JP2015086097A - (carbonate) calcium apatite containing strontium and method of producing fine particle of the same - Google Patents

Abstract

[PROBLEMS] To provide a simple and highly productive production method for obtaining strontium-containing (carbonated) calcium apatite with high purity by controlling the crystallinity by a single-step reaction, and the crystallinity is controlled, and the coating uses A method of producing (carbonic acid) calcium apatite fine particles containing strontium suitable for the above. A mixture containing a strontium salt and a calcium salt in an arbitrary ratio and a phosphate, carbonate or hydrogencarbonate at a specific molar ratio are mixed in water to carry out the reaction. The obtained calcium carbonate apatite containing strontium is wet-dispersed using a media mill. [Selection figure] None

Description

  INDUSTRIAL APPLICABILITY The present invention provides a simple and highly productive method for obtaining strontium-containing (carbonic acid) calcium apatite with high purity by controlling the crystallinity by a one-step reaction, and the crystallinity is controlled and the coating application It is related with the manufacturing method of the (carbonic acid) calcium apatite microparticles | fine-particles containing strontium suitable for.

  A preferred method of using hydroxyapatite as one of medical materials varies depending on the degree of crystallinity. Highly crystalline hydroxyapatite obtained by processing at high temperatures using methods such as sintering and hydrothermal treatment is extremely stable both physically and chemically. Often used as a permanent surface coat for implants. In contrast, the low crystalline hydroxyapatite synthesized under relatively low temperature conditions in water or oil as a wet method has relatively high solubility in the in vivo environment and is further absorbed by osteoclasts. It has a feature that it can be easily replaced and then replaced with living bones and can actively contribute to bone remodeling. Since these characteristics can be used, low crystalline hydroxyapatite is expected to play an effective role in bone regeneration treatment as a unique material having both bioresorption and osteoconductivity. In Non-Patent Document 1, when hydroxyapatite with different crystallinity is used and osteoblasts are cultured on the surface thereof, hydroxyapatite with lower crystallinity is superior in cell adhesion, It has been reported as a more preferred material. Patent Document 1 discloses a bioabsorbable implant containing non-baked hydroxyapatite having low crystallinity in an amorphous molded body. In the case where the effect of regenerative treatment is expected in a relatively short period of time, it is considered preferable to construct an implant material having a high bioabsorbability using such a low crystallinity hydroxyapatite. Furthermore, in the process of being decomposed in vivo, if the finely divided hydroxyapatite is peeled off, the highly crystalline hydroxyapatite granules may cause an inflammatory reaction, Since low crystalline hydroxyapatite is relatively excellent in biocompatibility, it can be preferably used as a safer material in vivo.

  As another approach for promoting the bone repair process, a method utilizing the pharmacological effect of a strontium compound has been attempted. Non-Patent Document 2 shows a favorable effect on alkaline phosphatase activity in cell culture using apatite containing strontium. Alternatively, Patent Document 2 discloses a pharmaceutical composition comprising a combination of strontium salt and vitamin D, which is effective in treating cartilage damage and bone injury, and Patent Document 3 further discloses a combination of strontium and an organic acid. Disclosed are pharmaceutical compositions that are effective in the treatment of cartilage disorders and bone injuries consisting of water-soluble strontium salts formed between them. Therefore, by using apatite containing strontium for the above-mentioned bioimplant use, a useful pharmacological action regarding bone treatment is also expected.

  It is also known that the pharmacological action of strontium compounds is dose-dependent and, if excessively administered, it has an adverse effect on bone regeneration. Therefore, it is preferable that the concentration of the eluting strontium compound is present in a controlled manner at a local site in the living body where bone regeneration is performed. Therefore, as a strontium compound, a compound having a moderate solubility in vivo is desired.

  From the technical background described above, by using (carbonic acid) calcium apatite containing strontium with controlled crystallinity in a field such as regenerative medicine of in vivo hard tissue, for example, utilizing the properties of low crystalline calcium apatite, If a low crystalline calcium apatite containing strontium that can be easily absorbed by a living body and can exhibit the sustained release of strontium can be realized, a very favorable effect is expected. In particular, if a low crystalline calcium apatite containing strontium in which strontium is introduced at an arbitrary ratio to a hydroxyapatite that has been actively used, a very favorable effect and safety can be expected. it is conceivable that. From such a viewpoint, for example, Non-Patent Document 3 shows an example of calcium carbonate apatite containing strontium. Here, the synthesis method, a disk made using this, and the initial adhesion, proliferation and activity of the cells when osteoblasts are cultured on the surface, the ratio of strontium contained in calcium carbonate apatite is evaluated. And the correlation between these properties. As a result, it has been reported that the introduction of strontium promotes the initial adhesion of cells, and that there is an optimum value for the bone alkaline phosphatase activity and the ratio of strontium in the cells. However, the calcium carbonate apatite containing strontium used in the above report is a gypsum containing calcium carbonate and strontium carbonate and immersed in an aqueous sodium phosphate solution for a long time of 7 days at 100 ° C. In order to produce industrially stable, there was a problem in the manufacturing method. In addition, the calcium carbonate apatite containing strontium obtained by the above method has a problem in purity because a trace amount of calcium carbonate is mixed as an impurity. Furthermore, the shape of the apatite to be used is not a fine particle or granule that is preferably used in applications such as bone filler, but is limited to a shape that can be molded in advance in the form of gypsum, or because it is hard and brittle. There were restrictions on how to use it.

  It is known that (carbonic acid) calcium apatite containing strontium is excellent in X-ray contrast properties as one of the unique characteristics, in addition to the fact that biocompatibility and safety to the living body have been confirmed. One of the uses of apatite containing strontium includes application to various living body (absorbable) implants in addition to the above-mentioned bone filler. For example, when it is assumed to be used as a coating material such as a surface coat of a living body (absorbable) implant, the coated surface exhibits biocompatibility and excellent osteoconductivity and can impart X-ray contrast properties. The advantage comes out.

  Furthermore, when the above-mentioned layer containing strontium-containing (carbonic acid) calcium apatite is formed by coating, the surface coating layer needs to have a uniform thickness and properties, and the coating suitability includes strontium (carbonic acid). Calcium apatite is as fine and uniform as possible, and the fine particles are stably dispersed in a coating solution containing a dispersion of (carbonic acid) calcium apatite fine particles containing strontium, and are settled or precipitated over time. The property which does not generate a thing and an aggregate is requested | required. Calcium carbonate apatite containing strontium obtained by various conventional production methods is obtained as a granular or massive powder, and it is difficult to obtain a stable and finely dispersed dispersion in a medium such as water. Therefore, it was difficult to apply to coating applications.

  Patent Document 4 discloses a method of forming a (carbonic acid) calcium apatite layer containing strontium on the surface of a biological implant. This method is based on a method of forming a calcium apatite layer on the surface of the base material from a simulated body fluid that has been studied in the past. (Calcium carbonate) containing strontium spontaneously from a solution containing a strontium salt on the surface of the implant base material Although it is a method of forming an apatite layer, it is difficult to control the thickness of the apatite layer, it takes a long time to form the layer, and in addition, the crystallinity of calcium carbonate apatite containing strontium is controlled. Was extremely difficult.

  Patent Document 5 discloses a bioimplant material made of calcium carbonate apatite containing strontium and / or strontium phosphate devitrifying glass containing strontium phosphate. A method exemplified as a method for producing this strontium phosphate devitrifying glass is a method in which strontium oxide is melted at a high temperature of 1600 ° C. by adding various oxides including silicon dioxide and alumina as a glass raw material component together with phosphorus pentoxide, The devitrified glass is produced by cooling. At this time, it is disclosed that a solid solution containing strontium and calcium in an arbitrary ratio in apatite can be obtained by mixing calcium oxide together with strontium oxide in an arbitrary ratio. When calcium carbonate apatite containing strontium was produced using this method, the product had extremely high crystallinity and poor bioabsorbability. Therefore, also in this case, there is a problem that it is difficult to obtain (carbonic acid) calcium apatite containing high-purity strontium in a controlled crystal form.

  Patent Document 6 discloses a medical or dental curable composition using a strontium phosphate devitrifying glass powder containing a strontium-containing (carbonic acid) calcium apatite and / or strontium phosphate and a kneading agent. Has been. In particular, it is preferable as a dental cement material because it has good curing characteristics and X-ray contrast ability, but in this case as well, it is limited to the method of use as a glass body containing (carbonic acid) calcium apatite containing strontium. There has been a demand for a method for producing calcium carbonate apatite containing high-purity strontium that does not contain components such as glass in a controlled form.

  In Patent Document 7, as a method for producing (carbonic acid) calcium apatite containing strontium, strontium hydrogen phosphate and strontium hydroxide or strontium carbonate are mixed using a pot mill, stirred, and mechanochemically reacted to form apatite containing strontium. A method for synthesizing (carbonic acid) calcium apatite containing strontium by pre-calcining the precursor at a temperature of about 800 ° C. is disclosed. Even in this method, low crystalline apatite cannot be obtained because it is processed at a high temperature, and further, it is necessary to stir the raw material powder for a long time, and it is also necessary to process at a high temperature in the subsequent calcination step. Therefore, slight differences in reaction conditions may greatly affect the purity, structure and crystallinity of the product, resulting in low productivity and high purity strontium in a controlled crystallinity (calcium carbonate) There was a problem that it was difficult to obtain apatite.

  Non-Patent Document 4 shows a method for synthesizing strontium apatite by a uniform precipitation method. Among them, as a method for synthesizing strontium apatite, a method for synthesizing strontium apatite using a precursor of a strontium phosphate salt using urea is shown. In this method, since the hydrolysis reaction of urea is used, the generated carbon dioxide may be taken into the apatite produced. This affects the crystallinity of the apatite to be produced, and the crystallinity changes variously depending on the reaction conditions. In addition, various impurities such as chlorine ions may be contained in addition to this, such a method. It was difficult to obtain (carbonic acid) calcium apatite containing high-purity strontium in a form in which the crystallinity targeted by the present invention was controlled using.

Japanese Patent No. 3597716 JP2012-193208A JP 2012-167100 A US Pat. No. 6,905,723 B2 JP-A-6-39031 Japanese Patent Laid-Open No. 5-23389 JP-A-5-310410

Balasundaram G., et al, BioMaterials, 27, 2798-2805, (2006) Zhang W et al, Acta Biomater., 7, 800-808, (2011) Sakai A., et al, Dental Materials Journal, 31 (2), 197-205, (2005) Chiharu Kato, Kazumi Fujita, Keizo Matsuda, Journal of the Chemical Society of Japan, No. 3, 321-227, (2002)

  INDUSTRIAL APPLICABILITY The present invention provides a simple and highly productive method for obtaining strontium-containing (carbonic acid) calcium apatite with high purity by controlling the crystallinity by a one-step reaction, and the crystallinity is controlled and the coating application An object of the present invention is to provide a method for producing (carbonic acid) calcium apatite fine particles containing strontium.

