RU2717275C2 - Method of producing granulated hydroxyapatite particles - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing granulated hydroxyapatite particles. Method of producing granulated hydroxyapatite particles involves preparation of precursors in the form of solutions containing calcium ions, ammonium ions and phosphate ions, formation of a hydroxyapatite precipitate from precursor solutions at constant pH, separation of the formed precipitate, drying and thermal treatment. Precursors used are calcium nitrate solution, ammonia solution and solution of phosphoric acid or ammonium phosphate. Formation of hydroxyapatite precipitate is carried out at constant ratio of Ca²⁺/PO₄ ^3-, lying in range of 1.5–1.8, and constant value of pH, which is in range of 7–9. Constancy of pH values and ratio of Ca²⁺/PO₄ ^3- in the reaction volume is maintained during the entire process of precipitate formation.

EFFECT: invention enables to obtain particles of spherical particles with size of 20–60 nm with narrow particle size distribution.

5 cl, 7 dwg

Description

The invention relates to technologies for the deposition of inorganic materials, and in particular to a method for producing spherical granular particles of hydroxyapatite, which can be used in medicine for the formation of biocompatible coatings by the method of thermal spraying.

Calcium hydroxyapatite is widely used in medicine for the production of materials that stimulate the restoration of defects in bone tissue, coatings of bone and dental implants, etc. The material used to form coatings by thermal spraying must satisfy a number of requirements in the shape and size of the particles.

The correct particle shape close to spherical determines the high flowability of powder materials, high bulk density, as well as low hydro- and aerodynamic resistance, which ensures uniform metering and fusion of powder particles during thermal spraying of coatings.

The diameter of the powder particles should be in a narrow range from 20 to 60 μm, which leads to high flowability of the powder materials and uniform melting of the particles during coating formation. When using smaller particles of powder, the flowability of the material is significantly reduced, which leads to its inhomogeneous supply to the coating forming device. When using large-diameter particles, the particles are not uniformly melted in the plasma or gas stream, which affects the properties of the final coating.

The task of forming spherical granular hydroxyapatite powders with a narrow particle size distribution from 20 to 60 microns is very relevant.

A known method (RU 2077475 dated 04/20/1997, C01B 25/32) for the production of hydroxyapatite particles, which involves mixing an aqueous suspension of calcium hydroxide with an aqueous solution of phosphoric acid, separating the reaction precipitate and drying it. The components are mixed with the continuous addition of an aqueous solution of phosphoric acid to a suspension of calcium hydroxide with successive passage of the reaction mixture through two zones, while in the first zone a constant pH of 10-11 is maintained, and the flow rate of the suspension is 0.8-1.5 m / s, then the mixture is fed into the second zone after 1.0-1.5 s, where it is diluted 400-500 times with the initial suspension of calcium hydroxide and returned to the first zone, providing a 4-5-fold circulation of the reaction mixture through both zones in a closed cycle for a time of 10-20 min, pic To this end, the acid supply is stopped and the suspension of the reaction product is additionally mixed in a closed cycle for 10-12 minutes.

A known method (US 4324772 from 04/13/1983, С01В 25/32) for producing hydroxyapatite particles, comprising a first stage with continuous loading of a two-stage reactor with a suspension of calcium oxide in water and a solution of phosphoric acid in water, which react in the first stage with strong stirring with the reaction pH mass so that the viscosity is close to minimum, i.e. pH 9.5 to 11; the second stage of the reactor with vigorous stirring with the continuous introduction of aqueous phosphoric acid in an amount sufficient to maintain the pH in the second stage near a value in the range from 7.0 to 7.4.

The disadvantages of the above methods are their multi-stage, which determines their technological complexity, as well as the heterogeneity of the particles of hydroxyapatite in shape and a wide distribution of particle size.

