FI64131C - FOERFARANDE FOER FRAMSTAELLNING AV POLYKRISTALLINT SINTRAT KERAMISKT 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/cm<SP>3</SP>, 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

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The present invention relates in particular to the manufacture of ceramic materials for use in dentistry and orthopedics.

Current dental research is largely focused on the manufacture of material that can be used as a tooth and bone substitute, as a dental repair material for fillings, shells and crowns, and as a prosthetic filling material. Dental research has also focused on preventing the formation of dental plaque in the teeth, which is considered to be the cause of both dental caries and periodontitis.

Fillers currently used in dental restorative compositions, such as quartz, alumina, silicates, glass beads, etc., resemble little tooth enamel chemically and physically. The actual weakness of these materials is the difference between the filling material and the coefficient of linear thermal expansion of the tooth, which can potentially cause cracks at the joints and re-formation of holes 2 641 31. Thus, in the treatment of teeth, a filling composition has long been desired, the physical properties of which closely correspond to those of natural teeth.

Surgical prostheses today consist primarily of a strong, non-corrosive alloy; however, a material that more closely resembles biological, hard tissues would be preferable because the difficulties in tissue acceptance and attachment have not yet been completely eliminated (Hulbert, et al., Material Science Research 5, 417 (1971)).

In research to find effective anti-rust chemotherapeutic agents, there has been a need for a standard test material with a surface resembling a tooth in terms of both tooth rust formation and chemical action. Although natural tooth has been used for this purpose, it has the disadvantage of high variability, relatively difficult availability in large quantities, and the complex cleaning required before use. Therefore, other materials that form dental rust, such as powdered hydroxylapatite, acrylic teeth, glass, and metal wire, have been used. Although they may be suitable for studying the formation of tooth rust per se, these materials bear little resemblance to the surface of a natural tooth and are thus not entirely suitable for finding an effective anti-rust agent. For example, it is known that chemicals that prevent rust from forming on teeth may not be effective on glass and metal wire (Turesky et al., J. Periodontology 43, 263 (1972)). Therefore, there is a need for a cheap, readily available material that is chemically similar to tooth enamel, is hard, dense, and highly polishable.

Base material for teeth and bones, hydroxylapatite,

Ca, Λ (PO.), (OH) -, also known as basic calcium orthophosphate, has been proposed for the various purposes set forth above; e.g., U.S. Patent 2,508,816 discloses a method for recovering hydroxylapatite from tooth enamel and using it as a prosthetic composition mixed with a synthetic resin. This method is long and laborious and is limited to the preparation of finely divided hydroxylapatite. In addition, the method depends on the availability of natural teeth.

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Kutty (Indian J. Chem. 11, 695 (1973)) discloses the preparation of mixtures of hydroxylapatite and whitlocyte by decomposing powdered hydroxylapatite at different temperatures.

Bett et. Oh. (J. Amer. Chem. Soc. 89, 5535 (1967)) disclose the preparation of a finely divided hydroxylapatite having a stoichiometric Ca / P ratio ranging from 1.67 to 1.57. The materials thus prepared contain large internal pores of the crystals. It has also been mentioned that when heated to 1000 ° C, the calcium-deficient hydroxylapat crystals are partially converted into whitlocyte crystals.

U.S. Patent No. 3,787,900 discloses a bone and dental prosthetic material containing a high melting material and a calcium phosphate compound, e.g., whitlocyte.

Several attempts have been made to obtain the macro form of hard, strong hydroxylapatite. However, no previously known form of hydroxylapatite has been completely satisfactory. Roy and Linne-han (Nature, 247, 220 (1974)) have proposed a complex hydrothermal exchange process in which the calcium carbonate backbone of sea coral was converted to hydroxylapatite. The material thus produced retains the highly porous properties of the coral structure, and in addition, its tensile strength is relatively low, about 19-33 kp / cm, which is a serious disadvantage of the prosthetic material.

Monroe, et al. (Journal of Dental Research 50, 860 (1971)) have disclosed sintered hydroxylapatite tablets for the manufacture of ceramic material. The material thus formed is a mixture of hydroxylapatite with about 30% Ot-whitloclite, Ca 2 iPO 2, i.e. tricalcium phosphate, as an ordered mosaic pattern of polyhedral crystallites and proved to be too porous to be used as a dental material.

Rao and Boehm (Journal of Dental Research 53, 1351 (1974)) have reported the preparation of a polycrystalline form of hydroxylapatite by isostatically pressing powdered hydroxylapatite into a mold and sintering the formed body isothermally. The formed ceramic body was porous and had a maximum compressive strength of about 1200 kp / cm2.

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Bhaskar et al., (Oral Surgery 32, 336 (1971)) disclose the use of a ceramic material containing biodegradable calcium phosphate in filling tooth cavities. The material is very porous, resorbed at its planting point and does not have the strength of a metal or non-dispersible ceramic spot.

The present invention relates to a process for preparing a polycrystalline, sintered, ceramic, macroporous material by reacting calcium and phosphate ions in an aqueous medium at a pH of about 10 to 12 to form a gelatinous precipitate of calcium phosphate in which the molar ratio of calcium to phosphorus is hydroxylate. and the approximate molar ratios of phosphorus and separating the precipitate from the solution.

The process according to the invention is characterized in that said cohesive gel-like precipitate is heated to a temperature of at least 1000 ° C but below the temperature at which significant decomposition of hydroxylapatite occurs and maintained at a temperature sufficient to sinter the product formed and produce substantially maximum compaction. the product is added to said precipitate with 5 to 25% by weight of an organic binder which evaporates during the heat treatment, and if it is desired to include fluoride in the product obtained, fluoride ions are added to the precipitate before it is separated from solution or the prepared sintered ceramic product is allowed to stand for about 0.5 to 5% in aqueous sodium fluoride solution for about 12 hours to 5 days.

