Method

Abstract

A method of forming calcium hydroxyapatite particles may comprise powder-melt processing of calcium hydroxyapatite powder in the presence of an oxy-hydrogen fuel. The particles may have a particle siz

Description

The invention relates to methods of forming calcium hydroxyapatite particles, methods of forming coatings and products. In particular, the invention relates to methods of forming calcium hydroxyapatite particles using powder-melt processing. Calcium hydroxyapatite is a synthetic analogue of natural bone mineral, and has a very similar lattice to natural bone mineral. It has low solubility in vivo and is highly biocompatible making it an excellent material for orthopaedic implants, for instance, it is commonly used as a coating on metal implants and can achieve rapid bone integration within the patient. Calcium hydroxyapatite is also used in particulate form in cosmetic applications, such as in dermal fillers; and in dental applications. However, current methods for the manufacture of calcium hydroxyapatite particles and coatings can be improved. For instance, it is common for calcium phosphate impurities to be introduced by poor process control, resulting from the degradation of the calcium hydroxyapatite lattice to orthorhombic or rhombohedral calcium phosphate lattices, which are sufficiently different to bone mineral that they are attacked by the osteoclasts in the body and removed. This process can weaken the coating adhesion and / or reduce the lifespan of the coating per se on the implant, requiring implant replacement; a process which almost always requires surgical intervention. Further, the degradation of the lattice results in decreased crystallinity, which increases hydroxyapatite solubility as dissolution is more thermodynamically favourable for non-crystalline forms. In addition, known systems for the manufacture of calcium hydroxyapatite coatings (as derived from feed powders) such as air, electric or vacuum plasma techniques, reduce the hexagonal crystallinity of the hydroxyapatite coating relative to the hexagonal crystallinity of a feed hydroxyapatite powder. This is because plasma techniques often partially 'dehydrate' the calcium hydroxyapatite lattice by removing hydroxyl groups from the lattice through a reaction of calcium hydroxyapatite to produce calcium phosphate, water and calcium oxide as shown below: Caio(P04)e(OH)2 3Ca3(PO4)2 + CaO + H2O The tri-calcium orthophosphate forms monoclinic a or hexagonal o' (metastable at >1450°C) lattices, resulting in particles that are more soluble than those with a high phase purity, resulting in a potential reduction of coating adhesion and / or resulting in a reduction in coating lifespan as described above. Further, the high solubility of the calcium oxide results in the formation of an unstable solid solution with the calcium phosphates, in which the calcium oxide is disassociated. This results in a local and general increase in the pH of the solid in solution relative to the pH of the hexagonal crystal structure of the calcium hydroxyapatite. This promotes solubility of the calcium oxide in vivo, causing dispersion through the body and potential cell damage as localised increases in pH result in increased inflammation, and more generally lead to coating degradation as a result of the increased porosity and reduced phase stability. CN109338268B describes a method of forming a hydroxyapatite coating with reduced phase decomposition. The method uses a supersonic oxygen / propane flame as a heat source for thermal spraying, and reduces the temperature of the flame through careful control of flow rates. As a result, phase decomposition is reduced, and a coating with good adhesion and biological performance is provided. The invention is intended to overcome or ameliorate at least some aspects of the above problems. Accordingly, in a first aspect of the invention there is provided a method of forming calcium hydroxyapatite particles comprising powder-melt processing of calcium hydroxyapatite powder in the presence of an oxy-hydrogen fuel. It has been found that through the use of powder-melt processing the particles produced have excellent surface smoothness and roundness. This allows particles as large as 40 pm to be injected through syringe needles where necessary, for instance when used as dermal fillers. The presence of oxy-hydrogen fuel which (unlike plasma systems) combusts to produce water, has been found to minimise or entirely prevent the dehydration of the lattice. As described above, this provides for high crystalline phase purity, leading to dense, phase pure particles, with low resorption rates. Additionally, the use of oxy-hydrogen fuel, as opposed to other oxy-fuels, retains the particle smoothness, and crystallinity described, as the flame temperature offers a good balance with the heat needed