(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)
`
`MILLENIUM EXHIBIT 2017
`Baxter Healthcare Corp. et. al. v. Millenium Biologix, LLC
`IPR2013-00582,-00583,-00590,-00591
`
`

`
`U.S. Patent
`
`Nov. 6,2001
`
`US 6,312,468 B1
`
`units)
`
`Intensity(arb.
`
`2 Theta
`
`/'/6.’ /.
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`20f6
`(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)
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`

`
`US 6,312,468 B1
`
`1
`SILICON-SUBSTITUTED APATITES AND
`PROCESS FOR THE PREPARATION
`THEREOF
`
`invention relates to a silicon-substituted
`The present
`apatite and to a process for the preparation thereof.
`The apatite group of minerals are based on calcium
`phosphate, with naturally occurring apatite having a molar
`ratio of Ca/P of 1.67. Hydroxyapatite, which has the chemi-
`cal formula Ca1O(PO4)5(OH)2, and hydroxyapatite—glass
`composites have been used in the recent past as skeletal
`reconstitution materials and it has been observed that bond-
`
`5
`
`10
`
`2
`the synthetic silicon-substituted apatite or
`Preferably,
`hydroxyapatite comprises from about 0.1 to about 1.6%,
`more preferably from about 0.5 to about 1.0% by weight of
`silicon.
`The present invention also provides for the preparation of
`a stoichiometric silicon-substituted apatite which, when
`heated and optionally sintered at a temperature of from
`about 500° C. to 1400° C., for example at about 1200° C.,
`produces an essentially single phase material with a crystal
`structure comparable to pure hydroxyapatite. The present
`invention therefore allows for the production of an essen-
`tially phase pure material of silicon-substituted
`hydroxyapatite, which contains substantially no impurity
`phases, such as calcium oxide or
`tricalcium phosphate
`(TCP).
`The silicon-substituted apatite or hydroxyapatite material
`may be used as a synthetic bone material, including dental
`materials, for example for use in bone substitution, implants,
`fillers and cements, coatings for metallic implants, and for
`making hydroxyapatite-polymer composites.
`In another aspect the present invention provides a pro-
`cess for the preparation of a silicon-substituted apatite,
`which process comprises reacting a calcium salt or calcium
`hydroxide with orthophosphoric acid or a salt of orthophos-
`phoric acid in the presence of a silicon-containing
`compound, the molar ratio of calcium ions to phosphorous-
`containing ions being from about 120.5 to about 120.7 and the
`molar ratio of calcium ions to silicon-containing ions being
`at
`least about 120.2, whereby a precipitate of a silicon-
`substituted apatite is formed. Under these conditions it is
`believed that
`the silicon-containing compound yields
`silicon-containing ions, such as silicon ions and/or silicate
`ions for example, which substitute in the apatite lattice.
`The molar ratio of calcium ions to phosphorous ions is
`preferably from about 120.55 to about 120.65 and the molar
`ratio of calcium ions to silicon ions is preferably at least
`about 120.16.
`The process of the present invention is advantageously
`carried out by reacting an aqueous solution comprising a
`calcium salt or calcium hydroxide and a silicon-containing
`compound at a pH of from about 9 to about 13 with an
`aqueous solution comprising a salt of orthophosphoric acid
`at a pH of from about 9 to about 13. 'lhe calcium salt is
`preferably calcium nitrate and, in particular, calcium nitrate
`4-hydrate. The salt of orthophosphoric is preferably diam-
`monium orthophosphate or triammonium orthophosphate.
`The pH of the aqueous solution of the calcium salt and/or the
`pH of the aqueous solution of the salt of orthophosphoric
`acid is preferably adjusted using ammonia, for example
`concentrated aqueous ammonia. The preferred pH of each
`solution is about pH 11.
`An alternative way of carrying out the process of the
`present invention comprises reacting an aqueous solution of
`calcium hydroxide and a silicon-containing compound with
`an aqueous solution of orthophosphoric acid. The pH of the
`aqueous solution of calcium hydroxide is preferably from
`about 10 to about 14, more preferably about 12.3. The pH of
`the aqueous solution of orthophosphoric acid is preferably
`from about 1 to about 3, more preferably from about 1 to
`about 1.5.
`
`In each of the embodiments of the process of the inven-
`tion the silicon-containing compound preferably comprises
`a silicon salt, such as a silicon carboxylate. Advantageously
`the silicon-containing compound comprises silicon acetate
`and, in particular, silicon acetate 4-hydrate.
