WO2015052495A1 - Phosphates métalliques du groupe 2 - Google Patents

Phosphates métalliques du groupe 2 Download PDF

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WO2015052495A1
WO2015052495A1 PCT/GB2014/053006 GB2014053006W WO2015052495A1 WO 2015052495 A1 WO2015052495 A1 WO 2015052495A1 GB 2014053006 W GB2014053006 W GB 2014053006W WO 2015052495 A1 WO2015052495 A1 WO 2015052495A1
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group
substituted
phosphate
calcium
doped
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Jawwad Darr
Aneela ANWAR
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Ucl Business Plc
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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0036—Crystallisation on to a bed of product crystals; Seeding
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
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    • C01—INORGANIC CHEMISTRY
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    • C01P2002/52—Solid solutions containing elements as dopants
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    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
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    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/85—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by XPS, EDX or EDAX data
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
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    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/86—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by NMR- or ESR-data
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/88—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by thermal analysis data, e.g. TGA, DTA, DSC
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/62—Submicrometer sized, i.e. from 0.1-1 micrometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
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    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/12—Surface area

Definitions

  • the present invention relates to group 2 metal phosphates, and particularly, although not exclusively, to methods for preparing calcium phosphates, such as hydroxyapatite.
  • the invention extends to the phosphate compounds per se that can be produced by these methods, and to a variety of biomedical applications of such materials, for example as bioceramic compounds, which can be used in whole or as part of materials for bone or teeth replacement procedures.
  • Calcium phosphates are well-known for their use as bone graft substitutes, coatings on metallic implants, reinforcements in biomedical composites and in bone and as components in dental cements.
  • Synthetic hydroxyapatite (HA), [Cai 0 (P0 4 )6(OH) 2 ] is similar to biological apatite, the main mineral constituent of teeth and bone because of its composition, biocompatibility, bioactivity and low solubility in wet media.
  • Synthetic HA and other calcium phosphates have been employed as scaffold materials to encourage new bone formation for osteoinductive coatings on metal implants, as the hard segment in biocomposites, as components in calcium phosphate bone cements and as bulk bone fillers.
  • a method of preparing a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof comprising contacting a first precursor comprising a group 2 metal and a second precursor comprising a phosphate source, to thereby form a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, characterised in that the method is carried out under continuous flow conditions at a temperature in the range of 20- ioo°C.
  • an apparatus for continuously producing a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof comprising a reactor in which a group 2 metal phosphate, or a doped, substituted or surface-functionalised phosphate compound thereof is formed, a first feed means for continuously feeding a first precursor comprising a group 2 metal to the reactor, a second feed means for continuously feeding a second precursor comprising a phosphate source to the reactor, characterised in that the reactor is a continuous flow reactor.
  • the inventors have demonstrated that the continuous hydrothermal flow synthesis (CHFS) method of the first aspect and the apparatus of the second aspect can be used to produce a wide range of group 2 metal phosphate compounds (e.g. calcium phosphates, such as stoichiometric hydroxyapatite or mixtures of two or more calcium phosphates, including doped, substituted and surface-functionalised group 2 metal phosphate compounds).
  • group 2 metal phosphate compounds e.g. calcium phosphates, such as stoichiometric hydroxyapatite or mixtures of two or more calcium phosphates, including doped, substituted and surface-functionalised group 2 metal phosphate compounds.
  • group 2 metal phosphate compounds e.g. calcium phosphates, such as stoichiometric hydroxyapatite or mixtures of two or more calcium phosphates, including doped, substituted and surface-functionalised group 2 metal phosphate compounds.
  • the inventors have demonstrated the rapid, single- step synthesis
  • the residence time under conditions of pH 10-11 from an aqueous solution of calcium nitrate tetrahydrate and diammonium hydrogen phosphate.
  • aqueous solution of calcium nitrate tetrahydrate and diammonium hydrogen phosphate there have been no reports of direct and rapid syntheses of phase pure stoichiometric HA by using a single-step continuous flow synthesis at reasonably mild temperature conditions, i.e. between 20 and ioo°C, and at atmospheric pressure.
  • the method of the first aspect makes it possible to rapidly make stoichiometric HA in a matter of seconds or minutes and under certain conditions can achieve nucleation but, importantly, retards the growth step substantially, such that the HA is stoichiometric HA, but having substantively smaller particle size than that which is made using more conventional synthesis methods.
  • the properties, nature and crystallinity of the precipitated HA formed by the method depended on the reaction variables which include, overall concentration, temperature, pH, time and variation in Ca:P ratio.
  • other calcium phosphate phases e.g. brushite, monetite, ⁇ -TCF, CD HA and biphasic HA / -TCP
  • brushite has raised great attention as a highly resorbable bioceramic, but it is rather difficult to prepare in a batch reaction because its synthesis is highly pH- and time-sensitive.
  • the method of the first aspect works very well at higher concentrations of precursors.
  • the particle size increases, with a subsequent lowering of surface area. Therefore, at higher concentrations of precursors, the method can still be used for the rapid and continuous manufacture of stoichiometric hydroxyapatite or other bioceramics (e.g. calcium phosphates and their derivatives).
  • the particles are typically around one hundred nanometres or more in length and surface areas are about 100 rr ⁇ g- 1 .
  • the properties of the precipitated material depended on the temperature, concentration, pH, time and other precipitation conditions such as variation in Ca:P ratio and residence time.
  • the method of the invention By tuning the reaction parameters in the method of the invention, products of any required particle size (ranging from 20-150 nm) and surface area (ranging from 95-300 m 2 g _1 ) can be produced.
  • the method of the invention has the potential to be used for the production of synthetic HA with trace element purity levels and thermal stability within the tolerances stipulated by ISO standards [e.g. ISO13779-3] for such bioceramics.
  • ISO standards e.g. ISO13779-3
  • the use of continuous flow has resolved the issues of pH control and long maturation times (at room temperature) that are normally required.
  • the process overcomes the problems of batch to batch variations in synthesis and overcomes difficulties presented for scale-up of batch processes.
  • the method and apparatus of the invention provides excellent control over pH conditions (with no need to monitor/control pH during synthesis as in a batch process) to synthesize high purity HA and other ceramic materials in a considerably short time period with very fine particle size.
  • a variety of ion substituted calcium phosphates (Mg, Sr, Zn, Fe, Ag, Mn, SiCV " , C0 3 2 ), nanocomposite materials (Fe 3 0 4 -HA, T1O2-HA) and surface modified organopolymer-nanoparticle dental composites have also been developed successfully by using the method.
  • the first precursor may be selected from a range of group 2 metal-containing compounds, for example hydrated or dehydrated group 2 metal salts, such as nitrate, hydroxide, chloride, carbonate, or oxide.
  • the first precursor comprises a group 2 metal selected from the group consisting of: beryllium, magnesium, calcium, strontium and barium. It is most preferred that the first precursor comprises calcium.
  • calcium- containing compounds which may be used as the first precursor may include calcium nitrate, calcium hydroxide or calcium chloride.
  • the first precursor comprises calcium nitrate, more preferably calcium nitrate tetrahydrate. It is preferred that the first precursor comprises an aqueous solution.
  • the second precursor may be selected from a range of phosphate-containing compounds, for example ammonium hydrogen phosphate, orthophosphoric acid, or sodium or potassium dihydrogen phosphate.
  • the second precursor comprises ammonium hydrogen phosphate, more preferably diammonium hydrogen phosphate. It is preferred that the second precursor comprises an aqueous solution.
  • the method preferably comprises feeding a calcium nitrate tetrahydrate solution via the first feed means and diammonium hydrogen phosphate solution via the second feed means to the reactor, such as tee-piece mixer or similar, where they react.
  • the apparatus preferably comprises a T-junction comprising three arms, wherein two of the arms correspond to the first and second feed means where the two precursors initially react, and the third arm corresponds to the reactor, where the two precursors react further together whilst being heated and the reaction reaches completion therein.
  • each feed means comprises a pump.
  • one pump is configured to pump the first precursor to the first arm of the T-junction, and the other pump is configured to pump the second precursor to the second arm of the T-junction.