According to one aspect of the present invention, there is provided a novel hydroxylapatite ceramic form which contains substantially pure hydroxylapatite and which is hard, dense and can be polished to a high gloss. Chemically, it resembles very much tooth enamel. In addition, this material can be prepared relatively simply from inexpensive starting materials and is obtained in a uniform quality, thus avoiding the unfavorable variability inherent in a natural tooth.

The use of a new ceramic form of hydroxylapatite in dental restorative compositions provides a dense filler material that is substantially free of jeriemi scattering in the same manner as natural dental floss.

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The dental and surgical implant material made in accordance with the invention is hard, strong and fully biocompatible and can be made into any desired shape without high pressures or other complicated procedures. In addition, as will be detailed later, any desired degree of porosity can be imparted to this material, allowing tissues to adhere.

The properties of the material produced by the method according to the invention also make it suitable for the production of discs, plates, rods, etc. used in the testing of anti-rust agents.

The biphasic ceramic material prepared according to the invention contains hydroxylapatite and whitlocyte. This biphasic material is hard, dense, non-porous, and biocompatible, readily prepared in any desired form, and useful as a strong, partially resorbable surgical implant material due to the known resorbable nature of whitlocyte.

While a certain degree of porosity in surgical implants may be advantageous to allow circulation of body fluids and tissue growth, porosity at the same time reduces the mechanical strength of the implant. The biphasic ceramic material of the invention, although dense, mechanically strong and substantially non-porous, nevertheless allows the circulation of body fluids and tissue adhesion because the whitlocyte phase it contains is slowly resorbed from the implanted body and replaced by natural, biological, hard tissue.

The new physical form of hydrolysis apatite, which differs from biological and geological forms and from all previously known synthetic forms, as shown below, consists of a strong, hard, dense, isotropically transparent, polycrystalline ceramic material containing predominantly pure hydroxylapatite 0.2 to 3 [mu] m, a density of about 3.10 to 3.14 g / cm and further characterized by the absence of pores and cracking along flat curved surfaces. In addition, when conventionally prepared, the above material has a compressive strength of about 2,500 to 8,500 kp / cm and a tensile strength of about 210 to 2,100 kp / cm, a linear coefficient of thermal expansion of about 6,646,13 10 to 12 ppm / ° C, a Knoop dryness of about 470 to 500 and an elastic modulus of about 5 2 4.2 x 10 kp / cm. The new material is not birefringent in polarized-sa light. Preliminary studies of the new hydrolysis apatite showed that it is a strong, hard, dense, white, transparent ceramic material consisting mainly of pure microcrystalline hydroxylapatite in a random, isotropic order 2 and having a compressive strength of about 2500 to 5000 kp / cm, a tensile strength of about 210 to 3500 kp / cm, a linear coefficient of thermal expansion of about 10 to 12 ppm / ° C, a Knoop hardness of about 470 to 500 and a modulus of elasticity of about 4.2 x 10 ^ kp / cm, and is characterized by cleavage along flat curved surfaces and absence of birefringence in polarized light .

The term dense, as used herein, refers to a very dense order of particles with virtually no voids.

In contrast to the form of hydroxylapatite described above, geological hydroxylapatite and synthetic hydroxylapatite prepared by a hydrothermal process are macrocrystalline, crack along planar surfaces, and are birefringent. Biological hydroxylapatite is characterized by the fact that it generally contains significant amounts of carbonate ions in the apatite structure and in its purest state, i. as a tooth enamel, it is anisotropically arranged into rotating radial rods so that it splits linearly along the joint surfaces of the enamel rods, and its 2 tensile strength is relatively small, 105 kp / cm.

The hydroxylapatite prepared according to the invention is also completely biologically acceptable and thus suitable as a dental and surgical prosthetic material. It can be cast or machined into dental crowns, artificial teeth, bone and bridge prostheses, cannulas, fasteners for artificial body members that can be attached to bone and extends through the skin, and test surfaces for the formation of dental rash, sciatica, caries for. Suitably ground, the novel ceramic material of the invention can be used as a synthetic bone filler in bone defect repair, as an abrasive, and as a dental replacement composition combined with conventional resins.

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As a test surface for the study of anti-corrosion agents, the new ceramic material can be processed into a body of suitable shape and size, preferably suitable for a normal test tube. This is conveniently done by cutting or machining a large plate-like piece of dried filter cake to a suitable size and then sintering. The sintered products can be polished and the formed bodies are then used as substrates in the study of anti-rust agents by the method of Turesky, et al., Supra. After use, the ceramic bodies are simply polished again to form a new moisture surface.

Conventionally made, the ceramic materials of this invention are not only dense but also non-porous, and although non-porous material is essential in dental applications, a certain degree of porosity in the implant material may be advantageous because it allows body fluids to circulate and tissues to grow. Various degrees of porosity can be formed in this ceramic material as described by Monroe, et al., Supra. In this case, an organic material such as starch, cellulose, cotton or collagen can be mixed with 5 to 25% by weight of the hydroxylapatite gel precipitate. In the sintering process, organic materials are removed by combustion, thus causing cavities and channels in the otherwise non-porous product. Alternatively, porosity can be achieved mechanically by drilling or machining holes or openings in the non-porous ceramic.

In this way, an artificial tooth formed of a ceramic material according to this aspect of the invention can be made porous at its implantation site and the bare tooth surface remains non-porous. Implantation can be performed as described by Hodosh, et al., Journal of the American Dental Association 70, 362 (1965). Alternatively, a polymerizable or polymerized bonding material may be added to the material of the invention, as described below, and the resulting composition may be used as a coating for metallic implants, as disclosed in U.S. Patent No. 3,609,867.

The biphasic, dense, isotropic, polycrystalline sintered ceramic product according to the invention contains, as one phase, about 14 to 18% by weight of hydroxylapatite and, as the other phase, about 2 to 86% by weight of whitlocyte, and is characterized by porous porosity and fracture-free porosity.

