CA1096582A - Ceramic hydroxylapatite material - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A novel ceramic form of hydroxylapatite and of a mixture of hydroxyiapatite and whitlockite, dental restorative compositions and dental and surgical phosthetic materials containing said form.
The ceramic is prepared by reacting calcium ion with phosphate ion in aqueous medium and at pH of about 10-12 to produce A gelatinous precipitate of a phosphate of calcium, separating said precipitate from solution, and heating said precipitate up to a temperature of at least 1000°C. but below that at which appreciable decomposition of hydroxylapatite occurs for sufficient time to effect the sintering and substantially maximum densification of the resulting product.

Description

;S~2 The present invention relates to ceramics, parti-cularly for use in dentistry and orthopedics, - Much current den~al research is focused on the preparation of materials which can be used as a substitute for tooth and bone, as a dental restorative material for fillings, caps and crowns and as a prosthetic filling mate-rial for bone. Den~al research also is directed to prevent-ing the formation of dental plaque, the putative agent of both dental caries and periodontal disease~
Currently used filler materials for dental restor-ative compositions such as quartz, alumina, silicates, glass beads, etc., bear little chemical or physical resemblance to tooth enamel. ~ particular deficiency of these materials lies in the incompatibility of the linear coefficients of expansion of filler material and tooth which can eventually result in marginal leakaye and new caries formation. The dental profession, therefore, has lon~ desired a dental filling composition with physical properties which closely conform to those of na~ural tooth structure.

2~ Furthermore, in the field of surgical prosthetic ma~erials, which is currently dominated by high-strength, non-corrosive alloys, there is a recognized need for a mate rial which more closely resembles biological hard tissue as the problems of tissue acceptance and adherence have not as yet been comple~ely resolved ~Hul~ert, et al., Materials `~

Science Research 5, 417 (1971)].
In research directed to ~he discovery of effective anti-plaque chemotherapeutic agents there is need for a standard test material having a tooth-like surface with re-spect to both plaque formation and substantiveness of chem-ical agents. Although natural teeth have been used for this purpose, these have the drawbacks of being highly variable, relatively unavailable in large numbers, and require elabor-ate cleaning before use. Consequently there are used other materials upon which dental plaque will accumulate such as powdered hydroxylapatite, acrylic tee~h, glass and wire.
Although perhaps adequate for studying plaque formation as such, these materials bear little resemblance to the natural tooth surface and are therefore not completely suitable for use in flnding effective anti-plaque agents. For example, it is known that chemicals which inhibit plaque formation on - teeth do not necessarily do so on glass and wire [Turesky et al., J. Periodontology 43, 263 (1972)]. There is a need then for an inexpensive, readily available material which is chemically similar to tooth enamel, hard, dense, and highly polished.
' Cal0(PO4~6~OH)2~ also known as basic calcium orthophospha~e, the mineral phase of tooth and bone, has been suggested as suited to the various purposes ou~lined above, and in fact United States Patent 2,508,816 discloses a method for obtaining the hydroxylapatite of tooth enamel and its use in admixture with a synthetic resin as a prosthetic tooth composition. This procedure is lengthy and laborious and limited to producing finely divided hydroxylapa-tite. Moreover, the method is of course dependent on the 6S~Z

availability of a supply of natural teeth.
Kutty [Indian J. Chem. 11, 695 (1973)] disclosed mixtures of hydroxylapatite and whitlockite produced by the decomposition of powdered hydroxylapatite at various tempera-tures.
Bett, et al., [J. Amer. Chem. Soc~ 89, 5535 (1967)]
described the preparation of particulate hydroxylapatite with stoichiometry varying from Ca/P = 1.67 to 1.57, The mate-rials so-produced contained large intercrystalline pores, It was also reported that upon heating up to 1000C. the calcium-deficient hydroxylapatites underwent partial trans-formation to the whitlockite phase.
United States Patent 3,787,900 discloses a bone and tooth prosthetic material comprising a refractory com-pound and a calcium phosphate compound, e.g,, whitlockite, Several attempts have been made to provide a hard, strong macroform of hydroxylapatite. However, none of the previously known forms of hydroxylapatite has provèn fully satisfactory. Thus, Roy and Linnehan [Nature, 247, 220 (1974)~ described ar. elaborate hydrothermal exchange process whereby the skeletal calcium carbonate of marine coral was converted to hydroxylapatite. The material so produced necsssarily retained the high porosity characteristic of the coral structure and moreover had a relatively low tensile strength of about 270-470 psi, a serious disadvantage in a prosthetic materialO
Monroe, et al. [Journal of Dental Research 50, 860 (1971~ reported the preparation of a ceramic material by sintering compressed tablets of hydroxylapatite. The material so produced was actually a mixture of hydroxylapatite ~6S8Z

and approximately 30 per cent ~-whitlockite, which is Ca3~PO4)2 or tricalcium phosphate, as an ordered mosaic array of polyhedral crystallites, and appeared to have too much porosity to make it suitable for use in a dental material.
Rao and Boehm [Journal of Dental Research 53, 1351 (1974)] disclosed a polycrystalline form of hydroxylapatite prepared by isostatically pressing powdered hydroxylapatite in a mold and isothermally sintering the molded form. The result-ing ceramic was porous and had a maximum compression strength of approximately 17,000 psi.
Bhaskar, et al., [Oral Surgery 32, 336 ~1971)] de-scribed the use of a biodeyradable calcium phosphate ceramic material to fill bone defects. The material is highly porous, is resorbed from the implant site and lacks the strength of a metal or nondegradable ceramic implant.
In accordance with the present invention there is provided a process for preparing a polycrystalline, sintered ceramic in macroform which comprises reacting calcium ion with phosphate ion in aqueous medium and at pH of about 10-12 to produce a gelatinous precipitate of a phosphate of calcium having a molar ratio of calcium to phosphorus between the approximate molar ratio of calcium to phosphorus in hydroxyl-apatite and that in whitlockite, separating said precipitate from solution, heating a cohesive ~elatinous mass of said pre-cipi~ate up to a temperature of at least 1000~C. but belowthat at which appreciable decomposition of hydroxylapatite occurs, and maintaining said temperature for sufficient t`ime to effect the sintering and substantially maximum densifica-tion of the resulting product.

s~ ~
The process of the present lnvention proYides a polycry~talline, isotropic sintered ceramic having clea~ag along smooth curved planes compr;sing either substantially p~re hydroxylapatite or biphasic hydroxylapatite-whitlockite. According to one aspect of the present invention said product is a translucent, isotropic, polycrystalline, sintered ceramic comprising substantially pure hydroxyl- ;
apat;te having an average crystallite size in tne approximate range 0.2 to 3 microns, said. ceramic having a densit~y in the approximate range 3.10 to 3.14 g/cm3, having suhstantially no pores~ and havins cleavage along smooth curved p'anes. in accordance with a second aspect of the present invention said product is a strong, hard, dense, ;sotropic, polycrystalline sintered biphasic ceramic comprisirlg as one phase from a~out 14 to 9~% by weight of hydroxylapatite and as a second phase from about 2 to 86% ~y weight of whitlockite, said ceramic ha~Jing clea~age along smooth curved planes.
The ceramic o-f the one aspect of the present inventioll ; ~5a ~0~6S~3~

comprising substantially pure hydroxylapatite is hard, dense, and takes a high polish. Chemically is it very similar to tooth enamel. Moreover, this new material can be prepared in a relatively simple manner from inexpen~ive starting materials and is obtained in uniform quality, thereby avoid-ing the undesirable variability inherent in natural teeth.
The incorporation of the novel ceramic form of hydroxylapatite in dental restorative compositions provides a dense filler material which has a coefficient of expansion virtually identical to ~hat of natural tooth enamel.
The dental and surgical implant material made available by the instant invention is hard, strong, and c~m-pletely bio-compatible, and can be fabricated in any desired shape without the need for high pressure or other elaborate techniques. Moreover, as described in detail hereinbelow, any desired degree of porosity can be imparted to such mate-rial, thereby permitting tissue ingrowth.