`The precipitated silicon-substituted apatite may be sepa-
`rated from the reaction mixture by, for example, filtration,
`
`ing of these bioactivc materials to living tissues is achieved
`through a bone-like apatite layer formed on their surfaces in
`a body environment. Formation of a bone-like apatite layer
`on implant material thus plays a vital role in osseointegra—
`tion of the implant.
`K. Hata et al., J. Am. Ceram. Soc., 78, 1049-1053 (1995)
`have shown that a bone—like apatite layer is formed on the
`surfaces of CaO and SiO2 glass-ceramics in simulated body '
`fluid. It is suggested by the authors that the mechanism of
`formation of the apatite layer comprises the dissolution of
`calcium and silicate ions from the glass surface wl1icl1 helps
`the formation of an apatite layer with silicate ions providing
`nucleation sites. Another mechanism proposed by Hench et
`al., J. Biomed. Mater. Res., 2, 117, 1971 is that the pH of the
`surface of the implant becomes alkaline due to dissolution of
`ions which in t11rn causes supersaturation resulting in the
`precipitation of a bone-like apatite layer. Other mechanisms
`have also been suggested, including the proposal by Li et al.,
`J. Mater. Sci. Mater. Med, 3, 452, 1992, that dissolution of
`amorphous calcium phosphate from the glass creates a
`negatively charged surface which attracts calcium ions to the
`implant surface and finally forms an apatite layer.
`Silicate sulphate apatite has been synthesised by a solid
`state method, K. S. Leshkivich et al., J. Mater. Sci. Mater.
`Med., 4, 86-94, 1993, and found excellent biocompatability
`in vivo tests and this material has been suggested for use as
`a low-load bearing bone graft material.
`Silicon has been shown, in small quantities, to have a
`significant effect on the development and growth of the hard
`tissue of living bodies.
`EP-A-0 540 819 relates to calcium phosphate and cal-
`cium carbonate materials with antibacterial properties, in
`which these materials are used as a carriers for silver and
`
`15
`
`7
`
`40
`
`45
`
`silicon. JP-A-7165518 relates to an antibacterial inorganic
`powder. JP-A-7008550 relates to a hydroxyapatite material
`for use in surgical replacement which contains Ba, Bi, Zr, Sr
`or Si to improve X-ray contrast. JP-A-60024848 relates to a
`tooth or bone repair composition comprising a mixture of
`apatite derived from the bones of fish or mammals and an
`oxide of Zr, Al, Si and Zn.
`We have now developed a silicon-substituted apatite
`material which has a much higher bioactivity than that of
`pure hydroxyapatite and which may be used as a synthetic
`bone material.
`Accordingly, the present invention provides a synthetic
`silicon-substituted apatite or hydroxyapatite which coni-
`prises from 0.1 to 5% by weight of silicon. By the term
`silicon-substituted is meant that silicon is substituted into the
`
`apatite crystal lattice and is not merely added, in contrast to
`the prior art. It is believed that the silicon enters the lattice
`on the phosphate site. The silicon is though to exist and/or
`substitute as a silicon ion or as a silicate ion.
`
`The silicon-substituted apatite or hydroxyapatite material
`according to the present invention may be an essentially
`single phase pure material.
`
`60
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`65
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`

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`US 6,312,468 B1
`
`3
`and then washed and dried to result in a silicon-substituted
`apatite material. The dried filter cake material may then be
`powdered using conventional techniques.
`The dried silicon-substituted apatite material may then be
`heated and optionally sintered using conventional
`techniques, for example at a temperature of about 1200° C.
`Upon heating, the silicon-substituted apatite material trans-
`forms to a silicon-substituted hydroxyapatite material,
`although some of the material may decompose to a mixture
`of hydroxyapatite and calcium oxide or hydroxyapatite and
`tricalcium phosphate (TCP), depending on the chemical
`composition of the material. If formed,
`then preferably
`substantially all of the TCP is on TCP. Ideally, little or no
`decomposition of the silicon-substituted apatite material
`occurs upon heating,
`thereby resulting in an essentially
`phase pure material of silicon-substituted hydroxyapatite. A
`phase purity, as measured by X-ray diffraction, of at least
`98% can be achieved, preferably at least 99%, more pref-
`erably approximately 100%. Because certain phases, for
`example TCP, are soluble in body fluids, a high phase purity r
`is beneficial to the long-term stability of the material. It will
`be appreciated, however, that a range of materials containing
`silicon-substituted hydroxyapatite in varying amounts may
`be prepared in accordance with the present
`invention
`depending on the concentrations of the various reactants.
