WO2011115092A1 - Method for producing high purity βtcp fine powder - Google Patents

Abstract

Disclosed is a method for producing βTCP fine powder having higher purity than conventional products. The method for producing high purity βTCP fine powder comprises 1) a first step wherein a slurry containing tricalcium phosphate is produced by reacting phosphate ions and a calcium salt in water, 2) a second step in which a wet crushed material that contains fine powder for the solid content is prepared by wet crushing this slurry or a moist solid portion obtained therefrom and 3) a third step for obtaining the βTCP fine powder by baking the wet crushed material.

Description

Manufacturing method of high purity βTCP fine powder

The present invention relates to a method for producing a novel high-purity βTCP (β-phase tricalcium phosphate) fine powder.

Since calcium phosphate is a component of bones, teeth, etc. or its similar components, it has high affinity and low biological rejection, so it is an indispensable material for biomaterial applications, especially orthopedics and dental fields. Yes. Among calcium phosphates, hydroxyapatite, βTCP, αTCP, dicalcium phosphate, tetracalcium phosphate (TTCP), and the like are widely used, and are used for various purposes by utilizing the characteristics of each substance. In particular, βTCP is frequently used in various fields such as orthopedics, dentistry and the like due to its high biocompatibility, including bone or tooth filling agents. In this case, there are cases where βTCP is used alone depending on the use, and other calcium phosphates (for example, hydroxyapatite, αTCP, anhydrous calcium phosphate (DCP)) are blended.

As the filler containing βTCP, those processed into a lump or paste like granules are commercially available. Some of the granular fillers have pores formed in the granules and are designed to assist the regeneration mechanism in the body because cells are easy to enter. The paste-like filler is placed in a syringe etc. It is used by the method of directly filling the defect part by injecting it.

For example, 1) A powdered raw material of βTCP is blended with other raw materials, kneaded, refired to a boundary temperature where α transition does not occur, sintered and hardened, and granulated. 2) A method of blending βTCP powder raw material with other raw materials and kneading and then forming a paste without sintering. 3) Transforming the wet-reaction synthesized calcium phosphate precipitate into β. There is a method of molding and β-transition by firing and sintering.

The quality required for the βTCP raw material of such a filler is required to be easy to process in addition to high purity. The high purity of βTCP is particularly important from the viewpoint of safety in applications that are embedded in a living body for a long period of time. In addition, since βTCP is almost always provided in the form of a paste or granule, the ease of processing (processability) of the raw material is also important, and the needs from the processing manufacturer are also high. . Incidentally, the most widely used raw material form is fine particle powder. In particular, the need for fine powder having an average particle size of about 1 to 3 μm is generally high. If the average particle size is too large, the dispersibility and uniformity of the blending deteriorates. Conversely, if the average particle size is too small, the oil absorption of the powder increases and affects the workability after blending. For example, in the case of a paste product, the viscosity becomes too high to make it difficult to use, or even in the process of preparing a granule product by kneading with an organic binder, processing cannot be performed unless a solvent or an additive is added more than necessary. Accordingly, in the present situation, commercially available βTCP powder products have the largest average particle size of 1 to 3 μm. In addition, the specific surface area of βTCP powder is considered to be an important index that affects the workability, and there is generally a high need for products having a low specific surface area of 1 to 5 m ² / g. The specific surface area can be adjusted by the firing temperature. The specific surface area decreases as the firing temperature is raised, but an appropriate adjustment is made according to the user's application. If the specific surface area is too large, the oil absorption of the solvent and additives will increase, the handling characteristics of kneading granulation will deteriorate, the viscosity of the paste product will be too high, and the discharge pressure of the syringe will become too high, which may reduce the commercial value. Absent. On the other hand, if the specific surface area is too small, the shrinkage rate at the time of sintering decreases, resulting in insufficient hardness of the product. In order to obtain a product with a low specific surface area of 1 to 5 m ² / g, the firing temperature is set to a temperature range of about 800 to 950 ° C. However, since it is affected by firing conditions and raw material impurity levels, this range is not necessarily limited. Not necessarily.

ΒTCP is calcium phosphate having a Ca / P molar ratio of 1.50 (or 3/2), and is usually generated by being transferred to the β phase at a temperature of 700 ° C. or higher, although there are differences depending on conditions. As the temperature is further raised, there is a difference in the transition point depending on the conditions, but the transition from about 1100 ° C. to the α phase begins, and after passing through a mixed crystal of α and β2 phases, finally a single phase compound of αTCP Can do. That is, the production of βTCP requires a step of baking at a certain high temperature. In addition, it is important to accurately adjust the Ca / P molar ratio to 1.50 before firing. When Ca / P <1.50, by-products such as calcium pyrophosphate (Ca / P = 1.0) is mixed as an impurity, and conversely, when Ca / P> 1.50, the by-product hydroxyapatite (Ca / P = 1.67) is necessarily mixed as an impurity after firing.

Various methods have been proposed for producing βTCP powder. For example, a step of preparing a raw material by blending calcium hydroxide powder and calcium hydrogen phosphate powder so that the molar ratio of calcium to phosphorus (Ca / P) is 1.45 to 1.72. And a step of preparing the calcium phosphate precursor by mixing and pulverizing the obtained raw material to cause a soft mechanochemical complexing reaction, and heat-treating the obtained precursor at a temperature of 600 ° C. or higher to obtain calcium phosphate powder. There is known a method for producing a calcium phosphate powder characterized by having a step of preparing a body (Patent Document 1).

In addition, a method of obtaining βTCP powder by grinding and reacting a mixed slurry containing calcium hydrogen phosphate and calcium carbonate in a pot mill for 24 hours, drying the slurry, and firing at 750 ° C. for 1 hour has been proposed. (Non-Patent Document 1).