As will be apparent, the chax~cteristics of the new article of manufacture herein described and claimed make it ideally ~uited to making disc~, plates~ rods, etc. for use in testing dental anti-plaque agents.
The novel biphasic ceramic material comprising hydroxylapatite and whitlocki~e i8 hard, dense, non-porous, bio-compatible, easily fabricated in any de~ired shape or form, and by virtue of the known resorbable nature of whitlockite, is useful a~ a strong, partially rescrbable ~urgical implant material.
~hile a certain degree of porosity in surgical im-S~2 plant materials may be advantageous in permitting circula-tion of body fluids and tlssue ingrowth, this same porosity necessarily reduces the mechanical strength of the implant.
The biphasic ceramic afforded by this invention, although dense, mechanically strong and substantially non-porous, may nonetheless permit circulation of body fluids and tissue in-growth because the whitlockite phase contained therein is slowly resorbed from the implant and replaced by natural biological hard tissue.
U~ jA~ pV~
The novel physical form of~hydroxyla'patite, which is distinguished from the biologlcal and geological forms and from all previously known synthe~ic forms as hereinafter indicated, consists of a strcng, hard, de~se, white, trans-lucent isotropic, polycrystalline sintered ceramic material comprising su~stantially pure hydroxylapatite having an aver-age crystallite size in the approximate range 0.2 to 3 microns, a density in the approximate range 3~10 to 3.14 g/cm3, and being further characterized by the absence of pores and by cleavage along smooth curved planes. Moreover, as ordinarily produced, the above ~escribed material has a compression strength in the approximate range 35,~00 to 125,000 psi, a tensile strength in the approximate range 3,000 to 30,000 psi, a linear thermal coefficient of expansion in the approximate range lO to 12 ppm per degree Centrigrade, a Xnoop hardness in the approximate range 470 to 500 and a modulus of elas-ticity of approximately 6 x 106 psi, and is non-bixefringent under polarized light~ The initial evaluation of the novel hydroxylapatite ceramic indicated that it was a strong, hard, dense, white, translucent ceramic comprising substantially pure microcrystalline hydroxylapatite in a random, isotropic array and having a compression strength in the approximate range 35,000 to 75,000 psi, a tensile strength in the approximate range 3,000 to 50,000 psi, a linear thermal coefficient of expansion in the approximate range 10 to 12 ppm per degree Centigrade, a Knoop hardness in the approx-imate range 470 to 500 and a modulus of elasticity of approx-imately 6 x 106 psi, and ~eing characterized by cleavage along smooth curved planes, and by the absence of birefringence under polarized light.
The term dense as used herein designates a highly compac~ arrangement of particles substantially lacking spaces or unfilled intervals therebetween.
In contrast to the above-described form of hydroxylapatite, geological hy~roxylapatite and synthetic hydroxylapatite prepared by a hydrothermal process are macro-crystalline, fracture along flat planes, and are birefringent.
Biological hydroxylapatite is distinguished by generally con-taining significant amounts of carbonate ion in the apatite lattice and in its purest state, i.e., in tooth enamel, by being anisotropically arranged in coiled radiating rods, so that it fractures in straight lines along the interface of these enamel rods and has a comparatively low tensile streng~h of 1500 psi.
In addition to the above-described properties of the novel ceramic form of hydroxylapati~e provided by this invention this material is also completely bio-compatible and therefore eminently suita~le as a dental and surgical prosthetic material. Thus~ the ceramic of this invention can be cast or machined into dental crowns, artificial teeth, bone and joint prostheses, cannulae, anchoring devices for ;58;Z

artificial limbs which can be attached to bone and protrude through the skin, and test surfaces for the study of dental plaque, caries formation, arthritis and other diseases which may affect teeth and bone. Suitably milled, the novel ceramic of this invention can be used as synthetic canncellus bone to repair bone defects, as an abrasive, and composited with standard resins as a dental restorative composition as described hereinbelow.
As a test surface for the evaluation of dental plaque-inhibiting agents the ceramic of this invention can be fabricated into bodies of any suitable size and shape~
preferably of a size and shape which can be easily inserted into a standard test tube. This is conveniently accomplished by cutting or machining large plate-like pieces of dried filter cake to an appropriate size and then sintering~ The sintered products are highly polished using standard lapidary techniques and the resulting bodies are then used as sub-strates in evaluating dental plaque-inhibiting agents accord-ing ~o the procedures described by Turesky, et al., sup~.
After use the ceramic bodies are simply re-polished to pro-vide a new test surface.
As ordinarily produced the ceramic of this inven-tion is not only dense but also non-porous, and whereas a non-porous material is essential for dental applications, a certain degree of porosi~y in implant devices may be ad-vantageous in permitting circulation of body fluids and tissue ingrowthO Varying degrees of porosity can be impart-ed to the instant ceramic in a manner similar to that describ-ed by Monroe, et al., supra. Thus, organic materials such as s~arch, cellulose, cotton, or collagen in amounts ranging ~g _ from about 5 to 25 per cent by weight are admixed with the gelatinous precipitate of hydroxylapatite. During the sub-sequent sintering process the organic materials are burned out thereby creating holes and channels in the otherwise non-porous ceramic product. Alternatively, porosity can be pro-duced mechanically by drilling or machining holes and open-ings in the non-porous ceramic.
In such manner an artificial tooth composed of the ceramic of this aspect of the invention can be made porous at the point of implantation while the exposed tooth surface remains non-porous. Implantation can be accomplished as re-ported by Hodosh, et al., Journal of the American Dental Associa~ion 70, 362 (1965~ Alternatively the ceramic pro-vided by the invention can be composited with a polymeriz-able or polymerized ~onding material as described herein-below and the resulting composition used as a coating for metal implants as described in United States Patent 3,6~9,867, issued October 5, 1971.
The second aspect of this invention mentioned above resides in a strong, hard, dense, white, isotropic, poly-crystalline sintered ceramic product comprising as one phase ~rom about 14 to 98~ by weight of hydroxylapatite and as a second phase ~rom about 2 to 8~ by weight of whitlockite and being characterized by the absence of pores and by cleavage along smooth curved planes.
Whitloakite, also known as tricalcium phosphate, is a mineral having the chemical formula Ca3(P04)2 and which may exist in either an ~ or ~ crystalline phase. The term whitlockite as used herein designates either the ~ or the phase or a mixture of the two phases.

The biphasic ceramic of this invention remains a non-porous polycrystalline material irrespective of the relative concentrations of hydroxylapatite and whitlockite contained therein. However, it will be appreciated that hydroxylapatite and whltlockite have different physical properties, and therefore the physical properties, e.g., density and op~ical properties of the ~iphasic ceramic will depend on the relative amounts of hydroxylapatite and whit-lockite present therein. For example, the theoretical density of whitlockite is less than that o~ hydroxylapatite and accordingly the observed density of a sample of biphasic ceramic containing about 40% hydroxylapatite and 60% whit-lockite was 2.98 g/cm3 compared to a density of 3.10 g/cm3 for a sample of hydroxylapatite ceramic.
The above-described biphasic ceramic is also bio-compatible and therefore suitable as a surgical prosthetic material. Thus, this material can be cast or machined into ~one and joint prostheses or into any shape suitable for filling a void or defect in a bone. The whitlockite contain-ed in a prosthetic article fabrica~ed from this biphasic c~ramic will eventually be resorbed and replaced by the in-growth of natural biological hard tissue. Of course, the extent of tissue ingrowth will depend on the amount of re-sorbable whitlockite contained in ~he ceramic, As ordinarlly produced the biphasic ceramic of this invention is non-porous. However, if desired, varying degrees of porosity can be imported to the ceramic as describ-ed hereinabove for khe novel ceramic form o~ hydroxylapatite.
The biphasic ceramic may also be rendered acid 3G resistant by fluoridation as described hereinbelow for ~65~

