysilane, 3-glycidyl-oxypropyltrimethoxysilane or 3-glycidyloxypropylmethyldiethoxysilane and then with carboxylic acids, sulfites, thiosulfates or amino-substituted carboxylic acids, nitrilotriacetic acids re or iminodiacetic acid can be implemented.

59. The method according to any one of the preceding claims, characterized in that the Si0-

Particles are reacted with substituted alkylalkoxysilanes of the general formula X- (CH ₂ ) _n -Si- (OR) ₃ , where X is a halogen, cyano, NH ₂ or mercapto radical, n = 1 to 6, preferably n = 3, and R is an alkyl, trialkysilyl radical or H.

60. The method according to the preceding claim, characterized in that ligands, for example peptides, subsequently to the Si0 ₂ particles,

Proteins and / or enzymes are covalently coupled.

61. The method according to any one of the preceding claims, characterized in that synthetic, semisynthetic and / or natural organic polymers are added to the Si0 ₂ hydrosol.

62. The method according to the preceding claim, characterized in that water-soluble and / or with the Si0 ₂ hydrosol homogeneous mixtures without phase separation polymers are used as organic polymers.

63. The method according to one of the two preceding claims, characterized in that organic polymers with a molecular weight between 15,000 and 250000 Da are added.

64. The method according to one of the three preceding claims, characterized in that as an organic see polymers polysaccharides, proteins, polyvinyl alcohol, dextran, starch, chitosan, alginate, ficoll, polyethyleneimine, agarose, polyacrylic acid, polyamino acids, polyvinylpyrrolidone, hyaluronic acid and / or pectinate.

65. The method according to any one of claims 61 to 64, characterized in that the organic polymers are added as a solution.

66. The method according to any one of claims 61 to 65, characterized in that the organic polymers are admixed as 0.5% to 5% solutions.

67. The method according to any one of claims 61 to 66, characterized in that the organic polymers are mixed in such a way that the proportion of the polymer solution in the hydrosol is between 1 and 30% by volume, advantageously between 5 and 25% by volume.

68. Magnetic Si0 ₂ particles obtainable by a method according to one of the preceding claims.

69. Magnetic Si0 ₂ particles, optionally after the preceding claim, with a particle diameter between 0.5 μm and 2000 μm, characterized in that ß in the Si0 ₂ particle over the entire Si0 ₂ -

Particles magnetic particles, for example as a magnetic colloid or ferrofluid, are homogeneously distributed and encapsulated, the proportion of the magnetic particles in the total weight of the SiO ₂ particle being between 10 and

Is 55%.

70. Particles according to one of the two preceding claims, characterized in that they contain between 2 and 25% by weight of organic polymers, polysaccharides and / or proteins.

71. Particle according to one of the three preceding claims, characterized in that the surface of the Si0 ₂ particles have groups containing oligopeptides, oligosaccharides, oligonucleotides, polypeptides, polynucleotides, polysaccharides, antibodies, antibody fragments and / or Enzymes can be coupled.

72. Particle according to one of claims 68 to 71, characterized in that the surface of the Si0 ₂ particles is epoxy-substituted.

73. Particle according to the preceding claim, characterized in that the epoxy-substituted Si0 ₂ particles with secondary or tertiary

Alkylamines are converted to anion exchangers.

74. Use of magnetic particles according to one of claims 68 to 73 for the purification or analysis of nucleic acids, proteins, peptides, antibodies or antibody fragments or other biomolecules or biotinylated derivatives thereof, as ion exchangers or metal chelate carriers, as carriers for biocatalysts such as Pep - tides, proteins and / or enzymes, as a biocatalyst in biotechnological fermentation processes, as a protein encapsulation matrix, as a "stimulus-response" gel, as an adsorber, for example in hemoperfusions.