JP2021070619A - Production method and particles of hydroxyapatite - Google Patents

Abstract

To provide a production method capable of producing particles of hydroxyapatite satisfying a standard from a powder containing particles of nonstandard hydroxyapatite not satisfying a prescribed condition.SOLUTION: A production method according to the present invention comprises a first step (S1B) of preparing a powder containing particles of nonstandard hydroxyapatite not satisfying a predetermined condition, a second step (S2B) of dissolving the powder containing the particles of nonstandard hydroxyapatite in a phosphoric acid solution, and a third step (S3B) of forming particles of hydroxyapatite by using the phosphoric acid solution in which at least a part of the powder containing secondary particles of the nonstandard hydroxyapatite is dissolved.SELECTED DRAWING: Figure 2

Description

The present invention relates to a production method capable of producing hydroxyapatite particles conforming to the standard from a powder containing non-standard hydroxyapatite particles that do not meet the predetermined conditions, and the hydroxyapatite particles.

In recent years, hydroxyapatite has been used as a material for a fixed layer of chromatography used for purifying and isolating biopharmaceuticals such as antibodies and vaccines because of its high biocompatibility and excellent safety. Widely used.

Hydroxyapatite (HAP) used as a material for a fixed layer of chromatography as described above is produced by applying, for example, the following production method.

That is, the first liquid containing calcium hydroxide and the second liquid containing phosphoric acid are reacted with stirring to obtain primary particles of hydroxyapatite, which contain the primary particles and their aggregates. Hydroxyapatite can be obtained as secondary particles thereof by drying the slurry and granulating them.

Then, by firing (sintering) a powder composed of particles containing the secondary particles, a sintered powder (hereinafter referred to as "sintered powder") is obtained, and the powder or the powder or The sintered powder is filled in a column (adsorption device) or the like and used as a material for a fixed layer (adsorbent) (see, for example, Patent Document 1).

By the way, the secondary particles contained in the fixed layer material, that is, the particles of hydroxyapatite, which are produced by using the above-mentioned production method, have a range in particle size distribution, and even if the production method is further devised. , There is a limit to narrowing the particle size distribution. Therefore, in order to make the particle size distribution of hydroxyapatite particles sharper, it is necessary to prepare a material having a standard size suitable for use as a material for a fixed layer. However, if prepared according to the size of the particle size of the secondary particles of hydroxyapatite, among these secondary particles, small and large particles whose particle size is out of the standard must be removed and discarded. The reality was that there was no such thing. Therefore, if small secondary particles having a particle size outside the standard and large secondary particles are discarded, that is, if secondary particles having a particle size outside the desired range are discarded, waste will naturally occur. , There arises a problem that productivity in producing hydroxyapatite particles is reduced.

Further, such a problem is not limited to the case of discarding secondary particles outside the desired range, and when the fixed layer material, that is, the hydroxyapatite particles have expired, the fixed layer material (adsorbent). Even if the particle size of the hydroxyapatite particles varies due to multiple uses, or if the material for the fixed layer contains a calcium phosphate compound different from the hydroxyapatite particles in excess of the specified amount. It is happening as well. The present inventor has found such a problem.

Japanese Unexamined Patent Publication No. 2011-68539

An object of the present invention is to provide a production method capable of producing hydroxyapatite particles conforming to the standard from a powder containing non-standard hydroxyapatite particles that do not satisfy a predetermined condition, and the hydroxyapatite particles. There is.

Such an object is achieved by the present invention described in the following (1) to (10).
(1) The first step of preparing a powder containing non-standard hydroxyapatite particles that do not meet the predetermined conditions, and
The second step of dissolving the powder containing the nonstandard hydroxyapatite particles in a phosphoric acid solution containing phosphoric acid, and
A production method comprising a third step of producing hydroxyapatite particles using the phosphoric acid solution in which at least a part of a powder containing non-standard hydroxyapatite particles is dissolved.

As a result, it is possible to produce hydroxyapatite particles conforming to the standard by effectively utilizing the powder containing the non-standard hydroxyapatite particles determined not to satisfy the predetermined conditions, and thus conform to the standard. The productivity of producing hydroxyapatite particles is improved.

(2) The production method according to (1) above, wherein in the first step, a powder containing hydroxyapatite particles having a particle size outside the desired range is prepared.

As described above, the production method of the present invention was determined to be a powder containing non-standard hydroxyapatite particles that do not satisfy the predetermined conditions, and is a powder containing hydroxyapatite particles that are out of the desired range. It is preferably applied to the thing.

(3) Prior to the first step, a step of preparing a powder containing hydroxyapatite particles is provided.
The production method according to (2) above, wherein in the first step, a powder containing hydroxyapatite particles whose particle size is out of the desired range is recovered.

By going through each step as described above, it is possible to recover the powder containing the particles of hydroxyapatite whose particle size is out of the desired range.

(4) In the second step, as the dissolution of the powder containing the nonstandard hydroxyapatite particles into the phosphoric acid solution progresses, the dissolution becomes possible while confirming the dissolution state. The production method according to any one of (1) to (3) above, wherein the dissolution conditions are adjusted so as to be or promoted.

As a result, even if the shape of the powder containing non-standard hydroxyapatite particles that do not meet the predetermined conditions, which should be dissolved, changes, the non-standard hydroxyapatite particles that do not meet the predetermined conditions are included. The powder can be efficiently dissolved in the phosphoric acid solution.

(5) The confirmation of the dissolved state of the powder containing the nonstandard hydroxyapatite particles in the phosphoric acid solution in the second step includes detecting the turbidity of the phosphoric acid solution. The production method according to (4).

Thereby, it is possible to confirm the dissolved state of the powder containing the nonstandard hydroxyapatite particles that do not satisfy the predetermined conditions in the phosphoric acid solution.

(6) The production method according to (4) or (5) above, wherein the adjustment of the dissolution conditions in the second step is carried out by an operation including adjustment of the stirring speed of the phosphoric acid solution and adjustment of the dissolution time. ..

Thereby, the dissolved amount (content) of the powder containing the nonstandard hydroxyapatite particles that do not satisfy the predetermined conditions in the phosphoric acid solution can be adjusted.

(7) In any of the above (4) to (6), in the second step, the powder containing the nonstandard hydroxyapatite particles is added to the phosphoric acid solution in a plurality of times. The production method described.

In this way, by adding the powder containing the non-standard hydroxyapatite particles that do not meet the predetermined conditions to the phosphoric acid solution in a plurality of times, the non-standard hydroxyapatite particles that do not meet the predetermined conditions can be obtained. It is possible to accurately suppress or prevent the contained powder from being added to the phosphoric acid solution in an appropriate amount or more. That is, it is possible to accurately suppress or prevent powder containing non-standard hydroxyapatite particles that do not satisfy the predetermined conditions from being added to the phosphoric acid solution in an amount exceeding the soluble capacity.

(8) Prior to the third step, among the powders containing the nonstandard hydroxyapatite particles, those which are not dissolved in the phosphoric acid solution are filtered, which are the steps (1) to (7). ) The production method described in any one of.

As a result, in the third step, the purity of the obtained hydroxyapatite particles can be improved.

(9) The third step is a step of producing primary particles of hydroxyapatite from the phosphoric acid solution in which at least a part of a powder containing particles of the nonstandard hydroxyapatite is dissolved, and the obtained hydroxyapatite. The production method according to any one of (1) to (8) above, which comprises a step of producing hydroxyapatite particles using primary particles of apatite.

As a result, in the third step, the hydroxyapatite particles conforming to the standard can be obtained as the hydroxyapatite particles.

(10) Hydroxyapatite particles obtained by the production method according to any one of (1) to (9) above.

