RU2776293C1 - Method for obtaining biocompatible bismuth-apatites - Google Patents

Abstract

FIELD: inorganic chemistry.

SUBSTANCE: invention relates to inorganic chemistry and concerns a method for producing biocompatible bismuth-apatites of the composition Ca_10-2xBi_xNa_x(PO₄)₆F₂, where x=1, 2, 3, 4, which can be used in medicine, including dentistry, for the production of medical ceramic materials that stimulate the restoration of bone defects, as well as providing protection against the development of bacterial infections. The method includes placing a stoichiometric mixture of four-water calcium nitrate, five-water bismuth nitrate, sodium nitrate, diammonium hydrophosphate and ammonium fluoride into an alundum crucible, after which the crucible is placed in a muffle furnace with a closed spiral and heated to a temperature of 300-350°C at a rate of 3-5 deg/min until the end of the dehydration of the initial crystalline hydrates and thermal decomposition of the reagents used. Then the crucible is cooled to room temperature and the mixture is dispersed in an agate mortar using ethanol to create additional disjoining pressure. The resulting monodisperse powder is placed in a crucible and calcined to 600-670°C at a rate of 5-7 deg/min with dispersion every hour for 10 minutes. Next, the mixture is calcined in an alundum crucible at a temperature of 950-1100°C for 7-9 hours.

EFFECT: simplification of the manufacture of bismuth apatite and reduction of production time.

3 cl, 2 dwg, 1 tbl, 2 ex

Description

SUBSTANCE: invention relates to inorganic chemistry, concerns a method for obtaining biocompatible bismuth-apatites, which can be used in medicine, including dentistry, for the production of medical ceramic materials that stimulate the restoration of bone tissue defects, and also provide protection against the development of bacterial infections.

One of the most serious consequences of surgery is the occurrence of periprosthetic infection. Periprosthetic infection (PJI) is one of the most serious and common consequences of joint replacement surgery. Periprosthetic infection is the second most common reason for revision of hip and knee endoprostheses. The frequency of PJI is about 1% after primary interventions and increases to 10% after revision surgeries. The reason for the development of this complication in most cases is intraoperative infection, less often - hematogenous.

The use of an antibacterial agent in the composition of the implant material will minimize the risk of infections after surgery and, accordingly, reduce the likelihood of a secondary operation. The use of bismuth included in the crystal structure of the implant material will increase the duration of the antimicrobial effect of such material, while not causing negative consequences for the body as a whole in view of the strong chemical binding of bismuth in the crystal lattice. Thus, the described approach is expected to be used to obtain substances on the basis of which ceramic biomaterials or coatings of metal biomaterials will be created.

Known composition for filling teeth and cementing dentures (RU 2097015 C1, class A61K 6/06, publ. 27.11.1997), including a charge containing zinc white, magnesium oxide, bismuth oxide, quartz sand, ammonium molybdate. According to the invention, the mixture additionally contains calcium hydroxide and sodium fluoride in the following ratio, wt.%: magnesium oxide 9.40 - 10.00; bismuth oxide 2.00 - 4.00; quartz sand 3.00 - 3.50; ammonium molybdate 2.40 - 3.50; calcium hydroxide 0.10 - 0.50; sodium fluoride 0.10 - 0.50; zinc white - the rest. As a result of batch sintering, particles of introduced calcium hydroxide Ca(OH) ₂ and sodium fluoride NaF saturate molybdenum oxide to the required limits, which remains after the combustion of ammonium and water. The resulting molybdenum complexes form long polymeric-inorganic chains, which enrich the material charge with the necessary property that affects the regeneration of damaged hard tissues of the tooth, dentin and enamel. The components of the mixture are fired at a temperature of 980-1000°C for 16-18 hours, the melt is cooled in running water and ground in a ball mill to a certain particle size (30 10 μm). The resulting powder fraction of the composition is sieved and packaged. EFFECT: invention ensures imparting regenerative properties to the material while maintaining high physical and mechanical properties. This invention does not specify the phase composition of the final product. In addition, the introduction of bismuth oxide, as well as a number of other additives, is carried out in order to impart regenerative properties to the material while maintaining high physical and mechanical properties.

