Chemistry of inorganic compounds – Phosphorus or compound thereof – Oxygen containing
Reexamination Certificate
2000-08-08
2003-07-01
Langel, Wayne A. (Department: 1754)
Chemistry of inorganic compounds
Phosphorus or compound thereof
Oxygen containing
C423S309000, C423S311000
Reexamination Certificate
active
06585946
ABSTRACT:
The present invention relates to a process for the preparation of single phase magnesium- and carbonate-substituted hydroxyapatite compositions which are stable on heating and which do not contain sodium or ammonium ions.
Synthetic hydroxyapatite Ca
10
(PO
4
)
6
(OH)
2
has been reported as having been used as a bone replacement material in porous, granular, plasma sprayed and dense forms. Investigations have shown hydroxyapatite to be similar structurally to bone material. However, hydroxyapatite is one of the range of stoichiometric calcium phosphate apatites. Human and animal bone have been shown to contain significant amounts of from 3 to 7 wt % of carbonate. Furthermore, human and animal bone also contains approximately 0.5% by weight of magnesium. There is evidence that the carbonate group can substitute in two sites, the phosphate and hydroxyl sites, termed B and A respectively; bone mineral being predominantly a B type apatite. As a result of this similarity in chemical composition, it is envisaged that a magnesium/carbonate-substituted hydroxyapatite will have better bioactivity than unsubstituted stoichmetric hydroxyapatite which is currently used in commercial applications such as plasma-sprayed coatings on metallic implants and porous hydroxyapatite ceramic bone substitutes. A magnesium/carbonate substituted apatite would also find application for use in chromatography and for purification, such as the removal of heavy metal ions by adsorption.
The preparation of magnesium/carbonate-substituted hydroxyapatite ceramic materials must be easy and reproducible in order to achieve commercial exploitation. Additionally, the magnesium/carbonate-substituted hydroxyapatite composition must be thermally stable such that it will not decompose to undesirable secondary phases (e.g. tricalcium phosphate or calcium oxide) upon calcining/sintering. Furthermore, during this heat treatment, the magnesium/carbonate-substituted hydroxyapatite must not loose the carbonate ions that have been substituted into hydroxyapatite structure.
Up to the present time, methods which have been reported to prepare magnesium/carbonate-substituted hydroxyapatite compositions have resulted in materials which are not stable on heating and which decompose to undesirable phases such as &bgr;-tricalcium phosphate.
e. g. A. Bigi, G. Falini, E. Foresti, M. Gazzano, A. Ripamonti and N. Roveri, “Magnesium influence on hydroxyapatite crystallisation”, J. Inorg. Biochem. 49 (1993) 69-78.
R. N. Correia, M. C. F. Magalhaes, P. A. A. P. Marques and A. M. R. Senos, “Wet synthesis and characterization of modified hydroxyapatite powders”, J. Mat. Sc. Mater. in Med. 7 (1996) 501-505.
R. Z. LeGeros, R. Kijkowska, C. Bautista and J. P. LeGeros, “Synergistic effects of magnesium and carbonate on properties of biological and synthesis apatites”, Conn. Tiss, Res. 33(1995) 203-209.
JP-A-6245992 discloses the preparation of a hydroxyaptite containing Ca, Mg, P and/or carbonate for repairing defective bones. The method as described therein is not a precipitation method and results in materials that are not single phase after sintering, but are biphasic comprising hydroxyapatite and &agr;- or &bgr;-Ca
3
(PO
4
)
2
or CaO. The resulting product had a (Ca+Mg/P) ratio of between 1.50 and 1.67.
Furthermore, the wet precipitation methods generally use Na
2
CO
3
or (NH
4
)
2
CO
3
as the source of carbonate ions. This causes the problem that the unwanted additional ions Na
+
or NH
4
+
are substituted into the hydroxyapatite structure.
It is due to the problems encountered with the stability of magnesium/carbonate-substituted hydroxyapatite that this material has not been developed commercially.