As a result, the hydroxyapatite particles conforming to the standard are produced as if the productivity was improved.

In the present invention, the powder containing non-standard hydroxyapatite particles prepared in the first step, which does not meet the predetermined conditions, is dissolved in the phosphoric acid solution in the second step, and then in the third step, Hydroxyapatite particles are produced using a phosphoric acid solution in which the powder is dissolved. According to the present invention having such a configuration, when producing hydroxyapatite particles, a phosphoric acid solution in which a powder containing non-standard hydroxyapatite particles that does not satisfy a predetermined condition is dissolved is used. That is, the hydroxyapatite particles conforming to the standard are produced by using the powder containing the non-standard hydroxyapatite particles that do not satisfy the predetermined conditions.

In this way, it is possible to produce hydroxyapatite particles conforming to the standard by effectively utilizing the powder containing the nonstandard hydroxyapatite particles determined not to satisfy the predetermined conditions, and thus conform to the standard. It is possible to improve the productivity when producing the particles of hydroxyapatite.

It is a vertical sectional view which shows an example of the adsorption apparatus provided with the adsorbent which can apply the production method of this invention. It is a flowchart which shows the method of producing the powder containing the particle of hydroxyapatite whose particle size conforms to the standard by applying the production method of this invention. It is a graph which shows the relationship between the addition amount of hydroxyapatite powder, and the turbidity of a phosphoric acid solution. It is a chart which shows the diffraction pattern by X-ray measured in the R-HAp secondary particle of Example 1 and the C-HAp secondary particle of Reference Example 1, respectively. It is a graph which shows the time transition of the turbidity in the phosphoric acid solution of a different concentration.

Hereinafter, the production method of the present invention and the particles of hydroxyapatite will be described in detail based on the preferred embodiments shown in the accompanying drawings.

First, prior to explaining the production method of the present invention and the particles of hydroxyapatite, an example of an adsorbent including an adsorbent to which the production method of the present invention can be applied will be described.

In the following, when a powder composed of particles containing particles of an adsorbent, that is, hydroxyapatite, provided in an adsorber is obtained in which the particle size conforms to the standard, the non-standard hydroxyapatite that does not satisfy the predetermined conditions is used. The case where the powder containing the particles is produced as being out of the desired range and the production method of the present invention is applied to the particles of hydroxyapatite which is out of the desired range will be described as an example.

<Adsorption device>
FIG. 1 is a vertical cross-sectional view showing an example of an adsorbent including an adsorbent to which the production method of the present invention can be applied. In the following description, the upper side in FIG. 1 is referred to as an "inflow side" and the lower side is referred to as an "outflow side".

Here, the inflow side refers to, for example, a sample liquid (a liquid containing a sample) or a liquid such as a phosphate-based buffer liquid which is an eluent when separating (purifying) an isolated product such as a protein to be separated. On the other hand, the outflow side refers to the side opposite to the inflow side, that is, the side on which the liquid flows out from the adsorption device.

The adsorbent 1 shown in FIG. 1, which separates (purifies) an isolated product such as a protein from a sample solution, comprises a column 2, a granular adsorbent (filler) 3, and two filter members 4 and 5. Have.

The column 2 is composed of a column main body 21 and caps (lids) 22 and 23 attached to the inflow side end portion and the outflow side end portion of the column main body 21, respectively.

The column body 21 is composed of, for example, a cylindrical member. Examples of the constituent materials of each part (each member) constituting the column 2 including the column body 21 include various glass materials, various resin materials, various metal materials, various ceramic materials and the like.

In the column main body 21, the filter members 4 and 5 are arranged so as to close the inflow side opening and the outflow side opening, respectively, and caps 22 and 23 are screwed to the inflow side end portion and the outflow side end portion, respectively. It will be installed depending on the situation.

In the column 2 having such a configuration, the adsorbent filling space 20 is defined by the column body 21 and the filter members 4 and 5 respectively. Then, at least a part of the adsorbent filling space 20 (in the present embodiment, almost the full amount) is filled with the adsorbent 3.

The volume of the adsorbent filling space 20 is appropriately set according to the volume of the sample liquid and is not particularly limited, but is preferably about 0.1 mL or more and 100 mL or less, and more preferably about 1 mL or more and 50 mL or less with respect to 1 mL of the sample liquid. ..

By setting the dimensions of the adsorbent-filled space 20 as described above and setting the dimensions of the adsorbent 3 described later as described below, the desired isolate is selectively isolated from the sample solution ( Purification), that is, isolation such as protein and impurities other than the isolate contained in the sample solution can be reliably separated.

The isolate isolated (purified) using the adsorbent 3 is not limited to proteins such as acidic proteins and basic proteins, and includes, for example, acidic amino acids, DNA, RNA, and negatively charged liposomes. Negatively charged substances, as well as positively charged substances such as basic amino acids, positively charged cholesterol and positively charged liposomes.

Further, with the caps 22 and 23 attached to the column body 21, the liquidtightness between them is ensured.

The inflow pipe 24 and the outflow pipe 25 are liquid-tightly fixed (fixed) to the centers of the caps 22 and 23, respectively. The liquid is supplied to the adsorbent 3 via the inflow pipe 24 and the filter member 4. Further, the sample liquid supplied to the adsorbent 3 passes between the adsorbents 3 (gap) and flows out of the column 2 through the filter member 5 and the outflow pipe 25. At this time, the isolate contained in the sample solution (sample) and the contaminants other than the isolate are separated based on the difference in the adsorptivity to the adsorbent 3 and the difference in the affinity for the eluate.

Each of the filter members 4 and 5 has a function of preventing the adsorbent 3 from flowing out from the adsorbent filling space 20. These filter members 4 and 5 are non-woven fabrics and foams (sponge-like porous bodies having communication holes) made of synthetic resins such as polyurethane, polyvinyl alcohol, polypropylene, polyether polyamide, polyethylene terephthalate, and polybutylene terephthalate, respectively. ), Woven cloth, mesh, etc.

In the adsorbent 1, the adsorbent 3 is composed of a powder composed of particles containing secondary particles of hydroxyapatite, or a sintered powder thereof.

The particles of hydroxyapatite include its secondary particles, as well as primary particles and multiple particles, and are mainly composed of the secondary particles.
Further, the _{secondary particles of hydroxyapatite (Ca 10} (PO ₄ ) ₆ (OH) ₂ ) were obtained by drying the slurry containing the primary particles and their aggregates and granulating them. It is mainly composed of hydroxyapatite. Further, in the present embodiment, the bulk density of the secondary particles is 0.65 g / mL or more, and the specific surface area is 70 m ² / g or more. Hydroxyapatite has a chemically stable apatite structure, and the powder containing the secondary particles of hydroxyapatite can be particularly preferably used for the adsorbent 3 included in the adsorbent 1. The hydroxyapatite is intended to have a Ca / P ratio of about 1.64 or more and 1.70 or less.

When the sample solution is supplied to the adsorbent 3 having such a structure, the isolate contained in the sample solution is specifically adsorbed by the adsorption (supporting) force peculiar to the sample solution, and the difference in the adsorption force is increased. It is separated and purified from impurities other than the isolate contained in the sample solution.

As described above, the bulk density of the secondary particles of hydroxyapatite is set to 0.65 g / mL or more in the present embodiment, but it is about 0.70 g / mL or more and 0.95 g / mL or less. Is more preferable. Secondary particles having a bulk density within such a range are considered to be heavy in weight and have few voids in the particles, and can be said to be particles having a high packing density, and thus exhibit high strength. Become. Therefore, when the powder containing the secondary particles is applied as the adsorbent 3, the life thereof can be extended.