  • the reactor comprises a tube in communication with the third arm along which the mixed and reacting precursors continuously pass as a result of the first and second pumps, preferably while being heated, and product material is collected at the end thereof.
  • the tube is preferably at least lorn long and can be made of a fluoropolymer which would give good resistance to strong pH's and be easy to clean.
  • the tube is heated externally via a heat exchanger disposed downstream of the T-junction mixing point.
  • the tube may be located inside an oil bath for some kind of heat exchanger downstream of the mixing point, allowing the reaction to go to completion.
  • the product is preferably collected from the end of the tube at ambient pressure.
  • the tube diameters, type of heat exchanger and flow rates and types of pumps would differ considerably depending on what is required to achieve similar performance and lab scale.
  • reaction or nucleation may occur in the T-junction when the two feeds meet and the pH will be well-defined and controlled at this point, allowing for phase pure materials to be formed collected when the mixture has passed through the heat exchanger, but in a relatively short amount of time.
  • the pH of the prior art batch processes is usually susceptible to pH fluctuation; this is because it usually requires the drop-wise addition of a basic precursor into another reagent resulting in a fluctuating pH.
  • the reaction is carried out normally at room temperature for example is in a batch process it ideally needs to be kept above a pH of 10 for example in order to ultimately deliver stoichiometric hydroxyapatite. Therefore pH cannot be readily controlled in the same way as the method of the invention.
  • the residence time in the reactor for producing the compounds described herein depends on the flow rates, pipe diameters (i.e. construction of the process), the pressure, reaction temperature.
  • the method is conducted at atmospheric pressure.
  • the method is carried out under continuous flow conditions at a temperature of 22-ioo°C, more preferably 30-ioo°C, even more preferably 50-ioo°C, even more preferably 55-ioo°C, still more preferably 6o-ioo°C, and most preferably 70-ioo°C.
  • the method is carried out under continuous flow conditions at a temperature of 20-95°C, more preferably 20-90°C, even more preferably 20-85°C, and more preferably 20-8o°C, and most preferably 20-70°C.
  • the method is carried out under continuous flow conditions at a temperature of 22-ioo°C, more preferably 30-90°C, more preferably 50-90°C, even more preferably 55-85°C, more preferably 6o-8o°C, and most preferably 70-8o°C.
  • a temperature of 22-ioo°C more preferably 30-90°C, more preferably 50-90°C, even more preferably 55-85°C, more preferably 6o-8o°C, and most preferably 70-8o°C.
  • the residence time for the method is between 10 seconds and 20 minutes, more preferably between 30 seconds and 10 minutes, still more preferably between 1 minute and 5 minutes, more preferably between 3 and 5 minutes, and most preferably about 4 minutes.
  • Any of the lower and upper residence times in the above ranges may be combined with each other.
  • any of temperature ranges given herein may be combined with any of the residence times.
  • the group 2 metal phosphate comprises calcium phosphate.
  • the group 2 metal phosphate comprises hydroxyapatite, i.e. Ca io (P0 4 ) 6 (OH) 2
  • the Ca:P ratio is as close to 1.67 as possible.
  • hydroxyapatite is produced within a pH range of 9.5- 12, which is described in Example 1.
  • the temperature of the reaction is maintained at 6o-8o°C.
  • the residence time for the reaction is 1-5 minutes.
  • apatite-like phase also referred to as prepared hydroxyapatite
  • iooo°C or even as high as 1200°C
  • the prepared group 2 metal phosphate comprises calcium- deficient hydroxyapatite, i.e. Ca 10 _ a (HPO ) b (PO ) 6 ⁇ ( ⁇ ) 2 _ -
  • the Ca:P ratio is in the range of 1.5 to 1.67.
  • prepared calcium-deficient hydroxyapatite is produced within a pH range of 6.5-9.5, which is described in Example 2.
  • the reaction temperature is maintained at 6o-8o°C.
  • the residence time for the reaction is 1-5 minutes.
  • the group 2 metal phosphate comprises ⁇ -tricalcium phosphate, i.e. -Ca 3 (P0 4 ) 2 _
  • the Ca:P ratio in the reagents is about 1.5.
  • a prepared calcium-deficient hydroxyapatite is initially produced at a pH of about 8, which is described in Example 2.
  • the temperature of the reaction is maintained at 60- 8o°C.
  • the residence time for the reaction is 1-5 minutes. After collection and cleaning of the resulting slurry and a further heat -treatment at iooo°C for lh in air (of the dry prepared powder), ⁇ -tricalcium phosphate is formed.
  • the group 2 metal phosphate comprises dicalcium phosphate dihydrate (brushite), i.e. CaHP0 4 .2H 2 0 (can directly be made in the process).
  • the Ca:P ratio in the reagents is about 0.8.
  • brushite is produced within a pH range of 2.0-6.0, which is described in Example 3.
  • the temperature of the reaction is maintained at 20-30°C, more preferably at 22-30°C.
  • the residence time for the reaction is 1-3 minutes.
  • the group 2 metal phosphate comprises anhydrous dicalcium phosphate (monetite), i.e. CaHP0 4
  • the Ca:P ratio for the reagents is about 0.8.
  • brushite is initially produced within a pH range of 2.0-6.0, which is described in Example 3.
  • the temperature of the reaction is maintained at about 22°C.
  • the residence time for the reaction is about 3 minutes (in this embodiment, time is important in order to obtain phase pure product).
  • a further heat-treatment is preferably conducted at about 300°C for about 1 h, to form phase pure monetite.
  • Monetite phase is typically formed in the wide temperature range of iio-300°C (from Brushite by heating in air at a heating rate of 10 °C/ min for 1 hr).
  • the group 2 metal phosphate comprises calcium pyrophosphate i.e. Ca 2 P 2 0 y-
  • the Ca:P ratio of the reagents is about 0.8.
  • brushite is initially produced within a pH range of 2.0-6.0, which is described in Example 3.
  • the temperature of the reaction is maintained at about 22°C.
  • the residence time for the reaction is about 3 minutes.
  • a further heat-treatment is preferably conducted at about 500°C for 1 h in air, to form calcium pyrophosphate.
  • Calcium pyrophosphate phase typically forms after heat treatment in the temperature range of 440-700°C using heating rate of 10 °C/ min for 1 hr.
  • calcium pyrophosphate can be made from heat-treatment of monetite (which in itself is made from Brushite) at about 500°C for 1 h.
  • monetite which in itself is made from Brushite
  • hydroxyapatite can be doped with a range of group 2 metal ions to produce a doped group 2 metal phosphate.
  • a doped group 2 metal phosphate comprises strontium doped in a group 2 metal phosphate, preferably strontium doped in a calcium phosphate, most preferably strontium doped in calcium hydroxyapatite.
  • a doped group 2 metal phosphate comprises barium doped in a group 2 metal phosphate, preferably barium doped in a calcium phosphate, most preferably barium doped in calcium hydroxyapatite.
  • the temperature of the synthesis reaction is maintained at 6o-8o°C.
  • the residence time for the reaction is 1-5 minutes.
  • doping of the strontium or barium in calcium hydroxyapatite results in materials that are phase pure and can be used in inorganic bone filler and related applications. Doping of these ions into calcium hydroxyapatite can also be used to alter the crystallinity, bioactivity, resorbability and antibacterial or X-ray opacity properties of the calcium phosphate.
  • hydroxyapatite can be substituted with a range of different anions or cations to produce a substituted group 2 metal phosphate.
  • the dopant cation or substituted anions are added on purpose to alter the biological or other properties of the HA.
  • a preferred substituted group 2 metal phosphate comprises an anion substituted group 2 metal phosphate.
  • Preferred anions which may be used include carbonate ions or silicate ions.
  • the substituted compound comprises carbonate substituted group 2 metal phosphate, more preferably carbonate substituted calcium phosphate, most preferably carbonate substituted hydroxyapatite.
  • the substituted compound comprises silicate substituted group 2 metal phosphate, more preferably silicate substituted calcium phosphate, most preferably silicate substituted hydroxyapatite.
  • the temperature of the reaction is maintained at 6o-8o°C.
  • the residence time for the reaction is 1-5 minutes.
  • these materials are more resorbable and thus can allow faster bone growth rates in embodiments where they are used as biomedical bone fillers or coatings and related bioceramics applications.