The problems of the present invention are basically solved by using the following manufacturing method.
1. A method for producing (carbonic acid) calcium apatite containing strontium, wherein a mixture containing a strontium salt and a calcium salt and a phosphate, and a carbonate or hydrogen carbonate are mixed in water and reacted. When the molar ratio of the sum of moles of strontium salt and calcium salt is A, the molar ratio of phosphate is B, and the molar ratio of carbonate or bicarbonate is C, the following (i) to (iii) The manufacturing method of the (carbonic acid) calcium apatite containing strontium which satisfy | fills any of these requirements and the pH of a reaction system exists in the range of 5-13.
(I) When the phosphate is a tertiary phosphate
A: B: C = 1: (0.6 to 0.8) α: (0.1 to 0.3) α.
(Ii) When the phosphate is hydrogen phosphate
A: B: C = 1: (0.6 to 1.2) α: p (0.3 to 0.5) α.
(Iii) When the phosphate is dihydrogen phosphate
A: B: C = 1: (0.6 to 1.2) α: p (0.7 to 1.0) α.
In the formula, α represents a real number of 0.1 ≦ α ≦ 10. p represents a coefficient, 1 for a carbonate, and 2 for a bicarbonate.
2. The molar ratio of the carbonate or bicarbonate is less than the molar ratio obtained by adding 0.1α in the case of the requirement (i) to the lower limit of the molar proportion of the carbonate or bicarbonate described above. In the case of (ii) or (iii), the method for producing calcium apatite containing strontium according to 1 above, wherein the molar ratio is less than 0.1 pα added.
3. In the case of the requirement (i) above, the molar ratio of the carbonate or hydrogencarbonate is not less than the molar ratio of the above-mentioned lower limit of the molar ratio of the carbonate or hydrogencarbonate. (Ii) In the case of (iii), the manufacturing method of the calcium carbonate apatite containing the strontium of said 1 which is more than the molar ratio which added 0.1 p (alpha).
4). The manufacturing method of the (carbonic acid) calcium apatite microparticles | fine-particles containing the strontium which carries out the wet dispersion process using the media mill for the (carbonic acid) calcium apatite containing the strontium obtained by the manufacturing method in any one of said 1-3.
5. 5. The method for producing (carbonic acid) calcium apatite fine particles containing strontium according to the above 4, wherein the wet dispersion treatment is performed by adding polyphosphoric acid (salt) when the wet dispersion treatment is performed.

  INDUSTRIAL APPLICABILITY According to the present invention, a simple and highly productive manufacturing method for obtaining a high-purity strontium-containing (carbonated) calcium apatite with controlled crystallinity by a one-step reaction, and the crystallinity is controlled and coated A method for producing calcium carbonate apatite fine particles containing strontium suitable for the application can be provided.

A wide angle X-ray diffraction pattern of calcium apatite containing calcium and strontium obtained in Example 1 in a ratio of 2: 8. A wide-angle X-ray diffraction pattern of calcium apatite containing calcium and strontium obtained in Example 2 in a ratio of 4: 6. A wide-angle X-ray diffraction pattern of calcium apatite containing calcium and strontium obtained in Example 3 in a ratio of 6: 4. A wide angle X-ray diffraction pattern of calcium apatite containing calcium and strontium obtained in Example 4 in a ratio of 8: 2. 4 is an FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 1 in a ratio of 2: 8. 4 is an FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 2 in a ratio of 4: 6. 4 is an FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 3 in a ratio of 6: 4. FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 4 in a ratio of 8: 2. 3 is a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing the calcium apatite containing strontium obtained in Example 1 without using a dispersant. The particle diameter distribution curve of the calcium apatite fine particle dispersion containing strontium obtained by performing the wet dispersion process for the calcium apatite containing strontium obtained in Example 2 without using a dispersant. 3 is a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing the calcium apatite containing strontium obtained in Example 3 without using a dispersant. 4 is a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing the calcium apatite containing strontium obtained in Example 4 without using a dispersant. The particle diameter distribution curve of the calcium apatite fine particle dispersion containing strontium obtained by performing the wet dispersion process for the calcium apatite containing strontium obtained in Example 1 using polyphosphoric acid. The particle diameter distribution curve of the calcium apatite fine particle dispersion containing strontium obtained by performing the wet dispersion process for the calcium apatite containing strontium obtained in Example 4 using polyphosphoric acid.

  First, the (carbonic acid) calcium apatite containing strontium targeted by the present invention will be described. In the present invention, the term (carbonic acid) calcium apatite containing strontium represents calcium apatite containing strontium or calcium carbonate apatite containing strontium. Specifically, the calcium apatite containing strontium of the present invention is a compound represented by the structure represented by the following general formula (I). However, as a compound generally referred to as apatite, the ratio of calcium atom and strontium atom, phosphate group and hydroxyl group is not uniquely determined as in the case of hydroxyapatite, and the composition represented by the general formula (I) A compound having a stoichiometric composition ratio slightly different before and after the ratio as a standard is also included as calcium apatite containing strontium of the present invention.

  In the general formula (I), x represents an arbitrary real number in the range of 0 <x <1.

  In the present invention, the calcium apatite in which a part of the phosphate group in the apatite is replaced with a carbonate group in the general formula (I) has a typical structure of the calcium carbonate apatite containing strontium of the present invention. is there.

  Next, the high purity standard referred to in the present invention will be described. The strontium-containing (carbonated) calcium apatite obtained in the present invention is intended to provide a highly safe and high-quality material on the premise of application to medical use. Therefore, it is preferable that the organic substance is not substantially contained, and even an inorganic substance does not contain a component that may cause safety concerns for a living body. As a criterion for high purity in the present invention, if it is an inorganic component such as a salt that is not concerned with safety, it is contained in a (carbonate) calcium apatite containing strontium obtained in the present invention if it is contained in a trace amount. Even if it exists, it is preferable that it is less than 5 mass% at the maximum as the upper limit, More preferably, it is less than 1 mass%. In the present invention, the phrase “substantially free of organic matter” means that the organic matter is less than 1% by mass with respect to (carbonate) calcium apatite containing strontium. More preferably, it is less than 0.1 mass%. In addition to these, it is important that impurities having safety concerns are not contained in the apatite obtained in the present invention.

  The (carbonic acid) calcium apatite containing strontium obtained in the present invention is characterized by being highly pure and capable of producing fine particles thereof. The size of the (carbonic acid) calcium apatite fine particles containing strontium referred to in the present invention is preferably 10 μm or less at the volume average particle diameter. The size of the strontium-containing (carbonic acid) calcium apatite fine particles obtained in the present invention is preferably in the range of 40 nm to 10 μm in the volume average particle diameter, and the smaller the volume average particle diameter, the more the case is applied to the coating application. Since the coating film excellent in uniformity was formed, it was considered more preferable. Furthermore, as a condition for being suitable for coating use in the present invention, the dispersion stability of the fine particles of the calcium carbonate apatite containing strontium containing the strontium used in the present invention is dispersed. It is preferable that the particles are not aggregated or settled during storage for a long period of time (for example, a storage period of 1 week at room temperature).

  As an element constituting the method for producing (carbonic acid) calcium apatite containing strontium given in the present invention, a mixture containing strontium salt and calcium salt in any proportion in water and a phosphate, and carbonate or bicarbonate Basically, the reaction is carried out by mixing. Each component will be described below.

  Compounds that can be preferably used in the present invention as strontium salts include strontium chloride and its hydrate, strontium bromide and its hydrate, strontium iodide and its hydrate, strontium acetate and its hydrate, nitric acid A strontium salt having a solubility in water at 10 ° C. of 1% by mass or more, such as strontium, strontium oxalate and its hydrate, strontium formate and its hydrate, strontium hydroxide and its hydrate, and strontium oxide It can be preferably used. In these strontium salts, it is preferable that impurities are not contained as much as possible, and as a purity, it is preferable that strontium salts and hydrates thereof are contained at a purity of at least 95% by mass, and further 98 masses. % Purity or higher is preferable.

  As a compound that can be preferably used in the present invention as a calcium salt, any calcium salt can be used as long as it is a water-soluble calcium salt. Preferred examples include calcium chloride, calcium nitrate, calcium acetate, and each of these. Hydrates can be preferably used. In addition, water solubility means here that the solubility with respect to 10 degreeC water is 1 mass% or more.

  The present invention is characterized by using a mixture containing a strontium salt and a calcium salt in an arbitrary ratio. When the sum of the molar ratios of both is constant, a mixture containing both strontium and calcium salts in various molar ratios is used in the reaction described below, so that the ratio of strontium ions and calcium ions contained in calcium apatite. It is one of the features of the present invention that can be controlled at an arbitrary ratio.

Examples of suitable raw materials for phosphate include disodium hydrogen phosphate, dipotassium hydrogen phosphate, dilithium hydrogen phosphate, diammonium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, phosphorus Particularly preferred examples include lithium dihydrogen oxide, ammonium dihydrogen phosphate, sodium phosphate, potassium phosphate, lithium phosphate, ammonium phosphate, and their respective hydrates. Also for these, a water-soluble phosphate having a solubility in water at 10 ° C. of 1% by mass or more can be preferably used. Hydrogen phosphate salt is the phosphate as described above _(HPO ^{4 -),} dihydrogen phosphate ^- there are three kinds of and tertiary phosphates ^{_{(PO 4 ---) (H 2}} PO 4) However, by selecting appropriate reaction conditions described below for each, any of them can be preferably used to obtain (carbonic acid) calcium apatite containing strontium of the present invention. In these phosphates, it is preferable that impurities are not contained as much as possible, and as a purity, it is preferable that the phosphate and its hydrate are contained at a purity of at least 95% by mass, The purity is preferably 98% by mass or more.

  Examples of the carbonate or bicarbonate that can be used in the present invention include 1 mass of solubility in 10 ° C. water of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, ammonium bicarbonate, ammonium carbonate and the like. % Or more water-soluble carbonate is particularly preferred. It is preferable that impurities are not contained in these carbonates as much as possible, and the purity is preferably at least 95% by mass or more, and carbonate or hydrogen carbonate is preferably contained, and further 98% by mass. It is preferable that it is the above purity. Since the molar ratio that can be used to obtain the (carbonic acid) calcium apatite containing strontium of the present invention is different between carbonate and hydrogencarbonate, the carbonate and hydrogencarbonate will be individually described in the text.