International Publication WO00 / 58210

However, in the conventional technology as described above, further improvement is necessary for obtaining a fine powder of βTCP with less impurities. That is, the method described in Non-Patent Document 1 or Patent Document 1 is also called a mechanochemical method, and has an advantage that it is easy to adjust the Ca / P ratio to 1.50. However, in these methods, since the calcium raw material and the phosphoric acid raw material are reacted, they are retained in a pulverizer such as a ball mill for a long time before firing, so even if a high-purity raw material is used, the pulverizer There is a disadvantage that a relatively large amount of material wear powder is mixed.

In general, impurities mixed in βTCP are classified according to the source of impurities: 1) derived from raw materials; impurities contained in raw materials such as Mg, Fe, Al, Si, etc., 2) derived from reaction; hydroxyapatite, calcium pyrophosphate (It occurs when the Ca / P ratio of the reaction shifts), 3) Origin of equipment; Coloring of acid insoluble matter (ceramic), Cr, Ni, Fe, or product.

Among these three classifications, the impurities derived from the raw material 1) can be reliably avoided by purchasing high-purity raw materials although they are expensive. Moreover, it is not difficult to avoid impurities derived from the reaction 2) unless an intermediate check is performed before the firing step and the adjustment is carefully repeated until Ca / P reaches 1.50. On the other hand, only the impurities derived from the equipment in 3) above, coupled with the strong abrasiveness of βTCP, increase the risk of contamination when trying to mechanically grind in order to obtain a finer powder, and avoid the contamination. It becomes extremely difficult. That is, if βTCP powder having excellent processability is to be obtained, the risk of lowering the purity must be borne.

Here, in order to obtain βTCP fine particles, means for mechanically performing secondary pulverization and means for reducing the basic particles for reaction precipitation in water, and means for maintaining the particle size until the time of raw material processing There are two possible ways.

As the former means, the method using a pulverizer is the theory, but since there are various merits in commercial pulverizers, there is no clear knowledge that which pulverizer is suitable for βTCP. The principle of grinding the material to be crushed directly with a hammer or the like (for example, a pulverizer) or cutting with a cutter (for example, a glow mill) is a pulverizer having a relatively high processing capacity corresponding to the equipment cost, but the viscosity of the βTCP powder itself Or because the adhesion to the equipment is in the way, and the hammer contact with the object does not reach the whole, pulverization unevenness occurs and coarse particles remain, so eventually a fine powder with a uniform particle size is used. It is difficult to get. For this reason, for example, it is difficult to obtain a uniform particle size distribution having an average particle size of 1 to 3 μm and a maximum particle size of 10 μm or less suitable for the preparation of pastes and the like.

In addition, the grinding type (for example, a ball mill) has a problem with the viscosity of βTCP powder itself or adhesion to equipment, but if the residence time is increased, a uniform particle size with an average particle size of 1 to 3 μm as described above can be obtained. Although it is possible, the probability that the abrasion powder of the pulverizing apparatus powder contact member will be mixed is increased.

The counter-type jet mill, known as an ultra-fine pulverizer, is a pulverizer with a relatively low probability of mixing with wear powder because the impact ratio to the pulverizer contact part is small because it is a system that makes particles collide with each other. . However, this is also inefficient due to the elasticity of βTCP powder itself, and in order to obtain a uniform particle size with an average particle size of 1 to 3 μm, it is necessary to reduce the amount of treatment, and the impact ratio to the powder contact portion of the pulverizer is small. Also have to carry the risk of contamination with some wear powder. Further, this pulverization equipment itself has a drawback that the equipment cost for the processing capacity becomes very expensive.

Next, since the latter means does not require a pulverizer, the risk of contamination can be greatly reduced. However, in order to avoid secondary condensation at the time of dehydration after the reaction, it is necessary to make the reaction particle size of one unit uniform. As a result, the volume of air space between the particles increases, resulting in a high bulk volume of the obtained powder, thereby increasing the amount of oil absorption and solvent absorption, resulting in poor workability.

From the above viewpoint, as a conclusion, it is said that the means of pulverization is unavoidable for the formation of fine particles in consideration of processability and the like, and therefore there is a limit even if the mixing of impurities is prevented. For this reason, development of a new technique for producing βTCP fine powder with higher purity than ever is eagerly desired.

Therefore, the main object of the present invention is to provide a βTCP fine powder having a purity higher than that of the conventional product.

As a result of intensive studies in view of the problems of the prior art, the present inventor has found that the above object can be achieved by adopting a method comprising a specific process, and has completed the present invention.

