KR102137406B1 - Calcium phosphate-based composition and method for producing the same - Google Patents

Abstract

The present invention relates to a calcium phosphate-based composition and a method for manufacturing the same, and more specifically, a calcium phosphate-based composition, hydroxyapatite, HAp, Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca/P: 1.67), In the synthesis of beta-tricalcium phosphate (β-TCP, Ca ₃ (PO ₄ ) ₂ , Ca/P: 1.5) and dicalcium phosphate dihydrate (DCPD, CaHPO ₄ .2H ₂ O, Ca/P: 1), aqueous calcium hydroxide solution The technical point is to perform ball milling after mixing the aqueous solution of phosphoric acid.
According to the present invention, it is possible to mass-produce by applying a simple and fast process, but it is excellent in reactivity, and not only can a fine powder be easily obtained, but also the product reacted by using an aqueous solution is water, so that various compositions can be obtained without a separate purification process. It is possible to produce the powder having the effect.

Description

Calcium phosphate-based composition and method for producing the same}

The present invention relates to a calcium phosphate-based composition and a method for manufacturing the same, and more specifically, to improve the raw material input and synthesis time that takes a long time due to the instability of the aqueous solution in the existing synthesis process through ball milling. It relates to a calcium phosphate-based composition and a method for manufacturing the same.

In modern times, as the life span of humanity increases and active efforts for a healthy life are combined, the rehabilitation of the damaged human body becomes an essential business as the population increases, and related bio ceramic materials have also become one of the promising industries.

In recent years, as interest in bio-ceramic materials, which have excellent bio-affinity and strength and superior to metals or polymers, has increased, ceramics have attracted attention as a material in the medical field, and research has begun in earnest.

Basically, the bio-ceramic material is not only capable of creating the same composition as the minerals of bones and teeth, but also has superior human affinity and activity than any other material, but due to the characteristics of ceramics, brittle fracture is likely to occur, resulting in poor processability and low fracture toughness. Have

Therefore, in order to obtain a sintered body having excellent physical properties, sintering using a fine powder with a large specific surface area is required, and for the application as a powder itself, the synthesis of a uniformly homogeneous nanometer-sized fine powder is required, thereby producing Wet synthetic methods using aqueous solutions have been developed and applied.

The most widely used biocompatible ceramic material is calcium phosphate, which is an effective substitute for bone tissue regeneration due to the chemical structural similarity between bone and bone.

Examples of the calcium phosphate (CP) system include hydroxyapatite, HAp, Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ), beta-tricalcium phosphate (β-TCP, Ca ₃ (PO ₄ ) ₂ ), and anhydrous dicalcium phosphate (DCPA, CaHPO ₄ ) and dicalcium phosphate dihydrate (DCPD, CaHPO ₄ .2H ₂ O).

Among calcium phosphates, apatite hydroxide (HAp) is a basic composition of bioactive materials, and its usefulness is evaluated as an artificial bone. Hydroxyapatite, an important inorganic component of teeth and bone, has excellent properties of biomaterials such as adsorption, bone binding and cell adhesion, and can form a dense and robust biomineral with collagen.

Among calcium phosphates, beta-tricalcium phosphate (β-TCP) is a biodegradable synthetic ceramic material and is used in various fields as a bone substitute.

Among calcium phosphates, DCPA and DCPD powders are used as polishers for toothpaste or cement materials for biomedical use.

Recently, attempts have been made to utilize the advantages of each composition by hybridizing calcium phosphate-based compositions with powder synthesis through an aqueous solution to obtain a synergistic effect.

An example of convergence is a hybrid material of hydroxyapatite (HAp) and β-TCP. β-TCP has the advantage of being biodegradable while directly binding to bone, while being rapidly absorbed before bone is regenerated, and HAp is a living body. The affinity is very good, but because it does not readily dissolve in the body, there is a disadvantage that eventually interferes with bone regeneration, and to overcome this, the two components are hybridized to use the advantages of each composition.

Calcium phosphate powder synthesis method using aqueous solution has been developed in various synthesis methods and has been suggested in papers and patents.

For example,'Method of manufacturing calcium phosphate-based material using egg shell and phosphate-ammonia solution (Publication No.: 10-2018-0024755)' has a problem that HAp can be obtained only by including a complicated pretreatment process for synthesis or heating at 700°C or higher. have.