Whitlocyte is a mineral with the chemical formula Ca ^ tPO ^^ · It can exist in either CC or β-crystal form. The term whitlocyte as used herein refers to either the Ct or ζβ form or a mixture of the two forms.

The biphasic ceramic material prepared according to the invention remains a non-porous polycrystalline material regardless of the relative concentrations of hydroxylapatite and whitlocyte contained therein. It should be noted, however, that the physical properties of hydroxylapatite and whitloclite are different and thus the physical properties of the biphasic ceramic material, e.g., density and optical properties, depend on the relative amounts of hydroxylapatite and whitloclite it contains. For example, the theoretical density of whitloclite is lower than that of hydroxylapatite, and thus the observed density of a biphasic ceramic material sample containing about 40% hydroxylapatite and 60% whitlocyte was 2.98 g / cm when the density of ceramic hydroxylapatite was 3.10.

The biphasic ceramic material described above is also biologically compatible and suitable as a surgical prosthetic material. It can be cast or machined into bone and joint prostheses or in any shape suitable for filling bone cracks and lesions. The whitlocyte contained in the prosthesis article made of a biphasic ceramic material is finally resorbed and replaced as the natural biological hard tissue grows into the prosthesis. Naturally, the amount of tissue growth in the prosthesis depends on the amount of whitlocyte contained in the ceramic material.

Normally made, the biphasic ceramic material of this invention is non-porous. However, if desired, varying degrees of porosity can be formed in the ceramic, as described above, to obtain a new ceramic form of hydroxylapatite.

Biphasic ceramics can also be made acid resistant by fluorination, as will be discussed later in connection with ceramic hydroxylapatite.

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According to the invention, the novel ceramic form of hydroxylapatite can be prepared by precipitating from an aqueous medium having a pH of about 10 to 12 hydroxylapatite having a molar ratio of calcium to phosphorus in the range of about 1.62 to 1.72, separating the precipitated hydroxylapatite from solution and heating the resulting hydroxylate. time at a sufficiently high temperature to sinter and maximally compact the hydroxylapatite without substantially decomposing it.

Thus, hydroxylapatite is precipitated from an aqueous medium by the reaction of calcium ions and phosphate ions at a pH of about 10 to 12. Any calcium or phosphate-containing compound which forms calcium and phosphate ions in an aqueous medium is suitable provided that the corresponding counterions of said compounds can be readily separate from the hydroxylapatite product, are not themselves associated with the hydroxylapatite structure or otherwise adversely affect the precipitation and separation of pure hydroxylapatite. Compounds that donate calcium ions include, for example, calcium nitrate, calcium hydroxide, calcium carbonate, and the like. Phosphate ions are obtained from diammonium hydrogen phosphate, ammonium phosphate, phosphoric acid and the like. In the present method, calcium nitrate and diammonium hydrogen phosphate are the preferred sources of calcium and phosphate ions, respectively.

The preparation of the new form of hydroxylapatite is suitably carried out as follows: First, calcium nitrate and diammonium hydrogen phosphate are allowed to interact in a molar ratio of 1.67: 1 in an aqueous solution at a pH of about 10 to 12 to form a gel-like hydroxylapatite precipitate. The procedure of Hayek, et al., Inorganic Syntheses 7, 63 (1963) is suitable for this purpose. The gel-like suspension of hydroxylapatite thus obtained is then allowed to contact the initial solution until the ratio of calcium to phosphorus in the suspended hydroxylapatite reaches a value of about 1.67 to 1.72. This is conveniently done either by stirring the suspension for 24 hours at room temperature or by boiling for 10-90 minutes and then 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 separated from the solution in a suitable manner, for example by centrifugation and vacuum filtration. The gel-like product thus obtained contains a large amount of water, which can be largely removed by compression.

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If desired, the wet clay-like material formed may be cut or shaped into a suitable shape or alternatively cast into a suitable mold. It should be noted that a shrinkage of about 25% usually occurs upon drying of wet hydroxylapatite and a further shrinkage of about 25% upon sintering is as follows. This must, of course, be taken into account when shaping or casting the material. The wet product can be slowly heated to a sintering temperature of 1000 to 1250 ° C, removing any remaining water. Maintaining the temperature at 1000 to 1250 ° C for about 20 minutes to 3 hours will cause sintering and maximum compaction of the product. It is usually recommended to isolate the dried product prior to sintering, in which case the moist product may be dried at a temperature of about 90 to 900 ° C for about 3 to 24 hours until the amount of water in it has decreased to 0 to about 2%. It is generally preferred to perform the drying at a temperature of about 90 to 95 ° C for about 15 hours, or until the water content has dropped to about 1-2%. The hydroxylapatite obtained in this way is brittle and porous, but its mechanical strength is relatively good. Slight separation or cracking may occur in the clay-like material during drying, especially if a thick filter cake is used. However, pieces as large as 100 cm in area 3a with a thickness of 3 mm are easily obtained. Separation or cracking during drying can be reduced or completely prevented by adding to the fresh, precipitated hydroxylapatite suspension about 0.4 to 0.6% by weight of an organic binder such as collagen or ground cellulose, preferably about 0.5% collagen. The organic binder evaporates during sintering and the physical properties of the ceramic product are essentially the same as those made without the binder. Naturally, large amounts of organic binder cause a porous ceramic product, as discussed above. Other organic and inorganic binders known in the ceramics field may be used.

It is generally appropriate at this stage to cut or shape the dried hydroxylapatite to approximately the desired shape from the final product, taking into account the aforementioned shrinkage in sintering.

