A method for preparing hydroxyapatite microspheres

Abstract

The application discloses a preparation method of hydroxyapatite microspheres, which comprises the following steps: 1) mixing hydroxyapatite raw materials with water to prepare hydroxyapatite slurry; 2) feeding the hydroxyapatite slurry obtained in the step 1) into a high gravity reactor, and mixing and modifying in situ by adding a surfactant in the high gravity reactor; 3) spray drying the modified slurry to obtain hydroxyapatite microspheres; and 4) sintering the microspheres to obtain the hydroxyapatite microspheres. The hydroxyapatite microspheres prepared by the method have a density of 3.10-3.20 g / cm 3 , a compactness of greater than or equal to 95%, a crystallinity of greater than or equal to 95%, a particle size of 20-60 mu m, a degradation rate of less than 2% after being soaked in a simulated body fluid for 30 days, a single crystal phase, complete crystallization, stable structure, and difficulty in degradation, and the obtained microspheres have high sphericity, good dispersity, excellent compactness and crystallinity.

Description

Technical Field

[0001] This invention belongs to the field of inorganic biomedical materials technology, specifically relating to a method for preparing hydroxyapatite microspheres, and more particularly to a method for preparing high-density, high-crystallinity hydroxyapatite microspheres using a supergravity mixing modification coupled with spray drying process. Background Technology

[0002] Hydroxyapatite (Ca 10 (OH)2(PO4)6, also known as hydroxyapatite calcium, basic calcium phosphate, or calcium apatite, is the main inorganic component of human bone and teeth. It has excellent bioactivity, biocompatibility, and osteoconductive properties. Microsphere materials prepared from it have important application value in the fields of bone tissue engineering, drug sustained-release carriers, and biological filler materials.

[0003] Microsphere materials possess superior properties not found in other irregularly shaped materials, such as good flowability, high bulk density, light weight, high strength, resistance to agglomeration, good injection performance, and low stress concentration when filled into composite materials.

[0004] Therefore, considering the advantages of hydroxyapatite microspheres, they are a promising medical material.

[0005] Micron-sized medical-grade hydroxyapatite microspheres are commonly used as structural support materials, for example, in the preparation of injectable fillers. If the particle size of the hydroxyapatite microspheres is too small, they are prone to migrating from the injection site to other sites or being phagocytosed by immune cells in the body. If the particle size is too large, there will be difficulties in the degradation of the injected hydroxyapatite microspheres.

[0006] Currently, the main methods for synthesizing hydroxyapatite microspheres include direct synthesis and secondary granulation. Direct synthesis methods are further divided into two types: one uses calcium salts and phosphates as raw materials, directly controlling the synthesis of hydroxyapatite microspheres by adjusting reaction parameters. However, the resulting hydroxyapatite microspheres have a wide particle size distribution and irregular morphology; this method is mainly used for synthesizing nanospheres. The other type uses flexible organic molecules with high structural variability as templates (soft template method) and substances with rigid structures as templates (hard template method). These methods synthesize hydroxyapatite microspheres with the desired structure and morphology through ion exchange reactions, but require template removal, making the operation cumbersome. Secondary granulation methods include plasma melting and spray drying. Plasma melting requires high operating temperatures, making it unsuitable for materials prone to high-temperature decomposition. Spray drying can significantly improve the yield and particle size uniformity of hydroxyapatite microspheres, facilitating mass production.

[0007] However, the hydroxyapatite microspheres produced by existing spray granulation technology have low density, low compactness, and low crystallinity, and are easily degraded after being implanted into the human body, which cannot meet the actual needs.