That is, the present invention relates to a method for producing the following high-purity βTCP fine powder.
1. A method for producing high purity βTCP fine powder,
1) The 1st process of producing | generating the slurry containing a tricalcium phosphate by making a phosphate ion and a calcium salt react in water,
2) a second step of preparing a wet pulverized product containing fine powder as a solid content by wet pulverizing the slurry or wet solid content obtained therefrom;
3) A method for producing a high-purity βTCP fine powder, comprising a third step of obtaining the βTCP fine powder by firing the wet pulverized product.
2. The manufacturing method of said claim | item 1 whose water content of the said slurry or the wet solid content obtained from it is 60 weight% or more.
3. Item 2. The production method according to Item 1, wherein the wet-grinding solvent is at least one of water and alcohol.
4). Item 2. The production method according to Item 1, wherein the wet-grinding solvent is water.
5. The manufacturing method of said claim | item 1 which performs a drying process with respect to the said wet-grinding processed material prior to a 3rd process.
6). Item 6. The method according to Item 5, wherein a dry crushing treatment is further performed after the drying treatment.
7). Item 2. The production method according to Item 1, wherein the high-purity βTCP fine powder has an average particle size of 5 µm or less and a hydrochloric acid insoluble content is 100 ppm by weight or less.
8). Item 2. The production method according to Item 1, wherein the slurry or a wet solid content obtained therefrom has a crystallinity of 75% or less.
9. A method for producing a precursor of high-purity βTCP fine powder,
1) The 1st process of producing | generating the slurry containing a tricalcium phosphate by making a phosphate ion and a calcium salt react in water,
2) a second step of preparing a wet pulverized product containing fine powder as a solid content by wet pulverizing the slurry or wet solid content obtained therefrom;
A method for producing a precursor of high-purity βTCP fine powder, comprising:
10. Item 10. The production method according to Item 9, wherein the water content of the slurry or wet solid content obtained from the slurry is 60% by weight or more.
11. Item 10. The production method according to Item 9, wherein the solvent for wet grinding is at least one of water and alcohol.
12 Item 10. The production method according to Item 9, wherein the precursor is in the form of a slurry, a wet solid or a dry powder.
13. Item 10. The method according to Item 9, wherein the slurry or the wet solid content obtained therefrom has a crystallinity of 75% or less.
14 A high-purity βTCP fine powder having an average particle diameter of 5 μm or less and a hydrochloric acid insoluble content of 100 ppm by weight or less.
15. Item 15. The high-purity βTCP fine powder according to Item 14, wherein the Fe content is 4 ppm by weight or less and the Cr content is 2 ppm by weight or less.
16. Item 15. The high-purity βTCP fine powder according to Item 14, wherein the specific surface area is 5 m ² / g or less.

In particular, the production method of the present invention is a mixture of impurities derived from equipment (particularly from a grinder) by wet-grinding a slurry containing tricalcium phosphate produced as a precursor of βTCP or wet solid content obtained therefrom. Can be significantly reduced or prevented, so that a finer βTCP fine powder can be provided even though it is a fine powder. At the same time, the load on the pulverizer can be reduced, which is an advantageous method in terms of equipment and economy.

According to the production method of the present invention, high-purity βTCP fine powder can be obtained. For example, a fine powder having an average particle size of 1 to 3 μm and a maximum particle size of 10 μm or less can be prepared. That is, a fine powder excellent in processability can be produced. Such a fine powder can be suitably used, for example, as a fine powder for paste.

The high-purity βTCP fine powder or the paste containing the same according to the production method of the present invention can be particularly suitably used as a biomaterial. For example, in addition to implant materials such as artificial bones, artificial joints, and artificial tooth roots, they can also be used for bone fillers, bone filling agents, and the like. In addition, it is also useful for dental use (toothpaste etc.) and polishing materials.

1. Manufacturing method of high purity βTCP fine powder The manufacturing method of the high purity βTCP fine powder of the present invention (the manufacturing method of the present invention)
1) a first step of generating a slurry containing tricalcium phosphate by reacting phosphate ions and calcium ions in water;
2) a second step of preparing a wet pulverized product containing fine powder as a solid content by wet pulverizing the slurry or wet solid content obtained therefrom;
3) It includes a third step of obtaining a βTCP fine powder by firing the wet pulverized product.

First Step In the first step, a slurry containing tricalcium phosphate is generated by reacting phosphate ions and calcium salt in water.

As the phosphate ion supply source, for example, phosphoric acid, water-soluble phosphate and the like can be used. More specifically, at least one of phosphoric acid, ammonium phosphate, diammonium hydrogen phosphate, and ammonium dihydrogen phosphate can be suitably used.

The calcium salt source is not particularly limited as long as it is a calcium compound, and calcium salts of inorganic acids or organic acids can be suitably used. More specifically, at least one of calcium chloride, calcium nitrate, calcium hydroxide, calcium carbonate, calcium gluconate and calcium acetate can be suitably used.

The phosphate ion and the calcium salt can be reacted by dissolving or suspending the compound serving as the phosphate ion supply source and the compound serving as the calcium salt supply source in water. In this case, in addition to the method of blending both in water simultaneously or sequentially, a method of mixing each aqueous solution or suspension after preparing each aqueous solution or suspension in advance can be employed. When mixing, it is preferable to make it react, stirring. For the stirring, a known stirring device or the like can be used.

The compounding ratio of the compound serving as the phosphate ion supply source and the compound serving as the calcium salt supply source may be reacted at a ratio that provides a stoichiometric ratio depending on the type of compound used. Further, the concentration is not particularly limited, and may be appropriately adjusted within the range of usually 0.1 to 40% by weight.

In the reaction between phosphate ion and calcium salt, a precipitate may be generated by adjusting the pH within the range of 2 to 10. As the pH adjuster, for example, at least one of ammonia, nitric acid, hydrochloric acid and the like can be suitably used. Although the reaction temperature is not particularly limited, it may usually be about 0 to 80 ° C.

Second Step In the second step, a wet pulverized processed product containing fine powder as a solid content is prepared by wet pulverizing the slurry or wet solid content obtained therefrom. That is, prior to crystallization to βTCP, a wet pulverization treatment is performed on a slurry containing tricalcium phosphate as a precursor (reaction product) or wet solid content obtained thereby. one of. In the present invention, wet pulverization in the second step is essential for producing high-purity βTCP fine powder. In addition, wet pulverization at this timing has the highest production efficiency (pulverization efficiency) and also has the advantage that the impact on the pulverization equipment can be minimized.

From this viewpoint, it is preferable that the solid content of the slurry or the wet solid content obtained from the slurry is lower in crystallinity. Therefore, a slurry whose crystallinity is usually 75% or less, particularly 70% or less is preferable. That is, it is preferable to perform the wet pulverization process of the second step on the slurry or wet solid content having a solid content crystallinity of 75% or less. The slurry or wet solid having such a crystallinity was adjusted in water content while maintaining the crystallinity of the solid in the slurry itself or the slurry obtained in the first step at 75% or less, for example. Wet solids can be suitably used.