to melt the powder and thermal degradation. Oxy-hydrogen fuels provide a high quality coating and sphericity, without degrading the lattice structure; a convenient flame size; and a flame temperature profile suitable for powder entrainment and melting. It has been found that with other oxy-fuel systems, the combustion temperature is either too hot (e.g. oxyacetylene) or too cool (oxy-propane) and the combined features of crystallinity and adhesion are lost. Further, as degradation by the plasma commonly used to form the coatings is minimised, calcium oxide formation is low reducing the potential for damage to cells in vivo. As used herein the terms "calcium hydroxyapatite" and "hydroxyapatite" are intended to be interchangeable, as relating to calcium hydroxyapatite, of general formula Caio(P04)6(OH)2. As used herein the term "crystalline phase purity" is intended to refer to the ratio of the hexagonal lattice to the other lattice forms present in the hydroxyapatite, for instance, from degradation of the hydroxyapatite to tricalcium phosphate which forms orthorhombic (monoclinic a or hexagonal a') or rhombohedral lattices. ISO 13779:3 (2018) is commonly used, this ISO considering the relative intensity of 10 characteristic X-ray peaks from the hydroxyapatite sample compared to the same sample after calcination at 1000°C for 15 hours. It is generally observed that the hydroxyapatite lattice is P63 / M a=b=9.432 A, c = 6.881 A and y=120°, although these parameters may be slightly distorted by interstitial elements, phase purity quantification is possible against the reference hydroxyapatite sample. It is desirable that the hydroxyapatite particles have a high hexagonal crystallinity ratio, for instance in the range 70% - 100%, often 70% or 80% - 90%. At these levels of crystallinity there is either no or minimal loss of the hexagonal phase during processing of the hydroxyapatite powder into the particles. It may be the case that the phase degradation comprises 20% or 10% of the original powder (retains 80% - 90% of the crystallinity ratio of the original powder), such that the hexagonal crystallinity ratio can be in the range 70% - 90%, such levels are markedly higher than those obtainable using known techniques which are deemed to provide for an acceptable crystallinity ratio. For instance, in known processes up to 55% loss of crystallinity is deemed to be acceptable (ISO 13779:2 (2018)). Maintaining such high levels of the hexagonal phase (crystalline phase purity) minimises the presence of other calcium phosphate lattice phases, or solid solutions of calcium phosphate with calcium oxide as described above. This provides for highly phase pure, crystalline, coatings with low solubility, offering excellent coating lifespans. Further, by minimising the presence of calcium oxide, the cell damage caused by dissolved calcium oxide in vivo is avoided. As such, it may be the case that the hydroxyapatite particles comprise less than 5 wt% non-hydroxyapatite phosphate salts, often in the range 0 wt% - 5 wt%, 1 wt% - 4 wt%, or in the range 2 wt% - 3 wt%. The non-hydroxyapatite phosphate salts may comprise, for instance: tricalcium phosphates, such as a-tricalcium orthophosphate and p-tricalcium phosphate; tetracalcium phosphate pyrophosphate, anhydrous oxyapatite, ACP (X-ray amorphous calcium phosphate), non-hydroxyapatite calcium phosphates with a Ca:P ratio in the range 0.5-2.2 or combinations thereof. As noted above, calcium oxide may also be present, often as a solid solution with the nonhydroxyapatite phosphate salts, such that it may be that the hydroxyapatite particles comprise less than 5 wt% non-hydroxyapatite phosphate salts, optionally combined with calcium oxide, often in the combined range 0 wt% - 5 wt%, 1 wt% - 4 wt%, or in the range 2 wt% - 3 wt%. The combustion of an oxy-hydrogen fuel mix produces water, providing for moisture in a reactive zone of the flame where the powder-melts. More specifically, without being bound by theory, the powder is believed to be surrounded by water molecules in the gaseous environment of the hot flame which makes the breakdown reaction from hydroxyapatite to phosphates and calcium oxide less energetically favourable. Therefore, it is generally the case that a combustion product of the oxy-hydrogen fuel is water. It is often the case that the water comprises or consists of water vapour and / or steam, the water vapour and / or steam being the products of combustion. The hydroxyapatite being in the presence of these (such that the water vapour and / or steam could be termed calcium hydroxyapatite water vapour or calcium hydroxyapatite steam), and often also atmospheric oxygen, nitrogen, argon, or a combination of these; additionally often unreacted oxygen from the oxy-hydrogen fuel. The presence of the water prevents dehydration of the lattice, as described above. As