USOO5939039A United States Patent (19) 11 Patent Number: 5,939,039 Sapieszko et al. (45) Date of Patent: Aug. 17, 1999

54 METHODS FOR PRODUCTION OF Mirtchi et al. Calcium phosphate cements: Effect of fluorides CALCUM PHOSPHATE on the Setting and hardening of beta-tricalcium phosphate -dicalcium phosphate -calcite cements Biomat. 1991 75 Inventors: Ronald S. Sapieszko, Woodbury, 12:505. No Month. Minn.; Erik M. Erbe, Berwyn, Pa. J.L. Lacout Calcium phosphate as bioceramicS Biomateri als-Hard Tissue Repair and Replacement 81-95 1992 73 Assignee: Orthovita, Inc., Malvern, Pa. Elsevier Science Publishers. No Month H. Monma et al. Properties of hydroxyapatite prepared by 21 Appl. No.: 08/784,439 the hydrolysis of triacalcium phosphate J. Chem. Tech. Biotechnol. 1981 31:15. No Month. 22 Filed: Jan. 16, 1997 H. Chaair et al. Precipitation of stoichiometric apatitic (51) Int. Cl." ...... C01B 15/16 tricalcium phosphate prepared by a continuous process J. Mater. Chem. 1995 5(6):895. No Month. 52 U.S. Cl...... 423/311; 423/305 R. Famery et al. Preparation of alpha-and beta-triacalcium 58 Field of Search ...... 423/305, 311, phosphate ceramics, with and without magnesium addition 423/314, 315 Ceram. Int. 1994 20:327. No Month. 56) References Cited Y. Fukase et al. Setting reactions and compressive Strengths of calcium phosphate cements J. Dent. Res. 1990 U.S. PATENT DOCUMENTS 69(12):1852. No Month. F. Abbona et al. Crystallization of calcium and magnesium 3,679,360 7/1972 Rubin et al...... 23/109 4,149,893 4/1979 Aoki et al...... 106/35 phosphate from Solutions of medium and low concentrations 4,612,053 9/1986 Brown et al...... 706/35 Cryst. Res. Technol. 1992 27:41. No Month. 4,673,355 6/1987 Farris et al...... 433/218 G.H. Nancollas The involvement of calcium phosphates in 4,711,769 12/1987 Inoue et al...... 423/305 biological mineralization and dimeralization processes Pure 4,849,193 7/1989 Palmer et al. ... 423/308 Appl. Chem. 1992 64(11):1673. No Month. 4,880,610 11/1989 Constantz ...... 423/305 G.H. Nancollas et al. Formation and dissolution mechanisms 4,891,164 1/1990 Gaffney et al...... 252/629 of calcium phosphates in aqueous Systems Hydroxyapatite 4,897.250 1/1990 Sumita ...... 423/308 and Related Materials 73–81 1994 CRC Press, Inc. No 5,034,352 7/1991 Vit et al...... 501/1 Month. 5,047,031 9/1991 Constantz. ... 606/77 5,129,905 7/1992 Constantz ...... 606/76 P.W. Brown et al. Variations in Solution chemistry during the 5,302,362 4/1994 Bedard ...... 423/306 low temperature formation of hydroxyapatite J. Am. Ceram. 5,322,675 6/1994 Hakamatsuka ... 423/311 Soc. 1991 74(8): 1848. No Month. 5,338,356 8/1994 Hirano et al...... 106/690 G. Vereecke et al. Calculation of the solubility diagrams in 5,409,982 4/1995 Imura et al...... 524/417 the system Ca(OH)-HPO-KOH-HNO-CO-HO J. 5,427,754 6/1995 Nagata et al...... 423/308 Cryst. Growth 1990 104:820. No Month. 5,496,399 3/1996 Ison et al...... 106/35 N.N. Greenwood et al. Oxoacids of phosphorus and their 5,522,893 6/1996 Chow et al...... 623/11 salts Chemistry of the Elements 586–595 1984 Pergamon 5,525,148 6/1996 Chow et al...... 106/35 Press. No Month. 5,545,254 8/1996 Chow et al...... 106/35 PCT International Search Report dated Apr. 10, 1998, 1 OTHER PUBLICATIONS page. KoutsoukOS et al. Crystallization of calcium phosphates. A Primary Examiner Michael Lewis constant composition study J. Am. Chem. Soc. 1980 ASSistant Examiner Stuart L. Hendrickson 102:1553. No Month. Attorney, Agent, or Firm Woodcock Washburn Kurtz Wong et al. Prediction of precipitation and transformation Mackiewicz & Norris LLP behavior of calcium phosphate in aqueous media Hydroxya 57 ABSTRACT patite and Related Materials 189-196 1994 CRC Press, Inc. No Month. Uniformly sized and shaped particles of metal Salts are G.H. Nancollas In vitro studies of calcium phosphate crys provided comprised of one or more metal cations in com tallization Biomineralization-Chemical and Biochemical bination with one or more simple oxoacid anions and a general method for the controlled precipitation of Said metal Perspectives 157–187 1989. No Month. Salts from aqueous Solutions. The methods proceed via the R.Z. LeGeros Preparation of octacalcium phosphate (OCP): in Situ homogeneous production of simple or complex A direct fast method Calcif. Tiss. Int. 1985 37:194. No OXoacid anions in which one or more of the nonmetallic Month. elements e.g. Group 5B and 6B (chalcogenides), and 7B Driessens et al. Effective formation for the preparation of (halides) comprising the first oxoacid anion undergo oxida calcium phosphate bone cements J. Mat. Sci. Mat. Med. tion to generate the precipitant anionic Species along with 1994 5:164. No Month. concurrent reduction of the nonmetallic element of a Second, R.Z. LeGeroS Biodegradation and bioresorption of calcium dissimilar oxoacid anion. The oxoacid anions are initially phosphate ceramics Clin. Mat. 1993 14(1):65. No Month. present in Solution with one or more metal cations known to K. Ishikawa Properties and mechanisms of fast-setting form insoluble Salts with the precipitant anion. calcium phosphate cements J. Mat. Sci. Mat. Med. 1995 6:258. No Month. 14 Claims, 22 Drawing Sheets U.S. Patent Aug. 17, 1999 Sheet 1 of 22 5,939,039

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s 000 AISuelu 5,939,039 1 2 METHODS FOR PRODUCTION OF phosphate granular cement and method for producing CALCUM PHOSPHATE same;” U.S. Pat. No. 5,427,754, F. Nagata, et al., “Method for production of platelike hydroxyapatite; U.S. Pat. No. FIELD OF THE INVENTION 5,496,399, I. C. Ison, et al., “Storage stable calcium phos This invention relates to methods for the preparation of 5 phate cements;” U.S. Pat. No. 5,522,893, L. C. Chow. et al., minerals, especially phosphorus containing minerals, to the “Calcium phosphate hydroxyapatite precursor and methods minerals thus prepared and to methods for their use. In for making and using same,” U.S. Pat. No. 5,545,254, L. C. accordance with certain embodiments, minerals are pro Chow, et al., "Calcium phosphate hydroxyapatite precursor Vided which are novel in that they are, at once, Substantially and methods for making and using same; U.S. Pat. No. homogeneous and non-Stoichiometric. They can be pro 3,679,360, B. Rubin, et al., “Process for the preparation of duced through novel, low temperature techniques which brushite crystals;” U.S. Pat. No. 5,525,148, L. C. Chow, et offer excellent control of composition and morphology. al., “Self-setting calcium phosphate cements and methods for preparing and using them;’ U.S. Pat. No. 5,034,352, J. BACKGROUND OF THE INVENTION Vit, et al., “Calcium phosphate materials;” and U.S. Pat. No. There has been a continuing need for improved methods 15 5,409,982, A. Imura, et all “Tetracalcium phosphate-based for the preparation of mineral compositions, especially materials and process for their preparation.” phosphorus-containing minerals. This long-felt need is While improvements have been made in ceramic process reflected in part by the great amount of research found in the ing technology leading to ceramic biomaterials with better pertinent literature. While such interest and need stems from control over Starting materials and, ultimately, the final a number of industrial interests, the desire to provide mate products, improved preparative methods are still greatly rials which closely mimic mammalian bone for use in repair desired. Additionally, methods leading to calcium phosphate and replacement of Such bone has been a major motivating containing biomaterials which exhibit improved biological force. Such minerals are principally calcium phosphate properties are also greatly desired despite the great efforts of apatites as found in teeth and bones. For example, type-B others to achieve Such improvements. carbonated hydroxyapatite Cas(PO) (CO)(OH) is the 25 Accordingly, it is a principal object of the present inven principal mineral phase found in the body, with variations in tion to provide improved minerals, especially phosphorus protein and organic content determining the ultimate containing minerals. composition, crystal size, morphology, and structure of the A further object of the invention is to provide methods for body portions formed therefrom. forming Such minerals with improved yields, lower proceSS Calcium phosphate ceramics have been fabricated and ing temperatures, greater flexibility and control of product implanted in mammals heretofore in many different forms formation, and the ability to give rise to minerals having including as shaped bodies, in cements and otherwise. improved uniformity, biological activity, and other proper Different Stoichiometric compositions Such as hydroxyapa ties. tite (HAp), tricalcium phosphate (TCP), and tetracalcium 35 Another object is to improve the yield and control of phosphate (TTCP), have all been employed to this end in an Synthetic mineral formation processes. attempt to match the adaptability, biocompatibility, Structure