We have now developed a novel process for the preparation of magnesium- and carbonate-substituted hydroxyapatite which results in a material which is stable on heating and which does not contain sodium or ammonium ions.
Accordingly, the present invention provides a process for the preparation of a single phase magnesium- and carbonate-substituted hydroxyapatite composition, which process comprises the steps of
(i) preparing an aqueous solution containing CO
3
2−
and PO
4
3−
ions in the substantial absence of cations other than H
+
ions:
(ii) mixing the solution from step (i) with an aqueous calcium- and magnesium-containing solution or suspension; and
(iii) collecting and drying the precipitate formed in step (ii);
the ratio of (Ca+Mg/P) in the calcium- and magnesium-containing solution or suspension and the phosphorus-containing solution, when mixed together, being maintained at 1.67, or above.
The magnesium- and carbonate-substituted hydroxyapatite produced according to the present invention are believed to be novel and accordingly, in a further aspect the present invention provides a single phase magnesium- and carbonate-substituted hydroxyapatite composition which comprises up to 0.5% by weight of magnesium and up to 1% by weight of carbonate substituted into the hydroxyapatite structure and which does not contain Na
+
or NH
4
ions, the ratio of (Ca+Mg/P) being greater than 1.67. Preferably, the ratio of (Ca+Mg/P) is 1.68 or above.
In carrying out the process of the present invention the aqueous solution of step (i) may be prepared by bubbling carbon dioxide through water to form carbonic acid, and then adding phosphoric acid, H
3
PO
4
, thereto, or by adding carbon dioxide gas to water under high pressure and then adding phosphoric acid thereto. The amount of carbon dioxide absorbed by the solution can be calculated from the pH of the solution prior to the addition of H
3
PO
4
. At a pH of about 4.0 the solution will be fully saturated with carbon dioxide. Generally H
3
PO
4
will be added to the solution of carbonic acid in order to provide the PO
4
3 −
ions for reaction.
Alternatively, the aqueous solution of step (i) may be prepared by bubbling carbon dioxide through a solution of H
3
PO
4
, or adding carbon dioxide under pressure to a solution of H
3
PO
4
, in order to form CO
3
2−
ions in situ. Furthermore, Co
2
may be introduced as a solid which carbonates the solution as it vaporises.
The solution from step (i) of the process is mixed in step (ii) with an aqueous calcium- and magnesium-containing solution or suspension. Calcium compounds which may be used include calcium nitrate, Ca(NO
3
)
2
, or calcium hydroxide, Ca(OH)
2
. Magnesium compounds which may be used include magnesium nitrate or magnesium acetate. Preferably the mixing will be carried out by dropwise addition of the solution from step (i) to the calcium- and magnesium-containing solution or suspension. However, bulk mixing of the solution from step (i) and the solution or suspension from step (ii) may be undertaken provided that the combined mixture is vigorously stirred in order to provide the precipitation reaction.
During the mixing in step (ii) of the process carbon dioxide may be bubbled through the mixture.
The ratio of Ca and Mg to P in the calcium- and magnesium-containing solution or suspension and the phosphorus-containing solution, when mixed together, is maintained at 1.67 or above.
Preferably the Ca and Mg/P ratio is maintained at 1.67.
After the addition of the reactants is complete, the pH of the mixture may be adjusted, if desired to pH 10 to 11 by the addition of ammonia. If ammonia is added in this manner then appropriate steps are taken to remove ammonia from the final product.
The dried precipitate from step (iii) of the process may be calcined/sintered in a wet carbon dioxide atmosphere according to the teaching of EP-0625490B. In particular, the dried precipitate may be calcined in carbon dioxide containing from 0.001 to 0.10 of grams of water per litre of gas at a temperature in the range of from 900° to 1200° C. Preferably the carbon dioxide used as the sintering atmosphere will contain from 0.01 to 0.02 grams of water per litre of gas. The sintering time will generally be up to 24 hours, preferably 10 minutes to 4 hours.
The sintering will generally be carried out at atm
Bonfield William
Gibson Iain Ronald
ApaTech Limited
Langel Wayne A.
LandOfFree
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