JPH0193409A - Production of hydroxyapatite - Google Patents

Abstract

PURPOSE:To readily obtain hydroxyapatite, useful as artificial bones, etc., in high quality and quality, by subjecting a specific compound and phosphoric acid to condensation reaction in an organic solvent and refluxing the resultant reaction product in the presence of neutral or alkaline water. CONSTITUTION:An organometallic compound, such as Ca(OCH3)2, is reacted with phosphoric acid capable of condensation reaction therewith in an organic solvent, such as alcohols, to provide a condensation reaction product, which is then refluxed in the presence of neutral or alkaline water by heating at about 25 deg.C for about 3hr to afford a reaction product. The obtained product is subsequently filtered, separated, washed, dried and calcined at about 1,200 deg.C for about 1hr to produce the aimed crystalline hydroxyapatite.

Description

Detailed Description of the Invention The present invention involves reacting an organometallic compound consisting of calcium with phosphoric acid in an organic solvent to obtain a condensation reaction product, which is then aged in a water-containing solvent to obtain crystalline hydroxyapatite. Regarding the manufacturing method.

Recently, it has been recognized that calcium phosphate-based substances are effective as raw materials for biomaterials and industrial materials, and it is expected that they will be in great demand in the future, especially as biomaterial-based materials. Especially hydroxyapatite (Ca5(PO4)3
(OH) ) is a main component of natural teeth and bones and exhibits excellent biocompatibility, making it a useful substance as a biomaterial for artificial teeth and bones.

Until now, methods for producing calcium phosphate-based substances have been known in basic chemical fields such as biochemistry and geological mineralogy, but this is only a part of research to obtain academic knowledge and is not intended for production purposes. It is only recently that studies have begun to be carried out.

The conventional production methods that have been reported so far can be roughly divided into two types: wet methods that involve reactions in aqueous solutions, including hydrothermal methods, and dry methods that involve solid phase reactions at high temperatures.

In other words, it can be summarized as follows.

(1) A wet synthesis method in which a water-soluble phosphate and a calcium salt are reacted in an aqueous solution.

(2) Wet synthesis method in which anhydrous calcium phosphate and phosphoric acid are subjected to a hydrothermal reaction in an autoclave.

(3) A dry synthesis method in which tricalcium phosphate and calcium oxide are reacted under a stream of steam at a high temperature of 900°C or higher.

However, in both of the above manufacturing methods (2) and (3), reactions are carried out at high temperature and high pressure, resulting in expensive equipment and an enormous amount of energy consumption. In the production method (1), the composition of the product is greatly affected by slight differences in conditions, and furthermore, it takes a long time of 20 days or more to obtain hydroxyapatite with a stoichiometric composition.

Moreover, during this time, p■, temperature, etc. must be strictly controlled, making the operation complicated, and as a result, the reproducibility of quality is poor.

Moreover, calcium-deficient hydroxyapatite with a calcium to phosphorus ratio (hereinafter referred to as Ca/P ratio) of 1.67 or less, which is the stoichiometric ratio, is likely to be produced, and such non-stoichiometric hydroxyapatite Apatite is less thermally stable than those with stoichiometric composition, and is easily decomposed into tricalcium phosphate, calcium pyrophosphate, and calcium oxide during sintering at high temperatures, making it unsuitable as a method for producing hydroxyapatite. .

On the other hand, attempts have been made to synthesize hydroxyapatite by an alkoxide method with the aim of achieving high purity and high homogeneity of the product. That is, using calcium nitrate as a calcium source and trimethyl phosphate as a phosphorus source, hydrolyzed and gelled in an organic solvent using aqueous ammonia and calcined to obtain hydroxyapatite. However, this alkoxide hydrolysis method requires gelation time of about 1 to 3 months;
This cannot be said to be a practical manufacturing method.

Therefore, the achievement of a simple method for producing highly pure and highly homogeneous stoichiometric hydroxyapatite has been an important technical challenge.

〔the purpose〕

Therefore, an object of the present invention is to provide a new manufacturing method that can easily produce large quantities of hydroxyapatite with high purity, high homogeneity, and a stoichiometric composition.