  • Preferred cations which may be used include magnesium, strontium, zinc, silver or manganese ions.
  • the substituted compound comprises magnesium, strontium, silver, zinc or manganese substituted group 2 metal phosphate, more preferably magnesium, strontium, silver, zinc or manganese substituted calcium phosphate, most preferably magnesium, strontium, silver, zinc or manganese substituted hydroxyapatite.
  • the temperature of the reaction is maintained at 6o-8o°C.
  • the residence time for the reaction is 1-5 minutes.
  • hydroxyapatite can be surface-modified with a range of different organic surface coordinated compounds. Indeed, such surface-modified (as prepared) hydroxyapatites may be obtained following a similar procedure as for pure nano-HA (mentioned above), except the calcium containing precursor additionally contained the appropriate amount of surface agents e.g. polyvinyl alcohol, carboxylic acid etc.
  • the surface-functionalised group 2 metal phosphate is preferably polyvinyl alcohol surface-functionalised group 2 metal phosphate, more preferably polyvinyl alcohol surface-functionalised calcium phosphate, most preferably polyvinyl alcohol surface-functionalised hydroxyapatite.
  • PVA-HA polyvinyl alcohol
  • the surface-functionalised group 2 metal phosphate is preferably adipic acid surface-functionalised group 2 metal phosphate, more preferably adipic acid surface-functionalised calcium phosphate, most preferably adipic acid surface- functionalised hydroxyapatite.
  • This compound is termed AA-HA (adipic acid).
  • the surface-functionalised group 2 metal phosphate is preferably citric acid surface-functionalised group 2 metal phosphate, more preferably citric acid surface-functionalised calcium phosphate, most preferably citric acid surface- functionalised hydroxyapatite.
  • This compound is termed CA-HA, (citric acid).
  • the surface-functionalised group 2 metal phosphate is preferably vinylphosphonic acid surface-functionalised group 2 metal phosphate, more preferably vinylphosphonic acid surface-functionalised calcium phosphate, most preferably vinylphosphonic acid surface-functionalised hydroxyapatite.
  • VPA- HA vinylphosphonic acid
  • the surface-functionalised group 2 metal phosphate is preferably methacrylic acid surface-functionalised group 2 metal phosphate, more preferably methacrylic acid surface-functionalised calcium phosphate, most preferably methacrylic acid surface-functionalised hydroxyapatite.
  • MA-HA methacrylic acid
  • the temperature of the reaction for each of the surface-functionalised compounds is maintained at 6o-8o°C.
  • the residence time for the reaction is 1-5 minutes.
  • the surface functionalised bioceramics are heat-treated, they normally form non-stoichiometric calcium phosphates depending on the conditions (because some of the organic acid groups are incorporated and replace some of the phosphate ions that would have typically been in the as-prepared material).
  • the materials obtained using the method of the invention can possess a substantially superior high temperature stability (e.g. hydroxyapatite can be made which is stable up to 1200°C because it is stoichiometric with a calcium to phosphorus ratio of 1.67) with remarkably high surface area (up to 263.9 rn 2 /g) and small particle size (typically 2onm) compared to that reported in the literature.
  • hydroxyapatite can be made which is stable up to 1200°C because it is stoichiometric with a calcium to phosphorus ratio of 1.6
  • remarkably high surface area up to 263.9 rn 2 /g
  • small particle size typically 2onm
  • nanoparticles are novel per se, and have a great range of applications for use in replacement of living hard tissues such as bone and teeth, as bone graft substitutes, injectables, coatings on metallic implants, as fillers or additives into commercial products such as toothpastes, materials for the controlled release of drugs or other controlled release therapies, reinforcements in biomedical composites and in bone and dental cements.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof obtained or obtainable by the method of the first aspect.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as a bone substitute material, optionally as a bone graft substitute material.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as a dental substitute material.
  • the compound may be used in bone and dental cements or any biomaterials material which is used to replace hard tissues in the body.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as a bioceramic material.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as an injectable formulation for bone repair, such as spinal fusion.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as a bioactive phase component in biomedical composites.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as a source for bioceramic coatings on metallic or polymeric implants.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as an additive for a toothpaste or other formulation.
  • a group 2 metal phosphate, or a doped, substituted or surface-functionalised compound thereof, of the second aspect as a component of a drug delivery system for the controlled release of a therapeutic agent.
  • Figure 4 [a] shows the effect of temperature on BET surface area and TEM particle size analysis; [b] shows the effect of concentration on BET surface area and TEM particle size analysis.
  • Figure 5 shows powder X-ray diffraction patterns of phase pure as-prepared hydroxyapatite made at temperature (a), 60 °C (sample HA60), (b), 70 °C (sample HA70), and (c), 80 °C (sample HA80);
  • Figure 6 shows heat-treatment of phase pure HA60 at different temperatures
  • Figure 7 shows XPS survey spectrum of phase pure HA60 sample
  • Figure 8 [a-c] shows XPS Spectra of Ca 2p,0 is and P 2p recorded from the phase pure HA60;
  • Figure 9 shows FTIR spectra of phase pure hydroxyapatite synthesized at (a), 60 °C (HA60) (b), 70 °C (HA70) and (c), 80 °C (HA80), respectively;
  • Figure 10 shows Raman spectra of phase pure hydroxyapatite synthesized at (a), 60 °C (HA60) (b), 70 °C (HA70) and (c), 80 °C (HA80), respectively;
  • Figure 11 shows MG63 viability on HA discs.
  • Figure 12 shows MG63 morphology on HA discs.
  • Cells were visualised at day 7 for cell nucleus (DAPI in blue) and cytoskeleton (phalloidin-FITC in green) for MG63S cultured on HA 60, HA 70, HA 80 and commercial HA.
  • Scale bar is 100 ⁇ ;
  • Figure 13 shows powder X-ray diffraction patterns of nonstoichiometric calcium
  • Figure 15 shows powder X-ray diffraction patterns of phase pure HA, CDHA, HA+TCP and Whitlockite, respectively;
  • Figure 16 shows FTIR spectra of different phases of calcium phosphates
  • Figure 17 shows human osteoblast cell proliferation after 1, 4 and 7 days of culture
  • Figure 19 shows heat-treatment of brushite at 300 0 , 500 0 and iooo°C;
  • Figure 20 shows FTIR spectra of brushite nanoparticles obtained at different temperatures
  • Figure 21 shows human osteoblast cell proliferation after 1, 4 and 7 days of culture
  • Figure 22 shows X-ray diffraction pattern of as-prepared Ba-HA
  • Figure 23 shows radiographical examination of pure strontium and Ba-HA
  • Figure 26 shows BET surface area of carbonate and silicate substituted samples as a function of substitution level;
  • Figure 27 shows powder X-ray diffraction patterns of heat-treated (iooo°C,ihr) C0 3 2 ⁇ - substituted hydroxyapatite powders made using CPFS at 70°C;
  • Figure 28 shows XRD patterns of heat-treated (1000 °C, 1 hr in air) Si-substituted hydroxyapatite powders made using CPFS at 70°C;
  • Figure 29 shows FTIR spectral data of C0 3 2 ⁇ substituted hydroxyapatite powders made using CPFS at 70°C;
  • Figure 30 shows FTIR spectral data of Si-substituted substituted hydroxyapatite powders made using CPFS at 70°C;
  • Figure 31 shows Human osteoblast cell proliferation after 1, 4 and 7 days of culture
  • Figure 32 shows powder X-ray diffraction patterns of heat-treated (1000 °C, sacred in air) Mg-substituted calcium phosphates.
  • the wt% values quoted are named values according to the amount of magnesium in the precursor feed;
  • Figure 34 shows BET surface area of as precipitated HA, Biphasic Mg-HA and Mg- whitlockite calcium phosphates.
