IE42442B1 - Ceramic material - Google Patents

Abstract

1522182 Calcium phosphate ceramics STERLING DRUG Inc 22 July 1975 [2 Aug 1974 7 July 1975] 30706/75 Heading C1A A polycrystalline, sintered ceramic for use as a bone or tooth substitute is made by reacting calcium ion with phosphate ions in aqueous medium at pH of 10-12 to produce a gelatinous calcium phosphate precipitate having a Ca:P molar ratio of 1À44-1À72, separating the precipitate from the solution and heating the precipitate to above 1000‹C but below the temperature at which appreciable decomposition of hydroxylapatite occurs and maintaining said temperature for a sufficient time to effect sintering and maximum densification. When the Ca:P molar ratio is in the range 1À62-1À72 a translucent, isotropic, polycrystalline hydroxylapatite having an average crystalite size of 0À2-3 microns, a density of 3À1-3À14 g/cm3, substantially no pores and having cleavage along smooth curved planes is obtained. When the Ca:P ratio is in the range 1À44-1À60, preferably 1À46-1À57 a dense isotropic two-phase ceramic is obtained comprising 14-98% hydroxylapatite and 2-86% whitlockite, said ceramic having substantially no pores and having cleavage along smooth curved planes. The reactants are preferably Ca(NO 3 ) 2 and (NH 4 ) 2 HPO 4 . 0À4-0À6% of an organic binder, e.g. collagen, may be added to the precipitate to prevent cracking during drying. Porous forms of the ceramic may be made by including 5-25% by weight of organic binders such as powdered cellulose, starch, cotton or collagen to the precipitate. Fluoride ions may be introduced into the ceramic, e.g. by standing in 0À5-5% aqueous NaF for 12 hours-5 days.

Description

PATENT APPLICATION BY (71) STERLING DRUG INC., A CORPORATION ORGANIZED UNDER THE LAWS OF THE STATE OF DELAWARE, UNITED STATES OF AMERICA, OF 90 PARK AVENUE, NEW YORK, STATE OF NEW YORK, UNITED STATES OF AMERICA.

Price 12Ap The present invention relates to ceramics and the preparation thereof, particularly for use in dentistry and orthopaedics.

Much current dental 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 material for bone. Dental research also is directed to preventing the formation of dental plague, the putative agent of both dental caries and periodontal disease. lo Currently used filler materials for dental restorative compositions such as quartz, alumina, silicates, glass beads, etc., bear little chemical or physical resemblance to tooth enamel. A 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 leakage and new caries formation. The dental profession, therefore, has long desired a dental filling composition with physical properties which closely conform Lo those of natural tooth structure.

Furthermore, in the field of surgical prosthetic materials, which is currently dominated by high-strength, non-corrosive alloys, there is a recognized need for a material which more closely resembles biological hard tissue as the problems of tissue acceptance and adherence have not as yet been completely resolved [Hulbert, et al., Materials 43443 Science Research 5^, 417 (1971) ] , In research directed to the discovery of effective anti-plaque chemotherapeutic agents there is need for a standard test material having a tooth-like surface with respect to both plaque formation and substantiveness of chemical 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 elaborate cleaning before use. Consequently there are used other materials upon which dental plaque will accumulate euch as powdered hydroxylapatite, acrylic teeth, 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 finding 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.

Hydroxylapatite, Ca10(PO4)6(OH)2, also known as basic calcium orthophosphate, the mineral phase of tooth and bone, has been suggested as suited to the various purposes outlined 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 hydroxylapatite. Moreover, the method is of course dependent on the 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 temperatures . · Bett, et al., [J. Amer. Chem. Soc. £9, 5535 (1967)] described the preparation of particulate hydroxylapatite with stoichiometry varying from Ca/P = 1.67 to 1.57. The materials so-produced contained large intercrystalline pores.

It was also reported that upon heating up to 1000°C. the calcium-deficient hydroxylapatites underwent partial transformation to the whitlockite phase.

United States Patent 3,787,900 discloses a bone and tooth prosthetic material comprising a refractory compound 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 proven fully satisfactory. Thus, Roy and Linnehan [Nature, 247, 220 (1974)] described an elaborate hydrothermal exchange process whereby the skeletal calcium carbonate of marine coral was converted to hydroxylapatite. The material so produced necessarily 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 material.

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 -442442 and approximately 30 per cent α-whitlockite, which is Ca3or 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 resulting ceramic was porous and held a maximum compression strength of approximately 17,000 psi.

Bhaskar et al., [Oral Surgery 32, 336 (1971)] described the use of a biodegradable 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 10-12 to produce a gelatinous precipitate of a phosphate of calcium having a molar ratio of calcium to phosphorus in the range of 1.44-1.72 (which is, in essence between the approximate molar ratio of calcium to phosphorus in hydroxylapatite and that in whitlockite), separating said precipitate from solution, heating 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 dehsification of the resulting product.

In accordance with one aspect of the present invention as specified in detail hereinafter there is provided a new ceramic form of hydroxylapatite - 5 4 2 4 12 comprising substantially pure hydroxylapatite which is hard, dense, and takes a high polish. Chemically it is very similar to tooth enamel. Moreover, this new material can be prepared in a relatively simple manner from inexpensive starting materials and is obtained in uniform quality, thereby avoiding 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 that of natural tooth enamel.

The dental and surgical impant material made available by the instant invention is hard, strong, and completely 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 material, thereby permitting tissue ingrowth.

As will be apparent, the characteristics of the new article of manufacture herein described and claimed make it ideally suited to making discs, plates or rods for use in testing dental anti-plaque agents.