Yet another object is to give rise to cement compositions and Strength of natural bone. Despite tremendous efforts useful in the repair or replacement of bone in Orthopaedic directed to the preparation of improved calcium phosphate and dental procedures. and precursor hydroxyapatite materials for Such uses, Sig 40 A further object is to provide minerals which are both nificant shortcomings Still remain. Substantially uniform and which are non-Stoichiometric. Early ceramic biomaterials exhibited problems derived from chemical and processing shortcomings that limited Further objects will become apparent from a review of the Stoichiometric control, crystal morphology, Surface present specification. properties, and, ultimately, reactivity in the body. Intensive 45 SUMMARY OF THE INVENTION milling and comminution of natural minerals of varying composition was required, followed by powder blending and The present invention is directed to create new methods ceramic processing at high temperatures to Synthesize new for the preparation of minerals, especially phosphorus phases for use in Vivo. containing minerals. The invention also gives rise to A number of patents have issued which relate to ceramic 50 uniquely formed minerals, including minerals having biomaterials. Among these are U.S. Pat. No. 4,880,610, B. improved compositional homogeneity and to minerals hav R. Constantz, "In Situ calcium phosphate minerals-method ing modified crystal Structures. New minerals are also pro and composition; U.S. Pat. No. 5,047,031, B. R. Constantz, vided by the invention, including “non-stoichiometric' “In situ calcium phosphate minerals method;’ U.S. Pat. No. minerals, which differ from commonly found minerals, 5,129,905, B. R. Constantz, “Method for in situ prepared 55 crystal Structures which are found in nature, and Structures calcium phosphate minerals;” U.S. Pat. No. 4,149,893, H. which have traditionally “allowed' ratios of constituent Aoki, et al., “Orthopaedic and dental implant ceramic com atoms in unit cells. position and proceSS for preparing Same,” U.S. Pat. No. The new paradigm created by this invention requires a 4,612,053, W. E. Brown, et al., “Combinations of sparingly Specification of terms used in this invention. The general Soluble calcium phosphates in Slurries and pastes as miner 60 method Starts from raw materials , which are described alizers and cements; U.S. Pat. No. 4,673,355 E. T. Farris, herein as Salts, aqueous Solutions of Salts, stable hydroSols or et al., “Solid calcium phosphate materials;” U.S. Pat. No. other Stable dispersions, and/or inorganic acids. The phases 4,849,193, J. W. Palmer, et al., “Process of preparing produced by the methods of this invention Redox Precipi hydroxyapatite;” U.S. Pat. No. 4,897.250, M. Sumita, “Pro tation Reaction (RPR) and HYdrothermal PRocessing cess for producing calcium phosphate,” U.S. Pat. No. 5,322, 65 (HYPR) are generally intermediate precursor minerals in 675, Y. Hakamatsuka, “Method of preparing calcium phos the physical form of powders, particulates, Slurries, and/or phate;” U.S. Pat. No. 5,338,356, M. Hirano, et al “Calcium pastes. These precursor minerals can be easily converted to 5,939,039 3 4 a myriad of mixed and pure mineral phases of known and, cm, and associated P-O, P=O vibrations, at 540–610, in Some cases, as yet unidentified mineral Stoichiometries, 1100–1250 cm respectively. A second FTIR plot (lower generally via a thermal treatment under modest firing con plot) of the material of FIG. 7 is also depicted to show lack ditions compared to known and practiced conventional art. of carbonate peaks at 880 cm. The methods of the invention are energy efficient, being FIG. 10 is an X-ray Diffraction (XRD) plot of RPR performed at relatively low temperature, have high yields generated Zinc phosphate precursor mineral heated to 500 and are amenable to careful control of product purity, C. for 1 hour. The peak position and relative intensities identity and quality. Employment as biological ceramicS is indicate the presence of the crystal phase Zn(PO). a principal use for the materials of the invention, with FIG. 11 is an X-ray Diffraction (XRD) plot of RPR improved properties being extant. Other uses of the minerals generated iron phosphate precursor mineral heated to 500 and processes of the invention are also within the Spirit of C. for 1 hour. The peak position and relative intensities the invention. indicate the presence of the crystal phase Graftonite Fe (PO). BRIEF DESCRIPTION OF THE DRAWINGS FIG. 12 is an X-ray Diffraction (XRD) plot of RPR FIG. 1 depicts an aggregated physical Structure of an RPR 15 generated aluminum phosphate precursor mineral heated to generated, multiphasic f-tricalcium phosphate (B-TCP)+ 500 C. for 1 hour. The peak position and relative intensities type-B carbonated apatite (c-HAp)f-Ca(PO)2+Cas(PO) indicate the presence of the crystal phase AlPO. (CO)(OH) prepared in accordance with one embodi FIG. 13 is an X-ray Diffraction (XRD) plot of HYPR ment this invention. The entire agglomerated particle is generated calcium phosphate precursor mineral heated to approximately 10 um, and the individual crystallites are 500 C. for 1 hour. The peak position and relative intensities typically less than about 1 um and relatively uniform in indicate the presence of an as yet unidentified calcium particle size and shape. phosphate crystal phase. FIG. 2 represents assembled monetite, CaHPO particles FIG. 14 is an X-ray Diffraction (XRD) plot of HYPR formed from a hydrothermal precipitation in accordance 25 generated calcium phosphate precursor mineral heated to with this invention. The entire particle assemblage is typi 500 C. for 1 hour. The peak position and relative intensities cally about 30 um and is comprised of relatively uniformly indicate the presence of an as yet unidentified calcium rectangular cubes and plate-like crystallites of various sizes phosphate crystal phase and minor amounts of HAp. and aspect ratios. FIG. 15 is an X-ray Diffraction (XRD) plot of HYPR FIG. 3 is an X-ray Diffraction (XRD) plot of RPR generated calcium phosphate precursor mineral heated to generated calcium phosphate precursor mineral heated to 500 C. for 1 hour. The peak position and relative intensities 100° C. for 1 hour. The peak position and relative intensities indicate the presence of the crystal phase monetite indicate the presence of the crystal phase monetite. CaHPO). FIG. 4 is an X-ray Diffraction (XRD) plot of an RPR FIG. 16 is an X-ray Diffraction (XRD) plot of RPR and generated calcium phosphate precursor mineral heated to 35 HYPR generated calcium phosphate precursor minerals, 300 C. for 1 hour. The peak position and relative intensities heated to 500 C. for 1 hour, and mixed as a cement. The indicate the presence of the crystal phase monetite. peak position and relative intensities indicate the presence of FIG. 5 is an X-ray Diffraction (XRD) plot of RPR the crystal phase monetite CaHPO mixed with B-TCP+ generated calcium phosphate precursor mineral heated to type-B, carbonated apatite (c-HAp) ?-Ca(PO4)2+Cas 500 C. for 1 hour. The peak position and relative intensities 40 (PO) (CO)(OH) crystallites. indicate the presence of the crystal phases p-tricalcium FIG. 17A is an X-ray Diffraction (XRD) plot of RPR and phosphate (B-TCP) major phase-calcium pyrophosphate HYPR generated calcium phosphate precursor minerals, (CaFIPO, ) minor phase. heated to 500 C. for 1 hour. The peak position and relative FIG. 6 is an X-ray Diffraction (XRD) plot of RPR intensities indicate the presence of the crystal phase generated calcium phosphate precursor mineral heated to 45 monetite, CaHPO, mixed with B-TCP+type-B, carbonated 500 C. for 1 hour. The peak position and relative intensities apatite (c-HAp) ?-Ca(PO)+Cas(PO) (CO)(OH) indicate the presence of the crystal phases 3-tricalcium crystallites. phosphate (B-TCP) major phase+apatite (Cas(PO)(OH)) FIG. 17B is an X-ray Diffraction (XRD) plot of RPR and minor phase. 