`For example,
`two phase materials comprising silicon-
`substituted hydroxyapatite and TCP or calcium oxide can
`still usefully be used and are intended to fall within the scope
`of the present invention.
`The present invention will now be described further, by
`way of example, with reference to the following drawing, in
`which:
`
`10
`
`15
`
`,
`
`FIG. 1 shows the distribution of X-ray inte11sity for the
`hydroxyapatite material of Example 6 (discussed below).
`The present
`invention will be further described with
`reference to the following Examples.
`EXAMPLE 1
`
`141.69 g of calcium nitrate 4-hydrate was dissolved in
`600 ml of double distilled water. The pH of solution was
`adjusted to about 11.0 using a concentrated ammonia solu-
`tion. 1200 ml of double distilled water was then added to the
`
`40
`
`4
`added to the constantly stirred solution. The solution was
`filtered. The solution was named as Solution B.
`
`Solution B was added dropwise to constantly stirred
`Solution A at the predetermined temperatures of 3°, 25°, 60°
`and 90° C. over a period of about 2 hours. The precipitates
`so formed (A,B,C and D, respectively) were each agitatcd at
`room temperature for one hour and left overnight. Each
`precipitate was filtered using a Buchner fimnel and washed
`several times using double distilled water. The filter cakes
`were dried for about 20 hours in a drier at about 85° C. in
`filtered air. The dried materials were powdered using a pestle
`and mortar.
`
`The microstructures of the precipitates were studied using
`a JEOL 100 CX transmission electron microscope (TEM).
`Carbon coatcd 200 mesh copper grids were dipped in a
`dilute suspension of the precipitate and examined in the
`bright field mode at a magnification of 50000>< using an
`accelerating voltage of 100 kV. The TEM micrographs
`indicated that the precipitate had a spheroidal shape when
`precipitated at 3° C. and an increasingly acicular shape when
`precipitated at 60° and 90° C.
`X-ray diffraction studies of powdered samples were per-
`formed using a Siemens D5000 diffractometer. CUKOL radia-
`tion (Ka=1.5418
`was used with a linear position scnsitivc
`detector and a nickel diffracted beam monochromator.
`
`Fourier transform infrared Nicolet 800 spectrometer
`(FTIR) with a Mtech photoacoustic (PAS) cell was used to
`analyse the powered samples. Spectra were obtained at 4
`cm'1 resolution averaging 128 scans. The FTIR spectra of
`the samples precipitated at 3° and 25° C. showed phosphate
`bands at 1085, 1030, 961, 600 and 563 cm”, carbonate
`bands at 1455, 1418, 1327 and 883 cm‘1 and a hydroxyl
`band at 3567 cm"1 with a broad peak.
`A GBC Integra XM sequential
`inductively coupled
`plasma spectrometer (ICPS) was used to analyse for
`calcium, phosphorous, silicon and other tracc clcmcnts in
`the prepared apatites. The carbonate content in the dry
`powder of silicon substituted apatite was determined as
`carbon using a Control Equipment Corporation Model 240
`XA CHN element analyser. The results are given in Table 1
`below:
`
`TABLE 1
`
`Ca
`mg/kg
`Sample
`450800
`A
`408800
`B
`417700
`C
`463100
`D
`35400
`HA at 3° C.
`HA at 90° C. 344000
`
`Si
`P
`mg/kg mg/kg
`185200
`10146
`181300
`10748
`176200
`8820
`182100
`10330
`181000
`34.0
`179000
`81.5
`
`Fe
`Al
`Na
`Mg
`mg/kg mgkg mg/kg mg/kg
`15.4
`4.98
`27.8
`25.8
`67.5
`24.0
`21.3
`22.2
`4.4
`10.6
`15.4
`23.5
`3.4
`18.7
`22.5
`26.7
`18.2
`106
`13.6
`<1.0
`17.8
`54.9
`155.0
`<1.0
`
`Cu
`m8’k8
`1.1
`<1.0
`2.6
`2.1
`3.2
`4.8
`
`Sr
`Ba
`mg/kg mg/kg
`<0.2
`65.5
`2.2
`61.1
`<0.2
`66.3
`<0.2
`68.1
`1.6
`66.2
`1.4
`56.0
`
`Carbonate
`mg/kg
`12500
`8000
`7000
`9000
`10000
`7000
`
`HA = hydroxyapatite
`
`solution. The solution was filtered. 8.46 g of silicon acetate
`4-hydrate was added to the constantly stirred calcium nitrate
`solution. The solution was heated at about 65° C. for about
`one hour, with stirring. Most of the silicon acetate 4-hydrate
`dissolved in the solution and only a very little rcmaincd
`suspended in the solution. The solution was constantly
`stirred and cooled down to the pre-determined temperature
`of the experiment. The solution was named as Solution A.