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The hydroxylapatite bodies must be smooth and free of defects before sintering. The presence of cracks and fissures causes the pieces to crack during sintering. The products are then sintered at a temperature of about 1000 to 1250 ° C for about 20 minutes to 3 hours, the temperature and time being inversely proportional to each other. The sintering is preferably carried out at a temperature of 1100 to 1200 ° C for 0.5 to 1 hour. The resulting hard, dense ceramic body can be polished or machined by conventional methods.

A critical step in the process described above is the precipitation of hydroxylapatite as a gel-like precipitate from aqueous solution, because only in this cohesive gel-like state can hydroxylapatite be shaped and then dried and sintered to obtain a macro-shaped ceramic body. Dry, finely divided or granular hydroxylapatite cannot be reconstituted into this cohesive, gel-like form. For example, if powdered hydroxylapatite is suspended in water and filtered, an inconsistent, fine filter cake is obtained which simply dries and crumbles and which cannot be shaped, cast or turned into a ceramic body. In addition, although powdered hydroxylapatite can be mechanically compressed into a shaped body, such as a tablet, sintering in accordance with the invention provides a highly porous product that does not crack along flat surfaces but merely crumbles into pieces.

Although the formation of hydroxylapatite in an aqueous medium is a complex and incompletely understood event, it is generally assumed that calcium and phosphate ions initially combine to form a calcium-deficient hydroxylapatite with a calcium to phosphorus ratio of about 1.5. In the presence of calcium ion, it then undergoes a slow conversion to hydroxylapatite, where the ratio of calcium to phosphorus is 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 product containing substantially pure hydroxylapatite in the process of the invention, it is necessary to allow the initially formed hydroxylapatite gel precipitate to contact the initial solution until the ratio of calcium to phosphorus reaches about 1.62 to 1.72. A significant deviation from this range results in a less transparent ceramic product. For example, if hydroxylapatite is precipitated at 12,641,311 room temperature and a precipitate is recovered from the disease within 2 hours, the ratio of calcium to phosphorus is about 1.55 to 1.57 and the ceramic product is opaque and consists of X-ray diffraction studies of hydroxylapatite and tite mixture. Such a material with a calcium to phosphorus ratio of about 1.44 to 1.60 is useful in making the above biphasic ceramic material. The formation of hydroxylapatite can be controlled by taking a sample of the hydroxylapatite suspension, separating the product, drying and sintering it as described above, and performing elemental and X-ray analysis on the ceramic thus formed.

Sintering time and temperature are also critical in the disclosed method. Unsynthetic hydroxylapatite having the desired ratio of calcium to phosphorus, 1.62 to 1.72, can be converted to a ceramic product by heating at a temperature of at least 1000 to 1250 ° C. At 1000 ° C, sintering and maximum condensation may take 2-3 hours, while at 1200 ° C the process is complete in 20-30 minutes. It is recommended to perform sintering at a temperature of about 1100 ° C for about an hour. Temperatures well below 1000 ° C cause incomplete sintering despite the length of the heating cycle, while heating above 1250 ° C for more than an hour causes partial decomposition of hydroxylapatite to whitlocyte.

The above biphasic ceramic material containing hydroxylapatite as one phase and whitlocyte as the other phase can be prepared by precipitating from an aqueous solution at a pH of about 10 to 12 a calcium phosphate compound having a molar ratio of calcium to phosphorus of 1.44 to 1.60, preferably 1.46 to 1, 57, separating the precipitate from the solution and then heating the resulting solid for a sufficient time at a sufficiently high temperature to obtain sintering and maximum condensation.

The calcium phosphate compound having the desired Ca / P ratio (1.44 to 1.60) is obtained by the reaction of calcium ion and phosphate ion in an aqueous medium at pH 10 to 12 using the same sources of calcium and phosphate ions as described above for the preparation of a single phase hydroxylapatite. Calcium nitrate and diammonium hydrogen phosphate are the recommended reagents.

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The biphasic ceramic material can be prepared by reacting calcium nitrate and diammonium hydrogen phosphate in a molar ratio of 1.67: 1, whereby the initially obtained gel precipitate is not heated but allowed to remain in contact with the original solution for up to 4 hours, or alternatively the molar ratio of calcium to phosphorus is maintained at 1.60 : 1.

As described above in connection with the preparation of a single-phase ceramic hydroxylapatite, the calcium phosphate precipitate is separated from the solution, washed, optionally shaped to a suitable shape and, if desired, dried and isolated before sintering.

The suspension of freshly precipitated calcium phosphate can also be treated with organic binders or fluoride ion, as described above for single-phase hydroxylapatite.

The sintering is performed by heating at a temperature of about 1000 to 1350 ° C for about 20 minutes to 3 hours.

The amount of whit-lactite contained in the ceramic material thus formed, which is 2 to 83%, depends on when the precipitate is separated from the original solution. If the product is isolated 5 minutes after precipitation, the ratio of calcium to phosphorus is 1.55 and the ceramic material finally formed contains about 83% whitlocyte. If the product is isolated 2 hours after precipitation, the ratio of calcium to phosphorus is 1.57, and the ceramic material formed contains about 61% whitlocyte. Isolation of the product 4.5 hours after precipitation gives a ceramic material containing about 2% whitlocyte, which is hardly detectable by X-ray diffraction with a minimum sensitivity of 2-3%. Of course, if the product is allowed to contact the initial solution for more than about 7 hours, the resulting ceramic material is essentially single phase hydroxyapatite.

Alternatively, the biphasic ceramic material can be prepared by reacting calcium ions and phosphate ions in a molar ratio of about 1.50 to 1.60: 1. In this case, the molar ratio of calcium to phosphorus cannot exceed about 1.60, and the time during which said precipitate remains in contact with the original solution does not affect the result.

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Thus, the preparation of the biphasic ceramic material is suitably carried out in the same manner as in the preparation of the single-phase ceramic hydroxylapatite except that the reactants, i. calcium nitrate and diammonium hydrogen phosphate are allowed to interact in a molar ratio of about 1.50 to 1.60: 1 to form a ceramic product containing about 30 to 50% hydroxylapatite and about 50 to 70% whitlocyte.