50 HYPR generated calcium phosphate precursor minerals, FIG. 7 is an X-ray Diffraction (XRD) plot of RPR heated to 500 C. for 1 hour, and mixed into a cement. The generated calcium phosphate precursor mineral, without peak position and relative intensities indicate the presence of added CO, heated to 500° C. for 1 hour. The peak the crystal phase B-TCP+type-B, carbonated apatite position and relative intensities indicate the presence of the (c-HAp) B-Ca(PO)+Cas(PO) (CO)(OH) crystal lites. crystal phases f-tricalcium phosphate (B-TCP) major 55 phase+apatite (Cas(PO4)(OH)) minor phase. FIG. 18A is an X-ray Diffraction (XRD) plot of RPR FIG. 8 is an X-ray Diffraction (XRD) plot of RPR generated neodymium phosphate precursor mineral heated generated calcium phosphate precursor mineral, with added to 500 C. for 1 hour. The peak position and relative CO, heated to 500° C. for 1 hour. The peak position and intensities indicate the presence of the crystal phase neody relative intensities indicate the presence of the crystal phases 60 mium phosphate hydrate NdPO-0.5H2O). f-tricalcium phosphate (B-TCP) major phase-apatite (Cas FIG. 18B is an X-ray Diffraction (XRD) plot of RPR (PO)(OH)) minor phase). The spectrum shows a signifi generated neodymium phosphate precursor mineral heated cant difference in the intensity of the HAp peaks, as com to 700° C. for 1 hour. The peak position and relative pared to that in FIG. 7. intensities indicate the presence of the crystal phase FIG. 9 depicts Fourier Transform Infrared (FTIR) spectra 65 Monazite-Nd NdPO). of calcium phosphate as used for FIG. 8, indicating the FIG. 18C is an X-ray Diffraction (XRD) plot of RPR presence of CO. vibrations, at 880, 1400, and 1450 generated cerium phosphate precursor mineral heated to 5,939,039 S 6 700 C. for 1 hour. The peak position and relative intensities not to be expected from prior methodologies. Thus, Such indicate the presence of the crystal phase Monazite-Ce precursor minerals can be, at once, non-Stoichiometric and CePO). possessed of uniform morphology. FIG. 18D is an X-ray Diffraction (XRD) plot of RPR It is preferred in connection with Some embodiments of generated yttrium phosphate precursor mineral heated to the present invention that the intermediate precursor miner 700 C. for 1 hour. The peak position and relative intensities als produced in accordance with the present methods be heated, or otherwise treated, to change their properties. indicate the presence of the crystal phase Xenotime IYPO). Thus, Such materials may be heated to temperatures as low DETAILED DESCRIPTION OF PREFERRED as 300° C. up to about 700° C. to give rise to certain EMBODIMENTS beneficial transformations. Such heating will remove extra neous materials from the mineral precursor, will alter its In accordance with the present invention, methods are composition and morphology in Some cases, and can confer provided for preparing an intermediate precursor mineral of upon the mineral a particularized and preselected crystalline at least one metal cation and at least one oxoanion. These Structure. Such heat treatment is to temperatures which are methods comprise preparing an aqueous Solution of the considerably less than are conventionally used in accordance metal cation and at least one oxidizing agent. The Solution 15 with prior methodologies used to produce the end product is augmented with at least one Soluble precursor anion mineral phases. Accordingly, the heat treatments of the oxidizable by Said oxidizing agent to give rise to the present invention do not, of necessity, give rise to the precipitant OXoanion. The oxidation-reduction reaction thus common crystalline morphologies Structures of monetite, contemplated is conventionally initiated by heating the dicalcium or tricalcium phosphate, tetracalcium phosphate, Solution under conditions of temperature and pressure effec etc., but, rather, to new and unobvious morphologies which tive to give rise to Said initiation. In accordance with have great utility in the practice of the present invention. preferred embodiments of the invention, the oxidation reduction reaction causes at least one gaseous product to In accordance with the present invention, the minerals evolve and the desired intermediate precursor mineral to formed hereby are useful in a wide variety of industrial, 25 medical, and other fields. Thus, calcium phosphate minerals precipitate from the Solution. produced in accordance with preferred embodiments of the The intermediate precursor mineral thus prepared can be present invention may be used in dental and orthopaedic treated in a number of ways. Thus, it may be heat treated in Surgery for the restoration of bone, tooth material and the accordance with one or more paradigms to give rise to a like. The present minerals may also be used as precursors in preSelected crystal Structure or other preselected morpho chemical and ceramic processing, and in a number of logical Structures therein. industrial methodologies, Such as crystal growth, ceramic In accordance with preferred embodiments, the oxidizing processing, glass making, catalysis, bioseparations, pharma agent is nitrate ion and the gaseous product is a nitrogen ceutical excipients, gem Synthesis, and a host of other uses. oxide, generically depicted as NO. It is preferred that the Uniform microStructures of unique compositions of miner precursor mineral provided by the present methods be 35 als produced in accordance with the present invention confer Substantially homogeneous. It is also preferred that the upon Such minerals wide utility and great “value added.” temperature reached by the oxidationreduction reaction not Improved precursors provided by this invention yield exceed about 150 C. unless the reaction is run under lower temperatures of formation, accelerated phase transi hydrothermal conditions or in a pressure vessel. tion kinetics, greater compositional control, homogeneity, In accordance with other preferred embodiments, the 40 and flexibility when used in chemical and ceramic pro intermediate precursor mineral provided by the present cesses. Additionally, these chemically-derived, ceramic pre invention is a calcium phosphate. It is preferred that Such cursors have fine crystal size and uniform morphology with mineral precursor comprise, in major proportion, a Solid Subsequent potential for more closely resembling or mim phase which cannot be identified Singularly with any con icking natural Structures found in the body. ventional crystalline form of calcium phosphate. At the same 45 Controlled precipitation of Specific phases from aqueous time, the calcium phosphate mineral precursors of the Solutions containing metal cations and phosphate anions present invention are Substantially homogeneous and do not represents a difficult technical challenge. For Systems con comprise a physical admixture of naturally occurring or taining calcium and phosphate ions, the situation is further conventional crystal phases. complicated by the multiplicity of phases that may be In accordance with preferred embodiments, the low tem 50 involved in the crystallization reactions as well as by the perature processes of the invention lead to the homogeneous facile phase transformations that may proceed during min precipitation of high purity powders from highly concen eralization. The Solution chemistry in aqueous Systems con trated Solutions. Subsequent modest heat treatments convert taining calcium and phosphate Species has been Scrupu the intermediate material to e.g. novel monophasic calcium lously investigated as a function of pH, temperature, phosphate minerals or novel biphasic B-tricalcium phoS 55 concentration, anion character, precipitation rate, digestion phate (B-TCP)+type-B, carbonated apatite (c-HAp) B-Ca time, etc. (P. Koutsoukos, Z. Amjad, M. B. Tomson, and G. (PO)+Cas(PO) (CO)(OH) particulates. H. Nancollas, “Crystallization of calcium phosphates. A In other preferred embodiments, calcium phosphate Salts constant composition study,” J. Am. Chem. Soc. 102: 1553 are provided through methods where at least one of the (1980); A. T. C. Wong. and J. T. Czernuszka, “Prediction of precursor anions is a phosphorus Oxoanion, preferably intro 60 precipitation and transformation behavior of calcium phos duced as hypophosphorus acid or a Soluble alkali or phate in aqueous media, in Hydroxyapatite and Related alkaline-earth hypophosphite Salt. For the preparation of Materials, pp 189-196 (1994), CRC Press, Inc.; G. H. Such calcium phosphates, it is preferred that the initial pH be Nancollas, “In vitro studies of calcium phosphate maintained below about 3, and still more preferably below crystallization,” in Biomineralization-Chemical and Bio about 1. 65 chemical Perspectives, pp 157-187 (1989)). The intermediate precursor minerals prepared in accor Solubility product considerations impose Severe limita dance with the present methods are, themselves, novel and tions on the solution chemistry. Furthermore, methods for 5,939,039 7 8 generating Specific calcium phosphate phases have been particular, in that the materials are precipitated from homo described in many technical articles and patents (R. Z. geneous Solution using a novel Redox Precipitation Reac LeGeros, “Preparation of octacalcium phosphate (OCP): A tion (RPR). They can be subsequently converted to TCP, direct fast method.” Calcif. Tiss. Int. 37: 194 (1985)). As HAp and/or combinations thereof at modest temperatures discussed above, none of this aforementioned art employs and short firing Schedules. Furthermore, precipitation from the present invention. homogeneous solution (PFHS) in accordance with this Several sparingly Soluble calcium phosphate crystalline invention, has been found to be a means of producing phases, So called “basic calcium phosphates, have been particulates of uniform Size and composition in a form characterized, including alpha- and beta-tricalcium phos heretofore not observed in the prior art. phate (O-TCP, B-TCP, Ca(PO)2), tetracalcium phosphate The use of hypophosphite HPO anion as a precursor (TTCPCa(PO).O), octacalcium phosphate (OCP, Cal H to phosphate ion generation has been found to be preferred (PO).