In the method for producing microgranules based on calcium hydroxyapatite (RU 2002128981 A, С01В 21/32, publ. 06/10/2004), mixing of calcium hydroxide and monosubstituted calcium phosphate, monohydrate, in a molar ratio of Ca / P = 1.67, is used, adding to this mixture an aqueous solution containing a hydrogel with a polymer concentration of 0.01-10.0 wt.%, stirring these substances at a temperature of 20-41°C at a neutral pH of 6.8-7.2, followed by filtration and drying of the precipitated final product in the form microgranules at a temperature of 105-160°C. In this case, hydroxyapatite is obtained as an inorganic substance for medical purposes, but organic substances, alkylresorcinols, are used as an antimicrobial agent.

Closest to the proposed invention is a method for producing cation-substituted calcium phosphate, protected by patent RU 2607743 C1, class. C01B 21/32, C01F11/00, C01F1/00, D82B3/00, publ. 01/10/2017, taken as the closest analogue (prototype).

In the method according to the prototype, cation-substituted tricalcium phosphate is obtained by precipitation of medium calcium phosphates formed by draining and constantly stirring aqueous solutions of calcium nitrate and disubstituted ammonium phosphate, taken in a molar ratio of 3:2, at pH 7.0, followed by filtering the precipitate formed and its thermal processing at temperatures of 700-1300°C. According to the invention, the calculated amount of solutions of salts of nitrates, or acetates, or chlorides of the following elements is added to the reaction mixture: iron, zinc, copper, sodium, potassium, strontium, barium, bismuth, silicon, in the following ratio of reagents, mol.%:

calcium nitrate - 40-59.9,

disubstituted ammonium phosphate - 40,

salt of iron, zinc, copper, sodium, potassium, strontium, barium, bismuth, silicon - 0.1-20.

The powders formed after heat treatment at 700–1300°C are characterized by a homogeneous phase composition corresponding to the whitlockite structure, a highly dispersed state with a particle size of 20 nm to 2 μm, and antimicrobial activity.

In this case, the introduction of bismuth into the crystal structure of a complex phosphate is used, similar in crystal structure to the considered apatites.

The disadvantage of this method is the formation of calcium phosphate, different in crystal structure from the bone tissue material (hydroxyapatite), and the absence of bismuth in the final product.

The objective of the invention is to create a new method for obtaining biocompatible bismuth-apatites.

The technical result from the use of the proposed invention is the simplification of manufacturing, reducing production time.

This is achieved by the fact that the method of obtaining biocompatible bismuth-apatites of the composition Ca _10-2x Bi _x Na _x (PO ₄ ) ₆ F ₂ , where x=1,2,3,4, includes placing a stoichiometric mixture of calcium nitrate tetrahydrate in an alundum crucible, bismuth nitrate pentahydrate, sodium nitrate, diammonium hydrophosphate and ammonium fluoride, after which the crucible is placed in a muffle furnace with a closed spiral and heated to a temperature of 300-350°C at a rate of 3-5 deg/min until the end of dehydration of the initial crystalline hydrates and thermal decomposition of the reagents used , then the crucible is cooled to room temperature and the mixture is dispersed in an agate mortar using ethyl alcohol to create additional disjoining pressure, the resulting monodisperse powder is placed in a crucible and calcined to 600-670°C at a rate of 5-7 deg/min with dispersion every hour in for 10 minutes, then the mixture is calcined in an alundum crucible at a temperature of 950-1100°C for 7-9 hours; the stoichiometric mixture is homogenized by dispersing in an agate mortar for 10 minutes and calcining at temperatures of 300-350 and 950-1100°C; use an alundum crucible of the "glass" or "boat" shape.