Another aspect of this invention as specified in detail hereinafter provides a novel two phase ceramic material comprising hydroxylapatite and whitlockite. As described more completely hereinbelow this two phase ceramic is hard, dense, non-porous, bio-compatible, easily fabricated in any desired shape or form, and by virtue of the known resorbable nature of whitlockite, is useful as a strong, partially resorbable surgical implant material and can also be incorporated in dental restorative compositions.

While a certain degree of porosity in surgical im6 43442 plant materials may be advantageous in permitting circulation of body fluids and tissue ingrowth, this same porosity necessarily reduces the mechanical strength of the implant.

The two phase ceramic afforded by this invention, although dense, mechanically strong and substantially non-porous, may nonetheless permit circulation of body fluids and tissue ingrowth because the whitlockite phase contained therein is slowly resorbed from the implant and replaced by natural biological hard tissue.

The novel physical form of hydroxylapatite, which is distinguished from the biological and geological forms and from all previously known synthetic forms as hereinafter indicated, consists of a strong, hard, dense, white, translucent isotropic, polycrystalline sintered ceramic material comprising substantially pure hydroxylapatite having an average crystallite size in the range 0.2 to 3 microns, a density in the range 3.10 to 3.14 g/cm , and having substantially no pores and having cleavage along smooth curved planes. Moreover, as ordinarily produced, the above described material has a compression strength in the range 35,000 to 125,000 psi, a tensile strength in the range 3,000 to 30,000 psi, a linear thermal coefficient of expansion in the range 10 to 12 ppm per degree Centrigrade, a Knoop hardness in the range 470 to 500 and a modulus of elasticity of approximately 6 x 10® psi, and is non-birefringent under polarized light. The initial evaluation of the novel hydroxylapatite ceramic had 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 range 35,000 to 75,000 psi, a tensile strength in the range 3,000 to 50,000 psi, a linear thermal coefficient of expansion in the range 10 to 12 ppm per degree Centigrade, a Knoop hardness in the range 470 to 500 and a modulus of elasticity of 6 χ 103 psi, and having cleavage along smooth curved pianos, and not having birefringence under polarized light.

The term dense as used herein designates a highly compact arrangment of particles substantially lacking spaces ox unfilled intervals therebetween.

In contrast to the above-described form of hydroxylapatite, geological hydroxylapatite and synthetic hydroxylapatite prepared by a hydrothermal process are macrocrystalline, fracture along flat planes, and are birefringent Biological hydroxylapatite is distinguished by generally containing 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 strength of 1500 psi.

In addition to the above-described properties of the novel ceramic form of hydroxylapatite provided by this invention this material is also completely bio-compatible and therefore eminently suitable 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 device for 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 substrates in evaluating dental plaque-inhibiting agents according to the procedures described by Turesky, et al., supra. After use the ceramic bodies are simply re-polished to provide a new test surface.

As ordinarily produced the ceramic of this invention is not only dense but also non-porous, and whereas a non-porous material is essential for dental applications, a certain degree of porosity in implant devices may be advantageous in permitting circulation of body fluids and tissue ingrowth. Varying degrees of porosity can be imparted to the instant ceramic in a manner similar to that described by Monroe, et al., supra. Thus, organic materials such as starch, cellulose, cotton, or collagen in amounts ranging 942442 from 5 to 25 per cent by weight may be admixed with the gelatinous precipitate of hydroxylapatite. During the subsequent sintering process the organic materials are burned out thereby creating holes and channels in the otherwise nonporous ceramic product. Alternatively, porosity can be produced mechanically by drilling or machining holes and openings 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 implantion while the exposed tooth surface remains non-porous. Implantation can be accomplished as reported by Hodosh, et al., Journal of the American Dental Association 70, 362 (1965). Alternatively the ceramic provided by the invention can be composited with a polymerizable or polymerized bonding material as described hereinbelow and the resulting composition used as a coating for metal implants as described in United States Patent 3,609,867 The second aspect of this invention comprises a strong, hard, dense, white, isotropic, polycrystalline sintered ceramic product comprising as one phase from 14 to 98% by weight of hydroxylapatite and as a second phase from 2 to 86% by weight of whitlockite and having substantially no pores and having cleavage along smooth curved planes.

Whitlockite, also known as tricalcium phosphate, is a mineral having the chemical formula Ca., (P0,)„ and which j 4 d. may exist in either an « or β crystalline phase. The term whitlockite as used herein designates either the u or the β phase or a mixture of the two phases.

The two phase 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 whitlockite have different physical properties, and therefore the physical properties, e.g., density and optical properties of the biphasic ceramic will depend on the relative amounts of hydroxylapatite and whitlockite present therein. For example, the theoretical density of whitlockite is less than that of hydroxylapatite and accordingly the observed density of a sample of biphasic ceramic containing about 40% hydroxylapatite and 60% whitlockite was 2.98 g/cm3 compared to a density of 3.10 g/cm3 for a sample of hydroxylapatite ceramic.

The above-described two phase ceramic is also biocompatible and therefore suitable as a surgical prosthetic material. Thus, this material can be cast or machined into bone and joint prostheses or into any shape suitable for filling a void or defect in a bone. The whitlockite contained in a prosthetic article fabricated from this two phase ceramic will eventually be resorbed and replaced by the ingrowth of natural biological hard tissue. Of course, the extent of tissue ingrowth will depend on the amount of resorbable whitlockite contained in the ceramic.

As ordinarily produced the two phase ceramic of this invention is non-porous. However, if desired, varying degrees of porosity can be imported to the ceramic as described hereinabove for the novel ceramic form of hydroxylapatite.

The two phase ceramic may also be rendered acid resistant by fluoridation as described hereinbelow for 11ceramic hydroxylapatite.