In addition,'the manufacturing method of the nano-sized calcium phosphate-based biomaterial particles and the nano-sized calcium phosphate-based biomaterial particles (registration number: 10-0999544)' require a long reaction time at room temperature for 24 to 48 hours for synthesis, There is a process problem that the residual amount of impurities must be removed by washing the precipitate with distilled water over a long period of time.

To solve these problems,'Amorphous nano ceramic powder manufacturing method (Registration No.: 10-1837430)' has been presented. This method claims to be possible to synthesize with a relatively short synthesis time, but since it is difficult to mass-produce and synthesize amorphous by using microwaves with limited penetration depth, there is a problem that it is impossible to confirm whether the composition is accurately synthesized. This is the time when technology development research is needed to improve.

Publication of Korean Patent Publication No. 10-2018-0024755, published on March 8, 2018. Registered in Korean Patent Registration No. 10-0999544, 2010.12.02. Registered in Korean Patent Registration No. 10-1837430, March 06, 2018.

The present invention was invented to solve the problem of the synthesis of a calcium phosphate-based composition that used an existing complex synthesis process or an aqueous solution that takes a long time, and uses a ball milling process to enable mass production in the synthesis process. By doing so, it is an object to provide an easy single or complex composition of a calcium phosphate-based composition and a method for manufacturing the same.

The present invention for achieving the above object, a first step of preparing a calcium hydroxide solution in which calcium hydroxide is dissolved and an aqueous solution of phosphoric acid containing phosphorus, such that the molar ratio of calcium (Ca) and phosphorus (P) is 1.67; A second step of preparing a synthetic reactant by mixing and reacting the aqueous calcium hydroxide solution with the aqueous phosphoric acid solution immediately after the first step; And a third step of ball milling the synthetic reactant at room temperature for 2 to 12 hours immediately after the second step to obtain a crystalline single-phase hydroxyapatite nanopowder. Is made without the addition of a pH adjusting agent, and in the third step, characterized in that ball milling is performed after adding a ball to a volume of 20 to 40 vol% compared to the volume of the synthetic reactants. Provided is a method for preparing a calcium phosphate-based composition for preparing crystalline apatite nanoparticles.

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The present invention for achieving the above other object, provides a calcium phosphate-based composition characterized in that the crystalline single phase hydroxyapatite (hydroxyapatite) nano powder produced by the above method.

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The calcium phosphate-based composition according to the present invention and a method for manufacturing the same according to the above-described solving means have the following effects.

First, compared to the conventional synthesis method, mass production is possible in a short time, and there is an effect that it can be manufactured simply by ball milling at room temperature.

Second, since an additional pH adjusting agent is not required, a separate filtration washing process is not required after ball milling, and it is only necessary to dry the moisture, thereby obtaining a powder having a desired composition.

1 is an exemplary view of a ball milling device according to a preferred embodiment of the present invention.
2 is a photograph of a ball according to a preferred embodiment of the present invention.
3 is an X-ray diffraction analysis result according to the ball milling time according to a preferred embodiment of the present invention.
4 is an X-ray diffraction analysis result without ball milling according to a preferred embodiment of the present invention.
5 is a light transmittance experiment of the calcium phosphate-based composition according to a preferred embodiment of the present invention.

Prior to explaining the present invention, conventionally, a pH adjusting agent was used at a high temperature condition for a chemical reaction between a calcium system and a phosphoric acid system, but in the present invention, a pH adjusting agent was not used at a room temperature condition for a chemical reaction between a calcium system and a phosphoric acid system. It is to suggest a method.

That is, the calcium phosphate-based composition of the present invention is characterized by preparing a calcium phosphate-based composition in powder form by ball milling a synthetic reaction product synthesized by adding an aqueous solution containing phosphoric acid to an aqueous solution containing Ca ²⁺ ions.

Hereinafter, with reference to the accompanying drawings, a preferred embodiment of the present invention will be described in detail as follows, the calcium phosphate-based composition is the first step (S1), the second step (S2) and the third step (S3) It can be manufactured through, and the process will be described in more detail below.