  In the present invention, the reaction is carried out by mixing a mixture of strontium salt and calcium salt with phosphate, and carbonate or bicarbonate in water, but the ratio of strontium salt and calcium salt is variously changed. It is the gist of the present invention to produce (calcium carbonate) calcium apatite containing strontium and containing ions of both strontium and calcium in an arbitrary ratio in the calcium apatite to be produced by performing the reaction using the mixed mixture. . At this time, as shown in Examples described later, it is possible to control the crystallinity of (carbonic acid) calcium apatite containing strontium obtained in accordance with the ratio of strontium ions contained in the apatite. Became clear. Furthermore, by using the production method of the present invention, the molar ratio of the strontium salt and calcium salt added during the synthesis is almost the same as each molar ratio contained in the (carbonic acid) calcium apatite containing the product strontium. From the agreement, it is a feature of the present invention that the ratio of strontium ions and calcium ions contained in the (carbonic acid) calcium apatite containing strontium can be strictly controlled.

  The method for producing (carbonic acid) calcium apatite containing strontium according to the present invention basically includes a mixture of a strontium salt and a calcium salt, a phosphate, and a carbonate or bicarbonate described later in water. As long as they are mixed with each other within a molar ratio range, they do not depend on their addition method. The most important feature of the present invention is that calcium carbonate apatite containing strontium can be produced by a one-step reaction of mixing as described above. As the mixing method, for example, each salt is added to water independently in the form of a solid (dispersion) or an aqueous solution, and stirring is performed so that each salt is uniformly mixed in water. May be. Alternatively, an aqueous solution in which phosphate and carbonate or hydrogen carbonate are both dissolved is prepared in advance, and this is used to add both the strontium salt and calcium salt to the dissolved aqueous solution. You may perform the method of adding the aqueous solution which melt | dissolved both the strontium salt and the calcium salt in the aqueous solution which melt | dissolved both acid salt and carbonate, or hydrogen carbonate. In the present invention, it is preferable that the phosphate and the carbonate or bicarbonate are mixed in a mixture of a strontium salt and a calcium salt while maintaining an appropriate molar ratio. As an addition method that can be most preferably used, an aqueous solution in which both a strontium salt and a calcium salt are dissolved and an aqueous solution in which both a phosphate and a carbonate or bicarbonate are dissolved is added. Can be mentioned. Thereby, (carbonic acid) calcium apatite containing higher purity strontium is obtained, which is preferable.

  It is not necessary to adjust the pH of the aqueous solution when both the strontium salt and the calcium salt are dissolved in water. In this case, the pH of the aqueous solution is usually about 5 to 7. When an aqueous solution containing both phosphate and carbonate or bicarbonate is mixed with the aqueous solution in which both the strontium salt and calcium salt are dissolved in accordance with the above preferred addition method, the pH of the latter aqueous solution is 5 It is preferable that it exists in the range of -13. Furthermore, the pH of the reaction system when the reaction is carried out by mixing an aqueous solution containing both phosphate and carbonate or bicarbonate with an aqueous solution containing both strontium salt and calcium salt is 5-13. It is preferable that it exists in the range. Usually, in the production conditions of the (carbonic acid) calcium apatite containing strontium of the present invention, the pH is kept within the above preferred range without any particular adjustment.

  The reaction temperature when the reaction is carried out by mixing a mixture of strontium salt and calcium salt with phosphate and carbonate or hydrogen carbonate in water is preferably in the range of 0 to 100 ° C, more preferably Is 20-70 ° C. When the reaction is performed by mixing a mixture of strontium salt and calcium salt, phosphate, and carbonate or bicarbonate in water at a reaction temperature outside these temperature ranges, it contains the desired strontium (carbonic acid) The yield of calcium apatite is reduced, and other compounds may be formed as by-products. In the present invention, the term “water” means that the above-described reaction is carried out in a medium containing at least 50% by mass of water, more preferably 60% by mass or more. You may react in the state which introduce | transduced various organic solvents to mix, or nitrogen, helium, a carbon dioxide gas, and other gas.

Next, the phosphate that can be used in the present invention will be described in more detail. The case where a tertiary phosphate is used as the phosphate that can be used in the present invention will be described. For example, when sodium phosphate (Na ₃ PO ₄ ) is used as the (third) phosphate, a mixture of this and the above strontium salt and calcium salt (hereinafter, a case of a mixture of strontium chloride and calcium chloride is shown as an example, In the reaction formula, both strontium ions and calcium ions are hereinafter abbreviated as M. M means a mixture of strontium ions and calcium ions in any proportion) (carbon carbonate apatite containing strontium). In order to obtain, what has been found in the present invention that the reaction for obtaining the apatite proceeds by adding carbonate (shown here as an example using sodium carbonate) as follows It is.

10MCl ₂ + 6Na ₃ PO ₄ + Na ₂ CO ₃ + 2H ₂ O
→ M ₁₀ (PO ₄ ) ₆ (OH) ₂ +20 NaCl + CO ₂ + H ₂ O

  Here, when a hydrogen carbonate is used instead of the carbonate, the pH of the tertiary phosphate is 11 or higher, so that the tertiary phosphate and the bicarbonate are in the same solution. When dissolved together, the hydrogen carbonate is neutralized with alkali and converted to carbonate. At that time, even when tertiary phosphate is changed to hydrogen phosphate by neutralization reaction, the molar ratio as phosphate does not change, so even when bicarbonate is used instead of carbonate, The molar ratios to be used are the same as in the previous carbonate.

  From the above chemical reaction equation, the molar ratio of each of the mixture of strontium salt and calcium salt, tertiary phosphate, and carbonate is calculated to be 1: 0.6: 0.1 in the ratio of strontium. It is suggested that it contributes to the reaction which forms (carbonic acid) calcium apatite containing. On the other hand, phosphate and carbonate react with strontium salt and calcium salt, respectively, and produce strontium hydrogen phosphate, calcium hydrogen phosphate, strontium carbonate, and calcium carbonate under the above reaction conditions. . Therefore, in the calculation, when the tertiary phosphate and the carbonate are both included at a ratio of 0.6: 0.1, the above strontium hydrogen phosphate, strontium carbonate, etc. are not generated, and the above It is expected that (carbonic acid) calcium apatite containing strontium of the following reaction formula is generated. From such assumptions, it is preferable to carry out the reaction by simultaneously mixing the tertiary phosphate and the carbonate in the presence of the mixture of the strontium salt and the calcium salt. The molar ratio is considered important. However, in an actual reaction system, the above reaction does not always proceed only at the above molar ratio, and the molar ratio includes the case of a ratio of 0.6: 0.1 respectively. It has been clarified in the present invention that the preferred range exists, including the examples described later.

  Further, within the range of the preferred molar ratio of tertiary phosphate to carbonate, the sum of the moles of strontium salt and calcium salt is present in the reaction system less than 1 mole ratio or exceeding 1 mole ratio. It turns out that there is no problem even if it does. That is, with respect to 1 mole ratio of the total number of moles of the mixture of strontium salt and calcium salt, tertiary phosphate and carbonate are, for example, maintained at a ratio of 0.6: 0.1 as an example of the preferred mole ratio. In the case where the tertiary phosphate and the carbonate are contained at a real number multiple of α represented by 0.6α: 0.1α (0.1 ≦ α ≦ 10), It became clear to progress. For example, when α is 1, the mixture of strontium salt and calcium salt, tertiary phosphate, and carbonate contribute to the reaction without excess and deficiency according to the above reaction formula, and the result with the best yield is obtained. It is thought to give. On the other hand, when α is less than 1, since the ratio of the mixture of strontium salt and calcium salt to the tertiary phosphate and carbonate is excessive, excess strontium salt and calcium salt are added to the reaction system at the end of the reaction. Although it remains, it can be easily removed from the produced apatite by a treatment such as washing with water. However, when α is less than 0.1, 90% or more of the total number of moles of the mixture of strontium salt and calcium salt to be used is excessive, so that the yield is lowered, which is not preferable. Furthermore, when α exceeds 1, both tertiary phosphate and carbonate are excessive with respect to the strontium salt and calcium salt to be used. In this case as well, it should be removed by washing or the like. I can do it. However, when α exceeds 10, since 90% or more of both the tertiary phosphate and carbonate to be used are excessive, the yield is lowered, which is not preferable.

  Regarding the molar ratio of the mixture of strontium salt and calcium salt and the tertiary phosphate in the reaction, at least the molar ratio of the mixture of strontium salt and calcium salt in the previous reaction formula is at least 1 molar ratio. Although it was estimated that it was necessary to include a 0.6α molar ratio, as shown in the examples described later, a result supporting this was also obtained in actual experimental results. However, the tertiary phosphate may be added to the reaction system in excess of 0.6α molar ratio, and when the molar ratio is within the range not exceeding 0.8α molar ratio, high purity strontium is added. It has been found that the containing (carbonic acid) calcium apatite can be obtained in high yield. That is, the molar ratio that can be used for the tertiary phosphate is (0.6 to 0.8) α molar ratio relative to 1 molar ratio of the total number of moles of the mixture of strontium salt and calcium salt. When the reaction is carried out at a ratio deviating from this range, compounds other than (carbonic acid) calcium apatite containing strontium are formed as a by-product, and the purity of the product is lowered.

  Next, regarding the ratio of carbonate, in the estimation from the above chemical formula, the molar ratio of 0.1α is included in the preferable range with respect to 1 mole ratio of the sum of the number of moles of the mixture of strontium salt and calcium salt. However, as shown in the examples described later, as a result of experiments conducted at various molar ratios, in a reaction system containing both tertiary phosphates within the above preferred molar ratio range. The preferred molar ratio range of the carbonate to be used is (0.1 to 0.3) α, in which case the high purity strontium targeted by the present invention is contained (carbonic acid). It has been found that calcium apatite can be obtained in high yield. To summarize the above, the triphosphate and carbonate have a (0.6 to 0.8) α molar ratio and (0. 0. 0), respectively, with respect to 1 mole ratio of the total number of moles of the strontium salt and calcium salt mixture. 1 to 0.3) When the reaction is carried out by mixing these in water within the range of α molar ratio, the high yield of the (carbonic acid) calcium apatite containing the high purity strontium targeted by the present invention is high. Can be obtained.

  The pH of the reaction system in the case of carrying out the reaction in the above combination does not need to be particularly controlled, and the aqueous solution of the tertiary phosphate to be used usually has a pH in the range of 11 to 13, so that the carbonate or hydrogen carbonate is added thereto. Since the pH of the aqueous solution to which the salt is added is also in this range, by mixing the aqueous solution containing the strontium salt in the range of pH 11 to 13 with the aqueous solution containing the tertiary phosphate and carbonate or bicarbonate. It is preferable to react both.

Next, the case where hydrogen phosphate is used as the phosphate that can be used in the present invention will be described in more detail. For example, when disodium hydrogen phosphate (Na ₂ HPO ₄ ) is used as the hydrogen phosphate, in order to obtain (carbonate) calcium apatite containing strontium between this and a mixture of the above strontium salt and calcium salt The present inventors have found that the reaction for obtaining the apatite proceeds by adding a carbonate (shown here as an example using sodium carbonate) as described below. In the following formula, M represents a mixture of calcium ions and strontium ions as described above, and the sum of the number of moles of both is 1 molar ratio.