The above-described ceramic form of hydroxylapatite can be prepared by precipitating from aqueous medium at a pH of 10-12 hydroxylapatite having a molar ratio of calcium to phosphorus in the range 1.62-1.72, separating the precipitated hydroxylapatite from the solution, and heating the hydroxylapatite thus obtained at a temperature of at least 1000°C and for a time sufficient to effect the sintering 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 10 - 12. Any calcium- or phosphate-containing compounds 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 hydroxylapatite lattice, or otherwise interfere with precipitation or isolation of substantially pure hydroxylapatite. Compound which provide calcium ion are, for example calcium nitrate, calcium hydroxide and calcium carbonate. Phosphate ion may be provided by diammonium hydrogen phosphate, ammonium phosphate and phosphoric acid. In the present method, calcium nitrate and diammonium hydrogen phosphate are the preferred sources of calcium and phosphate ions respectively.

The preparation of the novel form of hydroxylapatite is conveniently carried out wherein the ratio of reactants used in the reaction is chosen so that a precipitate having substantially the molar ratio of calcium to phosphorus in hydroxylapatite is formed. First, calcium nitrate and diammonium hydrogen phosphate in a molar ratio of 1.67 to 1 are interacted in aqueous solution 43443 at 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 time sufficient to allow the calcium to phosphorous ratio of the suspended hydroxylapatite to reach a value of about 1,62-1.72. This is conveniently accomplished either by stirring the suspension at room temperature for 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. Preferably the suspension is boiled for 10 minutes and then allowed to stand at room temperature for 15-20 hours. The hydroxylapatite is then separated from the solution by suitable means, for example by centrifugation and vacuum filtration. The gelatinous product thus collected contains a large amount of occluded water, much of which can be removed by pressing. If desired, the resulting wet claylike 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 be slowly heated up to the sintering temperature of 1050°C. to 1250°C. at which point all remaining water will have been driven off. Maintaining the temperature at 1050°C. to 1250°C. for approximately 20 minutes -1342442 to 3 hours will then effect the sintering and maximum densification of the product. Ordinarily it is preferred to isolate the dried product prior to sintering. Thus, the wet product may be dried at 90°C. to 900°C. for 3 to 24 hours or until the water content thereof has been reduced to 0 to 2 per cent. It is generally preferred to use drying conditions of 90°C. to 95°C. for about 15 hours or until the water content has been reduced to 1 to 2 per cent. The hydroxylapatite obtained in this manner is brittle and porous, but has considerable mechanical strength. Some separation or cracking of the clay-like material may occur on drying especially if a thick filter cake is used. However, pieces as large as 100 cm and 3 mm. in thickness are readily obtained. Separation or cracking during drying can be minimized or prevented by adding to the precipitated hydroxylapatite, usually the freshly precipitated suspension, 0.4 to 0.6 per cent by weight of an organic binder such as collagen, powdered cellulose or cotton, about 0.5 percent of collagen being preferred. The organic binder is volatilized during subsegu20 ent sintering and physical characteristics of the ceramic product appear substantially unchanged from those of the product produced in the absence of such a binder. Of course, the use of substantially larger amounts of organic binder will result in a porous ceramic product 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 precipitate into roughly the form desired as the end product, taking into account the shrinkage mentioned above which occurs on sintering.

The macroform bodies of precipitate prior to sintering should preferably be substantially uniform and free of defects. The presence of cracks or fissures can cause the pieces to fracture during the sintering process. The products are then sintered at 1000°C. to 125O°C. for 20 minutes to three hours, the temperatures and times being inversely related. Sintering is preferably effected at 1100°C. to 1200°C. for 0.5 to 1 hour. The hard, dense ceramic articles so produced can then be polished or machined using conventional techniques.

Xt is critical, in the above process, to prepare the hydroxylapatite as a geletinous precipitate from aqueous solution for it is only in this 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 hydroxylapatite cannot be reconstituted into this cohesive gelatinous state. If, for example, powdered hydroxylapatite is suspended in water and filtered there is obtained a non-cohesive, particulate filter cake which simply dries and crumbles and cannot be shaped, molded or converted into a macroform of the ceramic. Moreover, although powdered hydroxylapatite can be mechanically compressed Into a shaped body, such as a tablet, when sintered according to the method of this Invention the product obtained 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 process, it is generally believed that calcium and phosphate ions initially combined to form a calcium-deficient hydroxyl15 apatite having a calcium-to-phosphorus ratio of about 1.5.

In the presence of calcium ion, this species then undergoes slow transformation to hydroxylapatite with a calcium-tophosphorus ratio of 1.67. [Eanes et al., Nature 208, 365 (1965) and Bett et al., J. Amer. Chem. Soc. 89, 5535 (1967).] Thus, in order to obtain a ceramic comprising substantially pure hydroxylapatite it is imperative in the process of this invention that the initial gelatinous precipitate of hydroxylapatite 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 1.62 to 1,72. Substantial deviation from this range results in a less translucent ceramic product. For example, if hydroxylapatite is precipitated at room temperature and collected within 2 hours following precipitation the calcium to phosphorus ratio thereof is found to be about 1.55-1.57 and the ceramic ultimately, produced therefrom is opaque and found by X-ray diffraction to be a mixture comprising hydroxylapatite and whitlockite. In fact, as described more particularly hereinbelow, material having a calcium to phosphorus ratio of about 1.44-1.60 is useful in the preparation of the two phasic ceramic described hereinabove. Thus, while the process claimed herein affords a translucent ceramic comprising substantially pure hydroxylapatite, in view of the incompletely understood mode of formation of hydroxylapatite in aqueous medium it may be advantageous to monitor the hydroxylapatite formation in order to ascertain that the desired calcium to phosphorus stoichiometry has been achieved and that the product when sintered will comprise substantially pure hydroxylapatite. This is conveniently accomplished by -1642442 removing an aliquot of the hydroxylapatite suspension, separating the product, drying and sintering as described hereinabove, and subjecting 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 calcium-to-phosphorus of 1.62 - 1.72 is converted to the ceramic by heating at a temperature of from at least 1000°C. At 1000°C. complete sint0 tering and maximum densification may require 2-3 hours while at I2OO°C. the process may be complete in 20 - 30 minutes. It is preferred to effect sintering at a temperature of approximately 1100°C. for about one hour. A temperature substantially below 1000°C. will result in incomplete sintering irrespective of the length of heating whereas heating above 125O°C. for more than one hour will result in partial decomposition of hydroxylapatite to whitlockite. Heating at 135O°C. for over 20 minutes will also result in partial decomposition. 2o The above-described two phase ceramic comprising one phase of hydroxylapatite and a second phase of whitlockite can be prepared by precipitating from aqueous solution at a pH of 10 - 12 a calcium phosphate compound having a molar ratio of calcium to phosphorus in the range 1.44 - 1.60, preferably 1.46 - 1.57, separating the precipitate from the solution and heating the solid thus obtained at a temperature of at least 1000°C. and for a time sufficient to effect the sintering and maximum densification thereof.