Further, as described above, in the present embodiment, the specific surface area is ^{set to 70 m 2} / g or more, ^{but more preferably 75 m 2} / g or more and 100 m ² / g or less. When the powder containing the secondary particles having a high specific surface area in such a range is applied as the adsorbent 3, the chance that the isolate comes into contact with the adsorbent 3 increases, and the isolate and the adsorbent 3 are combined. Since the interaction between them is improved, the adsorbent 3 exhibits an excellent adsorbing ability on the isolated product.

Further, as shown in FIG. 1, the form (shape) of the secondary particles is preferably granular (granular), but the sphericity is about 0.95 or more and 1.00 or less. Is more preferable, and 0.97 or more and 1.00 or less is further preferable. As described above, when the secondary particles having high sphericity are applied as the adsorbent 3, the filling rate of the adsorbent 3 in the adsorbent filling space 20 can be improved.

The angle of repose of such secondary particles is preferably 27 ° or less, and more preferably 22 ° or more and 25 ° or less when classified into a size of 40 ± 4 μm. As described above, the secondary particles having a low angle of repose have high fluidity, and the operability (filling efficiency) when the secondary particles are filled in the adsorbent filling space 20 as the adsorbent 3 can be improved.

Further, in the sintered powder obtained by calcining the secondary particles, the average pore diameter of the pores formed on the surface thereof is preferably 0.07 μm or less when calcined at 700 ° C., and 0.04 μm or more and 0. It is more preferably about 06 μm or less. Further, when fired at 400 ° C., it is preferably 0.05 μm or less, and more preferably 0.02 μm or more and 0.04 μm or less. By keeping the average pore diameter of the pores within such a range, the specific surface area of the sintered powder can be surely increased.

In the present embodiment, the secondary particles as described above are prepared according to the size of the secondary particles, and the secondary particles having a particle size of 40 ± 4 μm are secondary particles of hydroxyapatite having a particle size conforming to the standard. It is selected as a particle and applied to the adsorbent 3. On the other hand, those having no size of 40 ± 4 μm are determined to be secondary particles of hydroxyapatite which are outside the desired range, and the production method of the present invention is applied. Will be described later.

Further, the compressed particle strength (fracture strength) of the secondary particles classified into a size of 40 ± 4 μm is preferably 2.0 MPa or more, and preferably 2.4 MPa or more and 3.0 MPa or less. More preferred. It can be said that the powder having the compressed particle strength in such a range has sufficient strength to be applied to the adsorbent 3.

In addition to the case where the adsorbent 3 is almost fully filled in the adsorbent filling space 20 as in the present embodiment, the adsorbing device 1 is a part of the adsorbent filling space 20 (for example, a part on the inflow pipe 24 side). ) May be filled with the adsorbent 3, and the other portions may be filled with another adsorbent.

<Manufacturing method of adsorbent>
The powder composed of particles containing secondary particles of hydroxyapatite as described above, that is, the adsorbent 3, is produced by the following powder production method.

That is, in the method for producing powder in the present embodiment, the first liquid containing a calcium source such as calcium hydroxide and the second liquid containing a phosphorus source such as phosphoric acid are reacted while stirring. A step of obtaining a slurry containing primary particles of hydroxyapatite and its aggregates [S1A] and a step of physically crushing the aggregates contained in the slurry and dispersing the crushed aggregates in the slurry [S2A]. A step [S3A] of obtaining a powder composed of particles mainly containing secondary particles of hydroxyapatite by drying the slurry and granulating the crushed aggregates.

Hereinafter, these steps will be described in sequence.
In the following, a case where calcium hydroxide is used as the calcium source and phosphoric acid is used as the phosphoric acid source will be described as an example.

[S1A: Step of obtaining a slurry containing agglomerates of hydroxyapatite]
In this step, calcium hydroxide and phosphoric acid are stirred while stirring a calcium hydroxide dispersion containing calcium hydroxide (first solution) and a phosphoric acid solution containing phosphoric acid (second solution). To obtain a slurry containing the primary particles of hydroxyapatite and their aggregates.

Specifically, for example, while stirring the calcium hydroxide dispersion (first solution) in a container (not shown), a phosphoric acid solution (second solution) is added dropwise to the dispersion. A mixed solution of a calcium hydroxide dispersion and a phosphoric acid solution is mixed, and calcium hydroxide and phosphoric acid are reacted in this mixed solution to obtain a slurry containing primary particles of hydroxyapatite and its aggregates.

In such a method, a wet synthesis method using a phosphoric acid solution containing phosphoric acid is used. As a result, hydroxyapatite (synthetic product) can be synthesized more easily and efficiently without the need for expensive manufacturing equipment. Further, in the reaction between calcium hydroxide and phosphoric acid, since the only by-product other than hydroxyapatite is water, no by-product remains in the formed secondary particles or sintered powder. Further, since this reaction is an acid-base reaction, there is an advantage that this reaction can be easily controlled by adjusting the pH of the calcium hydroxide dispersion and the phosphoric acid solution.

As the phosphoric acid solution containing phosphoric acid, in addition to the phosphoric acid aqueous solution, a small amount of other liquid such as alcohol may be added to the phosphoric acid aqueous solution.

Further, by carrying out this reaction with stirring, the reaction between calcium hydroxide and phosphoric acid can be efficiently promoted, that is, the efficiency of those reactions can be improved.

Further, the stirring power for stirring the mixed liquid containing the calcium hydroxide dispersion liquid and the phosphoric acid solution is not particularly limited, but the output is about 0.75 W or more and 2.0 W or less with respect to 1 L of the mixed liquid (slurry). It is preferable that the output is 0.925 W or more and 1.85 W or less. By setting the stirring power in such a range, the efficiency of the reaction between calcium hydroxide and phosphoric acid can be further improved.

The content of calcium hydroxide in the calcium hydroxide dispersion is preferably about 5 wt% or more and 15 wt% or less, and more preferably about 10 wt% or more and 12 wt% or less. The content of phosphoric acid in the phosphoric acid solution is preferably about 10 wt% or more and 25 wt% or less, and more preferably about 15 wt% or more and 20 wt% or less. By setting the contents of calcium hydroxide and phosphoric acid within such a range, the chance of contact between calcium hydroxide and phosphoric acid when dropping the phosphoric acid solution while stirring the calcium hydroxide dispersion is increased. Therefore, calcium hydroxide and phosphoric acid can be efficiently reacted, and hydroxyapatite can be reliably synthesized.

The rate at which the phosphoric acid solution is dropped is preferably about 1 L / hour or more and 40 L / hour or less, and more preferably about 3 L / hour or more and 30 L / hour or less. By mixing (adding) the phosphoric acid solution into the calcium hydroxide dispersion at such a dropping rate, calcium hydroxide and phosphoric acid can be reacted under milder conditions.

In this case, the time for dropping the phosphoric acid solution (addition time) is preferably 5 hours or more and 32 hours or less, and more preferably 6 hours or more and 30 hours or less. Hydroxyapatite can be sufficiently synthesized by reacting calcium hydroxide with phosphoric acid in such a dropping time. Even if the dropping time is lengthened beyond the above upper limit value, the progress of the reaction between calcium hydroxide and phosphoric acid cannot be expected any more.

Here, as the reaction between calcium hydroxide and phosphoric acid gradually progresses, fine particles of hydroxyapatite (synthesis) (hereinafter, simply referred to as "fine particles") are generated in the slurry. Then, these fine particles have a van der Waals force (intermolecular force) between the positively charged portion of one fine particle (primary particle) and the negatively charged portion of the other fine particles. By acting and aggregating them, agglomerates of hydroxyapatite (synthesis) (hereinafter, simply referred to as "aggregates") are produced. With the formation of this agglomerate, the viscosity of the slurry gradually increases.