  • the data points from left to right corresponded to samples oMg-CaP, lMg-CaP, 2Mg-CaP, 3Mg-CaP, 4Mg-CaP, 5Mg-CaP, 6Mg-CaP, 8Mg-CaP, loMg- CaP;
  • Figure 35[a-d] shows XPS Spectra of Ca 2p,0 is and P 2p and Mg is recorded from the synthesized CaP sample 8Mg-CaP;
  • Figure 36 shows human osteoblast cell proliferation after 1, 4 and 7 days of culture
  • Figure 37 shows powder X-ray diffraction patterns of heat-treated (1000 °C, sacred in air) Sr- substituted calcium phosphates. The wt% values quoted are named values according to the amount of magnesium in the precursor feed;
  • Figure 39 shows human osteoblast cell proliferation after 1, 4 and 7 days of culture
  • Figure 40 shows XPS survey spectrum of Strontium substituted hydroxyapatite (loSrHA);
  • Figure 41 [a-c] shows XPS Spectra of Ca 2p,0 is and P 2p recorded from loSrHA;
  • Figure 42 shows radiographical examination of 5, 10, 50 and 100% strontium- substituted HA
  • Figure 43 shows transmission electron microscope images of surface modified
  • Figure 44 shows BET surface area analysis of pure HA, surface modified PVA-HA
  • polyvinyl alcohol polyvinyl alcohol
  • AA-HA adipic acid
  • CA-HA citric acid
  • VPA-HA vinylphosphonic acid
  • MA-HA methacrylic acid
  • Figure 47 shows XPS spectra of Ca 2p, P 2p, O is and C is;
  • Figure 48 shows lH NMR spectrum of surface modified vinylphosphonic acid
  • Figure 49 shows BET surface area measurements of ungrafted and polymer grafted HA at 60, 70 and 80 °C.
  • Example 1 describes the synthesis of synthetic apatite like nanoparticles ( ⁇ ioo nm) in any dimension using a two pump continuous (plastic) flow reactor at reaction temperatures in the range 6o-8o°C and total reaction time of ca. 5 minutes from mixing of an aqueous solution of calcium nitrate tetrahydrate with diammonium hydrogen phosphate (at pH 10) The prepared material was heat-treated 1200°C in air for lh to give phase pure hydroxyapatite (HA). The lattice constants of hydroxyapatite (HA) were similar to reference JCPDS Pattern no. 09-432.
  • the samples were further characterized by techniques such as transmission electron microscopy (TEM), BET surface area analysis, X-ray powder diffraction, FTIR, Raman and X-ray photoelectron spectroscopy (XPS). Particles synthesized at 6o°C in 5 minutes residence time possessed remarkably high surface area value of 264m 2 g ⁇ 1 .
  • TEM transmission electron microscopy
  • BET surface area analysis BET surface area analysis
  • X-ray powder diffraction FTIR
  • Raman Raman
  • X-ray photoelectron spectroscopy XPS
  • phase pure calcium phosphates were also obtained by changing the Ca/P ratio and pH of the precursor solutions and in some cases using an additional heat treatments ( -TCP, calcium-deficient hydroxyapatite (CD HA), brushite, monetite, calcium pyrophosphates) - Examples 2 and 3;
  • Example 1 phase-pure stoichiometric hydroxyapatite using apatite made at 60. 70 and 8o°C
  • the nano-hydroxyapatite (HA) was-prepared as follows.
  • the reaction was carried out at 6o°C using a simple continuous (plastic) flow synthesis system (CPFS).
  • CPFS simple continuous flow synthesis system
  • 0.3 M diammonium hydrogen phosphate solution and 0.5 M calcium nitrate solutions were pumped into the CPFS (Ca:P molar ratio: 1.67) using pump 1 (Pi) and pump 2 (P2), respectively.
  • the pH of both the solutions prior to the reaction was kept at pH 10.
  • 5.0 mL and 15.0 mL of ammonium hydroxide were added to calcium nitrate (500 mL) and diammonium hydrogen phosphate solutions (500 mL), respectively.
  • Both reagent solutions were pumped at 20 mL min 1 , to meet at a 1/ 16 in. PolyflonTM T-piece through a 1/8 in. PolyflonTM Straight union reducer (D6-D1/8", PFA). This initial mixture were connected to 8 m long 1/16 in. PolyflonTM PTFE tubing (ID4.omm x OD6.omm) surrounded by an oil bath at the desired temperature. For flow rates of calcium nitrate and diammonium hydrogen phosphate for Pi and P2, respectively, this gives a total residence time of 5 minutes for the reaction. The product suspension was collected in a beaker at the exit point of the reactor. The aqueous suspension obtained was centrifuged at 4500 rpm for 10 minutes.
  • the clear liquid supernatant was removed and wet solid residue was redispersed in DI water using a vortex mixer (VWR model VM-300) for 5 minutes followed by three further centrifugation and washing cycles.
  • the wet residue obtained was freeze- dried using a VirTisTM Genesis Pilot Lyophilizer 35XL (SP Scientific, UK) at 0.3 Pa for 24 hours.
  • the same experiment was carried out by tailoring reaction temperature ideally at 70 and 8o°C, by keeping all other parameters the same.
  • the fine calcium apatite powders obtained from all three reactions were thus carried out at three different reaction temperatures (60, 70 and 8o°C) and are hereafter referred as HA60, HA70 and HA80, respectively.
  • the powders were compacted into cylindrical discs of 13 mm diameter and 2 mm thickness by using a hydraulic press at 10 MPa. These as-prepared pressed samples were used for cell viability studies after sterilization. The powders were also separately heat-treated to show that the as-prepared materials were able to form phase pure synthetic hydroxyapatite that was stable at 1200°C in air (this suggested that it was stoichiometric hydroxyapatite as it didn't decompose). Material and surface characterisation
  • Thermo Scientific K- Alpha X-ray photoelectron spectrometer with a two chamber vacuum system (loadlock and analysis chamber).
  • X-rays were microfocused at source to give a spot size on the sample in the range of 30 - 400 microns.
  • the monochromator was comprised of a single toroidal quartz crystal set in a Rowland circle with a radius 250mm.
  • the surface sensitivity typically in the range 40 - 100 A) makes this technique ideal for measurements of elemental ratio as oxidation states.
  • the vacuum analysis chamber pressure was at ⁇ 3x io ⁇ 8 Torr.
  • the spectrum collected included one at an energy of 150 eV for survey scans and one at 50 eV for high resolution regions.
  • the detector was a 128 channel position sensitive detector.
  • the spectral intensity of the Ag 3d 5/2 peak from a clean metal sample is >2.5 Mcps at a FWHM of 1.0 eV.
  • the XPS spectra were processed using CasaTM software.
  • the binding energy scale was calibrated by a C 1 s peak at 285.0 eV.
  • TEM images were collected using a JEOL JEM-1200EX II Electron Microscope. Digital images were taken with a side mounted AMT 2K high sensitivity digital camera (Debens, UK). A small amount of sample (less than 10 mg) was dispersed in neat methanol and then gently ultrasonicated for 2 minutes to yield a very dilute suspension. A few drops of the resulting suspension were then deposited on a carbon-coated copper grid (procured from Agar Scientific, UK) which was used as the TEM specimen. The grid was dried prior to use in the double tilt holder of the TEM. Image J software (version 5.0) was used for estimating particle sizes.
  • FTIR Transform Infrared spectroscopy
  • a Confocal Raman DXR Spectrometer (SP Thermo-Scientific, UK) was used. Each powders sample was deposited onto a 316L stainless steel block using a spatula. The block was wiped clean first using distilled water then acetone prior to sample analysis. The data was collected using 780 nm laser, ten times magnification lens with the scan time of 90 seconds for each sample.
  • MG63 human osteocarcoma-osteoblast cells were expanded in complete culture medium consisting of Dulbecco's Modified Eagle's Medium (DMEM) (Biosera, UK) supplemented with 10 % fetal calf serum (FCS), 2 mM L-glutamine and 100 mgmL 1 penicillin and streptomycin (Sigma-Aldrich, Dorset, UK). Cells were kept incubated at 37°C with a 95 % Oxygen and 5 % C0 2 humidified atmosphere and media changes were performed every 2-3 days. HA disc-shaped pellets (13 mm diameter) were sterilised in 70 % ethanol for 1 hour and then washed well with PBS.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS fetal calf serum
  • PCS penicillin and streptomycin
  • HA discs were then either soaked in PBS or FCS for 30 min prior to seeding with 25,000 cells per disc and MG63S were used between passages 60-65.