The water content of the slurry in the second step or the wet solid content (hydrated solid content) obtained from the slurry is not particularly limited, but is usually 5% by weight or more, preferably 30% by weight or more, more preferably 60% by weight or more. What should I do? The upper limit of the moisture content may be about 95% by weight.

In the second step, when the slurry produced in the first step is wet pulverized, the slurry may be pulverized as it is. In the present invention, in addition to the slurry, a wet solid content obtained from the slurry may be used. As the wet solid content, as described above, for example, the water content adjusted while maintaining the crystallinity of the solid content of the slurry at 75% or less can be suitably used. In the case of wet-grinding the wet solid content, first, a wet precipitate is obtained from the reaction slurry by solid-liquid separation, 1) a method in which the wet precipitate is pulverized as it is, and 2) the wet precipitate in water. A method of pulverizing a suspension obtained by suspending, 3) A method of pulverizing the wet precipitate, and 4) A suspension obtained by suspending the wet precipitate in water and suspending in water. Any method of pulverizing the liquid can be employed. In these methods, the above-mentioned solid-liquid separation method, water washing method, suspension method and the like can be carried out according to known methods.

The wet pulverization method is not particularly limited, and may be any method such as impact, shearing, grinding, compression, and vibration. Further, as a classification on the apparatus, any apparatus such as a high-pressure fluid collision mill, a high-speed rotating slit mill, an attritor, a ball mill, a bead mill, a roll mill, a ring-shaped grinding medium mill, and a high-speed rotating thin film mill may be used. As these devices themselves, known or commercially available devices can be used.

Among these wet pulverizers, for example, a bead mill can be preferably used in the present invention. When using a bead mill, it is preferable to use at least one of water and an organic solvent as the solvent, and it is more preferable to use at least one of water and alcohol. The medium is not limited, but, for example, beads made of a zirconia-based material can be preferably used. The size of the beads may be about 0.5 to 2 mm in diameter. The bead filling amount may be appropriately adjusted within a range of about 40 to 80% according to the type of apparatus used.

The degree of wet pulverization can be adjusted as appropriate according to the average particle size, particle size distribution, etc. of the desired fine powder, but it is usually preferable to adjust the average particle size to 5 μm or less, particularly 3 μm or less. More preferably, the average particle size is adjusted to 1 to 3 μm and the maximum particle size is 10 μm or less. The crushing at this timing has the highest production efficiency and the impact on the crushing equipment is the smallest.

In the production method of the present invention, prior to the third step, the wet pulverized product may be dried. As a drying method, in addition to normal drying (natural drying or heat drying), freeze drying, spray drying, or the like can be employed. The drying temperature is not particularly limited as long as it is equal to or lower than the temperature at which it does not change to βTCP. In the present invention, spray drying can be suitably employed. The spray drying method can be carried out by preparing a suspension of the wet pulverized product and spraying the obtained suspension. Also in this case, a known or commercially available spray drying apparatus can be used.

Also, by performing a drying treatment, some of the fine particles may be lightly aggregated to form an aggregate. In this case, it is desirable to perform a dry crushing process for the purpose of breaking up and redispersing the aggregate. As the dry pulverization treatment, for example, a dry fine powder obtained by drying (including freeze-drying) the wet pulverized product may be pulverized dry. What is necessary is just to implement as a method of crushing using the well-known or commercially available grinding | pulverization apparatus used for what is called roughing and middle crushing. For example, a feather mill (screen type crusher) or the like can be suitably used. In particular, in the case of freeze-drying, the dried product can be weakened by freeze-drying, energy during pulverization can be reduced, and the load on the pulverizer can be suppressed. Also, freeze pulverization can be employed as one of the dry pulverization treatments. The freeze pulverization basically uses the same pulverization principle when freeze-drying, but freeze pulverization pulverizes at a low temperature, so that the pulverization energy can be further saved.

Third Step In the third step, βTCP fine powder is obtained by firing the wet pulverized product. That is, by firing, tricalcium phosphate is crystallized into βTCP.

The firing temperature is usually 700 ° C. or higher, and particularly preferably 880 to 930 ° C. By setting to such a temperature range, good workability can be obtained and aggregation can be effectively suppressed. The firing atmosphere is preferably in the air or in an oxidizing atmosphere. The firing time can be appropriately set according to the amount of fine powder to be fired, the firing temperature, and the like. In this way, the high purity βTCP fine powder of the present invention can be obtained.

High purity βTCP fine powder obtained by the production method of the present invention The high purity βTCP fine powder of the present invention (the fine powder of the present invention) is characterized by being higher in purity than the conventional product, despite being miniaturized. Have.

The average particle diameter of the fine powder of the present invention is usually 5 μm or less, preferably 3 μm or less. More preferably, the average particle size is 1 to 3 μm, and the maximum particle size is 10 μm or less. The fine powder of the present invention having such a particle size is excellent in processability and the like, and a paste composition can be suitably prepared using this.

Also, as a high purity characteristic, the hydrochloric acid insoluble content of the fine powder of the present invention is preferably 100 ppm by weight or less, particularly preferably 80 ppm by weight or less. Examples of the hydrochloric acid insoluble component include components such as zirconia, alumina, and titanium. Further, the Fe content is preferably 4 ppm by weight or less, particularly preferably 2 ppm by weight or less. The Cr content is preferably 2 ppm by weight or less, particularly preferably 0.8 ppm by weight or less.

Further, the specific surface area of the fine powder of the present invention is not limited, but is usually 5 m ² / g or less, preferably 1 to 4 m ² / g, more preferably 1 to 3 m ² / g. Thus, when the specific surface area is relatively low, it is considered that the processability is excellent.