The calcium phosphate compound having the required )0 stoichiometry, viz. Ca/P = 1.44 - 1.60 is obtained by interacting calcium ion with phosphate ion in aqueous medium at - 17 424 42 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 hydrogen phosphate are the preferred reagents.

Thus, the two phase ceramic may be prepared by interacting calcium nitrate and diammonium hydrogen phosphate in a molar ratio of 1.67 to 1, i.e., as described hereinabove for the preparation of single phase ceramic hydroxylapatite provided that the initial gelatinous precipitate is not heated and is allowed to remain in contact with the original solution for a period not to exceed about 4 hours or alternatively that the molar ratio of clacium to phosphorus of the precipitate not be allowed to exceed a value of 1.60.

As described hereinabove for the preparation of single phase ceramic hydroxylapatite, the calcium phosphate precipitate is separated from the solution, washed, optionally shaped or molded into a convenient form, and if desired dried and isolated prior to sintering.

The precipitated calcium phosphate, usually the freshly precipitated suspension may also be treated with organic binders of fluoride ion as described hereinabove for single phase hydroxylapatite.

Sintering is usually effected by heating at 1000°C. for a minimum of 3 hours and up to 135O°C. for a maximum of 20 minutes.

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 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 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 about 61% whitlockite. Isolation of the product 4.5 hours following precipitation ultimately affords a ceramic containing an estimated 2% whitlockite, an amount barely detectable by X-ray diffraction which has a minimum concentration sensitivity of 2-3%. Of course, if the product is allowed to remain in contact with the original solution beyond about 7 hours the ceramic ultimately obtained is substantially single phase hydroxylapatite.

Alternatively, the two phase 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 biphasic ceramic is conveniently carried out as described hereinabove for the preparation of single phase ceramic hydroxylapatite with the exception that the reactants, viz. calcium nitrate and diammonium hydrogen phosphate are interacted 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 be further enriched in the whitloekite phase by combining the features of the two preceding procedures, i.e., by interacting calcium ion with phosphate -194 2 4 4 2 ion in a approximate molar ratio Of 1.50-1.60 to 1 and isolating the precipitated calcium phosphate compound within a short time, preferably 5 minutes to 4 hours, following precipitation. Ceramics so-produced comprise 10 - 30% hydroxylapatite and 70 - 90% whitlockite.

Hydroxylapatite is known to undergo decomposition to produce whitlockite at about 125O°C. and it will therefor be appreciated that prolonged heating of the single phase ceramic hydroxylapatite of this invention at temperatures of about 125O°C. or higher for sufficient time will result in partial decomposition of said hydroxylapatite to whitlockite.

The invention also deals with a dental restorative composition comprising a blend of a ceramic of this invention and a polymerizable or polymerized bonding material which is compatible with the conditions of the oral cavity. The dental restorative composition of this invention comprises from 10 - 90 per cent, preferably 60 to 80 per cent, by weight of finely divided ceramic of the invention, usually the hydroxylapatite, the remainder of said composition, from 10 - 90 per cent by weight, comprising a dentally acceptable polymerizable or polymerized bonding material together with known appropriate polymerization catalysts, such as, aliphatic ketone peroxides or benzoyl peroxide reactive 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, promoters, or accelerators such as metal acetyl acetonates, tertiary amines, e.g., Ν,N-bis-(2-hydroxyethy1)-p-toluidine, etc., 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, vinyltrichlorosilane, etc., may be 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 of the ceramic material to the resin and of the dental filling composition to the natural tooth. Thus, ceramic hydroxylapatite provided by this invention is comminuted to a suitable particle size of from about 5 to 100 microns I using conventional milling techniques and then blended with an appropriate amount of a standard resin known in the dental restorative art such as hydroxylethyl methacrylate, polymethyl methacrylate, polyacrylic acid, propylene glycol fumarate phthalate unsaturated polyesters such as sold by Allied Chemical Co. 23 LS8275 and by Pittsburgh Plate Class as Selectron 580001, styrene modified unsaturated polyesters such as Glidden Glidpol 1008, G-136 and 4CS50, epoxy resins such as Ciba Araldite 6020, 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 -2143442 principles known in 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 addi5 tion of the catalyst, hardener, cross-linking agent, promoter or accelerator. However, the order in which the ingredients 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 of 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 1 per cent fluoride ion such as ammonium or stannous fluoride to·the suspension of freshly precipitated hydroxylapatite. The ceramic produced by sintering of the resulting product is highly resistant to attack by lactic, acetic ox citric acid, a standard in vitro method of determining 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 aqueous sodium fluoride for approximately 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 -2242442 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 strontium 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 the latter with phosphate ion will ultimately result in a barium or strontium-doped hydroxylapatite ceramic which 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 promoting the crystallization of whitlockite (Eanes et al., Calc. Tiss. Res. 2., 32 (1968)]. Thus, the addition of a small amount of magnesium ion to the calcium ion prior to reaction of the latter with phosphate ion will favor the formation of whitlockite thereby ultimately affording a Whitlockite-enriched two phase ceramic.