-nH2O, where 2thiosulfate (SO), cements,” J. Dent. Res.69(12): 1852 (1990). tetrathionate (SO), dithionite (SO) trithionate The present invention represents a Significant departure 65 (S.O.), sulfite (SO), and dithionate (S.O.). In con from prior methods for Synthesizing metal phosphate min sideration of the complex inorganic chemistry of the oxoan erals in general, and calcium phosphate powders in ions of Groups 5B, 6B, and 7B elements, it is anticipated that 5,939,039 9 10 other examples of oxidizable anions can be utilized in the for the formation of Such materials. The combination of spirit of this invention. homogeneous generation of precipitating anion, rapid pre The cation introduced into the reaction mixture with cipitation kinetics, and unique thermodynamic regime either or both of the oxidizing or reducing agents are results in the formation of calcium phosphate precursors preferably oxidatively stable (i.e. in their highest oxidation 5 having unique size and morphological characteristics, Sur State). However, in certain preparations, or to effect certain face properties, and reactivities. reactions, the cations may be introduced in a partially The foregoing consideration will also apply to minerals reduced oxidation State. Under these circumstances, adjust other than the calcium phosphates. Per force, however, the ment in the amount of the oxidant will be necessary in order phase diagram, equilibrium condition and constituent min to compensate for the electrons liberated during the oxida eral phases will differ in each family of minerals. tion of the cations during RPR. Uniformly sized and shaped particles of metal Salts com It is well known in the art that for solutions in equilibrium prised of one or more metal cations in combination with one with ionic precipitates, the Solute concentrations of the or more oxoacid anions can result from the present general reactant ions are dictated by Solubility product relationships 15 method for the controlled precipitation of Said metal Salts and supersaturation limitations. For the Cat"-PO) from aqueous Solutions. These proceed via the in Situ System, these expressions are exceedingly complicated, due homogeneous production of Simple or complex Oxoacid in large part to the numerous pathways (i.e., Solid phases) for anions of one or more of the nonmetallic elements, Group relieving the SuperSaturation conditions. Temperature, pH, 5B and 6B (chalcogenides), and 7B (halides). The first ionic Strength, ion pair formation, the presence of extraneous oxoacid anion undergoes oxidation (increase in chemical cations and anions all can affect the various Solute Species oxidation State) to generate the precipitant anionic species equilibria and attainable or Sustainable SuperSaturation lev along with concurrent reduction (decrease in chemical oxi els (F. Abbona, M. Franchini-Angela, and R. Boistelle, dation state) of the nonmetallic element of a second, dis "Crystallization of calcium and magnesium phosphates from Similar oxoacid anion, all oxoacid anions initially being Solutions of medium and low concentrations, Cryst. Res. 25 present in Solution with one or more metal cations known to Technol. 27: 41 (1992); G. H. Nancollas, “The involvement form insoluble salts with the precipitant anion. The metal of calcium phosphates in biological mineralization and cations are, preferably, oxidatively stable, but may, undergo demineralization processes, Pure Appl. Chem. 64(11): oxidation State changes themselves under certain conditions. 1673 (1992); G. H. Nancollas and J. Zhang, “Formation and dissolution mechanisms of calcium phosphates in aqueous RPR is induced preferably by heating a homogeneous Systems,” in Hydroxyapatite and Related Materials, pp Solution, So as to promote the onset and continuation of an 73–81 (1994), CRC Press, Inc.; P. W. Brown, N. Hocker, and exothermic redox reaction. This exothermic reaction results S. Hoyle, “Variations in solution chemistry during the low in the generation of gases, usually various nitrogen oxide temperature formation of hydroxyapatite, J. Am. Ceram. gases such as NO, where 0.5Sulfate anion may give rise to yet Powder Preparation another beneficial calcium phase, whereby the hemihydrate 65 An aqueous solution of 8.51 g 50 wt % hypophosphorus Species, CaSO-/2H2O, would provide an additional Setting acid, HPO (Alfa/Aesar reagent #14142, CAS #6303-21-5), reaction when in contact with water, as with Plaster of Paris. equivalent to 71.95 wt % POI was combined with 8.00 5,939,039 13 14 g distilled water to form a clear, colorleSS Solution contained mately 20 minutes and divided into two portions prior to in a 250 ml Pyrex beaker. To this solution was added 22.85 heat treatment. g calcium nitrate tetrahydrate salt, Ca(NO).4H2O (ACS Heat treatment and X-ray diffraction of this solid were reagent, Aldrich Chemical Co., Inc. i23,712-4, CAS conducted as described in Example 1. Following heat treat #13477-34-4), equivalent to 16.97 wt % Ca. The molar ratio ment in air, XRD indicated the fired solids to be composed of Ca/phosphate in this mixture was 3/2 and the equivalent of: solids level as Ca(PO) was 25.4 wt %. Endothermic dissolution of the calcium nitrate tetrahydrate proceeded under ambient temperature conditions, eventually forming a Sample Heat treatment Major phase Minor phase homogeneous solution. Warming of this solution above 25 A. 500° C. 1 h Whitlockite HAp C. initiated a reaction in which the Solution vigorously If-Cas(PO). Cas(PO)(OH) bubbled while evolving red-brown acrid fumes characteris B 700° C. 1 h HAp Whitlockite tic of NO. The sample turned into a white, pasty mass Cas(PO)(OH) If-Cas(PO). which foamed and pulsed with periodic expulsion of NO, After approximately two minutes, the reaction was essen 15 tially complete, leaving a white, pasty mass which was Example 3 warm to the touch. After cooling to room temperature, the Solid (A) was stored in a polyethylene vial. Novel Low Temperature Calcium Phosphate Three days after its preparation, a few grams of the damp, Powder Preparation pasty Solid were immersed in 30 ml distilled water in order An aqueous solution of 8.51 g 50 wt % HPO was to “wash out any unreacted, water Soluble components. The combined with 8.00 g of 25.0 wt % aqueous solution of Solid was masticated with a spatula in order to maximize calcium acetate monohydrate, Ca(OCCH).HO (ACS Solid exposure to the water. After approximately 15 minutes, reagent, Aldrich Chemical Co., Inc. i40,285-0, CAS 5743 the Solid was recovered on filter paper and the damp Solid 26-0), equivalent to 5.69 wt % Ca, to give a clear, colorless (B) stored in a polyethylene vial. 25 solution contained in a 250 ml Pyrex beaker. To this solution X-ray diffraction (XRD) patterns were obtained from was added 20.17 g Ca(NO).4H2O salt. The molar ratio of packed powder samples using the Cu-KC line () =1.7889 Ca/phosphate in this mixture was 3/2 and the equivalent Angstrom) from a Rigaku Geigerflex instrument run at 45 solids level as Ca(PO) was 27.3 wt %. Endothermic kV/30 mA using a 3 degree/minute scan rate over the 20 dissolution of the calcium nitrate tetrahydrate Salt proceeded angular range from 15-50 or broader. Samples were run giving a homogeneous Solution once the sample warmed to either as prepared or following heat treatment in air in either room temperature. Further warming of this solution to >25 a Thermolyne type 47900 or a Ney model 3-550 laboratory C. on a hotplate initiated a reaction which proceeded as furnace. XRD results are as follows (see FIGS. 3, 4, 5, and described in Example 1. After approximately three minutes, 6): the reaction was essentially complete leaving a moist, white, 35 crumbly solid which was hot to the touch and which smelled of acetic acid. After cooling to room temperature, the Solid Heat was Stored in a polyethylene Vial. Sample treatment Major phase Minor phase Heat treatment and X-ray diffraction analysis of this solid Unwashed (A) As prepared Undetermined were conducted as described in Example 1. Following heat Unwashed (A) 300° C. 1 h Monetite CaHPO, 40 treatment in air at 500 C. for either 0.5 or 1 hour, XRD Unwashed (A) 500 C., 1 h Whitlockite B-Cas(PO), CaH2PO, Unwashed (A) 700° C., 1 h Whitlockite indicated the solid to be composed of whitlockite as the If-Ca(PO) + primary phase along with hydroxylapatite as the Secondary HApCas(PO4)(OH) phase. XRD results indicate that the relative ratio of the two Washed (B) As prepared Monetite CaHPO, calcium phosphate phases was dependent on the duration of D. I. water 45 Washed (B) 100° C., 1 h Monetite CaHPO, the heat treatment and the presence of the acetate anion, but D. I. water no attempts were made to quantify the dependence.