The whitlok phase can be further enriched in the ceramic material by combining the main features of the two methods described above, i. by allowing the calcium ions and phosphate ions to interact in a molar ratio of about 1.50 to 1.60: 1 and isolating the precipitated calcium phosphate compound shortly after precipitation, preferably from 5 minutes to 4 hours. The ceramic material thus formed contains about 10 to 30% hydroxylapatite and 70 to 90% whitloclite.

Hydroxyl apatite is known to decompose at about 1250 ° C to form whitlocyte, and thus it must be appreciated that prolonged heating of a single phase ceramic hydroxyl apatite at about 1250 ° C or higher temperatures preparation.

The hydroxylapatite prepared according to the invention can be used in a dental replacement composition comprising a mixture of hydroxylapatite and a polymerizable or polymerized binder suitable for oral conditions. The dental patch composition may contain from about 10 to 90% by weight, preferably from 60 to 80% by weight of finely divided ceramic hydroxylapatite, and from about 10 to 90% by weight of a dentally acceptable polymerizable or polymerized binder in combination with known polymerization catalysts such as aliphatic ketone peroxides. -yl peroxide, etc., reactive diluents such as di-, tri-, and tetraethylene glycol dimethacrylate, hardeners such as N-3-oxo-hydrocarbon-substituted acrylamide, promoters or accelerators such as metal acetylacetonates, tertiary amines, e.g. hydroxyethyl) -p-toludine, etc., or crosslinking agents such as zinc oxide, in amounts of about 0.01 to 45% of the total weight of the composition. The composition may also contain a surfactant comonomer such as the reaction product of N-phenylglycine and glycidyl methacrylate, methacryloxypropyltrimethoxysilane, 3,4-epoxycyclohexyltrimethoxysilane, vinyltrichlorosilane in amounts of 0.05 to 10% of the total composition. The binder promotes the adhesion of the ceramic material to the resin and the adhesion of the tooth replacement composition to the natural tooth. The dentition composition is prepared by grinding the ceramic hydroxylapatite to a suitable particle size, e.g. with polyesters, styrene-modified unsaturated polyesters, epoxy resins or a bisacrylate monomer made from glycidyl methacrylate and bisphenol A. If desired, colorants, inorganic pigments and fluorinating agents may be added. It is preferred to mix the resin, ceramic hydroxylapatite and any additives before adding the catalyst, hardener, crosslinking agent, promoter or accelerator. However, the order of mixing the ingredients is not critical and said ingredients may be mixed simultaneously. The composition thus prepared can be used as a dental filling material, a cement for dental care, a lining of dental cavities, a dental cortex shell material, or the composition can be molded in a suitable mold to make an artificial tooth or group of teeth.

It is, of course, highly preferred that the material used in the oral cavity be caries resistant. This is readily accomplished by adding about 0.01 to 1 percent fluoride ions, such as ammonium or tin fluoride, to the suspension of freshly precipitated hydroxylapatite. The ceramic material obtained by sintering the product formed is very resistant to lactic, acetic and citric acids, which are used in the in vitro method for determining caries resistance. Alternatively, resistance to caries can be obtained in the final ceramic material by maintaining it in a 0.5 to 5% aqueous solution of sodium fluoride for about 12 hours to 5 days. Preferably, the ceramic body is allowed to remain in about 5% aqueous sodium fluoride for about 4 days.

The properties of the ceramic materials were determined by the following test methods: Elemental analysis, density, X-ray diffraction, electron microscopy, microscopy using polarized light, and mechanical test methods.

The invention is illustrated by the following examples.

Example 1

To a stirred mixture of 130 mL of 1.63 M calcium nitrate (0.212 moles) and 125 mL of concentrated ammonia was added dropwise over about 20 minutes a mixture of 16.75 g (0.127 moles) of diammonium hydrogen phosphate, 400 mL of distilled water, and 150 ml of concentrated ammonia. The resulting suspension was boiled for 10 minutes, the suspension was cooled in an ice bath and filtered. The filter cake was pressed onto a rubber plate and then dried overnight at 95 ° C. A sample of the formed hard, porous, brittle cake was heated in an electric oven for 115 minutes to a final temperature of 1230 ° C and then cooled to room temperature to give a strong, hard, white transparent ceramic product.

Conventional elemental analyzes performed on the final ceramic product and also on the dried hydroxylapatite before sintering gave the following results:

Calculated Dried, sintered mat hydroxyl- Ceramic

Ca10 (PO4) 6 (OH) apatite product

Ca 39.89% 37.4% 39.6% P 18.5% 17.5% 18.9% h2o 0% 1% ---

Ca / P 1.667 1.65 1.62

When a thin ceramic plate was examined under a polarizing microscope at magnifications of 130X and 352X, the material was found to be substantially free of whitlocyte. Absence of birefringence and observable structural properties such as crystal form, orientation

II

i7 641 31 folding, interfaces, etc. showed the structure to be microcrystalline. Comparing the optical micrograph of the sintered compressed tablet disclosed by Monroe et al., (Supra), the two materials were found to be structurally similar.

X-ray diffraction measurements were performed in the normal manner. The distances between the crystal planes were calculated and found to be substantially identical to hydroxylapatite according to Doannay et al., Crystal Data, ACA Monogram No. 5,668 (1963). X-ray measurements further showed the absence or less than 2 to 3% of whitlocyte, which is the detection limit of the minimum concentration of the diffractometer.

