Chemistry of inorganic compounds – Oxygen or compound thereof – Metal containing
Reexamination Certificate
2002-04-01
2004-10-05
Bos, Steven (Department: 1754)
Chemistry of inorganic compounds
Oxygen or compound thereof
Metal containing
Reexamination Certificate
active
06800271
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of nanosized iron oxide by biomimetic route. The present invention particularly relates to a biomimetic process for preparation of nanosized magnetite particles used for the enhancement of magnetic resonance imaging contrast. The nanosized magnetite, a form of iron oxide, is biodegradable, nontoxic and has size in the range of 4-20 nanometer. The particles, being super-paramagnetic in nature and exhibiting a narrow size distribution, arte useful generally in the fields of medical treatment and specifically of Magnetic Resonance Imaging.
BACKGROUND OF THE INVENTION
Magnetic resonance imaging (MRI) is widely used for diagnostic imaging of the soft tissues and has been proven to be better to computed tomography for the detection of lever metastases. The screening and follow up of any kind of metastasis using contrast-enhanced MRI is an interesting tool for oncologists because ultrasound (US) is operator dependent and not always reproducible. Therefore, various contrast agents for an improved MR imaging have been developed by the pharmaceutical companies to serve the purpose.
Several metal chelates comprising of a highly magnetic cation Gd
3+
such as Gd-DTPA (Diethylene Triamine Pentaacetic Acid) are available for ready clinical use. These agents have been applied in enhancing the image contrast either as coating material in a therapeutic device or as directed agents for a specific organ. The only commercially available iron oxide for use in MRI contrast is ferumoxide, which has a supraparamagnetic crystalline core (nanosized magnetite) surrounded by dextra-coating. Being produced by conventional chemical method these magnetite particles suffer the limitations of the chemical synthesis route such as poor control over size and morphology. Thus, the supraparamagnetic behaviour of the particles ultimately deteriorates and makes them unsuitable for applications.
In a conventional method of production of nanosized magnetite particles developed by David and Welch. (I. David and A. J. E. Welch, Trans. Faraday Soc. 52 (1956) 1642) ferrous sulphate solution is heated to 90° C. and a solution of potassium hydroxide and potassium nitrate added drop-wise over a few minutes. The suspension was heated for 60 minutes with continuous stirring followed by cooling, washing and drying leading to the formation of black precipitate of magnetite powder. It is mandatory to carry out the entire under an atmosphere of nitrogen.
In another known process by Schikorr (G. Schikorr, Z. Electrochem 35 (1929) 65) alkaline hydrolysis of ferrous sulphate solution is carried out to yield ferrous hydroxide followed by it's further oxidation at 100° C. leading to the formation of magnetite powder along with evolution of hydrogen gas.
In another known process, reaction of ferrous/ferric solution under alkaline condition at 80° C. under nitrogen atmosphere leads to the formation of magnetite particles (Regazzoni A. E., Urrutia G. A., Blesa M. A. and Maroto A. J. G., Inorg. Nucl. Chem, 43 (1981) 1489).
In hitherto known processes the magnetite particles produced have poor crystallinity, a wide range of size distribution, random variation in morphology and magnetically induced agglomeration. The above limitations reduce the applicability of the magnetite particles in the field of medicine.
OBJECTS OF THE INVENTION
The main object of the invention is to provide a process for preparation of nanosized iron oxide by biomimetic route, which obviates the drawbacks as detailed above.
Another object of the invention is to provide a biomimetic process for preparation of nanosized magnetic particles used for enhancement of magnetic resonance imaging contrast.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparation of nanosized iron oxide by biomimetic route which comprises
i). mixing polyvinyl alcohol of strength ranging between 0.1-0.6% and disodium tetraborate solution of strength ranging between 0.1-0.6% in deionised water with continuous stirring
ii). mixing the above said reaction mixture with an iron salt solution of strength ranging between 0.01-0.02 M in deionised water under nitrogen atmosphere, at a pH in the range of 3-6 and stirring for about 20 minutes with a magnetic stirrer
iii). heating the above resultant solution at a temperature in the range of 40-60° C. for a period of about 24 hours under nitrogen atmosphere to obtain an iron ion loaded cross linked polymer gel
iv). soaking the above said polymer gel for a period ranging from 2 to 4 hours into sodium hydroxide solution of strength ranging between 0.00-0.009M, at a temperature ranging between 40-50° C.
v). washing the above soaked polymer gel with de-ionized water to remove the sodium chloride salt and recovering the nanosized iron oxide particles from the soaked polymer gel.
In one embodiment of the invention, the polyvinyl alcohol and disodium tetraborate solution are taken in a volumetric ratio ranging between 9:1 to 12:1
In another embodiment of the invention, the reaction mixture obtained in step (I) and the iron salt solution are taken in a volumetric ratio ranging from 2:1 to 5:1.
In an embodiment of the invention the iron salt solution used is a mixture of ferric chloride and ferrous chloride in de-ionized water.
DETAILED DESCRIPTION OF THE INVENTION
In nature, the synthesis of nano and micro sized inorganic particles is observed since the evaluation of life. The process is termed as bio-mineralization and it exhibits a high degree of control over the nucleation and growth of the synthesized particles, which perform different functions under different conditions and do not agglomerate. Our teeth, bones, shells, etc. are the products of biomineralization and nature carries out these in situ synthesis under the control of a biopolymeric matrix.
In the process of present invention in laboratory a method has been developed for in situ precipitation of nanosized magnetite particles in a pre-organized polymeric matrix made of a water-soluble polymer like polyvinyl alcohol at room temperature. The method produced magnetite particles in the size range of 5-10 nm having uniform morphology and orientation with supraparamagnetic behavior.
Under the optimum conditions of temperature, concentration, pH and a specific volumetric ratio, the underlying polymeric matrix provides a regularly arranged and uniformly distributed reaction as well as nucleation sites in the self assembled polymeric network formed as a result of gelation and cross-linking. The process involves a weak complexion (via dative bond formation) of ferrous/ferric ions (acceptor atom) with the active functional groups (donor atom) of the underlying polymer. An enhancement in the degree of saturation of ferrous/ferric ions locally at the complexion sites leads to the precipitation of nanosized magnetite particles under alkaline conditions at an optimum temperature. Adsorption of the polymer at the surface of the precipitate limits the dimensions of particles in nanometer size range and the polymer matrix anisotropy induces an orientation during the particle growth.
By the process of the present invention, a single phase agglomeration free magnetite particles in size range of 5-10 nanometer and oriented in form of linear arrays are produced.
The novelty of the present route is the in situ synthesis of the magnetite particles in preorganized polymer matrix. The polymer matrix controls the particles shape and size and regulates the precipitation process. The inventive step of the present invention is the chelation of ferrous ions by weak van der Wall bonds and hydrogen bonds present in cross-liked polymer matrix. The cross linking of the polymer provides a biopolymer like medium for mineralization which is characterized by regular arrangement of nano reactors and avoids agglomeration of the particles and induce precipitation under mild conditions of super saturation.
The following examples are given by way of illustration and should not be construed to limit the scope of
Chakraborty Jui
Das Samar
Das Swapan K.
Rao Patcha R.
Rao Venkatesh
Bos Steven
Council of Scientific and Industrial Research
Nixon & Vanderhye P.C.
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