Considerable amounts of NO, were evolved during firing Heated to 500° C., 1 h of the samples at or above 300° C. 50 (Major) Whitlockite B-Cas(PO), Example 2 (minor) Cas(PO) (CO)(OH) Novel Low Temperature Calcium Phosphate Powder Preparation Comparing the XRD spectra in FIGS. 7 and 8 shows the 55 difference in the amount of HAp-Cas(PO) (CO)(OH) Example 1 was repeated using five times the indicated phase present for each minor phase from Example 1 (which weights of reagents. The reactants were contained in a 5/2" had no acetate) and Example 3 (acetate present), respec diameter Pyrex crystallizing dish on a hotplate with no tively. This is indicative of the counteranion effect on crystal agitation. Warming of the homogeneous reactant Solution formation. above 25 C. initiated an exothermic reaction which evolved 60 Fourier Transform Infrared (FTIR) spectra were obtained red-brown acrid fumes characteristic of NO. Within a using a Nicolet instrument (model number 5DXC) run in the few Seconds following onset of the reaction, the Sample diffuse reflectance mode over the range of 400 to 4000 cm. turned into a white, pasty mass which continued to expel The presence of the carbonated form of HAp is confirmed by NO for Several minutes. After approximately five minutes, the FTIR spectra in FIG. 9 (400 to 1600 cm), which the reaction was essentially complete leaving a damp Solid 65 indicates the presence of peaks characteristic of IPO, mass which was hot to the touch. This solid was cooled to (580–600, 950–1250 cm) and of COI (880, 1400, & room temperature under ambient conditions for approxi 1450 cm). The P=O stretch, indicated by the strong peak 5,939,039 15 16 at 1150–1250 cm, suggests a structural perturbation of this Solution was added 28.78 g Zinc nitrate hexahydrate Salt, hydroxyapatite by the carbonate ion. Zn(NO),.6H2O (ACS reagent, Aldrich Chemical Co., Inc. #22,873-7, CAS #10196-18-6), equivalent to 21.97 wt % Example 4 Zn. The molar ratio of Zn/phosphate in this mixture was 3/2 Colloidal SiO, added to calcium phosphate and the equivalent solids level as Zn(PO) was 27.5 wt mixtures via RPR %. Endothernic dissolution of the zinc nitrate hexahydrate proceeded giving a homogeneous Solution once the Sample An aliquot of 8.00 g 34.0 wt % SiO hydrosol (Nalco warmed to room temperature. Further warming of this Chemical Co., Inc. #1034A, batch #B5G453C) was slowly added to 8.51 g 50 wt % aqueous solution of HPO with solution to >25 C. on a hotplate initiated a reaction in which rapid Stirring to give a homogeneous, weakly turbid colloi the solution vigorously evolved red-brown acrid fumes of dal dispersion. To this dispersion was added 22.85 g NO.(8) The reaction continued for approximately 10 minutes Ca(NO).4H2O salt such that the molar ratio of calcium/ while the Sample remained a clear, colorless Solution, abated phosphate in the mixture was 3/2. Endothermic dissolution Somewhat for a period of five minutes, then Vigorously of the calcium nitrate tetrahydrate proceeded giving a homo 15 resumed finally resulting in the formation of a mass of moist geneous colloidal dispersion once the Sample warmed to white solid, some of which was very adherent to the walls room temperature. The colloidal SiO was not flocculated of the Pyrex beaker used as a reaction vessel. The hot solid despite the high acidity and ionic strength in the sample. was allowed to cool to room temperature and was Stored in Warming of the sample on a hotplate to >25 C. initiated a a polyethylene Vial. reaction as described in Example 1. The resultant white, Heat treatment and X-ray diffraction of this solid were pasty Solid was Stored in a polyethylene Vial. conducted as described in Example 1. Following heat treat Heat treatment and X-ray diffraction of this solid were conducted as described in Example 1. Following heat treat ment in air at 500 C. for 1 hour, XRD indicated the solid ment in air at 500 C. for 1.0 hour, XRD indicated the solid to be composed of Zn(PO) (see FIG. 10). to be composed of whitlockite plus hydroxyapatite. 25 Heated to 500° C., 1 h (Major) Zn(PO4)2 Heated to 300° C., 2 h (Major) Calium pyrophosphate Ca2PO, (minor) Octacalcium phosphate CaFI(PO) 2HO Example 7 Heated to 500° C., 1 h Novel Low Temperature Iron Phosphate Powder (Major) Whitlockite B-Cas(PO). (minor) HAp Cas(PO)(OH) Preparation 35 An aqueous solution of 17.50 g 50 wt % HPO was Example 5 combined with 15.00 g distilled water to form a clear, colorless solution contained in a 250 ml Pyrex beaker on a Novel Low Temperature Calcium Phosphate hotplate/stirrer. To this solution was added 53.59 g ferric Powder Preparation nitrate nonahydrate salt, Fe(NO)-9HO (ACS reagent, 40 Example 1 was repeated with the addition of 10.00 g Alfa/Aesar reagent #33315, CAS #7782-61-8), equivalent to dicalcium phosphate dihydrate, DCPD, CaHPO4.2H2O 13.82 wt % Fe. The molar ratio of Fe/phosphate in this (Aldrich Chemical Co., Inc. #30,765-3, CAS #7789-77-7) to mixture was 1/1 and the equivalent solids level as FePO the homogeneous Solution following endothermic dissolu was 23.2 wt %. Endothermic dissolution of the ferric nitrate tion of the calcium nitrate salt. The DCPD was present both nonahydrate Salt proceeded partially with gradual warming as Suspended Solids and as precipitated material (no agita 45 of the reaction mixture, eventually forming a pale lavender tion used). Warming of the sample to >25 C. initiated an Solution plus undissolved salt. At Some temperature >25 C., exothermic reaction as described in Example 1, resulting in an exothermic reaction was initiated which evolved NO. the formation of a white, pasty Solid. Heat treatment and This reaction continued for approximately 15 minutes dur X-ray diffraction of this solid were conducted as described 50 ing which time the reaction mixture became Syrup-like in in Example 1. Following heat treatment in air at 500 C. for Viscosity. With continued reaction, Some pale yellow Solid 1 hour, XRD indicated the solid to be composed of whit began to form at the bottom of the beaker. After approxi lockite as the primary phase along with calcium pyrophoS mately 40 minutes of reaction, the Sample was allowed to phate (Ca2PO7) as the Secondary phase. cool to room temperature. The product consisted of an 55 inhomogeneous mixture of low density yellow Solid at the Heated to 500° C., 1 h top of the beaker, a brown liquid with the consistency of caramel at the center of the product mass, and a Sand colored (Major) Whitlockite B-Cas(PO), Solid at the bottom of the beaker. The Solids were collected (minor) CaPO, as Separate Samples insofar as was possible. 60 Heat treatment and X-ray diffraction of the solid collected Example 6 from the top of the beaker were conducted as described in Example 1. Following heat treatment in air at 500 C. for 1 Novel Low Temperature Zinc Phosphate Powder Preparation hour, XRD indicated the solid to be composed of graftonite 65 Fe(PO) plus Some amorphous material, Suggesting that An aqueous solution of 8.51 g 50 wt % HPO in 8.00 g the heat treatment was not Sufficient to induce complete distilled water was prepared as described in Example 1. To sample crystallization (see FIG. 11). 5,939,039 17 18