Closest to the claimed invention is a method (US 5405436 dated 04/11/1995, C01B 25/32) for the production of hydroxyapatite, which includes the steps of preparing precursors containing phosphate ions, hydroxyl ions and calcium cations, the calcium source being a precursor containing phosphate ions, which is a solution of phosphoric acid in water with a molar ratio of Ca: P of about 0.2: 1 to 1: 1, and a precursor containing hydroxyl ions, which is a suspension of calcium hydroxide in water; the formation of a precipitate of hydroxyapatite by initially forming the reaction mixture by simultaneously feeding a precursor containing calcium and phosphate ions and a precursor containing calcium and hydroxyl ions into the reactor with vigorous stirring so as to provide a ratio of Ca: P = 1.677 with further reaction at vigorous stirring at a temperature of the reaction mixture from 60 ° to 100 ° C and at a pH of the reaction mixture from 4 to 8; separating the hydroxyapatite phase from the mother liquor; flushing; drying.

This method allows to obtain particles with a narrow size distribution from 1 to 20 microns. The disadvantage of this method is the absence of a larger fraction of particles (with diameters from 20 to 60 μm) required for coating formation, the need to heat the reaction mixture, which increases the energy intensity of the process, as well as the increase in the synthesis time due to the presence of two sequential operations: first, feeding the precursors with a final ratio Ca: P = 1,667, then carrying out the reaction at elevated temperatures and constant pH.

The technical result of the proposed invention is to obtain spherical granular particles of hydroxyapatite with a narrow particle size distribution containing the target fraction from 20 to 60 microns.

и значения рН реакционной среды. Одновременное поддержание постоянными соотношения

и значения рН реакционной среды позволяет также уменьшить количество операций в синтезе гидроксиапатита, за счет чего уменьшается длительность синтеза по сравнению с аналогами.The claimed technical result is achieved by the formation of granular particles of hydroxyapatite directly during the hydrolysis of calcium salts while maintaining a constant ratio

and pH values of the reaction medium. Keeping ratios constant at the same time

and the pH of the reaction medium also allows to reduce the number of operations in the synthesis of hydroxyapatite, thereby reducing the duration of the synthesis compared to analogues.

At the first stage of obtaining granular particles of hydroxyapatite, a precursor containing calcium is prepared. As a precursor containing calcium, a solution of any water-soluble calcium salt, in particular, nitrate, chloride, acetate, etc. can be used. It is possible to prepare a calcium salt by dissolving anhydrous or aqueous calcium salt in water, dissolving calcium oxide or carbonate in nitrogen , hydrochloric or acetic acid, or in other ways. According to a preferred embodiment of the invention, anhydrous calcium nitrate and distilled water are used to prepare a calcium salt solution. The salt concentration may range from 0.5 to 3 mol / L.

In the second stage of hydroxyapatite production, a precursor is prepared containing phosphate ions. For this purpose, various solutions of the compounds can be used, in particular phosphoric acid, ammonium phosphate, sodium, potassium phosphate and any other soluble salts of phosphoric acid. It is preferable to use phosphoric acid with a concentration of 0.1-19.0 mol / L, most preferably 1.1-2.0 mol / L.

In a third step for preparing hydroxyapatite particles, a precursor is prepared containing hydroxyl ions. In this capacity, any base can be used, in particular hydroxides of potassium, sodium, etc., or an aqueous solution of ammonia. It is preferable to use an aqueous solution of ammonia, since in the process of thermal decomposition of the products of its interaction with calcium salt and phosphoric acid, there is no contamination of the product with metal cations. The concentration of the aqueous ammonia solution may be in the range from 1 to 13 mol / L, more preferably from 5 to 7 mol / L.

. Осаждение осуществляют путем дозирования прекурсора, содержащего кальций, прекурсора, содержащего фосфат-ионы, и прекурсора, содержащего гидроксил-ионы, в реакционный объем таким образом, что в реакционном объеме поддерживают постоянное значение рН в интервале от 7 до 9, более предпочтительно 7,5-8,5 единиц рН, и постоянное соотношение

в интервале от 1,5 до 1,8, более предпочтительно 1,66-1,68.In the fourth stage of obtaining granular hydroxyapatite, a precipitate of hydroxyapatite is formed by precipitation at constant values and pH of the reaction mixture, and the ratio

. Precipitation is carried out by dosing a precursor containing calcium, a precursor containing phosphate ions, and a precursor containing hydroxyl ions in the reaction volume so that a constant pH is maintained in the reaction volume in the range from 7 to 9, more preferably 7.5 -8.5 pH units, and constant ratio

in the range from 1.5 to 1.8, more preferably 1.66-1.68.