used herein the term "powder-melt" is intended to be given as its normal meaning in the art, namely, to refer to processes where powders are passed into a heat source, such as a stream of hot gas, a flame, plasma, or a laser such that they melt. The molten material then forms spherical droplets which cool into spherical particles which solidify as they pass away from the heat source. As noted above, hydroxyapatite particles are generally melted using air plasma (e.g. using argon gas), electric plasma or vacuum plasma methods. Such methods generally result in coatings with a crystallinity ratio of 60% or less (XRD analysis, ISO 13779:3). This is at least in part because of hexagonal lattice degradation resulting from dehydration of the lattice. The 'foreign' phase formed (monoclinic or rhombohedral) is influenced by the temperature of the plasma, for instance monoclinic a-tricalcium phosphate or hexagonal a' is favoured at high temperatures (>1450°C) and rhombohedral p-tricalcium phosphate is favoured at lower temperatures (<1450°C). However, an additional factor is the formation of amorphous phases (i.e. loss of crystallinity), such that the foreign phases may be visible but poorly crystalline. This may lead to a poor quality coating, despite being phase pure with hexagonally crystalline hydroxyapatite. The presence of amorphous phases can contribute to increased solubility and poorer performance in vivo. In addition to plasma technologies, flame spraying, high and low velocity oxy-fuel techniques are also known for the spray formation of hydroxyapatite particles, and their application to form coatings. It may be that the powder-melt process of the invention comprises flame spheroidization. Flame spheroidization is a process which uses high temperatures to melt a powder which on cooling in the gas stream prior to collection in a collection vessel densifies and forms a sphere due to surface tension effects. Alternatively, the spheres can form transiently "in flight" when flame spheroidization is used as part of a coating process, with the spheres being deposited directly onto a substrate, rather than being collected in a collection vessel. Where the spheres are formed transiently, they will generally impact the substrate at sufficient velocity to form "splats" which cool on the substrate and form the coating. However, when applied to hydroxyapatite, flame spheroidization can sometimes excessively heat the hydroxyapatite, damaging the crystal structure and so reducing the hexagonal crystallinity, and dehydrating the lattice. This results in a spherical particle of densified material formed with low crystallinity and a mixture of calcium phosphate phases, amorphous phases and hydroxyapatite throughout the particle. Such particles may not always be of sufficiently high quality to be used as dermal fillers. However, stable particles can be more reliably produced when the flame spheroidization comprises an oxy-hydrogen flame. It has been found that this fuel mixture can reduce or prevent degradation of the lattice structure and maintain crystallinity ratios in the range 70 -90% of the original powder, which in turn provides for a well densified free flowing powder with lower solubility in vivo. To help achieve these benefits, it will often be the case that a molar ratio of oxygen:hydrogen in the oxy-hydrogen fuel is in the range 2:1 -1:1, often around 1:1. It can be of use if the flame is subsonic, although supersonic flame speeds may be used. Using subsonic flame speeds, where the particles will form a coating, provides time for the coating to cool and solidify without being "blown off" the surface by the gases. Flame speed can also influence particle size, for instance, where the particles are being formed for storage and later use, slower flame speeds, such as subsonic flame speeds, provide for larger particle sizes than those formed in supersonic flames, as the shearing forces on the molten material are lower. It will often be the case that the hydroxyapatite powder is sintered. Sintering may be as an additional step (sintering the calcium hydroxyapatite powder) prior to powder-melt processing, or it may be an integral result of the powder-melt processing, with sintering occurring during melting of the powder, and so during powder-melt processing. It will often be the case that sintering, whether as a step prior to powder-melt processing, or as part of the powder-melt processing, will occur at a temperature in the range 1000°C - 1325°C, often 1100°C - 1200°C. If the temperature is too low, sintering is not achieved, however, at temperatures above 1325°C degradation of the hexagonal lattice is promoted, as the monoclinic and rhombohedral lattices of the high temperature calcium phosphate polymorphs are thermodynamically favourable. As such, sintering at temperatures above 1325°C reduces the