2. The manufacturing method of the precursor of high purity (beta) TCP fine powder This invention also includes the manufacturing method of the precursor of high purity (beta) TCP fine powder. That is, a method for producing a precursor of high purity βTCP fine powder,
1) The 1st process of producing | generating the slurry containing a tricalcium phosphate by making a phosphate ion and a calcium salt react in water,
2) a second step of preparing a wet pulverized product containing fine powder as a solid content by wet pulverizing the slurry or wet solid content obtained therefrom;
The manufacturing method of the precursor of the high purity (beta) TCP fine powder containing this is also included.

The first step and the second step are the same as those described in 1. The high-purity βTCP fine powder manufacturing method can be carried out in the same manner as in the first step and the second step.

Since the precursor obtained in this way is finely powdered by wet pulverization in the second step in particular, it can be used for various applications by processing it.

In addition, it is desirable that this precursor is usually provided in the form of a slurry, a wet solid or a dry powder. Such a form has an advantage that, for example, the hardness of the final molded product can be further increased during the sintering process.

The form of the precursor can be provided as it is when the wet pulverized product is already in the desired form. For example, when the precursor is provided in the form of a slurry, it can be provided as it is if the wet pulverized product is in the form of a slurry. On the other hand, when the said state is not in a desired form, what is necessary is just to adjust so that it may become a desired form, for example by giving well-known processing methods, such as drying, solid-liquid separation, suspension, and dilution.

Hereinafter, examples and comparative examples will be shown to describe the features of the present invention more specifically. However, the scope of the present invention is not limited to the examples.

Synthesis example 1
50 kg of JIS reagent calcium nitrate tetrahydrate (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in purified water to a total volume of 120 L. After adjusting the liquid temperature to 30 ° C., 9.0 kg of JIS reagent ammonia water (manufactured by Wako Pure Chemical Industries, Ltd.) was added while ensuring sufficient stirring, and diammonium hydrogen phosphate (Yoneyama Chemical Industries) was added to this liquid. A solution obtained by dissolving 19.5 kg in 65 L of purified water was supplied at a rate of 1 L per minute, and the liquid became cloudy. Further, the mixture was heated to 45 ° C. while continuing sufficient stirring, and this state was maintained for 60 minutes, and then the pH was adjusted to 5.8 with a nitric acid diluted aqueous solution. After cooling the liquid temperature to 30 ° C., it was put into a filter press and separated into solid and liquid, and then 500 L of purified water was passed through the compressed cake to wash the cake. The obtained cake was 75 kg wet (water content 72 wt%).

Synthesis example 2
Ultra high purity calcium carbonate (manufactured by Ube Material Co., Ltd., CS grade) was calcined at 900 ° C. for 12 hours, then roughly crushed with a hammer mill, 11.2 kg was suspended in 30 L of purified water, and stirred until the heat generation was finished. After the exotherm is completed, 30 L of purified water is added to lower the viscosity, and then 20 L of liquid diluted with 14.84 kg of purified water of 85% orthophosphoric acid (manufactured by Tosoh Corporation) is supplied at a rate of 70 mL per minute. 80 L of reaction slurry (water content 81% by weight) was obtained.

Example 1
8.8 kg of the compressed cake obtained in Synthesis Example 1 was collected, 3.2 L of purified water was added, and the mixture was stirred and dispersed to prepare a uniform slurry having a solid content of about 20% by weight (water content 80% by weight). The slurry is a DYNO mill (manufactured by Swiss Willy et Bacofen (WAB)) multi-lab type while stirring in a 20 L container (media material: zirconia, zirconia reinforced alumina, bead diameter 1.0 mm, gap width 0.3 mm, (Container size 1.4 L) The inside of the container was replaced with purified water under the conditions of a liquid supply speed of 25 L / H and a rotational speed of 10 m / s (circumferential speed), and then continuous wet pulverization was performed. The initial flow of 1.5 L of the pulverized liquid was not recovered, and after the completion of all the slurry processing, follow-up pulverization was performed with 2.0 L of purified water to obtain 12.6 kg of wet pulverized slurry. 6.0 kg of the pulverized slurry was transferred onto two 25 cm x 50 cm x 10 cm deep square stainless steel containers with a polypropylene sheet laid on them, and placed at 105 ° C for 20 hours in a shelf-type dryer (PH201 manufactured by Espec). Drying was performed (water content: 0.8% by weight). The dried lump was tapped with a pestle into small pieces, and then pulverized with a bantam mill (APB manufactured by Hosokawa Micron Corporation) to obtain 1150 g of a dry powder. The powder is divided into two 20 cm × 20 cm × 10 cm square containers made of highly dense alumina, heated in an electric furnace (KSO-35 type, manufactured by Kitamura Electric Furnace Co., Ltd.), at a heating rate of 70 ° C./H, and a temperature of 900 ° C. Was fired with a program for 3 hours. After standing to cool, the yield of the powder taken out from the electric furnace was 1070 g.

Example 2
The reaction slurry 13L (water content 81%) obtained in Synthesis Example 2 was collected, wet-pulverized under the same conditions as Example 1 with stirring, and dried on a shelf (water content: 0.9% by weight). ). The dried lump was tapped with a pestle into small pieces, and then pulverized with a bantam mill (APB manufactured by Hosokawa Micron Corporation) to obtain 3180 g of dry powder. Then, it baked on the same conditions as Example 1 further, and obtained powder. The yield of the obtained powder was 3000 g.