The ceramic materials obtained as described above were characterized on the basis of one or more of the following: elemental analysis, density, X-ray diffraction, transmission electron microscopy, polarized light microscopy and mechanical properties.

The invention is illustrated by the following examples without, however, being limited thereto.

EXAMPLE 1 To a stirred mixture containing 130 ml. of 1.63N calcium nitrate (0.212 mole) and 125 ml. of concentrated -2343442 ammonia there was added dropwise over a period of approximately 20 minutes a mixture containing 15.75 g. (0.127 mole) of diammonium hydrogen phosphate, 400 ml. of distilled water and 150 ml. of concentrated ammonia. The resulting suspension was boiled 10 minutes, cooled in an ice-bath and filtered. The filter cake was pressed with a rubber dam and then dried overnight at 95°C. A sample of the resulting, hard, porous, brittle cake was heated in an electric kiln over a period of 115 minutes up to a final temperature of 1230°C. 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 Ca-^PO^giOH^: Dried, Unsintered Calc'd Hydroxylapatite Ceramic Ca P V Ca/p 39.89% 37.4% 39.6% 18.5% 17.5% 18.9% 0% 1% ---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., indicated a microcrystalline structure. A comparison with the optical micrographs of a thin section of the sintered compressed tablet reported by Monroe et al. (supra) showed the two materials to be structurally dissimilar.

X-ray diffraction measurements were carried out in -2442442 conventional manner. The interplanar spacings were calculated and found to be virtually identical to the values given for hydroxylapatite by Donnay et al., Crystal Data, ACA Monogram 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.

EXAMPLE 2 A solution containing 79.2 g. (0.60 mole) of diammonium hydrogen phosphate in 1500 ml. of distilled water was adjusted to pH 11-12 with approximately 750 ml. of concentrated ammonia. Additional distilled water was added to dissolve precipitated ammonium phosphate giving a total volume of 3200 ml. If necessary the pH was again adjusted to 11-12. This solution was added dropwise over 30-40 minutes to a vigorously stirred solution containing 1 mole of calcium nitrate in 900 ml. of distilled water previously adjusted to pH 12 with approximately 30 ml. of concentrated aqueous ammonia and then diluted to a volume of 1800 ml, with distilled water. When the addition was complete, the resultant gelatinous suspension was stirred an additional 10 minutes, and then boiled 10 minutes, removed from the heat, 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 resulting sludge was re-suspended in 800 ml. of distilled water and again centrifuged at 2000 rpm for 10 minutes. Sufficient distilled water was added to the residual solids to give a total volume of 900 ml. Vigorous shaking afforded a homogeneous suspension essentially free of large fragments or aggregates. The -2542442 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 removed and the crack-free, intact filter cake was transferred to a flat surface, and dried 15 hours at 90-95°C. to give 90-100 g. of white, porous, brittle pieces of hydroxylapatite Fragments of from one to four cm2 and free of cracks and fissures were placed in an electric kiln and the temperature was raised to 1200°C. over a period of 100 min, after which time the kiln and its contents were allowed to cool to room temperature. There resulted pieces of hard, dense, nonporous, white, translucent ceramic material, Dried, Unsintered Analysis; Calc'd Hydroxylapatite Ceramic Ca P 39.89% 18.5% 36.5, 21.7% 36.8% 31.7, 38.0% 22.8, 19.0, 18.8 Ca/P 1.667 1.30, 1.31 1.08, 1.55, 1.56 Subsequent to carrying out the above analyses it was discovered that the analytical technique used did not allow complete dissolution of the samples and the results are therefore inaccurate and highly variable. Notwithstanding the above analytical data, the substantial homogeneity of this sample was confirmed by the following electron microscopic data. Moreover, the product of Example 3 Which was prepared by a procedure essentially identical to the procedure of Example 2 did have the expected analytical values and was further characterized as homogeneous hydroxylapatite By X-ray diffraction and electron microscopy.

Two-stage replica samples were made by shadowing -2643442 a collodion replica of the sample surface with chromium and then coating it with carbon. Transmission electron microscopic examination of the replicated samples revealed a fairly uniform grain size with no evidence of pores or second phase precipitate in either grain boundaries or within the grains themselves in any amount greater than about 0.5%, the minium concentration sensitivity of the electron microscope. A sample of the ceramic was then polished on Sic paper to 600 grit, then polished to 3 micrometer diamond paste on a metallographic wheel covered with fine nylon cloth, The sample was then etched with 4% hydrofluoric acid for 30 seconds, Replicas were then made of the polished and etched surface and then viewed by electron microscopy. Again no second phases were observed in the grain boundaries, however, there was some evidence of small second phase particles in the grain bulk.

Compression strength and modulus of elasticity were determined by conventional methods and found to be 56,462 psi i 16,733 psi and 6.3 χ 10^ psi, respectively, Tensile strength was determined by the standard three point bending test and found to be 9,650 psi ± 3,320 psi.

The thermal expansion coefficient was found to be linear between 25°C. and 225°C. with a value of 11 x 10"®/°C. ± 10%.

A hardness value of 480 was found using the standard Kiioop method. The same value was obtained irrespective of the direction of the applied force indicating thereby that the material was isotropic.