crystallinity ratio further relative to the feed powder than when processed at a temperature below 1325°C. Often the hydroxyapatite particles are of particle size range 1 pm to 100 pm, to provide for particles, and potentially coatings made from those particles, which are biocompatible. Within this range, the particles are large enough that they are not absorbed by the cells, something commonly observed with nanoscale particles, but small enough that they retain good processing properties, such as flowability and coating adhesion. Further, the use of particles in this size range provides for particles which can easily be manipulated using spray techniques. For some applications, such as where the particles are intended for use as dermal fillers, the particle size range may be 25 pm -45 pm, often 30 pm - 40 pm (mean diameter). It will often be the case that the particles have high sphericity, and so have a narrow particle size distribution, they can be sieved to provide for a yet narrower particle size distribution if appropriate. In many instances the particle size distribution of the particles intended for use in dermal fillers is such that generally 100% of the hydroxyapatite particles will be of mean particle diameter less than 45 pm, often 80 - 100% of the particles will be of mean particle diameter less than 40 pm. For coating applications, the particle size distribution for powders used for coating are commonly dv(50) in the range 25 - 75 pm, often 30 - 60 pm. It may be the case that the hydroxyapatite particles have a unimodal, bimodal, or multimodal particle size distribution. When intended for use in applications where packing is important, they will often have a bimodal particle size distribution. For applications where particle flow properties are important, for instance as dermal fillers where particles may need to be injected and so flow properties within the syringe must be considered, the particle size distribution will generally be monomodal. The bulk density of the hydroxyapatite particles (prior to incorporation into a further product) will often be in the range 1-2 g / cm3, or 1.25 - 1.75 g / cm3. The true density of each particle may be in the range 2.75 - 3.25 g / cm3, often around 2.9 - 3.1 g / cm3. Bulk densities in this range provide for individual particles of excellent density, which in turn offers a non-friable material with high flowability and mechanical resilience. This is ideal for space filling and neocollagenesis in dermal filler applications. When the particles have these densities, such that the powders are close to being fully dense, the specific surface area will often be in the range 0.05 - 0.1 m2 / g, often in the range 0.06 -0.08 m2 / g. There is provided, in a second aspect of the invention a method of forming a calcium hydroxyapatite coating, the method comprising powder-melt processing of calcium hydroxyapatite powder in the presence of an oxy-hydrogen flame and depositing the particles directly onto a substrate. As used herein, direct deposition is intended to mean application at the point of particle formation, as contrasted with storage and later application. Direct deposition generally results in the particles impacting the substrate at a sufficient velocity to form "splats" which cool on the substrate and form the coating. It has been found that when the particles are applied using this method, the coating formed has excellent adhesion, high density and high crystalline phase purity. It will often be the case that the deposition of the particles onto the substrate will be by spray coating. Spray coating allows for precise manipulation and deposition of particulate material onto surfaces. The spray coating may be cold or thermal spray coating, but will often be thermal spray coating, as heating of the particles just prior to application to the surface, whether to soften or sinter these, improves the adhesion of the particles to the surface and to one another. This allows for the formation of a dense, well adhered coating. It may be the case that the thermal spray coating comprises flame coating, or warm spray coating. It can be advantageous if the spray coating occurs at a distance from the substrate in the range 50 - 250 mm Application of the coating from this distance, for instance from a spray gun / nozzle positioned in this distance range from a surface of the substrate to be coated, provides for an excellent crystallinity ratio, and good adhesion of the coating to the substrate. For instance, ensuring that the distance is not too large, provides for minimal crystallinity loss during application, for instance less than 20%, or even less than 10%. However, ensuring that the distance is not too small, ensures that where the particles are formed directly before application to the substrate, they are sufficiently solidified before application to the coating