ceramic hydroxylapatite.
The above-described novel ceramic form of hydroxyl-apatite can be prepared by precipitating from aqueous medium at a pH of about 10-12 hydroxylapatite having a molar ratio of calcium to phosphorus in the approximate ranga 1.62-1.72, separating the precipitated hydroxylapatite from the solu-tion, and heating~the hydroxylapatite thus obtained at a temperature and for a time sufficient to effect the sinter-ing and maximum densification of said hydroxylapatite with essentially no decomposition thereof.
Thus, hydroxylapatite is precipitated from aqueous medium by reacting calcium ion with phosphate ion at a pH
of about 10-12. ~ny calci~- or phosphate-containing com-pounds which provide calcium and phosphate ions in aqueous medium are suitable provided that the respective counter ions of said compounds are easily separated from the hydroxylapatite product, are not themselves incorporated in the hydroxyl-apatite lattice, or othexwise interfere with precipitation or isola~ion of substantially pure hydroxylapatite. Compounds which provide calcium ion are, for example calcium nitrate, calcium hydroxide, calci~n carbonate and the like. Phosphate ion may be provided by diammonium hydrogen phosphate, ammonium phosphate, phosphoric acid and the like~ In the present method calcium nitrate and diammonium hydrogen phos-phate are the preferred sources of calcium and phosphate ions, respectively.
The preparation of the instantly clàimed novel form of hydroxylapatite is conveniently carried out as follows:
Firs~, calcium nitrate and diammonium hydrogen phosphate in a molar ratio of 1.67 to 1 are interacted in aqueous solution ~65~2 a a pH of about 10-12 to produce a gelatinous precipitate of hydroxylapatite. The procedure described by Hayek, et al,, Inorganic Syntheses 7 63 (1963) is satisfactory for this purpose. The gelatinous suspension of hydroxylapatite thus obtained is then allowed to remain in contact with the original solution for a ~ime sufficient to allow the calcium to phosphorous ratio of ~he suspended hydroxylapatite to reach a value of about 1.62-1.72. This is conveniently accomplished either by stirring the suspension at room temperature ~or a period of not less than 24 hours, or by boiling the suspension for a period of 10 to 90 minutes, or by a combination of boiling followed by standing at room temperature. Pxeferably the suspension is boiled for 10 minutes and thPn allowed to stand at room temperature for 15-20 hours. The hydroxylapatite is then separatéd from the solution by sultable means, for example by centrifugation and vacuum filtratlon. The gelatinous product thus collected contains a large amount of occluded water, much of which can be removed by pressingO If desired, the resulting wet clay-like material can be cut or shaped into a convenient form, or, alternatively, cast in a suitable mold. It should be noted that ordinarily a shrinkage of approximately 25 per cent occurs when the wet hydroxylapatite is dried and a further shrinkage of about 25 per cent takes place during the sintering hereinafter described. This should of course be taken into account when shaping or molding the material~
The wet product may ~e slowly heated up to the sintering /~o o~
B~ temp~rature of ~05~DC. to 1250C. at which point all remain-ing water will have been driven off. Maintaining the temp-/00 0 ~G
erature at }~ ~. to 1250C. for approximately 20 minutes 5~

to 3 hours will then effect the sintering and maximum densi-fication ~f the product. Ordinarily it is preferred to iso-late the dried produc~ prior to sintering. Thus, the wet product may be dried at about 90~C. to 900C. for approxim-ately 3 to 24 hours or until the water content thereof hasbeen reduced to 0 to about 2 per cent. It is generally pre-ferred to use drying conditions of approximately 90C. to 95C. for abcut 15 hours or until the water content has been reduced to about 1 to 2 per cent. The hydroxylapatite ob~ained in this manner is britt1e and porous, but has con-siderable mechanical strength. Some separation or cracking of the clay-like ma~erial may occur on drying especially if a thick filter cake is used. However, pieces as large as 100 cm2 and 3 mm. in thlckness are readily obtained. Separa-tion or cracking during drying can be minimized or preventedby adding to the suspension of freshly precipitated hydroxyl-apatite about 0.4 to 0.6 per cenk by weight of an organic binder such as collagen, powdered cellulose or cotton, about 0.5 per cent of collagen being preferred. The organic binder is volatilized during subsequent sintering and physical characteristics of the ceramic product appear substantially unchangsd from those of the product produced in the absence of such a binder. Of course, ~he use of substantially larger amounts of organic binder will result in a porous ceramic pxoduct as described above. Other conventional organic and inorganic binders known in the ceramics art can also be used.
It is usually convenient at this stage to further cut or shape the dried hydroxylapatite into roughly the form desired as the end product, taking into account the shrinkage mentioned above which occurs on sintering.

658%

The bodie~ of hydroxylapatite prior to sinterin~
should be uniform and free oE defects. The presence of cracks or fissures can cause the pieces to fracture during the sintering process~ The products are then sintered at /~ ~ O
B 5 about ~ 4~. to 1250C. for approximately 20 minutes to three hours, the temperatures and times being inv~rsely related. Sintering is preferably effected at 1100C. to 1200C. for approximately 0.5 to 1 hour. The hard, dense ceramic articles so produced can then be polished or machined using conventional techniques.
It is critical, in the above process, to prepare the hydroxylapatite as a gelatinous precipitate from aqueous solution for it is only in ~his cohesive gelatinous state that hydroxylapatite can be shaped or molded and then dried and sintered to produce the ceramic in macroform. Dry particulate or granular hydroxylapati~e cannot be reconsti-tuted into ~his cohesive gelatinous state. If, for example, powdered hydroxylapatite is suspended in water and filtered th~re i5 o~tained a non-cohesive, particulate filter cake which qimply dries and crumbles and cannot be shaped, molded or converted into a macroform of the ceramic. Moreover, although powdered hydroxylapatite can be mechanically com-pxessed into a shaped body, such as a tablet, when sintered according to the method of this invention the product obtain-ed is highly porous and does not fracture along smooth planes but simply shatters into rough pieces~
Although the formation of hydroxylapatite in aqueous medium is a complex and incompletely understood pro-cess, it is generally believed that calcium and phosphate ions initially combine to form a calcium-deficient hydroxyl-~IJ2~S8~:

apatite having a calcium-to-phosphorus ratio of about 1.5.
In the presence of calcium ion, this species thsn undergoes slow transformation ~o hydroxylapatite with a calcium-to-phosphorus ratio of 1.67. ~Eanes et al., Nature 208, 365 (1965) and ~ett et al., J. Amer. Chem. Soc. 89, 5535 (1967).
Thusj in order to obtain a ceramic comprising substantially pure hydroxylapatite it is imperative in the process o~ this invention that the initial gelatinous precipitate of hydroxyl-apatite be allowed to remain in contact with the original solution for a time sufficient to allow the calcium to phosphorus ratio thereof to reach a value of about l.h2 to 1.72. 5ubstantial deviation from this range results in a less translucent ceramic product. For example, if hydroxyl-apatite is precipitated at room temperature and collected within 2 hours following precipitation the calcium to phos-phorus ratio thereof is found to ~e about 1.5S-1.57 and the ceramic ultimately produced therefrom is opaque and found by X-ray diffraction ~o be a mixture compri~ing hydroxylapatite ; and whitlockite. In fact, as described more particularly hereinbelow, material having a calcium to phosphorus ratio of about 1.44~1.60 i~ useful in ~he preparation of the bi-phasic ceramic described hereinabove. Thus, while the pro-cess claimed herein affords a translucent ceramic comprising sub ~antially pure hydroxylapatite, in view of the incom-; 25 pletely understood mode of formation of hydroxylapatite in aqueous medium it may be advantageous to monitor the hydroxyl- --apatite formation in oxder to ascertain that the desired calcium to phosphorus stoichiometry has been achieved and that the product when ~intered will comprise substantially pure hydroxylapatite. This is conveniently accomplished by ~` lQ~58~

removing an aliquot of the hydroxylapatite suspension, sepa-rating the product, drying and sintering a~ de~cribed herein-above, and subjscting the ceramic so-produced to elemental and X-ray analysis.
The temperature and duration of sintering are also critical to the claimed process. Thus, unsintered hydroxylapatite having the desired ealcium-to-phosphorus of 1.62-1.72 can be converted to the ceramic of this invention by heating at a temperature of at least about 1000C.
At 1000C. complete sintering and maximum densification may require 2-3 hours while at 1200Cr the process may be complete in 20~30 minutes. It is preferred to effect sintering at a temperature of approximately 1100C~ for about one hour. A temperature substantially below 1000C. will result in incomplete sintering irrespective of the length of heating whereas heating above 1250C. for more than ~ne hour will result in partial decomposition of hydroxylapatite to whitlockite.
The above-described biphasic ceramic comprising one phase of hydroxylapatite and a second phase of whitlockite can be prepared by precipitating from aqueous solution at a pH of about 10-12 a calcium phosphate compound having a molar ratio of calcium to phosphorus in the approximate range 1.44-1.60, prPferably 1.46-1.57, separating the precipitate ~5 from the solukion and heating the solid thus obtained at a temperature and for a time ~ufficient to effect the sinter-ing and maximum den~ification thereof.
The calcium phosphate compound having the requixed ~toichiometry, viz, Ca/P - 1.44-1,60 is obtained by inter-acting calcium ion with pho~phate ion in aqueous medium at ;8~