  • the response of MG63S to the HA discs was evaluated by cell viability assay and cell
  • Resazurin (7-hydroxy-3H-phenoxazin-3-one-io-oxide) assay incorporates an oxidation-reduction (REDOX) indicator that fluoresces in response to metabolic activity from growing cells. Briefly, culture medium was removed from cells and a known amount of fresh medium containing 0.1 mM Resazurin sodium salt (Sigma-Aldrich, Dorset, UK) was added and cells were incubated at 37°C for 4 h. Negative controls or HA discs with no cells showed a blue coloured solution (oxidised) while samples with cells showed a purple-pink coloured solution (reduced). Reduction of Resazurin was detected using fluorescence in opaque 96-well plates on a FLx8oo microplate fluorescence reader (BioTek, UK) using wavelengths of 540 nm excitation and 635 nm emission.
  • REDOX oxidation-reduction
  • MG63S on HA discs were fixed in 3.7 % formaldehyde and permeabilized with 0.5 % Triton-Xioo before staining with DAPI (4',6-diamidino-2-phenylindole dihydrochloride) ( ⁇ g-ml/ 1 ) and phalloidin-TRITC (phalloidin-tetramethylrhodamine B isothiocyanate) ( ⁇ g/ml) (Sigma-Aldrich, Dorset, UK) for cell nucleus and actin-cytoskeleton respectively.
  • DAPI 4,6-diamidino-2-phenylindole dihydrochloride
  • phalloidin-TRITC phalloidin-tetramethylrhodamine B isothiocyanate
  • samples HA60, HA70 and HA80 heat-treated at 1200°C for one hour in air revealed surface areas of 9.5 ⁇ 0.1, 5.9 ⁇ 0.1 and 4.9 ⁇ 0.1 m 2 g _1 , respectively.
  • the powder X-ray diffraction data of as-prepared hydroxyapatites displayed broad peak typical of an apatite like structure (Fig. 5). Upon heat-treatment (i200°C for 1 hour), the X-ray diffraction peaks became considerably sharper and well resolved and gave a good match to the phase pure
  • the 2P peak can also be deconvoluted into two peaks with a spin orbit splitting for and p levels with binding energy 134.2 and 133.4 eV, respectively.
  • Fig. 8c depicts the core level spectrum of O is and the peaks at 530.4 and 531.8 eV are attributed to the phosphate group, and contribution of hydroxyl group in as-prepared hydroxyapatite crystal, respectively.
  • FTIR and Raman spectroscopy were used to analyze the samples and aid identification of different calcium phosphates.
  • FTIR data of as-prepared apatite samples revealed peak at 3570 cm 1 corresponding to stretching vibrations of the hydroxyl group associated with as-prepared HA.
  • the intensity of peak at 1639 cm 1 corresponding to the bending mode for lattice water suggested that loosely bonded OH groups became more incorporated into the lattice with an increase in temperature. Peaks at 1453 and 1414 cm 1 were assigned to the stretching modes, respectively, of some adsorbed carbonate ions on the surface of as-prepared HA.
  • Peaks at 1100 and 1031cm 1 corresponded to the (P-O) asymmetric stretching mode of phosphate, whilst the peaks at, 602 and 564 cm 1 revealed the presence of O-P-0 bending modes as shown in fig. 9.
  • Raman spectroscopy was conducted on the as-prepared HA in order to supplement crystallographic data and detect substitutions in the apatite lattice.
  • the peak at 965cm 1 corresponded to a symmetric stretching mode of the P-0 bond in phosphate. Peaks at 610, 593 and 583 cm 1 are likely to correspond to the bending mode of the O-P-0 linkage in phosphate.
  • Peaks at 1078, 1049 and 1030 cm 1 corresponded to asymmetric stretching modes of the P-0 bonds in phosphate as shown in Fig.10. An increase in intensity and sharpness of these peaks with temperature, indicated an increase in crystallinity with increasing temperature.
  • Human osteoblast cells (MG63) were cultured on HA samples synthesised using a continuous plastic flow synthesis and cell viability was studied over the course of 7 days ( Figure 11). At day 1, cell viability was similar on all HA samples indicating that initial cell attachment was not enhanced by any surface. At day 4, cell viability increased on both HA 60 and HA 70, while it remained constant on HA 80, when compared with day 1.
  • MG63 morphology was observed at day 7 (Figure. 12) on each HA type. Cells were evenly distributed on cHA and showed a typical square-like osteoblast morphology. MG63S were also evenly spread across the surface of HA 60 and showed an osteoblastic morphology but the cell cytoskeleton was also more elongated than on cHA and the cells appeared to form cell-cell bridges. On HA 70, cells were sparser and generally less-well spread than those on cHA and HA 60, with the majority showing a rounded morphology. MG63S on HA 80 were also generally quite rounded and formed clusters. These results indicate that even cell spreading and an ostoeblastic morphology are favoured on HA 60 compared with HA 70 and HA 80 and that the compare well with cHA.
  • CPFS continuous plastic flow synthesis
  • the as-prepared materials can be heat-treated to give phase pure bioceramics such as highly crystalline hydroxyapatite.
  • Example 2 Phase pure calcium phosphates other than stoichiometric Ca-HA. Calcium- deficient hydroxyapatite CCD HA), ⁇ -tri calcium phosphate. ( ⁇ -TCP) from heat-treatment of CDHA)
  • the weak absorption peak at 880 cm 1 was assigned to the P-O-H vibration in the HPO 4 2" group which exists in an apatite which was heat-treated to give non- stoichiometric HA.
  • Peak at 1031 cm 1 corresponds to the P-0 asymmetric stretching mode of phosphate, whilst the peaks at, 534 and 466 cm 1 correspond to O-P-0 bending modes.
  • FTIR was used to analyze the samples and aid identification of different calcium phosphates.
  • FTIR data revealed peaks at 3420 and 632 cm 1 (corresponding to stretching vibrations of the hydroxyl group in as-prepared HA.
  • the intensity of a peak at 1637 cm 1 corresponding to the bending mode for lattice water, was observed to decrease with increasing synthesis temperature.
  • Peaks at 1453 and 1414 cm 1 correspond to the stretching modes, respectively, of some substituted carbonate in the as-prepared HA.
  • Human osteoblast cell proliferation study was conducted on all 4 samples. The osteoblast cells cultured on all ceramic samples showed continuous proliferation. Cells were seen to attach, spread and grow on all types of samples as shown in fig. 17.
  • Continuous plastic flow synthesis (CPFS) technique provides a rapid (as low as 5 minutes), facile and economical pathway to obtain nano-sized HA and other calcium phosphate bioceramics with high purity, suitable size and ultra low level of impurities.
  • the results of the in vitro studies showed that the all 4 synthesized samples are non-cytotoxic and biocompatible.
  • the current work deals with the preparation of synthetic calcium phosphates with optimum properties closer to those of living hard tissues like bone and teeth, aiming at better and more effective biomedical ceramics for use as powders or as nanocomposites in future efforts.
  • the work is readily scalable and thus has promise for scale-up.
  • Example 3 Dicalcium phosphate dihydrate fbrushite, CaHPO d .2H 2 o), Dicalcium phosphate anhydrous fmonetite. CaHPO ⁇ ) and Calcium pyrophosphate (Ca 2 P 2 C from heat-treatment of brushite) Experimental
  • phase pure brushite was-prepared at room temperature using a simple continuous (plastic) flow synthesis (CPFS) system. 0.6 M diammonium hydrogen phosphate solution and 0.5 M calcium nitrate solutions were pumped in the CPFS (Ca : P molar ratio: 0.8) using pump 1 and pump 2, respectively.
  • CPFS continuous flow synthesis
  • Phase pure, stable brushite DCPD: dicalcium phosphate dihydrate: CaHP0 4 .2H 2 0
  • nanoparticles ⁇ ioonm
  • DCPD dicalcium phosphate dihydrate: CaHP0 4 .2H 2 0
  • CPFS continuous plastic flow synthesis
  • the product was obtained as a phase pure material with a Ca:P molar ratio for the reagents of 0.8, and without the need for an initial prolonged ageing step.