However, when preparing the calcium phosphate-based composition, there is no separate temperature control, and all processes are performed at room temperature.

First, the first step is to prepare an aqueous calcium solution containing calcium (Ca) and an aqueous phosphoric acid solution containing phosphorus (P). (S1)

First of all, the calcium phosphate (CP)-based composition to be prepared through the present invention includes hydroxyapatite, HAp, Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca/P: 1.67), beta-tricalcium phosphate, Ca phosphates and hydrogen phosphates and hydroxides such as β-TCP, Ca ₃ (PO ₄ ) ₂ , Ca/P: 1.5) and dicalcium phosphate dihydrate (DCPD, CaHPO ₄ .2H ₂ O, Ca/P: 1.0) , Or a mixture of these compositions.

In the case of calcium (Ca), Ca(OH) ₂ is used, or CaO (measures Ca(OH) _{2 to} form water), CaCO ₃ (to vaporize CO ₂ and to form Ca(OH) ₂ upon contact with acid), other of Ca If a Ca ²⁺ form in an aqueous solution can be provided using a raw material containing Ca such as water-soluble salts or alkoxides, there is no limitation on the use of the raw material.

For reference, it is preferable that the concentration of calcium is 0.3 to 1.5M in an aqueous solution. If the calcium concentration is less than 0.3M in the aqueous solution, there is a concern that the amount of powder obtained from the calcium phosphate-based composition is small, and if it exceeds 1.5M, the reaction efficiency with the aqueous phosphoric acid solution is poor, so the calcium concentration in the aqueous solution is 0.3 to 1.5M. Being able to do this is important.

In the case of phosphorus (P), an aqueous solution of phosphoric acid (H ₃ PO ₄ ), which is acidic in the aqueous solution, or phosphorous acid (H ₃ PO ₃ ) or hypophosphorous acid (H ₃ PO ₂ ) may be used. Phosphoric acid for phosphorus supply is used as an aqueous solution (mainly commercially available at 85%), or diluted in distilled water to neutralize the violent reaction in the process of mixing strong acid (H ₃ PO ₄ ) with strong alkali (Ca(OH) ₂ ) Although it can be used, it is preferable to supply it in accordance with a prescribed Ca/P molar ratio. However, it is desirable not to use elements that require separate filtration washing.

It will be important to determine the Ca/P molar ratio to obtain the desired composition. As described above, the molar ratio of Ca/P for apatite hydroxide is 1.67, the molar ratio of Ca/P for β-TCP is 1.5, and the molar ratio of Ca/P for DCPD is 1.0.

In preparing the synthesis of the calcium phosphate-based composition, in the first step, an aqueous solution of calcium hydroxide (Ca(OH) ₂ ) as a substance supplying calcium and phosphoric acid (H ₃₎ as a substance supplying phosphorus An aqueous solution of PO ₄ ) is prepared.

For example, Ca ^{+ 2} ion-containing raw materials (eg, powder) are mixed with distilled water and stirred. The Ca ⁺² ion-containing raw material mixed in the distilled water may be formed in a completely dissolved solution state in distilled water, but a homogeneous reaction is induced as it is completely reacted in the ball milling process of the third step even if it remains in powder form due to insufficient stirring. Process time can be shortened.

Next, the second step is a step of forming a synthetic reaction product by adding an aqueous phosphoric acid solution to the container 140 containing the aqueous calcium solution. (S2)

That is, the second step does not use any additives including a pH adjusting agent when synthesizing the calcium phosphate-based composition, and the Ca/P molar ratio of Ca(OH) ₂ aqueous solution and H ₃ PO ₄ aqueous solution under room temperature conditions It is a step to allow the aqueous solution of phosphoric acid to be mixed with the aqueous calcium solution only by (1.0 to 1.7).

At this time, since the acidic phosphoric acid aqueous solution, which is a source of phosphorus, can be additionally reacted through ball milling in a third step, it is possible to rapidly input in a second step.

In particular, in the past, in the reaction of Ca(OH) ₂ and H ₃ PO ₄ , a variable of pH was used depending on the amount of H ₃ PO _4. When the pH is low, a pH is increased by adding a separate pH adjusting agent such as NaOH. The process was carried out.