[0008] For example, Chinese patent application CN112875665A discloses a technical solution entitled "Hydroxyapatite Microspheres for Injectable Filler Formulations and Their Preparation Method". The preparation method includes: Step 1: Preparing calcium and phosphorus sources into calcium source solutions and phosphorus source solutions respectively, mixing them, adding a supporting electrolyte, adjusting the pH of the resulting mixed solution to slightly acidic, and then performing electrochemical deposition to obtain needle-like submicron / nanoscale hydroxyapatite primary product; Step 2: Grinding and pulverizing the hydroxyapatite primary product, and then preparing it into a slurry; Step 3: Spray drying the slurry to obtain crude hydroxyapatite microspheres; Step 4: Calcining the crude hydroxyapatite microspheres at high temperature; Step 5: Sieving the calcined crude hydroxyapatite microspheres to obtain the hydroxyapatite microspheres. The preparation method of this invention significantly improves production efficiency. However, this technical solution still has the following drawbacks: 1) The sphericity of hydroxyapatite microspheres is poor, and irregular particles and fragments are prone to appear, which makes it difficult to meet the strict requirements of injectable formulations; 2) High-temperature calcination can easily cause sintering and adhesion between microspheres, resulting in a wider particle size distribution and a lower product yield after sieving; 3) The production cost is relatively high.

[0009] For example, Chinese patent application CN117185266A discloses a technical solution entitled "Hydroxyapatite Microspheres and Preparation Method Thereof". The preparation method includes the following steps: dispersing hydroxyapatite powder in water to obtain a hydroxyapatite suspension; spray-drying the hydroxyapatite suspension to obtain hydroxyapatite microsphere powder; sintering the hydroxyapatite microsphere powder to obtain hydroxyapatite microsphere powder with a porous structure; and ball-milling the hydroxyapatite microsphere powder with a porous structure to obtain hydroxyapatite microspheres. This invention obtains hydroxyapatite microspheres with uniform particle size distribution, controllable morphology, and good dispersibility through spray drying, sintering, and ball milling. Furthermore, the preparation method offers high yield, low cost, simple and stable process, and is easy to scale up and industrialize. However, this technical solution still has the following defects: 1) Hydroxyapatite microspheres have poor sphericity and wide particle size distribution, and are prone to cracking and collapse after sintering, resulting in insufficient structural stability; 2) Later ball milling easily destroys the complete morphology of microspheres, generating a large amount of debris, and reducing dispersibility and suspension stability; 3) The porous structure and wide particle distribution (especially particles smaller than 20 micrometers) have uncontrollable degradation rates in the in vitro environment, making it difficult to meet the long-term requirements of clinical injection filling.

[0010] In summary, the hydroxyapatite microspheres obtained by existing technical solutions still have defects such as poor sphericity, wide particle size distribution, non-uniform pore structure, uncontrollable morphology and degradation rate, poor dispersibility and suspension stability, and poor process reproducibility during large-scale production. Summary of the Invention

[0011] The first technical problem this invention aims to solve is to provide a method for preparing hydroxyapatite microspheres. This method achieves a density of 3.10-3.20 g / cm³ for the hydroxyapatite microspheres through in-situ synergistic modification using a hypergravity field and surfactants. 3 The density is ≥95%, the crystallinity is ≥95%, the particle size is 20-60μm, the degradation rate is <2% after soaking in simulated body fluid for 30 days, the crystal phase is single, the crystal is complete, the structure is stable and not easily degraded, and the resulting microspheres have high sphericity, good dispersibility, and excellent density and crystallinity.

[0012] To solve the first technical problem mentioned above, the present invention adopts the following technical solution: A method for preparing hydroxyapatite microspheres includes the following steps: 1) Hydroxyapatite raw material is mixed with water to prepare hydroxyapatite slurry; 2) The hydroxyapatite slurry obtained in step 1) is fed into a high-gravity reactor, and a surfactant is added in the high-gravity reactor for in-situ mixing and modification. 3) The modified slurry was spray-dried to obtain crude hydroxyapatite microspheres; 4) The crude microspheres are sintered to obtain hydroxyapatite microspheres.

[0013] Preferably, in step 1), the mass ratio of the hydroxyapatite raw material to water is (40-80):(100-300).

[0014] Preferably, in step 1), the Ca / P molar ratio in the hydroxyapatite raw material is 1.65-1.68:1.

[0015] Preferably, the Ca / P molar ratio in hydroxyapatite raw material is tested using ICP (inductively coupled plasma spectroscopy).

[0016] Preferably, in step 1), the average particle size of the hydroxyapatite raw material is 20-100 nm.

[0017] Preferably, in step 2), the mixing temperature is 20-40°C and the mixing time is 30-60 min.

[0018] Preferably, in step 2), the rotor speed of the hypergravity reactor is 500-3000 r / min.