10MCl ₂ + 6Na ₂ HPO ₄ + 4Na ₂ CO ₃ + 2H ₂ O
→ M ₁₀ (PO ₄ ) ₆ (OH) ₂ +20 NaCl + 4CO ₂ + 4H ₂ O

  From the above chemical reaction equation, the molar ratio of each of the mixture of strontium salt and calcium salt, hydrogen phosphate, and carbonate is calculated to be 1: 0.6: 0.4. It is suggested that it contributes to the reaction which forms calcium carbonate apatite containing. On the other hand, hydrogen phosphate and carbonate react with strontium salt and calcium salt, respectively, and produce strontium hydrogen phosphate, calcium hydrogen phosphate, strontium carbonate, and calcium carbonate under the above reaction conditions. To do. Therefore, in the calculation, when both hydrogen phosphate and carbonate are included at a ratio of 0.6: 0.4, the above strontium hydrogen phosphate, strontium carbonate, etc. are not generated, and the above-mentioned It is expected that calcium carbonate apatite containing strontium in the reaction formula is generated. From such estimation, it is preferable to carry out the reaction by simultaneously mixing hydrogen phosphate and carbonate in the presence of a mixture of strontium salt and calcium salt, and the molar ratio of hydrogen phosphate and carbonate at that time Is considered important. However, in an actual reaction system, the above reaction does not always proceed only at the above molar ratio, and the molar ratio includes the case of a ratio of 0.6: 0.1 respectively. It has been clarified in the present invention that the preferred range exists, including the examples described later.

  Further, within the above range of the preferred molar ratio of hydrogen phosphate and carbonate, the sum of the number of moles of the mixture of strontium salt and calcium salt is less than 1 mole ratio or more than 1 mole ratio in the reaction system. It was found that there was no problem even if it existed. That is, hydrogen phosphate and carbonate maintained a ratio of, for example, 0.6: 0.4 as an example of the preferred molar ratio with respect to 1 mole ratio of the total number of moles of the mixture of strontium salt and calcium salt. The above reaction proceeds even in the case where hydrogen phosphate and carbonate are contained at a real number multiple of α represented by 0.6α: 0.4α (0.1 ≦ α ≦ 10). It became clear. For example, when α is 1, the mixture of strontium salt and calcium salt, hydrogen phosphate, and carbonate contribute to the reaction without excess and deficiency according to the above reaction formula, and the results with the best yield are obtained. It is thought to give. On the other hand, when α is less than 1, the ratio of the mixture of strontium salt and calcium salt to hydrogen phosphate and carbonate is excessive, so that excess strontium salt and calcium salt remain in the reaction system at the end of the reaction. However, it can be easily removed from the produced apatite by a treatment such as washing with water. However, when α is less than 0.1, 90% or more of the total number of moles of the mixture of strontium salt and calcium salt to be used is excessive, so that the yield is lowered, which is not preferable. Furthermore, when α exceeds 1, both hydrogen phosphate and carbonate are excessive with respect to the strontium salt and calcium salt to be used, but in this case as well, it can be removed by a treatment such as water washing. I can do it. However, when α exceeds 10, since 90% or more of both the hydrogen phosphate and carbonate used are excessive, the yield is lowered, which is not preferable.

  Regarding the molar ratio of the mixture of strontium salt and calcium salt to hydrogen phosphate when the reaction is performed, in the above reaction formula, at least 0 with respect to 1 molar ratio of the sum of the number of moles of the mixture of strontium salt and calcium salt. It was estimated that it was necessary to contain a .6α molar ratio. However, as shown in the examples described later, a result supporting this was obtained in actual experimental results. However, hydrogen phosphate may be added to the reaction system in excess of 0.6α molar ratio, and contains high-purity strontium when the molar ratio is within a range not exceeding 1.2α molar ratio as the upper limit. It has been found that (carbonic acid) calcium apatite can be obtained in high yield. That is, the molar ratio in which hydrogen phosphate can be used is within the range of (0.6 to 1.2) α molar ratio with respect to 1 molar ratio of the total number of moles of the mixture of strontium salt and calcium salt. When the reaction is carried out at a ratio deviating from this range, compounds other than (carbonic acid) calcium apatite containing strontium are formed as a by-product, and the purity of the product is lowered.

  Next, regarding the ratio of carbonate, in the estimation from the above chemical formula, the molar ratio of 0.4α is included in the preferable range with respect to 1 mole ratio of the sum of the number of moles of the mixture of strontium salt and calcium salt. However, as shown in the examples described later, as a result of actually conducting experiments at various molar ratios, in the reaction system containing both hydrogen phosphates within the preferred molar ratio range, The preferred molar ratio range of the carbonate to be used is (0.3 to 0.5) α, in which case the calcium carbonate containing the high purity strontium that is the object of the present invention. It has been found that apatite can be obtained in high yield. When the above is arranged, hydrogen phosphate and carbonate each have a (0.6 to 1.2) α molar ratio and (0.3) with respect to 1 molar ratio of the total number of moles of the mixture of strontium salt and calcium salt. -0.5) When the reaction is carried out by mixing them in water within the range of α molar ratio, the high-purity strontium-containing (carbonated) calcium apatite of the present invention can be obtained in a high yield. Can be obtained.

  Similarly, in the above chemical formula, when sodium hydrogen carbonate is used as the hydrogen carbonate instead of the carbonate, it is considered that the reaction for producing (carbonic acid) calcium apatite containing strontium proceeds as in the following formula. In the following formula, M represents a mixture of calcium ions and strontium ions, and the sum of the number of moles of both is 1 molar ratio.

10MCl ₂ + 6Na ₂ HPO ₄ +8 NaHCO ₃ + 2H ₂ O
→ M ₁₀ (PO ₄ ) ₆ (OH) ₂ +20 NaCl + 8CO ₂ + 8H ₂ O

  In the above reaction formula, when hydrogen carbonate is used instead of carbonate, the molar ratio of hydrogen phosphate with respect to 1 molar ratio of strontium salt is not affected, and the molar ratio of hydrogen phosphate is It was found to be (0.6 to 1.2) α. Further, it is apparent in the present invention that the range of the molar ratio of the hydrogen carbonate to the molar ratio of the strontium salt is twice as much as that in the case where the carbonate is used, as shown in Examples described later. became. Summarizing the above, when mixing and reacting hydrogen phosphate and carbonate or bicarbonate in water with strontium salt, the molar ratio of the mixture of strontium salt and calcium salt is 1 mole ratio. In contrast, hydrogen phosphate is (0.6 to 1.2) α molar ratio, carbonate or bicarbonate is p (0.3 to 0.5) α (p = 1 in the case of carbonate, In the case of hydrogen carbonate, when the reaction is carried out using a molar ratio of p = 2), the (carbonic acid) calcium apatite containing high-purity strontium targeted by the present invention can be obtained in high yield.

  It is not necessary to control the pH of the reaction system when the reaction is performed in the above combination, and the aqueous solution of hydrogen phosphate to be used usually has a pH in the range of 8 to 10, and carbonate or bicarbonate is added to this. Since the pH of the added aqueous solution is at most less than pH 11, even if it is used as it is for the reaction, the pH of the aqueous solution in which the mixture of the strontium salt and calcium salt is dissolved is around 5-7, so these are mixed. As a pH range of the reaction system, a mixture of a strontium salt and a calcium salt, a hydrogen phosphate salt, and a carbonate salt or a bicarbonate salt are mixed in water while being maintained in a pH range of 5 to 13, and the reaction is smoothly performed. Can be advanced.

Next, the case where dihydrogen phosphate is used as the phosphate that can be used in the present invention will be described in the same manner. For example, when sodium dihydrogen phosphate (NaH ₂ PO ₄ ) is used as the hydrogen phosphate, this is combined with a strontium salt and a calcium salt (for example, the case of chloride) and carbonate (for example, sodium carbonate is used). It is considered that the reaction for producing hydroxyapatite proceeds according to the following chemical formula.

  Here, as a preferable addition method described above, an aqueous solution in which phosphate and carbonate or hydrogen carbonate are mixed in advance is prepared, and an aqueous solution in which a mixture of strontium salt and calcium salt is dissolved is described. In this case, when dihydrogen phosphate is used as the phosphate, the neutralization reaction proceeds by mixing with carbonate or hydrogen carbonate, and the dihydrogen phosphate changes to hydrogen phosphate, It should be noted that although carbonates exist as bicarbonates, there is no change in the relationship between the molar ratios in the reaction, and as a result, the reaction formula is not different from the following formula. In this case as well, as in the case of using the hydrogen phosphate, the pH of the reaction system does not need to be particularly controlled, and the aqueous solution of dihydrogen phosphate to be used usually has a pH in the range of 4 to 5, Since the pH of the aqueous solution to which carbonate or hydrogen carbonate is added is at most less than pH 11, the pH of the aqueous solution in which the strontium salt is dissolved is around 6 to 7 even if it is used in the reaction as it is. As a pH range of the reaction system in which these are mixed, a mixture of a strontium salt and a calcium salt, a hydrogen phosphate, and a carbonate or bicarbonate are mixed in water while maintaining a pH of 5 to 10. The reaction can proceed smoothly.

10MCl ₂ + 6NaH ₂ PO ₄ + 7Na ₂ CO ₃ + 2H ₂ O
→ M ₁₀ (PO ₄ ) ₆ (OH) ₂ +20 NaCl + 7CO ₂ + 7H ₂ O

  From the above chemical reaction formula, the molar ratio of each of the mixture of strontium salt and calcium salt, dihydrogen phosphate and carbonate is calculated to be 1: 0.6: 0.7 in the ratio of strontium. It is suggested that it contributes to the reaction which forms (carbonic acid) calcium apatite containing. On the other hand, when dihydrogen phosphate and carbonate are each used alone and reacted with, for example, a strontium salt, strontium dihydrogen phosphate and strontium carbonate are generated, respectively. Therefore, in the calculation, when dihydrogen phosphate and carbonate are both contained in a ratio of 0.6: 0.7, the latter strontium phosphate or carbonate strontium salt is generated. It is expected that apatite containing strontium of the above reaction formula is generated. From this assumption, it is preferable to carry out the reaction by simultaneously mixing dihydrogen phosphate and carbonate in the presence of a mixture of strontium salt and calcium salt. In this case, the reaction of dihydrogen phosphate and carbonate is preferably performed. The molar ratio is considered important. However, in an actual reaction system, the above reaction does not always proceed only at the above molar ratio, and the molar ratio includes the case of a ratio of 0.6: 0.7, respectively. It has been clarified in the present invention that the preferred range exists, including the examples described later.