Further, as the reaction between calcium hydroxide and phosphoric acid proceeds, the ratios of positive charges and negative charges in the slurry approach each other. At this time, in the slurry, the repulsive force acting on the fine particles is reduced, the aggregation of the fine particles is further accelerated, and an agglomerate having a larger particle size is formed.

[S2A: Step of crushing and then dispersing agglomerates]
In this step, the aggregates of the primary particles of hydroxyapatite contained in the slurry obtained in the step [S1A] are physically pulverized, and the pulverized aggregates are dispersed in the slurry.

When the agglomerates contained in the slurry are crushed in this way, the particle size of the agglomerates contained in the slurry becomes small, and due to this, the secondary of hydroxyapatite obtained in the subsequent step [S3A] The particles can be set to have a bulk density of 0.65 g / mL or more and a specific surface area of 70 m ^{2 / g or more.}

The method for physically pulverizing the aggregates of the primary particles of hydroxyapatite is not particularly limited, and is composed of, for example, a wet jet mill method in which droplets of a slurry sprayed at high pressure collide with each other, and ceramics such as zirconia. Examples thereof include a ball mill method in which the slurry is stored in a closed container in the coexistence with the spheres to be formed and the closed container is rotated. Among these, the wet jet mill method is preferably used.

Here, in the wet jet mill method, a high pressure is applied to a slurry in which aggregates of primary particles of hydroxyapatite are dispersed, and the slurry is sprayed to form droplets in an opposed collision chamber, a ball collision chamber or a single nozzle. By introducing it into a chamber, these collide with each other and the agglomerates are crushed.

According to such a method, agglomerates of primary particles of hydroxyapatite can be reliably pulverized. Therefore, the secondary particles of hydroxyapatite obtained in the subsequent step [S3A] can be set to have a bulk density of 0.65 g / mL or more and a specific surface area of 70 m ² / g or more.

The average particle size of the crushed aggregate is preferably 1 μm or less, and more preferably 0.1 μm or more and 0.6 μm or less. By setting the average particle size of the pulverized aggregates within such a range, the bulk density and specific surface area of the secondary particles of hydroxyapatite obtained in the subsequent step [S3A] can be set within the above ranges. ..

As a method of dispersing the primary particles in the slurry, in addition to the method of physically crushing the aggregates of the primary particles as in the present embodiment, a surfactant or a dispersant for dispersing the primary particles in the slurry Is also conceivable. However, in the latter method, when the slurry is dried in the next step [S3A], the added surfactant and dispersant remain in the obtained hydroxyapatite powder. Therefore, in order to remove them, it is necessary to bake the hydroxyapatite powder at a temperature of 800 ° C. or higher. When fired at such a temperature, the specific surface area of the powder becomes small. Therefore, as described above, it is practically impossible to set the specific surface area to 70 m ² / g or more.

Further, as in the present embodiment, the secondary particles of hydroxyapatite obtained in the subsequent step [S3A] have a bulk density of 0.65 g / mL or more and a specific surface area of 70 m ² / g or more. When it is not necessary to set the above to be satisfactory, the physical pulverization of the aggregate in this step [S2A] can be omitted.

[S3A: Step of drying slurry to obtain hydroxyapatite powder]
In this step, the crushed agglomerates are granulated by drying the slurry containing the crushed agglomerates that has undergone the step [S2A], and the powder is mainly composed of secondary particles of hydroxyapatite. Obtain the body (dry powder).

In the above step [S2A], in the present embodiment, the agglomerates in which the primary particles of hydroxyapatite are agglomerated are pulverized, and the size of the agglomerates is reduced. Therefore, it can be satisfied that the hydroxyapatite powder obtained in this step [S3A] has a bulk density of 0.65 g / mL or more and a specific surface area of 70 m ² / g or more.

The method for drying the slurry is not particularly limited, but a spray drying method is preferably used. According to such a method, the crushed aggregate can be granulated to obtain a powder having a desired particle size more reliably and in a short time.

The drying temperature for drying the slurry is preferably 75 ° C. or higher and 250 ° C. or lower, and more preferably 95 ° C. or higher and 220 ° C. or lower. By setting within such a range, secondary particles having a high bulk density and a large specific surface area can be obtained.

In addition, such a powder (dry powder) can also be fired (sintered) to obtain a sintered powder. Thereby, the compressed particle strength (breaking strength) of the powder (sintered powder) can be further improved.

In this case, the firing temperature for firing the powder is preferably about 200 ° C. or higher and 900 ° C. or lower, and more preferably about 400 ° C. or higher and 700 ° C. or lower.

Through the above steps, a powder mainly composed of particles containing secondary particles of hydroxyapatite (synthetic product) can be obtained.

The powder composed of particles containing secondary particles of hydroxyapatite obtained as described above is classified, and in the present embodiment, those having a particle size of 40 ± 4 μm are desired to have a particle size. It is determined that the particles are secondary particles within the range of, and are used as the adsorbent 3 (material for fixed layer).

On the other hand, those having a particle size of 40 ± 4 μm, that is, those having a particle size smaller than 36 μm and those having a particle size larger than 44 μm are those having a particle size outside the desired range. Determined to be a particle. Then, by applying the production method of the present invention to the hydroxyapatite particles whose particle size is determined to be outside the desired range, the hydroxyapatite particles having a particle size within the desired range (the hydroxyapatite of the present invention). It is possible to regenerate the powder containing (apatite particles). As described above, by using the production method of the present invention, the hydroxyapatite particles having a particle size determined to be outside the desired range are not discarded, and the hydroxyapatite having a particle size within the desired range can be used. It can be used for regeneration of powder containing particles. Therefore, it is possible to improve the productivity when producing a powder containing hydroxyapatite particles having a particle size conforming to the standard.

<Regeneration method of hydroxyapatite particles whose particle size conforms to the standard>
Hereinafter, by applying the production method of the present invention, using hydroxyapatite particles whose particle size is determined to be out of the desired range, a powder containing hydroxyapatite particles whose particle size conforms to the standard is obtained. A reproduction method for reproduction (production) will be described.

FIG. 2 is a flowchart showing a method of producing a powder containing hydroxyapatite particles having a particle size conforming to the standard by applying the production method of the present invention.

As shown in FIG. 2, the production method of the present invention, which is applied to a regeneration method for regenerating hydroxyapatite particles having a particle size conforming to the standard, has a hydroxyapatite determined to have a particle size outside the desired range. A step of preparing a powder containing the particles of the above [S1B] and a step of dissolving the powder containing the particles of hydroxyapatite determined to have a particle size outside the desired range in a phosphoric acid solution [S2B]. , A powder containing hydroxyapatite particles having a particle size conforming to the standard using a phosphoric acid solution in which at least a part of the powder containing the hydroxyapatite particles determined to have a particle size outside the desired range is dissolved. It has a step of forming a body [S3B].

Hereinafter, these steps will be described in sequence.
[S1B: Step of preparing a powder containing hydroxyapatite particles determined to have a particle size outside the desired range (first step)]
In this step, powders containing hydroxyapatite particles whose particle size is determined to be outside the desired range (nonstandard) (hereinafter, may also be referred to as “nonstandard powder”). prepare.

In the present embodiment, among the particles containing the hydroxyapatite secondary particles obtained by applying the above-mentioned method for producing an adsorbent, that is, the above steps [S1A] to [S3A], for example, by classifying. Those determined to be secondary particles having a particle size within a desired range are used as the adsorbent 3. Then, those having a particle size larger than the secondary particles determined to have a particle size within a desired range, excluding the secondary particles used as the adsorbent 3, and those having a particle size within a desired range. A non-standard powder is prepared by collecting particles having a particle size smaller than that of the secondary particles determined to be.