[0019] Preferably, in step 2), the surfactant is one or more of polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), hexadecyltrimethylammonium bromide (CTAB), and triethanolamine (TEA); Preferably, in step 3), the inlet temperature of the spray dryer is 150-300℃ and the outlet temperature is 80-120℃.

[0020] Preferably, in step 3), the rotation speed of the atomizing disc in the spray drying is 10,000-20,000 r / min, and the slurry flow rate is 2-5 kg / h.

[0021] Preferably, in step 4), the sintering temperature is 600-1600℃ and the sintering time is 1-4h.

[0022] Preferably, in step 4), the sintering is carried out in a high-temperature kiln, wherein the high-temperature kiln includes any one of a muffle furnace, a tube furnace, a bell kiln, a tunnel kiln, and a roller kiln.

[0023] Preferably, in step 4), the density of the hydroxyapatite microspheres is 3.10-3.20 g / cm³. 3 It has a density of ≥95%, a crystallinity of ≥95%, a particle size of 20-60μm, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. It has a single crystal phase, complete crystallization, stable structure, and is not easily degraded.

[0024] Any range described in this invention includes the endpoint, any value between the endpoints, and any subrange consisting of the endpoint or any value between the endpoints.

[0025] Unless otherwise specified, all raw materials used in this invention can be obtained commercially, and the equipment used in this invention can be conventional equipment in the relevant field or refer to existing technology in the relevant field.

[0026] Compared with the prior art, the present invention has the following beneficial effects. : 1) This invention uses supergravity mixing modification as the core pretreatment process, which significantly enhances the slurry dispersion and mass transfer process, eliminates nanoparticle agglomeration, improves slurry uniformity and stability, and improves the microsphere molding quality from the source, so that the final microspheres have excellent density, compactness, crystallinity and anti-degradation properties.

[0027] 2) The present invention uses hydroxyapatite raw material and water in a specific mass ratio to prepare slurry, which can effectively control the solid content and viscosity of slurry, suppress excessive shrinkage and expansion and rupture of microspheres during spray drying, improve the sphericity and sphericity, and ensure the regularity of microsphere morphology.

[0028] 3) The present invention uses hydroxyapatite raw material with a Ca / P molar ratio of 1.65-1.68:1, which has high phase purity and good high temperature stability. Combined with a specific sintering process, it can promote full grain growth and structural densification, and further improve the crystallinity, density and structural stability of microspheres.

[0029] 4) This invention uses 20-100 nm nano-sized hydroxyapatite raw material, which has a large specific surface area and high sintering activity. Under the synergistic effect of hypergravity modification and high temperature sintering, the densification driving force is significantly improved, and the resulting microspheres have high density, complete crystallization, and significantly reduced degradation rate. Attached Figure Description

[0030] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings. Figure 1 This is a scanning electron microscope image of the hydroxyapatite microspheres obtained in Example 1 of this invention; Figure 2 This is a partial scanning electron microscope image of the hydroxyapatite microspheres obtained in Example 1 of this invention; Figure 3 These are scanning electron microscope images comparing the hydroxyapatite microspheres obtained in Example 5 of this invention with commercial powder; Figure 4 This is the X-ray diffraction pattern of the hydroxyapatite microspheres obtained in Example 1 of this invention; Figure 5 These are scanning electron microscope images of the hydroxyapatite microspheres obtained in Examples 2-4 of this invention; Figure 6 This is a scanning electron microscope image of the hydroxyapatite microspheres obtained in Comparative Example 1 of this invention. Figure 7 This is a particle size distribution diagram comparing the hydroxyapatite microspheres obtained in Comparative Example 1 with those in Example 1 of this invention; Figure 8 This is an X-ray diffraction pattern comparing the hydroxyapatite microspheres obtained in Comparative Example 2 with those in Example 1. Figure 9 This is a scanning electron microscope image of the hydroxyapatite microspheres obtained in Comparative Example 3 of this invention. Detailed Implementation

[0031] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments and accompanying drawings, further explains the invention. Similar components in the drawings are indicated by the same reference numerals. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.