  Further, within the above range of the preferred molar ratio of dihydrogen phosphate and carbonate, the sum of moles of strontium salt and calcium salt is present in the reaction system less than 1 mole ratio or exceeding 1 mole ratio. It turns out that there is no problem even if it does. That is, with respect to 1 mole ratio of the total number of moles of the mixture of strontium salt and calcium salt, dihydrogen phosphate and carbonate are, for example, maintained at a ratio of 0.6: 0.7 as an example of the preferred mole ratio. In the case where dihydrogen phosphate and carbonate are contained at a real number multiple of α represented by 0.6α: 0.7α (0.1 ≦ α ≦ 10), the above reaction is It became clear to progress. For example, when α is 1, the mixture of strontium salt and calcium salt, dihydrogen phosphate and carbonate according to the above reaction formula contribute to the reaction without excess and deficiency, respectively, and the results with the best yield are obtained. It is thought to give. On the other hand, when α is less than 1, since the ratio of the mixture of strontium salt and calcium salt to dihydrogen phosphate and carbonate is excessive, excess strontium salt and calcium salt are added to the reaction system at the end of the reaction. Although it remains, it can be easily removed from the (carbonic acid) calcium apatite containing strontium produced by a treatment such as washing with water. However, when α is less than 0.1, 90% or more of the total number of moles of the mixture of strontium salt and calcium salt to be used is excessive, so that the yield is lowered, which is not preferable. Further, when α exceeds 1, both dihydrogen phosphate and carbonate are excessive with respect to the mixture of strontium salt and calcium salt to be used, and this case also contains strontium that is produced (carbonic acid). It can be easily removed from the calcium apatite by a treatment such as washing with water. However, when α exceeds 10, since 90% or more of both the phosphate and carbonate to be used are excessive, the yield is lowered, which is not preferable.

  Regarding the molar ratio of the mixture of strontium salt and calcium salt and dihydrogen phosphate when the reaction is performed, in the previous reaction formula, at least with respect to the sum 1 molar ratio of the number of moles of the mixture of strontium salt and calcium salt Although it was estimated that it was necessary to include a 0.6α molar ratio, as shown in the examples described later, a result supporting this was also obtained in actual experimental results. However, dihydrogen phosphate may be added to the reaction system in excess of 0.6α molar ratio, and when the molar ratio is within the range not exceeding 1.2α molar ratio, high purity strontium is added. It has been found that the containing (carbonic acid) calcium apatite can be obtained in high yield. That is, the molar ratio that can be used for the dihydrogen phosphate is (0.6 to 1.2) in the range of α molar ratio with respect to 1 molar ratio of the total number of moles of the mixture of strontium salt and calcium salt. It has been found that when the reaction is carried out at a ratio deviating from this range, compounds other than (carbonic acid) calcium apatite containing strontium may be formed as a by-product and the purity of the product may be lowered.

  Next, regarding the ratio of the carbonate, in the estimation from the above chemical formula, the molar ratio of 0.7α is included in the preferable range with respect to 1 mole ratio of the sum of the number of moles of the mixture of strontium salt and calcium salt. However, as shown in the examples described later, as a result of experiments conducted at various molar ratios, in a reaction system containing both dihydrogen phosphates within the above preferred molar ratio range. The preferred molar ratio range of the carbonate to be used is (0.7 to 1.0) α, which contains the high-purity strontium that is the object of the present invention (carbonic acid). It has been found that calcium apatite can be obtained in high yield. To summarize the above, the dihydrogen phosphate and carbonate each have a (0.6 to 1.2) α molar ratio and (0. 0. 1) to the total 1 molar ratio of the number of moles of the mixture of strontium salt and calcium salt. 7-1.0) When the reaction is carried out by mixing them in water within the range of α molar ratio, the high yield of (carbonic acid) calcium apatite containing the high purity strontium of the present invention is obtained. Can be obtained.

  Alternatively, when sodium hydrogen carbonate is used as the hydrogen carbonate instead of the carbonate of the above formula, it is considered that the reaction for generating strontium apatite proceeds as in the following formula.

10MCl ₂ + 6NaH ₂ PO ₄ +14 NaHCO ₃ + 2H ₂ O
→ M ₁₀ (PO ₄ ) ₆ (OH) ₂ +20 NaCl + 14CO ₂ + 14H ₂ O

  In the above reaction formula, when hydrogen carbonate is used instead of carbonate, it affects the molar ratio of dihydrogen phosphate to the total molar ratio of 1 mole of the mixture of strontium and calcium salts. It was found that the molar ratio of dihydrogen phosphate was (0.6 to 1.2) α. Moreover, the range of the preferable molar ratio of hydrogencarbonate with respect to 1 molar ratio of the mixture of strontium salt and calcium salt is the range of (1.4 to 2.0) α molar ratio, and the mixture of strontium salt and calcium salt. For 1 mole ratio, dihydrogen phosphate and bicarbonate are in the range of (0.6 to 1.2) α mole ratio and (1.4 to 2.0) α mole ratio, respectively. When the reaction is carried out by mixing, calcium carbonate apatite containing high-purity strontium as the object of the present invention can be obtained in high yield. In summary, when a mixture of strontium salt and calcium salt is mixed with dihydrogen phosphate and carbonate or bicarbonate in water and reacted, 1 mole of mixture of strontium salt and calcium salt Ratio of hydrogen phosphate to (0.6 to 1.2) α molar ratio, and carbonate or bicarbonate to p (0.7 to 1.0) α (p = 1 for carbonate) In the case of hydrogen carbonate, p = 2) When the reaction is carried out using a molar ratio, it is possible to obtain the high-purity strontium-containing (carbonic acid) calcium apatite of the present invention in a high yield. .

  The pH of the reaction system in the case of carrying out the reaction in the above combination does not need to be particularly controlled, and the aqueous solution of dihydrogen phosphate to be used usually has a pH in the range of 4 to 5, which includes carbonate or bicarbonate. Since the pH of the aqueous solution added with strontium is in the range of 7 to 11, strontium salt, dihydrogen phosphate and carbonate or bicarbonate or bicarbonate in water in the range of 5 to 13 in water. It is preferable to carry out the reaction by mixing.

  Carbonate (hydrogen) salt is combined with strontium salt and calcium salt and tertiary phosphate within the range of molar ratio to be used for the above-mentioned carbonate or bicarbonate (hereinafter also referred to as carbonate (hydrogen) salt). When used, when the reaction is carried out at a molar ratio less than the molar ratio obtained by adding 0.1α to the lower limit of the molar ratio of the carbonic acid (hydrogen) salt, strontium salt and calcium salt, and hydrogen phosphate Alternatively, when carbonic acid (hydrogen) salt was used in combination with dihydrogen phosphate, the reaction was carried out at a molar ratio less than the molar ratio obtained by adding 0.1 pα to the lower limit of the molar ratio of carbonic acid (hydrogen) salt. In this case, the calcium carbonate apatite containing strontium to be produced does not contain carbonate ions or even if it is contained, it is at most 2% by mass with respect to the apatite. It was clarified that it can be used as calcium apatite containing strontium because the influence of carbonate ions is not substantially recognized.

  On the other hand, when a carbonic acid (hydrogen) salt is used as a combination of a strontium salt and a calcium salt and a tertiary phosphate within the range of the molar ratio of the carbonic acid (hydrogen) salt, the carbonic acid (hydrogen) salt is used. When the reaction is carried out at a molar ratio equal to or higher than the molar ratio obtained by adding 0.1α to the lower limit of the molar ratio of strontium carbonate and calcium salt, and a combination of hydrogen phosphate or dihydrogen phosphate with carbonic acid ( When (hydrogen) salt is used, it contains strontium that is produced when the reaction is carried out at a molar ratio equal to or higher than the molar ratio obtained by adding 0.1 pα to the lower limit of the molar ratio of carbonic acid (hydrogen) salt. Carbonate ions are contained in the apatite. In this case, as shown in Examples described later, the carbonate ions are contained in (carbonic acid) calcium apatite containing strontium. It has become clear that it can be introduced efficiently into In the present invention, the introduction of carbonate ions into (carbonic acid) calcium apatite containing strontium may reduce the crystallinity or increase the solubility in water or in vivo. The obtained calcium carbonate apatite containing strontium is particularly useful as a medical application, particularly as a bioabsorbable material.

  In the method for producing (carbonic acid) calcium apatite containing strontium according to the present invention, among the three components of a mixture of strontium salt and calcium salt, phosphate, and carbonate or bicarbonate, carbonate or bicarbonate is When it is contained at a molar ratio exceeding the above-mentioned upper limit, strontium carbonate, calcium carbonate and the like are easily formed as a by-product in addition to the (carbonic acid) calcium apatite containing strontium.

  Furthermore, in the method for producing (carbonic acid) calcium apatite containing strontium according to the present invention, among the three components of a mixture of strontium salt and calcium salt, phosphate and carbonate or bicarbonate, the phosphate is described above. When it is contained in a molar ratio exceeding the upper limit, strontium hydrogen phosphate, calcium hydrogen phosphate, and the like are easily formed as a by-product in addition to the (carbonic acid) calcium apatite containing strontium.

  The strontium-containing (carbonated) calcium apatite obtained above is a finely divided powder. When each powder is observed with a scanning electron microscope, fine particles of nanometer size gather to form a powder. It was found to be a porous powder having a very large specific surface area. These strontium-containing (carbonic acid) calcium apatites can be used as powders, for example, for chromatographic column carriers and for adsorbents for proteins and various substances. The fine particles can be atomized by performing fine dispersion, and the dispersion can be preferably used for coating applications as a dispersion in which individual (saltium) calcium apatite fine particles containing strontium are aggregated or dispersed in a medium.

  A particularly preferred method for the atomization method is to use a calcium carbonate apatite powder containing strontium obtained by the above method in a medium, and subject this to a wet dispersion treatment. In order to perform such wet dispersion treatment, various conventionally known wet dispersion treatment methods can be used. As a preferred wet dispersion method, a wet dispersion method using a media mill is particularly preferred. Specifically, in a medium into which (carbonic acid) calcium apatite containing strontium is introduced, usually glass beads, alumina beads, other It is possible to use a processing method in which a medium such as ceramic beads is added and shaken or stirred, and the strontium-containing (carbonic acid) calcium apatite particles and the beads mechanically collide and finely pulverize to perform atomization. I can do it. When processing a small amount by a batch system, a wet dispersion process can be performed by shaking for several hours using a paint conditioner as a media mill. Further, as the above-mentioned media mill, using a device capable of wet dispersion processing in a continuous manner such as dyno mill, a plurality of them may be arranged in series to perform wet dispersion treatment in one pass, or 1 It is also preferable to repeat the treatment a plurality of times using a single media mill. By carrying out such a wet dispersion treatment, strontium suitable for coating applications such as sedimentation with time, no generation of precipitates or aggregates, and a coating layer having a uniform thickness is obtained ( Carbonic acid) calcium apatite fine particles can be obtained.