pH 10-12, employing the same sources of calcium and phosphate ions described hereinabove for the preparation of single phase hydroxylapatite. Calcium nitrate and diammonium hydro-gen phosphate are the preferred reagents.
Thus, the biphasic ceramic may be prepared by interactiny calcium nitrate and diammonium hydrogen phos-phate in a molar ratio o 1.67 to 1, i.e,, as described hereinabove for the preparation of single phase ceramic ; hydroxylapatite provided that the initial gelatinous precipi-tate is not heated and is allowed to remain in contact with ; the original solution for a period not to exceed about 4 houxs or alternatively that the molar ratio of calcium to phosphorus of the precipitate not be allowed to exceed a value of about 1~60.
As descri~ed hereinabove for the preparation of single phase ceramic hydroxylapatite, the calcium phosphate precipitate is separated from the solution, washed, optionally haped or molded into a convenien~ form, and if desired dried and isolated prior to sintering.
The suspension of freshly precipitated calcium phos-phate may also be treated with organic binders or fluoride ion as described hereinabove for single phase hydroxylapatite.
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- D Sintering is effected by heating at about ~05~~_ to 1350~C. for approximately 20 minutes to 3 hours.
The amount of whitlockite contained in the ceramic so-produced will depend on the time at which the precipitate is separated from the original solution and may range from about 2 to 83%. Thus, when the product is isolated 5 minutes following precipitation, the calcium to phosphorus ratio thereof is 1.55 and the ceramic ultimately produced therefrom -1~

1~6~82 contains about 83% whitlockite. If the product is isolated 2 hours after precipitation the calcium to phosphorus ratio thereof is 1.57 and the resulting ceramic contains a~out 61%
whitlockite. Isolation of the product 4.5 hours following S precipitation ultimately affords a ceramic containing an estimated 2% whitlockite, an amount barely detectable by X-ray diffraction which has a minimum concentration sensi-tivi y of 2-3%. Of course, i the product is allowed to re-main in contact with the original solution beyond about 7 hours the ceramic ultimately obtained is substantially single ; phase hydroxylapatite.
Al~ernatively, the biphasic ceramic afforded by the present invention may be prepared by reacting calcium ion with phosphate ion in an approximate molar ratio of 1.50-1.60 to 1. In this way the molar ratio of calcium to phosphorus in the calcium phosphate precipitate cannot exceed a value of about 1,60 irrespective of the length of time said precipitate remains in contact with the original solution~
Thus, the preparation of the instantly claimed bi-phasic ceramic is conveniently carried out as described hereinabove for the preparation of single phase ceramic hydroxylapa~ite with the exception that the reactants, viz.
`i calcium nitrate and diammonium hydrogen phosphate are inter-'~ 25 acted in an approximate molar ratio of 1.50-1.60 to 1 to ; produce ceramics comprising about 30-50% hydroxylapatite and about 50-70% whitlockite.
The ceramic may ~e further enriched in the whit-lockite phase by com~ining the features of the two preceding procedures, i.e., by interacting calcium ion with phosphate ~0~6S~
ion in an approximate molar ratio of 1.50-1.60 to 1 and iso-lating the precipitated calcium phosphate compound within a short time, preferably about 5 minutes to 4 hours, following precipitation. Ceramics so-produced comprise about 10-30 hydroxylapatite and 70-90% whitlockite.
Hydroxylapatite is known tc undergo decomposition to produce whitlockite at about 1250C. and it will there-for be appreciated ~hat prolonged heating of the single phase ceramic hydroxylapatite of this invention at temperatures of about 1250~C. or higher will result in partial decomposi-tion of said hydroxylapatite ~o whitlockite thereby provid-ing yet another method of producing the instantly claimed biphasic ceramic.
The invention also deals with a dental restorative composition comprising a blend of the ceramic hydroxylapatite of this invention and a polymerizable or polymerized bonding material which is compatib~e with the conditions of the oral cavity. The dental restorative composition of this invention comprises from a~out 10-90 pex cent, preferably 60 to 80 per cent, by weight of finely divided ceramic hydroxylapatite, the remainder of said composition, from about 10-90 per cent by weight, comprising a dentally acceptable polymerizable or polymerized bondiny material together with known appropriate polymerization catalysts, such as, aliphatic ketone peroxides, benzoyl peroxide, etc., reackive diluents such as di-, tri-and tetraethylene glycol dimethacrylate, hardeners such as N-3-oxohydrocarbon-substituted acrylamides as described in United States Patent 3,277,056, issued October 4, 1966, pro-moters or accelerators such as metal acetyl acetonates, tertiary amines, e.g., N,N-bis-~2-hydroxyethyl)-~-toludine, ~20-58~

et~., or cross-linking agents such as zinc oxide, etc., which are present in an amount ranging from about 0.01 to 45 per cent by weight of the total composition. Although not essential, a surface-active comonomer or keying agent such as the reaction product of N-phenyl glycine and glycidyl methacrylate as described in United States Patent 3,200,142, issued August 10, 1965, methacryloxypropyltrimethoxysilane,

3,4-epoxycyclohexylethyltrimethoxysilane, vinyltrichloro-silane, etc., may he added to said composition in an amount ranging from 0.05 to 10 per cent by weight of the total composition. The bonding or keying agent promotes bonding o~ the ceramic material to the resin and of the dental filling composition to the natural ~ooth. Thus, ceramic hydroxylapa~ite provided by this invention is comminuted to a suitable particle size of from about 5 to 100 microns using conventional milling techniyues and then blended with an appropriate amount of a standard resin known in the dental ; restorative art such as hydroxyle~hyl methacrylate, poly-methyl methacrylate, polyacrylic acid, propylena glycol fumarate ph~halate unsaturated polyesters such as sold by Allied Chemical Co. 23 LS8275 and by Pittsburgh Plate Glass as Selectron 580001, styrene modified unsaturated polyesters such as Glidden Glidpol*1008, G-136 and 4CS50, epoxy resins such as Ciba Aral~ite*Ç020, Union Carbide ERL2774 and the bisacrylate monomer prepared from glycidyl methacrylate and bisphenol A shown in United States Patent 3,066,112, issued Nov. 27, 1962. The resin may comprise a single monomer or - a mixture of two or more comonomers. Additives such as dyes, inorganic pigments and fluorescent agents may be optionally added to the above composition according to the *-Registered Trade Mark -21-~3 principles known ln the art concerning these materials.It is convenient to blend the resin, ceramic hydroxylapatite and optional ingredients such as silane bonding agents, dyes, inorganiC pigments or fluorescent agents prior to the addi-tion of the catalyst, hardener, cross-linking agent, pro-moter or accelerator. However, the order in which the in-gredients are mixed is not critical and said ingredients may be blended simultaneously. Utilizing conventional techniques the composition thus produced can be used as a dental filling material, a dental cement, a cavity liner, a pulp capping agent or the composition can be cast in a suitable mold to produce an artificial tooth or set o teeth.
It is of course highly advantageous that material used in the oral cavity be caries resistant. This object is readily achieved in the practice of the present invention by adding from about 0.01 to l per cent fluoride ion such as ammonium or stannous fluoride to the suspension of freshly precipitated hydroxylapatite. The ceramic produced by sinter-ing of the resulting product is highly resistant to attack by lactic, acetic ox citric acidJ a standard ln vitro method of detexmining caries resistance, Alternatively, resistance to caries can be imparted to the finished ceramic by exposing the same to a 0.5 to 5 per cent aqueous solution of sodium fluoride for about 12 hours to five days, Preferably, the ceramic body is allowed to stand in about 5 per cent a~ueous sodium fluoride for appxoximately 4 days.
It will of course be appreciated by those skilled in the ceramics art that in addition to organic and inorganic binders and fluoride ion the ceramic materials provided by the present invention may also contain small amounts of other elements which although not changing the essential nAture of the ceramic products may impart useful characteristics thereto. For example, it is known that barium and stron-tium will incorporate into the apatite crystal lattice and that these elements are considerably more opaque to X-rays than calcium. Therefore the addition of a small amount of barium or strontium ion to the calcium ion prior to reaction of ~he latter with phosphate ion will ultimately result in a barium or strontium-doped hydroxylapatite ceramic which 1~ when used in a dental restorative composition as described hereinabove would provide sufficient X-ray absorption to allow detection of the filled tooth. Magnesium which will also incorporate into the apatite crystal lattice is known to retard the crystallization of hydroxylapatite while pro-moting the crystallization of whitlockite ~Eanes et al., Calc. Tiss. Res. 2, 32 (1968~]. Thus, the addition of a small amount ~f magnesium ion ~o the calcium ion prior to reaction of the latter with phosphate ion will favor the formation of whitlockite thereby ultimately affording a whitlockite-enriched biphasic ceramic.
The ceramic materials obtained as described above were characterized on ~he basis of one or more of the follow-ing: elemental analysis, d nsity, X-ray diffraction, trans-mission electron microscopy, polarized light microscopy and mechanical properties.
The invention is illustrated by the following ; examplés without, however, being limited thereto.
EX~MPLE 1 To a stirred mixture containing 130 ml. of 1.63N
calcium nitrate ~0.212 mole) and 125 ml. of concentrated ~Loq~582 ammonia there was added dropwise over a period of approxim-ately 20 minutes a mixture containing 16.75 g. (0.127 mole) of diammonium hydrogen phosphate, 400 ml of distilled water and 150 ml. of concentrated ammonia. The resulting suspen-sion was boiled 10 minutes, cooled in an ice-bath and filter-ed. The filter cake was pressed with a rubber dam and then dried overnight a~ 95C. A sample of the resulting, hard, porous, brittle cake was heated in an electric kiln over a period of 115 minu~es up to a final temperature of 1230C.
and then cooled to room temperature to give a strong, hard white translucent ceramic product.
Standard elemental analyses of the final ceramic product and also of the dried hydroxylapatite prior to sintering yielded the following results based on Cal0(PO4)6(OH)2:

Dried, Unsintered Calc'd _~y_~ ~ Ceramic Ca 39.89% 37.4~ 39.6%
P 18.5% 17.5% 18,9%
E20 0% 1~
Ca~P 1.667 1.65 1~62 Examination of a thin section of the ceramic by polarized light microscopy at 130X and 352X indicated the material to be essentially free of whitlockite. The absence of birefringence and discernible structural features such as crystallite shape, orientation, boundaries, etc., indicat-ed a microcrystalline structure. A comparison with the optical micrographs of a thin section of the sintered com-pressed tablet reported by Monroe et al. ~supra) showed the two materials to be structurally dissimilar.
X-ray diffraction measurements were carried out in ~6S8Z

conventional manner. The interplanar spacings were calculat-ed and found ~o be virtually identical to the values given for hydroxylapatite by Donnay et al., Crystal Data, ACA Mono-gram No. 5,668 (1963~. The X-ray data further indicated the absence of whitlockite in any amount greater than about 2 to 3 per cent, the minimum concentration sensitivity of the diffractometer.
EX~MP~E 2 A solution containing 79~2 g, (0.60 mole) of di-ammonium hydrogen phosphate in 1500 ml. of distilled water was adjusted to pH 11-12 with approximately 750 ml. of con-centrated ammonia. Addi~ional distilled water was added to dissolve precipi~ated ammonium phosphate giving a total volume ~f 3200 ml. If necessary the pH was again adjusted to 11-12. This solu~ion was added dropwise over 30-40 minutes to a vigorously s~ixred solutlon containing 1 mole of calcium nitrate in 900 ml, of dis~illed water previously adjusted to p~ 12 with approximately 30 ml. of concentrated aqueous ammonia and ~hen diluted to a volume ~f 1800 ml, with dis-tilled water. When the addition was complete, the resultant gelatinous suspension was stirred an additional 10 minutes, an~ then ~oiled 10 minute~, removed from the hea~, covered, and allowed to stand 15-20 hours at room temperature. The supernatant was decanted and the remaining suspension was centrifuged at 2000 rpm for 10 minutes, The resul~ing sludge was re-suspended in 800 ml. of ~istilled water and again centri~uged at 2000 rpm for 10 minutes. Sufficient distilled water was added to the reqidual solids to give a total volume of 900 ml. Vigorous shaking afforded a homogeneous suspen-sion essentially free of large fragments or aggregates. The 5~32 entire suspension was poured into a Buchner funnel at one time and filtered with application of a weak vacuum. When the filter cake began to crack a rubber dam was applied and the vacuum increased. After one hour, the dam was re-moved and the crack-free, intact f ilter cake wa~ transferred to a flat surface, and dried 15 hours at 90-95C. to give 90-100 g. of white, porous, ~rittle pieces of hydroxylapatite.
Fragmen~s of from one to four cm2 and free of cracks and flssuxes uere placed in an electric kiln and the temperature ~as rai~ed to 120QC, o~er a period of 100 min, after which time t~e kiln and its contents were allowed to cool to room I temperature. There resulted pieces of hard, dense, non-porous~ w~ite, translucent ceramic material~

Dried, Unsintered ~ ~ : Calc'd Hyd ~
Ca 39.89% 36.5, 36.8% 31.7 ! 38~0%
P 18.5% 21.7% 22.8, 19.0, 18.8 Ca/P 1.667 1.30, 1.31 1.08, 1.55, 1.56 5u~sequent to carrying out the above analyses it was disco~ered that the ~lytical techni~ue used did not allow complete dissolution of the samples and the results are therefore inaccurate and highly variable. Notwithstand-ing the above analytical data, the su~stantial homogeneity of this sample was confirmed by the following electron micro-scopic data. Moreover, the product of Example 3 which was prepared ~y a procedure essentially identical to the pro-cedure of Example 2 did have the expected analytical values and was further characterized as homogeneous hydroxylapatite by X-ray diffraction and electron microscopy.

Two~tage replica samples were made by shadowing i58Z

a collodion replica of the sam~le surface with chromium and then coating it with carbon. Transmission electron micro-scopic examination of the replicated samples revealed a fairly uniform grain size with no evidence of pores or S second phase precipitate .in either grain boundaries or within the ~ra~ns t~emselYes in any amount greater than a~out 0.5%, the ~in~mum concentrat1on sensiti~ity of t~e electron micro-scope. A sample of the ceramlc was then polished on SiC
paper to 6~ grit~ th n polis~ed to 3 micrometer diamond 1~ paste on a metallographlc wheel covered with fine nylon .~ cloth~ The sample ~as then etched with 4% hydrofluoric acid :~ for 30 seccnds~ Replicas were then made of the polished and etched surface and the~ viewed by electron microscopy.
: Again no second phases were o~served in the grain boundaries, hDweYer, there was s~a e~idence of small second phase parti-cles ~n the grain Eulk5 Compression strength and modulus of elasticity were determined by conven~ional methods and found to be 56,462 psi r 16 ~ 733 psi and 6.3 x 10~ psi, respectively.
Tens~l~ strength was determined ~y the standard three point ~ending test and found to ~e 9,650 psi + 3,320 pgi .
The thermal expan~ion coefficient was found to be linear between 25~C. and 225C. wi~h a value of 11 x 10-6/C.
+ 10%.
A ha~dne~ ~alue of 48n was found using the standard E~oop ~ethod, The ~ame value was o~tained irrespective of the direction of the applie~ force indicating thereby that the material was isotropic, Porosity was determined qualitatively by immersing 6~82 the test material in a fuchsin dye for 15 minutes, washing the same with water, drying, and then examining the test material for traces of remaining dye. This test was per-formed simultaneously on the non-porous form of the ceramic provided by this invention, a sintered compressed tablet of hydroxylapatite~ and a natural toothc The sintered com-pressed tahlet sho~ed considera~le retention of the dye w~ereas the no~el ceramic of the present invention and the natural tooth e~ ited no ~isifile retention of dye, In another method, the test material was immersed in 6N aqueous ammonia for 15 minutes, then washed with water, dried and wrapped in moist litmus paper, Any ammonia remaining entrap- -ped in surface pores causes the surrounding litmus paper to turn blue, When this test was performed simultaneously on the ceramic of this invention, a sintered compressed tablet O~ hydroxylapatite, and a natural tooth, the litmus paper in contact with the sintered compressed tablet turned blue thereby indicating the presence of entrapped ammonia in the tablet~ No color change was observed in the litmus paper contacting either the novel ceramic of the present invention sr the natural tooth.
EXAM
Following a procedure similar to ~hat described in Example 2 but starting with 3 moles of calcium nitrate and 1.8 moles of diammonium hydrogen phosphate there was ob-tained 3~4 g~ of ~hite, firittle~ porous hydroxylapatite~

.. .......... .
Analysis Calc'd Found Ca 39.89 40.0 P 18,5 18~6 Ca/P 1.667 1~66 ~658;~

Sintering at 1100C. for one hour produced a hard, white, translucant ceramic having a density of 3.10 g/cm3. X-ray diffraction indica~ed the material was homogeneous hydroxyl-apatite. Electron micro copic examination revealed a crys-S tallite size distribution in the range 0.7 to 3 microns andthe absence of pores or second phase precipitates.