That is, according to the above-mentioned method for producing an adsorbent, that is, the steps [S1A] to [S3A], a step of preparing a powder composed of particles containing secondary particles of hydroxyapatite prior to the main step [S1B] is performed. It is composed. In addition, this step [S1B] constitutes a first step of recovering the powder containing the particles of hydroxyapatite whose particle size is out of the desired range.

[S2B: Step of dissolving the prepared powder containing hydroxyapatite particles in a phosphoric acid solution (second step)]
In this step, the nonstandard powder is dissolved in the phosphoric acid solution by stirring in the phosphoric acid solution containing phosphoric acid.

Specifically, for example, while stirring the phosphoric acid solution in a container (not shown), a nonstandard powder is added to this solution, and the nonstandard powder is mixed with the phosphoric acid solution, and this mixing is performed. Dissolves the nonstandard powder in the phosphoric acid solution.

In such a method, when the dissolution in the phosphoric acid solution is carried out while stirring, the nonstandard powder can be efficiently dissolved in the phosphoric acid solution by appropriately setting the stirring conditions.

Here, the non-standard powder to be dissolved in the phosphoric acid solution includes both those having a larger particle size and those having a smaller particle size than the secondary particles having a particle size within a desired range in the present embodiment. In addition, its bulk density and specific surface area are both large.

As described above, the non-standard powder to be dissolved, that is, the particles containing the secondary particles of hydroxyapatite to be dissolved are not uniform in shape and have not constant physical properties such as bulk density and specific surface area. Is included. Therefore, the concentration (amount) of phosphoric acid in the preferred phosphoric acid solution to be used for dissolution varies from time to time. Specifically, if the concentration of phosphoric acid in the phosphoric acid solution becomes too high, the amount of hydroxyapatite dissolved decreases, which is not preferable. Further, if the concentration of phosphoric acid becomes too low, not only hydroxyapatite is not sufficiently dissolved, but also calcium phosphate other than apatite is precipitated, which is not preferable. Therefore, depending on the conditions of the adsorbent manufacturing method described above, it is necessary to efficiently dissolve the nonstandard powder in the phosphoric acid solution without being affected by the morphological change of the hydroxyapatite particles, which is changed, in the phosphoric acid solution. It is preferable to appropriately set the conditions for dissolving the non-standard powder while stirring.

That is, in this step [S2B], when the non-standard powder is dissolved in the phosphoric acid solution while stirring, the standard is confirmed while the dissolution state is confirmed as the non-standard powder is dissolved. It is preferable to adjust the dissolution conditions so as to enable or promote the dissolution of the outer powder. As a result, as described above, even if the shape of the nonstandard powder to be dissolved changes, the nonstandard powder can be efficiently dissolved in the phosphoric acid solution.

At this time, confirmation of the dissolved state of the nonstandard powder in the phosphoric acid solution is not particularly limited, but it is preferable to detect the turbidity of the phosphoric acid solution. By detecting the turbidity, the dissolved state of the nonstandard powder in the phosphoric acid solution can be confirmed relatively easily and reliably.

Further, the adjustment of the dissolution conditions for dissolving the nonstandard powder in the phosphoric acid solution based on the confirmation of the dissolution state is performed by an operation including adjustment of the stirring speed of the phosphoric acid solution and adjustment of the dissolution time in the phosphoric acid solution. It is preferable to carry out. Thereby, the dissolved amount (content) of the nonstandard powder in the phosphoric acid solution can be adjusted relatively easily and surely.

Further, when the non-standard powder is dissolved in the phosphoric acid solution while stirring, the non-standard powder may be added to the phosphoric acid solution in a plurality of times with respect to the phosphoric acid solution. preferable. In this way, by adding the non-standard powder to the phosphoric acid solution in a plurality of times, it is possible to accurately suppress or prevent the addition of the non-standard powder in an appropriate amount or more to the phosphoric acid solution. it can. That is, it is possible to accurately suppress or prevent the addition of non-standard powder having a capacity larger than the capacity that can be dissolved in the phosphoric acid solution into the phosphoric acid solution.

As described above, the dissolution conditions for dissolving the non-standard powder in the phosphoric acid solution are adjusted while confirming the dissolution state of the non-standard powder. Among such dissolution conditions, the phosphoric acid content in the phosphoric acid solution is adjusted. Is preferably 10 wt% or more and 25 wt% or less, and more preferably 15 wt% or more and 25 wt% or less. If the phosphoric acid content in the phosphoric acid solution exceeds the above upper limit value, the dissolved amount of hydroxyapatite decreases, which is not preferable. Further, if the phosphoric acid content is less than the above lower limit value, not only hydroxyapatite is not sufficiently dissolved, but also calcium phosphate other than apatite may be precipitated, which is not preferable.

The stirring force when the phosphoric acid solution is stirred by adding the non-standard powder is not particularly limited, but the output is about 0.75 W or more and 2.0 W or less with respect to 1 L of the phosphoric acid solution. Is preferable, and the output is more preferably 0.925 W or more and 1.85 W or less. By setting the stirring force in such a range, the efficiency of dissolving the nonstandard powder in the phosphoric acid solution can be further improved.

Further, the liquid temperature (temperature) of the phosphoric acid solution is not particularly limited, but is preferably set to about 0 ° C. or higher and 70 ° C. or lower, and more preferably about 25 ° C. or higher and 50 ° C. or lower. As a result, the non-standard powder can be dissolved in the phosphoric acid solution under milder conditions.

The time for adding the nonstandard powder and stirring the phosphoric acid solution is preferably 1 hour or more and 72 hours or less, and more preferably 6 hours or more and 72 hours or less. By dissolving the non-standard powder in the phosphoric acid solution with such a stirring time, the non-standard powder can be sufficiently dissolved in the phosphoric acid solution. Even if the stirring time is lengthened beyond the above upper limit value, the progress of dissolution in the nonstandard powder in the phosphoric acid solution cannot be expected any more.

By going through this step [S2B] as described above, the nonstandard powder can be dissolved in the phosphoric acid solution.

As described above, even if the dissolution conditions for dissolving the nonstandard powder in the phosphoric acid solution are adjusted while confirming the dissolved state of the nonstandard powder, the phosphoric acid solution in which the nonstandard powder is dissolved may be used. , A part of the non-standard powder may remain as a dispersion or a precipitate. Therefore, it is preferable to have a step of filtering the nonstandard powder remaining in the phosphoric acid solution without being dissolved after the main step [S2B], that is, prior to the post-step [S3B]. .. As a result, the non-standard powder remaining without being dissolved in the phosphoric acid solution can be reliably removed. Therefore, in the subsequent step [S3B], when a phosphoric acid solution in which a nonstandard powder is dissolved is used to generate a powder containing secondary particles of hydroxyapatite having a particle size conforming to the standard, the secondary is produced. It is possible to accurately suppress or prevent nonstandard powder remaining as an impurity from being mixed in the powder containing the secondary particles. Therefore, it is possible to improve the purity of the powder containing the secondary particles of hydroxyapatite having a particle size conforming to the standard, which is produced in the subsequent step [S3B]. Further, when the method of producing the powder containing the secondary particles is repeatedly carried out, the filtered nonstandard powder is used again as the powder to be dissolved in the phosphoric acid solution in the step [S1B]. , It is possible to further improve the regeneration efficiency of the powder containing the hydroxyapatite particles whose particle size conforms to the standard.