and that crystallinity is maintained. Where the particles are formed using melt-processing and direct application to the substrate, they will often be applied using spray techniques, at distances similar to those above. It will generally be the case that a thickness of the coating will be in the range 20 |jm -250 gm, in some cases 20 pm - 100 pirn, with thickness dependant on the end use application. For instance, 25 pm - 35 pm can be sufficient for some applications, providing a dense, well adhered coating. However, for other applications, for instance where the appearance of the product is important (e.g., dental implants, or other medical implants) a thicker coating of hydroxyapatite in the range 80 pm to 100 pm may be used, as increased thickness provides increased opacity and the coating transforms from a grey colour with thinner coatings to a brilliant white. Often the calcium hydroxyapatite coating has a porosity in the range 0.1 - 2%, often roughly 1%. Porosities in this range are an indication of excellent particle density and packing within the coating. The substrate may be selected from a wide range of materials including metals, metal alloys, non-metal composites and combinations thereof. For instance, the substrate may be selected from stainless steel, titanium, titanium alloy, cobalt chrome alloy, and combinations thereof. Often the substrate will have a surface roughness of at least 5 pm RA, to assist with the mechanical bonding of the coating with the substrate, thereby enhancing adhesion. Although some substrates will have natural surface roughness, it will generally be the case that the substrate will be processed to induce the surface roughness. For instance, grit-blasting is often used to prepare the substrate surface for coating. It may be the case that the substrate is 3D printed, and that the 3D printing process is designed to provide for a surface roughness without further processing. 3D printing offers an inexpensive and convenient method of introducing surface roughness without the need to provide equipment that can operate under the extreme conditions needed for processes such as grit-blasting. It may further be the case that where the substrate is 3D printed, coating adhesion can be further enhanced by incorporating hydroxyapatite particles directly into the substrate, such that on coating any hydroxyapatite particles appearing on the surface of the substrate will bond to the coating. In a third aspect of the invention there is provided a method of forming an orthopaedic implant comprising applying a method according to the second aspect of the invention to an implant substrate to form a coated substrate. Typically, the implant will be an implant which is coated to provide for cementless fixation. The implants produced using this method have coatings with high hexagonal crystallinity, which provides excellent stability as the solubility of the coating is reduced relative to known coatings, resulting in reduced inflammation in vivo and improved osseointegration and coating stability. In a further aspect of the invention there is provided a method of forming a dermal filler comprising providing calcium hydroxyapatite particles formed using a method according to the first aspect of the invention. These dermal fillers have a highly crystalline structure, can be easily injected due to the smooth surface of the particles, and have been found to be stable, with reduced inflammation in vivo. There is therefore provided a method of forming calcium hydroxyapatite particles often of hexagonal crystallinity ratio in the range 70% - 100% and / or less than 5 wt% nonhydroxyapatite phosphate salts, the method comprising flame spheroidization of calcium hydroxyapatite powder in the presence of an oxy-hydrogen fuel to provide water as a combustion product of the oxy-hydrogen fuel, wherein a ratio of oxygen:hydrogen in the oxy-hydrogen fuel is in the range 5:95 - 1:1. The water may be calcium hydroxyapatite water vapour and / or calcium hydroxyapatite steam. The method may comprise the additional step of sintering the calcium hydroxyapatite powder prior to powder-melt processing, or the calcium hydroxyapatite powder may be sintered during powder-melt processing, generally sintering in either method at a temperature in the range 1000°C -1325°C. Often the calcium hydroxyapatite particles are of particle size range 25pm -45pm and / or of bulk density in the range 1-2 g / cm3. There is also provided a method of forming a calcium hydroxyapatite coating, the method comprising powder-melt processing of calcium hydroxyapatite powder in the presence of an oxy-hydrogen flame and depositing the particles directly onto a substrate; wherein the deposition is by spray coating and wherein the spray coating comprises thermal spray coating. It may be that the spray coating occurs at a distance from the