[0032] For ease of description, the terms "first," "second," etc., used in this invention are for descriptive purposes only and should not be construed as indicating or implying their relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined with "first" or "second" may explicitly or implicitly include at least one of that feature. Furthermore, the technical solutions of various embodiments can be combined with each other, but this must be based on the ability of a person skilled in the art to implement them. If the combination of technical solutions is contradictory or impossible to implement, such a combination should be considered non-existent and not within the scope of protection claimed by this invention.

[0033] As one aspect of the present invention, a method for preparing hydroxyapatite microspheres includes the following steps: 1) Hydroxyapatite raw material is mixed with water to prepare hydroxyapatite slurry; 2) The hydroxyapatite slurry obtained in step 1) is fed into a high-gravity reactor, and a surfactant is added in the high-gravity reactor for in-situ mixing and modification. 3) The modified slurry was spray-dried to obtain crude hydroxyapatite microspheres; 4) The crude microspheres are sintered to obtain hydroxyapatite microspheres.

[0034] Preferably, in step 1), the mass ratio of the hydroxyapatite raw material to water is (40-80):(100-300).

[0035] In some embodiments of the present invention, in step 1), the Ca / P molar ratio in the hydroxyapatite raw material is 1.65-1.68:1.

[0036] In some embodiments of the present invention, ICP (inductively coupled plasma spectroscopy) is used to test the Ca / P molar ratio in hydroxyapatite raw materials.

[0037] In some embodiments of the present invention, in step 1), the average particle size of the hydroxyapatite raw material is 20-100 nm.

[0038] In some embodiments of the present invention, in step 2), the mixing temperature is 20-40°C and the mixing time is 30-60 min.

[0039] In some embodiments of the present invention, in step 2), the rotor speed of the hypergravity reactor is 500-3000 r / min.

[0040] In some embodiments of the present invention, in step 2), the surfactant is one or more of polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), hexadecyltrimethylammonium bromide (CTAB), and triethanolamine (TEA). In principle, the function and purpose of adding the surfactant in the present invention is to improve the dispersibility of hydroxyapatite powder, inhibit particle agglomeration, optimize the rheological properties of the slurry, and ensure the purity and biosafety of the material by decomposing it at high temperatures without residue.

[0041] In some embodiments of the present invention, in step 3), the inlet temperature of the spray dryer is 150-300°C and the outlet temperature is 80-120°C.

[0042] In some embodiments of the present invention, in step 3), the rotation speed of the atomizing disc in the spray drying is 10,000-20,000 r / min, and the slurry flow rate is 2-5 kg / h.

[0043] In some embodiments of the present invention, in step 4), the sintering temperature is 600-1600°C and the sintering time is 1-4 hours.

[0044] In some embodiments of the present invention, in step 4), the sintering is carried out in a high-temperature kiln, wherein the high-temperature kiln includes any one of a muffle furnace, a tube furnace, a bell kiln, a tunnel kiln, and a roller kiln.

[0045] In some embodiments of the present invention, in step 4), the density of the hydroxyapatite microspheres is 3.10-3.20 g / cm³. 3 It has a density of ≥95%, a crystallinity of ≥95%, a particle size of 20-60μm, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. It has a single crystal phase, complete crystallization, stable structure, and is not easily degraded. Example 1

[0046] A method for preparing hydroxyapatite microspheres, the specific steps of which are as follows: 1) Slurry preparation: Hydroxyapatite raw material with an average particle size of 20 nm and a Ca / P molar ratio of 1.67:1 was mixed with water at a mass ratio of 45:200 and stirred at 25°C for 30 min to obtain a uniform slurry; 2) Hypergravity mixing modification: The slurry is placed in a hypergravity reactor, and polyvinylpyrrolidone (PVP) is added at a rate of 0.5 wt% of the hydroxyapatite raw material. The modification is carried out at a rotor speed of 1000 r / min. 3) Preparation of hydroxyapatite microspheres: The slurry after being mixed and modified by gravity was spray-dried, wherein the atomizing disc rotation speed was 10,000 rpm, the slurry flow rate was 5 kg / h, the inlet temperature of the drying tower was 180℃, and the outlet temperature was 100℃, to obtain crude hydroxyapatite microspheres. 4) Sintering: The dried hydroxyapatite microspheres are placed in a corundum crucible and sintered at a temperature of 1200℃ for 2 hours to obtain hydroxyapatite microspheres.