Further, the pore size of the pores provided in the filtration filter used for filtering the phosphoric acid solution in which the nonstandard powder is dissolved is preferably 0.45 μm or less, more preferably 0.22 μm or less. As a result, non-standard powder having a particle size less than the lower limit of the pore size remains in the phosphoric acid solution in which the non-standard powder is dissolved, but such non-standard powder is contained. Even so, the fine non-standard powder having such a particle size is of a size that can be used as an agglomerate of primary particles of hydroxyapatite. Therefore, in the subsequent step [S3B], it is possible to more accurately suppress or prevent impurities from remaining in the standard powder generated by using the phosphoric acid solution in which the non-standard powder is dissolved.

Further, the particle size conforms to the standard by applying the production method of the present invention using the nonstandard powder having almost the same form without changing the shape such as the shape of the nonstandard powder to be dissolved. When the powder containing the secondary particles of hydroxyapatite is repeatedly generated (regenerated), in this step [S2B], the nonstandard powder is dissolved in the phosphoric acid solution while stirring. The conditions are almost constant. Therefore, in the first production of a powder containing hydroxyapatite particles having a particle size conforming to the standard, in this step [S2B], the dissolution conditions for efficiently dissolving the non-standard powder in the phosphoric acid solution. If is set, the setting of the dissolution condition in this step [S2B] can be omitted in the second and subsequent generations.

[S3B: A step of producing a powder containing secondary particles of hydroxyapatite having a particle size conforming to the standard by using a phosphoric acid solution in which a nonstandard powder is dissolved (third step)]
In this step, a powder containing hydroxyapatite particles having a particle size conforming to the standard is used using a phosphoric acid solution in which the non-standard powder is dissolved, which is obtained through the step [S2B] (hereinafter, "" Sometimes referred to as "standard powder").

In this step [S3B] of obtaining this standard powder, a phosphoric acid solution in which the non-standard powder is dissolved and a first liquid containing a calcium source such as calcium hydroxide are reacted with stirring to form a hydroxy. A step of obtaining a slurry containing primary particles of apatite and its aggregates [S3B-1], and a step of physically crushing the aggregates contained in the slurry and dispersing the crushed aggregates in the slurry [S3B-2]. ], And a step [S3B-3] of obtaining a powder containing hydroxyapatite particles having a particle size conforming to the standard by drying the slurry and granulating the crushed agglomerates.

Hereinafter, these steps [S3B-1] to [S3B-3] constituting the main step [S3B] will be sequentially described.

[S3B-1: Step of obtaining a slurry containing temporary particles and aggregates of hydroxyapatite]
In this step, calcium hydroxide and phosphoric acid are reacted while stirring a mixed solution containing a phosphoric acid solution in which a nonstandard powder is dissolved and a first solution containing a calcium source such as calcium hydroxide. To obtain a slurry containing the primary particles of hydroxyapatite and its aggregates.

Specifically, for example, while stirring the calcium hydroxide dispersion liquid (first liquid) in a container (not shown), a phosphoric acid solution in which a nonstandard powder is dissolved is added dropwise to the dispersion liquid. , A mixed solution of calcium hydroxide dispersion and a phosphoric acid solution in which nonstandard powder is dissolved is mixed, and calcium hydroxide and phosphoric acid are reacted in this mixed solution to obtain the primary particles of hydroxyapatite and its Obtain a slurry containing agglomerates.

In such a method, a wet synthesis method using a phosphoric acid solution in which a nonstandard powder is dissolved is used. As a result, temporary particles (synthesis) of hydroxyapatite can be synthesized more easily and efficiently without the need for expensive manufacturing equipment. Further, in the reaction between calcium hydroxide and phosphoric acid, since the only by-product other than hydroxyapatite is water, no by-product remains in the formed secondary particles or sintered powder. Further, since this reaction is an acid-base reaction, there is an advantage that this reaction can be easily controlled by adjusting the pH of the calcium hydroxide dispersion and the phosphoric acid solution.

Further, by carrying out this reaction while stirring, the reaction between calcium hydroxide and phosphoric acid is efficiently promoted in the liquid in which the phosphoric acid solution in which the nonstandard powder is dissolved is added to the calcium hydroxide dispersion liquid. That is, the efficiency of those reactions can be improved.

In the mixed solution containing the phosphoric acid solution in which the nonstandard powder is dissolved and the first solution containing calcium hydroxide, the condition for reacting the phosphoric acid and calcium hydroxide is in the step [S1A]. , Phosphoric acid and calcium hydroxide are reacted in a mixed solution containing a calcium hydroxide dispersion containing calcium hydroxide (first solution) and a phosphoric acid solution containing phosphoric acid (second solution). It is possible to set the same conditions as described as the conditions for causing.

In this embodiment, in order to generate a powder composed of particles containing secondary particles of hydroxyapatite having a particle size conforming to the standard by using a phosphoric acid solution in which a nonstandard powder is dissolved, this step [ After S3B-1], the subsequent steps [S3B-2] to [S3B-3] are carried out, but the primary particles of hydroxyapatite are obtained without obtaining a powder composed of particles containing secondary particles of hydroxyapatite. In the case of obtaining, the implementation of the subsequent steps [S3B-2] to [S3B-3] is omitted.

This step [S3B-1] constitutes a step of producing primary particles of hydroxyapatite.

[S3B-2: Step of crushing and then dispersing agglomerates]
In this step, the aggregates of the primary particles of hydroxyapatite contained in the slurry obtained in the step [S3B-1] are physically pulverized, and the pulverized aggregates are dispersed in the slurry.

When the aggregates contained in the slurry are crushed in this way, the particle size of the aggregates contained in the slurry becomes small, and due to this, the hydroxyapatite obtained in the subsequent step [S3B-3] The secondary particles can be set to have a bulk density of 0.65 g / mL or more and a specific surface area of 70 m ^{2 / g or more.}

As a method for physically pulverizing the aggregate of the primary particles of hydroxyapatite, the same method as described in the above step [S2A] can be used.

Further, as in the present embodiment, the secondary particles of hydroxyapatite obtained in the subsequent step [S3B-3] have a bulk density of 0.65 g / mL or more and a specific surface area of 70 m ² / g or more. When it is not necessary to set the content to be satisfactory, the physical pulverization of the aggregate in this step [S3B-2] can be omitted.

[S3B-3: Step of drying slurry to obtain hydroxyapatite powder having a particle size conforming to the standard]
In this step, the slurry containing the crushed agglomerates that has undergone the step [S3B-2] is dried.

As a result, the crushed agglomerates can be granulated to obtain a powder (dry powder) composed of particles containing secondary particles of hydroxyapatite having a particle size conforming to the standard.

In the above step [S3B-2], in the present embodiment, the agglomerates in which the primary particles of hydroxyapatite are agglomerated are pulverized, and the size of the agglomerates is reduced. Therefore, it can be satisfied that the hydroxyapatite powder obtained in this step [S3B-3] has a bulk density of 0.65 g / mL or more and a specific surface area of 70 m ² / g or more. ..

As a method for drying the slurry or the like, the same method or the like as described in the above step [S3A] can be used.

This step [S3B-3] constitutes a step of producing secondary particles of hydroxyapatite from the obtained primary particles of hydroxyapatite.

By going through the step [S3B] composed of the steps [S3B-1] to [S3B-3] as described above, a powder containing hydroxyapatite particles having a particle size conforming to the standard can be obtained.

Then, in such a step [S3B], it is possible to produce hydroxyapatite particles conforming to the standard by effectively utilizing the powder containing the non-standard hydroxyapatite particles determined not to satisfy the predetermined conditions. Therefore, it is possible to improve the productivity when producing the hydroxyapatite particles conforming to the standard.