  • the most common approach for synthesizing brushite is by adding water soluble calcium (e.g., CaCl 2 .2H 2 0, Ca(N0 3 ) 2 .4H 2 0, or Ca(CH 3 C00) 2 .H 2 0) and phosphate (e.g., NH 4 H 2 P0 4 , (NH 4 ) 2 HP0 4 , Na 2 HP0 4 , NaH 2 P0 4 , KH 2 P0 4 or K 2 HP0 4 ) salts upon adjusting the Ca/P molar ratio to 1.
  • the resultant product is usually washed with distilled H 2 0, and air-dried.
  • pure DCPD powders can also be synthesized by reacting a suspension of Ca(0H) 2 with stoichiometric amounts of H 3 P0 4 by keeping the solution pH in the acidic range. It may also be prepared by mixing two phosphate powders in the presence of water.
  • the starting powders are ⁇ -TCP (Ca 3 (P0 4 ) 2 ) and monocalcium phosphate monohydrate [Ca(H 2 P0 4 ) 2 ⁇ 2 0].
  • a small amount of sodium pyrophosphate Na 2 H 2 P 2 0 7 ) is added to the starting powders as a setting regulator. Mixing of the powders is done in a sulfuric acid solution.
  • Brushite is usually transformed into monetite by losing its crystal water upon heating at or above 110 °C. Relying on the experimental solubility values of different calcium phosphate phases recently reported by Tang et al., it is noted that brushite has 3.4 times greater dissolution rate as compare to TCP at a pH value of 5.5.
  • the main purpose of this study was to develop robust chemical synthesis procedure for the synthesis of high purity brushite and its thermal transformation to monetite and calcium pyrophosphates, respectively, by heat-treatment of the as-prepared materials at different temperatures. The precipitation of brushite does not take place at the start of the reaction.
  • Brushite is transformed into monetite by losing its crystal water upon heating above 110 °C as described in Eq. 3.
  • the presence of calcium pyrophosphate in a heat-treated sample indicates the presence of HP0 4 2_ in the as-prepared material.
  • Calcium pyrophosphate is formed by the loss of one H 2 0 molecule from two HP0 4 2 ⁇ groups of brushite under high- temperature conditions. The transition of monetite into pyrophosphate typically occurs at temperatures above 400 °C as described in Eq. 4.
  • pyrophosphate transition was completed above 440°C.
  • alpha calcium pyrophosphate phase was observed at 500°C and 700°C.
  • beta-calcium pyrophosphate phase obtained after heat-treatment in the range 850 - iooo°C.
  • Brushite formation was also confirmed by FTIR spectral analysis.
  • Fig. 20 shows the FTIR spectra of products obtained at different temperatures. The spectra exhibit easily distinguishable bands attributed to P0 4 3- for the as-prepared form of DCPD. Bands at around 525 crrr 1 and 575 cm-i were attributed to the v4 bending vibrations of the P-O-P mode.
  • the osteoblast cells cultured on as-prepared brushite samples showed continuous proliferation. Cells were seen to attach, spread and grow on all types of samples as shown in Fig. 21. A significant increase in the growth of osteoblast cells with culturing time was observed. Different phases were observed in the synthesis of brushite. The first phase was poorly crystalline HA followed by the appearance of few crystals of brushite. Both phases coexist in the solution for first two minutes and then finally poorly crystalline HA transformed to phase pure stable brushite crystals. The reaction pH and temperature play an important role in the formation of single phase as-prepared brushite.
  • the as-prepared pure strontium and Ba-hydroxyapatite were prepared at 6o°C using a simple continuous (plastic) flow synthesis system (CPFS) .
  • CPFS simple continuous (plastic) flow synthesis system
  • the pH of both the solutions prior to the reaction was ideally kept above pH 12. This initial mixture was connected to 8 m long pipe which was coiled inside an oil bath which gave an effective 5 minute residence time from the tee to the exit of the pipe.
  • Strontium and barium ions are divalent and have the ability to be incorporated into hydroxyapallte crystals.
  • strontium is of interest because of its beneficial effect on bone formation and prevention of bone resorption.
  • Strontium and barium hydroxyapatite (with no calcium) have gained interest in recent, years because of their high density and radiopaque properties.
  • the doping of Sr in the hydroxyapatite structure for implants has been shown to increase bone mineral density (BMD), bone mineral content (BMC), bone volume and
  • Radiopaque dental materials are beneficial in making diagnosis and monitoring existing restoration .However, there is still a lack of dental material that is tooth coloured, minimally invasive and has satisfactory radiopacity. In a recent study on dental restorative materials containing Sr and Ba-HA (no calcium), it was been found that Sr-HA appeared to be a better radiopaque filler when it is mixed as a composite with a polymeric matrix as shown in figure 23 ⁇
  • HA Biological and physiochemical properties of HA can be enhanced by the substitution with ions, some of which are also usually present in natural bone apatite. Most natural apatites are non-stoichiometric because of the presence of minor constituents such as metal cations (Mg 2+ , Mn 2+ , Ag + Zn 2+ , Na + , Sr 2+ ) or anions (HP0 4 2" or C0 3 2 -). HA is capable of
  • Silicon-substituted HA (incorporating silicate anions) has been synthesised using wet- precipitation and batch hydrothermal techniques. Gibson et al. produced phase pure Si-HA by an aqueous precipitation of a calcium containing solution and a phosphate containing solution at high pH by using Si acetate as the source of silicate ions. There have also been many reports on the development of silicon-substituted HA coatings on metallic substrates for enhanced osseointegration. Silicon enters the HA lattice in the form of silicate ions which substitute phosphate ions. Silicon levels up to 4 wt% in HA have been identified using a batch hydrothermal process.
  • carbonate and silicate substituted hydroxyapatite powder was synthesized via a continuous plastic flow synthesis reactor at 70°C in 5 minutes (residence time) at the conditions of pH 10-11.
  • An in-vitro study evaluated the biocompatibility and osteoblast cell proliferation / attachment on the surface of these nanoparticles as pressed disk.
  • the obtained powders were physically characterized using transmission electron microscopy, BET surface area analysis, X-ray powder diffraction analysis, and FTIR. Dynamic light scattering was used to evaluate the size of particles which were made at different
  • the average length along the longest axis of each particle was ⁇ 70 ⁇ 15 nm (200 particles sampled), with the particles having rod-like morphology.
  • TEM images were also collected for Si substituted HA to investigate the particle morphology and size with increasing silicon content.
  • Fig. 25(a) and (b) for sample 6S1-HA reveal distinct nanorods of size ⁇ 110 ⁇ 15 nm (200 particles sampled), along the longest axis.
  • Fig. 26 shows the trends in BET surface areas for the carbonate substituted calcium phosphate samples (determined using XPS). There was a little change in the BET surface area by increasing urea content. All carbonate substituted samples had the surface areas in the range 111 - 136 rr ⁇ g- 1 .
  • One of the possible reasons for lower surface area with small particle size was the increase in particle agglomeration with small size as observed in TEM (Fig 24(b)).
  • sample 6S1-HA showed a noticeable increase in surface area in the range 113 - 163 m 2 g _1 which might be due to a slight difference in size or agglomeration as compared to the carbonate [see Fig. 24 and 25(a) and (b)].
  • Particle size distribution was also calculated for selected samples, pure HA, 2CHA, 4CHA, 8CHA, 2S1HA, 4S1HA and 8S1HA, respectively.
  • DLS measurements of pure hydroxyapatite sample synthesized at 70 °C in 5 minutes residence time reveals average hydrodynamic radius of ca. 154 and polydispersity value of 0.201.
  • DLS measurements yielded average hydrodynamic radii of ca. 146, 142, 149, 156, 164, and 174 nm. Whilst PDI values of 0.268, 0.264, 0.272, 0.207, 0.239 and 0.231, respectively, were recorded. It was observed that the trends rather than the absolute values of the DLS measurements are in good agreement with TEM determined distributions.
  • Powder X-ray diffraction data was obtained for all samples to investigate how carbonate and silicate substitution influenced phase composition and phase purity.
  • the XRD pattern suggests an apatite-like structure (sample 2wt% C0 3 -HA in Fig. 27) and showed a good match to phase pure HA [compared to JCPDS pattern 09-432]. All XRD patterns for silicate- substituted samples in Fig. 28 have a good match to hydroxyapatite JCPDS pattern 09-432 (and are therefore phase pure).