`47.54 g of diammonium hydrogen orthophosphate was
`dissolved in 360 ml of double distilled water. The pH of the
`solution was adjusted to about 11 using a concentrated
`ammonia solution. 480 ml of double distilled water was then
`
`55
`
`60
`
`65
`
`EXAMPLE 2
`
`The procedure of Example 1 was repeated, using an
`amount of 4.23 g of silicon acetate 4-hydrate. Precipitation
`was again carried out at temperatures of 30, 25 °, 60° and 90°
`C. to form precipitates A, B, C and D.
`
`The precipitates were subjected to ICPS analysis, and the
`results are given in Table 2 below:
`
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`
`US 6,312,468 B1
`
`6
`
`TABLE 2
`
`Fe
`Al
`Na
`Mg
`Si
`P
`Ca
`Sample make make mgflig mg/kg make make mg/kg
`A
`458200
`191400
`4526
`7.8
`191
`23.6
`20.0
`B
`469700
`194200
`4188
`<1.0
`30.4
`20.2
`33.3
`c
`433400
`186600
`4429
`3.1
`30.3
`22.0
`44.9
`D
`454700
`185500
`4820
`1.8
`44.9
`28.6
`25.9
`
`Sr
`Ba
`Cu
`mg/l<g mgkg mg/kg
`<1.0
`0.3
`60.8
`1.2
`<0.2
`64.5
`2.0
`<0.2
`64.6
`<1.0
`<0.2
`65.3
`
`Carbonate
`mg/kg
`9000
`6000
`6000
`7000
`
`EXAMPLE 3
`
`The procedure of Example 1 was repeated, using amounts
`of 1.06 g and 12.69 g of silicon acetate 4-hydrate, respec-
`tivcly. The precipitations were carried out at 3° C. to give
`precipitates A and B, respectively.
`The precipitates were subjected to ICPS analysis and the
`results are given in Table 3 below:
`
`15
`
`the final temperature. The sintered sample was polished with
`diamond paper and a mirror-like surface was obtained.
`Hydroxyapatite was also pressed and sintered under the
`same conditions.
`
`The samples were soaked in a simulated body fluid. After
`1 day, thin film X-ray diffraction spectra indicated that the
`sintered silicon substituted apatite material of Example 2A
`had formed a bone-like apatite layer, whereas the sintered
`
`TABLE 3
`
`Fe
`Al
`Na
`Mg
`Si
`P
`Ca
`Sample mg/kg make make mg/kg make make mg/kg
`A
`424000
`252000
`1883
`0.9
`55.3
`37.6
`12.1
`B
`393000
`268000
`16101
`10.3
`64.9
`10.5
`24.6
`
`Sr
`Ba
`Cu
`make make mg/kg
`1.0
`<0.1
`63.6
`0.8
`3.6
`67.9
`
`Carbonate
`mg/kg
`11500
`16500
`
`EXAMPLE 4
`
`44.46 g of calcium hydroxide was dissolved in 600 ml of
`double distilled water. 0.564 g of silicon acetate 4-hydrate
`was dissolved in the calcium hydroxide solution. The solu-
`tion was named as Solution A.
`
`38.02 g of orthophosphoric acid was dissolved in 360 ml
`of double distilled water. The solution was named as Solu-
`tion B.
`
`Solution B was added dropwise to solution A over a
`period of about 2 hours at a temperature of about 3° C. The
`precipitate so formed, designated precipitate A, was stirred
`for 1 hour and left overnight. Precipitate Awas filtered using
`a Buchner funnel and washed several times using double
`distilled water. The filtered cake was dried for about 20
`hours in a drier at about 85° C. in filtered air. The dried
`material was powdered using a pestle and mortar.
`This procedure was repeated, using amounts of 2.82, 5.64
`and 8.46 g of silicon acetate 4-hydrate. The precipitations
`were again carried out at about 3° C. to give precipitates B,
`C and D, respectively.