In the present embodiment, the particle size is within the desired range as a powder (nonstandard powder) composed of particles containing secondary particles of hydroxyapatite determined to be outside the desired range. The case where both the particles having a larger particle size and the particles smaller than the secondary particles are contained has been described, but the nonstandard powder does not need to contain both of them, and the particle size is desired. It suffices to include either one having a particle size larger than that of the secondary particles within the range of and one having a smaller particle size. However, it is determined that the particles having a smaller particle size than the secondary particles having a particle size within a desired range are larger and smaller at the time of classification than those having a large particle size, and further, with respect to the phosphoric acid solution. It also has excellent solubility. Therefore, by selecting a non-standard powder containing a particle having a particle size smaller than that of the secondary particles having a particle size within a desired range, it is possible to produce hydroxyapatite particles conforming to the standard. The sex can be further improved.

Although the production method of the present invention has been described above, the present invention is not limited thereto.

For example, in the production method of the present invention, one or more steps can be added for any purpose.

Further, in the above-described embodiment, a powder composed of particles containing secondary particles of non-standard hydroxyapatite that do not satisfy the predetermined conditions is produced assuming that the particle size is out of the desired range, and this particle size is desired. Although the case where the production method of the present invention is applied to the hydroxyapatite particles outside the range of the above is described, the particle size of the powder containing the nonstandard hydroxyapatite particles that do not satisfy the predetermined conditions is large. It is not limited to those outside the desired range, and may be, for example, those shown below. That is, a powder containing particles of hydroxyapatite that has expired, a powder containing particles of hydroxyapatite whose particle size varies due to multiple uses as an adsorbent, and a calcium phosphate type different from hydroxyapatite. A powder containing hydroxyapatite particles in which a compound is mixed in an amount of a specified amount or more can also be used as a powder containing non-standard hydroxyapatite particles that do not satisfy a predetermined condition. The production method of the present invention can also be applied to these powders.

Next, specific examples of the present invention will be described.
The present invention is not limited to the description of these examples.

1. 1. Confirmation of solubility of hydroxyapatite particles in phosphoric acid solution [1A] First, hydroxyapatite particles (CHT 40 μm Type I, manufactured by BIO-RAD) were added to 50 mL of phosphoric acid solution (phosphoric acid concentration 14 wt%). , 1.00 g, 2.00 g, 3.00 g, 3.25 g, 3.50 g and 4.00 g, respectively, and then the phosphoric acid solution to which the hydroxyapatite particles were added was stirred using a stirrer. A phosphoric acid solution in which the addition of hydroxyapatite particles was omitted, that is, a phosphoric acid solution in which 0.00 g of hydroxyapatite particles were added was also stirred using a stirrer as a control.

[2A] Next, continue stirring with a stirrer, and measure the turbidity of the phosphoric acid solution 1 hour and 3 days later with an absorptiometer (“UV Spectrophotometer UV-1800” manufactured by Shimadzu Corporation). It was measured at a wavelength of 660 nm.
The result is shown in FIG.

As is clear from FIG. 3, three days after the start of stirring the phosphoric acid solution, the turbidity of the phosphoric acid solution became 0 when the amount of hydroxyapatite particles added to the phosphoric acid solution was in the range of 1.00 g to 3.25 g. It was confirmed that the hydroxyapatite particles were completely dissolved in the phosphoric acid solution. On the other hand, when the amount of hydroxyapatite particles added to the phosphoric acid solution was 3.50 g, no change was observed in the turbidity of the phosphoric acid solution between 1 hour and 3 days. Therefore, it was found that the hydroxyapatite particles were no longer dissolved in the phosphoric acid solution. Furthermore, when the amount of hydroxyapatite particles added to the phosphoric acid solution was 4.00 g, the result was obtained that the turbidity further increased with the passage of time, such as after 1 hour to 3 days. It was speculated that this was caused by the precipitation of other calcium phosphate compounds, which are different from the hydroxyapatite particles, in the phosphoric acid solution over time.

From the above, it is possible to dissolve the hydroxyapatite particles in the phosphoric acid solution by stirring the hydroxyapatite particles, and the maximum amount of the hydroxyapatite particles dissolved is 3 per 50 mL of the phosphoric acid solution (phosphoric acid concentration 14 wt%). It turned out to be .25 g.

2. Production of hydroxyapatite (Example 1)
[1B] First, 3.00 g of hydroxyapatite particles (CHT 40 μm Type I manufactured by BIO-RAD) was added per 50 mL of a phosphoric acid solution (phosphoric acid concentration 14 wt%), and then the hydroxyapatite particles were added. The phosphoric acid solution was stirred with a stirrer for 3 days to obtain a calcium ion-containing phosphoric acid solution in which hydroxyapatite particles were dissolved in the phosphoric acid solution.

[2B] Next, 2400 g of calcium hydroxide was dispersed in 60 L of pure water, and while this calcium hydroxide dispersion was placed in a tank and stirred, 4 L of a calcium ion-containing phosphoric acid solution was added thereto at a rate of 1 L / hour. Dropped. As a result, a slurry containing agglomerates in which the primary particles of hydroxyapatite were aggregated was obtained.

The temperature of the atmosphere during dropping was set to room temperature (25 ° C.).
The stirring force for stirring the mixed solution in which the phosphoric acid solution was added dropwise to the dispersion was set to an output of 1.7 W with respect to 1 L of the mixed solution (slurry).

[3B] Next, the agglomerates contained in the obtained slurry are pulverized by applying a high pressure of 200 MPa using a wet jet mill device (“Starburst” manufactured by Sugino Machine Limited). A slurry containing the agglomerates was obtained.

[4B] Next, the slurry containing the crushed agglomerates is spray-dried at 210 ° C. using a spray dryer (manufactured by Matsubo Co., Ltd., “MAD-6737R”) to obtain hydroxy in the slurry. The secondary particles (R-HAp secondary particles) of Example 1 were obtained by granulating apatite to form a spherical shape.

Regarding the secondary particles (R-HAp secondary particles) of Example 1, the above steps [1B] to [4B] were repeated three times to produce 3 lots of R-HAp secondary particles. did.

(Reference example 1)
The same as in Example 1 except that the step [1B] was omitted and a phosphoric acid solution (phosphoric acid concentration 14 wt%) was used instead of the calcium ion-containing phosphoric acid solution in the step [2B]. Then, the secondary particles (C-HAp secondary particles) of Reference Example 1 having a spherical shape were obtained.

3. 3. Evaluation of Hydroxyapatite Produced Hydroxyapatite was produced as the secondary particles of the R-HAp secondary particles of Example 1 and the C-HAp secondary particles of Reference Example 1 by using powder X-ray diffractometry. It was confirmed whether or not it was done.

The diffraction patterns of the R-HAp secondary particles of Example 1 and the C-HAp secondary particles of Reference Example 1 measured by X-rays are shown in FIG.

As is clear from FIG. 4, the R-HAp secondary particles of Example 1 show the same diffraction pattern as the C-HAp secondary particles of Reference Example 1 in each lot, and the C-HAp secondary particles of Reference Example 1 show the same diffraction pattern. It was clarified that it was composed of hydroxyapatite secondary particles as well as HAp secondary particles. That is, it is clear that even if a calcium ion-containing phosphoric acid solution in which hydroxyapatite particles are dissolved in a phosphoric acid solution is used as a phosphoric acid source in the same manner as a phosphoric acid solution, secondary particles of hydroxyapatite can be produced. became.

Therefore, even if powder consisting of particles containing secondary particles of non-standard hydroxyapatite determined not to satisfy the predetermined conditions is selected as the hydroxyapatite particles used for obtaining the calcium ion-containing phosphoric acid solution, even if the powder is selected. Since it is possible to produce particles of hydroxyapatite conforming to the standard, it is possible to produce particles of hydroxyapatite conforming to the standard from particles containing secondary particles of non-standard hydroxyapatite determined not to satisfy the predetermined conditions for regeneration of the particles of hydroxyapatite conforming to the standard. It was found that the following powder can be used.