〔overview〕

In the present invention, an organometallic compound having a structure in which calcium and an organic group are bonded via oxygen is reacted with phosphoric acid capable of a synthetic reaction in an organic solvent, and the resulting condensation reaction product is collected in the presence of water. A method for producing crystalline hydroxyapatite, which is characterized by crystallizing it by refluxing it under water and collecting the produced hydroxyapatite.

[Product properties]

The crystalline hydroxyapatite of the present invention is a mixture of crystalline and partially amorphous materials, but it can be produced as a crystalline material by adding a small amount of heat.

All of these crystals belong to hydroxyapatite.

The distribution of constituent elements of the hydroxyapatite of the present invention is uniform, and there is no difference in composition no matter which part is observed. This hydroxyapatite is composed of fine particles of submicrometer size or less.

Furthermore, it has excellent thermal stability, is stable for a long time even at 1200°C, and does not decompose into calcium oxide, tricalcium phosphate, etc.

〔Effect of the invention〕

1) Since the production method of the present invention allows reaction at a higher concentration than conventional methods, the ratio of the amount of solvent to the product can be reduced and the reaction time can be shortened. .

2) Since the composite oxide of the present invention is obtained by performing a selective reaction, the constituent elements are uniformly distributed and there is no segregation. As a result, the sintered body made from the hydroxyapatite powder according to the present invention has improved mechanical strength, etc., and is expected to improve the manufacturing process, thereby exhibiting a significantly useful effect.

3) Furthermore, the manufacturing method of the present invention does not require any special operations and is a simple operation. Moreover, since the reaction conditions are normal pressure and low temperature, there is no need to use complicated synthesis equipment.

[Application]

In other words, the crystalline hydroxyapatite of the present invention is particularly suitable for use as a biomaterial. In addition, in recent years, its use in humidity sensors and the like has been considered, and it is also used in electronic materials.

〔Production method〕

An organometallic compound having a structure in which calcium is bonded via an organic group and oxygen, and phosphoric acid without reacting with the compound,
It is added to a non-aqueous solvent or a non-aqueous dispersion medium to be dissolved or dispersed, and a selective condensation reaction occurs between different types of compounds to form an apatite precursor.The amorphous precursor is heated with water in order to react with water. This is a method for producing crystalline hydroxyapatite in which a product is obtained by refluxing.

〔material〕

■) Organometallic compound The above-mentioned organometallic compound is not particularly limited and any known one can be used, but in general, general 2Ca(OR)! A metal alkoxide compound represented by (where R is an alkyl group) or a compound represented by Ca(RCOO)n,
Compounds in which a metal and an organic group are bonded via oxygen, such as a compound having a structure that coordinates calcium such as a chelate, are preferable. Particularly illustrative of these compounds is Ca(
OCHs) t, C'a(OCJs) t, C
a(OCtl(CHs) t) t.

Ca(CIIaCOO) t , Ca(OCHtCH
tO), Ca(CH3COCHtCHa), etc., but these compounds are part of the raw materials that can be used in the present invention and are not limited thereto.

2) Phosphoric acid Although commercially available raw materials for phosphoric acid can be used as they are, those that have not been dehydrated and polymerized are preferred.

3) Water It is necessary to keep the pH of the water on the neutral or alkaline side.

〔solvent〕

The solvent can be used without particular limitation as long as it dissolves or disperses the metal compounds and organometallic compounds, but alcohols, glycols, aromatic Examples include, but are not limited to, amines, esters, etc. It is also possible to use a mixture of several types of these non-aqueous solvents.

[Flow of reaction]

The organometallic compound in the present invention is prepared by diluting it in a non-aqueous solvent or dispersion medium in advance.

On the other hand, the mixed solution and the reacted phosphoric acid are diluted and adjusted in advance with a non-aqueous solvent or dispersion medium.

Furthermore, if the concentration of the adjustment solution in which the raw materials are dissolved is too low, the amount of solvent used will increase, and if it is too high, it will be difficult to control the reaction and it will be inconvenient to handle, so it should be determined appropriately by taking this into account. .

Generally, the raw material concentration is 50% by weight or less, preferably 5 to 50% by weight.
It is preferred to use a concentration in the range of %wt. A phosphoric acid solution is added to the calcium solution, or each solution is added to a solvent or a dispersion medium to complete the first reaction.

Further, water is added into this reactor and heated to reflux at a predetermined temperature, for example, 25° C. for 3 hours, and then the second reaction is completed.