Heated to 500° C., 1 h (Major) Grafionite Fe(PO). Heated to 500° C., 1 h (Major) Whitlockite B-Cas(PO), Some mechanism apparently occurs by which Fe" was (minor) Cas(PO) (CO)(OH) reduced to Fe’". Example 8 Example 10 Novel Low Temperature Calcium Phosphate 1O Powder Preparation Novel Low Temperature Aluminum Phosphate An aqueous solution of 19.41 g 50 wt % HPO was Powder Preparation combined with 5.00 g distilled water to form a clear, colorless solution contained in a 250 ml Pyrex beaker. To An aqueous solution of 10.82 g 50 wt % HPO was this solution was added 34.72g Ca(NO).4H2O. The molar 15 combined with 2.00 g distilled water to form a clear, ratio of Ca/phosphate in this mixture was 1/1 and the colorless Solution contained in a 250 ml beaker. To this equivalent solids level as CaHPO was 33.8 wt %. Endot solution was added 30.78 g aluminum nitrate nonahydrate hermic dissolution of the calcium nitrate tetrahydrate pro Salt, Al(NO).9H2O (ACS reagent, Alfa/Aesar reagent ceeded under ambient temperature conditions, eventually #36291, CAS #7784-27-2), equivalent to 7.19 wt % Al. The forming a homogeneous Solution once the Sample warmed to molar ratio of Al/phosphate in this mixture was 1/1 and the room temperature. Warming of this solution above 25 C. equivalent solids level as AIPO was 22.9 wt %. Endot initiated a vigorous exothermic reaction which resulted in hermic dissolution of the aluminum nitrate nonahydrate the evolution of NO, rapid temperature increase of the proceeded giving a homogeneous Solution once the Sample sample to >100° C., and extensive foaming of the reaction warmed to room temperature. Further warning of this Solu mixture over the beaker rim, presumably due to flash boiling 25 tion to >25 C. on a hotplate initiated a reaction in which the of water at the high reaction temperature. After cooling to solution vigorously evolved red-brown acrid fumes of NO room temperature, the reaction product was collected as a (g). Reaction continued for approximately 15 minutes during dry, white foam which was consolidated by crushing to a which the Solution Viscosity increased considerably prior to powder. formation of a white Solid. Heat treatment and X-ray diffraction of this solid were conducted as described in Example 1. Results are as follows: Heat treatment and X-ray diffraction of this solid were conducted as described in Example 1. Following heat treat ment in air at 500 C. for 0.5 hour, XRD indicated the Solid Heated to 300° C., 2 h (Major) CaPO, to be composed of AlPO plus Some amorphous material, (minor) Octacalcium phosphate 35 CaH(PO)-2HO Suggesting that the heat treatment was not Sufficient to Heated to 500° C., 1 h (Major) CaPO, induce complete Sample crystallization (see FIG. 12). Example 11 Example 9 40 Novel Low Temperature Calcium Phosphate Novel Low Temperature Calcium Phosphate Powder Preparation Powder Preparation Example 3 was repeated using ten times the indicated An aqueous solution of 8.06 g 50 wt % HPO reagent weights of reagents. The reactants were contained in a 5/2" 45 was combined with 6.00 g distilled water to form a clear, diameter Pyrex crystallizing dish on a hotplate/stirrer. The colorless solution in a 250 ml Pyrex beaker on a hotplate/ reactants were Stirred continuously during the dissolution stirrer. To this solution was added 19.23g Ca(NO)4H.O. and reaction Stages. The chemical reaction initiated by The molar ratio of Ca/phosphate in this sample was 4/3 and heating the solution to >25 C. resulted in the evolution of the equivalent Solids as octacalcium phosphate, Cash NO, for several minutes with no apparent effect on the 50 (PO)-5HO was 30.0 wt %. Endothermic dissolution of Stability of the System, i.e. the Solution remained clear and the calcium nitrate tetrahydrate proceeded under ambient colorless with no evidence of Solid formation. After abating conditions, eventually forming a homogeneous Solution for Several minutes, the reaction resumed with increased once the Sample warmed to room temperature. Warming of intensity resulting in the voluminous generation of NO. the solution above 25 C. initiated a vigorous exothermic and the rapid appearance of a pasty white Solid material. The 55 reaction as described in Example 1. After approximately reaction vessel and product were both hot from the reaction three minutes, the reaction was essentially complete leaving exotherm. The product was cooled in air to a white crumbly a moist, white, pasty Solid. Solid which was Stored in a polyethylene Vial. Heat treatment and X-ray diffraction of this solid were Heat treatment and X-ray diffraction of this solid were conducted as described in Example 1. Following heat treat conducted as described in Example 1. Following heat treat 60 ment in air at 500 C. for 0.5 hour, XRD indicated the solid ment in air at 500 C. for either 0.5 or 1 hour, XRD indicated to be composed of whitlockite as the primary phase along the Solid to be composed of whitlockite as the primary phase with hydroxyapatite as the Secondary phase. There was no along with hydroxyapatite as the Secondary phase. XRD evidence for the formation of octacalcium phosphate (OCP), results indicate that the relative ratio of the two calcium despite the initial Sample Stoichiometry. This result Suggests phosphate phases was dependent on the duration of the heat 65 that (a) alternate heat treatments are necessary to crystallize treatment, but no attempts were made to quantify the depen OCP and/or (b) excess Ca is present in the intermediate dence. powder. 5,939,039 19 20 between the glass liner and the reactor vessel was filled with distilled water to the level of the sample. This ensured Heated to 500° C., 0.5 h maximum heat transfer to the Sample Since the reactor was (Major) Whitlockite B-Cas(PO), externally heated by an electric mantle. The approx. 100 ml (minor) HAp Cas (PO)(OH) Sample Volume left Sufficient head Space in the reactor to accommodate Solution expansion at elevated temperatures. The reactor was Sealed by compression of a Teflon gasket. Example 12 Heating of the reactor was performed at the maximum rate of the controller to a setpoint of 202 C. with constant Novel Low Temperature Calcium Phosphate Stirring (500 rp.m.). The heating profile, as monitored by a Powder Preparation thermocouple immersed in the reactant mixture, was as Example 11 was repeated except that no distilled water follows: was used in preparation of the reaction mixture. Warming of the homogeneous Solution above 25 C. initiated an exo REACTOR THERMAL PROFILE thermic reaction as described in Example 11. After approxi 15 mately three minutes, the reaction was essentially complete Time O 5 1O 15 2O 25 3O 35 36 (min) leaving a moist, pasty, white Solid. Temp. 22 49 103 122 145 155 179 197 2OO Heat treatment and X-ray diffraction of this solid were (°C.) (hold) (+/-2 °C.) conducted as described in Example 1. Following heat treat Pressure - 160 210 22O ment in air at 500 C. for 0.5 hour, XRD indicated the solid (psi) to be composed of calcium pyrophosphate (CalPO7). After holding at 200+/-3 C. for 12 minutes, the temperature Heated to 500° C., 0.5 h (Major) CaPO, rapidly increased to 216 C. with a resultant increase in 25 reactor preSSure to approximately 330 psi. This exothermic event quickly Subsided as evidenced by the rapid drop in Example 13 reactor temperature to 208 C. within two minutes as the Parr reactor approached thermal equilibrium via a near Novel Low Temperature Hydrothermal (HYPR) adiabatic process. After 15 minutes at 200 C., the reactor Calcium Phosphate Powder Preparation was removed from the heating mantle, quenched in a cold An aqueous solution of 50 wt % calcium nitrate water bath, and opened after the head Space was vented to tetrahydrate, Ca(NO)-4H2O (ACS reagent, Aldrich ambient pressure. Chemical Co., Inc. #23,712-4, CAS #13477-34-4) was pre A white precipitate was present in the glass liner. The pared by dissolving 250.0 g of the salt in 250.0 g distilled 35 solid was collected by vacuum filtration on a 0.45 micron water. This solution was equivalent to 8.49 wt % Ca. A total membrane filter (Millipore, Inc., Bedford, Mass., 01730), of 47.0 g of this Solution was added, with rapid agitation, to washed several times with distilled water, and dried at an aqueous Solution of 50 wt % Sodium hypophosphite approximately 55 C. in a forced convection oven. X-ray diffraction of this solid was conducted as described in monohydrate, NaH2PO-HO (Alfa/Aesar reagent #14104, Example 1. CAS #10039-56-2) also prepared by dissolving 250.0 g of 40 the salt in 250.0 g distilled water. The sodium hypophosphite X-Ray diffraction results indicate a unique, unidentifiable solution was equivalent to 44.80 wt % PO. The clear, diffraction pattern, see FIG. 13. colorless Solution of calcium nitrate and Sodium hypophoS phite was then diluted with 40.3 g distilled water. The molar Example 14 ratio of Ca/phosphate in this mixture was 5/3, and the 45 Novel Low Temperature Hydrothermal (HYPR) equivalent solids levelas Cas(PO)(OH) (hydroxyapatite) Calcium Phosphate Powder Preparation was 10.0 wt %. The sample wash ydrothemnally treated using a 300 cc Volume Stirred high pressure bench reactor Example 13 was repeated except that 40.3 g of 1.0 M (Model no. 4561 Mini Reactor, Parr Instrument Co., Moline, NaOH solution was added with rapid stirring to the homo Ill. 61265) equipped with a temperature controller/digital 50 geneous Solution of calcium nitrate and Sodium hypophos tachometer unit (Model no. 4842, Parr Instrument Co.) and phite instead of the distilled water. This base addition dial preSSure gauge. All wetted parts of the reactor were resulted in the formation of a milk white dispersion, pre fabricated from type 316 stainless steel. Ordinarily, type sumably due to precipitation of Ca(OH). 