. Для их поддержания на заданном уровне возможно регулирование скорости подачи как одного из прекурсоров, так и одновременно нескольких прекурсоров. Дозирование прекурсоров может быть выполнено при использовании перистальтических насосов, мембранных насосов, насосов прямого дозирования, центробежных насосов с регулируемой скоростью вращения, а также другими способами. Контроль рН реакционного объема ведут в течение всего процесса осаждения при помощи рН-метров с ион-селективными электродами или при помощи иных систем детектирования концентрации Н+ионов в растворе.The deposition can be performed in semi-continuous or continuous modes, while the precursors are dosed into the total reaction volume in which the selected pH value and ratio are maintained

. To maintain them at a given level, it is possible to control the feed rate of either one of the precursors or several precursors at the same time. Dosing of precursors can be performed using peristaltic pumps, diaphragm pumps, direct metering pumps, variable speed centrifugal pumps, and other methods. The pH of the reaction volume is monitored throughout the deposition process using pH meters with ion-selective electrodes or other systems for detecting the concentration of H + ions in solution.

After the operations of filtering, drying and firing the precipitate. Preferably, the precipitate is dried at a temperature of from 80 to 120 ° C to constant weight. The firing of the precipitate is preferably carried out at a temperature of from 300 to 1000 ° C.

The invention is illustrated by figures, which depict:

- in FIG. 1 is a table of parameters of hydroxyapatite samples synthesized in Examples 1-6;

- in FIG. 2 - particle size distribution of particles according to the size of hydroxyapatite synthesized in Example 1;

- in FIG. 3 - SEM image of the particles of the sample synthesized according to example 1.

- in FIG. 4 is a radiograph of hydroxyapatite synthesized in Example 1;

- in FIG. 5 - particle size distribution of hydroxyapatite synthesized in Example 6

- in FIG. 6 - SEM image of the particles of the sample synthesized according to Example 6.

- in FIG. 7 is an X-ray diffraction pattern of hydroxyapatite synthesized in Example 6.

Example 1

равным 1,67.This example relates to the precipitation of pure hydroxyapatite at pH = 8 with a concentration of precipitated calcium nitrate solution of 0.5 mol / l and the ratio

equal to 1.67.

Distilled water and 120.8 grams of anhydrous calcium nitrate Ca (NO ₃ ) ₂ (mass concentration 96%) are introduced into the first beaker with stirring, the volume of the solution is adjusted to 1 liter with distilled water. The resulting solution was kept under stirring for 2 hours before precipitation. 113 ml of concentrated phosphoric acid is introduced into the second beaker and adjusted to 1 liter with distilled water. To prepare a solution of a basic compound, 370 ml of concentrated ammonia solution (mass concentration 24%) is introduced into the third beaker and the volume is adjusted to 0.8 l with distilled water, after mixing the components, an aqueous ammonia solution is obtained with concentrations of 11 mass percent.

To carry out the deposition of granular particles of hydroxyapatite, 250 ml of distilled water is introduced into a three-liter beaker equipped with an overhead stirrer and a pH sensor. Next, a calcium nitrate solution at a rate of 10 ml / min, a phosphoric acid solution at a rate of 10 ml / min and an aqueous solution of ammonia at a rate of 6.5 ml / min are metered into a glass with stirring using peristaltic pumps, and the pH in the glass is maintained in the range from 7.8 to 8.2 units due to the periodic interruption of the dosing of an aqueous solution of ammonia. After the introduction of the entire volume of a solution of calcium nitrate and phosphoric acid, the resulting suspension is kept under stirring for 30 minutes, the suspension is filtered on a suction filter. Next, the precipitate is placed in an oven, and the precipitate is dried at a temperature of 80 ° C for 12 hours. After that, the precipitate is fired in a muffle furnace at a temperature of 600 ° C for 2 hours.

The particle size distribution was determined using the laser diffraction method using the Analysette 22 NanoTec instrument. In FIG. 2 shows the particle size distribution of the sample obtained according to Example 1. Particle morphology was studied using scanning electron microscopy; FIG. 3 is an electronic photograph of the particles of the sample obtained in Example 1. FIG. 4 shows the x-ray of pure hydroxyapatite obtained in example 1.