`The precipitates A, B, C and D were subjected to ICPS
`analysis and the results are given in Table 4 below:
`
`hydroxyapatite formed a similar layer only after immersion
`in the fluid for 14 days.
`EXAMPLE 6
`
`36.671 g of calcium hydroxide was dissolved in 1000 ml
`of do11ble distilled water. 1917 g of silicon acetate 4-hydrate
`was dissolved in the calcium hydroxide solution. The solu-
`tion was named as Solution A.
`
`40
`
`45
`
`33.331 g of orthophosphoric acid (GPR 85% assay) was
`dissolved in 1000 ml of double distilled water. The solution
`was named as Solution B.
`
`Solution B was added dropwise to Solution A over a
`period of about 2 hours at a temperature of approximately
`20° C. The pH of the mixture was adjusted to approximately
`10.5 using a concentrated ammonia solution. The precipitate
`so formed, designated precipitate A, was stirred for 1 hour
`and left overnight. Precipitate Awas filtered using a Buchner
`funnel and washed several
`times using double distilled
`water. The filtered cake was dried at about 85° C. in filtered
`air. The dried material was powdered using a pestle and
`mortar.
`
`The powder was then subjected to chemical analysis and
`the results are given in Table 5 below.
`
`TABLE 4
`
`Fe
`Al
`Na
`Mg
`Si
`P
`Ca
`Sample mg/kg make mg/kg mg/kg make mg/kg mg/kg
`A
`424000
`244000
`814
`41.0
`48.4
`17.5
`24.6
`B
`433000
`240000
`2957
`31.4
`115.3
`18.8
`27.1
`C
`395000
`250000
`5337
`27.5
`54.7
`22.3
`28.4
`D
`390000
`271000
`5634
`23.7
`27.1
`10.8
`31.6
`
`Sr
`Ba
`Cu
`mg/l<8 mg/kg mg/kg
`0.5
`2.6
`2.9
`<0.5
`<0.1
`2.1
`0.8
`<0.1
`4.5
`<0.5
`<0.1
`2.0
`
`Carbonate
`mg/kg
`50000
`45000
`60000
`110500
`
`EXAMPLE 5
`
`Next, the powder was heated at approximately 1200° C.
`
`The silicon-substituted apatite material of Example 2A 65 for about 2 hehrs ahd the Phases Presehl Were deterlhlhed
`using X-ray diffraction. With reference to FIG. 1, the heated
`was pressed and sintered at about 1200° C. at a heating rate
`of about 2.5° C./minute and a dwell time of about 4 hours at
`powder contained only one phase which matched the stan-
`
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`
`US 6,312,468 B1
`
`7
`dard diffraction pattern for pure hydroxyapatite (Joint Com-
`mittee for Powder Diffraction Standards, JCPDS Card no.
`9-432).
`The lattice parameters of the heated silicon-substituted
`hydroxyapatite were calculated from the diffraction data
`using a least squares refinement method. The values are
`listed in Table 6, along with the values for pure hydroxya-
`patite prepared by the above method, with 0.5 moles of
`Ca(OH)2 and 0.3 moles of HSPO4, which does not contain
`any silicon. The increase in the lattice parameters is evi-
`dence of the substitution of silicon in the hydroxyapatite
`lattice.
`
`5
`
`10
`
`8
`13. A process for the preparation of a silicon-substituted
`hydroxyapatite material, which process comprises:
`(i) reacting a calcium salt or calcium hydroxide with
`orthophosphoric acid or a salt of orthophosphoric acid
`in the presence of a silicon-containing compound, the
`molar ratio of calcium ions to phosphorous-containing
`ions being from 120.5 to 120.7 and the molar ratio of
`calcium ions to silicon-containing ions being at least
`120.2, whereby a precipitate of a silicon-substituted
`apatite is formed, and
`(ii) heating and/or sintering the silicon-substituted apatite,
`whereby part or substantially all of the silicon-
`
`TABLE 5
`
`Fe
`Al
`Na
`Mg
`Si
`P
`Ca
`Sample mg/kg mgkg mg/kg mg/kg mgkg mg/kg mg/kg
`A
`381600
`171900
`3410
`15
`65
`21
`32
`
`Cu
`mg/kg
`2
`
`Ba
`mg/kg
`0.2
`
`Sr
`mg/kg
`62
`
`Carbonate
`mg/kg
`5000
`
`TABLE 6
`
`a-axis (nm)
`
`c-axis (nm)
`
`0.94159 (1)
`0.94208 (2)
`
`0.68798 (1)
`0.68889 (2)
`
`Pure hydroxyapa ite
`Single phase silicon-substituted
`hydroxyapatite prepared in
`accordance with he invention
`
`What is claimed is:
`
`1. An essential y phase-pure synthetic silicon-suastituted
`hydroxyapati e material comprising from 0.1% to 1.6% by
`weight of silicon and having substantially no impurity
`phases of calcium oxide and/or tricalcium phosphate.