[0047] Figure 1 The image shows a scanning electron microscope image of the hydroxyapatite microspheres obtained in Example 1 of this invention. Figure 2 This is a partial scanning electron microscope image of the hydroxyapatite microspheres obtained in Example 1 of this invention; from Figure 1 It can be seen that the XRD diffraction peaks of the hydroxyapatite microspheres are in the same position as the standard hydroxyapatite spectrum (PDF#09-0432), and the diffraction peaks are sharp and narrow, indicating a high degree of crystallinity; from Figure 2 It can be seen that the surface of the hydroxyapatite microspheres is smooth and opaque, indicating that the spheres are highly compact.

[0048] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.18 g / cm³. 3 It has a density of 98%, a crystallinity of 99%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 25-45μm. Example 2

[0049] A method for preparing hydroxyapatite microspheres, the specific steps of which are as follows: 1) Slurry preparation: Hydroxyapatite raw material with an average particle size of 50 nm and a Ca / P molar ratio of 1.65:1 was mixed with water at a mass ratio of 40:100 and stirred at 20℃ for 40 min to obtain a uniform slurry; 2) Hypergravity mixing modification: The slurry is placed in a hypergravity reactor, and polyvinylpyrrolidone (PVP) is added at a rate of 1.0 wt% of the hydroxyapatite raw material. The modification is carried out at a rotor speed of 800 r / min. 3) Preparation of hydroxyapatite microspheres: The slurry after being modified by supergravity mixing was spray-dried, with the atomizing disc rotating at 12,000 rpm, the slurry flow rate at 4 kg / h, the inlet temperature of the drying tower at 170℃, and the outlet temperature at 90℃, to obtain crude hydroxyapatite microspheres. 4) Sintering: The dried crude hydroxyapatite microspheres are placed in a corundum crucible and sintered at a temperature of 1200℃ for 1 hour to obtain hydroxyapatite microspheres.

[0050] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.10 g / cm³. 3 It has a density of 96%, a crystallinity of 96%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 20-50 μm. Example 3

[0051] A method for preparing hydroxyapatite microspheres, the specific steps of which are as follows: 1) Slurry preparation: Hydroxyapatite raw material with an average particle size of 100 nm and a Ca / P molar ratio of 1.67:1 was mixed with water at a mass ratio of 80:300 and stirred at 25°C for 60 min to obtain a uniform slurry; 2) Hypergravity mixing modification: The slurry was placed in a hypergravity reactor, and sodium dodecyl sulfate (SDS) was added at a rate of 0.8 wt% of the hydroxyapatite raw material. The modification was carried out at a rotor speed of 3000 r / min. 3) Preparation of hydroxyapatite microspheres: The slurry after being mixed and modified by gravity was spray-dried, with the atomizing disc rotating at 20,000 rpm, the slurry flow rate at 2 kg / h, the inlet temperature of the drying tower at 300℃, and the outlet temperature at 120℃, to obtain crude hydroxyapatite microspheres. 4) Sintering: The dried crude hydroxyapatite microspheres are placed in a corundum crucible and sintered at a temperature of 1600℃ for 1 hour to obtain hydroxyapatite microspheres.

[0052] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.14 g / cm³. 3 It has a density of 96%, a crystallinity of 97%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 20-60 μm. Example 4

[0053] A method for preparing hydroxyapatite microspheres, the specific steps of which are as follows: 1) Slurry preparation: Hydroxyapatite raw material with an average particle size of 30 nm and a Ca / P molar ratio of 1.67:1 was mixed with water at a mass ratio of 50:150 and stirred at 30℃ for 30 min to obtain a uniform slurry; 2) Hypergravity mixing modification: The slurry was placed in a hypergravity reactor and hexadecyltrimethylammonium bromide (CTAB) was added at an amount of 1.0 wt% of the hydroxyapatite raw material. The modification was carried out at a rotor speed of 1500 r / min. 3) Preparation of hydroxyapatite microspheres: The slurry after being mixed and modified by gravity was spray-dried, with the atomizing disc rotating at 14,000 rpm, the slurry flow rate at 3 kg / h, the inlet temperature of the drying tower at 200℃, and the outlet temperature at 105℃, to obtain crude hydroxyapatite microspheres. 4) Sintering: The dried crude hydroxyapatite microspheres are placed in a corundum crucible and sintered at a temperature of 800℃ for 3 hours to obtain hydroxyapatite microspheres.