Example 2

равным 1,67.This example relates to the precipitation of pure hydroxyapatite at pH = 8 with a concentration of precipitated calcium nitrate solution of 3 mol / l and a ratio

equal to 1.67.

In this case, they do the same as in example 1, but distilled water and 724.8 grams of anhydrous calcium nitrate Ca (NO ₃ ) ₂ (mass concentration 96%) are introduced into the first beaker with stirring. The resulting solution was kept under stirring for 2 hours before precipitation. 678 ml of concentrated phosphoric acid is introduced into the second beaker and adjusted to 1 liter with distilled water. Precipitation and all further operations are carried out as described in example 1.

Example 3

равным 1,8.This example relates to the precipitation of pure hydroxyapatite at pH = 8 with a concentration of precipitated calcium nitrate solution of 0.5 mol / l and the ratio

equal to 1.8.

In this case, the procedure is the same as in example 1, but 122 ml of concentrated phosphoric acid are introduced into the second beaker and adjusted to 1 liter with distilled water. Precipitation and all further operations are carried out as described in example 1.

Example 4

равным 1,67.This example relates to the precipitation of pure hydroxyapatite at pH = 9 with a concentration of precipitated calcium nitrate solution of 0.5 mol / l and a ratio

equal to 1.67.

In this case, they do the same as described in example 1, only the precipitation of calcium hydroxyapatite is carried out at pH = 8.8-9.2.

Example 5

равным 1,67, но в качестве донора

-ионов выступает раствор аммония фосфорнокислого.This example relates to the precipitation of pure hydroxyapatite at pH = 8 with a concentration of precipitated calcium nitrate solution of 0.5 mol / l and the ratio

equal to 1.67, but as a donor

-ions favors a solution of ammonium phosphate.

In this case, they do the same as in example 1, but in the second beaker a solution of ammonium phosphate is prepared. To do this, distilled water and 121.6 grams of three-water ammonium phosphate (NH ₄ ) ₃ PO ₄ ⋅ 3H ₂ O are introduced into the glass and adjusted to 1 liter with distilled water. Precipitation and all further operations are carried out as described in example 1.

Example 6

равным 1,67.This example relates to the precipitation of hydroxyapatite at pH = 6 with a concentration of a precipitated solution of calcium nitrate of 0.5 mol / l and the ratio

equal to 1.67.

In this case, they do the same as described in example 1, only the precipitation of calcium hydroxyapatite is carried out at pH = 5.8-6.2.

In FIG. 5 shows the particle size distribution of the sample obtained in example 6. In FIG. 6 is an electronic photograph of the particles of the sample obtained in Example 6. FIG. 7 is an X-ray diffraction pattern of hydroxyapatite obtained according to Example 6, in which the phases of brushite and monetite are predominantly present.

Claims (5)

1. A method of producing granular particles of hydroxyapatite, including the preparation of precursors in the form of solutions containing calcium ions, ammonium ions and phosphate ions, the formation of a precipitate of hydroxyapatite from solutions of precursors at a constant pH value, separation of the precipitate formed, drying and heat treatment, characterized in that as precursors, a solution of calcium nitrate, a solution of ammonia and a solution of phosphoric acid or ammonium phosphate are prepared, the formation of a precipitate of hydroxyapatite is carried out at a constant enii Ca ²⁺ / PO ₄ ^3-, in the range of 1.5-1.8, and a constant pH in the range of 7-9, wherein the constancy of pH and ratio of Ca ²⁺ / PO ₄ ^3- in the reaction the volume is maintained throughout the entire process of sedimentation by simultaneously dispensing three streams of precursor solutions into the total reaction volume with adjusting the feed rate of one or more solutions. 2. The method according to p. 1, characterized in that as a precursor containing phosphate ions, an aqueous solution of ammonium phosphoric acid or phosphoric acid with a concentration of 1.1-2.0 mol / L is used. 3. The method according to PP. 1 and 2, characterized in that the ratio of CA ²⁺ / PO ₄ ^{3- is} maintained constant and equal to 1,667. 4. The method according to p. 1, characterized in that they use a solution of ammonia with a concentration of 5-7 mol / L. 5. The method according to p. 1, characterized in that they use a solution of calcium nitrate salt in water with a concentration of from 0.5 to 3 mol / L.

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