substrate in the range 50 - 250 mm and the thickness of the coating is in the range 20 pm - 250 pm. The substrate may be selected from stainless steel, titanium, titanium alloy, cobalt chrome alloy, and combinations thereof. Unless otherwise stated, each of the integers described may be used in combination with any other integer as would be understood by the person skilled in the art. Further, although all aspects of the invention preferably "comprise" the features described in relation to that aspect, it is specifically envisaged that they may "consist" or "consist essentially" of those features outlined in the claims. In addition, all terms, unless specifically defined herein, are intended to be given their commonly understood meaning in the art. Further, in the discussion of the invention, unless stated to the contrary, the disclosure of alternative values for the upper or lower limit of the permitted range of a parameter, is to be construed as an implied statement that each intermediate value of said parameter, lying between the smaller and greater of the alternatives, is itself also disclosed as a possible value for the parameter. In addition, unless otherwise stated, all numerical values appearing in this application are to be understood as being modified by the term "about". In order that the invention may be more readily understood, it will be described further with reference to the figures and to the specific examples hereinafter. Figure 1 is a schematic illustration of the apparatus used in the spray coating method of the invention; Figure 2 is a SEM image of calcium hydroxyapatite feed powder; Figure 3 is a SEM image of the particles of Example 2 after sieving to provide a monomodal particle size distribution in the range 25 pm - 45 pm (magnification x500); Figure 4 is a transmission optical image illustrating lens-like properties of the particles (magnification xlOO); Figure 5 is a SEM image showing the surface morphology of the coating of Example 3 (magnification x2000); and Figure 6 is a micrograph showing the thickness of the coating of Example 3 as shown in Figure 4 (magnification x200). Apparatus The particles of the invention may be formed using the apparatus 5 of Figure 1. This apparatus 5 provides flame spheroidization in the presence of an oxy-hydrogen fuel 10 (combustion gas and oxidant gas). Feed powder 15 is provided via a powder hopper 20, the flow rate being controlled by the flow of a carrier gas 25. The flame spheroidization apparatus 5, comprises a "gun" 30 which combines the combustion and oxidant gases and injects the powder 15 through the flame into a chamber 35 which receives molten droplets of hydroxyapatite allowing these to cool. In use, the oxy-hydrogen fuel 10 is ignited at low flow prior to adjusting to the operating flow (high heat) and then starting the powder feed 20, whereby carrier gas 25 enables flow of the powder 15 to gun 30. The gun 30 is then mounted onto a bracket (not shown) on the chamber 35 to provide a controlled spray distance of roughly 300 mm, such that the combustion gases and molten droplets are allowed to solidify while entrained in the air / gas flow stream. The gases and droplets of hydroxyapatite are subsequently separated from the gas and air stream, collected by cyclone apparatus 40 into a collection vessel 45. The extracted gases of combustion, moisture and cooling air are passed through an extraction 'vacuum' pump / blower 50 and discarded. Examples Methodology The following methodology was used to characterise the particles and coatings described. Density Tap density was measured using USP <616> Method 3, 3 mm drop height (position 2), with samples stored in a desiccator for at least 24 hours prior to use. Kausner Ratio (Flowability Index) and Carr Index (Compressibility Index) PBL standard operating procedure 094 was used, with tap density calculated using the density methodology above. Crystallinity and XRD Analysis Crystallinity was measured using ISO 13779:3 (2018). Calculation of crystallinity ratio is via comparison of the material's crystallinity (Sample A) with the crystallinity of an additional sample of the same material sintered at a temperature of 1000°C for 15 hours (Sample B). This is unless the figure for crystallinity from sample A is already greater than 95% in which case the figure, which is itself >95% is reported. Microscopy Transmission Optical Microscopy was conducted using a thin mono layer of powder on a glass slide, the images are captured using ImageFocus+V2 software with further image process I analysis using Image! and proprietary software. Particle Size Particle size was determined using laser diffraction particle size analysis (Malvern Mastersizer 3000) calibrated using beads of known size. Analysis was using particle-in-liquid methodology (filtered water). BET Surface Area The gas adsorption data