Example 3
10.6 kg of the compressed cake obtained in Synthesis Example 1 was collected, 1.3 L of purified water was added, and the mixture was stirred and dispersed to prepare a uniform slurry having a solid content of 25 wt% (water content 75 wt%). The pulverization was performed in the same manner as in Example 1 to obtain 12.5 kg of a wet pulverized slurry. The whole amount of the pulverized slurry was transferred to a 25 cm x 50 cm x 10 cm deep square stainless steel container with a polypropylene sheet spread on it, and dried at 105 ° C for 20 hours in a shelf-type dryer (PH201 manufactured by Espec). (Water content: 1.1% by weight). The dried lump was tapped with a pestle into small pieces, and then pulverized with a bantam mill (APB manufactured by Hosokawa Micron Corporation) to obtain 2900 g of a dry powder. The powder is divided into three dense 20 cm × 20 cm × 10 cm square containers made of alumina, and the temperature is raised at an electric furnace (KSO-35 type, manufactured by Kitamura Electric Furnace Co., Ltd.) at a heating rate of 70 ° C./H and a maximum temperature of 900 Firing was carried out with a program held at 3 ° C for 3 hours. After standing to cool, the yield of the powder taken out from the electric furnace was 2790 g.

Example 4
4.4 kg of the compressed cake obtained in Synthesis Example 1 was collected, 7.9 L of purified water was added, and the mixture was stirred and dispersed to prepare a uniform slurry (water content 90 wt%) having a solid content of about 10 wt%. The pulverization was performed in the same manner as in Example 1 to obtain 13.0 kg of a wet pulverized slurry. The whole amount of the pulverized slurry was transferred to a 25 cm x 50 cm x 10 cm deep square stainless steel container with a polypropylene sheet spread on it, and dried at 105 ° C for 20 hours in a shelf-type dryer (PH201 manufactured by Espec). (Water content: 0.9% by weight). The dried lump was tapped with a pestle into small pieces, and then pulverized with a bantam mill (APB manufactured by Hosokawa Micron Corporation) to obtain 1220 g of a dry powder. The powder is divided into two 20 cm × 20 cm × 10 cm square containers made of highly dense alumina, heated in an electric furnace (KSO-35 model, manufactured by Kitamura Electric Furnace Co., Ltd.), and the maximum temperature is 900 ° C./H. Firing was carried out with a program held at 3 ° C. for 3 hours. After standing to cool, the yield of the powder taken out from the electric furnace was 1140 g.

Example 5
8.8 kg of the compression cake of Synthesis Example 1 was sampled, 20 L of ethyl alcohol was added, and after stirring and dispersing, it was put into a filter press and filled with pressure at 0.2 MPa. Reagent 99.5 degrees of ethyl alcohol 60 L was passed through the cake in a packed state to perform solvent replacement. Furthermore, it was squeezed at 1.2 MPa for 10 minutes, sufficiently drained, and 4.2 kg (solid content 59 wt%, solvent content 41 wt%) was recovered as a wet solid. 99.5 degree ethyl alcohol 2L was added and suspended, and it was set as the alcohol slurry of about 5.8 kg (solid content 42 weight%, solvent content 58 weight%). The slurry is 99.5 degree ethyl alcohol with stirring and the solvent substituted DYNO mill (manufactured by Swiss Willy et Bacofen (WAB)) is a multi-lab type (media material: zirconia, zirconia reinforced alumina, bead diameter 1.0 mm, gap) Width 0.3mm, container size 1.4L) Wet pulverization is performed under conditions of a liquid supply speed of 25L / H and a rotational speed of 10m / s (circumferential speed). The pulverized slurry is 25cm x 50cm x 10cm deep square stainless steel container 2 The sheet was transferred onto a polypropylene sheet and dried for 2 hours at 105 ° C. in a shelf-type dryer (PH201 manufactured by Espec) with sufficient ventilation. The dried lump was pulverized with a feather mill (manufactured by Hosokawa Micron Corporation) to obtain 2230 g (water content: 0.3% by weight) of a dry powder. The powder is divided into two 20 cm × 20 cm × 10 cm square containers made of highly dense alumina, heated in an electric furnace (KSO-35 model, manufactured by Kitamura Electric Furnace Co., Ltd.), and the maximum temperature is 900 ° C./H. Firing was carried out with a program held at 3 ° C for 3 hours. After standing to cool, the yield of the powder taken out from the electric furnace was 2190 g.

Comparative Example 1
The remaining compressed cake of Synthesis Example 1 is evenly stacked with 5 sheets of 25 cm × 50 cm × 10 cm deep rectangular stainless steel sheets spread with a polypropylene sheet, and dried at 105 ° C. for 20 hours in a shelf-type dryer (PH201 manufactured by Espec). (Moisture content: 1.1% by weight). The dried product was coarsely pulverized with a feather mill (manufactured by Hosokawa Micron Corporation) to obtain 10.1 kg of a coarse powder sample. Of this, 4.0 kg of the coarse powder was fired under the same conditions as in Example 1, allowed to cool, and the yield of the coarse powder taken out from the electric furnace was 3750 g. This coarse powder was pulverized with a counter jet mill (manufactured by Hosokawa Micron Corporation; 200FG type) at a supply rate of 10 kg per hour to obtain 3350 g of fine powder.

Comparative Example 2
The slurry 40L of Synthesis Example 2 was dried at 105 ° C. for 20 hours in an evenly stacked plate type dryer (PH201 manufactured by Espec Co., Ltd.) in which a polypropylene sheet was spread on five 25 cm × 50 cm × 10 cm deep rectangular stainless steel containers. (Water content: 1.7% by weight). The dried product was roughly crushed with a feather mill (manufactured by Hosokawa Micron Corporation) to obtain a 9.9 kg coarse powder sample. 4.0 kg of the coarse powder was fired under the same conditions as in Example 1, allowed to cool, and then the yield of the coarse powder taken out from the electric furnace was 3860 g. The coarse powder was pulverized with a counter jet mill (manufactured by Hosokawa Micron Corporation; 200FG type) at a supply rate of 10 kg per hour to obtain 3590 g of fine powder.