;~ A. By followin~ a procedure similar to that described in Example 2 but employing one-half the quantities used therein, an estima~ed 50 g. of hydroxylapatite was precipita-ted from aqueous solution. Following centrifugation and de-cantation the residual mineral sludge was re-suspended in sufficient water to give a t~tal volume of 1 liter and homo-genized in a Waring blender for 2 minutes.
B. A mixture containing 0.5 g. of powdered cellulose (~O.S ~) in 200 ml. of water was blended in a Waring blender for 3 minutes. A 100 ml. aliquot of the homogeneous aqueous suspension of hydroxylapatite was then added and the result-ing mixture blended another 5 minutes. The suspension was then filtered, and the filter cake dried and sintered according to Example 2~ The filter cake after drying showed very little cracking and the ceramic product produced by sintering was sli~htly porous as indicated by ~he fuchsin dye test described hereinabove.
C. A mixtuxe containing 0.5 g. of shredded surgical cotton in 200 ml. of water was blended in a Waring blender for 45 minute~ or until a nearly homogeneous suspension was obtained. A 100 ml. aliquot of the homogeneous aqueous sus-pension of hydroxylapatite described in Example 4A was then added and blending continued an additional lS minutes. The _~9_ resulting suspension was filtered and the filter cake dried and sintered according to Example 2. The ceramic product remained intact and was visibly porous, A. A mixture containing 5 g. of collagen (bovine Achilles tendon~ in 300 ml, of water was blended in a Waring blender for 5 minu~es, The collagen occluded large amounts of water to form a thick gelatinous mass~ A small amount of finely divided collagen ~20-30 mg,) remained in suspension, B. The suspension of the finely divided collagen (250 ml.) was decanted and blended in a Waring blender for 5 minutes with a 100 ml, aliquot of the homogeneous aqueous suspension of hydroxylapatite described in Example 4A, The resulting mixture was filtered an~ the filter cake dried and sintered according to Exampl~ 2, The ceramic product re-mained intact and was substantially non-porous.
; C. Approximately 20 per cent of the thick gelatinous collagen was blended in a Waxing blender for 6 minutes with 150 ml. of the homogeneous aqueous suspension of hydroxyl-apa~ite descri~ed in Example 4A, The resulting mixture was filtered and the filter caXe dried and sintered according to Example 2. The dried cake prior to sintering remained intact and had considerable mechanical strength~ The ceramic produced by sintering was hard, strong and visibly p~rous.

Samples of the ceramic product prepared according to Example 2 were allowed to stand in 1 per cent aqueous sodium fluoride for 12 hours. These materials together with sampleq of untrea~ed ceramic and natural teeth were then ex-~6S82 posed to lO per cent lactic acid. After 3 days the fluoride-treated ceramic showed substantially less attack by lactic acid than either the untreated ceramic or the natural tooth enamel. When allowed to stand in 1 per cent aqueous sodium fluoride for 3 days the ceramic was not visibly attacked by lactic acid after 3 days, and after l month had undergone only slight decomposition whereas untreated samples were heavily decomposed, EX~MPLE 7 By following a procedure similar to that described in Example 2 bu~ employing one-half the quantities used therein, an estimated 50 g. of hydroxylapatite was precipita-ted from aqueous solution. Following centrifugation the mineral sludge was suspended in sufficient water to give a total volume of 500 ml. The suspension was divided into ten equal portions each of which was diluted with 50 ml, of water and treated with ammonium fluoride as follows: To samples 1, 2, 3, 4 and 5 there was added respectively 0, O.1, 0.5, l.0 and 2.0 ml. of aqueous ammonium fluoride containing 0.00085 g. F~/ml. Samples 6, 7 and 8 were treated with 0.5, 1.0 and lO.0 ml., respectively, o aqueous ammonium fluoride containing 0.0085 g. F~/ml. To samples 9 and lO were added 2.0 and 4,0 ml., respectively, of aqueous ammonium fluoride containing 0.045 g. F~/ml. The suspensions were then shaken on a rotary shaker for 1.5 hours and filtered. The filter cakes were pressed 15 minutes with a rubber dam, dried 2 days at 95C. and then heated in an electric kiln to a temperature of 1200C. The resulting ceramics wexe ground into fine powders and sieved through a No, 325 mesh screen. Eighty milligrams of each of the powder samples was mixed with 80 ml. o~ pH 4.1 sodiwm lactate buffer solution ~o~4rvl) at 23C.
and shaken on a Burrell wrist-action shaker. At times of 2, 9, 25 and 40 minu~es after mixing, a 3-ml. aliquot was removed from each sample mixture, immediately filtered to remove undissolved sample and the amount of solubilized ceramic determined by a colorimetric assay procedure. The results are given in Table A. For purposes of comparison a sintered portion of sample 1 was allowed to stand 4 days in 1 ml. of 5% sodium fluoride. The solid was separated, washed thoroughly with water, dried and then subjected to the above-described dissolution assay as Sample lA. The results ar~ included in Table A. It will, of course, be appreciated that the above-described experimental conditions do not approximate in v1vo conditions but were chosen so as to permit sufficient solu~ilization of sample within a reasonable length of time affording thereby an accurate assessment of the relative effect of fluoride ion concentra-tion. Thus, in vivo dissolution rates for ceramic hydroxyl-apatite are expected to be considerably less than the above-observed rates in the strong lactate buffer.
TABLE A

Relative Dissolution Rates of Fluoridated Ceramic Hydroxylapatite Sample Fluoride Conbent (PPM) % Dissolved No. I~a~r~ --- r.... ~~ ~
1 0 -- 9,2 18.5 32.0 39.7 2 17 19 9.2 18,8 29~3 39.0 3 85 lgOa 8.9 17.6 30.0 38.3

4 170 190 10.3 18,3 30.5 37.5

5 340 216 9,9 18,1 29,7 35.2 ~ 850 226 8,~ 17~1 27.7 33~0 71,7~0 470 7~9 18.1 25,7 29,8 817,000 1,4~0 6~7 12,1 19~7 23,3 ~18,000 1,700 6.3 11,5 19~7 23,3 3S 10 ~ 9 ~ `13 7 11-7 a. An apparently incorrect assay.

65~

.. .., . ~ _ Large fragments of dried filter cake about 3-4 mm.
thick prepared accoxding to Example 2 and having Ca/P - 1.64-1.66 were scored and broken into rectangular plates about 14-15 mm. long and 7-8 mm. wide and a small hole was bored through one end. One thousand of these plates were then sintered according ~o Example 2~ and polished to a high gloss using standard lapidary techniques. The resulting ceramic bodies having a density of 3.12-3.14 g/cm3 were in the form of rectangular plates approximately 10-ll mm, long, 4-5 mm, wide and 2-3 mm. thick and having a hole at one end through which a length o wire was attached. The plates, which could thereby be suspended to any desired depth in a test tube, were used as test surfaces in the evaluation of dental plaque inhibiting agents as descri~ed hereinabove.
EX~MPLE 9 A solution containing n. 24 mole of diammonium hydrogen phosphate in 600 ml. of distilled water was adjusted to pH 11~4 with 340 mlc of concentrated ammonia and the final volume brought to 1280 ml. with ~istilled water~ This solu-tion wa~ added ~ropwise over 30 minutes to a vigorously stirred solution containing 0.4 mole of calcium nitrate in 360 ml. of distilled water previously adjusted to pH 11 with concentrated ammonia and diluted to a volume of 720 ml, with distilled water. The resulting suspension was stirred with-out boiling and 250 ml. aliquots were periodically removed and the pro~ucts isolated, washed and dried as described in Example 2. All samples wera then heated one hour at 1100C.
and the composition of the resultant ceramic products deter-3~ mined by X-ray diffrac~ion. The results are given in Table B~

~65~3~

TABLE B

Phases observed by Standing X-ray Diffraction T~me % %
5SampleStirring Before Elemental Analysis Hydro~yl- Whit-No. Time Isolation % Ca _ Ca/Papatitelockite 5 min. -- 36.6 18.2 1.5517 83 2 45 min. ~ 21 79 3 2 k~r. -- 36.6 18.0 1.5739 61 10 4 4.5hr -- -- -- 98 2a 7 hr -- 37.0 17.0 1.6898 2a

6 7 hr. 17 hr. 37.2 17~0 1.69100 0

7 24 hr. -- 37,4 17.1 1.69100 0

8 48 hr. -- 37.~ 16.8 1.72100 0 15a. These values border on the minimum concentration sensitivity of ~he X~ray difractometer (2-3%) ; and the accuracy thereof is thus questionable.