In this first reaction step, phosphoric acid undergoes a nucleophilic substitution reaction with calcium, and due to the polyfunctional group, a condensation reaction progresses, and as a result, calcium and phosphorus are bonded via oxygen, resulting in uniform atoms. distribution and no segregation.

This reaction is very fast and does not require a catalyst.
For the purpose of controlling the reaction, a catalyst for controlling the first reaction rate can also be used.

The first condensate obtained in this way is amorphous calcium phosphate, and since the reaction system is anhydrous, it does not become hydroxyapatite even when fired, but oxyapatite (Ca +
o(POa)go).

Therefore, water is poured into the dispersed catalyst of amorphous calcium phosphate obtained in the first reaction, and a predetermined temperature, e.g.
Heating and refluxing at 0-100° C. is carried out for a predetermined period of time, for example θ to several hours. The resulting reaction product is separated from the filtrate, washed, dried, and calcined under predetermined conditions, for example, 1200° C. and 1hr, to obtain a calcined body of crystalline hydroxyapatite.

[Reaction mechanism]

First-stage reaction mechanism Calcium is a strongly positive element, and its alkoxide is known to act as a base. For this reason 1
As shown in the formula, a Ca-0-P bond is formed by an acid-base reaction between calcium alkoxide and phosphoric acid, and alcohol is produced as a by-product.

OHOH RO-Cm-OR10)-P-OH-e RO-Ca
-OR+: 0-P-OH0■ →RO-Cm -0-P -OH+ ROH(1)(R
is a furkyl group, etc.) The above reaction is repeated to produce amorphous calcium phosphate. When calcium flukoxide (Ca(OR)z) is reacted with phosphoric acid (H, PO,) at a molar ratio of 1.67, the Ca/P molar ratio of the amorphous calcium phosphate produced is 1.67. Therefore, this reaction is estimated to have the following reaction formula.

5Ca(OR)t+3HsPOi -Ca5(Po4)
s(OR)+9RO ■Second-stage reaction mechanism The amorphous calcium phosphate obtained by the above synthesis method is Ca/
Since the P ratio is 1,67, which is the same as that of apatite, it is presumed that crystalline apatite is formed in a relatively short time in the presence of water.

nHt.

Caw (PO-) 3 (OR) → Cas (PO4)
(OH) + ROB [Method for observing properties] (1) Identification of X-ray diffraction crystal phase Generally, the crystal structure can be confirmed by diffraction using an X-ray diffraction method.

In the experimental example, an X-ray diffraction device RAD- manufactured by Rigaku Denki Co., Ltd.
Using I[B, X-rays were generated in a Cu tube under load conditions of 40 kV and 20 mA, and the diffraction profile was measured.
The crystal structure was identified based on JCPDS powder diffraction standard data.

1 丑L1 Determined by the least squares method based on about 20 diffraction peak data from the above X-ray diffraction profile.

(2) Composition distribution The distribution of constituent elements is determined by EPM, which allows observation in the microscopic region.
A. The current evaluation method is to observe at several points using EDX, etc. and conclude that the composition is uniform.

In the experimental example, an operating electron microscope (JEOL Ltd.) was used.
Observation of the microstructure and analysis of the composition of the micro region were performed using an energy dispersive X-ray spectrometer (EDX) Q-200J manufactured by LINK.

(3) Chemical analysis The Ca content and P content in apatite were determined by EDTA back titration and molybdenum blue (ascorbic acid) spectrophotometry, respectively, to determine the Ca/P ratio.

[Experiment example]

Comparative Experiment The advantage of the present invention is that thermally stable apatite with good crystallinity can be obtained in a short time by water treatment.

Therefore, as a comparative experiment, we attempted to synthesize apatite using the conventional neutralization reaction of calcium salt and phosphate in an aqueous solution.

Calcium acetate 0.05 mof2 was dissolved in 200 mQ of water, and 100 mQ of 0.3 M phosphoric acid aqueous solution was added thereto to obtain a white precipitate, which was aged at 98°C for 6 hours, then filtered and dried at 150°C. , a white powder was obtained. 1st
The powder X-ray diffraction pattern of the product is shown in the figure, and the temperature at 800°C is shown in Figure 2.
The powder X-ray diffraction pattern of a sample fired for 2 hours is shown. From FIGS. 1 and 2, it was confirmed that the product was apatite with poor crystallinity, and decomposed into TCP at a low temperature of 800°C.