  • FTIR spectroscopy was carried out on all as-prepared carbonate- and silicate-substituted samples in order to aid observations made using XRD.
  • the FTIR analysis (Fig. 29) detected strong peaks at the wavenumbers of the B-type CHA (870, 1430 and 1450 cm 1 )- The typical peaks of the A-type CHA (880, 1450 and 1540 cm 4 ) were not evident.
  • the FTIR spectrum for as-prepared sample SiHA in Fig. 30 revealed peaks similar to those observed for as-prepared carbonate-substituted samples.
  • the weak band in the range 1565-1380 cm 1 (corresponding to asymmetric stretching of the C-0 band of C0 3 2 ⁇ group in both the as- prepared A- and B-type carbonate substitutions in HA) was understandably much lower in intensity as compared to the similar band seen in the FTIR spectrum of the carbonate substitution samples in Fig 30.
  • the weak peak centred at 872 cm 1 was due to the bending mode of the O-C-0 linkage in a small amount of carbonate which is present in the as- prepared material. This was also lower in intensity as compared to a similar peak observed at 876 cm 1 in Fig. 29 (due to higher amount of carbonate ions present in the carbonate- substituted samples).
  • results revealed better bone cell cytoskeletal organisation and greater growth activity for osteoblast cells cultured on as-prepared SiHA than on as-prepared CHA. This could be due to the faster dissolution or higher surface area of the SiHA samples compared to CHA.
  • a CPFS reactor was used to successfully synthesise ion substituted calcium phosphates from calcium nitrate tetrahydrate [(Ca(N0 3 ) 2 .4H 2 0), and diammonium hydrogen phosphate (NH 4 ) 2 HP0 4 )] precursor solutions at (near) ambient conditions in a rapid single step.
  • the obtained product is a promising material with biological properties and has potential to be used in biomedical applications where small size and fine particle size distribution control may be beneficial e.g. injectables for spinal fusion or as a filler in a biocomposite.
  • Nano-sized magnesium substituted calcium phosphate bioceramics (less than 100 nm) were prepared by using a continuous plastic flow synthesis (CPFS) system at 70 °C in 5 minutes (residence time) at a pH of ca. 10. Initially, phase pure hydroxyapatite and magnesium substituted hydroxyapatite were prepared with a BET surface area of 160 m 2 g _1 and 139 m 2 g _1 , respectively using the CPFS system. Biphasic mixtures of as- prepared Mg-HA and phase pure Mg-whitlockite were also obtained upon increasing the amount of magnesium in the reagents.
  • CPFS continuous plastic flow synthesis
  • constituents which include cations e.g. Mg 2+ , Mn 2+ , Ag + , Zn 2+ , Na + , Sr 2+ or anions e.g.
  • Synthetic HA is capable of accepting substitute ions within its lattice. Trace ions substituted in bioceramics can effect lattice parameters as well as crystallinity, dissolution kinetics and other physical properties.
  • magnesium (Mg 2+ ) is a divalent cationic substitute for calcium (Ca 2+ ) in the HA lattice. Such substitution often reduces crystallinity, increases solubility, and lowers the temperature at which conversion of as-prepared hydroxyapatite into ⁇ -TCP can occur. As the amount of substituted magnesium affects thermal stability of the apatite or other phases, this has implications for sintering behavior. For example, the ⁇ -TCP to a-TCP phase transformation normally occurs at ca. ii8o°C for the pure calcium-based compounds.
  • Mg 2+ substitution for Ca 2+ can increase the transformation temperature to ca. 1500 °C. This enables enhanced sintering of ⁇ -TCP at elevated temperatures without deleterious formation of a-TCP (the latter is a less bioactive polymorph).
  • Magnesium substitution levels of up to 1.6 wt% have been reported using wet precipitation reactions.
  • As much as ca. 28.4 wt% substitution of Mg 2+ for Ca 2+ in HA has also been claimed in the literature using mechano-chemical synthesis routes.
  • an excess of Mg 2+ can also be detrimental as it is known to reduce bioactivity in certain biomaterials.
  • Mg 2+ as one of the key substitutes for Ca 2+ in natural apatites is expected to have reasonable biocompatibility and biological properties.
  • Human bone, enamel and dentine comprise 0.72, 0.44, and 1.23 wt% of Mg 2+ , respectively, and this may play an important role in the initial formation of tooth apatites and have a significant effect on their physiochemical properties.
  • the complete substitution of Mg 2+ for Ca 2+ in HA has been shown to inhibit the formation of an extracellular matrix and has deleterious effect on bone cells.
  • Mg-HA As well as Mg-HA, other phases such as Mg-whitlockite (or Mg a-TCP), can also be made directly from precipitation reactions at relatively low temperatures (below 95°C) and acidic or neutral pH [15-16].
  • Mg 2+ ions can stabilise the formation of
  • the main aim of this present study is to produce ion substituted bioceramics with unique physical or compositional attributes (ion substitution level, particle size, crystallinity and phase composition) that may possess novel properties.
  • strontium has gained interest for its possible biological role.
  • Strontium is present in the mineral phase of the bone, and connective tissue has 320-400 mg of strontium.
  • Clinically strontium has been observed to exert several in vivo effects on bone especially at regions of high metabolic turn-over, and its beneficial effect in the treatment of osteoporosis is well known.
  • strontium increases the number of osteoblast cells followed by the reduction osteoclast cells, whereas strontium administration decreases bone resorption and stimulates bone formation.
  • strontium has been found to have anti-osteoporosis and
  • Strontium compounds have been demonstrated to have beneficial effects in osteoporosis by increasing mechanical performance of bone in animal models.
  • Strontium can replace calcium in the HA structure in the complete range of compositions.
  • the solid solutions which have been obtained by hydrothermal methods or by treatment at high temperatures, display a linear variation in the lattice parameters with composition, whereas different data are reported on the preferential replacement site of Sr for Ca in Ca- HA.
  • TEM images of samples oMg-CaP are shown in Fig. 33(a) reveals distinct nanorods of size ⁇ 85 ⁇ 15 nm (100 particles sampled), along the longest axis and ⁇ 15 ⁇ 5 nm (100 particles sampled), along the smaller axis, respectively.
  • TEM images of sample lMg-CaP [Fig. 33(b) ] reveal small rod shaped agglomerates with the average particle size of ⁇ 70 ⁇ 16 nm (100 particles sampled).
  • sample 6Mg-CaP [Fig. 33(c)] reveals semi-spherical shaped morphology, suggesting a deviation from the rod like morphology.
  • TEM images of sample loMg-CaP possessed spherical morphology in large agglomerations with the average particle size of ⁇ 35 ⁇ 15 nm (100 particles sampled).
  • the TEM images reveal that rounded Mg-whitlockite (identified from PXRD) particles are possibly hollow as shown in Fig. 33(d).
  • Fig. 34 shows the trends in BET surface areas for the magnesium substituted calcium phosphate samples. For phase pure HA, the BET surface area was 160 m 2 g 1 .
  • Samples from 4Mg-CaP and 7Mg-CaP had lower surface area of 91 and 75 m 2 g _1 , respectively and phase pure loMg-whitlockite had lower surface area than pure HA.
  • phase pure loMg-whitlockite had lower surface area than pure HA.
  • One of the possible reason of lower surface area is the particle agglomeration observed in TEM (Fig. 33 (c-d).
  • samples 8Mg-CaP and loMg-CaP (phase pure Mg-whitlockite) revealed a noticeable increase in surface area (102 rr ⁇ g- 1 ).
  • the afformentioned results can be supported by XRD and TEM as shown in Fig. 32 and Fig. 33 (d).
  • a chemical analysis of magnesium substituted sample (8Mg-CaP) were performed by using XPS analysis as shown in Fig. 35.
  • the general scan and the C is, P 2p, Ca 2p, O is, and Mg 2p core level spectra of Mg-HA were taken.
  • the Ca 2p spectrum could be resolved into two peaks for Ca 2p 3 / 2 and 2 i/ 2 at 347.4 and 351.3 eV, respectively, which are related to hydroxyapatite.