A, Following a p~ocedure similar to that described in 20Example 2 but using 0.3 moles of calcium nitrate and 0.2 moles of diammonium hydrogen phosphate there was obtained a hard, brittle, porous product having the following elemental composition: Ca = 38.3596; P = 19.77%; Ca/P = 1.52. This material was heate~ 1 hour at 1200~C. to give a strong, hard, 25 non-porous, white, somewhat opas~ue ceramic material compris-ing approximately 4096 hydroxylapatite and 60% whitlockite as indicated by X-ray ~iffraction.
B. When the above reaction was carried out wi~h in-vexse addition of ~he starting materials there was obtained 3n a product comprising approximately 40% hydroxylapatite and 60% whitlockite, and having Ca/P ~ 1.52 and a density of 2.982 g/cm3.
EX~IP~E 11 A solution containing 0.0625 mole o diammonium 35 hydrogen phosphate in 150 ml. of distilled water was treated with 95 ml. of concentrated ammonia and the final volume ~9658~

hrought to 320 ml, with distilled water. This solution was added dropwise over 30 minutes to a vigorously stirred solu-tion containing ~.1 mole of calcium nitrate and 2.5 ml. of concentrated ammonia in 180 ml, of distilled water. The re-sulting suspension was s~irred 5 minutes then cooled in ice for 45 minutes and the suspended solid isolated, washed and dried as described in Example 2 to give a hard, brittle, porous, white solid having the following elemental composi-tions: Ca = 35.4%; P = 18.59%; Ca/P = 1.46. This material 1~ was heated 1 hour a~ 1350C. ~o give a strong, hard, non-porous somewhat opaque ceramic product compri~ing approxim-ately 14~ hydroxylapatite and 86% whitlockite as indicated by X-ray diffraction.
The products of Examples 1-11 correspond to the articles of manufac~ure of this invention and have the physical characteristics thereof as described hereinabove.
The articles of manufacture produced according to Examples 1, 2, 3, 5B and 6-8 are strong, har~, dense, white, translucent ceramic bodies comprising substantially pure, iso~ropic polycrystalline hydroxylapati e free of pores, and having a compression strength in the approximate range 35,000 to 125,000 psi, a tensile strength in the approximate range 3,000 to 30,000 psi, a linear thermal coefficient of expansion in the approximate range 10 to 12 ppm per degree 2S Centigrade, a Xnoop hardness in the approximate range 470 to 500 and a modulus of elasticity of approximately 6 x 106 psi, and ~eing ~haracterized ~y cleavage along smooth curved planes, and ~y the a~sence of ~irefringence under polari~ed light.
~he articles of manufacture produced according 6~8%

to Examples 4 and 5C although comprising the same material produced according to Examples 1, 2, 3, 5B and 6-8 have in-troduced therein spaces or pores of varying number and size.
It will be obvious, of course, that the introduction of pores into said articles effects a change in the physical properties thereof, for example, a reduction in compressio~
strength, tensile strength, elasticity and hardness.

A composition suitable as a dental cement and dental filling agent was prepared as follows:
A To a solution containing 2~ mg, of thé condensa-tion product of N-phenylglycine and glycldyl methacrylate (descri~ed in United States Patent 3,200,142 and referred to therein as NPG-GMA) in 7 ml, of ethanol there was a~ded 2.0 g. of powdered ceramic hydroxylapatite. After swirling 5 minutes the ethanol was evaporated under vacuum at room temperature and the residual solid was dried 2 hrs. at 1 mm. Hg.
B. An 80-mg. sample of the above material was mixed with 0.4 mg. of benzyl peroxide and 30 mg. of a 1:2 mixture of hydroxyathyl methacrylate and the reaction product of bisphenol A and glycidyl methacrylate as described in United States Patent 3,066,112 an~ referred to in the art as Bis-GMA.
The resulting mixture was placed in a cylindrical steel mold wherein it hardened in 3-5 minutes. Compression strength was determined for four cylindrical plugs so-prepared. The average value was 24 r 350 psi, A mixture comprising 60 parts of powdered ceramic hydroxylapatite, 13 parts of hydroxyethyl methacrylate, 27 -36~

~0~6582 parts of the condensation product of bisphenol A and glycidyl methacrylate, 0.3 par~s of N,N-bis-(2-hydroxyethyl)-~-tolu-idine and 0.8 parts of benzoyl peroxide was blended thoroughly to give a thin, free-flowing formulation useful as a dental pit and fissure sealant. The mixture was poured into a cylindrical steel mold wherein it hardened in about 3 minutes.
Compression str~ngth was determined for seven cylindrical plugs so-prepared. The average value was 20,400 psi~
~XaMPLE 14 1~ The following is an example of a formulation useful as a dental filling material.
. To S ml. of 2-propanol was added O.S g. of powdered ceramic hy~roxylapatite. The 2-propanol was then evaporated under vacuum at room temperature in order to remove any water of hydxation from the surface of the ceramic. To 120 mg. of powdered hydroxylapatite so-treated was added 0.3 mg, of benzoyl peroxide followed by 40 mg. of a mixture comprising the condensation product of bisphenol A and glycidyl meth-acrylate, triethylene glycol dimethacrylate and N,N-bis-(2-hydroxyethyl)-~-toluidine which mixture is sold by Lee Pharmaceuticals under the tradename Epoxylite~ HL-72. The mixture was spatula~ed to a smooth paste and placed into cylindrical steel molds a~d allowed to stand 4 hours. The cylindrical plugs were removed from the molds and 3 specimens were tested and found to have an average compression strength of 22,300 psi.

To a solution containing 30 mg. of the condensa-tion product o N-phenylglycine and glycidyl methacrylate in 7 ml. of ethanol was added with swirling 1 g. of powdered z ceramic hydroxylapatit~. The ethanol was evaporated under vacuum at room temperature. To a mixture containing 180 mg, of powdered ceramic hydroxylapatite so-treated and 3,0 mg. of benzoyl peroxide was added to 74 mg. of a mixture containing 60 parts of the condensation product of bisphenol A and glycidyl methacrylate and 40 parts of triethylene glycol dimethacrylate and the resulting aggregate spatulated to a smooth pas~e which was placed into cylindrical steel molds and allowed to stand 3 hours. The cylindrical plugs were removed from the molds and 4 specimens were tested and found to have an average compression strength of 22,300 psi~

A composi~ion suitable as a dental and orthodontic cement or as a temporary dental filling agent was prepared by mixing together 1~0 mg. of powdered ceramic hydroxylapa-tite, 300 mg, of zinc oxide and 300 mg, of 40% aqueous poly-acrylic acid. The resulting mixture was placed in cylindri-cal steel molds wherein it hardened in about 3-5 minutes.
The cylindrical plugs were removed from the molds and 4 specimens were tes~ed and found t~ have an average compres-sion strength of 12,400 psi. Another 5 specimens were found to have an average diametral tensile strength of 1630 psi, The 40% aqueous polyacrylic acid and the zinc oxide were ob-tained as the liquid and solid components respectively of a commercial polycarboxylate cement available from ESPE G,m.b.H., West Germany, under the tradename Durelon~, EX~MPLE 17 A composition suita~le as a dental aement and dental filling agent was prepared by mixing together 6 parts by weight of 40 per cent aqueous polyacrylic acid with a mix-513~:

ture containing 6 parts by weight of powdered ceramic hydroxyl-apatite and 4 parts by weight of zinc oxide. The resulting composition had a setting time of about 5 to 10 minutes. The 40 per cent aqueous polyacrylic acid and the zinc oxide were obtained as the liquid and solid components respectively of a commercial polycarboxylate cement available from ESPE
G.m.b~H,, West Germany, under the tradename Durelon~.