316SS is not the material of choice for inorganic acid The Sample was hydrothermally processed as described in Systems. Such as the Solution precursors used in this 55 Example 13 with the temperature setpoint at 207 C. The invention, Since phosphoric acid can attack Stainless Steel at temperature ramp to 160° C. (25 minutes) was as indicated elevated temperatures and pressures. However, in the prac for Example 13. At 30 minutes into the run, an exotherm tice of this invention, direct contact (i.e. wetting) of the occurred causing the temperature of the reaction mixture to reactor Surfaces was avoided through the use of a Pyrex rise to a maximum of 221 C. within five minutes with a glass liner. Only the Stirrer and thermocouple sheath were 60 corresponding preSSure increase to 370 psi. At 38 minutes immersed in the reactant Solutions and no corrosion was into the experiment, the reactor was quenched to room observed. In addition, it is assumed that the high nitrate ion temperature. concentration in the reactant mixture provided a passivating The reaction product consisted of a Small amount of white environment for the type 316SS. precipitate. The material was collected as described in One hundred grams (approximately 100 ml) of the cal 65 Example 13. X-ray diffraction of the dried sample was cium nitrate-Sodium hypophosphite Solution was placed in conducted as described in Example 1. XRD results indicated the Pyrex liner of the reactor and the intervening Space the Solid to be comprised of the same unidentifiable pattern 5,939,039 21 22 (crystal phase) found in Example 13 and minor amounts of (PAA). PAA is used as a chelating Setting additive and HAp-Cas(PO)(OH)). (see FIG. 14). wetting agent. The above Solution was used with Several powder combinations to form setting cements. A 50/50 Example 15 powder mix of HYPR monetite Example 15 and RPR f8-TCP-HAp(CO) Example 3), approximately 0.7 g, was Novel Low Temperature Hydrothermal (HYPR) mixed with a glass spatula on a glass plate with 0.39 g of the Calcium Phosphate Powder Preparation 1% PAA-NaOH solution (powder to liquid ratio=1.73). The A total of 47.0 g of a 50 wt % aqueous solution of calcium cement was extruded through a 3 ml Syringe and was Set nitrate tetrahydrate was diluted with 53.0 g distilled water. after being left undisturbed for 20 minutes at room tempera Then, 6.00 g calcium hypophosphite salt, Ca(H2PO) (Alfa/ 10 ture (23° C). Aesar reagent #56168, CAS #7789-79–9), equivalent to 23.57 wt % Ca and 111.7 wt % PO, was slurried into the Examples 18-34 Ca(NO) Solution using rapid agitation. An unknown amount of the calcium hypophosphite remained undissolved in the room temperature sample. The solubility behavior of 15 Set Time Ca(HPO) in the Ca(NO) solution at elevated tempera- (min.) tures is unknown. The molar ratio of Ca/phosphate in this Powderf GilmoreNeedle system was 1.91. Liquid ratio (454 grams) This Sample was hydrothermally processed as described E. Powd Liquid (Con- 12O t : in Example 13 with the temperature setpoint at 212°C. The 20 - P. " LCL sistency) ( grams) temperature ramp to 200 C. was as indicated for Example 18 HYPR monetite + 7M NaOH 1/1f1.2 <20 min 13. At 39 minutes into the run, an exotherm occurred causing SEsOO (Ex.C. 1) AlkalineSoln (lightyepaste (#) the temperature of the reaction mXture to rSe to a maximum 19 HYPR nonette 7M NaOH 1/1f1.2 <20 min of 252 C. within three minutes with a. corresponding (Ex. 15) + Alkaline (wet paste) (#) preSSure increase to 640 psi. At 44 minutes into the 25 RPR (Ex. 1) Soln experiment, the reactor was quenched to room temperature. 700° C. 5 2O HYPR nonette 7M NaOH 1/1f1 15-18 min The reaction product appeared as a voluminous white (Ex. 15) + Alkaline (sl. wet precipitate plus Some Suspended Solids. The material was -50 um 45S5" Soln paste) collected as described in Example 13. X-ray diffraction of glass the dried solid was conducted as described in Example 1. ' ' SE Ex. 1) MNOH we >40 min XRD indicated the solid to be monetite, CaHPO, see FIG. neat Soln p 15. The unique crystal morphology is depicted in the Scan- 22 RPR (Ex. 1) 7M NaOH 1.7/1 40 min ning electron micrograph representation in FIG. 2. 300° C. -- Alkaline (sl. wet Mixtures of the above described RPR and HYPR powders 35 500RPR (Ex.Ex 9 ) SolOil paste)t are useful in the formation of Self-setting calcium phosphate 23 HYPR nonette 7M NaOH /1/1.4 No Set up to cements for the repair of dental and Orthopaedic defects. The (Ex. 15) + Alkaline (v. gritty, 24 hrs. addition of Specific components and Solubilizing liquids can special Soln wet) also be added to form the precursor bone mineral constructs 24 HYPR monetite 7M NaOH f1f1.4 20 min of this invention. 40 (Ex. 15) + Alkaline (slightly wet (#) RPR (Ex. 2) Soln paste) Example 16 500° C. 25 HYPR nonette 7M NaOH 1/1f1 <30 min Novel Cement Composition (Ex. 15) + Alk. Soln + (claylike sl. set RPR (Ex. 2) 20% PAA paste) Approximately 1.4 g of an alkaline Solution (7 molar) 500° C. formed using NaOH and distilled water, was mixed with 1.1 26 HYPR monetite 7M NaOH 1/1/1 35 min g of HYPR monetite Example 15 and 1.1 g of RPR S. G.") al -- (ty i f8-TCP-HAp(CO) Example 3 in a glass mortar and pestle 500° C. o for ~45 Seconds. After mixing, a Smooth paste was formed, 27 HYPR nonette 7M NaOH f1f1.2 12-15 min which was Scooped into a 3 ml polypropylene Syringe and (Ex. 15) + Alk. Soln + (slightly dry sealed for 20 minutes without being disturbed. Room tem- 50 SEs Ex. 11) 1% PAA paste) perature setting was observed after 20 minutes, which was 28 HYPR monetite 10 wt % f1f1.2 1 hr 15 min indicated by the use of a 454 gram Gilmore needle. The (Ex. 15) + Ca(H2PO), (very wet hardened cement was analyzed by X-ray diffraction which RPR (Ex. 1) (aq) paste) revealed a conversion to primarily type-B, carbonated apa- 29 Rei es 11) 10 wt % 1.7/1 45 min tite ". is the desired bone mineral precursor phase (see Sooo..." Ca(H2PO), (very wet FIG. : neat (aq) paste) 30 RPR (Ex. 11) 10 wt % 2.5/1 20 min 500° C. Ca(H2PO), (sl. dry Cement XRD revealed (Major) Cas(PO) (CO)(OH) neat (aq) paste? putty) (minor) Whitlockite If-Ca(PO). 60 31 RPR (Ex. 11) 10 wt % 2.25/1 15 min 500° C. Ca(HPO) + (very S. neat wt % paste? putty HPO, (aq) Example 17 32 HYPR monetite 3.5M 1/1f1 35 min. (Ex. 15) + NaOHAk. (good *12 min. Novel Cement Composition 65 SEs Ex. 11) Soln. paste? putty) A stock solution was formed with the approximately 7 M 33 HYPR monetite 3.5M 1/3/2 38 min. NaOH solution used in Example 1 and 1.0% polyacrylic acid 5,939,039 23 24 -continued wt % Ce. The molar ratio of the Ce/P in this mixture was 1/1 and the equivalent solids level (as CePO) was 37.6 wt %. Set Time Endothermic dissolution of the neodymium nitrate hexahy (min.) Powderf Gilmore drate Salt proceeded with gradual warming of the reaction Powderf Needle mixture, eventually forming a clear, homogeneous colorless Liquid ratio (454 grams) Solution at room temperature. Heating of this Solution with Exam- (Con- # = constant agitation to approximately 65 C. initiated a Vig ple Powder Liquid sistency) (1200 grams) orous endothermic reaction which resulted in the evolution (Ex. 15) + NaOHAk. paste? putty) *15 min. of NO, , rapid temperature increase of the sample to RPR (Ex. 11) Soln. approximately >100° C., and finally, formation of a pasty 500° C. 34 HYPR monetite Saline, 1/1f1 43 min. light grey mass. Heat treatment of the pasty Solid and (Ex. 15) + EDTA (good *20 min. Subsequent X-ray diffraction analysis of the fired solid were RPR (Ex. 11) buffered paste? putty) conducted as described in Example 1. Results are as follows 500° C. (see FIG. 18C): 15 *= Set Time at 37° C., 98% Relative Humidity. HYPR monetite = HYdrothermally PRocessed monetite (CaHPO). RPR = Reduction-oxidation Precipitation Reaction. Heated to 700° C., 45 min. (Major) Monazite-Ce CePO 45S5" glass = {24.5% CaO-24.5% NaO-6% P.O-45%. SiO, (wt %)}. PAA = Polyacrylic acid. Commercial B-TCP from Clarkson Chromatography Products, Inc. (S. Williamsport, PA) Example 37 Novel Low Temperature Yttrium Phosphate Powder Example 35 Preparation Novel Low Temperature Neodymium Phosphate 25 An aqueous solution of 14.36 g of 50 wt.