[0054] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.13 g / cm³. 3 It has a density of 95%, a crystallinity of 96%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 30-50 μm. Example 5

[0055] This embodiment provides a method for preparing hydroxyapatite microspheres, the specific steps of which are as follows: 1) Slurry preparation: Hydroxyapatite raw material with an average particle size of 40 nm and a Ca / P molar ratio of 1.66:1 was mixed with water at a mass ratio of 60:200 and stirred at 25°C for 45 min to obtain a uniform slurry; 2) Hypergravity mixing modification: The slurry was placed in a hypergravity reactor, and triethanolamine (TEA) was added at a rate of 1.5 wt% of the hydroxyapatite raw material mass. The modification was carried out at a rotor speed of 2000 r / min. 3) Preparation of hydroxyapatite microspheres: The slurry after being modified by supergravity mixing was spray-dried, with the atomizing disc rotating at 15,000 rpm, the slurry flow rate at 4 kg / h, the inlet temperature of the drying tower at 220℃, and the outlet temperature at 110℃, to obtain crude hydroxyapatite microspheres. 4) Sintering: The dried crude hydroxyapatite microspheres are placed in a corundum crucible and sintered at a temperature of 900℃ for 2 hours to obtain hydroxyapatite microspheres.

[0056] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.15 g / cm³. 3 It has a density of 97%, a crystallinity of 95%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 20-50 μm. Example 6

[0057] Example 4 was repeated, except that the average particle size of the hydroxyapatite raw material was 60 nm.

[0058] Testing showed that the performance of the hydroxyapatite microspheres obtained in this embodiment was similar to that in Example 4. Example 7

[0059] Example 1 was repeated, except that the Ca / P molar ratio in the hydroxyapatite raw material was 1.65:1.

[0060] Testing showed that the performance of the hydroxyapatite microspheres obtained in this embodiment was similar to that in Example 1. Example 8

[0061] Example 1 was repeated, except that the sintering temperature was 900°C.

[0062] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.16 g / cm³. 3 It has a density of 97%, a crystallinity of 95%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 20-50 μm. Example 9

[0063] Example 2 was repeated, except that the mass ratio of hydroxyapatite raw material to water was 50:200.

[0064] Testing showed that the performance of the hydroxyapatite microspheres obtained in this embodiment was similar to that in Example 2. Example 10

[0065] Example 3 was repeated, except that the mass ratio of hydroxyapatite raw material to water was 60:300.

[0066] Testing showed that the performance of the hydroxyapatite microspheres obtained in this example was similar to that in Example 3. Example 11

[0067] A method for preparing hydroxyapatite microspheres, the specific steps of which are as follows: 1) Slurry preparation: Hydroxyapatite raw material with an average particle size of 35 nm and a Ca / P molar ratio of 1.68:1 was mixed with water at a mass ratio of 50:160 and stirred at 30℃ for 50 min to obtain a uniform slurry; 2) Hypergravity mixing modification: The slurry is placed in a hypergravity reactor, and polyvinylpyrrolidone (PVP) is added at an amount of 1.5 wt% of the hydroxyapatite raw material. The rotor speed is 1400 r / min for modification treatment. 3) Preparation of hydroxyapatite microspheres: The slurry after being modified by supergravity mixing was spray-dried, with the atomizing disc rotating at 19,000 rpm, the slurry flow rate at 5 kg / h, the inlet temperature of the drying tower at 210℃, and the outlet temperature at 98℃, to obtain crude hydroxyapatite microspheres. 4) Sintering: The dried crude hydroxyapatite microspheres are placed in a corundum crucible and sintered at a temperature of 1500℃ for 1 hour to obtain hydroxyapatite microspheres.