was generated using a Micromeretics Tristar 3020 machine, comparison of two samples, in krypton. Helium Displacement Density The helium displacement density was calculated using a Micromeretics Accupy 1330. Example 1: Precipitation of Calcium Hydroxyapatite from Aqueous Solution of Phosphoric Acid and Calcium Hydroxide Calcium hydroxyapatite powder was prepared according to the reaction: 10Ca(OH)2 + 6H3PO4 >Caio(P04)6(OH)2 + 18H2O Calcium hydroxide and hydrogen phosphate were added to water with stirring. The rate of addition was managed using pH control and temperature control. The hydroxyapatite was precipitated from solution, separated and dried. The sprayed grade feed hydroxyapatite powder produced is shown in Figure 2, the powder is un-densified, and ready for melt-processing. Example 2: Formation of Calcium Hydroxyapatite Particles using Flame Spheroidization The hydroxyapatite powder of Example 1 was entrained into a nitrogen gas feed at a powder feed rate selected such that it did not cool the flame excessively, and subjected to flame spheroidization using the apparatus of Figure 1. After spheroidization, the hydroxyapatite particles were sieved to remove oversize and undersize particles and mis-shapes using an upper size sieve of 45 pm and a lower size sieve of 25 pm and quality controlled in respect of acceptable number of unmelts by inspection using a microscope. The images are qualitatively assessed for acceptable unmelts through in process quality assurance checks. . Figures 3 and 4 show the particles produced. The lens-like translucence of the particles of Figure 4 clearly show a successful spheroidization process, as particles that did not melt during the process appear opaque and do not have the smooth surface observed. In these particles the crystallinity was reduced by only 16 - 20% compared with the feed powder, and no impurity phases were formed as the lattice was not dehydrated during processing. Example 3: Calcium Hydroxyapatite Coating formation on a Titanium Alloy Substrate Coating was effected on a titanium alloy (6AQI-4V) substrate of surface roughness roughly in the range 6-8 pm, using the apparatus described above, but instead of the provision of a collection vessel for the particles, these were sprayed directly onto the roughened substrate from a distance in the range 50 - 250 mm. Often the process will involve multiple passes to build up layers of the coating, to reach the thickness necessary for the application. This was the case here. A coating was provided which offered an excellent crystalline phase purity, such that only a 10% loss in crystallinity is observed during coating. Figure 5 shows the surface morphology of the coated substrate, and Figure 6 the porosity and thickness of the coating. Example 4: Comparison of Particles of Example 2 with Cold-spraved Particles The impact of melt spraying the calcium hydroxyapatite particles was studied, with representative results provided in Table 1 below. Table 1 Material Bulk Density (g / cm3) Tapped Density (g / cm3) Carr Index Hausner Ratio Sprayed grade feed powder 0.71 0.92 22.64 1.29 Melt-sprayed particles 1.68 1.83-1.86 12.75-14.00 1.15-1.16 Melting the particles during formation has been shown to increase particle density and to reduce the Carr Index and Hausner Ratio. This illustrates that, relative to known techniques, the particles of Example 2 provide a denser material with a smaller difference between the bulk and tapped densities than the sprayed grade feed powder of Example 1 as indicated by the Carr Index, and improved flowability as indicated by the Hausner Ratio. Surface area was also determined by BET, the melt-sprayed particles exhibit a BET of 0.064 - 0.074 m2 / g which is significantly lower than the sprayed grade feed powder which generally exhibits a BET in the range 0.15 - 0.5 m2 / g. The helium displacement density of the particles of Example 2 was found to be in the range 3.057 - 3.065 g / cm3, a figure close to the theoretical maximum density for hydroxyapatite. Example 5: Effect of Particle Formation on Crystallinity The impact of particle formation from calcium hydroxyapatite feed powder (as described in Example 2 above) on the hexagonal crystallinity was studied, the mean crystallinity ratio of the final particles was found to be 78.2% (26 samples), compared to a mean of 97.8% for the powder prior to flame spheroidization (15 samples). This reduction of only 19.6% illustrates the excellent crystallinity retention of the methods of the invention, compared to known techniques which, based upon ISO 13779:2 (2018), provide for up to 55% loss of crystallinity before the particles are deemed unsuitable for the application. It would be appreciated that the methods of the invention are capable of being implemented in a variety of ways, only a few of which have been illustrated and described above.