In FIG. 1. powder X-ray patterns of the obtained substances of the composition Ca _10-2x Bi _x Na _x (PO ₄ ) ₆ F ₂ are presented, where x = 1,2,3,4.

In FIG. Figure 2 shows the AFM photograph and the surface spectrum of the Ca ₈ BiNa(PO ₄ ) ₆ F ₂ sample.

The proposed method for obtaining bismuth-apatite is carried out as follows.

The method for obtaining bismuth-containing apatite involves a chemical reaction in the solid phase. To do this, take the stoichiometric ratio of tetrahydrate calcium nitrate, pentahydrate bismuth nitrate, sodium nitrate, diammonium hydrogen phosphate and ammonium fluoride. The mixture is homogenized by dispersing in an agate mortar for 10 minutes. Then the resulting mixture is placed in an alundum crucible and subjected to stepwise heating in a muffle furnace in the temperature range from 25 to 1100°C with dispersion of the charge every 10 minutes or 2 hours, depending on the temperature regime.

For one mass part of ammonium fluoride take 10.70 wt. parts of ammonium hydrogen phosphate, 1.15x parts of sodium nitrate, 6.55x wt. parts of pentahydrate bismuth nitrate, 3.19⋅(10-2x) wt. parts of tetrahydrate calcium nitrate (x can take integer and fractional values in the range from 1 to 5).

The synthesis process can be described by the following chemical reaction equation:

(10-2x) Ca(NO ₃ ) ₂ ⋅4H ₂ O + x Bi(NO ₃ ) ₃ ⋅5H ₂ O + x NaNO ₃ + 6 (NH ₄ ) ₂ HPO ₄ + 2 NH ₄ F →

→ Ca _10-2x Bi _x Na _x (PO ₄ )6F ₂ + (50-3x) H ₂ O + 14 NH ₃ + 20 NO ₂ + 5O ₂

The control of the completeness of the course of the chemical reaction is carried out by the method of powder X-ray diffraction. Typical views of the obtained diffraction patterns are shown in Fig. one.

Additional control of the elemental composition is carried out by the method of probe microscopy. In FIG. Figure 2 shows the spectrum and micrograph of the surface area of one of the obtained samples.

To assess the cytotoxicity of the material, a standard MTT test was used. Passage 4-5 human dermal fibroblast culture was used as a test culture. The culture was sterile, not contaminated with mycoplasmas and viruses. The viability of cells in culture before entering into the experiment was 97%. The relative cell growth rate (RGR) was determined by the following formula:

RIR (%) = (mean OD in test culture - 100) / (mean OD in control),

where OP - optical density

The data obtained were evaluated using a rank scale for assessing cytotoxicity. The results are presented in table. one

The same cell culture is used as a control, but without the addition of any additional substances.

Table 1

Assessment of cytotoxicity of materials (extraction 7 days) Ca _10-2x Bi _x Na _x (PO ₄ ) ₆ F _2,

where x = 1,2,3,4.

Material X one 2 3 four Control
(n=8) OP(M±m) 0.210±0.026 0.242±0.025 0.257±0.053 0.251±0.041 FIR, % 100 100 100 100 Level of cytotoxicity 0 0 0 0 Extract
(n=8) OP(M±m) 0.246±0.045 0.227±0.033 0.319±0.044 0.261± 0.038 FIR, % 117 94 124 102 Level of cytotoxicity 0 0 0 0 Extract 1:1
(n=8) OP(M±m) 0.279±0.027 0.284±0.019 0.297±0.035 0.300±0.036 FIR, % 133 117 116 120 Level of cytotoxicity 0 0 0 0 Extract 1:2
(n=8) OP(M±m) 0.249±0.026 0.290±0.019 0.293±0.031 0.307±0.034 FIR, % 119 120 114 122 Level of cytotoxicity 0 0 0 0 Extract 1:3
(n=8) OP(M±m) 0.261±0.021 0.260±0.03 0.254±0.023 0.271±0.043 FIR, % 124 107 99 108 Level of cytotoxicity 0 0 one 0 Extract 1:4
(n=8) OP(M±m) 0.243±0.008 0.343±0.035 0.272±0.027 0.240±0.020 FIR, % 115 142 106 96 Level of cytotoxicity 0 0 0 one