  Suitable for coating use above means that the volume average particle size of the (carbonic acid) calcium apatite fine particles containing strontium contained in the coating layer is equal to or less than the thickness of the coating layer formed by coating. It is preferable that When fine particles having a size exceeding the thickness of the coat layer are contained, the fine particles may be exposed from the coat layer and the surface smoothness may be lost. Since the thickness of the coating layer formed by the coating intended by the present invention is at most 10 μm or less, therefore, the size of the (carbonic acid) calcium apatite fine particles containing strontium targeted by the present invention is the volume average particle diameter. Is preferably 10 μm or less. The size of the strontium-containing (carbonic acid) calcium apatite fine particles obtained in the present invention is preferably in the range of 40 nm to 10 μm in volume average particle diameter, and the smaller the volume average particle diameter, the more uniform it is applied to coating applications. It is more preferable because an excellent coating film is formed.

  Furthermore, as a condition for being suitable for coating use in the present invention, the dispersion stability of the fine particles of the calcium carbonate apatite containing strontium containing the strontium used in the present invention is dispersed. It is preferable that the particles are not aggregated or settled during storage for a long period of time (for example, a storage period of 1 week at room temperature).

  As a medium for dispersing (carbonic acid) calcium apatite containing strontium, water is most preferable. However, if the addition amount is less than 20% by mass with respect to water, alcohols such as methanol, ethanol, propanol, Add various solvents miscible with water, such as cyclic ethers such as 3-dioxolane, 1,4-dioxane, tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, polar solvents such as acetonitrile and dimethylformamide, etc. You can also.

  When performing wet dispersion treatment of (carbonic acid) calcium apatite containing strontium using the above-mentioned media, it is preferable to use ceramic beads as the media to be used. In particular, when dispersing (carbonic acid) calcium apatite containing strontium, it is preferable to prevent contamination of beads-derived impurities by polishing the beads. Specifically, ceramic beads containing zirconia such as ZrO, cubic zirconia, yttrium-stabilized zirconia, zirconia reinforced alumina, synthetic diamond, and silicon nitride beads can be most preferably used as ceramic beads that can be used for such purposes. . Moreover, it is preferable that the average diameter of a medium exists in the range of 0.01-10 mm, More preferably, it is 0.1-5 mm. The conditions for the wet dispersion treatment using a media mill using such media are treatments at room temperature that are usually performed, and there are no particular restrictions on treatment time, temperature, and the like. In addition, although one pass may be sufficient as the number of passes, strontium containing a narrower particle size distribution and excellent dispersion stability is obtained by performing the treatment with about 2 to 7 passes ( This can be preferably performed because a dispersion of calcium carbonate apatite fine particles is obtained.

  When producing a dispersion of (carbonic acid) calcium apatite fine particles containing the above strontium, strontium obtained by adding various surfactants, inorganic compounds and various water-soluble polymers as a dispersant, and performing a wet dispersion treatment It is preferable to further reduce the volume average particle size in the dispersion of (carbonic acid) calcium apatite fine particles containing.

  Examples of the anionic surfactant that can be used as the dispersant include higher fatty acid salts such as sodium laurate, sodium stearate and sodium oleate, alkyl sulfates such as sodium dioctylsulfosuccinate, sodium lauryl sulfate and sodium stearyl sulfate. Salts, higher alcohol sulfates such as sodium octyl alcohol sulfate, sodium lauryl alcohol sulfate, ammonium lauryl alcohol sulfate, aliphatic alcohol sulfates such as sodium acetyl alcohol sulfate, alkyl benzene sulfones such as sodium dodecylbenzene sulfonate Alkyl naphthates such as acid salts, sodium butyl naphthalene sulfonate, sodium isopropyl naphthalene sulfonate Len sulfonates, alkyl diphenyl ether disulfonates such as sodium alkyl diphenyl ether disulfonate, alkyl phosphate esters such as sodium lauryl phosphate and sodium stearyl phosphate, polyethylene oxide adducts of sodium lauryl ether sulfate, polyethylene oxide adducts of lauryl ether ammonium sulfate Polyethylene oxide adducts of alkyl ether sulfates such as polyethylene oxide adduct of lauryl ether sulfate triethanolamine, polyethylene oxide adducts of alkyl phenyl ether sulfates such as polyethylene oxide adduct of sodium nonylphenyl ether sulfate, lauryl Alkyl ethers such as polyethylene oxide adducts of sodium ether phosphate Polyethylene oxide adducts of salt, polyethylene oxide adducts of alkyl phenyl ether phosphate salts of polyethylene oxide adducts of nonyl phenyl ether sodium phosphate and the like.

  Nonionic surfactants that can be used as the dispersant include polyethylene oxide alkyl ethers and polyethylene oxide alkyl phenyl ethers in which alkyl groups, phenyl groups, and alkyl-substituted phenyl groups are bonded to polyethylene oxide of various chain lengths. Among these, sorbitan monoalkylate derivatives known as trade names TWEEN 20, 40, 60 and 80 can be most preferably used.

  Examples of the water-soluble polymer that can be used as the dispersant include gelatin, gelatin derivatives (eg, phthalated gelatin), hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl hydroxyethyl cellulose, polyvinyl pyrrolidone, poly Examples thereof include ethylene oxide, xanthan, cationic hydroxyethyl cellulose, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, polyacrylamide, polyvinyl pyrrolidone, starch, and various modified starches (for example, phosphate-modified starch).

  Examples of the inorganic compound that can be used as the dispersant include various phosphates, and particularly preferable examples include polyphosphoric acid (salt). In this case, the size of the fine particles contained in the obtained dispersion of (carbonic acid) calcium apatite fine particles containing strontium is dispersed in fine particles having a volume average particle diameter in the range of 40 to 900 nm, and substantially contains organic matter. In addition, since a dispersion of calcium carbonate apatite fine particles containing strontium having high purity and excellent dispersion stability can be obtained, it can be used very preferably. When the dispersion of (carbonic acid) calcium apatite fine particles containing strontium obtained by the present invention is used for coating applications, for example, when applied to the above-described biological implant, the dispersion of (carbonic acid) calcium apatite fine particles containing strontium When an organic substance is contained in the inside, the safety | security with respect to a biological body may be impaired. Therefore, it is preferable that the dispersion obtained by the method for producing (carbonic acid) calcium apatite fine particles containing strontium of the present invention does not contain an organic substance. In the present invention, the phrase “substantially free of organic matter” means that the organic matter is 1% by mass or less with respect to (carbonic acid) calcium apatite containing strontium. More preferably, it is 0.1 mass% or less.

  Examples of polyphosphoric acid (salts) that can be used above include linear acids such as pyrophosphoric acid (sodium), tripolyphosphoric acid (sodium), tetrapolyphosphoric acid (sodium), and linear polyphosphoric acid (sodium). Examples include polyphosphoric acid (salt) and hydrates thereof, or include hexametaphosphoric acid (sodium) that is a cyclic compound, and actually metaphosphoric acid (sodium) that is a polymer compound or a linear skeleton. In addition, examples include ultraphosphoric acid (sodium) containing a branched structure and hydrates thereof. These various polyphosphoric acids (salts) may be used in a mixture of a plurality of types at an arbitrary ratio. Here, polyphosphoric acid (salt) means polyphosphoric acid or a salt thereof.

  In the case of producing (carbonic acid) calcium apatite fine particles containing strontium using various dispersing agents as described above, there is a preferable range for the ratio of various dispersing agents to (carbonic acid) calcium apatite containing strontium. The amount of the dispersant used is most preferably 5 to 100 parts by mass with respect to 100 parts by mass of (carbonic acid) calcium apatite containing strontium.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. In addition, the percentage in an Example is a mass reference | standard unless there is a notice. Moreover, the purity of the used reagents is 98% by mass or more.

Examples 1 to 4 (Synthesis of calcium apatite containing strontium)
Strontium chloride hexahydrate (Reagent manufactured by Wako Pure Chemical Industries) and calcium chloride dihydrate (Reagent manufactured by Wako Pure Chemical Industries) were mixed in the proportions shown in Table 1, and each was transferred into a 1 liter Erlenmeyer flask. Then, 350 grams of ion exchange water was added and dissolved. Separately, in a 500 ml glass beaker, diammonium hydrogen phosphate (Wako Pure Chemical Industries reagent) 40 grams (0.3 mole) and sodium carbonate (Wako Pure Chemical Industries reagent) 16 grams (0.15 mole) ), And 300 grams of ion exchange water was added and dissolved. The aqueous solution in which both strontium chloride and calcium chloride prepared above were dissolved was transferred into an Erlenmeyer flask, and diammonium hydrogen phosphate and sodium carbonate were added thereto using a dropping funnel while stirring on a water bath adjusted to 50 ° C. The dissolved aqueous solution was gradually added dropwise over 1 hour. The pH of the reaction system during the reaction was 6.5. After completion of dropping, the mixture was further stirred for 1 hour. Thereafter, the Erlenmeyer flask was transferred from above the water bath and cooled to room temperature, and then the white precipitate formed using a glass filter was suction filtered. The white precipitate on the filter was further washed repeatedly with ion-exchanged water, and then dried for one day in a drier adjusted to 60 ° C. to obtain a white powder. The product yield was approximately 100% by weight with respect to each theoretical yield.

  When each product was analyzed using a wide-angle X-ray diffractometer, the results shown in FIGS. FIG. 1 shows a wide-angle X-ray diffraction pattern of calcium apatite obtained in Example 1 and containing calcium and strontium in a ratio of 2: 8. FIG. 2 shows a wide-angle X-ray diffraction pattern of calcium apatite containing calcium and strontium obtained in Example 2 in a ratio of 4: 6. FIG. 3 shows a wide-angle X-ray diffraction pattern of calcium apatite obtained in Example 3 and containing calcium and strontium in a ratio of 6: 4. FIG. 4 shows a wide-angle X-ray diffraction pattern of calcium apatite obtained in Example 4 and containing calcium and strontium in a ratio of 8: 2. From these results, the products obtained in Examples 1 to 4 have a relatively wide X-ray diffraction peak width, indicating the characteristics of low crystalline calcium apatite, and characteristics of (carbonic acid) calcium apatite containing strontium. The results clearly show that. For example, when the diffraction peak from the (002) plane where 2θ is around 25 ° is taken up as the half-value width of the diffraction peak, the half-value width of this peak shows a value exceeding 0.35 ° in all cases, and the low crystallinity. It showed certain characteristics. Furthermore, as the ratio of strontium ions to calcium ions in the apatite increased, the half-width of the peak gradually decreased and the crystallinity tended to be relatively high.