4. Confirmation of Concentration of Phosphoric Acid Solution for Dissolving Hydroxyapatite Particles [1C] First, 50 mL of phosphoric acid solution (phosphoric acid concentration 5 wt%, 10 wt%, 14 wt%, 25 wt%, 50 wt%, 85 wt%) was prepared. Later, 3.00 g of hydroxyapatite particles (CHT 40 μm Type I manufactured by BIO-RAD) were added to each phosphoric acid solution, and then the phosphoric acid solution to which the hydroxyapatite particles were added was added to the stirrer. Was stirred using.

[2C] Next, stirring with a stirrer was continued, and the turbidity of the phosphoric acid solution after 1 hour, 2 hours, 8 hours, 1 day, and 3 days was measured by an absorptiometer (Shimadzu Seisakusho Co., Ltd.). The measurement was performed at a wavelength of 660 nm using a “UV Spectrophotometer UV-1800” manufactured by the same manufacturer.
The result is shown in FIG.

As is clear from FIG. 5, 1 hour after the start of stirring, the hydroxyapatite particles were hardly dissolved in the 5 wt% phosphoric acid solution having a low phosphoric acid concentration. Further, in a phosphoric acid solution having a phosphoric acid concentration of 50 wt%, a result was obtained in which large lumps (not shown) formed due to the bonding of partially dissolved hydroxyapatite particles were precipitated. Therefore, as shown in FIG. 5, the result that the turbidity immediately after the start of stirring seems to be the lowest is shown. Further, in the 85 wt% phosphoric acid solution having the highest phosphoric acid concentration, the hydroxyapatite particles were hardly dissolved as in the 5 wt% phosphoric acid solution.

Further, looking at the change in turbidity with the passage of the stirring time, the turbidity of the 5 wt% phosphoric acid solution and the 85 wt% phosphoric acid solution was always 4 or more and hardly dissolved. Further, even with a 10 wt% phosphoric acid solution, the hydroxyapatite particles were dissolved to some extent, but the turbidity increased with time, indicating that other calcium phosphate compounds may have been precipitated. Furthermore, the turbidity tended to decrease with time in the 14 to 50 wt% phosphoric acid solution, and among them, the turbidity decrease rate increased in the 14 to 25 wt% phosphoric acid solution. From this, it was found that the hydroxyapatite particles can be dissolved with excellent solubility.

As described above, it was found that the amount of hydroxyapatite particles dissolved in the phosphoric acid solution changes depending on the phosphoric acid concentration in the phosphoric acid solution. Therefore, when dissolving the hydroxyapatite particles in the phosphoric acid solution, it was found that it is necessary to adjust the dissolution conditions for dissolving the hydroxyapatite particles while confirming the dissolution state as the dissolution progresses. ..

5. Confirmation of turbidity in a phosphoric acid solution in which hydroxyapatite particles are dissolved [1D] First, per 50 mL of a phosphoric acid solution (phosphoric acid concentration 14 wt%), hydroxyapatite particles (BIO-RAD, CHT 40 μm Type I) By adding 3.00 g and then stirring the phosphoric acid solution to which the hydroxyapatite particles were added for 3 hours using a stirrer, a calcium ion-containing phosphoric acid solution in which the hydroxyapatite particles were dissolved in the phosphoric acid solution was prepared. Obtained.

[2D] Next, the hydroxyapatite particles remaining in the calcium ion-containing phosphoric acid solution were filtered using a filtration filter having pores having a pore size of 0.45 μm.

At this time, before and after filtering the calcium ion-containing phosphoric acid solution using a filtration filter, the turbidity of the calcium ion-containing phosphoric acid solution was measured using an absorptiometer (“UV Spectrophotometer UV-1800” manufactured by Shimadzu Corporation). The measurement was performed at a wavelength of 660 nm.

The calcium ion-containing phosphoric acid solution was filtered using this filtration filter by repeating the steps [1D] to [2D] three times, and the calcium ion-containing phosphoric acid solution for three lots was subjected to the filtration.
The results are shown in Table 1.

As is clear from Table 1, the calcium ion-containing phosphoric acid solution in which the hydroxyapatite particles were dissolved showed a result that the turbidity of each lot after filtration by the filtration filter was lower than that before the filtration. ..

Therefore, it was clarified that the hydroxyapatite particles remaining in the calcium ion-containing phosphoric acid solution can be removed by filtering the calcium ion-containing phosphoric acid solution using a filtration filter.

Therefore, by using the filtered calcium ion-containing phosphoric acid solution as the phosphoric acid solution in which the non-standard powder is dissolved, a powder composed of particles containing secondary particles of hydroxyapatite having a particle size conforming to the standard can be obtained. It is possible to accurately suppress or prevent the nonstandard powder remaining as an impurity from being mixed in the powder containing the secondary particles to be produced at the time of production. Therefore, it is possible to improve the purity of the powder produced by using the filtered calcium ion-containing phosphoric acid solution and composed of particles containing secondary particles of hydroxyapatite having a particle size conforming to the standard. Furthermore, by using the filtered non-standard powder again as a powder to be dissolved in the phosphoric acid solution, the regeneration efficiency of the powder composed of particles containing secondary particles of hydroxyapatite having a particle size conforming to the standard can be further improved. It can be improved.

1 Adsorbent 2 Column 3 Adsorbent 4 Filter member 5 Filter member 20 Adsorbent filling space 21 Column body 22 Cap 23 Cap 24 Inflow pipe 25 Outflow pipe

Claims (10)

The first step of preparing a powder containing non-standard hydroxyapatite particles that do not meet the predetermined conditions, and
The second step of dissolving the powder containing the nonstandard hydroxyapatite particles in a phosphoric acid solution containing phosphoric acid, and
A production method comprising a third step of producing hydroxyapatite particles using the phosphoric acid solution in which at least a part of a powder containing non-standard hydroxyapatite particles is dissolved. The production method according to claim 1, wherein in the first step, a powder containing hydroxyapatite particles having a particle size outside the desired range is prepared. Prior to the first step, a step of preparing a powder containing hydroxyapatite particles is provided.
The production method according to claim 2, wherein in the first step, a powder containing hydroxyapatite particles whose particle size is out of the desired range is recovered. In the second step, as the dissolution of the powder containing the nonstandard hydroxyapatite particles into the phosphoric acid solution progresses, the dissolution is possible while confirming the dissolution state. The production method according to any one of claims 1 to 3, wherein the dissolution conditions are adjusted so as to promote the process. The fourth step, wherein the confirmation of the dissolved state of the powder containing the nonstandard hydroxyapatite particles in the phosphoric acid solution includes detecting the turbidity of the phosphoric acid solution. The production method described. The production method according to claim 4 or 5, wherein the adjustment of the dissolution conditions in the second step is carried out by an operation including adjustment of the stirring speed of the phosphoric acid solution and adjustment of the dissolution time. The production method according to any one of claims 4 to 6, wherein in the second step, the powder containing the nonstandard hydroxyapatite particles is added to the phosphoric acid solution in a plurality of times. .. Any one of claims 1 to 7, further comprising a step of filtering powder containing non-standard hydroxyapatite particles that is not dissolved in the phosphoric acid solution prior to the third step. The production method described in. The third step is a step of producing primary particles of hydroxyapatite from the phosphoric acid solution in which at least a part of the powder containing particles of the nonstandard hydroxyapatite is dissolved, and the primary of the obtained hydroxyapatite. The production method according to any one of claims 1 to 8, which comprises a step of producing particles of hydroxyapatite using particles. Hydroxyapatite particles obtained by the production method according to any one of claims 1 to 9.

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