Example 2

A solution of 79.2 g (0.60 moles) of diammonium hydrogen phosphate in 1500 ml of distilled water was adjusted to pH 11-12 by adding about 750 ml of concentrated ammonia. Distilled water was added to dissolve the precipitated ammonium phosphate to give a total volume of 3200 ml. If necessary, the pH was readjusted to 11-12. This solution was added dropwise over 30-40 minutes to a vigorously stirred solution of 1 mole of calcium nitrate in 900 ml of distilled water, previously adjusted to pH 12 with about 30 ml of concentrated ammonia solution, followed by dilution. distilled water until the volume was 1800 ml. After the addition was complete, the resulting gel suspension was stirred for an additional 10 minutes and then boiled for 10 minutes, the heat removed and the suspension allowed to stand at room temperature for 15-20 hours. The clear top was removed by decantation and the remaining suspension was centrifuged at 2000 rpm for 10 minutes. The resulting slurry was resuspended in 800 ml of distilled water and centrifuged again at 2000 rpm for 10 minutes. Distilled water was added to the solid residue to give a total volume of 900 ml. Shaking vigorously gave a uniform suspension with substantially no larger particles or agglomerates. The whole suspension was poured once into a BUcher funnel and suction filtered. As the filter cake began to crumble, a rubber plate was placed on top of it and the vacuum was increased. After 1 hour, the rubber plate was removed and the uncracked, intact filter cake was transferred to a flat surface and dried for 15 hours at 90-95 ° C to give 90-100 g of white, porous, brittle 2 hydroxylapatite pieces. Intact, non-cracked pieces 1 to 4 cm in size were placed in an electric oven and the temperature was raised to 1200 ° C within 100 minutes, after which the oven and its contents were allowed to cool to room temperature. This gave hard, dense, non-porous, white, transparent ceramic pieces.

Dried, unsintered

Analysis of Calculated Hydroxyapatite Ceramics

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

After performing the above analyzes, it was found that in the analytical methods used, the samples did not dissolve completely, and the results were therefore inaccurate and highly variable. However, the homogeneity of this sample was determined by electron microscopy.

Samples were prepared in two steps for transmission electron microscopy, which showed that the grain size was smooth and pore-free, and no second-phase precipitates were observed at the granule interfaces or in the granules. A sample of ceramic material was then polished with SiC paper to 600 mesh and then with 3 diamond paste. The sample was then etched with 4% hydrofluoric acid for 30 seconds. Copies of the polished and etched surface were then taken and examined by electron microscopy. In this case, no second phase was also observed at the interfaces of the granules, however, there were indications of a small number of particles in the second phase in the granules.

Compressive strength and modulus of elasticity were determined by conventional 2 2 methods. The compressive strength was 4000 kp / cm _ + 1150 kp / cm and the Kimmo-5 2 module was 4.4 x 10 kp / cm.

The tensile strength was determined by a standard three-point bending test 2 2, a value of 680 kp / cm _ + 230 kp / cm was obtained.

The coefficient of thermal expansion was linear between 25 ° C and -225 ° C and had a value of 11 x 10 * V ° C + 10%.

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The hardness determined by the conventional Knoop method was 480. The same value was obtained regardless of the direction of the applied force, indicating that the material was isotropic.

Porosity was determined qualitatively by immersing the sample material in magenta color for 15 minutes, washing it with water, drying, and then examining the sample material for color residues. This experiment was performed simultaneously on the non-porous form of the ceramic material prepared according to the present invention, a sintered compressed tablet of hydroxylapatite, and a natural tooth. The sintered compressed tablet showed considerable color retention, while no color residue was observed in the novel ceramic material and natural tooth of the invention. According to the second method, the test material was immersed in a 6 N aqueous ammonia solution for 15 minutes, washed with water, dried and wrapped in moist litmus paper. Any ammonia left in the surface pores will cause the surrounding litmus paper to turn blue. When this experiment was performed simultaneously on the above-mentioned materials, the litmus paper in contact with the sintered compressed tablet turned blue, thus indicating the presence of ammonia in the tablet. No discoloration was observed in litmus paper in contact with the ceramic material or natural tooth.

Example 3

Following the procedure described in Example 2, but starting with 3 moles of calcium nitrate and 1.8 moles of diammonium hydrogen phosphate, 304 g of white, brittle, porous hydroxylapatite were obtained.

Analysis Calculated Observed

Ca 39.89 40.0 P 18.5 18.6

Ca / P 1.667 1.66

Sintering at 1100 ° C for one hour gave a hard, white, transparent ceramic material with a density of 3.10 g / cm. X-ray diffraction indicated that the material was homogeneous hydroxyl apatite. Electron microscopic examination gave a crystallite size distribution of 0.7 to 3 Jim. There were no pores or second phase precipitates in the material.

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Example 4 A. The procedure set forth in Example 2 was followed except that half of the amounts set forth therein were used to precipitate about 50 g of hydroxylapatite from aqueous solution. After centrifugation and decantation, the mineral slurry obtained was re-extracted with water to a total volume of 1 liter and homogenized in a Waring mixer for 2 minutes.

B. The mixture containing 0.5 g of ground cellulose (<0.5 μια) in 200 ml of water was stirred · Waring mixer for 3 minutes. Then, 100 ml of a homogeneous suspension of hydroxylapatite was added, and the mixture was further stirred for 5 minutes. The suspension was filtered, the filter cake dried and sintered according to Example 2. There were very few cracks in the filter cake after drying, and the ceramic product obtained by sintering was slightly porous as determined by the magenta color test described above.

C. A mixture of 0.5 g of shredded surgical cotton in 200 ml of water was stirred in a Waring mixer for 45 minutes or until a nearly homogeneous suspension was obtained. Then, 100 ml of the homogeneous aqueous suspension of hydroxylapatite shown in Example 4A was added and stirring was continued for another 15 minutes. The resulting suspension was filtered, the filter cake was dried and sintered as described in Example 2. The ceramic product remained intact and was visibly porous.