Porosity was determined qualitatively by immersing -27the 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 performed simultaneously on the non-porous form of the ceramic provided by this invention, a sintered compressed tablet of hydroxylapatite, and a natural tooth. The sintered compressed tablet showed considerable retention of the dye whereas the novel ceramic of the present invention and the natural tooth exhibited no visible 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 cause the surrounding litmus paper to turn blue. When this test was performed simultaneously on the ceramic of this invention, a sintered compressed tablet of 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 cermic of the present invention or the natural tooth.

EXAMPLE 3 A. By following a procedure similar to that described in Example 2 but employing one-sixth the quantities used therein, an estimated 50 g. of hydroxylapatite was precipita5 ted from aqueous solution. Following centrifugation and decantation the residual mineral sludge was re-suspended in sufficient water to give a total volume of 1 liter and homogenized in a Waring blender for 2 minutes.

B. A mixture containing 0.5 g. of powdered cellulose (<0.5 μ) 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 resulting 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 slightly porous as indicated by the fuchsin dye test described hereinabove.

C. A mixture containing 0.5 g. shredded surgical cotton in 200 ml. of water was blended in a Waring blender for 45 minutes or until a nearly homogeneous suspension was obtained. A 100 ml. aliquot of the homogeneous aqueous suspension of hydroxylapatite described in Example 4A was then added and blending continued an additional 15 minutes. The resulting suspension was filtered and the filter cake dried and sintered according to Example 2. The ceramic product remained intact and,was visibly porous.

EXAMPLE 4 A. A mixture containing 5 g. of collagen (bovine Achilles tendon) in 300 ml. of water was blended in a Waring blender for 5 minutes. 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 3A.

The resulting mixture was filtered and the filter cake dried and sintered according to Example 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 Waring blender for 6 minutes with 150 ml. of the homogeneous aqueous suspension of hydroxyl20 apatite described in Example 3A. The resulting mixture was filtered and the filter cake 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 porous.

EXAMPLE 5 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 samples of untreated ceramic and natural teeth were then ex-3042442 posed to 10 per cent lactic acid. After 3 days the fluoridetreated 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 1 month had undergone only slight decomposition whereas untreated samples were heavily decomposed.

EXAMPLE 6 By following a procedure similar to that described in Example 2 but employing one-sixth the quantities used therein, an estimated 50 g. of hydroxylapatite was precipitated 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, 0.1, 0.5, 1.0 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 10.0 ml., respectively, of aqueous ammonium fluoride containing 0.0085 g. F®/ml. To samples 9 and 10 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 95°C. and then heated in an electric kiln to a temperature of 1200°C. The resulting ceramics were ground into fine powders and sieved through a No. 325 mesh screen (U.S. ASTM standard). Eighty milligrams of each of the powder samples was mixed with 80 -31ml. of pH 4.1 sodium lactate buffer solution (0.4M) at 23°C. and shaken on a Burrell wrist-action shaker. At times of 2, 9, 25 and 40 minutes 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 IA. The results are included in Table A. It will, of course, be appreciated that the above-described experimental conditions do not approximate in vivo conditions but were chosen so as to permit sufficient solubilization of sample within a reasonable length of time affording thereby an accurate assessment of the relative effect of fluoride ion concentration. Thus, in vivo dissolution rates for ceramic hydroxylapatite are expected to be considerably less than the aboveobserved rates in the strong lactate buffer.

TABLE A Relative Dissolution Rates of Fluoridated Ceramic Hydroxylapatite Sample Fluoride Content (PPM)__% Dissolved XT— — 1 ' A —n _ ΊΕ wL No. Added Found 2 min. 9 min. 25 min. 40 min, 1 0 _ 9.2 18.5 32.0 39.7 2 17 19 9.2 18.8 29.3 39.0 3 85 190a 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 6 850 226 8.8 17.1 27.7 33,0 7 1,700 470 7.9 18.1 25.7 29.8 8 17,000 1,460 6.7 12.1 19,7 23.3 9 18,000 1,700 6.3 11.5 19,7 23.3 10 36,000 2,307 5.9 11.3 17.6 21.0 IA — — 3.7 7.1 TS7J —1ST* a. An apparently incorrect assay. -3243442 EXAMPLE 7 Large fragments of dried filter cake about 3-4 mm. thick prepared according to Example 2 and having Ca/P " 1.641.66 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 to 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/cm2 were in the form of rectangular plates approximately 10-11 mm, long, 4-5 mm. wide and 2-3 mm. thick and having a hole at one end through which a length of 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 described hereinabove.

EXAMPLE 8 A solution containing 0.24 mole of diammonium hydrogen phosphate in 600 ml. of distilled water was adjusted to pH 11.4 with 340 ml. of concentrated ammonia and the final volume brought to 1280 ml. with distilled water. This solution was added dropwise over 30 minutes to a vigorouslystirred 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 without boiling and 250 ml. aliquots were periodically removed and the products isolated, washed and dried as described in Example 2. All samples were then heated one hour at 1100°C. and the composition of the resultant ceramic products determined by X-ray diffraction. The results are given in Table B. -33TABLE Β Phases observed by Saitple No. Stirring Time Standing Time Before Isolation Elemental Analysis X-ray Diffraction S Hydroxyl- apatite % Whit- lockite % Ca % P Ca/P 1 5 min. — 36.6 18.2 1.55 17 83 2 45 min. — — — 21 79 3 2 hr. — 36.6 18.0 1.57 39 61 10 4 4.5 hr. — — — — 98 2a 5 7 hr. — 37.0 17.0 1.68 98 2a 6 7 hr. 17 hr. 37.2 17.0 1.69 100 0 7 24 hr. . , — 37.4 17.1 1.69 100 0 8 48 hr. 37.4 16.8 1.72 100 0 15 a. These values border on the minimum concentration sensitivity of the X-ray diffractometer C2—3%) and the accuracy thereof is thus questionable.