  Further, FIGS. 5 to 8 show FT-IR spectrum charts of the powders obtained in the respective examples. FIG. 5 shows an FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 1 in a ratio of 2: 8. FIG. 6 shows an FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 2 at a ratio of 4: 6. FIG. 7 shows an FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 3 in a ratio of 6: 4. FIG. 8 shows an FT-IR spectrum chart of calcium apatite containing calcium and strontium obtained in Example 4 at a ratio of 8: 2.

In the FT-IR spectrum chart shown in FIG. 7, the absorption characteristic of carbonate ions was weakly observed in the vicinity of 1450 cm ⁻¹ and 1405 cm ⁻¹ , and carbonate ions were combined in the apatite containing strontium obtained in Example 3. It was found that it was included. The ratio calculation results of the content of carbonate ions from the absorption intensity of 1405cm ^-1 for absorption around 1010 cm ^-1 by phosphate ions, the carbonate ion is contained about 1.2% by weight% in said apatite I understood. In other examples, the presence of a very small amount of carbonate ion was recognized, but in any case, the ratio was 0.5% by mass or less, and the presence of carbonate ion substantially contributed to the properties of the apatite. The result was unaffected.

  The calcium apatite powder containing each strontium obtained in Examples 1 to 4 was fixed on a slide glass, and strontium and calcium present in each powder using energy dispersive X-ray spectroscopy (EDS). As a result, the calcium and strontium were uniformly distributed in each powder for each sample, and the mass ratio of calcium and strontium was determined during the synthesis in each example. The results were in good agreement with the mass ratios corresponding to the respective molar ratios used in. That is, the molar ratio of calcium / strontium used as the charging ratio in the synthesis and the molar ratio of calcium / strontium contained in the calcium apatite containing calcium and strontium were obtained. From this, it was revealed that calcium apatite having an arbitrary calcium / strontium molar ratio can be obtained according to the present invention. In addition to the results of the elemental analysis described above, in the products obtained in any of the examples, components other than apatite are not detected in X-ray diffraction and FT-IR spectra, and high-purity strontium is contained. It was revealed that calcium apatite was obtained.

(Production method and evaluation results of calcium apatite fine particles containing strontium when no dispersant is used)
Using the calcium apatite containing strontium obtained in Examples 1 to 4 above, wet dispersion treatment using a media mill was performed as follows to produce calcium apatite fine particles containing strontium. That is, 20 grams of calcium apatite containing strontium obtained in each of the above examples was transferred to a 0.2 liter polypropylene container, and 80 grams of ion exchange water and 160 grams of zirconia beads having a particle size of 0.3 mm were added and sealed. Then, a wet dispersion treatment was performed for 6 hours using a paint conditioner. Thereafter, zirconia beads were separated from the dispersion using a filter cloth. The solid content concentration of the obtained dispersion was 20% by mass. Using this, evaluation was performed as follows.

  In order to measure the size of calcium apatite fine particles containing dispersed strontium using the fine particle dispersion obtained in Examples 1 to 4, a light scattering diffraction particle size distribution meter (particle size distribution manufactured by Horiba, Ltd.) Measurement was performed using a measuring apparatus LA-920). The results are shown in FIGS. FIG. 9 shows a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing the calcium apatite containing strontium obtained in Example 1 without using a dispersant. The volume average particle diameter obtained from FIG. 9 is 3.4 μm in terms of median diameter, and it has been clarified that the particles have a relatively narrow particle diameter distribution. FIG. 10 shows a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing the calcium apatite containing strontium obtained in Example 2 without using a dispersant. The volume average particle diameter obtained from FIG. 10 is 2.9 μm in terms of median diameter, and it has been clarified that the particles have a relatively narrow particle diameter distribution. FIG. 11 shows a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing calcium apatite containing strontium obtained in Example 3 without using a dispersant. The volume average particle diameter obtained from FIG. 11 is 2.6 μm in terms of median diameter, and it has been clarified that the particles have a relatively narrow particle diameter distribution. FIG. 12 shows a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing calcium apatite containing strontium obtained in Example 4 without using a dispersant. The volume average particle diameter obtained from FIG. 12 is 2.5 μm in terms of median diameter, and it has been clarified that the particles have a relatively narrow particle diameter distribution. Moreover, in order to evaluate the dispersion stability of calcium apatite fine particles containing strontium contained in each dispersion obtained above, the dispersion was placed in a transparent glass container and allowed to stand at room temperature for 1 week. The state of the dispersion after standing was visually observed, but it was confirmed that there was no generation of precipitates or aggregates and that the dispersion was stably dispersed. Furthermore, as a result of performing application | coating and drying so that a coating thickness might be set to about 10 micrometers on a slide glass using the obtained dispersion, it confirmed that a transparent and uniform coating film was formed in any case.

(Production method and evaluation results of calcium apatite fine particles containing strontium when polyphosphoric acid (salt) is used)
20 grams of calcium apatite containing strontium obtained in Examples 1 to 4 above was transferred to a 0.2 liter polypropylene container, 2 grams of sodium polyphosphate (Wako Pure Chemical Industries, Ltd.) was added thereto, and ion-exchanged water was further added. 160 grams of zirconia beads having a particle size of 0.3 mm and 160 grams of zirconia beads were added and sealed, and the mixture was shaken for 6 hours using a paint conditioner. Thereafter, zirconia beads were separated from the dispersion using a filter cloth. The pH of each of the obtained dispersions was 7.5, and the solid content concentration was 22% by mass. Using the obtained dispersion, the size of the dispersed fine particles was measured in the same manner as in the previous case. FIG. 13 shows a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by wet-dispersing the calcium apatite containing strontium obtained in Example 1 using polyphosphoric acid. The volume average particle diameter obtained from FIG. 13 was 140 nm in median diameter, and it was revealed that the particles were relatively narrow in particle size distribution. FIG. 14 shows a particle size distribution curve of a calcium apatite fine particle dispersion containing strontium obtained by subjecting calcium apatite containing strontium obtained in Example 4 to wet dispersion treatment using polyphosphoric acid. The volume average particle diameter obtained from FIG. 14 is 770 nm in terms of median diameter, and it has been clarified that the particles have a relatively narrow particle diameter distribution. Similarly, the volume average particle diameter of the fine particles contained in the dispersion using calcium apatite containing strontium obtained in Example 2 was 250 nm, and in Example 3, it was 400 nm. Moreover, in order to evaluate the dispersion stability of calcium apatite fine particles containing strontium contained in each dispersion obtained above, the dispersion was placed in a transparent glass container and allowed to stand at room temperature for 1 week. The state of the dispersion after standing was visually observed, but it was confirmed that there was no generation of precipitates or aggregates and that the dispersion was stably dispersed. Furthermore, as a result of performing application | coating and drying so that the coating thickness might be set to about 2 micrometers on a slide glass using the obtained dispersion, it confirmed that a transparent and uniform coating film was formed in any case.

(Example 5) (Synthesis of calcium apatite containing strontium)
A white powder was obtained in the same manner as in Example 3 except that 20 grams (0.19 mol) of sodium carbonate was used. The yield of the product was approximately 100% by mass based on the theoretical yield calculated as calcium apatite containing strontium. As a result of analyzing the product obtained in the same manner as in Example 3, the product had the same structure as the calcium apatite containing strontium obtained in Example 3.

(Example 6) (Synthesis of calcium carbonate apatite containing strontium)
45 grams (0.3 mole) of calcium chloride dihydrate and 54 grams (0.2 mole) of strontium chloride hexahydrate were weighed into a 1 liter Erlenmeyer flask and dissolved by adding 350 grams of ion-exchanged water. . Separately, 40 g (0.3 mol) of diammonium hydrogen phosphate and 26.5 g (0.25 mol) of sodium carbonate were weighed in a 500 ml glass beaker and dissolved by adding 300 g of ion-exchanged water. did. Reaction was carried out in the same manner as in Examples 1 to 4 to obtain white powder. As a result of analyzing the obtained product using a wide-angle X-ray diffractometer, an X-ray diffraction pattern almost the same as that of apatite containing calcium and strontium in a ratio of 6: 4 obtained in Example 2 was obtained. It was. When further analyzing the product using FT-IR, 1435cm ^-1 and 1400 cm around ^-1 (B type) observed absorption peaks due to specific carbonate ions in apatite, 1010 cm absorbance of 1400 cm ^{-1 - According to} the method of Feathersotone et al. (JDB Featherstone, Caries Res., 18, 63-66 (1984)), the proportion of carbonate ions was calculated with respect to the absorbance of the absorption peak based on phosphate ions near ¹ . As a result, the product obtained in this example was calcium carbonate apatite containing strontium, and the proportion of carbonate ions contained in the apatite was calculated to be 12% by mass. From the above results, it was revealed that calcium carbonate apatite containing strontium was obtained in this example. Moreover, in X-ray diffraction and FT-IR spectrum, components other than apatite were not detected, and it was revealed that calcium carbonate apatite containing high-purity strontium was obtained.

(Example 7) (Synthesis of calcium apatite containing strontium)
A white powder was obtained in the same manner as in Example 3 except that 80 g (0.6 mol) of diammonium hydrogen phosphate was used. The product yield was approximately 100% by weight based on the theoretical yield calculated as strontium apatite. Further, the product obtained in the same manner as in Example 3 was analyzed using wide-angle X-ray diffraction and FT-IR, and as in Example 3, calcium apatite containing high-purity strontium was obtained. confirmed.

(Comparative Example 1)
A white powder was obtained in the same manner as in Example 3 except that 86 g (0.65 mol) of diammonium hydrogen phosphate was used. The product yield was approximately 100% by weight based on the theoretical yield calculated as strontium apatite. As a result of analyzing the product obtained in the same manner as in Example 3 using wide-angle X-ray diffraction, the product contains calcium hydrogen phosphate and strontium hydrogen phosphate as components other than calcium apatite containing strontium. Thus, calcium apatite containing high-purity strontium was not obtained.

(Comparative Example 2)
A white powder was obtained in the same manner as in Example 3 except that 33 grams (0.25 mol) of diammonium hydrogen phosphate was used. The product obtained in the same manner as in Example 3 was analyzed using wide-angle X-ray diffraction, and it was found that the product contained strontium carbonate and calcium carbonate as components other than calcium apatite containing strontium. However, calcium apatite containing high-purity strontium was not obtained.

(Comparative Example 3)
A white powder was obtained in the same manner as in Example 3 except that 11 grams (0.1 mol) of sodium carbonate was used. The product obtained in the same manner as in Example 3 was analyzed using wide-angle X-ray diffraction, and the product contained strontium hydrogen phosphate and calcium hydrogen phosphate as components other than calcium apatite containing strontium. As a result, calcium apatite containing high-purity strontium was not obtained.