Example 5 A. A mixture containing 5 g of collagen (bovine Achilles tendon) in 300 ml of water was stirred in a Waring mixer for 5 minutes. Collagen absorbed large amounts of water to form a thick gel-granular mass. A small amount of finely divided collagen (20-30 mg) remained in the suspension.

B. A suspension of finely divided collagen (250 ml) was decanted and mixed in a Waring mixer for 5 minutes with 100 ml of the homogeneous aqueous suspension of hydroxylapatite shown in Example 4A. The resulting mixture was filtered and the filter cake was dried and sintered according to Example 2. The ceramic product formed was intact and almost non-porous.

Il 21 64131 C. About 20% of the thick gel-like collagen was mixed in a Waring mixer for 6 minutes with 150 ml of the homogeneous aqueous suspension of hydroxylapatite shown in Example 4A. The resulting mixture was filtered and the filter cake was dried and sintered according to Example 2. The filter cake remained intact prior to sintering and had relatively good mechanical strength. The ceramic product obtained in sintering was hard, strong and visibly porous.

Example 6

Samples of the ceramic product prepared according to Example 2 were allowed to remain in a 1% aqueous solution of sodium fluoride for 12 hours. These materials, together with the untreated ceramic material and the natural tooth, were then exposed to 10% lactic acid. After three days, the effect of lactic acid was significantly less in the fluoride-treated ceramic product than in the untreated ceramic product or natural tooth enamel. If the ceramic product was allowed to stand in a 1% aqueous solution of sodium fluoride for 3 days, no effect of lactic acid was observed. After 3 days and 1 month, it was only slightly corroded, whereas the untreated samples were strongly corroded.

Example 7

The procedure of Example 2 was followed except that half of the amounts present were used to precipitate about 50 g of hydroxylapatite from aqueous solution. After centrifugation, the mineral slurry was suspended in water to a total volume of 500 ml. The suspension was divided into ten equal portions, each diluted with 50 ml of water and treated with ammonium fluoride as follows: to samples 1, 2, 3, 4 and 5 were added 0, 0.1, 0.5, 1.0 and 2.0 ml, respectively. aqueous ammonium fluoride solution containing 0.00085 g F / ml. Samples 6, 7 and 8 were treated with 0.5, 1.0 and 10.0 ml of aqueous ammonium fluoride solution containing 0.0085 g F / ml, respectively. To Samples 9 and 10, 2.0 and 4.0 ml of aqueous ammonium fluoride solution containing 0.045 g F / ml were added, respectively. The suspensions were then shaken on a rotary shaker for 1.5 hours and then filtered. The filter cakes 22,641 31 were pressed for 15 minutes with a rubber plate, dried for 2 days at 95 ° C and then heated in an electric oven to 1200 ° C. The resulting ceramic bodies were ground to a fine powder and sieved through a 325 mesh screen. 80 mg of each powder sample was mixed with 80 ml of pH 4.1 sodium lactate buffer solution (0.4 m) at 23 ° C and the mixtures were shaken on a Burrel joint shaker. After stirring for 2, 9, 25 and 40 minutes, a 3 ml sample was removed from each sample mixture, which was immediately filtered to remove insoluble matter, and the amount of dissolved ceramic was determined by colorimetric analysis. The results are given in Table A. For comparison, the sintered portion of Sample 1 was allowed to stand for 4 days in 1 ml of 5% sodium fluoride. The solids were removed, washed thoroughly with water, dried and then subjected to the above-mentioned dissolution analysis according to Sample 1A. The experimental conditions described above do not correspond to in vivo conditions. The conditions have been chosen so that the sample dissolves within a reasonable time for an accurate assessment of the relative effect of the fluoride ion content. Thus, the in vivo dissolution rates of ceramic hydroxylapatite are expected to be significantly lower than the rates observed above in strong lactate buffer.

Table A

Relative dissolution rates of fluorinated ceramic hydroxylapatite Sample Fluoride content (ppn) Dissolved% No. 1 -i set_detected 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 1700 470 7.9 18.1 25.7 29.8 8 17000 1460 6.7 12.1 19.7 23.3 9 18000 1700 6 .3 11.5 19.7 23.3 10 36000 2307 5.9 11.3 17.6 21.0 1 A - 3.7 7.1 13.7 18.7 a apparently incorrect analysis

II

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Example 8

Large pieces of dried filter cake about 3-4 mm thick prepared according to Example 2 and having a Ca / P ratio of 1.64 to 1.66 were grooved and broken into rectangular sheets about 14-15 mm long and 7-8 mm wide, having a small hole was drilled at one end. One thousand such plates were then sintered according to Example 2 and polished to a high gloss. The ceramic pieces formed had a density of 3.12 to 3.14 and were rectangular pieces about 10 to 11 mm long, 4 to 5 mm wide and 2 to 3 mm thick, and had a hole at one end through which a metal wire was inserted. The plates, which could thus be placed to the desired depth in the test tube, were used as test surfaces in the experiment of anti-rust agents.

Example 9

A solution of 0.24 moles of diammonium hydrogen phosphate in 600 ml of distilled water was adjusted to pH 11.4 by adding 340 ml of concentrated ammonia and then distilled water was added until the final volume was 1280 ml. This solution was added dropwise over 30 minutes to a vigorously stirred solution of 0.4 moles of calcium nitrate in 360 ml of distilled water, the pH of which had been previously adjusted to 11 with concentrated ammonia and diluted to a volume of 720 ml with distilled water. The resulting suspension was stirred uncooked and periodically taken as 250 ml samples, from which the products were separated, washed and dried as described in Example 2. All samples were then heated for one hour at 1100 ° C and the compositions of the formed ceramic products were determined by X-ray diffraction. The results are given in Table B.