EXAMPLE 9 A. Following a procedure similar to that described in Example 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 = 38.85%; P = 19.77%; Ca/P = 1.52. This material was heated 1 hour at 1200°C. to give a strong, hard, non-porous, white, somewhat opaque ceramic material comprising approximately 40% hydroxylapatite and 60% whitlockite as indicated by X-ray diffraction.

B. When the above reaction was carried out with inverse addition of the starting materials there was obtained a product comprising approximately 40% hydroxylapatite and 60% whitlockite, and having Ca/P - 1.52 and a density of 2.982 g/cm3.' EXAMPLE 10 A solution containing 0.0625 mole of diammonium hydrogen phosphate in 150 ml. of distilled water was treated with 95 ml. of concentrated ammonia and the final volume -3442442 brought to 320 ml. with distilled water. This solution was added dropwise over 30 minutes to a vigorously stirred solution containing 0.1 mole of calcium nitrate and 2.5 ml. of concentrated ammonia in 180 ml. of distilled water. The resulting suspension was stirred 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 compositions: Ca = 35.4%; P = 18.59%; Ca/P = 1.46. This material was heated 1 hour at 135O°C. to give a strong, hard, nonporous somewhat opaque ceramic product comprising approximately 14% hydroxylapatite and 86% whitlockite as indicated by X-ray diffraction.

The ceramics in macroform produced according to Examples 1,2, 4B and 5-7 are strong, hard, dense, white, translucent ceramic bodies comprising substantially pure, isotropic polycrystalline hydroxylapatite 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 Centigrade, a Knoop hardness in the approxinate range 470 to 500 and a modulus of elasticity of approximately 6 χ 106 psi, and being characterized by cleavage along smooth curved planes, and by the absence of birefringence under polarized light.

The ceramics in macroform produced according to Examples 3 and 4C' although comprising the same material produced according' to Examples 1, 2, 4B and 5-7 have introduced 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 compression strength, tensile strength, elasticity and hardness.

EXAMPLE 11 A composition suitable as a dental cement and 10 dental filling agent was prepared as follows: A. To a solution containing 20 mg, of the condensation product of N-phenylglycine and glycidyl methacrylate (described in United States Patent 3,200,142 and referred to therein as NPG-GMA) in 7 ml, of ethanol there was added 2.0 g. of powdered ceramic hydroxylapatite. After swirling 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 hydroxyethyl methacrylate and the reaction product of bisphenol A and glycidyl methacrylate as described in United States Patent 3,066,112 and 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 24,350 psi.

EXAMPLE 12 A mixture comprising 60 parts of powdered ceramic hydroxylapatite, 13 parts of hydroxyethyl methacrylate, 27 parts of the condensation product of bisphenol A and glycidyl methacrylate, 0.3 parts of Ν,Ν-bis-(2-hydroxyethyl)-jo-toluidine and 0.8 parts of benzoyl peroxide was blended thoroughly to give a thin, free-flowing formulation useful as a dental pit and fissure eealant. The mixture was poured into a cylindrical steel mold wherein it hardened in about 3 minutes. Compression strength was determined for seven cylindrical plugs so-prepared. The average value was 20,400 psi.

EXAMPLE 13 The following is an example of a formulation useful as a dental filling material.

To 5 ml. of 2-propanol was added 0.5 g, of powdered ceramic hydroxylapatite. The 2-propanol was then evaporated under vacuum at room temperature in order to remove any water of hydration 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 methacrylate, triethylene glycol dimethacrylate and N,N-bis-(2hydroxyethyl)-£-toluidine which mixture is sold by Lee Pharmaceuticals under the tradename Epoxylite HL-72. The mixture was worked with a spatula into a smooth paste and placed into cylindrical steel molds and 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.

EXAMPLE 14 To a solution containing 30 mg. of the condensation product of N-phenylglyoine and glycidyl methacrylate in 7 ml. of ethanol was added with swirling 1 g. of powdered -3742442 ceramic hydroxylapatite. 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 paste 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.

EXAMPLE 15 A composition suitable as a dental and orthodontic cement or as a temporary dental filling agent was prepared by mixing together 100 mg. of powdered ceramic hydroxylapatite, 300 mg. of zinc oxide and 300 mg. of 40% aqueous polyacrylic acid. The resulting mixture was placed in cylindrical steel molds wherein it hardened in about 3-5 minutes.

The cylindrical plugs were removed from the molds and 4 specimens were tested and found to have an average compression 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 obtained as the liquid and solid components respectively of a commercial polycarbqxylate cement available from ESPE G.m.b.H., West Germany, under the tradename Durelon .

EXAMPLE 16 A composition suitable as a dental cement and dental filling agent was prepared by mixing together 6 parts by weight of 40 per cent aqueous polyacrylic acid with a mix-3842442 ture containing 6 parte by weight of powdered ceramic hydroxylapatite 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 .

EXAMPLE 17 The following is an example of a dental filling composition: Ingredient Per cent by Weight Styrene modified polyester resin (Glidden Glidpol G-136) 29.2 Benzoyl peroxide 0.7 Styrene 0.6 Methacryloxypropyltrimethoxysilane 1.5 Ceramic hydroxylapatite 68.0 EXAMPLE 18 The following is an example of a composition suit- able as a dental cement, cavity liner and pulp capping agent: Ingredient Per Cent by Weight Epoxy resin (Union Carbide ERL2774) 67 N-3-oxo-l,1-dimethylbutylacrylamide 23 Ceramic hydroxylapatite 10 EXAMPLE 19 The following is an example of a composition suit30 able for the fabrication of an artificial tooth or set of teeth.

A mixture containing 60 parts by weight of ceramic hydroxylapatite of approximately 150 to 200 mesh (U.S.) and 40 parts 2442 by weight of powdered polymethyl methacrylate ia 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 mate5 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 boiling over a period of about one hour and maintained at that temperature for 30 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 confirmed 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.