% HPO was Powder Preparation diluted with 5.00 g distilled water to form a clear, colorless An aqueous solution of 11.04 g of 50 wt.% HPO was solution contained in a 250 ml fluoropolymer resin beaker diluted with 5.00 g distilled water to form a clear, colorless on a hotplate/magnetic Stirrer. Added to this Solution was solution contained in a 250 ml fluoropolymer resin beaker 41.66 g yttrium nitrate hexahydrate salt, Y(NO)-6H2O on a hotplate/magnetic Stirrer. Added to this Solution was (Alfa/Aesar reagent #12898, CAS #13494-98-9), equivalent 36.66 g neodymium nitrate hexahydrate salt, Nd(NO)- to 23.21 wt % Y. The molar ratio of the Y/P in this mixture 6H2O (Alfa/Aesar reagent #12912, CAS # 16454-60-7), was 1/1 and the equivalent solids level (as YPO) was 32.8 equivalent to 32.90 wt % Nd. The molar ratio of the Nd/P in wt %. Endothermic dissolution of the yttrium nitrate this mixture was 1/1 and the equivalent Solids level (as hexahydrate Salt proceeded with gradual warming of the NdPO) was 38 wt %. Endothermic dissolution of the 35 reaction mixture, eventually forming a clear, homogeneous neodymium nitrate hexahydrate Salt proceeded with gradual colorless Solution at room temperature. Heating of this warming of the reaction mixture, eventually forming a clear, Solution with constant agitation to approximately 75 C. homogeneous lavender Solution at room temperature. Heat initiated a vigorous endothermic reaction which resulted in ing of this Solution with constant agitation to approximately the evolution of NO, rapid temperature increase of the 70° C. initiated a vigorous endothermic reaction which 40 sample to approximately >100° C., and finally, formation of resulted in the evolution of NO, , rapid temperature a pasty white mass. Heat treatment of the pasty Solid and increase of the sample to approximately 100 C., and finally, Subsequent X-ray diffraction analysis of the fired solid were formation of a pasty lavender mass. Heat treatment of the conducted as described in Example 1. Results are as follows pasty Solid and Subsequent X-ray diffraction analysis of the (see FIG. 18D): fired Solid were conducted as described in Example 1. 45 Results are as follows (see FIGS. 18A & B): Heated to 700° C., 45 min. (Major) Xenotime YPO

Heated to 500 C., 45 min. (Major) Neodymium phosphate hydrate NdPO-0.5HO Heated to 700° C., 45 min. (Major) Monazite-Nd NdPO 50 Example 38 A wide variety of minerals can be made in accordance with the the present invention. In the following two tables, Example 36 oxidizing and reducing agents are listed. Any of the listed 55 oxidants can be reacted with any of the listed reducing Novel Low Temperature Cerium Phosphate Powder agents and, indeed, blends of each may be emloyed. Appro Preparation priate Stoichiometry will be employed Such that the afore An aqueous solution of 11.23g of 50 wt.% HPO was mentioned reaction is caused to proceed. Also specified are diluted with 5.00 g distilled water to form a clear, colorless possible additives and fillers to the reactions. The expected solution contained in a 250 ml fluoropolymer resin beaker 60 products are given as are Some of the expected fields of on a hotplate/magnetic Stirrer. Added to this Solution was application for the products. All of the following are 36.94 g cerium nitrate hexahydrate salt, Ce(NO)-6H2O expected generally to follow the methodology of Some or all (Johnson-Matthey reagent #11329-36), equivalent to 32.27 of the foregoing Examples. 5,939,039 25 26

Oxidizing Agents Reducing Agents Additives Product(s) Compounds of the form Oxoacids of Group 5B, 6B, Al2O3, ZrO2, TiO, SiO2, Ca(OH)2, XY(PO), XY(SO), XNO, where X = and 7B, (where 5B includes N, DCPD, DCPA, HAp, TCP, TTCP, XY(PO)(SO), H, Li, Na, K, Rb, Cs, P, and As; 6B includes S, Se, MCMP, ZrSiO, W-metal, Fe metal, Ti WXYZ(PO)(SO)(CO), Cu, Ag, and Hg. and Te; 7B includes Cl, Br, metal, Carbon black, C-fiber or flake, WXYZ(PO)(SO)(CO)(F,Cl, Compounds of the form and I). CaF2, NaF. carbides, nitrides, glass Br.I).WXYZ(PO)(SO) X(NO), where X = Be, Phosphorous oxoacid fibers, glass particulate, glass (CO)(F.C.Br.I)(OCl, OF, Mg, Ca, Sr. Ba, Cr, Mn, compounds: ceramics, alumina fibers, ceramic OBr, OI), in the form of fiber, Fe, Co, Ni, Cu, Zn, Rh, Hypophosphite (HPO); fibers, bioactive cerarmic fibers and flake, whisker, granule, Pd, Cd, Sn, Hg, and Pb Hypophosphoric acid particulates, polyacrylic acid, coatings, agglomerates and Compounds of the form (HPO); polyvinyl alcohol, polymethyl fine powders. X(NO), or XO(NO), Isohypophosphoric acid methacrylate, polycarbonate, and other where X = Al, Cr, Mn, (HPO); stable polymeric compounds. Fe, Co, Ni, GaAs, Y, Phosphonic acid or Acetates, formates, lactates, simple Nb, Rh, In, La, Tl, Bi, phosphorus acid (H3PO); carboxylates, and simple sugars. Ac, Ce, Pr, Nd, Sm, Eu, Diphosphonic acid (HPOs); Gd, Tb, Dy, Ho, Er, Phosphinic acid or Tm, Yb, Lu, U, and Pu hypophosphorus acid (HPO). Compounds of the form Sulfur oxoacid compounds: X(NO), or XO(NO), Thiosulfuric acid (HSO); where X = Mn, Sn, Pd, Dithionic acid (H2S2O); Zr, Pb, Ce, Pr, Tb, Th, Polythionic acid (HSO); Pa, U and Pu. Sulfurous acid (H2SOs); Halogen oxoacids: Disulfurous acid (H2SOs); perhalic acid (HOCIO, Dithionous acid (HSO). HOBrOs, HIOI); halic acid (HOCIO, HOBrO, HOIO); halous acid (HOCIO, HOBrO, HOIO)

The minerals prepared above may be used in a wide d. Said Salt precipitating from Said Solution. variety of applications. Exemplary of these applications are 2. The method of claim 1 further comprising a Second in pigments, phosphors, fluorescing agents, paint additives, heating Step, the Second heating Step being of Said Salt to Synthetic gems, chromatography media, gas Scrubber media, 35 confer a phase transition and/or crystallization thereupon. filtration media, bioSeparation media, Zeolites, catalysts, catalytic Supports, ceramics, glasses, glass-ceramics, 3. The method of claim 1 wherein Said oxidizing agent is cements, electronic ceramics, piezoelectric ceramics, nitrate and Said gaseous product is a nitrogen oxide. bioceramics, roofing granules, protective coatings, barnacle 4. The method of claim 1 wherein Said gaseous product is retardant coating, waste Solidification, nuclear waste NO. Solidification, abrasives, polishing agents, polishing pastes, 40 5. The method of claim 1 wherein said salt is substantially radiopharmaceuticals, medical imaging and diagnostics homogeneous. agents, drug delivery, excipients, tabletting excipients, bio 6. The method of claim 1 wherein said Salt is a calcium active dental and orthopaedic materials and bioactive phosphate. coatings, composite fillers, composite additives, Viscosity 7. The method of claim 1 wherein said solution comprises adjustment additives, paper finishing additives, optical 45 an alcohol. coatings, glass coatings, optical filters, fertilizers, Soil 8. The method of claim 1 wherein at least one precursor nutrient(s) additives. anion is a hypophosphite. What is claimed is: 9. The method of claim 1 wherein said metal cation forms 1. A method for preparing a Salt of calcium cation and at 50 part of Said oxidizing agent. least one phosphorous oxoanion comprising: 10. The method of claim 1 wherein said oxidizing agent a. Preparing an aqueous Solution of and metal cation comprise a metal nitrate. i. Said calcium cation; 11. The method of claim 1 wherein Said oxidizing agent ii. at least one oxidizing agent, and is a nitrate. iii. at least one precursor anion oxidizable by Said 55 12. The method of claim 1 wherein said reaction is oxidizing agent to form Said phosphorous oxoanion; maintained under acidic conditions. b. heating said Solution to a temperature up to about 250 13. The method of claim 1 conducted at pH below about C. under conditions of temperature and pressure effec 3. tive to initiate an oxidation-reduction reaction between 14. The method of claim 1 conducted at pH below about Said oxidizing agent and the precursor anion; 60 1.5. c. Said reaction evolving at least one gaseous product; and giving rise to Said phosphorous oxoanion;