  • the 2P peak can also be deconvoluted into two peaks for p ⁇ and p levels with binding energy 134.2 and 133.4 eV, respectively.
  • Fig. 35b the 2P peak can also be deconvoluted into two peaks for p ⁇ and p levels with binding energy 134.2 and 133.4 eV, respectively.
  • 35C depicts the core level spectrum of O is and the peaks at 530.4 and 531.8 ev are attributed to the phosphate group, and adsorbed water in hydroxyapatite crystal, respectively.
  • the Mg is core level spectrum could be resolved into two peaks with the binding energy 1304 and 1307 eV, respectively.
  • the magnesium substitution levels in powder samples as suggested by XPS analysis were 0.5 wt% for the small rods in lMg-CaP, 3.5 wt% for the agglomerates in 4Mg-CaP and 8.3 wt% for loMg-CaP, respectively.
  • continuous (plastic) flow synthesis (CPFS) technique provides a rapid pathway to synthesize pure HA and a series of Mg-substituted calcium phosphates from calcium nitrate tetrahydrate (Ca(N0 3 ) 2 .4H 2 0), and diammonium hydrogen phosphate (NH 4 ) 2 HP0 4 ) solutions as starting material at (near) ambient conditions.
  • Mg- substituted HA nanorods were obtained at low Mg-substitution levels. However at higher Mg-substitution levels, biphasic mixture and phase pure Mg-whitlockite were obtained, respectively. Cell toxicity analysis confirmed the high biocompatiblity of this material.
  • the obtained nanopowder is a promising material that has potential to be used in biomedical applications where bone regeneration / replacement or controlled resorbibility of bone grafts is a vital requirment.
  • the X-ray diffraction patterns of the solid products synthesized with different Sr molar ratios are shown in Figure 37. All the patterns indicated that they are constituted of hydroxyapatite as a unique crystalline phase.
  • the patterns of the samples containing both Ca and Sr generally exhibit broader diffraction peaks, in agreement with a reduced degree of crystallinity of the mixed strontium doped calcium hydroxyapatite. The broadening is more evident for the samples with smaller Sr contents, suggesting a greater difficulty for Ca-HA to host the larger strontium ion than for Sr-HA to host the smaller calcium ion.
  • hydroxyapatite made at 70 °C are presented in Figure 40.
  • the peaks at 134 eV corresponded to P 2p of the phosphate groups in hydroxyapatite.
  • the Ca 2p spectrum could be resolved into two peaks for Ca 2p 3 / 2 and 2 i/ 2 (two spin-orbit pairs) at 347.4 and 351.3 eV, respectively, which are related to hydroxyapatite.
  • the 2P peak can also be deconvoluted into two peaks with a spin orbit splitting for p ⁇ and p 3 / 2 levels with binding energy 134.2 and 133.4 eV, respectively.
  • the surface modified hydroxyapatites were obtained following a similar procedure as for pure nano-HA (mentioned above), except the calcium containing precursor additionally contained the appropriate amount of (0.05 M) functionalised carboxylic acid or organic phosphoric acid.
  • Resulting nanopowders were termed PVA-HA (polyvinyl alcohol), AA-HA (adipic acid), CA-HA, (citric acid), VPA-HA (vinylphosphonic acid) and MA-HA (methacrylic acid).
  • HA Hydroxyapatite
  • Dentine a natural composite is based on an organic matrix of mainly collagen with small quantity of citrate and an inorganic mineral phase (filler) consisting of nanosized (lo-ioonm) hydroxyapatite crystals.
  • Filler inorganic mineral phase
  • Synthetic HA resembles some of the properties of natural teeth in hardness and offers numerous promising advantages (intrinsic radio-opaque response, enhanced polishability, improved wear performance) in restorative dentistry.
  • the most abundant functional groups on HA surfaces are P-OH groups.
  • the main objective of this present study was to modify the surface of hydroxyapatite by using various reactive organic acid and then to use these modified HA's as a reinforcing filler component to develop radiopaque resin infiltrants for potential dental restorative materials.
  • the nanoparticles obtained after surface grafting possessed small particle size of ca. 25 ⁇ 5 nm (200 particles sampled) along the longest axis and of ca. 7 ⁇ 2 nm along the smaller axis as shown in Figure 43.
  • BET surface area measurements of as precipitated HA sample typically has BET sufrace areas of 180 m 2 g _1 while surface modified PVA-HA (polyvinyl alcohol), AA-HA (adipic acid), CA-HA, (citric acid), VPA-HA (vinylphosphonic acid) and MA-HA (methacrylic acid synthesized at the same conditions as pure HA possessed a surface area of 143, 208, 201, 225 and 231 m 2 g _1 , respectively (Fig. 44).
  • FTIR spectra of all five as-prepared surface modified HAs are shown in Figure 46. All spectra revealed peaks assigned to phosphate stretching and bending vibrations. The peaks at 1093 cm 1 and 1023 cm 1 correspond to asymmetric (P-O) stretching due to phosphate groups whilst peaks at 602 and 560 cm 1 correspond to the symmetric (P-O). The weak peak at 470 cm 1 was assigned to the phosphate bending mode.
  • the organic surface modified molecules that were used for the hydroxyapatites were investigated by NMR spectroscopy in solution, which required complete dissolution of in a deuterated solvent.
  • the presence of different proton environments associated with the carbon atoms in VPA has proved that surface modification of VPA on HA has occurred as shown in Fig. 48.
  • BET surface area measurements of as-prepared HA sample typically has BET surface areas of 264, 195 and 113 m 2 g _1 .
  • surface modified VPA-HA vinylphosphonic acid
  • MA- HA methacrylic acid synthesized at the same conditions as pure HA possessed a surface area of 254, 247, 210 m 2 g _1 and 265, 244 and 221 m 2 g _1 , respectively at reaction temperature of 60, 70 and 8o°C. This fact is attributed to the growth restriction of HA nanoparticle in the presence of surface modified agents and smooth increase in surface area at various selected

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Abstract

Cette invention concerne des phosphates métalliques du Groupe 2, et des procédés de préparation de phosphates de calcium, tels que l'hydroxyapatite. Des composés de phosphate en soi qui peuvent être produits par ces procédés, et diverses applications biomédicales de ces matériaux, par exemple à titre de composés biocéramiques, qui peuvent être utilisés à titre de tout ou partie des matériaux destinés à des procédures de substitution d'os ou de dents sont en outre décrits.
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CN106756925A (zh) * 2016-12-22 2017-05-31 武汉科技大学 一种镁合金或镁表面的载银羟基磷灰石涂层及其制备方法
US10336941B2 (en) 2017-06-13 2019-07-02 International Business Machines Corporation Impact-modified hydroxyapatite as flame retardant polymer fillers
JP2021029750A (ja) * 2019-08-27 2021-03-01 公立大学法人奈良県立医科大学 低結晶性ストロンチウムアパタイトとそれを利用した医療用インプラントおよびその製造方法
CN114191611A (zh) * 2021-12-27 2022-03-18 内蒙古工业大学 一种硒代羟基磷灰石涂层及其制备方法和应用
CN118002163A (zh) * 2024-04-09 2024-05-10 杭州山屿源环保科技有限公司 一种多孔型臭氧催化填料及其制备方法

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106756925A (zh) * 2016-12-22 2017-05-31 武汉科技大学 一种镁合金或镁表面的载银羟基磷灰石涂层及其制备方法
US10336941B2 (en) 2017-06-13 2019-07-02 International Business Machines Corporation Impact-modified hydroxyapatite as flame retardant polymer fillers
US10570336B2 (en) 2017-06-13 2020-02-25 International Business Machines Corporation Impact-modified hydroxyapatite as flame retardant polymer fillers
JP2021029750A (ja) * 2019-08-27 2021-03-01 公立大学法人奈良県立医科大学 低結晶性ストロンチウムアパタイトとそれを利用した医療用インプラントおよびその製造方法
CN114191611A (zh) * 2021-12-27 2022-03-18 内蒙古工业大学 一种硒代羟基磷灰石涂层及其制备方法和应用
CN118002163A (zh) * 2024-04-09 2024-05-10 杭州山屿源环保科技有限公司 一种多孔型臭氧催化填料及其制备方法

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