However, in this case, due to impurities generated in the solution (for example, Na), the filtering process has to be additionally performed, so the process is complicated with an additional device, or there is a problem in purity if distilled water is not sufficiently used. Moreover, in order not to use NaOH, if the addition of H ₃ PO ₄ is fast, a severe pH drop may occur locally and an unwanted phase may be formed, so it must be added very slowly, but in this case, it was inefficient because it was disadvantageous for mass production.

In order to improve this, in the present invention, when Ca(OH) ₂ is added to water, it is possible to synthesize at room temperature due to self-heating, in which the pH itself increases while the OH is dissolved in water.

Finally, the third step is a step of obtaining a calcium phosphate-based composition in powder form by ball milling the synthetic reactant under room temperature conditions. (S3)

As described in the first step, the calcium phosphate (CP)-based composition to be prepared through the present invention is hydroxyapatite, HAp, Ca ₁₀ (PO ₄ )6(OH) ₂ , Ca/P: 1.67 ), beta-tricalcium phosphate (β-TCP, Ca ₃ (PO ₄ ) ₂ , Ca/P:1.5) and dicalcium phosphate dihydrate (DCPD, CaHPO ₄ .2H ₂ O, Ca/P: 1).

When the Ca/P molar ratio is between 1.5 and 1.67, a powder containing crystalline HAp and amorphous β-TCP can be obtained, and when the Ca/P molar ratio is 1.67, HAp reactivity is high, making pure crystalline HAp easy. Synthesizable.

In other words, the third step is characterized in that the synthesis of the powdered calcium phosphate-based composition is completed through ball milling under room temperature conditions. When the calcium phosphate-based composition is synthesized in the second step, no additives including pH adjusting agents are used. , By controlling only Ca/P control of Ca(OH) ₂ aqueous solution and H ₃ PO ₄ aqueous solution, by-products (or impurities) after synthesis reaction as shown in [Formula 1] and [Formula 2] are only water (H _Since only ₂ O) is produced, post-treatment processes such as filtration and washing are not necessary.

[Equation 1] 10Ca(OH) ₂ + 6H ₃ PO ₄ → Ca ₁₀ (PO ₄ ) ₆ (HAp) + 18H ₂ O

[Equation 2] 3Ca(OH) ₂ + 2H ₃ PO ₄ → Ca ₃ (PO ₄ ) ₂ (TCP) + 6H ₂ O

However, in the prior art, in order to prevent formation of an impurity phase when inducing reactions between raw materials in the process of synthesizing an aqueous solution through the reactions of [Formula 1] and [Formula 2], the input rate of H ₃ PO ₄ should be low (8.0 ml/min or less) And, even after the pH adjustment reaction, there is a disadvantage that the desired composition is synthesized only when the holding time is longer than 24 hours.

In addition, since a non-uniform synthesis occurs due to a change in the local pH during the reaction, there is a disadvantage that a long filtration and washing process is required to remove unnecessary components such as Na after synthesis by maintaining the pH of the solution with NaOH or the like.

In order to solve this shortcoming, in the third step of the present invention, synthesis is performed through a ball milling process, and thus there is no limitation on the input speed of H ₃ PO ₄ , so that the reaction rate can be increased and the aqueous solution of calcium phosphate is added to the aqueous calcium hydroxide solution. Immediately afterwards, it can cause a complete reaction.

Since ball milling can be performed in the third step, it is possible to induce uniform synthesis, so no additional pH adjusting agent is required, so there is no need for a filtration and washing process after ball milling. It is to obtain a desired composition in the form of a powder of calcium phosphate.

1 is an exemplary view of a ball milling apparatus 100 according to a preferred embodiment of the present invention. Referring to FIG. 1, it can be seen that a ball milling of a container 140 containing a synthetic reactant in which a phosphate aqueous solution is mixed with an aqueous calcium hydroxide solution between a pair of rollers 120 being rotated is exemplified.

2 is a photograph of a ball B according to a preferred embodiment of the present invention. Referring to FIG. 2, it can be seen that a photograph of a ceramic ball (B) is introduced into a container 140 in which a synthetic reactant in which a calcium hydroxide aqueous solution and a phosphoric acid aqueous solution are mixed is accommodated.