Note: *p<0.05 Wilcoxon test

Thus, the data obtained demonstrate the absence of cytotoxicity of all the studied samples of materials, since in all series, the cytotoxicity rank is 0 - 1.

The use of a matrix in the form of a crystal-chemical analogue of native human bone tissue will ensure the compatibility of the material based on the described substance with bone tissue during implantation. Modification of the initial apatite with sodium ions is necessary to improve the properties of osteogenesis of the material, fluorine - for the possibility of using in dentistry and imparting stability to the material in the chemically active environment of the human body, bismuth - to ensure antimicrobial activity.

The use of calcium and bismuth nitrates instead of oxides of the corresponding elements makes it possible to significantly speed up the process of obtaining the target product due to the formation of finely dispersed corresponding oxides with a high degree of defectiveness of the crystal structure directly in the reaction medium.

Below are examples of specific implementation of the invention.

Example 1

1.4605 g of calcium nitrate tetrahydrate, 1.0000 g of bismuth pentahydrate nitrate, 0.1752 g of sodium nitrate, 0.8167 g of diammonium hydrogen phosphate, and 0.0764 g of ammonium fluoride were placed in an alundum crucible of the “glass” shape with dimensions of 55 mm x 42 mm. The crucible was placed in a closed coil muffle furnace and heated to a temperature of 300–350°C at a rate of 3–5 K/min. Then the crucible was cooled to room temperature and the mixture was dispersed in an agate mortar using ethanol to create additional disjoining pressure. The resulting monodisperse powder was placed in a crucible and heated to 600-670°C at a rate of 5-7 deg/min with dispersion every hour for 10 minutes. Next, the mixture is calcined in an alundum crucible at a temperature of 950-1100°C for 7-9 hours.

Example 2

Obtaining bismuth apatite is carried out analogously to example 1, but instead of a crucible of the standard form, a boat-shaped crucible is used, which makes it possible to increase the contact area of the reaction mixture with the atmosphere for easier removal of gaseous reaction products. The obtained bismuth-apatites are characterized by the same degree of purity and surface morphology, which indicates the absence of influence of the shape and volume of the crucible for carrying out the reaction with the indicated amounts of substances.

Claims (3)

1. A method for producing biocompatible bismuth-apatites of composition Ca _10-2x Bi _x Na _x (PO ₄ ) ₆ F ₂ , where x=1, 2, 3, 4, including placing a stoichiometric mixture of four-water calcium nitrate, five-water bismuth nitrate in an alundum crucible , sodium nitrate, diammonium hydrogen phosphate and ammonium fluoride, after which the crucible is placed in a muffle furnace with a closed spiral and heated to a temperature of 300-350°C at a rate of 3-5 deg./min until the end of the dehydration of the initial crystalline hydrates and thermal decomposition of the reagents used, then the crucible is cooled to room temperature and the mixture is dispersed in an agate mortar using ethyl alcohol to create additional disjoining pressure, the resulting monodisperse powder is placed in a crucible and calcined to 600-670°C at a rate of 5-7 deg./min with dispersion every hour for 10 minutes, then the mixture is calcined in an alundum crucible at a temperature of 950-1100°C for 7-9 hours. 2. The method according to p. 1, characterized in that the stoichiometric mixture is homogenized by dispersion in an agate mortar for 10 minutes and calcination at temperatures of 300-350°C and 950-1100°C. 3. The method according to p. 1, characterized in that an alundum crucible of the “glass” shape or the “boat” shape is used.

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