The following is an example of a dental filling composition:
_ Per cent by Wei~ht Styrene modifi~d polyester resin ~Glidden Glidpol G-136) 29.2 Benzoyl peroxide 0.7 Styrene 0.6 MethacryloY.ypropyltrimethoxysilane 1.5 Ceramic hydroxylapatite 6~.O
EX~MPLE 19 The following is an example of a composi~ion sui~-able as a dental cement, cavity liner and pulp capping agent:
In redient Epo~y resin (Union Carbide ERL2774) 67 N-3-oxo~ dimethylbutylacrylamide 23 Ceramic hydroxylapatite 10 The following is an example of a composition suit-a~le for the fa~rication of an artificial tooth or set of teeth.
A mixture containing 60 parts by weight of ceramic hydroxylapatite of approximately 150 to 200 mesh and 40 parts ~L~396~Z
by weight of powdered polymethyl methacrylate is blended with approximately 15 parts by weight of liquid monomeric methyl methacrylate and the resulting mixture allowed to stand in a sealed vessel at room temperature until the mate-rial no longer adheres to the walls of the vessel and has a non-sticky plastic consistency. The material is then packed into an appropriate mold and the mold and its contents immersed in water which is heated to ~oiling over a period of about one hcur and maintained at that temperature for 39 1~ minutes. The mold is then allowed to air cool for about 15 minutes and finally cooled in cold tap water.
The bio-compatibility of the novel ceramic form of hydroxylapatite afforded by the present invention was con-firmed by implantation studies wherein it was found that no inflammatory response was elicited when chips of the ceramic prepared according to the method of Example 1 were implanted intraperitoneally in rats or when inserted subcutaneously on the backs of rabbits, and no resorption of the ceramic was evident after 28 days, Pellet~ of ceramic hydroxylapatite prepared by a method similar to that described in Example 3 were surgically implanted in ~he femurs of dogs. The implants were monitored in vivo by periodic X-ray. After respective periods of one month and six months the animals were sacrificed and the femurs containing the implants were removed~ The femurs were sectioned at the implant site and examined ~y both optical and scanning electron microscopy. Both the one-month and six-months implants were characterized ~y normal healing, strong ~inding of new bone to the implant surface with no interven-ing fibrous tissue, no evidence of inflammation or foreign ~ody response and no resorption of the implant material.

Claims (24)

The embodiments of the invention in which an ex-clusive property or privilege is claimed are defined as follows:

1. A process for preparing a polycrystalline, sintered ceramic in macroform which comprises reacting calcium ion with phosphate ion in aqueous medium and at pH of about 10-12 to produce a gelatinous precipitate of a phosphate of calcium having a molar ratio of calcium to phosphorus between the approximate molar ratio of calcium to phosphorus in hydroxyl-apatite and that in whitlockite, separating said precipitate from solution, heating a cohesive gelatinous mass of said precipitate up to a temperature of at least 1000°C. but below that at which appreciable decomposition of hydroxylapatite occurs, and maintaining said temperature for sufficient time to effect the sintering and substantially maximum densification of the resulting product.

2. A process according to claim 1, in which the precipitate is heated to a temperature of at least about 1050°C.

3. A process according to claim 2, in which the ratio of reactants used in the reaction is chosen so that a pre-cipitate having substantially the molar ratio of calcium to phosphorus in hydroxylapatite is formed.

4. A process according to claim 3, in which the precipitate has a molar ratio of calcium to phosphorus in the approximate range of 1.62-1.72, the temperature being maintained up to about 1250°C for approximately 20 minutes to 3 hours.

5. A process according to claim 4, wherein the temper-ature is maintained at approximately 1100°C. to 1200°C. for approximately 0.5 to 1 hour.

6. A process according to claim 1, in which a precipi-tate having a molar ratio of calcium to phosphorus in the approximate range 1.44-1.60 is formed, said precipitate being heated up to a temperature of about 1350°C. for approximately 20 minutes to 3 hours.

7. A process according to any one of claims 1, 4 and 6, wherein the calcium ion is provided by calcium nitrate and the phosphate ion is provided by diammonium hydrogen phosphate.

8. A process according to claim 1, wherein the ceramic produced is allowed to stand in about 0.5 to 5 per cent aqueous sodium fluoride for about 12 hours to five days.

9. A process according to claim 1, wherein about 0.4 to 0.6 per cent by weight of an organic binder is added to the precipitate, said organic binder being volatilized during said heating process.

10. A process according to claim 9, wherein the organic binder is collagen.

11. A process according to claim 1, for producing a porous form of the ceramic, wherein about 5 to 25 par cent by weight of an organic binder is added to the precipitate, said organic binder being volatilized during said heating process.

12. A process according to claim 11, wherein the organic binder is powdered cellulose, cotton, or collagen.

13. A process according to claim 1, wherein 0.1 to 1 per cent by weight of fluoride ion is added to the precipi-tate prior to separating said precipitate from solution,

14. A process according to claim 1, in which a pre-cipitate having a molar ratio of calcium to phosphorus in the approximate range 1.46-1.57 is formed, said precipitate being heated up to a temperature of about 1350°C. for approximately 20 minutes to 3 hours

15. A process according to any one of claims 1, 4 and 6, wherein an integral mass of the precipitate subjected to the sintering is sufficiently free of cracks or fissures that said mass does not fracture during the sintering process.

16. A process according to any one of claims 1, 4 and 6, wherein a shaped product is produced by cutting, shaping or molding the precipitate while still in a cohesive gelatin-ous state prior to the sintering.

17. A process according to any one of claims 1, 4 and 6, wherein a shaped product is produced by cutting or shaping the precipitate after a preliminary drying of the gelatinous precipitate.

18. A polycrystalline, isotropic sintered ceramic having cleavage along smooth curved planes comprising either substantially pure hydroxylapatite or biphasic hydroxylapatite-whitlockite when produced by the process according to any one of claims 1, 3 or 6, or by an obvious chemical equivalent thereof

19. A translucent, isotropic, polycrystalline, sin-tered ceramic comprising substantially pure hydroxylapatite having an average crystallite size in the approximate range 0.2 to 3 microns, said ceramic having a density in the approximate range 3.10 to 3.14 g/cm3, having sub-stantially no pores, and having cleavage along smooth curved planes, when produced by the process according to claim 3 or 4, or by an obvious chemical equivalent thereof.

20. A strong, hard, dense, isotropic polycrystalline sintered biphasic ceramic comprising as one phase from about 14 to 98% by weight of hydroxylapatite and as a second phase from about 2 to 86% by weight of whitlockite, said ceramic having cleavage along smooth curved planes, when produced by the process according to claim 6, or by an obvious chemical equivalent thereof.

21. A translucent, isotropic, polycrystalline, sin-tered ceramic comprising substantially pure hydroxylapatite having an average crystallite size in the approximate range 0. 2 to 3 microns, said ceramic having a density in the approximate range 3.10 to 3 14 g/cm , having sub-stantially no pores, and having cleavage along smooth curved planes and having incorporated therein an amount of fluoride ion effective in substantially reducing the rate of decomposition of said ceramic by lactic acid when prepared by the process according to claim 8 or 13, or by an obvious chemical equivalent thereof.

22. A strong, hard, dense, isotropic, polycrystalline sintered biphasic ceramic comprising as one phase from about 14 to 98% by weight of hydroxylapatite and as a second phase from about 2 to 86% by weight of whitlockite, said ceramic having cleavage along smooth curved planes and having incorporated therein an amount of fluoride ion effective in substantially reducing the rate of decomposition of said ceramic by lactic acid when prepared by the process according to claim 8 or 13, or by an obvious chemical equivalent thereof.

23. A dental restorative composition which comprises about 10-90 per cent by weight of a ceramic according to claim 18, said ceramic being in finely divided form, and about 10-90 per cent by weight of a dentally acceptable polymerizable or polymerized bonding material,

24. A dental restorative composition which comprises about 10-90 per cent by weight of a ceramic produced by the process according to any one of claims 1, 3 and 6, said ceramic being in finely divided form, and about 10-90 per cent by weight of a dentally acceptable polymerizable or polymerized bonding material.