[0068] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.12 g / cm³. 3 It has a density of 98%, a crystallinity of 96%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 25-60μm. Example 12

[0069] A method for preparing hydroxyapatite microspheres, the specific steps of which are as follows: 1) Slurry preparation: Hydroxyapatite raw material with an average particle size of 45 nm and a Ca / P molar ratio of 1.67:1 was mixed with water at a mass ratio of 60:220 and stirred at 30℃ for 40 min to obtain a uniform slurry; 2) Hypergravity mixing modification: The slurry was placed in a hypergravity reactor, and triethanolamine (TEA) was added at a rate of 0.5 wt% of the hydroxyapatite raw material mass. The modification was carried out at a rotor speed of 1600 r / min. 3) Preparation of hydroxyapatite microspheres: The slurry after being mixed and modified by gravity was spray-dried, with the atomizing disc rotating at 15,000 rpm, the slurry flow rate at 3 kg / h, the inlet temperature of the drying tower at 230℃, and the outlet temperature at 100℃, to obtain crude hydroxyapatite microspheres. 4) Sintering: The dried crude hydroxyapatite microspheres are placed in a corundum crucible and sintered at a temperature of 1100℃ for 2 hours to obtain hydroxyapatite microspheres.

[0070] The density of the hydroxyapatite microspheres obtained in this embodiment was measured to be 3.13 g / cm³. 3 It has a density of 95%, a crystallinity of 97%, and a degradation rate of <2% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 30-60μm. Comparative Example 1

[0071] Repeat Example 1, except that: no supergravity reactor mixing modification is performed, only a conventional stirred reactor is used for mixing modification.

[0072] Testing revealed that the powder produced in this comparative example exhibited severe agglomeration, with large particle sizes and a wide particle size distribution of 10-100 μm. This demonstrates that the supergravity reactor has significant advantages over the conventional stirred reactor.

[0073] Figure 6 The scanning electron microscope images and particle size distribution diagrams of the powder product of Comparative Example 1 are shown to compare it with those of Example 1. Comparative Example 2

[0074] Repeat Example 1, except that step 4) sintering step is omitted.

[0075] Testing revealed that the crystallinity of the crude powder obtained in this comparative example was 56%. This demonstrates that sintering is a crucial technical step in obtaining the hydroxyapatite microspheres required by this invention.

[0076] Figure 7 The XRD pattern shows the product powder of Comparative Example 1 compared with that of Example 1. Comparative Example 3

[0077] Repeat Example 1, except that the spray drying in step 3 is replaced with conventional oven drying.

[0078] Testing revealed that, because this comparative example did not utilize spray drying, most of the product powder was broken and did not exhibit a spherical shape. Therefore, the spray drying technique used in the preparation method of this invention can suppress excessive shrinkage and expansion / breakage of the hydroxyapatite microspheres during the spray drying process, improving the sphericity and uniformity of the microspheres and ensuring their regular morphology.

[0079] Figure 8 This is a scanning electron microscope image of the product powder obtained in Comparative Example 3. Comparative Example 4

[0080] Repeat Example 1, except that in step 1), the hydroxyapatite raw material is mixed with water at a mass ratio of 25:100.

[0081] The density of the hydroxyapatite microspheres obtained in this comparative example was measured to be 3.08 g / cm³. 3 It has a density of 90%, a crystallinity of 95%, and a degradation rate of <10% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 10-80 μm.

[0082] Therefore, it is evident that because the ratio of hydroxyapatite raw material to water in this comparative example is outside the scope of protection of this application, the product spheres partially break and do not exhibit a spherical shape. Thus, the ratio of hydroxyapatite raw material to water has a significant impact on the sphericity of the microspheres. Comparative Example 5

[0083] Repeat Example 1, except that in step 1), the Ca / P molar ratio of the hydroxyapatite raw material is 1.5:1.

[0084] The density of the hydroxyapatite microspheres obtained in this comparative example was measured to be 3.11 g / cm³. 3 It has a density of 80%, a crystallinity of 80%, and a degradation rate of <10% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 10-90 μm.

[0085] It is evident that the Ca / P molar ratio of hydroxyapatite raw materials has a significant impact on the density and crystallinity of the product. Comparative Example 6

[0086] Repeat Example 1, except that in step 2), no surfactant polyvinylpyrrolidone is added for modification.