`2. An essential y phase-pure synthetic silicon-suastituted
`hydroxyapati e material as claimed in claim 1 having a
`phase purity, as measured by X-ray diffraction, of at least
`98%.
`3. An essential y phase-pure synthetic silicon-suastituted
`hydroxyapati e material as claimed in claim 2 having a
`phase purity, as measured by X-ray diffraction, of at least
`99%.
`4. An essential y phase-pure synthetic silicon-suastituted
`hydroxyapati e material as claimed in claim 3 having a
`phase purity, as measured by X-ray diffraction, of approxi-
`mately 100%.
`5. An essential y phase-pure synthetic silicon-suastituted
`hydroxyapati e as claimed in claim 1 comprising from 0.5%
`to 1.0% by weight of silicon.
`6. A synthetic bone material comprising an essentially
`phase-pure synthetic silicon-substituted hydroxyapatite
`material as c aimed in claim 1.
`7. Acomposition which comprises a synthetic bone mate-
`rial as claimed in claim 6 together with a pharmaceutically
`acceptable diluent or carrier.
`8. A bone implant, filler or cement which comprises a
`synthetic bone material as claimed in claim 6.
`9. Ahydroxyapatite-polymer composite material compris-
`ing a synthetic bone material as claimed in claim 6.
`10. A bone implant, filler or cement which comprises a
`composition as claimed in claim 7.
`11. A hydroxyapatite-polymer composition material com-
`prising a composition as claimed in claim 7.
`12. An essentially phase-pure synthetic silicon-substituted
`hydroxyapatite material as claimed in claim 1 comprising
`from 0.5% to 1.6% by weight of silicon.
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`substituted apatite transforms to silicon-substituted
`hydroxyapatite.
`14. Aprocess as claimed in claim 13, wherein the silicon-
`substituted apatite is heated and/or sintered at a temperature
`of from 500° C. to 1400° C.
`15. Aprocess as claimed in claim 13, wherein the molar
`ratio of calcium ions to phosphorous-containing ions is from
`120.55 to 120.65.
`
`16. Aprocess as claimed in claim 10, wherein the molar
`ratio of calcium ions to silicon-containing ions is at least
`120.16.
`
`17. Aprocess as claimed in claim 10, wherein an aqueous
`solution of a calcium salt and a silicon compound at a pH of
`from 9 to 13 is reacted with an aqueous solution comprising
`a salt of orthophosphoric acid at a pH of from 9 to 13.
`18. Aprocess as claimed in claim 10, wherein the calcium
`salt comprises calcium nitrate.
`19. A process as claimed in claim 10, wherein the salt of
`orthophosphoric acid comprises diammonium orthophos-
`phate.
`20. A process as claimed in claim 14, wherein the pH of
`the aqueous solution of the calcium salt and/or the pH of the
`aqueous solution of the salt of orthophosphoric acid is
`adjusted using ammonia.
`21. Aprocess as claimed in claim 20, wherein the pH of
`each solution is adjusted to approximately 11.
`22. Aprocess as claimed in claim 10, wherein an aqueous
`solution comprising calcium hydroxide and a silicon-
`containing compound is reacted with an aqueous solution
`comprising orthophosphoric acid.
`23. Aprocess as claimed in claim 10, wherein the silicon-
`containing compound comprises a silicon carboxylate.
`24. A process as claimed in claim 23, wherein the silicon
`carboxylate comprises silicon acetate.
`25. A process as claimed in claim 10, wherein the pre-
`cipitated silicon-substituted apatite is separated from the
`solution and dried prior to being heated and/or sintered.
`26. A process as claimed in claim 10, wherein the pre-
`cipitated silicon-substituted apatite material comprises from
`0.1% to 1.6% by weight of silicon, which material when
`heated and/or sintered transforms into an essentially phase-
`p11re synthetic silicon-substituted hydroxyapatite material
`having substantially no impurity phases of calcium oxide
`and/or tricalcium phosphate.
`
`60f6
`(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:25)