Experimental Example 1 Ethylene glycol 100m (! and metallic calcium 0.
After adding 05moQ and refluxing at 100 to 110°C for 3 hours, the mixture was cooled to room temperature to synthesize an ethylene glycol solution of calcium glycoxide. Further, a 0.6 M phosphoric acid ethanol solution was prepared, and 50 mρ was added to the calcium glycoxide ethylene glycol solution, followed by stirring for 1 hour to obtain a precipitate of amorphous calcium phosphate.

Further, 10.0 mQ of ion-exchanged water was added to this reaction system, and the mixture was refluxed at 97°C for 3 hours, and then filtered, washed with ethanol, and dried to obtain hydroxyapatite.

Figure 3 shows this X-ray diffraction diagram, and Figure 4 shows the temperature at 1200°C.

The X-ray diffraction pattern of the powder calcined in air for 2 hours is shown. Fourth
From the figure, the diffraction angle by CuXa rays is 31 and 7.

It had a main peak at 32.2.32.8°, which coincided with the characteristic diffraction peak of hydroxyapatite described in JCPDS card 9-432.

Chemical analysis of this hydroxyapatite powder revealed a Ca/P ratio of 1.67, which is approximately equal to 1.66 found from the theoretical composition.
I got it. Furthermore, even when observing the composition distribution using EDX, no uneven distribution was observed, and Ca/P was uniformly distributed over the entire field of view.
The ratio was 1.67.

The crystal phase of this hydroxyapatite is stable at high temperatures, and compared to the powder obtained in the comparative example, which was thermally decomposed at 800°C, the apatite structure remains stable even under an atmosphere of 1200°C for several hours. Was.

Example 2 Ion-exchanged water in the operation of Example 1 was p++t with hydrochloric acid.
Replace with water adjusted to , all other operations are examples! Synthesis was carried out using the same formula.

The X-ray diffraction diagram of the powder obtained as a result is shown in Figure 5 and 6.
The figure shows an X-ray diffraction pattern of the powder fired at 1200°C.

According to this result, the influence of water pl+ due to the second reaction is large, and decomposition into TCP and Ca*Pt0a is observed.

Therefore, if the pH of the water used in the second reaction is on the acid side, it inhibits the synthesis of apatite.

Example 3 I) In the operation of Example 2, water adjusted to pH 12 was used instead of water adjusted to Hl, and the other operations were as in Example 1.
．． Synthesis was carried out using the same conditions as 2.

FIG. 7 shows the X-ray diffraction pattern of the powder obtained as a result, and FIG. 8 shows the X-ray diffraction pattern of the powder fired at 1200°C.

From this result, only single-phase apatite was precipitated in this example where the pH of the water was on the alkaline side.

[Brief explanation of the drawing]

Figure 1 is an X-ray diffraction diagram of the powder synthesized in a comparative experiment.
Figure 2 is an X-ray diffraction diagram of the powder synthesized in a comparative experiment after heat treatment at 1200°C, Figure 3 is an X-ray diffraction diagram of the powder synthesized in Example 1, and Figure 4 is the X-ray diffraction diagram of the powder synthesized in Example 1. 1
X-ray diffraction diagram after heat treatment at 200°C. Figure 5 is an X-ray diffraction diagram of the powder synthesized in Example 2. Figure 6 is an X-ray diffraction diagram after heat treatment of the powder of Example 2 at 1200 °C. Figure 7 is an X-ray diffraction diagram of the powder synthesized in Example 3, and Figure 8 is an X-ray diffraction diagram of the powder of Example 3 after heat treatment at 1200°C.
It is a line diffraction diagram. Patent applicant Advance Co., Ltd. Figure 1 Figure 2 Figure 4 1υ 20 tK) 60 No. 6
figure

Claims (1)

[Claims] (1) An organometallic compound having a structure in which calcium and an organic group are bonded via oxygen is reacted with phosphoric acid that can undergo a condensation reaction in an organic solvent, and the resulting condensation reaction product is neutralized or alkaline. A method for producing crystalline hydroxyapatite, which comprises crystallizing it by refluxing in the presence of water.