Comparative Example 3
Of the remaining feather mill crushed product of Comparative Example 1, 2.0 kg of the powder was separated into two highly dense alumina 20 cm × 20 cm × 10 cm square containers, and an electric furnace (KSO—Kitamura Electric Furnace KSO— 35 type) was fired at a temperature rising rate of 70 ° C./H and a maximum temperature of 900 ° C. with a program for 3 hours. After standing to cool, the yield of the powder taken out from the electric furnace was 1920 g. The calcined powder is suspended in 3.5 L of ethyl alcohol to form a slurry, and the slurry is stirred with a DYNO mill (manufactured by Swiss Willy et Bacofen (WAB)) in a multi-lab type (media material: zirconia, zirconia reinforced) Alumina, bead diameter 1.0 mm, gap width 0.3 mm, container size 1.4 L) Wet pulverization is performed under conditions of a liquid supply speed of 12 L / H and a rotation speed of 10 m / s (circumferential speed). × Transferred on two 10 cm-depth stainless steel containers with a polypropylene sheet spread, and dried at 60 ° C. for 20 hours in a shelf-type dryer (PH201 manufactured by Espec). The dried lump was crushed with a feather mill (manufactured by Hosokawa Micron Corporation) to obtain 1850 g of a powder product.

Comparative Example 4
Of the remaining feather mill crushed product of Comparative Example 2, 2.0 kg was fired under the same conditions as in Comparative Example 3 to obtain 1950 g of a fired powder. The fired powder is suspended in 3.5 L of ethyl alcohol to form a slurry, and then wet pulverized under the same conditions as in Comparative Example 3. The pulverized slurry is a polypropylene sheet in two 25 cm × 50 cm × 10 cm deep square stainless steel containers. And then dried at 60 ° C. for 20 hours using a shelf-type dryer (PH201 manufactured by Espec Corp.). The dried lump was pulverized with a feather mill (manufactured by Hosokawa Micron) to obtain 1800 g of powder.

Comparative Example 5
4.0 kg of the coarsely pulverized feather mill of Comparative Example 3 was classified with an ACM pulverizer (manufactured by Hosokawa Micron), classification 60 Hz, bag filter collection, hammer; ) At a temperature rising rate of 70 ° C./H and a maximum temperature of 900 ° C. with a program for 3 hours. After standing to cool, the yield of the powder taken out from the electric furnace was 3470 g.

Comparative Example 6
3.9 kg of the coarsely milled feather mill of Comparative Example 4 was classified with an ACM pulverizer (manufactured by Hosokawa Micron Co., Ltd.), 60 Hz classification, bag filter collection, hammer; ) At a temperature rising rate of 70 ° C./H and a maximum temperature of 900 ° C. with a program for 3 hours. After standing to cool, the yield of the powder taken out from the electric furnace was 3320 g.

Comparative Example 7
After mixing 190 g of hydroxyapatite (manufactured by Tomita Pharmaceutical Co., Ltd.) and 60 g of anhydrous calcium hydrogen phosphate (manufactured by Tomita Pharmaceutical Co., Ltd.), the mixture was placed in a 7 L bowl mill (manufactured by alumina) and operated for 12 hours to obtain a powder having an average particle size of 2.3 μm. 217 g of product was obtained (water content: 1.5 weight). The powder is put into a 1.6-L capacity crucible made of high-density alumina and heated in an electric furnace (KSO-35 model, manufactured by Kitamura Electric Furnace Co., Ltd.) at a heating rate of 70 ° C / H and a maximum temperature of 900 ° C for 3 hours. Firing was carried out with a holding program. After standing to cool, the yield of the powder taken out from the electric furnace was 194 g. The powder product was again placed in a 7 L bowl mill (made of alumina) and allowed to operate for 12 hours to obtain 160 g of βTCP powder product having an average particle size of 2.3 μm.

Test example 1
The powders obtained in the examples and comparative examples were examined for the following physical properties. The results are shown in Tables 1 and 2. For comparison, the physical properties of commercial products (commercial products) were also examined. The results are also shown in Table 2.

(1) X-ray diffraction analysis The sample was subjected to X-ray diffraction analysis using a powder X-ray diffractometer "RINT 2100V" manufactured by Rigaku. It was confirmed that the obtained peak coincided with JCPDS No. 9-169 Whitlockite.
The hydroxyapatite content (HA (%)) is obtained from the measurement result obtained by X-ray diffraction to obtain the area ratio of the main peak of βTCP and the main peak of HA, and the HA (%) is calculated from the integrated intensity ratio. Asked. International standard reference ISO 13779-3: 2008 (E) "Implants for surgery-Hydroxyapatite"
(2) Calcium pyrophosphate (CPP)
The sample was confirmed for a signal derived from calcium pyrophosphate by FTIR “AVATAR 360” manufactured by Thermo Fisher.
(3) Average particle diameter and maximum particle diameter The sample was ultrasonically stirred (frequency: 400 Hz), then dispersed in water and measured in an aqueous solvent by a laser diffraction method. “MICROTRAC HRA Model”
No. 9320-X100 ”manufactured by Honeywell was used. The value with a cumulative frequency of 50% was taken as the average particle size, and the particle size with a cumulative frequency of 100% was taken as the maximum particle size.
(4) Specific surface area 0.5 g of a sample was pretreated (under reduced pressure, 105 ° C., 1 hour), and the specific surface area was measured by a nitrogen gas adsorption method. As a measuring device, “High-speed specific surface area / pore distribution measuring device NOVA 4000e” manufactured by Yuasa Ionics Co., Ltd. was used.
(5) Hydrochloric acid insoluble matter 10.0 g of sample was dissolved in 30 mL of hydrochloric acid and water, filtered to a membrane filter with a diameter of 4.7 mm and an aperture of 0.45 μm, and weighed to 4 digits below the decimal point, and purified water of 100 mL or more After thoroughly washing with, the weight after drying the filter paper at 40 ° C. is measured. The hydrochloric acid insoluble content is calculated by the following formula.
Hydrochloric acid insoluble matter (weight ppm) = (filter weight after filtration (g)-filter weight before use (g)) / 10.0 x 1000000
(6) Content of chromium and iron 5 mL of 6M hydrochloric acid was added to 1.0 g of the sample and dissolved to make exactly 50 mL. Using a plasma induced light emitting device “Vista Pro” manufactured by SII Nano Technologies, the concentration of chromium and iron was calculated by the standard addition method.
(7) Hunter Whiteness Using a color difference meter “Z-300A” manufactured by Nippon Denshoku Industries Co., Ltd., perfect white was taken as 100%, the reflectance at a wavelength of 457 μm was measured, and calculated according to the following formula.
W = 100 − [(100−L) ² + (a ² + b ² )] ^1/2
(8) Water content 2.0 g of a sample was measured with an infrared moisture meter at 105 ° C. for 30 minutes.