(Comparative Example 4)
A white powder was obtained in the same manner as in Example 3 except that 32 g (0.30 mol) of sodium carbonate was used. As a result of analyzing the product obtained in the same manner as in Example 3 using wide angle X-ray diffraction, it was found that the product contained calcium carbonate and strontium carbonate as components other than apatite. Calcium apatite containing high purity strontium was not obtained.

(Example 8) (Synthesis of calcium apatite containing strontium)
A white powder was obtained in the same manner as in Example 3 except that 25 grams (0.3 mol) of sodium bicarbonate was used instead of sodium carbonate. The product yield was approximately 100% by weight based on the theoretical yield calculated as strontium apatite. As a result of analyzing the product obtained in the same manner as in Example 3, the product had the same structure as the calcium apatite containing strontium obtained in Example 3.

(Example 9) (Synthesis of calcium carbonate apatite containing strontium)
A white powder was obtained in the same manner as in Example 6 except that 42 grams (0.5 mol) of sodium bicarbonate was used instead of sodium carbonate. As a result of analyzing the product obtained in the same manner as in Example 6, the product had the same structure as the calcium carbonate apatite containing strontium obtained in Example 6.

(Example 10) (Synthesis of calcium carbonate apatite containing strontium)
In the same manner as in Example 4, 59 grams (0.4 mole) of calcium chloride dihydrate and 27 grams (0.1 mole) of strontium chloride hexahydrate were weighed into a 1 liter Erlenmeyer flask, and ion-exchanged water. 350 grams were added and dissolved. Separately, weigh 47 grams (0.30 mole) of sodium dihydrogen phosphate dihydrate and 43 grams (0.4 mole) of sodium carbonate in a 500 ml glass beaker and add 300 grams of ion-exchanged water. And dissolved. Reaction was carried out in the same manner as in Example 4 to obtain a white powder. The yield of the product was almost 100% by mass based on the theoretical yield. Further, the product obtained in the same manner as in Example 4 was analyzed using a wide-angle X-ray diffractometer, and was in good agreement with the wide-angle X-ray diffraction pattern of calcium apatite containing strontium obtained in Example 4. In addition, only peaks derived from apatite were observed, and no other peaks due to impurities were observed. Thus, it was revealed that calcium apatite containing high-purity strontium was obtained. Results The product was analyzed using FT-IR, 1435cm ^-1 and 1400 cm around ^-1 (B type) observed absorption peaks due to specific carbonate ions in apatite, 1010 cm absorbance of 1400 cm ^{-1 According to} the method of Feathersotone et al. (JDB Featherstone, Caries Res., 18, 63-66 (1984)), the proportion of carbonate ions was calculated with respect to the absorbance of the absorption peak based on phosphate ions near ^-1 . As a result, the product obtained in this example was calcium carbonate apatite containing strontium, and the proportion of carbonate ions contained in the apatite was calculated to be 4.5% by mass. From the above results, it was revealed that calcium carbonate apatite containing high-purity strontium was obtained in this example.

(Example 11) (Synthesis of calcium apatite containing strontium)
In Example 10, a reaction was carried out in the same manner as in Example 10 except that 37 g (0.35 mol) of sodium carbonate was used to obtain a white powder. When the product obtained in the same manner as in Example 10 was analyzed using a wide-angle X-ray diffractometer and FT-IR, the product contained no carbonate ions and was obtained in Example 4. It has the same structure as calcium apatite containing strontium.

(Example 12) (Synthesis of calcium apatite containing strontium)
In Example 10, the reaction was conducted in the same manner as in Example 10 except that 94 g (0.6 mol) of sodium dihydrogen phosphate dihydrate and 37 g (0.35 mol) of sodium carbonate were used. A powder was obtained. When the product obtained in the same manner as in Example 10 was analyzed using a wide-angle X-ray diffractometer and FT-IR, the product contained no carbonate ions and was obtained in Example 4. It has the same structure as calcium apatite containing strontium.

(Example 13) (Synthesis of calcium carbonate apatite containing strontium)
In Example 10, a white powder was obtained in the same manner as in Example 10 except that 67 grams (0.8 mol) of sodium bicarbonate was used instead of sodium carbonate. When the product obtained in the same manner as in Example 1 was analyzed using a wide-angle X-ray diffractometer and FT-IR, the product contained 4.5% by mass of carbonate ions. It was revealed that calcium carbonate apatite containing high-purity strontium having the same structure as that obtained in 10 was obtained.

(Example 14) (Synthesis of calcium carbonate apatite containing strontium)
In Example 10, a white powder was obtained in the same manner as in Example 10 except that 84 g (1 mol) of sodium hydrogen carbonate was used instead of sodium carbonate. The product obtained in the same manner as in Example 4 was analyzed using a wide-angle X-ray diffractometer and FT-IR. As a result, the product contained 19% by mass of carbonate ions, and high-purity strontium. It was revealed that calcium carbonate apatite containing was obtained.

(Example 15) (Synthesis of calcium apatite containing strontium)
In the same manner as in Example 4, 59 grams (0.4 mole) of calcium chloride dihydrate and 27 grams (0.1 mole) of strontium chloride hexahydrate were weighed into a 1 liter Erlenmeyer flask, and ion-exchanged water. 350 grams were added and dissolved. Separately, weighed 115 grams (0.3 mole) of trisodium phosphate dodecahydrate and 5.5 grams (0.05 mole) of sodium carbonate in a 500 ml glass beaker, and 300 grams of ion-exchanged water. To dissolve. Reaction was carried out in the same manner as in Example 1 to obtain a white powder. The yield of the product was almost 100% by mass based on the theoretical yield. The obtained product was analyzed using a wide-angle X-ray diffractometer and was in good agreement with the wide-angle X-ray diffraction pattern of calcium apatite containing strontium obtained in Example 4. Furthermore, only peaks derived from calcium apatite containing strontium were observed, and no peaks derived from other impurities were observed, so it became clear that calcium apatite containing high-purity strontium was obtained. It was. In addition, when it analyzed using FT-IR, it confirmed that the carbonate ion was not contained in the product.

(Example 16) (Synthesis of calcium apatite containing strontium)
A calcium apatite containing strontium having the same structure as in Example 15 was reacted in the same manner as in Example 15 except that 150 g (0.4 mol) of trisodium phosphate dodecahydrate was used in Example 15. Was obtained in high purity.

(Example 17) (Synthesis of calcium carbonate apatite containing strontium)
The reaction was conducted in the same manner except that 16 grams (0.15 mol) of sodium carbonate was used in Example 15. As a result, the product was calcium carbonate apatite containing strontium, and no components other than apatite were contained. Was confirmed. When further analyzing the product using FT-IR, 1435cm ^-1 and 1400 cm around ^-1 (B type) observed absorption peaks due to specific carbonate ions in apatite, 1010 cm absorbance of 1400 cm ^{-1 - According to} the method of Feathersotone et al. (JDB Featherstone, Caries Res., 18, 63-66 (1984)), the proportion of carbonate ions was calculated with respect to the absorbance of the absorption peak based on phosphate ions near ¹ . As a result, the product obtained in this example was calcium carbonate apatite containing strontium, and the proportion of carbonate ions contained in the apatite was calculated to be 24.5% by mass. From the above results, it was revealed that calcium carbonate apatite containing high-purity strontium was obtained in this example.

(Example 18) (Synthesis of calcium apatite containing strontium)
The reaction was conducted in the same manner as in Example 15 except that 4.2 g (0.05 mol) of sodium hydrogen carbonate was used instead of sodium carbonate, and the resulting product was subjected to wide-angle X-ray diffraction and FT-IR. As a result, it was confirmed that calcium apatite containing high-purity strontium having the same structure as that of Example 15 was obtained.

(Example 19) (Synthesis of calcium carbonate apatite containing strontium)
The reaction was conducted in the same manner as in Example 15 except that 25 grams (0.15 mol) of sodium bicarbonate was used instead of sodium carbonate, and the obtained product was analyzed using wide-angle X-ray diffraction and FT-IR. As a result, it was revealed that the product contained 20% by mass of carbonate ions, and calcium carbonate apatite containing high-purity strontium was obtained.

  From the above results, according to the present invention, a simple and highly productive manufacturing method for obtaining (carbonic acid) calcium apatite containing strontium with high crystallinity, which is controlled in crystallinity by a one-step reaction, and crystallinity is improved. It was revealed that a method for producing calcium carbonate apatite fine particles containing strontium which is controlled and suitable for coating applications can be provided.

  The calcium carbonate apatite containing strontium obtained by the production method of the present invention can be used as a column support for chromatography and various adsorbents. Alternatively, it can be used as various bioactive implants. Furthermore, it is possible to provide various hydrophilic materials having affinity for a living body by performing a surface treatment on a film or fiber.

Claims (5)

A method for producing (carbonic acid) calcium apatite containing strontium, wherein a mixture containing a strontium salt and a calcium salt and a phosphate, and a carbonate or hydrogen carbonate are mixed in water and reacted. When the molar ratio of the sum of moles of strontium salt and calcium salt is A, the molar ratio of phosphate is B, and the molar ratio of carbonate or bicarbonate is C, the following (i) to (iii) The manufacturing method of the (carbonic acid) calcium apatite containing strontium which satisfy | fills any of these requirements and the pH of a reaction system exists in the range of 5-13.
(I) When the phosphate is a tertiary phosphate
A: B: C = 1: (0.6 to 0.8) α: (0.1 to 0.3) α.
(Ii) When the phosphate is hydrogen phosphate
A: B: C = 1: (0.6 to 1.2) α: p (0.3 to 0.5) α.
(Iii) When the phosphate is dihydrogen phosphate
A: B: C = 1: (0.6 to 1.2) α: p (0.7 to 1.0) α.
In the formula, α represents a real number of 0.1 ≦ α ≦ 10. p represents a coefficient, 1 for a carbonate, and 2 for a bicarbonate.   The molar ratio of the carbonate or bicarbonate is less than the molar ratio obtained by adding 0.1α in the case of the requirement (i) to the lower limit of the molar proportion of the carbonate or bicarbonate described above. The method for producing calcium apatite containing strontium according to claim 1, wherein in the case of (ii) or (iii), the molar ratio is less than 0.1 pα.   In the case of the requirement (i) above, the molar ratio of the carbonate or hydrogencarbonate is not less than the molar ratio of the above-mentioned lower limit of the molar ratio of the carbonate or hydrogencarbonate. In the case of (ii) or (iii), the method for producing calcium carbonate apatite containing strontium according to claim 1, wherein the molar ratio is 0.1 mol or more.   The (carbonic acid) calcium apatite fine particles containing strontium obtained by the production method according to any one of claims 1 to 3, wherein the (carbonic acid) calcium apatite containing strontium is wet-dispersed using a media mill. Manufacturing method.   The method for producing strontium-containing (carbonic acid) calcium apatite fine particles according to claim 4, wherein the wet dispersion treatment is performed by adding polyphosphoric acid (salt) when the wet dispersion treatment is performed.