Pellets of ceramic hydroxylapatite prepared by a method similar to that described in Example 3 were surgically implanted in the 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 by both optical and scanning electron microscopy. Both the one-month and sixmonths implants were characterized by normal healing, strong binding of new bone to the implant surface with no interven30 ing fibrous tissue, no evidence Of inflammation or foreign body response and no resorption of the implant material.

Claims (32)

1. CLAIMS:1A process for preparing a polycrystalline, sintered ceramic in macroform which comprises reacting calcium ion with phosphate ion in aqueous medium and at pH of 10-12 to produce a gelatinous precipitate of a phosphate of calcium having a molar ratio of calcium to phosphorus in the range of 1.44-1.72, separating said precipitate from solution, heating said precipitate up to a temperature of at least 1000°Cbut 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 1 or 2, in which the ratio of reactants used in the reaction is chosen so that a precipitate 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 range of 1.62-1.72, the temperature being maintained at at least 1OOO°C for a minimum of 20 minutes up to L25O°C. for a maximum of one hour.

5. A process according to claim 4, whererin the temperature is maintained at 1100°C. to 1200°C. for 0.5 to 1 hour.

6. A process according to claim 1 or 2, in which a precipitate having a molar ratio of calcium to phosphorus in the range 1.44-1.60 is formed, said precipitate being heated to a temperature of at least 1000°C. for a minimum of 20 minutes up to 125O°C. for a maximum of one hour. 4 2 4 4 2

7. A process according to claim 6, in which the molar ratio is in the range of 1.46-1.57.

8. A process according to any one of the preceding claims, wherein the calcium ion is provided by calcium nitrate and the phosphate ion is provided by diammonium hydrogen phosphate.

9. A process according to any one of the preceding claims, wherein an intergral mass of the precipitate subjecting to-the sintering is sufficient uniform and free defects.

10. A process according to any one of the preceding claims, wherein a shaped product is produced by cutting, shaping or molding the precipitate while still in a cohesive ( gelatinous state prior to the sintering.

11. A process according to any one of the preceding claims, wherein a shaped product is produced by cutting or shaping the precipitate after a preliminary drying of the gelatinous precipitate.

12. A process according to any one of the preceding claims, wherein the ceramic produce is allowed to stand in 0.5 to 5 percent aqueous sodium fluoride for 12 hours to five days.

13. A process according to any one of claims 1 to 11, wherein 0.1 to 1 percent by weight of fluoride ion is added to the precipitate prior to separating said precipitate from solution.

14. A process according to any one of the preceding claims, wherein 0.4 to 0.6 percent by weight of an organic binder is added to the precipitate, said organic binder being volatilized during said sintering process.

15. A process according to claim 14, wherein the organic binder is collagen.

16. A process according to any one of claims 1 to 12, for producing a porous form of the ceramic, wherein about 5 to 25 percent by weight of an organic binder is added to the precipitate, said organic binder being volatilized during said heating process.

17. A process according to claim 16, wherein the organic binder is powdered cellulose, cotton or collagen.

18. A process as claimed in claim 1 for preparing a polycrystailine, sintered ceramic substantially as herein described with reference to the Examples.

19. A ceramic when produced by the process according to any one of claims 1 to 18.

20. A translucent, isotropic, polycrystailine, sintered ceramic comprising substantially pure hydroxylapatite having an average crystallite size in the range 0.2 to 3 microns, said ceramic having a density in the range 3.10 to 3.14 g/cm 3 , and having substantially no pores and having cleavage along smooth curved planes.

21. A ceramic according to claim 20, comprising substantially pure microcrystalline hydroxyapatite in a random, isotropic araay and having a compression strength in the range 35,000 to 75,000 psi, a tensile strength in the range 3,000 to 50,000 psi, a linear thermal coefficient of expansion in the range LO to .12 ppm per degree centigrade, a Knoop hardness in the range 470 g to 500 and a modulus of elasticity of 6 x 10 psi, and not being birefringent under polarized light.

22. A ceramic according to either of claims 20 or 21, wherein there is incorporated therein an amount of fluoride ion effective in substantially reducing the rate of decomposition of said ceramic by lactic acid.

23. A ceramic according to claim 20, substantially as herein 4 3 4 4 2 described with reference to the Examples.

24. Λ strong, hard, dense, isotropic, polycrystalline sintered two phase ceramic comprising as one phase from 14 to 98% by weight of hydroxylapatite and as a second phase from 2 to 86% by weight of whitlockite, said ceramic having substantially no pores and having cleavage along smooth curved planes.

25. A ceramic according to claim 24, wherein there is incorporated therein an amount of fluoride ion effective in substantially reducing the rate of decomposition of said ceramic by lactic acid. (

26. A ceramic according to claim 24, substantially as herein described with reference to the Examples.

27. A dental restorative composition which comprises about 10-90 percent by weight of finely divided ceramic when produced according to any one of claims 1 to 15 and a dentally acceptable polymerizable or polymerized bonding material.

28. A dental restorative composition which comprises 1090 percent by weight of finely divided cerpmic according to any one of claims 20 to 22, and a dentally acceptable polymerizable or polymerized bonding material.

29. A dental restorative composition which comprises 10-90 percent by weight of finely divided ceramic according to either of claims 24 or 25, and a dentally acceptable polymerizable or polymerized bonding material.

30. A composition according to any one of claims 27 to 29, wherein the dentally acceptable bonding material is polyacrylic acid.

31. A composition according to any one of claims 27 to 29, wherein the dentally acceptable bonding material is the condensation product of bisphenol A and glycidyl methacrylate.

32. A dental restorative composition according to any one of claims 27,28 or 29, substantially as herein described with reference to the Examples 11-19.