As is clear from these results, it can be seen that the amount of impurities in the βTCP fine powder obtained by the production method of the present invention is greatly suppressed although it is a fine powder.

Test example 2
The slurry (slurry before wet pulverization) obtained in Example 1 was separated by filtration, and the crystallinity of the solid content contained in the slurry was examined. As a result, the crystallinity was 66%. For comparison, the slurry obtained by treating the slurry in an autoclave (150 ° C., 3 hours) was also examined in the same manner. As a result, the crystallinity was 77% (reference product 1). The βTCP powder was obtained using the slurry of Reference Product 1 under the same conditions as in Example 1. When the hydrochloric acid insoluble matter was measured for the obtained powder in the same manner as in Test Example 1 (5), the reference product 1 was 140 ppm and exceeded 100 ppm. In contrast, in Example 1 having a crystallinity of 66%, the insoluble content of hydrochloric acid is 50 ppm, and it can be seen that a predetermined βTCP powder can be obtained by wet-grinding a slurry or a wet solid having a low crystallinity. .

The crystallinity is measured by performing X-ray diffraction measurement under the following measurement conditions, cutting out a peak around 2θ = 30 ° to 35 ° using the attached application software, and then applying a background, amorphous This was carried out by separating the halo due to the component and the diffraction lines due to the crystal component, and calculating the crystallinity using the amorphous component and the integrated intensity of the crystal component. The measurement sample was subjected to X-ray diffraction measurement while holding the measurement sample in an atmosphere (50 ° C. or less and atmospheric pressure) in which the degree of crystallization of the solid content of the slurry or wet solid does not change.

Apparatus: X-ray diffractometer (RINT2000) manufactured by Rigaku Corporation
X-ray: Cu-Kα
Filter: Unused counter: Scintillation counter voltage: 40kV
Current: 20 mA
Scan mode: Continuous scan speed: 4.00 ° / min Scan step: 0.020 °
Divergence slit: 1 deg
Scattering slit: 1 deg
Receiving slit: 0.15 mm

Claims (16)

1. A method for producing high purity βTCP fine powder,
   1) The 1st process of producing | generating the slurry containing a tricalcium phosphate by making a phosphate ion and a calcium salt react in water,
   2) a second step of preparing a wet pulverized product containing fine powder as a solid content by wet pulverizing the slurry or wet solid content obtained therefrom;
   3) A method for producing a high-purity βTCP fine powder, comprising a third step of obtaining the βTCP fine powder by firing the wet pulverized product.
2. The manufacturing method of Claim 1 whose water content of the said slurry or the wet solid content obtained from it is 60 weight% or more.
3. The production method according to claim 1, wherein the solvent for wet grinding is at least one of water and alcohol.
4. The manufacturing method of Claim 1 whose solvent of a wet grinding is water.
5. The manufacturing method of Claim 1 which performs a drying process with respect to the said wet-grinding processed material prior to a 3rd process.
6. The production method according to claim 5, wherein a dry crushing process is further performed after the drying process.
7. The production method according to claim 1, wherein the high-purity βTCP fine powder has an average particle size of 5 µm or less and a hydrochloric acid insoluble matter is 100 ppm by weight or less.
8. The manufacturing method according to claim 1, wherein the slurry or the wet solid content obtained from the slurry has a crystallinity of 75% or less.
9. A method for producing a precursor of high-purity βTCP fine powder,
   1) The 1st process of producing | generating the slurry containing a tricalcium phosphate by making a phosphate ion and a calcium salt react in water,
   2) a second step of preparing a wet pulverized product containing fine powder as a solid content by wet pulverizing the slurry or wet solid content obtained therefrom;
   A method for producing a precursor of high-purity βTCP fine powder, comprising:
10. The manufacturing method of Claim 9 whose water content of the said slurry or the wet solid content obtained from it is 60 weight% or more.
11. The production method according to claim 9, wherein the solvent for wet grinding is at least one of water and alcohol.
12. The process according to claim 9, wherein the precursor is in the form of a slurry, wet solids or dry powder.
13. The manufacturing method of Claim 9 whose crystallization degree of the solid content of the said slurry or wet solid content obtained from it is 75% or less.
14. A high-purity βTCP fine powder having an average particle diameter of 5 μm or less and a hydrochloric acid insoluble content of 100 ppm by weight or less.
15. The high-purity βTCP fine powder according to claim 14, wherein the Fe content is 4 ppm by weight or less and the Cr content is 2 ppm by weight or less.
16. The high-purity βTCP fine powder according to claim 14, which has a specific surface area of 5 m ² / g or less.