[0087] The density of the hydroxyapatite microspheres obtained in this comparative example was measured to be 3.12 g / cm³. 3 It has a density of 85%, a crystallinity of 80%, and a degradation rate of <10% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 20-80 μm.

[0088] This shows that the presence of surfactants has a crucial impact on the density and crystallinity of products. Comparative Example 7

[0089] Repeat Example 1, except that the step of adding the surfactant polyvinylpyrrolidone for modification and the step of spray drying are interchanged (that is, the surfactant is added for modification after the crude hydroxyapatite microspheres are formed).

[0090] The density of the hydroxyapatite microspheres obtained in this comparative example was measured to be 3.12 g / cm³. 3 It has a density of 85%, a crystallinity of 80%, and a degradation rate of <10% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 20-90 μm.

[0091] Therefore, it is evident that the timing and steps of surfactant addition have a crucial impact on the density and crystallinity of the product. Comparative Example 8

[0092] Repeat Example 1, except that in step 1, the average particle size of the hydroxyapatite raw material used is 300 nm.

[0093] The density of the hydroxyapatite microspheres obtained in this comparative example was measured to be 3.12 g / cm³. 3 It has a density of 80%, a crystallinity of 85%, and a degradation rate of <10% after immersion in simulated body fluid for 30 days. The particle size of the hydroxyapatite microspheres is 10-70 μm.

[0094] It is evident that the average particle size and morphology of the raw hydroxyapatite meal have a significant impact on the density and crystallinity of the product.

[0095] In summary, the technical features of the preparation steps of this invention, such as the average particle size of the raw hydroxyapatite, the Ca / P molar ratio of the raw hydroxyapatite, the ratio of the raw hydroxyapatite to water, the use of a hypergravity reactor, the mixing and modification steps of the hypergravity reactor and surfactant, the spray drying step, and the sintering step, influence each other and coordinate with each other to form a unified overall technical solution. Exceeding any of these factors may lead to the failure of product preparation in this application.

[0096] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is impossible to exhaustively list all embodiments here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A method for preparing hydroxyapatite microspheres, characterized in that, Includes the following steps: 1) Hydroxyapatite raw material is mixed with water to prepare hydroxyapatite slurry; 2) The hydroxyapatite slurry obtained in step 1) is fed into a high-gravity reactor, and a surfactant is added in the high-gravity reactor for in-situ mixing and modification. 3) The modified slurry was spray-dried to obtain crude hydroxyapatite microspheres; 4) The crude microspheres are sintered to obtain hydroxyapatite microspheres.

2. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 1), the mass ratio of the hydroxyapatite raw material to water is (40-80):(100-300).

3. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 1), the Ca / P molar ratio in the hydroxyapatite raw material is 1.65-1.68:

1.

4. The method for preparing hydroxyapatite microspheres according to claim 3, characterized in that: The Ca / P molar ratio in hydroxyapatite raw materials was tested using ICP.

5. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 1), the average particle size of the hydroxyapatite raw material is 20-100 nm.

6. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 2), the mixing temperature is 20-40℃ and the mixing time is 30-60min.

7. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 2), the rotor speed of the hypergravity reactor is 500-3000 r / min.

8. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 2), the surfactant is one or more of polyvinylpyrrolidone, sodium dodecyl sulfate, hexadecyltrimethylammonium bromide, and triethanolamine.

9. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 3), the inlet temperature of the spray dryer is 150-300℃, and the outlet temperature is 80-120℃. Preferably, in step 3), the rotation speed of the atomizing disc in the spray drying is 10,000-20,000 r / min, and the slurry flow rate is 2-5 kg / h.

10. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step 4), the sintering temperature is 600-1600℃, and the sintering time is 1-4h; Preferably, in step 4), the sintering is carried out in a high-temperature kiln, wherein the high-temperature kiln includes any one of a muffle furnace, a tube furnace, a bell kiln, a tunnel kiln, and a roller kiln; Preferably, in step 4), the density of the hydroxyapatite microspheres is 3.10-3.20 g / cm³. 3 It has a density of ≥95%, a crystallinity of ≥95%, a particle size of 20-60μm, and a degradation rate of <2% after immersion in simulated body fluid for 30 days.

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