That is, the ball milling process is the friction (shear force) between the balls (B) and the tumbling of the balls (B) by rotating the container (140) into which the ceramic balls (B) are injected, and crushing of the synthetic powder through collision when falling. The uniform/homogeneous mixing effect and the diffusion distance of unreacted raw materials are shortened, so that the synthesis reaction can be achieved in a short time.

In addition, the impact of these balls (B) can cause temperature rise, pressure increase, and electron emission, thereby inducing additional mechanochemical reactions.

The aqueous solution mixed according to the Ca/P molar ratio is contained in the container 140 for ball milling without having to go through a holding time separately, wherein the ball B introduced into the container 140 is compared with the volume of the synthetic reactants. It is good to add it in 20-40 vol%.

If the ball (B) is added in an amount of less than 20 vol% compared to the volume of the synthetic reactant, the reaction is not sufficiently performed so that the peak on the impurity phase does not disappear and the efficiency is low. On the other hand, if the ball (B) is added in excess of 40 vol% compared to the volume of the synthetic reactant, it will not show more excellent effect as compared with the case where the ball (B) or less is added, and that the ball (B) is added a lot Since the efficiency is not good, the ball (B) is preferably added at 20-40 vol% (preferably 20-30 vol%, more preferably 25-27 vol%) to the volume of the synthetic reactants.

Also, it is recommended that ball milling is performed for 2 to 24 hours. If the ball is milled for less than 2 hours, the peaks of impurities do not disappear and remain, and ball milling for more than 24 hours does not matter, but ball milling is not required for more than 24 hours. It is not necessary to perform ball milling for more than 24 hours since the calcium phosphate-based composition can be obtained. It is preferable to perform ball milling for 6 to 18 hours (more preferably, 6 to 12 hours).

After completing the ball milling in this way, the ball (B) is separated from the container 140 and then the remaining material is dried, thereby obtaining a calcium phosphate-based composition in powder form.

Here, ball milling refers to all tools for mechanical reaction by placing a ball in a synthetic container, and is not limited by the shape of the synthetic container or the method of vibrating or rotating the synthetic container.

Hereinafter, a preferred embodiment of the present invention will be described in more detail.

<Example 1>

The process for preparing a calcium phosphate-based composition, hydroxyapatite, HAp, Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca/P: 1.67) is as follows.

In a 1 liter reactor with a stirrer, 225 ml of distilled water is added, and 74.1 g of white powdered Ca(OH) ₂ is added and stirred for 20 minutes. Subsequently, an aqueous phosphoric acid solution was added to which 50 ml of distilled water was added to neutralize the vigorous reaction in 69.4 g of 85% H ₃ PO ₄ aqueous solution, and then added to the stirred Ca(OH) ₂ aqueous solution within 20 minutes.

The prepared synthetic reactants were subjected to ball milling as they were, and additional stirring and mixing were performed. At this time, the number of balls is 60, which is added to be 27 vol% or more based on the volume of the synthetic reactants, and then undergoes an additional reaction process.

3 is an X-ray diffraction analysis result according to the ball milling time according to a preferred embodiment of the present invention. Referring to Figure 3, it can be seen that the synthesis process according to the ball milling time of the HAp prepared according to Example 1 above is shown as an X-ray diffraction analysis result.

For example, as shown in FIG. 3 a, it can be confirmed that synthesis was completed with HAp of a crystalline single phase through ball milling for 6 hours. In addition, the peak of HAp synthesized through ball milling for 18 hours can be confirmed, but the peak of HAp appears even if ball milling is not performed until 18 hours.

4 is an X-ray diffraction analysis result without ball milling according to a preferred embodiment of the present invention. Referring to FIG. 4, it can be seen that the HAp prepared according to Example 1 is a result of X-ray diffraction analysis showing the synthesis process by heating at a high temperature without going through ball milling.

That is, FIG. 4 shows the results of X-ray diffraction analysis when HAp, which can be easily synthesized through ball milling for 6 hours, does not perform ball milling, and DCPD and b of FIG. 4 are used to synthesize hydroxyapatite (HAp). It can be seen that this is not the desired material in this embodiment, and that peaks begin to be formed little by little when heated to 500°C or higher. In addition, it can be seen that the desired HAp peaks can be seen only at about 900°C as in c of FIG. 4, and in order to synthesize only pure HAp, it must be heated to 1,100°C or higher.