Claims

1. A method of forming calcium hydroxyapatite particles comprising powder-melt processing of calcium hydroxyapatite powder in the presence of an oxy-hydrogen fuel.

2. A method according to claim 1, wherein the calcium hydroxyapatite particles have a hexagonal crystallinity ratio in the range 60% - 100%.

3. A method according to claim 1 or claim 2, wherein the calcium hydroxyapatite particles comprise less than 5 wt% non-hydroxyapatite phosphate salts.

4. A method according to any preceding claim, wherein a combustion product of the oxy-hydrogen fuel is water.

5. A method according to claim 4, wherein the water is water vapour and / or steam.

6. A method according to any preceding claim, wherein the powder-melt processcomprises flame spheroidization.

7. A method according to any preceding claim, wherein a molar ratio of oxygen:hydrogen in the oxy-hydrogen fuel is in the range 2:1 - 1:1.

8. A method according to any preceding claim, comprising the additional step of sintering the calcium hydroxyapatite powder prior to powder-melt processing.

9. A method according to any of claims 1 to 7, wherein the calcium hydroxyapatite powder is sintered during powder-melt processing.

10. A method according to claim 8 or claim 9, wherein the calcium hydroxyapatite powder is melted at a temperature in the range 1000°C - 1325°C.

11. A method according to any preceding claim, wherein the calcium hydroxyapatite particles are of particle size range 25pm - 45pm.

12. A method according to any preceding claim, wherein the calcium hydroxyapatite particles are of bulk density in the range 1-2 g / cm3.

13. A method of forming a calcium hydroxyapatite coating, the method comprising powder-melt processing of calcium hydroxyapatite powder in the presence of an oxyhydrogen flame and depositing the particles directly onto a substrate.

14. A method according to claim 13, wherein the depositing of the particles directly onto the substrate comprises spray coating, wherein the spray coating is often thermal spray coating.

15. A method according to claim 14, wherein the spray coating occurs at a distance 5 from the substrate in the range 50 - 250 mm.

16. A method according to any of claims 13 to 15, wherein the substrate is selected from titanium, titanium alloy, cobalt chrome alloy, and combinations thereof.

17. A method of forming an orthopaedic implant comprising applying a method according to any of claims 13 to 16 to an implant substrate.10 18. A method of forming a dermal filler comprising providing calcium hydroxyapatiteparticles formed using a method according to any of claims 1 to 12.AMENDMENTS TO THE CLAIMS HAVE BEEN FILED AS FOLLOWS:Claims1. A method of forming calcium hydroxyapatite particles of particle size range 25pm - 45pm and monomodal particle size distribution, the method comprising the steps of: (i) powder-melt processing of calcium hydroxyapatite powder in the presence of an oxyhydrogen fuel; and(ii) sieving the calcium hydroxyapatite particles produced in step (i).

2. A method according to claim 1, wherein the calcium hydroxyapatite particles have a hexagonal crystallinity ratio in the range 60% - 100%.

3. A method according to claim 1 or claim 2, wherein the calcium hydroxyapatite particles comprise less than 5 wt% non-hydroxyapatite phosphate salts.

4. A method according to any preceding claim, wherein a combustion product of the oxy-hydrogen fuel is water.

5. A method according to claim 4, wherein the water is water vapour and / or steam.

6. A method according to any preceding claim, wherein the powder-melt processcomprises flame spheroidization.

7. A method according to any preceding claim, wherein a molar ratio of oxygen:hydrogen in the oxy-hydrogen fuel is in the range 2:1 - 1:1.

8. A method according to any preceding claim, comprising the additional step of sintering the calcium hydroxyapatite powder prior to powder-melt processing.

9. A method according to any of claims 1 to 7, wherein the calcium hydroxyapatite powder is sintered during powder-melt processing.

10. A method according to claim 8 or claim 9, wherein the calcium hydroxyapatite powder is melted at a temperature in the range 1000°C - 1325°C.

11. A method according to any preceding claim, wherein the calcium hydroxyapatite particles are of bulk density in the range 1-2 g / cm3.Application No: GB2401355.9 Examiner: Dr Danielle MerrikinClaims searched: 1-12Date of search: 29 July 2024Patents Act 1977: Search Report under Section 17Documents considered to be relevant:Category Relevant to claims Identity of document and passage or figure of particular relevance X 1-12 and 18 JPH01234308 A (TOKUYAMA SODA KK) see whole document X 1-12 and 18 US 8246924 B2 (HAVERTY) see whole document, in particular claims 12 and 13 X 1-12 and 18 CN 1775309 A (UNIV ZHEJIANG) see whole documentCategories:X Document indicating lack of novelty or inventive step A Document indicating technological background and / or state of the art. Y Document indicating lack of inventive step if P Document published on or after the declared priority date but combined with one or more other documents of same category. before the filing date of this invention. & Member of the same patent family E Patent document published on or after, but with priority date earlier than, the filing date of this application.Field of Search:International Classification:Subclass Subgroup Valid From C01B 0025 / 32 01 / 01 / 2006 A61C 0008 / 00 01 / 01 / 2006 A61C 0013 / 00 01 / 01 / 2006 A61F 0002 / 30 01 / 01 / 2006 A61K 0006 / 838 01 / 01 / 2020 A61L 0027 / 12 01 / 01 / 2006 A61L 0027 / 32 01 / 01 / 2006 A61L 0027 / 42 01 / 01 / 2006 B01J 0002 / 02 01 / 01 / 2006 C23C 0004 / 04 01 / 01 / 2006 C23C 0004 / 129 01 / 01 / 2016

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