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Table B

In X-ray diffraction Sample Mixing-Standing time Elemental analysis observed phases No. time before isolation-% Ca% P% Ca / p Hydroxyl- Whitlok- _ _ from_ _ apatite% titite% 1 5 min - 36.6 18.2 1 .55 17 83 2 45 min - - 21 79 3 2 h - 36.6 18.0 1.57 39 61 4 4.5 h - - 98 2a 5 7 h - 37.0 17.0 1.68 98 2a 6 7 h 17 h 37.2 17.0 1.69 100 0 7 24 h - 37.4 17.1 1.69 100 0 8 48 h - 37.4 16.8 1.72 100 0 these values are limited X-ray di f fractionatri resolution (minimum concentration 2 to 3%) and the result is therefore uncertain

Example 10 A. The procedure of Example 2 was followed except that 0.3 moles of calcium nitrate and 0.2 moles of diammonium hydrogen phosphate were used to give a hard, brittle, porous product having the following Elemental analysis: Ca = 38.85%, P = 19.77%,

Ca / P = 1.52. This material was heated at 1200 ° C for 1 hour to give a strong, hard, non-porous, white, partially opaque ceramic material containing about 40% hydroxylapatite and 60% whitlocyte as detected by X-ray diffraction.

B. Carrying out the above reaction by adding the starting materials in reverse order, a product was obtained which contained about 40% hydroxylapatite and 60% whitlocyte and had a Ca / Poly ratio of 1.52 and a density of 2.982.

Example 11

A solution of 0.0625 moles of diammonium hydrogen phosphate in 150 ml of distilled water was treated with 95 ml of concentrated ammonia and distilled water was added until the final volume was 320 ml. This solution was added dropwise over 30 minutes to a vigorously stirred solution of 0.1 mol of calcium nitrate and 2.5 ml of concentrated ammonia in 180 ml of distilled water.

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The resulting suspension was stirred for 5 minutes, cooled on ice for 45 minutes and the suspended solids separated, washed and dried as in Example 2 to give a hard, brittle, porous, white solid having the following Elemental Analysis: Ca = 35.4%, P = 18.59%, Ca / P = 1.46. This material was heated at 1350 ° C for 1 hour to give a strong, hard, non-porous, slightly opaque ceramic product containing about 14% hydroxylapatite and 86% whitlocyte as detected by X-ray diffraction.

The products of Examples 1-11 correspond to articles made in accordance with this invention and their physical properties are set forth above.

The products made according to Examples 1, 2, 3, 5 B and 6 to 8 are hard, strong, dense, white, transparent ceramic bodies containing mainly pure, non-porous, isotropic polycrystalline hydroxylapatite and having a compressive strength of about 2500 to 9000 kp / cm, tensile strength about 210 to 2100 kp / cm 2, linear coefficient of thermal expansion about 10 to 12 ppm / ° C, Knoop hardness about 470 to 500 and modulus of elasticity about 4.2 x 10 kp / cm and characterized by cleavage along flat, curved surfaces and the absence of birefringence in polarized light.

The products prepared according to Examples 4 and 5c, although containing the same material as those prepared in Examples 1, 2, 3, 5B and 6-8, have formed openings and pores of varying number and size. It is clear that the pores alter the physical properties of the substance, for example by lowering the compressive strength, tensile strength, elasticity and hardness.

The compatibility of the novel ceramic form of hydroxylapatite according to the invention with living tissue was established by implantation studies, which showed that when the ceramic bodies prepared according to Example 1 were implanted intraperitoneally in rats or subcutaneously in rabbits, no inflammation or resorption was observed after 28 days.

Ceramic hydroxylapatite pellets prepared as described in Example 3 were surgically implanted in the femurs of dogs. The implants were monitored in vivo from time to time by X-ray examination. After one month and six months, respectively, 26 64131 animals were sacrificed and thighs containing implanted objects were removed. Samples were excised from the femur sites at the implantation sites and examined using both optical and scanning electron microscopy. Both the one-month and six-month implants were characterized by normal healing, strong adherence of new bone to the implant surface without intervening fibrous tissues, no signs of inflammation or foreign body rejection, and no resorption of the implanted material was observed.

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Claims (9)

A process for preparing a polycrystalline, sintered, macroformed ceramic material by reacting calcium and phosphate ions in an aqueous medium at a pH of about 10-12 to form a gelatinous precipitate of calcium phosphate with a molar ratio between calcium and phosphorus between the approximate molar ratio of calcium to phosphorus in hydroxylapatite and whitloctite and, by separating the precipitate from the solution, characterized in that said cohesive, gelatinous precipitate is heated to a temperature of at least 1000 ° C, but below the temperature. temperature at which appreciable decomposition of hydroxylapatite occurs, and this temperature is maintained long enough to achieve sintering and substantially maximum compression in the formed product, and said precipitate, when desired to produce a porous ceramic product, is added 5-25. wt% organic binder, which evaporates during the heating treatment, and the precipitate, when desired to include fluoride in the product obtained, fluoride ions are added before being separated from the solution or the synthesized sintered ceramic product is allowed to boil in an approximately 0.5-5% aqueous solution of sodium fluoride from about 12 hours to 5 days. Process according to Claim 1, characterized in that the precipitate is heated to a temperature of at least 1,050 ° C. 3. A process according to claim 1, characterized in that the ratio of the reactants used in the reaction is chosen such that a precipitate is formed in which the calcium to phosphorus mole ratio is essentially the calcium to phosphorus mole ratio in hydroxylapatite. 4. A process according to claim 3, characterized in that the molar ratio of calcium to phosphorus in the precipitate is about 1.62 - 1.72, and that the temperature is poured in the range up to about 1,250 ° C from about 20 minutes to 3 hours. Process according to Claim 4, characterized in that the temperature is poured in the range of about 1 100 - 1200 ° C for about 0.5 - 1 hour. 6. A process according to claim 1 or 2, characterized in that a precipitate is formed in which the molar ratio of calcium to phosphorus is in the range of 1.44 to 1.60, preferably