In the present example by the rapid solution injection, an impurity phase such as a DCPD phase that is not desired to be synthesized is formed, and this impurity phase is easily eliminated through fire milling, and only desired HAp can be obtained. On the other hand, when the ball milling is not performed, these impurity phases are not easily removed, and only when heat treatment is performed at a high temperature, the desired HAp can be obtained. Accordingly, the present invention proceeding under room temperature conditions will have an important meaning.

<Example 2>

Hydroxyapatite (HAp, Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca/P: 1.67) and beta-tricalcium phosphate (β-TCP, Ca ₃ (PO ₄ ) ₂ , Ca/P: 1.5) The process for preparing the mixed composition is as follows.

In a 1 liter reactor with a stirrer, 225 ml of distilled water is added and 74.1 g of Ca(OH) ₂ is added and stirred for 20 minutes. Subsequently, a phosphoric acid aqueous solution in which 50 ml of distilled water is added to a 77.3 g of 85% H ₃ PO ₄ aqueous solution is prepared, and then added to the stirred Ca(OH) ₂ aqueous solution within 20 minutes.

The prepared synthetic reactants were ball-milled as they were, and additional agitation and mixing were performed. At this time, the number of balls was 60, and 27 vol% or more of the synthetic reactants were added to the mixture to undergo additional reaction.

5 is a light transmittance experimental diagram of a calcium phosphate-based composition according to a preferred embodiment of the present invention. 5 is to check the light transmittance by selecting the sintering method applied when using a calcium phosphate-based composition for bone replacement, Figure 5 (a) is a powder prepared in Example 1 in the form of pellets (pellts) It was made and sintered at 1,100°C for 2 hours, and then showed light transmittance. FIG. 5-(b) shows the light transmittance after sintering at 1,100°C for 2 hours by making the powder prepared through Example 2 into pellets. will be.

That is, it is possible to obtain a sintered body having excellent sintering characteristics with light transmission at a low temperature that cannot be obtained when a general powder with large particles is used. As examples 1 and 2, primary particles having a size of about 30 nm are aggregated as secondary particles. It can be said that sintering is good even at 1,100°C, which means that the light transmittance is excellent.

As described above, the calcium phosphate-based composition of the present invention has an effect of easily obtaining a fine powder having excellent reactivity and being capable of mass production by applying a simple process while being simple to synthesize under normal temperature conditions. In addition, the product to be reacted by using an aqueous solution is water (H ₂ O), so it is possible to produce powders having various compositions without the need for an additional purification process.

The above description is merely illustrative of the technical idea of the present invention, and those skilled in the art to which the present invention pertains may make various modifications and variations without departing from the essential characteristics of the present invention.

Therefore, the embodiments disclosed in the present invention are not intended to limit the technical spirit of the present invention, but to explain, and the scope of the technical spirit of the present invention is not limited by these embodiments.

The scope of protection of the present invention should be interpreted by the claims, and all technical ideas within the equivalent range should be interpreted as being included in the scope of the present invention.

100: ball milling device
120: roller
140: courage
B: Ball

Claims (6)

A first step of preparing an aqueous calcium hydroxide solution in which calcium hydroxide is dissolved and an aqueous phosphoric acid solution containing phosphorus so that the molar ratio of calcium (Ca) and phosphorus (P) is 1.67;
A second step of preparing a synthetic reactant by mixing and reacting the aqueous calcium hydroxide solution with the aqueous phosphoric acid solution immediately after the first step; And
And a third step of obtaining the hydroxyapatite nanopowder of the crystalline single phase by ball milling the synthetic reactant at room temperature for 2 to 12 hours immediately after the second step.
The second step is made without the addition of a pH adjusting agent,
In the third step,
Characterized in that the ball milling (ball milling) after adding the ball to the volume of the synthetic reactant to 20 to 40 vol%,
Method for preparing a calcium phosphate-based composition for preparing crystalline apatite hydroxide nanopowder at room temperature. delete A calcium phosphate-based composition, characterized in that it is a hydroxyapatite hydroxyapatite nanopowder prepared by the method of claim 1. delete delete delete

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